Document:

Credit Agreement

 Exhibit 10.25 
 CERTAIN MATERIAL (INDICATED BY AN ASTERISK) HAS BEEN OMITTED FROM THIS DOCUMENT PURSUANT TO A REQUEST FOR CONFIDENTIAL TREATMENT. THE OMITTED MATERIAL HAS BEEN FILED SEPARATELY WITH THE SECURITIES AND
EXCHANGE COMMISSION. 
 CREDIT AGREEMENT 
 Dated as of December 21, 2009 
 among 
 PROMETHEUS LABORATORIES INC., 
 as the Borrower, 
 THE GUARANTORS 
 FROM TIME TO TIME PARTY HERETO, 
 BANK OF AMERICA, N.A., 
 as Administrative Agent, Swing Line Lender and L/C Issuer,

 SUNTRUST BANK, 
 as Syndication Agent, 
 and 
 THE OTHER LENDERS PARTY HERETO 
 BANC OF AMERICA SECURITIES LLC 
 and 
 SUNTRUST ROBINSON HUMPHREY, INC., 
 as Joint Lead Arrangers and Joint Book Managers 
 GENERAL ELECTRIC CAPITAL
CORPORATION, 
 FIFTH THIRD BANK, 
 U.S. BANK NATIONAL ASSOCIATION, 
 BBVA COMPASS BANK and 
 DNB NOR BANK, ASA, 
 as Co-Documentation Agents 

 TABLE OF CONTENTS 
  

					
	ARTICLE I DEFINITIONS AND ACCOUNTING TERMS	  	1
	 1.01
	  	Defined Terms.	  	1
	 1.02
	  	Other Interpretive Provisions.	  	30
	 1.03
	  	Accounting Terms.	  	31
	 1.04
	  	Rounding.	  	32
	 1.05
	  	Times of Day.	  	32
	 1.06
	  	Letter of Credit Amounts.	  	32
	 1.07
	  	Exchange Rates; Currency Equivalents.	  	32
	ARTICLE II THE COMMITMENTS AND CREDIT EXTENSIONS	  	32
	 2.01
	  	Revolving Loans and Term Loan.	  	32
	 2.02
	  	Borrowings, Conversions and Continuations of Loans.	  	33
	 2.03
	  	Letters of Credit.	  	36
	 2.04
	  	Swing Line Loans.	  	43
	 2.05
	  	Prepayments.	  	46
	 2.06
	  	Termination or Reduction of Commitments.	  	48
	 2.07
	  	Repayment of Loans.	  	48
	 2.08
	  	Interest.	  	49
	 2.09
	  	Fees.	  	50
	 2.10
	  	Computation of Interest and Fees; Retroactive Adjustments of Applicable Rate.	  	50
	 2.11
	  	Evidence of Debt.	  	51
	 2.12
	  	Payments Generally; Administrative Agent’s Clawback.	  	51
	 2.13
	  	Sharing of Payments by Lenders.	  	53
	 2.14
	  	Cash Collateral and other Credit Support.	  	54
	 2.15
	  	Defaulting Lenders.	  	55
	 ARTICLE III TAXES, YIELD PROTECTION AND ILLEGALITY
	  	56
	 3.01
	  	Taxes.	  	56
	 3.02
	  	Illegality.	  	59
	 3.03
	  	Inability to Determine Rates.	  	60
	 3.04
	  	Increased Costs.	  	60
	 3.05
	  	Compensation for Losses.	  	62
	 3.06
	  	Mitigation Obligations; Replacement of Lenders.	  	62
	 3.07
	  	Survival.	  	63
	 ARTICLE IV GUARANTY
	  	63
	 4.01
	  	The Guaranty.	  	63
	 4.02
	  	Obligations Unconditional.	  	63
	 4.03
	  	Reinstatement.	  	64
	 4.04
	  	Certain Additional Waivers.	  	64
	 4.05
	  	Remedies.	  	65
	 4.06
	  	Rights of Contribution.	  	65
	 4.07
	  	Guarantee of Payment; Continuing Guarantee.	  	65
	 ARTICLE V CONDITIONS PRECEDENT TO CREDIT EXTENSIONS
	  	65
	 5.01
	  	Conditions of Closing.	  	65
	 5.02
	  	Conditions to all Credit Extensions.	  	68
	 ARTICLE VI REPRESENTATIONS AND WARRANTIES
	  	69
	 6.01
	  	Existence, Qualification and Power.	  	69
	 6.02
	  	Authorization; No Contravention.	  	69
	 6.03
	  	Governmental Authorization; Other Consents.	  	70

  

 i 

					
	 6.04
	  	Binding Effect.	  	70
	 6.05
	  	Financial Statements; No Material Adverse Effect.	  	70
	 6.06
	  	Litigation.	  	71
	 6.07
	  	No Default.	  	71
	 6.08
	  	Ownership of Property; Liens.	  	71
	 6.09
	  	Environmental Compliance.	  	72
	 6.10
	  	Insurance.	  	72
	 6.11
	  	Taxes.	  	72
	 6.12
	  	ERISA Compliance.	  	73
	 6.13
	  	Subsidiaries.	  	73
	 6.14
	  	Margin Regulations; Investment Company Act.	  	73
	 6.15
	  	Disclosure.	  	74
	 6.16
	  	Compliance with Laws and Material Contractual Obligations.	  	74
	 6.17
	  	Intellectual Property; Licenses, Etc.	  	74
	 6.18
	  	Solvency.	  	74
	 6.19
	  	Perfection of Security Interests in the Collateral.	  	75
	 6.20
	  	Business Locations.	  	75
	 6.21
	  	Labor Matters.	  	75
	 ARTICLE VII AFFIRMATIVE COVENANTS
	  	75
	 7.01
	  	Financial Statements.	  	75
	 7.02
	  	Certificates; Other Information.	  	76
	 7.03
	  	Notices.	  	78
	 7.04
	  	Payment of Obligations.	  	79
	 7.05
	  	Preservation of Existence, Etc.	  	79
	 7.06
	  	Maintenance of Properties.	  	79
	 7.07
	  	Maintenance of Insurance.	  	79
	 7.08
	  	Compliance with Laws.	  	80
	 7.09
	  	Books and Records.	  	80
	 7.10
	  	Inspection Rights.	  	80
	 7.11
	  	Use of Proceeds.	  	80
	 7.12
	  	Additional Subsidiaries.	  	81
	 7.13
	  	ERISA Compliance.	  	81
	 7.14
	  	Pledged Assets.	  	81
	 7.15
	  	Landlord Consents.	  	82
	 ARTICLE VIII NEGATIVE COVENANTS
	  	83
	 8.01
	  	Liens.	  	83
	 8.02
	  	Investments.	  	85
	 8.03
	  	Indebtedness.	  	86
	 8.04
	  	Fundamental Changes.	  	87
	 8.05
	  	Dispositions.	  	88
	 8.06
	  	Restricted Payments.	  	89
	 8.07
	  	Change in Nature of Business.	  	89
	 8.08
	  	Transactions with Affiliates and Insiders.	  	89
	 8.09
	  	Burdensome Agreements.	  	90
	 8.10
	  	Use of Proceeds.	  	91
	 8.11
	  	Financial Covenants.	  	91
	 8.12
	  	Capital Expenditures.	  	91
	 8.13
	  	Prepayment of Other Indebtedness, Etc.	  	92
	 8.14
	  	Organization Documents; Fiscal Year; Legal Name, State of Formation and Form of Entity.	  	92
	 8.15
	  	Ownership of Subsidiaries.	  	92

  

 ii 

					
	 8.16
	  	Sale Leasebacks.	  	92
	 ARTICLE IX EVENTS OF DEFAULT AND REMEDIES
	  	93
	 9.01
	  	Events of Default.	  	93
	 9.02
	  	Remedies Upon Event of Default.	  	95
	 9.03
	  	Application of Funds.	  	95
	 ARTICLE X ADMINISTRATIVE AGENT
	  	96
	 10.01
	  	Appointment and Authority.	  	96
	 10.02
	  	Rights as a Lender.	  	97
	 10.03
	  	Exculpatory Provisions.	  	97
	 10.04
	  	Reliance by Administrative Agent.	  	98
	 10.05
	  	Delegation of Duties.	  	98
	 10.06
	  	Resignation of the Administrative Agent.	  	98
	 10.07
	  	Non-Reliance on Administrative Agent and Other Lenders.	  	99
	 10.08
	  	No Other Duties; Etc.	  	99
	 10.09
	  	Administrative Agent May File Proof of Claims.	  	100
	 10.10
	  	Collateral and Guaranty Matters.	  	100
	 10.11
	  	Secured Hedge Agreements and Secured Cash Management Agreements.	  	101
	 ARTICLE XI MISCELLANEOUS
	  	101
	 11.01
	  	Amendments, Etc.	  	101
	 11.02
	  	Notices and Other Communications; Facsimile Copies.	  	103
	 11.03
	  	No Waiver; Cumulative Remedies; Enforcement.	  	105
	 11.04
	  	Expenses; Indemnity; Damage Waiver.	  	106
	 11.05
	  	Payments Set Aside.	  	107
	 11.06
	  	Successors and Assigns.	  	107
	 11.07
	  	Confidentiality.	  	111
	 11.08
	  	Set-off.	  	112
	 11.09
	  	Interest Rate Limitation.	  	112
	 11.10
	  	Counterparts.	  	113
	 11.11
	  	Integration.	  	113
	 11.12
	  	Survival of Representations and Warranties.	  	113
	 11.13
	  	Severability.	  	113
	 11.14
	  	Replacement of Lenders.	  	113
	 11.15
	  	Governing Law; Jurisdiction, Etc.	  	114
	 11.16
	  	California Judicial Reference.	  	115
	 11.17
	  	Waiver of Right to Trial by Jury.	  	115
	 11.18
	  	USA PATRIOT Act Notice.	  	115
	 11.19
	  	No Advisory or Fiduciary Relationship.	  	116
	 11.20
	  	Electronic Execution of Assignments and Certain Other Documents.	  	116
	 11.21
	  	Certain Matters Regarding the Proleukin Distribution Agreement.	  	116
	 11.22
	  	Waiver of Notice of Termination.	  	117

  

 iii 

					
		
	SCHEDULES	  	
			
	 2.01
	  	Commitments and Pro Rata Shares	  	
	 6.10
	  	Insurance	  	
	 6.17
	  	IP Rights	  	
	 6.20(a)
	  	Locations of Tangible Personal Property	  	
	 6.20(b)
	  	Location of Chief Executive Office, Etc.	  	
	 8.01
	  	Existing Liens	  	
	 8.02(b)
	  	Existing Investments	  	
	 8.02(c)
	  	Borrower Investment Policy	  	
	 8.03
	  	Existing Indebtedness	  	
	 11.02
	  	Certain Addresses for Notices	  	
		
	EXHIBITS	  	
			
	 A
	  	Form of Loan Notice	  	
	 B
	  	Form of Swing Line Loan Notice	  	
	 C-1
	  	Form of Revolving Note	  	
	 C-2
	  	Form of Swing Line Note	  	
	 C-3
	  	Form of Term Note	  	
	 D
	  	Form of Compliance Certificate	  	
	 E
	  	Form of Assignment and Assumption	  	
	 F
	  	Form of Joinder Agreement	  	
	 G
	  	Form of Collateral Questionnaire	  	
	 H
	  	Form of Pledge Agreement	  	

  

 iv 

 CREDIT AGREEMENT 
 This CREDIT AGREEMENT, dated as of December 21, 2009, is entered into by and among PROMETHEUS LABORATORIES INC., a California
corporation (the “Borrower”), the Guarantors (defined herein) who may become party hereto from time to time, each Lender from time to time party hereto (collectively, the “Lenders” and individually, a
“Lender”), BANK OF AMERICA, N.A., as Administrative Agent, Swing Line Lender and L/C Issuer, and SUNTRUST BANK, as Syndication Agent. 
 The Borrower has requested that the Lenders provide certain credit facilities for the purposes set forth herein, and the Lenders are willing to do so on the terms and conditions set forth herein.

 In consideration of the mutual covenants and agreements herein contained, the parties hereto covenant and agree as follows:

 ARTICLE I 
 DEFINITIONS AND ACCOUNTING TERMS 
  

	1.01	Defined Terms. 

 As used
in this Agreement, the following terms shall have the meanings set forth below: 
 “1996 License Agreement”
means that certain Exclusive License Agreement, dated as of August 14, 1996, by and among Cedars-Sinai Medical Center, the Regents of the University of California acting through its campus at Los Angeles, and the Borrower. 
 “Acquisition”, by any Person, means the acquisition by such Person on or after the Closing Date, in a single transaction or
in a series of related transactions, of (a) all or any substantial portion of the Property of another Person or at least a majority of the Voting Stock of another Person, or a business unit or division of a Person, in each case whether or not
involving a merger or consolidation with such other Person and whether for cash, Property, services, assumption of Indebtedness, securities or otherwise and (b) any patents, patent rights, licenses or other intellectual property rights of any
Person or agreements or contracts related thereto outside the ordinary course of business. 
 “Additional Term
Loan” has the meaning provided in Section 2.02(f). 
 “Administrative Agent” means Bank of
America in its capacity as administrative agent under any of the Loan Documents, or any successor administrative agent. 
 “Administrative Agent’s Office” means the Administrative Agent’s address and, as appropriate, account as set forth on Schedule 11.02 or such other address or account as the Administrative Agent may from
time to time notify the Borrower and the Lenders. 
 “Administrative Questionnaire” means an Administrative
Questionnaire in a form supplied by the Administrative Agent. 
 “Affiliate” means, with respect to any Person,
another Person that directly, or indirectly through one or more intermediaries, Controls or is Controlled by or is under common Control with the Person specified. 

 “Aggregate Revolving Commitments” means the Revolving Commitments of all
the Lenders. The initial amount of the Aggregate Revolving Commitments in effect on the Closing Date is FIFTY MILLION DOLLARS ($50,000,000). 
 “Agreement” means this Credit Agreement. 
 “Applicable
Rate” means the following percentages per annum, based upon the Consolidated Leverage Ratio as set forth in the most recent Compliance Certificate received by the Administrative Agent pursuant to Section 7.02(b): 
  

															
	 Pricing
Tier
	  	 Consolidated
 Leverage Ratio
	  	Eurodollar
Rate Loans	 	 	Letter of
Credit Fee	 	 	Base Rate
Loans	 	 	Commitment
Fee	 
	 1
	  	> 2.0:1.0	  	5.00	% 	 	5.00	% 	 	4.00	% 	 	0.75	% 
	 2
	  	< 2.0:1.0 but > 1.5:1.0	  	4.50	% 	 	4.50	% 	 	3.50	% 	 	0.75	% 
	 3
	  	< 1.5:1.0 but > 1.0:1.0	  	4.00	% 	 	4.00	% 	 	3.00	% 	 	0.50	% 
	 4
	  	< 1.0:1.0	  	3.50	% 	 	3.50	% 	 	2.50	% 	 	0.50	% 

 Any increase or decrease in the Applicable Rate resulting from a change in the
Consolidated Leverage Ratio shall become effective as of the first Business Day immediately following the date a Compliance Certificate is required to be delivered pursuant to Section 7.02(b); provided, however, that if a
Compliance Certificate is not delivered when due in accordance with such Section, then upon request of the Required Lenders, Pricing Tier 1 shall apply as of the first Business Day after the date on which such Compliance Certificate was required to
have been delivered and shall continue to apply until the first Business Day immediately following the date a Compliance Certificate is delivered pursuant to with Section 7.02(b), whereupon the Applicable Rate shall be adjusted based
upon the calculation of the Consolidated Leverage Ratio contained in such Compliance Certificate. Notwithstanding the foregoing, the Applicable Rate in effect from the Closing Date through the first Business Day immediately following the date a
Compliance Certificate is required to be delivered pursuant to Section 7.02(b) for the fiscal quarter ending March 31, 2010 shall be determined based upon Pricing Tier 2. Notwithstanding anything to the contrary contained in this
definition, the determination of the Applicable Rate for any period shall be subject to the provisions of Section 2.10(b). 
 “Approved Fund” means any Fund that is administered or managed by (a) a Lender, (b) an Affiliate of a Lender or (c) an entity or an Affiliate of an entity that administers or manages a Lender. 
 “Arrangers” means, collectively, Banc of America Securities LLC and SunTrust Robinson Humphrey, Inc., in their capacities
as joint lead arrangers and book managers, and “Arranger” means either of them. 
 “Assignee
Group” means two or more Eligible Assignees that are Affiliates of one another or two or more Approved Funds managed by the same investment advisor. 
 “Assignment and Assumption” means an Assignment and Assumption substantially in the form of Exhibit E. 
  

 2 

 “Attorney Costs” means and includes all reasonable fees, expenses and
disbursements of any law firm or other external counsel. 
 “Attributable Indebtedness” means, on any date,
(a) in respect of any Capital Lease of any Person, the capitalized amount thereof that would appear on a balance sheet of such Person prepared as of such date in accordance with GAAP, (b) in respect of any Synthetic Lease, the capitalized
amount of the remaining lease payments under the relevant lease that would appear on a balance sheet of such Person prepared as of such date in accordance with GAAP if such lease were accounted for as a Capital Lease, (c) in respect of any
Securitization Transaction of any Person, the outstanding principal amount of such financing, after taking into account reserve accounts and making appropriate adjustments, determined by the Administrative Agent in its reasonable judgment and
(d) in the case of any Sale and Leaseback Transaction, the present value (discounted in accordance with GAAP at the debt rate implied in the applicable lease) of the obligations of the lessee for rental payments during the term of such lease).

 “Audited Financial Statements” means the audited consolidated balance sheet of the Borrower and its
Subsidiaries for the fiscal year ended December 31, 2008, and the related consolidated statements of income or operations, shareholders’ equity and cash flows for such fiscal year of the Borrower and its Subsidiaries, including the notes
thereto. 
 “Availability Period” means, with respect to the Revolving Commitments, the period from and
including the Closing Date to the earliest of (a) the Maturity Date, (b) the date of termination of the Aggregate Revolving Commitments pursuant to Section 2.06, and (c) the date of termination of the commitment of each
Lender to make Revolving Loans and of the obligation of the L/C Issuer to make L/C Credit Extensions pursuant to Section 9.02. 
 “Bank of America” means Bank of America, N.A. and its successors. 
 “Base Rate” means for any day a fluctuating rate per annum equal to the highest of (a) the Federal Funds Rate plus 1/2 of 1% per annum, (b) the rate of interest in effect for such day as publicly announced
from time to time by Bank of America as its “prime rate” and (c) the Eurodollar Rate plus 1% per annum. The “prime rate” is a rate set by Bank of America based upon various factors including Bank of
America’s costs and desired return, general economic conditions and other factors, and is used as a reference point for pricing some loans, which may be priced at, above, or below such announced rate. Any change in such prime rate announced by
Bank of America shall take effect at the opening of business on the day specified in the public announcement of such change. 
 “Base Rate Loan” means a Loan that bears interest based on the Base Rate. 
 “Borrower” has the meaning specified in the introductory paragraph hereto. 
 “Borrower
Materials” has the meaning specified in Section 7.02. 
 “Borrowing” means a borrowing
consisting of simultaneous Loans of the same Type and, in the case of Eurodollar Rate Loans, having the same Interest Period made by each of the Lenders pursuant to Section 2.01. 
 “Business Day” means any day other than a Saturday, Sunday or other day on which commercial banks are authorized to close
under the Laws of, or are in fact closed in, the state where the Administrative Agent’s Office is located and, if such day relates to any Eurodollar Rate Loan, means any day that is also a London Banking Day. 
  

 3 

 “Businesses” means, at any time, a collective reference to the businesses
operated by the Loan Parties and their Subsidiaries at such time. 
 “Capital Lease” means, as applied to any
Person, any lease of any Property by that Person as lessee which, in accordance with GAAP, is required to be accounted for as a capital lease on the balance sheet of that Person. 
 “Cash Collateralize” means to pledge and deposit with or deliver to the Administrative Agent, for the benefit of the L/C
Issuer or Swing Line Lender (as applicable) and the Lenders, as collateral for L/C Obligations, Obligations in respect of Swing Line Loans, or obligations of Lenders to fund participations in respect of either thereof (as the context may require),
cash or deposit account balances pursuant to documentation in form and substance satisfactory to (a) the Administrative Agent and (b) the L/C Issuer or the Swing Line Lender (as applicable). “Cash Collateral” shall have a meaning
correlative to the foregoing. 
 “Cash Equivalents” means, as at any date, (a) securities issued or
directly and fully guaranteed or insured by the United States or any agency or instrumentality thereof (provided that the full faith and credit of the United States is pledged in support thereof) having maturities of not more than twelve months from
the date of acquisition, (b) Dollar denominated time deposits and certificates of deposit of (i) any Lender, (ii) any domestic commercial bank of recognized standing having capital and surplus in excess of $500,000,000 or
(iii) any bank whose short-term commercial paper rating from S&P is at least A-1 or the equivalent thereof or from Moody’s is at least P-1 or the equivalent thereof (any such bank being an “Approved Bank”), in each case with
maturities of not more than 270 days from the date of acquisition, (c) commercial paper and variable or fixed rate notes issued by any Approved Bank (or by the parent company thereof) or any variable rate notes issued by, or guaranteed by, any
domestic corporation rated A-1 (or the equivalent thereof) or better by S&P or P-1 (or the equivalent thereof) or better by Moody’s and maturing within six months of the date of acquisition, (d) repurchase agreements entered into by
any Person with a bank or trust company (including any of the Lenders) or recognized securities dealer having capital and surplus in excess of $500,000,000 for direct obligations issued by or fully guaranteed by the United States in which such
Person shall have a perfected first priority security interest (subject to no other Liens) and having, on the date of purchase thereof, a fair market value of at least 100% of the amount of the repurchase obligations and (e) Investments,
classified in accordance with GAAP as current assets, in money market investment programs registered under the Investment Company Act of 1940, as amended, which are administered by reputable financial institutions having capital of at least
$500,000,000 and the portfolios of which are limited to Investments of the character described in the foregoing subdivisions (a) through (d). 
 “Cash Management Agreement” means any agreement to provide cash management services, including treasury, depository, overdraft, credit or debit or purchasing card, electronic funds
transfer and other cash management arrangements. 
 “Cash Management Bank” means any Person that, at the time
it enters into a Cash Management Agreement, is a Lender or an Affiliate of a Lender, in its capacity as a party to such Cash Management Agreement. 
 “Change in Law” means the occurrence, after the date of this Agreement, of any of the following: (a) the adoption or taking effect of any law, rule, regulation or treaty,
(b) any change in any law, rule, regulation or treaty or in the administration, interpretation or application thereof by any Governmental Authority or (c) the making or issuance of any request, guideline or directive (whether or not having
the force of law) by any Governmental Authority. 
  

 4 

 “Change of Control” means an event or series of events by which:

 (a) any “person” or “group” (as such terms are used in Sections 13(d) and 14(d) of
the Securities Exchange Act of 1934, as amended, but excluding any employee benefit plan of such person or its subsidiaries, and any Person acting in its capacity as trustee, agent or other fiduciary or administrator of any such plan) becomes the
“beneficial owner” (as defined in Rules 13d-3 and 13d-5 under the Securities Exchange Act of 1934, except that a person or group shall be deemed to have “beneficial ownership” of all securities that such person or group has the
right to acquire (such right, an “option right”), whether such right is exercisable immediately or only after the passage of time), directly or indirectly, of thirty-five percent (35%) or more of the equity securities of
(i) from and after the consummation of the Reorganization as described in Section 8.04, Delaware Parent, or (ii) at all times prior thereto, the Borrower, in each case entitled to vote for members of the board of directors or
equivalent governing body of the Delaware Parent or the Borrower, as the case may be, on a fully-diluted basis (and taking into account all such securities that such person or group has the right to acquire pursuant to any option right); 

(b) during any period of twelve (12) consecutive months, a majority of the members of the board of directors or other
equivalent governing body of (A) from and after the consummation of the Reorganization as described in Section 8.04, Delaware Parent, or (B) at all times prior thereto, the Borrower, in each case cease to be composed of
individuals (i) who were members of that board or equivalent governing body on the first day of such period, (ii) whose election or nomination to that board or equivalent governing body was approved by individuals referred to in
clause (i) above constituting at the time of such election or nomination at least a majority of that board or equivalent governing body or (iii) whose election or nomination to that board or other equivalent governing body was approved by
individuals referred to in clauses (i) and (ii) above constituting at the time of such election or nomination at least a majority of that board or equivalent governing body (excluding, in the case of both clause (ii) and
clause (iii), any individual whose initial nomination for, or assumption of office as, a member of that board or equivalent governing body occurs as a result of an actual or threatened solicitation of proxies or consents for the election or
removal of one or more directors by any person or group other than a solicitation for the election of one or more directors by or on behalf of the board of directors); or 
 (c) if, at any time after the consummation of the Reorganization as described in Section 8.04, (i) Delaware
Parent shall cease, directly or indirectly, to own and control legally and beneficially all of the Equity Interests in Delaware Opco and the Borrower, or (ii) Delaware Opco shall cease, directly or indirectly, to own and control legally and
beneficially all of the Equity Interests in the Borrower. 
 “Closing Date” means the date hereof. 

“Colal-Pred® License Agreement” means the License Agreement dated as of November 29, 2007 between the Borrower
and Alizyme Therapeutics Limited. 
 “Collateral” means a collective reference to all real and personal
Property with respect to which Liens in favor of the Administrative Agent (for the benefit of the Secured Parties) are purported to be granted pursuant to and in accordance with the terms of the Collateral Documents. 
 “Collateral Documents” means a collective reference to the Security Agreement, the Pledge Agreement, the Mortgages and
other security documents as may be executed and delivered by the Loan Parties pursuant to the terms of Section 7.14. 
  

 5 

 “Collateral Questionnaire” means a certificate in the form of Exhibit
G or any other form approved by the Administrative Agent. 
 “Commitment” means, as to each Lender, the
Revolving Commitment of such Lender and/or the Term Loan Commitment of such Lender. 
 “Compliance Certificate”
means a certificate substantially in the form of Exhibit D. 
 “Consolidated Capital Expenditures”
means, for any period, for the Loan Parties and their Subsidiaries on a consolidated basis, all expenditures in respect of the purchase of any fixed or capital assets which are required to be capitalized in accordance with GAAP; provided that
Consolidated Capital Expenditures shall not include any expenditures for replacements or substitutions of fixed or capital assets to the extent made with insurance, condemnation or similar proceeds, in each case that are reinvested in Eligible
Assets within three hundred sixty-five (365) days of receipt of the same by any Loan Party. 
 “Consolidated Cash
Taxes” means, for any period, for the Loan Parties and their Subsidiaries on a consolidated basis, the aggregate of all income Taxes, as determined in accordance with GAAP, to the extent the same are paid in cash during such period.

 “Consolidated Current Assets” means, as of any date of determination, the total assets of the Loan Parties
and their Subsidiaries on a consolidated basis as of such date that may properly be classified as current assets in accordance with GAAP, excluding cash and Cash Equivalents. 
 “Consolidated Current Liabilities” means, as of any date of determination, the total liabilities of the Loan Parties and
their Subsidiaries on a consolidated basis as of such date that may properly be classified as current liabilities in accordance with GAAP, excluding the current portion of long term debt. 
 “Consolidated EBITDA” means, for any period, for the Loan Parties and their Subsidiaries on a consolidated basis, an amount
equal to Consolidated Net Income for such period plus (a) the following to the extent deducted in calculating such Consolidated Net Income: (i) Consolidated Interest Expense for such period, (ii) the provision for federal,
state, local and foreign income Taxes payable by the Loan Parties and their Subsidiaries for such period, (iii) the amount of depreciation and amortization expense for such period, and (iv) all (A) non-cash stock-based compensation
charges and option-based severance expenses incurred during such period and (B) non-cash, non-recurring charges incurred during such period; provided that such charges were not a cash item in the twelve (12) month period prior to
such incurrence, minus (b) to the extent included in calculating such Consolidated Net Income, (i) federal, state, local and foreign income tax credits of the Loan Parties and their Subsidiaries for such period and
(ii) interest income of the Loan Parties and their Subsidiaries on a consolidated basis for such period, all as determined in accordance with GAAP, plus (c) to the extent received during the applicable period and not otherwise
included in calculating Consolidated Net Income for such period, the amount of any termination payment received by the Loan Parties or their Subsidiaries pursuant to the Entocort® EC Distribution Agreement. Notwithstanding the foregoing, for
purposes of calculating Consolidated EBITDA for any period, the amount of Consolidated EBITDA for such period attributable to Non-Guarantor Subsidiaries shall not exceed fifteen percent (15%) of total Consolidated EBITDA for such period.

 “Consolidated Fixed Charge Coverage Ratio” means, as of any date of determination, the ratio of (a) the
sum of (i) Consolidated EBITDA for the period of the four (4) prior fiscal quarters ending on such date minus (ii) Consolidated Cash Taxes for such period to (b) the sum of (i) the amount of Consolidated Interest
Expense paid in cash during the period of the four (4) prior fiscal quarters ending on such date, plus (ii) Consolidated Scheduled Funded Debt Payments for the period of the four (4) fiscal quarters

  

 6 

 
immediately succeeding such date. Notwithstanding the foregoing, (x) for purposes of calculating the Consolidated Fixed Charge Coverage Ratio as of the fiscal quarter period ending
March 31, 2010, the amount of Consolidated Interest Expense paid in cash during the four (4) fiscal quarter period ending on such date shall be deemed to be the amount of Consolidated Interest Expense paid in cash during the fiscal quarter
period ending on such date multiplied by four, (y) for purposes of calculating the Consolidated Fixed Charge Coverage Ratio as of the fiscal quarter period ending June 30, 2010, the amount of Consolidated Interest Expense paid in cash
during the four (4) fiscal quarter period ending on such date shall be deemed to be the amount of Consolidated Interest Expense paid in cash during the two (2) fiscal quarter period ending on such date multiplied by two and (z) for
purposes of calculating the Consolidated Fixed Charge Coverage Ratio as of the fiscal quarter ending September 30, 2010, the amount of Consolidated Interest Expense paid in cash during the four (4) fiscal quarter period ending on such date
shall be deemed to be the amount of Consolidated Interest Expense paid in cash during the three (3) fiscal quarter period ending on such date multiplied by one and one third. 
 “Consolidated Funded Indebtedness” means the Funded Indebtedness of the Loan Parties and their Subsidiaries on a
consolidated basis determined in accordance with GAAP. 
 “Consolidated Interest Expense” means, for any
period, for the Loan Parties and their Subsidiaries on a consolidated basis, an amount equal to the sum of all interest, premium payments, debt discount, fees, charges and related expenses (whether cash or non-cash) of the Loan Parties and their
Subsidiaries, in each case to the extent treated as interest in accordance with GAAP (including, without limitation, (a) capitalized interest, (b) payments consisting of interest in respect of any Capital Lease or any Synthetic Lease or in
connection with the deferred purchase price of assets and (c) to the extent treated as interest during such period and identified as such on the applicable income statement for such period, any portion of the amount equal to the difference
between (i) the amount of any Extension Payment and (ii) the present value of such Extension Payment). 
 “Consolidated Leverage Ratio” means, as of any date of determination, the ratio of (a) Consolidated Funded Indebtedness as of such date to (b) Consolidated EBITDA for the four fiscal quarter period of the Borrower
most recently ended. 
 “Consolidated Net Income” means, for any period, for the Loan Parties and their
Subsidiaries on a consolidated basis, the net income or loss of the Loan Parties and their Subsidiaries (excluding extraordinary gains and extraordinary losses) for that period. 
 “Consolidated Scheduled Funded Debt Payments” means for any period for the Loan Parties and their Subsidiaries on a
consolidated basis, the sum of all scheduled payments of principal on Consolidated Funded Indebtedness, as determined in accordance with GAAP; provided, however, for purposes of calculating the Consolidated Fixed Charge Coverage Ratio,
the installment payments due hereunder after December 31, 2012 shall be deemed to be equal to the installment payment for the quarter ended December 31, 2012. For purposes of this definition, “scheduled payments of principal”
(a) shall be determined without giving effect to any reduction of such scheduled payments resulting from the application of any mandatory prepayments made during the applicable period (but, for the purpose of clarification, giving effect to any
reduction of such scheduled payments resulting from the application of voluntary prepayments made during the applicable period), (b) shall be deemed to include the Attributable Indebtedness in respect of Capital Leases, Synthetic Leases and
Sale and Leaseback Transactions and (c) shall not include any voluntary prepayments or mandatory prepayments required pursuant to Section 2.05. 
  

 7 

 “Consolidated Total Assets” means, as of any date of determination, all
assets of the Loan Parties and their Subsidiaries as determined according to the consolidated balance sheet contained in the most recent financial statements delivered pursuant to Section 7.01(a) or (b). 
 “Consolidated Working Capital” means, as of any date of determination, the excess of Consolidated Current Assets over
Consolidated Current Liabilities. 
 “Consolidated Working Capital Adjustment” means, for any fiscal year of
the Loan Parties and their Subsidiaries on a consolidated basis, the amount (which may be a negative number) by which Consolidated Working Capital as of the last day of such fiscal year exceeds (or is less than) Consolidated Working Capital as of
the first day of such fiscal year. 
 “Contractual Obligation” means, as to any Person, any provision of any
security issued by such Person or of any agreement, instrument or other undertaking to which such Person is a party or by which it or any of its property is bound. 
 “Control” means the possession, directly or indirectly, of the power to direct or cause the direction of the management or policies of a Person, whether through the ability to exercise
voting power, by contract or otherwise. “Controlling” and “Controlled” have meanings correlative thereto. Without limiting the generality of the foregoing, a Person shall be deemed to be Controlled by another Person
if such other Person possesses, directly or indirectly, power to vote 10% or more of the securities having ordinary voting power for the election of directors, managing general partners or the equivalent. 
 “Credit Extension” means each of the following: (a) a Borrowing and (b) an L/C Credit Extension. 
 “Debt Issuance” means the issuance by a Loan Party or any Subsidiary of any Indebtedness other than Indebtedness permitted
under Section 8.03. 
 “Debtor Relief Laws” means the Bankruptcy Code of the United States, and all
other liquidation, conservatorship, bankruptcy, assignment for the benefit of creditors, moratorium, rearrangement, receivership, insolvency, reorganization, or similar debtor relief Laws of the United States or other applicable jurisdictions from
time to time in effect and affecting the rights of creditors generally. 
 “Default” means any event or
condition that constitutes an Event of Default or that, with the giving of any notice, the passage of time, or both, would be an Event of Default. 
 “Default Rate” means an interest rate equal to (a) the Base Rate plus (b) the Applicable Rate, if any, applicable to Base Rate Loans plus (c) two percent
(2%) per annum; provided, however, that with respect to a Eurodollar Rate Loan, the Default Rate shall be an interest rate equal to the interest rate (including any Applicable Rate) otherwise applicable to such Loan plus two
percent (2%) per annum, in each case to the fullest extent permitted by applicable Laws. 
 “Defaulting
Lender” means any Lender that, as reasonably determined by the Administrative Agent, (a) has failed to perform its obligation to fund any portion of its Loans (or participations in respect of Letters of Credit or Swing Line Loans)
within three Business Days of the date required to be funded by it hereunder, unless such obligation is the subject of a good faith dispute, (b) has notified the Borrower, the Administrative Agent or any Lender in writing that (i) it does
not intend to comply with any of its funding obligations under this Agreement, unless such noncompliance is the subject of a good faith dispute, or (ii) has made a public statement that it does not intend to comply with its funding obligations
under this Agreement or generally under other agreements in which it commits to extend credit, (c) has

  

 8 

 
failed, within three Business Days after written request by the Administrative Agent, to confirm in a manner satisfactory to the Administrative Agent, the L/C Issuer and the Swing Line Lender
that it will comply with the terms of this Agreement relating to its obligations to fund prospective Loans (or participations in respect of Letters of Credit or Swing Line Loans), (d) otherwise has failed to pay over to the Administrative Agent
or any other Lender any other amount required to be paid by it hereunder within three Business Days of the date when due, unless the subject of a good faith dispute, or (e) has, or has a direct or indirect parent company that has,
(i) become the subject of a proceeding under any Debtor Relief Laws, (ii) had a receiver, conservator, trustee, administrator, assignee for the benefit of creditors or similar Person charged with reorganization or liquidation of its
business or a custodian appointed for it, or (iii) taken any action in furtherance of, or indicating its consent to, approval of or acquiescence in any such proceeding or appointment; provided that a Lender shall not be a Defaulting Lender
solely by virtue of the ownership or acquisition of any equity interest in such Lender or direct or indirect parent company thereof by a Governmental Authority. A Lender that has become a Defaulting Lender because of an event referenced in this
definition may cure such status and shall no longer constitute a Defaulting Lender as provided in the last paragraph of Section 2.15. 
 “Delaware Opco” has the meaning specified in Section 8.04. 
 “Delaware Parent” has the meaning specified in Section 8.04. 
 “Disposition” or
“Dispose” means the sale, transfer, license, lease or other disposition (including any Sale and Leaseback Transaction) of any Property by a Loan Party or any Subsidiary (including the Equity Interests of any Subsidiary), including
any sale, assignment, transfer or other disposal, with or without recourse, of any notes or accounts receivable or any rights and claims associated therewith, but excluding (i) the sale, lease, license, transfer or other disposition of
inventory in the ordinary course of business of the Loan Parties and their Subsidiaries, (ii) the sale, lease, license, transfer or other disposition of machinery and equipment no longer used or useful in the conduct of business of the Loan
Parties and their Subsidiaries, (iii) any sale, lease, license, transfer or other disposition of Property by a Loan Party or any Subsidiary to any Loan Party, provided that the Loan Parties shall cause to be executed and delivered such
documents, instruments and certificates as the Administrative Agent may request so as to cause the Loan Parties to be in compliance with the terms of Section 7.14 after giving effect to such transaction, (iv) any loss of, damage to
or destruction of, or any condemnation or other taking for public use of, any Property of a Loan Party or any of its Subsidiaries (or any settlement in lieu thereof), (v) the making of any Permitted Investment, (vi) any sale, lease,
license, transfer or other disposition of Property by any Foreign Subsidiary to another Foreign Subsidiary, (vii) any sale or other disposition by a Loan Party or any Subsidiary of accounts receivable related to diagnostic receivables that are
more than one hundred twenty (120) days past due in the ordinary course of business, (viii) any Equity Issuance and any transaction described in clauses (a) through (g) of the definition of Equity Issuance set forth herein,
(ix) any sale, transfer, license, lease or other disposition of any Property permitted by Section 8.04 or Section 8.06 (including, without limitation, in connection with the Reorganization), (x) any termination of a
lease or sublease with respect to real property or any other termination of any interest in leased real property, (xi) any sale, transfer or other disposition of cash and Cash Equivalents pursuant to transactions permitted hereunder,
(xii) any termination of any contract, license or other agreement, (xiii) the incurrence of any Permitted Lien, (xiv) with respect to any Property that is the subject of or used, developed or created by or for the benefit of a Loan
Party or a Subsidiary in connection with the Rosetta License Agreement, the Colal-Pred License Agreement, the Entocort® EC Distribution Agreement, the Proleukin® Distribution Agreement, the 1996 License Agreement, the Proleukin® Supply
Agreement, the Lotronex® Supply Agreement or any other similar intellectual property or product license agreement or distribution or supply agreement of any product, any sale, lease, license, transfer or other disposition of such Property
pursuant to such agreement, and (xv) any licensing of IP Rights by a Loan Party or a Subsidiary to another Person, provided that (A) any such licensing is on an arms-length basis on commercially

  

 9 

 
reasonable terms, (B) the Borrower shall deliver prior written notice to the Administrative Agent of any such transaction that provides annual revenue to the Loan Parties or their
Subsidiaries in excess of $1,000,000 per year and (C) if the Consolidated Leverage Ratio as of the end of the most recent fiscal quarter for which the Borrower has delivered financial statements pursuant to Section 7.01(a) or
(b), as applicable, was greater than 1.50 to 1.00, the Borrower shall prepay the Loans and Cash Collateralize the LC Obligations with 100% of the Net Cash Proceeds of any upfront, closing or similar payment received by the Loan Parties or any
Subsidiary in connection with the applicable licensing agreement (such prepayment to be applied as set forth in Section 2.05(b)(vii)). 
 “Dollar” and “$” mean lawful money of the United States. 
 “Dollar Equivalent” means, at any date, (a) with respect to any amount denominated in Dollars, such amount, and (b) with respect to any amount denominated in Euros, the
equivalent amount thereof in Dollars as determined by the Administrative Agent or the L/C Issuer, as the case may be, at such time on the basis of the Spot Rate (determined in respect of such date) for the purchase of Dollars with Euros. 

“Domestic Subsidiary” means any Subsidiary that is organized under the Laws of any political subdivision of the United
States. 
 “Earn Out Obligations” means, with respect to an Acquisition, all obligations of a Loan Party or any
Subsidiary to make earn out or other contingency payments pursuant to the documentation relating to such Acquisition (excluding (a) any such obligations or contingency payments required to be paid with common stock or nonredeemable preferred
stock (or warrants to purchase such securities) of the Borrower and (b) any Milestone Payments). For the avoidance of doubt, Earn Out Obligations shall not include any contractual royalty payments. The amount of any Earn Out Obligation shall be
deemed to be the aggregate liability in respect thereof as recognized on the consolidated balance sheet of the Loan Parties and their Subsidiaries in accordance with GAAP. 
 “Eligible Assets” means Property that is used or useful in the same or similar lines of businesses as the Borrower was
engaged in on the Closing Date (or any reasonable extensions or expansions thereof). 
 “Eligible Assignee”
means any Person that meets the requirements to be an assignee under Section 11.06(b)(iii) and (v) (subject to such consents, if any, as may be required under Section 11.06(b)(iii)). 
 “EMU Legislation” means the legislative measures of the European Council for the introduction of, changeover to or
operation of a single or unified European currency. 
 “Entocort® EC Distribution Agreement” means that
certain Distribution Agreement dated as of November 19, 2004 by and between AstraZeneca LP, a Delaware limited partnership, and the Borrower. 
 “Environmental Laws” means any and all federal, state, local, foreign and other applicable Laws, decrees, concessions, grants, franchises, agreements or governmental restrictions relating
to pollution and the protection of the environment or the release of any materials into the environment, including those related to Hazardous Materials, air emissions and discharges to waste or public systems. 
 “Environmental Liability” means any liability, contingent or otherwise (including any liability for damages, costs of
environmental remediation, fines, penalties or indemnities), of the Borrower, any other Loan Party or any of their respective Subsidiaries directly or indirectly resulting from or based upon (a) violation of any Environmental Law, (b) the
generation, use, handling, transportation, storage, treatment

  

 10 

 
or disposal of any Hazardous Materials, (c) exposure to any Hazardous Materials, (d) the release or threatened release of any Hazardous Materials into the environment or (e) any
contract, agreement or other consensual arrangement pursuant to which liability is assumed or imposed with respect to any of the foregoing. 
 “Equity Interests” means, with respect to any Person, all of the shares of equity interests of (or other ownership or profit interests in) such Person, all of the warrants, options or
other rights for the purchase or acquisition from such Person of shares of equity interests of (or other ownership or profit interests in) such Person, all of the securities convertible into or exchangeable for shares of equity interests of (or
other ownership or profit interests in) such Person or warrants, rights or options for the purchase or acquisition from such Person of such shares (or such other interests), and all of the other ownership or profit interests in such Person
(including partnership, member or trust interests therein), whether voting or nonvoting. 
 “Equity Issuance”
means any issuance by Delaware Parent, any Loan Party or any Subsidiary to any Person of its Equity Interests, other than (a) with respect to a Subsidiary, any issuance of its Equity Interests to the Borrower or any other Loan
Party, (b) any issuance of its Equity Interests pursuant to the exercise of options or warrants, (c) any issuance of its Equity Interests pursuant to the conversion of any debt securities to equity or the conversion of any class of equity
securities to any other class of equity securities, (d) any issuance of options, rights or warrants relating to its Equity Interests, (e) any issuance by a Loan Party or any Subsidiary of its Equity Interests as consideration for the
acquisition of any Property (other than cash and Cash Equivalents) by a Loan Party or any Subsidiary from any Person in connection with a transaction otherwise permitted hereunder, (f) any issuance by the Borrower of its Equity Interests
pursuant to the Lotronex® Acquisition Documents, (g) subject to the following clause (h)(ii), any issuance by a Loan Party or a Subsidiary of its Equity Interests to an existing shareholder of such Loan Party or Subsidiary, and (h) any
issuance by Delaware Parent of its Equity Interests (other than in connection with a Public Offering) to (i) an existing shareholder of Delaware Parent or (ii) any other Person so long as, in the case of this clause (h)(ii), no Net Cash
Proceeds of such Equity Issuance by Delaware Parent are contributed to or otherwise invested in Delaware Opco, the Borrower or a Subsidiary of either of them. The term “Equity Issuance” shall not be deemed to include any Disposition. For
the purpose of clarification, it is understood and agreed that (i) the Net Cash Proceeds of any Equity Issuance received by any of the Delaware Parent, any Loan Party or any Subsidiary in connection with a Public Offering by such Person and
(ii) any Net Cash Proceeds of any Equity Issuance by the Delaware Parent to a Person other than to a then existing shareholder of Delaware Parent that are subsequently contributed to or otherwise invested in Delaware Opco, the Borrower or a
Subsidiary shall, in each case, be applied to prepay the Loans and/or Cash Collateralize the L/C Obligations in accordance with and in the amounts required by Section 2.05(b)(v). 
 “ERISA” means the Employee Retirement Income Security Act of 1974. 
 “ERISA Affiliate” means any trade or business (whether or not incorporated) under common control with the Borrower within
the meaning of Section 414(b) or (c) of the Internal Revenue Code (and Sections 414(m) and (o) of the Internal Revenue Code for purposes of provisions relating to Section 412 of the Internal Revenue Code). 
 “ERISA Event” means (a) a Reportable Event with respect to a Pension Plan; (b) a withdrawal by the Borrower or
any ERISA Affiliate from a Pension Plan subject to Section 4063 of ERISA during a plan year in which it was a substantial employer (as defined in Section 4001(a)(2) of ERISA) or a cessation of operations that is treated as such a
withdrawal under Section 4062(e) of ERISA; (c) a complete or partial withdrawal by the Borrower or any ERISA Affiliate from a Multiemployer Plan or notification that a Multiemployer Plan is in reorganization; (d) the filing of a
notice of intent to terminate,

  

 11 

 
the treatment of a Plan amendment as a termination under Sections 4041 or 4041A of ERISA, or the commencement of proceedings by the PBGC to terminate a Pension Plan or Multiemployer Plan;
(e) an event or condition which constitutes grounds under Section 4042 of ERISA for the termination of, or the appointment of a trustee to administer, any Pension Plan or Multiemployer Plan; or (f) the imposition of any liability
under Title IV of ERISA, other than for PBGC premiums due but not delinquent under Section 4007 of ERISA, upon the Borrower or any ERISA Affiliate. 
 “Euro” means the lawful currency of the Participating Member States introduced in accordance with the EMU Legislation. 
 “Eurodollar Rate” means 
 (a) for any interest calculation with respect to a Loan other than a Base Rate Loan, for any Interest Period with respect to such Loan, the rate per annum equal to (i) the British Bankers Association
LIBOR Rate (“BBA LIBOR”), as published by Reuters (or other commercially available source providing quotations of BBA LIBOR as designated by the Administrative Agent from time to time) at approximately 11:00 a.m., London time, two
London Banking Days prior to the commencement of such Interest Period, for Dollar deposits (for delivery on the first day of such Interest Period) with a term equivalent to such Interest Period or (ii) if such rate is not available at such time
for any reason, the rate per annum determined by the Administrative Agent to be the rate at which deposits in Dollars for delivery on the first day of such Interest Period in same day funds in the approximate amount of the Eurodollar Rate Loan being
made, continued or converted by Bank of America and with a term equivalent to such Interest Period would be offered by Bank of America’s London Branch to major banks in the London interbank eurodollar market at their request at approximately
11:00 a.m. (London time) two London Banking Days prior to the commencement of such Interest Period; and 
 (b)
for any interest calculation with respect to a Base Rate Loan on any date, the rate per annum equal to (i) BBA LIBOR, at approximately 11:00 a.m., London time determined two London Banking Days prior to such date for Dollar deposits being
delivered in the London interbank market for a term of one month commencing that day or (ii) if such published rate is not available at such time for any reason, the rate per annum determined by the Administrative Agent to be the rate at which
deposits in Dollars for delivery on the date of determination in same day funds in the approximate amount of the Base Rate Loan being made, continued or converted by Bank of America and with a term equal to one month would be offered by Bank of
America’s London Branch to major banks in the London interbank Eurodollar market at their request at the date and time of determination. 
 “Eurodollar Rate Loan” means a Loan that bears interest at a rate based on clause (a) of the definition of “Eurodollar Rate.” 
 “Event of Default” has the meaning specified in Section 9.01. 
 “Excess Cash Flow” means, for any fiscal year of the Loan Parties and their Subsidiaries (subject to the proviso at the end
of this definition), the excess, (if any) of (a) Consolidated EBITDA for such fiscal year over (b) the sum of (for such fiscal year) (i) Consolidated Capital Expenditures paid in cash, (ii) the cash portion of Consolidated
Interest Expense, (iii) Consolidated Cash Taxes, (iv) Consolidated Scheduled Funded Debt Payments, (v) the Consolidated Working Capital Adjustment, (vi) voluntary and mandatory principal prepayments of the Loans and other
Indebtedness made by a Loan Party or any Subsidiary during such fiscal year (other than principal payments of Revolving Loans, Swing Line Loans or loans under any revolving credit facility, unless and to the extent that the applicable revolving
commitments are

  

 12 

 
permanently reduced in connection with such prepayment), (vii) the amount of Investments made in cash by the Loan Parties or their Subsidiaries during such fiscal year pursuant to
Section 8.02(g); provided that for the purposes of the calculation of Excess Cash Flow for any fiscal year, the amount included in such calculation pursuant to this clause (vii) shall not exceed 50% of the amount of such
Investments actually made in cash during the applicable fiscal year, and (viii) Milestone Payments and previously incurred Earn Out Obligations paid in cash during such fiscal year; provided, however, and notwithstanding the
foregoing, Excess Cash Flow for fiscal year 2010 shall be an amount equal to the greater of (i) Excess Cash Flow for such fiscal year as determined using the calculation set forth above and (ii) $15,000,000. 
 “Excluded Property” means, with respect to any Loan Party, (a) any owned or leased real or
personal Property which is located outside of the United States unless otherwise requested by the Administrative Agent or the Required Lenders, (b) any personal Property (including, without limitation, motor vehicles) in respect of which
perfection of a Lien is not either (i) governed by the Uniform Commercial Code or (ii) effected by appropriate evidence of the Lien being filed in either the United States Copyright Office or the United States Patent and Trademark Office,
unless otherwise requested by the Administrative Agent or the Lenders, (c) any Property which is subject to a Lien of the type described in Section 8.01(i) pursuant to documents which prohibit such Loan Party from granting any other
Liens in such Property, (d) the Entocort® EC Distribution Agreement, (e) any Property released from the Lien of the Administrative Agent pursuant to and in accordance with the Loan Documents, (f) any Property to the extent that
and for as long as (but only for so long as) the assignment thereof or the creation of a security interest therein (i) would constitute a breach or default under, result in a termination of or require any consent not obtained under, (A) if
the applicable Property is a contract, lease, license, permit or other agreement (including, without limitation, any Copyright License, Patent License or Trademark License (each as defined in the Security Agreement)), such contract, lease, license,
permit or other agreement, or (B) in the case of any Property, any contract, lease, license, permit or other agreement related to such Property (in each case as such contract, lease, license, permit or agreement is in effect on the date of this
Agreement or the date on which such contract, lease, license, permit or agreement is first entered into by or issued to the applicable Loan Party), (ii) is prohibited by any Law or (iii) requires a filing with or consent from any
Governmental Authority that has not been made or obtained, except to the extent that such Law is, or the provisions of any such contract, lease, license, permit or agreement are, ineffective under applicable Law and under Sections 9-406, 9-407,
9-408 or 9-409 of the Uniform Commercial Code in the applicable state to prevent the attachment of such security interest, (g) any New Product Regulatory Approvals or any other Regulatory Approval (as defined in the Proleukin® Distribution Agreement), (h) any leased or subleased office space of any Loan Party, (i) any automobile
lease of any Loan Party and (j) any “intent-to-use” application for registration of a Trademark (as defined in the Security Agreement) filed pursuant to Section 1(b) of the Lanham Act, 15 U.S.C. § 1051 prior to the
filing of a “Statement of Use” pursuant to Section 1(d) of the Lanham Act or an “Amendment to Allege Use” pursuant to Section 1(c) of the Lanham Act with respect thereto, solely to the extent, if any, that, and solely
during the period, if any, in which, the grant of a security interest therein would impair the validity or enforceability of any registration that issues from such intent-to-use application under applicable federal law. 
 “Excluded Taxes” means, with respect to the Administrative Agent, any Lender, the L/C Issuer or any other recipient of any
payment to be made by or on account of any obligation of the Borrower hereunder, (a) Taxes imposed on or measured by its overall net income (however denominated), and franchise Taxes imposed on it (in lieu of net income Taxes), by the
jurisdiction (or any political subdivision thereof) under the Laws of which such recipient is organized or in which its principal office is located or, in the case of any Lender, in which its applicable Lending Office is located, (b) any branch
profits Taxes imposed by the United States or any similar Tax imposed by any other jurisdiction in which the Borrower is located, (c) any backup withholding Tax that is required by the Internal Revenue Code to be withheld from amounts payable
to a Lender that has failed to comply with Section 3.01(e), and (d) in the case of a Foreign Lender (other than an assignee pursuant to a request by the Borrower under Section 

  

 13 

 
11.14), any United States withholding Tax that (i) is required to be imposed on amounts payable to such Foreign Lender pursuant to the Laws in force at the time such Foreign Lender
becomes a party hereto (or designates a new Lending Office) or (ii) is attributable to such Foreign Lender’s failure or inability (other than as a result of a Change in Law) to comply with Section 3.01(e), except to the extent
that such Foreign Lender (or its assignor, if any) was entitled, at the time of designation of a new Lending Office (or assignment), to receive additional amounts from the Borrower with respect to such withholding Tax pursuant to
Section 3.01(a)(ii). 
 “Existing Credit Agreement” means that certain Credit Agreement dated as of
September 21, 2007 among the Borrower, the lenders party thereto and Bank of America, as agent, as amended or modified from time to time. 
 “Existing Preferred Stock” means any of the outstanding Series A, B, C, D or E preferred stock of the Borrower (or warrants for such preferred stock) issued pursuant to the Amended and
Restated Articles of Incorporation of the Borrower as in effect on the Closing Date. 
 “Extension Payment” has
the meaning given in the definition of “Milestone Payments”. 
 “Extraordinary
Receipt” means any cash received by or paid to or for the account of a Loan Party or any Subsidiary from pension plan reversions, proceeds of insurance (including, without limitation, any key man life insurance but excluding proceeds of
business interruption insurance) and any loss of, damage to or destruction of, or any condemnation or other taking for public use of, any Property of a Loan Party or any of its Subsidiaries (and payments in lieu thereof), including, without
limitation, any termination payment received by the Borrower pursuant to the Entocort® EC Distribution Agreement or the Proleukin® Distribution Agreement; provided, however, that for the purposes of this Agreement and the other Loan Documents, cash receipts by any Loan Party in the
ordinary course of business shall not be deemed to be an Extraordinary Receipt. 
 “Facilities” means, at any
time, a collective reference to the facilities and real properties owned, leased or operated by a Loan Party or any Subsidiary. 
 “Federal Funds Rate” means, for any day, the rate per annum equal to the weighted average of the rates on overnight Federal funds transactions with members of the Federal Reserve System arranged by Federal funds brokers on
such day, as published by the Federal Reserve Bank of New York on the Business Day next succeeding such day; provided that (a) if such day is not a Business Day, the Federal Funds Rate for such day shall be such rate on such transactions
on the next preceding Business Day as so published on the next succeeding Business Day, and (b) if no such rate is so published on such next succeeding Business Day, the Federal Funds Rate for such day shall be the average rate (rounded upward,
if necessary, to a whole multiple of 1/100 of 1%) charged to Bank of America on such day on such transactions as determined by the Administrative Agent. 
 “Fee Letter” means the letter agreement, dated October 28, 2009 among the Borrower, the Administrative Agent, the Syndication Agent and the Arrangers. 
 “First-Tier Foreign Subsidiary” means each Foreign Subsidiary that is owned directly by a Loan Party and that has not
become a Guarantor pursuant to Section 7.12 hereof. 
 “Foreign Lender” means any Lender that is organized
under the Laws of a jurisdiction other than that in which the Borrower is resident for Tax purposes. For purposes of this definition, the United States, each State thereof and the District of Columbia shall be deemed to constitute a single
jurisdiction. 
  

 14 

 “Foreign Subsidiary” means any Subsidiary that is not a Domestic
Subsidiary. 
 “FRB” means the Board of Governors of the Federal Reserve System of the United States.

 “Fronting Exposure” means, at any time there is a Defaulting Lender, (a) with respect to the L/C
Issuer, such Defaulting Lender’s Pro Rata Share of the outstanding L/C Obligations other than L/C Obligations as to which (i) such Defaulting Lender’s participation obligation has been reallocated pursuant to
Section 2.15(c), or (ii) Cash Collateral or other credit support acceptable to the L/C Issuer shall have been provided in accordance with Section 2.03, and (b) with respect to the Swing Line Lender, such Defaulting
Lender’s Pro Rata Share of Swing Line Loans other than Swing Line Loans as to which (i) such Defaulting Lender’s participation obligation has been reallocated pursuant to Section 2.15(c), or (ii) Cash Collateral or
other credit support acceptable to the Swing Line Lender shall have been provided in accordance with Section 2.04. 
 “Fully Satisfied” means, with respect to the Obligations as of any date, that, as of such date, (a) all principal of and interest accrued to such date which constitute Obligations shall have been irrevocably paid in
full in cash, (b) all fees, expenses and other amounts then due and payable which constitute Obligations shall have been irrevocably paid in cash, (c) all outstanding Letters of Credit shall have been (i) terminated, (ii) fully
irrevocably Cash Collateralized or (iii) secured by one or more letters of credit on terms and conditions, and with one or more financial institutions, reasonably satisfactory to the L/C Issuer and (d) the Commitments shall have expired or
been terminated in full. 
 “Fund” means any Person (other than a natural person) that is (or will be) engaged
in making, purchasing, holding or otherwise investing in commercial loans and similar extensions of credit in the ordinary course of its activities. 
 “Funded Indebtedness” means, as to any Person at a particular time, without duplication, all of the following, whether or not included as indebtedness or liabilities in accordance with
GAAP: 
 (a) all obligations for borrowed money, whether current or long-term (including the Obligations) and all
obligations of such Person evidenced by bonds, debentures, notes, loan agreements or other similar instruments; 
 (b) all purchase money indebtedness; 
 (c) all direct obligations (which, for the avoidance of doubt,
shall not include contingent obligations) arising under letters of credit (including standby and commercial), bankers’ acceptances, bank guaranties, surety bonds and similar instruments; 
 (d) all obligations in respect of the deferred purchase price of Property or services, including without limitation, any Earn
Out Obligations; 
 (e) all Attributable Indebtedness; 
 (f) all obligations of such Person to purchase, redeem, retire, defease or otherwise make any payment in respect of any
Equity Interests in such Person or any other Person, valued, in the case of a redeemable preferred interest, at the greater of its voluntary or involuntary liquidation preference plus accrued and unpaid dividends; 
 (g) all Guarantees with respect to Funded Indebtedness of the types specified in clauses (a) through (f) above of
another Person; and 
  

 15 

 (h) all Funded Indebtedness of the types referred to in clauses
(a) through (g) above of any partnership or joint venture (other than a joint venture that is itself a corporation or limited liability company) in which such Person is a general partner or joint venturer, except to the extent that Funded
Indebtedness is expressly made non-recourse to such Person. 
 For purposes hereof, (x) the amount of any direct obligation arising under
letters of credit (including standby and commercial), bankers’ acceptances, bank guaranties, surety bonds and similar instruments shall be the maximum amount available to be drawn thereunder and (y) the amount of any Guarantee shall be the
amount of the indebtedness subject to such Guarantee. In addition, for the avoidance of doubt, the term “Funded Indebtedness” shall not include (i) obligations of a Person under purchase agreements pertaining to potential acquisitions
of such Person prior to consummation of any such acquisition, (ii) accrued Taxes, accrued compensation or other accruals of any Person incurred in the ordinary course of business, (iii) trade accounts payable of any Person incurred in the
ordinary course of business and that are due within sixty (60) days of the date of incurrence of the obligation in respect thereof, (iv) any such obligations or contingency payments of the type referred to in clause (d) above required
to be paid with common stock or nonredeemable preferred stock (or warrants to purchase such securities), (v) any Milestone Payments or (vi) any contractual royalty payments. 
 “GAAP” means generally accepted accounting principles in the United States set forth in the opinions and pronouncements of
the Accounting Principles Board and the American Institute of Certified Public Accountants and statements and pronouncements of the Financial Accounting Standards Board, consistently applied. 
 “Governmental Authority” means the government of the United States or any other nation, or of any political subdivision
thereof, whether state or local, and any agency, authority, instrumentality, regulatory body, court, central bank or other entity exercising executive, legislative, judicial, taxing, regulatory or administrative powers or functions of or pertaining
to government (including any supra-national bodies such as the European Union or the European Central Bank). 
 “Guarantee” means, as to any Person, without duplication (a) any obligation, contingent or otherwise, of such Person guaranteeing or having the economic effect of guaranteeing any Indebtedness or other obligation
payable or performable by another Person (the “primary obligor”) in any manner, whether directly or indirectly, and including any obligation of such Person, direct or indirect, (i) to purchase or pay (or advance or supply funds for
the purchase or payment of) such Indebtedness or other obligation, (ii) to purchase or lease property, securities or services for the purpose of assuring the obligee in respect of such Indebtedness or other obligation of the payment or
performance of such Indebtedness or other obligation, (iii) to maintain working capital, equity capital or any other financial statement condition or liquidity or level of income or cash flow of the primary obligor so as to enable the primary
obligor to pay such Indebtedness or other obligation, or (iv) entered into for the purpose of assuring in any other manner the obligee in respect of such Indebtedness or other obligation of the payment or performance thereof or to protect such
obligee against loss in respect thereof (in whole or in part), or (b) any Lien on any assets of such Person securing any Indebtedness or other obligation of any other Person, whether or not such Indebtedness or other obligation is assumed by
such Person. The amount of any Guarantee on any given date shall be deemed to be an amount equal to the stated or determinable amount of the related primary obligation, or portion thereof, in respect of which such Guarantee is made or, if not stated
or determinable, the maximum reasonably anticipated liability in respect thereof as determined by the guaranteeing Person in good faith. The term “Guarantee” as a verb has a corresponding meaning. 
  

 16 

 “Guarantors” means (a) each Subsidiary that joins this Agreement as a
Guarantor pursuant to Section 7.12 and (b) if the Reorganization occurs and Delaware Opco becomes a Guarantor pursuant to Section 8.04, Delaware Opco, in each case together with its successors and permitted assigns.

 “Guaranty” means the Guaranty made by the Guarantors in favor of the Secured Parties pursuant to Article
IV. 
 “Hazardous Materials” means all explosive or radioactive substances or wastes and all hazardous or
toxic substances, wastes or other pollutants, including petroleum or petroleum distillates, asbestos or asbestos-containing materials, polychlorinated biphenyls, radon gas, infectious or medical wastes and all other substances or wastes of any
nature regulated pursuant to any Environmental Law. 
 “Hedge Bank” means any Person that, at the time it
enters into an interest rate Swap Contract required or permitted under Article VII or VIII, is a Lender or an Affiliate of a Lender, in its capacity as a party to such Swap Contract. 
 “Honor Date” has the meaning specified in Section 2.03(c). 
 “Indebtedness” means, as to any Person at a particular time, without duplication, all of the following, whether or not
included as indebtedness or liabilities in accordance with GAAP: 
 (a) all Funded Indebtedness; 
 (b) net obligations under any Swap Contract; 
 (c) all direct or contingent obligations arising under letters of credit (including standby and commercial), bankers’
acceptances, bank guaranties, surety bonds and similar instruments; 
 (d) all Guarantees with respect to
outstanding Indebtedness of the types specified in clauses (a) through (b) above of any other Person; and 
 (e) all Indebtedness of the types referred to in clauses (a) through (d) above of any partnership or joint venture (other than a joint venture that is itself a corporation or limited liability company) in which a Loan Party or a
Subsidiary is a general partner or joint venturer, unless such Indebtedness is expressly made non-recourse to such Loan Party or such Subsidiary. 
 For purposes hereof (y) the amount of any net obligation under any Swap Contract on any date shall be deemed to be the Swap Termination Value thereof as of such date and (z) the amount of any Guarantee shall be the amount of the
Indebtedness subject to such Guarantee. 
 “Indemnified Taxes” means Taxes other than Excluded Taxes.

 “Indemnitees” has the meaning specified in Section 11.04(b). 
 “Interest Payment Date” means (a) as to any Loan other than a Base Rate Loan, the last day of each Interest Period
applicable to such Loan and the Maturity Date; provided, however, that if any Interest Period for a Eurodollar Rate Loan exceeds three (3) months, the respective dates that fall every three (3) months after the beginning of
such Interest Period shall also be Interest Payment Dates; and (b) as to any Base Rate Loan (including a Swing Line Loan), the last Business Day of each March, June, September and December and the Maturity Date. 
  

 17 

 “Interest Period” means, as to each Eurodollar Rate Loan, the period
commencing on the date such Eurodollar Rate Loan is disbursed or converted to or continued as a Eurodollar Rate Loan and ending on the date one, three or six months thereafter, as selected by the Borrower in its Loan Notice; provided that:

 (a) any Interest Period that would otherwise end on a day that is not a Business Day shall be extended to the
next succeeding Business Day unless such Business Day falls in another calendar month, in which case such Interest Period shall end on the next preceding Business Day; 
 (b) any Interest Period that begins on the last Business Day of a calendar month (or on a day for which there is no
numerically corresponding day in the calendar month at the end of such Interest Period) shall end on the last Business Day of the calendar month at the end of such Interest Period; and 
 (c) no Interest Period shall extend beyond the Maturity Date. 
 “Interim Financial Statements” means the unaudited consolidated balance sheets and statements of operations and cash flows
of the Borrower and its Subsidiaries for the fiscal quarters ended March 31, 2009, June 30, 2009 and September 30, 2009. 
 “Internal Revenue Code” means the Internal Revenue Code of 1986, as amended. 
 “Investment” means, as to any Person, any direct or indirect acquisition of another Person or investment by such Person in another Person, whether by means of (a) the purchase or
other acquisition of Equity Interests of another Person, (b) a loan, advance or capital contribution to, Guarantee or assumption of debt of, or purchase or other acquisition of any other debt or equity participation or interest in, another
Person, including any partnership or joint venture interest in such other Person, or (c) an Acquisition. For purposes of covenant compliance, the amount of any Investment shall be the amount actually invested, without adjustment for subsequent
increases or decreases in the value of such Investment. 
 “IP Rights” has the meaning specified in
Section 6.17. 
 “IRS” means the United States Internal Revenue Service. 
 “ISP” means, with respect to any Letter of Credit, the “International Standby Practices 1998” published by the
Institute of International Banking Law & Practice (or such later version thereof as may be in effect at the time of issuance). 
 “Issuer Documents” means with respect to any Letter of Credit, the Letter Credit Application, and any other document, agreement and instrument entered into by the L/C Issuer and the
Borrower or in favor of the L/C Issuer and relating to any such Letter of Credit. 
 “Joinder Agreement” means
a joinder agreement substantially in the form of Exhibit F executed and delivered by a Subsidiary in accordance with the provisions of Section 7.12 or Delaware Opco in accordance with the provisions of Section 8.04.

 “Laws” means, collectively, all international, foreign, federal, state and local statutes, treaties, rules,
guidelines, regulations, ordinances, codes and administrative or judicial precedents or authorities, including the interpretation or administration thereof by any Governmental Authority charged with the enforcement, interpretation or administration
thereof, and all applicable administrative orders, directed

  

 18 

 
duties, requests, licenses, authorizations and permits of, and agreements with, any Governmental Authority, in each case whether or not having the force of law. 
 “L/C Advance” means, with respect to each Lender, such Lender’s funding of its participation in any L/C Borrowing in
accordance with its Pro Rata Share. All L/C Advances shall be denominated in Dollars. 
 “L/C Borrowing” means
an extension of credit resulting from a drawing under any Letter of Credit which has not been reimbursed on the date when made or refinanced as a Borrowing of Revolving Loans. 
 “L/C Credit Extension” means, with respect to any Letter of Credit, the issuance thereof or extension of the expiry date
thereof, or the renewal or increase of the amount thereof. 
 “L/C Issuer” means Bank of America in its
capacity as issuer of Letters of Credit hereunder, or any successor issuer of Letters of Credit hereunder. 
 “L/C
Obligations” means, as at any date of determination, the Dollar Equivalent of the aggregate undrawn amount of all outstanding Letters of Credit plus the aggregate of all Unreimbursed Amounts, including all L/C Borrowings. For
purposes of computing the amount available to be drawn under any Letter of Credit, the amount of such Letter of Credit shall be determined in accordance with Section 1.06. For all purposes of this Agreement, if on any date of
determination a Letter of Credit has expired by its terms but any amount may still be drawn thereunder by reason of the operation of Rule 3.14 of the ISP, such Letter of Credit shall be deemed to be “outstanding” in the amount so remaining
available to be drawn. 
 “Lenders” means (a) each of the Persons identified as a “Lender” on
the signature pages hereto and their successors and assigns and, as the context requires, includes the L/C Issuer and the Swing Line Lender, and (b) each of the Persons who becomes a Lender hereunder pursuant to Section 2.02(f) and
their successors and assigns. 
 “Lending Office” means, as to any Lender, the office or offices of such Lender
described as such in such Lender’s Administrative Questionnaire, or such other office or offices as a Lender may from time to time notify the Borrower and the Administrative Agent. 
 “Letter of Credit” means any standby letter of credit issued hereunder. 
 “Letter of Credit Application” means an application and agreement for the issuance or amendment of a letter of credit in
the form from time to time in use by the L/C Issuer. 
 “Letter of Credit Expiration Date” means the day that
is seven (7) days prior to the Maturity Date then in effect (or, if such day is not a Business Day, the next preceding Business Day). 
 “Letter of Credit Fee” has the meaning specified in Section 2.03(h). 
 “Letter of Credit Sublimit” means an amount equal to the lesser of (a) the Aggregate Revolving Commitments and (b) $10,000,000. The Letter of Credit Sublimit is part of, and not
in addition to, the Aggregate Revolving Commitments. 
 “Lien” means any mortgage, pledge, hypothecation,
assignment, deposit arrangement, encumbrance, lien (statutory or other), charge, or preference, priority or other security interest or

  

 19 

 
preferential arrangement of any kind or nature whatsoever (including any conditional sale or other title retention agreement, and any financing lease having substantially the same economic effect
as any of the foregoing). 
 “Loan” means an extension of credit by a Lender to the Borrower under Article
II in the form of a Revolving Loan, Swing Line Loan or Term Loan. 
 “Loan Documents” means this Agreement,
each Note, each Letter of Credit, each Issuer Document, each Joinder Agreement, the Collateral Documents, each Request for Credit Extension, each Compliance Certificate, the Fee Letter, any agreement by a Loan Party creating or perfecting rights in
cash collateral or other credit support pursuant to the provisions of Section 2.14 of this Agreement, and each other document, instrument or agreement executed from time to time after the Closing Date by a Loan Party or any of its Subsidiaries
or any Responsible Officer thereof and delivered in connection with this Agreement. 
 “Loan Notice” means a
notice of (a) a Borrowing of Revolving Loans or any portion of the Term Loan, (b) a conversion of Loans from one Type to the other, or (c) a continuation of Eurodollar Rate Loans, pursuant to Section 2.02(a), which, if in
writing, shall be substantially in the form of Exhibit A. 
 “Loan Parties” means, collectively,
the Borrower and each Guarantor. 
 “London Banking Day” means any day on which dealings in Dollar deposits are
conducted by and between banks in the London interbank Eurodollar market. 
 “Lotronex® Acquisition
Agreement” means the Asset Purchase and Sale Agreement dated as of October 31, 2007 between the Borrower and SmithKline Beecham Corporation (d/b/a GlaxoSmithKline) and Glaxo Group Limited with respect to the Borrower’s purchase of
the therauputic product Lotronex® and related assets, together with all exhibits and schedules thereto. 
 “Lotronex® Acquisition Documents” means the Lotronex® Acquisition Agreement and all other agreements, instruments and documents executed and delivered in connection with the Borrower’s purchase of the
therauputic product Lotronex® and related assets. 
 “Lotronex® Supply Agreement” means the Supply
Agreement dated October 31, 2007 by and between Prometheus Laboratories Inc. and SmithKline Beecham Corporation d/b/a GlaxoSmithKline. 
 “Material Adverse Effect” means (a) a material adverse change in, or a material adverse effect upon, the business, assets, properties, liabilities (actual or contingent), condition
(financial or otherwise), operations or prospects of the Loan Parties and their Subsidiaries, taken as a whole; (b) a material impairment of the ability of the Loan Parties (taken as a whole) to perform their obligations under the Loan
Documents; or (c) a material adverse effect upon the legality, validity, binding effect or enforceability against any Loan Party of any Loan Document to which it is a party. 
 “Material Agreement” means the Entocort® EC Distribution Agreement, the Proleukin® Distribution Agreement, the
Proleukin® Supply Agreement, the 1996 License Agreement, the Lotronex® Supply Agreement and any other contract or agreement to which any Loan Party or any Subsidiary is a party for which the termination thereof could reasonably be expected
to have a Material Adverse Effect (taking into consideration any actual or reasonably viable replacements or substitutions therefore at the time such determination is made). 
  

 20 

 “Maturity Date” means December 31, 2013; provided that if such
date is not a Business Day, the Maturity Date shall be the next preceding Business Day. 
 “Milestone Payments”
means all obligations of a Loan Party or any Subsidiary to make earn out or other contingency payments pursuant to any of (a) the Lotronex® Acquisition Agreement, (b) the Proleukin® Distribution Agreement, (c) the
Colal-Pred® License Agreement or (d) the Rosetta License Agreement, including, without limitation, (i) the payment to be made pursuant to Section 2.6(b) of the Proleukin® Distribution Agreement (as in effect on the Closing
Date) and (ii) any payments (each, an “Extension Payment”) required to extend the term of such agreements. 
 “Moody’s” means Moody’s Investors Service, Inc. and any successor thereto. 
 “Mortgages” means the mortgages, deeds of trust or deeds to secure debt that purport to grant to the Administrative Agent a security interest in the fee interest and/or leasehold interests of any Loan Party in each real
Property (other than Excluded Property) acquired or leased by a Loan Party, as the same may be amended, modified, restated or supplemented from time to time. 
 “Multiemployer Plan” means any employee benefit plan of the type described in Section 4001(a)(3) of ERISA, to which the Borrower or any ERISA Affiliate makes or is obligated to make
contributions, or during the preceding five (5) plan years, has made or been obligated to make contributions. 
 “Net Cash Proceeds” means: 
 (a) with respect to any Disposition by any Loan Party or
any of its Subsidiaries, any upfront, closing or similar payment (each such payment, a “Licensing Payment”) received by a Loan Party or any Subsidiary in connection with the licensing of IP Rights by such Loan Party or Subsidiary to
another Person, any Extraordinary Receipt received or paid to the account of any Loan Party or any of its Subsidiaries or any Debt Issuance by any Loan Party or any of its Subsidiaries, the excess, if any, of the aggregate cash or Cash Equivalents
proceeds received by a Loan Party or any Subsidiary in respect of such Disposition, Licensing Payment, Extraordinary Receipt, or Debt Issuance, net of (i) direct costs incurred in connection therewith (including, without limitation, legal,
accounting and investment banking fees, and sales commissions), (ii) Taxes paid or payable as a result thereof, (iii) in the case of any Disposition or Licensing Payment, the amount necessary to retire any Indebtedness secured by a
Permitted Lien (ranking senior to any Lien of the Administrative Agent) on the related Property and (iv) in the case of any Disposition or Licensing Payment, a reasonable reserve for (A) any adjustment in respect of the sale price of the
applicable Property required pursuant to GAAP and/or (B) the after-tax costs of any liabilities associated with the applicable Property and retained by a Loan Party or a Subsidiary after the sale or other disposition thereof; it being
understood that (x) “Net Cash Proceeds” shall include, without limitation, any cash or Cash Equivalents received upon the sale or other disposition of any non-cash consideration received by a Loan Party or any Subsidiary in any
Disposition, Licensing Payment, Debt Issuance or Extraordinary Receipt and (y) any amounts excluded pursuant to the foregoing clause (iv) shall be included as Net Cash Proceeds at such time as any such reserve is no longer required.

 (b) with respect to the sale or issuance of any Equity Interest by Delaware Parent, any Loan Party or any
Subsidiary, the excess of (i) the sum of the cash and Cash Equivalents received in connection with such transaction over (ii) the underwriting discounts and commissions, and other reasonable and customary out-of-pocket expenses, incurred
by Delaware Parent, such Loan Party or such Subsidiary in connection therewith. 
  

 21 

 “New Product” means the Proleukin® (aldesleukin) pharmaceutical
products. 
 “New Product Regulatory Approval(s)” means the regulatory approvals, authorizations, licenses,
applications, supplements, variations, agreements, permits, INDs, NDAs, BLAs and other permissions which have been issued by any Governmental Authority (including any regulatory authority) with relevant jurisdiction, solely where and to the extent
relating to the New Product. 
 “Non-Guarantor Subsidiary” means any Subsidiary of a Loan Party that is not a
Loan Party. 
 “Note” or “Notes” means the Revolving Notes, the Swing Line Note and/or the
Term Notes, individually or collectively, as appropriate. 
 “Novartis” means Novartis Vaccines and
Diagnostics, Inc. 
 “Obligations” means all advances to, and debts, liabilities, obligations, covenants and
duties of, any Loan Party arising under any Loan Document or otherwise with respect to any Loan, Letter of Credit, Secured Hedge Agreement or Secured Cash Management Agreement, whether direct or indirect (including those acquired by assumption),
absolute or contingent, due or to become due, now existing or hereafter arising and including interest and fees that accrue after the commencement by or against any Loan Party of any proceeding under any Debtor Relief Laws naming such Loan Party as
the debtor in such proceeding, regardless of whether such interest and fees are allowed claims in such proceeding. 
 “Organization Documents” means, (a) with respect to any corporation, the certificate or articles of incorporation and the bylaws (or equivalent or comparable constitutive documents with respect to any non-U.S.
jurisdiction); (b) with respect to any limited liability company, the certificate or articles of formation or organization and operating agreement; and (c) with respect to any partnership, joint venture, trust or other form of business
entity, the partnership, joint venture or other applicable agreement of formation or organization and any agreement, instrument, filing or notice with respect thereto filed in connection with its formation or organization with the applicable
Governmental Authority in the jurisdiction of its formation or organization and, if applicable, any certificate or articles of formation or organization of such entity. 
 “Other Taxes” means all present or future stamp or documentary taxes or any other excise or property taxes, charges or similar levies arising from any payment made hereunder or under any
other Loan Document or from the execution, delivery or enforcement of, or otherwise with respect to, this Agreement or any other Loan Document 
 “Outstanding Amount” means (a) with respect to any Loans on any date, the aggregate outstanding principal amount thereof after giving effect to any borrowings and prepayments or
repayments of any Loans occurring on such date; and (b) with respect to any L/C Obligations on any date, the Dollar Equivalent of the amount of such L/C Obligations on such date after giving effect to any L/C Credit Extension occurring on such
date and any other changes in the aggregate amount of the L/C Obligations as of such date, including as a result of any reimbursements by the Borrower of Unreimbursed Amounts. 
 “Participant” has the meaning specified in Section 11.06(d). 
 “Participating Member State” means each state so described in any EMU Legislation. 
 “PBGC” means the Pension Benefit Guaranty Corporation. 
  

 22 

 “Pension Plan” means any “employee pension benefit plan” (as such
term is defined in Section 3(2) of ERISA), other than a Multiemployer Plan, that is subject to Title IV of ERISA and is sponsored or maintained by the Borrower or any ERISA Affiliate or to which the Borrower or any ERISA Affiliate contributes
or has an obligation to contribute, or in the case of a multiple employer or other plan described in Section 4064(a) of ERISA, has made contributions at any time during the immediately preceding five (5) plan years. 
 “Permitted Acquisitions” means Investments consisting of an Acquisition (other than the Proleukin® Transaction) by a
Loan Party or any Subsidiary of a Loan Party, provided that (i) if the aggregate consideration for such Acquisition exceeds $7,500,000, the Borrower has provided the Administrative Agent with prior written notice of such Acquisition,
which notice shall include a reasonably detailed description of such Acquisition, (ii) the Property acquired (or the Property of the Person acquired) in such Acquisition is used or useful in the same or a similar line of business as the
Borrower was engaged in on the Closing Date (or any reasonable extensions or expansions thereof), (iii) the Administrative Agent shall receive all items in respect of the Equity Interests or Property acquired in such Acquisition required to be
delivered by the terms of Section 7.12 and/or Section 7.14 within thirty (30) days after the consummation of such Acquisition, (iv) in the case of an Acquisition of the Equity Interests of another Person, the board
of directors (or other comparable governing body) of such other Person shall have duly approved such Acquisition, (v) if the aggregate consideration for such Acquisition exceeds $7,500,000 the Borrower shall have delivered to the Administrative
Agent a Pro Forma Compliance Certificate demonstrating that, upon giving effect to such Acquisition on a Pro Forma Basis, the Loan Parties would be in compliance with the financial covenants set forth in Section 8.11 as of the end of the
most recent fiscal quarter for which the Borrower has delivered financial statements pursuant to Section 7.01(a) or (b), (vi) if the aggregate consideration for such Acquisition exceeds $7,500,000 the representations and
warranties made by the Loan Parties in any Loan Document shall be true and correct in all material respects at and as if made as of the date of such Acquisition (after giving effect thereto) except to the extent such representations and warranties
expressly relate to an earlier date, (vii) if such transaction involves the purchase of an interest in a partnership between a Loan Party (or a Subsidiary of a Loan Party) as a general partner and entities unaffiliated with such Loan Party or
such Subsidiary as the other partners, such transaction shall be effected by having such equity interest acquired by a corporate holding company directly or indirectly wholly-owned by a Loan Party newly formed for the sole purpose of effecting such
transaction, (viii) in the case of an Acquisition of the Equity Interests of a Foreign Subsidiary, the Foreign Subsidiary acquired in connection with such Acquisition shall be a First-Tier Foreign Subsidiary (or shall become a Guarantor
pursuant to Section 7.12 of this Agreement), (ix) in the case of an Acquisition by an existing Foreign Subsidiary (other than a Foreign Subsidiary that is a Guarantor) (A) the Foreign Subsidiary making the Acquisition shall be
a First-Tier Foreign Subsidiary and (B) such Acquisition shall be an acquisition of Property (other than Equity Interests) or intellectual property rights (or the entering into of license agreements or similar agreements or contracts related
thereto) that will be owned directly by such Foreign Subsidiary after giving effect to such acquisition and not an acquisition by such Foreign Subsidiary of the Equity Interests of another Person, and (x) the aggregate consideration (including
cash and non-cash consideration, any assumption of Indebtedness, deferred purchase price and any Earn Out Obligations) for all such Acquisitions occurring during any fiscal year shall not exceed: 
 (A) with respect to fiscal year 2010, $50,000,000; 
 (B) with respect to fiscal year 2011 and each fiscal year thereafter (1) at all times prior to the date that the
Borrower has prepaid the Loans with the proceeds of the applicable termination payment under the Entocort® EC Distribution Agreement pursuant to Section 2.05(b)(iv), $50,000,000; and (2) at all times on or after the date of such
prepayment, the

  

 23 

 
applicable amount set forth in the table below if, prior to the consummation of a proposed Acquisition, the Borrower shall have delivered to the Administrative Agent a Pro Forma Compliance
Certificate demonstrating that, upon giving effect to such Acquisition on a Pro Forma Basis, the Consolidated Leverage Ratio would be within the range set forth below opposite such amount as of the end of the most recent fiscal quarter for which the
Borrower has delivered financial statements pursuant to Section 7.01(a) or (b): 
  

			
	 Aggregate Acquisition Consideration per year:
	  	 Pro Forma Consolidated Leverage Ratio:

		
	$30,000,000	  	Greater than 1.50 to 1.00
		
	$40,000,000	  	Less than or equal to 1.50 to 1.00 but greater than 1.00 to 1.00
		
	$60,000,000	  	Less than or equal to 1.00 to 1.00

 “Permitted Investments” means, at any time, Investments by a Loan
Party or any of its Subsidiaries permitted to exist at such time pursuant to the terms of Section 8.02. 
 “Permitted Liens” means, at any time, Liens in respect of Property of a Loan Party or any of its Subsidiaries permitted to exist at such time pursuant to the terms of Section 8.01. 
 “Person” means any natural person, corporation, limited liability company, trust, joint venture, association, company,
partnership, Governmental Authority or other entity. 
 “Plan” means any “employee benefit plan” (as
such term is defined in Section 3(3) of ERISA) established by the Borrower or, with respect to any such plan that is subject to Sections 412, 430 or 431 of the Internal Revenue Code or Title IV of ERISA, any ERISA Affiliate. 
 “Platform” has the meaning specified in Section 7.02. 
 “Pledge Agreement” means a pledge agreement in favor of the Administrative Agent, for the benefit of the Secured Parties,
substantially in the form of Exhibit H, executed and delivered by the Borrower, any applicable Subsidiary in accordance with the provisions of Section 7.12 and, if applicable, Delaware Opco in accordance with the provisions of
Section 8.04. 
 “Pro Forma Basis” means, for purposes of calculating the Consolidated Leverage
Ratio and the Consolidated Fixed Charge Coverage Ratio (utilizing the principles set forth in Section 1.03(c)), in respect of a proposed transaction, that such proposed transaction shall be deemed to have occurred as of the first day of the
most recent four fiscal quarter period preceding the date of such transaction and for which the Borrower has delivered the applicable financial statements pursuant to Section 7.01(a) or (b). 
  

 24 

 “Pro Forma Compliance Certificate” means a certificate of a Responsible
Officer of the Borrower containing reasonably detailed calculation of the financial covenants set forth in Section 8.11 as of the most recent fiscal quarter end for which the Borrower has delivered financial statements pursuant to
Section 7.01(a) or (b) after giving effect to the applicable transaction on a Pro Forma Basis. 
 “Pro Forma Financial Statements” means the unaudited consolidated balance sheet of the Borrower and its Subsidiaries as of September 30, 2009, and the related unaudited consolidated statements of income or operations,
shareholders’ equity and cash flows for the 12-month ended on such date, in each case giving effect to all elements of the Transaction to be effected on or before the Closing Date. 
 “Proleukin® Distribution Agreement” means the Distribution and Promotion Agreement dated as of the Closing Date, by and
between the Borrower and Novartis, together with all schedules and exhibits thereto. 
 “Proleukin® Supply
Agreement” means the Supply Agreement dated as of the Closing Date, by and between the Borrower and Novartis, together with all schedules and exhibits thereto. 
 “Proleukin® Transaction” means a transaction, evidenced by the Proleukin® Distribution Agreement, pursuant to which the Borrower will obtain the right to distribute, promote and
sell the New Product in the United States and Canada. 
 “Proleukin® Transaction Documents” means the
Proleukin® Distribution Agreement, the Proleukin® Supply Agreement and all other agreements, instruments and documents executed and delivered in connection with the Proleukin® Transaction, in each case together with all schedules and
exhibits thereto. 
 “Pro Rata Share” means, as to each Lender at any time, (a) with respect to such
Lender’s Revolving Commitment at any time, a fraction (expressed as a percentage, carried out to the ninth decimal place), the numerator of which is the amount of the Revolving Commitment of such Lender at such time (or, if the Revolving
Commitments have been terminated, the amount of the outstanding Revolving Loans and participations in L/C Obligations and Swing Line Loans of such Lender at such time) and the denominator of which is the amount of the Aggregate Revolving Commitments
at such time (or, if the Revolving Commitments have been terminated, the amount of the outstanding Revolving Loans and participations in L/C Obligations and Swing Line Loans of all Lenders at such time) and (b) with respect to such
Lender’s outstanding Term Loan at any time, a fraction (expressed as a percentage, carried out to the ninth decimal place), the numerator of which is the principal amount of the Term Loan held by such Lender at such time and the denominator of
which is the aggregate principal amount of the Term Loan at such time. The initial Pro Rata Share of each Lender is set forth opposite the name of such Lender on Schedule 2.01 or in the Assignment and Assumption pursuant to which such Lender
becomes a party hereto, as applicable. 
 “Property” means any interest of any kind in any property or asset,
whether real, personal, intellectual or mixed, or tangible or intangible. 
 “Public Lender” has the meaning
specified in Section 7.02. 
 “Public Offering” means, with respect to any Person, a public
offering of any Equity Interests of such Person pursuant to an effective registration statement under the Securities Act of 1933. 
  

 25 

 “Register” has the meaning specified in Section 11.06(c).

 “Related Parties” means, with respect to any Person, such Person’s Affiliates and the partners,
directors, officers, employees, agents and advisors of such Person and of such Person’s Affiliates. 
 “Reorganization” has the meaning specified in Section 8.04. 
 “Reportable
Event” means any of the events set forth in Section 4043(c) of ERISA, other than events for which the thirty (30)-day notice period has been waived. 
 “Request for Credit Extension” means (a) with respect to a Borrowing, conversion or continuation of Loans, a Loan Notice, (b) with respect to an L/C Credit Extension, a Letter
of Credit Application and (c) with respect to a Swing Line Loan, a Swing Line Loan Notice. 
 “Required
Lenders” means, as of any date of determination, Lenders (other than the L/C Issuer and the Swing Line Lender) holding more than fifty percent (50%) of the sum of the (a) Total Outstandings (with the aggregate amount of each
Lender’s risk participation and funded participation in L/C Obligations and Swing Line Loans being deemed “held” by such Lender for purposes of this definition) and (b) the aggregate unused Revolving Commitments; provided
that the unused Revolving Commitment of, and the portion of the Total Outstandings held or deemed held by, any Defaulting Lender shall be excluded for purposes of making a determination of Required Lenders. 
 “Required Revolving Lenders” means, as of any date of determination, Lenders (other than the L/C Issuer and the Swing Line
Lender) holding more than 50% of the sum of the (a) Total Revolving Outstandings (with the aggregate amount of each Lender’s risk participation and funded participation in L/C Obligations and Swing Line Loans being deemed “held”
by such Lender for purposes of this definition) and (b) aggregate unused Revolving Commitments; provided that the unused Revolving Commitment of, and the portion of the Total Revolving Outstandings held or deemed held by, any Defaulting
Lender shall be excluded for purposes of making a determination of Required Revolving Lenders. 
 “Responsible
Officer” means the chief executive officer, president or chief financial officer of a Loan Party. Any document delivered hereunder that is signed by a Responsible Officer of a Loan Party shall be conclusively presumed to have been
authorized by all necessary corporate, partnership and/or other action on the part of such Loan Party and such Responsible Officer shall be conclusively presumed to have acted on behalf of such Loan Party. 
 “Restricted Payment” means, with respect to any Person, any dividend or other distribution (whether in cash, securities or
other Property) with respect to any capital stock or other Equity Interest of such Person, or any payment (whether in cash, securities or other Property), including any sinking fund or similar deposit, on account of the purchase, redemption,
retirement, acquisition, cancellation or termination of any such capital stock or other Equity Interest, or on account of any return of capital to such Person’s stockholders, partners or members (or the equivalent Person thereof). 

“Revaluation Date” means, with respect to any Letter of Credit, each of the following: (i) each date of issuance of
a Letter of Credit denominated in Euros, (ii) each date of an amendment of any such Letter of Credit having the effect of increasing the amount thereof (solely with respect to the increased amount), (iii) each date of any payment by the
L/C Issuer under any Letter of Credit denominated in Euros, (iv) such other dates as the Borrower may reasonably request from time to time and (v) such other dates as the L/C Issuer or the Administrative Agent shall reasonably require
provided that the Borrower receives prompt notice thereof. 
  

 26 

 “Revolving Commitment” means, as to each Lender, its obligation to
(a) make Revolving Loans to the Borrower pursuant to Section 2.01 and shall include any commitments made by such Lender to make revolving loans pursuant to the terms of Section 2.02(f), (b) purchase participations
in L/C Obligations, and (c) purchase participations in Swing Line Loans, in an aggregate principal amount at any one time outstanding not to exceed the amount set forth opposite such Lender’s name on Schedule 2.01 or in the
Assignment and Assumption pursuant to which such Lender becomes a party hereto, as applicable, as such amount may be adjusted from time to time in accordance with this Agreement. 
 “Revolving Loan” has the meaning specified in Section 2.01(a). 
 “Revolving Note” has the meaning specified in Section 2.11(a). 
 “Rosetta License Agreement” means the License Agreement dated April 10, 2009 between the Borrower and Rosetta Genomics
Ltd. 
 “S&P” means Standard & Poor’s Ratings Services, a division of The McGraw-Hill
Companies, Inc. and any successor thereto. 
 “Sale and Leaseback Transaction” means, with respect to any
Person, any arrangement, directly or indirectly, with any other Person whereby the first Person shall sell or transfer any Property, used or useful in its business, whether now owned or hereafter acquired, and thereafter rent or lease such Property
or other Property that it intends to use for substantially the same purpose or purposes as the Property being sold or transferred. 
 “SEC” means the Securities and Exchange Commission, or any Governmental Authority succeeding to any of its principal functions. 
 “Secured Cash Management Agreement” means any Cash Management Agreement that is entered into by and between the Borrower and any Cash Management Bank. 
 “Secured Hedge Agreement” means any interest rate Swap Contract required or permitted under Article VII or
VIII that is entered into by and between the Borrower and any Hedge Bank. 
 “Secured Parties” means,
collectively, the Administrative Agent, the Lenders, the L/C Issuer, the Hedge Banks, the Cash Management Banks, and each sub-agent appointed by the Administrative Agent from time to time pursuant to Section 10.05. 
 “Securitization Transaction” means any financing transaction or series of financing transactions (including factoring
arrangements) pursuant to which any Loan Party or any Subsidiary may sell, convey or otherwise transfer, or grant a security interest in, accounts, payments, receivables, rights to future lease payments or residuals or similar rights to payment to a
special purpose Affiliate of such Loan Party or Subsidiary. 
 “Security Agreement” means the security
agreement dated as of the Closing Date executed in favor of the Administrative Agent, for the benefit of the Secured Parties, by each of the Loan Parties. 
 “Solvent” or “Solvency” means, with respect to any Person as of a particular date, that on such date (a) such Person is able to pay its debts and other liabilities,
contingent obligations and other commitments as they mature in the ordinary course of business, (b) such Person does not intend to, and does not believe that it will, incur debts or liabilities beyond such Person’s ability to pay as such
debts and

  

 27 

 
liabilities mature in their ordinary course, (c) such Person is not engaged in a business or a transaction, and is not about to engage in a business or a transaction, for which such
Person’s Property would constitute unreasonably small capital after giving due consideration to the prevailing practice in the industry in which such Person is engaged or is to engage, (d) the fair market value of the Property of such
Person is greater than the total amount of liabilities, including, without limitation, contingent liabilities, of such Person (other than, with respect to the Borrower, any liability relating to the Existing Preferred Stock) and (e) the present
fair saleable value of the assets of such Person is not less than the amount that will be required to pay the probable liability of such Person on its existing debts as they become absolute and matured (other than, with respect to the Borrower, any
liability relating to the Existing Preferred Stock). In computing the amount of contingent liabilities at any time, it is intended that such liabilities will be computed at the amount which is recognized by such Person on the balance sheet of such
Person in accordance with GAAP. 
 “Spot Rate” for Euros on any date means the rate quoted by the L/C Issuer as
the spot rate for the purchase by the L/C Issuer of Euros with Dollars through its principal foreign exchange trading office at approximately 11:00 a.m. on the date two Business Days prior to such date; provided that, if agreed to by the
Borrower, the L/C Issuer may obtain such spot rate from another financial institution designated by the L/C Issuer if the Person acting in such capacity does not have as of the date of determination a spot buying rate for Euros; and provided
further that the L/C Issuer may use such spot rate quoted on the date as of which the foreign exchange computation is made in the case of any Letter of Credit denominated in Euros. 
 “Subsidiary” of a Person means a corporation, partnership, joint venture, limited liability company or other business
entity of which a majority of the shares of Voting Stock is at the time beneficially owned, or the management of which is otherwise controlled, directly, or indirectly through one or more intermediaries, or both, by such Person. Unless otherwise
specified, all references herein to a “Subsidiary” or to “Subsidiaries” shall refer to a Subsidiary or Subsidiaries of the Borrower and, after consummation of the Reorganization, a Subsidiary or Subsidiaries of Delaware Opco.

 “Swap Contract” means (a) any and all rate swap transactions, basis swaps, credit derivative
transactions, forward rate transactions, commodity swaps, commodity options, forward commodity contracts, equity or equity index swaps or options, bond or bond price or bond index swaps or options or forward bond or forward bond price or forward
bond index transactions, interest rate options, forward foreign exchange transactions, related cap transactions, floor transactions and collar transactions, currency swap transactions, cross-currency rate swap transactions, currency options, spot
contracts, or any other similar transactions or any combination of any of the foregoing (including any options to enter into any of the foregoing), whether or not any such transaction is governed by or subject to any master agreement, and
(b) any and all transactions of any kind, and the related confirmations, which are subject to the terms and conditions of, or governed by, any form of master agreement published by the International Swaps and Derivatives Association, Inc., any
International Foreign Exchange Master Agreement, or any other master agreement (any such master agreement, together with any related schedules, a “Master Agreement”), including any such obligations or liabilities under any Master
Agreement. 
 “Swap Termination Value” means, in respect of any one or more Swap Contracts, after taking into
account the effect of any legally enforceable netting agreement relating to such Swap Contracts, (a) for any date on or after the date such Swap Contracts have been closed out and termination value(s) determined in accordance therewith, such
termination value(s), and (b) for any date prior to the date referenced in clause (a), the amount(s) determined as the mark-to-market value(s) for such Swap Contracts, as determined based upon one or more mid-market or other readily available
quotations provided by any recognized dealer in such Swap Contracts (which may include a Lender or any Affiliate of a Lender). 
  

 28 

 “Swing Line Lender” means Bank of America in its capacity as provider of
Swing Line Loans, or any successor swing line lender hereunder. 
 “Swing Line Loan” has the meaning specified
in Section 2.04(a). 
 “Swing Line Loan Notice” means a notice of a Borrowing of Swing Line Loans
pursuant to Section 2.04(b), which, if in writing, shall be substantially in the form of Exhibit B. 
 “Swing Line Note” has the meaning specified in Section 2.11(a). 
 “Swing Line
Sublimit” means an amount equal to the lesser of (a) $5,000,000 and (b) the Aggregate Revolving Commitments. The Swing Line Sublimit is part of, and not in addition to, the Aggregate Revolving Commitments. 
 “Syndication Agent” means SunTrust Bank, in its capacity as Syndication Agent under this Agreement, and its successors and
permitted assigns. 
 “Synthetic Lease” means any synthetic lease, tax retention operating lease, off-balance
sheet loan or similar off-balance sheet financing arrangement whereby the arrangement is considered borrowed money indebtedness for Tax purposes but is classified as an operating lease or does not otherwise appear on the balance sheet under GAAP.

 “Taxes” means all present or future taxes, levies, imposts, duties, deductions, withholdings (including
backup withholding), assessments, fees or other charges imposed by any Governmental Authority, including any interest, additions to tax or penalties applicable thereto. 
 “Term Loan” has the meaning specified in Section 2.01(b); provided, however, the term shall also include any additional term loans made to the Borrower pursuant to the
terms of Section 2.02(f) in the form of an increase to the Term Loan. 
 “Term Loan Commitment”
means, as to each Lender, its obligation to make its portion of the Term Loan to the Borrower pursuant to Section 2.01(b), in the principal amount set forth opposite such Lender’s name on Schedule 2.01 and shall include any
commitments made by such Lender to make term loans pursuant to the terms of Section 2.02(f) in the form of an increase to the Term Loan. The aggregate principal amount of the Term Loan Commitments of all of the Lenders as in effect on
the Closing Date is TWO HUNDRED TEN MILLION DOLLARS ($210,000,000). 
 “Term Note” has the meaning specified in
Section 2.11(a). 
 “Threshold Amount” means $5,000,000. 
 “Total Outstandings” means the aggregate Outstanding Amount of all Loans and all L/C Obligations. 
 “Total Revolving Outstandings” means the aggregate Outstanding Amount of all Revolving Loans, all Swing Line Loans and all
L/C Obligations. 
 “Transaction” means, collectively, (a) the entering into by the Borrower of the
Proleukin® Distribution Agreement and the other Proleukin® Transaction Documents, (b) the entering into by the Loan Parties of the Loan Documents to which they are a party and the initial Credit Extensions hereunder,

  

 29 

 
(c) the refinancing of all Indebtedness outstanding under the Existing Credit Agreement and termination of commitments with respect thereto and (d) the payment of all fees and expenses
incurred in connection with the foregoing. 
 “Type” means, with respect to any Loan, its character as a Base
Rate Loan or a Eurodollar Rate Loan. 
 “United States” and “U.S.” mean the United States of
America. 
 “Unreimbursed Amount” has the meaning specified in Section 2.03(c)(i). 
 “Voting Stock” means, with respect to any Person, Equity Interests issued by such Person, the holders of which are
ordinarily, in the absence of contingencies, entitled to vote for the election of directors (or persons performing similar functions) of such Person, even though the right so to vote has been suspended by the happening of such a contingency.

 “Wholly Owned Subsidiary” means, with respect to any Person, any other Person 100% of whose Equity Interests
are at the time owned by the first Person directly or indirectly through other Persons 100% of whose Equity Interests are at the time owned, directly or indirectly, by the first Person. 
  

	1.02	Other Interpretive Provisions. 

 With reference to this Agreement and each other Loan Document, unless otherwise specified herein or in such other Loan Document: 
 (a) The definitions of terms herein shall apply equally to the singular and plural forms of the terms defined. Whenever the context may require, any pronoun shall include the corresponding masculine,
feminine and neuter forms. The words “include,” “includes” and “including” shall be deemed to be followed by the phrase “without limitation.” The word “will” shall be
construed to have the same meaning and effect as the word “shall.” Unless the context requires otherwise, (i) any definition of or reference to any agreement, instrument or other document (including any Organization Document)
shall be construed as referring to such agreement, instrument or other document as from time to time amended, restated, supplemented, extended or otherwise modified (subject to any restrictions on such amendments, restatements, supplements,
extensions or modifications set forth herein or in any other Loan Document), (ii) any reference herein to any Person shall be construed to include such Person’s successors and assigns, (iii) the words “herein,”
“hereof” and “hereunder,” and words of similar import when used in any Loan Document, shall be construed to refer to such Loan Document in its entirety and not to any particular provision thereof, (iv) all
references in a Loan Document to Articles, Sections, Exhibits and Schedules shall be construed to refer to Articles and Sections of, and Exhibits and Schedules to, the Loan Document in which such references appear, (v) any reference to any Law
shall include all statutory and regulatory provisions consolidating, amending, replacing, supplementing or interpreting such Law and any reference to any Law shall, unless otherwise specified, refer to such Law as amended, modified or supplemented
from time to time, and (vi) the words “asset” and “property” shall be construed to have the same meaning and effect and to refer to any and all real and personal property and tangible and intangible assets and
properties, including cash, securities, accounts and contract rights. 
 (b) In the computation of periods of
time from a specified date to a later specified date, the word “from” means “from and including;” the words “to” and “until” each mean “to but excluding;” and the
word “through” means “to and including.” 
  

 30 

 (c) Section headings herein and in the other Loan Documents are included for
convenience of reference only and shall not affect the interpretation of this Agreement or any other Loan Document. 
  

	1.03	Accounting Terms. 

 (a)
Except as otherwise specifically prescribed herein, all accounting terms not specifically or completely defined herein shall be construed in conformity with, and all financial data (including financial ratios and other financial calculations derived
therefrom) required to be submitted pursuant to this Agreement shall be prepared in conformity with, GAAP applied on a consistent basis, as in effect from time to time as specified in Section 1.03(b) below, applied in a manner consistent
with that used in preparing the Audited Financial Statements; provided, however, that calculations of Attributable Indebtedness under any Synthetic Lease or the implied interest component of any Synthetic Lease shall be made by the Borrower in
accordance with accepted financial practice and consistent with the terms of such Synthetic Lease. 
 (b) The Borrower will
provide a written summary of material changes in GAAP affecting the Borrower’s financial statements and in the consistent application thereof with each annual and quarterly Compliance Certificate delivered in accordance with
Section 7.02(b). If at any time any change in GAAP would affect the computation of any financial ratio or requirement set forth in any Loan Document, and either the Borrower or the Required Lenders shall so request, the Administrative
Agent, the Lenders and the Borrower shall negotiate in good faith to amend such ratio or requirement to preserve the original intent thereof in light of such change in GAAP (subject to the approval of the Required Lenders, which shall not be
unreasonably withheld, delayed or conditioned); provided that, until so amended, (i) such ratio or requirement shall continue to be computed in accordance with GAAP prior to such change therein and (ii) the Borrower shall
provide to the Administrative Agent and the Lenders financial statements and other documents required under this Agreement or as reasonably requested hereunder setting forth a reconciliation between calculations of such ratio or requirement made
before and after giving effect to such change in GAAP. 
 (c) Notwithstanding the above, the parties hereto acknowledge and
agree that, for purposes of all calculations made in determining compliance for any applicable period with the financial covenants set forth in Section 8.11 (and, for the purposes of the definitions of “Applicable Rate” and “Pro
Forma Basis” set forth in Section 1.01), (i) with respect to any Disposition consummated during the applicable period and otherwise permitted hereunder (A) income statement and cash flow statement items (whether positive or
negative) attributable to the Property disposed of shall be excluded in such calculations for such period and such transaction shall be deemed to have occurred as of the first day of such period and (B) Indebtedness that is repaid with the
proceeds of such Disposition shall be excluded from such calculations for such period and deemed to have been repaid as of the first day of such period and (ii) with respect to any Permitted Acquisition consummated during the applicable period,
(A) income statement items (whether positive or negative) attributable to the Person or Property acquired shall be included in such calculations for such period (to the extent (1) such items are not otherwise included in such income
statement items for the Loan Parties and their Subsidiaries in accordance with GAAP or in accordance with any defined terms set forth in Section 1.01 and (2) such items are supported by audited financial statements or other
information reasonably satisfactory to the Administrative Agent) and such transaction shall be deemed to have occurred as of the first day of such applicable period, and (B) Indebtedness of an acquired Person or secured by the acquired Property
that is retired in connection with a Permitted Acquisition shall be excluded from such calculations and deemed to have been retired as of the first day of such applicable period. 
  

 31 

	1.04	Rounding. 

 Any financial
ratios required to be maintained by the Borrower pursuant to this Agreement shall be calculated by dividing the appropriate component by the other component, carrying the result to one place more than the number of places by which such ratio is
expressed herein and rounding the result up or down to the nearest number (with a rounding-up if there is no nearest number). 
  

	1.05	Times of Day. 

 Unless
otherwise specified, all references herein to times of day shall be references to Pacific time (daylight or standard, as applicable). 
  

	1.06	Letter of Credit Amounts. 

 Unless otherwise specified herein, the amount of a Letter of Credit at any time shall be deemed to be the stated amount of such Letter of Credit in effect at such time; provided, however, that with respect to any Letter of
Credit that, by its terms or the terms of any Issuer Document related thereto, provides for one or more automatic increases in the stated amount thereof, the amount of such Letter of Credit shall be deemed to be the maximum stated amount of such
Letter of Credit after giving effect to all such increases, whether or not such maximum stated amount is in effect at such time. 
  

	1.07	Exchange Rates; Currency Equivalents. 

 The L/C Issuer shall determine the Spot Rates as of each Revaluation Date to be used for calculating Dollar Equivalent amounts of L/C Credit Extensions and Outstanding Amounts denominated in Euros. Such
Spot Rates shall become effective as of such Revaluation Date and shall be the Spot Rates employed in converting any amounts between the applicable currencies until the next Revaluation Date to occur. Except for purposes of financial statements
delivered by Loan Parties hereunder or calculating financial covenants hereunder or except as otherwise provided herein, the applicable amount of Euros for purposes of the Loan Documents shall be such Dollar Equivalent amount as so determined by the
applicable L/C Issuer. 
 ARTICLE II 
 THE COMMITMENTS AND CREDIT EXTENSIONS 
  

	2.01	Revolving Loans and Term Loan. 

 (a) Revolving Loans. Subject to the terms and conditions set forth herein, each Lender severally agrees to make loans (each such loan, a “Revolving Loan”) to the Borrower in Dollars from time to time on any Business
Day during the Availability Period in an aggregate amount not to exceed at any time outstanding the amount of such Lender’s Revolving Commitment; provided, however, that after giving effect to any Borrowing of Revolving Loans,
(i) the Total Revolving Outstandings shall not exceed the Aggregate Revolving Commitments, and (ii) the aggregate Outstanding Amount of the Revolving Loans of any Lender, plus such Lender’s Pro Rata Share of the Outstanding
Amount of all L/C Obligations plus such Lender’s Pro Rata Share of the Outstanding Amount of all Swing Line Loans shall not exceed such Lender’s Revolving Commitment. Within the limits of each Lender’s Revolving Commitment, and
subject to the other terms and conditions hereof, the Borrower may borrow under this Section 2.01, prepay under Section 2.05, and reborrow under this Section 2.01. Revolving Loans may be

  

 32 

 
Base Rate Loans or Eurodollar Rate Loans, as further provided herein, provided, however, all Borrowings made on the Closing Date shall be made as Base Rate Loans. 
 (b) Term Loan. Subject to the terms and conditions set forth herein, each Lender severally agrees to make its portion of a term loan
(the “Term Loan”) to the Borrower in Dollars on the Closing Date in an amount not to exceed such Lender’s Term Loan Commitment. Amounts repaid on the Term Loan may not be reborrowed. The Term Loan may consist of Base Rate Loans
or Eurodollar Rate Loans, as further provided herein, provided, however, all Borrowings made on the Closing Date shall be made as Base Rate Loans. 
  

	2.02	Borrowings, Conversions and Continuations of Loans. 

 (a) Each Borrowing, each conversion of Loans from one Type to the other, and each continuation of Eurodollar Rate Loans shall be made upon the Borrower’s irrevocable notice to the Administrative
Agent, which may be given by telephone. Each such notice must be received by the Administrative Agent not later than 10:00 a.m. (i) three (3) Business Days prior to the requested date of any Borrowing of, conversion to or continuation of,
Eurodollar Rate Loans or of any conversion of Eurodollar Rate Loans to Base Rate Loans, and (ii) on the requested date of any Borrowing of Base Rate Loans. Each telephonic notice by the Borrower pursuant to this Section 2.02(b) must
be confirmed promptly by delivery to the Administrative Agent of a written Loan Notice, appropriately completed and signed by a Responsible Officer of the Borrower. Each Borrowing of, conversion to or continuation of Eurodollar Rate Loans shall be
in a principal amount of $2,000,000 or a whole multiple of $100,000 in excess thereof (or, if less, the entire principal amount thereof then available to be drawn or outstanding). Except as provided in Sections 2.03(c) and 2.04(c),
each Borrowing of or conversion to Base Rate Loans shall be in a principal amount of $1,000,000 or a whole multiple of $100,000 in excess thereof (or, if less, the entire principal amount thereof then available to be drawn or outstanding). Each Loan
Notice (whether telephonic or written) shall specify (i) whether the Borrower is requesting a Borrowing, a conversion of Loans from one Type to the other, or a continuation of Eurodollar Rate Loans, (ii) the requested date of the
Borrowing, conversion or continuation, as the case may be (which shall be a Business Day), (iii) the principal amount of Loans to be borrowed, converted or continued, (iv) the Type of Loans to be borrowed or to which existing Loans are to
be converted, and (v) if applicable, the duration of the Interest Period with respect thereto. If the Borrower fails to specify a Type of a Loan in a Loan Notice or if the Borrower fails to give a timely notice requesting a conversion or
continuation, then the applicable Loans shall be made as, or converted to, Base Rate Loans. Any such automatic conversion to Base Rate Loans shall be effective as of the last day of the Interest Period then in effect with respect to the applicable
Eurodollar Rate Loans. If the Borrower requests a Borrowing of, conversion to, or continuation of Eurodollar Rate Loans in any Loan Notice, but fails to specify an Interest Period, it will be deemed to have specified an Interest Period of one
(1) month. 
 (b) Following receipt of a Loan Notice, the Administrative Agent shall promptly notify each Lender of the
amount of its Pro Rata Share of the applicable Loans, and if no timely notice of a conversion or continuation is provided by the Borrower, the Administrative Agent shall notify each Lender of the details of any automatic conversion to Base Rate
Loans as described in the preceding subsection. In the case of a Borrowing, each Lender shall make the amount of its Loan available to the Administrative Agent in immediately available funds at the Administrative Agent’s Office not later than
1:00 p.m. on the Business Day specified in the applicable Loan Notice. Upon satisfaction of the applicable conditions set forth in Section 5.02 (and, if such Borrowing is the initial Credit Extension, Section 5.01), the
Administrative Agent shall make all funds so received available to the Borrower in like funds as received by the Administrative Agent either by (i) crediting the account of the Borrower on the books of Bank of America with the amount of such
funds or (ii) wire transfer of such funds, in each case in accordance with instructions provided to (and reasonably acceptable to) the Administrative Agent by

  

 33 

 
the Borrower; provided, however, that if, on the date of a Borrowing of Revolving Loans, there are L/C Borrowings outstanding, then the proceeds of such Borrowing shall be applied,
first, to the payment in full of any such L/C Borrowings, and second, to the Borrower as provided above. 
 (c)
Except as otherwise provided herein, a Eurodollar Rate Loan may be continued or converted only on the last day of the Interest Period for such Eurodollar Rate Loan. During the existence of a Default or Event of Default, no Loans may be requested as
or converted to Eurodollar Rate Loans without the consent of the Required Lenders, and the Required Lenders may demand that any or all of the then outstanding Eurodollar Rate Loans be converted immediately to Base Rate Loans. 
 (d) The Administrative Agent shall promptly notify the Borrower and the Lenders of the interest rate applicable to any Interest Period for
Eurodollar Rate Loans upon determination of such interest rate. The determination of the Eurodollar Rate by the Administrative Agent shall be conclusive in the absence of manifest error. At any time that Base Rate Loans are outstanding, the
Administrative Agent shall notify the Borrower and the Lenders of any change in Bank of America’s prime rate used in determining the Base Rate promptly following the public announcement of such change. 
 (e) After giving effect to all Borrowings, all conversions of Loans from one Type to the other, and all continuations of Loans as the same
Type, there shall not be more than three (3) Interest Periods in effect with respect to Revolving Loans and three (3) Interest Periods in effect with respect to the Term Loan. 
 (f) The Borrower may at any time and from time to time after the Closing Date and prior to the Maturity Date, upon prior written notice by
the Borrower to the Administrative Agent, request (1) an increase to the Revolving Commitments, (2) an increase to the Term Loan or any then existing Additional Term Loan and/or (3) additional commitments to make term loans to be
structured as a separate term loan tranche with terms different from the Term Loan or any other then existing Additional Term Loan (any such separate term loan, an “Additional Term Loan”), in an amount (for all such requests made
pursuant to this Section 2.02(f)) not to exceed FORTY MILLION DOLLARS ($40,000,000) with additional Revolving Commitments, Term Loan Commitments or commitments to make Additional Term Loans, as applicable, from any existing Lender or new
Revolving Commitments, Term Loan Commitments or commitments for Additional Term Loans, as applicable, from any other Person (other than an Affiliate of the Borrower) selected by the Borrower and approved by the Administrative Agent in its reasonable
discretion; provided that: 
 (i) any such increase shall be in a minimum principal amount of $5,000,000
and in integral multiples of $1,000,000 in excess thereof; 
 (ii) no Default or Event of Default shall be
continuing at the time of any such increase; 
 (iii) no existing Lender shall be under any obligation to
increase its Commitment and any such decision whether to increase its Commitment shall be in such Lender’s sole and absolute discretion; 
 (iv)(A) any new Lender shall join this Agreement by executing such joinder and/or commitment documents reasonably required by the Administrative Agent and reflecting such Person’s commitment (it
being understood that each such Person shall become a “Lender” hereunder upon executing such joinder documents), and (B) any existing Lender electing to increase its Commitment shall have executed a commitment agreement reasonably
satisfactory to the Administrative Agent; 
  

 34 

 (v) prior to the funding of any such increase of the Term Loan or any such
Additional Term Loan, the Borrower shall have delivered to the Administrative Agent a Pro Forma Compliance Certificate demonstrating that, upon giving effect to the funding of any such increase to the Term Loan or Additional Term Loan, as
applicable, on a Pro Forma Basis, the Loan Parties would be in compliance with the financial covenants set forth in Section 8.11 as of the end of the most recent fiscal quarter for which the Borrower has delivered financial statements
pursuant to Section 7.01(a) or (b); 
 (vi) the Borrower shall deliver to the Administrative
Agent a certificate of each Loan Party dated as of the date of such increase (in sufficient copies for each Lender) signed by a Responsible Officer of such Loan Party (A) certifying and attaching the resolutions adopted by such Loan Party
approving or consenting to such increase, and (B) in the case of the Borrower, certifying that, before and after giving effect to such increase, (1) the representations and warranties contained in Article VI and the other Loan
Documents are true and correct in all material respects on and as of the date of such increase, except to the extent that such representations and warranties specifically refer to an earlier date, in which case they are true and correct in all
material respects as of such earlier date, and except that for purposes of this Section 2.02(f), the representations and warranties contained in subsections (a) and (b) of Section 6.05 shall be deemed to refer to
the most recent statements furnished pursuant to clauses (a) and (b), respectively, of Section 7.01, and (2) no Default or Event of Default exists; and 
 (vii) with respect to any Additional Term Loan, (A) the obligations of the Loan Parties in respect of such Additional
Term Loan shall constitute Obligations under the Loan Documents, and shall be entitled to all of the benefits afforded by this Agreement and the other Loan Documents, and shall, without limiting the foregoing, benefit ratably from the Guaranty set
forth in Article IV hereunder and the security interests and Liens created by the Collateral Documents (and the Borrower shall take any actions reasonably required by the Administrative Agent to ensure and/or demonstrate that the requirements
of this clause (A) are satisfied after the establishment of any such Additional Term Loan), (B) the final maturity of such Additional Term Loan shall be no earlier than the Maturity Date of the Term Loan or the final maturity date of any
then existing Additional Term Loan, (C) the initial principal amount of such Additional Term Loan shall not amortize (pursuant to scheduled amortization) during any calendar year in a percentage amount greater than the percentage of the
outstanding principal amount of the Term Loan scheduled to amortize during such calendar year in accordance with Section 2.07(c), (D) the Lenders providing such Additional Term Loan shall be entitled to voting rights on a pro rata
basis with the Lenders holding the Term Loan and any Additional Term Loan then existing and shall be entitled to receive proceeds of prepayments on a pro rata basis with the Lenders holding the Term Loan and any Additional Term Loans then existing,
(E) the Borrower shall execute a promissory note in favor of any new Lender or any existing Lender providing additional commitments hereunder and requesting a note and (F) the interest rate applicable to such Additional Term Loan may be
higher than the highest interest rate then payable on any Term Loan, but by no more than 0.25% per annum (it being understood that the Applicable Rate on the Term Loan may be increased to the extent necessary to satisfy such requirement).

