Document:

Exhibit 10.11

 

Exhibit 10.11

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.

IV APAP AGREEMENT

(US and Canada)

by and between

BRISTOL-MYERS SQUIBB COMPANY

and

CADENCE PHARMACEUTICALS, INC.

February 21, 2006

 

 

TABLE OF CONTENTS

	 	 	 	 	 	 	 
	ARTICLE I –
	 	DEFINITIONS	 	 	1	 
	1.1
	 	Defined Terms	 	 	1	 
	 
	 	 	 	 	 	 
	ARTICLE II –
	 	GRANT OF U.S. AND CANADIAN RIGHTS AND RELATED TRANSFERS	 	 	12	 
	2.1
	 	Grant of Sublicense and License	 	 	12	 
	2.2
	 	No Implied Licenses; Reservation of Rights	 	 	13	 
	2.3
	 	Rights of Pharmatop	 	 	14	 
	2.4
	 	Further Sublicenses	 	 	15	 
	2.5
	 	Delegation of Manufacturing	 	 	16	 
	2.6
	 	Development and Commercialization Arrangements	 	 	17	 
	2.7
	 	Improvements	 	 	17	 
	2.8
	 	Transfer of Regulatory Filings; Communications with Regulatory Authorities	 	 	18	 
	2.9
	 	Transfer of Data and Transition Arrangements	 	 	19	 
	2.10
	 	Tech Transfer Plan	 	 	21	 
	2.11
	 	Technology Documentation	 	 	21	 
	2.12
	 	Technical Assistance	 	 	22	 
	2.13
	 	Cooperation	 	 	22	 
	2.14
	 	Additional Assistance	 	 	23	 
	2.15
	 	Pharmacovigilance; Adverse Event Reporting	 	 	23	 
	2.16
	 	Infringement – Pharmatop Patents	 	 	25	 
	2.17
	 	Infringement – BMS Patents	 	 	27	 
	2.18
	 	Maintenance of BMS Patents	 	 	27	 
	2.19
	 	Noncontravention	 	 	27	 
	2.20
	 	Patent Extensions	 	 	27	 
	2.21
	 	Data Exclusivity and Orange Book Listings	 	 	28	 
	2.22
	 	Notification of Patent Certifications	 	 	28	 
	2.23
	 	Audit, Inspection and Review	 	 	28	 
	2.24
	 	[***] Covenant; [***]Covenant	 	 	29	 
	 
	 	 	 	 	 	 
	ARTICLE III –
	 	ADDITIONAL COVENANTS	 	 	30	 
	3.1
	 	Annual Operating Plan	 	 	30	 
	3.2
	 	Development, Commercialization and Financial Reports and Consultations	 	 	30	 
	3.3
	 	Development Responsibilities and Costs	 	 	32	 
	3.4
	 	Obligations in respect of the Pharmatop License Agreement	 	 	33	 
	3.5
	 	Certain Rights and Obligations under the Pharmatop License Agreement	 	 	33	 
	3.6
	 	Conduct of Clinical Trials of Products by Cadence in	 	 	 	 
	 
	 	Clinical Study Countries 35	 	 	 	 
	3.7
	 	Conduct of US or Canadian Clinical Trials of Products by BMS	 	 	37	 

 

			
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ii

 

	 	 	 	 	 	 	 
	3.8
	 	Existing BMS Suppliers	 	 	38	 
	 
	 	 	 	 	 	 
	ARTICLE IV –
	 	FINANCIAL TERMS	 	 	38	 
	4.1
	 	Payments to BMS	 	 	38	 
	4.2
	 	Reduction of Certain Milestone Payments	 	 	39	 
	4.3
	 	Payments by Cadence to Pharmatop	 	 	40	 
	4.4
	 	Manner of Payment	 	 	41	 
	4.5
	 	Interest	 	 	41	 
	4.6
	 	Expenses; Taxes	 	 	41	 
	 
	 	(a)                                 Expenses	 	 	41	 
	 
	 	(b)                                 Transfer Taxes	 	 	41	 
	 
	 	(b)                                 Tax Withholding	 	 	41	 
	4.7
	 	Sales Reports and Royalty and Other Payments	 	 	41	 
	4.8
	 	Sales Record Audit	 	 	42	 
	 
	 	 	 	 	 	 
	ARTICLE V –
	 	MUTUAL COVENANTS OF THE PARTIES	 	 	42	 
	5.1
	 	Publicity	 	 	42	 
	5.2
	 	Confidentiality	 	 	43	 
	 
	 	(a)                                 Confidentiality Obligations	 	 	43	 
	 
	 	(b)                                 Limited Disclosure	 	 	43	 
	 
	 	(c)                                 Authorized Disclosure	 	 	44	 
	 
	 	(d)                                 Employees and Consultants	 	 	45	 
	 
	 	(d)                                 Securities Filings	 	 	45	 
	 
	 	(f)                                 Academic Publications	 	 	45	 
	 
	 	(g)  Additional Confidentiality Obligations under the Pharmatop	 	 	 	 
	 
	 	      License Agreement	 	 	46	 
	5.3
	 	Restrictions Binding on Affiliated Companies and Investors	 	 	46	 
	5.4
	 	Alliance Management	 	 	46	 
	5.5
	 	Liens	 	 	46	 
	5.6
	 	BMS Confidential Disclosure Agreements	 	 	47	 
	 
	 	 	 	 	 	 
	ARTICLE VI –
	 	REPRESENTATIONS AND WARRANTIES	 	 	47	 
	6.1
	 	Mutual Representations and Warranties	 	 	47	 
	 
	 	(a) Organization	 	 	47	 
	 
	 	(b) Authorization	 	 	47	 
	 
	 	(c) Binding Agreement	 	 	47	 
	 
	 	(d) No Conflicts; Consents	 	 	48	 
	 
	 	(e) Litigation	 	 	48	 
	6.2
	 	Additional Representations of Cadence	 	 	48	 
	 
	 	(a) Financial Statements	 	 	48	 
	 
	 	(b) Absence of Undisclosed Liabilities	 	 	49	 
	 
	 	(c) Absence of Material Adverse Effect	 	 	49	 
	 
	 	(d) Legal Matters	 	 	50	 
	 
	 	(e) Receipt of Financing; Restrictions	 	 	50	 
	6.3
	 	BMS Rights	 	 	50	 
	6.4
	 	BMS Patents and Know-How	 	 	51	 
	6.5
	 	DISCLAIMER	 	 	52	 

iii

 

	 	 	 	 	 	 	 
	6.6
	 	Limitation of Liability	 	 	52	 
	 
	 	 	 	 	 	 
	ARTICLE VII –
	 	INDEMNIFICATION; ARBITRATION	 	 	53	 
	7.1
	 	Mutual Indemnification	 	 	53	 
	7.2
	 	Additional Indemnification Obligations of Cadence	 	 	54	 
	7.3
	 	Additional Indemnification Obligations of BMS	 	 	54	 
	7.4
	 	Conditions to Indemnification; Third Party Claims	 	 	55	 
	7.5
	 	Insurance	 	 	55	 
	7.6
	 	Arbitration	 	 	56	 
	7.7
	 	Pharmatop Arbitration	 	 	57	 
	 
	 	 	 	 	 	 
	ARTICLE VIII
	 	TERM AND TERMINATION	 	 	58	 
	8.1
	 	Term	 	 	58	 
	8.2
	 	Automatic Termination	 	 	58	 
	8.3
	 	Termination by Either Party	 	 	58	 
	8.4
	 	Termination by BMS	 	 	59	 
	8.5
	 	Termination by Cadence	 	 	59	 
	8.6
	 	Scope of Termination	 	 	60	 
	8.7
	 	Effect of Termination	 	 	60	 
	8.8
	 	Transition	 	 	62	 
	8.9
	 	Survival	 	 	63	 
	8.10
	 	Bankruptcy	 	 	63	 
	 
	 	 	 	 	 	 
	ARTICLE IX –
	 	MISCELLANEOUS	 	 	63	 
	9.1
	 	Amendments	 	 	63	 
	9.2
	 	Counterparts; Facsimile Execution	 	 	63	 
	9.3
	 	Cumulative Remedies	 	 	63	 
	9.4
	 	Entire Agreement	 	 	63	 
	9.5
	 	Schedules	 	 	63	 
	9.6
	 	Force Majeure	 	 	64	 
	 
	 	(a) General	 	 	64	 
	 
	 	(b) Definition	 	 	64	 
	 
	 	(c) Duty to Mitigate	 	 	64	 
	 
	 	(d) Suspension of Certain Obligations	 	 	64	 
	9.7
	 	Assignment	 	 	64	 
	9.8
	 	Governing Law	 	 	65	 
	9.9
	 	Headings	 	 	65	 
	9.10
	 	Notices	 	 	65	 
	9.11
	 	Severability	 	 	66	 
	9.12
	 	No Third Party Beneficiaries	 	 	66	 
	9.13
	 	Waivers	 	 	66	 
	9.14
	 	Documentary Conventions	 	 	66	 
	9.15.
	 	Consents and Approvals	 	 	67	 
	9.16.
	 	Absence of Presumption	 	 	67	 
	9.17.
	 	Relationship of Parties	 	 	67	 

iv

 

	 	 	 	 	 	 	 
	Schedule 1.1
	 	BMS Patents	 	 	 	 
	Schedule 6.3(a)
	 	Pharmatop Patents	 	 	 	 

v

 

INDEX OF DEFINED TERMS

	 	 	 	 	 
	 	 	Section	 
	$ 
	 	 	1.1	 
	Adverse Event
	 	 	1.1	 
	Affiliated Company
	 	 	1.1	 
	Agreement Introductory Paragraph
Annual Operating Plan
	 	 	3.1	 
	[***]
	 	 	3.2	(c)
	Applicable Law
	 	 	1.1	 
	Approval
	 	 	1.1	 
	Available [***]
	 	 	2.24	 
	Balance Sheet
	 	 	6.2	(b)
	Balance Sheet Date
	 	 	6.2	(b)
	Bankruptcy
	 	 	1.1	 
	BMS Introductory Paragraph
[***]
	 	 	1.1	 
	BMS Indemnitees
	 	 	7.2	 
	BMS Know-How
	 	 	1.1	 
	[***]
	 	 	4.1	(g)
	BMS Patent Product
	 	 	1.1	 
	BMS Patent Royalty Term
	 	 	1.1	 
	BMS Patents
	 	 	1.1	 
	[***] Covenant
	 	 	2.24	(b)
	BMS Rights
	 	 	1.1	 
	Business Day
	 	 	1.1	 
	Cadence Introductory Paragraph
Cadence Claims
	 	 	6.2	(d)
	Cadence Indemnitees
	 	 	7.3	 
	Calendar Quarter
	 	 	1.1	 
	Calendar Year
	 	 	1.1	 
	[***]
	 	 	2.1	(c)(i)
	[***]
	 	 	2.24	(d)
	[***]
	 	 	2.24	 
	[***]
	 	 	3.2	(f)
	Clinical Study Countries
	 	 	1.1	 
	Clinical Supply Agreement
	 	 	1.1	 
	Clinical Testing Product
	 	 	1.1	 
	Confidential Information
	 	 	1.1	 
	Consent
	 	 	6.1	(d)
	Contract Research Organization
	 	 	1.1	 
	Contracts
	 	 	1.1	 
	Control
	 	 	1.1	 
	Controlled
	 	 	1.1	 
	Controlling
	 	 	1.1	 
	Covenant Termination Date
	 	 	2.24(c). 1.1	 
	Derivative
	 	 	1.1	 
	Development Plan
	 	 	3.3	 
	Disclosing Party
	 	 	1.1	 
	Dispute
	 	 	7.6	 
	Dollar
	 	 	1.1	 
	Drug Regulatory Authority
	 	 	1.1	 
	Effective
Date Introductory Paragraph
Equivalent Percentage
	 	 	4.1	(f)
	Exchange Act
	 	 	1.1	 
	[***] Date
	 	 	1.1	 
	[***] Period
	 	 	1.1	 
	[***] Date
	 	 	2.1	(c)
	Execution
Date Introductory Paragraph
FDA
	 	 	1.1	 
	FDCA
	 	 	1.1	 
	Financial Statements
	 	 	6.2	(a)
	Force Majeure
	 	 	9.6	(b)
	Governmental Entity
	 	 	1.1	 
	HSR Act
	 	 	1.1	 
	ICC
	 	 	7.6	(a)
	Improvement
	 	 	1.1	 
	In Accordance With GAAP
	 	 	6.2	(a)
	include
	 	 	9.14	 
	includes
	 	 	9.14	 
	including
	 	 	9.14	 
	IND
	 	 	1.1	 
	Indemnified Party
	 	 	7.4	 
	Indemnifying Party
	 	 	7.1	 
	Indemnitees
	 	 	7.1	 
	Judgments
	 	 	6.1	(d)
	License
	 	 	2.1	(a)
	Lien
	 	 	1.1	 
	Losses
	 	 	7.1	 
	Material Adverse Effect
	 	 	1.1	 
	NDA
	 	 	1.1	 
	NDA Acceptance
	 	 	1.1	 
	Net Sales
	 	 	1.1	 

 

			
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	 	 	Section	 
	[***] Date
	 	 	2.1	(c)
	[***] Date
	 	 	2.24	(d)
	Organizational Documents
	 	 	1.1	 
	Other Chemical Entity
	 	 	1.1	 
	Other Product Data
	 	 	2.9	 
	Other Reportable Information
	 	 	2.15	(e)
	Parties Introductory Paragraph
Party Introductory Paragraph
Patents
	 	 	1.1	 
	Person
	 	 	1.1	 
	Pharmatop Background
Pharmatop Know-How
	 	 	1.1	 
	Pharmatop
License Agreement Background
Pharmatop Patent Challenge
	 	 	2.16	(a)
	Pharmatop Patents
	 	 	1.1	 
	Pharmatop Royalty Term
	 	 	1.1	 
	Previously Disclosed
	 	 	1.1	 
	Proceedings
	 	 	6.1	(e)
	Product
	 	 	1.1	 
	Product Data
	 	 	1.1	 
	Qualifying [***]
	 	 	1.1	 
	Qualifying [***]
	 	 	1.1	 
	Receiving Party
	 	 	1.1	 
	Registrational Information
	 	 	1.1	 
	Regulatory Filings
	 	 	1.1	 
	[***] Product
	 	 	2.24	(b)
	Retained Sum
	 	 	4.2	(b)
	Royalties
	 	 	4.1	(h)
	Rules
	 	 	7.6	(a)
	[***]
	 	 	2.24	 
	Silicon Valley Loan Agreement
	 	 	6.2	(b)
	[***]
	 	 	2.24	 
	Specified Number of Days
	 	 	8.3	 
	Sublicense
	 	 	2.1	(a)
	Tax
	 	 	1.1	 
	Tech Transfer Period
	 	 	2.12	 
	Tech Transfer Plan
	 	 	2.10	 
	Technology
	 	 	1.1	 
	Technology Documentation
	 	 	1.1	 
	Territory
	 	 	1.1	 
	Third Party
	 	 	1.1	 
	[***]
	 	 	2.24	 
	Title 11
	 	 	8.10	 
	Transaction Documents
	 	 	1.1	 
	Transfer Taxes
	 	 	1.1	 
	[***]
	 	 	2.24	 
	Valid Claim
	 	 	1.1	 
	without limitation
	 	 	9.14	 

 

			
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IV APAP AGREEMENT

(US and Canada)

     This IV APAP Agreement (US and Canada) (the “Agreement”) is entered into as of February 21,
2006 (the “Execution Date”), by and between Bristol-Myers Squibb Company, a Delaware corporation
having an address at 345 Park Avenue, New York, New York 10154 (“BMS”), and Cadence
Pharmaceuticals, Inc., a Delaware corporation having an address at 12730 High Bluff Drive, San
Diego, California 92130 (“Cadence”), effective as of March 29, 2006 (the “Effective Date”).
Cadence and BMS are sometimes collectively referred to herein as the “Parties” and each
individually as a “Party.”

BACKGROUND

     1. BMS has licensed from SCR Pharmatop, a civil law partnership organized under the laws of
France, having its head office’s address at 10, Square St. Florentin, 78150 Le Chesnay, France,
recorded with the Register of Commerce and Companies of Versailles under No. 407552702
(“Pharmatop”), rights under certain patents and patent applications relating to parenteral
paracetamol (also referred to in the United States as “acetaminophen”) formulations in the United
States, Canada and Mexico.

     2. The License Agreement dated as of December 23, 2002, between Pharmatop and BMS (the
“Pharmatop License Agreement”) sets forth such rights.

     3. BMS desires to sublicense to Cadence BMS’s intellectual property rights and related
obligations under the Pharmatop License Agreement to Cadence with respect to the Territory (as
defined below) upon the terms and conditions set forth in this Agreement and to provide for certain
other matters.

AGREEMENT

     THEREFORE, the Parties, intending to be legally bound, agree as follows:

ARTICLE I – DEFINITIONS

     1.1 Defined Terms. As used in this Agreement, the following terms shall have the
following meanings:

     “Adverse Event” means any untoward medical occurrence in a patient or clinical investigation
subject administered any Product, and which does not necessarily have a causal relationship with
such product. An adverse event can therefore be any unfavorable and unintended sign (including an
abnormal laboratory finding, for example),

symptom or disease temporally associated with the use of a medicinal product, whether or not
considered related to the medicinal product. For the avoidance of doubt, in the U.S. an Adverse
Event shall include an adverse experience or test result in connection with the use of the Product

 

 

that requires a written IND safety report in accordance with 21 CFR Part 312.32(c), as amended or
superseded from time to time.

     “Affiliated Company” of a Party means any corporation, firm, partnership or other entity that
directly or indirectly Controls, is Controlled by or is under common Control with such Party at any
time during the term of this Agreement, but only for so long as such entity directly or indirectly
Controls, is Controlled by or is under common Control with such Party.

     “Agreement” has the meaning given to such term in the introductory paragraph hereof.

     “Annual Operating Plan” has the meaning given to such term in Section 3.1 hereof.

     “[***]” has the meaning given to such term in Section 3.2 hereof.

     “Applicable Law” means any applicable federal, state, local or foreign statute, law,
ordinance, rule or regulation, judicial order, or industry standard imposed by regulation or law,
including the laws of the United States and Canada, and regulations promulgated by any other
applicable Governmental Entity or Drug Regulatory Authority.

     “Approval” means, with respect to any Product in any regulatory jurisdiction, approval from
the applicable Drug Regulatory Authority sufficient for the importation, manufacture, distribution,
use and sale of the Product in such jurisdiction in accordance with Applicable Law, including
receipt of pricing and reimbursement approvals, where applicable.

     “Available [[***]” has the meaning set forth in Section 2.24(a).

     “Balance Sheet” has the meaning given to such term in Section 6.2(b) hereof.

     “Balance Sheet Date” has the meaning given to such term in Section 6.2(b) hereof.

     “Bankruptcy” means with respect to a Party the first to occur of:

(i) such Party shall have (A) voluntarily commenced any proceeding or filed any petition seeking
relief under Title 11 of the United States Code, or any other bankruptcy, insolvency or similar law
or any law for the protection of creditors of the United States, any state thereof, or any other
applicable jurisdiction, (B) applied for or consented to the appointment of a receiver,
trustee, custodian, sequestrator, conciliator, administrator or similar official for it or a
substantial part of its property, (C) filed an answer admitting the material allegations of a
petition filed
against or in respect of it in any such proceeding, (D) made a general assignment
for the benefit of creditors, (E) admitted in writing its inability, to pay its debts as they
become due or (F) taken corporate action for the purpose of effecting any of the foregoing; or

     (ii) an involuntary proceeding shall have been commenced or any involuntary petition
shall have been filed in a court of competent jurisdiction seeking (A) relief in respect of
such Party or of a substantial part of its or their property, under Title 11 of the

 

			
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United
States Code, or any other bankruptcy, insolvency or similar law of the United States, any
state thereof or any other applicable jurisdiction, (B) the appointment of a receiver,
trustee, custodian, sequestrator, conciliator, administrator or similar official for such
Party or all or substantially all of its property or (C) the winding-up or liquidation of
such Party; and such proceeding or petition shall have continued undismissed for 60 days or
an order or decree approving or ordering any of the foregoing shall have continued unstayed
and in effect for 30 days.

     “BMS” has the meaning given to such term in the introductory paragraph hereof.

     “[***]” means (i) [***]and (ii) [***].

     “BMS Indemnitees” has the meaning given to such term in Section 7.2 hereof.

     “BMS Know-How” means formulation and manufacturing know-how that is used by BMS and its
Affiliated Companies as of the Execution Date or during the Supply Term (as defined in the Clinical
Supply Agreement) to make or formulate the Product or the Clinical Testing Products (as defined in
the Clinical Supply Agreement) in the European Union.

     “BMS Patent Product” means any Product for which the manufacture, use, import, sale or offer
for sale in the United States would otherwise infringe a Valid Claim of any of the BMS Patents but
for the license rights granted by BMS in Article 2 hereof.