 Upon any increase of the Revolving Commitments or the Term Loan, as applicable, the outstanding Loans held by each Lender
thereunder (and, in the case of an increase of the Revolving Commitments, the participation interests of the Lenders having Revolving Commitments in outstanding L/C Obligations and Swing Line Loans) shall be reallocated (through assignments and
purchases of the necessary Commitments and outstanding Loans) amongst the applicable Lenders such that after giving affect to such reallocation, each of the

  

 35 

 
applicable Lenders will hold Revolving Loans or Term Loans, as applicable (and, in the case of an increase of the Revolving Commitments, the participation interests of the Lenders having
Revolving Commitments in outstanding L/C Obligations and Swing Line Loans) based on its Pro Rata Share of the applicable facility after giving effect to such increase. Such assignments shall not be subject to any processing and/or recordation fees
among the applicable Lenders, and the Borrower shall be responsible for any costs arising under Section 3.05 resulting from such reallocation, it being understood that the parties hereto shall use commercially reasonable efforts to avoid
prepayment or assignment of any affected Loan that is a Eurodollar Rate Loan on a day other than the last day of the Interest Period applicable thereto. 
  

	2.03	Letters of Credit. 

 (a)
The Letter of Credit Commitment. 
 (i) Subject to the terms and conditions set forth herein, (A) the
L/C Issuer agrees, in reliance upon the agreements of the Lenders set forth in this Section 2.03, (1) from time to time on any Business Day during the period from the Closing Date until the Letter of Credit Expiration Date, to issue
Letters of Credit denominated in Dollars or Euros for the account of the Borrower, and to amend Letters of Credit previously issued by it, in accordance with subsection (b) below, and (2) to honor drawings under the Letters of Credit; and
(B) the Lenders severally agree to participate in Letters of Credit issued for the account of the Borrower and any drawings thereunder; provided that after giving effect to any L/C Credit Extension with respect to any Letter of Credit,
(x) the Total Revolving Outstandings shall not exceed the Aggregate Revolving Commitments, (y) the aggregate Outstanding Amount of the Revolving Loans of any Lender, plus such Lender’s Pro Rata Share of the Outstanding Amount
of all L/C Obligations plus such Lender’s Pro Rata Share of the Outstanding Amount of all Swing Line Loans shall not exceed such Lender’s Revolving Commitment, and (z) the Outstanding Amount of the L/C Obligations shall not
exceed the Letter of Credit Sublimit. Each request by the Borrower for the issuance or amendment of a Letter of Credit shall be deemed to be a representation by the Borrower that the L/C Credit Extension so requested complies with the conditions set
forth in clauses (x) and (z) in the proviso to the preceding sentence. Within the foregoing limits, and subject to the terms and conditions hereof, the Borrower’s ability to obtain Letters of Credit shall be fully revolving, and
accordingly the Borrower may, during the foregoing period, obtain Letters of Credit to replace Letters of Credit that have expired or that have been drawn upon and reimbursed. 
 (ii) The L/C Issuer shall not issue any Letter of Credit, if: 
 (A) subject to Section 2.03(b)(iii), the expiry date of such requested Letter of Credit would occur more than
twelve months after the date of issuance or last extension, unless the Required Revolving Lenders have approved such expiry date; or 
 (B) the expiry date of such requested Letter of Credit would occur after the Letter of Credit Expiration Date, unless all the Lenders having Revolving Commitments have approved such expiry date.

 (iii) The L/C Issuer shall not be under any obligation to issue any Letter of Credit if: 
 (A) any order, judgment or decree of any Governmental Authority or arbitrator shall by its terms purport to enjoin or
restrain the L/C Issuer from issuing such Letter of Credit, or any Law applicable to the L/C Issuer or any request or directive (whether or not having the force of Law) from any Governmental Authority with

  

 36 

 
jurisdiction over the L/C Issuer shall prohibit, or request that the L/C Issuer refrain from, the issuance of letters of credit generally or such Letter of Credit in particular or shall impose
upon the L/C Issuer with respect to such Letter of Credit any restriction, reserve or capital requirement (for which the L/C Issuer is not otherwise compensated hereunder) not in effect on the Closing Date, or shall impose upon the L/C Issuer any
unreimbursed loss, cost or expense which was not applicable on the Closing Date and which the L/C Issuer in good faith deems material to it; 
 (B) the issuance of such Letter of Credit would violate one or more policies of the L/C Issuer applicable to letters of credit generally; 
 (C) except as otherwise agreed by the Administrative Agent and the L/C Issuer, such Letter of Credit is in an initial stated
amount less than $100,000; 
 (D) such Letter of Credit is to be denominated in a currency other than Dollars or
Euros; or 
 (E) any Lender with a Revolving Commitment is at such time a Defaulting Lender, unless the L/C
Issuer has entered into arrangements satisfactory to the L/C Issuer (in its sole discretion) with the Borrower or such Lender to eliminate the L/C Issuer’s actual or potential Fronting Exposure with respect to such Lender as to either the
Letter of Credit then proposed to be issued or such Letter of Credit and all other L/C Obligations as to which the L/C Issuer has such actual or potential risk, as it may elect in its sole discretion. 
 (iv) The L/C Issuer shall not amend any Letter of Credit if the L/C Issuer would not be permitted at such time to issue such
Letter of Credit in its amended form under the terms hereof. 
 (v) The L/C Issuer shall be under no obligation
to amend any Letter of Credit if (A) the L/C Issuer would have no obligation at such time to issue such Letter of Credit in its amended form under the terms hereof, or (B) the beneficiary of such Letter of Credit does not accept the
proposed amendment to such Letter of Credit. 
 (vi) The L/C Issuer shall act on behalf of the Lenders with
respect to any Letters of Credit issued by it and the documents associated therewith, and the L/C Issuer shall have all of the benefits and immunities (A) provided to the Administrative Agent in Article X with respect to any acts
taken or omissions suffered by the L/C Issuer in connection with Letters of Credit issued by it or proposed to be issued by it and Issuer Documents pertaining to such Letters of Credit as fully as if the term “Administrative Agent” as used
in Article X included the L/C Issuer with respect to such acts or omissions, and (B) as additionally provided herein with respect to the L/C Issuer. 
 (b) Procedures for Issuance and Amendment of Letters of Credit. 
 (i) Each Letter of Credit shall be issued or amended, as the case may be, upon the request of the Borrower delivered to the L/C Issuer (with a copy to the Administrative Agent) in the form of a Letter of Credit Application, appropriately
completed and signed by a Responsible Officer of the Borrower. Such Letter of Credit Application must be received by the L/C Issuer and the Administrative Agent not later than 11:00 a.m. at least two (2) Business Days (or such later date
and time as the Administrative Agent and the L/C Issuer may agree in a particular

  

 37 

 
instance in their sole discretion) prior to the proposed issuance date or date of amendment, as the case may be. In the case of a request for an initial issuance of a Letter of Credit, such
Letter of Credit Application shall specify in form and detail satisfactory to the L/C Issuer: (A) the proposed issuance date of the requested Letter of Credit (which shall be a Business Day); (B) the amount and requested currency thereof
(and in the absence of a specification of currency shall be deemed to be a request for a Letter of Credit denominated in Dollars); (C) the expiry date thereof; (D) the name and address of the beneficiary thereof; (E) the documents to
be presented by such beneficiary in case of any drawing thereunder; (F) the full text of any certificate to be presented by such beneficiary in case of any drawing thereunder; (G) the purpose and nature of the requested Letter of Credit;
and (H) such other matters as the L/C Issuer may reasonably require. In the case of a request for an amendment of any outstanding Letter of Credit, such Letter of Credit Application shall specify in form and detail satisfactory to the L/C
Issuer (A) the Letter of Credit to be amended; (B) the proposed date of amendment thereof (which shall be a Business Day); (C) the nature of the proposed amendment; and (D) such other matters as the L/C Issuer may reasonably
require. Additionally, the Borrower shall furnish to the L/C Issuer and the Administrative Agent such other documents and information pertaining to such requested Letter of Credit issuance or amendment, including any Issuer Documents, as the
L/C Issuer or the Administrative Agent may require. 
 (ii) Promptly after receipt of any Letter of Credit
Application, the L/C Issuer will confirm with the Administrative Agent (by telephone or in writing) that the Administrative Agent has received a copy of such Letter of Credit Application from the Borrower and, if not, the L/C Issuer will provide the
Administrative Agent with a copy thereof. Unless the L/C Issuer has received written notice from any Lender, the Administrative Agent or any Loan Party, at least one (1) Business Day prior to the requested date of issuance or amendment of the
applicable Letter of Credit, that one or more applicable conditions contained in (A) in the case of any Letter of Credit to be issued on the Closing Date, if applicable, Article V and (B) in the case of any Letter of Credit to be
issued after the Closing Date, Section 5.02, shall not then be satisfied, then, subject to the terms and conditions hereof, the L/C Issuer shall, on the requested date, issue a Letter of Credit for the account of the Borrower or enter
into the applicable amendment, as the case may be, in each case in accordance with the L/C Issuer’s usual and customary business practices. Immediately upon the issuance of each Letter of Credit, each Lender shall be deemed to, and hereby
irrevocably and unconditionally agrees to, purchase from the L/C Issuer a risk participation in such Letter of Credit in an amount equal to the product of such Lender’s Pro Rata Share times the amount of such Letter of Credit.

 (iii) If the Borrower so requests in any applicable Letter of Credit Application, the L/C Issuer may, in its
sole and absolute discretion, agree to issue a Letter of Credit that has automatic extension provisions (each, an “Auto-Extension Letter of Credit”); provided that any such Auto-Extension Letter of Credit must permit the L/C
Issuer to prevent any such extension at least once in each twelve-month period (commencing with the date of issuance of such Letter of Credit) by giving prior notice to the beneficiary thereof not later than a day (the “Non-Extension Notice
Date”) in each such twelve-month period to be agreed upon at the time such Letter of Credit is issued. Unless otherwise directed by the L/C Issuer, the Borrower shall not be required to make a specific request to the L/C Issuer for any such
extension. Once an Auto-Extension Letter of Credit has been issued, the Lenders shall be deemed to have authorized (but may not require) the L/C Issuer to permit the extension of such Letter of Credit at any time to an expiry date not later than the
Letter of Credit Expiration Date; provided, however, that the L/C Issuer shall not permit any such extension if (A) the L/C Issuer has determined that it would not be permitted, or would have no obligation, at such time to issue
such Letter of Credit in its revised form (as extended) under the terms hereof (by reason of the provisions of clause (ii) or (iii) of

  

 38 

 
Section 2.03(a) or otherwise), or (B) it has received notice (which may be by telephone or in writing) on or before the day that is seven (7) Business Days before the
Non-Extension Notice Date (1) from the Administrative Agent that the Required Revolving Lenders have elected not to permit such extension or (2) from the Administrative Agent, any Lender or the Borrower that one or more of the applicable
conditions specified in Section 5.02 is not then satisfied, and in each case directing the L/C Issuer not to permit such extension. 
 (iv) Promptly after its delivery of any Letter of Credit or any amendment to a Letter of Credit to an advising bank with respect thereto or to the beneficiary thereof, the L/C Issuer will also deliver to
the Borrower and the Administrative Agent a true and complete copy of such Letter of Credit or amendment. 
 (c) Drawings and
Reimbursements; Funding of Participations. 
 (i) Upon receipt from the beneficiary of any Letter of Credit
of any notice of a drawing under such Letter of Credit, the L/C Issuer shall notify the Borrower and the Administrative Agent thereof, including, in the case of a Letter of Credit denominated in Euros, both the Euro amount thereof and the estimated
Dollar Equivalent thereof. Not later than 11:00 a.m. on the date of any payment by the L/C Issuer under a Letter of Credit (each such date, an “Honor Date”), the Borrower shall reimburse the L/C Issuer through the
Administrative Agent in an amount equal to the amount of such drawing. In the case of a Letter of Credit denominated in Euros, the Borrower shall reimburse the L/C Issuer in the Dollar Equivalent of the amount of the applicable drawing in Euros as
so notified by the L/C Issuer. If the Borrower fails to so reimburse the L/C Issuer by such time, the Administrative Agent shall promptly notify each Lender of the Honor Date, the amount of the unreimbursed drawing (the “Unreimbursed
Amount”), and the amount of such Lender’s Pro Rata Share thereof. In such event, the Borrower shall be deemed to have requested a Borrowing of Revolving Loans that are Base Rate Loans to be disbursed on the Honor Date in an amount
equal to the Unreimbursed Amount, without regard to the minimum and multiples specified in Section 2.02 for the principal amount of Base Rate Loans, but subject to the conditions set forth in Section 5.02 (other than the
delivery of a Loan Notice) and provided that, after giving effect to such Borrowing, the Total Revolving Outstandings shall not exceed the Aggregate Revolving Commitments. Any notice given by the L/C Issuer or the Administrative Agent pursuant to
this Section 2.03(c)(i) may be given by telephone if immediately confirmed in writing; provided that the lack of such an immediate confirmation shall not affect the conclusiveness or binding effect of such notice. 
 (ii) Each Lender shall upon any notice pursuant to Section 2.03(c)(i) make funds available (including for this
purpose the application of available Cash Collateral and other credit support provided for this purpose pursuant to Section 2.03(a)(iii)(E)), in Dollars, to the Administrative Agent for the account of the L/C Issuer at the Administrative
Agent’s Office in an amount equal to its Pro Rata Share of the Unreimbursed Amount not later than 1:00 p.m. on the Business Day specified in such notice by the Administrative Agent, whereupon, subject to the provisions of
Section 2.03(c)(iii), each Lender that so makes funds available shall be deemed to have made a Base Rate Loan to the Borrower in such amount. The Administrative Agent shall remit the funds so received to the L/C Issuer. 
 (iii) With respect to any Unreimbursed Amount that is not fully refinanced by a Borrowing of Base Rate Loans because the
conditions set forth in Section 5.02 cannot be satisfied or for any other reason, the Borrower shall be deemed to have incurred from the L/C Issuer an L/C Borrowing in the amount of the Unreimbursed Amount that is not so refinanced,
which L/C Borrowing shall be due and payable on demand (together with interest) and shall bear interest at

  

 39 

 
the Default Rate. In such event, each Lender’s payment to the Administrative Agent for the account of the L/C Issuer pursuant to Section 2.03(c)(ii) shall be deemed payment in
respect of its participation in such L/C Borrowing and shall constitute an L/C Advance from such Lender in satisfaction of its participation obligation under this Section 2.03. 
 (iv) Until each Lender funds its Revolving Loan or L/C Advance pursuant to this Section 2.03(c) to reimburse the
L/C Issuer for any amount drawn under any Letter of Credit, interest in respect of such Lender’s Pro Rata Share of such amount shall be solely for the account of the L/C Issuer. 
 (v) Each Lender’s obligation to make Revolving Loans or L/C Advances to reimburse the L/C Issuer for amounts drawn under
Letters of Credit, as contemplated by this Section 2.03(c), shall be absolute and unconditional and shall not be affected by any circumstance, including (A) any setoff, counterclaim, recoupment, defense or other right which such
Lender may have against the L/C Issuer, the Borrower or any other Person for any reason whatsoever; (B) the occurrence or continuance of a Default, or (C) any other occurrence, event or condition, whether or not similar to any of the
foregoing; provided, however, that each Lender’s obligation to make Revolving Loans pursuant to this Section 2.03(c) is subject to the conditions set forth in Section 5.02 (other than delivery by the
Borrower of a Loan Notice). No such making of an L/C Advance shall relieve or otherwise impair the obligation of the Borrower to reimburse the L/C Issuer for the amount of any payment made by the L/C Issuer under any Letter of Credit, together with
interest as provided herein. 
 (vi) If any Lender fails to make available to the Administrative Agent for the
account of the L/C Issuer any amount required to be paid by such Lender pursuant to the foregoing provisions of this Section 2.03(c) by the time specified in Section 2.03(c)(ii), then, without limiting the other provisions of
this Agreement, the L/C Issuer shall be entitled to recover from such Lender (acting through the Administrative Agent), on demand, such amount with interest thereon for the period from the date such payment is required to the date on which such
payment is immediately available to the L/C Issuer at a rate per annum equal to the greater of the Federal Funds Rate and a rate determined by the L/C Issuer in accordance with banking industry rules on interbank compensation, plus any
administrative, processing or similar fees customarily charged by the L/C Issuer in connection with the foregoing. If such Lender pays such amount (with interest and fees as aforesaid), such amount shall constitute such Lender’s Revolving Loan
included in the relevant Borrowing or L/C Advance in respect of the relevant L/C Borrowing, as the case may be. A certificate of the L/C Issuer submitted to any Lender (through the Administrative Agent) with respect to any amounts owing under this
clause (vi) shall be conclusive absent manifest error. 
 (d) Repayment of Participations. 
 (i) At any time after the L/C Issuer has made a payment under any Letter of Credit and has received from any Lender such
Lender’s L/C Advance in respect of such payment in accordance with Section 2.03(c), if the Administrative Agent receives for the account of the L/C Issuer any payment in respect of the related Unreimbursed Amount or interest thereon
(whether directly from the Borrower or otherwise, including proceeds of cash collateral applied thereto by the Administrative Agent), the Administrative Agent will distribute to such Lender its Pro Rata Share thereof in the same funds as those
received by the Administrative Agent. 
 (ii) If any payment received by the Administrative Agent for the account
of the L/C Issuer pursuant to Section 2.03(c)(i) is required to be returned under any of the circumstances

  

 40 

 
described in Section 11.05 (including pursuant to any settlement entered into by the L/C Issuer in its discretion), each Lender shall pay to the Administrative Agent for the account
of the L/C Issuer its Pro Rata Share thereof on demand of the Administrative Agent, plus interest thereon from the date of such demand to the date such amount is returned by such Lender, at a rate per annum equal to the Federal Funds Rate from time
to time in effect. The obligations of the Lenders under this clause shall survive the payment in full of the Obligations and the termination of this Agreement. 
 (e) Obligations Absolute. The obligation of the Borrower to reimburse the L/C Issuer for each drawing under each Letter of Credit and to repay each L/C Borrowing shall be absolute, unconditional
and irrevocable, and shall be paid strictly in accordance with the terms of this Agreement under all circumstances, including the following: 
 (i) any lack of validity or enforceability of such Letter of Credit, this Agreement, or any other Loan Document; 
 (ii) the existence of any claim, counterclaim, setoff, defense or other right that any Loan Party or any Subsidiary may have
at any time against any beneficiary or any transferee of such Letter of Credit (or any Person for whom any such beneficiary or any such transferee may be acting), the L/C Issuer or any other Person, whether in connection with this Agreement, the
transactions contemplated hereby or by such Letter of Credit or any agreement or instrument relating thereto, or any unrelated transaction; 
 (iii) any draft, demand, certificate or other document presented under such Letter of Credit proving to be forged, fraudulent, invalid or insufficient in any respect or any statement therein being untrue
or inaccurate in any respect; or any loss or delay in the transmission or otherwise of any document required in order to make a drawing under such Letter of Credit; 
 (iv) any payment by the L/C Issuer under such Letter of Credit against presentation of a draft or certificate that does not
strictly comply with the terms of such Letter of Credit; or any payment made by the L/C Issuer under such Letter of Credit to any Person purporting to be a trustee in bankruptcy, debtor-in-possession, assignee for the benefit of creditors,
liquidator, receiver or other representative of or successor to any beneficiary or any transferee of such Letter of Credit, including any arising in connection with any proceeding under any Debtor Relief Law; or 
 (v) any other circumstance or happening whatsoever, whether or not similar to any of the foregoing, including any other
circumstance that might otherwise constitute a defense available to, or a discharge of, any Loan Party or any Subsidiary. 
 The
Borrower shall promptly examine a copy of each Letter of Credit and each amendment thereto that is delivered to it and, in the event of any claim of noncompliance with the Borrower’s instructions or other irregularity, the Borrower will
promptly notify the L/C Issuer. The Borrower shall be conclusively deemed to have waived any such claim against the L/C Issuer and its correspondents unless such notice is given as aforesaid. 
 (f) Role of L/C Issuer. Each Lender and the Borrower agree that, in paying any drawing under a Letter of Credit, the L/C Issuer shall
not have any responsibility to obtain any document (other than any sight draft, certificates and documents expressly required by such Letter of Credit) or to ascertain or inquire as to the validity or accuracy of any such document or the authority
of the Person executing or delivering any such document. None of the L/C Issuer, the Administrative Agent, any of

  

 41 

 
their respective Related Parties nor any correspondent, participant or assignee of the L/C Issuer shall be liable to any Lender for (i) any action taken or omitted in connection herewith at
the request or with the approval of the Lenders or the Required Lenders, as applicable; (ii) any action taken or omitted in the absence of gross negligence or willful misconduct; or (iii) the due execution, effectiveness, validity or
enforceability of any document or instrument related to any Letter of Credit or Issuer Document. The Borrower hereby assumes all risks of the acts or omissions of any beneficiary or transferee with respect to its use of any Letter of Credit;
provided, however, that this assumption is not intended to, and shall not, preclude the Borrower’s pursuing such rights and remedies as it may have against the beneficiary or transferee at law or under any other agreement. None of
the L/C Issuer, the Administrative Agent, any of their respective Related Parties nor any correspondent, participant or assignee of the L/C Issuer shall be liable or responsible for any of the matters described in clauses (i) through
(v) of Section 2.03(e); provided, however, that anything in such clauses to the contrary notwithstanding, the Borrower may have a claim against the L/C Issuer, and the L/C Issuer may be liable to the Borrower, to the
extent, but only to the extent, of any direct, as opposed to consequential or exemplary, damages suffered by the Borrower that the Borrower proves were caused by the L/C Issuer’s willful misconduct or gross negligence or the L/C Issuer’s
willful failure to pay under any Letter of Credit after the presentation to it by the beneficiary of a sight draft and certificate(s) strictly complying with the terms and conditions of a Letter of Credit. In furtherance and not in limitation of the
foregoing, the L/C Issuer may accept documents that appear on their face to be in order, without responsibility for further investigation, regardless of any notice or information to the contrary, and the L/C Issuer shall not be responsible for the
validity or sufficiency of any instrument transferring or assigning or purporting to transfer or assign a Letter of Credit or the rights or benefits thereunder or proceeds thereof, in whole or in part, which may prove to be invalid or ineffective
for any reason. 
 (g) Applicability of ISP. Unless otherwise expressly agreed by the L/C Issuer and the Borrower
when a Letter of Credit is issued, the rules of the ISP shall apply to each Letter of Credit. 
 (h) Letter of Credit
Fees. The Borrower shall pay to the Administrative Agent for the account of each Lender in accordance with its Pro Rata Share a Letter of Credit fee (the “Letter of Credit Fee”) for each Letter of Credit equal to the Applicable
Rate times the daily amount available to be drawn under such Letter of Credit, calculated in accordance with Section 2.10; provided, however, any Letter of Credit Fees otherwise payable for the account of a
Defaulting Lender with respect to any Letter of Credit as to which such Defaulting Lender has not provided Cash Collateral or other credit support arrangements satisfactory to the L/C Issuer pursuant to this Section 2.03,
Section 2.14 or any other provision hereof, shall be payable, to the maximum extent permitted by applicable law, to the other Lenders in accordance with the upward adjustments in their respective Pro Rata Shares allocable to such Letter
of Credit pursuant to Section 2.15(c), with the balance of such fee, if any, payable to the L/C Issuer for its own account. For purposes of computing the daily amount available to be drawn under any Letter of Credit, the amount of
such Letter of Credit shall be determined in accordance with Section 1.06. Letter of Credit Fees shall be (i) computed on a quarterly basis in arrears and (ii) due and payable on the first Business Day after the end of each
March, June, September and December, commencing with the first such date to occur after the issuance of such Letter of Credit, on the Letter of Credit Expiration Date and thereafter on demand. If there is any change in the Applicable Rate
during any quarter, the daily amount available to be drawn under each Letter of Credit shall be computed and multiplied by the Applicable Rate separately for each period during such quarter that such Applicable Rate was in effect. Notwithstanding
anything to the contrary contained herein, upon the request of the Required Lenders, while any Event of Default exists, all past due Letter of Credit Fees shall accrue at an amount equal to the Applicable Rate plus two percent (2%). 
 (i) Fronting Fee and Documentary and Processing Charges Payable to L/C Issuer. The Borrower shall pay directly to the L/C Issuer for
its own account a fronting fee, with respect to each

  

 42 

 
Letter of Credit, at the rate per annum specified in the Fee Letter, computed on the actual daily maximum amount available to be drawn under such Letter of Credit (whether or not such maximum
amount is then in effect under such Letter of Credit) on a quarterly basis in arrears, and due and payable on the first Business Day after the end of each March, June, September and December in respect of the most recently-ended quarterly
period (or portion thereof, in the case of the first payment), commencing with the first such date to occur after the issuance of such Letter of Credit, on the Letter of Credit Expiration Date and thereafter on demand. For purposes of computing the
daily amount available to be drawn under any Letter of Credit, the amount of such Letter of Credit shall be determined in accordance with Section 1.06. In addition, the Borrower shall pay directly to the L/C Issuer for its own account
the reasonable and customary issuance, presentation, amendment and other processing fees, and other standard costs and charges, of the L/C Issuer relating to letters of credit as from time to time in effect. Such customary fees and standard costs
and charges are due and payable on demand and are nonrefundable. 
 (j) Conflict with Issuer Documents. In the event of
any conflict between the terms hereof and the terms of any Issuer Document, the terms hereof shall control. 
 (k)
Determination of Exchange Rate. On each Revaluation Date with respect to each outstanding Letter of Credit denominated in Euros, the L/C Issuer shall determine the Spot Rate as of such Revaluation Date with respect thereto and shall promptly
notify the Administrative Agent and the Borrower thereof and of the Dollar Equivalent of all Letters of Credit denominated in Euros outstanding on such Revaluation Date. The Spot Rate so determined shall become effective on such Revaluation Date and
shall remain effective until the next succeeding Revaluation Date. 
  

	2.04	Swing Line Loans. 

 (a)
Swing Line Facility. Subject to the terms and conditions set forth herein, the Swing Line Lender, in reliance upon the agreements of the other Lenders set forth in this Section 2.04, may in its sole discretion make loans (each
such loan, a “Swing Line Loan”) to the Borrower in Dollars from time to time on any Business Day during the Availability Period (other than the Closing Date) in an aggregate amount not to exceed at any time outstanding the amount of
the Swing Line Sublimit, notwithstanding the fact that such Swing Line Loans, when aggregated with the Pro Rata Share of the Outstanding Amount of Revolving Loans and L/C Obligations of the Lender acting as Swing Line Lender, may exceed the amount
of such Lender’s Revolving Commitment; provided, however, that after giving effect to any Swing Line Loan, (i) the Total Revolving Outstandings shall not exceed the Aggregate Revolving Commitments, and (ii) the aggregate
Outstanding Amount of the Revolving Loans of any Lender, plus such Lender’s Pro Rata Share of the Outstanding Amount of all L/C Obligations, plus such Lender’s Pro Rata Share of the Outstanding Amount of all Swing Line Loans
shall not exceed such Lender’s Revolving Commitment, and provided, further, that the Borrower shall not use the proceeds of any Swing Line Loan to refinance any outstanding Swing Line Loan. Within the foregoing limits, and subject
to the other terms and conditions hereof, the Borrower may borrow under this Section 2.04, prepay under Section 2.05, and reborrow under this Section 2.04. Each Swing Line Loan shall be a Base Rate Loan.
Immediately upon the making of a Swing Line Loan, each Lender shall be deemed to, and hereby irrevocably and unconditionally agrees to, purchase from the Swing Line Lender a risk participation in such Swing Line Loan in an amount equal to the
product of such Lender’s Pro Rata Share times the amount of such Swing Line Loan. 
 (b) Borrowing
Procedures. Each Borrowing of Swing Line Loans shall be made upon the Borrower’s irrevocable notice to the Swing Line Lender and the Administrative Agent, which may be given by telephone. Each such notice must be received by the Swing Line
Lender and the Administrative Agent not later than 1:00 p.m. on the requested borrowing date, and shall specify (i) the amount to be

  

 43 

 
borrowed, which shall be a minimum principal amount of $100,000 and integral multiples of $100,000 in excess thereof, and (ii) the requested borrowing date, which shall be a Business Day.
Each such telephonic notice must be confirmed promptly by delivery to the Swing Line Lender and the Administrative Agent of a written Swing Line Loan Notice, appropriately completed and signed by a Responsible Officer of the Borrower. Promptly after
receipt by the Swing Line Lender of any telephonic Swing Line Loan Notice, the Swing Line Lender will confirm with the Administrative Agent (by telephone or in writing) that the Administrative Agent has also received such Swing Line Loan Notice and,
if not, the Swing Line Lender will notify the Administrative Agent (by telephone or in writing) of the contents thereof. Unless the Swing Line Lender has received notice (by telephone or in writing) from the Administrative Agent (including at the
request of any Lender) prior to 2:00 p.m. on the date of the proposed Borrowing of Swing Line Loans (A) directing the Swing Line Lender not to make such Swing Line Loan as a result of the limitations set forth in the proviso to the first
sentence of Section 2.04(a), or (B) that one or more of the applicable conditions specified in Section 5.02 is not then satisfied, then, subject to the terms and conditions hereof, the Swing Line Lender will, not later
than 3:00 p.m. on the borrowing date specified in such Swing Line Loan Notice, make the amount of its Swing Line Loan available to the Borrower. 
 (c) Refinancing of Swing Line Loans. 
 (i) The Swing Line
Lender at any time in its sole and absolute discretion may request, on behalf of the Borrower (which hereby irrevocably requests and authorizes the Swing Line Lender to so request on its behalf), that each Lender make a Revolving Loan that is a Base
Rate Loan in an amount equal to such Lender’s Pro Rata Share of the amount of Swing Line Loans then outstanding. Such request shall be made in writing (which written request shall be deemed to be a Loan Notice for purposes hereof) and in
accordance with the requirements of Section 2.02, without regard to the minimum and multiples specified therein for the principal amount of Base Rate Loans, but subject to the conditions set forth in Section 5.02 (other than
the delivery of a Loan Notice) and provided that, after giving effect to such Borrowing, the Total Revolving Outstandings shall not exceed the Aggregate Revolving Commitments. The Swing Line Lender shall furnish the Borrower with a copy of the
applicable Loan Notice promptly after delivering such notice to the Administrative Agent. Each Lender shall make an amount equal to its Pro Rata Share of the amount specified in such Loan Notice available (including for this purpose Cash Collateral
and other credit support made available with respect to the applicable Swing Line Loan) to the Administrative Agent in immediately available funds for the account of the Swing Line Lender at the Administrative Agent’s Office not later than 1:00
p.m. on the day specified in such Loan Notice, whereupon, subject to Section 2.04(c)(ii), each Lender that so makes funds available shall be deemed to have made a Revolving Loan that is a Base Rate Loan to the Borrower in such amount.
The Administrative Agent shall remit the funds so received to the Swing Line Lender. 
 (ii) If for any reason
any Swing Line Loan cannot be refinanced by such a Borrowing of Revolving Loans in accordance with Section 2.04(c)(i), the request for Base Rate Loans submitted by the Swing Line Lender as set forth herein shall be deemed to be a request
by the Swing Line Lender that each of the Lenders fund its risk participation in the relevant Swing Line Loan and each Lender’s payment to the Administrative Agent for the account of the Swing Line Lender pursuant to
Section 2.04(c)(i) shall be deemed payment in respect of such participation. 
 (iii) If any Lender
fails to make available to the Administrative Agent for the account of the Swing Line Lender any amount required to be paid by such Lender pursuant to the foregoing provisions of this Section 2.04(c) by the time specified in
Section 2.04(c)(i), the Swing Line Lender shall be entitled to recover from such Lender (acting through the Administrative

  

 44 

 
Agent), on demand, such amount with interest thereon for the period from the date such payment is required to the date on which such payment is immediately available to the Swing Line Lender at a
rate per annum equal to the greater of Federal Funds Rate and a rate determined by the Swing Line Lender in accordance with banking industry rules on interbank compensation, plus any administrative, processing or similar fees customarily charged by
the Swing Line Lender in connection with the foregoing. If such Lender pays such amount (with interest and fees as aforesaid), such amount shall constitute such Lender’s Revolving Loan included in the relevant Borrowing or funded participation
in the relevant Swing Line Loan, as the case may be. A certificate of the Swing Line Lender submitted to any Lender (through the Administrative Agent) with respect to any amounts owing under this clause (iii) shall be conclusive absent manifest
error. 
 (iv) Each Lender’s obligation to make Revolving Loans or to purchase and fund risk participations
in Swing Line Loans pursuant to this Section 2.04(c) shall be absolute and unconditional and shall not be affected by any circumstance, including (A) any set-off, counterclaim, recoupment, defense or other right that such Lender may
have against the Swing Line Lender, the Borrower or any other Person for any reason whatsoever, (B) the occurrence or continuance of a Default, or (C) any other occurrence, event or condition, whether or not similar to any of the
foregoing; provided, however, that each Lender’s obligation to make Revolving Loans pursuant to this Section 2.04(c) is subject to the conditions set forth in Section 5.02. No such purchase or funding of
risk participations shall relieve or otherwise impair the obligation of the Borrower to repay Swing Line Loans, together with interest as provided herein. 
 (d) Repayment of Participations. 
 (i) At any time after any
Lender has purchased and funded a risk participation in a Swing Line Loan, if the Swing Line Lender receives any payment on account of such Swing Line Loan, the Swing Line Lender will promptly distribute to such Lender its Pro Rata Share of such
payment in the same funds as those received by the Swing Line Lender. 
 (ii) If any payment received by the
Swing Line Lender in respect of principal or interest on any Swing Line Loan is required to be returned by the Swing Line Lender under any of the circumstances described in Section 11.05 (including pursuant to any settlement entered into
by the Swing Line Lender in its discretion), each Lender shall pay to the Swing Line Lender its Pro Rata Share thereof on demand of the Administrative Agent, plus interest thereon from the date of such demand to the date such amount is returned, at
a rate per annum equal to the Federal Funds Rate. The Administrative Agent will make such demand upon the request of the Swing Line Lender. The obligations of the Lenders under this clause shall survive the payment in full of the Obligations and the
termination of this Agreement. 
 (e) Interest for Account of Swing Line Lender. The Swing Line Lender shall be
responsible for invoicing the Borrower for interest on the Swing Line Loans. Until each Lender funds its Revolving Loans that are Base Rate Loans or risk participation pursuant to this Section 2.04 to refinance such Lender’s Pro
Rata Share of any Swing Line Loan, interest in respect of such Pro Rata Share shall be solely for the account of the Swing Line Lender. 
 (f) Payments Directly to Swing Line Lender. The Borrower shall make all payments of principal and interest in respect of the Swing Line Loans directly to the Swing Line Lender. 
  

 45 

	2.05	Prepayments. 

 (a)
Voluntary Prepayments of Loans. 
 (i) Revolving Loans and Term Loans. The Borrower may, upon
notice from the Borrower to the Administrative Agent, at any time or from time to time voluntarily prepay the Revolving Loans and the Term Loan in whole or in part without premium or penalty; provided that (A) such notice must be
received by the Administrative Agent not later than 11:00 a.m. (1) three (3) Business Days prior to any date of prepayment of Eurodollar Rate Loans and (2) on the date of prepayment of Base Rate Loans; (B) any such prepayment of
Eurodollar Rate Loans shall be in a principal amount of $2,000,000 or a whole multiple of $100,000 in excess thereof (or, if less, the entire principal amount thereof then outstanding); (C) any prepayment of Base Rate Loans shall be in a
principal amount of $1,000,000 or a whole multiple of $100,000 in excess thereof (or, if less, the entire principal amount thereof then outstanding) and (D) any prepayment of the Term Loan shall be applied to the remaining principal
amortization payments thereof in the direct order of maturity. Each such notice shall specify the date and amount of such prepayment and the Type(s) of Loans to be prepaid and, if Eurodollar Rate Loans are to be prepaid, the Interest Period(s) of
such Loans. The Administrative Agent will promptly notify each Lender of its receipt of each such notice, and of the amount of such Lender’s Pro Rata Share of such prepayment. If such notice is given by the Borrower, the Borrower shall make
such prepayment and the payment amount specified in such notice shall be due and payable on the date specified therein. Any prepayment of a Eurodollar Rate Loan shall be accompanied by all accrued interest thereon, together with any additional
amounts required pursuant to Section 3.05. Each such prepayment shall be applied to the Loans of the Lenders in accordance with their respective Pro Rata Shares. 
 (ii) Swing Line Loans. The Borrower may, upon notice to the Swing Line Lender (with a copy to the Administrative
Agent), at any time or from time to time, voluntarily prepay Swing Line Loans in whole or in part without premium or penalty; provided that (i) such notice must be received by the Swing Line Lender and the Administrative Agent not later
than 1:00 p.m. on the date of the prepayment, and (ii) any such prepayment shall be in a minimum principal amount of $500,000 or a whole multiple of $100,000 in excess thereof (or, if less, the entire principal thereof then outstanding). Each
such notice shall specify the date and amount of such prepayment. If such notice is given by the Borrower, the Borrower shall make such prepayment and the payment amount specified in such notice shall be due and payable on the date specified
therein. 
 (b) Mandatory Prepayments of Loans. 
 (i) Revolving Commitments. If for any reason the Total Revolving Outstandings at any time exceed the Aggregate
Revolving Commitments then in effect, the Borrower shall immediately prepay Revolving Loans and/or the Swing Line Loans and/or Cash Collateralize the L/C Obligations in an aggregate amount equal to such excess; provided, however, that
the Borrower shall not be required to Cash Collateralize the L/C Obligations pursuant to this Section 2.05(b)(i) unless after the prepayment in full of the Revolving Loans and the Swing Line Loans the Total Revolving Outstandings exceed
the Aggregate Revolving Commitments then in effect. If at any time after the Borrower delivers Cash Collateral pursuant to this Section 2.05(b)(i), the aggregate of such Cash Collateral and the Aggregate Revolving Commitments then in
effect exceed the Total Revolving Outstandings, such Cash Collateral, to the extent of any such excess, shall be returned to the Borrower promptly after the Administrative Agent’s receipt of a written request from the Borrower. 
  

 46 

 (ii) Dispositions. No later than the date that is three hundred
sixty-five (365) days following receipt by a Loan Party or any Subsidiary of Net Cash Proceeds of any Disposition, the Borrower shall prepay the Loans and Cash Collateralize the L/C Obligations as hereafter provided in an aggregate amount equal
to 100% of such Net Cash Proceeds, but only to the extent such Net Cash Proceeds are not reinvested in Eligible Assets within such three hundred sixty-five (365) day period; provided, however, that no amount shall be required to
be applied under this Section 2.05(b)(ii) until the aggregate Net Cash Proceeds from Dispositions that would otherwise be required to be applied as a mandatory prepayment during the then current fiscal year exceeds $750,000, and then
only the excess thereof shall be required to be applied. Any prepayment pursuant to this clause (ii) shall be applied as set forth in clause (vii) below. 
 (iii) Debt Issuances. Within five (5) Business Days following receipt by a Loan Party or any Subsidiary of the
Net Cash Proceeds of any Debt Issuance, the Borrower shall prepay the Loans and Cash Collateralize the L/C Obligations as hereafter provided in an aggregate amount equal to 100% of such Net Cash Proceeds (such prepayment to be applied as set forth
in clause (vii) below). 
 (iv) Extraordinary Receipts. Within five (5) Business Days following
receipt by a Loan Party or any Subsidiary of the Net Cash Proceeds of any Extraordinary Receipt (unless such Net Cash Proceeds constitute condemnation or insurance proceeds in which case such Loan Party or such Subsidiary shall have three hundred
sixty-five (365) days from the date of the receipt of such Extraordinary Receipt to reinvest such Net Cash Proceeds in Eligible Assets prior to being required to make any such prepayment), the Borrower shall prepay the Loans and Cash
Collateralize the L/C Obligations as hereafter provided in an aggregate amount equal to 100% of such Net Cash Proceeds (such prepayment to be applied as set forth in clause (vii) below). 
 (v) Equity Issuances. Within five (5) Business Days following receipt by the Delaware Parent, a Loan Party or any
Subsidiary of a Loan Party of the Net Cash Proceeds of any Equity Issuance, the Borrower shall prepay the Loans and/or Cash Collateralize the L/C Obligations in an aggregate amount equal to 50% of such Net Cash Proceeds (such prepayment shall be
applied as set forth in clause (vii) below). 
 (vi) Excess Cash Flow. No later than 90 days after
the end of each fiscal year of the Borrower, beginning with the fiscal year ending December 31, 2010, the Borrower shall prepay the Loans and/or Cash Collateralize the L/C Obligations in an amount equal to (A) (1) with respect to the
fiscal year ending December 31, 2010, 100% of Excess Cash Flow for such fiscal year and (2) with respect to each fiscal year ending thereafter, (I) 75% of Excess Cash Flow for such fiscal year if the Consolidated Leverage Ratio as of
the last day of such fiscal year is greater than or equal to 1.75 to 1.00 and (II) 50% of Excess Cash Flow for such fiscal year if the Consolidated Leverage Ratio as of the last day of such fiscal year is less than 1.75 to 1.00 (such prepayment to
be applied as set forth in clause (vii) below). 
 (vii) Application of Mandatory Prepayments. All
amounts required to be paid pursuant to this Section 2.05(b) shall be applied as follows: 
 (A)
with respect to all amounts prepaid pursuant to Section 2.05(b)(i), to the Revolving Loans and the Swing Line Loans and (after all Revolving Loans and all Swing Line Loans have been repaid) to ratably Cash Collateralize any L/C
Obligations; 
 (B) with respect to all amounts prepaid pursuant to Sections 2.05(b)(ii), (iii),
(iv), (v) and (vi), first to the Term Loan (ratably to the remaining principal amortization

  

 47 

 
payments thereof), second, after the Term Loan has been repaid in full, ratably to the L/C Borrowings and the Swing Line Loans, third, ratably to the Revolving Loans (without
a corresponding reduction of the Aggregate Revolving Commitments), and fourth, after all Revolving Loans, L/C Borrowings and Swing Line Loans have been repaid, ratably to Cash Collateralize any remaining L/C Obligations. 
 Within the parameters of the applications set forth above, prepayments shall be applied first to Base Rate Loans and then to
Eurodollar Rate Loans in direct order of Interest Period maturities. All prepayments under this Section 2.05(b) shall be subject to Section 3.05, but otherwise without premium or penalty, and shall be accompanied by interest
on the principal amount prepaid through the date of prepayment. 
 (viii) Deferral of Mandatory
Prepayment. Notwithstanding any of the other provisions of this Section 2.05(b), so long as no Default or Event of Default shall have occurred and be continuing on any date on which a prepayment of Eurodollar Rate Loans would
otherwise be required to be made pursuant to clause (ii), (iii), (iv), (v) or (vi) of this Section 2.05(b), the Borrower may defer such prepayment until the earlier to occur of (i) the end of the current Interest Period
applicable thereto and (ii) thirty (30) days following receipt by a Loan Party or a Subsidiary of the applicable Net Cash Proceeds. Upon the occurrence of an Event of Default during any such deferral period, the Borrower shall immediately
prepay the Loans and Cash Collateralize the L/C Obligations in the amount of all Net Cash Proceeds received by the Borrower and other amounts, as applicable, that are required to be so applied under this Section 2.05(b) (without giving
effect to the first sentence of this clause (vii)) but which have not previously been so applied. 
  

	2.06	Termination or Reduction of Commitments. 

 The Borrower may, upon notice to the Administrative Agent, terminate the Aggregate Revolving Commitments, or from time to time permanently reduce the Aggregate Revolving Commitments to an amount not less
than the Outstanding Amount of Revolving Loans, Swing Line Loans and L/C Obligations; provided that (i) any such notice shall be received by the Administrative Agent not later than 12:00 noon five (5) Business Days prior to the date
of termination or reduction, (ii) any such partial reduction shall be in an aggregate amount of $2,000,000 or any whole multiple of $500,000 in excess thereof and (iii) if, after giving effect to any reduction of the Aggregate Revolving
Commitments, the Swing Line Sublimit or the Letter of Credit Sublimit exceeds the amount of the Aggregate Revolving Commitments, such sublimit shall be automatically reduced by the amount of such excess. The Administrative Agent will promptly notify
the Lenders of any such notice of termination or reduction of the Aggregate Revolving Commitments. Any reduction of the Aggregate Revolving Commitments shall be applied to the Revolving Commitment of each Lender according to its Pro Rata Share. All
fees accrued with respect thereto until the effective date of any termination of the Aggregate Revolving Commitments shall be paid on the effective date of such termination. A notice of termination of all the Revolving Commitments delivered by the
Borrower may state that such notice is conditioned upon the effectiveness of other credit facilities and incurrence of indebtedness thereunder, in which case such notice may be revoked by the Borrower (by notice to the Administrative Agent on or
before the specified date) if such condition is not satisfied. 
  

	2.07	Repayment of Loans. 

 (a)
Revolving Loans. The Borrower shall repay to the Lenders on the Maturity Date the aggregate principal amount of all Revolving Loans outstanding on such date. 
  

 48 

 (b) Swing Line Loans. The Borrower shall repay each Swing Line Loan on the earlier to
occur of (i) the date ten (10) Business Days after such Loan is made and (ii) the Maturity Date. 
 (c) Term
Loan. The Borrower shall repay the outstanding principal amount of the Term Loan in installments on the dates and in amounts equal to the percentage of the initial principal amount of the Term Loan made on the Closing Date as set forth in the
table below (as such installments may hereafter be adjusted as a result of prepayments made pursuant to Section 2.05), unless accelerated sooner pursuant to Section 9.02: 
  

				
	 Payment Dates
	  	Principal Amortization
Payment	 
	 March 31, 2010
	  	3.75	% 
	 June 30, 2010
	  	3.75	% 
	 September 30, 2010
	  	3.75	% 
	 December 31, 2010
	  	3.75	% 
	 March 31, 2011
	  	3.75	% 
	 June 30, 2011
	  	3.75	% 
	 September 30, 2011
	  	3.75	% 
	 December 31, 2011
	  	3.75	% 
	 March 31, 2012
	  	5.00	% 
	 June 30, 2012
	  	5.00	% 
	 September 30, 2012
	  	5.00	% 
	 December 31, 2012
	  	5.00	% 
	 March 31, 2013
	  	12.50	% 
	 June 30, 2013
	  	12.50	% 
	 September 30, 2013
	  	12.50	% 
	 Maturity Date
	  	Outstanding Principal Balance
of Term Loan	  
  

  

	2.08	Interest. 

 (a) Subject to
the provisions of subsection (b) below, (i) each Eurodollar Rate Loan shall bear interest on the outstanding principal amount thereof for each Interest Period at a rate per annum equal to the sum of (A) the Eurodollar Rate for such
Interest Period plus (B) the Applicable Rate; provided, however, that the applicable interest rate for any Eurodollar Rate Loan with an Interest Period of less than three months shall be a rate per annum equal to the sum of
(A) the Eurodollar Rate that would be applicable to such Eurodollar Rate Loan if it had an Interest Period of three months plus (B) the Applicable Rate; (ii) each Base Rate Loan shall bear interest on the outstanding principal
amount thereof from the applicable borrowing date at a rate per annum equal to the Base Rate plus the Applicable Rate; and (iii) each Swing Line Loan shall bear interest on the outstanding principal amount thereof from the applicable
borrowing date at a rate per annum equal to the Base Rate plus the Applicable Rate. 
 (b) Upon the occurrence and during
the continuation of an Event of Default, the Borrower shall pay interest on the principal amount of all outstanding Loans at a fluctuating interest rate per annum at all times equal to the Default Rate to the fullest extent permitted by applicable
Laws. 
  

 49 

 (c) Interest on each Loan shall be due and payable in arrears on each Interest Payment Date
applicable thereto and at such other times as may be specified herein. Interest hereunder shall be due and payable in accordance with the terms hereof before and after judgment, and before and after the commencement of any proceeding under any
Debtor Relief Law. 
  

	2.09	Fees. 

 In addition to
certain fees described in subsections (h) and (i) of Section 2.03: 
 (a) Commitment
Fee. The Borrower shall pay to the Administrative Agent, for the account of each Lender in accordance with its Pro Rata Share of the Revolving Commitments, a commitment fee equal to the product of (i) the Applicable Rate times
(ii) the actual daily amount by which the Aggregate Revolving Commitments exceed the sum of (y) the Outstanding Amount of Revolving Loans and (z) the Outstanding Amount of L/C Obligations, subject to adjustment as provided in
Section 2.15. The commitment fee shall accrue at all times during the Availability Period, including at any time during which one or more of the conditions in Article V is not met, and shall be due and payable quarterly in arrears
on the last Business Day of each March, June, September and December, commencing with the first such date to occur after the Closing Date, and on the last day of the Availability Period. The commitment fee shall be calculated quarterly in arrears,
and if there is any change in the Applicable Rate during any quarter, the actual daily amount shall be computed and multiplied by the Applicable Rate separately for each period during such quarter that such Applicable Rate was in effect. For
purposes of clarification, Swing Line Loans shall not be considered outstanding for purposes of determining the unused portion of the Aggregate Revolving Commitments. 
 (b) Fee Letter. The Borrower shall pay to the Arrangers and the Administrative Agent for their own respective accounts
any fees in the amounts and at the times specified in the Fee Letter. Such fees shall be fully earned when paid and shall be non-refundable for any reason whatsoever. 
  

	2.10	Computation of Interest and Fees; Retroactive Adjustments of Applicable Rate. 

 (a) All computations of interest for Base Rate Loans (including Base Rate Loans determined by reference to the Eurodollar Rate) shall be made
on the basis of a year of 365 or 366 days, as the case may be, and actual days elapsed. All other computations of fees and interest shall be made on the basis of a 360-day year and actual days elapsed (which results in more fees or interest, as
applicable, being paid than if computed on the basis of a 365-day year). Interest shall accrue on each Loan for the day on which the Loan is made, and shall not accrue on a Loan, or any portion thereof, for the day on which the Loan or such portion
is paid, provided that any Loan that is repaid on the same day on which it is made shall, subject to Section 2.12(a), bear interest for one (1) day. Each determination by the Administrative Agent of an interest rate or fee
hereunder shall be conclusive and binding for all purposes, absent manifest error. 
 (b) If, as a result of any restatement of
or other adjustment to the financial statements of the Borrower or for any other reason, the Borrower or the Lenders determine that (i) the Consolidated Leverage Ratio as calculated by the Borrower as of any applicable date was inaccurate and
(ii) a proper calculation of the Consolidated Leverage Ratio would have resulted in higher pricing for such period, the Borrower shall immediately and retroactively be obligated to pay to the Administrative Agent for the account of the
applicable Lenders, promptly on demand by the Administrative Agent (or, after the occurrence of an actual or deemed entry of an order for relief with respect to the Borrower under the Bankruptcy Code of the United States, automatically and without
further action by the Administrative Agent, any Lender or the L/C Issuer), an amount equal to the excess of the amount of interest and fees

  

 50 

 
that should have been paid for such period over the amount of interest and fees actually paid for such period. This paragraph shall not limit the rights of the Administrative Agent, any Lender or
the L/C Issuer, as the case may be, under Section 2.03(c)(iii), 2.03(h) or 2.08(b) or under Article IX. The Borrower’s obligations under this paragraph shall survive the termination of the Commitments of all of
the Lenders and the repayment of all other Obligations hereunder. 
  

	2.11	Evidence of Debt. 

 (a)
The Credit Extensions made by each Lender shall be evidenced by one or more accounts or records maintained by such Lender and by the Administrative Agent in the ordinary course of business. The accounts or records maintained by the Administrative
Agent and each Lender shall be conclusive absent manifest error of the amount of the Credit Extensions made by the Lenders to the Borrower and the interest and payments thereon. Any failure to so record or any error in doing so shall not, however,
limit or otherwise affect the obligation of the Borrower hereunder to pay any amount owing with respect to the Obligations. In the event of any conflict between the accounts and records maintained by any Lender and the accounts and records of the
Administrative Agent in respect of such matters, the accounts and records of the Administrative Agent shall control in the absence of manifest error. Upon the request of any Lender made through the Administrative Agent, the Borrower shall execute
and deliver to such Lender (through the Administrative Agent) a promissory note, which shall evidence such Lender’s Loans in addition to such accounts or records. Each such promissory note shall (i) in the case of Revolving Loans, be in
the form of Exhibit C-1 (a “Revolving Note”), (ii) in the case of Swing Line Loans, be in the form of Exhibit C-2 (a “Swing Line Note”) and (iii) in the case of the Term Loan, be in the form
of Exhibit C-3 (a “Term Note”). Each Lender may attach schedules to its Note and endorse thereon the date, Type (if applicable), amount and maturity of its Loans and payments with respect thereto. 
 (b) In addition to the accounts and records referred to in subsection (a), each Lender and the Administrative Agent shall maintain in
accordance with its usual practice accounts or records evidencing the purchases and sales by such Lender of participations in Letters of Credit and Swing Line Loans. In the event of any conflict between the accounts and records maintained by the
Administrative Agent and the accounts and records of any Lender in respect of such matters, the accounts and records of the Administrative Agent shall control in the absence of manifest error. 
  

	2.12	Payments Generally; Administrative Agent’s Clawback. 

 (a) General. All payments to be made by the Borrower shall be made without condition or deduction for any counterclaim, defense, recoupment or setoff. Except as otherwise expressly provided herein,
all payments by the Borrower hereunder shall be made to the Administrative Agent, for the account of the respective Lenders to which such payment is owed, at the Administrative Agent’s Office in Dollars and in immediately available funds not
later than 2:00 p.m. on the date specified herein. The Administrative Agent will promptly distribute to each Lender its Pro Rata Share (or other applicable share as provided herein) of such payment in like funds as received by wire transfer to such
Lender’s Lending Office. All payments received by the Administrative Agent after 2:00 p.m. shall be deemed received on the next succeeding Business Day and any applicable interest or fee shall continue to accrue. Except as otherwise provided in
the definition of Interest Period with respect to Eurodollar Rate Loans, if any payment to be made by the Borrower shall come due on a day other than a Business Day, payment shall be made on the next following Business Day, and such extension of
time shall be reflected in computing interest or fees, as the case may be. 
 (b) (i) Funding by Lenders; Presumption by
Administrative Agent. Unless the Administrative Agent shall have received notice from a Lender prior to the proposed date of any Borrowing of Eurodollar Rate Loans (or, in the case of any Borrowing of Base Rate Loans, prior to 12:00

  

 51 

 
noon on the date of such Borrowing) that such Lender will not make available to the Administrative Agent such Lender’s share of such Borrowing, the Administrative Agent may assume that such
Lender has made such share available on such date in accordance with Section 2.02 (or, in the case of a Borrowing of Base Rate Loans, that such Lender has made such share available in accordance with and at the time required by
Section 2.02) and may, in reliance upon such assumption, make available to the Borrower a corresponding amount. In such event, if a Lender has not in fact made its share of the applicable Borrowing available to the Administrative Agent,
then the applicable Lender and the Borrower severally agree to pay to the Administrative Agent forthwith on demand such corresponding amount in immediately available funds with interest thereon, for each day from and including the date such amount
is made available to the Borrower to but excluding the date of payment to the Administrative Agent, at (A) in the case of a payment to be made by such Lender, the greater of the Federal Funds Rate and a rate determined by the Administrative
Agent in accordance with banking industry rules on interbank compensation, plus any administrative, processing or similar fees customarily charged by the Administrative Agent in connection with the foregoing, and (B) in the case of a payment to
be made by the Borrower, the interest rate applicable to Base Rate Loans. If the Borrower and such Lender shall pay such interest to the Administrative Agent for the same or an overlapping period, the Administrative Agent shall promptly remit to the
Borrower the amount of such interest paid by the Borrower for such period. If such Lender pays its share of the applicable Borrowing to the Administrative Agent, then the amount so paid shall constitute such Lender’s Loan included in such
Borrowing. Any payment by the Borrower shall be without prejudice to any claim the Borrower may have against a Lender that shall have failed to make such payment to the Administrative Agent. 
 (ii) Payments by Borrower; Presumptions by Administrative Agent. Unless the Administrative Agent shall have received notice from the
Borrower prior to the date on which any payment is due to the Administrative Agent for the account of the Lenders or the L/C Issuer hereunder that the Borrower will not make such payment, the Administrative Agent may assume that the Borrower has
made such payment on such date in accordance herewith and may, in reliance upon such assumption, distribute to the Lenders or the L/C Issuer, as the case may be, the amount due. In such event, if the Borrower has not in fact made such payment, then
each of the Lenders or the L/C Issuer, as the case may be, severally agrees to repay to the Administrative Agent forthwith on demand the amount so distributed to such Lender or the L/C Issuer, in immediately available funds with interest thereon,
for each day from and including the date such amount is distributed to it to but excluding the date of payment to the Administrative Agent, at the greater of the Federal Funds Rate and a rate determined by the Administrative Agent in accordance with
banking industry rules on interbank compensation. 
 A notice of the Administrative Agent to any Lender or the Borrower with
respect to any amount owing under this subsection (b) shall be conclusive, absent manifest error. 
 (c) Failure to
Satisfy Conditions Precedent. If any Lender makes available to the Administrative Agent funds for any Loan to be made by such Lender as provided in the foregoing provisions of this Article II, and such funds are not made available to the
Borrower by the Administrative Agent because the conditions to the applicable Credit Extension set forth in Article V are not satisfied or waived in accordance with the terms hereof, the Administrative Agent shall return such funds (in like
funds as received from such Lender) to such Lender, without interest. 
 (d) Obligations of Lenders Several. The
obligations of the Lenders hereunder to make Loans, to fund participations in Letters of Credit and Swing Line Loans and to make payments pursuant to Section 11.04(c) are several and not joint. The failure of any Lender to make any Loan,
to fund any such participation or to make any payment under Section 11.04(c) on any date required hereunder shall not relieve any other Lender of its corresponding obligation to do so on such date, and no Lender shall be

  

 52 

 
responsible for the failure of any other Lender to so make its Loan, to purchase its participation or to make its payment under Section 11.04(c). 
 (e) Funding Source. Nothing herein shall be deemed to obligate any Lender to obtain the funds for any Loan in any particular place or
manner or to constitute a representation by any Lender that it has obtained or will obtain the funds for any Loan in any particular place or manner. 
 (f) Insufficient Funds. If at any time insufficient funds are received by and available to the Administrative Agent to pay fully all amounts of principal, L/C Borrowings, interest and fees then due
hereunder, such funds shall be applied (i) first, toward costs and expenses (including Attorney Costs and amounts payable under Article III) incurred by the Administrative Agent and each Lender, (ii) second,
toward repayment of interest and fees then due hereunder, ratably among the parties entitled thereto in accordance with the amounts of interest and fees then due to such parties, and (iii) third, toward repayment of principal and L/C
Borrowings then due hereunder, ratably among the parties entitled thereto in accordance with the amounts of principal and L/C Borrowings then due to such parties. 
  

	2.13	Sharing of Payments by Lenders. 

 If any Lender shall, by exercising any right of setoff or counterclaim or otherwise, obtain payment in respect of any principal of or interest on any of the Loans made by it, or the participations in L/C Obligations or in Swing Line Loans
held by it resulting in such Lender’s receiving payment of a proportion of the aggregate amount of such Loans or participations and accrued interest thereon greater than its Pro Rata Share thereof as provided herein, then the Lender receiving
such greater proportion shall (a) notify the Administrative Agent of such fact, and (b) purchase (for cash at face value) participations in the Loans and subparticipations in L/C Obligations and Swing Line Loans of the other Lenders, or
make such other adjustments as shall be equitable, so that the benefit of all such payments shall be shared by the Lenders (in accordance with their Pro Rata Shares) ratably in accordance with the aggregate amount of principal of and accrued
interest on their respective Loans and other amounts owing them, provided that: 
 (i) if any such
participations or subparticipations are purchased and all or any portion of the payment giving rise thereto is recovered, such participations or subparticipations shall be rescinded and the purchase price restored to the extent of such recovery,
without interest; and 
 (ii) the provisions of this Section 2.13 shall not be construed to apply to
(A) any payment made by or on behalf of the Borrower pursuant to and in accordance with the express terms of this Agreement or any other Loan Document (including the application of funds arising from the existence of a Defaulting Lender and any
amounts applied by the Swing Line Lender to outstanding Swing Line Loans), (B) the application of collateral or other credit support (and proceeds thereof) in respect of obligations relating to Letters of Credit and Swing Line Loans (including
related Lender participation obligations) provided for in Section 2.14, or (C) any payment obtained by a Lender as consideration for the assignment of or sale of a participation in any of its Loans or subparticipations in L/C
Obligations or Swing Line Loans to any assignee or participant, other than an assignment to the Borrower or any Affiliate thereof (as to which the provisions of this Section shall apply. 
 Each Loan Party consents to the foregoing and agrees, to the extent it may effectively do so under applicable law, that any Lender acquiring a participation pursuant to the foregoing arrangements may
exercise against such Loan Party rights of setoff and counterclaim with respect to such participation as fully as if such Lender were a direct creditor of such Loan Party in the amount of such participation. 
  

 53 

	2.14	Cash Collateral and other Credit Support. 

 (a) Certain Credit Support Events; Grant of Security Interest. Upon the request of the Administrative Agent, (i) if the L/C Issuer has honored any full or partial drawing request under any
Letter of Credit and such drawing has resulted in an L/C Borrowing that remains unpaid or unreimbursed, or (ii) if, as of the Letter of Credit Expiration Date, any L/C Obligation for any reason remains outstanding, the Borrower shall, in each
case, immediately Cash Collateralize the then Outstanding Amount of all L/C Obligations. In addition, (x) Sections 2.05(b) and 9.02(c) set forth certain additional requirements to deliver Cash Collateral hereunder,
(y) Section 2.03(a)(iii)(E) contemplates the delivery of Cash Collateral or other credit support in certain circumstances to support the issuance of Letters of Credit, and (z) Section 2.04 contemplates the delivery
of Cash Collateral or other credit support in connection with the issuance of Swing Line Loans. The Borrower, and to the extent provided by any Lender, such Lender, hereby grants to the Administrative Agent, for the benefit of the Administrative
Agent, the L/C Issuer and the Lenders (including the Swing Line Lender), a security interest in all such cash, deposit accounts and all balances therein, and all other property provided as collateral pursuant to Section 2.03,
Section 2.04, Section 2.05(b) and Section 9.02(c), and all proceeds of the foregoing. Cash Collateral shall be maintained in blocked, interest bearing deposit accounts at Bank of America. For the avoidance of
doubt, to the extent that any other Person may have a claim, by virtue of an intercreditor arrangement, tag-along right or any other term in any other document or instrument, to share in any Cash Collateral or other credit support provided pursuant
to any of the aforementioned sections of this Agreement, the L/C Issuer, Swing Line Lender or Administrative Agent, as applicable, may take such provisions into account in determining whether Cash Collateral or other credit support is satisfactory.

 (b) Application. Notwithstanding anything to the contrary contained in this Agreement, (i) Cash Collateral or
other credit support (and proceeds thereof) provided by any Defaulting Lender pursuant to Sections 2.03 or 2.04 to support the obligations of such Lender in respect of Letters of Credit or Swing Line Loans shall be held and applied,
first, to fund the L/C Advances of such Lender, such Lender’s funding of participations in Swing Line Loans, or such Lender’s Pro Rata Share of Base Rate Loans used to repay L/C Borrowings, L/C Advances or Swing Line Loans with respect to
which such collateral or other credit support was provided, as applicable, and, second, to fund any interest accrued for the benefit of the L/C Issuer or Swing Line Lender pursuant to Sections 2.03(c)(vi) and 2.04(c)(iii) allocable to
such Lender, and (ii) Cash Collateral and other credit support (and proceeds thereof) otherwise provided by or on behalf of any Loan Party under Sections 2.03, 2.04, 2.05(b) or 9.02(c) to support L/C Obligations or
Swing Line Loans shall be held and applied, first, to the satisfaction of the specific L/C Obligations, Swing Line Loans or obligations to fund participations therein of the applicable Defaulting Lender for which the Cash Collateral or other credit
support was so provided and, second, if remedies under Section 9.02 shall have been exercised, to any other Obligations in accordance with Section 9.03. 
 (c) Release. Cash Collateral and other credit support provided under Sections 2.03 or 2.04 in connection with any Lender’s status as a Defaulting Lender shall be released (except
as the L/C Issuer, Swing Line Lender and the Person providing such collateral or other credit support may agree otherwise (as applicable)) promptly following the earlier to occur of (i) the termination of such Lender’s status as a
Defaulting Lender or (ii) following the L/C Issuer’s or Swing Line Lender’s (as applicable) good faith determination that there remain outstanding no L/C Obligations or Swing Line Loans, as applicable, as to which it has actual or
potential Fronting Exposure in relation to such Lender as to which it desires to maintain Cash Collateral or other credit support; subject, however, to the additional condition that, as to any such collateral or other credit support
provided by or on behalf of a Loan Party, no Default or Event of Default shall then have occurred and be continuing. 
  

 54 

	2.15	Defaulting Lenders. 

 Notwithstanding anything to the contrary contained in this Agreement, if any Lender becomes a Defaulting Lender, then, until such time as such Lender is no longer a Defaulting Lender, to the extent permitted by applicable Law: 

(a) Waivers and Amendments. Such Defaulting Lender’s right to approve or disapprove any amendment, waiver or
consent with respect to this Agreement or any other Loan Document shall be restricted as set forth in Section 11.01. 
 (b) Certain Fees. Such Defaulting Lender shall not be entitled to receive any commitment fee pursuant to Section 2.09(a) for any period during which such Lender is a Defaulting Lender
(and the Borrower shall not be required to pay any such fee that otherwise would have been required to have been paid to such Defaulting Lender). Such Defaulting Lender’s right to receive Letter of Credit Fees shall be limited as provided in
Section 2.03(h). 
 (c) Reallocation of Pro Rata Shares to Reduce Fronting Exposure. During any
period in which there is a Defaulting Lender as to which the L/C Issuer or Swing Line Lender (as applicable) has not received cash collateral or other credit support acceptable to it in respect of the related participation and funding obligations of
such Defaulting Lender, then upon the request of the L/C Issuer or Swing Line Lender (as applicable) to the Administrative Agent, for purposes of computing the amount of the obligation of each non-Defaulting Lender to acquire, refinance or fund
participations in Letters of Credit or Swing Line Loans pursuant to Sections 2.03 and 2.04, the “Pro Rata Share” of each non-Defaulting Lender shall be computed without giving effect to the Commitment of such Defaulting
Lender; provided, that, in all cases, the obligation of each non-Defaulting Lender to acquire, refinance or fund participations in Letters of Credit or Swing Line Loans pursuant to the foregoing provision shall not exceed the positive
difference, if any, between (i) the Revolving Commitment of such non-Defaulting Lender and (ii) the aggregate Outstanding Amount of the Revolving Loans of such Lender, plus such Lender’s Pro Rata Share of the Outstanding Amount of all
other L/C Obligations (prior to giving effect to such reallocation), plus such Lender’s Pro Rata Share of the Outstanding Amount of all other Swing Line Loans (prior to giving effect to such reallocation). 
 A Lender that has become a Defaulting Lender because of an event referenced in the definition of Defaulting Lender may cure such status and
shall no longer constitute a Defaulting Lender as a result of such event when (i) such Defaulting Lender shall have fully funded or paid, as applicable, all Loans, participations in respect of Letters of Credit or Swing Line Loans or other
amounts required to be funded or paid by it hereunder as to which it is delinquent (together, in each case, with such interest thereon as shall be required to any Person as otherwise provided in this Agreement), (ii) the Administrative Agent
and the Borrower shall have received a certification by such Defaulting Lender of its ability and intent to comply with the provisions of this Agreement going forward, and (iii) each of (x) the Administrative Agent, (y) the L/C
Issuer, the Swing Line Lender and any other Lender as to which a delinquent obligation was owed, and (z) in the case of the failure to fund any Loan, the Borrower, shall have determined (and notified the Administrative Agent) that they are
satisfied, in their sole discretion, that such Defaulting Lender intends to continue to perform its obligations as a Lender hereunder and has all approvals required to enable it, to continue to perform its obligations as a Lender hereunder. No
reference in this subsection to an event being “cured” shall by itself preclude any claim by any Person against any Lender that becomes a Defaulting Lender for such direct damages as may otherwise be available to such Person arising from
any failure to fund or pay any amount when due hereunder or from any other event that gave rise to such Lender’s status as a Defaulting Lender. 
  

 55 

 ARTICLE III 
 TAXES, YIELD PROTECTION AND ILLEGALITY 
  

	3.01	Taxes. 

 (a) Payments
Free of Taxes; Obligation to Withhold; Payments on Account of Taxes. 
 (i) Any and all payments by or on
account of any obligation of the Borrower hereunder or under any other Loan Document shall to the extent permitted by applicable Laws be made free and clear of and without reduction or withholding for any Taxes. If, however, applicable Laws require
the Borrower or the Administrative Agent to withhold or deduct any Tax, such Tax shall be withheld or deducted in accordance with such Laws as determined by the Borrower or the Administrative Agent, as the case may be, upon the basis of the
information and documentation to be delivered pursuant to subsection (e) below. 
 (ii) If the Borrower or
the Administrative Agent shall be required by the Internal Revenue Code to withhold or deduct any Taxes, including both United States Federal backup withholding and withholding taxes, from any payment, then (A) the Administrative Agent shall
withhold or make such deductions as are determined by the Administrative Agent to be required based upon the information and documentation it has received pursuant to subsection (e) below, (B) the Administrative Agent shall timely pay the
full amount withheld or deducted to the relevant Governmental Authority in accordance with the Internal Revenue Code, and (C) to the extent that the withholding or deduction is made on account of Indemnified Taxes or Other Taxes, the sum
payable by the Borrower shall be increased as necessary so that after any required withholding or the making of all required deductions (including deductions applicable to additional sums payable under this Section) the Administrative Agent, Lender
or L/C Issuer, as the case may be, receives an amount equal to the sum it would have received had no such withholding or deduction been made. 
 (b) Payment of Other Taxes by the Borrower. Without limiting the provisions of subsection (a) above, the Borrower shall timely pay any Other Taxes to the relevant Governmental Authority in
accordance with applicable Laws. 
 (c) Tax Indemnifications. 
 (i) Without limiting the provisions of subsection (a) or (b) above, the Borrower shall, and does hereby, indemnify
the Administrative Agent, each Lender and the L/C Issuer, and shall make payment in respect thereof within 10 days after written demand therefor, for the full amount of any Indemnified Taxes or Other Taxes (including Indemnified Taxes or Other Taxes
imposed or asserted on or attributable to amounts payable under this Section 3.01) withheld or deducted by the Borrower or the Administrative Agent or paid by the Administrative Agent, such Lender or the L/C Issuer, as the case may be,
and any penalties, interest and reasonable expenses arising therefrom or with respect thereto (but only to the extent such Taxes and penalties were not caused by the gross negligence or willful misconduct of the applicable Person seeking
indemnification hereunder), whether or not such Indemnified Taxes or Other Taxes were correctly or legally imposed or asserted by the relevant Governmental Authority. The Borrower shall also, and does hereby, indemnify the Administrative Agent, and
shall make payment in respect thereof within 10 days after written demand therefor, for any amount which a Lender or the L/C Issuer for any reason fails to pay indefeasibly to the Administrative Agent as required by clause (ii) of this
subsection; provided that (i) such indemnity shall not, as to the Administrative

  

 56 

 
Agent, be available to the extent that such amount resulted from the gross negligence or willful misconduct of the Administrative Agent and (ii) the Borrower shall retain all claims and
other rights against the applicable Lender or L/C Issuer in connection with a failure to make any such payment. A certificate as to the amount of any such payment or liability delivered to the Borrower by a Lender or the L/C Issuer (with a copy to
the Administrative Agent), or by the Administrative Agent on its own behalf or on behalf of a Lender or the L/C Issuer, together with any documentation reasonably requested by the Borrower, shall be conclusive absent manifest error. Notwithstanding
the foregoing, the Borrower shall not be required to indemnify the Administrative Agent, such Lender or the L/C Issuer pursuant to the foregoing provision for any Indemnified Taxes or Other Taxes (including Indemnified Taxes or Other Taxes imposed
or asserted on or attributable to amounts payable under this Section 3.01) for which written notice was received by the Administrative Agent, such Lender or the L/C Issuer from the appropriate Governmental Authority more than six months
prior to the date that the Administrative Agent, such Lender or the L/C Issuer, as the case may be, notifies the Borrower of such Indemnified Taxes or Other Taxes. 
 (ii) Without limiting the provisions of subsection (a) or (b) above, each Lender and the L/C Issuer shall, and does
hereby, indemnify the Borrower and the Administrative Agent, and shall make payment in respect thereof within 10 days after written demand therefor, against any and all Taxes and any and all related losses, claims, liabilities, penalties, interest
and expenses (including the fees, charges and disbursements of any counsel for the Borrower or the Administrative Agent) incurred by or asserted against the Administrative Agent or the Borrower by any Governmental Authority as a result of the
failure by such Lender or the L/C Issuer, as the case may be, to deliver, or as a result of the inaccuracy, inadequacy or deficiency of, any documentation required to be delivered by such Lender or the L/C Issuer, as the case may be, to the Borrower
or the Administrative Agent pursuant to subsection (e). Each Lender and the L/C Issuer hereby authorizes the Administrative Agent to set off and apply any and all amounts at any time owing to such Lender or the L/C Issuer, as the case may be, under
this Agreement or any other Loan Document against any amount due to the Administrative Agent under this clause (ii). The agreements in this clause (ii) shall survive the resignation and/or replacement of the Administrative Agent, any assignment
of rights by, or the replacement of, a Lender or the L/C Issuer, the termination of the Commitments and the repayment, satisfaction or discharge of all other Obligations. 
 (d) Evidence of Payments. Upon request by the Borrower or the Administrative Agent, as the case may be, after any payment of Taxes by the Borrower or by the Administrative Agent to a Governmental
Authority as provided in this Section 3.01, the Borrower shall make reasonable efforts to obtain and deliver to the Administrative Agent or the Administrative Agent shall make reasonable efforts to obtain and deliver to the Borrower, as
the case may be, the original or a certified copy of a receipt issued by such Governmental Authority evidencing such payment, a copy of any return required by Laws to report such payment or other evidence of such payment reasonably satisfactory to
the Borrower or the Administrative Agent, as the case may be. 
 (e) Status of Lenders; Tax Documentation. 
 (i) Each Lender shall deliver to the Borrower and to the Administrative Agent, at the time or times prescribed by applicable
Laws or when reasonably requested by the Borrower or the Administrative Agent, such properly completed and executed documentation prescribed by applicable Laws or by the taxing authorities of any jurisdiction and such other reasonably requested
information as will permit the Borrower or the Administrative Agent, as the case may be, to determine (A) whether or not payments made hereunder or under any other Loan Document

  

 57 

 
are subject to Taxes, (B) if applicable, the required rate of withholding or deduction, and (C) such Lender’s entitlement to any available exemption from, or reduction of,
applicable Taxes in respect of all payments to be made to such Lender by the Borrower pursuant to this Agreement or otherwise to establish such Lender’s status for withholding tax purposes in the applicable jurisdiction. 
 (ii) Without limiting the generality of the foregoing, if the Borrower is resident for tax purposes in the United States,

 (A) any Lender that is a “United States person” within the meaning of Section 7701(a)(30) of
the Internal Revenue Code shall deliver to the Borrower and the Administrative Agent executed originals of Internal Revenue Service Form W-9 or such other documentation or information prescribed by applicable Laws or reasonably requested by the
Borrower or the Administrative Agent as will enable the Borrower or the Administrative Agent, as the case may be, to determine whether or not such Lender is subject to backup withholding or information reporting requirements; and 
 (B) each Foreign Lender that is entitled under the Internal Revenue Code or any applicable treaty to an exemption from or
reduction of withholding tax with respect to payments hereunder or under any other Loan Document shall deliver to the Borrower and the Administrative Agent (in such number of copies as shall be requested by the recipient) on or prior to the date on
which such Foreign Lender becomes a Lender under this Agreement (and from time to time thereafter upon the request of the Borrower or the Administrative Agent, but only if such Foreign Lender is legally entitled to do so), whichever of the following
is applicable: 
  

	 	(I)	executed originals of Internal Revenue Service Form W-8BEN claiming eligibility for benefits of an income tax treaty to which the United States is a party,

  

	 	(II)	executed originals of Internal Revenue Service Form W-8ECI, 

  

	 	(III)	executed originals of Internal Revenue Service Form W-8IMY and all required supporting documentation, 

  

	 	(IV)	in the case of a Foreign Lender claiming the benefits of the exemption for portfolio interest under section 881(c) of the Internal Revenue Code, (x) a certificate
to the effect that such Foreign Lender is not (A) a “bank” within the meaning of section 881(c)(3)(A) of the Internal Revenue Code, (B) a “10 percent shareholder” of the Borrower within the meaning of section
881(c)(3)(B) of the Internal Revenue Code, or (C) a “controlled foreign corporation” described in section 881(c)(3)(C) of the Internal Revenue Code and (y) executed originals of Internal Revenue Service Form W-8BEN, or

  

	 	(V)	executed originals of any other form prescribed by applicable Laws as a basis for claiming exemption from or a reduction in United States Federal withholding tax
together with such supplementary documentation as may be prescribed by applicable Laws to permit the Borrower or the Administrative Agent to determine the withholding or deduction required to be made. 

  

 58 

 (iii) Each Foreign Lender shall take any action (including entering into an
agreement with the Internal Revenue Service) and comply with any information gathering and reporting requirements, in each case, that are required to obtain the maximum available exemption from U.S. federal withholding taxes under Chapter 4 (Taxes
to Enforce Reporting on Certain Foreign Accounts) of the Internal Revenue Code (the “FACTA Provisions”), if enacted, or under legislation that is substantially similar to the FACTA Provisions with respect to payments received by or on
behalf of such Foreign Lender, if enacted. 
 (iv) Each Lender shall promptly (A) notify the Borrower and
the Administrative Agent of any change in circumstances which would modify or render invalid any claimed exemption or reduction, and (B) take such steps as shall not be materially disadvantageous to it, in the reasonable judgment of such
Lender, and as may be reasonably necessary (including the re-designation of its Lending Office) to avoid any requirement of applicable Laws of any jurisdiction that the Borrower or the Administrative Agent make any withholding or deduction for taxes
from amounts payable to such Lender. 
 (f) Treatment of Certain Refunds. Unless required by applicable Laws, at no time
shall the Administrative Agent have any obligation to file for or otherwise pursue on behalf of a Lender or the L/C Issuer, or have any obligation to pay to any Lender or the L/C Issuer, any refund of Taxes withheld or deducted from funds paid for
the account of such Lender or the L/C Issuer, as the case may be. If the Administrative Agent, any Lender or the L/C Issuer determines, in its sole discretion, that it has received a refund of any Taxes or Other Taxes as to which it has been
indemnified by the Borrower or with respect to which the Borrower has paid additional amounts pursuant to this Section, it shall pay to the Borrower an amount equal to such refund (but only to the extent of indemnity payments made, or additional
amounts paid, by the Borrower under this Section with respect to the Taxes or Other Taxes giving rise to such refund), net of all out-of-pocket expenses incurred by the Administrative Agent, such Lender or the L/C Issuer (to the extent not due to
the gross negligence or willful misconduct of the Person seeking reimbursement of such expenses), as the case may be, and without interest (other than any interest paid by the relevant Governmental Authority with respect to such refund),
provided that the Borrower, upon the request of the Administrative Agent, such Lender or the L/C Issuer, agrees to repay the amount paid over to the Borrower (plus any penalties, interest or other charges imposed by the relevant Governmental
Authority) to the Administrative Agent, such Lender or the L/C Issuer in the event the Administrative Agent, such Lender or the L/C Issuer is required to repay such refund to such Governmental Authority. This subsection shall not be construed to
require the Administrative Agent, any Lender or the L/C Issuer to make available its tax returns (or any other information relating to its taxes that it deems confidential) to the Borrower or any other Person. 
  

	3.02	Illegality. 

 If any
Lender determines that any Law has made it unlawful, or that any Governmental Authority has asserted that it is unlawful, for any Lender or its applicable Lending Office to make, maintain or fund Loans whose interest is determined by reference to
the Eurodollar Rate, or to determine or charge interest rates based upon the Eurodollar Rate, then, on notice thereof by such Lender to the Borrower through the Administrative Agent, (a) any obligation of such Lender to make or continue
Eurodollar Rate Loans or to convert Base Rate Loans to Eurodollar Rate Loans shall be suspended and (b) if such notice asserts the illegality of such Lender making or maintaining Base Rate Loans the interest rate on which is determined by
reference to the Eurodollar Rate component of the Base Rate, the interest rate on the Base Rate Loans of such Lender shall, if necessary to avoid such illegality, be determined by the Administrative Agent without reference to the Eurodollar Rate
component of the Base Rate, in each case until such Lender notifies the Administrative Agent and the Borrower that the circumstances giving rise to such

  

 59 

 
determination no longer exist. Upon receipt of such notice, the Borrower shall, upon demand from such Lender (with a copy to the Administrative Agent), prepay or, if the Borrower elects, convert
all Eurodollar Rate Loans of such Lender to Base Rate Loans (the interest rate on which Base Rate Loans of such Lender shall, if necessary to avoid such illegality, be determined by the Administrative Agent without reference to the Eurodollar Rate
component of the Base Rate), either on the last day of the Interest Period therefor, if such Lender may lawfully continue to maintain such Eurodollar Rate Loans to such day, or immediately, if such Lender may not lawfully continue to maintain such
Eurodollar Rate Loans. Upon any such prepayment or conversion, the Borrower shall also pay accrued interest on the amount so prepaid or converted. Each Lender agrees to designate a different Lending Office if such designation will avoid the need for
such notice and will not, in the good faith judgment of such Lender, otherwise be materially disadvantageous to such Lender. 
  

	3.03	Inability to Determine Rates. 

 If the Required Lenders determine that for any reason in connection with any request for a Eurodollar Rate Loan or a conversion to or continuation thereof that (a) Dollar deposits are not being offered to banks in the London interbank
eurodollar market for the applicable amount and Interest Period of such Eurodollar Rate Loan, (b) adequate and reasonable means do not exist for determining the Eurodollar Rate for any requested Interest Period with respect to a proposed
Eurodollar Rate Loan or in connection with an existing or proposed Base Rate Loan, or (c) the Eurodollar Rate for any requested Interest Period with respect to a proposed Eurodollar Rate Loan does not adequately and fairly reflect the cost to
such Lenders of funding such Loan, the Administrative Agent will promptly so notify the Borrower and each Lender. Thereafter, (x) the obligation of the Lenders to make or maintain Eurodollar Rate Loans shall be suspended, and (y) in the
event of a determination described in the preceding sentence with respect to the Eurodollar Rate component of the Base Rate, the utilization of the Eurodollar Rate component in determining the Base Rate shall be suspended, in each case until the
Administrative Agent (upon the instruction of the Required Lenders) revokes such notice. Upon receipt of such notice, the Borrower may revoke any pending request for a Borrowing of, conversion to or continuation of Eurodollar Rate Loans or, failing
that, will be deemed to have converted such request into a request for a Borrowing of Base Rate Loans in the amount specified therein. 
  

	3.04	Increased Costs. 

 (a)
Increased Costs Generally. If any Change in Law shall: 
  

	 	(i)	impose, modify or deem applicable any reserve, special deposit, compulsory loan, insurance charge or similar requirement against assets of, deposits with or for the
account of, or credit extended or participated in by, any Lender (except any reserve requirement reflected in the Eurodollar Rate) or the L/C Issuer; 

  

	 	(ii)	subject any Lender or the L/C Issuer to any tax of any kind whatsoever with respect to this Agreement, any Letter of Credit, any participation in a Letter of Credit or
any Eurodollar Rate Loan made by it, or change the basis of taxation of payments to such Lender or the L/C Issuer in respect thereof (except for Indemnified Taxes or Other Taxes covered by Section 3.01 and the imposition of, or any
change in the rate of, any Excluded Tax payable by such Lender or the L/C Issuer); or 

  

	 	(iii)	impose on any Lender or the L/C Issuer or the London interbank market any other condition, cost or expense affecting this Agreement or Eurodollar Rate Loans made by
such Lender or any Letter of Credit or participation therein; 

  

 60 

 and the result of any of the foregoing shall be to increase the cost to such Lender of making or maintaining
any Loan the interest on which is determined by reference to the Eurodollar Rate (or of maintaining its obligation to make any such Loan), or to increase the cost to such Lender or the L/C Issuer of participating in, issuing or maintaining any
Letter of Credit (or of maintaining its obligation to participate in or to issue any Letter of Credit), or to reduce the amount of any sum received or receivable by such Lender or the L/C Issuer hereunder (whether of principal, interest or any other
amount) then, upon request of such Lender or the L/C Issuer, the Borrower will pay to such Lender or the L/C Issuer, as the case may be, such additional amount or amounts as will compensate such Lender or the L/C Issuer, as the case may be, for such
additional costs incurred or reduction suffered. 
 (b) Capital Requirements. If any Lender or the L/C Issuer determines
that any Change in Law affecting such Lender or the L/C Issuer or any Lending Office of such Lender or such Lender’s or the L/C Issuer’s holding company, if any, regarding capital requirements has had the effect of reducing the rate of
return on such Lender’s or the L/C Issuer’s capital or on the capital of such Lender’s or the L/C Issuer’s holding company, if any, as a consequence of this Agreement, the Commitments of such Lender or the Loans made by, or
participations in Letters of Credit held by, such Lender, or the Letters of Credit issued by the L/C Issuer, to a level below that which such Lender or the L/C Issuer or such Lender’s or the L/C Issuer’s holding company could have achieved
but for such Change in Law (taking into consideration such Lender’s or the L/C Issuer’s policies and the policies of such Lender’s or the L/C Issuer’s holding company with respect to capital adequacy), then from time to time the
Borrower will pay to such Lender or the L/C Issuer, as the case may be, such additional amount or amounts as will compensate such Lender or the L/C Issuer or such Lender’s or the L/C Issuer’s holding company for any such reduction
suffered. 
 (c) Certificates for Reimbursement. A certificate of a Lender or the L/C Issuer setting forth the amount or
amounts necessary to compensate such Lender or the L/C Issuer or its holding company, as the case may be, as specified in subsection (a) or (b) of this Section and delivered to the Borrower shall be conclusive absent manifest error. The
Borrower shall pay such Lender or the L/C Issuer, as the case may be, the amount shown as due on any such certificate within 10 days after receipt thereof. 
 (d) Delay in Requests. Failure or delay on the part of any Lender or the L/C Issuer to demand compensation pursuant to the foregoing provisions of this Section shall not constitute a waiver of such
Lender’s or the L/C Issuer’s right to demand such compensation, provided that the Borrower shall not be required to compensate a Lender or the L/C Issuer pursuant to the foregoing provisions of this Section for any increased costs
incurred or reductions suffered more than six months prior to the date that such Lender or the L/C Issuer, as the case may be, notifies the Borrower of the Change in Law giving rise to such increased costs or reductions and of such Lender’s or
the L/C Issuer’s intention to claim compensation therefor (except that, if the Change in Law giving rise to such increased costs or reductions is retroactive, then the six-month period referred to above shall be extended to include the period
of retroactive effect thereof). 
 (e) Reserves on Eurodollar Rate Loans. The Borrower shall pay to each Lender, as long
as such Lender shall be required to maintain reserves with respect to liabilities or assets consisting of or including Eurocurrency funds or deposits, additional interest on the unpaid principal amount of each Eurodollar Rate Loan equal to the
actual costs of such reserves allocated to such Loan by such Lender (as determined by such Lender in good faith, which determination shall be conclusive absent manifest error), which shall be due and payable on each date on which interest is payable
on such Loan, provided the Borrower shall have received at least 10 days’ prior notice (with a copy to the Administrative Agent) of such additional interest from such Lender. If a Lender fails to give notice 10 days prior to the relevant
Interest Payment Date, such additional interest shall be due and payable 10 days from receipt of such notice. 
  

 61 

	3.05	Compensation for Losses. 

 Upon demand of any Lender (with a copy to the Administrative Agent) from time to time, the Borrower shall promptly compensate such Lender for and hold such Lender harmless from any actual, direct loss, cost or expense incurred by it as a
result of: 
 (a) any continuation, conversion, payment or prepayment of any Loan other than a Base Rate Loan on
a day other than the last day of the Interest Period for such Loan (whether voluntary, mandatory, automatic, by reason of acceleration, or otherwise); 
 (b) any failure by the Borrower (for a reason other than the failure of such Lender to make a Loan) to prepay, borrow, continue or convert any Loan other than a Base Rate Loan on the date or in the amount
notified by the Borrower; or 
 (c) any assignment of a Eurodollar Rate Loan on a day other than the last day of
the Interest Period therefor as a result of a request by the Borrower pursuant to Section 11.14; 
 including any loss of
anticipated profits and any loss or expense arising from the liquidation or reemployment of funds obtained by it to maintain such Loan or from fees payable to terminate the deposits from which such funds were obtained. The Borrower shall also pay
any reasonable and customary administrative fees charged by such Lender in connection with the foregoing. 
 For purposes of
calculating amounts payable by the Borrower to the Lenders under this Section 3.05, each Lender shall be deemed to have funded each Eurodollar Rate Loan made by it at the Eurodollar Rate used in determining the Eurodollar Rate for such
Loan by a matching deposit or other borrowing in the London interbank eurodollar market for a comparable amount and for a comparable period, whether or not such Eurodollar Rate Loan was in fact so funded. 
  

	3.06	Mitigation Obligations; Replacement of Lenders. 

 (a) Designation of a Different Lending Office. If any Lender or the L/C Issuer requests compensation under Section 3.04, or the Borrower is required to pay any additional amount to any
Lender, the L/C Issuer, or any Governmental Authority for the account of any Lender or the L/C Issuer pursuant to Section 3.01, or if any Lender or the L/C Issuer gives a notice pursuant to Section 3.02, then such Lender or
the L/C Issuer shall, as applicable, use reasonable efforts to designate a different Lending Office for funding or booking its Loans and/or Letters of Credit, as applicable, hereunder or to assign its rights and obligations hereunder to another of
its offices, branches or affiliates, if, in the judgment of such Lender or the L/C Issuer, such designation or assignment (i) would eliminate or reduce amounts payable pursuant to Section 3.01 or 3.04, as the case may be, in
the future, or eliminate the need for the notice pursuant to Section 3.02, as applicable, and (ii) in each case, would not subject such Lender or the L/C Issuer, as the case may be, to any unreimbursed cost or expense and would not
otherwise be disadvantageous to such Lender or the L/C Issuer, as the case may be. The Borrower hereby agrees to pay all reasonable costs and expenses incurred by any Lender or the L/C Issuer in connection with any such designation or assignment.

 (b) Replacement of Lenders. If any Lender requests compensation under Section 3.04, or if the Borrower is
required to pay any additional amount to any Lender or any Governmental Authority for the account of any Lender pursuant to Section 3.01, or if any Lender delivers a notice pursuant to Section 3.02, the Borrower may replace
such Lender in accordance with Section 11.14. 
  

 62 

	3.07	Survival. 

 All of the
Borrower’s obligations under this Article III shall survive termination of the Aggregate Revolving Commitments and repayment of all other Obligations hereunder. 
 ARTICLE IV 
 GUARANTY 
  

	4.01	The Guaranty. 

 Each of
the Guarantors hereby jointly and severally guarantees to each Secured Party, as primary obligor and not as surety, the prompt payment of the Obligations in full when due (whether at stated maturity, as a mandatory prepayment, by acceleration, as a
mandatory cash collateralization or otherwise) strictly in accordance with the terms thereof. The Guarantors hereby further agree that if any of the Obligations are not paid in full when due (whether at stated maturity, as a mandatory prepayment, by
acceleration, as a mandatory cash collateralization or otherwise), the Guarantors will, jointly and severally, promptly pay the same, without any demand or notice whatsoever, and that in the case of any extension of time of payment or renewal of any
of the Obligations, the same will be promptly paid in full when due (whether at extended maturity, as a mandatory prepayment, by acceleration, as a mandatory cash collateralization or otherwise) in accordance with the terms of such extension or
renewal. 
 Notwithstanding any provision to the contrary contained herein or in any other of the Loan Documents, Secured Hedge
Agreements or Secured Cash Management Agreements, the obligations of each Guarantor under this Agreement and the other Loan Documents shall be limited to an aggregate amount equal to the largest amount that would not render such obligations subject
to avoidance under the Debtor Relief Laws or any comparable provisions of any applicable state Law. 
  

	4.02	Obligations Unconditional. 

 The obligations of the Guarantors under Section 4.01 are joint and several, absolute and unconditional, irrespective of the value, genuineness, validity, regularity or enforceability of any of the Loan Documents, Secured Hedge
Agreements or Secured Cash Management Agreements, or any other agreement or instrument referred to therein, or any substitution, release, impairment or exchange of any other guarantee of or security for any of the Obligations, and, to the fullest
extent permitted by applicable Law, irrespective of any other circumstance whatsoever which might otherwise constitute a legal or equitable discharge or defense of a surety or guarantor, it being the intent of this Section 4.02 that the
obligations of the Guarantors hereunder shall be absolute and unconditional under any and all circumstances. Each Guarantor agrees that such Guarantor shall have no right of subrogation, indemnity, reimbursement or contribution against the Borrower
or any other Guarantor for amounts paid under this Article IV until such time as the Obligations have been Fully Satisfied. Without limiting the generality of the foregoing, it is agreed that, to the fullest extent permitted by Law, the
occurrence of any one or more of the following shall not alter or impair the liability of any Guarantor hereunder, which shall remain absolute and unconditional as described above: 
 (a) at any time or from time to time, without notice to any Guarantor, the time for any performance of or compliance with any
of the Obligations shall be extended, or such performance or compliance shall be waived; 
  

 63 

 (b) any of the acts mentioned in any of the provisions of any of the Loan
Documents, Secured Hedge Agreements or Secured Cash Management Agreements, or any other agreement or instrument referred to in the Loan Documents or such Secured Hedge Agreements or Secured Cash Management Agreements shall be done or omitted;

 (c) the maturity of any of the Obligations shall be accelerated, or any of the Obligations shall be modified,
supplemented or amended in any respect, or any right under any of the Loan Documents, any Secured Hedge Agreements, any Secured Cash Management Agreements, or any other agreement or instrument referred to in the Loan Documents, such Secured Hedge
Agreements or such Secured Cash Management Agreements shall be waived or any other guarantee of any of the Obligations or any security therefor shall be released, impaired or exchanged in whole or in part or otherwise dealt with; 
 (d) any Lien granted to, or in favor of, the Administrative Agent or any Lender, or Lenders as security for any of the
Obligations shall fail to attach or be perfected; or 
 (e) any of the Obligations shall be determined to be void
or voidable (including, without limitation, for the benefit of any creditor of any Guarantor) or shall be subordinated to the claims of any Person (including, without limitation, any creditor of any Guarantor). 
 With respect to its obligations hereunder, each Guarantor hereby expressly waives diligence, presentment, demand of payment, protest and all
notices whatsoever, and any requirement that the Administrative Agent or any Lender exhaust any right, power or remedy or proceed against any Person under any of the Loan Documents, any Secured Hedge Agreements, any Secured Cash Management
Agreements, or any other agreement or instrument referred to in the Loan Documents, the Secured Hedge Agreements or the Secured Cash Management Agreements, or against any other Person under any other guarantee of, or security for, any of the
Obligations. 
  

	4.03	Reinstatement. 

 The
obligations of the Guarantors under this Article IV shall be automatically reinstated if and to the extent that for any reason any payment by or on behalf of any Person in respect of the Obligations is rescinded or must be otherwise
restored by any holder of any of the Obligations, whether as a result of any proceedings in bankruptcy or reorganization or otherwise, and each Guarantor agrees that it will indemnify the Administrative Agent and each Lender on demand for all
reasonable costs and expenses (including, without limitation, Attorney Costs) incurred by the Administrative Agent or such Lender in connection with such rescission or restoration, including any such costs and expenses incurred in defending against
any claim alleging that such payment constituted a preference, fraudulent transfer or similar payment under any bankruptcy, insolvency or similar Law; provided that such costs and expenses were not caused by the gross negligence or willful
misconduct of the Administrative Agent or any Lender. 
  

	4.04	Certain Additional Waivers. 

 Each Guarantor agrees that such Guarantor shall have no right of recourse to security for the Obligations, except through the exercise of rights of subrogation pursuant to Section 4.02 and through the exercise of rights of
contribution pursuant to Section 4.06. 
  

 64 

	4.05	Remedies. 

 The Guarantors
agree that, to the fullest extent permitted by Law, as between the Guarantors, on the one hand, and the Administrative Agent and the Lenders, on the other hand, the Obligations may be declared to be forthwith due and payable as provided in
Section 9.02 (and shall be deemed to have become automatically due and payable in the circumstances provided in said Section 9.02) for purposes of Section 4.01 notwithstanding any stay, injunction or other
prohibition preventing such declaration (or preventing the Obligations from becoming automatically due and payable) as against any other Person and that, in the event of such declaration (or the Obligations being deemed to have become automatically
due and payable), the Obligations (whether or not due and payable by any other Person) shall forthwith become due and payable by the Guarantors for purposes of Section 4.01. The Guarantors acknowledge and agree that their obligations
hereunder are secured in accordance with the terms of the Collateral Documents and that the Lenders may exercise their remedies thereunder in accordance with the terms thereof. 
  

	4.06	Rights of Contribution. 

 The Guarantors hereby agree as among themselves that, in connection with payments made hereunder, each Guarantor shall have a right of contribution from each other Guarantor in accordance with applicable Law. Such contribution rights shall
be subordinate and subject in right of payment to the Obligations until such time as the Obligations have been Fully Satisfied, and none of the Guarantors shall exercise any such contribution rights until the Obligations have been Fully Satisfied.

  

	4.07	Guarantee of Payment; Continuing Guarantee. 

 The guarantee in this Article IV is a guaranty of payment and not of collection, is a continuing guarantee, and shall apply to all Obligations whenever arising. 
 ARTICLE V 
 CONDITIONS PRECEDENT TO CREDIT EXTENSIONS 
  

	5.01	Conditions of Closing. 

 The obligation of the Administrative Agent, the L/C Issuer and each Lender to enter into this Agreement and to make the initial Credit Extension hereunder on the Closing Date is subject to the satisfaction of the following conditions
precedent: 
 (a) Loan Documents. Receipt by the Administrative Agent of executed counterparts of this
Agreement and the other Loan Documents required to be entered into on the Closing Date, each properly executed by a Responsible Officer of the signing Loan Party and, in the case of this Agreement, by each Lender. 
 (b) Opinions of Counsel. Receipt by the Administrative Agent of opinions of legal counsel to the Loan Parties,
addressed to the Administrative Agent and each Lender, dated as of the Closing Date, and in form and substance reasonably satisfactory to the Arrangers and the Administrative Agent. 
 (c) Financial Statements. The Administrative Agent and the Arrangers shall have received: 
 (i) the Audited Financial Statements; 
  

 65 

 (ii) the Interim Financial Statements; 
 (iii) the Pro Forma Financial Statements; and 
 (iv) a pro forma financial model as to the Borrower and its Subsidiaries and forecasts prepared by management of the
Borrower of consolidated balance sheets, income statements and cash flow statements of the Borrower and its Subsidiaries, each on an annual basis beginning January 1, 2010 and ending with the fiscal year ending December 31, 2013, in each
case giving effect to all elements of the Transaction to be effected on or before the Closing Date. 
 (d) No
Material Adverse Change. There shall not have occurred since December 31, 2008, a material adverse change in the business, assets, properties, liabilities (actual or contingent), operations, condition (financial or otherwise) or prospects
of (i) the Borrower and its Subsidiaries, taken as a whole or (ii) the New Product. 
 (e)
Litigation. There shall not exist any action, suit, investigation or proceeding pending or, to the knowledge of the Borrower, the Administrative Agent or the Lenders, threatened in any court or before an arbitrator or Governmental Authority
that could reasonably be expected to have a Material Adverse Effect. 
 (f) Organization Documents,
Resolutions, Etc. Receipt by the Administrative Agent of the following in form and substance satisfactory to the Arrangers and the Administrative Agent and their legal counsel: 
 (i) the Organization Documents of each Loan Party certified to be true and complete as of a recent date by the appropriate
Governmental Authority of the state or other jurisdiction of its incorporation or organization (it being understood that each Loan Party’s bylaws will not be certified by a Governmental Authority), where applicable, and certified by a secretary
or assistant secretary of such Loan Party to be true and correct as of the Closing Date; 
 (ii) such
certificates of resolutions or other action, incumbency certificates (including specimen signatures) and/or other certificates of Responsible Officers of each Loan Party as the Administrative Agent may require evidencing the identity, authority and
capacity of each Responsible Officer thereof authorized to act as a Responsible Officer in connection with this Agreement and the other Loan Documents to which such Loan Party is a party; and 
 (iii) certification from the state of organization or formation of each Loan Party stating that such Loan Party is in
“good standing” in such state. 
 (g) Perfection and Priority of Liens. Receipt by the
Administrative Agent of the following: 
 (i) (A) searches of Uniform Commercial Code filings in the
jurisdiction of formation of each Loan Party or where a filing would need to be made in order to perfect the Administrative Agent’s security interest in the Collateral, and copies of the financing

  

 66 

 
statements on file in such jurisdictions evidencing that no Liens exist other than Permitted Liens and (B) tax lien, judgment and pending litigation searches. 
 (ii) searches of ownership of, and Liens on, intellectual property of each Loan Party in the appropriate governmental
offices; 
 (iii) duly executed notices of grant of security interest in the form required by the Security
Agreement as are necessary, in the Administrative Agent’s sole discretion, to perfect the Administrative Agent’s security interest in the intellectual property of the Loan Parties; and 
 (iv) a completed and duly executed Collateral Questionnaire, dated on or before the Closing Date. 
 (h) Evidence of Insurance. Receipt by the Administrative Agent of copies of insurance policies or certificates of
insurance of the Loan Parties evidencing liability and casualty insurance meeting the requirements set forth in the Loan Documents, including, but not limited to, naming the Administrative Agent as additional insured (in the case of liability
insurance) or loss payee (in the case of hazard insurance) on behalf of the Lenders. 
 (i) Closing
Certificate. Receipt by the Administrative Agent and the Arrangers of a certificate signed by a Responsible Officer of the Borrower (A) certifying that the conditions specified in Sections 5.01(d), (e) and
(l) and Sections 5.02(a) and (b) have been satisfied as of the Closing Date, (B) certifying as to the Solvency of the Borrower and its Subsidiaries on a consolidated basis, after giving effect to the Transaction,
and (C) certifying and demonstrating that (1) Consolidated EBITDA for the 12-month period ended September 30, 2009 was not less than $100,000,000 and (2) the ratio of (I) Consolidated Funded Indebtedness as of the Closing
Date to (II) Consolidated EBITDA for the 12-month period ended as of September 30, 2009 is not greater than 2.25 to 1.00. For the purposes of the calculations required by this subsection (i), (x) Consolidated EBITDA and the ratio described
in clause (C)(2) shall each be calculated reflecting the Transaction (including the entering into of the Proleukin® Distribution Agreement) on a pro forma basis, and (y) Consolidated EBITDA and Consolidated Funded Indebtedness shall
otherwise be calculated in a manner consistent with the definitions thereof set forth in this Agreement, with such modifications or adjustments thereto for the purposes of this Section 5.01(i) as are reasonably acceptable to the
Arrangers and the Administrative Agent. 
 (j) Consummation of Proleukin® Transaction. The
Proleukin® Transaction shall have been consummated (or shall be consummated on the Closing Date) in accordance with the terms of the Proleukin® Transaction Documents and in compliance with all applicable Laws and regulatory approvals. The
Administrative Agent and the Arrangers shall have received and reviewed, prior to execution by the Borrower, the final draft of the Proleukin® Distribution Agreement and the other material Proleukin® Transaction Documents (it being
understood that certain immaterial information may be redacted in part from the exhibits thereto at the request of Novartis and in a manner acceptable to the Lenders), the terms of which shall be reasonably satisfactory to the Arrangers and the
Administrative Agent, and such agreement shall not have been altered, changed or supplemented in any material respect or any material conditions therein waived without the prior written consent of the Administrative Agent and the Arrangers. The
Administrative Agent and the Arrangers shall have received a copy, certified by a Responsible Officer of the Borrower as true and complete, of the Proleukin® Distribution Agreement and other material Proleukin® Transaction Documents as
originally executed and delivered (it being

  

 67 

 
understood that certain immaterial information may be redacted in part from the exhibits thereto at the request of Novartis and in a manner acceptable to the Lenders). 
 (k) Availability. After giving effect to the Transaction, including the Loans made hereunder on the Closing Date, the
Total Revolving Outstandings shall not exceed $25,000,000. 
 (l) Consents. All governmental, shareholder
and third party consents and approvals necessary in connection with the Transaction shall have been obtained; all such consents and approvals shall be in force and effect; and all applicable waiting periods shall have expired without any action
being taken by any authority that could restrain, prevent or impose any material adverse condition on the Transaction or that could seek or threaten any of the foregoing, and no Law shall be applicable which has, or could reasonably be expected to
have, such effect. 
 (m) Termination of Existing Credit Agreement. Receipt by the Administrative Agent of
evidence that the Existing Credit Agreement has been or concurrently with the Closing Date is being terminated and that provisions acceptable to the Administrative Agent shall have been made for the termination and release of all Liens securing
obligations under the Existing Credit Agreement. 
 (n) Fees. Receipt by the Administrative Agent, the
Arrangers and the Lenders of any fees required to be paid on or before the Closing Date. 
 (o) Attorney
Costs. Unless waived by the Administrative Agent, the Borrower shall have paid all Attorney Costs of the Administrative Agent, the Syndication Agent and the Arrangers to the extent invoiced prior to or on the Closing Date. 
 Without limiting the generality of the provisions of the last paragraph of Section 10.03, for purposes of determining compliance
with the conditions specified in this Section 5.01, each Lender that has signed this Agreement shall be deemed to have consented to, approved or accepted or to be satisfied with, or waived, each document or other matter required
thereunder to be consented to, approved by or acceptable or satisfactory to a Lender unless the Administrative Agent shall have received notice from such Lender prior to the proposed Closing Date specifying its objection thereto. 
  

	5.02	Conditions to all Credit Extensions. 

 The obligation of each Lender to honor any Request for Credit Extension (excluding a Loan Notice requesting a conversion of a Loan of one Type to the other Type, or a continuation of a Eurodollar Rate
Loan) is subject to the following conditions precedent: 
 (a) The representations and warranties of the Borrower
and each other Loan Party contained in Article VI or any other Loan Document shall be true and correct in all material respects on and as of the date of such Credit Extension, except to the extent that such representations and warranties
specifically refer to an earlier date, in which case they shall be true and correct in all material respects as of such earlier date, and except that for purposes of this Section 5.02, the representations and warranties contained in
subsections (a) and (b) of Section 6.05 shall be deemed to refer to the most recent statements furnished pursuant to clauses (a) and (b), respectively, of Section 7.01. 
 (b) No Default shall exist, or would result from such proposed Credit Extension or from the application of the proceeds
thereof. 
  

 68 

 (c) There shall not have been commenced against the Borrower or any
Subsidiary an involuntary case under any applicable Debtor Relief Law, now or hereafter in effect, or any case, proceeding or other action for the appointment of a receiver, liquidator, assignee, custodian, trustee, sequestrator (or similar
official) of such Person or for any substantial part of its Property or for the winding up or liquidation of its affairs, in each case that remains undismissed. 
 (d) The Administrative Agent and, if applicable, the L/C Issuer or the Swing Line Lender shall have received a Request for
Credit Extension in accordance with the requirements hereof. 
 (e) There shall not have occurred (A) any
payment default under the Proleukin® Distribution Agreement (unless the unpaid amount giving rise to such default shall have been paid or waived) nor (B) any other default under such agreement that has not been cured or waived, or any other
event that is continuing, which default or other event permits Novartis to terminate, or results in the termination of, the Proleukin® Distribution Agreement. 
 Each Request for Credit Extension (excluding a Loan Notice requesting a conversion of a Loan of one Type to the other Type, or a continuation of a Eurodollar Rate Loan) submitted by the Borrower shall be
deemed to be a representation and warranty that the conditions specified in Sections 5.02(a), (b) and (c) have been satisfied on and as of the date of the applicable Credit Extension. 
 ARTICLE VI 
 REPRESENTATIONS AND WARRANTIES 
 The Loan Parties represent and warrant to the Administrative Agent and the Lenders
that: 
  

	6.01	Existence, Qualification and Power. 

 Each Loan Party (a) is a corporation, partnership or limited liability company duly organized or formed, validly existing and in good standing under the Laws of the jurisdiction of its incorporation
or organization, (b) has all requisite power and authority and all requisite governmental licenses, authorizations, consents and approvals to (i) own its assets and carry on its business and (ii) execute, deliver and perform its
obligations under the Loan Documents to which it is a party, and (c) is duly qualified and is licensed and in good standing under the Laws of each jurisdiction where its ownership, lease or operation of properties or the conduct of its business
requires such qualification or license; except in each case referred to in clause (b)(i) or (c), to the extent that the failure to have any such power and authority, license, authorization, consent, approval or qualification, or to be so licensed or
in good standing, could not reasonably be expected to have a Material Adverse Effect. 
  

	6.02	Authorization; No Contravention. 

 The execution, delivery and performance by each Loan Party of each Loan Document to which such Person is party, have been duly authorized by all necessary corporate or other organizational action, and do not (a) contravene the terms of
any of such Person’s Organization Documents; (b) conflict with or result in any breach or contravention of, or the creation of any Lien under (i) any Contractual Obligation to which such Person is a party or (ii) any order,
injunction, writ or decree of any Governmental Authority or any arbitral award to which such Person or its Property is subject; or (c) violate any Law (including, without limitation, Regulation U or Regulation X issued by the FRB) except in
each case referred to in

  

 69 

 
clause (b) or (c), to the extent that such any such conflict, breach, contravention, creation of a Lien or violation could not reasonably be expected to have a Material Adverse Effect.

  

	6.03	Governmental Authorization; Other Consents. 

 No approval, consent, exemption, authorization, or other action by, or notice to, or filing with, any Governmental Authority or any other Person is necessary or required in connection with the execution,
delivery or performance by, or enforcement against, any Loan Party of this Agreement or any other Loan Document other than (i) those that have already been obtained and are in full force and effect and (ii) filings to perfect the Liens
created by the Collateral Documents. All applicable waiting periods in connection with the Transaction have expired without any action having been taken by any Governmental Authority restraining, preventing or imposing materially adverse conditions
upon the Transaction or the rights of the Loan Parties or their Subsidiaries freely to transfer or otherwise dispose of, or to create any Lien on, any properties now owned or hereafter acquired by any of them. The Proleukin® Transaction has been
consummated in accordance with the Proleukin® Transaction Documents and applicable Law. 
  

	6.04	Binding Effect. 

 This
Agreement and each other Loan Document has been duly executed and delivered by each Loan Party that is party thereto. This Agreement and each other Loan Document constitutes a legal, valid and binding obligation of each Loan Party that is party
thereto, enforceable against each such Loan Party in accordance with its terms, except as enforceability may be limited by Debtor Relief Laws or by other equitable remedies as a matter of judicial discretion. 
  

	6.05	Financial Statements; No Material Adverse Effect. 

 (a) The Audited Financial Statements (i) were prepared in accordance with GAAP consistently applied throughout the period covered thereby, except as otherwise expressly noted therein;
(ii) fairly present in all material respects the financial condition of the Borrower and its Subsidiaries as of the date thereof and their results of operations for the period covered thereby in accordance with GAAP consistently applied
throughout the period covered thereby, except as otherwise expressly noted therein; and (iii) show all material indebtedness and other liabilities, direct or contingent, of the Borrower and its Subsidiaries as of the date thereof, including
liabilities for Taxes, material commitments and Indebtedness required to be shown thereon in accordance with GAAP. 
 (b) The
Interim Financial Statements (i) were prepared in accordance with GAAP consistently applied throughout the period covered thereby, except as otherwise expressly noted therein; (ii) fairly present in all material respects the financial
condition of the Borrower and its Subsidiaries as of the date thereof and their results of operations for the period covered thereby, subject, in the case of clauses (i) and (ii), to the absence of footnotes and to year-end audit adjustments;
and (iii) show all material indebtedness and other liabilities, direct or contingent, of the Borrower and its Subsidiaries as of the date thereof, including liabilities for Taxes, material commitments and Indebtedness required to be shown
thereon in accordance with GAAP. 
 (c) The Pro Forma Financial Statements fairly present in all material respects (with respect
to the effect of the Proleukin® Transaction, based on assumptions derived from unaudited historical financial information provided by Novartis) the consolidated pro forma financial condition (giving effect to all elements of the Transaction to
be effected on or before the Closing Date) of the Borrower and its Subsidiaries as at September 30, 2009, and the consolidated pro forma results of operations of the Borrower and its Subsidiaries for the 12-month period ended on such date, all
in accordance with GAAP, subject to the absence of footnotes and to normal year-end audit adjustments. 
  

 70 

 (d) From the date of the Audited Financial Statements to and including the Closing Date,
there has been no receipt of an Extraordinary Receipt by the Borrower or any Subsidiary, no Disposition by the Borrower or any Subsidiary of any material part of the business or Property of the Borrower and its Subsidiaries, taken as a whole, and no
purchase or other acquisition by any of them of any business or Property (including any Equity Interests of any other Person) material in relation to the consolidated financial condition of the Borrower and its Subsidiaries, taken as a whole, in
each case, which is not reflected in the foregoing financial statements (including the Interim Financial Statements) or in the notes thereto or has not otherwise been disclosed in writing to the Lenders on or prior to the Closing Date. 

(e) The forecasts delivered pursuant to Section 5.01(c)(iv) were prepared in good faith on the basis of the assumptions
stated therein, which assumptions were reasonable in light of the conditions existing at the time of delivery of such forecasts, and represented, at the time of delivery, the Borrower’s good faith estimate of its future financial performance
during the period covered by such forecasts. The Administrative Agent, the L/C Issuer and the Lenders hereby acknowledge that forecasts and estimates of future financial performance are inherently uncertain and no assurances have been given, and no
representations or warranties have been made by any Loan Party, that the results reflected in the forecasts will be achieved. 
 (f) Since the date of the Audited Financial Statements there has been no event or circumstance, either individually or in the aggregate, that has had or could reasonably be expected to have a Material Adverse Effect. 
  

	6.06	Litigation. 

 There are no
actions, suits, proceedings, claims or disputes pending or, to the knowledge of the Responsible Officers of the Loan Parties, threatened in writing, at law, in equity, in arbitration or before any Governmental Authority, by or against a Loan Party
or any of its Subsidiaries or against any of their properties or revenues that (a) purport to affect or pertain to this Agreement or any other Loan Document, the Transaction, or any of the other transactions contemplated hereby or (b) if
determined adversely, could reasonably be expected to have a Material Adverse Effect. 
  

	6.07	No Default. 

 (a) No Loan
Party nor any Subsidiary is in default under or with respect to any Contractual Obligation that could reasonably be expected to have a Material Adverse Effect. 
 (b) No Default has occurred and is continuing. 
  

	6.08	Ownership of Property; Liens. 

 Each Loan Party and its Subsidiaries has good record and marketable title in fee simple to, or valid leasehold interests in, all real property necessary or used in the ordinary conduct of its business, except for such defects in title as
could not, individually or in the aggregate, reasonably be expected to have a Material Adverse Effect. The property of the Loan Parties and their Subsidiaries is subject to no Liens, other than Permitted Liens. 
  

 71 

	6.09	Environmental Compliance. 

 Except as could not reasonably be expected to have a Material Adverse Effect: 
 (a) To the knowledge of
the Responsible Officers of the Loan Parties, (i) all operations at the Facilities and each of the Facilities are in compliance with all applicable Environmental Laws, (ii) there is no violation of any Environmental Law with respect to the
Facilities or the Businesses, and (iii) there are no conditions relating to the Facilities or the Businesses that could give rise to liability under any applicable Environmental Laws. 
 (b) To the knowledge of the Responsible Officers of the Loan Parties, none of the Facilities contains, or has previously
contained, any Hazardous Materials at, on or under the Facilities in amounts or concentrations that constitute or constituted a violation of, or could give rise to liability under, Environmental Laws. 
 (c) No Loan Party nor any Subsidiary has received any written or to the knowledge of the Responsible Officers of the Loan
Parties, oral notice of, or inquiry from any Governmental Authority regarding, any violation, alleged violation, non-compliance, liability or potential liability regarding environmental matters or compliance with Environmental Laws with regard to
any of the Facilities or the Businesses. 
 (d) Hazardous Materials have not been transported or disposed of from
the Facilities, or generated, treated, stored or disposed of at, on or under any of the Facilities or any other location, in each case by or on behalf a Loan Party or any Subsidiary in violation of, or in a manner that would be reasonably likely to
give rise to liability under, any applicable Environmental Law. 
 (e) No judicial proceeding or governmental or
administrative action is pending or, to the knowledge of the Responsible Officers of the Loan Parties, threatened in writing, under any Environmental Law to which a Loan Party or any Subsidiary is or will be named as a party, nor are there any
consent decrees or other decrees, consent orders, administrative orders or other orders, or other administrative or judicial requirements outstanding under any Environmental Law with respect to a Loan Party, any Subsidiary, the Facilities or the
Businesses. 
 (f) To the knowledge of the Responsible Officers of the Loan Parties, there has been no release or
threat of release of Hazardous Materials at or from the Facilities, or arising from or related to the operations (including, without limitation, disposal) of any Loan Party or any Subsidiary in connection with the Facilities or otherwise in
connection with the Businesses, in violation of or in amounts or in a manner that could give rise to liability under Environmental Laws. 
  

	6.10	Insurance. 

 The
properties of the Loan Parties and their Subsidiaries are insured with financially sound and reputable insurance companies not, to the knowledge of the Responsible Officers of the Loan Parties, Affiliates of the Borrower, in such amounts, with such
deductibles and covering such risks as are customarily carried by companies engaged in similar businesses and owning similar properties in localities where the applicable Loan Party or the applicable Subsidiary operates. The insurance coverage of
the Loan Parties as in effect on the Closing Date is outlined as to carrier, policy number, expiration date, type, amount and deductibles on Schedule 6.10. 
  

	6.11	Taxes. 

 The Loan Parties
and their Subsidiaries have (a) filed all federal Tax returns and reports required to be filed, (b) filed or will file all material state and other material Tax returns and reports required to be

  

 72 

 
filed, and (c) paid all federal taxes and have paid all material state and other material taxes, assessments, fees and other governmental charges levied or imposed upon them or their
properties, income or assets otherwise due and payable, except those which are being contested in good faith by appropriate proceedings diligently conducted and for which adequate reserves have been provided in accordance with GAAP. To the knowledge
of the Responsible Officers of the Borrower, there is no proposed Tax assessment against a Loan Party or any Subsidiary that would, if made, have a Material Adverse Effect. No Loan Party nor any Subsidiary thereof is party to any Tax sharing
agreement. 
  

	6.12	ERISA Compliance. 

 (a)
Each Plan is in compliance in all material respects with the applicable provisions of ERISA, the Internal Revenue Code and other federal or state Laws. Each Plan that is intended to qualify under Section 401(a) of the Internal Revenue Code has
received a favorable determination letter from the IRS or an application for such a letter is currently being processed by the IRS with respect thereto and, to the knowledge of the Responsible Officers, nothing has occurred which would prevent, or
cause the loss of, such qualification. Each Loan Party and each ERISA Affiliate have made all required contributions to each Plan subject to Section 412, Section 430 or Section 431 of the Internal Revenue Code, and no application for
a funding waiver or an extension of any amortization period pursuant to Section 412, Section 430 or Section 431 of the Internal Revenue Code has been made with respect to any Plan. 
 (b) There are no pending or, to the knowledge of the Responsible Officers, threatened claims, actions or lawsuits, or action by any
Governmental Authority, with respect to any Plan that could be reasonably be expected to have a Material Adverse Effect. There has been no prohibited transaction or violation of the fiduciary responsibility rules with respect to any Plan that has
resulted or could reasonably be expected to result in a Material Adverse Effect. 
 (c) (i) No ERISA Event has occurred or
is reasonably expected to occur; (ii) the minimum required contribution (as defined in Section 430(a) of the Internal Revenue Code) has been made for each Pension Plan; (iii) no Loan Party or any ERISA Affiliate has incurred, or
reasonably expects to incur, any liability under Title IV of ERISA with respect to any Pension Plan (other than premiums due and not delinquent under Section 4007 of ERISA); (iv) no Loan Party or any ERISA Affiliate has incurred, or
reasonably expects to incur, any liability (and no event has occurred which, with the giving of notice under Section 4219 of ERISA, would result in such liability) under Sections 4201 or 4243 of ERISA with respect to a Multiemployer Plan; and
(v) no Loan Party or any ERISA Affiliate has engaged in a transaction that could be subject to Section 4069 or 4212(c) of ERISA. 
  

	6.13	Subsidiaries. 

 The
Borrower has no Subsidiaries as of the Closing Date. The outstanding Equity Interests of each Subsidiary of any Loan Party are validly issued, fully paid and non-assessable. 
  

	6.14	Margin Regulations; Investment Company Act. 

 (a) The Borrower is not engaged and will not engage, principally or as one of its important activities, in the business of purchasing or carrying margin stock (within the meaning of Regulation U issued by
the FRB), or extending credit for the purpose of purchasing or carrying margin stock. Following the application of the proceeds of each Borrowing or drawing under each Letter of Credit, not more than 25% of the value of the assets (either of the
Borrower only or of the Borrower and its Subsidiaries on a consolidated basis), subject to the provisions of Section 8.01 or Section 8.05 or subject to any restriction contained in any agreement or instrument between the
Borrower and any Lender or any Affiliate of any Lender relating to Indebtedness, will be margin stock. 
  

 73 

 (b) No Loan Party or any Subsidiary is or is required to be registered as an
“investment company” under the Investment Company Act of 1940, as amended. 
  

	6.15	Disclosure. 

 No report,
financial statement, certificate or other information furnished (whether in writing or orally) by or on behalf of any Loan Party to the Administrative Agent or any Lender in connection with the transactions contemplated hereby or delivered hereunder
or under any other Loan Document (in each case, as modified or supplemented by other information so furnished) contains any material misstatement of fact or omits to state any material fact necessary to make the statements therein, in the light of
the circumstances under which they were made, not misleading; provided that, with respect to projected financial information, the Loan Parties represent only that such information was prepared in good faith based upon assumptions believed by
them to be reasonable at the time. 
  

	6.16	Compliance with Laws and Material Contractual Obligations. 

 Each Loan Party and each Subsidiary is in compliance with the requirements of all Laws and all orders, writs, injunctions and decrees applicable to it or to its properties, and all Contractual
Obligations, except in such instances in which (a) such requirement of Law or order, writ, injunction or decree is being contested in good faith by appropriate proceedings diligently conducted or (b) the failure to comply therewith could
not reasonably be expected to have a Material Adverse Effect. 
  

	6.17	Intellectual Property; Licenses, Etc. 

 The Loan Parties and their Subsidiaries own, or possess the legal right to use, all of the trademarks, service marks, trade names, copyrights, patents, patent rights, franchises, licenses and other
intellectual property rights (collectively, “IP Rights”) that are reasonably necessary for the operation of their Businesses. Set forth on Schedule 6.17 is a list of all (a) trademarks, patents and copyrights registered
or pending registration with the United States Copyright Office or the United States Patent and Trademark Office and owned by a Loan Party as of the Closing Date and (b) all other material patents, trademarks and copyrights which a Loan Party
has the legal right to use pursuant to a license in favor of such Loan Party as of the Closing Date. Except for such claims and infringements that could not reasonably be expected to have a Material Adverse Effect, (a) no claim has been
asserted and is pending by any Person challenging or questioning the use of (i) any copyrights, patents or trademarks owned by a Loan Party or (ii) as of the Closing Date, to the Loan Parties’ knowledge, any copyrights, patents or
trademarks material to the business of the Loan Parties that are used by the Loan Parties pursuant to a license in favor of a Loan Party, or the validity or effectiveness of any such copyrights, patents or trademarks, and (b) to the knowledge
of the Responsible Officers of the Loan Parties, neither the use of any IP Rights by a Loan Party or any Subsidiary nor the licensing of such IP Rights by a Loan Party or any Subsidiary to another Person infringes on the rights of any Person. As of
the Closing Date, none of the copyrights, patents or trademarks owned by any of the Loan Parties is subject to any licensing agreement, franchise agreement or similar arrangement except as set forth on Schedule 6.17. 
  

	6.18	Solvency. 

 The Loan
Parties are Solvent on a consolidated basis. 
  

 74 

	6.19	Perfection of Security Interests in the Collateral. 

 The Collateral Documents create valid security interests in, and Liens on, the Collateral purported to be covered thereby, which security interests and Liens upon filing of all applicable financing
statements, filing of all applicable notices with the United States Copyright Office and United States Patent and Trademark Office and delivery of Collateral, as applicable, and except as otherwise contemplated or otherwise not required by the
Collateral Documents, will be perfected security interests and Liens, prior to all other Liens other than Permitted Liens. 
  

	6.20	Business Locations. 

 As
of the Closing Date, no Loan Party owns any real Property. Set forth on Schedule 6.20(a) is a list of all locations where any tangible personal property of any Loan Party (other than any tangible personal Property in the possession of a sales
representative of any Loan Party) is located as of the Closing Date. Set forth on Schedule 6.20(b) is the chief executive office, federal tax payer identification number and organizational identification number of each Loan Party as of the
Closing Date. The exact legal name and state of organization of each Loan Party as of the Closing Date is as set forth on the signature pages hereto. 
  

	6.21	Labor Matters. 

 There are
no collective bargaining agreements or Multiemployer Plans covering the employees of a Loan Party or any Subsidiary as of the Closing Date and no Loan Party nor any Subsidiary has suffered any strikes, walkouts, work stoppages or other material
labor difficulty within the last five (5) years prior to the Closing Date. Neither the business nor properties of any Loan Party are affected by any strikes, walkouts, work stoppages or other labor dispute that could reasonably be expected,
individually or in the aggregate, to have a Material Adverse Effect. 
 ARTICLE VII 
 AFFIRMATIVE COVENANTS 
 Until such time as the Obligations are Fully Satisfied, each Loan Party shall, and shall cause each Subsidiary to: 
  

	7.01	Financial Statements. 

 Deliver to the Administrative Agent for the Administrative Agent to deliver to each Lender, in form and detail reasonably satisfactory to the Administrative Agent: 
 (a) as soon as available, but in any event within ninety (90) days after the end of each fiscal year of the Borrower, a
consolidated balance sheet of (i) prior to giving effect to the Reorganization, the Borrower and its Subsidiaries and (ii) after giving effect to the Reorganization, Delaware Opco and its Subsidiaries, in either case as at the end of such
fiscal year, and the related consolidated statements of income or operations and cash flows for such fiscal year, setting forth in each case in comparative form the figures for the previous fiscal year, all in reasonable detail and prepared in
accordance with GAAP, audited and accompanied by a report and opinion of (i) any “Big Four” public accounting firm or (ii) any other independent, certified public accounting firm of nationally recognized standing reasonably
acceptable to the Required Lenders, which report and opinion shall be prepared in accordance with generally accepted auditing standards and shall not be subject to any “going concern” or like qualification or exception or any qualification
or exception as to the scope of such audit; and 
  

 75 

 (b) as soon as available, but in any event within forty-five (45) days
after the end of each of the first three (3) fiscal quarters of each fiscal year of the Borrower, a consolidated balance sheet of (i) prior to giving effect to the Reorganization, the Borrower and its Subsidiaries and (ii) after
giving effect to the Reorganization, Delaware Opco and its Subsidiaries, in either case as at the end of such fiscal quarter, and the related consolidated statements of income or operations and cash flows for such fiscal quarter and for the portion
of the Borrower’s fiscal year then ended, setting forth in each case in comparative form the figures for the corresponding fiscal quarter of the previous fiscal year and the corresponding portion of the previous fiscal year, all in reasonable
detail and certified by a Responsible Officer of the Borrower as fairly presenting in all material respects the financial condition, results of operations, shareholders’ equity and cash flows of the Borrower and its Subsidiaries or Delaware
Opco and its Subsidiaries, as applicable, in accordance with GAAP, subject only to year-end audit adjustments and the absence of footnotes. 
 As to any information contained in materials furnished pursuant to Section 7.02(f), the Borrower shall not be separately required to furnish such information under clause (a) or
(b) above, but the foregoing shall not be in derogation of the obligation of the Borrower to furnish the information and materials described in subsections (a) and (b) above at the times specified therein. 
  

	7.02	Certificates; Other Information. 

 Deliver to the Administrative Agent for the Administrative Agent to deliver to each Lender, in form and detail reasonably satisfactory to the Administrative Agent: 
 (a) concurrently with the delivery of the financial statements referred to in Section 7.01(a), a certificate of
its independent certified public accountants certifying such financial statements and stating that in making the examination necessary therefor no knowledge was obtained of any Event of Default under Section 8.11 or, if any such Event of
Default shall exist, stating the nature and status of such event; 
 (b) concurrently with the delivery of the
financial statements referred to in Sections 7.01(a) and (b), a duly completed Compliance Certificate signed by a Responsible Officer of the Borrower; 
 (c) at least thirty (30) days prior to the end of each fiscal year of the Borrower, beginning with the fiscal year
ending December 31, 2010, an annual budget of the Loan Parties and their Subsidiaries containing, among other things, financial information for each quarter of the next fiscal year; 
 (d) concurrently with the delivery of the financial statements referred to in Sections 7.01(a) and (b), a
certificate of a Responsible Officer of the Borrower containing information regarding the amount of all Dispositions, Debt Issuances, Extraordinary Receipts and Acquisitions that occurred during the period covered by such financial statements;

 (e) (i) promptly after any request by the Administrative Agent or any Lender, copies of any detailed
audit reports, management letters or recommendations submitted to the board of directors (or the audit committee of the board of directors) of a Loan Party by independent accountants in connection with the accounts or books of such Loan Party or any
Subsidiary, or any audit of any of them; and (ii) promptly after the furnishing thereof, copies of any notice received by a Loan Party or any Subsidiary that such Loan Party or Subsidiary is in default under

  

 76 

 
any Material Agreement or the Colal-Pred License Agreement, which copies are not otherwise required to be furnished to the Administrative Agent pursuant to Section 7.01 or any other
clause of this Section 7.02; 
 (f) promptly after the same are available (but in any event not later
than ten (10) Business Days after delivery), (i) copies of each annual report, proxy or financial statement sent to the stockholders of the Borrower (and, if the Reorganization has occurred, the stockholders of Delaware Parent and Delaware
Opco) and copies of all annual, regular, periodic and special reports and registration statements which the Borrower, Delaware Opco or Delaware Parent may file or be required to file with the SEC under Section 13 or 15(d) of the Securities
Exchange Act of 1934, as amended, or sent to a holder of any Indebtedness owed by a Loan Party or any Subsidiary in its capacity as such a holder and not otherwise required to be delivered to the Administrative Agent pursuant hereto and
(ii) upon the request of the Administrative Agent, all reports and written information to and from the United States Environmental Protection Agency, or any state or local agency responsible for environmental matters, the United States
Occupational Health and Safety Administration, or any state or local agency responsible for health and safety matters, or any successor agencies or authorities concerning environmental, health or safety matters; 
 (g) promptly, such additional information regarding the business, financial or corporate affairs of a Loan Party or any
Subsidiary, or compliance with the terms of the Loan Documents, as the Administrative Agent or any Lender may from time to time reasonably request; and 
 (h) concurrently with the delivery of the financial statements referred to in Section 7.01(a), a certificate of a Responsible Officer of the Borrower (i) listing (A) all
applications, if any, for Copyrights, Patents or Trademarks (each such term as defined in the Security Agreement) made since the date of the prior certificate (or, in the case of the first such certificate, the Closing Date), (B) all issuances
of registrations or letters on existing applications for Copyrights, Patents and Trademarks (each such term as defined in the Security Agreement) received since the date of the prior certificate (or, in the case of the first such certificate, the
Closing Date), (C) all Trademark Licenses, Copyright Licenses and Patent Licenses (each such term as defined in the Security Agreement) entered into since the date of the prior certificate (or, in the case of the first such certificate, the
Closing Date) and (D) each material Copyright, Trademark and Patent (each such term as defined in the Security Agreement) that has expired or become unenforceable since the date of the prior certificate (or, in the case of the first such
certificate, the Closing Date), and (ii) attaching the insurance binder or other evidence of insurance for any insurance coverage of a Loan Party or any Subsidiary that was renewed, replaced or modified during the period covered by such
financial statements. 
 Documents required to be delivered pursuant to Section 7.01(a) or (b) or
Section 7.02(f) (to the extent any such documents are included in materials otherwise filed with the SEC) may be delivered electronically and if so delivered, shall be deemed to have been delivered on the date (i) on which the
Borrower posts such documents, or provides a link thereto on the Borrower’s website on the Internet at the website address listed on Schedule 11.02; or (ii) on which such documents are posted on the Borrower’s behalf on
IntraLinks/IntraAgency or another relevant website, if any, to which each Lender and the Administrative Agent have access (whether a commercial, third-party website or whether sponsored by the Administrative Agent); provided that:
(A) the Borrower shall deliver paper copies of such documents to the Administrative Agent or any Lender that requests the Borrower to deliver such paper copies until a written request to cease delivering paper copies is given by the
Administrative Agent or such Lender and (B) the Borrower shall notify (which may be by facsimile or electronic mail) the

  

 77 

 
Administrative Agent and each Lender of the posting of any such documents and provide to the Administrative Agent by electronic mail electronic versions (i.e., soft copies) of such
documents. Notwithstanding anything contained herein, in every instance the Borrower shall be required to provide paper copies of the Compliance Certificates required by Section 7.02(b) to the Administrative Agent. Except for such
Compliance Certificates, the Administrative Agent shall have no obligation to request the delivery or to maintain copies of the documents referred to above, and in any event shall have no responsibility to monitor compliance by the Borrower with any
such request for delivery, and each Lender shall be solely responsible for requesting delivery to it or maintaining its copies of such documents. 
 The Borrower hereby acknowledges that (a) the Administrative Agent, the Syndication Agent and/or the Arrangers will make available to the Lenders and the L/C Issuer materials and/or information
provided by or on behalf of the Borrower hereunder (collectively, the “Borrower Materials”) by posting the Borrower Materials on IntraLinks or another similar electronic system (the “Platform”) and (b) certain of the
Lenders (each, a “Public Lender”) may have personnel who do not wish to receive material non-public information with respect to the Borrower or its Affiliates, or the respective securities of any of the foregoing, and who may be
engaged in investment and other market-related activities with respect to such Person’s securities. The Borrower hereby agrees that (w) all Borrower Materials that are to be made available to Public Lenders shall be clearly and
conspicuously marked “PUBLIC” which, at a minimum, shall mean that the word “PUBLIC” shall appear prominently on the first page thereof; (x) by marking Borrower Materials “PUBLIC,” the Borrower shall be deemed to
have authorized the Administrative Agent, the Syndication Agent, the Arrangers and the Lenders to treat such Borrower Materials as not containing any material non-public information with respect to the Borrower or its securities for purposes of
United States federal and state securities laws (provided, however, that to the extent such Borrower Materials constitute Information (as defined in Section 11.07), they shall be treated as set forth in
Section 11.07); (y) all Borrower Materials marked “PUBLIC” are permitted to be made available through a portion of the Platform designated as “Public Investor;” and (z) the Administrative Agent, the
Syndication Agent and the Arrangers shall be entitled to treat any Borrower Materials that are not marked “PUBLIC” as being suitable only for posting on a portion of the Platform not marked as “Public Investor.” Notwithstanding
the foregoing, the Borrower shall be under no obligation to mark any Borrower Materials “PUBLIC”. 
  

	7.03	Notices. 

 Promptly notify the
Administrative Agent, for further dissemination to the Lenders, of: 
 (a) The occurrence of any Default. 
 (b) Any matter that has resulted in a Material Adverse Effect, including, if applicable (i) breach or non-performance of, or any
default under, a Contractual Obligation of a Loan Party or any Subsidiary; (ii) any dispute, litigation, investigation, proceeding or suspension between a Loan Party or any Subsidiary and any Governmental Authority; or (iii) the
commencement of, or any material development in, any litigation or proceeding affecting a Loan Party or any Subsidiary, including pursuant to any applicable Environmental Laws. 
 (c) The occurrence of any ERISA Event. 
 (d) Any material change in accounting policies or financial reporting practices by a Loan Party or any Subsidiary, including any determination by the Borrower referred to in Section 2.10(b).

  

 78 

 Each notice pursuant to this Section 7.03(a) through (d) shall be
accompanied by a statement of a Responsible Officer of the Borrower setting forth details of the occurrence referred to therein and stating what action the Borrower has taken and proposes to take with respect thereto. 
  

	7.04	Payment of Obligations. 

 Pay and discharge as the same shall become due and payable, all its material obligations and liabilities, including (a) all material Tax liabilities, assessments and governmental charges or levies upon it or its properties or assets,
unless the same are being contested in good faith by appropriate proceedings diligently conducted and reserves reasonably believed by the Responsible Officers of the Borrower or such Subsidiary to be adequate and in accordance with GAAP are being
maintained by the applicable Loan Party or such Subsidiary; (b) all lawful claims which, if unpaid, would by Law become a Lien upon its property (other than any Permitted Lien); and (c) all Indebtedness, as and when due and payable, but
subject to any subordination provisions contained in any instrument or agreement evidencing such Indebtedness. 
  

	7.05	Preservation of Existence, Etc. 

 (a) Preserve, renew and maintain in full force and effect its legal existence and good standing under the Laws of the jurisdiction of its organization except in a transaction permitted by Section 8.04 or 8.05. 

(b) Take all reasonable action to maintain all rights, privileges, permits, licenses and franchises necessary or desirable in the normal
conduct of its business, except to the extent that the failure to do so could not reasonably be expected to have a Material Adverse Effect. 
 (c) Preserve or renew all of its material registered patents, trademarks, trade names and service marks, the non-preservation or non-renewal of which could reasonably be expected to have a Material
Adverse Effect. 
  

	7.06	Maintenance of Properties. 

 (a) Maintain, preserve and protect in a commercially reasonable manner all of its material properties and equipment necessary in the operation of its business in good working order and condition, ordinary wear and tear excepted. 

(b) Make all necessary repairs thereto and renewals and replacements thereof, except where the failure to do so could not reasonably be
expected to have a Material Adverse Effect. 
 (c) Use the standard of care typical in the industry in the operation and
maintenance of its facilities. 
  

	7.07	Maintenance of Insurance. 

 Maintain in full force and effect insurance (including worker’s compensation insurance, liability insurance, casualty insurance and business interruption insurance) with financially sound and reputable insurance companies not, to the
knowledge of the Responsible Officers of the Loan Parties, Affiliates of the Borrower, in such amounts, with such deductibles and covering such risks as are customarily carried by companies engaged in similar businesses and owning similar properties
in localities where the Borrower or the applicable Subsidiary operates. The Administrative Agent shall be named as Lender’s loss payee or mortgagee, as its interest may appear, and/or additional insured with respect to any such

  

 79 

 
insurance providing coverage in respect of any Collateral, and each provider of any such insurance shall agree, by endorsement upon the policy or policies issued by it or by independent
instruments furnished to the Administrative Agent, that it will give the Administrative Agent thirty (30) days (or ten (10) days, in the case of cancellation for non-payment of premiums) prior written notice before any such policy or
policies shall be canceled. The Borrower agrees that it shall provide prompt notice to the Administrative Agent of any material alteration or cancellation of any of the above-referenced insurance, together with a reasonably detailed description of
such alteration or cancellation. 
  

	7.08	Compliance with Laws. 

 Comply with the requirements of all Laws and all orders, writs, injunctions and decrees applicable to it or to its business or property, except in such instances in which (a) such requirement of Law or order, writ, injunction or decree
is being contested in good faith by appropriate proceedings diligently conducted; or (b) the failure to comply therewith could not reasonably be expected to have a Material Adverse Effect. 
  

	7.09	Books and Records. 

 (a)
Maintain proper books of record and account, in which full, true and correct entries in conformity in all material respects with GAAP consistently applied shall be made of all financial transactions and matters involving the assets and business of
such Loan Party or such Subsidiary, as the case may be. 
 (b) Maintain such books of record and account in material conformity
with all applicable requirements of any Governmental Authority having regulatory jurisdiction over such Loan Party or such Subsidiary, as the case may be. 
  

	7.10	Inspection Rights. 

 (a)
Permit representatives and independent contractors of (i) the Administrative Agent, at the reasonable expense of the Borrower no more than once in any calendar year, and (ii) each Lender, at such Lender’s expense no more than once in
any calendar year, to visit and inspect any of its properties, to examine its corporate, financial and operating records, and make copies thereof or abstracts therefrom, and to discuss its affairs, finances and accounts with its directors, officers,
and independent public accountants at such reasonable times during normal business hours, upon reasonable advance notice to the Borrower; provided, however, that when an Event of Default exists the Administrative Agent or any Lender
(or any of their respective representatives or independent contractors) may do any of the foregoing at the expense of the Borrower at any time during normal business hours upon advance notice of at least one (1) Business Day. 
 (b) If an Event of Default has occurred and is continuing, (i) permit the Administrative Agent, and its representatives, upon
reasonable advance notice to the Borrower, to conduct an audit of the Collateral at the expense of the Borrower and (ii) promptly deliver to the Administrative Agent (to the extent requested by the Administrative Agent in its sole discretion)
(A) asset appraisal reports with respect to the Collateral, and (B) a written audit of the accounts receivable, inventory, payables, controls and systems of the Loan Parties and their Subsidiaries. 
  

	7.11	Use of Proceeds. 

 Use the
proceeds of the Credit Extensions (a) on the Closing Date, to finance the Proleukin® Transaction, to refinance Indebtedness outstanding under the Existing Credit Agreement and to pay fees

  

 80 

 
and expenses incurred in connection with the Transaction and (b) thereafter, for working capital, capital expenditures and other lawful corporate purposes; provided that in no event
shall the proceeds of the Credit Extensions be used in contravention of any Law or of any Loan Document. 
  

	7.12	Additional Subsidiaries. 

 Within thirty (30) days after the acquisition or formation of any direct or indirect Subsidiary: 
 (a) notify the Administrative Agent thereof in writing, together with the (i) jurisdiction of formation, (ii) number of shares of each class of Equity Interests outstanding, (iii) number and percentage of outstanding shares
of each class owned (directly or indirectly) by a Loan Party or any Subsidiary and (iv) number and effect, if exercised, of all outstanding options, warrants, rights of conversion or purchase and all other similar rights with respect thereto;

 (b) if such Subsidiary is (A) a Domestic Subsidiary that is a Wholly Owned Subsidiary of a Loan Party
(and not a Subsidiary of a non-Guarantor Foreign Subsidiary), (B) a Domestic Subsidiary (other than a Subsidiary of a non-Guarantor Foreign Subsidiary) that is not a Wholly Owned Subsidiary but could become a Guarantor without violating the
terms of its organizational documents, or (C) a Foreign Subsidiary that the Borrower elects in its sole discretion to cause to become a Guarantor, cause such Person to (1) become a Guarantor by executing and delivering to the
Administrative Agent a Joinder Agreement or such other documents as the Administrative Agent shall deem appropriate for such purpose, and (2) if requested by the Administrative Agent, deliver to the Administrative Agent documents of the types
referred to in Sections 5.01(b), (f) and (g), all in form, content and scope reasonably satisfactory to the Administrative Agent; and 
 (c) if such Subsidiary is the first Subsidiary of the Borrower to be acquired or formed after the Closing Date, cause to be a
delivered to the Administrative Agent (i) a fully executed counterpart of the Pledge Agreement, properly executed by the Borrower and, if the applicable Subsidiary will be a Guarantor, such Subsidiary and (ii) an opinion of legal counsel
to the Borrower and, if applicable, such Subsidiary, dated as of the date of the Pledge Agreement and in form and substance reasonably satisfactory to the Administrative Agent. 
  

	7.13	ERISA Compliance. 

 Do,
and cause each of its ERISA Affiliates to do, each of the following: (a) maintain each Plan in compliance in all material respects with the applicable provisions of ERISA, the Internal Revenue Code and other federal or state Law; (b) cause
each Plan that is qualified under Section 401(a) of the Internal Revenue Code to maintain such qualification; and (c) make all required contributions to any Plan subject to Section 412, Section 430 or Section 431 of the
Internal Revenue Code. 
  

	7.14	Pledged Assets. 

 (a) Each
Loan Party will (i) cause all of its owned and leased real and personal Property other than Excluded Property to be subject at all times to first priority, perfected (other than deposit accounts and cash and except as otherwise contemplated or
otherwise not required by the Collateral Documents) and, in the case of real Property which is ground leased or owned, title insured Liens in favor of the Administrative Agent to secure the Obligations pursuant to the terms and conditions of the
Collateral Documents or, with respect to any such Property acquired subsequent to the Closing Date, such other additional security documents as the Administrative Agent shall reasonably request, subject in any case to Permitted Liens and
(ii) deliver such other documentation as the Administrative Agent may

  

 81 

 
reasonably request in connection with the foregoing, including, without limitation, appropriate UCC-1 financing statements, real estate title insurance policies, surveys, environmental reports,
landlord’s waivers, certified resolutions and other organizational and authorizing documents of such Person, favorable opinions of counsel to such Person (which shall cover, among other things, the legality, validity, binding effect and
enforceability of the documentation referred to above and the perfection of the Administrative Agent’s Liens thereunder) and other items of the types required to be delivered pursuant to Section 5.01(g), all in form, content and
scope reasonably satisfactory to the Administrative Agent. 
 (b) Each Loan Party will cause (i) 100% of the issued and
outstanding Equity Interests owned by it of (A) each Domestic Subsidiary (other than a Subsidiary of a non-Guarantor Foreign Subsidiary) and (B) each Foreign Subsidiary that the Borrower elects to cause to become a Guarantor pursuant to
Section 7.12, and (ii) sixty-five percent (65%) (or such greater percentage that, due to a change in applicable Law after the date hereof, (A) could not reasonably be expected to cause the undistributed earnings of such
First-Tier Foreign Subsidiary as determined for United States federal income Tax purposes to be treated as a deemed dividend to such First-Tier Foreign Subsidiary’s United States parent and (B) could not reasonably be expected to cause any
material adverse Tax consequences) of the issued and outstanding Equity Interests entitled to vote (within the meaning of Treas. Reg. Section 1.956-2(c)(2)) and one hundred percent (100%) of the issued and outstanding Equity Interests
owned by it that are not entitled to vote (within the meaning of Treas. Reg. Section 1.956-2(c)(2)) of each First-Tier Foreign Subsidiary to be subject at all times to a first priority, perfected Lien in favor of the Administrative Agent
pursuant to the terms and conditions of the Collateral Documents or such other security documents as the Administrative Agent shall reasonably request. In addition, with respect to any Foreign Subsidiary the Equity Interests of which are required to
be pledged hereunder, and without limitation of the foregoing, the Loan Parties shall cause to be delivered to the Administrative Agent (i) such local law security documents as the Administrative Agent shall reasonably request and deem
necessary for the purpose of effecting such Lien on the issued and outstanding Equity Interests of such Foreign Subsidiary that are required to be pledged hereunder and ensuring the validity and enforceability of such Lien under applicable local
law, and (ii) to the extent reasonably requested by the Administrative Agent, a customary legal opinion (taking into consideration, among other things, local customs regarding the issuance of legal opinions) covering the creation and perfection
of such Lien under such applicable local law. 
 (c) Notwithstanding anything to the contrary in this Section 7.14,
paragraphs (a) and (b) of this Section 7.14 shall not require the creation or perfection of a security interest in favor of the Administrative Agent or any holder of any Obligation in, or the obtaining of title insurance,
surveys or any other documents with respect to, any Property acquired after the Closing Date if and for so long as the Administrative Agent has determined in its sole discretion that the collateral value thereof is insufficient to justify the cost
of creating or perfecting such security interests in such Property or obtaining title insurance, surveys or such other documents in respect of such Property. 
  

	7.15	Landlord Consents; Etc. 

 (a) Upon the request of the Administrative Agent, the Loan Parties shall use commercially reasonable efforts to obtain and deliver to the Administrative Agent, in the case of any personal Property Collateral located at a premises not owned
by a Loan Party (other than leased office space), estoppel letters, consents and waivers from the landlords, warehousemen or bailees, as applicable, with respect to such personal Property in form and substance reasonably satisfactory to the
Administrative Agent. 
 (b) Upon the request of the Administrative Agent, the Borrower shall use commercially reasonable
efforts to file or cause to be filed such documents with the U.S. Patent and Trademark Office

  

 82 

 
as reasonably requested by the Administrative Agent so that the applicable records correctly reflect the Borrower’s ownership of all registered patents and trademarks (and applications
therefore). 
 ARTICLE VIII 
 NEGATIVE COVENANTS 
 Until such time as the Obligations are Fully Satisfied, no
Loan Party shall, nor shall it permit any Subsidiary to, directly or indirectly: 
  

	8.01	Liens. 

 Create, incur,
assume or suffer to exist any Lien upon any of its property, assets or revenues, whether now owned or hereafter acquired, other than the following: 
 (a) Liens pursuant to any Loan Document; 
 (b) Liens existing on
the Closing Date and listed on Schedule 8.01 and any renewals or extensions thereof, provided that (i) the property covered thereby is not changed, (ii) the amount secured or benefited thereby is not materially increased,
(iii) the direct or any contingent obligor with respect thereto is not changed, and (iv) any renewal or extension of the obligations secured or benefited thereby is permitted by Section 8.03(b); 
 (c) Liens (other than Liens imposed under ERISA) for taxes, assessments or governmental charges or levies not yet due or
which are being contested in good faith and by appropriate proceedings diligently conducted, if adequate reserves with respect thereto are maintained on the books of the applicable Person in accordance with GAAP; 
 (d) statutory Liens of landlords and Liens of carriers, warehousemen, mechanics, materialmen and suppliers and other Liens
imposed by Law or pursuant to customary reservations or retentions of title arising in the ordinary course of business, provided that such Liens secure only amounts not yet due and payable or, if due and payable, no action (other than the
filing of such Lien) has been taken to enforce the same or the same are being contested in good faith by appropriate proceedings for which adequate reserves determined in accordance with GAAP have been established; 
 (e) pledges or deposits in the ordinary course of business in connection with workers’ compensation, unemployment
insurance and other social security legislation, other than any Lien imposed by ERISA; 
 (f) deposits to secure
the performance of bids, trade contracts and leases (other than Indebtedness), statutory obligations, surety bonds (other than bonds related to judgments or litigation), performance bonds and other obligations of a like nature incurred in the
ordinary course of business; 
 (g) easements, rights-of-way, restrictions and other similar encumbrances
affecting real property which, in the aggregate, are not substantial in amount, and which do not in any case materially detract from the value of the property subject thereto or materially interfere with the ordinary conduct of the business of the
applicable Person; 
  

 83 

 (h) Liens securing judgments for the payment of money (or appeal or other
surety bonds relating to such judgments) not constituting an Event of Default under Section 9.01(i); 
 (i) Liens securing Indebtedness permitted under Section 8.03(e); provided that (i) such Liens do not at any time encumber any Property other than the Property financed by such Indebtedness, (ii) the Indebtedness
secured thereby does not exceed the cost or fair market value, whichever is lower, of the Property being acquired on the date of acquisition and (iii) such Liens attach to such Property concurrently with or within ninety (90) days after
the acquisition thereof; 
 (j) licenses, leases or subleases granted to others either in the ordinary course of
business not interfering in any material respect with the business of the Loan Parties and their Subsidiaries or otherwise not prohibited hereunder; 
 (k) any interest of title of a lessor or a licensor (including any direct or indirect lessor or licensor of Property to a Loan Party or a Subsidiary (as lessee or licensee)) (or any secured creditor of
any such lessor or licensor) under, and Liens arising from UCC financing statements (or equivalent filings, registrations or agreements in foreign jurisdictions) relating to, leases and/or licenses permitted by this Agreement; 
 (l) Liens deemed to exist in connection with Investments in repurchase agreements permitted under Section 8.02;

 (m) normal and customary rights of setoff upon deposits of cash in favor of banks or other depository
institutions; 
 (n) Liens of a collection bank arising under Section 4-210 of the Uniform Commercial Code
on items in the course of collection; 
 (o) Liens of sellers of goods to a Loan Party and any of its
Subsidiaries arising under Article II of the Uniform Commercial Code or similar provisions of applicable Law in the ordinary course of business, covering only the goods sold and securing only the unpaid purchase price for such goods and related
expenses; 
 (p) Liens consisting of or incurred pursuant to an agreement to sell, transfer, lease or dispose of
any Property in a sale, lease, transfer or other disposition, solely to the extent such sale, lease, transfer or other disposition would have been permitted on the date of the creation of such Lien; 
 (q) with respect to any Property that is the subject of or used, developed or created by or for the benefit of a Loan Party
or any of its Subsidiaries in connection with the Entocort® EC Distribution Agreement, the Proleukin® Distribution Agreement, the Rosetta License Agreement, the Colal-Pred License Agreement, the 1996 License Agreement, the Proleukin®
Supply Agreement, the Lotronex® Supply Agreement or any other similar intellectual property or product license agreement or supply or distribution agreement entered into by a Loan Party or any Subsidiary in connection with a transaction
otherwise permitted hereunder, respectively, Liens on such Property arising under or granted pursuant to the applicable foregoing agreement, respectively; and 
 (r) Liens, if any, in favor of the Administrative Agent, for the benefit of the L/C Issuer, the Swing Line Lender and/or the
Lenders arising under agreements or arrangements to cash collateralize or otherwise secure the obligations of a Defaulting Lender to fund risk participations hereunder; 
  

 84 

 (s) Liens securing Indebtedness permitted under Section 8.03(h),
so long as such Liens attach only to the insurance policies with respect to which such Indebtedness is incurred, the proceeds thereof, or deposits made as security for the obligations thereunder; and 
 (t) additional Liens not otherwise permitted by this Section 8.01 and not securing Indebtedness; provided
that neither (i) the aggregate outstanding amount of the applicable obligations secured thereby nor (ii) the aggregate book value (determined, in the case of each such Lien, as of the date such Lien is incurred) of the assets subject
thereto exceeds $1,000,000. 
 Notwithstanding anything to the contrary in this Agreement, no Loan Party shall, nor shall it
permit any Subsidiary to, directly or indirectly, create, incur, assume or suffer to exist any Lien (other than Liens described in clauses (c), (h), (j), (k) and (q) above) upon the Proleukin® Distribution Agreement, the Entocort®
EC Distribution Agreement and/or any rights of the Borrower under either such document other than Liens in favor of the Administrative Agent (for the benefit of the Secured Parties). 
  

	8.02	Investments. 

 Make any
Investments, except: 
 (a) Investments held by such Loan Party or such Subsidiary in the form of cash or Cash
Equivalents; 
 (b) Investments existing as of the Closing Date and set forth in Schedule 8.02(b);

 (c) Investments made in compliance with the investment policy identified in Schedule 8.02(c) (including
any Investments existing on the Closing Date made pursuant to such investment policy); 
 (d) (i)
Investments in any Person that is a Loan Party and (ii) Investments consisting of loans to Subsidiaries that are not Loan Parties, in the case of this clause (ii), in an aggregate principal amount not to exceed $7,500,000 at any time
outstanding; 
 (e) Investments consisting of extensions of credit in the nature of accounts receivable or notes
receivable arising from the grant of trade credit in the ordinary course of business, and Investments received in satisfaction or partial satisfaction thereof from financially troubled account debtors to the extent reasonably necessary in order to
prevent or limit loss; 
 (f) Guarantees permitted by Section 8.03; 
 (g) (i) Permitted Acquisitions and (ii) Investments consisting of loans or capital contributions by a Loan Party to
any First-Tier Foreign Subsidiary the proceeds of which will be used by such First-Tier Foreign Subsidiary to fund a Permitted Acquisition; 
 (h) Investments by the Loan Parties or any of their Subsidiaries consisting of advances or loans to directors, officers or employees in an aggregate principal amount not to exceed $500,000 in the
aggregate at any time outstanding; provided, that all such advances shall be in compliance with all Laws; 
  

 85 

 (i) Investments made by a Loan Party or any of its Subsidiaries in
connection with its employee deferred compensation plans; 
 (j) the Proleukin® Transaction on the Closing
Date; 
 (k) promissory notes and other non-cash consideration received by a Loan Party or any of its
Subsidiaries in connection with Dispositions and any other sale, transfer or other disposition of any Property permitted hereunder; 
 (l) Investments (other than Acquisitions) consisting of the purchase or other acquisition by a Loan Party or any of its Subsidiaries of less than 50% of the issued and outstanding Equity Interests of
another Person in an amount not to exceed 7,500,000 in the aggregate during the term of this Agreement; and 
 (m) additional Investments not otherwise permitted in the foregoing clauses in an amount not to exceed $7,500,000 in the aggregate at any time outstanding. 
  

	8.03	Indebtedness. 

 Create,
incur, assume or suffer to exist any Indebtedness, except: 
 (a) Indebtedness under the Loan Documents;

 (b) Indebtedness of the Borrower existing on the Closing Date and set forth in Schedule 8.03 (and
renewals, refinancings and extensions thereof on terms and conditions not materially less favorable to the applicable debtor(s)); 
 (c) intercompany Indebtedness permitted under Section 8.02(d); 
 (d) obligations (contingent or otherwise) of a Loan Party or any Subsidiary existing or arising under any Swap Contract, provided that (i) such obligations are (or were) entered into by such Person in the ordinary course of
business for the purpose of directly mitigating risks associated with liabilities, commitments, investments, assets, or property held or reasonably anticipated by such Person, or changes in the value of securities issued by such Person, and not for
purposes of speculation or taking a “market view;” and (ii) such Swap Contract does not contain any provision exonerating the non-defaulting party from its obligation to make payments on outstanding transactions to the defaulting
party; 
 (e) purchase money Indebtedness (including obligations in respect of Capital Leases or Synthetic
Leases) hereafter incurred by a Loan Party or any of its Subsidiaries to finance the purchase of fixed assets, and renewals, refinancings and extensions thereof, provided that (i) the total of all such Indebtedness for all such Persons
taken together shall not exceed an aggregate principal amount of $5,000,000 at any one time outstanding; (ii) such Indebtedness when incurred shall not exceed the purchase price of the asset(s) financed; (iii) no such Indebtedness shall be
refinanced for a principal amount in excess of the principal balance outstanding thereon at the time of such refinancing; 
 (f) Indebtedness that may exist or may be deemed to exist under the Lotronex® Acquisition Documents, the Entocort® EC Distribution Agreement, the Proleukin® Transaction Documents, the 1996
License Agreement and any other agreements providing for

  

 86 

 
indemnification, purchase price adjustments and similar obligations (including Earn-Out Obligations) in connection with the lease, license, purchase or sale of assets effected in accordance with
the requirements of this Agreement; 
 (g) to the extent constituting Indebtedness, agreements to finance the
deferred payment of premiums owing by a Loan Party or any of its Subsidiaries under any insurance policies required hereunder or under the other Loan Documents or obtained in the ordinary course of business; 
 (h) (A) to the extent constituting Indebtedness, obligations under Cash Management Agreements and (B) Indebtedness
incurred by a Loan Party or any of its Subsidiaries in respect of netting services, overdraft protections and similar arrangements in each case in connection with cash management or deposit accounts. 
 (i) other unsecured Indebtedness of the Loan Parties and their Subsidiaries in an aggregate principal amount for all such
Indebtedness not to exceed $7,500,000 at any one time outstanding; provided, that (i) no Default or Event of Default exists prior to or immediately after giving effect to the incurrence of such Indebtedness and (ii) if such
Indebtedness results from seller financing, such Indebtedness is not evidenced by a demand note but rather has a stated maturity; and 
 (j) Guarantees with respect to Indebtedness permitted under clauses (a) through (i) of this Section 8.03. 
  

	8.04	Fundamental Changes. 

 Merge, dissolve, liquidate, consolidate with or into another Person, or Dispose of (whether in one transaction or in a series of transactions) all or substantially all of its assets (whether now owned or hereafter acquired) to or in favor
of any Person; provided that, notwithstanding the foregoing provisions of this Section 8.04 but subject to the terms of Sections 7.12 and 7.14, (a) the Borrower may merge or consolidate with any Subsidiary,
provided that the Borrower shall be the continuing or surviving corporation, (b) Delaware Opco may merge or consolidate with any Subsidiary other than the Borrower, provided that Delaware Opco shall be the continuing or surviving
corporation, (c) subject to the foregoing clauses (a) and (b), any Loan Party may merge or consolidate with any other Loan Party, (c) any Foreign Subsidiary may be merged or consolidated with or into any Loan Party provided that such
Loan Party shall be the continuing or surviving Person, (d) any Foreign Subsidiary may be merged or consolidated with or into any other Foreign Subsidiary; (e) any Subsidiary of a Loan Party may merge with any Person that is not a Loan
Party in connection with a Permitted Acquisition provided that, if such Permitted Acquisition involves the Borrower or Delaware Opco, the Borrower or Delaware Opco, as applicable, shall be the continuing or surviving corporation, (f) any
Loan Party may Dispose of any or all of its Property (upon voluntary liquidation or otherwise) to any other Loan Party, and (g) the Borrower may consummate the Reorganization pursuant to and in accordance with the following paragraph of this
Section 8.04. 
 Notwithstanding the foregoing, but subject to the following provisions of this paragraph, the
Borrower will be permitted to effect an internal reorganization (the “Reorganization”) that will result in the Borrower becoming a Subsidiary of a Delaware corporation and that will be accomplished as follows: 
  

	 	(a)	 The Borrower will create or acquire a new, direct Wholly Owned Subsidiary incorporated in the State of Delaware (“Delaware Parent”),
and Delaware Parent will in turn will create a new, direct Wholly Owned Subsidiary incorporated in the State of Delaware

  

 87 

	 	 
(“Delaware Opco”), neither of which will, immediately prior to the consummation of the Reorganization, have outstanding any Indebtedness or other material liabilities;

  

	 	(b)	Delaware Opco will create a new, direct Wholly Owned Subsidiary incorporated in the State of California (“MergerCo”) that will not, immediately prior
to the consummation of the Reorganization, have outstanding any Indebtedness or other material liabilities; 

  

	 	(c)	the Borrower will merge with and into MergerCo, with the Borrower being the surviving corporation of such merger and after giving effect to such merger, a direct,
Wholly Owned Subsidiary of Delaware Opco; and 

  

	 	(d)	immediately after the consummation of the Reorganization, the management and controlling ownership of Delaware Parent will be substantially similar to that of the
Borrower immediately prior to consummation of the Reorganization. 

 Notwithstanding anything to the contrary
contained herein, the Lenders hereby agree that the Borrower shall be permitted to consummate the Reorganization so long as the consummation of the Reorganization shall not result in a material and adverse impact to the interests of the
Administrative Agent and/or the Lenders under this Agreement and the other Loan Documents or otherwise result in a Material Adverse Effect. The Loan Parties hereby agree (i) to provide the Administrative Agent and the Lenders with at least
thirty (30) days advance written notice of the Reorganization and such additional information and documents related to the Reorganization as may be reasonably requested by the Administrative Agent and/or any Lender and (ii) to execute and
deliver (or to cause to be executed and delivered) prior to or concurrently with the consummation of the Reorganization such appropriate amendments, corporate authority documents and other supporting documents to or under this Agreement or the other
Loan Documents evidencing any changes made necessary by the consummation of the Reorganization. In addition, the Loan Parties agree that concurrently with the consummation of the Reorganization, Delaware Opco will (1) become a Guarantor
hereunder by executing and delivering to the Administrative Agent a Joinder Agreement or such other documents as the Administrative Agent shall reasonably deem appropriate for such purpose and, if requested by the Administrative Agent, deliver to
the Administrative Agent documents of the types referred to in Section 5.01(b), (f) and (g), all in form, content and scope reasonably acceptable to the Administrative Agent, and (2) subject to any applicable
limitations set forth in Section 7.14 and/or the Collateral Documents, will enter into or become a party to the Pledge Agreement and cause all of its owned and leased real and personal Property to be subject to a first priority,
perfected lien in favor of the Administrative Agent to secure the Obligations (including without limitation 100% of the issued and outstanding Equity Interests of the Borrower owned by Delaware Opco after giving effect to the Reorganization). The
Borrower acknowledges that the agreement of the Lenders evidenced in this paragraph is given in reliance upon the foregoing conditions and agreements and shall be deemed revoked if any such condition or agreement is breached. 
  

	8.05	Dispositions. 

 Make any
Disposition unless (a) the consideration paid in connection therewith shall be cash or Cash Equivalents paid contemporaneously with consummation of the transaction and shall be in an amount not less than the fair market value of the Property
disposed of, (b) if such transaction is a Sale and Leaseback Transaction, such transaction is not prohibited by the terms of Section 8.16, (c) such transaction does not involve the sale or other disposition of a minority equity
interest in any Subsidiary, (d) such transaction does not involve a sale or other disposition of receivables other than receivables owned by or attributable to other Property concurrently being disposed of in a transaction otherwise permitted
under this Section 8.05 and (e) the aggregate fair market value of all the assets sold or

  

 88 

 
otherwise disposed of by the Loan Parties and their Subsidiaries in all such transactions during the term of this Agreement shall not exceed 10% of Consolidated Total Assets at the time of any
such Disposition. 
  

	8.06	Restricted Payments. 

 Declare or make, directly or indirectly, any Restricted Payment, or incur any obligation (contingent or otherwise) to do so, except that: 
 (a) (i) each Subsidiary may make Restricted Payments (directly or indirectly) to any Loan Party or to any other Person that owns a direct Equity Interest in such Subsidiary, ratably according to
their respective holdings of the type of Equity Interest in respect of which such Restricted Payment is being made; 
 (b) each Loan Party and each Subsidiary may declare and make dividend payments or other distributions payable solely in the Equity Interests of such Person; 
 (c) (i) prior to the Reorganization, the Borrower may make cash payments to its shareholders and (ii) after the
Reorganization, Delaware Opco may make cash payments to Delaware Parent; provided that (A) the aggregate amount of all such payments made in reliance on this Section 8.06(c) shall not exceed $500,000 during the term of this
Agreement and (b) such payments are not dividend payments or similar type distributions; 
 (d) if
(i) the Reorganization shall have occurred and Delaware Opco and the Borrower shall have become Wholly Owned Subsidiaries of Delaware Parent and (ii) Delaware Parent and its Subsidiaries file a consolidated tax return, Delaware Opco may
declare and pay cash dividends to Delaware Parent not to exceed an amount necessary to permit Delaware Parent to pay the direct tax liabilities of Delaware Parent attributable to the net income or gains of Delaware Opco and its Subsidiaries with
respect to such tax year; and 
 (e) so long as no Event of Default shall have occurred and be continuing or
would result therefrom, the Borrower may (or, if the Reorganization has occurred, Delaware Opco may make Restricted Payments to Delaware Parent for the purpose of enabling Delaware Parent to) purchase Equity Interests from present or former
officers, directors and employees of Delaware Parent, any Loan Party or any Subsidiary of a Loan Party (or the estate, heirs, family members, spouse or former spouse of any of the foregoing) pursuant to the terms of any incentive, benefit,
compensation, employee or restricted equity interests purchase plan, equity option plan or other employee benefit or equity based compensation plan established by Delaware Parent, any Loan Party or any Subsidiary, as applicable; provided that
the aggregate amount of all such Restricted Payments made in reliance on this clause (e) shall not exceed $1,000,000 in any fiscal year. 
  

	8.07	Change in Nature of Business. 

 Engage in any material line of business substantially different from those lines of business conducted by the Borrower and its Subsidiaries on the Closing Date or any business substantially related or incidental thereto. 
  

	8.08	Transactions with Affiliates and Insiders. 

 Enter into or permit to exist any transaction or series of transactions with any officer or director of such Person or with any Person known to be an Affiliate of such Person other than (a) advances
of working capital to any Loan Party, (b) transfers of cash and assets to any Loan Party and any other

  

 89 

 
transactions among the Loan Parties, (c) intercompany transactions expressly permitted by Section 8.02, Section 8.03, Section 8.04,
Section 8.05 or Section 8.06, (d) normal and reasonable compensation and reimbursement of expenses of officers and directors and (e) except as otherwise specifically limited in this Agreement, other transactions
which are entered into on terms and conditions substantially as favorable to such Person as would be obtainable by it in a comparable arms-length transaction with a Person other than an officer, director or Affiliate. 
  

	8.09	Burdensome Agreements. 

 (a) Enter into, or permit to exist, any Contractual Obligation that encumbers or restricts the ability of any such Person to (i) pay dividends or make any other distributions to any Loan Party on its Equity Interests or with respect to
any other interest or participation in, or measured by, its profits, (ii) pay any Indebtedness or other obligation owed to any Loan Party, (iii) make loans or advances to any Loan Party, (iv) sell, lease or transfer any of its
Property to any Loan Party, (v) pledge its Property pursuant to the Loan Documents or any renewals, refinancings, exchanges, refundings or extension thereof (provided that the Loan Parties may enter into and permit to exist Contractual
Obligations that contain customary “no assignment” provisions) or (vi) act as a Loan Party pursuant to the Loan Documents or any renewals, refinancings, exchanges, refundings or extension thereof, except (in respect of any of the
matters referred to in clauses (i)-(v) above) for (1) this Agreement and the other Loan Documents, (2) any document or instrument governing Indebtedness incurred pursuant to Section 8.03(e), provided that any such
restriction contained therein relates only to the asset or assets constructed or acquired in connection therewith, (3) any Permitted Lien or any document or instrument governing any Permitted Lien, provided that any such restriction
contained therein relates only to the asset or assets subject to such Permitted Lien, (4) customary restrictions and conditions contained in any agreement relating to the sale of any Property permitted under Section 8.05 pending the
consummation of such sale, (5) the Lotronex® Acquisition Documents, (6) the Proleukin® Transaction Documents, (7) customary provisions restricting assignment or transfer of any license for intellectual property or in any other
agreement entered into not otherwise in violation of this Agreement and (8) exclusivity provisions with respect to licenses granted by any Loan Party or similar rights restricting the ability of the Loan Parties to use, transfer, assign or
license the rights subject to such license. 
 (b) Enter into, or permit to exist, any Contractual Obligation that prohibits or
otherwise restricts the existence of any Lien upon any of its Property in favor of the Administrative Agent (for the benefit of the Lenders) for the purpose of securing the Obligations, whether now owned or hereafter acquired, or requiring the grant
of any security for any obligation if such Property is given as security for the Obligations, except (i) any document or instrument governing Indebtedness incurred pursuant to Section 8.03(e), provided that any such
restriction contained therein relates only to the Property constructed or acquired in connection therewith, (ii) in connection with any Permitted Lien or any document or instrument governing any Permitted Lien, provided that any such
restriction contained therein relates only to the Property subject to such Permitted Lien, (iii) pursuant to customary restrictions and conditions contained in any agreement relating to the sale of any Property permitted under
Section 8.05, pending the consummation of such sale, (iv) Lotronex® Acquisition Documents, (v) the Proleukin® Transaction Documents, (vi) customary provisions restricting assignment or transfer of any license for
intellectual property or in any other agreement entered into not otherwise in violation of this Agreement and (vii) exclusivity provisions with respect to licenses granted by any Loan Party or similar rights restricting the ability of the Loan
Parties to use, transfer, assign or license the rights subject to such license. 
  

 90 

	8.10	Use of Proceeds. 

 Use the
proceeds of any Credit Extension, whether directly or indirectly, and whether immediately, incidentally or ultimately, to purchase or carry margin stock (within the meaning of Regulation U of the FRB) or to extend credit to others for the
purpose of purchasing or carrying margin stock or to refund indebtedness originally incurred for such purpose. 
  

	8.11	Financial Covenants. 

 (a)
Consolidated Leverage Ratio. Permit the Consolidated Leverage Ratio as of the end of any fiscal quarter of the Borrower (beginning with the fiscal quarter ending March 31, 2010) to be greater than 2.50:1.00. 
 (b) Consolidated Fixed Charge Coverage Ratio. Permit the Consolidated Fixed Charge Coverage Ratio as of the end of any fiscal quarter
of the Borrower (beginning with the fiscal quarter ending March 31, 2010) to be less than the ratio set forth below opposite such fiscal quarter: 
  

							
	Fiscal Quarter Ending:	  	Minimum
Coverage Ratio:	  	Fixed	  	Charge
				
	 March 31, 2010 through December 31, 2010
	  	1.75 to 1.00	  		  	
				
	 March 31, 2011
	  	1.50 to 1.00	  		  	
				
	 June 30, 2011 through December 31, 2012
	  	1.25 to 1.00	  		  	
				
	 March 31, 2013
	  	1.50 to 1.00	  		  	
				
	 June 30, 2013 and each fiscal quarter thereafter
	  	1.75 to 1.00	  		  	

  

	8.12	Capital Expenditures. 

 Permit Consolidated Capital Expenditures in any fiscal year, commencing with the fiscal year ending December 31, 2009, to exceed the sum of (a) $8,000,000 plus (b) any unused amount available for Consolidated Capital
Expenditures under this Section 8.12 for the immediately preceding fiscal year (excluding any carry forward available from any prior fiscal year). 
  

 91 

	8.13	Prepayment of Other Indebtedness, Etc. 

 (a) Amend or modify any of the terms of any Indebtedness of the Borrower existing on the Closing Date (excluding Indebtedness arising under the Loan Documents) if such amendment or modification would
(i) add or change any terms in a manner materially adverse to the Loan Parties or any Subsidiary or (ii) shorten the final maturity or average life to maturity or require any payment to be made sooner than originally scheduled or increase
the interest rate applicable thereto. 
 (b) Make (or give any notice with respect thereto) any voluntary or optional payment,
prepayment, redemption or acquisition for value of (including without limitation, by way of depositing money or securities with the trustee with respect thereto before due for the purpose of paying when due), refund, refinance or exchange of
(i) if an Event of Default shall have occurred and be continuing, any Indebtedness of a Loan Party or any Subsidiary (other than Indebtedness arising under the Loan Documents) or (ii) the Existing Preferred Stock (other than in exchange
for Equity Interests of the Delaware Parent in connection with the Reorganization). 
 (c) Amend or modify any of the terms of
the Entocort® EC Distribution Agreement, the Proleukin® Distribution Agreement, the Rosetta License Agreement, the Colal-Pred® License Agreement and/or the 1996 License Agreement, in each case if such amendment or modification would add
or change any terms in a manner materially adverse to the Borrower, any Subsidiary or any Lender. 
 (d) Make any Extension
Payment. 
  

	8.14	Organization Documents; Fiscal Year; Legal Name, State of Formation and Form of Entity. 

 (a) Amend, modify or change its Organization Documents in a manner materially adverse to the Lenders. 
 (b) Change its fiscal year. 
 (c) Without providing ten (10) days prior written notice to the Administrative Agent, change its name, state of formation or form of organization. 
 provided, however, that this Section 8.14 shall not be construed to prohibit the consummation of a Reorganization permitted
pursuant to Section 8.04 hereof. 
  

	8.15	Ownership of Subsidiaries. 

 Notwithstanding any other provisions of this Agreement to the contrary, (a) permit any Subsidiary of the Borrower to issue or have outstanding any shares of preferred Equity Interests, (b) following the consummation of the
Reorganization, permit the Borrower to issue or have outstanding any shares of preferred Equity Interests, (c) create, incur, assume or suffer to exist any Lien on any Equity Interests of any Subsidiary of the Borrower owned directly or
indirectly by the Borrower, except for Permitted Liens and (d) following consummation of the Reorganization, create, incur, assume or suffer to exist any Lien on any Equity Interests of the Borrower or any Subsidiary of Delaware Opco owned
directly or indirectly by Delaware Opco, except for Permitted Liens. 
  

	8.16	Sale Leasebacks. 

 Enter
into any Sale and Leaseback Transaction. 
  

 92 

 ARTICLE IX 
 EVENTS OF DEFAULT AND REMEDIES 
  

	9.01	Events of Default. 

 Any
of the following shall constitute an Event of Default: 
 (a) Non-Payment. The Borrower or any other Loan
Party fails to pay (i) when and as required to be paid herein, any amount of principal of any Loan or any L/C Obligation, or (ii) within three (3) days after the same becomes due, any interest on any Loan or on any L/C Obligation, or
any commitment fee or other fee due hereunder, or (iii) within five (5) days after the same becomes due, any other amount payable hereunder or under any other Loan Document; or 
 (b) Specific Covenants. Any Loan Party fails to perform or observe any term, covenant or agreement contained in any of
Sections 7.02(a), (b) or (d), 7.03(a), 7.05(a) or 7.11 or Article VIII; or 
 (c) Other Covenants. Any Loan Party fails to perform or observe any term, covenant or agreement contained in Section 7.01, subsections (b) or (d) of Section 7.03
or Section 7.10, and such failure continues for ten (10) Business Days; 
 (d) Other
Defaults. Any Loan Party fails to perform or observe any other covenant or agreement (not specified in subsection (a), (b) or (c) above) contained in any Loan Document on its part to be performed or observed and such failure continues
for thirty (30) days after the earlier of (i) the date on which a Responsible Officer of a Loan Party becomes aware of such failure or (ii) the date on which notice thereof shall have been given to the Borrower by the Administrative
Agent or any Lender; or 
 (e) Representations and Warranties. Any representation, warranty, certification
or statement of fact made or deemed made by or on behalf of the Borrower or any other Loan Party herein, in any other Loan Document, or in any document delivered in connection herewith or therewith shall be incorrect or misleading in any material
respect when made or deemed made; or 
 (f) Cross-Default. (i) A Loan Party or any Subsidiary
(A) fails to make any payment when due (whether by scheduled maturity, required prepayment, acceleration, demand, or otherwise) in respect of any Indebtedness (other than Indebtedness hereunder and Indebtedness under Swap Contracts between any
Loan Party and any Lender or any Affiliate of a Lender) having an aggregate principal amount (including undrawn committed or available amounts and including amounts owing to all creditors under any combined or syndicated credit arrangement) of more
than the Threshold Amount, or (B) fails to observe or perform any other agreement or condition relating to any such Indebtedness or contained in any instrument or agreement evidencing, securing or relating thereto, or any other event occurs,
the effect of which default or other event is to cause, or to permit the holder or holders of such Indebtedness (or a trustee or agent on behalf of such holder or holders) to cause, with the giving of notice if required, such Indebtedness to be
demanded or to become due or to be repurchased, prepaid, defeased or redeemed (automatically or otherwise), or an offer to repurchase, prepay, defease or redeem such Indebtedness to be made, prior to its stated maturity, or to become payable or cash
collateral in respect thereof to be demanded; (ii) there occurs under any Swap Contract an Early Termination

  

 93 

 
Date (as defined in such Swap Contract) resulting from (A) any event of default under such Swap Contract as to which a Loan Party or any Subsidiary is the Defaulting Party (as defined in
such Swap Contract) or (B) any Termination Event (as so defined) under such Swap Contract as to which a Loan Party or any Subsidiary is an Affected Party (as so defined) and, in either event, the Swap Termination Value owed by such Loan Party
or such Subsidiary as a result thereof is greater than the Threshold Amount; or (iii) there occurs any default under the Proleukin® Distribution Agreement, or any other event occurs, in each case that results in the termination of such
agreement and the rights of the Borrower thereunder. 
 (g) Insolvency Proceedings, Etc. Any Loan Party or
any of its Subsidiaries institutes or consents to the institution of any proceeding under any Debtor Relief Law, or makes an assignment for the benefit of creditors; or applies for or consents to the appointment of any receiver, trustee, custodian,
conservator, liquidator, rehabilitator or similar officer for it or for all or any material part of its property; or any receiver, trustee, custodian, conservator, liquidator, rehabilitator or similar officer is appointed without the application or
consent of such Person and the appointment continues undischarged or unstayed for sixty (60) calendar days; or any proceeding under any Debtor Relief Law relating to any such Person or to all or any material part of its property is instituted
without the consent of such Person and continues undismissed or unstayed for sixty (60) calendar days, or an order for relief is entered in any such proceeding; or 
 (h) Inability to Pay Debts; Attachment. (i) A Loan Party or any Subsidiary becomes unable or admits in writing
its inability or fails generally to pay its debts as they become due, or (ii) any writ or warrant of attachment or execution or similar process is issued or levied against all or any material part of the property of any such Person and is not
released, vacated or fully bonded within thirty (30) days after its issue or levy; or 
 (i)
Judgments. There is entered against a Loan Party or any Subsidiary (i) one or more final judgments or orders for the payment of money in an aggregate amount exceeding the Threshold Amount (to the extent not covered by independent
third-party insurance as to which the insurer does not dispute coverage), or (ii) any one or more non-monetary final judgments that have, or could reasonably be expected to have, individually or in the aggregate, a Material Adverse Effect and,
in either case, (A) enforcement proceedings are commenced by any creditor upon such judgment or order, or (B) there is a period of thirty (30) consecutive days during which a stay of enforcement of such judgment, by reason of a
pending appeal or otherwise, is not in effect; or 
 (j) ERISA. (i) An ERISA Event occurs with
respect to a Pension Plan or Multiemployer Plan which has resulted or could reasonably be expected to result in liability of the Borrower under Title IV of ERISA to the Pension Plan, Multiemployer Plan or the PBGC in an aggregate amount in
excess of the Threshold Amount, or (ii) the Borrower or any ERISA Affiliate fails to pay when due, after the expiration of any applicable grace period, any installment payment with respect to its withdrawal liability under Section 4201 of
ERISA under a Multiemployer Plan in an aggregate amount in excess of the Threshold Amount; or 
 (k)
Invalidity of Loan Documents. This Agreement, any Note or any Collateral Document, at any time after its execution and delivery and for any reason other than as expressly permitted hereunder or thereunder or the Obligations being Fully
Satisfied, ceases to be in full force and effect; or any Loan Party or any other Person contests in any manner the validity or enforceability of any Loan Document; or any Loan Party denies that it has any or further liability or obligation under any
Loan Document, or purports to revoke, terminate or rescind any Loan Document; or 
  

 94 

 (l) Change of Control. There occurs any Change of Control.

  

	9.02	Remedies Upon Event of Default. 

 If any Event of Default occurs and is continuing, the Administrative Agent shall, at the request of, or may, with the consent of, the Required Lenders, take any or all of the following actions: 
 (a) declare the commitment of each Lender to make Loans and any obligation of the L/C Issuer to make L/C Credit Extensions to
be terminated, whereupon such commitments and obligation shall be terminated; 
 (b) declare the unpaid principal
amount of all outstanding Loans, all interest accrued and unpaid thereon, and all other amounts owing or payable hereunder or under any other Loan Document to be immediately due and payable, without presentment, demand, protest or other notice of
any kind, all of which are hereby expressly waived by the Borrower; 
 (c) require that the Borrower Cash
Collateralize the L/C Obligations (in an amount equal to the then Outstanding Amount thereof); and 
 (d)
exercise on behalf of itself and the Lenders all rights and remedies available to it and the Lenders under the Loan Documents or applicable Law; 
 provided, however, that upon the occurrence of an actual or deemed entry of an order for relief with respect to the Borrower under the Bankruptcy Code of the United States, the obligation of each Lender to make Loans and any
obligation of the L/C Issuer to make L/C Credit Extensions shall automatically terminate, the unpaid principal amount of all outstanding Loans and all interest and other amounts as aforesaid shall automatically become due and payable, and the
obligation of the Borrower to Cash Collateralize the L/C Obligations as aforesaid shall automatically become effective, in each case without further act of the Administrative Agent or any Lender. 
  

	9.03	Application of Funds. 

 After the exercise of remedies provided for in Section 9.02 (or after the Loans have automatically become immediately due and payable and the L/C Obligations have automatically been required to be Cash Collateralized as set
forth in the proviso to Section 9.02), any amounts received on account of the Obligations shall, subject to the provisions of Sections 2.14 and 2.15, be applied by the Administrative Agent in the following order:

 First, to payment of that portion of the Obligations constituting fees, indemnities, expenses and other amounts
(including Attorney Costs and amounts payable under Article III) payable to the Administrative Agent in its capacity as such; 
 Second, to payment of that portion of the Obligations constituting fees, indemnities and other amounts (other than principal and interest and Letter of Credit Fees) payable to the Lenders and the L/C Issuer arising under the Loan
Documents (including Attorney Costs and amounts payable under Article III), ratably among them in proportion to the amounts described in this clause Second payable to them; 
 Third, to payment of that portion of the Obligations constituting accrued and unpaid Letter of Credit Fees and interest on the Loans,
L/C Borrowings and other Obligations arising under the

  

 95 

 
Loan Documents, ratably among the Lenders and the L/C Issuer in proportion to the respective amounts described in this clause Third held by them; 
 Fourth, to payment of that portion of the Obligations constituting unpaid principal of the Loans, L/C Borrowings and Obligations then
owing under Secured Hedge Agreements and Secured Cash Management Agreements, ratably among the Lenders, the L/C Issuer, the Hedge Banks and the Cash Management Banks in proportion to the respective amounts described in this clause Fourth held
by them; and 
 Fifth, to the Administrative Agent for the account of the L/C Issuer, to Cash Collateralize that portion
of the L/C Obligations comprised of the aggregate undrawn amount of Letters of Credit to the extent not otherwise Cash Collateralized by the Borrower pursuant to Sections 2.03 and 2.14; and 
 Last, the balance, if any, after all of the Obligations (other than contingent reimbursement or indemnification obligations) have been
indefeasibly paid in full, to the Borrower or as otherwise required by Law. 
 Subject to Section 2.03(c) and
2.14, amounts used to Cash Collateralize the aggregate undrawn amount of Letters of Credit pursuant to clause Fifth above shall be applied to satisfy drawings under such Letters of Credit as they occur. If any amount remains on deposit
as Cash Collateral after all Letters of Credit have either been fully drawn or expired, such remaining amount shall be applied to the other Obligations, if any, in the order set forth above. 
 Notwithstanding the foregoing, Obligations arising under Secured Cash Management Agreements and Secured Hedge Agreements shall be excluded from the
application described above if the Administrative Agent has not received written notice thereof, together with such supporting documentation as the Administrative Agent may reasonably request, from the applicable Cash Management Bank or Hedge Bank,
as the case may be. Each Cash Management Bank or Hedge Bank not a party to the Credit Agreement that has given the notice contemplated by the preceding sentence shall, by such notice, be deemed to have acknowledged and accepted the appointment of
the Administrative Agent pursuant to the terms of Article X hereof for itself and its Affiliates as if a “Lender” party hereto. 
 ARTICLE X 
 ADMINISTRATIVE AGENT 
  

	10.01	Appointment and Authority. 

 (a) Each of the Lenders and the L/C Issuer hereby irrevocably appoints Bank of America to act on its behalf as the Administrative Agent hereunder and under the other Loan Documents and authorizes the Administrative Agent to take such
actions on its behalf and to exercise such powers as are delegated to the Administrative Agent by the terms hereof or thereof, together with such actions and powers as are reasonably incidental thereto. The provisions of this Article are solely
for the benefit of the Administrative Agent, the Lenders and the L/C Issuer, and neither the Borrower nor any other Loan Party shall have rights as a third party beneficiary of any of such provisions. 
 (b) The Administrative Agent shall also act as the “collateral agent” under the Loan Documents, and each of the Lenders and
the L/C Issuer hereby irrevocably appoints and authorizes the Administrative Agent to act as the agent of such Lender and the L/C Issuer for purposes of acquiring,

  

 96 

 
holding and enforcing any and all Liens on Collateral granted by any of the Loan Parties to secure any of the Obligations, together with such powers and discretion as are reasonably incidental
thereto. In this connection, the Administrative Agent, as “collateral agent” and any co-agents, sub-agents and attorneys-in-fact appointed by the Administrative Agent pursuant to Section 10.05 for purposes of holding or
enforcing any Lien on the Collateral (or any portion thereof) granted under the Collateral Documents, or for exercising any rights and remedies thereunder at the direction of the Administrative Agent), shall be entitled to the benefits of all
provisions of this Article X and Article XI (including Section 11.04(c), as though such co-agents, sub-agents and attorneys-in-fact were the “collateral agent” under the Loan Documents) as if set forth in full
herein with respect thereto. 
  

	10.02	Rights as a Lender. 

 The
Person serving as the Administrative Agent hereunder shall have the same rights and powers in its capacity as a Lender as any other Lender and may exercise the same as though it were not the Administrative Agent and the term “Lender” or
“Lenders” shall, unless otherwise expressly indicated or unless the context otherwise requires, include the Person serving as the Administrative Agent hereunder in its individual capacity. Such Person and its Affiliates may accept deposits
from, lend money to, act as the financial advisor or in any other advisory capacity for and generally engage in any kind of business with any Loan Party or any Subsidiary or other Affiliate thereof as if such Person were not the Administrative Agent
hereunder and without any duty to account therefor to the Lenders. 
  

	10.03	Exculpatory Provisions. 

 The Administrative Agent shall not have any duties or obligations except those expressly set forth herein and in the other Loan Documents. Without limiting the generality of the foregoing, the Administrative Agent: 
 (a) shall not be subject to any fiduciary or other implied duties, regardless of whether a Default has occurred and is
continuing; 
 (b) shall not have any duty to take any discretionary action or exercise any discretionary powers,
except with respect to the Administrative Agent’s discretionary rights and powers expressly contemplated hereby or by the other Loan Documents that the Administrative Agent is required to exercise as directed in writing by the Required Lenders
(or such other number or percentage of the Lenders as shall be expressly provided for herein or in the other Loan Documents), provided that the Administrative Agent shall not be required to take any action that, in its opinion or the opinion
of its counsel, may expose the Administrative Agent to liability or that is contrary to any Loan Document or applicable Law; and 
 (c) shall not, except as expressly set forth herein and in the other Loan Documents, have any duty to disclose, and shall not be liable for the failure to disclose, any information relating to any Loan
Party or any of its Affiliates that is communicated to or obtained by the Person serving as the Administrative Agent or any of its Affiliates in any capacity. 
 The Administrative Agent shall not be liable to any Lender for any action taken or not taken by it (i) with the consent or at the request of the Required Lenders (or such other number or percentage
of the Lenders as shall be necessary, or as the Administrative Agent shall believe in good faith shall be necessary, under the circumstances as provided in Sections 11.01 and 9.02) or (ii) in the absence of its own gross
negligence or willful misconduct. The Administrative Agent shall be deemed not to have knowledge of any Default unless and until notice describing such Default is given to the Administrative Agent by the Borrower, a Lender or the L/C Issuer.

  

 97 

 The Administrative Agent shall not be responsible for or have any duty to ascertain or
inquire into (i) any statement, warranty or representation made in, or in connection with, this Agreement or any other Loan Document, (ii) the contents of any certificate, report or other document delivered hereunder or thereunder or in
connection herewith or therewith, (iii) the performance or observance of any of the covenants, agreements or other terms or conditions set forth herein or therein or the occurrence of any Default, (iv) the validity, enforceability,
effectiveness or genuineness of this Agreement, any other Loan Document or any other agreement, instrument or document or (v) the satisfaction of any condition set forth in Article V or elsewhere herein, other than to confirm receipt of
items expressly required to be delivered to the Administrative Agent. 
  

	10.04	Reliance by Administrative Agent. 

 The Administrative Agent shall be entitled to rely upon, and shall not incur any liability for relying upon, any notice, request, certificate, consent, statement, instrument, document or other writing (including any electronic message,
Internet or intranet website posting or other distribution) believed by it to be genuine and to have been signed, sent or otherwise authenticated by the proper Person. The Administrative Agent also may rely upon any statement made to it orally or by
telephone and believed by it to have been made by the proper Person, and shall not incur any liability for relying thereon. In determining compliance with any condition hereunder to the making of a Loan, or the issuance of a Letter of Credit, that
by its terms must be fulfilled to the satisfaction of a Lender or the L/C Issuer, the Administrative Agent may presume that such condition is satisfactory to such Lender or the L/C Issuer unless the Administrative Agent shall have received notice to
the contrary from such Lender or the L/C Issuer prior to the making of such Loan or the issuance of such Letter of Credit. The Administrative Agent may consult with legal counsel (who may be counsel for the Borrower), independent accountants and
other experts selected by it, and shall not be liable for any action taken or not taken by it in accordance with the advice of any such counsel, accountants or experts. 
  

	10.05	Delegation of Duties. 

 The Administrative Agent may perform any and all of its duties and exercise its rights and powers hereunder or under any other Loan Document by or through any one or more sub-agents appointed by the Administrative Agent. The Administrative
Agent and any such sub-agent may perform any and all of its duties and exercise its rights and powers by or through their respective Related Parties. The exculpatory provisions of this Section shall apply to any such sub-agent and to the Related
Parties of the Administrative Agent and any such sub-agent, and shall apply to their respective activities in connection with the syndication of the credit facilities provided for herein as well as activities as the Administrative Agent. 

 

	10.06	Resignation of the Administrative Agent. 

 The Administrative Agent may at any time give notice of its resignation to the Lenders, the L/C Issuer and the Borrower. Upon receipt of any such notice of resignation, the Required Lenders shall have the
right, in consultation with the Borrower (provided that no such consultation shall be required if an Event of Default then exists), to appoint a successor, which shall be a bank with an office in the United States, or an Affiliate of any such bank
with an office in the United States. If no such successor shall have been so appointed by the Required Lenders and shall have accepted such appointment within 30 days after the retiring Administrative Agent gives notice of its resignation, then
the retiring Administrative Agent may on behalf of the Lenders and the L/C Issuer, and in consultation with the Borrower (provided that no such consultation shall be required if an Event of Default then exists), appoint a successor Administrative
Agent meeting the qualifications set forth above; provided that if the

  

 98 

 
Administrative Agent shall notify the Borrower and the Lenders that no qualifying Person has accepted such appointment, then such resignation shall nonetheless become effective in accordance with
such notice and (1) the retiring Administrative Agent shall be discharged from its duties and obligations hereunder and under the other Loan Documents (except that in the case of any collateral security held by the Administrative Agent on
behalf of the Lenders or the L/C Issuer under any of the Loan Documents, the retiring Administrative Agent shall continue to hold such collateral security until such time as a successor Administrative Agent is appointed) and (2) all payments,
communications and determinations provided to be made by, to or through the Administrative Agent shall instead be made by or to each Lender and the L/C Issuer directly, until such time as the Required Lenders appoint a successor Administrative Agent
as provided for above in this Section. Upon the acceptance of a successor’s appointment as Administrative Agent hereunder, such successor shall succeed to and become vested with all of the rights, powers, privileges and duties of the retiring
(or retired) Administrative Agent, and the retiring Administrative Agent shall be discharged from all of its duties and obligations hereunder or under the other Loan Documents (if not already discharged therefrom as provided above in this Section).
The fees payable by the Borrower to a successor Administrative Agent shall be the same as those payable to its predecessor unless otherwise agreed between the Borrower and such successor. After the retiring Administrative Agent’s resignation
hereunder and under the other Loan Documents, the provisions of this Section and Section 11.04 shall continue in effect for the benefit of such retiring Administrative Agent, its sub-agents and their respective Related Parties in respect
of any actions taken or omitted to be taken by any of them while the retiring Administrative Agent was acting as Administrative Agent. 
 Any resignation by Bank of America as Administrative Agent pursuant to this Section shall also constitute its resignation as L/C Issuer and Swing Line Lender. Upon the acceptance of a successor’s appointment as Administrative
Agent hereunder, (a) such successor shall succeed to and become vested with all of the rights, powers, privileges and duties of the retiring L/C Issuer and Swing Line Lender, (b) the retiring L/C Issuer and Swing Line Lender shall be
discharged from all of their respective duties and obligations hereunder or under the other Loan Documents, and (c) the successor L/C Issuer and Swing Line Lender shall issue letters of credit in substitution for the Letters of Credit, if any,
outstanding at the time of such succession or make other arrangements satisfactory to the retiring L/C Issuer and Swing Line Lender to effectively assume the obligations of the retiring L/C Issuer and Swing Line Lender with respect to such Letters
of Credit. 
  

	10.07	Non-Reliance on Administrative Agent and Other Lenders. 

 Each Lender and the L/C Issuer acknowledges that it has, independently and without reliance upon the Administrative Agent or any other Lender or any of their Related Parties and based on such documents
and information as it has deemed appropriate, made its own credit analysis and decision to enter into this Agreement. Each Lender and the L/C Issuer also acknowledges that it will, independently and without reliance upon the Administrative Agent or
any other Lender or any of their Related Parties and based on such documents and information as it shall from time to time deem appropriate, continue to make its own decisions in taking or not taking action under or based upon this Agreement, any
other Loan Document or any related agreement or any document furnished hereunder or thereunder. 
  

	10.08	No Other Duties; Etc. 

 Anything herein to the contrary notwithstanding, none of the bookrunners, arrangers, syndication agents, documentation agents or co-agents shall have any powers, duties or responsibilities under this Agreement or any of the other Loan
Documents, except in its capacity, as applicable, as the Administrative Agent, a Lender or the L/C Issuer hereunder. 
  

 99 

	10.09	Administrative Agent May File Proof of Claims. 

 In case of any proceeding under any Debtor Relief Law or any other judicial proceeding relative to any Loan Party, the Administrative Agent (irrespective of whether the principal of any Loan or L/C
Obligation shall then be due and payable as herein expressed or by declaration or otherwise and irrespective of whether the Administrative Agent shall have made any demand on the Borrower) shall be entitled and empowered, by intervention in such
proceeding or otherwise: 
 (a) to file and prove a claim for the whole amount of the principal and interest
owing and unpaid in respect of the Loans, L/C Obligations and all other Obligations (other than obligations under Swap Contracts between a Loan Party and any Lender, or any Affiliate of a Lender, to which the Administrative Agent is not a party)
that are owing and unpaid and to file such other documents as may be necessary or advisable in order to have the claims of the Lenders, the L/C Issuer and the Administrative Agent (including any claim for the reasonable compensation, expenses,
disbursements and advances of the Lenders, the L/C Issuer and the Administrative Agent and their respective agents and counsel and all other amounts due the Lenders, the L/C Issuer and the Administrative Agent under Sections 2.03(h) and
(i), 2.09 and 11.04) allowed in such judicial proceeding; and 
 (b) to collect and receive
any monies or other property payable or deliverable on any such claims and to distribute the same; 
 and any custodian, receiver, assignee,
trustee, liquidator, sequestrator or other similar official in any such judicial proceeding is hereby authorized by each Lender and the L/C Issuer to make such payments to the Administrative Agent and, in the event that the Administrative Agent
shall consent to the making of such payments directly to the Lenders and the L/C Issuer, to pay to the Administrative Agent any amount due for the reasonable compensation, expenses, disbursements and advances of the Administrative Agent and its
agents and counsel, and any other amounts due the Administrative Agent under Sections 2.09 and 11.04. 
 Nothing contained herein shall be deemed to authorize the Administrative Agent to authorize or consent to or accept or adopt on behalf of any Lender or the L/C Issuer any plan of reorganization, arrangement, adjustment or composition
affecting the Obligations or the rights of any Lender or to authorize the Administrative Agent to vote in respect of the claim of any Lender in any such proceeding. 
  

	10.10	Collateral and Guaranty Matters. 

 The Lenders and the L/C Issuer irrevocably authorize and direct the Administrative Agent: 
 (a) to
release any Lien on any property granted to or held by the Administrative Agent, as applicable, under any Loan Document (i) at such time as the Obligations are Fully Satisfied, (ii) that is sold or to be sold as part of or in connection
with any sale permitted hereunder or under any other Loan Document, or (iii) subject to Section 11.01, if approved, authorized or ratified in writing by the Required Lenders; 
 (b) to subordinate any Lien on any property granted to or held by the Administrative Agent under any Loan Document to the
holder of any Lien on such property that is permitted by Section 8.01(i); and 
 (c) to release any
Guarantor from its obligations under the Guaranty if such Person ceases to be a Subsidiary as a result of a transaction permitted hereunder. 
  

 100 

 In connection with any termination or release pursuant to this Section 10.10, the
Administrative Agent shall promptly execute and deliver to the Borrower or the applicable Loan Party, at the Borrower’s expense, all documents that the Borrower or such Loan Party shall reasonably request to evidence such termination or
release. Upon request by the Administrative Agent at any time, the Required Lenders will confirm in writing the Administrative Agent’s authority to release or subordinate its interest in particular types or items of property, or to release any
Guarantor from its obligations under the Guaranty pursuant to this Section 10.10. 
  

	10.11	Secured Hedge Agreements and Secured Cash Management Agreements. 

 Except as otherwise expressly set forth herein or in any Collateral Document, no Cash Management Bank or Hedge Bank that obtains the benefits of Section 9.03 or of any Collateral by virtue of
the provisions hereof or of any Collateral Document shall have any right to notice of any action or to consent to, direct or object to any action hereunder or under any other Loan Document or otherwise in respect of the Collateral (including the
release or impairment of any Collateral) in its capacity as a Hedge Bank or Cash Management Bank. Notwithstanding any other provision of this Article X to the contrary, the Administrative Agent shall not be required to verify the payment of,
or that other satisfactory arrangements have been made with respect to, Obligations arising under Secured Cash Management Agreements and Secured Hedge Agreements unless the Administrative Agent has received written notice of such Obligations,
together with such supporting documentation as the Administrative Agent may reasonably request, from the applicable Cash Management Bank or Hedge Bank, as the case may be. 
 ARTICLE XI 
 MISCELLANEOUS 
  

	11.01	Amendments, Etc. 

 No
amendment or waiver of any provision of this Agreement or any other Loan Document, and no consent to any departure by the Borrower or any other Loan Party therefrom, shall be effective unless in writing signed by the Required Lenders and the
Borrower or the applicable Loan Party, as the case may be, and acknowledged by the Administrative Agent, and each such waiver or consent shall be effective only in the specific instance and for the specific purpose for which given; provided,
however, that no such amendment, waiver or consent shall: 
 (a) extend or increase the Commitment of any
Lender (or reinstate any Commitment terminated pursuant to Section 9.02) without the written consent of such Lender (it being understood and agreed that no waiver or amendment of or consent to any departure from of any condition
precedent set forth in Section 5.02, or of any covenant, Default or Event of Default or of a mandatory reduction in Commitments shall constitute an extension or increase in Commitments of any Lender); 
 (b) postpone any date fixed by this Agreement or any other Loan Document for any payment of principal (excluding mandatory
prepayments), interest, fees or other amounts due to the Lenders (or any of them) hereunder or under any other Loan Document without the written consent of each Lender directly affected thereby; 
 (c) reduce the principal of, or the rate of interest specified herein on, any Loan or L/C Borrowing, or any fees or other
amounts payable hereunder or under any other Loan

  

 101 

 
Document without the written consent of each Lender directly affected thereby; provided, however, that only the consent of the Required Lenders shall be necessary (i) to amend
the definition of “Default Rate” or to waive any obligation of the Borrower to pay interest at the Default Rate or (ii) to amend any financial covenant hereunder (or any defined term used therein) even if the effect of such amendment
would be to reduce the rate of interest on any Loan or L/C Borrowing or to reduce any fee payable hereunder; 
 (d) change Section 9.03 in a manner that would alter the pro rata sharing of payments required thereby without the written consent of each Lender directly affected thereby; 
 (e) change any provision of this Section or the definition of “Required Lenders” or any other provision hereof
specifying the number or percentage of Lenders required to amend, waive or otherwise modify any rights hereunder or make any determination or grant any consent hereunder without the written consent of each Lender directly affected thereby;

 (f) except in connection with a Disposition permitted under Section 8.05, release all or
substantially all of the Collateral without the written consent of each Lender directly affected thereby; 
 (g)
release the Borrower or, except in connection with a merger or consolidation permitted under Section 8.04 or a Disposition permitted under Section 8.05, all or substantially all of the Guarantors, from its or their
obligations under the Loan Documents without the written consent of each Lender directly affected thereby; 
 (h)
without the consent of Lenders (other than Defaulting Lenders) holding in the aggregate at least a majority of the Revolving Commitments (or if the Revolving Commitments have been terminated, the outstanding Revolving Loans (and participations in
any Swing Line Loans and Letters of Credit)), (i) waive any Default or Event of Default for purposes of Section 5.02 for purposes of any Revolving Loan borrowing or L/C Credit Extension and (ii) amend, change, waive, discharge
or terminate Section 2.01(a), 2.02, 2.03, 2.05(b)(i) or 2.06 or any term, covenant or agreement contained in Article VIII or Article IX; or 
 (i) without the consent of Lenders (other than Defaulting Lenders) holding in the aggregate at least a majority of the
outstanding Term Loan (and participations therein), amend, change, waive, discharge or terminate Section 2.05(b)(vii) so as to alter the manner of application of proceeds of any mandatory prepayment required by
Section 2.05(b)(ii), (iii), (iv), (v) or (vi) hereof; 
 and, provided further,
that (i) no amendment, waiver or consent shall, unless in writing and signed by the L/C Issuer in addition to the Lenders required above, affect the rights or duties of the L/C Issuer under this Agreement or any Letter of Credit Application
relating to any Letter of Credit issued or to be issued by it; (ii) no amendment, waiver or consent shall, unless in writing and signed by the Swing Line Lender in addition to the Lenders required above, affect the rights or duties of the Swing
Line Lender under this Agreement or any other Loan Document, (iii) no amendment, waiver or consent shall, unless in writing and signed by the Administrative Agent in addition to the Lenders required above, affect the rights or duties of the
Administrative Agent under this Agreement or any other Loan Document; and (iv) the Fee Letter may be amended, or rights or privileges thereunder waived, in a writing executed only by the parties thereto. 
 Notwithstanding anything to the contrary herein, no Defaulting Lender shall have any right to approve or disapprove any amendment, waiver or consent
hereunder (and any amendment, waiver or consent which

  

 102 

 
by its terms requires the consent of all Lenders or each affected Lender may be effected with the consent of all Lenders or all affected Lenders, as the case may be, other than Defaulting
Lenders), except that (a) the Commitment of such Lender may not be increased or extended without the consent of such Lender and (b) any waiver, amendment or consent which by its terms requires the consent of all Lenders or each affected
Lender and that by its terms affects any Defaulting Lender more adversely than other affected Lenders shall require the consent of such Defaulting Lender. 
 Notwithstanding the fact that the consent of all the Lenders is required in certain circumstances as set forth above, (x) each Lender is entitled to vote as such Lender sees fit on any bankruptcy
reorganization plan that affects the Loans, and each Lender acknowledges that the provisions of Section 1126(c) of the Bankruptcy Code supersedes the unanimous consent provisions set forth herein and (y) the Required Lenders shall
determine whether or not to allow a Loan Party to use cash collateral in the context of a bankruptcy or insolvency proceeding and such determination shall be binding on all of the Lenders. 
 Notwithstanding anything herein to the contrary, the Administrative Agent is authorized by the Lenders and the L/C Issuer to enter into amendments to this
Agreement and any other Loan Document with any Loan Party or its Subsidiaries, without any further consent of the Lenders or the L/C Issuer, for the purpose of (a) implementing the additional Commitments (and any extensions of credit
thereunder) and/or to implement and set forth the terms of any Additional Term Loans, in each case as contemplated by and subject to the limitations set forth in Section 2.02(f), including without limitation such amendments as may be
necessary to (i) provide for ratable sharing of benefits of this Agreement and the other Loan Documents in respect of the extensions of credit from time to time outstanding in the form of Additional Term Loans (including changes to
Section 2.05 to provide any Additional Term Loan the right to ratable (with the Term Loan and each other Additional Term Loan then outstanding) prepayment in connection with any voluntary or mandatory prepayment), (ii) include
appropriately the lenders providing any Additional Term Loan in any determination of the Required Lenders and/or the determination of the requisite Lenders under subsections (f) and (j) of Section 11.01 corresponding to the
consent rights of the other Lenders thereunder and (iii) make such other changes as the Borrower and the Administrative Agent shall deem necessary or advisable in connection with the establishment of any Additional Term Loan, or (b) curing
any typographical error, incorrect cross-reference, defect in form, non-material inconsistency, non-material omission or ambiguity in this Agreement or any other Loan Document to which it is a party. 
  

	11.02	Notices and Other Communications; Facsimile Copies. 

 (a) Notices Generally. Except in the case of notices and other communications expressly permitted to be given by telephone (and except as provided in subsection (b) below), all notices
and other communications provided for herein shall be in writing and shall be delivered by hand or overnight courier service, mailed by certified or registered mail or sent by telecopier as follows, and all notices and other communications expressly
permitted hereunder to be given by telephone shall be made to the applicable telephone number, as follows: 
 (i)
if to the Borrower or any other Loan Party, the Administrative Agent, the L/C Issuer or the Swing Line Lender, to the address, telecopier number, electronic mail address or telephone number specified for such Person on Schedule 11.02;
and 
 (ii) if to any other Lender, to the address, telecopier number, electronic mail address or telephone
number specified in its Administrative Questionnaire (including, as appropriate, notices delivered solely to the Person designated by a Lender on its Administrative Questionnaire then in effect for the delivery of notices that may contain material
non-public information relating to any Loan Party, any Subsidiary or any of their Affiliates). 
  

 103 

 Notices and other communications sent by hand or overnight courier service, or mailed by certified or
registered mail, shall be deemed to have been given when received; notices sent by telecopier shall be deemed to have been given when sent (except that, if not given during normal business hours for the recipient, shall be deemed to have been given
at the opening of business on the next business day for the recipient). Notices and other communications delivered through electronic communications to the extent provided in subsection (b) below, shall be effective as provided in such
subsection (b). 
 (b) Electronic Communications. Notices and other communications to the Lenders and the L/C Issuer
hereunder may be delivered or furnished by electronic communication (including e-mail and Internet or intranet websites) pursuant to procedures approved by the Administrative Agent; provided that the foregoing shall not apply to notices to
any Lender or the L/C Issuer pursuant to Article II if such Lender or the L/C Issuer, as applicable, has notified the Administrative Agent that it is incapable of receiving notices under such Article by electronic communication. The
Administrative Agent or the Borrower may, in its discretion, agree to accept notices and other communications to it hereunder by electronic communications pursuant to procedures approved by it; provided that approval of such procedures may be
limited to particular notices or communications. 
 Unless the Administrative Agent otherwise prescribes, (i) notices and
other communications sent to an e-mail address shall be deemed received upon the sender’s receipt of an acknowledgement from the intended recipient (such as by the “return receipt requested” function, as available, return e-mail or
other written acknowledgement); provided that if such notice or other communication is not sent during the normal business hours of the recipient, such notice or communication shall be deemed to have been sent at the opening of business on
the next business day for the recipient, and (ii) notices or communications posted to an Internet or intranet website shall be deemed received upon the deemed receipt by the intended recipient at its e-mail address as described in the foregoing
clause (i) of notification that such notice or communication is available and identifying the website address therefor. 
 (c) The Platform. THE PLATFORM IS PROVIDED “AS IS” AND “AS AVAILABLE.” THE AGENT PARTIES (AS DEFINED BELOW) DO NOT WARRANT THE ACCURACY OR COMPLETENESS OF THE BORROWER MATERIALS OR THE ADEQUACY OF THE PLATFORM,
AND EXPRESSLY DISCLAIM LIABILITY FOR ERRORS IN OR OMISSIONS FROM THE BORROWER MATERIALS. NO WARRANTY OF ANY KIND, EXPRESS, IMPLIED OR STATUTORY, INCLUDING ANY WARRANTY OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, NON-INFRINGEMENT OF THIRD
PARTY RIGHTS OR FREEDOM FROM VIRUSES OR OTHER CODE DEFECTS, IS MADE BY ANY AGENT PARTY IN CONNECTION WITH THE BORROWER MATERIALS OR THE PLATFORM. In no event shall the Administrative Agent or any of its Related Parties (collectively, the
“Agent Parties”) have any liability to the Borrower, any Lender, the L/C Issuer or any other Person for losses, claims, damages, liabilities or expenses of any kind (whether in tort, contract or otherwise) arising out of the
Borrower’s or the Administrative Agent’s transmission of Borrower Materials through the Internet, except to the extent that such losses, claims, damages, liabilities or expenses are determined by a court of competent jurisdiction to have
resulted from the gross negligence or willful misconduct of such Agent Party; provided, however, that in no event shall any Agent Party have any liability to the Borrower, any Lender, the L/C Issuer or any other Person for indirect,
special, incidental, consequential or punitive damages (as opposed to direct or actual damages). 
 (d) Change of Address,
Etc. Each of the Borrower, the Administrative Agent, the L/C Issuer and the Swing Line Lender may change its address, telecopier, telephone number or electronic mail address for notices and other communications hereunder by notice to the other
parties hereto. Each other Lender may change its address, telecopier, telephone number or electronic mail address for notices and other communications hereunder by notice to the Borrower, the Administrative Agent, the L/C Issuer and

  

 104 

 
the Swing Line Lender. In addition, each Lender agrees to notify the Administrative Agent from time to time to ensure that the Administrative Agent has on record (i) an effective address,
contact name, telephone number, telecopier number and electronic mail address to which notices and other communications may be sent and (ii) accurate wire instructions for such Lender. Furthermore, each Public Lender agrees to cause at least
one individual at or on behalf of such Public Lender to at all times have selected the “Private Side Information” or similar designation on the content declaration screen of the Platform in order to enable such Public Lender or its
delegate, in accordance with such Public Lender’s compliance procedures and applicable Law, including United States Federal and state securities Laws, to make reference to Borrower Materials that are not made available through the “Public
Side Information” portion of the Platform and that may contain material non-public information with respect to the Borrower, its Affiliates or their respective securities for purposes of United States Federal or state securities laws.

 (e) Reliance by Administrative Agent, L/C Issuer and Lenders. The Administrative Agent, the L/C Issuer and the Lenders
shall be entitled to rely and act upon any notices (including telephonic Loan Notices and Swing Line Loan Notices) purportedly given by or on behalf of the Borrower even if (i) such notices were not made in a manner specified herein, were
incomplete or were not preceded or followed by any other form of notice specified herein, or (ii) the terms thereof, as understood by the recipient, varied from any confirmation thereof. The Borrower shall indemnify the Administrative Agent,
the L/C Issuer, each Lender and the Related Parties of each of them from all losses, costs, expenses and liabilities resulting from the reliance by such Person on each notice purportedly given by or on behalf of the Borrower. All telephonic notices
to and other telephonic communications with the Administrative Agent may be recorded by the Administrative Agent, and each of the parties hereto hereby consents to such recording. 
  

	11.03	No Waiver; Cumulative Remedies; Enforcement. 

 No failure by any Lender or the Administrative Agent to exercise, and no delay by any such Person in exercising, any right, remedy, power or privilege hereunder shall operate as a waiver thereof; nor
shall any single or partial exercise of any right, remedy, power or privilege hereunder preclude any other or further exercise thereof or the exercise of any other right, remedy, power or privilege. The rights, remedies, powers and privileges herein
provided are cumulative and not exclusive of any rights, remedies, powers and privileges provided by law. 
 Notwithstanding
anything to the contrary contained herein or in any other Loan Document, the authority to enforce rights and remedies hereunder and under the other Loan Documents against the Loan Parties or any of them shall be vested exclusively in, and all
actions and proceedings at law in connection with such enforcement shall be instituted and maintained exclusively by, the Administrative Agent in accordance with Section 9.02 for the benefit of all the Lenders and the L/C Issuer;
provided, however, that the foregoing shall not prohibit (a) the Administrative Agent from exercising on its own behalf the rights and remedies that inure to its benefit (solely in its capacity as Administrative Agent) hereunder
and under the other Loan Documents, (b) the L/C Issuer or the Swing Line Lender from exercising the rights and remedies that inure to its benefit (solely in its capacity as L/C Issuer or Swing Line Lender, as the case may be) hereunder and
under the other Loan Documents, (c) any Lender from exercising setoff rights in accordance with Section 11.08 (subject to the terms of Section 2.13), or (d) any Lender from filing proofs of claim or appearing and
filing pleadings on its own behalf during the pendency of a proceeding relative to any Loan Party under any Debtor Relief Law; and provided, further, that if at any time there is no Person acting as Administrative Agent hereunder and
under the other Loan Documents, then (i) the Required Lenders shall have the rights otherwise ascribed to the Administrative Agent pursuant to Section 9.02 and (ii) in addition to the matters set forth in clauses (b),
(c) and (d) of the

  

 105 

 
preceding proviso and subject to Section 2.13, any Lender may, with the consent of the Required Lenders, enforce any rights and remedies available to it and as authorized by the
Required Lenders. 
  

	11.04	Expenses; Indemnity; Damage Waiver. 

 (a) Costs and Expenses. The Borrower shall pay (i) all reasonable, documented out-of-pocket expenses incurred by the Administrative Agent and its Affiliates (including the reasonable fees,
charges and disbursements of counsel for the Administrative Agent), in connection with the syndication of the credit facilities provided for herein, the preparation, negotiation, execution, delivery and administration of this Agreement and the other
Loan Documents or any amendments, modifications or waivers of the provisions hereof or thereof (whether or not the transactions contemplated hereby or thereby shall be consummated), (ii) all reasonable, documented out-of-pocket expenses
incurred by the L/C Issuer in connection with the issuance, amendment, renewal or extension of any Letter of Credit or any demand for payment thereunder and (iii) all reasonable, documented out-of-pocket expenses incurred by the Administrative
Agent, any Lender or the L/C Issuer (including the Attorney Costs for the Administrative Agent, any Lender or the L/C Issuer), in connection with the enforcement or protection of its rights (A) in connection with this Agreement and the other
Loan Documents, including its rights under this Section, or (B) in connection with the Loans made or Letters of Credit issued hereunder, including all such out-of-pocket expenses incurred during any workout, restructuring or negotiations in
respect of such Loans or Letters of Credit. 
 (b) Indemnification by the Borrower. The Borrower shall indemnify the
Administrative Agent (and any sub-agent thereof), each Lender and the L/C Issuer, and each Related Party of any of the foregoing Persons (each such Person being called an “Indemnitee”) against, and hold each Indemnitee harmless
from, any and all losses, claims, damages, liabilities and related expenses (including the Attorney Costs of any Indemnitee), incurred by any Indemnitee or asserted against any Indemnitee by any third party or by the Borrower or any other Loan Party
arising out of, in connection with, or as a result of (i) the execution or delivery of this Agreement, any other Loan Document or any agreement or instrument contemplated hereby or thereby, the performance by the parties hereto of their
respective obligations hereunder or thereunder, the consummation of the transactions contemplated hereby or thereby, or, in the case of the Administrative Agent (and any sub-agent thereof) and its Related Parties only, the administration of this
Agreement and the other Loan Documents (including in respect of any matters addressed in Section 3.01), (ii) any Loan or Letter of Credit or the use or proposed use of the proceeds therefrom (including any refusal by the L/C Issuer
to honor a demand for payment under a Letter of Credit if the documents presented in connection with such demand do not strictly comply with the terms of such Letter of Credit), (iii) any actual or alleged presence or release of Hazardous
Materials on or from any property owned or operated by a Loan Party or any of its Subsidiaries, or any Environmental Liability related in any way to a Loan Party or any of its Subsidiaries, or (iv) any actual or prospective claim, litigation,
investigation or proceeding relating to any of the foregoing, whether based on contract, tort or any other theory, whether brought by a third party or by the Borrower or any other Loan Party, and regardless of whether any Indemnitee is a party
thereto; provided that such indemnity shall not, as to any Indemnitee, be available to the extent that such losses, claims, damages, liabilities or related expenses (x) resulted from the gross negligence or willful misconduct of such
Indemnitee or (y) resulted from a claim brought by the Borrower or any other Loan Party against an Indemnitee for breach in bad faith of such Indemnitee’s obligations hereunder or under any other Loan Document. 
 (c) Reimbursement by Lenders. To the extent that the Borrower for any reason fails to indefeasibly pay any amount required under
subsection (a) or (b) of this Section to be paid by it to the Administrative Agent (or any sub-agent thereof), the L/C Issuer or any Related Party of any of the foregoing, each Lender severally agrees to pay to the Administrative
Agent (or any such sub-agent), the L/C Issuer or such Related Party, as the case may be, such Lender’s Pro Rata Share (determined as of the

  

 106 

 
time that the applicable unreimbursed expense or indemnity payment is sought) of such unpaid amount, provided that the unreimbursed expense or indemnified loss, claim, damage, liability or
related expense, as the case may be, was incurred by or asserted against the Administrative Agent (or any such sub-agent) or the L/C Issuer in its capacity as such, or against any Related Party of any of the foregoing acting for the Administrative
Agent (or any such sub-agent) or L/C Issuer in connection with such capacity. The obligations of the Lenders under this subsection (c) are subject to the provisions of Section 2.12(f). 
 (d) Waiver of Consequential Damages, Etc. To the fullest extent permitted by applicable Law, the Borrower shall not assert, and
hereby waives, any claim against any Indemnitee, on any theory of liability, for special, indirect, consequential or punitive damages (as opposed to direct or actual damages) arising out of, in connection with, or as a result of, this Agreement, any
other Loan Document or any agreement or instrument contemplated hereby, the transactions contemplated hereby or thereby, any Loan or Letter of Credit or the use of the proceeds thereof. No Indemnitee referred to in subsection (b) above shall be
liable for any damages arising from the use by unintended recipients of any information or other materials distributed to such unintended recipients by such Indemnitee through telecommunications, electronic or other information transmission systems
in connection with this Agreement or the other Loan Documents or the transactions contemplated hereby or thereby other than for direct or actual damages resulting from the gross negligence or willful misconduct of such Indemnitee. 
 (e) Payments. All amounts due under this Section shall be payable not later than ten (10) Business Days after demand
therefor. 
 (f) Survival. The agreements in this Section shall survive the resignation of the Administrative Agent,
the L/C Issuer and the Swing Line Lender, the replacement of any Lender, the termination of the Commitments and the repayment, satisfaction or discharge of all the other Obligations. 
  

	11.05	Payments Set Aside. 

 To
the extent that any payment by or on behalf of any Loan Party is made to the Administrative Agent or any Lender, or the Administrative Agent or any Lender exercises its right of set-off, and such payment or the proceeds of such set-off or any part
thereof is subsequently invalidated, declared to be fraudulent or preferential, set aside or required (including pursuant to any settlement entered into by the Administrative Agent or such Lender in its discretion) to be repaid to a trustee,
receiver or any other party, in connection with any proceeding under any Debtor Relief Law or otherwise, then (a) to the extent of such recovery, the obligation or part thereof originally intended to be satisfied shall be revived and continued
in full force and effect as if such payment had not been made or such set-off had not occurred, and (b) each Lender severally agrees to pay to the Administrative Agent upon demand its applicable share of any amount so recovered from or repaid
by the Administrative Agent, plus interest thereon from the date of such demand to the date such payment is made at a rate per annum equal to the Federal Funds Rate from time to time in effect. 
  

	11.06	Successors and Assigns. 

 (a) Successors and Assigns Generally. The provisions of this Agreement shall be binding upon and inure to the benefit of the parties hereto and their respective successors and assigns permitted hereby, except that neither the
Borrower nor any other Loan Party may assign or otherwise transfer any of its rights or obligations hereunder without the prior written consent of the Administrative Agent and each Lender, other than in connection with a Reorganization permitted by
Section 8.04 hereof, and no Lender may assign or otherwise transfer any of its rights or obligations hereunder except (i) to an assignee in accordance with the provisions of Section 11.06(b), (ii) by way of
participation in accordance with the provisions of Section 11.06(d), or (iii) by way of pledge or assignment of a security interest subject to the

  

 107 

 
restrictions of Section 11.06(f) (and any other attempted assignment or transfer by any party hereto shall be null and void). Nothing in this Agreement, expressed or implied, shall be
construed to confer upon any Person (other than the parties hereto, their respective successors and assigns permitted hereby, Participants to the extent provided in subsection (d) of this Section and, to the extent expressly contemplated
hereby, the Related Parties of each of the Administrative Agent, the L/C Issuer and the Lenders) any legal or equitable right, remedy or claim under or by reason of this Agreement. 
 (b) Assignments by Lenders. Any Lender may at any time assign to one or more assignees all or a portion of its rights and obligations
under this Agreement (including all or a portion of its Commitment(s) and the Loans (including for purposes of this Section 11.06(b), participations in L/C Obligations and in Swing Line Loans) at the time owing to it); provided
that any such assignment shall be subject to the following conditions: 
 (i) Minimum Amounts. 

(A) in the case of an assignment of the entire remaining amount of the assigning Lender’s Commitment under the
revolving or term loan credit facility hereunder together with the Loans at the time owing to it under such facility or in the case of an assignment to a Lender, an Affiliate of a Lender or an Approved Fund, no minimum amount need be assigned; and

 (B) in any case not described in subsection (b)(i)(A) of this Section, the aggregate amount of the Commitment
(which for this purpose includes Loans outstanding thereunder) or, if the Commitment is not then in effect, the principal outstanding balance of the Loans of the assigning Lender subject to each such assignment, determined as of the date the
Assignment and Assumption with respect to such assignment is delivered to the Administrative Agent or, if “Trade Date” is specified in the Assignment and Assumption, as of the Trade Date, shall not be less than $2,000,000 unless each of
the Administrative Agent and, so long as no Event of Default has occurred and is continuing, the Borrower otherwise consents (each such consent not to be unreasonably withheld or delayed); provided, however, that concurrent assignments
to members of an Assignee Group and concurrent assignments from members of an Assignee Group to a single Eligible Assignee (or to an Eligible Assignee and members of its Assignee Group) will be treated as a single assignment for purposes of
determining whether such minimum amount has been met; 
 (ii) Proportionate Amounts. Each partial
assignment shall be made as an assignment of a proportionate part of all the assigning Lender’s rights and obligations under this Agreement with respect to the Loans or the Commitment assigned, except that this clause (ii) shall not
(A) apply to the Swing Line Lender’s rights and obligations in respect of Swing Line Loans or (B) prohibit any Lender from assigning all or a portion of its rights and obligations among the revolving or term loan credit facility
hereunder on a non-pro rata basis; 
 (iii) Required Consents. No consent shall be required for any
assignment except to the extent required by subsection (b)(i)(B) of this Section and, in addition: 
 (A) the
consent of the Borrower (such consent not to be unreasonably withheld or delayed) shall be required unless (1) an Event of Default has occurred and is continuing at the time of such assignment or (2) such assignment is to a Lender, an
Affiliate of a Lender or an Approved Fund; provided that the Borrower shall be deemed to have consented to any such assignment unless it shall object thereto by written notice to the Administrative Agent within five (5) Business Days after
having received notice thereof; 
  

 108 

 (B) the consent of the Administrative Agent (such consent not to be
unreasonably withheld or delayed) shall be required for assignments in respect of (1) any Revolving Commitment if such assignment is to a Person that is not a Lender with a Revolving Commitment, an Affiliate of such Lender or an Approved Fund
with respect to such Lender or (2) any Term Loan to a Person that is not a Lender, an Affiliate of a Lender or an Approved Fund; 
 (C) the consent of the L/C Issuer (such consent not to be unreasonably withheld or delayed) shall be required for any assignment that increases the obligation of the assignee to participate in exposure
under one or more Letters of Credit (whether or not then outstanding); and 
 (D) the consent of the Swing Line
Lender (such consent not to be unreasonably withheld or delayed) shall be required for any assignment of a Revolving Commitment if such assignment is to a Person that is not a Lender with a Revolving Commitment. 
 (iv) Assignment and Assumption. The parties to each assignment shall execute and deliver to the Administrative Agent
an Assignment and Assumption, together with a processing and recordation fee in the amount of $3,500; provided, however, that the Administrative Agent may, in its sole discretion, elect to waive such processing and recordation fee in
the case of any assignment. The assignee, if it is not a Lender, shall deliver to the Administrative Agent an Administrative Questionnaire. 
 (v) No Assignment to Certain Persons. No such assignment shall be made (A) to the Borrower or any of the Borrower’s Affiliates or Subsidiaries, (B) to any Defaulting Lender or any of
its Subsidiaries, or any Person who, upon becoming a Lender hereunder, would constitute any of the foregoing Persons described in this clause (B), or (C) to a natural person. 
 (vi) Certain Additional Payments. In connection with any assignment of rights and obligations of any Defaulting Lender
hereunder, no such assignment shall be effective unless and until, in addition to the other conditions thereto set forth herein, the parties to the assignment shall make such additional payments to the Administrative Agent in an aggregate amount
sufficient, upon distribution thereof as appropriate (which may be outright payment, purchases by the assignee of participations or subparticipations, or other compensating actions, including funding, with the consent of the Borrower and the
Administrative Agent, the applicable pro rata share of Loans previously requested but not funded by the Defaulting Lender, to each of which the applicable assignee and assignor hereby irrevocably consent), to (A) pay and satisfy in full all
payment liabilities then owed by such Defaulting Lender to the Borrower, the Administrative Agent or any Lender hereunder (and interest accrued thereon) and (B) acquire (and fund as appropriate) its full pro rata share of all Loans and
participations in Letters of Credit and Swing Line Loans in accordance with its Pro Rata Share. 
 Subject to acceptance and
recording thereof by the Administrative Agent pursuant to subsection (c) of this Section, from and after the effective date specified in each Assignment and Assumption, the assignee thereunder shall be a party to this Agreement and, to the
extent of the interest assigned by such Assignment and Assumption, have the rights and obligations of a Lender under this Agreement, and the assigning Lender thereunder shall, to the extent of the interest assigned by such

  

 109 

 
Assignment and Assumption, be released from its obligations under this Agreement (and, in the case of an Assignment and Assumption covering all of the assigning Lender’s rights and
obligations under this Agreement, such Lender shall cease to be a party hereto) but shall continue to be entitled to the benefits of Section 3.01, 3.04, 3.05, and 11.04 with respect to facts and circumstances
occurring prior to the effective date of such assignment. Upon request, the Borrower (at its expense) shall execute and deliver a Note to the assignee Lender (which shall be exchanged for any Note of the assigning Lender, if applicable). Any
assignment or transfer by a Lender of rights or obligations under this Agreement that does not comply with this subsection shall be treated for purposes of this Agreement as a sale by such Lender of a participation in such rights and obligations in
accordance with subsection (d) of this Section. 
 (c) Register. The Administrative Agent, acting solely for this
purpose as an agent of the Borrower (such agency being solely for tax purposes), shall maintain at the Administrative Agent’s Office a copy of each Assignment and Assumption delivered to it and a register for the recordation of the names and
addresses of the Lenders, and the Commitments of, and principal amounts of the Loans and L/C Obligations owing to, each Lender pursuant to the terms hereof from time to time (the “Register”). The entries in the Register shall be
conclusive absent manifest error, and the Borrower, the Administrative Agent and the Lenders may treat each Person whose name is recorded in the Register pursuant to the terms hereof as a Lender hereunder for all purposes of this Agreement,
notwithstanding notice to the contrary. In addition, the Administrative Agent shall maintain on the Register information regarding the designations, and revocation of designation, of any Lender as a Defaulting Lender. The Register shall be available
for inspection by the Borrower and any Lender at any reasonable time and from time to time upon reasonable prior notice. 
 (d)
Participations. Any Lender may at any time, without the consent of, or notice to, the Borrower or the Administrative Agent, sell participations to any Person (other than a natural person, a Defaulting Lender, the Borrower or any of the
Borrower’s Affiliates or Subsidiaries) (each, a “Participant”) in all or a portion of such Lender’s rights and/or obligations under this Agreement (including all or a portion of its Commitment and/or the Loans (including
such Lender’s participations in L/C Obligations and/or Swing Line Loans) owing to it); provided that (i) such Lender’s obligations under this Agreement shall remain unchanged, (ii) such Lender shall remain solely
responsible to the other parties hereto for the performance of such obligations and (iii) the Borrower, the Administrative Agent, the Lenders and the L/C Issuer shall continue to deal solely and directly with such Lender in connection with such
Lender’s rights and obligations under this Agreement. 
 Any agreement or instrument pursuant to which a Lender sells such
a participation shall provide that such Lender shall retain the sole right to enforce this Agreement and to approve any amendment, modification or waiver of any provision of this Agreement; provided that such agreement or instrument may
provide that such Lender will not, without the consent of the Participant, agree to any amendment, waiver or other modification described in the first proviso to Section 11.01 that affects such Participant. Subject to subsection (e)
of this Section, the Borrower agrees that each Participant shall be entitled to the benefits of Sections 3.01, 3.04 and 3.05 to the same extent as if it were a Lender and had acquired its interest by assignment pursuant to
subsection (b) of this Section. To the extent permitted by Law, each Participant also shall be entitled to the benefits of Section 11.08 as though it were a Lender; provided such Participant agrees to be subject to
Section 2.13 as though it were a Lender. 
 (e) Limitations upon Participant Rights. A Participant shall not
be entitled to receive any greater payment under Section 3.01, 3.04 or 3.05 than the applicable Lender would have been entitled to receive with respect to the participation sold to such Participant, unless the sale of the
participation to such Participant is made with the Borrower’s prior written consent. A Participant that would be a Foreign Lender if it were a Lender shall not be entitled to the benefits of Section 3.01 unless the Borrower is

  

 110 

 
notified of the participation sold to such Participant and such Participant agrees, for the benefit of the Borrower, to comply with Section 3.01(e) as though it were a Lender.

 (f) Certain Pledges. Any Lender may at any time pledge or assign a security interest in all or any portion of its
rights under this Agreement (including under its Note, if any) to secure obligations of such Lender, including any pledge or assignment to secure obligations to a Federal Reserve Bank; provided that no such pledge or assignment shall release
such Lender from any of its obligations hereunder or substitute any such pledgee or assignee for such Lender as a party hereto. 
 (g) Resignation as L/C Issuer or Swing Line Lender after Assignment. Notwithstanding anything to the contrary contained herein, if at any time Bank of America assigns all of its Commitment and Loans pursuant to subsection (b)
above, Bank of America may, (i) upon 30 days’ notice to the Borrower and the Lenders, resign as L/C Issuer and/or (ii) upon 30 days’ notice to the Borrower, resign as Swing Line Lender. In the event of any such resignation as L/C
Issuer or Swing Line Lender, the Borrower shall be entitled to appoint from among the Lenders a successor L/C Issuer or Swing Line Lender hereunder; provided, however, that no failure by the Borrower to appoint any such successor shall
affect the resignation of Bank of America as L/C Issuer or Swing Line Lender, as the case may be. If Bank of America resigns as L/C Issuer, it shall retain all the rights, powers, privileges and duties of the L/C Issuer hereunder with respect to all
Letters of Credit outstanding as of the effective date of its resignation as L/C Issuer and all L/C Obligations with respect thereto (including the right to require the Lenders to make Base Rate Loans or fund risk participations in Unreimbursed
Amounts pursuant to Section 2.03(c)). If Bank of America resigns as Swing Line Lender, it shall retain all the rights and duties of the Swing Line Lender provided for hereunder with respect to Swing Line Loans made by it and outstanding
as of the effective date of such resignation, including the right to require the Lenders to make Base Rate Loans or fund risk participations in outstanding Swing Line Loans pursuant to Section 2.04(c). Upon the appointment of a successor
L/C Issuer and/or Swing Line Lender, (a) such successor shall succeed to and become vested with all of the rights, powers, privileges and duties of the retiring L/C Issuer or Swing Line Lender, as the case may be, and (b) the successor L/C
Issuer shall issue letters of credit in substitution for the Letters of Credit, if any, outstanding at the time of such succession or make other arrangements satisfactory to Bank of America to effectively assume the obligations of Bank of America
with respect to such Letters of Credit. 
  

	11.07	Confidentiality. 

 Each of
the Administrative Agent, the Lenders and the L/C Issuer agrees to maintain the confidentiality of the Information (as defined below), except that Information may be disclosed (a) to its Affiliates and to its and its Affiliates’ respective
partners, directors, officers, employees, agents, advisors and representatives (it being understood that the Persons to whom such disclosure is made will be informed of the confidential nature of such Information and instructed to keep such
Information confidential), (b) to the extent requested by any regulatory authority purporting to have jurisdiction over it (including any self-regulatory authority, such as the National Association of Insurance Commissioners), (c) to the
extent required by applicable Laws or by any subpoena or similar legal process, (d) to any other party hereto, (e) to the extent reasonably necessary, in connection with the exercise of any remedies hereunder or under any other Loan
Document or any action or proceeding relating to this Agreement or any other Loan Document or the enforcement of rights hereunder or thereunder, (f) subject to an agreement containing provisions substantially the same as those of this Section
(with the applicable Loan Party, Subsidiary or Affiliate as an express third-party beneficiary), to (i) any assignee of or Participant in, or any prospective assignee of or Participant in, any of its rights or obligations under this Agreement
or any Person invited to become a Lender under Section 2.02(f) or (ii) any actual or prospective counterparty (or its advisors) to any swap or derivative transaction relating to the Borrower and its obligations, (g) with the
consent of the Borrower or (h) to the extent such Information (x) becomes

  

 111 

 
publicly available other than as a result of a breach of this Section or (y) becomes available to the Administrative Agent, any Lender, the L/C Issuer or any of their respective
Affiliates on a nonconfidential basis from a source other than a Loan Party, a Subsidiary or an Affiliate thereof. 
 For
purposes of this Section, “Information” means all information received from a Loan Party, any Subsidiary or any of their Affiliates relating to a Loan Party or any Subsidiary or any of their respective businesses or Affiliates,
other than any such information that is available to the Administrative Agent, any Lender or the L/C Issuer on a nonconfidential basis prior to disclosure by a Loan Party, any Subsidiary or such Affiliate. Any Person required to maintain the
confidentiality of Information as provided in this Section shall be considered to have complied with its obligation to do so if such Person has exercised the same degree of care to maintain the confidentiality of such Information as such Person
would accord to its own confidential information. 
 Each of the Administrative Agent, the Lenders and the L/C Issuer acknowledges that
(a) the Information may include material non-public information concerning the Loan Parties, their respective Subsidiaries or their respective Affiliates, as the case may be, (b) it has developed compliance procedures regarding the use of
material non-public information and (c) it will handle such material non-public information in accordance with applicable Law, including United States Federal and state securities Laws. 
  

	11.08	Set-off. 

 If an Event of
Default shall have occurred and be continuing, each Lender, the L/C Issuer and each of their respective Affiliates is hereby authorized at any time and from time to time, after obtaining the prior written consent of the Administrative Agent, to the
fullest extent permitted by applicable law, to set off and apply any and all deposits (general or special, time or demand, provisional or final, in whatever currency) at any time held and other obligations (in whatever currency) at any time owing by
such Person to or for the credit or the account of the Borrower or any other Loan Party against any and all of the obligations of the Borrower or such Loan Party now or hereafter existing under this Agreement or any other Loan Document to such
Lender or the L/C Issuer, irrespective of whether or not such Lender or the L/C Issuer shall have made any demand under this Agreement or any other Loan Document and although such obligations of the Borrower or such Loan Party may be contingent or
unmatured or are owed to a branch or office of such Lender or the L/C Issuer different from the branch or office holding such deposit or obligated on such indebtedness. The rights of each Lender, the L/C Issuer and their respective Affiliates under
this Section are in addition to other rights and remedies (including other rights of setoff) that such Lender, the L/C Issuer or their respective Affiliates may have. Each Lender and the L/C Issuer agrees to notify the Borrower and the
Administrative Agent promptly after any such setoff and application, provided that the failure to give such notice shall not affect the validity of such setoff and application. 
  