     “BMS Patent Royalty Term” means the date commencing upon the expiration of the Pharmatop
Royalty Term in the United States and terminating upon the date that the manufacture, use, import,
sale or offer for sale of BMS Patent Products in the United States is no longer covered by any
Valid Claim of a BMS Patent (including any patent term extensions, such as pediatric exclusivity
extensions, as may be available under Applicable Law) or covered by any data or regulatory
exclusivity.

     “BMS Patents” means the Patents listed on Schedule 1.1.

     “BMS Rights” means (i) BMS’s rights under the Pharmatop Patents and Pharmatop Know-How with
respect to the Products in the Territory licensed to BMS under the Pharmatop License Agreement
during the term of this Agreement, subject to the limitations, terms and conditions set forth in
the Pharmatop License Agreement and (ii) the right granted to BMS in Section 2.1 of the Pharmatop
License Agreement to make and have made the Products outside the Territory for use within the
Territory.

     “Business Day” means any day other than a Saturday, a Sunday or a United States Federal
holiday.

     “Cadence” has the meaning given to such term in the introductory paragraph hereof.

 

			
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     “Cadence Claims” has the meaning given to such term in Section 6.2(d) hereof.

     “Cadence Indemnitees” has the meaning given to such term in Section 7.3 hereof.

     “Calendar Quarter” means each of the periods of time from (a) January 1 through March 31; (b)
April 1 through June 30; (c) July 1 through September 30; and (d) October 1 through December 31.

     “Calendar Year” means a year that begins on January 1 and ends on December 31.

     “[***]” has the meaning set forth in Section 2.1(c)(i).

     “[***]” has the meaning set forth in Section 2.24(d).

     “[***]” has the meaning set forth in Section 2.24(a).

     “[***]” has the meaning set forth in Section 3.2(f).

     “Clinical Study Countries” means the countries set forth on a list of such countries that has
been Previously Disclosed, as such list is amended from time to time in accordance with the last
paragraph of Section 3.6.

     “Clinical Supply Agreement” means the Clinical Supply Agreement dated as of the Execution Date
between Lawrence Laboratories and Cadence (and BMS, as guarantor).

     “Clinical Testing Product” has the meaning set forth in the Clinical Supply Agreement.

“Confidential Information” means (a) with respect to a Party and its Affiliated Companies
(collectively, the “Receiving Party”), all information,
Technology and confidential or proprietary materials which are disclosed by the other Party and its
Affiliated Companies (collectively, the “Disclosing Party”) to the Receiving Party hereunder or
under the Clinical Supply Agreement or that has previously been disclosed under the Mutual
Confidential Disclosure Agreement between the Parties dated July 6, 2005, as amended, or to any of
its employees, consultants, Affiliated Companies or sublicensees and any information that
is considered Confidential Information for purposes of the Clinical Supply Agreement, (b) the Product
Data, which shall be Confidential Information of BMS to the extent resulting from work, trials or
studies conducted by or on behalf of BMS and which shall be Confidential Information of Cadence to
the extent resulting from work, trials or studies conducted by or on behalf of Cadence, (c)
correspondence with Drug Regulatory Authorities, which shall be Confidential Information of the
Party that conducted such correspondence, and (d) all reports (including any development,
commercialization and/or financial reports), plans (including the Development Plan and the Annual
Operating Plan) and other documents and budgets provided by Cadence and/or its Affiliated Companies
to BMS pursuant to this Agreement, all of which shall be considered Confidential Information of
Cadence except, in each of (a), (b),(c) or (d), to the extent that any such information (i) as of
the date of disclosure is known to the Receiving Party

 

			
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or its Affiliated Companies, as demonstrated
by credible written documentation existing and in the possession of the Receiving Party prior to
the date of disclosure, other than by virtue of a prior confidential disclosure to such Receiving
Party; (ii) as of the date of disclosure is in, or subsequently enters, the public domain, through
no fault or omission of the Receiving Party; (iii) is obtained without restriction from a Third
Party having a lawful right to make such disclosure free from any obligation of confidentiality to
the Disclosing Party; or (iv) is independently developed by or for the Receiving Party without
reference to or reliance upon any Confidential Information of the Disclosing Party as demonstrated
by credible written documentation. The amount of the payments made to BMS under this Agreement
shall be Confidential Information of both BMS and Cadence. A Party’s Affiliated Company that has
disclosed Confidential Information to a Receiving Party shall continue to be considered a
Disclosing Party even after it ceases to be an Affiliated Company of such Party. A Party’s
Affiliated Company that has received Confidential Information from a Disclosing Party shall
continue to be considered a Receiving Party even after it ceases to be an Affiliated Company of
such Party.

     “Consent” has the meaning given to such term in Section 6.1(d) hereof.

     “Contract Research Organization” means a reputable Third Party research or development
organization one of whose principal businesses is the provision of contract research or development
services to unrelated Persons.

     “Contracts” means all contracts, agreements, commitments and other legally binding
arrangements, whether oral or written.

     “Control” means (a) with respect to any intellectual property (including any Patents or
Technology), the possession by a Party of the ability to grant a license or sublicense of such
intellectual property without violating the terms of, or requiring a consent under, any agreement
or arrangement between such Party and any Third Party and (b) when used
with respect to any Person means the power to direct or cause the direction of the management
or policies of such Person, directly or indirectly, whether through the ownership of voting
securities, by contract, or otherwise. “Controlled” and “Controlling” shall have correlative
meanings.

     “Covenant Termination Date” has the meaning set forth in Section 2.24(c).

     “Derivative” of paracetamol means any compound whose chemical structure is derived from the
chemical structure for paracetamol through structural modifications and/or chemical changes that
retain those portions of paracetamol’s chemical

structure that are known to contribute materially to the activity, specificity and selectivity of
paracetamol.

     “Development Plan” has the meaning given to such term in Section 3.3 hereof.

     “Disclosing Party” has the meaning given to such term in the definition of “Confidential
Information” herein.

     “Dispute” has the meaning given to such term in Section 7.6 hereof.

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     “Dollar” or “$ ” means United States dollars, the lawful currency of the United States.

     “Drug Regulatory Authority” means any Governmental Entity with responsibility for granting any
licenses, approvals or authorizations or granting pricing and/or reimbursement approvals necessary
for the marketing and sale of pharmaceutical products in any regulatory jurisdiction.

     “Effective Date” has the meaning given to such term in the introductory paragraph hereof.

     “Exchange Act” means the Securities Exchange Act of 1934, as amended from time to time.

     “[***] Date” means [***] on which (i) [***], (ii) [***] or (iii) [***]; provided that (A)
[***] and (B) [***].

     “[***] Period” means the [***] not include any period during which [***].

     “[***] Date” has the meaning given to such term in Section 2.1(c).

     “Execution Date” has the meaning given to such term in the introductory paragraph hereof.

     “FDA” means the United States Food and Drug Administration or any successor agency.

     “FDCA” means the Federal Food, Drug & Cosmetics Act, 21 U.S.C. 321 et seq., any amendments or
supplements thereto, or any regulations promulgated or adopted thereunder or any successor act
thereof.

     “Financial Statements” has the meaning given to such term in Section 6.2(a) hereof.

     “Force Majeure” has the meaning given to such term in Section 9.6(b) hereof.“Governmental
Entity” means any Federal, state, local or foreign government or any court of competent
jurisdiction, regulatory or administrative agency or commission or other governmental authority or
instrumentality, domestic or foreign.

     “HSR Act” means the Hart-Scott-Rodino Antitrust Improvements Act of 1976, as amended.

     “ICC” has the meaning given to such term in Section 7.6(a) hereof.

     “Improvement” means any adaptation, improvement, enhancement or upgrade with respect to the
formulation and/or manufacture of the Products, whether such Improvement can be protected by patent
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     “In Accordance With GAAP” has the meaning given to such term in Section 6.2(a) hereof.

     “IND” means an Investigational New Drug Application (as defined in 21 CFR Part 312.3, as
amended or superseded from time to time) that is required to be filed with the FDA before beginning
clinical testing of a Product in human subjects in the United States, or any successor application
or procedure.

     “Indemnified Party” has the meaning given to such term in Section 7.4 hereof.

     “Indemnifying Party” has the meaning given to such term in Section 7.1 hereof.

     “Indemnitees” has the meaning given to such term in Section 7.1 hereof.

     “Judgments” has the meaning given to such term in Section 6.1(d) hereof.

     “License” has the meaning given to such term in Section 2.1(a) hereof.

     “Lien” means any pledge, encumbrance, mortgage, security interest, purchase option, call or
similar right.

     “Loan Agreement” has the meaning given to such term in Section 6.2(b) hereof.

     “Losses” has the meaning given to such term in Section 7.1 hereof.

     “Material Adverse Effect” means, with respect to any applicable representation and warranty of
a Party or to any other matter to which such phrase is applied, a material adverse change in or
effect on (i) such Party’s (and its subsidiaries’) business, operations, assets, condition
(financial or otherwise) taken as a whole or (ii) such Party’s ability to perform its obligations
under any Transaction Document to which it is a party.

“NDA” means a new drug application or an abbreviated new drug application (as described in 21 CFR
314.50), including any amendments or supplements thereto, filed with the FDA pursuant to the FDCA
and includes any Common Technical Document for the Registration of Pharmaceuticals for Human Use
filed with the FDA or any Drug Regulatory Authority in Canada.

     “NDA Acceptance” means the earlier of (i) the date Cadence receives written notice from the
FDA of acceptance by the FDA of an NDA filed by or on behalf of Cadence or its licensees with
respect to any Product in the United States, or (ii) sixty (60) days following filing of such NDA
with the FDA, provided that Cadence has not received a “Notice of Refusal to File” from the FDA
with respect to such NDA.

     “Net Sales” means the total revenue invoiced by Cadence, its Affiliated Companies,
sublicensees, co-promotion and co-marketing partners and any other Person selling or promoting
Products on behalf of any such Person from the sale of a Product to independent Third Parties in
the Territory less the following amounts: (a) credits, allowances and rebates to, and chargebacks
from the account of, such customers for spoiled, damaged, out-dated and returned Product;

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(b) trade
discounts, cash discounts, quantity discounts, rebates and other price reduction programs, and
other charge back payments; (c) sales, value-added and other similar taxes (including duties or
other governmental charges levied on, absorbed or otherwise imposed on the sales of Products
including governmental charges otherwise measured by the billing amount); (d) customs duties,
surcharges and other governmental charges incurred in connection with the exportation or
importation of the Product; and (e) bad debts on Product sales written off in accordance with
generally accepted accounting principles, consistently applied. For the purposes of this
definition, samples distributed by Cadence, its Affiliated Companies, sublicensees, co-promotion
and co-marketing partners and any other Person selling or promoting Products on behalf of any such
Person to their customers free of charge, and any Product used or provided for clinical or research
purposes, shall not be included in Net Sales.