	11.09	Interest Rate Limitation. 

 Notwithstanding anything to the contrary contained in any Loan Document, the interest paid or agreed to be paid under the Loan Documents shall not exceed the maximum rate of non-usurious interest permitted by applicable Law (the
“Maximum Rate”). If the Administrative Agent or any Lender shall receive interest in an amount that exceeds the Maximum Rate, the excess interest shall be applied to the principal of the Loans or, if it exceeds such unpaid
principal, refunded to the Borrower. In determining whether the interest contracted for, charged, or received by the Administrative Agent or a Lender exceeds the Maximum Rate, such Person may, to the extent permitted by applicable Law,
(a) characterize any payment that is not principal as an expense, fee, or premium rather than interest, (b) exclude voluntary prepayments and the effects thereof, and (c) amortize, prorate, allocate, and spread in equal or unequal
parts the total amount of interest throughout the contemplated term of the Obligations hereunder. 
  

 112 

	11.10	Counterparts. 

 This
Agreement may be executed in one or more counterparts, each of which shall be deemed an original, but all of which together shall constitute one and the same instrument. Delivery of an executed counterpart by electronic transmission shall be
effective as delivery of a manually executed counterpart. 
  

	11.11	Integration. 

 This
Agreement, together with the other Loan Documents, comprises the complete and integrated agreement of the parties on the subject matter hereof and thereof and supersedes all prior agreements, written or oral, on such subject matter. In the event of
any conflict between the provisions of this Agreement and those of any other Loan Document, the provisions of this Agreement shall control; provided that the inclusion of supplemental rights or remedies in favor of the Administrative Agent or
the Lenders in any other Loan Document shall not be deemed a conflict with this Agreement. Each Loan Document was drafted with the joint participation of the respective parties thereto and shall be construed neither against nor in favor of any
party, but rather in accordance with the fair meaning thereof. 
  

	11.12	Survival of Representations and Warranties. 

 All representations and warranties made hereunder and in any other Loan Document or other document delivered pursuant hereto or thereto or in connection herewith or therewith shall survive the execution
and delivery hereof and thereof. Such representations and warranties have been or will be relied upon by the Administrative Agent and each Lender, regardless of any investigation made by the Administrative Agent or any Lender or on their behalf and
notwithstanding that the Administrative Agent or any Lender may have had notice or knowledge of any Default at the time of any Credit Extension, and shall continue in full force and effect until such time as the Obligations are Fully Satisfied.

  

	11.13	Severability. 

 If any
provision of this Agreement or the other Loan Documents is held to be illegal, invalid or unenforceable, (a) the legality, validity and enforceability of the remaining provisions of this Agreement and the other Loan Documents shall not be
affected or impaired thereby and (b) the parties shall endeavor in good faith negotiations to replace the illegal, invalid or unenforceable provisions with valid provisions the economic effect of which comes as close as possible to that of the
illegal, invalid or unenforceable provisions. The invalidity of a provision in a particular jurisdiction shall not invalidate or render unenforceable such provision in any other jurisdiction. Without limiting the foregoing provisions of this
Section 11.13, if and to the extent that the enforceability of any provisions in this Agreement relating to Defaulting Lenders shall be limited by Debtor Relief Laws, as determined in good faith by the Administrative Agent, the L/C Issuer or
the Swing Line Lender, as applicable, then such provisions shall be deemed to be in effect only to the extent not so limited. 
  

	11.14	Replacement of Lenders. 

 If (a) any Lender requests compensation under Section 3.04, (b) the Borrower is required to pay any additional amount to any Lender or any Governmental Authority for the account of any Lender pursuant to Sections
3.01 or 3.04, (c) any Lender is subject to illegality under Section 3.02, (d) a Lender (a “Non-Consenting Lender”) does not consent to a proposed change, waiver, discharge or termination with respect
to any Loan Document that has been approved by the Required Lenders as provided in Section 11.01 but requires unanimous consent of all Lenders or all Lenders directly affected thereby (as applicable) or (e) any Lender is a
Defaulting Lender, then, so long as an Event of Default does not then

  

 113 

 
exist, the Borrower may, at its sole expense and effort, upon notice to such Lender and the Administrative Agent, require such Lender to assign and delegate, without recourse (in accordance with
and subject to the restrictions contained in, and consents required by, Section 11.06), all of its interests, rights and obligations under this Agreement and the Loan Documents to an assignee that shall assume such obligations (which
assignee may be another Lender, if a Lender accepts such assignment), provided that: 
 (i) Administrative
Agent shall have received the assignment fee specified in Section 11.06(b); 
 (ii) such Lender shall
have received payment of an amount equal to the outstanding principal of its Loans and L/C Advances, accrued interest thereon, accrued fees and all other amounts payable to it hereunder and under the other Loan Documents (including any amounts under
Section 3.05) from the assignee (to the extent of such outstanding principal and accrued interest and fees) or the Borrower (in the case of all other amounts); 
 (iii) in the case of any such assignment resulting from a claim for compensation under Section 3.04 or payments
required to be made pursuant to Section 3.01, such assignment will result in a reduction in such compensation or payments thereafter; 
 (iv) such assignment does not conflict with applicable Laws; and 
 (v) in the case of any such assignment resulting from a Non-Consenting Lender’s failure to consent to a proposed change, waiver, discharge or termination with respect to any Loan Document, the applicable assignee consents to the
proposed change, waiver, discharge or termination; provided that the failure by such Non-Consenting Lender to execute and deliver an Assignment and Assumption shall not impair the validity of the removal of such Non-Consenting Lender and the
mandatory assignment of such Non-Consenting Lender’s Commitments and outstanding Loans and participations in L/C Obligations and Swing Line Loans pursuant to this Section 11.14 shall nevertheless be effective without the execution
by such Non-Consenting Lender of an Assignment and Assumption. 
 A Lender shall not be required to make any such assignment or
delegation if, prior thereto, as a result of a waiver by such Lender or otherwise, the circumstances entitling the Borrower to require such assignment and delegation cease to apply. 
  

	11.15	Governing Law; Jurisdiction, Etc. 

 (a) THIS AGREEMENT SHALL BE GOVERNED BY, AND CONSTRUED IN ACCORDANCE WITH, THE LAW OF THE STATE OF NEW YORK, WITHOUT GIVING EFFECT TO ITS PRINCIPLES OR RULES OF CONFLICTS OF LAWS TO THE EXTENT THAT THE SAME ARE NOT MANDATORILY APPLICABLE BY
STATUTE AND THE APPLICATION OF THE LAWS OF ANOTHER STATE WOULD BE REQUIRED THEREBY; PROVIDED THAT THE BORROWER, THE ADMINISTRATIVE AGENT AND EACH LENDER SHALL RETAIN ALL RIGHTS ARISING UNDER FEDERAL LAW. 
 (b) ANY LEGAL ACTION OR PROCEEDING WITH RESPECT TO THIS AGREEMENT OR ANY OTHER LOAN DOCUMENT MAY BE BROUGHT IN THE COURTS OF THE STATE OF
NEW YORK SITTING IN NEW YORK, NEW YORK OR OF THE UNITED STATES FOR THE SOUTHERN DISTRICT OF SUCH STATE, AND BY EXECUTION AND DELIVERY OF THIS AGREEMENT, EACH PARTY HERETO CONSENTS, FOR ITSELF AND IN RESPECT OF ITS PROPERTY, TO THE NON-EXCLUSIVE
JURISDICTION OF THOSE COURTS. EACH PARTY

  

 114 

 
HERETO IRREVOCABLY WAIVES ANY OBJECTION, INCLUDING ANY OBJECTION TO THE LAYING OF VENUE OR BASED ON THE GROUNDS OF FORUM NON CONVENIENS, WHICH IT MAY NOW OR HEREAFTER HAVE TO THE BRINGING
OF ANY ACTION OR PROCEEDING IN SUCH JURISDICTION IN RESPECT OF ANY LOAN DOCUMENT OR OTHER DOCUMENT RELATED THERETO. 
 (c) EACH
PARTY HERETO IRREVOCABLY CONSENTS TO SERVICE OF PROCESS IN THE MANNER PROVIDED FOR NOTICES IN SECTION 11.02. NOTHING IN THIS AGREEMENT WILL AFFECT THE RIGHT OF ANY PARTY TO SERVE PROCESS IN ANY OTHER MANNER PERMITTED BY APPLICABLE LAW.

  

	11.16	California Judicial Reference. 

 If any action or proceeding is filed (other than by an Indemnitee) in a court of the State of California by or against any party hereto in connection with any of the transactions contemplated by this Agreement or any other Loan Document,
(a) the court shall, and is hereby directed to, make a general reference pursuant to California Code of Civil Procedure Section 638 to a referee (who shall be a single active or retired judge) to hear and determine all of the issues in
such action or proceeding (whether of fact or of law) and to report a statement of decision, provided that at the option of any party to such proceeding, any such issues pertaining to a “provisional remedy” as defined in California
Code of Civil Procedure Section 1281.8 shall be heard and determined by the court, and (b) without limiting the generality of Section 11.04, the Borrower shall be solely responsible to pay all fees and expenses of any referee
appointed in such action or proceeding; provided, that the Borrower shall not be responsible for or required to pay any such fees or expenses to the extent that any such action or proceeding arises or results from, or in connection with, the
gross negligence or willful misconduct of any Indemnitee or any claim brought by any Loan Party or Subsidiary against an Indemnitee for breach in bad faith by such Indemnitee of such Indemnitee’s obligations hereunder or under any other Loan
Document. 
  

	11.17	Waiver of Right to Trial by Jury. 

 EACH PARTY HERETO HEREBY IRREVOCABLY WAIVES, TO THE FULLEST EXTENT PERMITTED BY APPLICABLE LAW, ANY RIGHT IT MAY HAVE TO A TRIAL BY JURY IN ANY LEGAL PROCEEDING DIRECTLY OR INDIRECTLY ARISING OUT OF OR RELATING TO THIS AGREEMENT OR ANY
OTHER LOAN DOCUMENT OR THE TRANSACTIONS CONTEMPLATED HEREBY OR THEREBY (WHETHER BASED ON CONTRACT, TORT OR ANY OTHER THEORY). EACH PARTY HERETO (A) CERTIFIES THAT NO REPRESENTATIVE, AGENT OR ATTORNEY OF ANY OTHER PERSON HAS REPRESENTED,
EXPRESSLY OR OTHERWISE, THAT SUCH OTHER PERSON WOULD NOT, IN THE EVENT OF LITIGATION, SEEK TO ENFORCE THE FOREGOING WAIVER AND (B) ACKNOWLEDGES THAT IT AND THE OTHER PARTIES HERETO HAVE BEEN INDUCED TO ENTER INTO THIS AGREEMENT AND THE OTHER
LOAN DOCUMENTS BY, AMONG OTHER THINGS, THE MUTUAL WAIVERS AND CERTIFICATIONS IN THIS SECTION. 
  

	11.18	USA PATRIOT Act Notice. 

 Each Lender that is subject to the Act (as hereinafter defined) and the Administrative Agent (for itself and not on behalf of any Lender) hereby notifies the Borrower that pursuant to the requirements of the USA PATRIOT Act (Title III
of Pub. L. 107-56 (signed into Law October 26, 2001)) (the “Act”), it is required to obtain, verify and record information that identifies the Borrower, which information includes the name and address of the Borrower and other
information that will allow such Lender or the Administrative Agent, as applicable, to identify the Borrower in accordance with the Act. The Borrower

  

 115 

 
shall, promptly following a request by the Administrative Agent or any Lender, provide all documentation and other information that the Administrative Agent or such Lender reasonably requests in
order to comply with its ongoing obligations under applicable “know your customer” and anti-money laundering rules and regulations, including the Act. 
  

	11.19	No Advisory or Fiduciary Relationship. 

 In connection with all aspects of each transaction contemplated hereby (including in connection with any amendment, waiver or other modification hereof or of any other Loan Document, the Borrower
acknowledges and agrees, and acknowledges its Affiliates’ understanding, that: (a)(i) the arranging and other services regarding this Agreement provided by the Administrative Agent, the Syndication Agent, the Arrangers and, if applicable, any
other Lender, are arm’s-length commercial transactions between the Borrower and its Affiliates, on the one hand, and the Administrative Agent, the Syndication Agent, the Arrangers and, if applicable such Lender, on the other hand, (ii) the
Borrower has consulted its own legal, accounting, regulatory and tax advisors to the extent it has deemed appropriate, and (iii) the Borrower is capable of evaluating, and understands and accepts, the terms, risks and conditions of the
transactions contemplated hereby and by the other Loan Documents; (b)(i) the Administrative Agent, the Syndication Agent, each Arranger and each Lender each is and has been acting solely as a principal and, except as expressly agreed in writing by
the relevant parties, has not been, is not and will not be acting as an advisor, agent or fiduciary, for the Borrower or any of its Affiliates or any other Person and (ii) neither the Administrative Agent, the Syndication Agent, either Arranger
nor any Lender has any obligation to the Borrower or any of its Affiliates with respect to the transactions contemplated hereby except those obligations expressly set forth herein and in the other Loan Documents; and (c) the Administrative
Agent, the Syndication Agent, the Arrangers, the Lenders and their respective Affiliates may be engaged in a broad range of transactions that involve interests that differ from those of the Borrower and its Affiliates, and none of the Administrative
Agent, the Syndication Agent, either Arranger nor any Lender has any obligation to disclose any of such interests to the Borrower or its Affiliates. To the fullest extent permitted by law, the Borrower hereby waives and releases, any claims that it
may have against the Administrative Agent, the Syndication Agent, either Arranger or any Lender with respect to any breach or alleged breach of agency or fiduciary duty in connection with any aspect of any transaction contemplated hereby.

  

	11.20	Electronic Execution of Assignments and Certain Other Documents. 

 The words “execution,” “signed,” “signature” and words of like import in any Assignment and Assumption or in any amendment or other modification hereof (including waivers and
consents) shall be deemed to include electronic signatures or the keeping of records in electronic form, each of which shall be of the same legal effect, validity or enforceability as a manually executed signature or the use of a paper-based
recordkeeping system, as the case may be, to the extent and as provided for in any applicable law, including the Federal Electronic Signatures in Global and National Commerce Act, the New York State Electronic Signatures and Records Act, or any
other similar state laws based on the Uniform Electronic Transactions Act. 
  

	11.21	Certain Matters Regarding the Proleukin Distribution Agreement. 

 Each of the Administrative Agent and the other Secured Parties hereby acknowledges and agrees that (a) pursuant to Section 10.7(d) of the Proleukin Distribution Agreement, upon expiration or
termination of the Proleukin Distribution Agreement, all New Product Regulatory Approvals shall be transferred and assigned to Novartis and (b) pursuant to Section 10.9 of the Proleukin Distribution Agreement, Borrower has designated and
appointed Novartis as its attorney-in-fact to execute and deliver all such agreements, instruments, certificates and other documents, file any of the foregoing with

  

 116 

 
applicable regulatory authorities and other Governmental Authorities, and take all other actions as are reasonably necessary, upon expiration or termination of the Proleukin Distribution
Agreement for any reason (other than termination by Borrower pursuant to Sections 10.2, 10.3, 10.4 or 10.6 thereof), to effectuate the provisions of Section 10.7(d) and Section 10.9 of the Proleukin Distribution Agreement, including to
submit a transfer letter to the Food and Drug Administration in a form agreed upon by the Borrower and Novartis. No rights of the Secured Parties shall serve and the Secured Parties shall take no action to, interfere with such transfer and
assignment. 
  

	11.22	Waiver of Notice of Termination. 

 Those Lenders party hereto which are also party to the Existing Credit Agreement hereby waive any prior notice requirement under the Existing Credit Agreement with respect to the termination of commitments thereunder and the making of any
prepayments thereunder. 
 [SIGNATURE PAGES FOLLOW] 
  

 117 

 IN WITNESS WHEREOF, the parties hereto have caused this Agreement to be duly executed as of
the date first above written. 
  

					
	 BORROWER:
	 	 PROMETHEUS LABORATORIES INC.,
 a California corporation

			
		 	By:	 	 /s/ Joseph M. Limber

		 	Name:	 	Joseph M. Limber
		 	Title:	 	President & Chief Executive Officer

  

 PROMETHEUS LABORATORIES INC. 
 2009 CREDIT AGREEMENT 

					
	 ADMINISTRATIVE
 AGENT:
	 	 BANK OF AMERICA, N.A.,
 as Administrative Agent

			
		 	By:	 	 /s/ Brenda H. Little

		 	Name:	 	Brenda H. Little
		 	Title:	 	Vice President

  

 PROMETHEUS LABORATORIES INC. 
 2009 CREDIT AGREEMENT 

					
	LENDERS:	 	 BANK OF AMERICA, N.A.,
 as a Lender, L/C Issuer and Swing Line Lender

			
		 	By:	 	 /s/ Karen S. Barnes

		 	Name:	 	Karin S. Barnes
		 	Title:	 	Senior Vice President

  

 PROMETHEUS LABORATORIES INC. 
 2009 CREDIT AGREEMENT 

					
		 	SUNTRUST BANK
		 	as a Lender and as Syndication Agent
			
		 	By:	 	 /s/ Subhadra Shrivastava

		 	Name:	 	Subhadra Shrivastava
		 	Title:	 	Vice President

  

 PROMETHEUS LABORATORIES INC. 
 2009 CREDIT AGREEMENT 

					
		 	 GENERAL ELECTRIC CAPITAL CORPORATION,
 as a Lender

			
		 	By:	 	 /s/ Andrew D. Moore

		 	Name:	 	Andrew D. Moore
		 	Title:	 	Duly Authorized Signatory

  

 PROMETHEUS LABORATORIES INC. 
 2009 CREDIT AGREEMENT 

					
		 	 FIFTH THIRD BANK,
 as a Lender

			
		 	By:	 	 /s/ Jeffrey A. Thieman

		 	Name:	 	Jeffrey A. Thieman
		 	Title:	 	Vice President

  

 PROMETHEUS LABORATORIES INC. 
 2009 CREDIT AGREEMENT 

					
		 	 U.S. BANK NATIONAL ASSOCIATION,
 as a Lender

			
		 	By:	 	 /s/ Daar Woods

		 	Name:	 	Daar Woods
		 	Title:	 	SVP

  

 PROMETHEUS LABORATORIES INC. 
 2009 CREDIT AGREEMENT 

					
		 	 COMPAS BANK,
 as a
Lender

			
		 	By:	 	 /s/ Jason Consoli

		 	Name:	 	Jason Consoli
		 	Title:	 	Senior Vice President

  

 PROMETHEUS LABORATORIES INC. 
 2009 CREDIT AGREEMENT 

					
		 	 DNB NOR BANK ASA, NY BRANCH,
 as a Lender

			
		 	By:	 	 /s/ Thomas Tangen

		 	Name:	 	Thomas Tangen
		 	Title:	 	Senior Vice President
		 		 	Head of Corporate Banking
			
		 	By:	 	 /s/ Philip F. Kurpiewski

		 	Name:	 	Philip F. Kurpiewski
		 	Title:	 	Senior Vice President

  

 PROMETHEUS LABORATORIES INC. 
 2009 CREDIT AGREEMENT 

					
		 	 COMERICA BANK,
 as
a Lender

			
		 	By:	 	 /s/ Steven J. Stuckey

		 	Name:	 	Steven J. Stuckey
		 	Title:	 	Senior Vice President

  

 PROMETHEUS LABORATORIES INC. 
 2009 CREDIT AGREEMENT 

					
		 	 BANK OF THE WEST,
 as a Lender

			
		 	By:	 	 /s/ Kris Ilkov

		 	Name:	 	Kris Ilkov
		 	Title:	 	Vice President

  

 PROMETHEUS LABORATORIES INC. 
 2009 CREDIT AGREEMENT 

					
		 	 CALIFORNIA BANK & TRUST,
 as a Lender

			
		 	By:	 	 /s/ Steve DeLong

		 	Name:	 	Steve DeLong
		 	Title:	 	Senior Vice President

  

 PROMETHEUS LABORATORIES INC. 
 2009 CREDIT AGREEMENT 

					
		 	 CREDIT SUISSE AG, CAYMAN ISLANDS BRANCH,
 as a Lender

			
		 	By:	 	 /s/ Karim Blasetti

		 	Name:	 	Karim Blasetti
		 	Title:	 	Vice President
			
		 	By:	 	 /s/ Mikhail Faybusovich

		 	Name:	 	Mikhail Faybusovich
		 	Title:	 	Vice President

  

 PROMETHEUS LABORATORIES INC. 
 2009 CREDIT AGREEMENT 

					
		 	 WELLS FARGO BANK, N.A.,
 as a Lender

			
		 	By:	 	 /s/ Susan Worsham

		 	Name:	 	Susan Worsham
		 	Title:	 	VP/SRM

  

 PROMETHEUS LABORATORIES INC. 
 2009 CREDIT AGREEMENT 

					
		 	 GOLDMAN SACHS BANK USA,
 as a Lender

			
		 	By:	 	 /s/ Mark Walton

		 	Name:	 	Mark Walton
		 	Title:	 	Authorized Signatory

  

 PROMETHEUS LABORATORIES INC. 
 2009 CREDIT AGREEMENT 

					
		 	 UNION BANK, N.A.,
 as a Lender

			
		 	By:	 	 /s/ Paul K. Moyer

		 	Name:	 	Paul K. Moyer
		 	Title:	 	Vice President

  

 PROMETHEUS LABORATORIES INC. 
 2009 CREDIT AGREEMENT 

					
		 	 STATE BANK OF INDIA, LOS ANGELES AGENCY,
 as a Lender:

			
		 	By:	 	 /s/ Sanjay Gautam

		 	Name:	 	Sanjay Gautam
		 	Title:	 	V.P. (Credit & Operations)

  

 PROMETHEUS LABORATORIES INC. 
 2009 CREDIT AGREEMENT 

 Schedule 2.01 
 Commitments and Pro Rata Shares 
  

													
	 Lender
	  	Revolving
Commitment	  	Pro Rata Share	 	 	Term Loan
Commitment	  	Pro Rata Share	 
					
	 Bank of America, N.A.
	  	$	5,288,461.53	  	10.576923060	% 	 	$	22,211,538.47	  	10.576923081	% 
					
	 SunTrust Bank
	  	$	5,288,461.53	  	10.576923060	% 	 	$	22,211,538.47	  	10.576923081	% 
					
	 General Electric Capital Corporation
	  	$	4,615,384.62	  	9.230769240	% 	 	$	19,384,615.38	  	9.230769229	% 
					
	 Fifth Third Bank
	  	$	4,615,384.62	  	9.230769240	% 	 	$	19,384,615.38	  	9.230769229	% 
					
	 U.S. Bank National Association
	  	$	4,615,384.62	  	9.230769240	% 	 	$	19,384,615.38	  	9.230769229	% 
					
	 Compass Bank
	  	$	4,615,384.62	  	9.230769240	% 	 	$	19,384,615.38	  	9.230769229	% 
					
	 DnB NOR Bank ASA, NY Branch
	  	$	4,615,384.62	  	9.230769240	% 	 	$	19,384,615.38	  	9.230769229	% 
					
	 Comerica Bank
	  	$	3,461,538.46	  	6.923076920	% 	 	$	14,538,461.54	  	6.923076924	% 
					
	 Bank of the West
	  	$	2,403,846.15	  	4.807692300	% 	 	$	10,096,153.85	  	4.807692310	% 
					
	 California Bank & Trust
	  	$	2,019,230.77	  	4.038461540	% 	 	$	8,480,769.23	  	4.038461538	% 
					
	 Credit Suisse AG, Cayman Islands Branch
	  	$	2,019,230.77	  	4.038461540	% 	 	$	8,480,769.23	  	4.038461538	% 
					
	 Wells Fargo Bank, N.A.
	  	$	2,019,230.77	  	4.038461540	% 	 	$	8,480,769.23	  	4.038461538	% 
					
	 Goldman Sachs Bank USA
	  	$	1,730,769.23	  	3.461538460	% 	 	$	7,269,230.77	  	3.461538462	% 
					
	 Union Bank, N.A.
	  	$	1,730,769.23	  	3.461538460	% 	 	$	7,269,230.77	  	3.461538462	% 
					
	 State Bank of India, Los Angeles Agency
	  	$	961,538.46	  	1.923076920	% 	 	$	4,038,461.54	  	1.923076924	% 
		  	 	 	  			 	 	 	  		
					
	 Total:
	  	$	50,000,000.00	  	100.000000000	% 	 	$	210,000,000.00	  	100.000000000	% 

 SCHEDULE 6.10 
 INSURANCE 
 See attached document 

 [* * *] 
  

											
	 Line
	  	 Policy #
	  	 Carrier
	  	Expiration
Date	 	 Limits
	  	 Deductibles

	 [* * *]
	  	[* * *]	  	 [* * *]
	  	[* * *]	 	[* * *]	  	[* * *]
						
	Property	  		  		  		 	[* * *]	  	[* * *]
						
	 [* * *]
	  		  		  		 	[* * *]	  	[* * *]
						
	GL	  		  		  		 	[* * *]	  	
						
	 [* * *]
	  	[* * *]	  	 [* * *]
	  	[* * *]	 	[* * *]	  	[* * *]
						
	 [* * *]
	  	[* * *]	  	 [* * *]
	  	[* * *]	 	[* * *]	  	
						
	 [* * *]
	  	[* * *]	  	 [* * *]
	  	[* * *]	 	[* * *]	  	
						
	Professional Liability	  	[* * *]	  	Landmark American Ins	  	10/1/2010	 	[* * *]	  	[* * *]
						
	 [* * *]
	  	[* * *]	  	 [* * *]
	  	[* * *]	 	[* * *]	  	[* * *]
						
	Products Liability	  	[* * *]	  	Federal Insurance Co	  	4/30/2010	 	[* * *]	  	[* * *]
						
	Products Liability	  	[* * *]	  	Chubb Argentina de	  	1/25/2010	 	[* * *]	  	[* * *]
						
	(Local Admitted Cov)	  		  	Serguros S.A.	  		 		  	
						
	Argentina	  		  		  		 		  	
						
	Products Liability	  	[* * *]	  	Lexington Insurance Co	  	4/30/2010	 	[* * *]	  	[* * *]
						
	Products Liability	  	[* * *]	  	Illinois Union Ins. Co.	  	4/30/2010	 	[* * *]	  	[* * *]
						
	 [* * *]
	  	[* * *]	  	 [* * *]
	  	[* * *]	 	[* * *]	  	[* * *]
						
	D&O/EPL	  	[* * *]	  	AWAC	  	10/1/2010	 	[* * *]	  	[* * *]
						
	 [* * *]
	  	[* * *]	  	 [* * *]
	  	[* * *]	 	[* * *]	  	[* * *]
						
	 [* * *]
	  	[* * *]	  	 [* * *]
	  	[* * *]	 	[* * *]	  	[* * *]
						
	 [* * *]
	  	[* * *]	  	 [* * *]
	  	[* * *]	 	[* * *]	  	[* * *]
						
	 [* * *]
	  	[* * *]	  	 [* * *]
	  	[* * *]	 	[* * *]	  	[* * *]

  

	***	Certain information on this page has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with
respect to the omitted portions. 

  

 SCHEDULE 6.17 
 IP RIGHTS 
 See attached schedule 

 Schedule 6.17 
 The following is a list of patents wholly or jointly owned, as indicated below, by Prometheus Laboratories Inc. (“PLI”): 
  

							
	Title	 	 Application No.
 Filing Date
	 	 Patent No.
 Filing
Date
	 	Ownership
				
	 Inflammatory Bowel
 Disease First Step
 Assay System
	 	 09/079435
 05/15/1998
	 	 6218129
 04/17/2001
	 	PLI
	 Method of Determining
 Thiopurine
 Methyltransferase
 Activity
	 	 09/859819
 05/16/2001
	 	 6576438
 06/10/2003
	 	PLI
	 Method of Determining
 Thiopurine
 Methyltransferase
 Activity
	 	 10/428272
 05/02/2003
	 	 7138250
 11/21/2006
	 	PLI
	 Methods of Diagnosing
 Liver Fibrosis
	 	 10/087188
 02/28/2002
	 	 6986995
 01/17/2006
	 	PLI
	 Methods for Direct
 Detection of Individual
 Methotrexate
 Metabolites
	 	 10/384066
 03/07/2003
	 	 6921667 (1)
 07/26/2005

	 	PLI
	 Methods of Diagnosing
 Clinical Subtyptes of
 Crohn’s Disease with
 Characteristic
 Responsiveness to Anti-
 TH1 Cytokine
Therapy
	 	 08/855825
 05/12/1997
	 	 6183951
 02/06/2001
	 	PLI and Cedars-Sinai Medical Center
	 Methods of Diagnosing
 Clinical Subtypes of
 Crohn’s Disease
	 	 08/837059
 04/11/1997
	 	 5932429
 08/03/1999
	 	PLI and Cedars-Sinai Medical Center
	 Methods for Optimizing
 Clinical Responsiveness
 to Methotrexate
 Therapy Using
 Metabolite Profiling and
 Pharmacogenetics
	 	 10/927904 (1)
 08/26/2004

	 	 7582282
 09/01/2009
	 	PLI
	 Methods of Quantifying
 Methotrexate
 Metabolites
	 	 10/232760 (1)
 08/30/2002

	 	 7563590
 07/21/2009
	 	PLI
	 Methods for Treating
 Irritable Bowel
 Syndrome
	 	 10/166401
 06/10/2002
	 	 6593336
 07/15/2003
	 	PLI
	 Medicaments for the
 Treatment of Non-
 Constipated Female
 Irritable Bowel
	 	 09529050
 04/05/2000
	 	 6284770
 09/04/2001
	 	PLI

							
	Title	 	 Application No.
 Filing Date
	 	 Patent No.
 Filing
Date
	 	Ownership
				
	 Syndrome
 Process for the
 Preparation of Lactam
 Derivatives
	 	  
 08/137228
 10/18/1993
	 	 6175014
 01/16/2001
	 	PLI
	 Tetrahydro-1h-
 Pyrido[4,3-B]Indol-1-
 One Derivatives
	 	 07/741570
 08/07/1991
	 	 5360800
 11/01/1994
	 	PLI
	 5-Ht[Sub]3 Receptor
 Antagonists for the
 Treatment of Autism
	 	 07/941951
 09/08/1992
	 	 5225407
 07/06/1993
	 	PLI
	 Process for the
 Preparation of Lactam
 Derivatives
	 	 07/704099
 05/22/1991
	 	 5196534
 03/23/1993
	 	PLI
	 Lactam Derivatives
	 	 07/691814
 04/26/1991
	 	 5183820
 02/02/1993
	 	PLI

  

	(1)	Patents licensed to Cypress Inc 

 The following is a list of wholly owned or jointly owned patent applications held by Prometheus Laboratories
Inc.: 
  

							
	Title	 	 Application No.
 Filing Date
	 	 Patent No.
 Issue Date
	 	 Status
 Remarks

				
	[***]	 	[***]	 		 	 Pending
 Published

	[***]	 	[***]	 		 	 Pending
 Published

	[***]	 	[***]	 		 	 Pending
 Published

	[***]	 	[***]	 		 	 Pending
 Published

	[***]	 	[***]	 		 	 Pending
 Published

	[***]	 	[***]	 		 	 Pending
 Published

	[***]	 	[***]	 		 	 Pending
 Published

	[***]	 	[***]	 		 	 Pending
 Published

	[***]	 	[***]	 		 	 Pending
 Published

	[***]	 	[***]	 		 	 Pending
 Published

	[***]	 	[***]	 		 	 Pending
 Published

	[***]	 	[***]	 		 	 Pending
 Published

	[***]	 	[***]	 		 	 Pending
 Published

	[***]	 	[***]	 		 	 Pending
 Published

	[***]	 	[***]	 		 	 Pending-
 Published

	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending

  

	**	Certain information on this page has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with
respect to the omitted portions. 

							
	Title	 	 Application No.
 Filing Date
	 	 Patent No.
 Issue Date
	 	 Status
 Remarks

				
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
				
	[***]	 	[***]	 		 	Pending
				
	[***]	 	[***]	 		 	Pending
				
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending

 [***] 
  

	**	Certain information on this page has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with
respect to the omitted portions. 

 The following is a list of patents and patent applications to which Prometheus Laboratories Inc. has certain
rights pursuant to a license, sublicense or other agreement: 
  

							
	Title	 	 Application No.
 Filing Date
	 	 Patent No.
 Issue Date
	 	 Status
 Remarks

				
	 Genes Involved in
 Intestinal
Inflammatory
 Diseases and Uses
 Thereof
	 	 10/240046
 01/15/2003
	 	 7592437
 09/22/2009
	 	Granted
	[***]	 	[***]	 		 	 Pending
 Published

	 Method for Optimizing
 the Use
of 6-
 Mercaptopurine in the
 Treatment
of Immune-
 Mediated
 Gastrointestinal

 Disorders
	 	 09/288344
 04/08/1999
	 	 6355623
 03/12/2002
	 	Granted
	 Method for Optimizing
 the Use
of 6-
 Mercaptopurine in the
 Treatment
of Immune-
 Mediated
 Gastrointestinal

 Disorders
	 	 10/034456
 12/27/2001
	 	 6680302
 01/20/2004
	 	Granted
	 Method of Optimizing
 Drug
Therapeutic
 Efficacy for Treatment
 of
Immune-Mediated
 Gastrointestinal
 Disorders
	 	 10/703920
 11/06/2003
	 	 6987097
 01/17/2006
	 	Granted
	 Methods of Optimizing
 Drug
Therapeutic
 Efficacy for Treatment of
 Immune-Mediated Gastrointestinal
 Disorders
	 	 11/152866
 06/14/2005
	 	 7105497
 09/12/2006
	 	Granted
	 Methods of Optimizing
 Drug
Therapeutic
 Efficacy For Treatment
 Of
Immune-Mediated
 Gastrointestinal
 Disorders
	 	 11/420694
 05/26/2006
	 	 7326694
 02/05/2008
	 	Granted
	 Methods of Optimizing
 Drug
Therapeutic
 Efficacy for Treatment
 of
Immune-Mediated
 Gastrointestinal
 Disorders
	 	 11/689472
 03/21/2007
	 	 7429570
 09/30/2008
	 	Granted

  

	**	Certain information on this page has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with
respect to the omitted portions. 

							
	Title	 	 Application No.
 Filing Date
	 	 Patent No.
 Issue Date
	 	 Status
 Remarks

				
	 Methods of Optimizing
 Drug
Therapeutic
 Efficacy for Treatment
 of
Immune-Mediated
 Gastrointestinal
 Disorders
	 	 11/690073
 03/22/2007
	 	 7425546
 09/16/2008
	 	Granted
	[***]	 	[***]	 		 	 Pending-
 Allowed

	 Compositions and
 Methods for
the
 Therapy and Diagnosis
 of
Inflammatory Bowel
 Disease
	 	 10/449857
 05/30/2003
	 	 7361733
 04/22/2008
	 	Granted
	[***]	 	[***]	 		 	 Pending
 Published

	[***]	 	[***]	 		 	 Pending
 Published

	 NOD2 Nucleic Acids
 and
Proteins
	 	10/014269	 	 6835815
 12/28/04
	 	Granted
	 NOD2 Nucleic Acids
 and
Proteins
	 	10/984710	 	 7060493
 6/13/06
	 	Granted
	 NOD2 Nucleic Acids
 and
Proteins
	 	10/002974	 	 6858391
 12/22/05
	 	Granted
	 Modulators on Nod2
 signaling

	 	 10/314506
 12/09/2002
	 	 7060442
 06/13/2006
	 	Granted
	[***]	 	[***]	 		 	 Pending–
 Allowed

	 Compositions and
 Methods Using
Bismuth
 Salts and Antimicrobials
 for
Treatment of Upper
 GI Disorders
	 	7/26/1991	 	 5256684
 10/26/1993
	 	Granted
	 Methods of Using
 Bismuth Salts
for
 Treatment of Upper GI
 Disorders
Associated
 with H.Pylori
	 	7/08/1987	 	 5601848
 2/11/1997
	 	Granted
	 Combination of H2
 Antagonists
and
 Bismuth Salts to Treat
 Gastrointestinal
 Disorders
	 	1/10/92	 	 5407688
 4/18/1995
	 	Granted
	 Combination of H2
 Antagonists
and Anti-
 infectives to Treat
 Gastrointestinal
 Disorders
	 	10/30/92	 	 6821739
 11//23/2004
	 	Granted

  

	**	Certain information on this page has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with
respect to the omitted portions. 

							
	 Diagnosis, Prevention
 and
Treatment of
 Ulcerative Colitis
 and
Clinical Subtypes
 Thereof Using
 Microbial UC Panca
 Antigen
	 	 09/041889
 03/12/1998
	 	 6033864
 03/07/2000
	 	Granted
	 Diagnosis, Prevention
 and
Treatment of
 Ulcerative Colitis, and
 Clinical Subtypes
 Thereof, Using
 Microbial UC Panca
 Antigen
	 	 10/229567
 08/27/2002
	 	 7183065
 02/27/2007
	 	Granted
	 Diagnosis, Prevention
 and
Treatment of
 Ulcerative Colitis and
 Clinical Subtypes
 Thereof Using
 Microbial UC Panca
 Antigen
	 	 09/417264
 10/12/1999
	 	 6537768
 03/25/2003
	 	Granted
	 Methods of Diagnosing
 and
Treating Crohn’s
 Disease Using
 Pseudomonas Antigens
	 	 09/976451
 10/12/2001
	 	 6821739
 11/23/2004
	 	Granted
	 IBD-Associated
 Microbial
Antigens and
 Methods of Using Same
	 	 09/303120
 04/30/1999
	 	 6309643
 10/30/2001
	 	Granted
	 IBD-Associated
 Microbial
Nucleic Acid
 Molecules
	 	 09/966608
 09/27/2001
	 	 6759530
 07/06/2004
	 	Granted
	 IBD-Associated
 Microbial
Nucleic Acid
 Molecules
	 	 10/835914
 04/30/2004
	 	 7557194
 07/07/2009
	 	Granted
	 IBD-Associated
 Microbial
Nucleic Acid
 Molecules
	 	 09/820576
 03/28/2001
	 	 6320037
 11/20/2001
	 	Granted
	 Anti-VH3-15 Reagents
 and
Methods for their
 Use
	 	 08/309025
 09/19/1994
	 	 5738847
 04/14/1998
	 	Granted
	 Methods of Screening for
 Ulcerative Colitis
 and Crohn’s Disease by
 Detecting Vh3-15
 Autoantibody and
 pANCA
	 	 08/320515
 10/07/1994
	 	 5691151
 11/25/1997
	 	Granted
	 Methods for Selectively
 Detecting Perinuclear
 Anti-Neutrophil
 Cytoplasmic Antibody
 of Ulcerative Colitis,
 Primary Sclero
	 	 08/480753
 06/07/1995
	 	 5830675
 11/03/1998
	 	Granted

							
	 Methods for Selectively
 Detecting Perinuclear
 Anti-Neutrophil
 Cytoplasmic Antibody
 of Ulcerative Colitis,
 Primary Sclero
	 	 08/320163
 10/07/1994
	 	 5750355
 05/12/1998
	 	Granted
	 Diagnosis, Prevention
 and
Treatment of
 Ulcerative Colitis, and
 Clinical Subtypes
 Thereof, Using Histone
 H1
	 	 08/837058
 04/11/1997
	 	 6074835
 06/13/2000
	 	Granted
	 Methods of Diagnosing
 a
Clinical Subtype of
 Crohn’s Disease With
 Features of Ulcerative
 Colitis
	 	 08/689870
 08/15/1996
	 	 5874233
 02/23/1999
	 	Granted
	 Methods of Diagnosing
 a
Clinical Subtype of
 Crohn’s Disease with
 Features of Ulcerative
 Colitis
	 	 08/689873
 08/15/1996
	 	 5916748
 06/29/1999
	 	Granted
	 Methods of Determining
 the
Risk of Pouchitis
 Development
	 	 08/833388
 04/04/1997
	 	 5937862
 04/17/1999
	 	Granted
	 Methods of Diagnosing
 a
Medically Resistant
 Clinical Subtype of
 Ulcerative Colitis
	 	 08/837302
 04/11/1997
	 	 5968741
 10/19/1999
	 	Granted
	 Diagnosis, Prevention
 and
Treatment of Crohn’s
 Disease Using the
 OMPC Antigen
	 	 09/575061
 05/19/2000
	 	 7138237
 11/21/2006
	 	Granted
	[***]	 	[***]	 		 	 Pending
 Published

	 Diagnostic Methods for
 Therapeutic Compounds
 and Methods for
 Monitoring
 Azathioprine Therapy
	 	 11/003306
 12/02/2004
	 	 7524851
 04/28/2009
	 	Granted
	[***]	 	[***]	 		 	 Pending-
 Published

	[***]	 	[***]	 		 	 Pending-
 Published

	[***]	 	[***]	 		 	 Pending-
 Published

	[***]	 	[***]	 		 	 Pending-
 Published

  

	***	Certain information on this page has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with
respect to the omitted portions. 

							
	[***]	 	[***]	 		 	 Pending-
 Published

	[***]	 	[***]	 		 	 Pending-
 Published

	 Genetic Testing for
 Determining the Risk of
 Pouchitis Development
	 	 09/556868
 04/12/2000
	 	 6348316
 02/19/2002
	 	Granted
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	Pending
	 Delayed release
 Formulations
(COLAL
 Delivery Systems)
 (Licensed
from
 Alizyme)
	 	 07/867696
 07/07/1992
	 	 5294448
 03/19/1994
	 	Granted
	[***]	 	[***]	 		 	 Pending
 Published

	 Control Release
 Formulations
(COLAL
 Cold Process Patents)
 (Licensed from
 Alizyme)
	 	 09/516253
 03/01/2000
	 	 6534549
 03/18/2003
	 	Granted
	 Low Temperature
 Coatings
(COLAL Cold
 Process Patents)
 (Licensed from
 Alizyme)
	 	 10/137702
 05/03/2002
	 	 6743445
 06/01/2004
	 	Granted
	[***]	 	[***]	 		 	Pending
	[***]	 	[***]	 		 	 Pending
 Published

	[***]	 	[***]	 		 	 Pending
 Published

	[***]	 	[***]	 		 	 Pending
 Published

	[***]	 	[***]	 		 	Pending
	 Oral Controlled Release
 Pellet
Formulation
 Containing Budesonide
 (licensed from
 AstraZeneca)
	 		 	 5643602
 07/01/997
	 	Granted
	 Method of Treatment of
 Ulcerative Colitis
 (licensed from
 AstraZeneca)
	 		 	 6423340
 07/23/2002
	 	Granted

 See also patents listed on Exhibit D to
Proleukin® Distribution Agreement 
  

	***	Certain information on this page has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with
respect to the omitted portions. 

					
	Mark	  	Jurisdiction	  	Status
			
	PROMETHEUS (amended from PROMETHEUS LABORATORIES)	  	United States	  	Registered (No. 2,121,190)
			
	PRO-PREDICTRX (Stylized)	  	United States	  	Registered (No. 2,372,151)
			
	PRO-PREDICTRX TPMT	  	United States	  	Registered (No. 2,389,196)
			
	PP (AND DESIGN)	  	United States	  	Registered (No. 2,321,695)
			
	PP (AND DESIGN)	  	United States	  	Registered (No. 2,825,361)
			
	IBD FIRST STEP	  	State of California	  	Registered (No. 107496)
			
	IBD FIRST STEP	  	State of California	  	Registered (No. 55061)
			
	IMURAN	  	United States	  	Registered (No. 732,654)
			
	ZYLOPRIM	  	United States	  	Registered (No. 773,095)
			
	TRANDATE	  	United States	  	Registered (No. 1,090,154)
			
	MISCELLANEOUS DESIGN	  	United States	  	Registered (No. 1,421,681)
			
	RIDAURA	  	United States	  	Registered (No. 2,823,218)
			
	RIDAURA (AND DESIGN)	  	United States	  	Registered (No. 1,382,960)
			
	HELIDAC	  	United States	  	Registered (No. 2,049,745)
			
	PRO-GENOLOGIX	  	United States	  	Registered (No. 2,887,629)
			
	PRO-GENOLOGIX (DESIGN)	  	United States	  	Registered (No. 2,887,630)
			
	PROMETHEUS (amended from PROMETHEUS LABORATORIES)	  	United States	  	Registered (No. 2,901,792)
			
	FIBROSPECT	  	United States	  	Registered (No. 2,910,143)
			
	CELIAGENE	  	United States	  	Registered (No. 3,101,234)
			
	CELIAPLUS	  	United States	  	Registered (No. 3,114,641)
			
	LACTOTYPE	  	United States	  	Registered (No. 3,114,642)
			
	FOR THE PERSON IN EVERY PATIENT	  	United States	  	Registered (No. 3,370,303)

					
			
	MISCELLANEOUS INTERLINK DESIGN	  	United States	  	Registered (No. 3,395,897)
			
	PRACTICE TO PRACTICE	  	United States	  	Registered (No. 3,338,711)
			
	MISCELLANEOUS INTERLINK DESIGN	  	United States	  	Registered (No. 3,587,887)
			
	FROM INFORMATION TO INSIGHT	  	United States	  	Pending (No. 77/525,225)
			
	MYCELIACID	  	United States	  	Pending (No. 77/693,740)
			
	MYCELIACID (AND DESIGN)	  	United States	  	Pending (No. 77/712,467)
			
	HELIX DESIGN	  	United States	  	Pending (No. 77/724,628)
			
	LOTRONEX	  	United States	  	Registered (No. 2,238,126)
			
	PROONC SQUAMOUSDX	  	United States	  	Pending (No. 77/739,339)
			
	PROONC MESOTHELIOMADX	  	United States	  	Pending (No. 77/739,346)
			
	PROONC TUMORSOURCEDX	  	United States	  	Pending (No. 77/739,359)
			
	PROONC	  	United States	  	Pending (No. 77/739,368)
			
	TUMORSOURCE	  	United States	  	Pending (No. 77/739,379)
			
	IBD FIRST STEP	  	United States	  	Pending (No. 77/760,154)
			
	COLAL-PRED (licensed from Alizyme)	  	United States	  	Registered (No. 3,216,889)
			
	COLALPRED (licensed from Alizyme)	  	United States	  	Registered (No. 2,901,032)
			
	COLAL (licensed from Alizyme)	  	United States	  	Registered (No. 2,516,171)

 See also trademarks listed on
Exhibit C to Proleukin® Distribution Agreement 

 Following is a list of U.S. Registered Copyrights either owned or jointly owned, as indicated below, by
Prometheus Laboratories Inc. (“PLI”). 
  

							
	Title	 	Registration No.	 	Registration Date	 	Ownership
				
	New advances in IBD therapeutic management	 	SR294234	 	8/21/2000	 	LI and Ernest Seidman
				
	A pathway to diagnosing IBD	 	SR281299	 	05/30/2000	 	PLI and Maria Dubinsky

 SCHEDULE 6.20(a) 
 LOCATION OF TANGIBLE PERSONAL PROPERTY 
  

					
	 Name of Party with Possession
	  	 Location (Street Address)
	  	 Description of
Equipment/Inventory/Goods

			
	Prometheus Laboratories Inc.	  	 9410 Carroll Park Drive
 San
Diego, CA 92121
	  	Laboratory equipment, furniture and fixtures, etc.
			
	TW Telecom	  	3944 Silvestri Lane Las Vegas, NV, 89120	  	IT Equipment to provide redundant systems
			
	ICS	  	420 International Blvd, Suite 500 Brooks, KY 40109	  	Warehouse/distribution for all pharmaceutical products
			
	Sharp Corporation	  	23 Carland Rd. Conshohocken, PA 19428	  	Helidac – Packaging as well as three drugs that are included in package – Bismuth, Tetracycline and Metronidizole
			
	Catalent Pharma Solutions	  	1100 Enterprise Drive Winchester KY 40391	  	Ridaura drug product
			
	Catalent Pharma Solutions	  	3001 Red Lion Rd. Philadelphia, PA 19114-1123	  	Ridaura drug product
			
	Stason Pharmaceuticals, Inc.	  	11 Morgan Irvine, CA 92618-2005	  	Mercaptopurine Active Pharmaceutical Ingredient and Mercaptopurine drug product prior to shipment to Par Pharmaceuticals.
			
	Patheon, Inc.	  	2100 Syntex Court Mississuaga, Ontario L5N 7K9 Canada	  	Lotronex drug product

 SCHEDULE 6.20(b) 
 LOCATION OF CHIEF EXECUTIVE OFFICE, ETC. 
  

							
	 Legal name of the Loan Party/
Address of Chief Executive Office
	 	 Jurisdiction of Incorporation/
 Formation
	 	 Federal Taxpayer
Identification
Number
	 	 Organizational
 Number

				
	 Prometheus Laboratories Inc.
 9410 Carroll Park Drive
 San Diego, CA 92121
	 	California	 	33-0685754	 	C 1954499

 SCHEDULE 8.01 
 EXISTING LIENS 
 None 

 SCHEDULE 8.02(b) 
 EXISTING INVESTMENTS 
  

						
	 Issuer
	  	Number of
Shares/Units	  	Percentage
Ownership	 
	 Rosetta Genomics
	  	2,000,000	  	Approx 12	% 
	 Alizyme PLC
	  	100	  	< 1	% 

 SCHEDULE 8.02(c) 
 BORROWER SUMMARY INVESTMENT POLICY 
 The Company’s Investment
Policy contemplates investments of the types below: 
  

			
	 Type
	  	 Maximum Maturity

		
	Direct obligations of the US Government (including Treasury Bills, Notes and Bonds) and permitted US Federal agencies and Government sponsored enterprises	  	24 months
	Commercial Paper	  	9 months
	Certificates of Deposit, Time Deposits & Bank Notes	  	24 months
	Repurchase Agreements	  	91 days
	Long-term Municipal Securities (fixed and floating rate)	  	24 months
	Variable Rate Demand Notes	  	91 days
	Money Market Funds	  	N/A
	Corporate Bonds, Medium Term Notes and Master Notes	  	24 months

 Repurchase Agreements shall be 102%
collateralized by U.S. Treasuries or Agencies, or a money market fund, with an AA equivalent counterparty risk. A master repurchase agreement must be executed prior to entering into a repurchase agreement. 
 All Money Market Funds must have an average weighted maturity of 90 days or less and abide by SEC regulations; funds must receive the highest rating by at
least one of the three nationally recognized rating agencies. 
 All Variable Rate Demand Notes and tax-exempt securities must be rated at least
“Aaa” by Moody’s and “AAA” by Standard and Poor’s (“S&P”). 
 Commercial paper must be rated at
least “A-1” or “P-1” by S&P or Moody’s, respectively. 
 Corporate bonds must be rated at least “AA” by
S&P and “Aa1” by Moody’s nor shall they be on credit watch for down grade at point of purchase. 
 Money Market Mutual Funds
must be rated “AAA” or “Aaa” by S&P or Moody’s respectively, nor shall they be on credit watch for down grade at point of purchase. 

 SCHEDULE 8.03 
 EXISTING INDEBTEDNESS 
 None 

 Schedule 11.02 
 CERTAIN ADDRESSES FOR NOTICES 
 1. Address for Loan Parties: 
 Prometheus Laboratories Inc. 
 9410 Carroll Park
Drive 
 San Diego, California 92121 

			
	 Telephone:
	  	858-410-6824
	 Facsimile:
	  	858-332-3402
	 Attention:
	  	Mark Spring
	 E-mail:
	  	mspring@prometheuslabs.com
	 Website:
	  	www.prometheuslabs.com

 With Copies to: 

Latham & Watkins LLP 
 12636 High Bluff
Drive 
 Suite 400 
 San Diego
California 92130 

			
	Attention:	  	Cheston Larson
	Telephone:	  	858-523-5400
	Facsimile:	  	858-523-5450
	E-mail:	  	cheston.larson@lw.com

 2. Addresses for Administrative
Agent, Swing Line Lender and L/C Issuer: 
 Agent’s Office: 
 (for payments and requests) 
 Bank of America, N.A. 
 Credit Services 
 CA4-7102-02-05 
 2001 Clayton Road Floor 2 
 Concord, California
94520 

			
	Attention:	  	Remy David
	Telephone:	  	925-675-8416
	Facsimile:	  	888-217-4730
	E-mail:	  	remedios.a.david@bankofamerica.com

 Wiring instructions: 
 Bank of America, N.A. 
 Dallas, Texas 

			
	 ABA #:
	  	[***]
	 Acct #:
	  	[***]
	 Account Name:
	  	Corporate FTA
	 Attention:
	  	Remy David
	 Ref:
	  	Prometheus Laboratories Inc.

 Other Notices to
Administrative Agent: 
 Bank of America, N.A. 
 Agency Management 
 WA1-501-17-32 
 800 5th Avenue, Floor 17 
 Seattle, Washington 98104 

			
	Attention:	  	Brenda H. Little, VP
	Telephone:	  	206-358-0048
	Telecopier:	  	415-343-0557
	E-mail:	  	brenda.h.little@bankofamerica.com

 For Notices as
L/C Issuer: 
 Bank of America, N.A. 
 Trade Operation 
 CA9-705-07-05 
 1000 W Temple ST Floor 7 
 Los Angeles, California 90012 

			
	Attention:	  	Bolivar Carrillo
	Telephone:	  	213-481-7842
	Facsimile:	  	213-580-8841
	E-mail:	  	bolivar.carrillo@bankofamerica.com

 For Notices as
Swing Line Lender: 
 (daily borrowing/repaying activity) 
 Bank of America, N.A. 
 Credit Services 
 CA4-7102-02-05 
 2001 Clayton Road, Floor 2

 Concord, California 94520 

			
	Attention:	  	Remy David
	Telephone:	  	925-675-8416
	Facsimile:	  	888-217-4730
	E-mail:	  	remedios.a.david@bankofamerica.com

  

	***	Certain information on this page has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with
respect to the omitted portions. 

 Wiring Instructions: 
 Bank of America, N.A. 
 Dallas, Texas 

			
	ABA #:	  	[***]
	Acct #:	  	[***]
	Account Name:	  	Corporate FTA
	Attention:	  	Remy David
	Ref:	  	Prometheus Laboratories Inc.

  

	***	Certain information on this page has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with
respect to the omitted portions. 

 EXHIBIT A 
 FORM OF LOAN NOTICE 
 Date:
                ,          
  

	To:	Bank of America, N.A., as Administrative Agent 

 Ladies and Gentlemen: 
 Reference is made to that certain Credit Agreement (as amended, modified, supplemented or
extended from time to time, the “Credit Agreement”) dated as of December 21, 2009 among Prometheus Laboratories Inc., a California corporation (the “Borrower”), the Guarantors from time to time party thereto,
the Lenders from time to time party thereto, Bank of America, N.A., as Administrative Agent, Swing Line Lender and L/C Issuer, and SunTrust Bank, as Syndication Agent. Capitalized terms used but not otherwise defined herein have the meanings
provided in the Credit Agreement. 
 The undersigned hereby requests (select one): 
  

			
	 ̈  A Borrowing of Revolving Loans	  	 ̈  A conversion or continuation of Revolving Loans
		
	 ̈  A Borrowing of the Term Loan	  	 ̈  A conversion or continuation of Term Loans

  

	1.	On                     , 20     (which is a
Business Day). 

  

	2.	In the amount of $            . 

  

	3.	Comprised of                  (Type of Loan requested). 

  

	4.	For Eurodollar Rate Loans: with an Interest Period
of                     months. 

 (a) With respect to any Borrowing of Revolving Loans requested herein, the Borrower hereby represents and warrants that after giving effect to such Borrowing, the Total Revolving Outstandings shall not
exceed the Aggregate Revolving Commitments and (b) with respect to any Borrowing, each of the conditions set forth in Section 5.02 of the Credit Agreement has been satisfied on and as of the date of such Borrowing. 
 The undersigned is executing this Loan Notice not in the undersigned’s individual capacity, but in the undersigned’s capacity as a
Responsible Officer of the Borrower. 
  

			
	PROMETHEUS LABORATORIES INC.,
	a California corporation
		
	By:	 	  

	Name:	 	
	Title:	 	

 EXHIBIT B 
 FORM OF SWING LINE LOAN NOTICE 
 Date:
                    ,          
  

	To:	Bank of America, N.A., as Swing Line Lender 

 Bank of America, N.A., as Administrative Agent 
 Ladies and Gentlemen: 
 Reference is made to that certain Credit Agreement (as amended, modified, supplemented or extended from time to time, the “Credit
Agreement”) dated as of December 21, 2009 among Prometheus Laboratories Inc., a California corporation (the “Borrower”), the Guarantors from time to time party thereto, the Lenders from time to time party thereto, Bank
of America, N.A., as Administrative Agent, Swing Line Lender and L/C Issuer, and SunTrust Bank, as Syndication Agent. 
 The
undersigned hereby requests a Swing Line Loan: 
  

	 	1.	On                  (a Business Day). 

  

	 	2.	In the amount of $            . 

 The Borrower hereby represents and warrants that each of the conditions set forth in Section 5.02 of the Credit Agreement have
been satisfied on and as of the date of the requested Borrowing of a Swing Line Loan. 
 The undersigned is executing this Swing
Line Loan Notice not in the undersigned’s individual capacity, but in the undersigned’s capacity as a Responsible Officer of the Borrower. 
  

			
	PROMETHEUS LABORATORIES INC.,
	a California corporation
		
	By:	 	  

	Name:	 	
	Title:	 	

 EXHIBIT C-1 
 FORM OF REVOLVING NOTE 
                     ,          
 FOR VALUE RECEIVED, the undersigned (the “Borrower”), hereby promises to pay to
                    or its registered assigns (the “Lender”), in accordance with the provisions of the Credit Agreement (as
hereinafter defined), the principal amount of each Revolving Loan from time to time made by the Lender to the Borrower under that certain Credit Agreement dated as of December 21, 2009 (as amended, modified, supplemented or extended from time
to time, the “Credit Agreement”) among the Borrower, the Guarantors from time to time party thereto, the Lenders from time to time party thereto, Bank of America, N.A., as Administrative Agent, Swing Line Lender and L/C Issuer and,
and SunTrust Bank, as Syndication Agent. Capitalized terms used but not otherwise defined herein have the meanings provided in the Credit Agreement. 
 The Borrower promises to pay interest on the unpaid principal amount of each Revolving Loan from the date of such Revolving Loan until such principal amount is paid in full, at such interest rates and at such times as provided in the Credit
Agreement. All payments of principal and interest shall be made to the Administrative Agent for the account of the Lender in Dollars in immediately available funds at the Administrative Agent’s Office. If any amount is not paid in full when due
hereunder, such unpaid amount shall bear interest, to be paid upon demand, from the due date thereof until the date of actual payment computed at the per annum rate set forth in the Credit Agreement. 
 This Revolving Note is one of the Revolving Notes referred to in the Credit Agreement, is entitled to the benefits thereof and may be prepaid in whole or in
part subject to the terms and conditions provided therein. This Revolving Note is also entitled to the benefits of the Guaranty, and is secured by the Collateral. Upon the occurrence and during the continuation of one or more of the Events of
Default specified in the Credit Agreement, all amounts then remaining unpaid on this Revolving Note shall become, or may be declared to be, immediately due and payable all as provided in the Credit Agreement. Revolving Loans made by the Lender shall
be evidenced by one or more loan accounts or records maintained by the Lender in the ordinary course of business. The Lender may also attach schedules to this Revolving Note and endorse thereon the date, amount and maturity of its Revolving Loans
and payments with respect thereto. 
 The Borrower, for itself, its successors and assigns, hereby waives diligence, presentment, protest and
demand and notice of protest, demand, dishonor and nonpayment of this Revolving Note. 
 THIS REVOLVING NOTE SHALL BE GOVERNED BY AND CONSTRUED
IN ACCORDANCE WITH THE LAWS OF THE STATE OF NEW YORK. 
  

			
	PROMETHEUS LABORATORIES INC.,
	a California corporation
		
	By:	 	  

	Name:	 	
	Title:	 	

 EXHIBIT C-2 
 FORM OF SWING LINE NOTE 
                     ,          
 FOR VALUE RECEIVED, the undersigned (the “Borrower”), hereby promises to pay to BANK OF AMERICA, N.A. or its registered assigns (the
“Swing Line Lender”), in accordance with the provisions of the Credit Agreement (as hereinafter defined), the principal amount of each Swing Line Loan from time to time made by the Swing Line Lender to the Borrower under that
certain Credit Agreement dated as of December 21, 2009 (as amended, restated, extended, supplemented or otherwise modified in writing from time to time, the “Credit Agreement”) among the Borrower, the Guarantors from time to
time party thereto, the Lenders from time to time party thereto, Bank of America, N.A., as Administrative Agent, Swing Line Lender and L/C Issuer, and SunTrust Bank, as Syndication Agent. Capitalized terms used but not otherwise defined herein have
the meanings provided in the Credit Agreement. 
 The Borrower promises to pay interest on the unpaid principal amount of each Swing Line Loan
from the date of such Swing Line Loan until such principal amount is paid in full, at such interest rates and at such times as provided in the Credit Agreement. All payments of principal and interest shall be made directly to the Swing Line Lender
as provided in Section 2.04 of the Credit Agreement. If any amount is not paid in full when due hereunder, such unpaid amount shall bear interest, to be paid upon demand, from the due date thereof until the date of actual payment computed at
the per annum rate set forth in the Credit Agreement. 
 This Swing Line Note is the Swing Line Note referred to in the Credit Agreement, is
entitled to the benefits thereof and may be prepaid in whole or in part subject to the terms and conditions provided therein. This Swing Line Note is also entitled to the benefits of the Guaranty and is secured by the Collateral. Upon the occurrence
and during the continuation of one or more of the Events of Default specified in the Credit Agreement, all amounts then remaining unpaid on this Swing Line Note shall become, or may be declared to be, immediately due and payable all as provided in
the Credit Agreement. Swing Line Loans made by the Swing Line Lender shall be evidenced by one or more loan accounts or records maintained by the Swing Line Lender in the ordinary course of business. The Swing Line Lender may also attach schedules
to this Swing Line Note and endorse thereon the date, amount, currency and maturity of its Swing Line Loans and payments with respect thereto. 
 The Borrower, for itself, its successors and assigns, hereby waives diligence, presentment, protest and demand and notice of protest, demand, dishonor and non-payment of this Swing Line Note. 
 THIS SWING LINE NOTE SHALL BE GOVERNED BY AND CONSTRUED IN ACCORDANCE WITH THE LAWS OF THE STATE OF NEW YORK. 
  

			
	PROMETHEUS LABORATORIES INC.,
	a California corporation
		
	By:	 	  

	Name:	 	
	Title:	 	

 EXHIBIT C-3 
 FORM OF TERM NOTE 
                     ,          
 FOR VALUE RECEIVED, the undersigned (the “Borrower”), hereby promises to pay to
                     or its registered assigns (the “Lender”), in accordance with the provisions of the Credit Agreement (as
hereinafter defined), the principal amount of each Term Loan from time to time made by the Lender to the Borrower under that certain Credit Agreement dated as of December 21, 2009 (as amended, modified, supplemented or extended from time to
time, the “Credit Agreement”) among the Borrower, the Guarantors from time to time party thereto, the Lenders from time to time party thereto and Bank of America, N.A., as Administrative Agent, Swing Line Lender and L/C Issuer, and
SunTrust Bank, as Syndication Agent. Capitalized terms used but not otherwise defined herein have the meanings provided in the Credit Agreement. 
 The Borrower promises to pay interest on the unpaid principal amount of each Term Loan from the date of such Term Loan until such principal amount is paid in full, at such interest rates and at such times as provided in the Credit
Agreement. All payments of principal and interest shall be made to the Administrative Agent for the account of the Lender in Dollars in immediately available funds at the Administrative Agent’s Office. If any amount is not paid in full when due
hereunder, such unpaid amount shall bear interest, to be paid upon demand, from the due date thereof until the date of actual payment computed at the per annum rate set forth in the Credit Agreement. 
 This Term Note is one of the Term Notes referred to in the Credit Agreement, is entitled to the benefits thereof and may be prepaid in whole or in part
subject to the terms and conditions provided therein. This Term Note is also entitled to the benefits of the Guaranty and is secured by the Collateral. Upon the occurrence and during the continuation of one or more of the Events of Default specified
in the Credit Agreement, all amounts then remaining unpaid on this Term Note shall become, or may be declared to be, immediately due and payable all as provided in the Credit Agreement. Term Loans made by the Lender shall be evidenced by one or more
loan accounts or records maintained by the Lender in the ordinary course of business. The Lender may also attach schedules to this Term Note and endorse thereon the date, amount and maturity of its Term Loans and payments with respect thereto.

 The Borrower, for itself, its successors and assigns, hereby waives diligence, presentment, protest and demand and notice of protest, demand,
dishonor and nonpayment of this Term Note. 
 THIS TERM NOTE SHALL BE GOVERNED BY AND CONSTRUED IN ACCORDANCE WITH THE LAWS OF THE STATE OF NEW
YORK. 
  

			
	PROMETHEUS LABORATORIES INC.,
	a California corporation
		
	By:	 	  

	Name:	 	
	Title:	 	

 EXHIBIT D 
 FORM OF COMPLIANCE CERTIFICATE 
 Financial Statement Date:
                    ,          
  

	To:	Bank of America, N.A., as Administrative Agent 

 Ladies and Gentlemen: 
 Reference is made to that certain Credit Agreement, dated as of December 21, 2009 (as
amended, restated, extended, supplemented or otherwise modified in writing from time to time, the “Credit Agreement;” the terms defined therein being used herein as therein defined), among Prometheus Laboratories Inc., a California
corporation (the “Borrower”), the Guarantors from time to time party thereto, the Lenders from time to time party thereto, and Bank of America, N.A., as Administrative Agent, Swing Line Lender and L/C Issuer, and SunTrust Bank, as
Syndication Agent. 
 The undersigned Responsible Officer hereby certifies as of the date hereof that he/she is the
                         of the Borrower, and that, in his/her capacity as such, he/she is authorized to execute and deliver this
Compliance Certificate to the Administrative Agent on the behalf of the Borrower, and that: 
 [Use following paragraph 1 for
fiscal year-end financial statements] 
 1. Attached hereto as Schedule 1 are the year-end audited financial
statements required by Section 7.01(a) of the Credit Agreement for the fiscal year of the Borrower ended as of the above date, together with the report and opinion of an independent certified public accountant required by such section.
Such financial statements fairly present in all material respects the financial condition and results of operations of the Borrower and its Subsidiaries in accordance with GAAP as at such date and for such period. 
 [Use following paragraph 1 for fiscal quarter-end financial statements] 
 1. Attached hereto as Schedule 1 are the unaudited financial statements required by Section 7.01(b) of the Credit
Agreement for the fiscal quarter of the Borrower ended as of the above date. Such financial statements fairly present in all material respects the financial condition and results of operations of the Borrower and its Subsidiaries in accordance with
GAAP as at such date and for such period, subject to year-end audit adjustments and the absence of footnotes. 
 2. The
undersigned has reviewed and is familiar with the terms of the Credit Agreement and has made, or has caused to be made under his/her supervision, a reasonably detailed review of the transactions and condition (financial or otherwise) of the Loan
Parties during the accounting period covered by the attached financial statements. 
 3. A review of the activities of the Loan
Parties during such fiscal period has been made under the supervision of the undersigned with a view to determining whether during such fiscal period each Loan Party performed and observed all its Obligations under the Loan Documents, and

 [select one:] 
 [to the knowledge of the undersigned, each Loan Party performed and observed each covenant and condition of the Loan Documents applicable to it, and no Default or Event of Default has occurred and is
continuing.] 

 —or— 
 [the following covenants or conditions have not been performed or observed and the following is a list of each such Default or Event of
Default and its nature and status:] 
 4. The financial covenant analyses and information set forth on Schedule 2
attached hereto are true and accurate in all material respects on and as of the date of this Compliance Certificate. 
 The
undersigned is executing this Compliance Certificate not in the undersigned’s individual capacity, but in the undersigned’s capacity as a Responsible Officer of the Borrower. 
 IN WITNESS WHEREOF, the undersigned has executed this Compliance Certificate as of
                    ,         . 
  

			
	PROMETHEUS LABORATORIES INC.,
	a California corporation
		
	By:	 	  

	Name:	 	  

	Title:	 	  

 For the Quarter/Year ended
                         
 [ 
 SCHEDULE 2 
 to the Compliance Certificate 
 ($ in 000’s) 
  

	I.	Section 8.11(a) – CONSOLIDATED LEVERAGE RATIO. 

  

							
	(a)	  	Consolidated Funded Indebtedness	  	$                
			
	(b)	  	Consolidated EBITDA	  	
				
		  	(i)	  	Consolidated Net Income	  	$                
				
		  	(ii)	  	Consolidated Interest Expense1	  	$                
				
		  	(iii)	  	 provision for federal, state,
 local and foreign income taxes1
	  	$                
				
		  	(iv)	  	depreciation and amortization expense1	  	$                
				
		  	(v)	  	 non-cash stock-based compensation charges
 and option-based severance expenses,
 and non-cash, non-recurring charges1,2
	  	$                
				
		  	(vi)	  	 federal, state, local and foreign income
 tax credits3

	  	$                
				
		  	(vii)	  	 interest income of the Loan Parties and
 their Subsidiaries on a consolidated basis3
	  	$                
				
		  	(viii)	  	 termination payment received pursuant to
 Entocort® EC Distribution Agreement4
	  	$                
				
		  	(ix)	  	 Consolidated EBITDA
 [(i) +
(ii) + (iii) + (iv) + (v) – (vi) – (vii) + (viii)]
	  	$                
			
	(c)	  	 Consolidated Leverage Ratio
 [(a) / (b)(ix)]
	  	                  :1.0

  

	1	 To the extent deducted in calculating Consolidated Net Income. 

	2	 Subject to the proviso set forth in the definition of “Consolidated EBITDA” in the Credit Agreement. 

	3	 To the extent included in calculating Consolidated Net Income. 

	4	 To the extent received during the applicable period and not otherwise included in calculating Consolidated Net Income. 

	II.	Section 8.11(b) – CONSOLIDATED FIXED CHARGE COVERAGE RATIO.

  

							
	 (a)
	  	 Consolidated EBITDA [I(b)(ix) above]
	  	$                
			
	(b)	  	 Consolidated Cash Taxes
	  	$                
			
	(c)	  	 Consolidated Fixed Charges
	  	
				
		  	(i)	  	 Consolidated Interest Expense paid in cash
	  	$                
				
		  	(ii)	  	Consolidated Scheduled Funded Debt Payments	  	$                
				
		  	(iii)	  	 Consolidated Fixed Charges
 [(i) + (ii)]
	  	$                
			
	 (d)
	  	 Consolidated Fixed Charge Coverage Ratio
 [((a) – (b)) / (c)(iii)]
	  	$                

 EXHIBIT E 
 FORM OF ASSIGNMENT AND ASSUMPTION 
 This Assignment
and Assumption (this “Assignment and Assumption”) is dated as of the Effective Date set forth below and is entered into by and between [the][each] Assignor identified in item 1 below ([the][each, an] “Assignor”) and
[the][each] Assignee identified in item 2 below ([the][each, an] “Assignee”). [It is understood and agreed that the rights and obligations of [the Assignors][the Assignees] hereunder are several and not joint.] Capitalized terms
used but not defined herein shall have the meanings given to them in the Credit Agreement identified below (the “Credit Agreement”), receipt of a copy of which is hereby acknowledged by [the][each] Assignee. The Standard Terms and
Conditions set forth in Annex 1 attached hereto are hereby agreed to and incorporated herein by reference and made a part of this Assignment and Assumption as if set forth herein in full. 
 For an agreed consideration, [the][each] Assignor hereby irrevocably sells and assigns to [the Assignee][the respective Assignees], and
[the][each] Assignee hereby irrevocably purchases and assumes from [the Assignor][the respective Assignors], subject to and in accordance with the Standard Terms and Conditions and the Credit Agreement, as of the Effective Date inserted by the
Administrative Agent as contemplated below (i) all of [the Assignor’s][the respective Assignors’] rights and obligations in [its capacity as a Lender][their respective capacities as Lenders] under the Credit Agreement and any other
documents or instruments delivered pursuant thereto to the extent related to the amount and percentage interest identified below of all of such outstanding rights and obligations of [the Assignor][the respective Assignors] under the respective
facilities identified below (including, without limitation, the Letters of Credit and the Swing Line Loans included in such facilities) and (ii) to the extent permitted to be assigned under applicable Law, all claims, suits, causes of action
and any other right of [the Assignor (in its capacity as a Lender)][the respective Assignors (in their respective capacities as Lenders)] against any Person, whether known or unknown, arising under or in connection with the Credit Agreement, any
other documents or instruments delivered pursuant thereto or the loan transactions governed thereby or in any way based on or related to any of the foregoing, including, but not limited to, contract claims, tort claims, malpractice claims, statutory
claims and all other claims at law or in equity related to the rights and obligations sold and assigned pursuant to clause (i) above (the rights and obligations sold and assigned by [the][any] Assignor to [the][any] Assignee pursuant to clauses
(i) and (ii) above being referred to herein collectively as [the][an] “Assigned Interest”). Each such sale and assignment is without recourse to [the][any] Assignor and, except as expressly provided in this Assignment and
Assumption, without representation or warranty by [the][any] Assignor. 
  

							
	1.	  	Assignor[s]:	 	                                         
                     
	  	
				
		  		 	  
	  	
				
	2.	  	Assignee[s]:	 	  
	  	
				
		  		 	  
	  	
	
	[for each Assignee, indicate [Affiliate][Approved Fund] of [identify Lender]]
		
	3.	  	Borrower: Prometheus Laboratories Inc., a California corporation
		
	4.	  	Administrative Agent: Bank of America, N.A., as the administrative agent under the Credit Agreement
		
	5.	  	Credit Agreement: Credit Agreement, dated as of December 21, 2009, among Prometheus Laboratories Inc., a California corporation (the
“Borrower”), the Guarantors from time to time party thereto, the Lenders from time to time party thereto, Bank of America, N.A., as Administrative Agent, Swing Line Lender and L/C Issuer, and SunTrust Bank, as Syndication Agent.

 6.         Assigned Interest: 
  

																
	 Assignor[s]1
	  	Assignee[s]2	  	Facility
Assigned3	  	Aggregate
Amount of
Commitment/Loans
for all Lenders4	  	Amount of
Commitment/
Loans
Assigned	  	Percentage
Assigned of
Commitment/
Loans5	 	 	CUSIP
Number
		  		  	             	  	$	            	  	$	            	  	            	% 	 	
		  		  	             	  	$	            	  	$	            	  	            	% 	 	
		  		  	             	  	$	            	  	$	            	  	            	% 	 	

  

	[7.	 Trade Date:
                        ]6 

 Effective Date:                     , 20     [TO BE INSERTED BY ADMINISTRATIVE AGENT AND WHICH SHALL BE THE EFFECTIVE
DATE OF RECORDATION OF TRANSFER IN THE REGISTER THEREFOR.] 
 The terms set forth in this Assignment and Assumption are hereby agreed to:

  

			
	ASSIGNOR
	[NAME OF ASSIGNOR]
		
	By:	 	  

	Title:	 	
	
	ASSIGNEE
	[NAME OF ASSIGNEE]
		
	By:	 	  

	Title:	 	

 [Consented to and]7 Accepted: 
  

			
	BANK OF AMERICA, N.A.,
	as Administrative Agent
		
	By:	 	  

	Title:	 	

  

	1	 List each Assignor, as appropriate. 

	2	 List each Assignee, as appropriate. 

	3	 Fill in the appropriate terminology for the types of facilities under the Credit Agreement that are being assigned under this Assignment (e.g.
“Revolving Commitment”, “Term Loan Commitment”, etc.). 

	4	 Amounts in this column and in the column immediately to the right to be adjusted by the counterparties to take into account any payments or prepayments
made between the Trade Date and the Effective Date. 

	5	 Set forth, to at least 9 decimals, as a percentage of the Commitment/Loans of all Lenders thereunder. 

	6	 To be completed if the Assignor and the Assignee intend that the minimum assignment amount is to be determined as of the Trade Date.

	7	 To be added only if the consent of the Administrative Agent is required by the terms of the Credit Agreement. 

			
	[Consented to:]8
		
	By:	 	  

	Title:	 	

  

	8	 To be added only if the consent of the Borrower and/or other parties (e.g. Swing Line Lender, L/C Issuer) is required by the terms of the Credit
Agreement. 

 ANNEX 1 TO ASSIGNMENT AND ASSUMPTION 
 STANDARD TERMS AND CONDITIONS FOR 
 ASSIGNMENT AND ASSUMPTION 
 1. Representations and Warranties.

 1.1. Assignor. [The][Each] Assignor (a) represents and warrants that (i) it is the legal and beneficial
owner of [the][[the relevant] Assigned Interest, (ii) [the][such] Assigned Interest is free and clear of any lien, encumbrance or other adverse claim and (iii) it has full power and authority, and has taken all action necessary, to execute
and deliver this Assignment and Assumption and to consummate the transactions contemplated hereby; and (b) assumes no responsibility with respect to (i) any statements, warranties or representations made in or in connection with the Credit
Agreement or any other Loan Document, (ii) the execution, legality, validity, enforceability, genuineness, sufficiency or value of the Loan Documents or any collateral thereunder, (iii) the financial condition of the Borrower, any of its
Subsidiaries or Affiliates or any other Person obligated in respect of any Loan Document or (iv) the performance or observance by the Borrower, any of its Subsidiaries or Affiliates or any other Person of any of their respective obligations
under any Loan Document. 
 1.2. Assignee. [The][Each] Assignee (a) represents and warrants that (i) it has
full power and authority, and has taken all action necessary, to execute and deliver this Assignment and Assumption and to consummate the transactions contemplated hereby and to become a Lender under the Credit Agreement, (ii) it meets all the
requirements to be an assignee under Section 11.06(b)(iii) and (v) of the Credit Agreement (subject to such consents, if any, as may be required under Section 11.06(b)(iii) of the Credit Agreement),
(iii) from and after the Effective Date, it shall be bound by the provisions of the Credit Agreement as a Lender thereunder and, to the extent of [the][the relevant] Assigned Interest, shall have the obligations of a Lender thereunder,
(iv) it is sophisticated with respect to decisions to acquire assets of the type represented by [the][such] Assigned Interest and either it, or the Person exercising discretion in making its decision to acquire [the][such] Assigned Interest, is
experienced in acquiring assets of such type, (v) it has received a copy of the Credit Agreement, and has received or has been accorded the opportunity to receive copies of the most recent financial statements delivered pursuant to
Section 7.01 thereof, as applicable, and such other documents and information as it deems appropriate to make its own credit analysis and decision to enter into this Assignment and Assumption and to purchase [the][such] Assigned Interest,
(vi) it has, independently and without reliance upon the Administrative Agent or any other Lender and based on such documents and information as it has deemed appropriate, made its own credit analysis and decision to enter into this Assignment
and Assumption and to purchase [the][such] Assigned Interest, and (vii) if it is a Foreign Lender, attached hereto is any documentation required to be delivered by it pursuant to the terms of the Credit Agreement, duly completed and executed by
[the][such] Assignee; and (b) agrees that (i) it will, independently and without reliance upon the Administrative Agent, [the][any] Assignor or any other Lender, and based on such documents and information as it shall deem appropriate at
the time, continue to make its own credit decisions in taking or not taking action under the Loan Documents, and (ii) it will perform in accordance with their terms all of the obligations which by the terms of the Loan Documents are required to
be performed by it as a Lender. 
 2. Payments. From and after the Effective Date, the Administrative Agent shall make
all payments in respect of [the][each] Assigned Interest (including payments of principal, interest, fees and other amounts) to [the][the relevant] Assignor for amounts which have accrued to but excluding the Effective Date and to [the][the
relevant] Assignee for amounts which have accrued from and after the Effective Date. 
 3. General Provisions. This
Assignment and Assumption shall be binding upon, and inure to the benefit of, the parties hereto and their respective successors and assigns. This Assignment and

 
Assumption may be executed in any number of counterparts, which together shall constitute one instrument. Delivery of an executed counterpart of a signature page of this Assignment and Assumption
by telecopy shall be effective as delivery of a manually executed counterpart of this Assignment and Assumption. This Assignment and Assumption shall be governed by, and construed in accordance with, the Law of the State of New York. 

 EXHIBIT F 
 FORM OF JOINDER AGREEMENT 
 THIS JOINDER AGREEMENT (the
“Agreement”) dated as of                     , 20         is by and among
                    , a                     (the
“New Loan Party”), and Bank of America, N.A., in its capacity as Administrative Agent under that certain Credit Agreement dated as of December 21, 2009 (as amended, restated, modified, supplemented or extended from time to
time, the “Credit Agreement”) among Prometheus Laboratories Inc., a California corporation (the “Borrower”), the Guarantors from time to time party thereto, the Lenders from time to time party thereto, Bank of
America, N.A., as the Administrative Agent, Swing Line Lender and L/C Issuer, and SunTrust Bank, as Syndication Agent. Capitalized terms used herein and not otherwise defined herein shall have the meanings assigned to such terms in the Credit
Agreement. 
 The Loan Parties are required by [Section 7.12] [Section 8.04]13 of the Credit Agreement to cause the New Loan Party to become a “Guarantor” thereunder. Accordingly, the New
Loan Party hereby agrees as follows with the Administrative Agent, for the benefit of the Lenders: 
 1. The New Loan Party
hereby acknowledges, agrees and confirms that, by its execution of this Agreement, the New Loan Party will be deemed to be a party to the Credit Agreement and a “Guarantor” for all purposes of the Credit Agreement, and shall have all of
the obligations of a Guarantor thereunder as if it had executed the Credit Agreement. The New Loan Party hereby ratifies, as of the date hereof, and agrees to be bound by, all of the terms, provisions and conditions applicable to the Guarantors
contained in the Credit Agreement. Without limiting the generality of the foregoing terms of this paragraph 1, the New Loan Party hereby jointly and severally together with the other Guarantors, guarantees to each Secured Party, as provided in
Article IV of the Credit Agreement, the prompt payment and performance of the Obligations in full when due (whether at stated maturity, as a mandatory prepayment, by acceleration, as a mandatory cash collateralization or otherwise) strictly
in accordance with the terms thereof. 
 2. The New Loan Party hereby acknowledges, agrees and confirms that, by its execution
of this Agreement, the New Loan Party will be deemed to be a party to the Security Agreement and a “Grantor” for all purposes of the Security Agreement, and shall have all the obligations of a Grantor thereunder as if it had executed the
Security Agreement. The New Loan Party hereby ratifies, as of the date hereof, and agrees to be bound by, all of the terms, provisions and conditions contained in the Security Agreement. Without limiting the generality of the foregoing terms of this
paragraph 2, the New Loan Party hereby grants to the Administrative Agent, for the benefit of the holders of the Secured Obligations (as defined in the Security Agreement), a continuing security interest in any and all right, title and interest of
the New Loan Party in and to the Collateral (as defined in the Security Agreement) of the New Loan Party to secure the prompt payment and performance in full when due, whether by lapse of time, acceleration, mandatory prepayment or otherwise, of the
Secured Obligations (as defined in the Security Agreement). 
 [3. The New Loan Party hereby acknowledges, agrees and confirms
that, by its execution of this Agreement, the New Loan Party will be deemed to be a party to the Pledge Agreement and a “Pledgor” for all purposes of the Pledge Agreement, and shall have all the obligations of a Pledgor thereunder as if it
had executed the Pledge Agreement. The New Loan Party hereby ratifies, as of the date hereof, and agrees to be bound by, all of the terms, provisions and conditions contained in the Pledge 
  

	13	 Use Section 7.12 reference if a Subsidiary. Use Section 8.04 reference if Delaware Opco.

 
Agreement. Without limiting the generality of the foregoing terms of this paragraph 3, the New Loan Party hereby grants, pledges and assigns to the Administrative Agent, for the benefit of the
holders of the Secured Obligations (as defined in the Pledge Agreement), a continuing security interest in any and all right, title and interest of the New Loan Party in and to the Equity Interests identified on Schedule 7 hereto and all
other Pledged Collateral (as defined in the Pledge Agreement) of the New Loan Party to secure the prompt payment and performance in full when due, whether by lapse of time, acceleration, mandatory prepayment or otherwise, of the Secured Obligations
(as defined in the Pledge Agreement).]14 
 4. The New Loan Party hereby represents and warrants to the Administrative Agent and the Lenders that as of the date hereof: 
 (a) The New Loan Party’s exact legal name and state of formation are as set forth on the signature pages hereto.

 (b) The New Loan Party’s chief executive office is located at the location set forth on Schedule 1
hereto. The New Loan Party’s federal taxpayer identification number and organization number are set forth on Schedule 1 hereto. 
 (c) Other than as set forth on Schedule 2 hereto, the New Loan Party has not changed its legal name, changed its state of formation, been party to a merger, consolidation or other change in
structure or used any tradename in the five years preceding the date hereof. 
 (d) Schedule 3 hereto
includes all of the trademarks, service marks, trade names, copyrights, patents, patent rights, franchises, licenses and other intellectual property rights (collectively, “IP Rights”) registered or pending with published
registration with the United States Copyright Office or the United States Patent and Trademark Office and owned by the New Loan Party as of the date hereof. As of the date hereof, none of the IP Rights of the New Loan Party set forth in Schedule
3 hereto is subject to any licensing agreement or similar arrangement, except as set forth on Schedule 3 hereto. 
 (e) Schedule 4 hereto includes all Commercial Tort Claims (as defined in the Security Agreement) seeking damages in excess of $500,000 before any Governmental Authority by or in favor of the New
Loan Party. 
 (f) Schedule 5 hereto lists all real property located in the United States that is owned or
leased by the New Loan Party. 
 (g) Schedule 6 hereto lists all locations in the United States of
tangible personal property (other than any tangible personal property that is in the possession of a sales representative of any Loan Party) that is owned or leased by the New Loan Party. 
 (h) Schedule 7 hereto includes each Subsidiary of the New Loan Party, including (i) jurisdiction of formation,
(ii) number of shares of each class of Equity Interests outstanding, (iii) the certificate number(s) of the certificates evidencing such Equity Interests and number and percentage of outstanding shares of each class owned by the New Loan
Party (directly or indirectly) of such Equity Interests and (iv) number and effect, if exercised, of all outstanding options, warrants, rights of conversion or purchase and all other similar rights with respect thereto. 
  

	14	 Paragraph 3 not necessary if Pledge Agreement to be put in place simultaneously with joinder. 

 5. The address of the New Loan Party for purposes of all notices and other communications is
the address designated for the Borrower on Schedule 11.02 to the Credit Agreement or such other address as the New Loan Party may from time to time notify the Administrative Agent in writing. 
 6. The New Loan Party hereby waives acceptance by the Secured Parties of the guaranty by the New Loan Party under Article IV of the
Credit Agreement upon the execution of this Agreement by the New Loan Party. 
 7. This Agreement may be executed in multiple
counterparts, each of which shall be deemed an original but all of which when taken together shall constitute one contract. 
 8. THIS AGREEMENT SHALL BE GOVERNED BY AND CONSTRUED AND INTERPRETED IN ACCORDANCE WITH THE LAWS OF THE STATE OF NEW YORK. 

 IN WITNESS WHEREOF, the New Loan Party has caused this Agreement to be duly executed by its
authorized officer, and the Administrative Agent, for the benefit of the Lenders, has caused the same to be accepted by its authorized officer, as of the day and year first above written. 
  

			
	[NEW LOAN PARTY]
		
	By:	 	  

	Name:	 	
	Title:	 	

 Acknowledged and accepted: 
  

			
	BANK OF AMERICA, N.A.,
	as Administrative Agent
		
	By:	 	  

	Name:	 	
	Title:	 	

 Schedule 1 
 Location of Chief Executive Office; 
 Federal Taxpayer
Identification Number; Organizational Number 
 Schedule 2 
 Changes in Legal Name or State of Formation; 
 Mergers,
Consolidations and other Changes in Structure; Tradenames 
 Schedule 3 
 IP Rights 
 Schedule 4 
 Commercial Tort Claims 
 Schedule 5 
 Real Property Locations 
 Schedule 6 
 Tangible Personal Property Locations 
 Schedule 7 
 Subsidiaries 
  

 2 

 EXHIBIT G 
 FORM OF COLLATERAL QUESTIONNAIRE 
 Prometheus
Laboratories Inc. (the “Borrower”) 
 The following terms used herein shall have the meaning given to such terms in the Uniform
Commercial Code as in effect in the state of New York: Certificated Security, Commercial Tort Claim, Deposit Account, Documents, Equipment, Goods, Instruments, Inventory, Securities Account, Securities Intermediary and Tangible Chattel Paper. As
used herein, “Loan Party” means the Borrower and each subsidiary or affiliate of the Borrower that will guarantee the obligations of the Borrower under the applicable credit documents. 
  

	1.	Names/Identification. 

  

	 	(a)	The following information is set forth on Schedule 1(a) hereto: (i) the exact legal name of each Loan Party (as it appears in its certificate of
incorporation or similar organizational document); (ii) the jurisdiction of incorporation/formation for each Loan Party; (iii) the federal taxpayer identification number for each Loan Party; and (iv) the organizational number, if any,
of each Loan Party. 

  

	 	(b)	Set forth on Schedule 1(b) hereto is each other legal name each Loan Party has had since its organization, if any, together with the date of the relevant
change. 

  

	 	(c)	Set forth on Schedule 1(c) hereto is a list of all other names (including trade names or similar appellations) used by each Loan Party or any of its divisions or
other business units at any time during the past five years, together with information regarding the state(s)/country in which such other name is/was used. 

  

	 	(d)	Except as set forth on Schedule 1(d) hereto, no Loan Party has been party to a merger, consolidation or other change in corporate structure within the past five
years. 

  

	2.	Subsidiaries. Set forth on Schedule 2 hereto is a complete and accurate list of the exact legal name of each subsidiary (as it appears in its certificate
of incorporation or similar organizational document) of each Loan Party (collectively, the “Subsidiaries”), together with (a) the jurisdiction of incorporation/formation of each Subsidiary, (b) the federal taxpayer
identification number of each Subsidiary, (c) the organizational number, if any, of each Subsidiary, (d) the number of shares of each class of capital stock or other equity interests outstanding, (e) the number and percentage of
outstanding shares of each class owned (directly or indirectly) by the applicable Loan Party and (f) an indication as to whether the shares are certificated. 

  

	3.	Locations. 

  

	 	(a)	Set forth on Schedule 3(a) hereto is the location (including street address) of the chief executive office of each Loan Party. 

  

	 	(b)	Set forth on Schedule 3(b) hereto is a list of all locations (including street address) of real property owned by each Loan Party. 

  

	 	(c)	Set forth on Schedule 3(c) hereto is a list of all locations (including street address) of real property leased by each Loan Party. 

  

 3 

	 	(d)	Set forth on Schedule 3(d) hereto is a list of all locations (other than the locations identified in 3(a), (b) or (c) above) where each Loan Party
maintains any (i) tangible personal property or (ii) Equipment, Inventory or other Goods. 

  

	 	(e)	Set forth on Schedule 3(e) hereto is a list of all persons, including addresses, other than the Loan Parties, (i) that have possession of any of the
Equipment, Inventory or other Goods owned by a Loan Party or in which such Loan Party has any interest and (ii) with whom Inventory has been lodged at any time during the past four months. 

  

	 	(f)	Set forth on Schedule 3(f) hereto is a list of any other location (street address) or place of business maintained by each Loan Party at any time during the past
five years (other than those locations listed on Schedules 3(a), 3(b) or 3(c)). 

  

	4.	Patents, Trademarks, Copyrights. Set forth on Schedule 4 hereto is a list of (a) all registered patents, trademarks and copyrights owned by each Loan
Party as of the date hereof and (b) all patent applications, trademark applications and copyright applications made by each Loan Party as of the date hereof. None of the registered patents, trademarks or copyrights or [published] patent
applications, trademark applications or copyright applications owned by the Loan Parties are subject to any licensing agreement, franchise agreement or similar arrangement except as set forth on Schedule 4. 

  

	5.	Other Certificated Securities. A complete and accurate list of all Certificated Securities (other than those of Subsidiaries identified pursuant to
Section 2 above and those held in a Securities Account) owned by each Loan Party is set forth on Schedule 5 hereto. 

  

	6.	Instruments, Tangible Chattel Paper and Documents. A complete and accurate list of all Instruments, Tangible Chattel Paper and Documents with a value in excess
of $500,000 that are owned by each Loan Party is set forth on Schedule 6 hereto. 

  

	7.	Insurance. A complete and accurate list of all insurance policies currently maintained by each Loan Party is set forth on Schedule 7 hereto.

  

	8.	Deposit Accounts. A complete and accurate list of all Deposit Accounts maintained by each Loan Party is identified on Schedule 8 hereof, including
(a) the financial institution with which such account is maintained, (b) the name of such account, (c) the account number, (d) a recent value for such account (and the date of such value) and (e) whether such account is a
payroll, withholding tax or other fiduciary account. 

  

	9.	Securities Accounts. A complete and accurate list of all Securities Accounts maintained by such Loan Party is identified on Schedule 9 hereof,
including (a) the Securities Intermediary with which such account is maintained, (b) the name of such account, (c) the account number, (d) a recent value for such account (and the date of such value) and (e) whether such
account is a fiduciary account. 

  

	10.	Commercial Tort Claims. A complete and accurate list of all Commercial Tort Claims of each Loan Party seeking damages in excess of $500,000 is set forth on
Schedule 10 hereto. 

  

	11.	Material Contracts. Set forth on Schedule 11 hereof is a complete list of the material contracts of the Loan Parties identified on the Borrower’s
Form S-1, Amendment 10, filed November 10, 2009. 

  

 4 

 IN WITNESS WHEREOF, the undersigned has executed this Collateral Questionnaire as of
December     , 2009. 
  

			
	PROMETHEUS LABORATORIES INC.,
	a California corporation
		
	By:	 	  

	Name:	 	  

	Title:	 	  

  

 5 

 EXHIBIT H 
 FORM OF 
 PLEDGE AGREEMENT 
 THIS PLEDGE AGREEMENT dated as of , 20[            ] (as
amended, modified, restated or supplemented from time to time, the “Pledge Agreement”) is by and among the parties identified as “Pledgors” on the signature pages hereto and such other parties as may become Pledgors
hereunder after the date hereof (individually a “Pledgor”, and collectively the “Pledgors”) and BANK OF AMERICA, N.A., as administrative agent (in such capacity, the “Administrative Agent”) for the
holders of the Secured Obligations (defined below). 
 W I T N E S S E T H 
 WHEREAS, credit facilities have been established in favor of Prometheus Laboratories Inc., a California corporation (the
“Borrower”), pursuant to the terms of that certain Credit Agreement (as amended, modified, restated, supplemented or extended from time to time, the “Credit Agreement”) dated as of December 21, 2009 among the
Borrower, the Guarantors from time to time party thereto, the Lenders from time to time party thereto and Bank of America, N.A., as Administrative Agent, Swing Line Lender and L/C Issuer; 
 WHEREAS, this Pledge Agreement is required under the terms of the Credit Agreement; and 
 NOW, THEREFORE, in consideration of these premises and other good and valuable consideration, the receipt and sufficiency of which are
hereby acknowledged, the parties hereto agree as follows: 
  

	1.	Definitions. 

 (a) Capitalized terms used
and not otherwise defined herein shall have the meanings provided in the Credit Agreement. 
 (b) As used herein, the following terms shall have
the meanings assigned thereto in the UCC: Accession, Financial Asset, Proceeds and Security. 
 (c) As used herein, the following terms shall
have the meanings set forth below: 
 “Administrative Agent” has the meaning provided in the
introductory paragraph hereof. 
 “Fully Satisfied” means, with respect to the Secured
Obligations as of any date, that, as of such date, (a) all principal of and interest accrued to such date which constitute Secured Obligations shall have been irrevocably paid in full in cash, (b) all fees, expenses and other amounts then
due and payable which constitute Secured Obligations shall have been irrevocably paid in cash, (c) all outstanding Letters of Credit shall have been (i) terminated, (ii) fully irrevocably Cash Collateralized or (iii) secured by
one or more letters of credit on terms and conditions, and with one or more financial institutions, reasonably satisfactory to the L/C Issuer and (d) the Commitments shall have expired or been terminated in full. 
 “Pledged Collateral” has the meaning provided in Section 2 hereof. 
 “Pledged Equity” has the meaning provided in Section 2 hereof. 
  

 6 

 “Secured Obligations” means, without duplication,
(a) the Obligations and (b) all reasonable costs and expenses incurred in connection with enforcement and collection of the Obligations including, without limitation, Attorney Costs; provided, that (x) the obligations,
liabilities, covenants, and duties owing from any Loan Party under any Secured Hedge Agreement or any Secured Cash Management Agreement shall be secured pursuant to this Pledge Agreement only to the extent that, and for so long as, the other
Obligations are so secured and (y) any release of Collateral or Pledgors effected in the manner permitted by this Pledge Agreement, the Credit Agreement or any other Loan Document shall not require the consent of holders of obligations under
any Secured Hedge Agreement or any Secured Cash Management Agreement. 
 “UCC” means the Uniform
Commercial Code as in effect from time to time in the State of New York, except as such term may be used in connection with the perfection of the Administrative Agent’s security interest in the Collateral, in which case “UCC” shall
mean the Uniform Commercial Code as in effect from time to time in the applicable jurisdiction with respect to such affected Pledged Collateral. 
 2. Pledge and Grant of Security Interest. To secure the prompt payment and performance in full when due, whether by lapse of time, acceleration, mandatory prepayment or otherwise, of the Secured
Obligations, each Pledgor hereby grants, pledges and assigns to the Administrative Agent, for the benefit of the holders of the Secured Obligations, a continuing security interest in any and all right, title and interest of such Pledgor in and to
the following, whether now owned or existing or owned, acquired, or arising hereafter (collectively, the “Pledged Collateral”): 
 (a) Pledged Equity. (i) One hundred percent (100%) (or, if less, the full amount owned by such Pledgor) of the issued and outstanding Equity Interests owned by such Pledgor of
(A) each Domestic Subsidiary set forth on Schedule 2(a) attached hereto and (B) each Foreign Subsidiary set forth on Schedule 2(a) attached hereto that is also a Guarantor and (ii) sixty-five percent (65%) (or, if less,
the full amount owned by such Pledgor) of the issued and outstanding Equity Interests entitled to vote (within the meaning of Treas. Reg. Section 1.956-2(c)(2)) (“Voting Equity”) and one hundred percent (100%) (or, if
less, the full amount owned by such Pledgor) of the issued and outstanding Equity Interests not entitled to vote (within the meaning of Treas. Reg. Section 1.956-2(c)(2)) (“Non-Voting Equity”) owned by such Pledgor of each
First-Tier Foreign Subsidiary set forth on Schedule 2(a) attached hereto, in each case together with the certificates (or other agreements or instruments), if any, representing such Equity Interests, and all options and other rights,
contractual or otherwise, with respect thereto (collectively, together with the Equity Interests described in Section 2(b) and 2(c) below, the “Pledged Equity”), including, but not limited to, the following:

 (A) all shares, securities, membership interests or other equity interests representing a dividend on any of
the Pledged Equity, or representing a distribution or return of capital upon or in respect of the Pledged Equity, or resulting from a stock split, revision, reclassification or other exchange therefor, and any subscriptions, warrants, rights or
options issued to the holder of, or otherwise in respect of, the Pledged Equity; and 
 (B) without affecting
the obligations of the Pledgors under any provision prohibiting such action hereunder or under the Credit Agreement, in the event of any consolidation or merger involving the issuer of any Pledged Equity and in which such issuer is not the surviving
entity, all Equity Interests of the successor entity formed by or resulting from such consolidation or merger. 
  

 7 

 (b) Additional Shares. (i) One hundred percent (100%) (or,
if less, the full amount owned by such Pledgor) of the issued and outstanding Equity Interests owned by such Pledgor of any Person that hereafter becomes a (A) Domestic Subsidiary or (B) a Foreign Subsidiary that is also a Guarantor and
(ii) sixty-five percent (65%) (or, if less, the full amount owned by such Pledgor) of the Voting Equity and one hundred percent (100%) (or, if less, the full amount owned by such Pledgor) of the Non-Voting Equity owned by such Pledgor
of any Person that hereafter becomes a First-Tier Foreign Subsidiary, including, without limitation, the certificates (or other agreements or instruments) representing such Equity Interests. 
 (c) Accessions and Proceeds. All Accessions and all Proceeds of any and all of the foregoing. 
 Without limiting the generality of the foregoing, it is hereby specifically understood and agreed that a Pledgor may from time to time
hereafter deliver additional Equity Interests to the Administrative Agent as collateral security for the Secured Obligations. Upon delivery to the Administrative Agent, such additional Equity Interests shall be deemed to be part of the Pledged
Collateral of such Pledgor and shall be subject to the terms of this Pledge Agreement whether or not Schedule 2(a) is amended to refer to such additional Equity Interests. 
 Notwithstanding anything to the contrary contained herein, in no event shall the security interest granted under this Section 2 attach
to, nor shall the Pledged Collateral include (i) any Excluded Property or (ii) any Equity Interests of a Foreign Subsidiary that does not constitute Pledged Equity. 
 3. Security for Secured Obligations. The security interest created hereby in the Pledged Collateral of each Pledgor constitutes
continuing collateral security for all of the Secured Obligations (subject to Section 23 hereof). 
 4. Delivery
of the Pledged Collateral. Each Pledgor hereby agrees that: 
 (a) Delivery of Certificates. Each
Pledgor shall deliver to the Administrative Agent (i) simultaneously with or prior to the execution and delivery of this Pledge Agreement, all certificates representing the Pledged Equity of such Pledgor and (ii) promptly upon the receipt
thereof by or on behalf of a Pledgor, all other certificates and instruments constituting Pledged Collateral of a Pledgor. Prior to delivery to the Administrative Agent, all such certificates and instruments constituting Pledged Collateral of a
Pledgor shall be held in trust by such Pledgor for the benefit of the Administrative Agent pursuant hereto. All such certificates and instruments shall be delivered in suitable form for transfer by delivery or shall be accompanied by duly executed
instruments of transfer or assignment in blank, substantially in the form provided in Exhibit 4(a) attached hereto. 
 (b) Additional Securities. If such Pledgor shall receive by virtue of its being or having been the owner of any Pledged Collateral, any (i) certificate, including without limitation, any
certificate representing a dividend or distribution in connection with any increase or reduction of capital, reclassification, merger, consolidation, sale of assets, combination of shares or membership or other equity interests, stock splits,
spin-off or split-off, promissory notes or other instruments; (ii) option or right, whether as an addition to, substitution for, or an exchange for, any Pledged Collateral or otherwise; (iii) dividends payable in securities; or
(iv) distributions of securities or other equity interests in connection with a partial or total liquidation, dissolution or reduction of capital, capital surplus or paid-in surplus, then such Pledgor shall receive such certificate, instrument,
option, right or distribution in trust for the benefit of the Administrative Agent, shall segregate it from such Pledgor’s other property and shall deliver it forthwith to the Administrative Agent in the exact form received together with any
necessary endorsement and/or

  

 8 

 
appropriate stock power duly executed in blank, substantially in the form provided in Exhibit 4(a), to be held by the Administrative Agent as Pledged Collateral and as further collateral
security for the Secured Obligations. 
 (c) Financing Statements. Each Pledgor authorizes the
Administrative Agent to file one or more financing statements (with collateral descriptions broader and/or less specific than the description of the Pledged Collateral contained herein, including without limitation “all assets” and/or
“all personal property” collateral descriptions) disclosing the Administrative Agent’s security interest in the Pledged Collateral. Each Pledgor agrees to execute and deliver to the Administrative Agent such financing statements and
other filings as may be reasonably requested by the Administrative Agent in order to perfect and protect the security interest created hereby in the Pledged Collateral of such Pledgor. 
 5. Representations and Warranties. Each Pledgor hereby represents and warrants to the Administrative Agent, for the benefit of the
holders of the Secured Obligations, that: 
 (a) Authorization of Pledged Equity. The Pledged Equity is
duly authorized and validly issued, fully paid and, to the extent applicable, nonassessable and is not subject to the preemptive rights of any Person. 
 (b) Title. Each Pledgor has good and indefeasible title to the Pledged Collateral of such Pledgor and is the legal and beneficial owner of such Pledged Collateral free and clear of any Lien, other
than Permitted Liens. There exists no “adverse claim” within the meaning of Section 8-102 of the UCC with respect to the Pledged Equity of such Pledgor. 
 (c) Exercising of Rights. There are no restrictions in any Organization Documents governing any Pledged Equity or any
other document related thereto that would limit or restrict (i) the grant of a Lien pursuant to this Agreement, (ii) the perfection of such Lien or (iii) the exercise of remedies in respect of such perfected Lien in the Pledged Equity
as contemplated by this Agreement (except in each case where any necessary waiver of such restriction or other necessary consent has been obtained). 
 (d) Pledgor’s Authority. Except as may be required by applicable foreign Laws affecting the pledge of Equity Interests of Foreign Subsidiaries, no authorization, approval or action by, and no
notice or filing with any Governmental Authority or with the issuer of any Pledged Collateral is required either (i) for the pledge made by such Pledgor or for the granting of the security interest by such Pledgor pursuant to this Pledge
Agreement (except as have been already obtained) or (ii) for the exercise by the Administrative Agent or the holders of the Secured Obligations of their rights and remedies hereunder (except as may be required by the UCC or Laws affecting the
offering and sale of securities). 
 (e) Security Interest/Priority. This Pledge Agreement creates a valid
security interest in favor of the Administrative Agent for the benefit of the holders of the Secured Obligations in the Pledged Collateral and, when properly perfected by filing of a financing statement, shall constitute a valid and perfected, first
priority security interest, subject to Permitted Liens, in all uncertificated Pledged Equity consisting of partnership or limited liability company interests, if any, that do not constitute Securities. The taking of possession by the Administrative
Agent of the certificates representing the Pledged Equity that constitutes Securities of a Domestic Subsidiary, and that have been indorsed to the Administrative Agent or in blank by an effective endorsement, all in the manner provided by applicable
law, will perfect and establish the first priority of the Administrative Agent’s security interest in such Pledged Equity consisting of certificated securities of Domestic Subsidiaries. Except as set forth in this Section 5(e) and
except as may be required by applicable foreign Laws affecting the pledge of Equity Interests of Foreign Subsidiaries, no action is necessary to perfect or otherwise protect such security interest. 
  

 9 

 (f) Partnership and Membership Interests. Except as previously
disclosed to the Administrative Agent, none of the Pledged Equity consisting of partnership or limited liability company interests (i) is dealt in or traded on a securities exchange or in a securities market, (ii) by its terms expressly
provides that it is a security governed by Article 8 of the UCC, (iii) is an investment company security, (iv) is held in a securities account or (v) constitutes a Security or a Financial Asset. 
 (g) No Other Interests. As of the date hereof, no Pledgor owns any Equity Interests in any Subsidiary other than as
set forth on Schedule 2(a) attached hereto. 
 6. Covenants. Each Pledgor hereby covenants that until such time as
the Secured Obligations are Fully Satisfied, such Pledgor shall: 
 (a) Defense of Title. Warrant and
defend, as may be commercially reasonable, title to and ownership of the Pledged Collateral of such Pledgor at its own expense against the claims and demands of all other parties claiming an interest therein, other than the holders of Permitted
Liens, keep the Pledged Collateral free from all Liens, except for Permitted Liens, and not sell, exchange, transfer, assign, lease or otherwise dispose of any Pledged Collateral of such Pledgor or any interest therein, except as permitted under the
Credit Agreement and the other Loan Documents. 
 (b) Further Assurances. Promptly execute and deliver at
its expense all further instruments and documents and take all further action that may be necessary and desirable or that the Administrative Agent may reasonably request in order to (i) perfect and protect the security interest created hereby
in the Pledged Collateral of such Pledgor (including, without limitation, any and all action necessary to satisfy the Administrative Agent that the Administrative Agent has obtained a first priority perfected security interest in all Pledged
Collateral, subject to Permitted Liens); (ii) enable the Administrative Agent to exercise and enforce its rights and remedies hereunder in respect of the Pledged Collateral of such Pledgor; and (iii) otherwise effect the purposes of this
Pledge Agreement, including, without limitation and if requested by the Administrative Agent, delivering to the Administrative Agent irrevocable proxies in respect of the Pledged Collateral of such Pledgor. 
 (c) Amendments. Not make or consent to any amendment or other modification or waiver with respect to any of the
Pledged Collateral of such Pledgor or enter into any agreement or allow to exist any restriction with respect to any of the Pledged Collateral of such Pledgor, in each case other than pursuant hereto or as may be permitted under the Credit
Agreement. 
 (d) Compliance with Securities Laws. File all reports and other information now or hereafter
required to be filed by such Pledgor with the United States Securities and Exchange Commission and any other state, federal or foreign agency in connection with the ownership of the Pledged Collateral of such Pledgor unless the failure to do so will
not materially adversely affect the Administrative Agent or the holders of the Secured Obligations hereunder. 
 (e) Issuance or Acquisition of Equity Interests. Not, without executing and delivering, or causing to be executed and delivered, to the Administrative Agent such agreements, documents and instruments as the Administrative Agent may
reasonably request for the purpose of perfecting its security interest therein, issue or acquire any Equity Interests constituting Pledged Collateral consisting of an interest in a partnership or a limited liability company that (i)

  

 10 

 
is dealt in or traded on a securities exchange or in a securities market, (ii) by its terms expressly provides that it is a security governed by Article 8 of the UCC, (iii) is an
investment company security, (iv) is held in a securities account or (v) constitutes a Security or a Financial Asset. 
 7. Advances by Holders of the Secured Obligations. Upon the occurrence of an Event of Default and during the continuation thereof, on the failure of any Pledgor to perform any of the covenants and agreements contained herein, the
Administrative Agent may, at its sole option and in its sole discretion, upon notice to the Pledgors, perform the same and in so doing may expend such sums as the Administrative Agent may reasonably deem advisable under the circumstances (including
taking into account the value of the Pledged Collateral) in the performance thereof, including, without limitation, the payment of any insurance premiums, the payment of any taxes, a payment to obtain a release of a Lien, expenditures made in
defending against any adverse claim and all other expenditures that the Administrative Agent or the holders of the Secured Obligations may make for the protection of the security hereof or may be compelled to make by operation of Law. All such sums
and amounts so expended shall be repayable by the Pledgors on a joint and several basis (subject to Section 23 hereof) promptly upon timely notice thereof and demand therefor, shall constitute additional Secured Obligations and shall
bear interest from the date said amounts are expended at the Default Rate. No such performance of any covenant or agreement by the Administrative Agent or the holders of the Secured Obligations on behalf of any Pledgor, and no such advance or
expenditure therefor, shall relieve the Pledgors of any Default or Event of Default. Upon the occurrence of an Event of Default and during the continuation thereof, upon reasonable (and in any event after ten (10) Business Days) prior written
notice to the Pledgor, the holders of the Secured Obligations may make any payment hereby authorized in accordance with any bill, statement or estimate procured from the appropriate public office or holder of the claim to be discharged without
inquiry into the accuracy of such bill, statement or estimate or into the validity of any tax assessment, sale, forfeiture, tax lien, title or claim except to the extent such payment is being contested in good faith by a Pledgor in appropriate
proceedings and against which reserves reasonably believed by the Responsible Officers of such Pledgor to be adequate and in accordance with GAAP are being maintained by such Pledgor. 
 8. Remedies. 
 (a) General Remedies. Upon the occurrence of an Event of Default and during the continuation thereof, the Administrative Agent and the holders of the Secured Obligations shall have, in addition to the rights and remedies provided
herein, in the Loan Documents, in any other documents relating to the Secured Obligations, or by Law (including, without limitation, levy of attachment and garnishment), the rights and remedies of a secured party under the Uniform Commercial Code of
the jurisdiction applicable to the affected Pledged Collateral. 
 (b) Sale of Pledged Collateral. Upon the occurrence of
an Event of Default and during the continuation thereof, without limiting the generality of this Section 8 and without notice, the Administrative Agent may, in its sole discretion, sell or otherwise dispose of or realize upon the Pledged
Collateral, or any part thereof, in one or more parcels, at public or private sale, at any exchange or broker’s board or elsewhere, at such price or prices and on such other terms as the Administrative Agent may deem commercially reasonable,
for cash, credit or for future delivery or otherwise in accordance with applicable Law. To the extent permitted by Law, any holder of the Secured Obligations may in such event, bid for the purchase of such securities. Each Pledgor agrees that, to
the extent notice of sale shall be required by Law and has not been waived by such Pledgor, any requirement of reasonable notice shall be met if notice, specifying the place of any public sale or the time after which any private sale is to be made,
is personally served on or mailed, postage prepaid, to such Pledgor, in accordance with the notice provisions of Section 11.02 of the Credit Agreement at least ten (10) days before the time of such sale. The Administrative Agent
shall not be obligated to make any sale of Pledged Collateral of such Pledgor regardless of notice of sale having been given. The Administrative Agent may adjourn any public or private sale from time to time by announcement at the time and place
fixed therefor, and such sale may, without further notice, be made at the time and place to which it was so adjourned. 
  

 11 

 (c) Private Sale. Upon the occurrence of an Event of Default and during the
continuation thereof, the Pledgors recognize that the Administrative Agent may deem it impracticable to effect a public sale of all or any part of the Pledged Equity or any of the securities constituting Pledged Collateral and that the
Administrative Agent may, therefore, determine to make one or more private sales of any such Pledged Collateral to a restricted group of purchasers who will be obligated to agree, among other things, to acquire such Pledged Collateral for their own
account, for investment and not with a view to the distribution or resale thereof. Each Pledgor acknowledges that any such private sale may be at prices and on terms less favorable to the seller than the prices and other terms that might have been
obtained at a public sale and, notwithstanding the foregoing, agrees that such private sale shall be deemed to have been made in a commercially reasonable manner and that the Administrative Agent shall have no obligation to delay sale of any such
Pledged Collateral for the period of time necessary to permit the issuer of such Pledged Collateral to register such Pledged Collateral for public sale under the Securities Act of 1933 (as amended or modified, the “Securities Act”)
or under applicable state securities laws. Each Pledgor further acknowledges and agrees that any offer to sell such Pledged Collateral that has been (i) publicly advertised on a bona fide basis in a newspaper or other publication of general
circulation in the financial community of New York, New York (to the extent that such offer may be advertised without prior registration under the Securities Act), or (ii) made privately in the manner described above shall be deemed to involve
a “public sale” under the UCC, notwithstanding that such sale may not constitute a “public offering” under the Securities Act, and the Administrative Agent or any holder of any of the Secured Obligations may, in such event, bid
for the purchase of such Pledged Collateral. 
 (d) Retention of Pledged Collateral. To the extent permitted under
applicable Law, in addition to the rights and remedies hereunder, upon the occurrence and during the continuation of an Event of Default, the Administrative Agent may, after providing the notices required by Sections 9-620 and 9-621 of the UCC or
otherwise complying with the requirements of applicable Law of the relevant jurisdiction, accept or retain all or any portion of the Pledged Collateral in satisfaction of the Secured Obligations. Unless and until the Administrative Agent shall have
provided such notices, however, the Administrative Agent shall not be deemed to have accepted or retained any Pledged Collateral in satisfaction of any Secured Obligations for any reason. 
 (e) Deficiency. In the event that the proceeds of any sale, collection or realization are insufficient to pay all amounts to which
the Administrative Agent or the holders of the Secured Obligations are legally entitled, the Pledgors shall be jointly and severally liable (subject to Section 23 hereof) for the deficiency, together with interest thereon at the Default
Rate, together with the reasonable costs of collection and Attorney Costs. Any surplus remaining after the full payment and satisfaction of the Secured Obligations shall be returned to the Pledgors or to whomsoever a court of competent jurisdiction
shall determine to be entitled thereto. 
 9. Rights of the Administrative Agent. 
 (a) Power of Attorney. Each Pledgor hereby designates and appoints the Administrative Agent, on behalf of the holders of the Secured
Obligations, and each of its designees or agents, as attorney-in-fact of such Pledgor, irrevocably and with power of substitution, with authority to take any or all of the following actions upon the occurrence and during the continuation of an Event
of Default: 
 (i) to ask for or demand, collect, settle, compromise or adjust any and all monies and other
amounts due and to become due at any time in respect of or arising out of any Pledged Collateral, all as the Administrative Agent may reasonably deem appropriate; 
  

 12 

 (ii) to commence and prosecute any actions at any court for the purposes of
collecting any of the Pledged Collateral and enforcing any other right in respect thereof; 
 (iii) to defend,
settle or compromise any action brought with respect to the Collateral and, in connection therewith, give such discharge or release as the Administrative Agent may reasonably deem appropriate; 
 (iv) to pay or discharge taxes, liens, security interests or other encumbrances levied or placed on or threatened against the
Pledged Collateral as the Administrative Agent may deem reasonably appropriate; 
 (v) to direct any parties
liable for any payment in connection with any of the Pledged Collateral to make payment of any and all monies due and to become due thereunder directly to the Administrative Agent or as the Administrative Agent shall direct; 
 (vi) to receive payment of and receipt for any and all monies, claims, and other amounts due and to become due at any time in
respect of or arising out of any Pledged Collateral; 
 (vii) to sign and endorse any drafts, assignments,
proxies, stock powers, verifications, notices and other documents relating to the Pledged Collateral; 
 (viii)
to execute and deliver all assignments, conveyances, statements, financing statements, renewal financing statements, security and pledge agreements, affidavits, notices and other agreements, instruments and documents that the Administrative Agent
may reasonably deem appropriate in order to perfect and maintain the security interests and liens granted in this Pledge Agreement and in order to fully consummate all of the transactions contemplated therein; 
 (ix) to exchange any of the Pledged Collateral or other property upon any merger, consolidation, reorganization,
recapitalization or other readjustment of the issuer thereof and, in connection therewith, deposit any of the Pledged Collateral with any committee, depository, transfer agent, registrar or other designated agency upon such terms as the
Administrative Agent may reasonably deem appropriate; 
 (x) to vote for a shareholder or member resolution, or
to sign an instrument in writing, sanctioning the transfer of any or all of the Pledged Collateral into the name of the Administrative Agent or one or more of the holders of the Secured Obligations or into the name of any transferee to whom the
Pledged Collateral or any part thereof may be sold pursuant to Section 8 hereof; and 
 (xi) to do
and perform all such other acts and things as the Administrative Agent may reasonably deem appropriate or convenient in connection with the Pledged Collateral. 
 This power of attorney is a power coupled with an interest and shall be irrevocable until such time as the Secured Obligations are Fully Satisfied. The Administrative Agent shall be under no duty to
exercise or withhold the exercise of any of the rights, powers, privileges and options expressly or implicitly granted to the Administrative Agent in this Pledge Agreement, and shall not be liable for any failure to do so or any delay in doing so.
The Administrative Agent shall not be liable for any act or omission or for any error of judgment or any mistake of fact or Law in its individual capacity or its capacity as attorney-in-fact except acts or omissions resulting from the gross
negligence or willful misconduct of the Administrative Agent or its Related Parties. This power of attorney is conferred on the Administrative Agent solely to protect, preserve and realize upon its security interest in the Pledged Collateral.