     When Products are sold for monies other than Dollars, the monies due will first be determined
in the foreign currency of the country in which such Products were sold and then converted into
equivalent Dollars, on a monthly basis, using the applicable U.S. Federal Reserve rate in effect on
the last business day of each calendar month.

     In the event that Cadence makes sales of Products to an Affiliated Company, sublicensee,
co-promotion or co-marketing partner or any other person selling or promoting Products on behalf of
any such Person, the calculation of Net Sales shall be based on the greater of (x) the revenue
received by Cadence from its sale of Products to the Affiliated Company, sublicensee, co-promotion
or co-marketing partner or other person selling or promoting Products on behalf of any such Person,
as the case may be, and (y) the revenue received by the Affiliated Company, sublicensee,
co-promotion or co-marketing partner or other person selling or promoting Products on behalf of any
such Person from its sale of Products to Third Parties.

     “[***] Date” has the meaning set forth in Section 2.1(c).

     “[***] Date” has the meaning set forth in Section 2.24(d).

     “Organizational Documents” means, with respect to any Person at any time, such Person’s
certificate or articles of incorporation, by-laws, memorandum and articles of association,
certificate of formation of limited liability company,

limited liability company agreement, and other similar organizational or constituent documents, as
applicable, in effect at such time.

     “Other Chemical Entity” means any chemical entity that is not parenteral paracetamol or a
Derivative thereof.

     “Other Reportable Information” has the meaning set forth in Section 2.15(e).

     “Parties” has the meaning given to such term in the introductory paragraph hereof.

     “Party” has the meaning given to such term in the introductory paragraph hereof.

 

			
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     “Patents” means, to the extent that they have been or are filed or issued in the Territory:
(a) patents and patent applications existing as of the Execution Date and/or at any time
thereafter; and (b) any divisionals, continuations, substitutions, continuations-in-part,
extensions, renewals, re-examinations or reissues of such patents and/or applications as of the
Execution Date and/or at any time thereafter.

     “Person” means any individual, firm, corporation, partnership, limited liability company,
trust, joint venture, governmental authority or other entity.

     “Pharmatop” has the meaning given to such term in Background.

     “Pharmatop Know-How” means the Know-How (as such term is defined in the Pharmatop License
Agreement) licensed to BMS under the Pharmatop License Agreement.

     “Pharmatop License Agreement” has the meaning given to such term in Background.

     “Pharmatop Patent Challenge” has the meaning given to such term in Section 2.16(a).

     “Pharmatop Patents” means the Licensed Patents (as such term is defined in the Pharmatop
License Agreement) filed or issued in the Territory and licensed to BMS under the Pharmatop License
Agreement.

     “Pharmatop Royalty Term” means, with respect to each country in the Territory on a
country-by-country basis, the date commencing with the date of first commercial sale of a Product
in such country, and terminating upon the latest of (a) the date that is ten (10) years after such
first commercial sale in such country, (b) the date that the manufacture, use and sale of a Product
in such country is no longer covered by any Valid Claim of a Pharmatop Patent in such country
(including any patent term extensions, such as pediatric exclusivity extensions, as may be
available under Applicable Law) or (c) the date that the obligation of BMS to pay royalties to
Pharmatop (or any successor licensor), pursuant to the Pharmatop License Agreement, terminates.

     “Previously Disclosed” means with respect to any document or information, a document or
information set forth in a mutually agreed letter or
memorandum delivered by Cadence or BMS to the other contemporaneously with the execution of this
Agreement which identifies such document or information as “Previously Disclosed” for purposes of
this Agreement.

     “Proceedings” has the meaning given to such term in Section 6.1(e) hereof.

     “Product” means (i) any parenterally administered dosage form containing paracetamol (or any
Derivative thereof) alone or in combination with one or more other drugs (as defined, as of
December 23, 2002, in Section 201 of the FDCA), and for which the manufacture, use or sale in a
country in the Territory (x) would otherwise infringe any of the Pharmatop Patents or BMS Patents
but for the license rights granted by BMS in Article 2 hereof, and/or (y) incorporates or uses to
any material extent any Pharmatop Know-How and/or (ii) any parenterally administered dosage form
containing paracetamol (or any Derivative thereof) alone or in combination with

9

 

one or more other
drugs (as defined, as of December 23, 2002, in Section 201 of the FDCA) that is manufactured by a
process that incorporates or uses to any material extent any BMS Know-How. When used with respect
to any jurisdiction outside the Territory, “Product” shall refer to any parenterally administered
dosage form containing paracetamol (or any Derivative thereof) alone or in combination with one or
more other drugs (as defined, as of December 23, 2002, in Section 201 of the FDCA).

     “Product Data” means data, information and conclusions resulting from any analytical,
galenical, stability, toxicology or pharmacokinetic work and/or clinical studies and/or clinical
trials relating to, or conducted by or on behalf of BMS or Cadence and filed in support of,
Approval of Products in the United States.

     “Qualifying [***]” means a [***], with respect to which [***].

     “Qualifying [***]” means any [***] (i) [***], (ii) [***], and (iii) [***].

     “Receiving Party” has the meaning given to such term in the definition of “Confidential
Information” herein.

     “Registrational Information” has the meaning set forth in the Pharmatop License Agreement.

     “Regulatory Filings” means, collectively, any and all INDs, NDAs or any other filings
(including any foreign equivalents) as may be required by any Drug Regulatory Authority for the
development, manufacture or commercialization of Products, as applicable.

     “[***] Product” has the meaning given to such term in Section 2.24(b) hereof.

     “Royalties” has the meaning given to such term in Section 4.1(h) hereof.

     “Rules” has the meaning given to such term in Section 7.6(a) hereof.

     “[***]” has the meaning given to such term in Section 2.24(a).

     “[***]” has the meaning set forth in Section 2.24(a).

     “Specified Number of Days” has the meaning given to such term in Section 8.3.

     “Sublicense” has the meaning given to such term in Section 2.1(a) hereof.

     “Tax” means all taxes, charges, fees, levies or other assessments, and all estimated payments
thereof, including income, excise, license, severance, stamp, occupation, premium, profits,
windfall profits, customs duties, capital stock, employment, disability, registration, alternative
or add-on minimum, property, sales, use, value added, environmental, franchise, payroll, transfer,
gross receipts, withholding, social security or similar unemployment taxes, and any other tax of
any kind whatsoever, imposed by any federal, state, local or foreign

 

			
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governmental authority,
including any interest, penalties and additions to tax relating to such taxes, charges, fees,
levies or other assessments.

     “Tech Transfer Period” has the meaning given to such term in Section 2.12 hereof.

     “Tech Transfer Plan” has the meaning given to such term in Section 2.10 hereof.

     “Technology” means and includes all inventions, discoveries, Improvements, trade secrets,
know-how, processes, procedures, research records, records of inventions, test information, market
surveys and other similar proprietary methods, materials or property, whether or not patentable,
relating to Products, including (a) samples of, methods of production or use of, and structural and
functional information pertaining to, chemical compounds, proteins or other biological substances,
(b) data, formulations, techniques and know-how (including any negative results), and (c) rights
under patents, patent applications and copyrights.

     “Technology Documentation” means a written description of the BMS Know-How.

     “Territory” means the United States (including Puerto Rico and all U.S. possessions and
territories) and Canada.

     “Third Party” means any Person other than Cadence, BMS and their respective Affiliated
Companies.

     “Title 11” has the meaning given to such term in Section 8.10 hereof.

     “Transaction Documents” means this Agreement and the Clinical Supply Agreement.

     “Transfer Taxes” means taxes and assessments imposed upon the transfer, such as transfer,
sales, value added, and stamp taxes, and not Taxes measured by income or gain, but including any
interest, penalties or other additions thereto.

     “[***]” has the meaning set forth in Section 2.24(a).

     “[***]” has the meaning set forth in Section 2.24(a).

     “Valid Claim” means a claim in any unexpired issued Pharmatop Patent or BMS Patent that has
not been held invalid or unenforceable by a non-appealed or unappealable decision by a court or
other appropriate body of competent jurisdiction, and which is not admitted to be invalid through
disclaimer, dedication to the public, and which has not been cancelled or abandoned in accordance
with and as permitted by (i) both the terms of this Agreement and the Pharmatop License Agreement
in the case of the Pharmatop Patents, or (ii) the terms of this Agreement in the case of the BMS
Patents.

 

			
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ARTICLE II – GRANT OF U.S. AND CANADIAN RIGHTS AND RELATED TRANSFERS

     2.1 Grant of Sublicense and License .

          (a) Effective as of the Effective Date and subject to Section 3.4 and the reservation of
rights set forth in Section 2.2 and subject to early termination as provided in Article VIII, BMS
hereby grants to Cadence on behalf of itself and its Affiliated Companies:

          (i) subject to the terms, conditions and limitations set forth in the Pharmatop License
Agreement and subject to Section 2.1(c):

     (A) an exclusive (even as to BMS), royalty-bearing sublicense under the BMS Rights with
the right to sublicense as provided in Section 2.4, to import, use, sell and offer for sale
Products in the Territory;

     (B) an exclusive (even as to BMS) sublicense under the BMS Rights, with the right to
sublicense as provided in Section 2.4, to make and have made the Products in the Territory
solely for (1) import, use, sale and offer for sale within the Territory or (2) import and
use in clinical trials in the Clinical Study Countries as permitted by Section 3.6; and

     (C) an exclusive (even as to BMS) sublicense under the BMS Rights, with the right to
sublicense as provided in Section 2.4, to make and have made the Products anywhere in the
world solely for (1) import, use, sale and offer for sale within the Territory, subject to
the limitations set forth in Section 2.1 of the Pharmatop License Agreement (other than the
consent of UPSA S.A., which has been obtained as of the Effective Date) and subject to
Section 3.8, or (2) import or use in Cadence’s clinical trials in the Clinical Study
Countries as permitted by Section 3.6 hereof;

          (ii) a non-exclusive license under the BMS Patents, with the right to sublicense as provided
in Section 2.4, to import, use, sell and offer for sale Products in the Territory; provided,
however, that the license granted in this paragraph shall not grant any right to the composition of
matter of any Other Chemical Entity, or the right to import, use, sell or offer for sale any Other
Chemical Entity or to any use not claimed by the BMS Patents;

          (iii) a non-exclusive license under the BMS Patents, with the right to sublicense as provided
in Section 2.4, to make and have made the Products in the Territory solely for import, use, sale
and offer for sale within the Territory; provided, however, that the license granted in this
paragraph shall not grant any right to the composition of matter of any Other Chemical Entity, or
the right to make or have made any Other Chemical Entity or to any use not claimed by the BMS
Patents;

          (iv) a non-exclusive license under the BMS Know-How, with the right to sublicense as provided
in Section 2.4, to make and have made the Products anywhere in the world solely for (1) use and
sale within the Territory and (2) import and use in clinical trials in the Clinical Study Countries
as permitted by Section 3.6; and.