  

 13 

 (b) Assignment by the Administrative Agent. The Administrative Agent may from time to
time assign the Pledged Collateral and any portion thereof to a successor agent in accordance with the Credit Agreement, and the assignee shall be entitled to all of the rights and remedies of the Administrative Agent under this Pledge Agreement in
relation thereto. 
 (c) The Administrative Agent’s Duty of Care. Other than the exercise of reasonable care to
assure the safe custody of the Pledged Collateral while being held by the Administrative Agent hereunder, the Administrative Agent shall have no duty or liability to preserve rights pertaining thereto, it being understood and agreed that the
Pledgors shall be responsible for preservation of all rights in the Pledged Collateral, and the Administrative Agent shall be relieved of all responsibility for the Pledged Collateral upon surrendering it or tendering the surrender of it to the
Pledgors. The Administrative Agent shall be deemed to have exercised reasonable care in the custody and preservation of the Pledged Collateral in its possession if such Pledged Collateral is accorded treatment substantially equal to that which the
Administrative Agent accords its own property, which shall be no less than the treatment employed by a reasonable and prudent agent in the industry, it being understood that the Administrative Agent shall not have responsibility for
(i) ascertaining or taking action with respect to calls, conversions, exchanges, maturities, tenders or other matters relating to any Pledged Collateral, whether or not the Administrative Agent has or is deemed to have knowledge of such
matters, or (ii) taking any necessary steps to preserve rights against any parties with respect to any of the Pledged Collateral. 
 (d) Voting Rights in Respect of the Pledged Collateral. 
 (i) So long as no Event of Default
shall have occurred and be continuing, to the extent permitted by Law, each Pledgor may exercise any and all voting and other consensual rights pertaining to the Pledged Collateral of such Pledgor or any part thereof for any purpose which would not
(A) be inconsistent with the terms of this Pledge Agreement or the Credit Agreement or (B) materially impair the Pledged Collateral; and 
 (ii) Upon the occurrence and during the continuance of an Event of Default, all rights of a Pledgor to exercise the voting and other consensual rights that it would otherwise be entitled to exercise
pursuant to paragraph (i) of this subsection shall cease and all such rights shall thereupon become vested in the Administrative Agent, which shall then have the sole right to exercise such voting and other consensual rights. 
 (e) Dividend Rights in Respect of the Pledged Collateral. 
 (i) So long as no Event of Default shall have occurred and be continuing and subject to Section 4(b) hereof, each
Pledgor may receive and retain any and all dividends (other than stock dividends and other non-cash dividends constituting Pledged Collateral addressed hereinabove) or interest paid in respect of the Pledged Collateral to the extent they are allowed
under the Credit Agreement. 
 (ii) Upon the occurrence and during the continuance of an Event of Default:

 (A) all rights of a Pledgor to receive the dividends and interest payments that it would otherwise be
authorized to receive and retain pursuant to paragraph (i) of this subsection shall cease and all such rights shall thereupon be vested in the Administrative Agent, which shall then have the sole right to receive and hold as Pledged Collateral
such dividends and interest payments; and 
  

 14 

 (B) all dividends and interest payments that are received by a Pledgor
contrary to the provisions of paragraph (A) of this subsection shall be received in trust for the benefit of the Administrative Agent, shall be segregated from other property or funds of such Pledgor, and shall be forthwith paid over to the
Administrative Agent as Pledged Collateral in the exact form received, to be held by the Administrative Agent as Pledged Collateral and as further collateral security for the Secured Obligations. 
 (f) Release of Pledged Collateral. The Administrative Agent may release any of the Pledged Collateral from this Pledge Agreement or
may substitute any of the Pledged Collateral for other Pledged Collateral without altering, varying or diminishing in any way the force, effect, lien, pledge or security interest of this Pledge Agreement as to any Pledged Collateral not expressly
released or substituted, and this Pledge Agreement shall continue as a first priority lien, subject to Permitted Liens, on all Pledged Collateral not expressly released or substituted. 
 10. Rights of Required Lenders. All rights of the Administrative Agent hereunder, if not exercised by the Administrative Agent, may
be exercised by the Required Lenders, but for the avoidance of doubt, and notwithstanding any other provision hereof to the contrary, no Lender or other holder of Secured Obligations (other than the Administrative Agent) may exercise any rights
hereunder unless directed to do so by the Required Lenders. 
 11. Application of Proceeds. Upon the occurrence and
during the continuation of an Event of Default, any payments in respect of the Secured Obligations and any proceeds of the Pledged Collateral, when received by the Administrative Agent or any of the holders of the Secured Obligations in cash or its
equivalent, will be applied in reduction of the Secured Obligations in the order set forth in Section 9.03 of the Credit Agreement, and each Pledgor irrevocably waives the right to direct the application of such payments and proceeds.

 12. Continuing Agreement. 
 (a) This Pledge Agreement shall be a continuing agreement in every respect and shall remain in full force and effect until such time as the Secured Obligations are Fully Satisfied. At such time as the
Secured Obligations are Fully Satisfied, this Pledge Agreement and the liens and security interests of the Administrative Agent hereunder shall be automatically terminated and the Administrative Agent shall, upon the request and at the expense of
the Pledgors, execute and deliver all UCC termination statements and/or other documents reasonably requested by the Pledgors evidencing such termination. Notwithstanding the foregoing, all releases and indemnities provided hereunder shall survive
termination of this Pledge Agreement. 
 (b) This Pledge Agreement shall continue to be effective or be automatically
reinstated, as the case may be, if at any time payment, in whole or in part, of any of the Secured Obligations is rescinded or must otherwise be restored or returned by the Administrative Agent or any holder of the Secured Obligations as a
preference, fraudulent conveyance or otherwise under any bankruptcy, insolvency or similar Law, all as though such payment had not been made; provided that in the event payment of all or any part of the Secured Obligations is rescinded or must be
restored or returned, all reasonable costs and expenses (including, without limitation, attorneys’ fees and disbursements) incurred by the Administrative Agent or any holder of the Secured Obligations in defending and enforcing such
reinstatement shall be deemed to be included as a part of the Secured Obligations. 
 13. Amendments and Waivers. This
Pledge Agreement and the provisions hereof may not be amended, waived, modified, changed, discharged or terminated except as set forth in Section 11.01 of the Credit Agreement. 
  

 15 

 14. Successors in Interest. This Pledge Agreement shall create a continuing security
interest in the Pledged Collateral and shall be binding upon each Pledgor, its successors and assigns, and shall inure, together with the rights and remedies of the Administrative Agent and the holders of the Secured Obligations hereunder, to the
benefit of the Administrative Agent and the holders of the Secured Obligations and their successors and permitted assigns; provided, however, that, except as provided in the Credit Agreement, none of the Pledgors may assign its rights or
delegate its duties hereunder without the prior written consent of the requisite Lenders under the Credit Agreement. To the fullest extent permitted by Law, each Pledgor hereby releases the Administrative Agent and each holder of the Secured
Obligations, and their respective successors and assigns, from any liability for any act or omission relating to this Pledge Agreement or the Pledged Collateral, except for any liability arising from the gross negligence or willful misconduct of the
Administrative Agent or such holder, or their respective Related Parties. 
 15. Notices. All notices required or
permitted to be given under this Pledge Agreement shall be given as provided in Section 11.02 of the Credit Agreement. 
 16. Counterparts. This Pledge Agreement may be executed in any number of counterparts, each of which where so executed and delivered shall be deemed an original, but all of which taken together shall constitute one and the same
instrument. It shall not be necessary in making proof of this Pledge Agreement to produce or account for more than one such counterpart. 
 17. Headings. The headings of the sections and subsections hereof are provided for convenience only and shall not in any way affect the meaning or construction of any provision of this Pledge
Agreement. 
 18. Governing Law; Submission to Jurisdiction; Venue; WAIVER OF JURY TRIAL. The terms of Sections 11.15,
11.16 and 11.17 of the Credit Agreement with respect to governing law, submission to jurisdiction, venue and waiver of jury trial are incorporated herein by reference, mutatis mutandis, and the parties hereto agree to such terms. 

19. Severability. If any provision of this Pledge Agreement is determined to be illegal, invalid or unenforceable, such provision
shall be fully severable and the remaining provisions shall remain in full force and effect and shall be construed without giving effect to the illegal, invalid or unenforceable provisions. 
 20. Entirety. This Pledge Agreement and the other Loan Documents represent the entire agreement of the parties hereto and thereto,
and supersede all prior agreements and understandings, oral or written, if any, including any commitment letters or correspondence relating to the Loan Documents, any other documents relating to the Secured Obligations, or the transactions
contemplated herein and therein. 
 21. Survival. All representations and warranties of the Pledgors hereunder shall
survive the execution and delivery of this Pledge Agreement and the other Loan Documents, the delivery of the Notes and the extension of credit thereunder or in connection therewith. 
 22. Other Security. To the extent that any of the Secured Obligations are now or hereafter secured by property other than the Pledged
Collateral (including, without limitation, real and other personal property owned by a Pledgor), or by a guarantee, endorsement or property of any other Person, then the Administrative Agent shall have the right to proceed against such other
property, guarantee or endorsement upon the occurrence and during the continuation of any Event of Default, and the Administrative Agent shall have the right, in its sole discretion, to determine which rights, security, liens, security interests or
remedies the Administrative Agent shall at any time pursue, relinquish, subordinate,

  

 16 

 
modify or take with respect thereto, without in any way modifying or affecting any of them or the Secured Obligations or any of the rights of the Administrative Agent or the holders of the
Secured Obligations under this Pledge Agreement, under any of the other Loan Documents or under any other document relating to the Secured Obligations. 
 23. Joint and Several Obligations of Pledgors. 
 (a) Subject to subsection
(c) of this Section 23, each of the Pledgors is accepting joint and several liability hereunder in consideration of the financial accommodation to be provided by the holders of the Secured Obligations, for the mutual benefit,
directly and indirectly, of each of the Pledgors and in consideration of the undertakings of each of the Pledgors to accept joint and several liability for the obligations of each of them. 
 (b) Subject to subsection (c) of this Section 23, each of the Pledgors jointly and severally hereby irrevocably and
unconditionally accepts, not merely as a surety but also as a co-debtor, joint and several liability with the other Pledgors with respect to the payment and performance of all of the Secured Obligations arising under this Pledge Agreement and the
other Loan Documents, it being the intention of the parties hereto that all the Secured Obligations shall be the joint and several obligations of each of the Pledgors without preferences or distinction among them. 
 (c) Notwithstanding any provision to the contrary contained herein, in any other of the Loan Documents or in any other documents relating to
the Secured Obligations, the obligations of each Guarantor under the Credit Agreement, the other Loan Documents and the documents relating to the Secured Obligations shall be limited to an aggregate amount equal to the largest amount that would not
render such obligations subject to avoidance under Section 548 of the United States Bankruptcy Code or any comparable provisions of any applicable state Law. 
 [Signature Pages Follow] 
  

 17 

 Each of the parties hereto has caused a counterpart of this Pledge Agreement to be duly
executed and delivered as of the date first above written. 
  

					
	PLEDGORS:	 	PROMETHEUS LABORATORIES INC.,
		 	a California corporation
			
		 	By:	 	  

		 	Name:	 	
		 	Title:	 	
		
		 	[IF APPLICABLE, INCLUDE ANY GUARANTORS IN EXISTENCE AT TIME OF EXECUTION AND DELIVERY OF PLEDGE AGREEMENT]

 Accepted and agreed to as of the date first above written. 
  

			
	BANK OF AMERICA, N.A.,
	as Administrative Agent
		
	By:	 	  

	Name:	 	
	Title:	 	

 SCHEDULE 2(a) 
 EQUITY INTERESTS 
  

									
	Pledgor	  	Issuer	  	 Number of
 Shares/Units
	  	 Certificate
 Number
	  	Percentage
Ownership

 EXHIBIT 4(a) 
 FORM OF IRREVOCABLE STOCK POWER 
 FOR VALUE RECEIVED, the
undersigned hereby sells, assigns and transfers to 
 the following shares of capital stock of
                        , a
                         corporation: 
  

			
	 Number of Shares
	  	 Certificate Number

 and irrevocably appoints
                        its agent and attorney-in-fact to transfer all or any part of such capital stock and to take all
necessary and appropriate action to effect any such transfer. The agent and attorney-in-fact may substitute and appoint one or more persons to act for him. 
  

			
	[HOLDER]
		
	By:	 	  

	Name:	 	
	Title:Distribution and Promotion Agreement

 Exhibit 10.41 
 CERTAIN MATERIAL (INDICATED BY AN ASTERISK) HAS BEEN OMITTED FROM THIS DOCUMENT PURSUANT TO A REQUEST FOR CONFIDENTIAL TREATMENT. THE OMITTED MATERIAL HAS BEEN FILED SEPARATELY WITH THE SECURITIES AND
EXCHANGE COMMISSION. 
 DISTRIBUTION AND PROMOTION AGREEMENT 
 THIS DISTRIBUTION AND PROMOTION AGREEMENT (this “Agreement”) is entered into as of the 21st day of December, 2009 (the “Effective Date”),
by and between Prometheus Laboratories Inc., a corporation organized under the laws of California, having a place of business at 9410 Carroll Park Drive, San Diego, CA 92121 (“Prometheus”) and Novartis Vaccines and Diagnostics,
Inc., a Delaware corporation, with its principal place of business at 350 Massachusetts Avenue, Cambridge, MA 02139 (“Novartis”). Prometheus and Novartis are sometimes collectively referred to herein as the
“Parties” and separately as a “Party.” 
 RECITALS 
 WHEREAS, Novartis is the owner of all right, title and interest in or otherwise has the right to grant rights under certain Patents,
Trademarks, Know-How and Regulatory Approvals related to the Products (each as hereinafter defined); 
 WHEREAS, Prometheus
desires to obtain from Novartis, and Novartis agrees to grant to Prometheus, the right to co-exclusively Develop and exclusively Commercialize the Products in the Field in the Territory during the Term (each as hereinafter defined); 
 WHEREAS, the Parties or their Affiliates will enter into a Supply Agreement concurrently with the execution of this Agreement which will set
forth the terms and conditions under which Novartis or its Affiliates (or its designated Third Party manufacturer) will manufacture and supply to Prometheus, and Prometheus will purchase from Novartis or its Affiliates, all of Prometheus’ and
its Affiliates’ and Sublicensees’ requirements for filled and finished Existing Product. 
 AGREEMENT

 NOW, THEREFORE, in consideration of the mutual covenants and agreements set forth herein and other good and valuable
consideration, the receipt and legal sufficiency of which are hereby mutually acknowledged, Prometheus and Novartis hereby agree as follows: 
 SECTION 1. 
 DEFINITIONS 
 1.1 Definitions. The following capitalized terms will have the meanings set forth below when used in this Agreement: 
 “Accounting Standards” with, respect to Prometheus, means that Prometheus shall maintain records and books of accounts in
accordance with GAAP in the United States and in accordance with IFRS outside the United States and, with respect to Novartis, means that Novartis shall maintain records and books of accounts in accordance with IFRS. Prometheus shall promptly notify
Novartis in the event that it changes the accounting principles pursuant to which its records shall be maintained, it being understood that only internationally recognized accounting principles may be used. 

 “Additional Product Mark” will have the meaning set forth in
Section 4.4(a). 
 “Additional Regulatory Approvals” means any Regulatory Approvals other than those
existing Regulatory Approvals held by Novartis or its Affiliates for the Product as of the Effective Date which are transferable to Prometheus in accordance with this Agreement and Applicable Law. 
 “Affiliate” of a Party or Person means any Person, whether de jure or de facto, that directly or indirectly, controls, is
controlled by, or is under common control with such Party or Person, as applicable. Solely as used in this definition, “control” means direct or indirect ownership of more than [* * *] percent ([* * *]%) of the equity (or such lesser
percentage which is the maximum allowed to be owned by a foreign corporation in a particular jurisdiction) having the power to vote on or direct the affairs of such Party or Person, or (ii) means the possession of the power to direct or cause
the direction of the management and policies of a person, whether through the ownership of voting securities, by contract, or otherwise. In the case of Novartis, for purposes of Sections 2.8 (Certain Exclusions) and 9 (Confidentiality),
“Affiliate” shall also include [* * *] Novartis and/or its Affiliates. 
 “Agreement” will have the
meaning set forth in the Introduction. 
 “AMP” will have the meaning set forth in Section 4.8(a).

 [* * *]. 
 “Anti-Kickback Statute” means the Medicare and Medicaid Anti-Kickback Statute set forth in 42 U.S.C. §1320a-7b(b). 
 “Applicable Law” means (a) all applicable provisions of any and all federal, national, state, provincial, and local statutes, laws, rules, regulations, codes, ordinances, decrees,
orders, decisions, injunctions, awards, judgments, permits and licenses of or from governmental authorities relating to or governing the use or regulation of the subject item, including, without limitation, the Anti-Kickback Statute, the FD&C
Act and the PDMA, and all applicable foreign equivalents of any of the foregoing laws, and (b) any guidelines and policies, solely where and to the extent that such guidelines and policies are incorporated into or promulgated under any of the
laws set forth in subsection (a), or which are issued by any applicable Regulatory Authorities with jurisdiction in the Territory. 
 “Approval Period” will have the meaning set forth in Section 10.5. 
 “Approved Successor” means any Third Party who is [* * *]. 
 “ASP” will have the
meaning set forth in Section 4.8(a). 
 “Average Daily Usage” will have the meaning set forth in
Exhibit K. 
  
 *** Certain information on this page has been
omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 2 

 “BLA” means a biologics license application filed with the FDA for any
product, requesting permission to place a biological product on the market in accordance with 21 CFR Part 601.2, and all amendments or supplements filed pursuant to the requirements of the FDA. 
 “Business Day” means any day that is not a Saturday, a Sunday, or other day (i) which is a public holiday in the
canton of Basel, Switzerland, or (ii) which is a recognized Federal holiday in the United States of America. 
 “Calendar Quarter” means a period of three (3) consecutive months ending on the last day of March, June, September, or December, respectively. 
 “Canada” will have the meaning set forth in the definition of Territory. 
 “Canada Election Date” will have the meaning set forth in Section 2.6(a). 
 “Canada First Sales Booking Date” means a date to be mutually agreed in writing by the Parties, which date shall be as soon
as reasonably practicable after the date that the applicable Regulatory Authorities in Canada provide written notification that the transfer of all of the Regulatory Approvals in Canada is complete (the “Canada Regulatory Approvals
Completion Date”), but in no event later than twenty (20) days after the Canada Regulatory Approvals Completion Date. 
 “Canada Regulatory Approvals Completion Date” will have the meaning set forth in the definition of “Canada First Sales Booking Date.” 
 “Canada Transfer Criteria” means the terms and conditions set forth on Exhibit Z as applied to Canada and each of its territories, commonwealths and possessions. 

“Catastrophic Breach Date” will have the meaning set forth in Section 10.7(f). 
 “Change in Control Default Event” means the occurrence of any of the following: (i) the acquisition by any Person or
group of Persons acting in concert, other than an Approved Successor, through any transaction or series of related transactions, of control of Prometheus (unless immediately after such acquisition, the Person or Persons who controlled Prometheus
prior to the acquisition continue to control Prometheus or its successor); (ii) Prometheus consolidates with or merges with or into any Person other than an Approved Successor, or any Person other than an Approved Successor consolidates or
merges with or into Prometheus, in either case whether or not Prometheus is the surviving entity of such transaction (unless immediately after such consolidation or merger, the Person or Persons who controlled Prometheus prior to the transaction
control such surviving entity); or (iii) a sale or other transfer of all or a substantial portion of the assets or business of Prometheus to any Person other than an Approved Successor. For the purposes of this definition, “control”
or “controlled” means the beneficial ownership, directly or indirectly, of securities representing more than [* * *] percent ([* * *]%) of the total voting power entitled to vote in elections of the board of directors or other governing
authority of Prometheus. 
  
 *** Certain information on this page has
been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 3 

 “Change in Control Transaction” will have the meaning set forth in
Section 10.5. 
 “Claim” or “Claims” means any charge, allegation, notice, civil,
criminal or administrative claim, demand, complaint, cause of action, Proceeding or investigation. 
 “Clinical
Trial” means any Phase I Clinical Trial, Phase II Clinical Trial, Phase III Clinical Trial, as applicable, as each such term is defined in 21 C.F.R. §312.21, or any Phase IV Clinical Trial, as such term is defined in 21 C.F.R.
§312.85, and any foreign equivalent thereof. 
 “CMS” means the Centers for Medicare and Medicaid
Services. 
 “Code” will have the meaning set forth in Section 10.3(b). 
 “Combination Product” means a product or combination of products containing or including one or more Products and one or
more other components, kits, tests, items of equipment, active ingredients, products, systems, or processes. 
 “Commercialize” means to import, market, Detail, promote, advertise, distribute and sell; and “Commercialization” or “Commercializing” will have the corresponding meaning. 
 “Commercially Reasonable Efforts” means (i) in the case of Novartis, that level of efforts and resources consistent
with the usual practice followed by Novartis and its Affiliates in the exercise of reasonable business discretion relating to other pharmaceutical products owned by it or to which it has exclusive rights, which is of similar market potential and at
a similar stage in development or product life, and (ii) in the case of Prometheus, that level of efforts and resources consistent with such efforts and resources as would normally be exerted or employed by a similarly-situated pharmaceutical
company for a product of similar market potential and at a similar stage in development or product life. Such level of efforts shall take into account issues of patent coverage, safety and efficacy, product profile, the competitiveness of the
marketplace, the proprietary position of the compound or product, the regulatory structure involved, the profitability of the products (including, without limitation, pricing and reimbursement status achieved), and other relevant factors, including
without limitation technical, legal, scientific, and/or medical factors. 
 “Competitive Product” means any
product other than the Product which is approved for [* * *]. 
 “Confidential Information” of a Party means
all confidential or proprietary Know-How or other information, including, without limitation, data and results derived from any Clinical Trials conducted by a Party or its Affiliates, proprietary information and materials (whether or not
patentable), regarding such Party’s or its Affiliates’ products, business or objectives that is communicated in any way or form by the disclosing Party or its Affiliates to the receiving Party or its Affiliates, either prior to or after
the Effective Date, and whether or not such Know-How or other information is identified as confidential at the time of disclosure. For the avoidance of doubt, (i) Prometheus’ Confidential Information shall include all Prometheus

  
 *** Certain information on this page has been omitted and filed
separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 4 

 
Improvements; and (ii) Novartis’ Confidential Information shall include all Novartis Improvements. This Agreement and the terms hereof shall constitute Confidential Information of
Novartis and Prometheus respectively and thus subject to the non-disclosure obligations of Section 9.1. 
 “Consent” will have the meaning set forth in Section 11.17. 
 “Contract Year”
means each of the successive twelve-month periods during the Term, with the first Contract Year commencing on the First Sales Booking Date for the United States and ending on the earlier of the one-year anniversary thereof or the last day of the
Term. 
 “Control” or “Controlled” means, with respect to Know-How, Trademarks or Patents of a
Party, that such Party and/or its Affiliates owns or has licensed (or otherwise has obtained rights to or under) such Know-How, Trademarks or Patents and such Party and/or its Affiliates has the right to grant licenses or sublicenses, as applicable,
to such Know-How, Trademarks or Patents to the other Party as contemplated by this Agreement. 
 “Core Product Patent
Rights” means those Product Patent Rights which are necessary to Commercialize the Product, as listed in Section 1 of Exhibit D, as may be amended from time to time upon the mutual agreement of the Parties. 
 “Cure Period” will have the meaning set forth in Section 10.2(a). 
 “Customers” means Third Party wholesalers, group purchasing organizations or other organizations similar to those that
purchase the Existing Product from Novartis as of the Effective Date in the Territory. 
 “DDMAC” means the
FDA’s Division of Drug Marketing, Advertising and Communications. 
 “Debt” means (i) indebtedness
for borrowed money, (ii) obligations evidenced by bonds, debentures, notes or other similar instruments, (iii) obligations to pay the deferred purchase price of property or services, excluding accounts payable arising in the ordinary
course of business but including, with respect to property, all liabilities created or arising under any conditional sale or other title retention agreement with respect to such property, (iv) obligations as lessee under leases which shall have
been or should be, in accordance with Accounting Standards, recorded as capital leases, and (v) obligations under direct or indirect guaranties in respect of, and obligations (contingent or otherwise) to purchase or otherwise acquire, or
otherwise to assure a creditor against loss in respect of, indebtedness or obligations of others of the kinds referred to in clauses (i) through (iv) above. 
 “Debt for Borrowed Money” means any Debt described in clauses (i) or (ii), or in clause (v) as it relates to clauses (i) and (ii), of the definition of “Debt” set
forth above. 
 “Detail” means an interactive face-to-face visit in the Territory by a sales representative of
Prometheus with a physician or his or her legally empowered designee, during which the approved indicated uses, safety and effectiveness of the Product and other relevant characteristics of the Products may be described by such sales representative
in a fair and

  

 5 

 
balanced manner consistent with Applicable Law, and using, as necessary or desirable, the product labeling or the Prometheus Promotional Materials; however, incidental contacts between such sales
representatives and a physician will not constitute a Detail. When used as a verb, “Detail” means to engage in a Detail. 
 “Develop” or “Development” means activities directly and specifically relating to the pre-clinical and clinical drug development of a Product or the updating or review of the Product labeling, including
test method development and stability testing, assay development, toxicology, formulation, quality assurance/quality control development, statistical analysis, pharmacokinetic studies, Clinical Trials (including research to design Clinical Trials)
and any other research and development activities with respect to a Product, to the extent that the foregoing activities are permitted by and subject to the terms of this Agreement. 
 “Diagnostic Improvement” means any Improvement which is a diagnostic kit, device or system for use with the Product and
which is developed by or on behalf of Prometheus or its Affiliates during the Term. 
 “Dispute” will have the
meaning set forth in Section 11.1. 
 “Dossier” means the package of technical and clinical information
(but excluding any Manufacturing Know-How, except to the extent such Manufacturing Know-How is required to support Regulatory Approvals to be held in the name of Prometheus and/or its Affiliates or Sublicensees) developed and maintained by Novartis
as of the Effective Date and in the format that such information exists as of the Effective Date, concerning the Products that was utilized for obtaining and maintaining Regulatory Approvals for the Products in the Field in the Territory and which
may be further utilized by Prometheus for maintaining existing Regulatory Approvals and obtaining Additional Regulatory Approvals for the Products in the Field in the Territory. 
 “Effective Date” will have the meaning set forth in the Introduction. 
 “Encumbrance” means any lien, pledge, security interest, right of first refusal, option, title defect, license,
restriction, or other adverse claim or interest or encumbrance of any kind or nature whatsoever, whether or not perfected, including any restriction on use, transfer, receipt of income or exercise of any other attribute of ownership. 
 “Excess Pipeline Days” will have the meaning set forth in Exhibit K. 
 “Exhibit N Countries” will have the meaning set forth in Exhibit N. 
 “Existing Discount Agreements” will have the meaning set forth in Section 4.6. 
 “Existing Product” will have the meaning set forth in the definition of Product. 
 “Extension Term” will have the meaning set forth in Section 10.1. 
 “FDA” means the United States Food and Drug Administration, or any successor agency thereto. 
  

 6 

 “FD&C Act” means the Federal Food, Drug and Cosmetic Act, as amended,
and the regulations promulgated thereunder from time to time. 
 “Field” means metastatic melanoma and
metastatic renal cell carcinoma; provided that the “Field” may be extended with the express written consent of both Parties to cover [* * *] which may be approved by the Parties for further Development by either Party in accordance
with Section 3.2(e). 
 “Financing Default” means that (i) Prometheus shall fail to pay any principal
of or premium or interest on any of its Debt which is outstanding in a principal amount of at least [* * *] million U.S. dollars ($[* * *]) when the same becomes due and payable (whether by scheduled maturity, required prepayment, acceleration,
demand or otherwise); (ii) any other event shall occur or condition shall exist under any agreement or instrument relating to any such Debt which remains uncured or un-waived for a period of more than [* * *] ([* * *]) days if the effect of
such event or condition, if uncured or un-waived, would be to accelerate, or to permit the acceleration of, the maturity of such Debt; or (iii) any such Debt that constitutes Debt for Borrowed Money shall be declared to be due and payable, or
required to be prepaid (other than by a required prepayment that is not due to a breach or default under the agreements governing such Debt), redeemed, purchased or defeased, or an offer to repay, redeem, purchase or defease such Debt shall be
required to be made, in each case prior to the stated maturity thereof. 
 “First Sales Booking Date” means
February 1, 2010 with respect to the United States, and the Canada First Sales Booking Date with respect to Canada. 
 “FSS” will have the meaning set forth in Section 4.7(c). 
 “GAAP” means U.S.
generally accepted accounting principles, consistently applied. 
 “Generic” means a generic version or
alternative formulation of aldesleukin or interleukin-2 that has demonstrated bioequivalence to the Products and which is approved by the FDA in the United States or by the applicable Regulatory Authority in any other country within the Territory
for the same indications as the Product in such applicable country in accordance with the regulatory approval process under the Applicable Law of such country. 
 “IFRS” means International Financial Reporting Standards, as consistently applied by Novartis worldwide and Prometheus outside the U.S., if applicable. 
 “Improvements” means new improvements, discoveries, inventions, developments, enhancements, derivative works, technology,
Know-How and other Intellectual Property, whether or not patentable or protectable. 
 “Incremental Product Net Sales
Milestone” will have the meaning set forth in Section 5.5. 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 7 

 “Indemnitee” will have the meaning set forth in Section 7.3.

 “Indemnitor” will have the meaning set forth in Section 7.3. 
 “Ineligible Person” means an individual or entity who: (a) is currently excluded, debarred, suspended or otherwise
ineligible to participate in the Federal health care programs or in Federal procurement or nonprocurement programs, or (b) has been convicted of a criminal offense that falls within the ambit of 42 U.S.C. 1320a-7(a), but has not yet been
excluded, debarred, suspended or otherwise declared ineligible. 
 “Initial Term” will have the meaning set
forth in Section 10.1. 
 “Insolvency Event” means, in relation to either Party, any of the following:
(a) that Party becomes Insolvent; (b) that Party shall commence any case, Proceeding or other action (i) under any existing or future law of any jurisdiction relating to bankruptcy, insolvency, reorganization or relief of debtors,
seeking to have an order for relief entered with respect to it, or seeking to adjudicate it as bankrupt or Insolvent, or seeking reorganization, arrangement, adjustment, winding-up, liquidation, dissolution, composition or other relief with respect
to it or its debts, or (ii) seeking appointment of a receiver, trustee, custodian, conservator or other similar official for it or for all or any substantial part of its assets, or any such Party shall make a general assignment for the benefit
of its creditors; (c) there shall be commenced against such Party any case, Proceeding or other action of a nature referred to in clause (b) above that (I) results in the entry of an order for relief or any such adjudication or
appointment or (II) remains undismissed, undischarged or unbonded for a period of sixty (60) days; (d) there shall be commenced against such Party any case, proceeding or other action seeking issuance of a warrant of attachment, execution,
distraint or similar process against all or any substantial part of its assets that results in the entry of an order for any such relief that shall not have been vacated, discharged, or stayed or bonded pending appeal within sixty (60) days
from the entry thereof; or (e) such Party shall take any action in furtherance of, or indicate its consent to, approval of, or acquiescence in, any of the acts set forth in clauses (b), (c) or (d) above. 
 “Insolvent” means, in relation to either Party, (a) that the sum of such Party’s debts is greater than all of
such Party’s property, at a fair valuation; or (b) that such Party shall generally not, or shall be unable to, or shall admit in writing its inability to, pay its debts as they become due. 
 “Intellectual Property” means intellectual property rights, including Trademarks, copyrights, Know-How and Patents, whether
registered or unregistered, and all applications and registrations therefor. 
 “Investigator-Initiated Trials”
will have the meaning set forth in Section 3.1(c)(ii). 
 “JDC” will have the meaning set forth in
Section 3.1(a). 
 “Joint Improvement” will have the meaning set forth in Section 8.6(a). 

“Know-How” means research and development data, information, reports, studies, validation methods and procedures,
unpatented inventions, knowledge, trade secrets,

  

 8 

 
technical or other data or information, or other materials, methods, procedures, processes, flow diagrams, materials, developments or technology, including all biological, chemical,
pharmacological, toxicological, clinical, manufacturing, analytical, safety, quality assurance, quality control and other data, information, reports or studies, other than any of the foregoing which is or becomes during the Term the subject of a
Patent. 
 “Losses” will have the meaning set forth in Section 7.1. 
 “M&S Expenses” means, to the extent incurred, recorded and executed by Prometheus in accordance with GAAP, the
Out-of-Pocket Costs incurred for the items listed on Exhibit B for marketing and selling spend associated with the Product(s), including but not limited to the PDE Value multiplied by the number of PDE’s performed by Prometheus’
Sales Force during the applicable accounting period up to a maximum of [* * *] percent ([* * *]%) of the total M&S Expenses for such period, to the extent directly applicable to the advertising and promotion of the Products in accordance with
this Agreement. Notwithstanding the foregoing, in no event will any of the following constitute M&S Expenses: costs of Clinical Trials and distribution costs. In the event that Out-of-Pocket Costs are incurred in connection with the advertising
and promotion of a Prometheus Combination Product, then the portion of such Out-of-Pocket Costs that shall constitute “M&S Expenses” for purposes hereof shall be calculated using the same proportional ratio as that of the relative Net
Sales price of the respective products in the Prometheus Combination Product if sold separately, or, if not sold separately, then in accordance with the proportional ratio used for calculating Prometheus Combination Product royalties described in
Section 5.4(b) of this Agreement. 
 “Manufacturing Know-How” means Know-How related to the manufacture,
formulation, testing and/or packaging of Product. 
 “Marketing Plan” means the marketing plan for the
Territory which meets the criteria set forth in Exhibit I. 
 “Medicaid Rebate Law” means §1927 of
the Social Security Act (42 U.S.C. §1396r-8). 
 “Medicaid Regulations” means the Final Rule, Medicaid
Program—Prescription Drugs as published at 72 Fed. Reg. 39142 (July 17, 2007) (codified at 42 C.F.R. Part 447). 
 “Milestone Events” will have the meaning set forth in Section 5.5. 
 “Minimum Detail
Requirements” means the minimum Detail requirements, including any requirements with respect to the conduct of PDEs, in the Field in the Territory set forth on Exhibit H attached hereto. 
 “Minimum Marketing and Promotion Investment” means, collectively, the Minimum Marketing Spend and the Minimum Detail
Requirements. 
  
 *** Certain information on this page has been
omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 9 

 “Minimum Marketing Spend” means Prometheus’ minimum M&S Expenses
incurred directly in support of the Commercialization of the Products for each Contract Year during the Term in the Field in the Territory as set forth on Exhibit H attached hereto. 
 “MTA” will have the meaning set forth in Section 3.2(f). 
 “NDA” means a New Drug Application filed with the FDA for any product, requesting permission to place a drug on the market
in accordance with 21 CFR Part 314, and all amendments or supplements filed pursuant to the requirements of the FDA. 
 “NDC” means National Drug Code. 
 “Necessary Diagnostic Improvements” will have the
meaning set forth in Section 8.6(b)(i)(B). 
 “Necessary Prometheus Improvements” will have the meaning
set forth in Section 8.6(b)(i)(B). 
 “Net Sales” with respect to any Product means the gross amount
actually invoiced by Prometheus, its Affiliates and their Sublicensees for sales by Prometheus and its Affiliates and Sublicensees of each Product to Third Parties in a bona-fide, arms-length transaction, as determined by Prometheus’ usual and
customary accounting methods, which are in accordance with Prometheus’ Accounting Standards as consistently applied, less the following deductions from such gross amounts which are actually incurred, allowed, accrued or specifically allocated
in accordance with Prometheus’ standard business practices, such deductions not to exceed with respect to the United States only, in the aggregate, [* * *] percent ([* * *]%) of such gross amount (the “Net Sales Deduction
Cap”); provided that (a) where and to the extent that changes to Applicable Law or government purchasing policies following the First Sales Booking Date require Prometheus to increase the amount of credits, discounts,
allowances, chargebacks, and/or rebates given to any government purchasing entity above those amounts given as of the First Sales Booking Date, then the amount of such increase shall be excluded from those deductions subject to the Net Sales
Deduction Cap, (b) the Net Sales Deduction Cap shall be increased to [* * *] percent ([* * *]%) for the duration of any Significant Market Event, and (c) the Net Sales Deduction Cap shall not apply during any Calendar Quarter in which the
Prometheus Average Net Selling Price for the Products is greater than the Novartis Net Selling Price for the same Calendar Quarter: 
 (i) credits, price adjustments or allowances for damaged or recalled Product, and returns or rejections of Product; 
 (ii) trade, cash and quantity discounts, allowances and credits; and 
 (iii) chargebacks and rebates (or the equivalent thereof) granted to group purchasing organizations, managed health care
organizations or to federal, state/provincial, local and other governments, including their agencies, or to trade Customers. 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the
omitted portions. 
  

 10 

 The foregoing deductions shall only be deducted to the extent they were initially included in, and not
otherwise deducted from, gross amounts invoiced. For the avoidance of doubt, sales or other transfers of Product between or among any Prometheus and/or its Affiliates and/or their Sublicensees shall not be counted for purposes of determining Net
Sales, but resale of such Product by Prometheus or any Affiliate or Sublicensee to Third Parties shall be counted for purposes of determining Net Sales. Furthermore, Net Sales shall not include use of or sale at or below the Transfer Price by
Prometheus, its Affiliates and/or their Sublicensees of Product for non-clinical or clinical studies, patient-assistance programs, charitable donations or compassionate use. Net Sales, as set forth in this definition, shall be calculated, in
accordance with GAAP applied in a consistent manner. 
 “Net Sales Average” means the average quarterly Net
Sales for the four (4) consecutive Calendar Quarters occurring immediately prior to the applicable market event(s) giving rise to a Significant Market Event; provided that, following any SME Termination, the Net Sales Average used to
determine the occurrence of a subsequent Significant Market Event shall be as follows: (a) if Net Sales after the SME Termination Date, during any four (4) consecutive Calendar Quarters, do not exceed the Net Sales Average for the period
prior to the initial Significant Market Event, then the Net Sales Average prior to the initial Significant Market Event shall continue to apply, or (b) if Net Sales during any four (4) consecutive Calendar Quarters after the SME
Termination Date do exceed the Net Sales Average for the period prior to the initial Significant Market Event, then the average quarterly Net Sales for the four (4) consecutive Calendar Quarters occurring immediately prior to the applicable
market event(s) giving rise to such subsequent Significant Market Event shall apply as the new Net Sales Average from such point forward. 
 “Net Sales Deduction Cap” will have the meaning set forth in the definition of “Net Sales”. 
 “New Indications” means any indication for the Product(s) (other than those Product indications approved in the Territory as of the Effective Date) which are approved by the FDA or other
applicable Regulatory Authority in the Territory. 
 “Novartis” will have the meaning set forth in the
Introduction. 
 “Novartis Brands” means the Trademarks owned, licensed, controlled or used by Novartis or its
Affiliates, whether or not registered, other than the Product Marks and Product Trade Dress. 
 “Novartis Catastrophic
Breach” will have the meaning set forth in Section 10.2(b). 
 “Novartis CoC Waiver” will have
the meaning set forth in Section 10.5. 
  

 11 

 “Novartis Competitor” means any Third Party who, individually or with its
Affiliates [* * *], provided that such Third Party shall only be considered a “Novartis Competitor” [* * *]. 
 “Novartis Disclosure Schedule” means the (i) the Original Novartis Disclosure Schedule, and, if applicable, (ii) the ROW Novartis Disclosure Schedule. 
 “Novartis Excluded Products” will have the meaning set forth in Section 2.8. 
 “Novartis Improvement” means any Improvement to one or more Products developed by Novartis or its Affiliates during the
Term which are owned or Controlled by Novartis or its Affiliates. 
 “Novartis Indemnitees” will have the
meaning set forth in Section 7.2. 
 “Novartis NDC” will have the meaning set forth in
Section 4.2(b). 
 “Novartis Net Selling Price” means the 2009 price per unit of Product multiplied by [*
* *] percent ([* * *]%), which equals [* * *] U.S. dollars and [* * *] cents ($[* * *]), subject to a [* * *] percent ([* * *]%) increase with effect on and from each subsequent anniversary of the First Sales Booking Date for the duration of the
Term. 
 “Novartis Promotional Guidelines” will have the meaning set forth in Section 4.1(h). 

“Novartis Promotional Materials” will have the meaning set forth in Section 2.4(d). 
 “Novartis Training Materials” will have the meaning set forth in Section 4.11(a). 
 “Original Novartis Disclosure Schedule” means the disclosure schedule delivered by Novartis to Prometheus as of the
Effective Date setting forth any exceptions to the representations and warranties given by Novartis pursuant to Section 6.2 with respect to the Territory as of the Effective Date. 
 “Other Product” will have the meaning set forth in Section 8.6(b)(i). 
 “Out-of-Pocket Costs” means direct expenses actually paid to Third Parties and specifically identifiable as relating to and
incurred in connection with the referenced activity; such expenses to have been recorded as income statement items in accordance with the Accounting Standards and for the avoidance of doubt shall not include pre-paid amounts or capital expenditures.

 “PAP Transition Date” will have the meaning set forth in Section 4.2(c). 
 “PAP Transition Period” will have the meaning set forth in Section 4.2(c). 
  
 *** Certain information on this page has been omitted and filed separately with
the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 12 

 “Party” or “Parties” will have the meaning set forth in
the Introduction. 
 “Patents” means patents, patent applications, patent disclosures, invention disclosures
and similar rights (and all rights related thereto, including all reissues, reexaminations, divisions, continuations, continuations-in-part, provisionals, continued prosecution applications, substitutions, reissues, extensions or renewals of any of
the foregoing) in the Territory. 
 “PDE” means a primary detail equivalent where a Primary Product Detail has
a value of [* * *] primary detail equivalent and a Secondary Product Detail has a value of [* * *] primary detail equivalent. 
 “PDE Value” means [* * *] U.S. dollars ($[* * *]) per PDE. 
 “PDMA” means the
Prescription Drug Marketing Act of 1987, as amended, and the regulations promulgated thereunder from time to time. 
 “Permitted Encumbrances” means (i) liens for current taxes not yet due and payable or that are being contested in good faith by appropriate proceedings and that are not material; (ii) deposits or pledges made in
connection with, or to secure payment of, workers’ compensation, unemployment insurance or similar programs mandated by Applicable Law; and (iii) statutory or common law liens in favor of carriers, warehousemen, mechanics and materialmen,
to secure claims for labor materials or supplies; and any other similar liens. 
 “Person” means any
individual, corporation, partnership, firm, association, joint venture, joint stock company, trust or other entity. 
 “Pipeline Inventory Adjustment” means the amount payable by Novartis to Prometheus with respect to certain sales of Products made by Novartis to its wholesalers and distributors prior to the First Sales Booking Date, as
calculated in accordance with Exhibit K attached hereto. 
 “Primary Product Detail” means a Detail in
which the primary focus of the Detail is a Product and at least [* * *] percent ([* * *]%) of the time of the Detail is spent discussing such Product. 
 “Proceeding” means any action, arbitration, hearing, litigation or suit (whether civil, criminal, administrative, investigative or informal) by or before, or otherwise involving any
governmental entity or arbitrator. 
 “Processing Handover Date” means May 1, 2010. 
 “Product(s)” means (i) the PROLEUKIN® (aldesleukin) pharmaceutical product(s) currently Commercialized by Novartis
and its Affiliates in the Territory as of the Effective Date (the “Existing Product”), as described on Exhibit A attached hereto, and (ii) all 
  

 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with
respect to the omitted portions. 
  

 13 

 
future formulations, presentations, line extensions and modes of administration thereof Developed by or on behalf of Novartis and/or Prometheus during the Term in accordance with this Agreement.

 “Product Intellectual Property” means the Product Patent Rights, Product Know-How, Product Marks, Novartis
Improvements (where and to the extent that such Novartis Improvements have application in the Field) and Product Trade Dress. 
 “Product Know-How” means the Know-How which is necessary or useful to Develop the Products in the Territory as such Development has been approved by the JDC or Novartis, as applicable, pursuant to Section 3 hereto, or
Commercialize the Products in the Field in the Territory, and which is owned or Controlled by Novartis or any of its Affiliates as of the Effective Date or during the Term, including without limitation, any Novartis Improvements (where and to the
extent that such Novartis Improvements have application in the Field), but expressly excluding any Manufacturing Know-How. 
 “Product Liability Claim” means any Claim of product liability or damage to person or property or death resulting from the use or consumption of the Products in the Territory. 
 “Product Mark(s)” means the Trademark(s) set forth on Exhibit C attached hereto. 
 “Product Patent Rights” means (a) the Patents owned or Controlled by Novartis or any of its Affiliates, as of the
Effective Date or at any time during the Term, which cover the Product, including those set forth on Exhibit D as attached hereto, as may be amended from time to time, and (b) all Patents in the Territory owned or Controlled by Novartis
or its Affiliates (i) to which any of the Patents set forth on Exhibit D claim priority, or (ii) for which any of the Patents on Exhibit D form a basis for priority, including any reissues, reexaminations, divisions,
continuations, continuations-in-part, provisionals, continued prosecution applications, substitutions, reissues, extensions or renewals of such Patents listed on Exhibit D. 
 “Product Trade Dress” means the trade dress set forth on Exhibit E attached hereto to the extent created for, and
used only on, Product as of the Effective Date, but specifically excluding, without limitation, any elements of trade dress consisting of any company name, business name, trade name, trademark, corporate logo, or other element that uses or
incorporates the word “NOVARTIS” or any other corporate indicia of Novartis or any of its Affiliates, including without limitation any division, business unit or business franchise of Novartis. 
 “Product Websites” will have the meaning set forth in Section 4.4(d). 
 “Prometheus” will have the meaning set forth in the Introduction. 
 “Prometheus Average Net Selling Price” means the average Net Sales of Product by Prometheus, its Affiliates and its
Sublicensees (measured over the immediately prior [* * *] 
  
 ***
Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 14 

 
([* * *]) consecutive months) divided by the total number of units of Product sold by Prometheus, its Affiliates and its Sublicensees during such applicable period on a country-by-country basis
in the Territory. 
 “Prometheus Combination Product” means a Combination Product Commercialized by Prometheus
or its Affiliates. 
 “Prometheus Improvement” will have the meaning set forth in Section 8.6(b).

 “Prometheus Indemnitees” will have the meaning set forth in Section 7.1. 
 “Prometheus NDC” will have the meaning set forth in Section 4.2(b). 
 “Prometheus Promotional Materials” will have the meaning set forth in Section 4.3(a)(i). 
 “Prometheus Stock Exhaustion” will have the meaning set forth in Section 10.2(b)(i). 
 “Prometheus Training Materials” will have the meaning set forth in Section 4.11(a). 
 “Promotional Activities” will have the meaning set forth in Section 4.3(b)(i). 
 “Promotional Materials” means any active materials used to promote or market the Products in the Field in the Territory,
including advertisements, brochures and other written material, audio and video material, computer based material, web sites, display panels, permissible educational give-aways, or any other marketing materials aimed at physicians, patients,
Customers, or organized Customer groups. 
 “Reduced Royalties” will have the meaning set forth in
Section 5.4(c). 
 “Regulatory Approval(s)” means the regulatory approvals, authorizations, licenses,
applications, supplements, variations, agreements, permits, INDs, NDAs, BLAs and other permissions, and any foreign equivalents of the foregoing, held by a Party or its Affiliates at any time during the Term to the extent relating to the Products
and issued by Regulatory Authorities in the Territory, including but not limited to those Regulatory Approvals held by Novartis or its Affiliates as of the Effective Date and set forth on Exhibit F attached hereto and all Additional
Regulatory Approvals obtained by Prometheus or its Affiliates during the Term as permitted by this Agreement. For the avoidance of doubt, “Regulatory Approvals” shall not include any portion of the foregoing approvals, authorizations,
licenses, applications, supplements, variations, agreements, permits, INDs, NDAs, BLAs and other permissions that relate to other products of Novartis or its Affiliates. 
  

 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with
respect to the omitted portions. 
  

 15 

 “Regulatory Approval Reversion Date” will have the meaning set forth in
Section 10.7(d). 
 “Regulatory Authority” means any federal, state or local regulatory authority,
regulatory agency or other governmental body in the Territory, including but not limited to the FDA and Health Canada. 
 “Regulatory Transfer Commencement Date” will have the meaning set forth in Section 3.2(a). 
 “Representative” will have the meaning set forth in Section 9.2. 
 “ROW
Amendment” will have the meaning set forth in Section 2.6(b). 
 “ROW Negotiation Period” will
have the meaning set forth in Section 2.6(b). 
 “ROW Novartis Disclosure Schedule” means the disclosure
schedule delivered by Novartis to Prometheus as of the date of the ROW Amendment setting forth any exceptions to the representations and warranties given by Novartis pursuant to Section 6.2 with respect to the ROW Territory. 
 “ROW Option” will have the meaning set forth in Section 2.6(b). 
 “ROW Option Conditions” will have the meaning set out in Section 2.7. 
 “ROW Option Expiration Date” means the first (1st) anniversary of the First Sales Booking Date. 
 “ROW Territory” means all countries and territories of the world outside the Territory. 
 “Royalty” will have the meaning set forth in Section 5.2. 
 “Sales Force” means Sales Representatives, field sales managers, district sales managers, regional sales managers, national
sales managers, trainers, managed care account directors and other individuals acting in a capacity customarily comprising a pharmaceutical company’s product sales force who are appointed to act on behalf of Prometheus in connection with its
Commercialization of the Product. 
 “Sales Representative” will have the meaning set forth in Exhibit
H. 
 “SEC” will have the meaning set forth in Section 9.2. 
 “Secondary Product Detail” means a Detail in which the primary focus of the Detail is a product other than the Product and
the secondary focus of the Detail is the Product, provided that at least [* * *] percent ([* * *]%) of the time of the Detail is spent discussing the Product. 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been
requested with respect to the omitted portions. 
  

 16 

 “Secondary Product Patent Rights” means those Product Patent Rights which
cover the Product but are not necessary to Commercialize the Product, including without limitation, those listed in Section 2 of Exhibit D, as may be amended from time to time. 
 “Sell-Off Period” will have the meaning set forth in Section 10.7(b)(ii). 
 “Significant Market Event” or “SME” means any market event(s), the occurrence of which, individually or in
the aggregate, causes the average Net Sales for [* * *] ([* * *]) consecutive Calendar Quarters to be reduced by [* * *] percent ([* * *]%) or more when compared to the Net Sales Average. 
 “SME Termination” means, following a Significant Market Event, the occurrence of [* * *] ([* * *]) consecutive Calendar
Quarters in which the average Net Sales for such period exceeds [* * *] percent ([* * *]%) of the Net Sales Average applicable to such Significant Market Event. 
 “SME Termination Date” means the first day of the immediately subsequent Calendar Quarter to occur after the SME Termination. 
 “Sublicense” will have the meaning set forth in Section 2.3(b). 
 “Sublicensee” means any Person other than an Affiliate of Prometheus that is granted a Sublicense by Prometheus in
accordance with this Agreement. 
 “Supply Agreement” means that certain Supply Agreement entered into between
the Parties or their Affiliates in conjunction with this Agreement on the Effective Date. 
 “Tax” or
“Taxes” means any and all taxes, assessments, levies, tariffs, amounts subject to escheat, duties or other charges, or impositions in the nature of a tax (together with any and all interest, penalties, additions to tax and
additional amounts imposed with respect thereto) imposed by any applicable Regulatory Authority. 
 “Term” will
have the meaning set forth in Section 10.1. 
 “Territory” means (i) the United States of America,
including each of its territories, commonwealths and possessions (the “United States” or “U.S.”), and (ii) upon the Canada Election Date, Canada, including each of its territories, commonwealths and possessions
(“Canada”). 
 “Third Party(ies)” means any Person other than the Parties or their respective
Affiliates. 
  
 *** Certain information on this page has been omitted
and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 17 

 “Third Party Agreement” will have the meaning set forth in
Section 11.17. 
 “Third Party Product” means any product, which is not owned, licensed or otherwise
controlled by Prometheus or its Affiliates as of the Effective Date, which is approved for use with the Product and which is being Commercialized by a Third Party in the Territory. Examples of Third Party Products, when and if approved, are [* * *].

 “Trademark” means trademarks, service marks, certification marks, trade dress, internet domain names, trade
names, identifying symbols, designs, product names, company names, slogans, logos or insignia, whether registered or unregistered, and all common law rights, applications and registrations therefor, and all goodwill associated therewith. 

“Transfer Price” means the price set forth in the Supply Agreement for Novartis to supply the Product to Prometheus in
accordance with the terms and conditions of the Supply Agreement. 
 “Transition Contracts” will have the
meaning set forth in Section 10.7(e). 
 “Transition Services” will have the meaning set forth in
Exhibit S. 
 “Transition Services Period” will have the meaning set forth in Section 4.2(a).

 “United States” or “U.S.” will have the meaning set forth in the definition of Territory.

 “Units Sold” will have the meaning set forth in Exhibit K. 
 “Up-Front Payment” will have the meaning set forth in Section 5.1(a). 
 “Upstream License Agreements” means the following license agreements between Novartis or its Affiliates and a Third Party
pursuant to which certain Product Intellectual Property Controlled by Novartis is licensed to Novartis or its Affiliates by such Third Party, as may be amended from time to time: (a) that certain License Agreement [* * *], and (b) that
certain [* * *]. 
 “Upstream Licensed Product Patent Rights” means any Product Patent Rights Controlled but
not owned by Novartis that are licensed to Novartis or its Affiliates pursuant to an Upstream License Agreement. 
 “Upstream Licensor” means each of the licensors pursuant to the Upstream License Agreements. 
 “Wholesaler Pipeline Days” will have the meaning set forth in Exhibit K. 
 “Wholesaler
Pipeline MoH” will have the meaning set forth in Exhibit K. 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 18 

 1.2 Interpretation. Unless the context of this Agreement otherwise requires:
(a) words of any gender include each other gender; (b) words using the singular or plural number also include the plural or singular number, respectively; (c) the terms “hereof,” “herein,” “hereby,” and
derivative or similar words refer to this entire Agreement; (d) the terms “Section” or “Exhibit” refer to the specified Section or Exhibit of this Agreement; (e) the term “including” means “including
without limitation”; (f) “days” refers to calendar days and (g) the term “knowledge”, with respect to Novartis, means the [* * *]. All accounting terms used but not otherwise defined herein shall have the meanings
ascribed to such terms under the applicable Accounting Standards as applied to a Party. All references to “$” amounts hereunder shall be deemed to be U.S. Dollars, and all payments due hereunder shall be made in U.S. Dollars. 

SECTION 2. 
 LICENSE GRANTS AND APPOINTMENT 
 2.1 License Grants and Appointment. 
 (a) Development License. Subject to the terms and conditions of this Agreement (including Section 3.2(e) and the
Novartis Disclosure Schedule), on and from the Effective Date and for the duration of the Term, Novartis hereby grants to Prometheus a co-exclusive (together with Novartis and its Affiliates, provided that neither Novartis nor any of its
Affiliates shall have the right to license its co-exclusive Development rights, other than to a contract research organization or in connection with Development activities pursuant to Section 3.2(e), non-sublicensable, royalty-bearing (in
accordance with Section 5) license under the Product Intellectual Property to Develop the Products, subject to the restrictions set forth in this Agreement. 
 (b) Commercialization License. Subject to the terms and conditions of this Agreement (including the Novartis
Disclosure Schedule), on and from the Effective Date and for the duration of the Term, Novartis hereby appoints Prometheus as Novartis’ exclusive (even as against Novartis and its Affiliates) distributor of the Products in the Territory, and,
in connection therewith, grants to Prometheus the exclusive, non-sublicensable (except in accordance with Section 2.3), royalty-bearing (in accordance with Section 5) license under the Product Intellectual Property to Commercialize the
Products in the Territory. The foregoing license does not include the right to, and Prometheus agrees that it shall not, (i) market, Detail, promote, or advertise the Products for use outside the Field or (ii) Commercialize in any manner
the Products outside the Territory. For the avoidance of doubt, subject to the above referenced obligations of Prometheus and its other obligations hereunder including its obligation to comply with all Applicable Laws, the writing of a prescription
in the Territory for the Product for an unapproved use shall not, in and of itself, constitute a breach of this Agreement. For so long as the scope of the license granted pursuant to this Section 2.1(b) does not cover the ROW Territory,
Novartis shall use efforts consistent with the measures that it uses with respect to its other Oncology products to prevent cross-border transactions with respect to the Products between the United States and Mexico. 
  
 *** Certain information on this page has been omitted and filed separately with
the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 19 

 (c) Right of Reference. Novartis hereby grants to Prometheus, solely
to the extent required to obtain and maintain the Regulatory Approvals in the Field in the Territory, a right of reference to any drug master files relating to the manufacture of the Products, in connection with the Development and Commercialization
of the Products in the Territory in accordance with this Agreement. 
 2.2 Novartis Retained Rights; Compliance with Upstream
License Agreements. 
 (a) Novartis Retained Rights. Notwithstanding Section 2.1 or any other
provision of this Agreement, Novartis will retain the exclusive right to manufacture or have manufactured and supply the Products in or outside the Territory, provided that Novartis will not supply Products to any Third Party in the
Territory, other than to Prometheus, its Affiliates and Sublicensees for Development and Commercialization in the Territory in accordance with this Agreement or as otherwise expressly contemplated by this Agreement. In addition, notwithstanding
Section 2.1 or any other provision of this Agreement, Prometheus acknowledges that (i) Novartis will continue to Commercialize the Products in each country in the Territory until the applicable First Sales Booking Date for such country;
(ii) Novartis will continue to supply Products in each country in the Territory until the applicable First Sales Booking Date for such country; and (iii) Novartis will perform its obligations under Sections 3.2(f), (g) and
(h) and Section 4.2(c). Furthermore, subject to the ROW Option, Novartis shall retain the right to Develop (subject to Section 3.2(e)) the Product in the Territory and outside the Territory and the right to Commercialize the Product
outside the Territory. 
 (b) Compliance with Upstream License Agreements. Prometheus agrees that it and
its Affiliates and Sublicensees shall comply with those additional terms and conditions mandated by the Upstream License Agreements which are expressly set forth in Exhibit T. 
 2.3 Right to Appoint Sublicensees and Subcontractors. 
 (a) No Development Sublicenses. Prometheus shall not have the right to grant sublicenses under, appoint subcontractors
or distributors, or otherwise assign or transfer its right to Develop the Products pursuant to Section 2.1(a), unless otherwise agreed by Novartis in writing. Notwithstanding the foregoing, Prometheus shall have the right to retain Third Party
contract research organizations to perform Development activities which are permitted hereunder with respect to the Products for and on behalf of Prometheus and/or its Affiliates, provided that the applicable subcontractor shall be required
to comply with the applicable terms and conditions of this Agreement and Prometheus shall remain responsible for the performance of this Agreement notwithstanding its entry into any such subcontract. 
  

 20 

 (b) Right to Appoint Commercialization Sublicensees. Prometheus shall
have the right to grant sublicenses to Third Parties (each a “Sublicense”) under its right to Commercialize the Products pursuant to Section 2.1(b) solely for the territory of Canada, provided that (i) each
Sublicensee shall be subject to the prior written approval of Novartis, such approval not to be unreasonably withheld, (ii) in connection with exercising such right to grant Sublicenses, Prometheus and the applicable Sublicensee shall prepare a
plan wherein Prometheus and the Sublicensee will use Commercially Reasonable Efforts to minimize any risks of parallel trade, (iii) any agreement between Prometheus and such a Sublicensee shall allow, at Novartis’ option, upon termination
or expiration of this Agreement, for (y) assignment of the relevant agreement to Novartis, its Affiliate or its designee, or (z) termination of the relevant agreement without penalty upon reasonably prior written notice to such
Sublicensee, (iv) such Third Party shall not have the right to grant further sublicenses, (v) in connection with any such Sublicense, Novartis shall receive the payments contemplated by Section 5.1(b) from Prometheus, (vi) with
respect to Product Intellectual Property licensed to Novartis pursuant to any Upstream License Agreement, the Sublicensee shall be required to comply with the applicable terms and conditions of such Upstream License Agreement set forth in Exhibit
T, and (vii) the Sublicensee shall be required to comply with the applicable terms and conditions of this Agreement and Prometheus shall remain responsible for performance of this Agreement, including, the obligation to make all payments
under this Agreement directly to Novartis, notwithstanding any Sublicenses granted by Prometheus. Except as expressly provided in the preceding sentence, Prometheus shall not have the right to grant sublicenses under, appoint subcontractors or
distributors, or otherwise assign or transfer its right to Commercialize the Products pursuant to Section 2.1(b). For clarification purposes, Prometheus shall not require Novartis’ prior written approval to enter into an agreement with any
Third Party contract sales organization who is performing Commercialization activities for and on behalf of Prometheus and/or its Affiliates in Canada or any Third Party who distributes and sells the Product in Canada but does not have the right to
perform any other Commercialization activities, in either case, where such Third Party does not receive a sublicense of Prometheus’ rights under Section 2.1(b), provided that the applicable Third Party shall be required to comply
with the applicable terms of this Agreement and any applicable Upstream License Agreements and Prometheus shall remain responsible for the performance of this Agreement notwithstanding its entry into any such agreement. In addition, Prometheus shall
not be required to obtain Novartis’ consent to enter into any agreements with wholesale distributors of the Product in the Territory during the Term, provided such wholesale distributor is acting exclusively in the capacity of wholesaler and
not providing any other Commercialization activities and such wholesale distributor shall not be considered to be a Sublicensee for the purposes of this Agreement. 
 2.4 Disclosure of Product Intellectual Property. Promptly following the Effective Date, and in any event within thirty (30) days thereafter (unless a longer period of time is specified below),
Novartis shall disclose to Prometheus, or provide Prometheus with the following Product Intellectual Property to the extent in the possession and Control of Novartis or its Affiliates as of the Effective Date, and Novartis shall provide Prometheus
with updates to such Product Intellectual Property throughout the Term as soon as reasonably practicable following creation of any amendments thereto or new Product Intellectual Property described in this Section 2.4 not previously disclosed to
Prometheus in accordance with Section 2.4: 
 (a) Copies of all the Regulatory Approvals for the Products in
the Territory held by Novartis and its Affiliates as of the Effective Date, including those Regulatory Approvals in the Territory listed on Exhibit F, to the extent disclosure thereof is permitted by Applicable Law, and copies of all
Dossiers for the Products; 
  

 21 

 (b) Copies of material written communications (i) (x) with the FDA
from [* * *], through the Effective Date, within thirty (30) days after the Effective Date; and (y) that Novartis has in its possession, with the FDA [* * *], within ninety (90) days following the Effective Date, and (z) with any
Regulatory Authorities in Canada, within ninety (90) days following the Canada Election Date. Such written communications shall include the minutes of any meetings with the FDA and such other applicable Regulatory Authorities regarding the
Regulatory Approvals or Commercialization of the Products in the Territory, in each case relating to the Products; 
 (c) Copies of all existing Product Marks and Product Trade Dress; 
 (d) Copies of current samples of
Promotional Materials in Novartis’ possession or control and actively used by Novartis as of the Effective Date relating to the Products in the Field in the Territory, which materials are specifically listed on Exhibit G attached hereto
(“Novartis Promotional Materials”); and 
 (e) Copies of current manufacturing, stability and
release testing documentation used in the Territory, including but not limited to master and executed manufacturing batch records, test methods, release and stability protocols, stability results, manufacturing guides, conformance guides, and
specifications for the Products solely to the extent necessary to obtain or maintain the Regulatory Approvals in the Field in the Territory. 
 (f) For the avoidance of doubt, Novartis is not required to disclose to Prometheus any Product Know-How that is outside the Field except, and only to the extent, that any such Product Know-How is
necessary or useful to Development activities of Prometheus that have been approved by Novartis or the JDC, as applicable, pursuant to Section 3 hereto. Notwithstanding anything to the contrary set forth herein, subject to the rights and
licenses granted to Prometheus pursuant to this Agreement, Novartis or its Affiliates or the Upstream Licensors, as applicable, shall retain all right, title and interest in and to all Product Intellectual Property. 
 2.5 Non-Compete. 
 (a) Novartis Non-Compete. During the Term, neither Novartis nor any of its Affiliates shall, directly or indirectly, sell, have sold, offer for sale, market, promote, 
  
 *** Certain information on this page has been omitted and filed separately with
the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 22 

 
distribute or otherwise commercially dispose of [* * *] ([* * *]) in the Territory, nor shall Novartis assist or license any Third Party the right to do any of the foregoing, unless otherwise
agreed to by Prometheus in writing or expressly contemplated by this Agreement. 
 (b) Prometheus
Non-Compete. 
 (i) During the Term, neither Prometheus nor any of its Affiliates shall, directly or
indirectly, sell, have sold, offer for sale, market, promote, distribute or otherwise commercially dispose of any pharmaceutical product other than the Product in the Territory for the treatment of renal cell carcinoma and/or melanoma, nor shall
Prometheus assist or license any Third Party the right to do any of the foregoing, unless otherwise agreed to by Novartis in writing. Notwithstanding the foregoing, in the event that Prometheus or any of its Affiliates [* * *]. Novartis shall give
due consideration to any requests for exemption by Prometheus from its obligations pursuant to the foregoing sentence, and shall provide its acceptance or rejection of any such requests as soon as reasonably practicable following receipt of the
request from Prometheus. For the avoidance of doubt, the foregoing non-compete in this Section 2.5(b) shall not apply to any pharmaceutical product that is primarily indicated for the treatment of any side effects or symptoms resulting from or
related to the use of the Product, but which is not indicated for any indication for which the Product is approved. 
 (ii) Upon the termination of this Agreement by Novartis pursuant to Section 10.2, for a period of [* * *] ([* * *]) years after the date of termination of this Agreement, neither Prometheus nor any of its Affiliates shall, directly or
indirectly, sell, have sold, offer for sale, market, promote, distribute or otherwise commercially dispose of any pharmaceutical product for the treatment of renal cell carcinoma and/or melanoma in the Territory, nor shall Prometheus assist or
license any Third Party the right to do any of the foregoing, unless otherwise agreed to by Novartis in writing. 
 (iii) Upon the termination or expiration of this Agreement for any reason except for a termination of this Agreement by Prometheus pursuant to Section 10.2, for a period of [* * *] ([* * *]) years after the date of termination or
expiration of this Agreement, neither Prometheus nor any of its Affiliates shall, directly or indirectly, sell, have sold, offer for sale, market, promote, distribute or otherwise commercially dispose of aldesleukin, any pharmaceutical product
containing aldesleukin, or any Generic, in the Territory, nor shall Prometheus assist or license any Third Party the right to do any of the foregoing, unless otherwise agreed to by Novartis in writing. For purposes of this subsection (iii)
only, “Generic” shall mean a generic version or alternative formulation of aldesleukin or interleukin-2 that has demonstrated bioequivalence to the Products and which is approved by the FDA in the United States or by the applicable

  
 *** Certain information on this page has been omitted and filed
separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 23 

 
Regulatory Authority in any other country within the Territory for any indications in such applicable country in accordance with the regulatory approval process under the Applicable Law of such
country. 
 (iv) For the avoidance of doubt, it shall not be deemed a breach of Prometheus’ obligations
hereunder as a result of Prometheus’ development of a diagnostic product which is used in combination with a Third Party’s Competitive Product. 
 (c) Enforcement of Non-Compete. Each Party recognizes that the restrictions contained in, and the terms of, this Section 2.5 are properly required for the adequate protection of the other
Party’s rights hereunder, and agrees that if any provision in this Section 2.5 is determined by any court to be unenforceable by reason of its duration or scope, or by reason of its being too extensive in any other respect, such covenant
shall be interpreted to extend only for the longest duration and scope, and to otherwise have the broadest application as shall be enforceable. 
 2.6 Option to Extend the Territory. 
 (a) Canada
Option. Subject to Prometheus fulfilling the Canada Transfer Criteria as set forth in Exhibit Z and its compliance with the terms and conditions set forth under this Agreement, Prometheus shall have the right, in its sole discretion, to
elect to extend the Territory for purposes of this Agreement to include Canada by providing [* * *] ([* * *]) days prior written notice of such election to Novartis. In the event that Prometheus elects to extend the Territory to include Canada then,
on the [* * *] ([* * *]) day following the date that Novartis receives the notice provided by Prometheus in accordance with this Section 2.6(a) (the “Canada Election Date”), Canada shall automatically be
deemed to be included in the definition of “Territory” for purposes of this Agreement as of the Canada Election Date, and the terms and conditions of this Agreement shall apply to the Development and Commercialization of the Products by or
on behalf of Prometheus and its Affiliates in Canada. Notwithstanding the foregoing, if Novartis subsequently discloses any Existing Discount Agreement applicable to Canada which has terms and conditions which are unacceptable to Prometheus,
Prometheus shall have the right to revoke its election by providing written notice to Novartis of the same within [* * *] ([* * *]) days of Novartis’ disclosure of the Existing Discount Agreement and the Canada Election Date will be deemed to
have not occurred. 
 (b) ROW Option. Subject to Prometheus fulfilling the ROW Option Conditions set forth
in Section 2.7 and its compliance with the terms and conditions set forth under this Agreement, Prometheus shall have the right, in its sole discretion, to elect to extend the scope of this Agreement to cover the ROW Territory (the “ROW
Option”) by providing notice of such election in writing to Novartis on or prior to the ROW Option Expiration Date. In the event that Prometheus elects to exercise the ROW Option and Novartis receives the notice provided by Prometheus in
accordance with this 
  
 *** Certain information on this page has
been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 24 

 
Section 2.6(b), the Parties shall enter into negotiations in good faith for the amendment of this Agreement to cover the ROW Territory (or if necessary to address Novartis corporate
structure and/or asset ownership issues, then a separate ROW agreement) that shall include the financial terms set forth on Exhibit M (in either case, the “ROW Amendment”). Prior to the ROW Option Expiration Date and for
such period after Prometheus exercises the ROW Option during which Prometheus and Novartis are continuing to negotiate the ROW Amendment in good faith (such period not to exceed [* * *] ([* * *]) days, except that such period shall automatically be
extended for an additional period of [* * *] ([* * *]) days if the Parties in good faith are not able to complete the negotiations during the initial [* * *] ([* * *]) day period and wish to continue such negotiations) (the “ROW Negotiation
Period”), Novartis shall not negotiate with, solicit or enter into any definitive agreement with any Third Party (other than the continuation of existing agreements) regarding the acquisition or license of the Product and/or the Product
Intellectual Property in all or any portion of the ROW Territory that would be covered by the ROW Amendment. 
 2.7 ROW
Option Conditions. Prometheus’ right to exercise such ROW Option shall be subject to Prometheus’ satisfaction on or before the ROW Option Expiration Date of the terms and conditions (the “ROW Option Conditions”) set
forth on Exhibit N attached hereto. 
 2.8 Certain Exclusions. 
 (a) Notwithstanding any other provision of this Agreement (including Sections 2.5(b), 3.1(c) and 3.2(e)), Novartis and
its Affiliates shall have the unrestricted right to pursue the Development and Commercialization of the two (2) products described on Exhibit Q (“Novartis Excluded Products”) without restriction and without the review or
approval of Prometheus or the JDC. 
 (b) With regards to Novartis Excluded Product 1 described on
Exhibit Q, it is contemplated that the development path of this product will include Clinical Trials in the Territory whose dosing and administration call for use of the Product with Novartis Excluded Product 1 in patients whose
underlying medical condition is in the Field. For any patient in such Clinical Trial in the Territory (a) whose underlying condition is in the Field and (b) whose medical insurance or other healthcare reimbursement does not cover the
market cost of the Product used for treatment of such patient in the Clinical Trial, Novartis shall be permitted, at its sole discretion, to provide the Product to the patient free of charge (or at any nominal charge) and shall compensate Prometheus
for each such vial used for such patient at a rate of [* * *] percent ([* * *]%) of the Prometheus Average Net Selling Price in the applicable country in the Territory. Within [* * *] ([* * *]) days after the end of each Calendar Quarter during the
Term, Novartis shall submit to Prometheus a report setting forth the number of vials provided to patients in accordance with this Section 2.8, following which Prometheus shall provide Novartis with an invoice setting forth the applicable
amounts due from Novartis for the applicable Calendar Quarter which shall be due and payable within [* * *] ([* * *]) days of receipt by Novartis. 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the
omitted portions. 
  

 25 

 (c) In the event that Novartis Excluded Product 1 is approved by the
applicable Regulatory Authorities and Commercialized by Novartis, its Affiliates or their licensees or sublicensees, and as a result of such Commercialization is considered a Third Party Product for the purposes of this Agreement, Prometheus shall
be permitted to offset against any Incremental Product Net Sales Milestone by an amount equivalent to the aggregate amount paid or due to Prometheus from Novartis for vials of Product given to such patients free of charge (or at a nominal fee)
during the development of Novartis Excluded Product 1. For avoidance of doubt, if Commercialized in the Territory, Novartis Excluded Product 1 shall be considered a Third Party Product for purposes of this Agreement even if it is Commercialized by
Novartis, its Affiliates or their licensees; provided that Prometheus shall have the exclusive right in the Territory to Commercialize any Products labeled for use in connection with Novartis Excluded Product 1 during the Term. 
 (d) If Novartis Excluded Product 1 is approved for use by applicable Regulatory Authorities in the Territory in conjunction
with the Product, Prometheus shall use Commercially Reasonable Efforts to update the Product’s label at Novartis’ cost to indicate such non-exclusive usage with Novartis Excluded Product 1. 
 SECTION 3. 
 DEVELOPMENT 
 3.1 Joint Development Committee. 
 (a) Formation. Within thirty (30) days after the Effective Date, the Parties shall establish a joint development
committee (“JDC”) to facilitate co-operation between the Parties with respect to the clinical Development activities that may be undertaken by each Party for the Products. The JDC will be composed of [* * *] ([* * *])
representatives of each Party who shall be appointed (and may be replaced at any time) by such Party on prior written notice to the other Party in accordance with this Agreement. 
 (b) Meetings. The JDC shall meet not less frequently than [* * *] ([* * *]) times per calendar year throughout the
Term, or at such greater frequency as agreed by the respective committee members. Meetings of the JDC shall be at such locations as the Parties agree or if acceptable to both Parties, then such meetings may be held via video-conference or other like
manner, and the Parties may otherwise communicate regularly by telephone, electronic mail, facsimile and/or video conference. Additional representative(s) or consultant(s) may from time to time be invited to attend JDC meetings, subject to such
representative’s or consultant’s written agreement to comply 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 26 

 
with the requirements of Section 9; provided that, in the case of a consultant or other non-employee representative of a Party or its Affiliates, the other Party’s consent to the
attendance of such consultant or representative must be obtained prior to the JDC meeting. Each Party shall be responsible for its own expenses for participating in the JDC. Meetings of the JDC shall be effective only if at least one
(1) representative of each Party is present or participating. In the event that the JDC cannot reach unanimous agreement on any issue for which the JDC (as opposed to any individual party) has decision-making power under this Agreement, the
matter shall be escalated in accordance with Section 11.1 of this Agreement. Notwithstanding any such escalation of the issue pursuant to Section 11.1, in the event that the designated executives of each Party are not able to resolve the
issue within the scope and time frames set forth in Section 11.1, then neither Party shall have the right to pursue or undertake such matter which is the subject of escalation unless and until the Parties have reached unanimous agreement with
respect thereto. 
 (c) Responsibilities. The JDC shall have the responsibility and authority to:

 (i) Subject to Section 3.2(e), discuss and make decisions regarding the further Development of, or
activities aimed at the purpose of changing the Product in any way, including, the proposed conduct by either Party or its Affiliates of any Clinical Trial for any Improvement to the Product, any New Indication for the Product, any Combination
Product that would require a modification of or supplement to the labeling for the Product or any activities seeking to generate data allowing for Product labeling, formulation or delivery method changes. If Development or other Product Improvement
or requirement is mandated by a Regulatory Authority in relation to the Product, both Parties agree that such mandated Development, Improvement or other requirement must be implemented and one Party shall not have the authority to block the other
Party from performing the necessary activities to comply with the Regulatory Authority’s mandate; provided that each Party shall cooperate with the other Party in good faith to minimize the potential adverse effects of any such mandated
activities. 
 (ii) Subject to Section 3.2(e), discuss and make decisions regarding the conduct of any
investigator-initiated Clinical Trials commenced by Novartis or its Affiliates prior to the Effective Date or planned for initiation by Novartis or its Affiliates following the Effective Date, in each case solely as set forth on
Exhibit L attached hereto (the “Investigator-Initiated Trials”). 
 (iii) Perform
such other functions as the Parties may agree in writing. 
 3.2 Development and Regulatory Activities and
Responsibilities. 
 (a) Novartis Responsibilities. Promptly following the Effective Date, in the case
of the United States, and the Canada Election Date, in the case of Canada (as applicable, the “Regulatory Transfer Commencement Date”), but in no event later than five (5) Business Days after the Effective Date (in the case of
the United States) or

  

 27 

 
fourteen (14) days after the Canada Election Date (in the case of Canada), as applicable, Novartis shall deliver to Prometheus, electronically and in hard copy, executed letters (in mutually
acceptable form) addressed to the applicable Regulatory Authorities requesting the transfer, to the extent transferable, of the Regulatory Approvals listed on Exhibit F, from Novartis to Prometheus. Novartis shall use Commercially Reasonable
Efforts to transfer and assign to Prometheus as soon as reasonably practicable following the applicable Regulatory Transfer Commencement Date all such Regulatory Approvals and any other Regulatory Approvals held by Novartis or its Affiliates as of
the Effective Date. Furthermore, Novartis shall be solely responsible for, and bear all costs associated with, generating, preparing and providing to Prometheus, in accordance with Section 2.4(a) for the United States, and within twenty
(20) Business Days following the applicable Regulatory Transfer Commencement Date for Canada, a copy of all Dossiers which Novartis reasonably determines are required by Prometheus in order to perform its rights and obligations pursuant to
Section 3.2(b). During the Term, Novartis shall cooperate with Prometheus at Prometheus’ cost in connection with the performance by Prometheus of its rights and obligations under Sections 3.2(b) and (c), and shall execute, acknowledge
and deliver such further instruments and do such other acts and provide such other information at Prometheus’ reasonable request and expense, which are necessary and reasonably requested for Prometheus to obtain and maintain all required
Regulatory Approvals with respect to the Territory. Notwithstanding the foregoing, Novartis shall not be obligated to provide any Manufacturing Know-How or other manufacturing information other than that expressly identified in this Agreement or the
Supply Agreement. For the avoidance of doubt, all rights, interests and title in and to the Dossier(s) shall remain with and be solely owned by Novartis. 
 (b) Prometheus Responsibilities. Prometheus shall be responsible for, and bear the cost of (i) obtaining and maintaining all Additional Regulatory Approvals which are necessary for Prometheus
to Develop and Commercialize the Products in the Territory, and (ii) maintaining and submitting renewals for all required Regulatory Approvals that are transferred and assigned to it by Novartis in accordance with Section 3.2(a), but
excluding any manufacturing establishment fees, which shall be the sole responsibility of Novartis. For the avoidance of doubt, all rights, interests and title to all Regulatory Approvals transferred and assigned to Prometheus in accordance with
Section 3.2(a) and all Additional Regulatory Approvals obtained by Prometheus in accordance with this Section 3.2(b) shall be solely owned and held in the name of Prometheus during the Term, subject to Prometheus’ obligations to
maintain, in good standing, the Regulatory Approvals in the Territory during the Term and to transfer and assign all such Regulatory Approvals over to Novartis following termination or expiration of this Agreement in accordance with
Section 10.7(e). 
 (c) Prometheus Control of Regulatory Activities. Subject to Section 3.2(e)
and the other terms and conditions of this Agreement, Prometheus shall be responsible and have final decision-making authority, as to whether and how to obtain, supplement, amend or otherwise alter the Regulatory Approvals for Commercialization of
the Products in the Territory, for communicating with any Regulatory Authorities in the Territory with respect to Regulatory Approvals held in Prometheus’ name regarding the Commercialization of the Products in the Territory, and otherwise with
respect to any

  

 28 

 
issues raised by any Regulatory Authorities in connection with Prometheus’ Commercialization of the Products in the Territory. Furthermore, Prometheus shall have the right to communicate
with any Regulatory Authorities in the Territory with respect to any issues raised in connection with any Development of the Products in the Territory by Prometheus which has been approved by the JDC, except that all final decision-making authority
with regard to the Development of the Products remains with the JDC or as otherwise expressly set forth under this Agreement. Notwithstanding the foregoing, to the extent applicable to the Product and permitted by Applicable Law, Prometheus will
communicate to Novartis, and provide Novartis with copies of all material communications proposed to be submitted by Prometheus to any applicable Regulatory Authority if and as soon as reasonably practicable after their preparation, including any
applications or other communications with regards to obtaining Regulatory Approvals, following which Novartis shall, if reasonably practical, have a period of ten (10) days to provide comments on such communications to Prometheus. Prometheus
shall consider such comments in good faith, but shall have final decision-making authority as to whether to incorporate such comments into its final communications. Prometheus shall provide copies of all final written material communications between
Prometheus and any Regulatory Authority to Novartis within a reasonable period of time following such communication. 
 (d) Notification of Breach of Applicable Law. In the event that either Party receives notice or otherwise becomes aware of any alleged or actual violation of Applicable Law related to the Development or Commercialization of the
Products in the Territory, whether received from any Regulatory Authority or otherwise, the receiving Party shall promptly provide written notice of the same to the other Party together with copies of any material notices or communications in
connection therewith. 
 (e) Conduct of Development and Regulatory Activities for Product Improvements or New
Indications. 
 (i) The Parties acknowledge and agree that during the Term, neither Party shall have the
right to conduct or perform any Clinical Trials and/or seek any Regulatory Approvals with respect to Improvements to or New Indications for or uses of the Products in connection with either Party’s Development activities without first obtaining
the prior written approval of the other Party. It is understood that such approval may be conditioned by the other Party on having reached agreement with respect to modified financial terms or other provisions applicable to such Improvement or New
Indication. 
 (ii) Without limiting the foregoing, notwithstanding anything to the contrary set forth herein
(other than the exclusions applicable to the Novartis Excluded Products), neither Party shall (A) commence Development of any Improvement to a Product, any New Indication for a Product, any Combination Product that would require a modification
of or supplement to the labeling for the Product or any activities seeking to generate data for the purpose of obtaining a change to the Product labeling, or (B) seek any Additional Regulatory Approval for an Improvement to a Product or a New
Indication or use for the Product,

  

 29 

 
without the prior written consent of the JDC. Notwithstanding anything to the contrary set forth herein, Novartis reserves all rights, and the JDC shall have no authority, with respect to
(i) Improvements or modifications to be made to any manufacturing processes; and (ii) any updates or upgrades to be made with respect to manufacturing facilities; provided that where and to the extent any updates, Improvements or
modifications contemplated by the foregoing subsections (i) and/or (ii) cover or relate to the Products or the Product Intellectual Property, are reasonably likely to have an adverse impact upon the Regulatory Approvals in the Territory,
or materially increase Prometheus’ obligations in connection therewith, such matters shall be subject to review and agreement by the JDC. 
 (f) Material Transfer Agreements and Investigator-Initiated Trials. Commencing on the First Sales Booking Date, and so long as Prometheus is contractually and legally able to do so prior to any
assignment of the relevant Investigator Initiated Trial agreements and/or MTA, Prometheus shall bear all responsibility for managing the Investigator-Initiated Trials set forth on Exhibit L, and the studies and trials contemplated by the
Material Transfer Agreements (collectively, the “MTA”) set forth on Exhibit L through the completion of such studies and trials, including making all payments that are due thereunder on or after the First Sales Booking Date
and managing the relationships with the investigators with respect to each such individual study or trial. Novartis shall assign, and Prometheus shall assume, all of the MTAs and the underlying agreements with respect to the studies and trials,
including the Investigator-Initiated Trials, set forth on Exhibit L as soon as reasonably practicable after the Effective Date, but no later than [* * *] ([* * *]) days after the Effective Date. Novartis shall supply the Products for
such studies and trials until the date that the Parties shall enter into an agreement with respect to such supply under this subsection (f), which agreement shall be negotiated in good faith by the Parties and entered into by the Parties as soon as
reasonably practicable after the Effective Date, but no later than [* * *] ([* * *]) days after the Effective Date. Prior to the date that the Parties have entered into such supply agreement, Novartis shall have the sole obligation to supply the
Products for such studies and trials. After the date that the Parties have entered into such supply agreement, Prometheus shall have the sole obligation to supply the Products for such studies and trials. The Parties agree that notwithstanding the
foregoing (i) Novartis shall bear the costs of supplying the Products for the studies and trials that are specifically set forth on Exhibit L; and (ii) the Parties shall [* * *] in connection with such studies and trials set
forth on Exhibit L as of the First Sales Booking Date, which Out-of-Pocket Costs shall be first processed and paid in full by Prometheus, and then invoiced by Prometheus to Novartis for reimbursement of [* * *]
([* * *]%) of such Out-of-Pocket Costs. For the avoidance of doubt, Prometheus shall receive no compensation with respect to Products supplied to conduct the foregoing studies and trials or to meet the obligations of the MTA or other
agreements relating to the Investigator-Initiated Trials. 
  
 ***
Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 30 

 (g) Ongoing Phase IV Clinical Trial Commitments to FDA. Novartis
shall be responsible to manage and complete the outstanding Phase IV Clinical Trial commitments to the FDA solely as specifically set forth on Exhibit X with regard to the Products on behalf of Prometheus. Upon completion, Novartis shall
provide a study report for such Phase IV Clinical Trial to Prometheus for Prometheus to submit to the FDA. Novartis shall supply the Products for such Phase IV Clinical Trial until the date that the Parties shall enter into an agreement with respect
to such supply under this subsection (g), which agreement shall be negotiated in good faith by the Parties and entered into by the Parties as soon as reasonably practicable after the Effective Date, but no later than [* * *] ([* * *]) days after the
Effective Date. After the date that the Parties have entered into such supply agreement, Prometheus shall have the sole obligation to supply the Products for such Phase IV Clinical Trial. Notwithstanding the foregoing, the Parties agree that solely
with respect to such Phase IV Clinical Trial commitment set forth on Exhibit X, Novartis shall bear the costs of supplying the Products for such Phase IV Clinical Trial. For the avoidance of doubt, Prometheus shall receive no compensation
with respect to the supply of the Products to conduct the foregoing Phase IV Clinical Trial. 
 (h)
Investigator Initiated Trials outside of the Territory. Responsibility for managing and continuing to meet outstanding financial and product commitments to the Investigator-Initiated Trials outside of the Territory, as set forth on Exhibit
Y, will remain with Novartis and will not be subject to JDC or Prometheus review or approval. 
 SECTION 4.

 COMMERCIALIZATION 
 4.1 Prometheus Commercialization Rights and Obligations. Subject to the terms and conditions of this Agreement, Prometheus shall solely control and assume all responsibility, at its own cost, for
conducting all Commercialization activities relating to the Products in the Territory. In fulfillment of its Commercialization rights and obligations under this Agreement, as of the First Sales Booking Date and continuing during the Term Prometheus
shall without limitation: 
 (a) market, promote, offer for sale and Detail the Product solely within the Field
and within such jurisdictions in the Territory for which Prometheus has obtained all necessary Regulatory Approvals to Commercialize the Products; 
 (b) accept orders for the Products in the Territory from customers; 
 (c) establish and maintain systems for supporting and responding to medical and customer inquiries in the Territory; 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the
omitted portions. 
  

 31 

 (d) communicate with wholesale distributors in connection with the
distribution of the Product in the Territory; 
 (e) purchase the Products from Novartis in accordance with the
Supply Agreement; 
 (f) in accordance with the terms of Section 4.7, report rebates for the Products to
Novartis and/or the applicable Regulatory Authorities, as the case may be, and maintain the systems necessary to conduct such reporting activities; 
 (g) ensure that all Products are properly marked with the patent numbers in a manner consistent with such marking on the Existing Product; 
 (h) comply with Novartis’ promotion guidelines set forth in Exhibit J attached hereto with respect to
Prometheus’ Commercialization of the Products (“Novartis Promotional Guidelines”); 
 (i)
comply with Applicable Law in relation to its rights and obligations in relation to the Product or the Commercialization of the Product; 
 (j) not take any action that could reasonably be expected at the time of taking such action to have a material adverse effect on any Regulatory Approvals for one or more Products in the Territory or
outside the Territory; and 
 (k) once per calendar year during the Term, provide Novartis with a copy of
Prometheus’ Marketing Plan for the following calendar year after finalization thereof by Prometheus, but in any event no later than thirty (30) days prior to commencement of such following year; provided that Prometheus shall have
the right in its discretion to modify any Marketing Plan at any time and shall promptly provide a copy of any material updates to the Marketing Plan to Novartis and, in any event, no later than thirty (30) days following such update.

 4.2 Transition. 
 (a) Transition Services. On or before the First Sales Booking Date, Novartis shall notify all of its Customers in the Territory for the Products existing immediately prior to the First Sales
Booking Date that future orders for the Products in the Territory after the First Sales Booking Date shall be placed with Prometheus, and Novartis shall provide Prometheus with [* * *] for use by Prometheus solely to Commercialize the
Products in the Territory during the Term. Any orders held by Novartis for the purchase of Products in the Territory by Customers on the Effective Date which require delivery after the First Sales Booking Date shall be passed to Prometheus by
Novartis. Novartis shall refer to Prometheus any orders for Products that it receives in the Territory which provide for delivery after the First Sales Booking Date. On and from the First Sales Booking Date, Prometheus shall be responsible for
supplying Products in fulfillment of 
  
 *** Certain information on
this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 32 

 
such orders. In accordance with the terms and conditions set forth on Exhibit S, Novartis shall provide certain Transition Services as set forth in Exhibit S to Prometheus
concerning the transition of the Commercialization of the Products to Prometheus in a commercially reasonable manner, provided that the transition services shall not continue for a period longer than three (3) months after the Effective
Date (the “Transition Services Period”). 
 (b) NDC and Labeling Transition. On or before
the First Sales Booking Date, Prometheus shall provide to Novartis its five (5) digit NDC labeler code to be used to establish the ten (10) digit NDC and the Parties shall mutually agree on the ten (10) digit NDC number for Product to
be sold by Prometheus hereunder (or any foreign equivalent thereof, the “Prometheus NDC”). Prometheus will distribute the Product intended for consumption in the United States under Novartis’ and its Affiliates’ NDC
numbers (or any foreign equivalent thereof, the “Novartis NDC”) and with labeling and packaging incorporating the Novartis Brands for a mutually agreed period after the First Sales Booking Date, until Novartis is able to supply
Product bearing the Prometheus NDC and labeling and packaging which does not incorporate any Novartis Brands, anticipated to be approximately six (6) months after the First Sales Booking Date. 
 (c) Patient Assistance Programs. As soon as reasonably practicable following the Effective Date, but no later than one
hundred and twenty (120) days after the Effective Date (the “PAP Transition Period”) and for the remainder of the Term, Novartis shall supply the Products to Prometheus’ designated vendor/service provider who will
coordinate patient assistance programs on behalf of Prometheus. During the PAP Transition Period, Novartis shall continue to supply Product to all patients enrolled in existing patient assistance programs established by Novartis and its Affiliates
for the Products as of the Effective Date. During the PAP Transition Period, (i) the Parties shall cooperate in good faith with regards to the transfer of Novartis and its Affiliates’ obligations under existing patient assistance programs
to Prometheus; and (ii) Novartis shall provide transition support, including, if permitted and desired by Prometheus, the assignment of its existing agreement(s) with Third Party vendors with regards to its existing patient assistance programs
to Prometheus. Upon the expiration of the PAP Transition Period or on such earlier date as the Parties shall mutually agree (the “PAP Transition Date”), Novartis shall refer all new patients interested in participating in patient
assistance programs relating to the Products in the Territory to Prometheus and shall have no obligations or responsibilities with regards to patient assistance programs relating to the Products in the Territory except for supplying the patient
assistance program vendor/services provider with Products as contemplated herein. As of the PAP Transition Date and thereafter during the Term, Prometheus shall ensure that all patients in existing patient assistance programs of Novartis and its
Affiliates shall continue to receive the Products as their needs require in accordance with the established criteria for the Product patient assistance programs. After the PAP Transition Date and during the Term, Prometheus will offer a patient
assistance program for indigent patients who have been prescribed the Products. Prometheus shall have the discretion to modify the Product patient assistance program criteria in its reasonable discretion, provided, however, that
(i) any patients enrolled as of the PAP Transition Period shall continue to be determined eligible for the Prometheus Product patient assistance program based on the Novartis

  

 33 

 
patient assistance program criteria, unless the Prometheus criteria are more generous/less restrictive; and (ii) Prometheus shall not materially modify the eligibility criteria for patients
to participate in the patient assistance programs relating to the Products so as to make it materially more difficult for patients to qualify without Novartis’ prior written consent, such consent not to be unreasonably withheld, conditioned or
delayed. Prior to the Effective Date Novartis has provided to Prometheus the relevant Novartis eligibility criteria for patient participation/enrollment in the Novartis patient assistance program for the Existing Product. Prometheus shall continue
during the Term to enroll new patients into such patient assistance programs, including any patients referred to Prometheus from key patient referral centers as identified by Novartis to Prometheus during the PAP Transition Period. Upon the PAP
Transition Date and thereafter, Prometheus shall be liable for all administrative, reporting and related responsibilities with respect to such patient assistance programs. Novartis shall supply the Products to the applicable vendors/services
providers for such patient assistant programs until the date that the Parties shall enter into an agreement with respect to such supply under this Section 4.2(c), which agreement shall be negotiated in good faith by the Parties and entered into
by the Parties as soon as reasonably practicable after the Effective Date, but no later than [* * *] ([* * *]) days after the Effective Date. After the date that the Parties have entered into such supply agreement, Prometheus shall have the sole
obligation to supply the Products to the applicable vendors/services providers for such patient assistant programs. Notwithstanding the foregoing, Novartis shall bear the costs of supplying the Products for the applicable vendors/services providers
for the patient assistance programs set forth under this Section 4.2(c). For the avoidance of doubt, Prometheus shall receive no compensation with respect to any and all Products supplied with respect to such patient assistance programs.

 (d) Pipeline Inventory Adjustment. The Pipeline Inventory Adjustment shall be handled by the Parties as
set forth in Exhibit K. 
 4.3 Promotional Materials and Promotional Activities. 
 (a) Novartis Promotional Materials and Prometheus Promotional Materials. 
 (i) During the Term, Prometheus shall have the right, subject to ongoing compliance with Applicable Law, to use the Novartis
Promotional Materials to design and prepare new Promotional Materials for use in Commercializing the Products in the Field in the Territory in accordance with this Agreement (collectively, the “Prometheus Promotional Materials”). In
addition, during the Term Prometheus shall have the right to submit to applicable Regulatory Authorities for review and approval any Prometheus Promotional Materials prepared by or for Prometheus. It is understood that the Prometheus Promotional
Materials may include use of all or a portion of the Novartis Promotional Materials, provided, however, that Prometheus shall not (i) be authorized to utilize any Novartis Promotional Materials (other than the Product 

 
 *** Certain information on this page has been omitted and filed separately
with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 34 

 
labeling and packaging subject to Section 4.2(b)) that include the Novartis name or corporate brands or logos (or other like company identifiers) to Detail the Product in the Field in the
Territory, and (ii) may not use, or create derivative works utilizing, any patient or physician testimonials or other personally identifiable information regarding patients or physicians (or named institutions) that are part of the Novartis
Promotional Materials without first obtaining the consent of such patient and/or physician (or institution) (or reconsenting such person or institution as applicable) in accordance with Applicable Law. Accordingly, Novartis hereby grants to
Prometheus a non-exclusive license during the Term in the Field in the Territory to update, adapt, use and create derivative works of such Novartis Promotional Materials to design and create the Prometheus Promotional Materials; provided that
this license is being granted only under any copyright of Novartis in the Novartis Promotional Materials and does not grant any license or right to use any Novartis Brands or other Intellectual Property of Novartis included in any Novartis
Promotional Materials. Prometheus shall have no rights to copy, distribute, use, perform or display the Novartis Promotional Materials other than for the limited purposes expressly stated in this Section 4.3(a). 
 (ii) During the Term, Novartis and its applicable Affiliates reserve and retain title and all rights not expressly granted
hereunder, including copyright rights, in and to all Novartis Promotional Materials, whether written, visual or electronic works provided by any of them to Prometheus under this Agreement. 
 (b) Promotional Activities Conducted by Prometheus. 
 (i) During the Term, subject to the terms and conditions of this Agreement, Prometheus will be solely responsible, at its
sole expense and under its sole control, for designing and conducting all promotional activities used in Commercializing the Products in the Territory during the Term in accordance with this Agreement (the “Promotional Activities”).

 (ii) Prometheus will ensure that all Promotional Activities comply with the applicable labeling and Regulatory
Approval for each Product and Applicable Law. Subject to the terms and conditions of this Agreement, Prometheus will be solely responsible for fulfilling regulatory requirements pertaining to its Promotional Activities. To this effect, Novartis
will, upon the applicable Regulatory Transfer Commencement Date, or as soon thereafter as is reasonably practicable (not to exceed six (6) months after the applicable Regulatory Transfer Commencement Date), place a letter on file with DDMAC and
other equivalent Regulatory Authorities in all such other countries of the Territory where Regulatory Approvals for the Products have been obtained, advising such Regulatory Authorities that Prometheus will be the sole marketer and promoter of the
Products in the applicable country in the Territory commencing on the First Sales Booking Date and requesting that such Regulatory Authorities address regulatory inquiries and concerns regarding Prometheus’ Promotional Activities solely with
Prometheus. Subject to Prometheus’ obligation to provide copies of

  

 35 

 
material correspondence with Regulatory Authorities in accordance with this Section 4.3(b) or as otherwise provided herein, Prometheus will not be required to notify Novartis of any
Promotional Activities. 
 4.4 Use of Trademarks and Trade Dress. During the Term, and subject to the terms and
conditions of this Agreement: 
 (a) Prometheus will Commercialize the Products in the Territory under the
Product Marks and will not identify any Product by any designation other than the Product Marks; provided that Prometheus may identify itself as distributor of the Products and the labeling for the Products and the Prometheus Promotional
Materials may contain the Prometheus corporate name and logo in accordance with the Product labeling requirements set forth in the Supply Agreement. From time to time, Prometheus may propose to Novartis that an additional Trademark be used in
connection with the Commercialization of the Product in the Territory (each an “Additional Product Mark”). No Additional Product Mark shall be used in connection with the Commercialization of the Product in the Territory unless and
until Novartis approves such Additional Product Mark for use in connection with the Commercialization of the Product in writing in advance. Any Additional Product Mark so approved by Novartis shall be deemed to be a Product Mark for purposes of this
Agreement, and Prometheus hereby assigns to Novartis any right, title and interest in and to any such Additional Product Marks. Prometheus will use the Product Marks and Product Trade Dress solely with respect to the Products purchased from Novartis
or its designee as provided in this Agreement. 
 (b) During the Term, whenever Prometheus uses the Product Marks
in any Prometheus Promotional Materials or in any other manner in connection with any Product, Prometheus will clearly indicate that the Product Marks are owned by the Novartis group of companies pursuant to a notice approved by Novartis. When using
the Product Marks and Product Trade Dress under this Agreement, Prometheus will comply with all Applicable Law pertaining to the Product Marks and Product Trade Dress in force at any time in any jurisdiction in the Territory where Prometheus is
Commercializing the Products. 
 (c) Prometheus acknowledges and agrees that Novartis and/or its Affiliates, is,
and at all times will remain the owner of the Product Marks and Product Trade Dress during the Term and that all use of the Product Marks and Product Trade Dress by Prometheus or its Sublicensees shall inure to the benefit and be on behalf of
Novartis and/or its Affiliates. Prometheus will not at any time knowingly do, or knowingly cause to be done, or permit its Affiliates or Sublicensees or any of its or its Affiliates’ or Sublicensees’ employees, agents, contractors and
subcontractors to commit any act inconsistent with, contesting or in any way impairing, or tending to impair, such ownership. 
 (d) Notwithstanding any license granted hereunder or any other provision granting Prometheus a right or license to use any Product Intellectual Property, any such right or license granted hereunder to use
such Product Intellectual Property is limited in connection with use on or in connection with the Internet as follows: (i) all use in

  

 36 

 
connection with the Internet must be in compliance with Applicable Law regarding sale, distribution, and advertising of the Products on the Internet; (ii) Prometheus hereby receives an
exclusive license during the Term and subject to the terms hereof to use and maintain the domain name www.proleukin.com, and, as of the Canada Election Date, www.proleukin.ca, and any other domain names incorporating the Products Marks which are
approved for registration and use in the Territory by Novartis from time to time in accordance with this Section 4.4(d) (the “Product Websites”), including the right to update, adapt, use and create derivative works of the web
sites located at such domain names in accordance with Section 4.3(a); and (iii) Prometheus shall be entitled to use the Product Intellectual Property on the Internet or on any similar online interactive media only on the Product Websites;
provided that the content on any such Product Websites shall target only audiences in the Territory and Prometheus shall not knowingly consent to links to such Product Websites that may originate outside the Territory without the prior
written consent of Novartis and shall promptly notify Novartis of any such links of which it becomes aware and remove such links upon Novartis’ request. Prometheus shall include on any websites permitted hereunder prominent disclaimers
notifying visitors to the sites that they are intended only for residents within the Territory. Prometheus shall host the Product Websites on its own server or retain a Third Party to do so. Except as provided in this paragraph, Prometheus shall not
use the Product Intellectual Property on or in connection with the Internet or any similar online interactive media. In addition to the foregoing, Prometheus shall not register or use a new domain name that incorporates a Product Mark unless and
until Novartis approves such domain name for use in connection with the Commercialization of the Product in writing in advance. Any such approved domain name shall be registered in the name of Novartis or its Affiliates, and Prometheus hereby
assigns to Novartis any right, title and interest in and to any such domain name, provided that such domain name shall be licensed to Prometheus as a Product Website in accordance with this Section 4.4. Prometheus shall also limit use of
the INN “aldesleukin” on or in connection with the Internet to the same extent and upon the same terms as are set forth above with respect to a Product Mark. 
 (e) Notwithstanding anything to the contrary set forth in this Agreement, nothing in this Agreement grants to Prometheus or
any of its Affiliates or Sublicensees any rights or licenses to use any Trademarks or names of any Upstream Licensors or any of their respective inventors and Affiliates. Prometheus and its Affiliates and Sublicensees shall not use the name of any
inventor of the Upstream Licensed Product Patent Rights, or any institution with which he or she has been or is connected, or any Upstream Licensor and its Affiliates, or any adaptation of any of them, in any advertising, promotion or sales
literature or otherwise for commercial purposes, without the prior written consent of Novartis. 
 4.5 Quality Control.
Prometheus shall use all Product Marks and Product Trade Dress in accordance with Novartis’ Trademark Guidelines set forth on Exhibit R. Novartis or its authorized representatives shall have the right to inspect at any time during normal
business hours and after reasonable notice, the business premises of Prometheus and its Affiliates to ensure that the character and quality of the goods used or services offered in association with the Trademarks are in compliance with the terms of
this Agreement. Prometheus will, upon the request of Novartis, supply to Novartis or its authorized

  

 37 

 
representatives, samples of the goods in association with which it uses any such Product Marks and Product Trade Dress. To the extent Prometheus may be permitted hereunder to sublicense its
rights in connection with the Product Marks and Product Trade Dress, it shall impose on any Sublicensee the duties and obligations imposed hereunder in this Section 4.5. 
 4.6 Pricing and Sales Terms. During the Term, Prometheus will have the sole authority to determine the prices of the Products sold by
it and to establish its own terms and conditions of sale and pricing policies for the Products in the Territory, including price increases or decreases and the timing thereof, subject to complying as of the First Sales Booking Date and thereafter
with the terms and conditions of those existing agreements with the group purchasing organizations, managed health care organizations or similar entities set forth in Section 1 of Exhibit U and that shall (subject to the terms of
Section 11.17) be assigned by Novartis in whole or in part to Prometheus, and shall be assumed in whole or in part, as applicable, by Prometheus, pursuant to an Assignment and Assumption Agreement in the form attached in Section 2 of
Exhibit U (“Existing Discount Agreements”). Notwithstanding the foregoing, Prometheus shall not be required to assume any Existing Discount Agreement if the terms of such Existing Discount Agreement as they relate to the
Products were not disclosed to Prometheus prior to the First Sales Booking Date. 
 4.7 Rebates and Chargebacks.

 (a) Government Rebates. Novartis shall process and be financially responsible for all rebates pursuant
to any government rebate programs for all Product payable to State Medicaid Agencies and State Assistance Programs with a Novartis NDC prior to the Processing Handover Date. If the Processing Handover Date is not at the start of a Calendar Quarter,
the quarterly rebates will be billed to Prometheus based on a ratio of days that Prometheus is financially responsible (i.e. if the Processing Handover Date is February 11, 2010, the rebates billed Prometheus would be fifty-three and one
third percent (53.33%) of 1Q2010 claimed amounts. The fifty-three and one third percent (53.33%) is based on Prometheus’ responsibility for forty-eight (48) days out of ninety (90) days in the Calendar Quarter). The claimed
Calendar Quarter shall be based on the Calendar Quarter claimed in the rebate submissions by the respective states or the District of Columbia without regard to dispensing date since State Medicaid claims are based on when the state reimburses the
pharmacy and not the dispensing date. For Product claimed with a Novartis NDC on or after the Processing Handover Date, Novartis shall continue to process government rebates, and Prometheus will reimburse Novartis for all such rebates. Prometheus
will also be responsible for utilization changes and rebate changes (associated AMP and “best price” (as defined in the Medicaid Prescription Drug Improvement and Modernization Act of 2003) changes) related to the time period after the
Processing Handover Date. Prometheus shall process and be financially responsible for all rebates pursuant to State Medicaid Agencies and State Assistance Programs related to Product labeled with a Prometheus NDC. Novartis shall provide Prometheus
with quarterly corresponding utilization summary reports within ninety (90) days after the end of the applicable Calendar Quarter that describe the requested payments in reasonable detail. If it is determined that Novartis owes Prometheus
monies for rebates pursuant to State Medicaid Agencies and State Assistance Programs based on resubmissions or rebate changes related to claims after or on the Processing Handover Date, Novartis will pay Prometheus with the corresponding utilization
summary reports, upon receipt of invoice issued by Prometheus. 
  

 38 

 (b) Commercial Rebates. Novartis shall process and be financially
responsible for all commercial rebates related to Product sold by Third Parties until the First Sales Booking Date; provided, however, that Prometheus shall reimburse Novartis for all commercial rebates related to the Product sold in
connection with any of the agreements set forth in Section 1 of Exhibit U which are for sales booked by Prometheus on or after the First Sales Booking Date but before the date of assignment of the applicable agreement set forth in
Section 1 of Exhibit U pursuant to Section 4.6 above. Prometheus shall process and be financially responsible for all commercial rebates related to Product sold by Third Parties on or after the First Sales Booking Date. To the
extent that a Party processes, issues credits or remits payment for commercial rebates in respect of Product for which the other Party is financially responsible under this Section 4.7(b), such Party shall provide the other Party with monthly
reports within sixty (60) days after the end of the applicable month setting forth in reasonable detail the amount of all such issued credits or remitted payments, and (i) with respect to all amounts owed by Novartis to Prometheus,
Prometheus shall submit an invoice to be paid by Novartis within sixty (60) days after Novartis’ receipt of such invoice, and (ii) with respect to all amounts owed by Prometheus to Novartis, Prometheus shall pay such amounts to
Novartis together with its next payment of Royalties in accordance with Section 5.6. 
 (c) Chargeback
Claims. Novartis shall process and be financially responsible for all chargeback claims related to Product sold by Third Parties with a ship date/invoice date on or before January 31, 2010, and Prometheus shall process and be financially
responsible for all chargeback claims related to Product sold by Third Parties with a ship date/invoice date on or after February 1, 2010. Notwithstanding the foregoing, the Parties acknowledge that the VA National Acquisition Center must
approve the removal of the Product from Novartis’ Federal Supply Schedule (“FSS”). Prometheus shall work with Novartis to coordinate the addition of the product to the Prometheus FSS to coincide with Novartis removing the
product from the Novartis FSS. Novartis and Prometheus will coordinate the addition and removal of the Product from the FSS so the switch over occurs as close to January 31, 2010 as possible, with consideration to FSS regulations. Prometheus
and Novartis agree that Novartis shall have no financial liability for chargeback claims with a ship date/invoice date after January 31, 2010. To the extent that a Party processes, issues credits or remits payment for chargeback claims in
respect of Product for which the other Party is financially responsible under this Section 4.7(c), such Party shall provide the other Party with monthly reports within sixty (60) days after the end of the applicable month setting forth in
reasonable detail the amount of all such processed chargeback claims, and (i) with respect to all amounts owed by Novartis to Prometheus, Prometheus shall submit an invoice to be paid by Novartis within sixty (60) days after Novartis’
receipt of such invoice, and (ii) with respect to all amounts owed by Prometheus to Novartis, Prometheus shall pay such amounts to Novartis together with its next payment of Royalties in accordance with Section 5.6. 
  

 39 

 4.8 Government Pricing Information. 
 (a) With respect to Product sold by Prometheus after the First Sales Booking Date that bears a Novartis NDC, Prometheus will
deliver and certify to Novartis, as established by the Final Rule to Implement Medicaid Drug Pricing and Reimbursement Provisions of the Deficit Reduction Act of 2005, within fifteen (15) calendar days after the end of each Calendar Quarter or
reporting period as designated by CMS to include the following information: (i) on a quarterly basis, the “best price” (as defined in the Medicaid Prescription Drug Improvement and Modernization Act of 2003) for all Product,
identified by NDC number, in the format set forth in Exhibit V; (ii) on a monthly and quarterly basis, the average manufacturer price (“AMP”) (as defined under the Social Security Act, 42 USC § 1396r-8(k)(1))
and the relevant summarized units and dollars for AMP calculation components such as Gross Sales, Non-Retail Chargeback Sales, Retail Chargebacks, etc, and AMP eligible sales dollar amounts, as well as the number of AMP eligible units for all of
such Product, each identified by NDC number, in the format set forth in Exhibit V; and (iii) on a quarterly basis, the Manufacturer’s Average Selling Price (“ASP”) (as defined in the Medicaid Prescription Drug
Improvement and Modernization Act of 2003) and the relevant summarized units and dollars for ASP calculation components such as Gross Sales, Non-Government Retail Chargeback Sales, Retail Chargebacks, etc, and ASP eligible sales dollar amounts, as
well as the number of ASP eligible units for all of such Product, each identified by NDC number, in the format set forth in Exhibit V. 
 (b) For existing, if any, or new patient assistance programs or patient transaction programs (card/voucher/coupon), Prometheus agrees to ensure that, with respect to Third Party vendors whose agreements
have been assigned by Novartis pursuant to Section 4.2(c), each such Third Party vendor shall continue to provide patient transaction data that bears a Novartis NDC and is required for government pricing calculations, as previously agreed with
such Third Party vendor under pre-established data feeds and layouts as set forth in Exhibit W. 
 (c)
Novartis agrees to provide Prometheus with any government mandated prices that Prometheus cannot calculate based off the Processing Handover Date. Novartis will provide Prometheus with two Calendar Quarters of PHS pricing after the Processing
Handover Date and 2010 FSS pricing. The Parties agree that each Party may use all information described in this Section 4.8 in reporting to the CMS and other government agencies. The Parties further agree that all Medicaid pricing data
described in this Section 4.8(c) that is included in any report to the other Party will be calculated utilizing systems, processes, policies, practices and pricing methodologies that comply with the requirements of the Medicaid Rebate Law, the
Medicaid Regulations, the applicable Medicaid agreement, if any, the Secretary of Health and Human Services and applicable CMS Medicaid rebate program releases. 
 (d) Novartis will provide Prometheus with Medicaid pricing data for the Product required to support continued filings with
CMS after the transition to Prometheus NDC number, including, Base Date Average Manufacturer’s Price as defined under the Medicaid Rebate Law. 
  

 40 

 4.9 Product Returns and Customer Complaints. 
 (a) As of the First Sales Booking Date, Prometheus shall process all returns of any Product, including issuing payment for
such returns to the applicable customer that are made in compliance with Prometheus’ returned goods policy, irrespective of the NDC number (or foreign equivalent) or seller. Prometheus shall bear the costs of all returns of Product that are
under a Prometheus NDC. With regards to returned Product under a Novartis NDC, each Party shall bear the cost of returns on Products which it sold, and all reasonable measures (including lot identification) will be taken to identify which Party was
responsible for selling such returned Product under a Novartis NDC. Notwithstanding the above, Novartis will only be financially responsible for returns of the Product under a Novartis NDC if such returns will have been returned in compliance with
Prometheus’ returned goods policy, and Novartis will base any return credit for such Products on the Novartis [* * *] ([* * *]%). To the extent that a Party processes, issues credits or remits payment for returns in respect of Products for
which the other Party is financially responsible under this Section 4.9(a), such Party shall provide the other Party with monthly reports within sixty (60) days after the end of the applicable month setting forth in reasonable detail the
amount of all such issued credits or remitted payments for returns, and (i) with respect to all amounts owed by Novartis to Prometheus, Prometheus shall submit an invoice for such amounts to Novartis to be paid within sixty (60) days
thereafter, or (ii) with respect to all amounts owed by Prometheus to Novartis, Prometheus shall pay such amounts to Novartis together with its next payment of Royalties in accordance with Section 5.6. Returned Product shall not be
transferred between the Parties, but instead shall be destroyed by the receiving Party. Each Party shall destroy, or cause to be destroyed, all such returned Product in a manner consistent with Applicable Law, and the costs of such destruction shall
not be reimbursed. 
 (b) Neither Party shall instruct, recommend or attempt to induce Customers who have
previously purchased Product from it to (i) return such Product when that would not otherwise have been the case but for such Party’s instructions, recommendations or inducement or (ii) delay the return of such Products. For the
avoidance of doubt, Prometheus’ shipment units of Products to Customers in the ordinary course will not be deemed to violate this Section 4.9(b). 
 (c) For the period from the Effective Date up to the First Sales Booking Date, Novartis will continue to provide all customer service at a level comparable to that which was provided prior to the
Effective Date. On and from the First Sales Booking Date, through the completion of the Term, Prometheus shall assume all customer service responsibility and provide all customer service required by its Customers with respect to the Products. As of
the First Sales Booking Date, and through the completion of the Term, all customer service requests relating to the Product coming to Novartis will be referred to Prometheus at the following contact information: 
 Executive Director, Client Operations 
 Phone: 888-423-5227 
 Fax: 877-816-4019 
 Website: prometheuslabs.com 
 Address: 9410 Carroll Park Drive, San Diego, CA 92121 
 Email: contactus@prometheuslabs.com
<mailto:contactus@prometheuslabs.com 
  
 *** Certain information
on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 41 

 4.10 Pharmacovigilance. 
 The Parties have entered into a Pharmacovigilance Agreement as of the Effective Date. Such Pharmacovigilance Agreement shall govern each
Party’s respective obligations with respect to adverse event reporting, monitoring, maintenance of safety databases and submissions to Regulatory Authorities and other similar obligations with respect to the Products. 
 4.11 Sales Force. 
 (a) Promptly following the Effective Date, and in any event no longer than thirty (30) days thereafter, Novartis shall disclose to Prometheus, or provide Prometheus with representational samples of
Product-specific training materials in Novartis’ possession or control which are actively used by Novartis for its training purposes in connection with the Products as of the Effective Date (“Novartis Training Materials”) and
which are reasonable in order to train representatives for Detailing the Product. During the Term, Prometheus shall have the right to use the Novartis Training Materials to design and prepare new training materials for use in the training of the
Prometheus Sales Force in Detailing and otherwise Commercializing the Products in the Field in the Territory in accordance with this Agreement (collectively, the “Prometheus Training Materials”). It is understood that the Prometheus
Training Materials may include use of all or a portion of the Novartis Training Materials (other than any Novartis Brands incorporated therein). Accordingly, Novartis hereby grants to Prometheus a non-exclusive license during the Term in the
Territory to update, adapt, use and create derivative works of such Novartis Training Materials to design and create the Prometheus Training Materials; provided that this license is being granted only under any copyright of Novartis in the
Novartis Training Materials and does not grant any license or right to use any Novartis Brands or other Intellectual Property of Novartis included in any Novartis Training Materials. Prometheus shall have no rights to copy, distribute, use, perform
or display the Novartis Training Materials other than for the limited purposes expressly stated in this Section 4.11(a). 
 (b) Novartis shall be responsible for conducting mutually agreed upon initial training support with respect to the Products to Prometheus’ sales trainers at a time and place mutually agreed upon by
the Parties, subject to Prometheus reimbursing Novartis for its Out-of-Pocket Costs for travel associated with its provision of such training, and provided that such initial training support shall occur within the first [* * *] ([* * *])
months after the Effective Date and shall not exceed the amount shown in Exhibit S. 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 42 

 
Notwithstanding the provision of such training materials to Prometheus or the conduct of Prometheus Sales Force training by Novartis, Prometheus alone shall be solely responsible for determining
the appropriateness of such training materials and for ensuring that all Product training for the Prometheus Sales Force complies with Applicable Laws. Ongoing training of Prometheus’ Sales Force will be the sole responsibility of Prometheus at
its cost and expense. For clarification purposes, after the earlier to occur of (i) the conduct of the initial training support and (ii) [* * *] ([* * *]) months after the Effective Date, Novartis shall not have any obligation to provide
any training support to Prometheus. Other than with respect to the initial services and training materials supplied by Novartis as set forth hereunder, the contents of any training provided by Prometheus that relates to the Products will be
developed and coordinated by Prometheus, and Prometheus will be solely responsible for training its Sales Force with regard to Applicable Law and directing such Sales Force personnel to be compliant with Applicable Law. 
 4.12 Minimum Marketing and Promotion Investment. 
 (a) In each Contract Year during the Term, Prometheus shall expend at least the Minimum Marketing Spend in support of its
Commercialization of the Products in the Field in the Territory in accordance with this Agreement (as set forth on Exhibit H); provided that with respect to any expenditure on promoting the Products made by Prometheus in excess of the
Minimum Marketing Spend in any Contract Year, such excess amount may be carried over to the next Contract Year up to an amount not to exceed [* * *] percent ([* * *]%) of the next Contract Year’s Minimum Marketing Spend. 
 (b) In the event that in any Contract Year during the Term, Prometheus expends greater than or equal to [* * *]
percent [* * *]%) of the Minimum Marketing Spend for such Contract Year but [* * *], then Prometheus [* * *], and such failure to satisfy the Minimum Marketing Spend shall not [* * *]. 
 (c) In the event a Significant Market Event occurs during any Contract Year during the Term, the Minimum Marketing Spend and
the Minimum Detail Requirements shall be reduced on a pro rata basis for the period of time during the applicable Contract Year which is affected by such Significant Market Event (for example, if such Significant Market Event lasts for thirty
(30) days, then the Minimum Marketing Spend and the Minimum Detail Requirements would be reduced by 30/365 (or 30/366 in a leap year)). 
 (d) Within forty-five (45) days after the end of each Calendar Quarter during the Term following the First Sales Booking Date, Prometheus shall prepare and deliver to Novartis a report setting out
the amount of its M&S Expenses incurred in marketing, Detailing (including, in sufficient detail to allow for Novartis to determine the number of Details to Tier 1 and Tier 2 physicians, as well as the number of Primary Product Details and
Secondary Product Details to such Tier 1 and Tier 2 physicians) and promoting the 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 43 

 
Products in the Field in the Territory during the previous Calendar Quarter. In addition, within forty-five days after the end of each Calendar Quarter in which the last day of the applicable
Contract Year shall occur, Prometheus shall provide a report setting out the total amount of its M&S Expenses incurred for such Contract Year. Novartis shall be entitled, at its own expense, to audit Prometheus’ books and records in
accordance with Section 5.7 for the purposes of determining Prometheus’ compliance with its Minimum Marketing Spend obligations for the applicable Contract Year in which such Calendar Quarter falls. 
 (e) In each Contract Year, Prometheus shall meet at least the Minimum Detail Requirements in the Field in support of its
Commercialization of the Products in the Territory. For purposes of the Minimum Detail Requirements specified in Exhibit H to this Agreement, it shall only be considered to be a Detail to the extent that such Detail is a Primary Product
Detail or a Secondary Product Detail. 
 SECTION 5. 
 PAYMENTS 
 5.1 Up-front Payment. 
 (a) Prometheus Up-Front Payment. In consideration of Novartis entering into this Agreement, on or prior to
December 30, 2009, Prometheus shall pay to Novartis a non-refundable up-front payment of one hundred eighty five million U.S. dollars ($185,000,000) (the “Up-Front Payment”). 
 (b) Sublicense Payments. In consideration of Novartis entering into this Agreement and subject to the terms and
conditions stated herein, Novartis shall receive [* * *] percent ([* * *]%) of the amount or value of any upfront or milestone payments or other rights (including rights to any Third Party or “quid” product) received by Prometheus or its
Affiliates from a Sublicensee in connection with or as a consideration for the grant of, a Sublicense; provided that in the case of other rights received by Prometheus, in the event that the Parties cannot agree upon the appropriate valuation
of such rights, such matter shall be referred to a mutually acceptable Third Party expert with relevant pharmaceutical product valuation experience for a final and binding determination of the value of the applicable rights. In the event that the
Parties, after good faith discussions and consideration, cannot agree upon the Third Party expert, then each Party shall individually appoint a Third Party expert with relevant pharmaceutical product valuation experience and these Third Party
experts shall, in turn, appoint a Third Party expert with relevant, similar experience. The three Third Party experts shall then perform the valuation contemplated by this Section 5.1(b) and shall, together, make a final and binding
determination of the value of the applicable rights. For the avoidance of doubt, the following amounts received by Prometheus from its Sublicensees are deemed not to be upfront or milestone payments the subject of this Section 5.1(b):

  
 *** Certain information on this page has been omitted and filed
separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 44 

 
(i) equity investments made by, or loans granted by, the Sublicensee to Prometheus at fair market value in the course of further financing Prometheus, and (ii) payments made by the
Sublicensee to Prometheus to reimburse Prometheus, at fair market value, for its actual, reasonable and documented costs in performing activities or services in connection with the Sublicense granted on the Products. 
 5.2 Royalties. In consideration of Novartis entering into this Agreement and subject to the terms and conditions stated herein,
Prometheus shall pay Novartis a royalty (“Royalty”) on Net Sales of the Products at the royalty rate calculated in accordance with the provisions below, subject to a reduction, if any, as set forth in Section 5.4. 