12

 

          (v) a non-exclusive right to use, copy, translate, display and distribute (subject to any
confidentiality obligations), improve and make derivative works of the BMS Technology Documentation
for the purpose of making and having made the Products consistent with the license set forth above
with respect to the BMS Know-How.

          The sublicenses granted in Section 2.1(a)(i) are referred to herein collectively as the
“Sublicense”), and the licenses granted in Sections 2.1(a)(ii), (iii), (iv) and (v) are referred to
herein collectively as the “License”).

          The Sublicense granted to Cadence hereby shall only permit Cadence to sell Products that are
packaged, finished products ready for use, and the Sublicense shall not extend to any sales in bulk
or of semi-finished products except to permitted sublicensee(s) of Cadence. Except as may be
otherwise agreed in writing by BMS in its sole discretion, the License granted to Cadence hereby
shall only permit Cadence to sell Products that are packaged, finished products ready for use, and
the License shall not extend to any sales in bulk or of semi-finished products except to permitted
sublicensee(s) of Cadence.

          (b) Cadence hereby (i) accepts such Sublicense and License, (ii) acknowledges that the
Sublicense rights granted hereunder are subject and subordinate to the rights of Pharmatop under,
and all the terms and conditions of, the Pharmatop License Agreement and (iii) agrees to comply
with all the restrictions of the Pharmatop License Agreement that relate to the exercise of the
rights sublicensed to Cadence hereunder.

          (c) If on the [***], then [***]; provided that:

          (i) [***] (A) Cadence may [***] and (B) such [***]. Cadence shall provide to BMS
evidence reasonably satisfactory to BMS of the accuracy of such report. Notwithstanding the
foregoing, [***] (A) [***] or (B) [***]. In the event [***] as provided in this Section
2.1(c).

          (ii) Such [***].

          (iii) Such [***].

          Each date, if any, as of which such [***].

          (d) Any Affiliated Companies on whose behalf BMS has made any of the foregoing license grants
that hereafter ceases to be an Affiliated Company of BMS shall
nevertheless continue to be obligated under such license grants in accordance with the terms
of this Agreement.

     2.2 No Implied Licenses; Reservation of Rights.

          (a) Cadence shall have no licenses or other rights other than those expressly granted in this
Agreement, and, in particular and without limiting the foregoing, nothing in this

 

			
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Agreement shall
be construed to grant Cadence any licenses or other rights in any intellectual property rights,
information or data (i) owned or Controlled by BMS or any of its Affiliated Companies, except as
expressly set forth in this Agreement or (ii) owned or Controlled by Pharmatop or any of its
Affiliated Companies that is not licensed by Pharmatop to BMS under the Pharmatop License
Agreement.

          (b) Cadence acknowledges that BMS or one or more of its Affiliated Companies holds certain
license rights from Pharmatop (whether under the Pharmatop License Agreement or otherwise) relating
to countries outside the Territory, and, except for the right of cross-reference provided for in
Section 2.8(d), the rights granted to Cadence under this Agreement do not include any license or
other rights with respect to such other rights of BMS and its Affiliated Companies, all of which
are expressly reserved to BMS and its Affiliated Companies.

          (c) Notwithstanding the exclusivity of any rights granted under Section 2.1, BMS hereby
reserves the non-exclusive, sublicensable right under the BMS Rights, BMS Patents and BMS Know-How
(i) to make and have made the Products in the Territory for supply to Cadence, or to the extent
otherwise necessary or appropriate for BMS or any of its Affiliated Companies or sublicensees to
perform its obligations, under the Clinical Supply Agreement, (ii) to make and have made the
Products anywhere in the world for import, use, sale and offer for sale outside the Territory and
(iii) to import, make, have made and use Products in the Territory for any non-clinical or clinical
research purpose of BMS and its Affiliated Companies (subject, to the extent applicable, to Section
3.7) or in support of any Regulatory Filings or other activities outside the Territory (subject, to
the extent applicable, to Section 3.7); provided that the rights reserved pursuant to clause (iii)
above shall not be sublicensable.

          (d) BMS is not sublicensing or granting to Cadence, and Cadence acknowledges and agrees that
it is not receiving any rights under Section 2.10 or the proviso of the last sentence of Section
2.3 of the Pharmatop License Agreement, all of which are reserved to BMS.

          (e) BMS shall have no licenses or other rights other than those expressly granted in this
Agreement, and, in particular and without limiting the foregoing, nothing in this Agreement shall
be construed to grant BMS any licenses or other rights in any intellectual property rights,
information or data owned or Controlled by Cadence or any of its Affiliated Companies, except as
expressly set forth in this Agreement.

     2.3 Rights of Pharmatop.

          (a) Nothing in this Agreement shall reduce or limit any of Pharmatop’s rights under the
Pharmatop License Agreement.

          (b) Pharmatop shall have the same right to supervise the activities of Cadence hereunder as
Pharmatop has with respect to BMS’s activities under the Pharmatop License Agreement.

          (c) Pharmatop shall have the same rights to audit Cadence’s (and any of its sublicensee’s)
activities relevant to this Agreement, and to inspect Cadence’s (and any

14

 

sublicensee’s) facilities
involved in the manufacture of Products, in the same manner as Pharmatop has with respect to BMS’s
activities and facilities under the Pharmatop License Agreement.

     2.4 Further Sublicenses.

          (a) Except as set forth in Section 2.5, the rights licensed to Cadence under Section 2.1 shall
be sublicensable to a Third Party [***] (except to the extent otherwise agreed to by BMS in writing
in its sole discretion, which writing shall, to the extent applicable, specifically waive
compliance with this Section 2.4(a)): (i) such sublicense shall refer to this Agreement and shall
be subject and subordinate to this Agreement and, with respect to the Sublicense, the Pharmatop
License Agreement, (ii) the sublicensee shall assume and agree in writing to be bound by and comply
with the terms and conditions of this Agreement in the same manner as Cadence, and without limiting
the generality of the foregoing to maintain insurance coverage at the same levels and on the same
terms and conditions as set forth in Section 7.5, provide sales reports pursuant to Section 4.7
hereof and keep books and records and permit BMS to review such books and records pursuant to
Section 4.8 hereof, (iii) BMS shall be made an express third party beneficiary of the sublicensee’s
obligations under such sublicense that relate to compliance with the terms and conditions of this
Agreement with the express right to enforce the same directly against the sublicensee, (iv) a copy
of the proposed sublicense (except that any confidential financial terms may be redacted) shall be
provided to BMS at the time Cadence seeks BMS’s consent to such sublicense as aforesaid, (v) an
executed copy of the sublicense (except that any confidential financial terms may be redacted)
shall be provided to BMS promptly after execution, (vi) each sublicense or other right granted by
Cadence with respect to any right licensed to it hereunder shall terminate immediately upon the
termination of the Sublicense or License from BMS to Cadence with respect to such right; and (vii)
such sublicensees shall not have the right to grant further sublicenses or otherwise transfer any
rights sublicensed to them with respect to the Products except in accordance with and subject to
this Section 2.4 and all of the other terms and conditions of this Agreement. The foregoing shall
also apply in the event of any subsequent amendment or modification of such sublicense agreement.
In the event Cadence desires to effect any such sublicense, it shall provide BMS with such
information concerning the proposed arrangement as BMS may reasonably request. BMS shall
use reasonable efforts to provide its response within [***] ([***])[***] (or, if BMS so
requests, [***] ([***])[***]) after receiving such information. The failure of BMS to consent to
or disapprove of such proposed sublicense within such [***] period shall not constitute a consent
to such sublicense.

          (b) Cadence may grant sublicenses to its Affiliated Companies under the Sublicense and the
License [***], subject, in the case of a sublicense of rights licensed to Cadence pursuant to the
Sublicense, to compliance with the Pharmatop License, and then shall be sublicensable only as
follows (except to the extent otherwise agreed to by BMS in writing in its sole discretion, which
writing shall, to the extent applicable, specifically waive compliance with this Section 2.4(a)):
(i) such sublicense shall be subject and subordinate to this Agreement and, with respect to the
Sublicense, the Pharmatop License Agreement, (ii) such sublicense shall

 

			
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terminate immediately in
the event such Affiliated Company ceases to be an Affiliated Company of Cadence, (iii) an executed
copy of the sublicense shall be provided to BMS promptly after execution, (iv) each sublicense or
other right granted by Cadence with respect to any right licensed to it hereunder shall terminate
immediately upon the termination of the Sublicense or License from BMS to Cadence with respect to
such right and (v) such sublicensees shall not have the right to grant further sublicenses or
otherwise transfer any rights sublicensed to them with respect to the Products except in accordance
with and subject to this Section 2.4 and all of the other terms and conditions of this Agreement.
The foregoing shall also apply in the event of any subsequent amendment or modification of such
sublicense agreement. Without limiting any of Cadence’s responsibilities under Section 2.4(c),
Cadence shall cause its Affiliated Company to comply with the terms and conditions of this
Agreement in the same manner as Cadence.

          (c) Cadence shall be primarily responsible for all payments due and the making of reports
under this Agreement by its sublicensees and for compliance with all applicable terms of this
Agreement, and Cadence shall remain jointly and severally liable with each of its sublicensees
(whether or not such sublicensee is an Affiliated Company of Cadence) for any failure by such
sublicensee to perform, observe or comply with the terms and conditions of this Agreement or the
Pharmatop License Agreement.

          (d) Any purported sublicense hereunder not entered into in compliance with this Section 2.4
shall be null and void and without effect.

          (e) Cadence or its Affiliated Companies may engage a Third Party, including a contractor,
consultant, or Contract Research Organization, to perform research or development activities with
respect to Products on behalf of Cadence or its Affiliated Companies and such activities shall not
be deemed a sublicense if no rights under the BMS Rights, BMS Patents or BMS Know-How are licensed
or granted; provided, that (i) none of the rights of BMS hereunder are diminished or otherwise
adversely affected as a result of such engagement, (ii) any such Third Party shall enter into an
appropriate written agreement obligating such Third Party to be bound by obligations of
confidentiality and restrictions on use of Confidential Information that
are no less restrictive than the obligations in this Agreement; and (iii) Cadence shall at all
times be responsible for the performance of such Third Party. Cadence shall use all reasonable
efforts to cause such Third Party to agree in writing to assign to Cadence inventions made by such
Third Party in performing such services for Cadence.

     2.5 Delegation of Manufacturing. Subject to the scope of the rights granted to
Cadence in the Sublicense and the License and subject to Section 3.8, Cadence may arrange by
written agreement to have the Products manufactured by a Third Party manufacturer without the prior
consent of BMS but subject to compliance with the Pharmatop License Agreement with respect to
sublicensing, if applicable, and subject to clauses (i), (iii), (v), (vi) and (vii) of Section
2.4(a) and the provision to BMS of a copy of the agreement or agreements relating to such
manufacturing arrangement (subject to redaction of confidential financial terms) promptly after the
execution thereof. If the Products are manufactured by a Third Party manufacturer (other than
pursuant to the Clinical Supply Agreement), Cadence shall notify BMS and Pharmatop and shall
provide BMS and Pharmatop with the identity of each such manufacturer and provide proof to BMS and
Pharmatop that (a) each such manufacturer has been informed in writing that the products to be made
are subject to the Licensed Patents (as defined in the

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Pharmatop License Agreement) held by
Pharmatop and (b) each such manufacturer has agreed to manufacture the Products only pursuant to a
written agreement with Cadence and solely for the benefit of Cadence and its sublicensees. In
addition Cadence shall use reasonable efforts to have such Third Party agree in writing to assign
or license to Cadence Improvements made by such Third Party with respect to the manufacture of the
Products, which license if obtained by Cadence shall include the right to sublicense such rights to
BMS and Pharmatop as contemplated by Section 2.7. The above restrictions do not apply to raw
materials, packaging items or other incidental articles from outside suppliers, or to the
performance of packing operations in accordance with customary practices in the pharmaceutical
industry.

     2.6 Development and Commercialization Arrangements. Cadence shall not enter into any
co-development or other development collaboration with any Third Party with respect to the Products
without the prior written consent of BMS. The engagement of a Contract Research Organization to
perform research or development services on behalf of Cadence or its Affiliated Companies, which
research is funded entirely by Cadence and its Affiliated Companies (and not indirectly by a Third
Party through Cadence or any of its Affiliated Companies), shall not constitute a co-development or
other development collaboration that requires the consent of BMS. In the event Cadence enters into
any co-promotion or co-marketing arrangement with any Third Party with respect to the Products or
any other arrangement with a Third Party whereby such Third Party would distribute or commercialize
any Product, Cadence shall include in the quarterly reports provided to BMS pursuant to Section 3.2
information concerning the activities of the other party to such co-promotion, co-marketing,
distribution or commercialization arrangement. In connection with any arrangement with a Third
Party whereby such Third Party would distribute, co-promote, co-market or otherwise develop or
commercialize any Product (or collaborate with Cadence in the development or commercialization of
any Product), Cadence shall comply, and shall cause such Third Party to comply, with all applicable
terms and
conditions of this Agreement and the Pharmatop License Agreement. Cadence shall remain
jointly and severally liable with any such Third Party for any failure by such Third Party to
perform, observe or comply with the terms and conditions of this Agreement or the Pharmatop License
Agreement.

     2.7 Improvements.

          (a) BMS shall inform Cadence in a timely manner of any Improvements made by Pharmatop (or any
Third Party sublicensees of Pharmatop) as to which BMS receives notice pursuant to Section 2.2 or
Article 8 of the Pharmatop License Agreement. If requested by Cadence, BMS will request that
Pharmatop license such Improvements to BMS and, upon receipt of such license, shall sublicense such
Improvements to Cadence on a non-exclusive, [***] basis ([***]), consistent with the license
thereof from Pharmatop and the Pharmatop License Agreement, to the extent not already covered by
the Sublicense.

          (b) BMS shall notify Cadence in writing of any Improvements made in whole or in part by its
(and its Affiliated Companies’) employees, agents, sublicensees and Third Party manufacturers after
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Affiliated Companies. Upon the
request of Cadence, BMS shall grant Cadence a non-exclusive, [***] license to practice and use such
Improvements, including the right to grant sublicenses, anywhere in the world to make and have made
Products solely (i) to import, use, sale and offer for sale within the Territory and (ii) to import
and use in clinical trials in the Clinical Study Countries as permitted by Section 3.6. BMS shall
provide Cadence with such information in BMS’s possession as may be reasonably requested by Cadence
in order to practice such Improvements.

          (c) Cadence shall notify BMS and Pharmatop in writing of any Improvements made in whole or in
part by its (and its Affiliated Companies’) employees, agents, sublicensees and Third Party
manufacturers after the Effective Date and Controlled and implemented by Cadence and its Affiliated
Companies, and Cadence shall license such Improvements to Pharmatop on the basis described in
Article 8 of the Pharmatop License Agreement. In addition, upon the request of BMS, Cadence shall
grant BMS a non-exclusive [***] license to practice and use such Improvements, including the right
to grant sublicenses, anywhere in the world (i) to make and have made the Products in the Territory
for supply to Cadence, or to the extent otherwise necessary or appropriate for BMS or any of its
Affiliated Companies or sublicensees to perform its obligations, under the Clinical Supply
Agreement, (ii) to make and have made the Products anywhere in the world for import, use, sale and
offer for sale outside the Territory and (iii) to import, make, have made and use Products in the
Territory for any non-clinical or clinical research purpose of BMS and its Affiliated Companies
(subject, to the extent applicable, to Section 3.7) or in support of any Regulatory Filings or
other activities outside the Territory (subject, to the extent applicable, to Section 3.7);
provided that the rights granted pursuant to
clause (iii) above shall not be sublicensable. Cadence shall provide BMS with such
information in Cadence’s possession as may be reasonably requested by BMS in order to practice such
Improvements.

     2.8 Transfer of Regulatory Filings; Communications with Regulatory Authorities.

          (a) As of the Effective Date, BMS hereby cedes and assigns to Cadence all right, title and
interest in and to the Regulatory Filings with Drug Regulatory Authorities in the Territory
relating to the Products and shall use reasonable efforts to take any actions with the applicable
Drug Regulatory Authority in the Territory that are necessary to transfer ownership and control of
such Regulatory Filings to Cadence not later than five (5) days after the Effective Date.

          (b) During the [***]([***])[***] period following the Effective Date, BMS shall transfer to
Cadence copies of all Regulatory Filings with Drug Regulatory Authorities in the Territory relating
to Products and shall provide Cadence with copies of all material correspondence with Drug
Regulatory Authorities in the Territory relating to Products. Following the Effective Date,
Cadence shall have sole responsibility for (i) communicating with Drug Regulatory Authorities in
the Territory with respect to Products, including responsibility for all Regulatory Filings in the
Territory and all associated official correspondence and informal communications, and (ii) subject
to Section 2.15, reporting to Drug Regulatory Authorities in the Territory any Adverse Event
relating to Products in compliance with the requirements of Applicable Law in the Territory. If
BMS maintains such Regulatory Filings and correspondence

 

			
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in electronic form, BMS shall provide such
copies to Cadence in electronic form, but BMS shall have no obligation to reformat or otherwise
alter or modify any materials or to create or recreate any such materials in electronic form in
order to provide them to Cadence.

          (c) BMS and its Affiliated Companies and licensees and, subject to the terms of Sections 3.1
and 3.3 of the Pharmatop License Agreement, Pharmatop shall have a right to cross-reference, file
or incorporate by reference any Regulatory Filings in the Territory transferred hereunder or
subsequently made by Cadence and its Affiliated Companies and sublicensees with respect to Products
in the Territory (and any data contained therein) to support Regulatory Filings by BMS and its
Affiliated Companies and licensees for Products outside the Territory.

          (d) Cadence and its Affiliated Companies and licensees shall have a right to cross-reference,
file or incorporate by reference any Regulatory Filings made by BMS and its Affiliated Companies
and sublicensees of the BMS Rights with respect to Products outside the Territory (and any data
contained therein) to support Regulatory Filings by Cadence and its Affiliated Companies and
licensees in the Territory (or Regulatory Filings in such additional jurisdictions where Cadence
may in the future acquire rights).

     2.9 Transfer of Data and Transition Arrangements. Following the Effective Date:

          (a) During the [***] ([***])[***] period following the Effective Date, BMS shall provide to
Cadence a copy of (i) all Product Data, (ii) other written information, data and reports in BMS’s
possession that relate exclusively to the Products to the extent such information, data and reports
are necessary (in the reasonable judgment of both BMS and Cadence) to the development of the
Products in the Territory, and (iii) the full Marketing Authorization dossier submitted to Drug
Regulatory Authorities in the EU with respect to the Products (in non-Common Technical Document
format) and the variation dossiers submitted to Drug Regulatory Authorities in the EU with respect
to the Products after the initial Approval, including (1) with respect to Perfalgan (A) copies of
the applicable clinical study reports (and the appendices, tables, listings and graphs therein),
(B) copies of the raw data from the applicable clinical studies included in the Marketing
Authorization Application, (C) to the extent available, rendered PDF copies of such clinical study
reports (and such appendices, tables, listings and graphs) and (D) to the extent available, SAS
data sets containing such raw data and (2) with respect to ProDafalgan, to the extent they exist,
(A) copies of the applicable clinical study reports (and the appendices, tables, listings and
graphs therein), (B) copies of the raw data from the applicable clinical studies included in the
Marketing Authorization Application, (C) rendered PDF copies of such clinical study reports (and
such appendices, tables, listings and graphs) and (D) SAS data sets containing such raw data, but
only to the extent such information, data and reports described in clauses (i), (ii) and (iii)
above are reasonably available to BMS or its Affiliated Companies without undue searching (the
information, data and reports described in clauses (ii) and (iii) above being referred to herein as
“Other Product Data”); provided, however, that the foregoing shall in no event require BMS or its
Affiliated Companies to provide copies of laboratory notebooks or manufacturing run records
required to be maintained by BMS or its Affiliated Companies under Applicable Law. If BMS or its
Affiliated Company maintains

 

			
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such Product Data or Other Product Data in electronic form, BMS shall
provide such copies to Cadence in electronic form, but BMS shall have no obligation to reformat or
otherwise alter or modify any materials or to create or recreate any such materials in electronic
form in order to provide them to Cadence. BMS shall retain ownership of such Product Data and
Other Product Data, may retain a copy of the Product Data and Other Product Data and retains the
right to use and reference such Product Data and Other Product Data for any purpose to the extent
consistent with BMS’s other retained rights and the rights granted to Cadence hereunder, including
the right to cross-reference, file or incorporate by reference such Product Data and Other Product
Data and to assign, transfer or license to other Persons any or all of such rights of use and
reference. Cadence shall have the right to use such Product Data and Other Product Data for any
purpose in connection with the exercise of the rights granted to Cadence under this Agreement. In
the event that any such Regulatory Filing is supplemented or modified, BMS shall notify Cadence
that supplements or modifications have been made not later
than [***] ([***])[***] after such supplementation or modification, and BMS shall provide
Cadence with copies thereof upon Cadence’s request.