(a) [* * *] percent ([* * *]%) of aggregate Net Sales of the Products in the Territory in each calendar year up to and
including [* * *] U.S. dollars ($[* * *]); 
 (b) [* * *] percent ([* * *]%) of aggregate Net Sales of the
Products in the Territory in each calendar year above [* * *] U.S. dollars ($[* * *]) up to and including [* * *] U.S. dollars ($[* * *]); and 
 (c) [* * *] percent ([* * *]%) of aggregate Net Sales of the Products in the Territory in each calendar year above [* * *] U.S. dollars ($[* * *]). 
 Notwithstanding anything to the contrary set forth herein, in the event that there are Net Sales on Products manufactured by an Alternate
Manufacturer (as that term is defined in the Supply Agreement), the Royalty to be paid by Prometheus with respect to such Net Sales shall be the Royalty rates set forth above plus [* * *] percent ([* * *]%) (i.e., [* * *] percent ([* * *]%)
shall be added to each tier of Royalties described above). The annual Net Sales of the Products set forth above shall be measured from the beginning of each calendar year (or from the First Sales Booking Date for the first calendar year of the
Term), and the royalty rates set forth above shall re-set at the beginning of each calendar year. Royalties payable under this Section 5.2 will be payable only once with respect to a particular unit of Product and will be paid only once
regardless of the number of Patents, if any, with claims covering a Product. 
 5.3 Annual Extension Fee. For each
Extension Term, Prometheus shall pay to Novartis an amount of [* * *] U.S. dollars ($[* * *]) at the time when it provides notice to Novartis of its election to extend in accordance with Section 10.1 (the “Annual Extension
Fee”). Notwithstanding the foregoing, if at any time during the Term a Significant Market Event occurs in the Territory, then commencing with the next occurring Extension Term and for all remaining Extension Terms thereafter until the first
Extension Term occurring after the SME Termination Date, Prometheus shall not be liable to pay any Annual Extension Fees in consideration for its right to extend the Term. After the SME Termination Date, Prometheus shall pay the Annual Extension Fee
for the first Extension Term occurring after the SME Termination Date and for all remaining Extension Terms thereafter, subject to the continuing applicability of this Section 5.3. 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been
requested with respect to the omitted portions. 
  

 45 

 5.4 Permitted Royalty Reductions. 
 (a) License of Third Party Intellectual Property. The Royalty during the Term may be reduced in a country in the
Territory to account for any and all royalties or other payments paid by Prometheus, its Affiliates and/or Sublicensees to any Third Party in such country, up to a maximum reduction of [* * *] percent ([* * *]%) in the aggregate of the applicable
Royalty, under (i) any license of additional intellectual property that is required and necessary in order to enable Prometheus to continue to Commercialize the Existing Product in accordance with the terms of this Agreement as such Product is
Commercialized by Novartis as of the Effective Date in the Field in such country, or (ii) as otherwise agreed upon by the Parties. Prometheus shall provide written notice to Novartis prior to obtaining any such license and this
Section 5.4(a) shall apply only to the extent Novartis fails to indemnify Prometheus for infringement of the applicable additional intellectual property pursuant to Section 7.1(h) or where Prometheus has been enjoined from Commercializing
the Products. Prometheus shall use Commercially Reasonable Efforts to minimize any such royalties or other payments to Third Parties on account of sales of Product hereunder. For the avoidance of doubt, this Section 5.4(a) shall not apply to
any Products other than the Existing Product. 
 (b) Prometheus Combination Products. The Royalty payable
by Prometheus to Novartis with respect to each Prometheus Combination Product shall be based on the Net Sales price of the Product when sold separately, such Net Sales price to be calculated based on the average Net Sales price of such Product over
the [* * *] ([* * *]) complete Calendar Quarters immediately prior to commencement by Prometheus or its Affiliates of Commercialization of any Prometheus Combination Product in the Territory. By way of example only, if Prometheus sells a Product at
a unit price of [* * *] U.S. dollars ($[* * *]), sells a second product at a unit price of [* * *] U.S. dollars ($[* * *]), and sells a Prometheus Combination Product including such Product and such second product at a unit price of [* * *] U.S.
dollars ($[* * *]), Royalties payable hereunder on such Prometheus Combination Product shall be calculated using a Product unit price of [* * *] U.S. dollars ($[* * *]). 
 (c) Significant Market Event. If at any time during the Term a Significant Market Event occurs (including, without
limitation, as a result of the marketing and/or sale of a Competitive Product) in a country in the Territory, then the actual Royalty rate payable to Novartis in such country during the continuance of such Significant Market Event in such country
shall be reduced by [* * *] percentage point (i.e., [* * *] percent ([* * *]%) shall be deducted from each tier of Royalties described above) for each [* * *] percentage point by which Prometheus’ Net Sales are reduced below [* * *]
percent ([* * *]%) of the [* * *] (the “Reduced Royalties”), up to a maximum reduction of [* * *] of the original Royalty rate. Prometheus shall continue to pay the Reduced Royalties with respect to all Net Sales of the
Products in the applicable country in the Territory until the SME Termination Date, following which Prometheus shall once again pay the Royalties for the applicable country in accordance with Section 5.2 subject to the continuing 
  
 *** Certain information on this page has been omitted and filed separately with
the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 46 

 
applicability of this Section 5.4. In the event of a Significant Market Event, Prometheus shall provide Novartis notice thereof within [* * *] ([* * *]) days after the [* * *] ([* * *]) of
the [* * *] ([* * *]) consecutive Calendar Quarters in which reduced sales triggered the Significant Market Event (as described in the definition of Significant Market Event) together with documentation in reasonable detail evidencing such
Significant Market Event; provided that if Prometheus fails to provide notice within such [* * *]-day period, such failure to notify shall not constitute a breach of this Agreement but Prometheus shall only be entitled to a
reduction in Royalties pursuant to this Section 5.4(c) for a period commencing [* * *] ([* * *]) days prior to the date on which Prometheus actually provides notice to Novartis of the occurrence of the applicable Significant Market Event.
Reduced Royalties shall then apply beginning with the Calendar Quarter immediately following such [* * *] ([* * *]) Calendar Quarter. 
 5.5 Milestone Payments. In consideration of Novartis entering into this Agreement and subject to the terms and conditions stated herein, Prometheus (or a designated Affiliate) shall make one-time milestone payments to Novartis with
respect to aggregate annual Net Sales (based on a calendar year) of the Products in the Territory deemed to be sold as a consequence of sales of Third Party Products (as determined in accordance with this Section 5.5). As of the Effective Date,
there are no Third Party Products approved for use in the Territory. If Third Party Products are sold in the Territory during the Term, the following one-time milestone payments due to Novartis (“Incremental Product Net Sales
Milestone”) shall be payable upon the first achievement of each of the following milestone events (the “Milestone Events”): 
 (a) [* * *] thousand U.S. dollars ($[* * *]) payable upon the achievement of aggregate annual Net Sales of the Products in the Territory deemed sold as a consequence of sales of Third Party Products equal
to [* * *] U.S. dollars ($[* * *]); 
 (b) [* * *] U.S. dollars ($[* * *]) payable upon the achievement of
aggregate annual Net Sales of the Products in the Territory deemed sold as a consequence of sales of Third Party Products equal to [* * *] U.S. dollars ($[* * *]); 
 (c) [* * *] U.S. dollars ($[* * *]) payable upon the achievement of aggregate annual Net Sales of the Products in the
Territory deemed sold as a consequence of sales of Third Party Products equal to [* * *] thousand U.S. dollars ($[* * *]); and 
 (d) [* * *] U.S. dollars ($[* * *]) payable upon the achievement of aggregate annual Net Sales of the Products in the Territory deemed sold as a consequence of sales of Third Party Products equal to [* *
*] U.S. dollars ($[* * *]). 
 The Parties acknowledge and agree that there is a potential for the product [* * *] to be
approved as a Third Party Product in the Territory. If [* * *] is approved as a Third Party Product in the Territory, the Parties agree that the incremental Product Net Sales achieved as a consequence of the approval and marketing of [* * *] in the
Territory, such sales to be used as a 
  
 *** Certain information on
this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 47 

 
measure of achievement of Milestone Events, are calculated based on the following methodology and assumptions: (i) the [* * *] plus Product dosage and administration (as per the pivotal
trial protocol) is 0.5 mg of [* * *], bid, sub-q + Interleukin-2: 16,400 IU/kg, bid, sub-q, (ii) a 69 Kg average weight per patient translates to an average dose of 1,131,600 IU of Product to be used in conjunction with [* * *], (iii) a
vial of Product contains 18,000,000 IU, and assuming a [* * *] percent ([* * *]%) wastage due to multiple draw-ups from each vial, this translates to [* * *] ([* * *]) whole doses of Product per vial, and (iv) based on the foregoing
assumptions, the ratio of [* * *] to Product is 0.5 mgs to [* * *] ([* * *]) of a vial, or [* * *] mgs of [* * *] to [* * *] vial of Product. Using this [* * *] ratio, the aggregate sales of Product will be determined by multiplying annual [* * *]
sales in milligrams by [* * *] to arrive at the total incremental vials of Product. This volume will be multiplied by the average unit vial price of the Product on a country-by-country basis weighted by the geographic split of [* * *] sales to
arrive at the incremental Net Sales of Product achieved as a consequence of the sale of [* * *]. Key data sources to be relied on for [* * *] sales will be (in priority order) direct sales information provided by [* * *]. 
 Notwithstanding the foregoing, the Parties contemplate that additional Third Party Products may also be approved for sale in the Territory
during the Term. In such event, the annual incremental Net Sales of the Products deemed sold as a consequence of sales of Third Party Products (including [* * *]) in the Territory shall be aggregated to determine when a Milestone Event is achieved;
provided that if any Third Party Product is indicated for use in conjunction with the Product in a ratio other than [* * *], then the dollar value which such Third Party Product contributes to the aggregation used to determine when a
Milestone Event is achieved shall be adjusted proportionately according to such different ratio. For each additional Third Party Product that is Commercialized in the Territory, the Parties agree to work together in good faith to find mutually
acceptable solutions (in the spirit of the methodology set forth above for [* * *]) to determine aggregate Product Net Sales deemed to be sold as a consequence of sales of such Third Party Products. 
 The Incremental Product Net Sales Milestone payments shall be paid by Prometheus, or its designated Affiliate, within thirty (30) days
after the occurrence of the applicable Milestone Event set forth above. Notwithstanding anything to the contrary in this Agreement, only one (1) milestone payment due pursuant to this Section 5.5 shall be payable in any single calendar
year during the Term. In the event that two (2) or more Incremental Product Net Sales Milestone payments become due to Novartis in any single calendar year during the Term pursuant to this Section 5.5, the first milestone payment shall be
due and payable by Prometheus as set forth herein, and the payment date for any subsequent milestone payments accrued during the applicable calendar year shall be automatically delayed until the date that is thirty (30) days after the last day
of the calendar year in which the immediately preceding accrued milestone payment has been paid. 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 48 

 5.6 Payment and Reports; Conversion. 
 (a) Payments and Reports. Within twenty-eight (28) days after the end of each Calendar Quarter during the Term,
Prometheus shall provide Novartis with a written report setting forth on a Product-by-Product and country-by-country basis the Net Sales, including number of Units Sold, during such Calendar Quarter and the calculation of the Royalty payable to
Novartis for such Net Sales pursuant to this Section 5, including all permitted reductions to or deductions from gross sales taken by Prometheus in accordance with this Agreement and the number of units sold on a Product-by-Product and
country-by-country basis. Such report shall be accompanied by a payment equal to the total Royalty due, if any, to Novartis pursuant to this Section 5. All payments shall be made to Novartis on or before the due date for each such report
following the end of the applicable Calendar Quarter in United States Dollars and by wire transfer to the designated account in accordance with the wire instructions provided by Novartis in writing to Prometheus. 
 (b) Conversion. Any Royalties on or other payments relating to transactions in a foreign currency shall be converted
into United States dollars in accordance with applicable Accounting Standards using a methodology which is consistently applied by Prometheus with respect to external reporting (including any annual, regular or periodic reports and registration
statements that Prometheus may file or be required to file with the SEC pursuant to Applicable Laws), or, if Prometheus does not report externally, then in a manner consistent with the methodology used by Prometheus to present its financials to
institutional lenders in the context of financing transactions, applicable to transactions under exchange regulations for the particular currency during the accounting period for which such royalty or other payment is due. 
 5.7 Audit Rights. Novartis shall have the right for a period of [* * *] ([* * *]) years after receiving any report or statement with
respect to royalties or milestones, to appoint an internationally-recognized independent Third Party accounting firm to audit the books and records of Prometheus, its Affiliates and its Sublicensees to verify the accuracy of the reports, statements,
books of accounts and payments made hereunder, as applicable, and Prometheus shall, and shall cause its Affiliates and its Sublicensees to keep for [* * *] ([* * *]) years from the end of the year to which the royalties or milestone pertains,
complete and accurate records of sales of each Product in sufficient detail to allow the royalties and milestones accruing to be determined accurately. Prometheus shall maintain all records in accordance with Prometheus’ Accounting Standards as
consistently applied. Such audit shall be conducted upon at least thirty (30) days advanced written notice to Prometheus and shall commence on a date reasonably acceptable to both Parties. Such audit shall only be during Prometheus’ normal
business hours. Such audit shall not be more frequent than once (1) per calendar year unless a prior audit has revealed deficiencies, in which case, an additional audit may be conducted within the same calendar year if elected by Novartis. The
auditing party shall be required to sign a confidentiality agreement for the benefit of, and in a form reasonably acceptable to, Prometheus. Prometheus shall be provided the opportunity to discuss any discrepancies of greater than five 

 
 *** Certain information on this page has been omitted and filed separately
with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 49 

 
percent (5%) found during such audit with the auditors prior to such auditor issuing its final report. In addition, the auditors shall redact any Confidential Information disclosed in the
proposed final report identified by Prometheus as confidential and, which the auditors agree is not necessary for purposes of calculating the Royalty or any milestones owed. The final report shall be shared with both of the Parties. If any audit
discloses any underpayments by Prometheus to Novartis, then unless contested by Prometheus within thirty (30) days after receipt of the necessary documentation of the amount owed, any underpayment shall be paid by Prometheus to Novartis within
thirty (30) days of it being so disclosed. If any audit discloses any overpayments by Prometheus to Novartis, then unless contested by Novartis within thirty (30) days after receipt of the necessary documentation of the amount owed,
Prometheus shall have the right to credit the amount of the overpayment against each subsequent quarterly payment due to Novartis until the overpayment has been fully applied. If the overpayment is not fully applied prior to the final quarterly
payment of Royalties due hereunder, Novartis shall promptly refund an amount equal to any such remaining overpayment. If Novartis’ audit demonstrates an underpayment of more than five percent (5%) for the payment due to Novartis during the
audited period, Prometheus shall be liable for Novartis’ reasonable cost of the audit that discovered such underpayment. Otherwise, Novartis shall bear the costs of such audits. 
 5.8 Withholding Taxes. Where required to do so by Applicable Law or order of a governmental body, a Party making payments hereunder
shall withhold Taxes required to be paid to a taxing authority in connection with any payments to the other Party hereunder, and, upon request of the Party to which the payment is due, the paying Party shall furnish the receiving Party with
satisfactory evidence of such withholding and payment. Any amounts withheld pursuant to this Section 5.8 shall be treated as having been paid by the Party making such withholding for all purposes under this Agreement. To the extent any payments
are made hereunder without withholding (at the request of the Party which was to receive such payment), and withholding is later determined to have been required, or is assessed, by any governmental entity, the Party receiving such payments shall
indemnify the other Party, including, without limitation, for any withholding Tax, interest and/or penalties thereon, and any other reasonable expenses related thereto. The Parties shall give reasonable assistance to each other in obtaining
exemption from withholding Taxes where available under Applicable Law, or recovering the same where an exemption is not available. 
 5.9 Late Payments. Any amounts due to Novartis under this Agreement or any portion thereof which are not paid when due, shall bear interest equal to Twelve Month LIBOR plus two percent (2%) as set by the British Bankers
Association as of the due date, or, if lower, the highest rate permitted under applicable law, calculated on the number of days such payment is delinquent. 
  

 50 

 SECTION 6. 
 REPRESENTATIONS AND WARRANTIES 
 6.1
Representations and Warranties of Both Parties. Each Party hereby represents and warrants to the other Party, as of the Effective Date, that: 
 (a) Good Standing. Such Party is duly organized, validly existing and in good standing under the Applicable Law of the state of its incorporation, is duly qualified to transact the business in
which it is engaged in each jurisdiction where failure to be so qualified would have a material adverse effect upon its business as currently conducted. 
 (b) Power and Authority. Such Party has the requisite power and authority and the legal right to enter into this Agreement, and to perform its obligations hereunder, and has taken all necessary
corporate action on its part to authorize the execution and delivery of the Agreement and the performance of its obligations hereunder. All Persons who have executed this Agreement on behalf of such Party, or who will execute on behalf of such Party
any agreement or instrument contemplated hereby, have been duly authorized to do so by all necessary corporate action. 
 (c) Binding Obligation. This Agreement has been duly executed and delivered on its behalf and (assuming the due execution and delivery hereof by the other Party) is a legal and valid obligation binding upon it and is enforceable in
accordance with its terms. 
 6.2 Representations and Warranties of Novartis. Except as set forth in, and subject to, the
Novartis Disclosure Schedule, Novartis makes the representations and warranties set forth in this Section 6.2 as of the Effective Date solely with respect to the Territory and Canada (excluding the representation and warranty made in
Section 6.2(g) which is only made with respect to the United States) (and with respect to the ROW Territory, to the extent that any matter occurring in the ROW Territory could adversely affect the representations and warranties set forth in
this Section 6.2 as they relate to the Territory and Canada), and as of the date of the ROW Amendments with respect to ROW Territory. 
 (a) No Violation of Instruments or Contracts. The execution and the delivery of this Agreement and the consummation of the transactions contemplated hereby will not: 
 (i) violate the Certificate of Incorporation or By-Laws of Novartis; 
 (ii) to Novartis’ knowledge, materially conflict with or result in a material breach of any of the terms, conditions or
provisions of, or constitute an express event of default under, any material instrument, agreement (including any Upstream License Agreement), mortgage, judgment, order, award, or decree to which Novartis is a party or by which it is bound; or

 (iii) require the affirmative approval, consent, authorization or other order or action of any court,
Regulatory Authority or of any creditor of Novartis

  

 51 

 
or any of its Affiliates the absence of which would have a material adverse effect on the rights and licenses granted to Prometheus hereunder, or to the extent that any such approval, consent or
other action is required, it either has been obtained or completed by Novartis prior to the Effective Date or is contemplated by this Agreement to be obtained after the Effective Date. 
 (b) Compliance with Applicable Law. Novartis and its Affiliates are, in connection with their activities of Developing
and Commercializing the Product in the Territory, in material compliance with all requirements of Applicable Law. 
 (c) Legal Proceedings. Except as listed on Schedule 6.2(c) of the Novartis Disclosure Schedule, there is no pending Proceeding or, to its knowledge, investigation by any Regulatory Authority (i) by or against Novartis or any of
its Affiliates that relates to any product liability, personal injury or death, breaches of applicable advertising or consumer protection laws, safety or efficacy concerns, citizens petitions, FDA inquiries or clearance issues, in each case relating
to the Products, or (ii) that challenges, or may reasonably be expected to have the effect of preventing, delaying, making illegal, or otherwise interfering with, any of the transactions contemplated by this Agreement. To Novartis’
knowledge, no such Proceeding is threatened. 
 (d) Intellectual Property. 
 (i) As of the Effective Date, Exhibit D sets forth a true, correct and complete list of all Product Patent Rights
owned or Controlled by Novartis or its Affiliates which are necessary or required to Commercialize the Existing Product; 
 (ii) Novartis has the right to grant the rights and licenses to Prometheus that are set forth in this Agreement and owns or Controls all right, title and interest in and to the Product Intellectual
Property; 
 (iii) Except as listed on Schedule 6.2(d)(iii) of the Novartis Disclosure Schedule, Novartis
has not granted any rights in the Product Intellectual Property that are inconsistent with or that limit the rights granted to Prometheus under this Agreement; 
 (iv) Except as listed on Schedule 6.2(d)(iv) of the Novartis Disclosure Schedule, Novartis has not assigned, licensed,
sublicensed, or granted any interest in or options to the Product Intellectual Property or the Products in the Territory to any Third Party in violation of this Agreement; 
 (v) The Product Intellectual Property is free and clear of all Encumbrances created by Novartis or any of its predecessors
that would (if foreclosed upon or otherwise) (A) restrict Prometheus’ rights and licenses thereunder as granted under this Agreement or use thereof as otherwise permitted under this Agreement, or (B) provide a Third Party with rights
in the Product Patent Rights which conflict with Prometheus’ exclusive rights and licenses granted pursuant to this Agreement; 
  

 52 

 (vi) Since [* * *], Novartis has not received any written Claim alleging
that Novartis’ or its licensees’ Development, use or Commercialization of the Products in the Territory infringe or misappropriate any Intellectual Property of any Third Party (including any Claim that Novartis or its licensees must
license or refrain from using any Intellectual Property of any Third Party in order to Develop or Commercialize the Products); 
 (vii) To Novartis’ knowledge, the Commercialization of the Existing Product, in the Territory in accordance with this Agreement, does not and will not during the Term infringe upon, or
misappropriate, any Intellectual Property rights of any Third Party; 
 (viii) To Novartis’ knowledge, no
Third Party is interfering with, infringing upon, or misappropriating the Product Intellectual Property in any material respect in the Territory; 
 (ix) To Novartis’ knowledge, the Product Patent Rights existing as of the Effective Date are valid and enforceable; 
 (x) To Novartis’ knowledge, no Claim is pending or is threatened in writing which challenges the legality, validity,
enforceability, use, or ownership of any Product Intellectual Property; 
 (xi) Schedule 6.2(d)(xi) of the
Novartis Disclosure Schedule lists all Upstream License Agreements. Novartis has made available to Prometheus true and correct copies of all Upstream License Agreements; provided that such copies may have been redacted to prevent disclosure
of financial information. As of the Effective Date, Novartis is not in material breach, violation or default (and would not by the lapse of time or the giving of notice or both, be in material default) under any of the Upstream License Agreements.

 (e) Product Inventory. During the ninety (90) day period prior to the Effective Date, Novartis and
its Affiliates have not sold the Products to any Third Party in the Territory other than in the ordinary course of business. 
 (f) Product Liability. Since [* * *], Novartis has not received any Product Liability Claims with respect to the Products in the Territory and no Product Liability Claim is pending. 
 (g) Existing Discount Agreements. Schedule 6.2(g)(1) of the Novartis Disclosure Schedule lists all Existing
Discount Agreements. Except as set forth on Schedule 6.2(g)(2) of the Novartis Disclosure Schedule, Novartis has made available to Prometheus true and correct copies of all Existing Discount Agreements; provided that such copies
may have been redacted to prevent disclosure of information not related to the Existing Product. As of the Effective Date, Novartis is not in material breach, violation or default (and would not by the lapse of time or the giving of notice or both,
be in material default) under any of the Existing Discount Agreements. 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 53 

 (h) Regulatory Approvals. 
 (i) As of the Effective Date, Exhibit F sets forth a true, correct and complete list of all material Regulatory
Approvals owned or Controlled by Novartis or its Affiliates which are used to Commercialize the Existing Product in the Territory. 
 (ii) The Regulatory Approvals set forth in Exhibit F are in full force and effect. There is no proceeding by any Regulatory Authority pending or, to Novartis’ knowledge, threatened seeking the
revocation or suspension of any such Regulatory Approval. 
 (iii) To Novartis’s knowledge, there are no
facts which would reasonably be expected to cause (i) market withdrawal, recall or suspension of the Product, (ii) a change in the marketing classification of any Product in the Territory, (iii) a material change in the labeling of
the Product in the Territory or (iv) termination or suspension of marketing of the Product. 
 (iv) To
Novartis’ knowledge, all contract manufacturers, packagers, and other third party contractors involved in the manufacture, processing, testing, promoting or advertising of the Product are in material compliance with all applicable FDA
regulations with respect to the Product. 
 (i) Terminology. For purposes of this Section 6.2 only,
the term “Territory” shall be as defined as the United States and Canada, including their territories and possessions. 
 6.3 Representations and Warranties of Prometheus. Prometheus hereby represents and warrants to Novartis, as of the Effective Date, that: 
 (a) No Violation of Instruments or Contracts. The execution and the delivery of this Agreement and the consummation of the transactions contemplated hereby will not: 
 (i) violate the Certificate of Incorporation or By-Laws of Prometheus; 
 (ii) materially conflict with or result in a material breach of any of the terms, conditions or provisions of, or constitute
an express event of default under, any material instrument, agreement, mortgage, judgment, order, award, or decree to which Prometheus is a party or by which it is bound; and 
 (iii) require the affirmative approval, consent, authorization or other order or action of any court, Regulatory Authority or
of any creditor of Prometheus or any of its Affiliates, or to the extent that any such approval, consent or other action is required, it has been obtained or completed by Prometheus prior to the Effective Date. 
  

 54 

 6.4 Covenants of Novartis. 
 (a) Upstream License Agreements. During the Term, Novartis shall not take any action, or intentionally omit to take
any action required thereby, which would result in a material breach or early termination of any of the Upstream License Agreements or any material rights thereunder. Novartis shall not amend, modify or supplement the terms of, or waive any rights
under, any Upstream License Agreement without the prior written consent of Prometheus where and to the extent that any such amendment or waiver would materially and adversely affect the rights and licenses granted to Prometheus pursuant to this
Agreement. Novartis shall promptly notify Prometheus upon receipt by Novartis of any notice from any Upstream Licensor of any actual or alleged breach under any Upstream License Agreement that could result in the termination of such agreement or any
material reduction or other material limitation in Novartis’ rights thereunder. 
 (b) Ineligible
Persons. During the Term, Novartis will not hire or employ an Ineligible Person as either an employee or independent contractor to conduct any activities relating to the Products in the Territory under this Agreement or the Supply Agreement.

 (c) Compliance with Applicable Law. Novartis and its Affiliates will ensure that they remain
throughout the Term, in material compliance with all requirements of Applicable Law within the Territory in connection with all activities conducted under this Agreement or the Supply Agreement. 
 (d) Assignment. During the Term, Novartis will not assign, license, sublicense, or grant any interest in or options to
the Product Intellectual Property or the Products in the Territory to any Third Party in violation of this Agreement. 
 (e) ROW Territory. From the Effective Date until the ROW Option Expiration Date, Novartis shall: 
 (i) use Commercially Reasonable Efforts to maintain all Regulatory Approvals held in its name outside the Territory immediately prior to the Effective Date in the same or a substantially similar manner as maintained by Novartis in the
[* * *] ([* * *]) months prior to the Effective Date, and 
 (ii) not take any action relating to the
Product or the Commercialization of the Product outside the Territory which would reasonably be expected to constitute a violation of Applicable Law. 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the
omitted portions. 
  

 55 

 6.5 Covenants of Prometheus. 
 (a) Compliance with Applicable Law. Prometheus and its Affiliates will ensure that they remain throughout the
Term, in material compliance with all requirements of Applicable Law within the Territory in connection with all activities conducted under this Agreement or the Supply Agreement. 
 (b) Ineligible Persons. During the Term, Prometheus will not hire or employ an Ineligible Person as either an employee
or independent contractor to conduct any Commercialization, Development and/or any other activities relating to the Products in the Territory under this Agreement or the Supply Agreement. 
 (c) Financial Reporting Obligations. Prometheus shall deliver to Novartis: 
 (i) as soon as available, but in any event within ninety (90) days after the end of each fiscal year of Prometheus, a
consolidated balance sheet of Prometheus and its Affiliates as at the end of such fiscal year, and the related consolidated statements of income or operations and cash flows for such fiscal year, setting forth in each case in comparative form the
figures for the previous fiscal year, all in reasonable detail and prepared in accordance with GAAP, audited and accompanied by a report and opinion of an internationally recognized independent certified public accounting firm, which report and
opinion shall be prepared in accordance with generally accepted auditing standards and any written communication to Prometheus’ Audit Committee of its Board of Directors from its auditors setting forth a dispute with management regarding
accounting or auditing matters; 
 (ii) as soon as available, but in any event within forty-five (45) days
after the end of each of the first three (3) fiscal quarters of each fiscal year of Prometheus, a consolidated balance sheet of Prometheus and its Affiliates as at the end of such fiscal quarter, and the related consolidated statements of
income or operations and cash flows for such fiscal quarter and for the portion of Prometheus’ fiscal year then ended, setting forth in each case in comparative form the figures for the corresponding fiscal quarter of the previous fiscal year
and the corresponding portion of the previous fiscal year, all in reasonable detail and certified by the chief executive officer or chief financial officer of Prometheus as fairly presenting in all material respects the financial condition, results
of operations, shareholders’ equity and cash flows of Prometheus and its Affiliates in accordance with GAAP; 
 (iii) concurrently with delivery to the applicable lender(s), a copy of any certificates, reports or statements (including accountants’ certifications and compliance certificates) provided by Prometheus or its officers to its lenders
under agreements, documents and instruments governing Debt; 
 (iv) written notice to Novartis on the same day as
any written notice is provided by Prometheus to any lender relating to any default or breach, however

  

 56 

 
designated, by Prometheus under any Debt or any agreement, document or instrument related thereto, together with a reasonable description of such default or breach; 
 (v) written notice to Novartis within one (1) Business Day of Prometheus’ receipt of any notice from a lender
relating to a default or breach, however designated, by Prometheus, under any Debt or any agreement, document or instrument related thereto, or any acceleration of any Debt, together with a detailed description of such default, breach or
acceleration; 
 (vi) written notice to Novartis within one (1) Business Day of initiation of any
substantive discussions between Prometheus and any lender regarding a breach or default or impending breach or default, however designated, by Prometheus under any Debt or any agreement, document or instrument related thereto, together with a
detailed description of such default or breach; and 
 (vii) copies of all agreements, documents or instruments
relating to Debt for Borrowed Money entered into by Prometheus within fifteen (15) days after execution by the parties thereof, which copies may be redacted to remove the interest rate charged by the lender(s) thereof; 
 (viii) provided that, in the case of each of (i) and (ii) above, Prometheus shall be deemed to have
delivered the applicable statements or documentation if such statements or documentation are filed with the SEC and made public by the SEC, such delivery to be deemed effective as of the date the applicable statement or documentation is publicly
available. Furthermore, with respect to each of Prometheus’ obligations set forth in this Section 6.5(c), Novartis shall maintain such information as Confidential Information and, solely with respect to the agreements, documents and
instruments set forth in Section 6.5(c)(vii), Novartis shall execute any confidentiality or non-disclosure agreements required by a Third Party in order for Prometheus to comply with its obligations set forth herein. 
 (d) No Encumbrances. Prometheus shall not grant, permit or otherwise suffer to exist any Encumbrances on Regulatory
Approvals other than Permitted Encumbrances. 
 (e) No Implied Representations or Warranties. OTHER THAN
AS EXPRESSLY SET FORTH IN THIS SECTION 6, NEITHER PARTY MAKES OR GIVES ANY OTHER REPRESENTATIONS OR WARRANTIES UNDER OR RELATING TO THIS AGREEMENT OR THE TRANSACTIONS CONTEMPLATED HEREBY WHATSOEVER, AND EXPRESSLY DISCLAIMS ALL OTHER REPRESENTATIONS
AND WARRANTIES, WHETHER EXPRESS, IMPLIED, OR STATUTORY, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, WARRANTIES ARISING FROM COURSE OF DEALING OR USAGE OF TRADE. 
  

 57 

 SECTION 7. 
 INDEMNIFICATION; LIMITATION OF LIABILITY; INSURANCE 
 7.1 Novartis Indemnification Obligations. Novartis will defend Prometheus, its Affiliates and Sublicensees and each of their respective officers, directors, trustees, agents and employees (collectively, “Prometheus
Indemnitees”) from and against all Claims, and indemnify and hold harmless such Prometheus Indemnitees from and against any and all losses, liabilities, obligations, awards, settlements, penalties, fines, sanctions, damages and reasonable
costs (including awards of court costs and reasonable attorneys’ fees) (collectively, “Losses”) that result from any such Claims, where and to the extent that such Claims are made or brought against any Prometheus Indemnitee by
or on behalf of a Third Party, and solely to the extent such Claim is based on or arises out of: 
 (a) the
negligent, reckless or willful actions or omissions of Novartis or its Affiliates in performing Novartis’ obligations under this Agreement; 
 (b) the material breach of any obligation, covenant, warranty or representation made by Novartis under this Agreement; 
 (c) the Development or Commercialization of any Product outside the Territory and/or outside the Field by or on behalf of
Novartis and/or its Affiliates or licensees at any time prior to or following the Effective Date; 
 (d) the
Development or Commercialization of any Product in the Territory by or on behalf of Novartis and/or its Affiliates or licensees prior to the Effective Date or after the Term (provided that any Product Liability Claims shall be subject to defense and
indemnification in accordance with Section 7.4); 
 (e) the Development of any Product in the Territory by
or on behalf of Novartis and/or its Affiliates or licensees during the Term; 
 (f) any violation of Applicable
Law by Novartis, its Affiliates or agents; 
 (g) a Novartis Indemnitee’s breach of any Upstream License
Agreement or any indemnification Claim by an Upstream Licensor that a Prometheus Indemnitee’s exercise of Prometheus’ rights or performance of Prometheus’ obligations in accordance with this Agreement constitutes a breach of any
applicable Upstream License Agreement; 
 (h) any Claim that the Commercialization of the Existing Product
infringes upon or misappropriates the Intellectual Property or proprietary rights of any Third Party (other than to the extent that such Claim relates to any Prometheus Improvements); 
 (i) any Claim arising under any MTA or any Existing Discount Agreement prior to its assignment to Prometheus pursuant to
Section 3.2(f) or Section 4.6, as applicable; or 
 (j) Taxes (or the non-payment thereof) that are the
responsibility of Novartis; 
  

 58 

 provided, however, except in each case to the extent that such Claim or Loss is attributable
to any matter for which Prometheus is obligated to indemnify a Novartis Indemnitee pursuant to Section 7.2 below or the Supply Agreement. For the avoidance of doubt, the disclosures made by Novartis pursuant to the Novartis Disclosure Schedule
shall not limit Novartis’ indemnification obligations set forth under this Section 7.1, except for Section 7.1(b). 
 7.2 Prometheus Indemnification Obligations. Prometheus will defend Novartis, its Affiliates, and the Upstream Licensors and each of their respective officers, directors, trustees, agents, employees and sublicensees (collectively,
“Novartis Indemnitees”), from and against all Claims, and indemnify and hold harmless such Novartis Indemnitees from and against any and all Losses that result from such Claims, where and to the extent that such Claims are made or
brought against any Novartis Indemnitee by or on behalf of a Third Party, and solely to the extent such Claim is based on or arises out of: 
 (a) the negligent, reckless or willful actions or omissions of Prometheus or its Affiliates in performing Prometheus’ obligations under this Agreement; 
 (b) the material breach of any obligation, covenant, warranty or representation made by Prometheus under this Agreement;

 (c) the Development or Commercialization of any Product by Prometheus and/or its Affiliates or Sublicensees in
the Territory during the Term (provided that any Product Liability Claims shall be subject to defense and indemnification in accordance with Section 7.4); 
 (d) any violation of Applicable Law by Prometheus, its Affiliates or agents; 
 (e) the content of the Prometheus Promotional Materials (excluding Novartis Promotional Materials); 
 (f) any Claim that the Development or Commercialization of any Prometheus Improvements or Necessary Diagnostic Improvements
infringe upon or misappropriate the Intellectual Property or proprietary rights of any Third Party (other than to the extent that such Claim relates to the underlying Product Intellectual Property); 
 (g) Taxes (or the non-payment thereof) that are the responsibility of Prometheus; or 
 (h) any Claim arising under any MTA or any Existing Discount Agreement as of or after its assignment to Prometheus pursuant
to Section 3.2(f) or Section 4.6, as applicable; 
 provided, however, except in each case to the extent that such Claim
or Loss is attributable to any matter for which Novartis is obligated to indemnify a Prometheus Indemnitee pursuant to Section 7.1 above or the Supply Agreement. 
 7.3 Indemnity Procedures. A Person entitled to indemnification pursuant to either Section 7.1 or Section 7.2 will hereinafter be referred to as an “Indemnitee.” A Party

  

 59 

 
obligated to indemnify an Indemnitee hereunder will hereinafter be referred to as an “Indemnitor.” In the event an Indemnitee is seeking indemnification under either
Section 7.1 or Section 7.2, the Indemnitee will inform the Indemnitor of a Claim as soon as reasonably practicable after it receives notice of the Third Party Claim, it being understood and agreed that the failure by an Indemnitee to give
notice of a Third Party Claim as provided in this Section 7.3 will not relieve the Indemnitor of its indemnification obligation under this Agreement except and only to the extent that such Indemnitor is actually and materially prejudiced as a
result of such failure to give notice. The Indemnitee will permit the Indemnitor to assume direction and control of the defense of the Claim, and, at the Indemnitor’s expense, will co-operate as reasonably requested in the defense of the Claim.
The Indemnitee will have the right to retain its own counsel at its own expense; provided, that, if the Indemnitor assumes control of such defense and the Indemnitee reasonably concludes, based on advice from counsel, that the Indemnitor and
the Indemnitee have conflicting interests with respect to such Claim, the Indemnitor will be responsible for the cost of one counsel for the Indemnitee (and all other Indemnitees in connection with the same Claim or multiple Claims arising out of
the same events or circumstances). The Indemnitor may not settle such Claim, or otherwise consent to an adverse judgment in such Claim without the Indemnitee’s prior written consent, not to be unreasonably withheld or delayed; provided
that the Indemnitor shall not require such consent with respect to the settlement of any Claim where the sole relief provided is for monetary damages that are paid in full by the Indemnitor, which would not materially diminish or limit or otherwise
adversely affect the rights, activities or financial interests of the Indemnitee, and which does not result in any finding or admission of fault by the Indemnitee. 
 7.4 Defense of and Indemnification for Product Liability Claims. With respect to any Product Liability Claims resulting from the use or consumption of the Product in the Territory during the Term,
the Parties agree that: 
 (a) Each Party will indemnify and hold harmless the Novartis Indemnitees or the
Prometheus Indemnitees, as applicable, from and against [* * *] percent ([* * *]%) of (i) any and all Losses finally awarded by a court of competent jurisdiction or imposed by a Regulatory Authority against either Party, in each case that
result from any Product Liability Claim made or brought against any Novartis Indemnitee or Prometheus Indemnitee, as applicable, by or on behalf of a Third Party and (ii) all Losses resulting from any settlements entered into by a Party
pursuant to Section 7.4(d) relating to any Product Liability Claim made or brought against any Novartis Indemnitee or Prometheus Indemnitee. 
 (b) If either Party becomes aware of any Product Liability Claim, it shall inform the other Party as soon as reasonably practicable after it receives notice of such Product Liability Claim, it being
understood and agreed that the failure by either Party to give notice of a Product Liability Claim will not relieve the other Party of its obligations under this Agreement except and only to the extent that such the other Party is actually and
materially prejudiced as a result of such failure to give notice. 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 60 

 (c) Novartis shall assume direction and control of the defense of any
Product Liability Claim, and Prometheus will cooperate as reasonably requested in the defense of such Product Liability Claim; provided that Novartis shall (i) use counsel reasonably acceptable to Prometheus; and provided
further that, if Prometheus reasonably concludes, based on advice from counsel, that Novartis and Prometheus have conflicting interests with respect to such Product Liability Claim, Prometheus shall have the right to obtain counsel of its
own, (ii) keep Prometheus reasonably informed as to the status of the defense, and (iii) consult with Prometheus in good faith with regard to all material litigation strategy decisions in connection with such defense, including without
limitation, joining Prometheus as a co-party. All reasonably incurred, direct Out-of-Pocket Costs incurred by either Party with respect to the defense of any Product Liability Claim shall be borne equally by the Parties. Novartis shall provide
Prometheus an invoice for [* * *] percent ([* * *]%) of such costs each Calendar Quarter during the Term, and Prometheus shall pay the amount set forth in such invoice to Novartis within sixty (60) days after receipt. 
 (d) Neither Party may settle any Product Liability Claim, or otherwise consent to an adverse judgment in any Product
Liability Claim without the other Party’s prior written consent, not to be unreasonably withheld or delayed. 
 (e) Each Calendar Quarter during the Term, Novartis shall provide Prometheus will a full accounting of all Losses incurred (if any) in connection with any Product Liability Claim for which each Party is obligated to indemnify the other
pursuant to Section 7.4(a), together with an invoice for [* * *] percent ([* * *]%) of such Losses. Unless otherwise disputed by Prometheus in good faith, Prometheus shall pay the amount set forth in such invoice to Novartis within sixty
(60) days after receipt. 
 7.5 No Punitive or Exemplary Damages. NEITHER PARTY SHALL BE LIABLE TO THE OTHER PARTY
UNDER ANY CIRCUMSTANCES OR ANY LEGAL OR EQUITABLE THEORY, WHETHER IN CONTRACT, STRICT LIABILITY OR OTHERWISE, FOR ANY CONSEQUENTIAL, INDIRECT, SPECIAL, EXEMPLARY, OR PUNITIVE DAMAGES, EVEN IF ADVISED OF THE POSSIBILITY OF SUCH DAMAGES, SUFFERED BY
THE OTHER PARTY UNDER THIS AGREEMENT. FOR THE AVOIDANCE OF DOUBT, ANY CONSEQUENTIAL, INCIDENTAL, INDIRECT OR SPECIAL DAMAGES AWARDED TO A THIRD PARTY IN RELATION TO A CLAIM FOR WHICH A PARTY HAS AN INDEMNIFICATION OBLIGATION PURSUANT TO
SECTION 7.1 OR SECTION 7.2 OF THIS AGREEMENT, SHALL BE CONSIDERED DIRECT DAMAGES INCURRED BY THE INDEMNIFIED PARTY UNDER THIS AGREEMENT. 
 7.6 Insurance. During the Term of this Agreement, each Party shall at all times maintain insurance policies or self-insurance in such amounts and with such scope of coverage as are adequate to
cover such Party’s obligations under this Agreement. If requested by the other Party, the insured Party shall furnish a Certificate of Insurance or other reasonable 
  

 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with
respect to the omitted portions. 
  

 61 

 
proof of coverage (which may be a certificate or other evidence issued by a Party under a program of self-insurance) evidencing the requisite coverage required under this Section during the
Term of the Agreement. 
 SECTION 8. 
 INTELLECTUAL PROPERTY RIGHTS 
 8.1 Prosecution and Maintenance of
Product Patent Rights and Product Marks. 
 (a) As between the Parties, (i) Novartis shall have the
right and obligation, at its sole cost and expense, to conduct and control prosecution, maintenance, challenges against validity and unenforceability or patentability with respect to the Core Product Patent Rights and the Product Marks in the
Territory, or to use Commercially Reasonable Efforts to cause its Upstream Licensors to do the same, consistent with past practice for the Products, and (ii) Novartis shall have the initial right (but not the obligation), at its sole cost and
expense, to conduct and control prosecution, maintenance, challenges against validity and unenforceability or patentability with respect to the Secondary Product Patent Rights in the Territory existing as of the Effective Date, or to use
Commercially Reasonable Efforts to cause its Upstream Licensors to do the same, consistent with past practice for the Products. At Novartis’ request, Prometheus shall cooperate, and shall cause its Affiliates and Sublicensees to cooperate, with
and assist Novartis and its Upstream Licensors, as applicable, in connection with such activities. If Novartis creates any Improvements to the Product after the Effective Date which are patentable, the JDC shall discuss in good faith whether
Novartis shall prosecute and maintain Patents covering the Product and/or the applicable Improvement to the Products in such jurisdictions. 
 (b) Prometheus shall not use a Product Mark in breach of the Novartis Trademark Guidelines set forth on Exhibit R. Prometheus shall promptly notify Novartis of its intention to cease using or not
to initiate use of any Product Mark or Additional Product Mark, but in any event not less than [* * *] ([* * *]) days of the last use of such Product Mark or of the decision not to initiate use of such Product Mark or Additional Product Mark.

 (c) Novartis shall not abandon, and, to the extent it has rights to do so under the Upstream License
Agreements, shall not permit its Upstream Licensors to abandon, (i) any Product Patent Rights in the Territory, or (ii) subject to Prometheus complying with its obligations under subsection (b) of this Section 8.1, any of the
Product Marks in the Territory, without providing in each case reasonable prior written notice to Prometheus of such intention to abandon such Product Patent Rights or Product Marks (which notice shall, in any event and to the extent Novartis
receives such notice from its applicable Upstream Licensor, be given no later than sixty (60) days prior to the loss of any rights in such Product Patent Rights and/or Product Marks) and, only to the extent 
  
 *** Certain information on this page has been omitted and filed separately with
the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 62 

 
permitted by any applicable Upstream License Agreement, providing Prometheus an opportunity to assume responsibility for the prosecution and maintenance in Prometheus’ name of such Product
Patent Rights and/or Product Marks, as applicable, at Novartis’ sole cost and expense with respect to any Core Product Patent Rights or Product Marks, or at Prometheus’ sole cost and expense with respect to any Secondary Product Patent
Rights. 
 (d) If Prometheus reasonably believes that Novartis or its Upstream Licensor may fail to make any
required payments or take any action required for the preparation, filing, prosecution, defense or maintenance of any Product Patent Rights and/or Product Marks in the Territory within a reasonable time, Prometheus shall provide Novartis with
written notice of the same. If, having received such notice, and after discussion with Novartis, Novartis or the Upstream Licensor fails to take the required action at least [* * *] ([* * *]) Business Days before the deadline for taking such action
unless Novartis has notified Prometheus in writing within [* * *] ([* * *]) Business Days of receiving such notice that it will either take action or its Upstream Licensors will take action by the deadline or that it has elected not to take action
and not take action and does not permit Prometheus to take further action, Prometheus shall have the right (but with respect to Product Patent Rights licensed under the Upstream License Agreements, solely to the extent that Novartis has the right to
do so under the applicable Upstream License Agreement) to thereafter make any such required payments or take any such required action and (i) with respect to any Core Product Patent Rights, obtain reimbursement from Novartis for such payments
in the amounts set forth in paragraph (e) below; and (ii) with respect to any Secondary Product Patent Rights, make such payments and take any such required action at Prometheus’ sole cost and expense. 
 (e) In the event Prometheus elects to assume responsibility for any Core Product Patent Rights and/or Product Marks in
accordance with Section 8.1(c) or incurs any costs and expenses in accordance with Section 8.1(d), Novartis shall reimburse Prometheus, within forty-five (45) days after the date of a reasonably detailed invoice and back-up therefor
provided by Prometheus, [* * *] percent ([* * *]%) of Prometheus’ [* * *] associated with the prosecution and maintenance of any Core Product Patent Rights and/or Product Marks. 
 8.2 Co-Operation and Exchange of Information. Except to the extent restricted by any of the Upstream License Agreements, Novartis
shall (a) keep Prometheus reasonably informed as to the status of any of the Product Intellectual Property in the Territory (which obligation shall be deemed satisfied by Novartis by the provision to Prometheus of a bi-annual status report),
(b) consider in good faith the reasonable requests, suggestions and advice of Prometheus with respect to the prosecution, maintenance and defense of the Product Patent Rights and Product Marks in the Territory, (c) provide Prometheus with
copies of material reports and correspondence (both received and filed from/with) the receiving office of any PCT application, the U.S. Patent and Trademark Office and/or other equivalent intellectual property Regulatory Authorities in the Territory
to the extent that they relate to the Core Product Patent 
  
 ***
Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 63 

 
Rights or Product Marks, and (d) provide Prometheus with a reasonable opportunity to comment on (and consider all such comments in good faith) any correspondence or filings with or to the
examiner of any Core Product Patent Rights. 
 8.3 Infringement or Misappropriation of Product Intellectual Property.

 (a) Notice of Infringement by Third Parties. If either Party should become aware of any Claim,
infringement or misappropriation or threatened Claim, infringement or misappropriation of the Product Intellectual Property by a Third Party or that the manufacture, use, importation or sale of the Product is infringing any Third Party Intellectual
Property in the Territory, it shall promptly notify the other Party in writing and provide any information available to that Party relating to such alleged infringement. 
 (b) Responsibility for Enforcement. 
 (i) Novartis shall have the initial right to bring or control, at its own expense, any enforcement action directed to an
alleged infringement or misappropriation of the Product Intellectual Property owned by Novartis or its Affiliates in the Territory, but shall consult with Prometheus in good faith with regard to all material litigation strategy decisions to the
extent permissible by the Upstream License Agreements, including without limitation, joining Prometheus as a co-party (e.g., if necessary in order for the party plaintiffs to have standing and/or a viable claim for lost profit damages).

 (ii) To the extent permitted by the applicable Upstream License Agreement, Novartis shall have the initial
right to bring or control, at its own expense, any enforcement action directed to an alleged infringement or misappropriation of the Upstream Licensed Patents and/or the Upstream Licensed Know-How in the Territory, but shall consult Prometheus in
good faith with regard to all material litigation strategy decisions, including without limitation, joining Prometheus as a co-party (e.g., if necessary in order for the party plaintiffs to have standing and/or a viable claim for lost profit
damages). 
 (iii) In the event that the enforcement of any Upstream Licensed Patent and/or any Upstream Licensed
Know-How is the responsibility of the applicable Upstream Licensor pursuant to Upstream License Agreements or an enforcement action cannot be brought by Novartis for lack of standing, Novartis agrees that, to the extent that Novartis has the right
to do so under the Upstream License Agreement, Novartis (i) shall use Commercially Reasonable Efforts to cause such Upstream Licensor to bring or control in accordance with the applicable Upstream License Agreement, any enforcement action
directed to an alleged infringement or misappropriation of the Upstream Licensed Patents and/or the Upstream Licensed Know-How in the Territory, (ii) shall consult Prometheus in good faith with regard to all material litigation strategy
decisions, including without limitation, whether to join Prometheus and/or Novartis as co-parties, and (iii) shall not permit such Upstream Licensor to settle (or make any stipulation during) such enforcement action in a manner that would
negatively affect

  

 64 

 
Prometheus’ rights and licenses pursuant to this Agreement without first obtaining Prometheus’ prior written consent, which consent shall not be unreasonably withheld, delayed or
conditioned. 
 (iv) In the event that Novartis or an Upstream Licensor does not file suit against or commence
settlement negotiations with the party responsible for an alleged infringement of any Product Intellectual Property within [* * *] ([* * *]) days of receipt of a written demand from Prometheus that Novartis and/or its Upstream Licensor bring suit,
and it is determined by Prometheus after good faith consultation with Novartis that a suit should be filed by Novartis and/or the applicable Upstream Licensor, but Novartis and/or the applicable Upstream Licensor does not file suit or commence
settlement negotiations forthwith against the infringer, then Prometheus shall have the right, at its own expense, to bring or control any enforcement action directed to the alleged infringement on behalf of itself, Novartis, and/or the Upstream
Licensor, to the extent permitted by the relevant Upstream License Agreement. 
 8.4 Cooperation and Joinder. 

(a) Prometheus shall reasonably cooperate in any enforcement action brought by Novartis or an Upstream Licensor pursuant
to Section 8.3(b)(i), (ii) or (iii) above. In addition, to the extent determined in accordance with such Sections that Prometheus should be joined as a party, be permitted to join or be joined as a party therein, then, to the extent
such cooperation or joinder came as a result of Novartis’ or the Upstream Licensor’s request, Novartis or the Upstream Licensor, as applicable, agrees to reimburse Prometheus for all Out-of-Pocket Costs (excluding reasonable
attorneys’ fees unless the Parties are unable to utilize the same legal counsel due to an ethical conflict), that it may incur in connection with such assistance or joinder, including any award of costs against it. 
 (b) To the extent required or permitted in accordance with the applicable Upstream License Agreements, Novartis shall
reasonably cooperate in any enforcement brought by an Upstream Licensor pursuant to Section 8.3(b)(iii), and as necessary join or be joined as a party therein. 
 (c) Novartis shall and shall cause the applicable Upstream Licensor to the extent permitted by the relevant Upstream License
Agreement to reasonably cooperate in any enforcement brought by Prometheus pursuant to Section 8.3(b)(iv), and as necessary join or be joined as a party therein, provided Prometheus agrees to reimburse Novartis and/or the Upstream Licensor, as
applicable, for all Out-of-Pocket Costs, damages and expenses, (excluding reasonable attorneys’ fees unless the Parties are unable to utilize the same legal counsel due to an ethical conflict), that it may incur in connection with such
assistance or joinder, including any award of costs against it. 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 65 

 (d) Any costs, expenses or damages hereunder to be reimbursed by one Party
to the other shall be paid by the owing Party within sixty (60) days of receipt of an invoice therefor, including evidence that such costs, expenses or damages have been incurred. 
 8.5 Retention of Amounts Recovered. Except as otherwise required by the terms of any applicable Upstream License Agreements, any
amount recovered in any action or suit brought in accordance with Section 8.3, whether by judgment or settlement, shall be applied as follows, unless otherwise agreed in writing by the Parties: 
 (a) First, to reimburse the Parties for their respective costs and expenses incurred in connection with such action or suit
in accordance with Sections 8.3 and 8.4; and 
 (b) Second, if 
 (i) Novartis or an Upstream Licensor brings an enforcement action, then any amounts remaining shall be allocated
[* * *] percent ([* * *]%) to Prometheus and [* * *] percent ([* * *]%) to Novartis and/or its Upstream Licensor, as applicable; or 
 (ii) Prometheus or its Affiliates or a Sublicensee brings an enforcement action, then any amounts remaining shall be allocated [* * *] percent ([* * *]%) to Prometheus and/or its Sublicensee, as
applicable, and [* * *] percent ([* * *]%) to Novartis and/or its Upstream Licensor, as applicable; 
 In the event of any
inconsistency between the terms of this Section 8.5 and the terms of any Upstream License Agreement, amounts recovered in any enforcement action or suit brought in accordance with Section 8.3 that pertain to the Upstream License Agreement
shall be paid or retained in accordance with the terms of the applicable Upstream License Agreement. 
 8.6 Improvements.

 (a) Ownership of Intellectual Property. The Parties agree that all determinations of inventorship shall
be made in accordance with United States patent laws. Subject to the licenses granted pursuant to this Agreement, each Party or its Affiliates shall retain all right, title and interest in and to all Intellectual Property developed or acquired by
such Party or its Affiliates prior to the Effective Date or during the Term which is outside the scope of this Agreement. The Parties shall jointly own all Improvements to one or more Products which are invented jointly by at least one employee or
agent of each Party or its Affiliates (each a “Joint Improvement”). Prometheus and Novartis, as joint owners, shall each have the right to practice and to grant licenses under any Patent Rights covering Joint Improvements without
the other Party’s consent or a duty of accounting, except as otherwise provided in this Agreement or agreed in writing by the Parties or as required by Applicable Law. The Parties shall 
  
 *** Certain information on this page has been omitted and filed separately with
the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 66 

 
determine the responsible Party for prosecution, maintenance and enforcement of Patents covering Joint Improvements, and the allocation of costs and recoveries associated with these activities,
through mutual agreement on a case-by-case basis. Further, as between the Parties: 
 (i) Prometheus shall
exclusively own: (A) any Prometheus Confidential Information; (B) the Prometheus Improvements; and (C) any and all Regulatory Approvals filed or awarded to Prometheus or its Affiliates during the Term in any jurisdiction in the
Territory related to the Products, all subject to Section 10.7(d). 
 (ii) Novartis shall exclusively own:
(A) any Novartis Confidential Information; and (B) the Novartis Improvements. 
 (b) Licenses to
Novartis. If during the Term Prometheus or its Affiliates develops any Improvements (expressly excluding any Diagnostic Improvements) to one or more Products (each a “Prometheus Improvement”) or any Necessary (as defined below)
Diagnostic Improvements, Prometheus hereby grants to Novartis, and Novartis shall receive: 
 (i) Licenses to
Novartis Necessary for the Products. 
 (A) a [* * *] license under all Intellectual Property controlled by
Prometheus or any of its Affiliates covering the Prometheus Improvements solely for the purpose of manufacturing, Developing, using and/or Commercializing the Products in or outside the Territory after (but not during) the Term; 
 (B) a [* * *] license under all Intellectual Property controlled by Prometheus or any of its Affiliates covering any
Necessary Diagnostic Improvements solely for the purpose of manufacturing, Developing, using and/or Commercializing the Products in or outside the Territory after (but not during) the Term; provided that Prometheus shall have the right to
continue to perform all diagnostic testing covered by any Necessary Diagnostic Improvements (as applicable) on commercially reasonable terms and compensation to be agreed upon by the Parties. For the purposes hereof, “Necessary”
with respect to Prometheus Improvements or Diagnostic Improvements, shall mean that such Prometheus Improvements or Diagnostic Improvements, as the case may be, are included in the labeling for any of the Products or are required to be incorporated
into or used in conjunction with the Products by any Applicable Law or any Regulatory Authority; and 
 (C) a [*
* *] license under all Intellectual Property controlled by Prometheus or any of its Affiliates covering any and all Necessary Prometheus Improvements or Necessary Diagnostic Improvements, in each case, solely for the purpose of manufacturing,
Developing, using and/or Commercializing the Products outside the Territory at any time during the Term. 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 67 

 For the avoidance of doubt, to the extent the Intellectual Property covering the Prometheus
Improvements and Necessary Diagnostic Improvements licensed to Novartis pursuant to this subsection (i) have applicability to any product (an “Other Product”) outside of the Product(s) or any Generic of the Product, nothing in
this section shall be construed as preventing Prometheus from licensing such Intellectual Property to any Third Party for use with such Other Product, provided that such license does not interfere with the licenses granted to Novartis hereunder.

 (ii) Other Licenses to Novartis. 
 (A) a [* * *] license under all Intellectual Property owned or licensed (with right to further sublicense) by Prometheus or
any of its Affiliates covering such Prometheus Improvements that are not included in subsection (i) above, but which Novartis elects to receive solely in order to manufacture, Develop, use and/or Commercialize the Products outside the Territory
at any time during or after the Term or in the Territory after the Term; and 
 (B) in the event that Prometheus
or its Affiliates ceases commercializing any Diagnostic Improvement used in conjunction with the Product (and is not being licensed to Novartis pursuant to Section 8.6(b)(i) above), [* * *] license under all Intellectual Property owned or
licensed (with right to further sublicense) by Prometheus or any of its Affiliates covering such Diagnostic Improvement solely in order to manufacture, Develop, use and/or Commercialize the Products outside the Territory at any time after the Term.

 To the extent any Prometheus Improvement or any Diagnostic Improvement described above has been licensed to Prometheus or its
Affiliates from a Third Party, Prometheus shall ensure that the license(s) granted under this Section 8.6(b) shall include a sublicense under such license on the same terms and conditions (including any royalty or other payment provisions) that
such Third Party has granted such license to Prometheus or its Affiliates, as applicable. If, however, after using Commercially Reasonable Efforts in good faith, Prometheus and/or its Affiliates cannot [* * *] with respect to a Prometheus
Improvement or Diagnostic Improvement, Prometheus and/or its Affiliates shall assign such license to Novartis or its Affiliate in lieu of granting a sublicense, provided that Novartis shall have the right to refuse such assignment, in its
sole discretion, in which case it will forego rights under such license. Notwithstanding the foregoing, if Prometheus and/or its Affiliates has [* * *], Prometheus and/or its Affiliates shall have the right to assign such license to Novartis or its
Affiliate in lieu of granting a sublicense, provided that Novartis shall have the right to refuse such assignment, in its sole discretion, in which case it will forego rights under such license. 
  
 *** Certain information on this page has been omitted and filed separately with
the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 68 

 (c) Prosecution and Maintenance. Prometheus shall have the right (but
not the obligation), at its sole cost and expense, to conduct and control prosecution, challenges against validity and unenforceability or patentability with respect to any Patents in the Territory covering Prometheus Improvements. If Prometheus or
its Affiliates create any Prometheus Improvements which are patentable, Prometheus shall promptly consult with Novartis and the Parties shall mutually agree in writing to the allocations of responsibility and control regarding the conduct of
prosecution and maintenance regarding any Patents outside of the Territory covering such Prometheus Improvements. If Prometheus intends to abandon its prosecution and maintenance of any such Patents, whether in the Territory or outside the
Territory, it shall provide reasonable prior written notice to Novartis of such intention to abandon such Patents (which notice shall be given no later than [* * *] ([* * *]) days prior to the loss of any rights in such Patents) and shall provide
Novartis or the Upstream Licensors an opportunity to assume responsibility for the prosecution and maintenance of such Patents in Novartis’ name or the Upstream Licensor’s name, as applicable. 
 (d) Enforcement. If either Party becomes aware of any actual or threatened infringement or misappropriation of any
Prometheus Improvements by a Third Party or that the practice of any Prometheus Improvements is infringing any Third Party Intellectual Property, it shall promptly notify the other Party in writing and provide any information available to it
relating to such alleged infringement. Prometheus shall have the right (but not the obligation) to bring or control, at its own expense, any enforcement action directed to an alleged infringement or misappropriation of any Prometheus Improvements,
provided that if Prometheus does not file suit against or commence and conclude settlement negotiations with the party responsible for an alleged infringement of any Prometheus Improvement within ninety (90) days of receipt of a written
demand from Novartis to bring suit and such Prometheus Improvement is licensed to Novartis pursuant to Section 8.6(b)(i), Novartis shall have the right, at its own expense, to bring or control any enforcement action directed to the alleged
infringement on behalf of itself and Prometheus. Each Party shall reasonably cooperate in any enforcement action brought by the other Party with respect to any Prometheus Improvements in accordance with this Section, and as necessary join or be
joined as a party therein, provided the other Party agrees to reimburse it for all Out-of-Pocket Costs, damages and expenses (excluding reasonable attorneys’ fees unless the Parties are unable to utilize the same legal counsel due to an ethical
conflict) that it may incur in connection with such assistance or joinder, including any award of costs against it. Any amount recovered in any action or suit brought in accordance with this Section, whether by judgment or settlement, shall be
applied (unless otherwise agreed in writing by the Parties) first, to reimburse the Parties for their respective costs and expenses (including reasonable attorneys’ fees and costs) incurred in prosecuting such infringement action, and any
remaining amounts shall be retained by the Party bringing such action. 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 69 

 SECTION 9. 
 CONFIDENTIALITY 
 9.1 Nondisclosure.
Confidential Information of the other Party shall be kept strictly confidential by the receiving Party and, except as expressly permitted herein or otherwise mutually agreed to by the Parties, shall not be disclosed to any Third Party by the
receiving Party in any manner whatsoever, in whole or in part, without first obtaining the other Party’s prior written consent to such disclosure. The standard of care required of each Party in protecting the confidentiality of the other
Party’s Confidential Information shall be at least the same standard of care that the receiving Party uses in protecting its own confidential and trade secret information, but in no event shall either Party use less than a reasonable standard
of care. Except as mutually agreed upon by the Parties, Confidential Information may be used by the receiving Party or its Affiliates only for the purpose of exercising its rights and performing its obligations under this Agreement. 
 9.2 Permitted Exceptions. Each Party may disclose the other Party’s Confidential Information (i) to its employees, outside
advisors, Affiliates, and in the case of Novartis its Upstream Licensors, or in the case of Prometheus its Sublicensees who reasonably need to know such information for the purpose of advising or assisting it in connection with this Agreement or in
connection with exercising rights or performing obligations under the Upstream License Agreements or any Sublicense, as applicable, and, in addition, Prometheus may disclose the terms of this Agreement to any institutional investors or lenders of
Prometheus who reasonably need to know such information for the purposes of evaluating Prometheus’ finances (each such employee, outside advisor, Affiliate, Upstream Licensor, Sublicensee, investor or lender being referred to herein as a
“Representative”), (ii) to Regulatory Authorities in furtherance of obtaining and maintaining the Regulatory Approvals, Development of the Products or the prosecution of Product Patent Rights, and (iii) to any Third
Parties if required by Applicable Law, subject to Section 9.5. Prior to disclosing any Confidential Information to any Representative pursuant to this Section 9.2, the receiving Party will inform such Representative of the proprietary
nature of the Confidential Information and will require such Representative to agree in writing (except in the case of Affiliates or outside legal advisors or auditors, who may orally agree) to be bound by obligations of confidentiality and non-use
no less restrictive than the requirements of this Section 9. Each Party agrees to be responsible for any breach of these confidentiality obligations by its Representatives. Either Party may disclose the existence of this Agreement and the terms
and conditions hereof, without the prior written consent of the other Party, as may be required by applicable Law (including, without limitation, disclosure requirements of the Securities and Exchange Commission (“SEC”), NYSE, or
any other stock exchange or NASDAQ), in which case the Party seeking to disclose the information shall give the other Party reasonable advance notice and the right to review and comment on any such disclosure (including any proposed filing of this
Agreement with the SEC or equivalent governing body outside the U.S.) and shall seek confidential treatment of such Confidential Information to the extent possible under Applicable Law. Furthermore, notwithstanding anything to the contrary set forth
herein, Novartis and its Affiliates shall have the right to disclose the existence of this Agreement and the terms and conditions hereof to any of the Upstream Licensors, to the extent required by the applicable Upstream License Agreements.

  

 70 

 9.3 Consent. Confidential Information of the other Party shall not be utilized by a
receiving Party except as expressly permitted herein, without first obtaining the other Party’s prior written consent to such utilization. 
 9.4 Excluded Information. Notwithstanding any provision herein to the contrary, the requirements of this Section 9 shall not apply to any information of either Party which: 
 (a) at the time of disclosure hereunder is generally available to the public; 
 (b) after disclosure hereunder becomes generally available to the public, except through breach of this Section 9 by the
receiving Party or its Representatives; 
 (c) was not acquired directly or indirectly from the disclosing Party
or its Affiliates and which the receiving Party lawfully had in its possession prior to disclosure by the disclosing Party or its Affiliates; 
 (d) is independently developed by employees or agents of the receiving Party or its Affiliates without the use of the Confidential Information of the disclosing Party or its Affiliates; or 
 (e) becomes available to the receiving Party from a Third Party that is not legally prohibited from disclosing such
Confidential Information, provided such information was not acquired directly or indirectly from the disclosing Party or its Affiliates. 
 9.5 Notification of Mandatory Disclosure. 
 (a)
Procedures. In the event that either Party is required by Applicable Law or by judicial or administrative process to disclose any part of the other Party’s Confidential Information, such Party shall (i) promptly notify the other
Party of each such requirement and identify the documents so required thereby, with a view to permitting the other Party to seek an appropriate protective order or other remedy and/or waive compliance by the first Party with the provisions of this
Section 9, (ii) consult with the other Party on the advisability of taking legally available steps to resist or narrow the scope of such requirement, (iii) assist the other Party in seeking a protective order or equivalent, and
(iv) comply with any applicable protective order or equivalent. 
 (b) Limitations. If, in the
absence of such a protective order or such a waiver by the other Party of the provisions of this Section 9, the first Party is nonetheless required by Applicable Law to disclose any part of the other Party’s Confidential Information, the
first Party may disclose such of the other Party’s Confidential Information without liability under this Agreement, except that the first Party shall (i) furnish only that portion of the other Party’s Confidential Information which is
legally required and (ii) use its best efforts to obtain an order or other reliable assurances that confidential treatment will be accorded to the portion of such Confidential Information so required to be disclosed. 
  

 71 

 9.6 Publicity. All publicity, press releases and public announcements, in each case
relating to the Products (other than press releases or public announcements by Novartis or its Affiliates outside the Territory which would not reasonably be expected to have an impact on the Development or commercialization of the Product in the
Territory) and/or the transactions contemplated hereby shall be reviewed in advance by, and shall be subject to the written approval (such approval not to be unreasonably withheld) of both Parties; provided that such publicity, press releases
and other public announcements shall not disclose any Confidential Information of the other Party hereunder and shall give appropriate attribution to the other Party’s role(s) in the project contemplated herein. Notwithstanding the foregoing,
the Parties have agreed to the initial press release attached hereto as Exhibit O to be issued after January 25, 2010, and further disclosures of substantially the same information included therein. Each Party shall provide the other
Party an opportunity to review and comment on the language of such attribution prior to first use thereof in a press release or other public disclosure. Furthermore, each Party shall notify the other Party prior to the first public disclosure of any
data generated by it, its Affiliates, Sublicensees or licensees (as applicable) relating to the Products in the Territory, and shall provide the other Party an opportunity to review and comment on the language of such disclosure. Any information
that is contained in an approved disclosure as described in the preceding sentences may be disclosed subsequently by either Party without the need to seek any further approval, subject to any restrictions that apply to the original disclosure.
Notwithstanding anything to the contrary set forth herein, no publicity, press releases or public announcements, in each case relating to the Products or the terms of this Agreement or the Supply Agreement or the transactions contemplated hereby and
thereby, shall be made by either Party prior to January 25, 2010; provided, however, that each of Novartis and Prometheus shall have the right to notify or inform its Customers, suppliers, vendors and any other Persons regarding the
transactions contemplated by this Agreement and/or the Supply Agreement in order to carry out the assignments, transfers, deliveries and other obligations as contemplated by this Agreement. Furthermore, it shall not constitute a breach of this
Section 9.6 where and to the extent that (i) Novartis or its Affiliates contact any healthcare providers or institutions or any other Persons who utilize the Product or treat patients with the Product in the Field who Novartis or its
Affiliates normally call upon in the ordinary course of business in order to inform them of the transfer of Product responsibility from Novartis to Prometheus; and (ii) subject to the penultimate sentence of Section 9.2, Prometheus makes
any disclosures or submit any filings to the SEC prior to January 18, 2010 relating to the Products or the terms of this Agreement or the Supply Agreement or the transactions contemplated hereby and thereby. The Parties shall mutually agree in
writing to a public statement that either Party is permitted to make in the event a Person contacts such Party with regards to this Agreement and/or the Supply Agreement and/or the transactions contemplated hereby or thereby, during the period
commencing on the Effective Date and ending on January 24, 2010. 
 9.7 Non-Disparagement. During the Term, Novartis
agrees not to, and to cause its Affiliates, directors, officers, and senior management, not to, disseminate or publish in the context of professional or business activities any written, oral or electronically transmitted statement that is
disparaging, deleterious or damaging to the integrity, reputation or goodwill of the Products, and will inform its directors, officers and senior management of the terms of this Section. For the avoidance of doubt, the publication of any scientific
or clinical data, and any factual statements or required disclosures by Novartis or its Affiliates, directors, officers and senior management regarding such results or data shall not be considered a breach of this

  

 72 

 
Section 9.7. The Parties also agree that the promotion by Novartis or its Affiliates of any drug in compliance with Applicable Laws and the guidelines of any Regulatory Authorities shall not
in and of itself constitute a breach of this Section 9.7. 
 SECTION 10. 
 TERM AND TERMINATION 
 10.1 Term. The term of this Agreement will commence on the Effective Date and, unless sooner terminated as provided in this Section 10, shall continue until January 31, 2016 (the
“Initial Term”), following which Prometheus shall have the sole right to extend the term of this Agreement on an annual basis for up to six (6) additional one-year (1) periods, subject to early termination as provided in
this Section 10 (each an “Extension Term”) by providing notice of its election to extend not less than one hundred and twenty (120) days prior to the expiration of the Initial Term or the then-current Extension Term, as
applicable, and paying the applicable Annual Extension Fee in accordance with Section 5.3. The Initial Term together with all Extension Terms shall be referred to herein as the “Term”. 
 10.2 Termination for Material Breach. 
 (a) Each Party will be entitled to terminate this Agreement in its entirety at any time during the Term by written notice to the other Party in the event that the other Party is in material default or
breach of any material representation, warranty or obligation of such Party hereunder or under the Supply Agreement, and fails to remedy any such default or breach within the Cure Period (as defined below) after notice thereof by the
non-defaulting/non-breaching Party. If such default or breach is not corrected within the applicable Cure Period, the non-defaulting/non-breaching Party will have the right to immediately terminate this Agreement by giving written notice to the
Party in default or breach. For the avoidance of doubt, the following events shall be deemed to be a material breach of this Agreement by Prometheus: (i) the failure by Prometheus to pay any material amounts owing hereunder or under the Supply
Agreement as set forth in this Agreement or the Supply Agreement, as applicable; (ii) the failure by Prometheus to meet any Minimum Marketing Spend or Minimum Detail Requirements in accordance with this Agreement, except as otherwise expressly
permitted pursuant to Section 4.12(b); or (iii) the occurrence of a Financing Default. The “Cure Period” shall be ten (10) days in the event of a breach described in clause (i) of the preceding sentence, and, in
all other cases shall be sixty (60) days; except that there shall be no Cure Period for a Financing Default. Notwithstanding anything to the contrary set forth under this Section 10.2(a) or under this Agreement, in the event of a Financing
Default, (A) Novartis shall have the right to terminate this Agreement immediately upon the occurrence of such Financing Default and for a period of thirty (30) days thereafter, such termination being effective immediately upon
Novartis’ written notice of termination; and (B) if Novartis so terminates this Agreement, such termination shall be deemed to be effective irrespective of whether such Financing Default is subsequently cured or waived. 
 (b) In addition, Prometheus will be entitled to terminate this Agreement in its entirety at any time during the Term by
written notice to Novartis in the event of a

  

 73 

 
Novartis Catastrophic Breach, such written notice to be given no later than sixty (60) days after the occurrence of the Novartis Catastrophic Breach unless otherwise agreed to by the Parties
in writing. Failure to give such notice within such sixty (60) day period shall constitute forfeiture of Prometheus’ right to terminate this Agreement pursuant to this Section 10.2(b) as a result of such Novartis Catastrophic Breach.
Notwithstanding the forfeiture or election of Prometheus not to terminate pursuant to this Section 10.2(b), Prometheus shall retain all other rights and remedies available to it at law, in equity or provided under this Agreement. For purposes
hereof, “Novartis Catastrophic Breach” means the occurrence of any of the following: 
 (i)
Novartis’ breach of [* * *] due to a [* * *] (as defined in [* * *]) which breach both continues uncured for a period of [* * *] ([* * *]) consecutive months after the expiration of the [* * *] and results in a [* * *] for a period of more than
[* * *] ([* * *]) days. For the purposes hereof, “[* * *]” means that [* * *] shall be [* * *], which the Parties agree shall mean [* * *] of [* * *] ([* * *]) days [* * *], provided that [* * *]; 
 (ii) Novartis’ breach of any of clauses [* * *] of Section 6.2(d) (provided, that for purposes of this
Section 10.2(b)(i) only, [* * *] which: 
 (A) results in Prometheus being required to [* * *] for a period
of more than [* * *] ([* * *]) days pursuant to an injunction or order of a court of competent jurisdiction or any Regulatory Authority with jurisdiction in the United States, or 
 (B) permits the continued sale of the Products in the Territory but [* * *]; or 
 (iii) an [* * *]; 
 provided that with respect to any event contemplated by Sections 10.2(b)(ii)(B) or 10.2(b)(iii), as the case may be, a “Catastrophic Breach” shall not be deemed to have occurred unless and until the applicable breach (and
not any market event(s)) under this Section 10.2(b) causes a Significant Market Event. 
 With respect to the [* * *] ([* * *])-[* * *]
periods referred to in Sections 10.2(b)(i) and 10.2(b)(ii)(A), (x) Novartis shall be entitled to extend [* * *] ([* * *])-[* * *] periods for an additional [* * *] ([* * *]) days by written notice of such extension to Prometheus,
provided that Novartis shall be obligated to reimburse Prometheus for the cost of its Sales Representatives responsible for promoting the Products at a rate of [* * *] U.S. dollars ($[* * *]) per FTE, but not to exceed an aggregate of [* * *]
U.S. dollars ($[* * *]) for such thirty (30)-day period, and (y) Prometheus will be relieved of a pro rata portion of its Minimum Marketing and Promotion Investment obligations for the calendar year in which such 60-day period (together with
any extensions thereof) occurs (at a rate of a reduction of [* * *] for each [* * *] ([* * *]) day period). 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 74 

 10.3 Bankruptcy. 
 (a) Either Prometheus or Novartis may terminate this Agreement without notice if an Insolvency Event occurs in relation to
the other Party. In any event when a Party first becomes aware of the likely occurrence of any Insolvency Event in regard to that Party, it shall promptly so notify the other Party in sufficient time to give the other Party sufficient notice to
protect its interests under this Agreement. 
 (b) Novartis may terminate this Agreement in the event Prometheus
rejects this Agreement under Section 365 of the United States Bankruptcy Code, 11 U.S.C. §§ 101 et seq. (the “Code”). 
 10.4 Termination for a Significant Market Event. Prometheus shall have the right to terminate this Agreement in its entirety by giving [* * *] ([* * *]) days prior written notice to Novartis in the
event that a Significant Market Event occurs for a continuous period of [* * *] ([* * *]) months or more. 
 10.5 Termination
for Change in Control of Prometheus. Any transaction that would, if consummated, result in a Change in Control Default Event (a “Change in Control Transaction”) shall be subject to the provisions of this Section 10.5.
Prometheus shall notify Novartis in writing of a proposed Change in Control Transaction as soon as reasonably practicable after Prometheus determines to enter into such transaction. Such notice shall identify the other party or parties to the
proposed Change in Control Transaction and shall provide Novartis with information material to the proposed transaction for the purpose of enabling, and that is reasonably sufficient for, Novartis to decide whether to exercise its rights under this
Section 10.5; provided, however, that Prometheus shall not be required to disclose any information (other than the identity of the other party or parties to the proposed Change in Control Transaction) that Prometheus is prohibited
from disclosing under the terms of a confidentiality agreement or covenant relating to such transaction. In the event that a transaction to which Prometheus is not a party occurs (or is proposed to occur) that results in (or would result in) a
Change in Control Default Event (for example, by way of a sale of Prometheus voting securities by existing stockholders without the involvement of Prometheus), Prometheus shall notify Novartis in writing of such transaction immediately after
Prometheus becomes aware of such transaction. Following the provision of notice by Prometheus of a proposed Change in Control Transaction in accordance with this Section 10.5, Novartis shall have a period of [* * *] ([* * *]) days during which
to approve or reject such proposed Change in Control Transaction by providing notice in writing of such election to Prometheus (the “Approval Period”). If Novartis approves the Change in Control Transaction within the Approval
Period, or if Novartis fails to reject the Change in Control Transaction within the Approval Period (in either case, a “Novartis CoC Waiver”), then Novartis shall be deemed to have waived its right to terminate this Agreement
pursuant to this Section 10.5 as a result of the closing of such Change in Control 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 75 

 
Transaction, provided that the closing takes place not more than one hundred eighty (180) days after the earlier of (i) expiration of the Approval Period or
(ii) Novartis’ notice of approval of the Change of Control Transaction. Novartis shall have the right, in its sole discretion, to elect to terminate this Agreement following the closing of a Change in Control Transaction (other than any
Change in Control Transaction with respect to which a valid Novartis CoC Waiver has been given or deemed given and remains in effect as provided above), provided that Novartis must exercise such right to terminate within [* * *] ([* * *])
days after closing of the Change in Control Transaction. Such termination of this Agreement shall be effective on the date upon which is [* * *] ([* * *]) days after Novartis’ notice of termination or such later date as the Parties may agree in
writing. 
 10.6 Termination for Convenience by Prometheus. Prometheus may terminate this Agreement for convenience and
without cause upon not less than [* * *] ([* * *]) days written notice to Novartis. 
 10.7 Effect of Termination.

 (a) Termination of Licenses. Upon termination or expiration of this Agreement for any reason, all
licenses and rights granted to Prometheus by Novartis under this Agreement, including, without limitation, under the Product Intellectual Property, will terminate, and all rights therein will revert to Novartis. The license granted to Novartis
pursuant to Section 8.6(b) with respect to the Prometheus Improvements and Diagnostic Improvements shall survive termination or expiration of this Agreement in accordance with the terms set forth therein. 
 (b) Prometheus Promotional Materials; Remaining Inventory; Disclosure of Information. Upon termination or expiration
of this Agreement for any reason: 
 (i) Prometheus shall cease using all Prometheus Promotional Materials except
to the extent necessary to sell its current stock of Products in accordance with sub-paragraph (ii) below. Following the Sell-Off Period, Prometheus shall provide to Novartis a representational sample of all Prometheus Promotional Materials and
training materials in Prometheus’ possession or Control and actively used by Prometheus as of the effective date of termination or expiration relating to the Products in the Territory. Novartis shall have the right, subject to compliance with
Applicable Law, to use the Prometheus Promotional Materials to design and prepare new Promotional Materials for use in Commercializing the Products in the Territory and may copy, modify and use such Prometheus Promotional Materials in the same or
similar manner as Novartis permitted Prometheus the use of the Novartis Promotional Materials pursuant to Section 4.3(a) of this Agreement, provided that, for the avoidance of doubt, nothing in this Section shall grant Novartis any
rights to copy, modify or otherwise use any Prometheus Trademarks, logos or names for any purposes without the prior express written consent of Prometheus. 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the
omitted portions. 
  

 76 

 (ii) Except in the case of expiration of this Agreement or termination by
Novartis pursuant to Section 10.2 or 10.3 or termination by Prometheus pursuant to Section 10.6, Prometheus shall have a period of ninety (90) days from the effective date of termination (the “Sell-Off Period”) during
which to sell its remaining stock of the Products in accordance with the terms and conditions of this Agreement. After such Sell-Off Period, Prometheus shall cease all Commercialization of the Products in the Territory; provided that Novartis
shall repurchase all remaining Product from Prometheus at the Transfer Price paid by Prometheus therefor, but in no case to exceed the equivalent of [* * *] ([* * *]) [* * *] of Product based on historical sales rates over the prior calendar year.

 (iii) Prometheus shall provide to Novartis (A) copies of all material written communication with the FDA
and other Regulatory Authorities during the Term within ninety (90) days after the termination or expiration of this Agreement; (B) copies of all existing Product Marks and Product Trade Dress and (C) copies of any Product release
data, stability documentation and/or other manufacturing, stability and release testing documentation to the extent generated by or on behalf of, or made available to, Prometheus or its Affiliates. 
 (c) Return of Confidential Information. At any time following termination or expiration of this Agreement, upon the
request of the other Party, to the extent such Confidential Information is not reasonably necessary to enable a Party to perform its remaining obligations under this Agreement, the receiving Party shall promptly return to the other Party or destroy
the other Party’s Confidential Information, and shall destroy all copies thereof, together with all notes, drawings, abstracts and other information relating to the other Party’s Confidential Information prepared by the receiving Party or
any of its Representatives, regardless of the medium in which such information is stored; provided, however, that the receiving Party may maintain a single archival copy of the other Party’s Confidential Information in its files
for purposes of establishing the extent of disclosures by the other Party under this Agreement. At either Party’s written request, such Party’s Confidential Information that is otherwise required to be returned to it shall be destroyed by
the receiving Party and such destruction shall be certified in writing by an authorized officer of the receiving Party. The return and/or destruction of such Confidential Information as provided above shall not relieve the receiving Party of its
other obligations under Section 9. 
 (d) Assignment of Regulatory Approvals. Prometheus shall have
no further right to file for or obtain Regulatory Approvals for the Product after the effective date of any expiration or termination of this Agreement. As of the Regulatory Approval Reversion Date, all Regulatory Approvals shall be and hereby are
transferred and assigned to Novartis. In furtherance thereof, promptly, but in no event later than five (5) Business Days after the Regulatory Approval Reversion Date, Prometheus shall deliver to Novartis, electronically and in hard copy,
executed letters (in a form pre-approved by Novartis) addressed to all applicable Regulatory Authorities in the jurisdictions in the 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the
omitted portions. 
  

 77 

 
Territory where Prometheus or its Affiliates has applied for, holds or has obtained Regulatory Approvals for the Products as of the effective date of expiration or termination, instructing the
applicable Regulatory Authorities to transfer of all such Regulatory Approvals from Prometheus or its Affiliates to Novartis. Prometheus shall execute, acknowledge and deliver such further instruments, and shall use Commercially Reasonable Efforts
to do all such other acts, necessary to effect the transfer of such Regulatory Approvals and all activities in connection therewith to Novartis, in each case at Novartis’ request. In the case of termination by Prometheus pursuant to
Section 10.2 or 10.3, Novartis shall reimburse Prometheus for reasonable costs incurred in connection therewith. For purposes hereof, the “Regulatory Approval Reversion Date” shall mean, as applicable: (i) the expiration
date of this Agreement, (ii) in the case of termination of this Agreement by Novartis pursuant to Section 10.2 or 10.3 or by Prometheus pursuant to Section 10.6, the date of such termination, or (iii) in the case of termination
of this Agreement for any other reason, the expiration date of the Sell-Off Period. 
 (e) Transition of
Products Following Termination or Expiration. Upon expiration or termination of this Agreement, the Parties shall reasonably cooperate in good faith to facilitate an orderly transition of responsibility for the Products back to Novartis.
Prometheus shall deliver to Novartis copies of such documents, records and information as are reasonably necessary to achieve such transition and to enable Novartis to assume complete internal responsibility for the Commercialization of the Products
in the same or similar manner as the transition services were provided by Novartis to Prometheus under the Transition Services Agreement and for reasonable compensation to be agreed upon by the Parties. Novartis shall be entitled to continue to
manufacture and sell, at its sole cost and risk, Products in packaging that bears Prometheus’ name and bearing Prometheus’ NDC until Novartis has alternative packaging available to it, which Novartis shall use best efforts to obtain as
soon as practicable and in no event later than ninety (90) days after the date of expiration or termination of this Agreement. Novartis shall indemnify Prometheus in connection with such manufacture and sale of Product bearing Prometheus’
name and/or a Prometheus NDC pursuant to Section 7.1. During the Term of this Agreement, Prometheus shall use Commercially Reasonable Efforts to procure and ensure the assignability to Novartis of all purchase orders, contracts, agreements, and
governmental programs with respect to the Products which Prometheus enters into in connection with Prometheus’ performance of its obligations under this Agreement which Novartis could be reasonably expected to assume in order to continue the
Development or to Commercialize the Product upon the expiration or earlier termination of this Agreement. Novartis, or any Person designated by Novartis, shall have the right, but not the obligation, to assume upon termination or expiration of this
Agreement any or all of such purchase orders, contracts, agreements, governmental programs and other arrangements with respect to the Products entered into by Prometheus that are still in force at the time of such expiration or termination
(“Transition Contracts”). Upon expiration or termination, Prometheus shall provide to Novartis a copy of all Transition Contracts and shall assign to Novartis, or any Person designated by Novartis, in a manner reasonably acceptable
to Novartis, each Transition Contract designated by Novartis; provided, however, that Novartis shall neither have nor assume any liability with respect to Prometheus’ obligations and liabilities arising prior to the effective date
of such assignment. In addition, if requested by Novartis and solely to the

  

 78 

 
extent permitted by Applicable Laws, Prometheus shall provide Novartis with [* * *] for the Products and Novartis and its Affiliates and Sublicensees shall be entitled to use such list and
contact information with regards to Prometheus Customers to continue the Development or to Commercialize the Products in the Territory upon the termination or expiration of this Agreement and thereafter. Notwithstanding anything contained in this
Section, Prometheus shall have no obligation to discuss, disclose or assign any Transition Contract to Novartis (and/or its designee) unless Prometheus has the right to do so and any such discussion, disclosure and/or assignment will be subject to
the terms and conditions of such Transition Contracts and Prometheus’ rights thereunder. 
 (f) [* * *]. For
the purposes hereof, “Catastrophic Breach Date” means: 
 (i) with respect to a Novartis
Catastrophic Breach covered by Section 10.2(b)(i), the [* * *] of the [* * *] ([* * *]) [* * *] grace period set forth in Section [* * *] for the applicable purchase order); 
 (ii) with respect to a Novartis Catastrophic Breach covered by Section 10.2(b)(ii)(A), the date that is the [* * *];

 (iii) with respect to a Novartis Catastrophic Breach covered by Sections 10.2(b)(ii)(B) or 10.2(b)(iii),
the [* * *]; 
 In the event this Agreement is [* * *] and the [* * *] Catastrophic Breach Date occurs within the [* * *] ([* * *]) years after
the Effective Date, then Prometheus shall be entitled to the following [* * *]: 
 (A) in the event that
Prometheus so terminates this Agreement and the applicable Catastrophic Breach Date occurs [* * *] of the Effective Date: [* * *] US dollars ($[* * *]); 
 (B) in the event that Prometheus so terminates this Agreement and the applicable Catastrophic Breach Date occurs
[* * *] of the Effective Date but prior to the second anniversary of the Effective Date: [* * *] US dollars ($[* * *]); and 
 (C) in the event that Prometheus so terminates this Agreement and the applicable Catastrophic Breach Date occurs [* * *] of the Effective Date but prior to the third anniversary of the Effective
Date: [* * *] US dollars ($[* * *]). 
 The Parties acknowledge and agree that, notwithstanding any other provision of this Agreement or the
Supply Agreement, with respect to any [* * *] pursuant to this Section 10.7(f), (w) [* * *], (x) damages resulting from the Novartis Catastrophic Event for which Prometheus has terminated the Agreement pursuant to Section 10.2(b)
[* * *], (y) [* * *]; and (z) notwithstanding any other provision of this Agreement, the payment of such amount by Novartis as set forth under this Section 10.7(f) shall serve [* * *], other than, if applicable, Novartis’
obligations to indemnify the Prometheus Indemnitees in connection with Third Party Claims pursuant to Section 7.1 and Product Liability Claims pursuant to Section 7.4. 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been
requested with respect to the omitted portions. 
  

 79 

 (g) Pricing. During (i) any notice period given by a terminating
Party pursuant to Section 10; and (ii) any transition period following the termination or expiration of this Agreement as provided under Section 10.7, Prometheus shall continue to price and discount the Products consistent with past
practice over the prior twelve (12) months. 
 (h) Accrued Rights and Obligations. Except as provided
in Section 10.7(f), expiration or termination of this Agreement will not relieve the Parties of any liability or obligation which accrued hereunder prior to the effective date of such termination, including any payment obligations, nor preclude
either Party from pursuing all rights and remedies it may have hereunder or at law or in equity with respect to any breach of this Agreement nor prejudice either Party’s right to obtain performance of any obligation. 
 10.8 Survival Upon Termination or Expiration. The following provisions will survive any expiration or termination of this Agreement
for the time period specified in such Sections, or if no such time period is specified, indefinitely: 
 (a)
Sections 1, 2.5(b)(ii) & (iii), 2.5(c), 5.7, 7.1-7.5, 8, 9.1-9.5, 10.7, 10.8, 10.9 and 11; and 
 (b) Section 1 for the sole purposes of interpreting the obligations and liabilities between the Parties surviving expiration or termination of this Agreement. 
 10.9 Irrevocable Power of Attorney. Prometheus hereby irrevocably appoints Novartis as its true and lawful attorney-in-fact, with
full power of substitution, to execute and deliver all such agreements, instruments, certificates and other documents, file any of the foregoing with applicable Regulatory Authorities, and take any and all other actions as are reasonably necessary
or appropriate, upon expiration or termination of this Agreement for any reason (other than termination by Prometheus pursuant to Sections 10.2, 10.3, 10.4 or 10.6) to effectuate the provisions of Section 10.7(d) and this Section 10.9,
including to submit the transfer letter set forth on Exhibit AA to the FDA. The power of attorney granted hereunder is coupled with an interest, and shall survive any Insolvency Event. 
 SECTION 11. 
 MISCELLANEOUS PROVISIONS

 11.1 Dispute Resolution. Subject to Section 11.13, in the event of any controversy, dispute or claim arising
out of, in connection with, or in relation to the interpretation, performance, or alleged breach of this Agreement (the “Dispute”), prior to instituting any Proceeding on account of such Dispute, the Parties shall attempt in good
faith to settle such Dispute first by negotiation and consultation between themselves, including referral of such Dispute to the Chief Executive Officer of Prometheus and the head of the Oncology division of Novartis or his/her designee. In the
event said executives are unable to resolve such

  

 80 

 
Dispute or agree upon a mechanism to resolve such Dispute within thirty (30) days of the first written request for dispute resolution under this Section 11.1 and provided that
the ultimate decision-making authority is not otherwise expressly provided for in this Agreement, then the Parties shall be free to pursue any available remedy, including commencing legal Proceedings. 
 11.2 Force Majeure. Any delays in performance by any Party under this Agreement, other than with respect to Novartis’ obligation
to grant the licenses hereunder and Prometheus’ obligations to make payments hereunder, shall not be considered a breach of this Agreement if and to the extent caused by occurrences beyond the reasonable control of the Party affected, including
but not limited to acts of God, embargoes, governmental restrictions, terrorism, fire, flood, explosion, earthquake, hurricanes, storms, tornadoes, riots, wars, civil disorder, labor disturbances, acts of terrorism or compliance with any order of
any Regulatory Authority acting within color of right. The Party suffering such occurrence shall notify the other Party as soon as practicable of such inability and of the period for which such inability is expected to continue, and any time for
performance hereunder shall be extended by the actual time of delay caused by the occurrence; provided, that the Party suffering such occurrence uses Commercially Reasonable Efforts to mitigate any damages incurred by the other Party and
shall use Commercially Reasonable Efforts to resume full performance of its obligations under this Agreement as soon as reasonably practicable. 
 11.3 Standard Forms. In all communications, Novartis and Prometheus may employ their standard forms, but nothing in those forms shall be construed to modify or amend the terms and conditions of
this Agreement, and, in the case of any conflict herewith, the terms and conditions of this Agreement shall control. 
 11.4
Notices. In addition to any other specific procedures for notification required herein, all notices, demands, requests and other communications made hereunder shall be in writing and shall be given either by personal delivery, by nationally
recognized overnight courier (with charges prepaid), or by facsimile transmission (with telephone confirmation), and shall be deemed to have been given or made: (i) if personally delivered, on the day of such delivery; (ii) if sent by
overnight courier, on the day following the date deposited with such overnight courier service; or (iii) if by facsimile transmission, on the date transmitted to receiving facsimile machine with written confirmation of receipt, in each case
pending the designation of another address, addressed as follows: 
 If to Novartis: 
 Novartis Vaccines and Diagnostics, Inc. 
 350 Massachusetts Avenue 
 Cambridge, MA 02139 
 [* * *] 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the
omitted portions. 
  

 81 

 With a copy (which shall not constitute notice) to: 
 Novartis Vaccines and Diagnostics, Inc. 
 350 Massachusetts Avenue 
 Cambridge, MA 021139 
 [* * *] 
 and

 Novartis Pharmaceuticals Corporation 
 180 Park Avenue/Building 105 
 Florham Park, New Jersey 07932 
 [* * *] 
 If to
Prometheus: 
 Prometheus Laboratories Inc. 
 9410 Carroll Park Drive 
 San Diego, CA 92121 
 Attn: President 
 Facsimile: (858) 410-1945 
 With a copy (which shall not constitute notice) to: 
 Prometheus Laboratories Inc. 
 9410 Carroll Park Drive 
 San Diego, CA 92121 
 Attn: Legal Department 
 Facsimile: (858) 332-3393 
 11.5 Independent Contractors. In the exercise of its obligations and in
respect of its rights and entitlements hereunder or in respect hereof, Prometheus and Novartis are and shall in all respects be treated as independent contractors with respect to each other. Neither Party shall be deemed to be a co-venturer or
partner of the other. Neither Party is an employee or a legal representative of the other Party for any purpose. Neither Party shall have the authority to enter into any contracts in the name of or on behalf of the other Party. Except as otherwise
provided in this Agreement, each Party shall be solely responsible for the acts, conduct and expenses of its own employees, Affiliates, and agents and shall pay all of its own expenses imposed or otherwise incurred in connection with the obligations
of such Party under this Agreement. Neither Party shall incur any expense that is reimbursable by the other Party unless such expense has been previously approved by the other Party in writing or is otherwise provided for in this Agreement.

  
 *** Certain information on this page has been omitted and filed
separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 82 

 11.6 Assignment; Binding Effect. Neither this Agreement, nor any of the rights or
obligations of a Party may be directly or indirectly assigned, sold, delegated or otherwise disposed of without the prior written consent of the other Party; provided, however, that (i) Novartis may assign this Agreement to an
Affiliate or to a successor to all or substantially all of its assets relating to the Product Intellectual Property or the Product, and (ii) Prometheus may assign this Agreement to an Affiliate or to a successor to all or substantially all of
its business to which this Agreement relates, provided that (x) the total revenue derived by Prometheus from the sales of the Products by Prometheus and its Affiliates and Sublicensees in the immediately prior [* * *] ([* * *]) month
period represents no more than [* * *] percent ([* * *]%) of the aggregate revenues of such business to which this Agreement relates for the immediately prior [* * *] month period, each as determined in accordance with Prometheus’ Accounting
Standards as consistently applied and (y) in no event may Prometheus assign this Agreement to any Person who itself, or through its Affiliates or licensees, is Commercializing a Competitive Product. Notwithstanding the foregoing, with respect
to Product Intellectual Property licensed to Novartis pursuant to any Upstream License Agreement and sublicensed to Prometheus hereunder, such sublicense shall not be assignable by Prometheus to the extent such assignment is not permitted by the
applicable Upstream License Agreement. Any assignment or transfer of rights in breach of this Section 11.6 shall be null and void. 
 11.7 Amendment. Any amendment, modification or supplement of or to any provision of this Agreement, including the Exhibits hereto, shall be effective only in a writing and signed by a duly
authorized officer of suitable title of all Parties hereto. The Parties hereto waive the right to amend the provisions of this Section 11.7 orally. 
 11.8 Severability. If and to the extent that any court of competent jurisdiction holds any provision (or any part thereof) of this Agreement to be invalid or unenforceable, such holding shall in no
way affect the validity or enforceability of the remainder of this Agreement, and the invalid or unenforceable provision shall be fully severed from this Agreement and there shall automatically be added in lieu thereof a provision as similar in
terms and intent to such severed provision as may be legal, valid and enforceable. 
 11.9 Waiver. Any failure of
Prometheus or Novartis to comply with any obligation, covenant, agreement or condition herein contained may be expressly waived, in writing only, by the other Party hereto and such waiver shall be effective only in the specific instance and for the
specific purpose for which made or given. 
 11.10 Drafting Ambiguities. Each Party to this Agreement and its counsel
have reviewed and revised this Agreement. The rule of construction to the effect that any ambiguities are to be resolved against the drafting Party shall not be employed in the interpretation of this Agreement or any amendment or Schedule to this
Agreement. 
 11.11 Headings. The headings of the Sections of this Agreement are for reference purposes only, are not
part of this Agreement and shall not in any way affect the meaning or interpretation of this Agreement. 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 83 

 11.12 Exhibits. All Exhibits delivered pursuant to this Agreement shall be deemed
part of this Agreement and incorporated herein by reference, as if fully set forth herein. All provisions contained in any Exhibit delivered by or on behalf of the Parties hereto, or in connection with the transactions contemplated hereby, are an
integral part of this Agreement. 
 11.13 Injunctive Relief. Each of the Parties agrees that if certain material
obligations under this Agreement are not performed in accordance with their specific terms or are otherwise breached, (a) severe and irreparable damage would occur, (b) no adequate remedy at law would exist, and (c) damages would be
difficult to determine. Each of the Parties agrees that, in such case, the injured Party shall be authorized and entitled to obtain from any court of competent jurisdiction injunctive relief, whether preliminary or permanent, as well as any other
relief permitted by Applicable Law, and the breaching Party shall waive any requirement that such Party post bond as a condition for obtaining any such relief. 
 11.14 Extension to Novartis Affiliates. Novartis shall have the right to extend the rights granted to Novartis in this Agreement or transfer its obligations under this Agreement to, or have its
obligations or responsibilities under this Agreement performed by, one or more of its Affiliates. All applicable terms and conditions of this Agreement shall apply to any such Affiliate to which this Agreement has been extended or transferred to the
same extent as such terms and conditions apply to Novartis. 
 11.15 Governing Law. This Agreement (including any claim
or controversy arising out of or relating to this Agreement) shall be governed by the law of the State of New Jersey without regard to conflict of law principles that would result in the application of any Applicable Law other than the laws of the
State of New Jersey. 
 11.16 Applicability of Section 365(n) of the Bankruptcy Code. In the event either Party
becomes a debtor under Title 11 of the U.S. Code, this Agreement shall be deemed to be, for purposes of Section 365(n) of Title 11, a license to “Intellectual Property” as defined therein and the other Party and its Affiliates, and
each of their successors and assigns as licensees shall have the rights and elections as specified in Section 365(n) of Title 11 of the U.S. Code. Without limiting the foregoing, upon termination of this Agreement by a trustee or executor of
either Party which has rejected this Agreement pursuant to any non-contractual rights afforded to it by applicable bankruptcy law and/or a U.S. or foreign bankruptcy court or other tribunal of competent jurisdiction, all rights and licenses herein
granted to the other Party shall nonetheless continue in full force and effect in accordance with the terms of this Agreement. 
 11.17 Consents to Assignment. Notwithstanding anything to the contrary contained in this Agreement, to the extent that the transfer or assignment by Novartis of an agreement with a Third Party (each a “Third Party
Agreement”) as set forth herein would require any Third Party authorizations, approvals, consents or waivers (collectively, the “Consent”), and such Consent shall not have been obtained prior to or as of the effective date
of assignment, then after the Effective Date, the Parties shall cooperate to obtain promptly such Consent. Pending receipt of any such Consent, the Parties shall use their Commercially Reasonable Efforts to implement an alternative arrangement to
permit Prometheus to receive substantially similar rights and for Prometheus to assume substantially similar obligations under any such Third Party Agreement as if such impediment to assignment or transfer did not exist, and Novartis shall, if

  

 84 

 
directed by Prometheus and on Prometheus’ behalf, exercise its right, if any, [* * *], except that Novartis shall not be obligated to [* * *] if Novartis agrees to bear
any costs and expenses associated with the [* * *]. 
 11.18 Further Actions. Each Party agrees to execute,
acknowledge and deliver such further instruments, and to do all such other commercially reasonable acts, as may be necessary or appropriate in order to carry out the purposes and intent of this Agreement. 
 11.19 Counterparts. This Agreement may be executed in one or more counterparts, each of which shall be deemed to be an original but
all of which together shall constitute one and the same instrument. 
 11.20 Entire Understanding. This Agreement, the
Exhibits attached hereto, the Novartis Disclosure Schedule, the Supply Agreement, the QA Agreement (as defined in the Supply Agreement), the Pharmacovigilance Agreement and any other agreement expressly identified herein, represent the entire
understanding and agreement between the Parties hereto with respect to the subject matter hereof, and supersede all prior and contemporaneous agreements and understandings between the Parties with respect to such subject matter, which are hereby
expressly terminated. In the event of any conflict between the terms of this Agreement and the terms of any Exhibit, the terms of this Agreement shall control and prevail. 
 [The remainder of this page is intentionally left blank.] 
  

 85 

 [Signature Page to Distribution and Promotion Agreement] 
 IN WITNESS WHEREOF, the Parties have caused this Distribution Agreement to be executed by their duly authorized representatives as of the
Effective Date. 
  

									
	NOVARTIS VACCINES AND DIAGNOSTICS, INC.	 		 	PROMETHEUS LABORATORIES INC.
					
	By:	 	 /s/ Maureen A. Rogers
	 		 	By:	 	 /s/ Joseph M. Limber

	Name:	 	 Maureen A. Rogers
	 		 	Name:	 	 Joseph M. Limber

	Title:	 	 Vice President
	 		 	Title:	 	 President and CEO

 EXHIBIT A 
 PRODUCTS 
 Human recombinant Interleukin-2 (rhIL-2) in a lyophilized
cake in vials containing 18 MIU each, as Commercialized by Novartis as of the Effective Date in the Territory. 
  

 A-1 

 EXHIBIT B 
 M&S EXPENSES 
  

					
	 Category
	  	 Activity
	  	 Description

	PROMOTIONAL	  		  	PROMOTIONAL
	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]
	  	[* * *]	  	[* * *]
	  	[* * *]	  	[* * *]
	  	[* * *]	  	[* * *]
	  	[* * *]	  	[* * *]
	  	[* * *]	  	
	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]
	  	[* * *]	  	
	  	[* * *]	  	
	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]
	  	[* * *]	  	[* * *]
	  	[* * *]	  	[* * *]
	  	[* * *]	  	[* * *]
	  	[* * *]	  	
	  	[* * *]	  	[* * *]
	  	[* * *]	  	
	  	[* * *]	  	
	  		  	
		  	[* * *]	  	
	[* * *]	  	[* * *]	  	[* * *]
	  	[* * *]	  	
	  	[* * *]	  	[* * *]
	  	[* * *]	  	[* * *]
	  	[* * *]	  	
	  	[* * *]	  	[* * *]
	  	[* * *]	  	[* * *]
	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]
	  	[* * *]	  	[* * *]
	  	[* * *]	  	
	  	[* * *]	  	[* * *]
	  	[* * *]	  	[* * *]
	  	[* * *]	  	
	[* * *]	  		  	[* * *]
	[* * *]	  	[* * *]	  	
	  	[* * *]	  	[* * *]
	  	[* * *]	  	
	  	[* * *]	  	[* * *]
	  	[* * *]	  	[* * *]
	  	[* * *]	  	[* * *]
	  	[* * *]	  	[* * *]

  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 B-1 

 EXHIBIT C 
 PRODUCT MARKS 
  

											
	 Trademark
	 	 Country
	 	 Registered Owner
	 	 Reg. No.
	 	 Renew
Date
	 	 Current
Status

	PROLEUKIN	 	Canada	 	Novartis Vaccines and Diagnostics, Inc.	 	330083	 	17-Jul-2017	 	Registered
	PROLEUKIN	 	US	 	Novartis Vaccines and Diagnostics, Inc.	 	1,369,770	 	12-Nov-2015	 	Registered
	PROLEUKIN & Swirl Design	 	US	 	Novartis Vaccines and Diagnostics, Inc.	 	2,857,698	 	29-Jun-2014	 	Registered

  

 C-1 

 EXHIBIT D 
 PRODUCT PATENT RIGHTS 
 [* * *] 
  
 *** Certain information on this page has been omitted and filed separately with
the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 D-1 

 [* * *] 
  

													
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]

 [* * *] 
  

													
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]

  
 *** Certain information
on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 D-2 

													
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  		  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]

 [* * *] 
  

													
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]

  
 *** Certain information
on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 D-3 

													
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]

 [* * *] 
  

													
	 [* * *]
	  	 Ctry
	  	 Filing
 Number
	  	 Publication
	  	 Grant
 Number
	  	 Grant
	  	 [* * *]

	[* * *]	  	AU	  	35756/84	  	18 Jan 1990	  	592527	  	04 Jun 1998	  	[* * *]
	[* * *]	  	AU	  	35756-84	  		  		  		  	[* * *]

  
 *** Certain information
on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 D-4 

													
	 [* * *]
	  	 Ctry
	  	 Filing
 Number
	  	 Publication
	  	 Grant
 Number
	  	 Grant
	  	 [* * *]

	[* * *]	  	CA	  	468658	  		  		  		  	[* * *]
	[* * *]	  	CA	  	468658	  		  		  		  	[* * *]
	[* * *]	  	DK	  	5607-84	  		  		  		  	[* * *]
	[* * *]	  	DK	  	5607-84	  	27 Nov 1984	  	164174	  	05 Oct 1992	  	[* * *]
	[* * *]	  	EP	  	84308153.0	  	19 Jun 1985	  		  		  	[* * *]
	[* * *]	  	EP	  	91105904.6	  		  		  		  	[* * *]
	[* * *]	  	EP	  	96201538.4	  	02 Jan 1997	  		  		  	[* * *]
	[* * *]	  	EP	  	96201538.4	  		  		  		  	[* * *]
	[* * *]	  	GR	  	81040-A	  		  		  		  	[* * *]
	[* * *]	  	GR	  	81040-A	  	26 Nov 1984	  	81040	  	26 Nov 1984	  	[* * *]
	[* * *]	  	IE	  	3032-84	  		  		  		  	[* * *]
	[* * *]	  	IE	  	1984/3032	  		  		  		  	[* * *]
	[* * *]	  	JP	  	225079/83	  		  		  		  	[* * *]
	[* * *]	  	MY	  	PI87002002	  	05 May 1994	  	MY103892A	  	30 Oct 1993	  	[* * *]
	[* * *]	  	MY	  	PI8702002	  		  	MY103892A	  	30 Oct 1993	  	[* * *]
	[* * *]	  	NZ	  	210352	  	02 May 1989	  	210352	  	02 May 1989	  	[* * *]
	[* * *]	  	NZ	  	210352	  		  	210352	  	02 May 1989	  	[* * *]
	[* * *]	  	PH	  	31488	  	28 Apr 2000	  	1-1984-31488	  	28 Apr 2000	  	[* * *]
	[* * *]	  	PH	  	31488	  		  	1-1984-31488	  	28 Apr 2000	  	[* * *]
	[* * *]	  	SG	  	9604789-9	  	20 Feb 1998	  	46452	  	20 Feb 2001	  	[* * *]
	[* * *]	  	SG	  	9604789-9	  		  		  		  	[* * *]
	[* * *]	  	US	  	07/298228	  		  		  		  	[* * *]
	[* * *]	  	US	  	07/582778	  		  		  		  	[* * *]
	[* * *]	  	US	  	07/942358	  	07 Nov 1995	  	5464939	  	07 Nov 1995	  	[* * *]
	[* * *]	  	US	  	06/674556	  		  		  		  	[* * *]
	[* * *]	  	ZA	  	84-9221	  	26 Nov 1984	  	84-9221	  	26 Nov 1984	  	[* * *]
	[* * *]	  	ZA	  	84-9221	  		  		  		  	[* * *]

 [* * *] 
  

													
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]

  
 *** Certain information
on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 D-5 

													
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]

 [* * *] 
  

													
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]

 [* * *] 
  

													
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  		  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]

  
 *** Certain information
on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 D-6 

													
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]

 [* * *] 
  

													
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]

 [* * *] 
  

													
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]

 [* * *] 
  

													
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  		  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]

  
 *** Certain information
on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 D-7 

													
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]

 [* * *] 
  

													
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]

 [* * *] 
  

													
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]

  
 *** Certain information
on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 D-8 

													
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]

 [***] 
  

													
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  		  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  		  		  		  	[* * *]
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  		  	[* * *]

  
 *** Certain information
on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 D-9 

 EXHIBIT E 
 PRODUCT TRADE DRESS 
  

 E-1 

 

 
 NDC 0078-0495-61 Rx only 
 Aldesleukin 
 Proleukin® for Injection 
 22 million IU 1.3 mg 
 SINGLE USE VIAL 
 FOR IV USE ONLY 
 REFRIGERATE NO PRESERVATIVE

 NOVARTIS 
 See package insert for usual dose, reconstitution directions, and complete prescribing information. Store in refrigerator 2°-8°C (36°-46°F). PROTECT FROM LIGHT. Store in
carton until time of use. Mfd. by: Novartis Vaccines and Diagnostics, Inc., Emeryville, CA 94608 ©Novartis US Lic. No. 1751 
 RSS Bar Code Area 
 Lot # 
 Exp. 
 5000916 
 E-2 
  

 E-2 

 

 
 UPC Bar Code Area 0078-0495-61 
 NDC 0078-0495-61 
 Aldesleukin Proleukin® 
 For Injection

 22 million IU 1.3 mg 
 SINGLE-USE VIAL 
 FOR IV USE ONLY 
 REFRIGERATE 
 Rx only 
 Novartis 
 Lot # 
 Exp. 
 5000917 
 Before and after reconstitution, store in a refrigerator at 2°-8°C (36°-46°F). PROTECT FROM LIGHT. Store in
carton until time of use. Use within 48 hours after reconstitution. 
 RECONSTITUTE WITH 1.2 ML STERILE WATER FOR

 INJECTION, USP. WHEN RECONSTITUTED, EACH ML CONTAINS 18 MILLION IU (1.1 MG) PROLEUKIN, 50 mg mannitol, 0.18 mg
sodium dodecyl sulfate buffered with 0.17 mg monobasic sodium phosphate and 0.89 mg dibasic sodium phosphate. Swirl gently. 
 DO NOT SHAKE. Contains no preservative. Discard unused portion. 
 See package insert for usual
dose and complete prescribing information. 
 Aldesleukin Proleukin® 
 For Injection 
 22 million IU 3.1 mg 
 See bottom panel for
Lot No. and Exp. Date. 
 PROLEUKIN should be administered only to well-informed patients in a hospital setting
under the supervision of a qualified physician experienced in the use of cancer therapeutic agents. 
 Professional assistance is available by calling toll-free: 
 1-888-NOW-NOVA 
 (1-888-669-6682). 
 Manufactured by: Novartis Vaccines and Diagnostics, Inc. Emeryville, CA 94608 Distributed by: 
 Novartis Pharmaceuticals Corp. East Hanover, NJ 07936 US Lic No. 1751 US Patents: RE33653; 4,530,787; 4,569,790; 4,604,377; 4,959,314; 4,853,332; 4,748,234; 4,572,798; 5,464,939
©Novartis 
 E-3 
  

 E-3 

 

 
 NOVARTIS 
 PROLEUKIN® (aldesleukin) 
 Lyophilized powder for solution for intravenous use 
 Rx Only 
 WARNINGS 
 Therapy with PROLEUKIN® (aldesleukin) should be restricted to patients with normal cardiac and pulmonary functions as defined by thallium stress testing and formal pulmonary function
testing. Extreme caution should be used in patients with a normal thallium stress test and a normal pulmonary function test who have a history of cardiac or pulmonary disease. 
 PROLEUKIN should be administered in a hospital setting under the supervision of a qualified physician experienced in the use
of anticancer agents. An intensive care facility and specialists skilled in cardiopulmonary or intensive care medicine must be available. 
 PROLEUKIN administration has been associated with capillary leak syndrome (CLS) which is characterized by a loss of vascular tone and extravasation of plasma proteins and fluid into the
extravascular space. CLS results in hypotension and reduced organ perfusion which may be severe and can result in death. CLS may be associated with cardiac arrhythmias (supraventricular and ventricular), angina, myocardial infarction, respiratory
insufficiency requiring intubation, gastrointestinal bleeding or infarction, renal insufficiency, edema, and mental status changes. 
 PROLEUKIN treatment is associated with impaired neutrophil function (reduced chemotaxis) and with an increased risk of disseminated infection, including sepsis and bacterial endocarditis. Consequently, preexisting bacterial
infections should be adequately treated prior to initiation of PROLEUKIN therapy. Patients with indwelling central lines are particularly at risk for infection with gram positive microorganisms. Antibiotic prophylaxis with oxacillin, nafcillin,
ciprofloxacin, or vancomycin has been associated with a reduced incidence of staphylococcal infections. 
 PROLEUKIN administration should be withheld in patients developing moderate to severe lethargy or somnolence; continued administration may result in coma. 
 E-4 
  

 E-4 

 

 
 DESCRIPTION 
 PROLEUKIN® (aldesleukin), a human recombinant interleukin-2 product, is a highly purified protein with a molecular weight
of approximately 15,300 daltons. The chemical name is des-alanyl-1, serine-125 human interleukin-2. PROLEUKIN, a lymphokine, is produced by recombinant DNA technology using a genetically engineered E. coli strain containing an analog of the human
interleukin-2 gene. Genetic engineering techniques were used to modify the human IL-2 gene, and the resulting expression clone encodes a modified human interleukin-2. This recombinant form differs from native interleukin-2 in the following ways: a)
PROLEUKIN is not glycosylated because it is derived from E. coli; b) the molecule has no N-terminal alanine; the codon for this amino acid was deleted during the genetic engineering procedure; c) the molecule has serine substituted for cysteine at
amino acid position 125; this was accomplished by site specific manipulation during the genetic engineering procedure; and d) the aggregation state of PROLEUKIN is likely to be different from that of native interleukin-2. 
 The in vitro biological activities of the native nonrecombinant molecule have been reproduced with PROLEUKIN.1,2 

PROLEUKIN is supplied as a sterile, white to off-white, lyophilized cake in single-use vials intended for intravenous (IV)
administration. When reconstituted with 1.2 mL Sterile Water for Injection, USP, each mL contains 18 million IU (1.1 mg) PROLEUKIN, 50 mg mannitol, and 0.18 mg sodium dodecyl sulfate, buffered with approximately 0.17 mg monobasic and 0.89 mg
dibasic sodium phosphate to a pH of 7.5 (range 7.2 to 7.8). The manufacturing process for PROLEUKIN involves fermentation in a defined medium containing tetracycline hydrochloride. The presence of the antibiotic is not detectable in the final
product. PROLEUKIN contains no preservatives in the final product. 
 PROLEUKIN biological potency is determined
by a lymphocyte proliferation bioassay and is expressed in International Units (IU) as established by the World Health Organization 1st International Standard for Interleukin-2 (human). The relationship between potency and protein mass is as
follows: 
 18 million (18 x 106) IU PROLEUKIN = 1.1 mg protein 
 E-5 
  

 E-5 

 

 
 CLINICAL PHARMACOLOGY 
 PROLEUKIN® (aldesleukin) has been shown to possess the biological activities of human native interleukin-2.1,2 In vitro
studies performed on human cell lines demonstrate the immunoregulatory properties of PROLEUKIN, including: a) enhancement of lymphocyte mitogenesis and stimulation of long-term growth of human interleukin-2 dependent cell lines; b) enhancement of
lymphocyte cytotoxicity; c) induction of killer cell (lymphokine-activated (LAK) and natural (NK)) activity; and d) induction of interferon-gamma production. 
 The in vivo administration of PROLEUKIN in animals and humans produces multiple immunological effects in a dose dependent manner. These effects include activation of cellular immunity with
profound lymphocytosis, eosinophilia, and thrombocytopenia, and the production of cytokines including tumor necrosis factor, IL-1 and gamma interferon.3 In vivo experiments in murine tumor models have shown inhibition of tumor growth.4 The exact
mechanism by which PROLEUKIN mediates its antitumor activity in animals and humans is unknown. 
 Pharmacokinetics 
 PROLEUKIN exists as biologically active, non-covalently bound microaggregates
with an average size of 27 recombinant interleukin-2 molecules. The solubilizing agent, sodium dodecyl sulfate, may have an effect on the kinetic properties of this product. 
 The pharmacokinetic profile of PROLEUKIN is characterized by high plasma concentrations following a short IV infusion, rapid
distribution into the extravascular space and elimination from the body by metabolism in the kidneys with little or no bioactive protein excreted in the urine. Studies of IV PROLEUKIN in sheep and humans indicate that upon completion of infusion,
approximately 30% of the administered dose is detectable in plasma. This finding is consistent with studies in rats using radiolabeled PROLEUKIN, which demonstrate a rapid (<1 min) uptake of the majority of the label into the lungs, liver,
kidney, and spleen. 
 The serum half-life (T 1/2) curves of PROLEUKIN remaining in the plasma are derived from
studies done in 52 cancer patients following a 5-minute IV infusion. These patients were shown to have a distribution and elimination T 1/2 of 13 and 85 minutes, respectively. 
 Following the initial rapid organ distribution, the primary route of clearance of circulating PROLEUKIN is the kidney. In
humans and animals, PROLEUKIN is cleared from the circulation by both glomerular filtration and peritubular extraction in the kidney.5-8 This dual mechanism for delivery of PROLEUKIN to the proximal tubule may account for the preservation of
clearance in patients with rising serum creatinine values. Greater than 80% of the amount of PROLEUKIN distributed to plasma, cleared from the circulation and presented to the kidney is metabolized to 
 E-6 
  

 E-6 

 

 
 amino acids in the cells lining the proximal convoluted tubules. In humans, the
mean clearance rate in cancer patients is 268 mL/min. 
 The relatively rapid clearance of PROLEUKIN has led to
dosage schedules characterized by frequent, short infusions. Observed serum levels are proportional to the dose of PROLEUKIN. 
 CLINICAL STUDIES 
 Safety and efficacy were studied in a series of single and multicenter,
historically controlled studies enrolling a total of 525 patients with metastatic renal cell carcinoma or melanoma. Eligible patients had an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 and normal organ function as
determined by cardiac stress test, pulmonary function tests, and creatinine £1.5 mg/dL. Studies excluded patients with brain metastases, active infections, organ allografts and diseases requiring steroid
treatment. 
 The same treatment dose and schedule was employed in all studies demonstrating efficacy. PROLEUKIN
was given by 15 min IV infusion every 8 hours for up to 5 days (maximum of 14 doses). No treatment was given on days 6 to 14 and then dosing was repeated for up to 5 days on days 15 to 19 (maximum of 14 doses). These 2 cycles constituted 1 course of
therapy. Patients could receive a maximum of 28 doses during a course of therapy. In practice >90% of patients had doses withheld. Doses were withheld for specific toxicities (See “DOSAGE AND ADMINISTRATION” section, “Dose
Modifications” subsection and “ADVERSE REACTIONS” section). 
 Metastatic Renal Cell Cancer

 Two hundred fifty-five patients with metastatic renal cell cancer (metastatic RCC) were treated with single
agent PROLEUKIN in 7 clinical studies conducted at 21 institutions. Metastatic RCC patients received a median of 20 of 28 scheduled doses of PROLEUKIN. 
 In the renal cell cancer studies (n=255), objective response was seen in 37 (15%) patients, with 17 (7%) complete and 20 (8%) partial responders (See Table I). The 95% confidence
interval for objective response was 11% to 20%. Onset of tumor regression was observed as early as 4 weeks after completion of the first course of treatment, and in some cases, tumor regression continued for up to 12 months after the start of
treatment. Responses were observed in both lung and non-lung sites (e.g., liver, lymph node, renal bed occurrences, soft tissue). Responses were also observed in patients with individual bulky lesions and high tumor burden. 
 E-7 
  

 E-7 

 

 
 TABLE 1: PROLEUKIN CLINICAL RESPONSE DATA 
 Metastatic RCC 
 CR’s 
 PR’s 
 PR’s + CR’s 
 Number of Responding Patients (response rate) 
 17
(7%) 
 20 (8%) 
 37 (15%) 
 Median Response Duration in Months
(range) 
 80+* (7 to 131+) 
 20 (3 to 126+) 
 54 (3 to 131+) 
 (+) sign means ongoing 
 * Median duration not yet observed; a conservative value is presented which represents the minimum median duration of response. 
 Lack of efficacy with low dose PROLEUKIN regimens 
 Sixty-five patients with metastatic renal cell cancer were enrolled in a single center, open label, non-randomized trial that
sequentially evaluated the safety and antitumor activity of two low dose PROLEUKIN regimens. The regimens administered 18 x 106 IU PROLEUKIN as a single subcutaneous injection, daily for 5 days during week 1; PROLEUKIN was then administered at 9 x
106 IU days 1-2 and 18 x 106 IU days 3-5, weekly for an additional 3 weeks (n=40) followed by a 2 week rest or 5 weeks (n=25) followed by a 3 week rest, for a maximum of 3 or 2 treatment cycles, respectively. 
 These low dose regimens yielded substantially lower and less durable responses than those observed with the approved regimen.
Based on the level of activity, these low dose regimens are not effective. 
 Metastatic Melanoma 
 Two hundred seventy patients with metastatic melanoma were treated with single agent PROLEUKIN in 8 clinical studies
conducted at 22 institutions. Metastatic melanoma patients received a median of 18 of 28 scheduled doses of PROLEUKIN during the first course of therapy. In the metastatic melanoma studies (n=270), objective response was seen in 43
(16%) patients, with 17 (6%) complete and 26 (10%) partial responders (See Table II). The 95% confidence interval for objective response was 12% to 21%. Responses in metastatic melanoma patients were observed in both visceral and
non-visceral sites (e.g., lung, liver, lymph node, soft tissue, adrenal, subcutaneous). Responses were also observed in patients with individual bulky lesions and large cumulative tumor burden. 
 E-8 
  

 E-8 

 

 
 TABLE 2: PROLEUKIN CLINICAL RESPONSE DATA 
 Metastatic Melanoma 
 CR’s 
 PR’s 
 PR’s + CR’s 
 Number of Responding Patients (response rate) 
 17
(6%) 
 26 (10%) 
 43 (16%) 
 Median Response Duration in Months
(range) 
 59+* (3 to 122+) 
 6 (1 to 111+) 
 9 (1 to 122+) 
 (+) sign means ongoing 
 * Median duration not yet observed; a conservative value is presented which represents the minimum median duration of response. 
 INDICATIONS AND USAGE 
 PROLEUKIN® (aldesleukin) is indicated for the treatment of adults with metastatic renal cell carcinoma (metastatic RCC). 
 PROLEUKIN is indicated for the treatment of adults with metastatic melanoma. 
 Careful patient selection is mandatory prior to the administration of PROLEUKIN. See “CONTRAINDICATIONS”,
“WARNINGS” and “PRECAUTIONS” sections regarding patient screening, including recommended cardiac and pulmonary function tests and laboratory tests. 
 Evaluation of clinical studies to date reveals that patients with more favorable ECOG performance status (ECOG PS 0) at treatment initiation respond better to PROLEUKIN, with a higher
response rate and lower toxicity (See “CLINICAL PHARMACOLOGY” section, “Clinical Experience” subsection and “ADVERSE REACTIONS” section). Therefore, selection of patients for treatment should include assessment of
performance status. 
 Experience in patients with ECOG PS >1 is extremely limited. CONTRAINDICATIONS

 PROLEUKIN® (aldesleukin) is contraindicated in patients with a known history of hypersensitivity to
interleukin-2 or any component of the PROLEUKIN formulation. PROLEUKIN is contraindicated in patients with an abnormal thallium stress test or abnormal pulmonary function tests and those with organ allografts. Retreatment with PROLEUKIN is
contraindicated in patients who have experienced the following drug-related toxicities while receiving art earlier course of therapy: 
 Sustained ventricular tachycardia (35 beats) 
 Cardiac arrhythmias not controlled or unresponsive to management 
 Chest pain with ECG changes,
consistent with angina or myocardial infarction 
 Cardiac tamponade 
 Intubation for >72 hours 
 Renal failure requiring dialysis >72 hours 
 E-9

  

 E-9 

 

 
 Coma or toxic psychosis lasting >48 hours 
 Repetitive or difficult to control seizures 
 Bowel ischemia/perforation 
 GI bleeding requiring
surgery 
 WARNINGS 
 See boxed “WARNINGS” 
 Because of the
severe adverse events which generally accompany PROLEUKIN® (aldesleukin) therapy at the recommended dosages, thorough clinical evaluation should be performed to identify patients with significant cardiac, pulmonary, renal, hepatic, or CNS
impairment in whom PROLEUKIN is contraindicated. Patients with normal cardiovascular, pulmonary, hepatic, and CNS function may experience serious, life threatening or fatal adverse events. Adverse events are frequent, often serious, and sometimes
fatal. 
 Should adverse events, which require dose modification occur, dosage should be withheld rather than
reduced (See “DOSAGE AND ADMINISTRATION” section, “Dose Modifications” subsection). 
 PROLEUKIN has been associated with exacerbation of pre-existing or initial presentation of autoimmune disease and inflammatory disorders. Exacerbation of Crohn’s disease, scleroderma, thyroiditis, inflammatory arthritis,
diabetes mellitus, oculo-bulbar myasthenia gravis, crescentic IgA glomerulonephritis, cholecystitis, cerebral vasculitis, Stevens-Johnson syndrome and bullous pemphigoid, has been reported following treatment with IL-2. 
 All patients should have thorough evaluation and treatment of CNS metastases and have a negative scan prior to receiving
PROLEUKIN therapy. New neurologic signs, symptoms, and anatomic lesions following PROLEUKIN therapy have been reported in patients without evidence of CNS metastases. Clinical manifestations included changes in mental status, speech difficulties,
cortical blindness, limb or gait ataxia, hallucinations, agitation, obtundation, and coma. Radiological findings included multiple and, less commonly, single cortical lesions on MRI and evidence of demyelination. Neurologic signs and symptoms
associated with PROLEUKIN therapy usually improve after discontinuation of PROLEUKIN therapy; however, there are reports of permanent neurologic defects. One case of possible cerebral vasculitis, responsive to dexamethasone, has been reported. In
patients with known seizure disorders, extreme caution should be exercised as PROLEUKIN may cause seizures. 
 PRECAUTIONS 
 General 
 Patients should have normal cardiac, pulmonary, hepatic, and CNS function at the start of therapy. (See
“PRECAUTIONS” section, “Laboratory Tests” subsection). Capillary leak syndrome (CLS) begins immediately after PROLEUKIN® 
 E-10 
  

 E-10 

 

 
 (aldesleukin) treatment starts and is marked by increased capillary permeability
to protein and fluids and reduced vascular tone. In most patients, this results in a concomitant drop in mean arterial blood pressure within 2 to 12 hours after the start of treatment. With continued therapy, clinically significant hypotension
(defined as systolic blood pressure below 90 mm Hg or a 20 mm Hg drop from baseline systolic pressure) and hypoperfusion will occur. In addition, extravasation of protein and fluids into the extravascular space will lead to the formation of edema
and creation of new effusions. 
 Medical management of CLS begins with careful monitoring of the patient’s
fluid and organ perfusion status. This is achieved by frequent determination of blood pressure and pulse, and by monitoring organ function, which includes assessment of mental status and urine output. Hypovolemia is assessed by catheterization and
central pressure monitoring. 
 Flexibility in fluid and pressor management is essential for maintaining organ
perfusion and blood pressure. Consequently, extreme caution should be used in treating patients with fixed requirements for large volumes of fluid (e.g., patients with hypercalcemia). Administration of IV fluids, either colloids or crystalloids is
recommended for treatment of hypovolemia. Correction of hypovolemia may require large volumes of IV fluids but caution is required because unrestrained fluid administration may exacerbate problems associated with edema formation or effusions. With
extravascular fluid accumulation, edema is common and ascites, pleural or pericardial effusions may develop. Management of these events depends on a careful balancing of the effects of fluid shifts so that neither the consequences of hypovolemia
(e.g., impaired organ perfusion) nor the consequences of fluid accumulations (e.g., pulmonary edema) exceed the patient’s tolerance. 
 Clinical experience has shown that early administration of dopamine (1 to 5 μg/kg/min) to patients manifesting capillary leak syndrome, before the onset of hypotension, can help to
maintain organ perfusion particularly to the kidney and thus preserve urine output. Weight and urine output should be carefully monitored. If organ perfusion and blood pressure are not sustained by dopamine therapy, clinical investigators have
increased the dose of dopamine to 6 to 10 μg/kg/min or have added phenylephrine hydrochloride (1 to 5 μg/kg/min) to low dose dopamine (See “ADVERSE REACTIONS” section). Prolonged use of pressors, either in combination or as
individual agents, at relatively high doses, may be associated with cardiac rhythm disturbances. If there has been excessive weight gain or edema formation, particularly if associated with shortness of breath from pulmonary congestion, use of
diuretics, once blood pressure has normalized, has been shown to hasten recovery. NOTE: Prior to the use of any product mentioned, the physician should refer to the package insert for the respective product. 
 PROLEUKIN® (aldesleukin) treatment should be withheld for failure to maintain organ perfusion as demonstrated by altered
mental status, reduced urine output, a fall in the systolic blood pressure below 90 mm Hg or onset of cardiac arrhythmias (See “DOSAGE AND ADMINISTRATION” section, “Dose Modifications” 
 E-11 
  

 E-11 

 

 
 subsection). Recovery from CLS begins soon after cessation of PROLEUKIN therapy.
Usually, within a few hours, the blood pressure rises, organ perfusion is restored and reabsorption of extravasated fluid and protein begins. 
 Kidney and liver function are impaired during PROLEUKIN treatment. Use of concomitant nephrotoxic or hepatotoxic medications may further increase toxicity to the kidney or liver.

 Mental status changes including irritability, confusion, or depression which occur while receiving PROLEUKIN
may be indicators of bacteremia or early bacterial sepsis, hypoperfusion, occult CNS malignancy, or direct PROLEUKIN-induced CNS toxicity. Alterations in mental status due solely to PROLEUKIN therapy may progress for several days before recovery
begins. Rarely, patients have sustained permanent neurologic deficits (See “PRECAUTIONS” section “Drug Interactions” subsection). 
 Exacerbation of pre-existing autoimmune disease or initial presentation of autoimmune and inflammatory disorders has been reported following PROLEUKIN alone or in combination with
interferon (See “PRECAUTIONS” section “Drug Interactions” subsection and “ADVERSE REACTIONS” section). Hypothyroidism, sometimes preceded by hyperthyroidism, has been reported following PROLEUKIN treatment. Some of
these patients required thyroid replacement therapy. Changes in thyroid function may be a manifestation of autoimmunity. Onset of symptomatic hyperglycemia and/or diabetes mellitus has been reported during PROLEUKIN therapy. 
 PROLEUKIN enhancement of cellular immune function may increase the risk of allograft rejection in transplant patients.

 Laboratory Tests 
 The following clinical evaluations are recommended for all patients, prior to beginning treatment and then daily during drug administration. 
 Standard hematologic tests-including CBC, differential and platelet counts 
 Blood chemistries-including electrolytes, renal and hepatic function tests 
 Chest x-rays 
 Serum creatinine should be £1.5 mg/dL prior to initiation of PROLEUKIN treatment. 
 All patients should have baseline pulmonary function tests with arterial blood gases. Adequate pulmonary function should be
documented (FEV1 >2 liters or 375% of predicted for height and age) prior to initiating therapy. 
 All patients should be screened with a stress thallium study. Normal ejection fraction and unimpaired wall motion should be documented. If a thallium stress test suggests minor wall motion
abnormalities further testing is suggested to exclude significant coronary artery disease. 
 E-12 
  

 E-12 

 

 
 Daily monitoring during therapy with PROLEUKIN should include vital signs
(temperature, pulse, blood pressure, and respiration rate), weight, and fluid intake and output. In a patient with a decreased systolic blood pressure, especially less than 90 mm Hg, constant cardiac rhythm monitoring should be conducted. If an
abnormal complex or rhythm is seen, an ECG should be performed. Vital signs in these hypotensive patients should be taken hourly. 
 During treatment, pulmonary function should be monitored on a regular basis by clinical examination, assessment of vital signs and pulse oximetry. Patients with dyspnea or clinical signs of respiratory impairment (tachypnea
or rales) should be further assessed with arterial blood gas determination. These tests are to be repeated as often as clinically indicated. 
 Cardiac function should be assessed daily by clinical examination and assessment of vital signs. Patients with signs or symptoms of chest pain, murmurs, gallops, irregular rhythm or
palpitations should be further assessed with an ECG examination and cardiac enzyme evaluation. Evidence of myocardial injury, including findings compatible with myocardial infarction or myocarditis, has been reported. Ventricular hypokinesia due to
myocarditis may be persistent for several months. If there is evidence of cardiac ischemia or congestive heart failure, PROLEUKIN therapy should be held, and a repeat thallium study should be done. 
 Drug Interactions 
 PROLEUKIN may affect central nervous function. Therefore, interactions could occur following concomitant administration of psychotropic drugs (e.g., narcotics, analgesics, antiemetics,
sedatives, tranquilizers). 
 Concurrent administration of drugs possessing nephrotoxic (e.g., aminoglycosides,
indomethacin), myelotoxic (e.g., cytotoxic chemotherapy), cardiotoxic (e.g., doxorubicin) or hepatotoxic (e.g., methotrexate, asparaginase) effects with PROLEUKIN may increase toxicity in these organ systems. The safety and efficacy of PROLEUKIN in
combination with any antineoplastic agents have not been established. 
 In addition, reduced kidney and liver
function secondary to PROLEUKIN treatment may delay elimination of concomitant medications and increase the risk of adverse events from those drugs. 
 Hypersensitivity reactions have been reported in patients receiving combination regimens containing sequential high dose PROLEUKIN and antineoplastic agents, specifically, dacarbazine,
cis-platinum, tamoxifen and interferon-alfa. These reactions consisted of erythema, pruritus, and hypotension and occurred within hours of administration of chemotherapy. These events required medical intervention in some patients. 
 Myocardial injury, including myocardial infarction, myocarditis, ventricular hypokinesia, and severe rhabdomyolysis appear to
be increased in patients receiving PROLEUKIN and interferon-alfa concurrently. 
 E-13 
  

 E-13 

 

 
 Exacerbation or the initial presentation of a number of autoimmune and
inflammatory disorders has been observed following concurrent use of interferon-alfa and PROLEUKIN, including crescentic IgA glomerulonephritis, oculo-bulbar myasthenia gravis, inflammatory arthritis, thyroiditis, bullous pemphigoid, and
Stevens-Johnson syndrome. 
 Although glucocorticoids have been shown to reduce PROLEUKIN-induced side effects
including fever, renal insufficiency, hyperbilirubinemia, confusion, and dyspnea, concomitant administration of these agents with PROLEUKIN may reduce the antitumor effectiveness of PROLEUKIN and thus should be avoided.12 
 Beta-blockers and other antihypertensives may potentiate the hypotension seen with PROLEUKIN. 
 Delayed Adverse Reactions to lodinated Contrast Media 
 A review of the literature revealed that 12.6% (range 11-28%) of 501 patients treated with various interleukin-2 containing
regimens who were subsequently administered radiographic iodinated contrast media experienced acute, atypical adverse reactions. The onset of symptoms usually occurred within hours (most commonly 1 to 4 hours) following the administration of
contrast media. These reactions include fever, chills, nausea, vomiting, pruritus, rash, diarrhea, hypotension, edema, and oliguria. Some clinicians have noted that these reactions resemble the immediate side effects caused by interleukin-2
administration, however the cause of contrast reactions after interleukin-2 therapy is unknown. Most events were reported to occur when contrast media was given within 4 weeks after the last dose of interleukin-2. These events were also reported to
occur when contrast media was given several months after interleukin-2 treatment.13 
 Carcinogenesis,
Mutagenesis, Impairment of Fertility 
 There have been no studies conducted assessing the carcinogenic or
mutagenic potential of PROLEUKIN. 
 There have been no studies conducted assessing the effect of PROLEUKIN on
fertility. It is recommended that this drug not be administered to fertile persons of either gender not practicing effective contraception. 
 Pregnancy 
 Pregnancy Category C. 
 PROLEUKIN has been shown to have embryolethal effects in rats when given in doses at 27 to 36 times the human dose (scaled by
body weight). Significant maternal toxicities were observed in pregnant rats administered PROLEUKIN by IV injection at doses 2.1 to 36 times higher than the human dose during critical period of organogenesis. No evidence of teratogenicity was
observed other than that attributed to maternal toxicity. There are no adequate well-controlled studies of 
 E-14 
  

 E-14 

 

 
 PROLEUKIN in pregnant women. PROLEUKIN should be used during pregnancy only if
the potential benefit justifies the potential risk to the fetus. 
 Nursing Mothers 
 It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the
potential for serious adverse reactions in nursing infants from PROLEUKIN, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 
 Pediatric Use 
 Safety and effectiveness in children under 18 years of age have not been established. 
 Geriatric Use 
 There were a small number of
patients aged 65 and over in clinical trials of PROLEUKIN; experience is limited to 27 patients, eight with metastatic melanoma and nineteen with metastatic renal cell carcinoma. The response rates were similar in patients 65 years and over as
compared to those less than 65 years of age. The median number of courses and the median number of doses per course were similar between older and younger patients. 
 PROLEUKIN is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. The pattern of organ
system toxicity and the proportion of patients with severe toxicities by organ system were generally similar in patients 65 and older and younger patients. There was a trend, however, towards an increased incidence of severe urogenital toxicities
and dyspnea in the older patients. 
 ADVERSE REACTIONS 
 The rate of drug-related deaths in the 255 metastatic RCC patients who received single-agent PROLEUKIN® (aldesleukin) was
4% (11/255); the rate of drug-related deaths in the 270 metastatic melanoma patients who received single-agent PROLEUKIN was 2% (6/270). 
 The following data on common adverse events (reported in greater than 10% of patients, any grade), presented by body system, decreasing frequency and by preferred term (COSTART) are based
on 525 patients (255 with renal cell cancer and 270 with metastatic melanoma) treated with the recommended infusion dosing regimen. 
 E-15 
  

 E-15 

 

 
 TABLE 3: ADVERSE EVENTS OCCURRING IN 310% OF PATIENTS ( n=525) 
 Body System 
 Body as a Whole 
 Chills 
 Fever 
 Malaise 
 Asthenia 
 Infection 
 Pain 
 Abdominal pain 
 Abdomen enlarged 
 Cardiovascular 
 Hypotension 
 Tachycardia 
 Vasodilation 
 Supraventricular 
 tachycardia 
 Cardiovascular disordera 
 Arrhythmia 
 Digestive 
 Diarrhea 
 Vomiting 
 Nausea 
 Stomatitis 
 Anorexia 
 Nausea and vomiting 
 Hemic and Lymphatic 
 Thrombocytopenia 
 Anemia 
 Leukopenia 
 % 
 Patients 
 52 
 29 
 27 
 23 
 13 
 12 
 11 
 10 
 71 
 23 
 13 
 12 
 11 
 10 
 67 
 50 
 35 
 22 
 20 
 19 
 37 
 29 
 16 
 Body System 
 Metabolic and Nutritional Disorders

 Bilirubinemia 
 Creatinine increase 
 Peripheral edema 

SGOT increase 
 Weight gain 
 Edema 
 Acidosis 
 Hypomagnesemia 
 Hypocalcemia 
 Alkaline phosphatase increase 
 Nervous 
 Confusion 
 Somnolence 
 Anxiety 
 Dizziness 
 Respiratory 
 Dyspnea 
 Lung disorderb 
 Respiratory disorderc 
 Cough increase 
 Rhinitis 
 Skin and Appendages 
 Rash 
 Pruritus 
 Exfoliative dermatitis 
 Urogenital 
 Oliguria 
 % 
 Patients 
 40 
 33 
 28 
 23 
 16 
 15 
 12 
 12 
 11 
 10 
 34 
 22 
 12 
 11 
 43 
 24 
 11 
 11 
 10 
 42 
 24 
 18 
 63 
 a Cardiovascular disorder: fluctuations in blood pressure, asymptomatic ECG changes, CHF. 
 b Lung disorder: physical findings associated with pulmonary congestion, rales, rhonchi. a Respiratory disorder: ARDS, CXR
infiltrates, unspecified pulmonary changes. 
 The following data on life-threatening adverse events (reported in
greater than 1% of patients, grade 4), presented by body system, and by preferred term (COSTART) are based on 525 patients (255 with renal cell cancer and 270 with metastatic melanoma) treated with the recommended infusion dosing regimen.

 E-16 
  

 E-16 

 

 
 TABLE 4: LIFE-THREATENING (GRADE 4) ADVERSE EVENTS (n= 525) 
 Body System 
 Body as a Whole 
 Fever 
 Infection 
 Sepsis 
 Cardiovascular 
 Hypotension 
 Supraventricular tachycardia 
 Cardiovascular disordera 
 Myocardial infarct 
 Ventricular tachycardia 
 Heart arrest 

Digestive 
 Diarrhea 
 Vomiting 
 Hemic and Lymphatic 
 Thrombocytopenia 
 Coagulation disorderb

 #(%) Patients 
 5 (1%) 
 7 (1%) 
 6 (1%) 
 15 (3%) 
 3 (1%) 
 7 (1%) 
 7 (1%) 
 5 (1%) 
 4 (1%) 
 10 (2%) 
 7 (1%) 
 5 (1%) 
 4 (1%) 
 Body System 
 Metabolic and Nutritional Disorders 
 Bilirubinemia 
 Creatinine increase 
 SGOT increase 
 Acidosis 
 Nervous 
 Confusion 
 Stupor 
 Coma 
 Psychosis 
 Respiratory 
 Dyspnea 
 Respiratory disorderc 
 Apnea 
 Urogenital 
 Oliguria 
 Anuria 
 Acute kidney failure 
 # (%) Patients 
 13 (2%) 
 5 (1%) 
 3 (1%) 
 4 (1%) 
 5 (1%) 
 3 (1%) 
 8 (2%) 
 7 (1%) 
 5 (1%) 
 14 (3%) 
 5 (1%) 
 33 (6%) 
 25 (5%) 
 3 (1%) 
 a Cardiovascular disorder: fluctuations in blood pressure. 
 b Coagulation disorder: intravascular coagulopathy. 
 c Respiratory disorder: ARDS, respiratory failure, intubation. 
 The following life-threatening (grade 4) events were reported by <1% of the 525 patients: hypothermia; shock; bradycardia;
ventricular extra systoles; myocardial ischemia; syncope; hemorrhage; atrial arrhythmia; phlebitis; AV block second degree; endocarditis; pericardial effusion; peripheral gangrene; thrombosis; coronary artery disorder; stomatitis; nausea and
vomiting; liver function tests abnormal; gastrointestinal hemorrhage; hematemesis; bloody diarrhea; gastrointestinal disorder; intestinal perforation; pancreatitis; anemia; leukopenia; leukocytosis; hypocalcemia; alkaline phosphatase increase; BUN
increase; hyperuricemia; NPN increase; respiratory acidosis; somnolence; agitation; neuropathy; paranoid reaction; convulsion; grand mal convulsion; delirium; asthma, lung edema; hyperventilation; hypoxia; hemoptysis; hypoventilation; pneumothorax;
mydriasis; pupillary disorder; kidney function abnormal; kidney failure; acute tubular necrosis. 
 In an
additional population of greater than 1,800 patients treated with PROLEUKIN-based regimens using a variety of doses and schedules (e.g., subcutaneous, continuous infusion, administration with LAK cells) the following serious adverse events were
reported: duodenal ulceration; bowel necrosis; myocarditis; supraventricular tachycardia; permanent or transient blindness secondary to optic neuritis; transient ischemic attacks; meningitis; cerebral edema; pericarditis; allergic interstitial
nephritis; tracheo-esophageal fistula. 
 E-17 
  

 E-17 

 

 
 In the same clinical population, the following fatal events each occurred with a
frequency of <1%: malignant hyperthermia; cardiac arrest; myocardial infarction; pulmonary emboli; stroke; intestinal perforation; liver or renal failure; severe depression leading to suicide; pulmonary edema; respiratory arrest; respiratory
failure. In patients with both metastatic RCC and metastatic melanoma, those with ECOG PS of 1 or higher had a higher treatment-related mortality and serious adverse events. 
 Most adverse reactions are self-limiting and, usually, but not invariably, reverse or improve within 2 or 3 days of
discontinuation of therapy. Examples of adverse reactions with permanent sequelae include: myocardial infarction, bowel perforation/infarction, and gangrene. 
 Immunogenicity 
 Fifty-seven of 77 (74%) metastatic
renal cell carcinoma patients treated with an every 8-hour PROLEUKIN regimen and 33 of 50 (66%) metastatic melanoma patients treated with a variety of IV regimens developed low titers of non-neutralizing anti-PROLEUKIN antibodies. Neutralizing
antibodies were not detected in this group of patients, but have been detected in 1/106 (<1%) patients treated with IV PROLEUKIN using a wide variety of schedules and doses. The clinical significance of anti-PROLEUKIN antibodies is unknown.

 Post Marketing Experience 
 The following adverse reactions have been identified during post-approval use of PROLEUKIN. Because these reactions are reported voluntarily from a population of uncertain size, it Is not
always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 
 Anaphylaxis; cellulitis; injection site necrosis; retroperitoneal hemorrhage; cardiomyopathy; cerebral hemorrhage; fatal endocarditis ; hypertension; cholecystitis; colitis; gastritis; hepatitis; hepatosplenomegaly; intestinal
obstruction; hyperthyroidism; neutropenia; myopathy; myositis; rhabdomyolysis; cerebral lesions; encephalopathy; extrapyramidal syndrome; insomnia; neuralgia; neuritis; neuropathy (demyelination); urticaria; pneumonia (bacterial, fungal, viral).

 Exacerbation or initial presentation of a number of autoimmune and inflammatory disorders have been reported
(See “WARNINGS” section, “PRECAUTIONS” section, “Drug Interactions” subsection). Persistent but nonprogressive vitiligo has been observed in malignant melanoma patients treated with interleukin-2. Synergistic, additive
and novel toxicities have been reported with PROLEUKIN used in combination with other drugs. Novel toxicities include delayed adverse reactions to iodinated contrast media and hypersensitivity reactions to antineoplastic agents (See
“PRECAUTIONS” section, “Drug Interactions” subsection). 
 Experience has shown the following
concomitant medications to be useful in the management of patients on PROLEUKIN therapy: a) standard antipyretic therapy, 
 E-18 
  

 E-18 

 

 
 including nonsteroidal anti-inflammatories (NSAIDs), started immediately prior to
PROLEUKIN to reduce fever. Renal function should be monitored as some NSAIDs may cause synergistic nephrotoxicity; b) meperidine used to control the rigors associated with fever; c) H2 antagonists given for prophylaxis of gastrointestinal irritation
and bleeding; d) antiemetics and antidiarrheals used as needed to treat other gastrointestinal side effects. Generally these medications were discontinued 12 hours after the last dose of PROLEUKIN. 
 Patients with indwelling central lines have a higher risk of infection with gram positive organisms.9-11 A reduced incidence
of staphylococcal infections in PROLEUKIN studies has been associated with the use of antibiotic prophylaxis which includes the use of oxacillin, nafcillin, ciprofloxacin, or vancomycin. Hydroxyzine or diphenhydramine has been used to control
symptoms from pruritic rashes and continued until resolution of pruritus. Topical creams and ointments should be applied as needed for skin manifestations. Preparations containing a steroid (e.g., hydrocortisone) should be avoided. NOTE: Prior to
the use of any product mentioned, the physician should refer to the package insert for the respective product. 
 OVERDOSAGE 
 Side effects following the use of PROLEUKIN® (aldesleukin) appear to be
dose-related. Exceeding the recommended dose has been associated with a more rapid onset of expected dose-limiting toxicities. Symptoms which persist after cessation of PROLEUKIN should be monitored and treated supportively. Life-threatening
toxicities may be ameliorated by the intravenous administration of dexamethasone, which may also result in loss of the therapeutic effects of PROLEUKIN.12 NOTE: Prior to the use of dexamethasone, the physician should refer to the package insert for
this product. 
 DOSAGE AND ADMINISTRATION 
 The recommended PROLEUKIN® (aldesleukin) treatment regimen is administered by a 15-minute IV infusion every 8 hours.
Before initiating treatment, carefully review the “INDICATIONS AND USAGE”, “CONTRAINDICATIONS”, “WARNINGS”, “PRECAUTIONS”, and “ADVERSE REACTIONS” sections, particularly regarding patient selection,
possible serious adverse events, patient monitoring and withholding dosage. The following schedule has been used to treat adult patients with metastatic renal cell carcinoma (metastatic RCC) or metastatic melanoma. Each course of treatment consists
of two 5-day treatment cycles separated by a rest period. 
 600,000 lU/kg (0.037 mg/kg) dose administered every
8 hours by a 15-minute IV infusion for a maximum of 14 doses. Following 9 days of rest, the schedule is repeated for another 14 doses, for a maximum of 28 doses per course, as tolerated. During clinical trials, doses were frequently withheld for
toxicity (See “Clinical Experience” and “Dose Modifications” subsections). Metastatic RCC patients treated with this 
 E-19 
  

 E-19 

 

 
 schedule received a median of 20 of the 28 doses during the first course of
therapy. Metastatic melanoma patients received a median of 18 doses during the first course of therapy. 
 Retreatment 
 Patients should be evaluated for response approximately 4 weeks after completion
of a course of therapy and again immediately prior to the scheduled start of the next treatment course. Additional courses of treatment should be given to patients only if there is some tumor shrinkage following the last course and retreatment is
not contraindicated (See “CONTRAINDICATIONS” section). Each treatment course should be separated by a rest period of at least 7 weeks from the date of hospital discharge. 
 Dose Modifications 
 Dose modification for toxicity should be accomplished by withholding or interrupting a dose rather than reducing the dose to be given. Decisions to stop, hold, or restart PROLEUKIN therapy
must be made after a global assessment of the patient. With this in mind, the following guidelines should be used: 
 Retreatment with PROLEUKIN is contraindicated in patients who have experienced the following toxicities: 
 Body System 
 Cardiovascular 
 Respiratory 
 Urogenital 
 Nervous 
 Digestive 
 Sustained ventricular tachycardia (35 beats) 
 Cardiac rhythm disturbances not controlled or unresponsive to management 
 Chest pain with ECG
changes, consistent with angina or myocardial infarction 
 Cardiac tamponade 
 Intubation for >72 hours 
 Renal failure requiring dialysis >72 hours 
 Coma or toxic psychosis lasting >48 hours 
 Repetitive or difficult to control seizures

 Bowel ischemia/perforation 
 Gl bleeding requiring surqery 
 Doses should be
held and restarted according to the following: 
 Body System 
 Cardiovascular 
 Hold dose for 
 Atrial fibrillation,
supraventricular tachycardia or bradycardia that requires treatment or is recurrent or persistent 
 Systolic bp
<90 mm Hg with increasing requirements for pressors 
 Any ECG change consistent with 
 Subsequent doses may be given if 
 Patient is asymptomatic with full recovery to normal sinus rhythm 
 Systolic bp 390 mm Hg and stable or improving requirements for pressors 
 Patient is asymptomatic, Ml and 
 E-20 
  

 E-20 

 

 
 Respiratory 
 Nervous 
 Body as a Whole 
 Urogenital 
 Digestive 
 Skin 
 Ml, ischemia or myocarditis with or without chest pain; suspicion of cardiac
ischemia 
 02 saturation <90% 
 Mental status changes, including moderate confusion or agitation 
 Sepsis syndrome, patient is clinically unstable 
 Serum creatinine >4.5 mg/dL or a serum
creatinine of 34 mg/dL in the presence of severe volume overload, acidosis, or hyperkalemia 
 Persistent oliguria, urine output of <10 mL/hour for 16 to 24 hours with rising serum creatinine 
 Signs of hepatic failure including encephalopathy, increasing ascites, liver pain, hypoglycemia 
 Stool guaiac repeatedly >3-4+ 
 Bullous
dermatitis or marked worsening of pre-existing skin condition, avoid topical steroid therapy 
 myocarditis have
been ruled out, clinical suspicion of angina is low; there is no evidence of ventricular hypokinesia 
 02
saturation >90% 
 Mental status changes completely resolved 
 Sepsis syndrome has resolved, patient is clinically stable, infection is under treatment 
 Serum creatinine <4 mg/dL and fluid and electrolyte status is stable 
 Urine output >10 mL/hour with a decrease of serum creatinine >1.5 mg/dL or normalization of serum creatinine

 All signs of hepatic failure have resolved* 
 Stool guaiac negative 
 Resolution of all signs of bullous dermatitis 
 *
Discontinue all further treatment for that course. A new course of treatment, if warranted, should be initiated no sooner than 7 weeks after cessation of adverse event and hospital discharge. 
 Reconstitution and Dilution Directions: Reconstitution and dilution procedures other than those recommended may alter the
delivery and/or pharmacology of PROLEUKIN and thus should be avoided. 
 1. PROLEUKIN® (aldesleukin) is a
sterile, white to off-white, preservative-free, lyophilized powder suitable for IV infusion upon reconstitution and dilution. EACH VIAL CONTAINS 22 MILLION IU (1.3 MG) OF PROLEUKIN AND SHOULD BE RECONSTITUTED ASEPTICALLY WITH 1.2 ML OF STERILE WATER
FOR INJECTION, USP. WHEN RECONSTITUTED AS DIRECTED, EACH ML CONTAINS 18 MILLION IU (1.1 MG) OF PROLEUKIN. The resulting solution should be a clear, colorless to slightly yellow liquid. The vial is for single-use only and any unused portion should be
discarded. 
 2. During reconstitution, the Sterile Water for Injection, USP should be directed at the side of
the vial and the contents gently swirled to avoid excess foaming. DO NOT SHAKE. 
 3. The dose of PROLEUKIN,
reconstituted with Sterile Water for Injection, USP (without preservative) should be diluted aseptically in 50 mL of 5% Dextrose Injection, USP (D5W) and infused over a 15-minute period. 
 In cases where the total dose of PROLEUKIN is 1.5 mg or less (e.g., a patient with a body weight of less than 40 kilograms),
the dose of PROLEUKIN should 
 E-21 
  

 E-21 

 

 
 be diluted in a smaller volume of D5W. Concentrations of PROLEUKIN below 30
μg/mL and above 70 μg/mL have shown increased variability in drug delivery. Dilution and delivery of PROLEUKIN outside of this concentration range should be avoided. 
 4. Glass bottles and plastic (polyvinyl chloride) bags have been used in clinical trials with comparable results. It is
recommended that plastic bags be used as the dilution container since experimental studies suggest that use of plastic containers results in more consistent drug delivery. In-line filters should not be used when administering PROLEUKIN. 

5. Before and after reconstitution and dilution, store in a refrigerator at 2° to 8°C (36° to 46°F). Do
not freeze. Administer PROLEUKIN within 48 hours of reconstitution. The solution should be brought to room temperature prior to infusion in the patient. 
 6. Reconstitution or dilution with Bacteriostatic Water for Injection, USP, or 0.9% Sodium Chloride Injection, USP should be avoided because of increased aggregation. PROLEUKIN should not
be coadministered with other drugs in the same container. 
 7. Parenteral drug products should be inspected
visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 
 HOW SUPPLIED 
 PROLEUKIN® (aldesleukin) is supplied in individually boxed singie-use vials.
Each vial contains 22 x 106 IU of PROLEUKIN. Discard unused portion. 
 NDC 0078-0495-61 Individually boxed
single-use vial 
 Store vials of lyophilized PROLEUKIN in a refrigerator at 2° to 8°C (36° to
46°F). PROTECT FROM LIGHT. Store in carton until time of use. 
 Reconstituted or diluted PROLEUKIN is stable
for up to 48 hours at refrigerated and room temperatures, 2° to 25°C (36° to 77°F). However, since this product contains no preservative, the reconstituted and diluted solutions should be stored in the refrigerator. 
 Do not use beyond the expiration date printed on the vial. NOTE: This product contains no preservative. 
 Rx Only 
 REFERENCES 
 1. Doyle MV, Lee MT, Fong S. Comparison of the biological activities of
human recombinant interleukin-2125 and native interleukin-2. J Biol Response Mod 1985; 4:96-109. 
 2. Ralph P,
Nakoinz I, Doyle M, et al. Human B and T lymphocyte stimulating properties of interleukin-2 (IL-2) muteins. In: Immune Regulation By Characterized Polypeptides. Alan R. Liss, Inc. 1987; 453-62, 
 E-22 
  

 E-22 

 

 
 3. Winkelhake JL and Gauny SS. Human recombinant interleukin-2 as an experimental
therapeutic. Pharmacol Rev 1990; 42:1-28. 
 4. Rosenberg SA, Mule JJ, Spiess PJ, et al. Regression of
established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin-2. J Exp Med 1985; 161:1169-88. 
 5. Konrad MW, Hemstreet G, Hersh EM, et al. Pharmacokinetics of recombinant interleukin-2 in humans. Cancer Res 1990; 50:2009-17. 
 6. Donohue JH and Rosenberg SA. The fate of interleukin-2 after in vivo administration. J Immunol 1983; 130:2203-8.

 7. Koths K, Halenbeck R. Pharmacokinetic studies on 35S-labeled recombinant interleukin-2 in mice. In: Sorg C
and Schimpl A, eds. Cellular and Molecular Biology of Lymphokines. Academic Press: Orlando, FL, 1985;779. 
 8.
Gibbons JA, Luo ZP, Hansen ER, et al. Quantitation of the renal clearance of interleukin-2 using nephrectomized and ureter ligated rats, J Pharmacol Exp Ther 1995; 272: 119-125. 
 9. Bock SN, Lee RE, Fisher B, et al. A prospective randomized trial evaluating prophylactic antibiotics to prevent
triple-lumen catheter-related sepsis in patients treated with immunotherapy. J Clin Oncol 1990; 8:161-69. 
 10.
Hartman LC, Urba WJ, Steis RG, et al. Use of prophylactic antibiotics for prevention of intravascular catheter-related infections in interleukin-2-treated patients. J Natl Cancer Inst 1989; 81:1190-93. 
 11. Snydman DR, Sullivan B, Gill M, et al. Nosocomial sepsis associated with interleukin-2. Ann Intern Med 1990; 112:102-07.

 12. Mier JW, Vachino G, Klempner MS, et al. Inhibition of interleukin-2-induced tumor necrosis factor release
by dexamethasone: Prevention of an acquired neutrophil chemotaxis defect and differential suppression of interleukin-2 associated side effects. Blood 1990; 76:1933-40. 
 13. Choyke PL, Miller DL, Lotze MT, et al. Delayed reactions to contrast media after interleukin-2 immunotherapy. Radiology 1992; 183:111-114. 
 Manufactured by: 
 Novartis Vaccines and Diagnostics, Inc. Emeryville, CA 94608 U.S. License No. 1751 
 At 
 Bayer Healthcare Pharmaceuticals Emeryville,
CA 94608 
 Distributed by: 
 Novartis Pharmaceuticals Corporation East Hanover, NJ 07936 
 For additional information, contact Novartis Pharmaceuticals Corporation 1-888-669-6682. 
 E-23

  

 E-23 

 

 
 U.S. Patent Nos. RE 33653; 4,530,787; 4,569,790; 4,604,377; 4,748,234; 4,572,798;
4,853,332; 4,959,314; 5,464,939 
 REV: April, 2009 ©Novartis 
 E-24 
  

 E-24 

 

 
 NOVARTIS 
 PROLEUKIN* (aldesleukin) 
 Interleukin-2 22 million IU/vial 
 Pharmaceutical Standard: Biologic Response Modifier 
 ACTIONS, CLINICAL PHARMACOLOGY 

PROLEUKIN* (aldesleukin) an analogue of human interleukin-2 produced by recombinant DNA technology, has been shown to
possess the biological activities of human native interleukin-2. PROLEUKIN exhibits antitumor activity; the exact mechanism by which PROLEUKIN mediates its antitumor activity in animals and humans is unknown. 
 In vitro studies performed on human cell lines demonstrate the immunoregulatory properties of PROLEUKIN, including: a)
enhancement of lymphocyte mitogenesis and stimulation of long-term growth of human interleukin-2 dependent cell lines; b) enhancement of lymphocyte cytotoxicity; c) induction of killer cell (lymphokine-activated (LAK) and natural (NK)) activity; and
d) induction of interferon-gamma production. 
 The in vivo administration of PROLEUKIN in animals and humans
produces multiple immunological effects in a dose dependent manner. These effects include activation of cellular immunity with profound lymphocytosis, eosinophilia, and thrombocytopenia, and the production of cytokines including tumor necrosis
factor, IL-1 and gamma interferon. In vivo experiments in murine tumor models have shown inhibition of tumor growth. Pharmacokinetics: PROLEUKIN exists as biologically active, non-covalently bound microaggregates with an average size of 27
recombinant interleukin-2 molecules. The solubilizing agent, sodium dodecyl sulfate, may have an effect on the kinetic properties of this product. The pharmacokinetic profile of PROLEUKIN is characterized by high plasma concentrations following a
short intravenous (IV) infusion, rapid distribution into the extravascular space and elimination from the body by metabolism in the kidneys with little or no bioactive protein excreted in the urine. 
 Studies of IV PROLEUKIN in sheep and humans indicated that upon completion of infusion approximately 30% of the administered
dose is detectable in plasma. This finding is consistent with studies in rats using radiolabeled PROLEUKIN, which demonstrate a rapid (<1 minute) uptake of the majority of the label into the lungs, liver, kidney, and spleen. 
 The serum half-life (T1/2) curves of PROLEUKIN remaining in the plasma are derived from studies done in 52 cancer patients
following a 5-minute IV infusion. These patients were shown to have a distribution and elimination T1/2 of 13 and 85 minutes, respectively. 
 The relatively rapid clearance rate of PROLEUKIN has led to dosage schedules characterized by frequent, short infusions. Observed serum levels are proportional to the dose of PROLEUKIN.

 Following the initial rapid organ distribution, the primary route of clearance of circulating PROLEUKIN is the
kidney. In humans and animals, PROLEUKIN is cleared from the circulation by both glomerular filtration and peritubular extraction in the kidney. This dual mechanism for delivery of PROLEUKIN to the proximal tubule may account for the preservation of
clearance in patients with rising serum creatinine values. Greater than 80% of the amount of PROLEUKIN distributed to plasma, cleared from the circulation and presented to the kidney is metabolized to amino acids in the cells lining the proximal
convoluted tubules. In humans, the mean clearance rate in cancer patients is 268 mL/min. 
 INDICATIONS AND
CLINICAL USE 
 PROLEUKIN* (aldesleukin) is indicated for the treatment of adults (318 years of age) with metastatic renal cell carcinoma (metastatic RCC). PROLEUKIN is indicated for the treatment of adults (318 years of age) with metastatic
malignant melanoma. 
 In the renal cell cancer studies (n=255), objective response was seen in 37
(15%) patients, with 17 (7%) complete and 20 (8%) partial responders. In the metastatic malignant melanoma studies (n=270), objective response was seen in 43 (16%) patients, with 17 (6%) complete and 26 (10%) partial
responders. Prior to enrollment into the studies, patients had progression of disease after prior therapies. A majority (96%) of patients had previous surgical resection of their primary lesions, lymph node dissections, or area of relapse.

 Careful patient selection is mandatory prior to the administration of PROLEUKIN. See
“CONTRAINDICATIONS,” “WARNINGS,” and “PRECAUTIONS” sections regarding patient screening, including recommended cardiac and pulmonary function tests and laboratory tests. 
 Evaluation of clinical studies to date reveals that patients with more favorable ECOG performance status (ECOG PS 0) at
treatment initiation respond better to PROLEUKIN, with a higher response rate and lower toxicity (see “ADVERSE REACTION” section). Therefore, selection of patients for treatment should include assessment of performance status. Experience
in patients with ECOG PS >1 is limited. 
 TABLE I: PROLEUKIN CLINICAL RESPONSE BY ECOG PERFORMANCE STATUS
(PS) 
 Pretreatment METASTATIC RCC METASTATIC MALIGNANT MELANOMA 
 ECOG PS CR PR CR PR 
 0 14/166 (8%) 16/166 (10%) 14/191 (7%) 22/191 (12%) 
 >1 3/89 (3%) 4/89 (4%) 3/79 (4%) 4/79 (5%) 
 CONTRAINDICATIONS

 PROLEUKIN* (aldesleukin) is contraindicated in patients with a known history of hypersensitivity to
interleukin-2 or any component of the PROLEUKIN formulation. 
 PROLEUKIN is contraindicated in patients with an
abnormal thallium stress test or abnormal pulmonary function tests and those with organ allo-grafts. Retreatment with PROLEUKIN is contraindicated in patients who experienced the following drug related toxicities while receiving an earlier course of
therapy: 
 Sustained ventricular tachycardia (35 beats) 

Cardiac arrhythmias not controlled or unresponsive to management 
 Chest pain with electrocardiogram (ECG) changes, consistent with angina or myocardial infarction 
 Cardiac tamponade 
 Intubation required >72 hours 
 Renal failure
requiring dialysis >72 hours 
 Coma or toxic psychosis lasting >48 hours 
 Repetitive or difficult to control seizures 
 Bowel ischemia/perforation 
 GI bleeding requiring
surgery 
 WARNINGS 
 PROLEUKIN* (aldesleukin) should be administered only to well informed patients in a hospital setting under the supervision of a qualified physician experienced in the use of anti-cancer
agents. An intensive care facility and specialists skilled in cardiopulmonary or intensive care medicine must be available. 
 PROLEUKIN administration has been associated with capillary leak syndrome (CLS) which is characterized by a loss of vascular tone and extravasation of plasma proteins and fluid into the extravascular space. CLS results in hypotension
and reduced organ perfusion, which may be severe and can result in death. CLS may be associated with cardiac arrhythmias (supraventricular and ventricular), angina, myocardial infarction, respiratory insufficiency requiring intubation,
gastrointestinal bleeding or infarction, renal insufficiency, edema and mental status changes. Because of the severe adverse events which generally accompany PROLEUKIN therapy at the recommended dosages, thorough clinical evaluation should be
performed to identify patients with significant cardiac, pulmonary, renal, hepatic, or central nervous system (CNS) impairment; PROLEUKIN is contraindicated in these patients. 
 Therapy with PROLEUKIN should be restricted to patients with normal cardiac and pulmonary functions as defined by thallium
stress testing and formal pulmonary function testing. Extreme caution should be used in patients with normal thallium stress tests and pulmonary function tests who have a history of prior cardiac or pulmonary disease. 
 Patients with normal cardiovascular, pulmonary, hepatic, and CNS function may experience serious, life threatening or fatal
adverse events. Adverse events are frequent, often serious, and sometimes fatal. 
 Should adverse events, which
require dose modification occur, dosage should be withheld rather than reduced (see “DOSAGE AND ADMINISTRATION” section, “Dose Modifications” subsection). 
 PROLEUKIN has been associated with exacerbation of pre-existing or initial presentation of autoimmune disease and
inflammatory disorders. Exacerbation of Crohn’s disease, scleroderma, thyroiditis, inflammatory arthritis, diabetes mellitus, oculo-bulbar myasthenia gravis, crescentic IgA glomerulonephritis, cholecystitis, cerebral vasculitis, Stevens-Johnson
syndrome and bullous pemphigoid, has been reported following treatment with IL-2. 
 All patients should have
thorough evaluation and treatment of CNS metastases and have a negative scan prior to receiving PROLEUKIN therapy. New neurologic signs, symptoms, and anatomic lesions following PROLEUKIN therapy have been reported in patients without evidence of
CNS metastases. Clinical manifestations included changes in mental status, speech difficulties, cortical blindness, limb or gait ataxia, hallucinations, agitation, obtundation, and coma. Radiological findings included multiple and, less commonly,
single cortical lesions on MRI and evidence of demyelination. Neurologic signs and symptoms associated with PROLEUKIN therapy usually improve after discontinuation of PROLEUKIN therapy; however, there are reports of permanent neurologic defects. One
case of possible cerebral vasculitis, responsive to dexamethasone, has been reported. In patients with known seizure disorders, extreme caution should be exercised as PROLEUKIN may cause seizures. 
 PROLEUKIN administration should be held in patients developing moderate to severe lethargy or somnolence; continued
administration may result in coma. 
 PROLEUKIN treatment is associated with impaired neutrophil function
(reduced chemotaxis) and with an increased risk of disseminated infection, including sepsis and bacterial endocarditis. Consequently, pre-existing bacterial infections should be adequately treated prior to initiation of PROLEUKIN therapy. Patients
with indwelling central lines are particularly at risk for infection with gram positive microorganisms. Antibiotic prophylaxis with oxacillin, nafcillin, ciprofloxacin, or vancomycin has been associated with a reduced incidence of staphylococcal
infections. Disseminated infections acquired in the course of PROLEUKIN treatment are a major contributor to treatment morbidity and use of antibiotic prophylaxis and aggressive treatment of suspected and documented infections may reduce the
morbidity of PROLEUKIN treatment. NOTE: Prior to the use of any product mentioned in this paragraph, the physician should refer to the Product Monograph for the respective product. PRECAUTIONS 
 General: Patients should have normal cardiac, pulmonary, hepatic, and CNS function at the start of therapy. Metastatic renal
cell carcinoma patients who have had a nephrectomy are eligible for treatment if they have serum creatinine levels £1.5 mg/dL. 
 Patients with normal cardiovascular, pulmonary, hepatic, and CNS function may experience serious life threatening or fatal adverse events. Adverse events are frequent, often serious, and
sometimes fatal. 
 Capillary leak syndrome (CLS) begins immediately after PROLEUKIN* (aldesleukin) treatment
starts and is marked by increased capillary permeability to protein and fluids and reduced vascular tone. In most patients, this results in a concomitant drop in mean arterial blood pressure within 2 to 12 hours after the start of treatment. With
continued therapy, clinically significant hypotension (defined as systolic blood pressure below 90 mm Hg or a 20 mm Hg drop from baseline systolic pressure) and hypoperfusion will occur. In addition, extravasation of protein and fluids into the
extravascular space will lead to the formation of edema and creation of new effusions. 
 Medical management of
CLS begins with careful monitoring of the patient’s fluid and organ perfusion status. This is achieved by frequent determination of blood pressure and pulse, and by monitoring organ function, which includes assessment of mental status and urine
output. Hypovolemia is assessed by catheterization and central pressure monitoring. 
 Flexibility in fluid and
pressor management is essential for maintaining organ perfusion and blood pressure. Consequently, extreme caution should be used in treating patients with fixed requirements for large volumes of fluid (e.g., patients with hypercalcemia). 

Administration of IV fluids, either colloids or crystalloids is recommended for treatment of hypovolemia. IV fluids are
usually given when the central venous pressure (CVP) is below 3 to 4 mm H2O. Correction of hypovolemia may require large volumes of IV fluids but caution is required because unrestrained fluid administration may exacerbate problems associated with
edema formation or effusions. 
 With extravascular fluid accumulation, edema is common and ascites, pleural or
pericardial effusions may develop. Management of these events depends on a careful balancing of the effects of fluid shifts so that neither the consequences of hypovolemia (e.g., impaired organ perfusion) nor the consequences of fluid accumulations
(e.g., pulmonary edema) exceeds the patient’s tolerance. 
 Clinical experience has shown that early
administration of dopamine (1 to 5 μg/kg/min) to patients manifesting capillary leak syndrome, before the onset of hypotension, can help to maintain organ perfusion particularly to the kidney and thus preserve urine output. Weight and urine
output should be carefully monitored. If organ perfusion and blood pressure are not sustained by dopamine therapy, clinical investigators have increased the dose of dopamine to 6 to 10 μg/kg/min or have added phenylephrine hydrochloride (1 to
5 μg/kg/min) to low dose dopamine. Prolonged use of pressors, either in combination or as individual agents, at relatively high doses, may be associated with cardiac rhythm disturbances. If there has been excessive weight gain or edema
formation, particularly if associated with shortness of breath from pulmonary congestion, use of diuretics, once blood pressure has normalized, has been shown to hasten recovery. NOTE: Prior to the use of any product mentioned, the physician should
refer to the Product Monograph for the respective product. 
 PROLEUKIN treatment should be withheld for failure
to maintain organ perfusion, as demonstrated by altered mental status, reduced urine output, a fall in the systolic blood pressure below 90 mm Hg or onset of cardiac arrhythmias (see “DOSAGE AND ADMINISTRATION” section, “Dose
Modification” subsection). Recovery from CLS begins soon after cessation of PROLEUKIN therapy. Usually, within a few hours, the blood pressure rises, organ perfusion is restored and reabsorption of extravasated fluid and protein begins.

 Oxygen is given to the patient if pulmonary function monitoring confirms that PaO2 is decreased. 

PROLEUKIN administration may cause anemia and/or thrombocytopenia. Packed red blood cell transfusions have been given both
for relief of anemia and to insure maximal oxygen carrying capacity. Platelet transfusions have been given to resolve absolute thrombocytopenia and to reduce the risk of GI bleeding. In addition, leukopenia and neutropenia are observed. 

PROLEUKIN administration results in fever, chills, rigors, pruritus, and gastrointestinal side effects in most patients
treated at recommended doses. These side effects have been aggressively managed as described in the “ADVERSE REACTIONS” section. 
 Kidney and liver function are impaired during PROLEUKIN treatment. Use of concomitant nephrotoxic or hepatotoxic medications may further increase toxicity to the kidney or liver.

 Mental status changes including irritability, confusion, or depression which occur while receiving PROLEUKIN
may be indicators of bacteremia or early bacterial sepsis, hypoperfusion, occult CNS malignancy, or direct PROLEUKIN-induced CNS toxicity. Alterations in mental status due solely to PROLEUKIN may progress for several days before recovery begins.
Rarely, patients have sustained permanent neurologic deficits (see 
 “ADVERSE REACTIONS” section).

 Exacerbation of preexisting autoimmune disease or initial presentation of autoimmune and inflammatory
disorders has been reported following PROLEUKIN alone or in combination with interferon (see “ADVERSE REACTIONS” section). Impairment of thyroid function, sometimes preceded by hyperthyroidism, has been reported following PROLEUKIN
treatment. Some of these patients required thyroid replacement therapy. Changes in thyroid function may be a manifestation of autoimmunity. Onset of symptomatic hyperglycemia and/or diabetes mellitus has been reported during PROLEUKIN therapy.

 PROLEUKIN enhancement of cellular immune function may increase the risk of allograft rejection in transplant
patients. 
 Laboratory Tests: The following clinical evaluations are recommended for all patients, prior to
beginning treatment and then daily during drug administration. 
 Standard hematologic tests - including complete
blood count (CBC), differential and platelet counts 
 Blood chemistries - including electrolytes, renal and
hepatic function tests 
 Chest x-rays 
 Serum creatinine should be £1.5 mg/dL prior to initiation of PROLEUKIN
treatment. 
 All patients should have baseline pulmonary function tests with arterial blood gases. Adequate
pulmonary function should be documented (FEV1 >2 liters or 375% of predicted for height and age) prior to initiating therapy. All patients should be screened with a stress thallium study. Normal
ejection fraction and unimpaired wall motion should be documented. If a thallium stress test suggests minor wall motion abnormalities further testing is suggested to exclude significant coronary artery disease. 
 Daily monitoring during therapy with PROLEUKIN should include vital signs (temperature, pulse, blood pressure, and
respiration rate), weight, and fluid intake and output. In a patient with a decreased systolic blood pressure, especially less than 90 mm Hg, constant cardiac rhythm monitoring should be conducted. If an abnormal complex or rhythm is seen, an ECG
should be performed. Vital signs in these hypotensive patients should be taken hourly. 
 During treatment,
pulmonary function should be monitored on a regular basis by clinical examination, assessment of vital signs and pulse oximetry. Patients with dyspnea or clinical signs of respiratory impairment (tachypnea or rales) should be further assessed with
arterial blood gas determination. These tests are to be repeated as often as clinically indicated. 
 Cardiac
function should be assessed daily by clinical examination and assessment of vital signs. Patients with signs or symptoms of chest pain, murmurs, gallops, irregular rhythm or palpitations should be further assessed with an ECG examination and cardiac
enzyme evaluation. Evidence of myocardial injury, including findings compatible with myocardial infarction or myocarditis, has been reported. Ventricular hypokinesia due to myocarditis may be persistent for several months. If there is evidence of
cardiac ischemia or congestive heart failure, PROLEUKIN therapy should be held, and a repeat thallium study should be done. 
 Drug Interactions: PROLEUKIN may affect central nervous function. Therefore, interactions could occur following concomitant administration of psychotropic drugs (e.g., narcotics, analgesics, antiemetics, sedatives, and
tranquilizers). 
 Concurrent administration of drugs possessing nephrotoxic (e.g., aminoglycosides,
indomethacin), myelotoxic (e.g., cytotoxic chemotherapy), cardiotoxic (e.g., doxorubicin) or hepatotoxic (e.g., methotrexate, asparaginase) effects with PROLEUKIN may increase toxicity in these organ systems. The safety and efficacy of PROLEUKIN in
combination with any antineoplastics have not been established. 
 In addition, reduced kidney and liver function
secondary to PROLEUKIN treatment may delay elimination of concomitant medications and increase the risk of adverse events from those drugs. 
 Hypersensitivity reactions have been reported in patients receiving combination regimens containing sequential high dose PROLEUKIN and anti-neoplastic agents, specifically, dacarbazine,
cis-platinum, tamoxifen and interferon-alfa. These reactions consisted of erythema, pruritus, and hypotension and occurred within hours of administration of chemotherapy. These events required medical intervention in some patients. Myocardial
injury, including myocardial infarction, myocarditis, ventricular hypokinesia, and severe rhabdomyolysis appear to be increased in patients receiving PROLEUKIN and interferon-alfa concurrently. 
 Exacerbation or the initial presentation of a number of autoimmune and inflammatory disorders has been observed following
concurrent use of interferon-alfa and PROLEUKIN, including crescentic IgA glomerulonephritis, oculo-bulbar myasthenia gravis, inflammatory arthritis, thyroiditis, bullous pemphigoid, and Stevens-Johnson syndrome. 
 Although glucocorticoids have been shown to reduce PROLEUKIN-induced side effects including fever, renal insufficiency,
hyperbilirubinemia, confusion, and dyspnea, concomitant administration of these agents with PROLEUKIN may reduce the antitumor effectiveness of PROLEUKIN and thus should be avoided. 
 Beta-blockers and other antihypertensives may potentiate the hypotension seen with PROLEUKIN. 
 Delayed adverse reactions to iodinated contrast media: A review of the literature revealed that 12.6% (range 11-28%) of 501
patients treated with various interleukin-2 containing regimens who were then subsequently administered radiographic iodinated contrast media experienced acute, atypical adverse reactions. The onset of symptoms usually occurred within hours (most
commonly 1 to 4 hours) following the administration of contrast media. These reactions include fever, chills, nausea, vomiting, pruritus, rash, diarrhea, hypotension, edema, and oliguria. Some clinicians have noted that these reactions resemble the
immediate side effects caused by interleukin-2 administration, however the cause of contrast reactions after interleukin-2 therapy is unknown. Most events were reported to occur when contrast media was given within 4 weeks after the last dose of
interleukin-2. These events were also reported to occur when contrast media was given several months after interleukin-2 treatment. Carcinogenesis, Mutagenesis, Impairment of Fertility: There have been no studies conducted assessing the carcinogenic
or mutagenic potential of PROLEUKIN. 
 There have been no studies conducted assessing the effect of PROLEUKIN on
fertility. It is recommended that this drug not be administered to fertile persons of either gender not practicing effective contraception. 
 Use in Pregnancy: PROLEUKIN has been shown to have embryolethal effects in rats when given in doses at 27 to 36 times the human dose (scaled by body weight). Significant maternal
toxicities were observed in pregnant rats administered PROLEUKIN by IV injection at doses 2.1 to 36 times higher than the human dose during critical period of organogenesis. No evidence of teratogenicity was observed other than that attributed to
maternal toxicity. There are no adequate well-controlled studies of PROLEUKIN in pregnant women. PROLEUKIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 
 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk
and because of the potential for serious adverse reactions in nursing infants from PROLEUKIN, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

 Use in Children: Safety and effectiveness in children under 18 years of age have not been established.

 ADVERSE REACTIONS 
 The rate of drug-related deaths in the 255 metastatic RCC patients who received single-agent PROLEUKIN* (aldesleukin) was 
 4% (11/255); the rate of drug-related deaths in the 270 metastatic malignant melanoma patients who received single-agent
PROLEUKIN was 2% (6/270). 
 The following data on common adverse events (reported in greater than 10% of
patients, any grade), presented by body system, decreasing frequency and by preferred term (COSTART) are based on 525 patients (255 with renal cell cancer and 270 with metastatic malignant melanoma) treated with the recommended infusion dosing
regimen. 
 TABLE II: ADVERSE EVENTS OCCURRING IN 310% OF PATIENTS
(n=525) 
 Body System% of patients Body System% of patients 
 Body as a Whole Metabolic and Nutritional Disorders 
 Chills 52 Bilirubinemia 40 
 Fever 29 Creatinine increased 33 
 Malaise 27
Peripheral edema 28 
 Asthenia 23 SGOT increased 23 
 Infection 13 Weight gain 16 
 Pain 12 Edema 15 
 Abdominal pain 11 Acidosis 12

 Abdomen enlarged 10 Hypomagnesemia 12 
 Cardiovascular System Hypocalcemia 11 
 Hypotension 71 Alkaline phosphatase increased 10 
 Tachycardia 23 Nervous System 
 Vasodilation 13 Confusion 34 
 Supraventricular tachycardia 12 Somnolence 22 
 Cardiovascular disordera 11 Anxiety 12 
 Arrhythmia
10 Dizziness 11 
 Digestive System Respiratory System 
 Diarrhea 67 Dyspnea 43 
 Vomiting 50 Lung disorderb 24 
 Nausea 35
Respiratory disorderc 11 
 Stomatitis 22 Cough increase 11 
 Anorexia 20 Rhinitis 10 
 Nausea and vomiting 19 Skin and Appendages 
 Hemic
and Lymphatic System Rash 42 
 Thrombocytopenia 37 Pruritus 24 
 Anemia 29 Exfoliative dermatitis 18 
 Leukopenia 16 Urogenital System 
 Oliguria 63

 a Cardiovascular disorder: fluctuations in blood pressure, asymptomatic ECG changes, CHF. b Lung disorder:
physical findings associated with pulmonary congestion, rales, and rhonchi. c Respiratory disorder: ARDS, CXR infiltrates, unspecified pulmonary changes. 
 The following data on life-threatening adverse events (reported in greater than 1% of patients, grade 4), presented by body system, and by preferred term (COSTART) are based on 525
patients (255 with renal cell cancer and 270 with metastatic malignant melanoma) treated with the recommended infusion dosing regimen. 
 E-25 
  

 E-25 

 

 
 TABLE III: LIFE-THREATENING (GRADE 4) ADVERSE EVENTS (n= 525) 
 Body System # (%) of PatientsBody System # (%) of Patients 
 Body as a Whole Metabolic and Nutritional Disorders 
 Fever 5 (1%) Bilirubinemia 13 (2%) 
 Infection 7 (1%) Creatinine increased 5 (1%) 
 Sepsis 6 (1%) SGOT increased 3 (1%) 
 Cardiovascular Acidosis 4 (1%) 
 Hypotension 15 (3%) Nervous 
 Supraventricular tachycardia 3 (1%) Confusion 5 (1%) 
 Cardiovascular disordera 7 (1%) Stupor 3 (1%) 
 Myocardial infarct 7 (1%) Coma 8 (2%)

 Ventricular tachycardia 5 (1%) Psychosis 7 (1%) 
 Heart arrest 4 (1%) Respiratory 
 Digestive Dyspnea 5 (1%) 
 Diarrhea 10
(2%) Respiratory disorderc 14 (3%) 
 Vomiting 7 (1%) Apnea 5 (1%) 
 Hemic and Lymphatic Urogenital 
 Thrombocytopenia 5 (1%) Oliguria 33 (6%) 
 Coagulation disorderb 4 (1%) Anuria 25 (5%) 
 Acute kidney failure 3 (1%) 
 a Cardiovascular disorder: fluctuations in blood pressure. b Coagulation disorder: intravascular coagulopathy. c Respiratory
disorder: ARDS, respiratory failure, intubation. 
 The following life threatening (grade 4) adverse events were
reported by <1% of the 525: reaction unevaluable; hypothermia; shock; bradycardia; ventricular extrasystoles; myocardial ischemia; syncope; hemorrhage; atrial arrhythmia; phlebitis; AV block second degree; endocarditis; pericar-dial effusion;
peripheral gangrene; thrombosis; coronary artery disorder; stomatitis; nausea and vomiting; liver function tests abnormal; gastrointestinal hemorrhage; hematemesis; bloody diarrhea; gastrointestinal disorder; intestinal perforation; pancreatitis;
anemia; leukopenia; leukocytosis; hypocalcemia; alkaline phosphatase increased; BUN increased; hyperuricemia; NPN increase; respiratory acidosis; somnolence; agitation; neuropathy; paranoid reaction; convulsion; grand mal convulsion; delirium; lung
edema; hyperventilation; hypoxia; hemoptysis; hypoventilation; pneu-mothorax; mydriasis; pupillary disorder; kidney function abnormal; kidney failure; acute tubular necrosis. 
 In an additional population of greater than 1,800 patients treated with PROLEUKIN-based regimens using a variety of doses and
schedules (e.g., subcutaneous, continuous infusion, administration with LAK cells) the following serious adverse events were reported: duodenal ulceration; bowel necrosis; myocarditis; supraventricular tachycardia; permanent or transient blindness
secondary to optic neuritis; transient ischemic attacks; meningitis; cerebral edema; pericarditis; allergic interstitial nephritis; tracheo-esophageal fistula. 
 In the same clinical population, the following events which were fatal or resulted in death each occurred with a frequency of <1%: liver or renal failure; intestinal perforation;
cardiac arrest; myocardial infarction; malignant hyperthermia; pulmonary edema; respiratory arrest; respiratory failure; stroke; pulmonary emboli; severe depression leading to suicide. 
 In world-wide postmarketing experience, the following serious adverse events have been reported in a variety of treatment
regimens that include interleukin-2: hypertension; pneumonia (bacterial, fungal, viral); neutropenia; cholecystitis; colitis; gastritis; hepatitis; hepatosplenomegaly; intestinal obstruction; retroperitoneal hemorrhage; cerebral lesions; cerebral
hemorrhage; encephalopathy; extrapyramidal syndrome; neuralgia; neuritis; neuropathy (demyelination); rhabdomyolysis; myopathy; myositis; hyperthyroidism; anaphylaxis; cellulitis; injection site necrosis; insomnia. Exacerbation or initial
presentations of a number of autoimmune and inflammatory disorders have been reported (see “WARNINGS” section). Persistent but non-progressive vitiligo has been observed in metastatic malignant melanoma patients treated with interleukin-2.
Synergistic, additive and novel toxicities have been reported with PROLEUKIN used in combination with other drugs. Novel toxicities include delayed adverse reactions to iodinated contrast media and hypersensitivity reactions to antineoplastic agents
(see 
 “PRECAUTIONS” section). 
 Experience has shown the following concomitant medications to be useful in the management of patients on PROLEUKIN therapy:
a) standard antipyretic therapy, including non-steroidal anti-inflammatories (NSAIDs), started immediately prior to PROLEUKIN to reduce fever. Renal function should be monitored as some NSAIDs may cause synergistic nephrotoxicity; b) meperidine used
to control the rigors associated with fever; c) H2 antagonists given for prophylaxis of gastrointestinal irritation and bleeding; d) antiemetics and antidiarrheals used as needed to treat other gastrointestinal side effects. Generally these
medications were discontinued 12 hours after the last dose of PROLEUKIN. 
 Patients with in-dwelling central
lines have a higher risk of infection with gram positive organisms. A reduced incidence of staphylococcal infections in PROLEUKIN studies has been associated with the use of antibiotic prophylaxis which includes the use of oxacillin, nafcillin,
ciprofloxacin, or vancomycin. Hydroxyzine or diphenhydramine have been used to control symptoms from pruritic rashes and continued until resolution of pruri-tus. Topical creams and ointments should be applied as needed for skin manifestations.
Preparations containing a steroid (e.g., hydrocortisone) should be avoided. NOTE: Prior to the use of any product mentioned, the physician should refer to the Product Monograph for the respective product. 
 Immunogenicity: Fifty-seven of 77 (74%) metastatic renal cell carcinoma patients treated with an every 8-hour PROLEUKIN
regimen and 33 of 50 (66%) metastatic malignant melanoma patients treated with a variety of IV regimens developed low titers of non-neutralizing anti-PROLEUKIN antibodies. Neutralizing antibodies were not detected in this group of patients, but
have been detected in 1/106 (<1%) patients treated with IV PROLEUKIN using a wide variety of schedules and doses. The clinical significance of anti-PROLEUKIN antibodies is unknown. 
 SYMPTOMS AND TREATMENT OF OVERDOSAGE 
 Side effects following the use of PROLEUKIN*(aldesleukin) appear to be dose-related. Exceeding the recommended dose has been associated with a more rapid onset of expected dose-limiting
toxicities. Symptoms which persist after cessation of PROLEUKIN should be monitored and treated supportively. Life-threatening toxicities may be ameliorated by the intravenous administration of dexamethasone, which may result in loss of the
therapeutic effects of PROLEUKIN. NOTE: Prior to the use of dexamethasone, the physician should refer to the Product Monograph for this product. 
 DOSAGE AND ADMINISTRATION 
 The recommended
PROLEUKIN* (aldesleukin) treatment regimen is administered by a 15- minute IV infusion every 8 hours. Before initiating treatment, carefully review the “INDICATIONS AND CLINICAL USE,” “CONTRAINDICATIONS,” “WARNINGS,”
“PRECAUTIONS,” and “ADVERSE REACTIONS” sections, particularly regarding patient selection, possible serious adverse events, patient monitoring and withholding dosage. 
 The following schedule has been used to treat adult patients with metastatic renal cell carcinoma (metastatic RCC) or
metastatic malignant melanoma. Each course of treatment consists of two 5-day treatment cycles separated by a rest period. 
 600,000 IU/kg (0.037 mg/kg) dose administered every 8 hours by a 15-minute IV infusion for a maximum of 14 doses. Following 9 days of rest, the schedule is repeated for another 14 doses, for a maximum of 28 doses per course, as
tolerated. During clinical trials, doses were frequently withheld for toxicity (see “Clinical Experience” and “Dose Modifications” subsections). Metastatic RCC patients treated with this schedule received a median of 20 of the 28
doses during the first course of therapy. Metastatic malignant melanoma patients received a median of 18 doses during the first course of therapy. 
 Retreatment: Patients should be evaluated for response approximately 4 weeks after completion of a course of therapy and again immediately prior to the scheduled start of the next
treatment course. Additional courses of treatment should be given to patients only if there is some tumor shrinkage following the last course and retreatment is not contraindicated (see “CONTRAINDICATIONS” section). Each treatment course
should be separated by a rest period of at least 7 weeks from the date of hospital discharge. 
 Dose
Modifications: Dose modification for toxicity should be accomplished by withholding or interrupting a dose rather than reducing the dose to be given. Decisions to stop, hold, or restart PROLEUKIN therapy must be made after a global assessment of the
patient. With this in mind, the following guidelines should be used: 
 Retreatment with PROLEUKIN is
contraindicated in patients who experience the following toxicities: 
 Body System 
 Cardiovascular Sustained ventricular tachycardia (35 beats) 
 Cardiac rhythm disturbances not controlled or unresponsive to management 
 Chest pain with ECG changes, consistent with angina or myocardial infarction 
 Cardiac tamponade 
 Respiratory Intubation for > 72 hours 
 Urogenital Renal failure requiring dialysis > 72 hours 
 Nervous Coma or toxic psychosis
lasting > 48 hours 
 Repetitive or difficult to control seizures 
 Digestive Bowel ischemia/perforation 
 GI bleeding requiring surgery 
 Doses should be
held and restarted according to the following: 
 Body System Hold dose for Subsequent doses may be given if

 Cardiovascular Atrial fibrillation, supraventricular tachycardia, Patient is asymptomatic with full recovery
to 
 or bradycardia that requires treatment or is normal sinus rhythm 
 recurrent or persistent 
 Systolic bp <90 mm Hg with increasing Systolic bp 390 mm Hg and stable or improving 
 requirements for pressors requirements for pressors 
 Any ECG change consistent with MI, ischemia Patient is asymptomatic, MI and myocarditis have 
 or myocarditis with or without chest pain; been ruled out, clinical suspicion of angina is low; 
 suspicion of cardiac ischemia there is no evidence of ventricular hypokinesia 
 Respiratory O2 saturation < 94% on room air or O2 saturation > 94% on room air or > 90% 
 < 90% with 2 liters O2 by nasal prongs with 2 liters O2 by nasal prongs 
 Nervous Mental status changes, including moderate Mental status changes completely resolved 
 confusion or agitation 
 Body as a Whole Sepsis syndrome, patient is clinically unstable Sepsis syndrome has resolved, patient is 
 clinically stable, infection is under treatment 
 Urogenital Serum creatinine > 4.5 mg/dL or a serum Serum creatinine < 4 mg/dL and fluid and 
 creatinine of 34 mg/dL in the presence of electrolyte status is stable 
 severe volume overload, acidosis, or 
 hyperkalemia 
 Persistent oliguria, urine output of Urine output >10 mL/hour with a decrease of 
 < 10 mL/hour for 16 to 24 hours with serum creatinine > 1.5 mg/dL or 
 rising serum creatinine normalization of serum creatinine 
 Digestive Signs of hepatic failure including All signs of hepatic failure have resolved* 
 encephalopathy, increasing ascites, 
 liver pain, hypoglycemia 
 Stool guaiac repeatedly
>3-4+ Stool guaiac negative 
 Skin Bullous dermatitis or marked worsening of pre-existing skin condition,
avoid topical steroid therapy 
 Resolution of all signs of bullous dermatitis 
 *Discontinue all further treatment for that course. A new course of treatment, if warranted, should be initiated no sooner
than 7 weeks after cessation of adverse event and hospital discharge. 
 PHARMACEUTICAL INFORMATION 

PROLEUKIN* (aldesleukin), a human recombinant interleukin-2 product, is a highly purified protein with a molecular weight
of approximately 15,300 daltons. The chemical name is des-alanyl-1, serine-125 human interleukin-2. PROLEUKIN, a lymphokine, is produced by recombinant DNA technology using a genetically engineered E. coli strain containing an analog of the human
interleukin-2 gene. Genetic engineering techniques were used to modify the human interleukin-2 gene, and the resulting expression clone encodes a modified human interleukin-2. This recombinant form differs from native interleukin-2 in the following
ways: a) PROLEUKIN is not glycosylated because it is derived from E. coli; b) the molecule has no N-terminal alanine; the codon for this amino acid was deleted during the genetic engineering procedure; c) the molecule has serine substituted for
cysteine at amino acid position 125; this was accomplished by site specific manipulation during the genetic engineering procedure; and d) the aggregation state of PROLEUKIN is likely to be different from that of native interleukin-2. 
 The in vitro biological activities of the native non-recombinant molecule have been reproduced with PROLEUKIN. 
 PROLEUKIN biological potency is determined by a lymphocyte proliferation bioassay and is expressed in International Units
(IU) as established by the World Health Organization 1st International Standard for Interleukin 2 (human). The relationship between potency and protein mass is as follows: 18 million (18x106) IU PROLEUKIN = 1.1 mg protein Composition:
PROLEUKIN is supplied as a sterile, white to off-white, lyophilized cake in single-use vials intended for intravenous (IV) administration. When reconstituted with 1.2 mL Sterile Water for Injection, USP, each mL contains 18 million IU (1.1 mg)
PROLEUKIN, 50 mg mannitol, and 0.18 mg sodium dodecyl sulfate, buffered with approximately 0.17 mg monobasic and 0.89 mg dibasic sodium phosphate to a pH of 7.5 (range 7.2 to 7.8). The manufacturing process for PROLEUKIN involves fermentation in a
defined medium containing tetracycline hydrochloride. The presence of the antibiotic is not detectable in the final product. PROLEUKIN contains no preservatives in the final product. 
 Stability and Storage Recommendations: Store vials of lyophilized PROLEUKIN in a refrigerator at 2° to 8°C (36°
to 46°F). Avoid exposure to heat and light. 
 Reconstituted or diluted PROLEUKIN is stable for up to 48
hours at refrigerated and room temperatures, 2° to 25°C (36° to 77°F). However, since this product contains no preservative, the reconstituted and diluted solutions should be stored in the refrigerator. 
 Do not use beyond the expiration date printed on the vial. NOTE: This product contains no preservative. 
 Reconstitution: Reconstitution and dilution procedures other than those recommended may alter the delivery and/or
pharmacology of PROLEUKIN and thus should be avoided. 
 1. PROLEUKIN* (aldesleukin) is a sterile, white to
off-white, preservative-free, lyophilized powder suitable for IV infusion upon reconstitution and dilution. EACH VIAL CONTAINS 22 MILLION IU (1.3 MG) OF PROLEUKIN AND SHOULD BE RECONSTITUTED ASEPTICALLY WITH 1.2 ML 
 OF STERILE WATER FOR INJECTION, USP. WHEN RECONSTITUTED AS DIRECTED, EACH ML CONTAINS 18 MILLION IU (1.1 MG) OF PROLEUKIN.
The resulting solution should be a clear, colorless to slightly yellow liquid. The vial is for single-use only and any unused portion should be discarded. 
 2. During reconstitution, the Sterile Water for Injection, USP should be directed at the side of the vial and the contents gently swirled to avoid excess foaming. DO NOT SHAKE. 

3. The dose of PROLEUKIN, reconstituted with Sterile Water for Injection, USP (without preservative) should be diluted
aseptically in 50 mL of 
 5% Dextrose Injection, USP (D5W) and infused over a 15-minute period. 
 In cases where the total dose of PROLEUKIN is 1.5 mg or less (e.g., a patient with a body weight of less than 40 kilograms),
the dose of PROLEUKIN should be diluted in a smaller volume of D5W. 
 Concentrations of PROLEUKIN below 30
μg/mL and above 70 μg/mL have shown increased variability in drug delivery. Dilution and delivery of PROLEUKIN outside of this concentration range should be avoided. 
 4. Glass bottles and plastic (polyvinyl chloride) bags have been used in clinical trials with comparable results; it is
recommended that plastic bags be used as the dilution container since experimental studies suggest that use of plastic containers results in more consistent drug delivery. 
 In-line filters should not be used when administering PROLEUKIN. 
 5. Before and after reconstitution and dilution, store in a refrigerator at 2° to 8°C (36° to 46°F). Do not freeze. Administer PROLEUKIN within 48 hours of reconstitution. The solution should be brought to room
temperature prior to infusion in the patient. 
 6. Reconstitution or dilution with Bacteriostatic Water for
Injection, USP, or 0.9% Sodium Chloride Injection, USP should be avoided because of increased aggregation PROLEUKIN should not be co-administered with other drugs in the same container. 
 7. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration,
whenever solution and container permit. 
 DOSAGE FORMS 
 Availability: PROLEUKIN* (aldesleukin) is supplied as a sterile, white to off-white, preservative-free lyophilized product in
single-use vials containing 22 million IU (1.3 mg) intended for intravenous (IV) administration. When reconstituted with 1.2 mL Sterile Water for Injection, USP, each mL 
 contains 18 million IU (1.1 mg) of PROLEUKIN. Discard unused portion. 
 PHARMACOLOGY 
 Clinical: The pharmacokinetic profile of PROLEUKIN* (aldesleukin) is characterized by high plasma concentrations following a short intravenous infusion, rapid distribution to
extravascular, extracellular space, and elimination from the body by metabolism in the kidneys with little or no bioac-tive protein excreted in the urine. In humans the half lives for distribution and elimination are 13 and 85 minutes, respectively.
A third, slower phase of clearance has been observed in laboratory animals. The relatively rapid clearance rate of interleukin-2 has led to dosage schedules characterized by frequent bolus administrations or infusions. 
 PROLEUKIN is cleared from the body primarily (80-90%) by metabolism to amino acids in the cells lining the proximal
convoluted tubules of the kidneys. Access of the protein to the tubules is apparently by direct filtration at the glomerular membrane of Bowman’s capsule, and by peritubular extraction from the efferent arterioles surrounding the proximal
tubules. This dual mechanism for access to the tubules may account for the normal clearance pattern of interleukin-2 in patients experiencing kidney toxicity with serum creatinine values between 1.5 and 3 mg/dL. Limited data suggest that serum
creatinine greater than 3 mg/dL may correlate with an extended elimination half life. 
 In clinical studies,
PROLEUKIN was diluted in 5% Dextrose Injection, USP (D5W), D5W containing 0.1% human serum albumin (HSA), or 5% HSA in normal saline. Pharmacokinetic studies showed that a higher amount of bioactive drug was found in the circulation of animals dosed
with solutions containing HSA. Preclinical efficacy studies in a murine tumor model showed no differences when the dose was diluted in either 5% HSA in normal saline or 0.1% HSA in D5W. However, it appeared that no difference in either objective
response rate, or on-study mortality were observed in groups of patients receiving PROLEUKIN diluted in different ways. 
 CLINICAL EXPERIENCE 
 Two hundred fifty-five patients with metastatic renal cell cancer
(metastatic RCC) were treated with single agent PROLEUKIN in 7 clinical studies conducted at 21 institutions. Two hundred seventy patients with metastatic malignant melanoma were treated with single agent PROLEUKIN in 8 clinical studies conducted at
22 institutions. Patients enrolled in trials of single agent PROLEUKIN were required to have an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 and normal organ function as determined by cardiac stress test, pulmonary
function tests, and creatinine ?1.5 mg/dL. Patients with brain metastases, active infections, organ allografts and diseases requiring steroid treatment were excluded. 
 PROLEUKIN was given by 15 min IV infusion every 8 hours for up to 5 days (maximum of 14 doses). No treatment was given on days 6 to 14 and then dosing was repeated for up to 5 days on days
15 to 19 (maximum of 14 doses). These 2 cycles constituted 1 course of therapy. Patients could receive a maximum of 28 doses during a course of therapy. In practice >90% of patients had doses withheld. Metastatic RCC patients received a median of
20 of 28 scheduled doses of PROLEUKIN. Metastatic malignant melanoma patients received a median of 18 of 28 scheduled doses of PROLEUKIN during the first course of therapy. Doses were withheld for specific toxicities (see “DOSAGE AND
ADMINISTRATION” section, “Dose Modifications” subsection and “ADVERSE REACTIONS” section). 
 In the renal cell cancer studies (n=255), objective response was seen in 37 (15%) patients, with 17 (7%) complete and 20 (8%) partial responders. The 95% confidence interval for objective response was 11% to 20%. Onset
of tumor regression was observed as early as 4 weeks after completion of the first course of treatment, and in some cases, tumor regression continued for up to 12 months after the start of treatment. The median duration of response for all
responding patients is 54 months (3 to 131+ months). The median duration for patients with complete responses has not yet been observed and for patients with partial response was 20 months. Twelve patients who achieved a complete response and six
patients who achieved a partial response had responses ongoing at the time of last contact. The median progression-free survival for all responding patients was 55 months. Responses were observed in both lung and non-lung sites (e.g., liver, lymph
node, renal bed occurrences, and soft tissue). Of the 37 responding patients, 12 patients with individual bulky lesions (largest lesion > 25 cm2) and 22 patients with large cumulative tumor burden (total > 26 cm2) achieved responses.

 In the metastatic malignant melanoma studies (n=270), objective response was seen in 43 (16%) patients,
with 17 (6%) complete and 26 (10%) partial responders. The 95% confidence interval for objective response was 12% to 21%. The median duration of response for all responding patients was 9 months (1 to 122+ months); the median duration of
objective complete responses has not been observed and the median duration for partial response was 6 months. Ten patients who achieved a complete response and three patients who achieved a partial response had responses ongoing at the time of last
contact. The median progression-free survival for the 43 responding patients was 13 months. Responses in metastatic malignant melanoma patients were observed in both visceral and non-visceral sites (e.g., lung, liver, lymph node, soft tissue,
adrenal, subcutaneous). Of the 43 responding patients, 14 patients with individual bulky lesions (largest lesion > 25 cm2) and 21 patients with large cumulative tumor burden (total > 25 cm2) achieved responses. 
 TABLE IV: PROLEUKIN CLINICAL RESPONSE DATA 
 METASTATIC RCC METASTATIC MALIGNANT MELANOMA 
 Number of Median Response Number of Median Response 
 Responding Patients Duration in Months
Responding Patients Duration in Months 
 (response rate)(range)(response rate)(range) 
 CR’s 17 (7%) 80+* (7 to 131+) 17 (6%) 59+* (3 to 122+) 
 PR’s 20 (8%) 20 (3 to 126+) 26 (10%) 6 (1 to 111+) 
 PR’s + CR’s 37 (15%) 54 (3 to 131+) 43 (16%) 9 (1 to 122+) 
 (+) sign means ongoing 
 *Median duration not yet observed; a conservative value is presented which represents the minimum median duration of response. 
 *PROLEUKIN is a registered trademark of Novartis Vaccines and Diagnostics, Inc. used under permission by Novartis
Pharmaceuticals Canada inc. 
 Novartis Pharmaceuticals Canada inc., 385 Bouchard Blvd., Dorval, Quebec H9S 1A9

 709558-EI 
 Last Revised: July 6th, 2006 
 E-26

  

 E-26 

 

 
 Novartis 
 PROLEUKIN* (aldesleukine) 
 Interleukine-2 22 millions IU/Flacon 
 Norme
pharmaceutique: Modificateur de la réponse biologique 
 ACTIONS, PHARMACOLOGIE CLINIQUE 
 PROLEUKIN* (aldesleukine) est analogue à l’interteukine-2 humaine, et elle est produite par technologie
d’ADN recombinant, elle possède une activité biologique analogue à celle de l’interteukine-2 native humaine. PROLEUKIN possède un pouvoir antitumoral, on ignore par quel mécanisme précis PROLEUKIN
exerce son pouvoir antitumoral chez les animaux et chez les humains. 
 Des études in vitro sur des
lignée cellulaires humaines démontrent les propriétés immunorégulatoires de PROLEUKIN, incluant: a) une mitogénèse accrue des lymphocytes et stimulation d’une croissance à long terme des
lignées cellulaires humaines dépendantes de l’interleukine-2; b) une lymphocytoxicité plus poussée; c) une induction de l’activité des cellules tueuses dites LAK (lymphokine activated killer) et NK
(natural killer); et, d) l’induction de la production d’interféron gamma. 
 L’administration in vivo de PROLEUKIN chez les animaux et les humains entraîne de multiples effets immunologiques liés à la dose. Ces effets comprennent l’activation de l’immunité cellulaire
avec lymphocytose, eosinophilie et thrombocytopénie importantes, et la production de cytokines, dont le facteur de nécrose des tumeurs, IL-1 et l’interféron gamma. Les études in vivo sur des modèles de tumeur
murine ont démontré une inhibition de la croissance de la tumeur. 
 Pharmacocinétique :
PROLEUKIN se compose de micro-agrégats biologiquement actifs, à liaisons non covalentes, dont la taille moyenne est de 27 molécules d’interleukine-2 recombinante. L’agent de solubilité, le dodécytsulfate
de sodium, peut avoir un effet sur les propriétés cinétiques de ce produit. Le profil pharmacocinétique de PROLEUKIN se caractérise par des concentrations plasmatiques élevées suite à une
perfusion intraveineuse (IV) de courte durée, une distribution rapide dans l’espace extravasculaire et par élimination rénale, avec peu à aucune protéine bioactive excrétée dans les urines.

 Les études au cours desquelles PROLEUKIN a été injectée par IV à des
moutons et des humains ont montré qu’une fois la perfusion terminée, environ 30 % de la dose administrée est détectable dans le plasma. Ceci concorde avec les études faites sur les rats à
l’aide de PROLEUKIN radio-marquée qui démontrent une capture rapide (< 1 minute) de la quasi-totalité du marqueur dans les poumons, le foie, les reins et la rate. 
 Les courbes de demi-vie sérique (T1/2) de PROLEUKIN restant dans le plasma sont tirées d’études
conduites sur 52 patients atteints d’un cancer, après qu’ils ont reçu une perfusion IV de 5 minutes. Les études ont montré que chez ces patients, le temps de distribution et d’élimination de T1/2
était respectivement de 13 et 85 minutes. 
 Le taux de clairance relativement rapide de PROLEUKIN a
conduit à des schémas posologiques caractérisés par des perfusions fréquentes et de courte durée. Les taux sériques observés sont proportionnels à la dose de PROLEUKIN. 
 Après la distribution initiale rapide dans les organes, la voie de clairance principale du PROLEUKIN en circulation
est le rein. Chez les humains et les animaux, l’élimination de PROLEUKIN se fait par filtration glomérulaire et par extraction péritubulaire dans le rein. Il est possible que ce double mécanisme de livraison de
PROLEUKIN au tube proximal soit responsable de la préservation de la clairance chez les patients dont les valeurs de créatinine sérique sont en hausse. Plus de 80 % de la quantité PROLEUKIN qui est distribuée
au plasma, éliminée de la circulation et délivrée aux reins se métabolise en acide aminé dans les cellules qui tapissent les tubes contournés proximaux. Chez les humains, le taux de clairance moyen
des patients cancéreux est de 268 mL/mn. 
 INDICATIONS ET UTILISATION CLINIQUE 
 PROLEUKIN* (aldesleukine) est indiquée pour le traitement d’adultes (de 18 ans ou plus) atteints d’un
adénocarcinome rénal métastatique. PROLEUKIN est indiquée pour le traitement d’adultes (de 18 ans ou plus) atteints d’un mélanome malin métastatique. 
 Parmi les 255 patients atteints d’un adénocarcinome rénal métastatique, une réponse
objective fut observée chez 37 des patients (15 %), avec 17 (7 %) patients répondeurs complets (PRC) et 20 (8 %) patients répondeurs partiels (PRP). Parmi les 270 patients atteints d’un mélanome malin
métastatique, une réponse objective fut observée chez 43 des patients (16 %), avec 17 (6 %) patients répondeurs complets et 26 (10 %) patients répondeurs partiels. Avant de prendre part à ces études,
les patients avaient vu leur maladie progresser après avoir suivi des thérapies antérieures. Une majorité des patients (96 %) avaient déjà subi une résection chirurgicale de leur lésion
primaire, un curage ganglionnaire ou montré une zone de récidive. 
 Il est obligatoire de bien
choisir les patients avant d’administrer PROLEUKIN. Voir les sections « CONTRE-INDICATIONS », 
 « AVERTISSEMENTS » et « MISES EN GARDE » en ce qui concerne la sélection des patients, y compris les examens recommandés de la fonction cardiaque et respiratoire et les analyses de laboratoire.

 À ce jour, l’évaluation des études cliniques révèle que les patients
ayant un indice fonctionnel ECOG plus favorable, c’est-à-dire égal à 0, au début du traitement répondent mieux à PROLEUKIN, ils ont un taux de réponse plus élevé et une
toxicité plus faible (voir la section « EFFETS INDESIRABLES »). C’est pourquoi l’évaluation de l’indice fonctionnel doit être inclue lors de la sélection des patients pour le traitement.
L’expérience avec des patients ayant un indice fonctionnel ECOG > 1 est limitée. 
 TABLEAU
I : RÉPONSE CLINIQUE À PROLEUKIN PAR ÉTAT D’INDICE FONCTIONNEL (IF) ECOG 
 Prétraitement ADÉNOCARCINOME RÉNAL MÉTASTATIQUE MÉLANOME MALIN MÉTASTATIQUE 
 IF ECOG PRC PRP PRC PRP 
 0 14/166 (8 %) 16/166 (10 %) 14/191 (7 %) 22/191 (12 %)

 > 1 3/89 (3 %) 4/89 (4 %) 3/79 (4 %) 4/79 (5 %) 
 CONTRE-INDICATIONS 
 PROLEUKIN* (aldesleukine) est contre-indiquée chez les patients ayant des antécédents connus d’hypersensibilité à l’interleukine-2 ou tout
autre composant entrant dans la composition de PROLEUKIN. 
 Les patients qui obtiennent des résultats
anormaux à l’épreuve d’effort au thallium ou aux examens de la fonction respiratoire et ceux qui ont des allogreffes d’organe ne doivent pas être traités avec PROLEUKIN. De plus, une réadministration
de PROLEUKIN est contre-indiquée chez les patients qui ont manifesté les toxicités suivantes lors d’une première cure : 
 Tachycardie ventriculaire prolongée (??5 battements) 
 Troubles du rythme cardiaque non maîtrisés ou ne répondant pas 
 Douleur
thoracique récurrente accompagnée de modifications de poitrine ou un infarctus du myocarde 
 Tamponnade cardiaque 
 Intubation exigée > 72 heures 
 Dysfonctionnement rénal exigeant une dialyse > 72 heures 
 Coma ou psychose toxique se prolongeant au-delà de 48 heures 
 Crises à répétitions ou difficiles à calmer 
 Ischémie ou perforation intestinale 
 Hémorragie gastro-intestinale nécessitant une intervention chirurgicale 
 AVERTISSEMENTS 
 PROLEUKIN* (aldesleukine) ne doit
être administrée qu’à des patients ayant été bien informés, dans un cadre hospitalier, sous la surveillance d’un médecin qualifié et rompu au traitement du cancer par agents
thérapeutiques. Une unité de soins intensifs et des spécialistes compétents en médecine cardio-pulmonaire ou en soins intensifs doivent être disponibles. 
 L’administration de PROLEUKIN a été associée au syndrome de fuite capillaire (SFC) qui se
caractérise par la perte de tonicité vasculaire, l’épanchement de protéines et de fluide du plasma dans l’espace extravasculaire. Le SFC entraîne une hypotension et une réduction de
l’irrigation sanguine des organes qui peut être grave et causer la mort. Le SFC peut être associé à des arythmies cardiaques (supraventriculaires et ventriculaires), angine de poitrine, infarctus du myocarde,
insuffisance respiratoire nécessitant une intubation, hémorragie gastro-intestinale ou infarctus de l’intestin, insuffisance rénale, œdème et changements de l’humeur. 
 En raison des effets indésirables graves qui accompagnent généralement le traitement par PROLEUKIN aux
posologies recommandées, une évaluation clinique approfondie doit être effectuée pour identifier les patients qui ont d’importantes insuffisances cardiaques, pulmonaires, rénales, hépatiques ou du
système nerveux central car PROLEUKIN est contre-indiquée chez ces patients. 
 Le traitement par
PROLEUKIN doit être réservé aux patients dont les fonctions pulmonaire et cardiaque sont normales d’après les résultats de l’épreuve au thallium et les examens de la fonction respiratoire. Il faut
faire preuve d’une extrême prudence chez les patients avec des résultats normaux à l’épreuve au thallium et aux examens de la fonction respiratoire qui ont des antécédents de maladie cardiaque ou
pulmonaire. 
 Les patients ayant une fonction cardio-vasculaire, pulmonaire, hépatique et nerveuse
normale peuvent subir des effets indésirables graves, mettant leur vie en danger ou entraînant leur décès. Les effets indésirables sont fréquents, souvent graves et entraînent parfois la mort. Si des
effets indésirables apparaissent et que la dose doit être modifiée, il est préférable d’interrompre le posologie plutôt que de la réduire (voir le paragraphe « Modification de le dose »
dans le section « POSOLOGIE ET ADMINISTRATION »). 
 L’administration de PROLEUKIN a
été associée à une exacerbation d’une maladie auto-immune préexistante ou débutante et des troubles inflammatoires. Une exacerbation des maladies suivantes a été rapportée
après un traitement avec l’IL-2 : maladie de Crohn, sclérodermie, thyroïdite, arthrite inflammatoire, diabète sucré, myasthénie grave oculobulbaire, néphropathie à lgA en forme de croissant,
cholécystite, vascularite cérébrale, syndrome de Stevens-Johnson et pemphigoïde bulleuse. 
 Tous les patients doivent subir une évaluation approfondie, un traitement des métastases du S.N.C. et avoir un scintigramme négatif avant de débuter la PROLEUKIN. De nouveaux signes et symptômes
neurologiques et lésions anatomiques sont apparus à la suite d’un traitement par PROLEUKIN chez des patients qui ne montraient aucune évidence de métastases du S.N.C. Les manifestations cliniques incluent des
changements de l’humeur, troubles de la parole, cécité corticale, ataxie des membres, hallucinations, agitation, obnubilation et coma. Les images obtenues par I.R.M. ont montré de multiples, et moins souvent, de simples
lésions corticales et mis en évidence une démyélinisation. Les signes et symptômes neurologiques associés à la prise de PROLEUKIN disparaissent normalement à l’arrêt du traitement;
cependant, des anomalies neurologiques permanentes ont été signalées. Un cas de vascularite cérébrale, en réponse à la dexaméthasone, a été rapporté. Il faut faire preuve
d’une extrême prudence avec les patients ayant des antécédents de crises épileptiques, du fait que PROLEUKIN peut provoquer des crises d’épilepsie. 
 L’administration de PROLEUKIN doit être suspendue chez les patients qui manifestent des états
léthargiques ou somnolents modérés ou profonds, la poursuite du traitement pouvant entraîner un coma. 
 Le traitement par PROLEUKIN a été associé à une détérioration de la fonction neutrophile (chimiotactisme réduit) et à des risques accrus d’infection
disséminée, y compris les septicémies et endocardites bactériennes. Par conséquent, il importe de traiter convenablement toutes les infections bactériennes préexistantes avant de débuter la
thérapie par PROLEUKIN. Les patients qui ont des lignées germinales à demeure sont particulièrement exposés aux risques d’infection par des micro-organismes Gram positifs. La prophylaxie antibiotique qui a
été associée à une incidence réduite d’infections staphylococciques comprend l’usage d’oxacilline, de nafcilline, de ciprofloxacine ou de vancomycine. Les infections disséminées
acquises durant le traitement par PROLEUKIN contribuent largement à la morbidité liée au traitement et l’utilisation d’une prophylaxie antibiotique et un traitement agressif des infections soupçonnées ou
documentées pourraient réduire la morbidité liée au traitement par PROLEUKIN. REMARQUE : Avant d’utiliser tout produit mentionné dans ce paragraphe, le médecin devra consulter la monographie du produit
utilisé. 
 MISES EN GARDE 
 Mises en garde générales : Les patients doivent avoir une fonction cardiaque, pulmonaire, hépatique et nerveuse normale en début de traitement. Les patients
atteints d’un adénocarcinome rénal métastatique ayant subi une néphrectomie peuvent quand même être admis si leur taux de créatinine sérique est ?1,5 mg/dL. 
 Les patients ayant une fonction cardio-vasculaire, pulmonaire, hépatique et nerveuse normale peuvent subir des effets
indésirables graves, mettant leur vie en danger ou entraînant leur décès. Les effets indésirables sont fréquents, souvent graves et entraînent parfois la mort. Le syndrome de fuite capillaire (SFC.) se
produit immédiatement après le commencement du traitement par PROLEUKIN* (aldesleukine) et se traduit par une augmentation de la perméabilité capillaire aux protéines et aux fluides et par une perte de
tonicité. Chez la plupart des patients, ceci résulte en une chute concomitante de la tension artérielle moyenne dans les 2 à 12 heures qui suivent le début du traitement. Si le traitement est poursuivi, il en
résultera une hypotension significative du point de vue clinique (définie en tant que pression sanguine systolique en dessous de 90 mm Hg ou une chute de 20 mm Hg par rapport à la pression systolique à sa valeur initiale)
et une hypoperfusion s’en suivra. En outre, un épanchement de protéines et de liquides dans l’espace extravasculaire entraînera des œdèmes et de nouveaux épanchements. 
 La prise en charge médicale du syndrome de fuite capillaire commence par une surveillance vigilante de
l’état hydrique et d’irrigation d’organe du patient. Ceci s’accomplit en mesurant fréquemment la tension artérielle et le pouls et en surveillant la fonction des organes, ce qui comprend
l’évaluation de l’état mental et du débit urinaire. L’hypovolémie est évaluée au moyen d’un cathétérisme et en surveillant la pression veineuse centrale. 
 Une gestion souple des fluides et des vasopresseurs est indispensable pour le maintien de l’irrigation d’organe et
de la tension artérielle. Par conséquent, il faudra faire preuve d’une extrême prudence dans le traitement de patients qui exigent ponctuellement de grandes quantités de liquides (par ex. les patients souffrant
d’hypercalcémie). 
 La prise en charge des patients qui ont une hypovolémie implique
l’administration de liquides intraveineux, soit colloïdes, soit cristalloïdes. Les liquides intraveineux sont généralement administrés lorsque le pression veineuse centrale (P.V.C.) est en dessous de 3 à 4
mm H2O. Il se peut qu’il faille employer d’importantes quantités de liquides IV afin de corriger une hypovolémie, mais il faut alors être très prudent car l’administration non limitée de liquides peut
exacerber les problèmes liés à la formation d’œdèmes ou aux épanchements. 
 Lorsqu’il y a une accumulation de liquides extravasculaires, la formation d’œdèmes est commune et des ascites ainsi que des épanchements pleuraux ou péricardiques peuvent se développer. La
prise en charge de ces événements repose sur un équilibre judicieux des effets des échanges hydriques de façon à ce que ni les conséquences de l’hypovolémie (par ex. réduction de
l’irrigation sanguine des organes) ni les conséquences de l’accumulation de liquide (par ex. oedème pulmonaire) ne dépassent la tolérance du patient. 
 L’étude clinique a démontré que l’administration précoce de dopamine (1 à 5
μg/kg/mn) aux patients manifestant un syndrome de fuite capillaire, avant l’apparition de l’hypotension, peut aider à maintenir l’irrigation sanguine de l’organe particulièrement du rein, préservant
ainsi le débit urinaire. Le poids et le débit urinaire doivent être soigneusement surveillés. Si l’irrigation sanguine d’organe et la pression artérielle se sont pas entretenues par une thérapie par
dopamine, les experts cliniciens ont augmenté la dose de dopamine de 6 à 10 μg/kg/mn ou ont ajouté du chlorhydrate de phényléphrine (1 à 5 μg/kg/mn) à une faible dose de dopamine.
L’utilisation prolongée de vasopresseurs, que ce soit un seul ou une combinaison de plusieurs, à des doses relativement élevées peut être associée à des troubles du rythme cardiaque. Il a
été démontré que l’emploi de diurétiques (une fois que la pression artérielle est redevenue normale) accélère le rétablissement dans les cas où il y a eu une prise de poids
excessive ou la formation d’un œdème, notamment associées à un essoufflement dû à une congestion pulmonaire. REMARQUE : Avant d’utiliser tout produit mentionné dans ce paragraphe, le
médecin devra consulter la monographie du produit utilisé. 
 Une irrigation d’organe
insuffisamment maintenue, se traduisant par une modification de la conscience, une réduction du débit urinaire, une chute de la pression systolique au-dessous de 90 mm Hg ou le début d’arythmies cardiaques, entraînera
automatiquement la suspension du traitement par PROLEUKIN (voir le paragraphe « Modification de la dose » dans la section « POSOLOGIE ET ADMINISTRATION »). Le syndrome de fuite capillaire commence à se corriger peu
après la fin du traitement par PROLEUKIN. Normalement, en quelques heures la tension artérielle augmente, l’irrigation sanguine d’organe se rétablit et une réabsorption des liquides et protéines
épanchés commencent à se produire. On administrera de l’oxygène au patient si la surveillance de la fonction respiratoire confirme que la PaO2 a baissé. 
 Il est possible que l’administration de PROLEUKIN cause une anémie et (ou) une thrombocytopénie. On
administre des transfusions d’hématites concentrées, à la fois pour soigner l’anémie et pour garantir un transport d’oxygène maximal. On administre des transfusions de plaquettes pour corriger une
thrombocytopénie absolue et pour réduire les risques d’hémorragie gastro-intestinale. En outre, on observe des leucopénies et des neutropénies. 
 L’administration de PROLEUKIN entraîne des effets secondaires tels que fièvre, frissons, raideurs, prurits
et troubles gastro-intestinaux chez la plupart des patients traités aux doses recommandées. Ces effets secondaires ont été énergiquement maîtrisés de la manière décrite dans la partie
intitulée « EFFETS INDESIRABLES ». 
 Les fonctions rénale et hépatique sont
insuffisantes pendant le traitement par PROLEUKIN. L’utilisation de médicaments concomitants connus pour leurs effets néphrotoxiques ou hépatotoxiques augmente probablement davantage les effets toxiques sur le rein ou le
foie. 
 Les changements d’humeur tels qu’une irritabilité, une confusion ou une
dépression au cours du traitement par PROLEUKIN peuvent être le signal d’une bactériémie ou d’une septicémie bactérienne à ses débuts, d’une hypoperfusion, une malignité
occulte du S.N.C. ou une toxicité du S.N.C. directe provoquée par PROLEUKIN. Les changements d’humeur qui sont uniquement dus à PROLEUKIN peuvent progresser pendant plusieurs jours avant que le rétablissement ne
commence. Il est rare que les patients souffrent d’anomalies neurologiques permanentes (voir la section « EFFETS INDESIRABLES »). 
 Une exacerbation d’une maladie auto-immune pré-existante ou débutante et des troubles inflammatoires a été signalée suite au traitement par
PROLEUKIN employée seule ou en combinaison avec l’interféron (voir la section « EFFETS INDESIRABLES »). Suite au traitement par PROLEUKIN, on a noté une insuffisance de la fonction thyroïdienne qui est
quelquefois précédée d’une hyperthyroïdie. Un petit nombre de ces patients a nécessité une thérapie thyroïdienne de remplacement. Il se peut que cette insuffisance de la fonction
thyroïdienne soit une manifestation d’auto-immunité. L’apparition d’hyperglycémie et (ou) de diabète sucré a été signalée au cours du traitement par PROLEUKIN. Le renforcement de
la fonction d’immunité cellulaire causé par PROLEUKIN peut augmenter les risques de rejet d’allogreffes chez les patients qui ont reçu un transplant. 
 Tests de laboratoire : Les évaluations cliniques suivantes sont recommandées pour tous les patients, avant que
ne commence le traitement, puis quotidiennement pendant la durée d’administration du médicament. 
 Analyses hématologiques standard, y compris hémogramme, formule leucocytaire et numération plaquettaire 
 Analyses de chimie sanguine, y compris ionogramme sanguin, épreuves fonctionnelles hépatiques et rénales 
 Radiographies pulmonaires 
 Le taux de créatinine sérique doit être ?1,5 mg/dL avant de débuter le traitement par PROLEUKIN. 
 Tous les patients doivent passer un examen de la fonction respiratoire à l’état de base avec
gazométrie artérielle. Une fonction pulmonaire 
 adéquate doit être relevée
(FEV1 > 2 litres ou ??75 % du résultat prévu pour un sujet de cette taille et de cet âge) avant de commencer le traitement.Tous les patients doivent subir un dépistage au moyen d’une épreuve d’effort au
thallium. Les résultats doivent montrer une fraction d’éjection normale et un mouvement normal de la paroi. Si l’épreuve au thallium décèle des anomalies du mouvement de la paroi mineure, d’autres
tests sont suggérés afin d’exclure une maladie coronarienne significative. 
 La surveillance
quotidienne pendant le traitement par PROLEUKIN doit inclure la surveillance des signes vitaux (température, pouls, tension artérielle et taux respiratoire), du poids ainsi que de la prise et du rejet des liquides. Chez les patients
dont la tension artérielle est en baisse, notamment en dessous de 90 mm Hg, on doit surveiller en permanence le rythme cardiaque. Si on note un complexe ou un rythme anormal, il faut effectuer un électrocardiogramme. Les signes vitaux
des patients qui sont hypotensifs doivent être mesurés toutes les heures. Pendant le traitement, il faut surveiller de façon routinière la fonction respiratoire par des examens cliniques, l’évaluation des
signes vitaux et oxymétrie du pouls. Les sujets manifestant une dyspnée ou les signes cliniques d’une insuffisance respiratoire (trachypnée ou râles) doivent subir des examens plus poussés par gazométrie
artérielle. On doit répéter ces tests aussi souvent qu’ils seront cliniquement indiqués. La fonction cardiaque doit être mesurée quotidiennement par examen clinique et par évaluation des signes
vitaux. Les patients qui manifestent des signes ou des symptômes de douleurs thoraciques, souffles du cœur, bruits de galop, rythmes cardiaques irréguliers ou de palpitations doivent être soumis à un ECG et une analyse
de la créatine-phosphokinase (CPK). Des lésions myocardiaques ont été rapportées, y compris des observations compatibles avec un infarctus du myocarde ou une myocardite. Une hypocinésie ventriculaire due
à une myocardite peut durer pendant plusieurs mois. Si des examens montrent l’existence d’ischémie ou d’insuffisance cardiaque congestive, il faut arrêter le traitement par PROLEUKIN et procéder de nouveau
à une épreuve au thallium. 
 Interactions médicamenteuses : PROLEUKIN peut affecter la
fonction nerveuse centrale. Par conséquent, des interactions peuvent se produire suite à l’administration concomitante de médicaments psychotropiques tels que narcotiques, analgésiques, antiémétiques,
sédatifs et tranquillisants. 
 L’administration de médicaments ayant des effets
néphrotoxiques (par exemple des aminosides, de l’indométhacine), myélotoxiques (par exemple une chimiothérapie cytotoxique), cardiotoxiques (par exemple la doxorubicine) ou hépatotoxiques (par exemple le
méthotrexate ou l’asparaginase), en concomitance avec PROLEUKIN peut accroître la toxicité dans ces systèmes d’organe. La sécurité et l’efficacité de PROLEUKIN en combinaison avec des
antinéplastiques n’ont pas été établies. 
 De plus, l’insuffisance
rénale et hépatique secondaire au traitement par PROLEUKIN peut retarder l’élimination des médicaments concomitants et augmenter le risque des effets indésirables de ces médicaments. 
 Des réactions d’hypersensibilité ont été rapportées chez les patients recevant des
schémas de combinaisons contenant une dose élevée séquentielle de PROLEUKIN et des agents anticancéreux, notamment de la dacarbazine, du cis-platinum, du tamoxifène et de l’interféron alpha. Ces
réactions consistent en un érythème, un prurit et une hypotension et sont apparues dans les heures qui ont suivi l’administration de la chimiothérapie. Pour certains patients, ces réactions ont demandé
une intervention médicale. Il semble que les lésions myocardiques, y compris un infarctus du myocarde, une myocardite, une hypocinésie ventriculaire et une rhabdomyolyse sévère soient plus nombreuses chez les
patients recevant PROLEUKIN et l’interféron alpha simultanément. 
 Suite à
l’administration concomitante d’interféron alpha et de PROLEUKIN, on a observé l’exacerbation ou le début de nombreux troubles auto-immuns et inflammatoires tels néphropathie à IgA en forme de
croissant, myasthénie grave oculobulbaire, arthrite inflammatoire, thyroïdite, pemphigoïde bulleuse et syndrome de Stevens-Johnson. 
 Bien qu’on ait démontré que les glucocorticoïdes réduisent les effets secondaires provoqués par PROLEUKIN, y compris fièvre, insuffisance
rénale, hyperbilirubinémie, confusion et dyspnée, l’administration concomitante de ces agents avec PROLEUKIN peut limiter l’efficacité antitumorale de PROLEUKIN et doit, par conséquent, être
évitée. 
 Les inhibiteurs B-adrénergiques et autres antihypotenseurs peuvent exacerber
l’hypotension que l’on remarque avec PROLEUKIN. 
 Réactions indésirables à
retardement des produits de contraste iodés : Une analyse de la documentations a révélé que 12,6 % (plage entre 11 et 28 %) des 501 patients traités par divers régimes à base
d’interleukine-2, auxquels on avait ensuite administré des produits de contraste iodés, manifestèrent des réactions indésirables aiguës atypiques. Les symptômes apparaissaient en
général dans les quelques heures (le plus souvent d’une à quatre heures) après l’administration des produits de contraste. Ces réactions comprennent fièvre, frissons, nausée, vomissement,
prurit, éruption cutanée, diarrhée, hypotension, œdème et oligurie. Certains cliniciens ont remarqué que ces réactions ressemblent aux effets secondaires immédiats provoqués par
l’administration d’interleukine-2; on ignore toutefois la cause des réactions indésirables aux produits de contraste suivant un traitement par interleukine-2. On a remarqué que la plupart de ces incidents se
produisaient lorsque des produits de contraste étaient administrés dans les quatre semaines qui suivaient la dernière prise d’interleukine -2. Ces incidents ont également été signalés lorsque les
produits de contraste étaient utilisés plusieurs mois après le traitement à base d’interleukine-2. Carcinogenèse, mutagenèse, altération de la fécondité : Aucune étude
n’a été menée afin d’évaluer le potentiel carcinogénique ou mutagénique de PROLEUKIN. 
 Aucune étude n’a été menée afin d’évaluer les effets de PROLEUKIN sur la fécondité. Par conséquent, le produit ne doit
être administré qu’à des sujets se soumettant à une méthode efficace de contraception. 
 Utilisation pendant la grossesse : Donnée à des rats des doses de 27 à 36 fois celles des humains (calculées par poids corporel), PROLEUKIN a montré avoir des effets mortels sur l’embryon. Des
toxicités maternelles ont été observées chez les rates enceintes chez qui on avait administré PROLEUKIN par injection IV à des doses 2,1 à 36 fois supérieures à la dose humaine durant la
période critique de l’organogenèse. Aucune tératogénicité autre que celle attribuée à la toxicité maternelle n’a été observée. Il n’y a aucune étude
contrôlée adéquate concernant PROLEUKIN chez les femmes enceintes. PROLEUKIN ne doit être administrée durant la grossesse que si le bénéfice potentiel pour la femme enceinte justifie le risque potentiel
pour le fœtus. 
 Utilisation pendant l’allaitement : L’excrétion de PROLEUKIN dans le lait
maternel n’a pas été étudiée. Étant donné qu’un grand nombre de médicaments est excrété dans le lait maternel et en raison du potentiel d’effets indésirables graves
provoqués par PROLEUKIN sur les nourrissons allaités, on doit prendre la décision soit d’arrêter l’allaitement soit d’arrêter le traitement, en tenant compte de l’importance du médicament
pour la mère. 
 Usage pédiatrique : La sécurité et l’efficacité de ce
médicament chez les enfants de moins de 18 ans n’ont pas été établies. 
 EFFETS
INDESIRABLES 
 Le taux de morbidité liée au traitement parmi les 255 patients atteints d’un
adénocarcinome rénal métastatique ayant reçu l’agent unique PROLEUKIN* (aldesleukine) s’est élevé à 4 % (11 sur 255). Le taux de morbidité au traitement parmi les 270 patients
atteints d’un mélanome malin métastatique ayant reçu l’agent unique PROLEUKIN (aldesleukine) s’est élevé à 2 % (6 sur 270). 
 Les données sur les effets indésirables communs ci-dessous (rapportés chez plus de 10 % des
patients, quel que soit le stade) sont présentées par organe, par fréquence d’apparition et par terme de préférence (COSTART). Ces données sont basées sur 525 patients (255 souffrant d’un
adénocarcinome rénal métastatique et 270 souffrant d’un mélanome malin métastatique) auxquels les doses recommandées ont été injectées. 
 TABLEAU II : EFFETS INDÉSIRABLES RAPPORTÉS CHEZ PLUS DE 10 % DES PATIENTS (N=525) 
 Organe% de patients Organe% de patients 
 Manifestations générales Troubles métaboliques et nutritionnels 
 Frissons 52 Bilirubinémie 40 
 Fièvre
29 Elévation de la créatinine 33 
 Malaise général 27 Œdème
périphérique 28 
 Asthénie 23 Élévation de la SGDl 23 
 Infection 13 Prise de poids 16 
 Douleur générale 12 Œdème 15 
 Douleur abdominale 11 Acidose 12 
 Augmentation de l’abdomen 10
Hypomagnésémie 12 
 Manifestations cardio-vasculaires Hypocalcémie 11 
 Hypotension 71 Élévation des phosphatases alcalines 10 
 Tachycardie 23 Manifestations neuropsychiques 
 Vasodilatation 13 Contusion 34 
 Tachycardie
supraventriculaire 12 Somnolence 22 
 Trouble cardio-vasculairesa 11 Anxiété 12 
 Arythmie 10 Vertiges 11 
 Troubles digestifs Manifestations respiratoires 
 Diarrhée 67 Dyspnée 43 
 Vomissement 50 Trouble pulmonaireb 24 
 Nausée 35 Trouble respiratoirec 11 
 Stomatite 22 Augmentation de la toux 11 
 Anorexie
20 Rhinite 10 
 Nausée et vomissement 19 Atteinte de la peau et des annexes cutanées 

Manifestations hématologiques Eurythème 42 
 Thrombocytopénie 37 Prurit 24 
 Anémie 29 Eczéma exfoliatif 18 
 Leucopénie 16 Troubles génito-urinaires 
 Oligurie 63 
 E-27 
  

 E-27 

 

 
 a Trouble cardio-vasculaire : fluctuations de la pression artérielle,
modifications électrocardiographies asymptomatiques, insuffisance cardiaque congestive. 
 b Trouble
pulmonaire : observations physiques associées à une congestion pulmonaire, râle et ronchus. 
 c Trouble respiratoire : SDRA, infiltrats observés lors d’une radiographie du poumon, changements pulmonaires non spécifiés. 
 Les données suivantes sur les effets indésirables qui mettent en danger la vie du patient (rapportés chez plus de 1 % des patients, stade IV), par organe, par
fréquence d’apparition et par terme de préférence (COSTART). Ces données sont basées sur 525 patients (255 souffrant d’un adénocarcinome rénal métastatique et 270 souffrant d’un
mélanome malin métastatique) auxquels les doses recommandées ont été injectées. 
 TABLEAU III : EFFETS INDÉSIRABLES METTANT EN DANGER LA VIE DU PATIENT (STADE IV) (N 525) 
 Organe Nombre de patients (%) Organe Nombre de patients (%) 
 Manifestations
générales Troubles métaboliques et nutritionnels 
 Fièvre 5 (1 %)
Bilirubinémie 13 (2 %) 
 Infection 7 (1 %) Elévation de la créatinine 5 (1 %) 

Septicémie 6 (1 %) Elévation de la SGDl 3 (1 %) 
 Manifestations cardio-vasculaires Acidose 4 (1 %) 
 Hypotension 15 (3 %) Manifestations neuropsychiques 
 Tachycardie supraventriculaire 3 (1 %) Confusion 5 (1 %) 
 Trouble cardio-vasculairea 7 (1 %) Stupeur 3 (1 %) 
 Infarctus myocardique 7 (1 %) Coma 8 (2 %) 
 Tachycardie ventriculaire 5 (1 %) Psychose 7 (1 %) 
 Arrêt cardiaque 4 (1 %) Manifestations respiratoires 
 Troubles digestifs Dyspnée 5
(1 %) 
 Diarrhée 10 (2 %) Trouble respiratoirec 14 (3 %) 
 Vomissement 7 (1 %) Apnée 5 (1 %) 
 Manifestations hématologiques Troubles génito-urinaires 
 Thrombocytopénie 5 (1 %) Oligurie 33 (6 %) 
 Trouble de la coagulationb 4 (1 %)
Anurie 25 (5 %) 
 Insuffisance rénale aiguë 3 (1 %) 
 a Trouble cardio-vasculaire : oscillations tensionnelles. 
 b Trouble de la coagulation : coagulopathie intravasculaire. 
 c Trouble respiratoire : SDRA, insuffisance respiratoire, intubation. 
 Les effets indésirables mettant en danger la vie du patient (stade IV) suivants ont été signalés
chez < 1 % des 525 patients : réaction non évaluable; hypothermie; état de choc; bradycardie; extrasystoles ventriculaires; ischémie myocardique; syncope; hémorragie; arythmie auriculaire; phlébite;
bloc auriculo-ventriculaire de second degré; endocardite; épanchement péricardique; gangrène périphérique; thrombose; trouble coronaire; stomatite; nausée et vomissement; tests anormaux de la fonction
hépatique; hémorragie gastro-intestinale; hématémèse; diarrhée sanglante; trouble gastro-intestinal; perforation intestinale; pancréatite; anémie; leucopénie; leucocytose;
hypocalcémie; élévation des phosphatases alcalines; élévation de l’azote uréïque du sang; hyperuricémie; élévation de l’azote non protéique; acidose respiratoire;
somnolence; agitation; neuropathie; réaction paranoïde; convulsion; épilepsie; tonicoclonique; délire; œdème pulmonaire; hyperventilation; hypoxie; hémoptysie; hypoventilation; pneumothorax; mydriase;
trouble pupillaire; fonction rénale anormale; insuffisance rénale; néphrite interstitielle aiguë. 
 D’autres effets indésirables graves ont été signalés au cours d’une étude à laquelle participaient plus de 1 800 patients traités par des régimes à base de
PROLEUKIN à différentes doses et suivant différents schémas posologiques (par ex : sous-cutané, perfusion continue, administration de cellules LAK). Ces effets incluaient : ulcération duodénale;
nécrose intestinale; myocardite; tachycardie supraventriculaire; cécité permanente ou transitoire secondaire à une névrite optiqué; attaques ischémiques transitoires; méningite;
œdème cérébral; péricardite; néphrite interstitielle allergique;fistule œsophago-trachéale. 
 Parmi ces 1 800 patients, les incidents suivants qui furent mortels ou entraînèrent la mort se sont produits à une fréquence de < 1 % etincluent :insuffisance
hépatique ou rénale;perforation intestinale arrêt cardiaque;infarctus du myocarde hyperthermie maligne;œdèmepulmonaire;arrêt respiratoire;insuffisance respiratoire;accident vasculaire
cérébral;embolie pulmonaire;dépression sévère menant ausuicide. 
 Lors
d’une étude post-marketing menée au niveau international, les effets indésirables suivants ont été rapportés au cours de différents régimes de traitements par interleukine-2 :
hypertension; pneumonie (bactérienne, fongique, virale); neutropénie; cholécystite; colite; gastrite; hépatite; hépato-splénomégalie; obstruction intestinale; hémorragie
rétropéritonéale; lésions cérébrales; hémorragie cérébrale; encéphalopathie; syndrome extrapyramidal; névralgie; névrite; neuropathie
(démyélinisation); rhabdomyolyse; myopathie; myosite; hyperthyroïdie; anaphylaxie; cellulite; nécrose du site d’injection; insomnie. 
 L’exacerbation ou le début de nombreux troubles auto-immuns et inflammatoires ont été rapportés (voir la section 
 « AVERTISSEMENT »). Chez les patients atteints d’un mélanome malin métastatique traités
par interleukine-2, on a observé un vitiligo persistent mais non progressif. Des toxicités synergiques, additives et nouvelles ont été observées lorsque PROLEUKIN est combinée avec d’autres
médicaments. Les toxicités nouvelles incluent des réactions adverses différées aux produits de contraste et des réactions d’hypersensibilité aux agents anticancéreux (voir la section
« MISES EN GARDE »). 
 L’expérience a montré que les médicaments
concomitants peuvent s’avérer utiles dans la prise en charge des patients traités par PROLEUKIN : a) traitement antipyrétique standard, y compris les anti-inflammatoires non stéroïdiens, débuté
immédiatement avant le traitement par PROLEUKIN pour réduire la fièvre. La fonction rénale doit être surveillée étant donné que les anti-inflammatoires non stéroïdiens peuvent causer
une néphrotoxicité synergique; b) mépéridine utilisée pour contrôler les rigueurs associées à la fièvre; c) inhibiteurs de l’H2 donnés pour la prophylaxie de l’irritation
et de l’hémorragie gastro-intestinales; d) antiémétiques et antidïarrhéiques utilisés, le cas échéant, pour traiter les effets secondaires gastro-intestinaux. Généralement, ces
médicaments sont arrêtés 12 heures après la dernière dose de PROLEUKIN. 
 Les
patients qui ont des lignées germinales à demeure sont plus exposés aux risques d’infection par des micro-organismes Gram positifs.9.11 L’incidence réduite d’infections staphylococciques dans les
études sur PROLEUKIN a été associée à l’utilisation d’une antibiothérapie qui inclut l’utilisation de l’oxacilline, de la nafcilline, de la ciprofloxacine ou de la vancomycine.
L’hydroxyzine ou la diphénhydramine ont été utilisées pour contrôler les symptômes d’eczémas prurigineux et continuées jusqu’à la résolution du prurit. Des
crèmes et des pommades locales doivent être appliquées, le cas échéant, pour les manifestations cutanées. Les préparations contenant un stéroïde (par ex. hydrocortisone) doivent être
évitées. REMARQUE : Avant d’utiliser tout produit mentionné dans ce paragraphe, le médecin devra consulter la monographie du produit utilisé. 
 Immunogénicité : Cinquante-sept des 77 (74 %) patients atteints d’un adénocarcinome rénal
métastatique traités avec un régime de PPOLEUKIN administrée toutes les 8 heures et 33 des 50 (66 %) patients atteints d’un mélanome malin métastatique traités avec une variété de
régime d’IV développèrent de faibles titres d’anticorps anti-PROLEUKIN non neutralisants. Des anticorps neutralisants n’ont pas été détectés dans ce groupe de patients, mais ont
été détectés chez 1/106 (<1 %) des patients recevant PROLEUKIN par IV au moyen d’une grande variété de schémas et de doses. On ignore la significativité clinique des anticorps
anti-PROLEUKIN. 
 SYMTÔMES ET TRAITEMENT D’UN SURDOSAGE 
 Les effets indésirables qui suivent l’utilisation de PROLEUKIN* (aldesleukine) semblent liés à la
dose administrée. Un dépassement de la dose recommandée a été associé à un début plus rapide des toxicités limitantes de la dose. Les symptômes qui persistent après
l’arrêt de PROLEUKIN doivent être surveillés et doivent faire l’objet d’un traitement de soutien. Les toxicités qui mettent en danger la vie du patient peuvent être améliorées par
administration intraveineuse de dexaméthasone, qui peut entraîner une perte des effets thérapeutiques de PROLEUKIN. REMARQUE : Avant d’utiliser tout produit mentionné dans ce paragraphe, le médecin devra
consulter la monographie du produit utilisé. 
 POSOLOGIE ET ADMINISTRATION 
 Le régime de traitement recommandé pour PROLEUKIN* (aldesleukine) est administré par perfusion IV de 15
minutes toutes les 8 heures. Avant de débuter le traitement, revoir soigneusement les sections « INDICATIONS ET UTILISATION CLINIQUE », « CONTRE-INDICATIONS », « AVERTISSEMENTS», « MISES EN GARDE
» et « EFFETS INDÉSIRABLES », particulièrement en ce qui concerne la sélection des patients, les possibles effets indésirables graves, la surveillance des patients et la suspension des doses. 