          (b) Cadence shall notify BMS in writing of the completion of any additional registrational
clinical trials or studies (Phase I – Phase III) or large-scale safety studies performed by or on
behalf of Cadence relating to Products within [***]([***])[***] after the final study report
relating to such trial or study has been completed and received all necessary internal Cadence
approvals in accordance with Cadence’s customary procedures. Cadence shall provide BMS
semi-annually with copies of any such final study reports and copies of the final study reports
relating to any non-registrational clinical trials or studies performed by or on behalf of Cadence
relating to Products that have received all necessary internal Cadence approvals in accordance with
Cadence’s customary procedures, in each case that have received such necessary approvals in the
preceding semi-annual period, and BMS and its Affiliated Companies and licensees shall have a right
to cross-reference, file or incorporate by reference such final study reports and any existing or
future Regulatory Filings (and any data contained therein) made or maintained by Cadence and its
Affiliated Companies for Products in the Territory (including the foreign equivalent of any NDA
relating to Products) to support Regulatory Filings by BMS and its Affiliated Companies and
licensees for Products outside the Territory and to use such final study reports, Regulatory
Filings and data for other commercially reasonable uses to support commercialization activities
outside the Territory. In the event that any such Regulatory Filing is supplemented or modified,
Cadence shall notify BMS that supplements or modifications have been made not later than
[***]([***])[***] after such supplementation or modification, and Cadence shall provide BMS with
copies thereof upon Cadence’s request.

          (c) BMS shall notify Cadence in writing of the completion of any additional registrational
clinical trials or studies (Phase I — Phase III) or large-scale safety studies done within the then
existing label performed by or on behalf of BMS relating to Products within [***]([***])[***] after
the final study report relating to such trial or study has been completed and received all
necessary internal BMS approvals in accordance with BMS’s customary procedures. BMS shall provide
Cadence semi-annually with copies of any such final study reports and copies of the final study
reports relating to any non-registrational clinical trials or

 

			
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studies performed by or on behalf of
BMS relating to Products that have received all necessary internal BMS approvals in accordance with
BMS’s customary procedures, in each case that have received such necessary approvals in the
preceding semi-annual period, and Cadence and its Affiliated Companies and licensees shall have a
right to cross-reference, file or incorporate by reference such final study reports and any
existing or future Regulatory Filings (and any data contained therein) made or maintained by BMS
and its Affiliated Companies for Products outside the Territory (including the foreign equivalent
of any NDA relating to Products) to support Regulatory Filings by Cadence and its Affiliated
Companies and licensees for Products in the Territory and to use such final study reports,
Regulatory Filings and data for other commercially reasonable uses to support commercialization
activities in the Territory.

          (d) BMS shall provide Cadence with prompt written notice of any Registrational Information of
Pharmatop made available to BMS pursuant to Article III of the Pharmatop License Agreement. To the
extent permitted by the Pharmatop License Agreement, Cadence and its Affiliated Companies and
licensees shall have a right to cross-reference, file or incorporate by reference any such
Registrational Information to support Regulatory Filings by Cadence and its Affiliated Companies
and licensees for Products in the Territory, provided [***] reimburses [***] directly (or
indirectly through payment to [***]) [***] ([***]) of the [***] to develop or obtain such Pharmatop
Registrational Information consistent with Sections 3.1 and 3.3 of the Pharmatop License Agreement.

     2.10 Tech Transfer Plan. Within [***]([***])[***] of the Effective Date, the Parties
shall meet to develop a technology transfer plan (the “Tech Transfer Plan”) containing a plan and
schedule for transferring and otherwise providing Cadence access to the BMS Know-How and Technology
Documentation.

     2.11 Technology Documentation. Pursuant to the Tech Transfer Plan, BMS shall provide
Cadence with one (1) copy (which may be in paper or electronic form as provided below) of the
Technology Documentation to which BMS or its Affiliated Companies have access to without undue
searching (unless such documents are material to the manufacture of the Products or Clinical
Testing Products in which case BMS shall use all reasonable commercial efforts to locate such
Technology Documentation); provided, however, that the foregoing shall in no event require BMS to
provide copies of laboratory notebooks or manufacturing run records required to be maintained by
BMS under Applicable Law (other than one blank batch record which shall be provided to Cadence).
If BMS maintains such Technology Documentation in electronic form, BMS shall provide such
Technology Documentation to Cadence in electronic form. Otherwise, BMS may provide such Technology
Documentation in paper form. All Technology Documentation shall be in the English language,
reasonably comprehendible and, if any Technology Documentation requires translation, authenticated
translation shall be provided by BMS at no cost to Cadence. BMS shall not have any obligation to
translate any documentation relating to the Pharmatop Know-How. The Technology Documentation at
the time provided to Cadence shall be written with sufficient detail and clarity for Cadence, a
Cadence Affiliated Company or a Third Party sublicensee or supplier of Cadence to practice and/or
otherwise utilize the manufacturing processes disclosed thereunder. The Technology

 

			
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Documentation
shall not be used by Cadence for any purpose other than to manufacture the Products and Clinical
Testing Products as permitted under this Agreement and the Clinical Supply Agreement. The
Technology Documentation shall be Confidential Information of BMS, and Cadence shall have full
responsibility and liability to BMS for any unauthorized use or disclosure of such Confidential
Information; provided that Cadence shall have the right to disclose and otherwise provide such
Technology Documentation to one or more Third Party manufacturers and/or suppliers so long as such
Third Parties agree to maintain the confidentiality of such information. BMS shall be
responsible for the cost of providing one (1) set of copies only; provided, however, that BMS
shall have no obligation to reformat or otherwise alter or modify any such materials to the extent
provided consistent with this Section 2.11, or to create materials in electronic form, in order to
provide them to Cadence.

     2.12 Technical Assistance. During the period commencing on the Effective Date and
ending on [***] (the “Tech Transfer Period”), BMS shall provide the technical assistance provided
for in this Section 2.12. During the Tech Transfer Period, BMS shall provide Cadence with the
assistance of up to [***] of BMS employees having knowledge relevant to the Clinical Testing
Products, the Technology Documentation and the BMS Know-How to provide Cadence with a reasonable
level of technical assistance and consultation in connection with the technology transfer and
implementation of the manufacturing processes included in the Technology Documentation for the
purpose of assisting Cadence in assuming the responsibility for manufacturing the Products. The
first [***]([***])[***] of such technical assistance and consultation shall be without charge to
Cadence other than for the reasonable out-of-pocket costs of BMS and its Affiliated Companies. For
technical assistance and consultation in excess of [***]([***])[***], Cadence shall pay BMS for
such technical assistance and consultation at the rate of [***]. [***]. Cadence shall bear [***]
implementing the Technology Documentation, including all costs and expenses it incurs in connection
with such technology transfer, process development, manufacturing scale-up, quality control and
quality assurance. BMS makes no warranty, express or implied, that Cadence shall be able to
successfully implement and use the Technology Documentation. Cadence shall be responsible for
ensuring that its personnel who receive such assistance are appropriately qualified and experienced
for such purpose. At Cadence’s written request, BMS shall, during the Tech Transfer Period and
upon reasonable prior notice and subject to BMS’s customary rules and restrictions with respect to
site visits by non-BMS personnel, permit Cadence’s technical personnel to visit the facilities
utilized by BMS for the supply of Clinical Testing Products under the Clinical Supply Agreement for
the purpose of personally observing the production of the Clinical Testing Products. The time of
BMS employees expended in connection with any such visit (but not visits contemplated by the
Clinical Supply Agreement) shall be charged against the [***] of technical assistance and
consultation to be provided by BMS hereunder and compensated as provided in this Section 2.12. BMS
shall not have any obligation to provide any such technical assistance or consultation following
the expiration of the Tech Transfer Period.

     2.13 Cooperation. The Parties shall cooperate to implement processes to ensure a
close, cooperative working relationship between the Parties and their respective technical
personnel in order to facilitate the technology transfer assistance contemplated above.

 

			
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     2.14 Additional Assistance. In the event Cadence desires any additional technical
assistance or consultation, Cadence may request such
additional technical assistance or consultation from BMS. BMS shall consider such request in
good faith, but BMS shall not have any obligation to provide any such additional technical
assistance or consultation unless BMS agrees in writing in its sole discretion to provide such
additional technical assistance or consultation. In the event BMS agrees in its sole discretion to
provide any such additional technical assistance or consultation, Cadence shall pay BMS for such
additional technical assistance or consultation at a rate equal to [***].

     2.15 Pharmacovigilance; Adverse Event Reporting. Subject to the terms of this
Agreement, and within [***] ([***])[***] after the Effective Date of this Agreement, BMS and
Cadence (under the guidance of their respective Pharmacovigilance Departments, or equivalent
thereof) shall in good faith define and finalize the responsibilities the Parties shall employ to
protect patients and promote their well-being in their respective territories. These
responsibilities shall include mutually acceptable guidelines and procedures for the receipt,
investigation, recordation, communication, and exchange (as between the Parties) of adverse event
reports, pregnancy reports, and any other information concerning the safety of the Product. Such
guidelines and procedures shall be in accordance with, and enable the Parties and their Affiliated
Companies to fulfill, local and international regulatory reporting obligations to government
authorities. Furthermore, such agreed procedures shall be consistent with relevant International
Council for Harmonization guidelines, except where said guidelines may conflict with existing local
regulatory safety reporting requirements, in which case local reporting requirements shall prevail.

     Until such guidelines and procedures are set forth in an agreement between the Parties,
hereafter referred to as the Safety Data Exchange Agreement, the terms of paragraphs (a) – (d) and
(f) below, of this Section, shall apply. Following the execution of the Safety Data Exchange
Agreement, paragraphs (a) – (d) and (f) shall have no further force or effect.

          (a) Each Party shall notify the other Party as soon as practicable, but not later than
[***]([***])[***] after it receives information about the initiation of any investigation, review
or inquiry by any Drug Regulatory Authority concerning the safety of the Product.

          (b) Individual Case Safety Reports and pregnancy reports which come to the attention of either
Party shall be notified to the other Party, in English, in the form of a source document or CIOMS
Form by secure email or fax within [***]([***])[***] of receipt.

          (c) Each Party is responsible for complying with all applicable investigational and
post-marketing safety reporting regulations with respect to the use of the Product in the territory
in which its affiliated companies, its sublicensees, its agents, or its contractors promotes the
Product, as subject to the terms of this Agreement. This includes the submission of expedited and
periodic reports to the appropriate Drug Regulatory Authority(s).