Le schéma posologique suivant a été utilisé pour traiter les patients adultes atteints
d’un adénocarcinome rénal métastatique ou d’un mélanome malin métastatique. Chaque cycle de la cure consiste en deux cycles de traitement de cinq jours interrompus par une période de repos.

 Une dose de 600 000 UI/kg (0,037 mg/kg) fut administré en perfusion intraveineuse de 15 minutes (14
doses maximum) toutes les 8 heures, suivie d’un repos thérapeutique de 9 jours; après ce repos, ce schéma est répété pour 14 nouvelles doses, pour un maximum de 28 doses par cure, tant que les doses
sont tolérées. Durant les études cliniques, les doses furent souvent suspendues pour des raisons de toxicité (voir les paragraphes « Expérience clinique » et « Modifications de la dose »).
Les patients atteints d’un adénocarcinome rénal métastatique et traités avec ce schéma reçurent une moyenne de 20 doses sur les 28 doses prévues au cours de la première cure. Les patients
souffrant d’un mélanome malin métastatique reçurent une moyenne de 18 doses durant la première cure. 
 Réadministration : On doit évaluer une réponse des patients environ 4 semaines après qu’ils ont complété une cure, puis de nouveau immédiatement avant le début
prévu de la cure suivante. Les patients ne pourront recevoir d’autres cures que s’il y a eu une diminution de la 
 taille de leur tumeur suite à la cure effectuée et si une réadministration n’est pas contre-indiquée (voir la section « CONTRE-INDICATIONS »). Chaque cure devra être suivie
d’une période d’au moins 7 semaines de repos thérapeutique, à partir de la date de sortie d’hôpital. 
 Modifications de la dose : Une modification de la dose en raison de la toxicité se fera en suspendant ou en interrompant la dose plutôt qu’en la réduisant. On
décidera d’arrêter, de suspendre ou de reprendre le traitement par PROLEUKIN uniquement après avoir procédé à une évaluation globale du patient. Tenant compte de cela, on devra suivre les lignes
de conduite suivantes : 
 Un nouveau traitement avec PROLEUKIN est contre-indiqué chez les patients qui
développent les toxicités suivantes : 
 Organe 
 Manifestations 
 cardio-vasculaires 
 Manifestations respiratoires

 Troubles 
 génito-urinaires 
 Manifestations

 neuropsychiques 
 Troubles digestifs 
 Les doses doivent être
suspendues et reprises dans les conditions suivantes : 
 Organe 
 Manifestations 
 cardio-vasculaires 
 Manifestations respiratoires

 Manifestations 
 neuropsychiques 
 Manifestations
générales 
 Troubles 
 génito-urinaires 
 Troubles digestifs

 Dermatologique 
 Tachycardie ventriculaire prolongée (35 battements) 
 Troubles du rythme cardiaque non maîtrisés ou ne répondant pas aux mesures palliatives Douleur thoracique récurrente accompagnée de modifications de
l’électrocardiogramme (ECG), concordant avec une angine de poitrine ou un infarctus du myocarde Tamponnade cardiaque 
 Intubation de plus de 72 heures 
 Dysfonctionnement rénal exigeant une dialyse
> 72 heures 
 Coma ou psychose toxique se prolongeant au-delà de 48 heures 
 Crises à répétitions ou difficiles à calmer 
 Ischémie ou perforation intestinale 
 Hémorrahie gastro-intestinale nécessitant une intervention chirurgicale 
 Suspendre la dose en cas de : 
 Fibrillation
auriculaire, tachycardie 
 supraventriculaire ou bradycardie exigeant un traitement ou qui est récurrente
ou persistante TA systolique < 90 mm Hg et de plus en plus de vasopresseurs Toute modification de l’ECG compatible avec un infarctus du myocarde ou une myocardite, avec ou sans douleurs de poitrine, ischémie cardiaque
soupçonnée 
 Saturation en O2 < 94 % à partir de l’air ambiant 
 ou < 90 % avec 2 litres d’O2 par fourche nasale 
 Changement d’humeur incluant confusion ou 
 agitation modérée 
 Syndrome
septicémique, le sujet est cliniquement 
 instable 
 Créatinine sérique > 4,5 mg/dL ou créatinine 
 sérique 34 mg/dL en présence d’une surcharge volumique
importante, acidose ou hyperkalémie Oligurie persistante, débit urinaire < 10 mL/heure pendant 16 à 24 heures avec élévation de la créatinine sérique 
 Signes d’insuffisance hépatique, y compris encéphalopathie, augmentations d’ascites, douleur au foie,
hypoglycémie. Sang occulte dans les selles régulièrement > 3-4+ 
 Eczéma bulleux
ou aggravation d’une affection cutanée pré-existante (éviter tout traitement local à base de stéroïde) 
 Les doses peuvent être reprises si : 
 Le
sujet est asymptomatique et a retrouvé un 
 rythme sinusal normal 
 TA systolique 390 mm Hg et l’administration exigés de vasopresseurs
se stabilise ou diminue Le sujet est asymptomatique, l’infarctus du myocarde et la myocardite ont été exclus, l’angine de poitrine est cliniquement peu probable, il n’y a aucune évidence d’hypocinésie
ventriculaire 
 Saturation en O2 > 94 % à partir de l’air ambiant 
 ou > 90 % avec 2 litres d’O2 par fourche nasale 
 Disparition des changements d’humeur 
 Syndrome septicémique résolu, le sujet est 
 cliniquement stable et l’infection sous traitement 
 Créatinine sérique <
4 mg/dL et état électrolytique 
 et hydrique stable Débit urinaire > 10 mL/heure avec
baisse de la créatinine sérique > 1,5 mg/dL ou retour à la créatinine normale 
 Les signes d’insuffisance hépatique ont entièrement disparu* Absence de sang occulte dans les selles 
 Toute manifestation d’eczéma bulleux a disparu 
 *Arrêter
complètement le traitement pour cette cure. Prévoir de commencer une nouvelle cure, si elle est justifiée, 7 semaines au moins après disparition des effets indésirables et sortie d’hôpital. 

INFORMATIONS PHARMACEUTIQUES 
 PROLEUKIN*(aldesleukine), l’interleukine-2 humaine recombinante est une protéine fortement purifiée d’un poids moléculaire proche de 
 15 300 daltons. Son nom chimique est des-alanyl-1, sérine 125-interleukine-2 humaine. PROLEUKIN, une lymphokine, est
produite par technologie d’ADN recombinant sur souche d’E. coli dans laquelle se trouve un analogue du gène de l’interleukine-2 humaine. Des techniques de génie génétique ont été
utilisées pour modifier le gène de l’interleukine-2 humaine pour obtenir un clone d’expressivité codé pour l’interteukine-2 humaine modifiée. Cette forme recombinante diffère de
l’interleukine-2 native par : a) absence de glycosylation (production par la souche d’E coli; b) absence d’alanine N-terminale (perte du codon pour l’alanine durant la procédure de génie génétique); c)
la substitution de la cystéïne en position 125 par la sérine; ceci a été obtenu en manipulant le site spécifique durant la procédure de génie génétique et d) l’état
d’agrégation de PROLEUKIN sera vraisemblablement différent de celui de l’interleukine-2 native. 
 L’activité biologique in vitro de la molécule non recombinante native a été reproduite avec PROLEUKIN.1,2 
 Le pouvoir biologique de PROLEUKIN est déterminé par dosage biologique de la prolifération lymphocytaire et s’exprime en Unités Internationales (Ul), selon
la Première norme internationale de l’O.M.S. pour l’interleukine 2 humaine. La relation entre pouvoir et masse protéique est la suivante : 18 millions (18 x 106) UI de PROLEUKIN = 1,1 mg de protéine Composition :
PROLEUKIN se présente sous flacon de lyophilisat stérile, blanc ou blanc cassé, à usage unique destiné à être administré par perfusion intraveineuse (IV). Après reconstitution avec 1,2 mL
d’eau stérile pour préparation injectable, USP (Pharmacopée des États-Unis), chaque mL contient 18 millions Ul (1,1 mg) de PROLEUKIN, 50 mg de mannitol et 0,18 mg de dodécylsulfate de sodium tamponné
avec environ 0,17 mg de phosphate de sodium monobasique et 0,89 mg de phosphate de sodium dibasique à un pH de 7,5 (allant de 7,2 à 7,8). Le procédé de fabrication de PROLEUKIN implique la fermentation dans un milieu
défini contenant du chlorhydrate de tétracycline. La présence de cet antibiotique n’est pas décelable dans le produit fini. PROLEUKIN ne contient aucun conservateur dans le produit fini. Stabilité et
conservation : Conserver les flacons de lyophilisat PROLEUKIN dans le réfrigérateur entre 2° et 8° C (36° et 46° F). Éviter toute exposition à la chaleur et à la lumière. 
 Le produit reconstitué ou dilué PROLEUKIN est stable pendant 48 heures au réfrigérateur ou
à température ambiante, 2° à 25° C (36° à 77° F). Toutefois, comme ce produit ne contient pas de conservateur, les solutions reconstituées et diluées devront être conservées au
réfrigérateur. Ne pas utiliser au-delà de la date de péremption indiquée sur le flacon. REMARQUE : Ce produit ne contient aucun conservateur. 
 Reconstitution : Des procédures de reconstitution et de dilution autres que celles recommandées pourraient
altérer les propriétés de délivrance et/ou pharmacologiques et doivent par conséquent être évitées. 
 1. PROLEUKIN* (aldesleukine) est un lyophilisat stérile, blanc ou blanc cassé, sans conservateur, prévu pour être administré par perfusion IV après
reconstitution et dilution. CHAQUE FLACON CONTIENT 22 MILLIONS UI (1,3 MG) DE PROLEUKIN ET DOIT ÊTRE RECONSTITUÉ DANS DES CONDITIONS ASEPTIQUES AVEC 1,2 ML D’EAU STÉRILE POUR PRÉPARATION INJECTABLE, USP. UNE FOIS
RECONSTITUÉ COMME INDIQUE, CHAQUE ML CONTIENT 18 MILLIONS UI (1,1 MG) DE PROLEUKIN. La solution obtenue doit être un liquide clair, transparent ou légèrement jaunâtre. Le flacon est prévu pour un usage unique
et il faut veiller à jeter toute portion inutilisée du produit. 
 2. Au cours de la
reconstitution, on doit diriger l’eau stérile pour préparation injectable, USP, au contact de la paroi interne du flacon, puis remuer doucement le contenu en tournant pour éviter la formation de mousse excessive. NE PAS
SECOUER. 
 3. La dose de PROLEUKIN, reconstituée avec de l’eau stérile pour
préparation injectable, USP (sans conservateur) doit être diluée dans des conditions aseptiques dans 50 mL de 5 % de dextrose pour préparation injectable, USP (D5W) et administrée par perfusion intraveineuse
pendant 15 minutes. 
 Dans les cas où la dose totale de PROLEUKIN est de 1,5 mg ou moins (par ex. un
patient dont le poids est inférieur à 40 kilogrammes), la dose de PROLEUKIN doit alors être diluée dans un plus petit volume de D5W. 
 Les concentrations de PROLEUKIN inférieures à 30 μg/mL et supérieures à 70 μg/mL ont montré des variabilités croissantes lors de la
délivrance du médicament. Une dilution et une délivrance de PROLEUKIN en dehors de ces plages doivent être évitées. 
 4. Bien qu’on ait utilisé avec des résultats comparables des flacons de verre et des poches en plastique (chlorure de polyvinyle) pendant les essais cliniques, il est
recommandé de choisir les poches en plastique comme récipient de dilution; en effet, des études expérimentales ont indiqué qu’on obtenait une délivrance du médicament plus homogène avec
les poches en plastique. On ne doit pas employer de filtres internes intratubulaires pendant l’administration de PROLEUKIN. 
 5. Avant et après reconstitution et dilution, conserver au réfrigérateur entre 2° et 8° C (36° et 46° F). Ne pas congeler. Administrer PROLEUKIN dans les 48 heures qui suivent la
reconstitution. La solution doit être amenée à température ambiante avant d’être administrée au patient. 
 6. Il faut éviter de reconstituer ou de diluer le lyophilisat avec de l’eau bactériostalique pour préparation injectable, USP, ou 0,9 % de chlorure de sodium pour
préparation injectable, USP en raison de l’hyperagrégabilité qui en résulte. PROLEUKIN ne doit pas être mélangée dans un même récipient avec d’autres médicaments.

 7. Avant de commencer l’administration, inspecter visuellement, chaque fois que la solution et le flacon
le permettent, les produits pharmaceutiques parentéraux pour déceler d’éventuelles particules ou décolorations. 
 FORMES POSOLOGIQUES 
 Forme : PROLEUKIN*
(aldesleukine) est fournie sous forme de lyophilisat stérile, blanc ou blanc cassé, sans conservateur. Chaque flacon à usage unique contient 22 millions UI (1,3 mg) et est destiné à une administration par injection
intraveineuse (IV). Une fois reconstitué avec 1,2 mL d’eau stérile pour préparation injectable, USP, chaque mL contient 18 millions UI (1,1 mg) de PROLEUKIN. Jeter toute portion non utilisée. 
 PHARMACOLOGIE 
 Clinique : Le profile pharmacocinétique de PROLEUKIN* (aldesleukine) se caractérise par des concentrations plasmatiques élevées suite à une perfusion
intraveineuse (IV) de courte durée, une distribution rapide aux espaces extravasculaire et extracellulaire et par élimination rénale, avec peu ou aucune protéine bioactive excrétée dans les urines. Chez les
sujets humains, la demi-vie de distribution et d’élimination sont respectivement de 13 et 85 minutes. On a observé une troisième phase de clairance, plus lente, chez l’animal de laboratoire. Le taux de clairance
relativement rapide de l’interleukine-2 a donné lieu à des schémas posologiques se caractérisant par une administration sous forme de bolus fréquents de médicament ou de perfusions. 
 PROLEUKIN est éliminée de l’organisme en majeure partie (80 à 90 %) par métabolisme en
aminoacides dans les cellules qui tapissent le tube proximal contourné des reins. Il apparaît que les protéines accèdent à ce tube par infiltration directe au travers de la membrane glomérulaire de la capsule
de Bowman, ainsi que par une extraction péritubulaire des artérioles efférentes qui entourent le tube proximal. Il est possible que ce double mécanisme d’accès au tube proximal permette le schéma normal
d’élimination de l’interleukine-2 chez les patients qui ont une toxicité rénale avec des valeurs de créatinine sérique entre 1,5 et 3 mg/dL. Le peu de données dont on dispose suggère que la
créatinine sérique supérieure à 3 mg/dL puisse avoir une corrélation avec une demi-vie d’élimination prolongée. 
 Dans les études cliniques, PROLEUKIN a été diluée dans 5 % de dextrose pour préparation injectable, USP (D5W), D5W contenant 0,1 % de
sérum-albumine humaine (SAH) ou 5 % de SAH. Les études pharmacocinétiques montrent qu’on retrouve des quantités plus élevées du médicament bioactif dans la circulation d’animaux dont
les doses contiennent de la BAH dans une solution saline normale. Des études précliniques sur l’efficacité sur un modèle de tumeur murine n’indiquent aucune différence, que les doses aient
été diluées dans 5 % de BAH dans une solution salée normale ou dans 0,1 % de BAH dans D5W.Toutefois, il semblerait qu’il n’y ait aucune différence du taux de réponses objectives ou du taux de
mortalité en cours d’étude entre les groupes de patients recevant PROLEUKIN diluée de différentes façons. 
 EXPÉRIENCE CLINIQUE 
 Deux cent
cinquante-cinq patients atteints d’un adénocarcinome rénal métastatique furent traités par agent unique PROLEUKIN au cours de 
 7 études cliniques conduites dans 21 établissements. Deux cent soixante-dix patients atteints d’un mélanome malin métastatique furent traités par
agent unique PROLEUKIN au cours de 8 études cliniques conduites dans 22 établissements. Pour pouvoir prendre part à ces études, les patients devaient avoir un indice fonctionnel (IF) égal à 0 ou 1 tel que le
définit le Eastern Cooperative Oncology Group (ECOG) et une fonction d’organe normale définie par une épreuve d’effort cardiaque, des examens de la fonction respiratoire et un taux de créatinine ?1,5 mg/dL. Les
patients avec des métastases cérébrales, des infections actives, allogreffes d’organes et des maladies exigeant un traitement à base de stéroïde furent exclus des études. 
 PROLEUKIN fut administrée par perfusion IV de 15 minutes toutes les 8 heures pendant un maximum de 5 jours (14 doses
maximum). Le traitement fut suspendu du 6e au 14e jour inclusivement, puis le schéma posologique fut répété pendant un maximum de 5 jours du 15e au 19e jour (14 doses maximum). Ces deux cycles ont constitué une
cure. Durant une cure, les patients pouvaient recevoir un maximum de 28 doses. En fait, plus de 90 % des patients n’ont pas reçu toutes les doses. Les patients atteints d’un adénocarcinome rénal
métastatique reçurent une moyenne de 20 à 28 doses prévues de PROLEUKIN. Les patients souffrant d’un mélanome malin métastatique reçurent une moyenne de 18 à 28 doses prévues de
PROLEUKIN durant la première cure. Les doses furent suspendues en raison de toxicités spécifiques (voir le paragraphe 
 « Modification de la dose » dans la section « POSOLOGIE ET ADMINISTRATION » et la section « EFFETS INDESlRABLES »). 
 Parmi les 255 patients atteints d’un adénocarcinome rénal métastatique, une réponse
objective fut observée chez 37 des patients (15 %), avec 
 17 (7 %) patients répondeurs complets
(PRC) et 20 (8 %) patients répondeurs partiels (PRP). L’intervalle de confiance de 95 % pour la réponse objective fut compris entre 11 % et 20 %. On a pu observer un début de régression tumorale dès
les 4 semaines suivant la fin de la première cure et, dans certains cas, la régression a continué jusqu’à 12 mois après le début du traitement. La durée moyenne des réponses de tous les
patients qui ont répondu est de 54 mois (3 à + de 131 mois). La durée moyenne des réponses complètes objectives n’a pas été observée et pour la réponse partielle, elle fut de 20
mois. Douze des patients qui avaient atteint une réponse complète et six de ceux qui avaient atteint une réponse partielle avaient des réponses en cours au moment de la dernière visite. La survie moyenne sans
progression pour tous les patients répondeurs fut de 55 mois. Les réponses furent observées sur les sites pulmonaires et non pulmonaires (par ex. foie, ganglion lymphatique, phénomènes de lit rénaux et tissu
mou). Sur les 37 patients répondeurs, 12 patients avec de grosses lésions individuelles (la lésion la plus grande étant 325 cm2) et 22 patients avec un grand nombre de tumeurs
cumulatives (total 325 cm2) ont eu des réponses. 
 Parmi les
270 patients atteints d’un mélanome malin métastatique, une réponse objective fut observée chez 43 des patients (16 %), avec 17 
 (6 %) patients répondeurs complets et 26 (10 %) patients répondeurs partiels. L’intervalle de confiance de 95 % pour la réponse objective fut compris entre
12 % et 21 %. La durée moyenne de le réponse objective (partielle ou complète) fut de 9 mois (1 à 122+ mois); la durée moyenne des réponses complètes objectives n’a pas été
observée et pour la réponse partielle, elle fut de 6 mois. Dix des patients qui avaient atteint une réponse complète et trois de ceux qui avaient atteint une réponse partielle avaient des réponses en cours
au moment de la dernière visite. La survie moyenne sans progression pour tous les 43 patients répondeurs fut de 13 mois. Les réponses furent observées sur les sites viscéraux et non viscéraux (par ex.
poumon, foie, ganglion lymphatique, tissu mou, surrénal et sous-cutané). Sur les 43 patients répondeurs, 14 patients avec de grosses lésions individuelles (la lésion la plus grande étant 325 cm2) et 21 patients avec un grand nombre de tumeurs cumulatives (total 325 cm2) ont eu des réponses. 
 TABLEAU IV : DONNÉES DE RÉPONSE CLINIQUE À PROLEUKIN 
 ADÉNOCARCINOME RÉNAL MÉTASTATIQUE MÉLANOME MALIN MÉTASTATIQUE 
 Nombre de Durée de Nombre de Durée de 
 patients répondeurs Réponse moyenne en mois patients répondeurs Réponse moyenne en mois

 (taux de réponse)(plage)(taux de réponse)(plage) 
 PRC 17 (7 %) 80+* (7 à 131+) 17 (6 %) 59+* (3 à 122+) 
 PRP 20 (8 %) 20 (3 à 126+) 26 (10 %) 6 (1 à 111+) 
 PRP + PRC 37 (15 %) 54 (3 à 131+) 43 (16 %) 9 (1 à 122+) 
 Le signe (+) signifie en cours 
 * La durée médiane n’est pas encore observée; une valeur prudente est donnée, elle représente la durée de réponse moyenne minimale.

 *PROLEUKIN et une marque de commerce déposée de Novartis Vaccins et Diagnostiques,
utilisées sous permission par Novartis Pharma Canada inc. 
 Novartis Pharma Canada inc., 385 boul.
Bouchard, Dorval (Québec) H9S 1A9 
 709558-FI 
 Derniére mise à jour: 06 juillet 2006 
 E-28 
  

 E-28 

 

 
 *Registered trademark/*Marque déposée Novartis Pharmaceuticals
Canada Inc./ Novartis Pharma Canada inc. 
 385 Bouchard, Dorval, Quebec, H9S1A9 
 0 63601 09558 5 
 Pr 
 DIN: 02130181 
 Proleukin* 
 Aldesleukin 
 FOR IV USE ONLY 
 POUR ADMINISTRATION 
 IV UNIQUEMENT 
 22 million IU [1.3 mg] 22
millions UI [1,3 mg] 
 SINGLE-USE VIAL REFRIGERATE 
 AVOID EXPOSURE TO HEAT AND LIGHT 
 AMPOULE À USAGE UNIQUE RÉFRIGÉRER 
 ÉVITER TOUTE EXPOSITION À LA CHALEUR ET À LA LUMIÈRE 
 Novartis

 Lot 
 Exp. 
 709558-C 
 Before and after reconstitution, store in a refrigerator at 2°-8°C (36°-46°F). Use within 48 hours after
reconstitution. 
 RECONSTITUTE WITH 1.2 ML STERILE WATER FOR INJECTION, USP. SWIRL GENTLY. DO NOT SHAKE WHEN
RECONSTITUTED, EACH ML CONTAINS 
 18 MILLION IU (1.1 MG) PROLEUKIN*, 50 mg mannitol, 0.18 mg sodium dodecyl
sulfate buffered with 0.17 mg monobasic sodium phosphate and 0.89 mg dibasic sodium phosphate. 
 Contains no
preservative. Discard unused portion. 
 See package insert for usual dose and complete prescribing information.

 Pr 
 Proleukin* Aldesleukin 
 FOR IV USE ONLY POUR
ADMINISTRATION IV UNIQUEMENT 
 22 million IU [1.3 mg] 22 millions UI [1,3 mg] 
 SEE BOTTOM PANEL FOR LOT NO. AND EXP DATE 
 Avant et après reconstitution, conserver au réfrigérateur entre 2°-8°C 
 (36°-46°F). Utiliser dans les 48 heures après reconstitution. 
 RECONSTITUER AVEC 1,2 ML D’EAU STÉRILE POUR PREPARATION INJECTABLE, USP. REMUER DOUCEMENT EN TOURNANT. NE PAS SECOUER. APRÈS RECONSTITUTION, CHAQUE ML CONTIENT 18
MILLIONS UI (1,1 MG) DE PROLEUKIN*, 50 mg de mannitol, 0,18 mg de dodécylsulfate de sodium tamponné avec 0,17 mg de phosphate monobasique de sodium et 0,89 mg de phosphate dibasique de sodium. Ne contient pas de conservateur. Jeter la
portion inutilisée. 
 Voir la notice accompagnant le produit pour la posologie usuelle et les conditions
complètes de délivrance. 
 Description: Aldesleukin Proleukin 1.3 mg Canadian Carton LD&C:
Date: 
 Material Group No.: Component No.: Supersedes Component No.: 
 ZNV 709558-C 10004534 LD&C: Date: 
 Engineer: Date: 
 Dimensions: 
 Number of Colors: 2 Black PMS 520 PMS 520 @ 40% 
 Do Not Print Dotted Lines FPO - For Position Only - Do Not Print 
 Novartis 
 E-29 
  

 E-29 

 

 
 Canadian Proleukin P/N 709558-VL 2-1/2 X 3/4” Corner .125”R Colors: 2 -
Black & PMS 520 
 Pr Proleukin* DIN: 02130181 
 Aldesleukin 
 22 million IU [1.3 mg] 
 22 millions UI [1,3 mg] 
 FOR IV USE ONLY 
 ADMINISTRATION IV UNIQUEMENT 
 SINGLE-USE VIAL NO
PRESERVATIVE 
 REFRIGERATE 2°-8°C (36°-46°F) 
 AVOID EXPOSURE TO HEAT AND LIGHT 
 USAGE UNIQUE PAS DE CONSERVATEUR 
 CONSERVER ENTRE
2°-8°C (36°-46°F). 
 ÉVITER TOUTE EXPOSITION À LA 
 CHALEUR ET À LA LUMIÈRE 
 See product leaflet for usual dose reconstitution directions, and complete prescribing information. 
 Voir la notice accompagnant le produit pour plus d’informations sur la posologie usuelle, le mode de reconstitution et les conditions complètes de délivrance.

 *Registered trademark/*Marque déposée Novartis Pharmaceuticals Canada Inc. Novartis Pharma
Canada inc. 
 385 Bouchard, Dorval, Quebec, H9S 1A9 
 Novartis 
 LOT 
 EXP. 
 10011500 9/06 709558-VL 
 E-30 
  

 E-30 

 EXHIBIT F 
 REGULATORY APPROVALS 
 US Regulatory Approvals for Product
Indications 
 Metastatic Renal Cell Carcinoma 
 FDA Reference nos: 88-0659 and 88-0660 
 Approved May 5, 1992 
 Metastatic Melanoma 
 FDA Reference nos: 96-1367,
97-0501, and 97-0522 
 Approved on January 9, 1998. 
 Canada Main Notices of Compliance (NOC) for Product Indications 
 Manufacturer:
CHIRON CORPORATION 
 NOC Date: 1994-09-15 
 Medicinal Ingredients: ALDESLEUKIN 
 DIN: 02130181 
 Reason for submission (NDS): indication for the treatment of adults with metastatic renal cell carcinoma 
 Control number:08524 
 Manufacturer: CHIRON CORPORATION 
 NOC Date: 1998-12-10 
 Medicinal Ingredients: ALDESLEUKIN 
 DIN: N/A 
 Reason for submission (SNDS): New
indication: Treatment of patients with Metastatic melanoma 
 Control number:051232 
 Manufacturer: NOVARTIS PHARMACEUTICALS CANADA INC. 
 NOC Date: 2006-07-06 
 Medicinal Ingredients: ALDESLEUKIN 
 DIN: 02130181 
 Reason for submission (NDS): Change in Manufacturer To Novartis 
 Control number:106086 
  

 F-1 

 EXHIBIT G 
 NOVARTIS PROMOTIONAL MATERIALS 
 As of the Effective Date, the
Novartis Promotional Materials consist of the following: 
  

	 	•	 	 The Product web site located at www.proleukin.com 

  

	 	•	 	 The following items: 

  

			
	 ITEM
	  	 DESCRIPTION

	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]
	[* * *]	  	[* * *]

  
 *** Certain information
on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 G-1 

 EXHIBIT H 
 MINIMUM MARKETING AND PROMOTION INVESTMENT 
 MINIMUM MARKETING
SPEND: 
 During the first Contract Year, Prometheus’ Minimum Marketing Spend shall be [***] U.S. dollars ($[* * *]). 
 During the second Contract Year, Prometheus’ Minimum Marketing Spend shall be [* * *] U.S. dollars ($[* * *]). 
 During the third Contract Year, Prometheus’ Minimum Marketing Spend shall be [* * *] U.S. dollars ($[* * *]). 
 During the fourth Contract Year, Prometheus’ Minimum Marketing Spend shall be [* * *] U.S. dollars ($[* * *]). 
 During the fifth Contract Year, Prometheus’ Minimum Marketing Spend shall be [* * *] U.S. dollars ($[* * *]). 
 MINIMUM DETAIL REQUIREMENTS: 
 Prometheus’ annual Minimum Detail Requirement shall be [* * *] ([* * *]) PDEs during each of the first [* * *] ([* * *]) Contract Years of the Term. 
 With respect to the PDEs annual Minimum Detail Requirement in any Contract Year, the compensation structure for the applicable members of Prometheus’ oncology Sales Force who are responsible for
performing such PDEs for the Products (each a “Sales Representative”) shall, unless otherwise agreed to by the Parties, include a [* * *] component based on the Promotion of the Products, as described below: 
 (a) At least [* * *] percent ([* * *]%) of the [* * *] for each Sales Representative for the [* * *] ([* * *]) Contract Year shall be based
on his/her performance related to the Detailing of the Product. 
 (b) At least [* * *] percent ([* * *]%) of the [* * *] for
each Sales Representative for the [* * *] ([* * *]) Contract Year shall be based on his/her performance related to the Detailing of the Product. 
 (c) At least [* * *] percent ([* * *]%) of the [* * *] for each Sales Representative for the [* * *] ([* * *]) Contract Year shall be based on his/her performance related to the Detailing of the Product.

  
 *** Certain information on this page has been omitted and filed
separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 H-1 

 (d) At least [* * *] percent ([* * *]%) of the [* * *] for each Sales Representative for the
[* * *] ([* * *]) Contract Year shall be based on his/her performance related to the Detailing of the Product. 
 (e) At least
[* * *] percent ([* * *]%) of the [* * *] for each Sales Representative for the [* * *] ([* * *]) Contract Year shall be based on his/her performance related to the Detailing of the Product. 
 For purposes of this Exhibit H, the applicable [* * *] for a particular Contract Year will be measured based on the targeted [* * *] set forth in
Prometheus’ compensation plan for such Contract Year, not based on the [* * *] amounts earned or paid for such Contract Year. 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the
omitted portions. 
  

 H-2 

 EXHIBIT I 
 MARKETING PLAN CRITERIA 
 Beginning on the First Sales Booking Date,
the marketing and promotional activities of Prometheus will be conducted materially in accordance with an annual marketing plan (“Marketing Plan”). The Marketing Plan will set forth the strategy and key marketing issues in the
following operational sub-plans: 
 (a) a promotional strategy (including activity regarding KOLs); 
 (b) a budget for M&S Expenses by media category; 
 (c) a Product Sales Force deployment plan; and 
 (d) a Detail management plan,
which will include PDEs (including number of Primary Product Presentations) by the Prometheus Sales Force and a targeting plan for the Prometheus Sales Force. 
  

 I-1 

 EXHIBIT J 
 NOVARTIS PROMOTION GUIDELINES 
 See attached.

  

 Page J-1 

 

 

 TABLE OF CONTENTS 
  
  
  

					
	1	  	PREAMBLE	  	3
	2	  	TERMS	  	3
	3	  	SCOPE	  	3
	4	  	COMPLIANCE WITH LAWS AND INDUSTRY CODES	  	3
	5	  	COMMON PRINCIPLES	  	4
	    5.1	  	Independence of Healthcare Professionals	  	4
	    5.2	  	Interactions with Healthcare Professionals	  	4
	    5.3	  	Separation between promotion and non-promotion	  	4
	    5.4	  	Promotional content	  	4
	    5.5	  	No pre-approval and off-label promotion	  	4
	    5.6	  	Adverse events reporting	  	4
	    5.7	  	Privacy of patient data	  	4
	6	  	STANDARDS FOR MOST COMMON PRACTICES	  	5
	    6.1	  	Events	  	5
	    6.2	  	Promotional Content	  	6
	       6.2.1	  	Consistency with approvals	  	6
	       6.2.2	  	Accuracy	  	6
	       6.2.3	  	Substantiation	  	6
	    6.3	  	Promotional interactions with HCPs	  	6
	       6.3.1	  	Gifts	  	6
	       6.3.2	  	Samples	  	7
	    6.4	  	Non-promotional interactions with HCPs	  	7
	       6.4.1	  	Consultants / Advisory Boards	  	7
	       6.4.2	  	Studies in humans	  	7
	       6.4.3	  	Market Research	  	7
	       6.4.4	  	Investigator meetings	  	7
	    6.5	  	Communication with patients	  	8
	       6.5.1	  	Direct-to-consumer (DTC) promotion	  	8
	       6.5.2	  	Unsolicited queries	  	8
	       6.5.3	  	Disease awareness programs	  	8
	       6.5.4	  	Patient compliance programs	  	8
	    6.6	  	Interactions with patients as a source of knowledge to Novartis Pharma	  	8
	       6.6.1	  	Consultants / Patient Advisory Boards	  	8
	       6.6.2	  	Speakers	  	9
	7	  	GRANTS	  	9
	    7.1	  	Research / Educational grants	  	9
	    7.2	  	Image-building grants	  	10
	8	  	RESPONSIBILITIES	  	10
	    8.1	  	Global level	  	10
	    8.2	  	CPO / local level	  	10
	    8.3	  	Interpretation and implementation	  	10
	9	  	PUBLIC OFFICIALS/INSTITUTIONS	  	11
	    9.1	  	Additional standards for interactions with HCPs which are Public Officials	  	11
	    9.2	  	Additional Standards relating to Grants to Public Institutions	  	11

 NP4-as approved by PEC
January 22, 2008 
  

 Page 2 

			
	1	  	PREAMBLE
		  	  

		
		  	Responsible behaviour of all associates is vital to support our mission “to discover, develop and successfully market innovative products to prevent and cure diseases, to
ease suffering and to enhance the quality of life.” This document serves as a guide to ethical business practices in Novartis Pharma and supports our ambition to do business with integrity.

  

			
	2	  	TERMS
		  	  

		
		  	The term “Novartis Pharma” includes Novartis Pharma AG, its affiliates and subsidiaries and all respective associates which form part of the Pharma
Division.
		
		  	The term “product/products” includes all products marketed by Novartis Pharma.
		
		  	The term “promote/promotion/promotional” includes any activity/content whose purpose is to encourage the prescription, dispensing, supply, purchase,
administration, recommendation or consumption of products.
		
		  	The term “Healthcare Professionals/HCPs” includes any member of the medical, dental, pharmacy or nursing professions or any other person who in the
course of his or her professional activities may prescribe, dispense, recommend, purchase, supply or administer a product.
		
		  	The term “patient/patients” includes any person who may purchase, consume or receive a prescription for a product.
		
		  	The term “grant/grants” means a substantial and tangible benefit conveyed to a third party, without agreement or intent to receive a tangible return in exchange.

  

			
	3	  	SCOPE *
		  	  

		
		  	This document applies to all Novartis Pharma associates in all of their professional activities.

  

			
	4	  	COMPLIANCE WITH LAWS AND INDUSTRY CODES*
		  	  

		
		  	Novartis Pharma must at all times comply with the principles contained in this document. The document defines global minimal standards for the most common practices. In
addition, any practice must comply with all applicable international and national law and industry codes, as well as with local Novartis Pharma standards, which may impose more stringent requirements.
		
		  	All companies that are part of Novartis Pharma will adopt Principles and Practices consistent with this document in accordance with their statutory governance processes and local
law. The respective guidance and SOPs that are part of those Principles and Practices will be at least as stringent as the Principles and Practices contained in this document.

  

	*	Chapters/sections marked with an asterisk are explained in the ‘Guidelines for the interpretation and implementation of NP4’ 

NP4-as approved by PEC January 22, 2008 
  

 Page 3 

			
	5	  	COMMON PRINCIPLES
		  	  

		
	5.1	  	Independence of Healthcare Professionals
		
		  	Nothing may be offered or provided to a HCP intended to have an inappropriate influence on the HCP’s decision to prescribe, dispense, recommend, purchase, supply or
administer products.
		
	5.2	  	Interactions with Healthcare Professionals
		
		  	The ultimate purpose of all interactions with HCPs is to enhance patient care and/or the practice of medicine.
		
	5.3	  	Separation between promotion and non-promotion*
		
		  	Activities/interactions which are motivated by the objective to promote products must be openly considered as promotion and be managed accordingly.
		
		  	Activities/interactions with the purpose to receive knowledge-enhancing information and advice or to obtain important scientific input or data - such as advisory boards and
post-marketing studies - must not have the promotion of products as their purpose.
		
	5.4	  	Promotional content
		
		  	All promotional content produced/disseminated by Novartis Pharma (in printed/electronic form and communicated orally) must be accurate, scientifically sound, objective, reflect
the current state of knowledge and must be consistent with the prescribing information as approved by local regulatory authorities (or the Core Data Sheet in case of global use).
		
	5.5	  	No pre-approval and off-label promotion *
		
		  	Novartis Pharma shall not promote a product until all necessary approvals have been received. Products must only be promoted for use in indications as approved by local
regulatory authorities.
		
	5.6	  	Adverse events reporting *
		
		  	All Novartis Pharma associates are required to inform local Clinical Safety and/or Medical Departments without delay of any adverse event information or new data on products
which they receive.
		
	5.7	  	Privacy of patient data
		
		  	Novartis Pharma must safeguard all confidential patient data in its possession against misuse or inappropriate disclosure and avoid any unauthorized access in accordance with
applicable law.

 NP4-as approved by PEC January 22, 2008 
  

 Page 4 

			
	6	  	STANDARDS FOR MOST COMMON PRACTICES
		  	  

		
	6.1	  	Events*
		
		  	The purpose of Events is to inform HCPs about products and/or to provide scientific/educational information. They must comply with the following requirements:
		
		  	Funding
		
		  	Novartis Pharma may fund HCPs to attend events and/or associations to organize events under the following conditions:
		
		  	 •    Funding must not interfere with the independence of HCPs.

		
		  	 •    Funding is limited to travel, meals, accommodation and registration fees; HCPs must not be
compensated for time spent.

		
		  	 •    Novartis Pharma must not pay for any costs associated with persons accompanying
HCPs.

		
		  	Venue
		
		  	Events should be held in appropriate venues only, which are suitable to achieve the purpose of the meeting. Novartis may not organize or fund events at extravagant
places.
		
		  	Hospitality/Entertainment
		
		  	Hospitality is limited to refreshments and/or meals, which must be modest and secondary to the event’s purpose.
		
		  	Entertainment of modest nature in connection with and secondary to meals/refreshments is permitted. Stand-alone entertainment is not allowed.
		
		  	As a general rule, the value of hospitality/entertainment should not exceed what HCPs would be prepared to pay for personal purposes.
		
		  	Speakers
		
		  	The purpose of engaging HCPs to speak at events is to share relevant scientific/educational information. Accordingly engaged HCPs must be experts in a given field. The engagement
must be based on a written contract containing a clear description of tasks and responsibilities. Fees and expenses must be reasonable and fair market value in relation to the services rendered. The engagement of HCPs as speakers must not interfere
with their independence.
		
		  	International Events
		
		  	Rules relating to events (funding the organisation and/or attendance of/to events, venue, hospitality, engagement of speakers, promotional content) may differ significantly from
one country to another. Therefore international events must be reviewed by qualified Novartis Pharma Associates (see Guidelines for further details).

 NP4-as approved by PEC January 22, 2008 
  

 Page 5 

					
		
	6.2	  	Promotional Content*
			
		  	6.2.1	  	Consistency with approvals
		
		  	Promotional content must be consistent with the prescribing information as approved by local regulatory authorities or otherwise meet the requirements of local
regulatory authorities.
			
		  	6.2.2	  	Accuracy
		
		  	Promotional content must be clear, balanced, and sufficiently complete to enable the recipient to form his/her own opinion of the therapeutic value of a product. It
must be based on an up-to-date evaluation of all relevant evidence. It must not be false or misleading.
			
		  	6.2.3	  	Substantiation
		
		  	Promotional content must be substantiated by reference to prescribing information as approved by local regulatory authorities or by additional scientific evidence
meeting the requirements of local regulatory authorities. Such additional evidence should be made available to HCPs upon request.
		
	6.3	  	Promotional interactions with HCPs
		
		  	Promotional interactions must not interfere with the independence of HCPs.
			
		  	6.3.1	  	Gifts *
		
		  	Promotional Gifts
		
		  	The purpose of promotional gifts is to raise awareness of Novartis Pharma and its products. Promotional gifts must not be given with the intention of interfering with
the independence of HCPs or to provide a personal benefit to HCPs. Therefore, they must be relevant to the practice of medicine and useful in HCPs’ day to day practice.
		
		  	They should not be given frequently and should be inexpensive compared to local average HCPs salaries. If appropriate, promotional gifts should be branded with the
Novartis and/or a product name.
		
		  	Courtesy Gifts
		
		  	The purpose of courtesy gifts is to abide by local cultural customs. These gifts are permitted only on culturally recognized occasions, such as significant national,
cultural or religious holidays. While these gifts do not necessarily need to be relevant to the practice of medicine, they have to be socially acceptable, i.e. in good taste and accepted under local culture. They must be inexpensive compared to
local average HCPs salaries.
		
		  	No cash
		
		  	Payments in cash or cash equivalents (e.g. vouchers) are not allowed.

 NP4-as approved by PEC January 22, 2008 
  

 Page 6 

					
			
		  	6.3.2	  	Samples*
		
		  	Samples are defined as products supplied to HCPs to be given to patients for free. Samples shall enable HCPs to familiarize with products and to gain experience on
the efficacy, tolerability and side effect profile, in order to enhance the practice of medicine. Sampling must strictly follow applicable law. Samples may not be sold under any circumstances.
		
	6.4	  	Non-promotional interactions with HCPs
		
		  	Novartis Pharma’s non-promotional interactions with HCPs aim at exchanging scientific/educational information with HCPs as experts in order to enhance patient
care and the practice of medicine. Such interactions must not interfere with the independence of HCPs.
			
		  	6.4.1	  	Consultants / Advisory Boards* 
		
		  	The purpose of engaging HCPs as consultants and/or members of advisory boards is to receive specific, knowledge-enhancing information and advice. Accordingly engaged
HCPs must be experts in a given field. The engagement must be based on a written contract containing clear tasks and responsibilities, compensation and confidentiality stipulations. Fees and expenses must be reasonable and fair market value in
relation to the services rendered. Venue of meetings and hospitality provided must comply with the standards described in this document (see 6.1).
		
		  	Interactions with consultants and advisory board members must not have the promotion of products as their purpose. The information derived from such interactions may
subsequently be translated into marketing activities/promotional content.
			
		  	6.4.2	  	Studies in humans*
		
		  	Any types of studies/research programmes involving humans (pre- and post-authorisation, interventional and non-interventional) must be conducted in compliance with
the principles of Good Clinical Practice as laid down in the Declaration of Helsinki. All such studies must address meaningful medical or scientific topics, e.g. the clinical profile of a product such as safety, efficacy, modes of action or
performance related to other treatments. The well-being and personal integrity of participants must always be of highest priority.
		
		  	Studies in humans must not have the promotion of products as their purpose. Data derived from such studies may subsequently be translated into marketing
activities/promotional content.
			
		  	6.4.3	  	Market Research
		
		  	Market research must be consistent with EPhRMA or comparable local guidelines.
		
		  	Market research must not have the promotion of products as its purpose. Statistics and data derived from market research may subsequently be translated into marketing
activities/promotional content.
			
		  	6.4.4	  	Investigator meetings
		
		  	The purpose of investigator meetings is to discuss clinical studies of Novartis Pharma products with an audience entirely composed of the investigators who are
participating in the studies. Venue of meetings and hospitality provided must comply with the standards described in this document (see 6.1).

 NP4-as approved by PEC January 22, 2008 
  

 Page 7 

							
		
	6.5	  	Communication with patients
		
		  	Communication with patients should aim at supporting better healthcare. As consumers or caregivers have not received the same medical education as HCPs, careful
consideration needs to be made about the appropriateness, language and style of communication. Therapeutic decisions must be made by HCPs only.
			
		  	6.5.1	  	Direct-to-consumer (DTC) promotion
		
		  	Promotion of prescription-only products to patients (so-called direct-to-consumer promotion, “DTC”) is not allowed in most countries. Where such promotion is
allowed, it must strictly follow the applicable law, industry codes and local Novartis standards.
			
		  	6.5.2	  	Unsolicited queries
		
		  	Upon unsolicited request, information relating to the administration of products may be given by the Medical function to patients who have been put on therapy by an HCP.
Such information must be accurate, balanced and in suitable language for a layperson. Advice on personal medical matters must be refused and the enquirer should be recommended to consult his/her prescribing HCP.
			
		  	6.5.3	  	Disease awareness programs
		
		  	Any pre- and post-launch disease awareness programs targeted at potential patients must be accurate, balanced and written in appropriate language for the public. The
purpose of such programs is to enhance public awareness of disease, to encourage members of the public to seek treatment for their symptoms and thereby save and/or improve the lives of potential patients while not promoting the use of any specific
product1
			
		  	6.5.4	  	Patient compliance programs
		
		  	The purpose of patient compliance programs is to ensure patients who have been prescribed products are provided with information to enhance their compliance/concordance
with prescribed medication. Such programs must not have the promotion of products as their purpose1. Confidential patient data obtained through patient compliance programs may not be held by Novartis Pharma and such programs may only be conducted through third parties unaffiliated with Novartis Pharma
2.
		
	6.6	  	Interactions with patients as a source of knowledge to Novartis Pharma
		
		  	Novartis Pharma’s interactions with patients as a source of knowledge aim at the exchange of information on disease and treatment experiences with Novartis Pharma,
other patients, HCPs, caregivers and the public in order to enhance patient care and the practice of medicine. Such interactions must adhere to all relevant data privacy requirements.
			
		  	6.6.1	  	Consultants / Patient Advisory Boards
		
		  	The purpose of engaging patients as consultants and/or members of patient advisory boards is to receive specific, knowledge- enhancing information and advice.
Accordingly, engaged patients must have experience with a specific disease and its treatment. The engagement must be based

  

	1	 In countries where direct-to-consumer promotion is allowed, disease awareness and patient compliance programs may refer patients to product specific information. 

	2	 Unless permitted by local law 

 NP4-as approved by PEC January 22, 2008 
  

 Page 8 

					
		
		  	on a written contract containing clear tasks and responsibilities, compensation and confidentiality stipulations. Fees and expenses must be reasonable and fair market
value in relation to the services rendered. Venue of meetings and hospitality provided must comply with the standards described in this document (see 6.1).
		
		  	Interactions with Consultants and Patient Advisory Board members must not have the promotion of products as their purpose. The information derived from such
interactions may subsequently be translated into marketing activities/promotional content.
			
		  	6.6.2	  	Speakers
		
		  	The purpose of engaging patients to speak at events is to share relevant experiences. The engagement must be based on a written contract containing a clear
description of tasks and responsibilities. Fees and expenses must be reasonable and fair market value in relation to the services rendered.
	  
 7
	  	  
 GRANTS*

		  	  

		
		  	Grants can only be given to reputable institutions, organizations or associations related to healthcare but not to individuals.
		
		  	Grants must be provided without agreement or intent to receive a tangible return in exchange and they must not have the promotion of products as their purpose. Grants
must not interfere with the independence of grants recipients and their associates. All grants must be properly documented.
		
		  	Grants3 must be given only to further research (research grants), to support education (educational grants) or as a gesture of goodwill (image-building grants).
		
	7.1	  	Research / Educational grants
		
		  	The purpose of research and educational grants is to enhance the practice of medicine by supporting basic or applied research (research grants) or by supporting the
education of HCPs and/or patients (educational grants).
		
		  	Educational grants relating to events
		
		  	Funding events and/or funding participation to events constitutes an educational grant if the event organiser is solely responsible for developing and delivering the
content of the event.
		
		  	Educational grants relating to patient associations
		
		  	Funding patient associations, without agreement or intent to receive a tangible return in exchange constitutes an educational grant; further details relating to
Novartis Pharma’s relationship with patient associations are contained in a separate guideline (“Practical Guidelines for Patient Group Interactions”).

  

	3	 Donations are regulated by the Management Authorization Levels. A donation is defined by its
altruistic purpose. 

 NP4-as approved by PEC January 22, 2008 
  

 Page 9 

			
		
	7.2	  	Image-building grants
		
		  	The purpose of image-building grants is to support healthcare institutions in improving infrastructure.
		
	8	  	RESPONSIBILITIES*
		  	  

		
	8.1	  	Global level
		
		  	Overall responsibility for ensuring compliance with this document at global level is allocated to the Business Franchise Heads, Development Franchise Heads and Business Unit
Heads respectively. In particular, they are responsible for the implementation and oversight of appropriate processes in their respective areas of responsibility, including ensuring (1) sufficient review and approval of all promotional content
produced, (2) appropriateness of interactions with HCPs and patients, (3) sufficient review and approval of grants provided at global level4 and (4) associates are trained on NP4.
		
		  	Delegation of responsibilities, as well as review, approval and documentation processes must be clearly defined in SOPs. These SOPs must be approved by qualified representatives
from the DRA, Medical, Marketing, Finance, Legal and Compliance functions.
		
		  	For grants approved and funded on global level but carried out in CPOs, the respective local legal function must be involved.
		
	8.2	  	CPO / local level
		
		  	Overall responsibility for ensuring compliance with this document at local level is allocated to the CPO Heads. In particular, they are responsible for the implementation and
oversight of appropriate processes in their respective areas of responsibility, including ensuring (1) sufficient review and approval of all promotional content produced, (2) appropriateness of interactions with HCPs and patients,
(3) sufficient review and approval of grants provided at local level4 and (4) associates are trained on NP4.
		
		  	Delegation of responsibilities, as well as review, approval and documentation processes must be clearly defined in SOP’s. These SOPs must be approved by qualified
representatives from the DRA, Medical, Marketing, Finance, Legal and Compliance functions.
		
		  	Local review shall also include activities initiated and/or content provided by global functions to ensure compliance with local law, industry codes and local Novartis Pharma
standards.
		
	8.3	  	Interpretation and implementation
		
		  	The Divisional Compliance Committee (DCC) is ultimately responsible for providing guidance on the interpretation, implementation of and deviation from this document. Written
guidance on implementation and interpretation is contained in the “Guidelines”, which will be updated from time to time by the DCC.

  

	4	 In some countries the marketing/sales function should not oversee the grants process. 

 NP4-as approved by PEC January 22, 2008 
  

 Page 10 

					
	9	  	PUBLIC OFFICIALS/INSTITUTIONS*
		  	  

		
	9.1	  	Additional standards for interactions with HCPs which are Public Officials
		
		  	HCPs working at public hospitals or government institutions may be defined as ‘public officials’ by anti-corruption laws. In order to ensure strict compliance
with national and international anti-corruption laws, such as the US Foreign Corrupt Practices Act (FCPA) and the OECD Anti-Bribery Convention, interactions with public officials must comply with the following additional requirements (please note
that an increasing number of countries have changed/are changing their laws to extend the applicability of these anti-corruption requirements to interactions with private persons):
			
		  	•	  	All benefits conveyed to public officials must be fully transparent, properly documented and accounted for; and
			
		  	•	  	If required by local law, Novartis Pharma shall demand written assurance from the relevant public hospitals/government institutions, that benefits conveyed (e.g. funding attendance
to events or engaging public officials as experts/speakers) do not violate applicable local law and regulations.
		
	9.2	  	Additional Standards relating to Grants to Public Institutions
		
		  	In order to ensure strict compliance with national and international anti-corruption laws, such as the US Foreign Corrupt Practices Act (FCPA) and the OECD Anti-Bribery
Convention, grants to public institutions, organizations or associations must comply with the following additional requirements: (please note that an increasing number of countries have changed/are changing their laws to extend the applicability of
these anti-corruption requirements to grants made to private institutions)
			
		  	•	  	All grants to public institutions must be fully transparent, properly documented and accounted for; and
			
		  	•	  	Grants should be made pursuant to a formal agreement endorsed by responsible representatives of the public institution. The existence of similar agreements between the public
institution and other private sector parties may be a useful factor in determining whether the proposed grant is acceptable in a certain country; and
			
		  	•	  	In addition to the internal review of grants, a formal process should exist for the selection, implementation and ongoing supervision of grants, involving representatives from the
public institution; and
			
		  	•	  	Any grant to a public institution would be particularly sensitive if Novartis Pharma conducts or is anticipating specific business with the public institution;
			
		  	•	  	In case of educational grants providing for scholarships or participation to similar long-term programs, the public institution should select the HCPs who will be invited to
participate; and
			
		  	•	  	Any grant to both public and private institutions that is suggested by a government official of a public institution who is in a position to influence Novartis Pharma’s
business interests has to be considered carefully.

 NP4-as approved by PEC January 22, 2008 
  

 Page 11 

 EXHIBIT K 
 PIPELINE INVENTORY ADJUSTMENT 
  

	I.	Definitions 

 “Average Daily
Usage” means the “sold volume” of Product dispensed by Novartis in the Territory over the six (6) months prior to the Effective Date as calculated by dividing the Units Sold by the number of Business Days in such period per
the relevant IMS 852 reports. 
 “Units Sold” means the number of units of retail Product dispensed by the Top 3 Customers in
the Territory in a period as presented in the Top 3 Customer’s 852 reports. 
 [***]. 
  

	II.	Pipeline Inventory Adjustment as of the First Sales Booking Date 

 In order to calculate the Pipeline Inventory Adjustment: 
 [* * *] 
  
 *** Certain information on this page has been omitted and filed separately with
the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 K-1 

 EXHIBIT L 
 INVESTIGATOR-INITIATED CLINICAL TRIALS AND 
 PRE-CLINICAL MATERIAL TRANSFER AGREEMENTS 
 See below. 
  

 L-1 

 MTAs 
  

					
	 Project Name
	  	 Study description
	  	 Recipient

	[* * *]	  	[* * *]	  	[* * *]
			
	[* * *]	  	[* * *]	  	[* * *]

 Proleukin Investigator-Initiated
Trials Program 
 Active studies with open enrollment: 15 
  

																							
	 NCC Study Code
	  	 Protocol Title
	  	 Remain to
pay as of
Nov 09
	  	 2009
Budget
	  	 2010
Budget
	  	 Budget
after
2010
	  	 Drug
Support
 Vials
remaining
	  	 Trial
Status
	  	 Enrolment
Target
	  	 Current
Enrolment
	  	 FPFV
	  	 Est.
LPFV,
LPLV

	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
												
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
												
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
												
	[* * *]	  	Multicenter Phase II Trial of High-Dose Interleukin-2 (IL-2) with Priming and Concomitant Sargramostim (GM-CSF) in Patients with Advanced Melanoma	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]

  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 L-2 

																							
	 NCC Study Code
	  	 Protocol Title
	  	 Remain to
pay as of
Nov 09
	  	 2009
Budget
	  	 2010
Budget
	  	 Budget
after
2010
	  	 Drug
Support
 Vials
remaining
	  	 Trial
Status
	  	 Enrolment
Target
	  	 Current
Enrolment
	  	 FPFV
	  	 Est.
LPFV,
LPLV

	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
												
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
												
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
												
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
												
	[* * *]	  	Phase II Study of Metastatic cancer that Overexpresses p53 Using Lymphodepleting Conditioning Followed by Infusion of Anti-p53 TCR-Gene Engineered Lymphoctes	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  	[* * *]
												
	[* * *]	  	Phase II Study of Metastatic Melanoma Using Lymphodepleting Conditioning Followed by Infusion of Anti-gp 100:154-162 TCR -Gene Engineered Lymphocytes	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  	[* * *]
												
	[* * *]	  	Phase II Study of Metastatic Melanoma Using Lymphodepleting Conditioning Followed by Infusion of Anti- Mart-1 F5 TCR-Gene Engineered Lymphocytes	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  	[* * *]
												
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  		  	[* * *]

  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 L-3 

																							
	 NCC Study Code
	  	 Protocol Title
	  	 Remain to
pay as of
Nov 09
	  	 2009
Budget
	  	 2010
Budget
	  	 Budget
after
2010
	  	 Drug
Support
 Vials
remaining
	  	 Trial
Status
	  	 Enrolment
Target
	  	 Current
Enrolment
	  	 FPFV
	  	 Est.
LPFV,
LPLV

	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
												
	[* * *]	  	Epstein-Barr Virus-Specific Adoptive Immunotherapy for Nasopharyngeal Carcinoma: A Phase II Trial	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
												
	[* * *]	  	A Phase II Study Using Short-Term Cultured Anti-Tumor Autologous Lymphocytes Following a Non-Myeloablative Lymphocyte Depleting Chemotherapy Regimen in Metastatic
Melanoma	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]

 (* NIH studies were considered as one trial under a
mast agreement) 
 Studies with enrollment closed: 9 
  

																					
	 NCC Study Code
	  	 Protocol Title
	  	 Remaining
to pay as
of Nov
	  	 2009
Budget
	  	 2010
Budget
	  	 Budget
after
2010
	  	 Drug
Support
	  	 Trial
Status
	  	 Enrolment
Target
	  	 Current
Enrollment
	  	 LPFV

	[* * *]	  	Phase III Trial of High Dose Interferon Alfa 2-b versus Cisplatin, Vinblastine, DTIC Plus IL-2 and Interferon in Patients with High Risk Melanoma	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
											
	[* * *]	  	A Limited Dose Exploration / Phase II Study of Bevacizumab and Aldesleukin in Patients with Metastatic Renal Cell Carcinoma (RCC)	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
											
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]

  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 L-4 

																					
	 NCC Study Code
	  	 Protocol Title
	  	 Remaining
to pay as
of Nov
	  	 2009
Budget
	  	 2010
Budget
	  	 Budget
after
2010
	  	 Drug
Support
	  	 Trial
Status
	  	 Enrolment
Target
	  	 Current
Enrollment
	  	 LPFV

	[* * *]	  	Phase II Study of Immuno-modulation with GM-CSF, IL-2 and Rituximab in Patients with Relapsed/Refractory B Cell Lymphoma, or Hodgkin’s Lymphoma or Mantle Cell Lymphoma
Following High Dose Chemotherapy and Stem Cell Rescue	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
											
	[* * *]	  	A Phase II Trial using a Universal GM-CSF-Producing and CD40L-Expressing Bystander Cell Line (GM. CD40L) in the Formulation of Autologous Tumor Cell-Based Vaccines for Patients with
Mantle Cell Lymphoma	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
											
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
											
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
											
	[* * *]	  	A Phase III Multi-Institutional Randomized Study of Immunization with the gp 100; 209-217(210M) Peptide followed by High Dose IL-2 vs. High Dose IL-2 Alone in Patients with
Metastatic Melanoma	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
											
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]

  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 L-5 

 Studies to start-up: 3 
  

																	
	 NCC Study Code
	  	 Protocol Title
	  	 Remaining
to pay as
of Nov
	  	 2009
Budget
	  	 2010
Budget
	  	 Budget
after
2010
	  	 Drug
Support
	  	 Trial
Status
	  	 Enrolment
Total

	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
									
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]
									
	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]	  	[* * *]

  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 L-6 

 EXHIBIT M 
 PRE-AGREED ROW AMENDMENT TERMS 
 The pre-agreed terms in principle of
the ROW Amendment shall be as follows, which terms shall not be subject to amendment or renegotiation in connection with such ROW Amendment and shall be incorporated into the ROW Amendment as set forth in this Exhibit M: 
 – Territory: The Territory shall include all countries of the world excluding the U.S. and Canada. 
 – Product, Field, Term, Grant of Rights, Sublicensing, Compliance, Product Intellectual Property, Non-Compete, Change of Control, and
Transitional Services: The terms of the ROW Amendment shall be generally consistent with the terms set forth in this Agreement. 
 – Marketing and Selling Investment: The terms of the ROW Amendment shall be generally consistent with the terms set forth in this Agreement, except that the ROW Amendment shall not introduce any additional minimum marketing and
promotion investment commitments for Prometheus. 
 – Manufacture and Supply and Alternate Manufacturer: The terms of the
ROW Amendment shall be generally consistent with the terms set forth in the Supply Agreement, except that the Novartis point(s) of delivery of Product to Prometheus in the ROW Amendment shall be defined therein and the nature of final labeling and
packaging for the Product for the ROW Territory may differ from that for the Product as delivered for the U.S. and Canada. 
 – Consideration: 
  

	 	•	 	 A non-refundable, upfront payment of [***] U.S. dollars ($[* * *]) in cash to be paid to Novartis within [* * *] ([* * *]) Business Days
after the effective date of the ROW Amendment; 

  

	 	•	 	 Royalties: The royalties on aggregate Net Sales of the Products set forth in the ROW Amendment shall be at the royalty rate calculated in accordance
with the provisions below: 

 (a) [* * *] percent ([* * *]%) of aggregate worldwide Net Sales of the Products
in each calendar year up to and including [* * *] U.S. dollars ($[* * *]); 
 (b) [* * *] ([* * *]%) of aggregate worldwide Net
Sales of the Products in each calendar year above [* * *] U.S. dollars ($[* * *]) up to and including [* * *] U.S. dollars ($[* * *]); and 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the
omitted portions. 
  

 M-1 

 (c) [* * *] percent ([* * *]%) of aggregate worldwide Net Sales of the Products in each
calendar year above [* * *] U.S. dollars ($[* * *]). 
 To be clear, the above royalties shall apply worldwide and shall replace
the royalties under this Agreement. 
  

	 	•	 	 Annual Option Fee: The terms applicable to the extension of the Term of this Agreement and the payment by Prometheus of the applicable annual option
fee [* * *] as a result of the ROW Amendment, and extension of this Agreement with respect to the ROW Territory may only be done in conjunction with extension of this Agreement as a whole. 

  

	 	•	 	 Milestone Payments: The terms of the ROW Amendment under the milestone payments section shall be consistent with the terms specified in this Agreement,
except that the milestone payments due to Novartis and corresponding thresholds in the milestone payments section of this Agreement (the “Incremental Product Net Sales Milestones”) shall be superseded (solely to the extent that any
milestone has not already been realized and the corresponding milestone payment already has not already been paid by Prometheus) by the following milestone payments due to Novartis and corresponding thresholds: 

 (a) [* * *] U.S. dollars ($[* * *]) payable upon the achievement of aggregate worldwide annual Net Sales of the Products deemed sold as a
consequence of sales of Third Party Products equal to [* * *] U.S. dollars ($[* * *]); 
 (b) [* * *] U.S. dollars ($[* * *])
payable upon the achievement of aggregate worldwide annual Net Sales of the Products deemed sold as a consequence of sales of Third Party Products equal to [* * *] U.S. dollars ($[* * *]); 
 (c) [* * *] U.S. dollars ($[* * *]) payable upon the achievement of aggregate worldwide annual Net Sales of the Products deemed sold as a
consequence of sales of Third Party Products equal to [* * *] U.S. dollars ($[* * *]); and 
 (d) [* * *] U.S. dollars ($[* *
*]) payable upon the achievement of aggregate worldwide annual Net Sales of the Products deemed sold as a consequence of sales of Third Party Products equal to [* * *] U.S. dollars ($[* * *]). 
  
 *** Certain information on this page has been omitted and filed separately with
the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 M-2 

 EXHIBIT N 
 ROW OPTION CONDITIONS 
 Prometheus may exercise the ROW Option only
after it has demonstrated to Novartis that it has fulfilled the following requirements for each and all of the countries listed below (the “Exhibit N Countries”) (the Parties acknowledge that once the ROW Option is properly
exercised, that the Territory shall not be limited to only the countries set forth below but shall include the entire world). 
  

	
	 [* * *]

	 [* * *]

	 [* * *]

	 [* * *]

	 [* * *]

	 [* * *]

	 [* * *]

	 [* * *]

	 [* * *]

	 [* * *]

	 [* * *]

	 [* * *]

	 [* * *]

	 [* * *]

	 [* * *]

	 [* * *]

	 [* * *]

	 [* * *]

	 [* * *]

	 [* * *]

	 [* * *]

	 [* * *]

	 [* * *]

	 [* * *]

	 [* * *]

	 [* * *]

 Prometheus shall demonstrate to Novartis that, upon exercise of its ROW Option, 
 Prometheus has established an Affiliate, including a warehouse in [* * *], provided that the Affiliate and warehouse may be in different countries upon approval of Novartis, such approval not to be unreasonably withheld, and is capable of
fulfilling the following requirements: 
  

	 	–	ability to receive the goods for all ROW countries 

  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the
omitted portions. 
  

 N-1 

	 	–	warehousing for the Product which complies with Applicable Law 

  

	 	–	ability to distribute the Product to the ROW countries in compliance with Applicable Law and all relevant agreements 

  

	 	–	ability to receive the invoices from Novartis Pharma AG or its Affiliates for the ROW countries 

  

	 	–	ability to pay the invoices for the ROW countries on a timely basis, according to the terms of this Agreement 

  

	 	–	ability to issue invoices to Affiliates or established pharmaceutical distributors in each Exhibit N Country 

 and 
 Prometheus has either 
  

	 	(a)	established Affiliates, or 

  

	 	(b)	entered into written agreements with established pharmaceutical distributors, reasonably acceptable to Novartis to service each Exhibit N Country, which are
capable of fulfilling the following minimum requirements: 

  

	 	–	maintain and operate a supply chain which distributes the Product in each Exhibit N Country without interruption 

  

	 	–	maintain and operate a regulatory set-up as required by Applicable Law 

  

	 	–	take over the applicable Regulatory Approvals for the Product on a timely basis in each Exhibit N Country 

  

	 	–	perform the product release to market (minimum of (1) trained and assigned person for this specific task is required) 

  

	 	–	perform pharmacovigilance and provide Novartis with the pharmacovigilance data 

  

	 	–	maintain and operate a commercial organization with resources and expertise to take over from Novartis the Product under the terms, conditions and timelines contained
in this Agreement. 

 Prometheus and Novartis will jointly carry out an analysis to determine whether any anti-trust approvals or
notifications from the relevant merger control authorities are required in connection with the transaction contemplated by this Agreement, and will seek approvals or make notifications as required. 
  

 N-2 

 Prometheus agrees that the Product will be shipped under the trade term [***] in the ROW Territory to
Prometheus’ designated delivery point, such delivery point to be located in [* * *], provided that the Affiliate and warehouse may be in different countries upon approval of Novartis, such approval not to be unreasonably withheld. 

 
 *** Certain information on this page has been omitted and filed separately
with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 N-3 

 EXHIBIT O 
 INITIAL PRESS RELEASE 

 

 

 Prometheus Acquires Exclusive Rights to PROLEUKIN® (aldesleukin) in the U.S. 
 Company to distribute, promote and sell Proleukin under long-term commercialization 
 agreement with Novartis 
 San Diego, January 26, 2010 – Prometheus Laboratories Inc., a specialty
pharmaceutical and diagnostic company, today announced the execution of a commercialization agreement with Novartis under which Prometheus acquired exclusive rights to distribute, promote and sell PROLEUKIN® (aldesleukin) in the United States. Proleukin is a recombinant human interleukin-2 for treatment in adults with metastatic melanoma and metastatic
kidney cancer. Net sales for Proleukin were approximately $65 million in the U.S. in 2008. 
 Under the terms of the agreement, Novartis
received an upfront fee and will receive royalties on net sales of Proleukin in the U.S. Novartis is also eligible to receive potential sales milestone payments. Prometheus will have the option to extend the initial six-year term on an annual basis
for up to an additional six years. In addition, the companies will have an option to amend the agreement to include the rest of the world upon the completion of certain conditions. 
 “This represents a transformational event for Prometheus as we continue to build our oncology presence and execute on our
integrated therapeutics and diagnostics business model,” said Joseph M. Limber, President and Chief Executive Officer of Prometheus. “We have established ourselves as a leader in the gastroenterology market by offering a complementary
portfolio of pharmaceutical and diagnostic products promoted via Prometheus’ highly trained sales force. Now, following the recent launch of our three ProOncDx microRNA-based diagnostic tests and the continued development of our emerging and proprietary diagnostics platform, we
are well positioned to repeat this success in the oncology market.” 
 A portion of the proceeds from Prometheus’ previously announced
$260 million Senior Secured Credit Facility was used to finance this transaction. 
 About Proleukin 
 PROLEUKIN® (aldesleukin) for injection is a recombinant human interleukin-2 for treatment in adults with metastatic melanoma and metastatic kidney cancer. Proleukin therapy is a
form of immunotherapy that enhances the body’s natural immune system to help fight these types of cancer. Proleukin has been used for over 10 years in the treatment of metastatic melanoma and over 15 years in the treatment of metastatic kidney
cancer (renal cell carcinoma). For complete prescribing information, please visit www.Proleukin.com. 
 Important Safety Information

 Therapy with PROLEUKIN® (aldesleukin) for injection should be restricted to patients with normal cardiac and pulmonary functions as defined by thallium stress testing and formal pulmonary
function testing. Extreme caution should be used in patients with a normal thallium stress test and a normal pulmonary function test who have a history of cardiac or pulmonary disease. 
  

 O-1 

 Proleukin should be administered in a hospital setting under the supervision of a qualified physician
experienced in the use of anticancer agents. An intensive care facility and specialists skilled in cardiopulmonary or intensive care medicine must be available. 
 Proleukin administration has been associated with capillary leak syndrome (CLS) which is characterized by a loss of vascular tone and extravasation of plasma proteins and fluid into the extravascular
space. CLS results in hypotension and reduced organ perfusion which may be severe and can result in death. CLS may be associated with cardiac arrhythmias (supraventricular and ventricular), angina, myocardial infarction, respiratory insufficiency
requiring intubation, gastrointestinal bleeding or infarction, renal insufficiency, edema, and mental status changes. 
 Proleukin treatment is
associated with impaired neutrophil function (reduced chemotaxis) and with an increased risk of disseminated infection, including sepsis and bacterial endocarditis. Consequently, preexisting bacterial infections should be adequately treated prior to
initiation of Proleukin therapy. Patients with indwelling central lines are particularly at risk for infection with gram positive microorganisms. Antibiotic prophylaxis with oxacillin, nafcillin, ciprofloxacin, or vancomycin has been associated with
a reduced incidence of staphylococcal infections. 
 Proleukin administration should be withheld in patients developing moderate to severe
lethargy or somnolence; continued administration may result in coma. 
 About Interleukin-2 
 Interleukin-2 (IL-2) is a protein that occurs naturally in the body and plays an important role in activating the immune system. The immune system protects
the body from foreign substances, cells, and tissues by responding to and resisting diseases. Proleukin therapy is a genetically engineered or recombinant version of IL-2. Proleukin therapy possesses the same properties as naturally occurring IL-2
and helps activate the immune system to recognize and eliminate certain kinds of cancer cells. 
 About Prometheus 
 Prometheus Laboratories Inc. is a specialty pharmaceutical and diagnostic company committed to developing and commercializing novel pharmaceutical and
diagnostic products to help physicians individualize patient care. Prometheus is a leader in applying the principles of personalized medicine to the diagnosis and treatment of gastrointestinal diseases and is applying these principles to oncology.
Its strategy includes the marketing and delivery of pharmaceutical products complemented by proprietary diagnostic testing services. By integrating pharmaceutical products and diagnostic testing services, Prometheus believes it can address the full
continuum of care, thereby providing physicians with a comprehensive solution to treat chronic diseases. Prometheus’ corporate offices are located in San Diego, California. 
 PROLEUKIN is a registered trademark of Novartis. 
  

 O-2 

 ProOncDx is a trademark of Prometheus Laboratories Inc. 
 Contact: 
 Pete De Spain 
 Director, Investor Relations 
 & Corporate Communications 
 Prometheus Laboratories Inc. 
 (858) 587-4117

 pdespain@prometheuslabs.com 
  

 O-3 

 EXHIBIT P 
 NOVARTIS KNOWLEDGE 
 [* * *] 
  
 *** Certain information on this page has been omitted and filed separately with
the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 P-1 

 EXHIBIT Q 
 NOVARTIS EXCLUDED PRODUCTS 
 Product 1) [* * *] 
 Product 2) [* * *] 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 Q-1 

 EXHIBIT R 
 NOVARTIS TRADEMARK GUIDELINES 
 Prometheus shall use the Product Marks
and Product Trade Dress in accordance with the guidelines and policies of Novartis or use of Novartis trademarks and trade dress in the Territory. In the case of any conflict between such policies and guidelines supplied and the terms of the
Agreement and/or Applicable Law, the terms of the Applicable Law shall first apply, following which the terms of this Agreement shall control. 
 Such policies and guidelines are as follows: 
  

	1.	[* * *]. 

  

	2.	[* * *]. 

  

	3.	[* * *]. 

 Proper Use of
Trademarks Guide 
 In order for a trademark to remain legally valid, correct use is essential. Incorrect use may result in the loss of
trademark rights. In particular, a trademark must be recognizable as such. For this, the following rules must be observed (subject to change in the event of any order given by applicable Regulatory Authorities or due to a change in Applicable Law):

 DO 
 [* * *] 
 DON’T 
 [* * *] 
 [* * *] 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 R-1 

 EXHIBIT S 
 TRANSITION SERVICES 
 During the Transition Services Period, Novartis
shall provide the following transition services (“Transition Services”) in the Territory: 
 (a) Disclosure of
Product Intellectual Property as detailed in Section 2.4; 
 (b) Provide all existing and available regulatory
documentation concerning the Product owned or controlled by Novartis; 
 (c) NDC and labeling transition as detailed in
Section 4.2(b); 
 (d) Conduct mutually agreed upon initial training support with respect to the Products to
Prometheus’ sales trainers at a time and place mutually agreed upon by the Parties, subject to the conditions that (1) Prometheus reimburse Novartis for its [***] associated with providing such training, and (2) such training shall
not exceed [* * *] ([* * *]) hours in the aggregate; 
 (e) Conduct mutually agreed upon initial marketing, medical information
or scientific communications support with respect to the Products to respective marketing, medical information, or scientific communications persons at Prometheus at a time and place mutually agreed upon by the Parties, subject to Prometheus
reimbursing Novartis for its [* * *] associated with its provision of such training and such training shall not exceed [* * *] ([* * *]) hours in the aggregate; 
 (f) In the case that Novartis agencies or vendors need to provide services for the transition (for example, the marketing transition), Prometheus will reimburse Novartis for the applicable agency fees
plus Out-of-Pocket Costs for such transition service, provided that Novartis will obtain Prometheus’ consent prior to engaging such agency or vendor to provide such transition services. In the case of marketing projects which are being
performed by external vendors on behalf of Novartis and which have been completed in the period October through December 2009, or which are work in progress as of the Effective Date, and which are anticipated to impact sales in 2010 and future years
and which the Parties agree will be handed over to Prometheus, if Prometheus elects to assume responsibility for such marketing projects, Prometheus will reimburse Novartis for [* * *] percent ([* * *]%) of the costs incurred by Novartis prior to
the Effective Date for such projects, and will assume all costs incurred on or after the Effective Date for all such projects and their respective deliverables including any charges or fees arising from a change in scope of any such project as
applicable. For all such projects agreed to be handed over to Prometheus, Novartis will fulfill all obligations relating to the projects including payments and settlement with vendors in the case where a project is not assigned/assignable to
Prometheus for any cause. If Novartis incurs any expenses that are reimbursable by Prometheus under this Section, it will issue an invoice to Prometheus and Prometheus will pay such invoice within sixty (60) days of receipt; and 
  
 *** Certain information on this page has been omitted and filed separately with
the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 S-1 

 (g) To ensure continuity of the patient assistance programs, meet via conference call with
Prometheus to discuss patient assistance programs and answer any questions (limit of [***] ([* * *]) hours). 
 Novartis is under no obligation
to provide additional services beyond the Transition Services Period and the scope of the Transition Services as set forth above. Upon Prometheus’ request and Novartis’ consent, Novartis may elect to extend the scope and time of the
Transition Services which will be billed to Prometheus at a cost of [* * *] U.S. dollars ($[* * *]) per person per day, or if a person works for a portion of a day, the fee will be reduced proportionally based upon an 8-hour day, plus Out-of-Pocket
Costs. 
  
 *** Certain information on this page has been omitted and
filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 S-2 

 EXHIBIT T 
 COMPLIANCE WITH UPSTREAM LICENSE AGREEMENTS 
 [***]

  
 *** Certain information on this page has been omitted and filed
separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 T-1 

 EXHIBIT U 
 Section 1 
 EXISTING DISCOUNT
AGREEMENTS 
 The following Agreements, to the extent in effect on the First Sales Booking Date: 
  

	1.	Product Purchase Agreement, dated as of [* * *], among [* * *], as amended to date. 

  

	2.	Institutional Sales Segment Agreement, dated as of [* * *], between [* * *] and [* * *], as amended to date. 

  

	3.	Purchasing Agreement, dated as of [* * *], between [* * *] and the [* * *], as amended to date. 

  

	4.	Performance Purchasing Agreement, dated as of [* * *], between [* * *] and [* * *], as amended to date. 

  

	5.	Performance Purchasing Agreement, dated as of [* * *], between [* * *] and [* * *], as amended to date. 

  

	6.	Performance Purchasing Agreement, dated as of [* * *] between [* * *] and [* * *], as amended to date. 

  
 *** Certain information on this page has been omitted and filed separately with
the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 U-1 

 Section 2 
 ASSIGNMENT AND ASSUMPTION AGREEMENT 
 This Assignment
and Assumption Agreement (the “Agreement”) is made and effective as of                     , 20     (the
“Effective Date”), by and between Novartis Pharmaceuticals Corporation, a Delaware corporation, with its principal place of business at 59 Route 10, East Hanover, NJ 07936 (“Novartis”) and Prometheus Laboratories Inc., a
corporation organized under the laws of California, having a place of business at 9410 Carroll Park Drive, San Diego, CA 92121 (“Prometheus”). 
 INTRODUCTION 
 A. Novartis and [Name of Purchasing Entity] are parties to
the [Title of Purchase Agreement] dated                      (the “Product Purchase Agreement”), which agreement covers [various
pharmaceutical products and services], including Proleukin (NDC number 0078049561) (“Proleukin”). 
 B.
Pursuant to the Distribution and Promotion Agreement, dated as of December     , 2009, between Novartis Vaccines and Diagnostics, Inc. (“NVAD”) and Prometheus, NVAD has licensed to Prometheus certain exclusive
rights to Commercialize Proleukin in the United States. 
 C. Novartis therefore wishes to assign all of its rights under the
Product Purchase Agreement to Prometheus with respect to Proleukin and Prometheus wishes to assume all of Novartis’ obligations thereunder with respect to Proleukin, in each case, effective as of the Effective Date (the
“Assignment”). 
 NOW THEREFORE, for and in consideration of the mutual covenants contained in this
Agreement, Novartis and Prometheus agree: 
 1. Assignment and Assumption. Novartis hereby agrees to assign to
Prometheus, and Prometheus hereby agrees to accept and assume all of Novartis’ rights and obligations with respect to periods after the Effective Date under the Product Purchase Agreement relating to Proleukin. For the avoidance of doubt,
Novartis’ rights and obligations under the Product Purchase Agreement that relate to products and services other than Proleukin (the “Excluded Liabilities”) shall not be assigned to and assumed by Prometheus under this
Agreement, and such rights and obligations shall be retained by Novartis. From and after the Effective Date, Novartis shall have no further liabilities or obligations under the Product Purchase Agreement with respect to Proleukin. Notwithstanding
anything herein to the contrary, (a) Prometheus shall have no liability for any Claim or obligation arising out of or in connection with: (i) the Product Purchase Agreement prior to the Effective Date, or (ii) the Excluded
Liabilities, and in each case (i) and (ii), Novartis shall indemnify the Prometheus Indemnitees in connection with any such Claims or obligations in accordance with Section 7.1 of the Distribution Agreement;

  

 U-2 

 
and (b) Novartis shall have no liability for any Claim or obligation relating to Proleukin arising out of or in connection with the Product Purchase Agreement on or after the Effective Date,
and Prometheus shall indemnify the Novartis Indemnitees in connection with any such Claims or obligations in accordance with Section 7.2 of the Distribution Agreement. 
 2. Further Actions. Each of the parties hereto covenants and agrees to do, execute, acknowledge and deliver, at the request of the
other party hereto, all such further acts, assurances, deeds, assignments, transfers, conveyances and other instruments and papers as may be reasonably required or appropriate to carry out the assignments and assumptions contemplated by this
Agreement. 
 3. Counterparts This Agreement may be executed in one or more counterparts, each of which shall be deemed
to be an original but all of which together shall constitute one and the same instrument. 
 [Remainder of page intentionally
left blank.] 
  

 U-3 

 IN WITNESS WHEREOF, the parties hereto have caused this Agreement to be executed by their duly
authorized representatives as of the Effective Date. 
  

			
		 	NOVARTIS PHARMACEUTICALS CORPORATION
		
	By:	 	  

		 	Name:
		 	Title:
		
		 	PROMETHEUS LABORATORIES INC.
		
	By:	 	  

		 	Name:
		 	Title:

  

 U-4 

 [To be used only if applicable] 
 Consent to Assignment and Assumption Agreement between Novartis Pharmaceuticals 
 Corporation and Prometheus Laboratories Inc. attached hereto 
 In consideration of the substantial benefits that will accrue to us as a result of the Assignment contemplated in this Agreement, we hereby
consent to such Assignment by Novartis to Prometheus of all of Novartis’ rights and obligations under the Product Purchase Agreement as relating to Proleukin. We acknowledge that such rights and obligations will be performed by Prometheus as of
the Effective Date and Novartis shall have no further liabilities or obligations under the Product Purchase Agreement relating to Proleukin from and after the Effective Date. All capitalized terms not defined herein shall be as defined in the
Agreement. 
  

			
		 	[NAME OF PURCHASING ENTITY]
		
	By:	 	  

		 	Name:
		 	Title:

  

 U-5 

 EXHIBIT V 
 PRICING DATA FORMAT 
 “Best Price” (BP)
Template 
 External Feed 
  

	
	Company ID-Alpha numeric name of your company
	
	Trans Year-The Year being filed
	
	Trans Period-Quarter being filed
	
	Trans Rep. Period-Q = Quarter, 1 = First Quarter etc.
	
	XDNDC-10 Digit NDC leaving off first 0 e.g. 00078 = 0078
	
	WAC Price-Not used for this transaction type fill with zero
	
	Price Paid per Package-Enter BP per package
	
	Class Code-Not used for this transaction type fill with zero
	
	Trans Type-Numeric value used to identify this transaction, 10720 = BP Achieved, 10710 = BP Possible
	
	No. of Packages-Not used for this transaction type fill with zero
	
	No. of units-Not used for this transaction type fill with zero
	
	Total Dollars-Not used for this transaction type fill with zero
	
	No. Of Lines-1 as component summaries will be used
	
	[* * *]
	[* * *]

  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 V-1 

																										
	 Company ID
	  	 Trans
Year
	  	 Trans Period
	  	 Trans Rep.
Period
	  	 XDNDC
	  	 WAC
	  	 Paid Price per
Package
	  	 Class Code
	  	 Trans Type
	  	 No. of
Packages
	  	 No. of units
	  	Total Dollars	  	 No. Of
Lines

	 COMPANY NAME
	  	2009	  	4	  	Q	  	0078-0495-61	  	0	  	[* * *]	  	0	  	10720	  	0	  	0	  	$	—  	  	1
													
	 COMPANY NAME
	  	2009	  	4	  	Q	  	0078-0495-61	  	0	  	[* * *]	  	0	  	10710	  	0	  	0	  	$	—  	  	1

 Please complete this, and for each
component take into account Your companies definitions in compliance with the Medicaid Legislation and CMS Medicaid Releases. 
 DO NOT FILL
IN 
 FILL IN 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the
omitted portions. 
  

 V-2 

 AMP Template 
  

			
	 Company ID
	  	 Novartis’ Definition’s

	Wholesale Gross Sales	  	[* * *]
		
	Smoothed Non-Retail Rebate Sales	  	[* * *]
		
	Smoothed Non-Retail Chargeback Sales	  	[* * *]
		
	Smoothed Credits	  	[* * *]
		
	Non-Customary Prompt Pay Discount Dollars	  	[* * *]
		
	Smoothed Stocking Allowance Dollars	  	[* * *]
		
	Smoothed PA Credit	  	[* * *]
		
	Other Adjustment Dollars	  	[* * *]
		
	Smoothed FFS	  	[* * *]
		
	Smoothed Retail Chargeback Dollars	  	[* * *]
		
	Smoothed Retail Rebate Dollars	  	[* * *]
		
	Smoothed Patient Transaction Dollars	  	[* * *]
		
	Smoothed PAP Fee Dollars	  	[* * *]

 External Feed 

Company ID-Alpha numeric name of your company 
 Trans Year-The Year being filed 
 Trans Period-Month being filed 1 = January,
2 = February etc.... 
 Trans Rep. Period. M=Month 
 XDNDC-10 Digit NDC leaving off first 0 e.g. 00078 = 0078 
 WAC Price-Not used
for this transaction type fill with zero. 
 Price Paid per Unit-not used for this transaction, fill with zero 

Class Code-Identifies this as AMP Retail/NonRetail as defined by your company in compliance with the Medicare Legislation., RTL=Retail NRT
=Non-Retail 
 Trans Type-Numeric value used to identify this transaction. Only “Other Adjustment Dollars”
component’s number needs to be entered.  
 No. of Packages-Number of packages of that product in the transaction, Generally
only Gross Sales are a positive number, all else should be negative. Packages are needed for Sales Components and Smoothed Credits all else can be left blank. 
 No. of units-Numeric value of the total number of packages * package size. Generally only Gross Sales are a positive number, all else should be negative. Units are needed for Sales Components and
Smoothed Credits all else can be left blank. Depending on the adjustment type, Other Adjustments component may have units entered. 
  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the
omitted portions. 
  

 V-3 

 Total Dollars-In general only Gross Sales will be a positive number and all other components will be
negatives. However, in some cases it is possible for other components to be a positive number. As frequently happens with PA credits. 
 No. Of Lines-1 as component summaries will be used. 
  

 V-4 

																											
	 Component
	  	 Company ID
	  	 Trans
Year
	  	 Trans
Period
	  	 Trans Rep.
Period
	  	 XDNDC
	  	 WAC
	  	 Paid Price
per unit
	  	 Class
Code
	  	 Trans
Type
	  	 No. of
Packages
	  	 No. of
units
	  	 [***]
	  	 No.
Of
Lines

	 Wholesale Gross Sales
	  	COMPANY NAME	  	2009	  	4	  	M	  	0078-0495-61	  	0	  	0	  	WHS	  	15100	  	[* * *]	  	[* * *]	  	[* * *]	  	1
	 Smoothed Non-Retail Rebate Sales
	  	COMPANY NAME	  	2009	  	4	  	M	  	0078-0495-61	  	0	  	0	  	NRT	  	15600	  	[* * *]	  	[* * *]	  	[* * *]	  	1
	 Smoothed Non-Retail Chargeback Sales
	  	COMPANY NAME	  	2009	  	4	  	M	  	0078-0495-61	  	0	  	0	  	NRT	  	15200	  	[* * *]	  	[* * *]	  	[* * *]	  	1
	 Smoothed Credits
	  	COMPANY NAME	  	2009	  	4	  	M	  	0078-0495-61	  	0	  	0	  	RTL	  	15860	  	[* * *]	  	[* * *]	  	[* * *]	  	1
	 Non-Customary Prompt Pay Discount Dollars
	  	COMPANY NAME	  	2009	  	4	  	M	  	0078-0495-61	  	0	  	0	  	RTL	  	15520	  	[* * *]	  	[* * *]	  	[* * *]	  	1
	 Smoothed Stocking Allowance Dollars
	  	COMPANY NAME	  	2009	  	4	  	M	  	0078-0495-61	  	0	  	0	  	RTL	  	N/A	  	[* * *]	  	[* * *]	  	[* * *]	  	1
	 Smoothed PA Credit
	  	COMPANY NAME	  	2009	  	4	  	M	  	0078-0495-61	  	0	  	0	  	RTL	  	N/A	  	[* * *]	  	[* * *]	  	[* * *]	  	1
	 Other Adjustment Dollars
	  	COMPANY NAME	  	2009	  	4	  	M	  	0078-0495-61	  	0	  	0	  	RTL	  	**	  	[* * *]	  	[* * *]	  	[* * *]	  	1
	 Smoothed FFS
	  	COMPANY NAME	  	2009	  	4	  	M	  	0078-0495-61	  	0	  	0	  	RTL	  	15870	  	[* * *]	  	[* * *]	  	[* * *]	  	1
	 Smoothed Retail Chargeback Dollars
	  	COMPANY NAME	  	2009	  	4	  	M	  	0078-0495-61	  	0	  	0	  	RTL	  	15200	  	[* * *]	  	[* * *]	  	[* * *]	  	1
	 Smoothed Retail Rebate Dollars
	  	COMPANY NAME	  	2009	  	4	  	M	  	0078-0495-61	  	0	  	0	  	RTL	  	15600	  	[* * *]	  	[* * *]	  	[* * *]	  	1
	 Smoothed Patient Transaction Dollars
	  	COMPANY NAME	  	2009	  	4	  	M	  	0078-0495-61	  	0	  	0	  	RTL	  	15840	  	[* * *]	  	[* * *]	  	[* * *]	  	1
	 Smoothed PAP Fee Dollars
	  	COMPANY NAME	  	2009	  	4	  	M	  	0078-0495-61	  	0	  	0	  	RTL	  	15850	  	[* * *]	  	[* * *]	  	[* * *]	  	1

 Please complete this and for each
component take into account your company’s definitions in compliance with the Medicaid Legislation and CMS Medicaid Releases. 
 DO NOT
FILL IN 
 FILL IN 
 ** See
Definitions & Details tab 
  
 *** Certain information on
this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 V-5 

 ASP Template 
  

			
	 Company ID
	  	 Novartis’ Definition

	ASP Gross Sales	  	[* * *]
		
	Non-ASP Eligible Chargeback Sales	  	[* * *]
		
	Non-ASP Eligible Avg Quarter SPAP Sales	  	[* * *]
		
	Non-ASP Eligible Avg Quarter Rebate Sales	  	[* * *]
		
	ASP Nominal Sales	  	[* * *]
		
	ASP Nominal Chargeback Sales	  	[* * *]
		
	ASP Eligible Chargebacks	  	[* * *]
		
	ASP Eligible other Adjustments	  	[* * *]
		
	ASP Eligible Avg Qtr Fee For Service Adjustments	  	[* * *]
		
	ASP Eligible Avg Qtr Price Adjustments	  	[* * *]
		
	ASP Eligible Avg Qtr Stocking Allowance	  	[* * *]
		
	ASP Eligible Avg Qtr Rebates	  	[* * *]
		
	ASP Eligible Avg Qtr SPAP Rebates	  	[* * *]

  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 V-6 

 External Feed 
 Company ID-Alpha numeric name of your company 
 Trans Year-The Year being
filed 
 Trans Period-Quarter being filed 
 Trans Rep. Period-Q=Quarter, 1 = First Quarter etc. 
 XDNDC-10 Digit NDC
leaving off first 0 e.g. 00078 = 0078 
 WAC Price-Not used for this transaction type fill with zero. 
 Price Paid per Unit-not used for this transaction, fill with zero EXCEPT NOMINAL fill this with number 
 Class Code-Identifies that this is ASP Eligible as defined by your company in compliance with the Medicare Legislation., ASP=Eligible NAS
=Ineligible 
 Trans Type-Numeric value used to identify this transaction. No need to fill in. 
 No. of Packages-Number of packages of that product in the transaction. No need to fill in. 
 No. of units-Numeric value of the total number of packages * package size-Fill with zero not used in this price type 
 Total Dollars-In general only Gross Sales will be a positive number and all other components will be negatives. However, in some cases it is possible
for other components to be a positive number.  
 No. Of Lines-1 as component summaries will be used. 
  

 V-7 

																											
	 Component
	  	 Company ID
	  	Trans
Year	  	Trans
Period	  	 Trans Rep.
Period
	  	XDNDC	  	 WAC
	  	 Paid Price per
unit
	  	 Class
Code
	  	Trans
Type	  	 No. of
Packages
	  	 No. of
units
	  	 Total Dollars
	  	No.
Of
Lines
	 ASP Gross Sales
	  	COMPANY NAME	  	2009	  	4	  	Q	  	0078-0495-61	  		  		  	ASP	  	30100	  	[* * *]	  	[* * *]	  	[* * *]	  	1
	 Non-ASP Eligible Chargeback Sales
	  	COMPANY NAME	  	2009	  	4	  	Q	  	0078-0495-61	  		  		  	NAS	  	30200	  	[* * *]	  	[* * *]	  	[* * *]	  	1
	 Non-ASP Eligible Avg Quarter SPAP Sales
	  	COMPANY NAME	  	2009	  	4	  	Q	  	0078-0495-61	  		  		  	NAS	  		  	[* * *]	  	[* * *]	  	[* * *]	  	1
	 Non-ASP Eligible Avg Quarter Rebate Sales
	  	COMPANY NAME	  	2009	  	4	  	Q	  	0078-0495-61	  		  		  	NAS	  	30600	  	[* * *]	  	[* * *]	  	[* * *]	  	1
	 ASP Nominal Sales
	  	COMPANY NAME	  	2009	  	4	  	Q	  	0078-0495-61	  		  		  	NAS	  	30100	  	[* * *]	  	[* * *]	  	[* * *]	  	1
	 ASP Nominal Chargeback Sales
	  	COMPANY NAME	  	2009	  	4	  	Q	  	0078-0495-61	  		  		  	NAS	  	30200	  	[* * *]	  	[* * *]	  	[* * *]	  	1
	 ASP Eligible Chargebacks
	  	COMPANY NAME	  	2009	  	4	  	Q	  	0078-0495-61	  		  		  	ASP	  	30200	  	[* * *]	  	[* * *]	  	[* * *]	  	1
	 ASP Eligible other Adjustments
	  	COMPANY NAME	  	2009	  	4	  	Q	  	0078-0495-61	  		  		  	ASP	  	30420	  	[* * *]	  	[* * *]	  	[* * *]	  	1
	 ASP Eligible Avg Qtr Fee For Service Adjustments
	  	COMPANY NAME	  	2009	  	4	  	Q	  	0078-0495-61	  		  		  	ASP	  		  	[* * *]	  	[* * *]	  	[* * *]	  	1
	 ASP Eligible Avg Qtr Price Adjustments
	  	COMPANY NAME	  	2009	  	4	  	Q	  	0078-0495-61	  		  		  	ASP	  		  	[* * *]	  	[* * *]	  	[* * *]	  	1
	 ASP Eligible Avg Qtr Stocking Allowance
	  	COMPANY NAME	  	2009	  	4	  	Q	  	0078-0495-61	  		  		  	ASP	  		  	[* * *]	  	[* * *]	  	[* * *]	  	1
	 ASP Eligible Avg Qtr Rebates
	  	COMPANY NAME	  	2009	  	4	  	Q	  	0078-0495-61	  		  		  	ASP	  	30600	  	[* * *]	  	[* * *]	  	[* * *]	  	1
	 ASP Eligible Avg Qtr SPAP Rebates
	  	COMPANY NAME	  	2009	  	4	  	Q	  	0078-0495-61	  		  		  	ASP	  		  	[* * *]	  	[* * *]	  	[* * *]	  	1

 Please complete this and for each
component take into account Your companies definitions in compliance with the Medicaid Legislation and CMS Medicaid Releases. 
 DO NOT FILL IN

  
 *** Certain information on this page has been omitted and filed
separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 V-8 

 EXHIBIT W 
 THIRD PARTY PAP VENDOR LAYOUT FOR PATIENT TRANSACTION DATA 
  

 W-1 

 

 

 Government Pricing File Interface 
 Agreement 
 (VENDOR NAME) 
 Version: 1.1 
 Date: January 22, 2009 
 W-2 
  

 W-2 

 

 

 Novartis Government Pricing File Interface Agreement 12/10/2009 
 Background 
 As a part of the Novartis’ requirements for compliance with the Deficit Reduction Act II (DRA II), Novartis requires prescription data and pricing for coupon, voucher and Patient Assistance Programs. This document
reviews the overall process and desired data formats to support this process. 
 Overview of Process 

To provide additional background on the fulfillment process, this section provides high level steps of the activities in
and around the fulfillment processes. 
 1.1.1. Campaign Setup Example of DENDRITE 
 1. Campaign definitions (Campaign, Fulfillment, and Segment names, descriptions, dates and relationships) are entered in TACT

 2. Campaign specifications (which Individuals qualify for which Fulfillment or Solicitation) are provided to
Harte Hanks from Novartis using the existing business process. 
 3. Harte Hanks creates an extract and sends to
Vendor (Dendrite) the individuals who qualify for the campaign using the existing technical process. Harte Hanks and IRMA record the fulfilled records as a contact event. 
 1.1.2. Campaign Execution/Fulfillment 
 4. VENDOR
executes the campaign to the individuals provided and creates an acknowledgement file with the individuals provided. 
 5. Consumers use the card, and Vendor collects card activity associated with the usage. 
 6.
Harte Hanks and IRMA store the data as needed in their database as contact events. 
 1.1.3. Campaign Analysis

 7. Novartis loads the data to IRMA and EDNA for reporting and analysis purposes. 
 1.1.4. Government Pricing Reporting 
 8. Novartis loads the data to the Imany Government Pricing system for use in calculations of Best Price Possible, Best Price Achieved and Average Manufacturers Price, per the Deficit
Reduction Act regulations. 
  

 W-3 

 

 

 Novartis Government Pricing File Interface Agreement 12/10/2009 
 Summary of File Exchange 
 1.1.5. Card Usage From Vendor to Government Pricing (GP) 
 File Description Transactional Data 
 File Frequency & Timing Monday through Friday at 10pm

 Week-end processing:- 
 When the process runs on Monday, it will concatenate Saturday, and Sunday file data into the Monday file. 
 Holiday schedule:- 
 The next business day after
the holiday(s); the skipped file will be concatenated into the current file for processing. 
 For Example:- If
Tuesday (09/25/2005) is a holiday, then the 09/25/2005 file will be concatenated to the 09/26/2005 file for processing. 
 File Naming Convention (Vendor short Name)_NOV_GP_USG_YYYYMMDDHHMMSS.txt.pgp 
 File Format See
section 5 below 
 File Transport Via FTP, secured by encryption using PGP 
 File Location Vendor will place the file in a directory on the Vendor ftp server, for Novartis processes to “get.”

 Login/Password Production login: ***** 
 Test login: ****** 
 Password will be supplied under separate cover. 
 1.1.6. Data Structure 
 Files will be ASCII text with a tilde (“~”) delimiter., with
carriage return (ASCII 13) and linefeed (ASCII 10) delimiting each record. 
 Alert and Error Notifications

 When an alert on processing or other error that impacts processing, the following individuals will be
notified: 
 Company Name Contact Address 
 VENDOR 
 VENDOR 
 Novartis Tim Puskas Tim.Puskas@novartis.com 
 Novartis Sachin Nevasekar Sachin.Nevasekar@novartis.com 
 Novartis Kaustubh Churi kaustubh.churi@novartis.com 
  

 W-4 

 

 

 Novartis Government Pricing File Interface Agreement 12/10/2009 
 File Layout - Card Usage File 
 Field Start Position End Position Length Data Type Description 
 Transaction Type n/a n/a 1 A C=Claim, R=Reversal Note: 
 before reversals were negative numbers,
now they are positive numbers. A Reversal will be applied to the first Claim that matches based on Pharmacy NABP, RX Number, and New/Refill Indicator. 
 Rx Number n/a n/a 8 N 
 Date Filled n/a n/a 8 D Rx
date of service 
 Product Service Code n/a n/a 15 A NDC Number 
 New/Refill Indicator n/a n/a 2 N 0 = New otherwise it’s the refill number 
 Quantity Dispensed n/a n/a 8 M max value 99999.99 
 Patient Paid Amount n/a n/a 7 $ Patient’s Out-of-pocket expense after adjudication by primary insurance company. If
there is no primary insurer, this is the pharmacy’s full cash price. 
 Total Amount Authorized n/a n/a 7 $
Amount of the copay discount benefit to be applied towards Patient Paid Amount. 
 Fee n/a n/a 7 $ Pharmacy
incentive fee paid for processing the copay or voucher. 
 ProviderReimb n/a n/a 7 $ Sum of Total Amount
Authorized and Fee fields. 
 MemberPays n/a n/a 7 $ 1. Copay: Patient out-of-pocket expense after Total Amount
Authorized has been applied. 
 2. Voucher: Always Zero. 
 Coupon Amount n/a n/a 7 $ Same as Total Amount Authorized. 
 Status n/a n/a 1 N How the claim came into OPUS Health (1=electronic, 2=mail-in pharmacy, 3=mail-in patient). 
 Group Number n/a n/a 9 A Group number associated with this claim 
 Card Number n/a n/a 12 A Vendor Card Number / Member number or coupon serial number associated with this claim 
 Time Stamp n/a n/a 14 T Date and Time to the milli-second that the claim was processed. Map to Vendor Card number in the db

 Pharmacy NABP n/a n/a 10 A 
 Pharmacy Name n/a n/a 100 A 
  

 W-5 

 

 

 Novartis Government Pricing File Interface Agreement 12/10/2009 
 Pharmacy Address n/a n/a 100 A 
 Line 1 
 Pharmacy Address n/a n/a 35 A 

Line 2 
 Pharmacy Address n/a n/a 35 A 
 Line 3 
 Pharmacy City n/a n/a 35 A 
 Pharmacy State n/a n/a 2 A 
 Pharmacy Zip n/a n/a
10 A 
 Doctor DEA n/a n/a 9 A May or may not be present 
 Doctor City n/a n/a 35 A May or may not be present 
 Doctor State n/a n/a 2 A May or may not be present 
 Doctor ZIP n/a n/a 10 A May or may not be present 
 Novartis ID n/a n/a 9 A 
 ME Number n/a n/a 10 A 
 Doctor Last Name n/a n/a
40 A 
 Doctor First Name n/a n/a 30 A 
 Doctor Middle Name n/a n/a 30 A 
 Doctor Title Code n/a n/a 5 A 
 Doctor Address
Line1 n/a n/a 100 A 
 Doctor Address Line2 n/a n/a 80 A 
 Doctor Address Line3 n/a n/a 80 A 
 License Number n/a n/a 20 A 
 (SLN) 
 SLN State n/a n/a 2 A 
 Plan Type n/a n/a 1 A 
 AWP n/a n/a 7 $ Voucher
Programs: Amount supplied to OPUS by Medispan or First Databank. 
 Pharmacy DEA # n/a n/a 9 A 
 Plan Effective Date n/a n/a 8 D 
 Plan Expiration Date n/a n/a 8 D 
 Plan Termination
n/a n/a 8 D 
 Date 
 The daily transaction feed between VENDOR and Novartis Government Pricing should INCLUDE data from California residents. 
 The feed should include data for all programs administered by Vendor on behalf of Novartis. 
 The existing feeds between VENDOR and Novartis for IRMA and Harte-Hanks should not be impacted by this. The feed described in
this document is an additional feed. 
  

 W-6 

 

 

 Novartis Government Pricing File Interface Agreement 12/10/2009 
  

 W-7 

 

 

 Novartis Government Pricing File Interface Agreement 12/10/2009 
 6.0 Approval 
 For Vendor For Novartis Pharmaceuticals Corporation 
 (signature) (signature) 
 (name printed) (name printed) 
 (title) (title) 
 (date) 
  

 W-8 

 EXHIBIT X 
 OUTSTANDING PHASE IV CLINICAL TRIAL COMMITMENT 
 Commitment #3 from
the May 5, 1992 approval letter from FDA being satisfied through clinical trial study CPRL002A2201 
 To obtain additional clinical data to
determine the effects of antibodies and elevated creatinine on the pharmacokinetics of Aldesleukin 
  

 X-1 

 EXHIBIT Y 
 INVESTIGATOR-INITIATED TRIALS OUTSIDE OF THE TERRITORY 
 See below. 
  

 Y-1 

 PROLEUKIN EX-US IIRP PROGRAM 
 Active studies with open enrollment: 
  

																							
	 NCC Study Code
	  	 Protocol Title
	  	Remain
to pay
as of
Aug 09	  	2009
Budget	  	2010
Budget	  	Budget
after
2010	  	Drug
Support
Vials
remaining	  	Trial
Status	  	Enrolment
Target	 	Current
Enrolment	 	FPFV	  	Est.
LPFV,
LPLV
	 [* * *]
	  	Immunotherapy of maintenance in patients with metastatic melanoma in clinical benefit after chemo-immunotherapy	  	NA	  	Local
CPO	  	Local
CPO	  	N/A	  	NA	  	Active	  	[* * *]	 	[* * *]	 	6/5/09	  	LPLV –
02/15/2012
												
	 [* * *]
	  	 Adoptive therapy with Tumor-Infiltrating Lymphocytes following non-myeloablative conditioning and followed by high dose bolus IL-2
infusion: a randomized phase II study.
  
 Prof. John Haanen, Netherlands
Cancer Institute, Amsterdam
	  	NA	  	Local
CPO	  	Local
CPO	  	complete	  	complete	  	Active	  	[* * *]	 	[* * *]	 	NA	  	NA

  
 *** Certain information on this page has been omitted and filed separately with the Commission. Confidential treatment has been requested with respect to the omitted portions. 
  

 Y-2 

 EXHIBIT Z 
 CANADA TRANSFER CRITERIA 
 Prometheus may extend the Territory to
include Canada pursuant to Section 2.6(a) only after it has demonstrated to Novartis that it has fulfilled the following Canada Transfer Criteria. 
 Prometheus shall demonstrate to Novartis as of the Canada Effective Date that it has either: 
  

	 	(a)	established an Affiliate in Canada, or 

  

	 	(b)	entered into written agreements with an established pharmaceutical distributor, which is a legal entity in Canada, responsible for the sale and distribution of the
Product in Canada, fully accountable for the product in Canada; 

 either entity identified in (a) or (b) above being
capable to fulfill the following minimum requirements in accordance with Applicable Law: 
  

	 	-	import and receive goods for sale in Canada 

  

	 	-	warehouse the Product 

  

	 	-	maintain and operate a supply chain within Canada which distributes the Product without interruption 

  

	 	-	maintain and operate a regulatory set-up 

  

	 	-	take over the applicable Regulatory Approvals in Canada or related to the Product in Canada on a timely basis and assume the same or similar obligations that Prometheus
is required to perform for such Regulatory Approvals in Canada as Prometheus is required to perform or assume in relation to the Regulatory Approvals in US. 

  

	 	-	perform the product release to market 

  

	 	-	perform pharmacovigilance and provide Novartis or Prometheus, as the case may be, with the pharmacovigilance data and in accordance with the Pharmacovigilance Agreement
between the parties 

  

	 	-	have the resources and expertise in place to take over from Novartis the Product under the terms, conditions and timelines contained in this Agreement.

 Prometheus and Novartis will jointly carry out an analysis to determine whether any anti-trust approvals or notifications from
the relevant merger control authorities in Canada are required in connection with the transaction contemplated by this Agreement, and will seek approvals or make notifications as required and applicable. 
  

 Z-1 

 EXHIBIT AA 
 Regulatory Approvals Transfer Letter 
 (FDA DIRECTOR’S NAME TBD),
MD 
 Director 
 Center for Drug
Evaluation and Research 
 Division of Therapeutic Biological Oncology Products 
 Food and Drug Administration 
 5901-B Ammendale Road 
 Beltsville, MD 20705-1266 
 Attn: Document Control
Room 
 Re: BLA 103293; Proleukin® (ALDESLEUKIN) For Injection 
 General Correspondence:
Transfer of Ownership – Effective Date To Be Determined 
 Dear Dr. (FDA DIRECTOR TBD): 
 Reference is made to the aforementioned Biologics License Application for Proleukin® (ALDESLEUKIN) for Injection. 
 In accordance
with 21 CFR 314.72(a)(1), the purpose of this correspondence is to notify the Division that ownership rights to this BLA will transfer from Prometheus Laboratories Inc. (Prometheus) to Novartis Vaccines and Diagnostics, Inc. 
 Full copies of the BLA and all amendments and supplements thereto, along with all correspondence, will be provided to Novartis. 
 After the transfer date, Novartis shall be solely responsible for any and all regulatory filing matters related to this application. 
 Further questions, comments, or correspondence may be directed to the new owner’s responsible official listed below: 
 Novartis Contact 
 Novartis Vaccines and
Diagnostics, Inc., 
 350 Massachusetts Avenue, 
 Cambridge, MA 02139 
 Sincerely, 
 Regulatory Affairs, 
 Prometheus Laboratories Inc. 
  

 AA-1

Source: [{"source": "alea-institute/alea-institute/kl3m-data-edgar-agreements/train-00170-of-00352.parquet"}, [{"source": "alea-institute/alea-institute/kl3m-data-edgar-agreements/train-00170-of-00352.parquet"}]]