 

			
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          (d) All information to be reported to a Party under this Section shall be sent as follows (or
to such other address, contact person, telephone number, facsimile number or e-mail address as may
be specified in writing to the other Party):

(i) To BMS, at:

Bristol-Myers Squibb Company

Global Pharmacovigilance

Adverse Event Processing

311 Pennington-Rocky Hill Road

Mail Stop HW 19-1.01

Pennington, NJ 08534

USA

FAX Number: 609-818-3804

Email: worldwide.safety@bms.com

(ii) To Cadence, at:

Cadence Pharmaceuticals, Inc.

12730 High Bluff Drive, Suite 410

San Diego, CA 92130

Attention: Vice President, Regulatory Affairs and Quality Assurance

Telephone: [***]

Facsimile: 858-436-1401

Email: [***]

          (e) A Party’s costs incurred in connection with receiving, investigating, recording,
reviewing, communicating, and exchanging Adverse Events and Other Reportable Information shall be
borne solely by such Party. As used herein, “Other Reportable Information” means any communication
or other information that questions the purity, identity, potency or quality of the Product and all
reports of Product exposure during pregnancy and Product overdose whether or not resulting in an
Adverse Event.

          (f) If any Drug Regulatory Authority (1) should contact Cadence with respect to the improper
development, use, distribution, manufacture or commercialization of any Product, (2) conducts, or
gives notice of its intent to conduct, an inspection at Cadence’s facilities, or (3) takes, or
gives notice of its intent to take, any other regulatory action with respect to any activity of
Cadence that could reasonably be expected to adversely affect any development or commercialization
activities of any Product under this Agreement, then Cadence shall promptly notify BMS of such
contact or notice. Cadence shall provide BMS with copies of all pertinent information and
documentation issued by any such Drug Regulatory Authority within two (2) Business Days of receipt
and copies of any responses to such Drug Regulatory
Authority that pertain to the Products promptly after the submission thereof to such Drug
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     2.16 Infringement – Pharmatop Patents.

          (a) In the event either Party becomes aware that the Pharmatop Patents (or their inventorship)
have become the subject to an administrative or judicial action, suit or challenge by a Third Party
(including any reexamination or other proceeding challenging the validity or enforceability of the
Pharmatop Patents) with respect to the Territory (to the extent relating to the Territory, a
“Pharmatop Patent Challenge”), such Party shall promptly notify the other Party and BMS and Cadence
shall consult with each other in order to attempt to determine the appropriate response to such
Pharmatop Patent Challenge. If Pharmatop undertakes the defense thereof, Cadence shall have the
right, to the extent permitted by the Pharmatop License Agreement, to participate and be
represented in any such Pharmatop Patent Challenge by its own counsel [***]. To the extent Cadence
is not permitted by the Pharmatop License Agreement to participate directly in such Pharmatop
Patent Challenge, BMS shall (i) consult with Cadence during the defense of such Pharmatop Patent
Challenge and (ii) if requested by Cadence, participate in such Pharmatop Patent Challenge [***]
and cooperate with Cadence, [***], to arrange for the interests of the Parties (including Cadence)
to be represented in such Pharmatop Patent Challenge.

          If Pharmatop does not defend any such Pharmatop Patent Challenge, BMS shall provide written
notice to Cadence promptly after receiving notice of Pharmatop’s decision not to defend and shall
consult with Cadence concerning the defense of such Pharmatop Patent Challenge. BMS shall use
reasonable efforts (in light of relevant time and other deadlines) to determine whether it will
defend such Pharmatop Patent Challenge and, if BMS elects not to defend such Pharmatop Patent
Challenge, shall use reasonable efforts to provide Cadence with sufficient notice to permit Cadence
to defend such Pharmatop Patent Challenge as permitted by Section 6.3 of the Pharmatop License
Agreement and as set forth in this Section 2.16.

          If BMS elects to defend against any such Pharmatop Patent Challenge as permitted by Section
6.3 of the Pharmatop License Agreement, BMS shall consult with Cadence during the defense of such
Pharmatop Patent Challenge and BMS shall permit Cadence to participate and be represented in any
such Pharmatop Patent Challenge by its own counsel [***].

          The Parties shall reasonably assist Pharmatop and the other Party in the defense of any
Pharmatop Patent Challenge. In the event the Party defending such Pharmatop Patent Challenge
requests the assistance of the other Party, [***] shall reimburse the [***] for its [***] incurred
in connection with such assistance. BMS shall not, without the written consent of Cadence, consent
to the entry into any such settlement agreement by Pharmatop, that would
restrict the scope, or adversely affect the enforceability or validity of, any of the
Pharmatop Patents in the Territory.

          If neither Pharmatop nor BMS elects to defend against a Pharmatop Patent Challenge, then BMS
shall provide written notice to Cadence promptly after the later of BMS receiving notice of such
decision by Pharmatop or such decision by BMS (in accordance with the last sentence of the second
paragraph of this Section 2.16(a)) and, to the extent permitted by the

 

			
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Pharmatop License Agreement,
Cadence shall have the right to defend [***] any such Pharmatop Patent Challenge in accordance with
Section 6.3(b) of the Pharmatop License Agreement, and BMS shall be entitled to participate and be
represented in any such Pharmatop Patent Challenge by its own counsel [***]. Cadence shall not
enter into any settlement agreement with respect to such Pharmatop Patent Challenge, without the
written consent of Pharmatop to the extent required by the Pharmatop License Agreement, and the
written consent of BMS. If Cadence is not permitted by the Pharmatop License Agreement to defend
such Pharmatop Patent Challenge, then at the written request of Cadence, BMS shall defend such
action, suit or challenge as provided above, at [***].

          (b) In the event either Party becomes aware of any infringement of a Valid Claim in the
Territory under the Pharmatop Patents, such Party shall promptly notify the other Party and BMS and
Cadence shall consult with each other and with Pharmatop in order to attempt to end such
infringement, consistent with the Pharmatop License Agreement and shall take all appropriate action
to do so. BMS shall have the right in the first instance, but not the obligation, to initiate
legal action against an infringing party. Cadence shall reasonably assist BMS and Pharmatop in any
action or proceeding prosecuted against the infringing Person by BMS or Pharmatop. If neither
Pharmatop nor BMS prosecutes a legal action against the infringing Person (or if Pharmatop or BMS
ceases to pursue or withdraws from such action), Cadence may initiate and prosecute such action (or
substitute itself for Pharmatop or BMS in such action) at its own expense to the extent permitted
by and in accordance with Section 6.5 of the Pharmatop License Agreement. Cadence shall not enter
into a settlement agreement concerning such action, suit or challenge without the written consent
of BMS.

          If neither Pharmatop nor BMS prosecutes a legal action against the infringing Person (or if
Pharmatop or BMS ceases to pursue or withdraws from such action) and Cadence is not permitted by
Section 6.5 of the Pharmatop License Agreement to initiate and prosecute such action (or substitute
itself for Pharmatop or BMS in such action), then at the written request of Cadence, BMS shall
initiate and prosecute such action at the expense of Cadence and shall not, without the written
consent of Cadence, enter into a settlement agreement with such infringing Person that would
restrict the scope, or adversely affect the enforceability or validity of, any of the Pharmatop
Patents in the Territory.

          (c) Subject to the rights of Pharmatop set forth in the Pharmatop License Agreement, in the
event either Party recovers any damages or other sums in such action in
relation to any infringement of a Valid Claim under a Pharmatop Patent in the Territory or in
settlement thereof, such damages or other sums recovered shall first be applied to all
out-of-pocket costs and expenses incurred by the Parties in connection therewith, including
attorneys fees, subject to any allocation due to Pharmatop pursuant to the Pharmatop License
Agreement. If such recovery (after giving effect to any allocation due to Pharmatop pursuant to
the Pharmatop

 

			
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License Agreement) is insufficient to cover all such costs and expenses of both
Parties, it shall be shared in proportion to the total of such costs and expenses incurred by each
Party. If after such reimbursement any funds shall remain from such damages or other sums
recovered (after giving effect to any allocation due to Pharmatop pursuant to the Pharmatop License
Agreement), such funds shall be shared [***] ([***]) by Cadence and [***] ([***]) by BMS. In the
event any such action involves patent rights outside the Territory, Cadence shall be entitled to
share only in the portion of any recovery that relates to infringement of any Pharmatop Patents in
the Territory and shall not have any right to share in any recovery with respect to rights outside
the Territory.

     2.17 Infringement – BMS Patents.

          (a) In the event the BMS Patents (or their inventorship) become the subject to an
administrative or judicial challenge by a Third Party with respect to the Territory, BMS shall
notify Cadence of such challenge within [***]([***])[***] of receipt of notice of such challenge.
BMS shall have the right, but not the obligation, to defend such action, suit or challenge, and BMS
shall notify Cadence of its decision regarding whether or not it will defend such action, suit or
challenge. If BMS decides in its sole discretion to enter into any settlement agreement with
respect to such action, suit or proceeding, BMS shall notify Cadence of such intent. If such
settlement restricts the scope, or adversely affects the license to the BMS Patents granted to
Cadence under Section 2.1, Cadence shall have the right, but not the obligation, to enter into
discussions with BMS for the purpose of renegotiating the terms of said license in view of such
settlement.

          (b) If BMS does not defend any such action, suit or challenge and Cadence disagrees with BMS’s
decision, Cadence shall have the right, but not the obligation, to (i) enter into discussion with
BMS for the purpose of renegotiating the terms of the license to the BMS Patents granted to Cadence
under Section 2.1 or (ii) notwithstanding Article 8 of this Agreement, terminate the License
granted under Sections 2.1(a)(ii) – (v) subject to the confidentiality provisions set forth in
Sections 5.2 and 5.3.

     2.18 Maintenance of BMS Patents. In the event BMS determines that it no longer
desires to maintain any of the BMS Patents, BMS shall notify Cadence in writing of the BMS Patents
that it no longer desires to maintain, and Cadence shall have the right to retain counsel of its
own choosing to prosecute and maintain such BMS Patents and to make all maintenance and other
payments as may be necessary to maintain such BMS Patents in effect.

     2.19 Noncontravention. Neither BMS nor Cadence shall be required to take any action
pursuant to Section 2.16, 2.17, 2.21 and 2.22 that it determines in its sole judgment and
discretion conflicts with or violates any court or government order or decree to which it is then
subject.

     2.20 Patent Extensions. Subject to applicable terms of the Pharmatop License
Agreement, BMS and Cadence shall each cooperate with one another to obtain patent term extensions
(including any pediatric exclusivity extensions as may be available) or supplemental protection
certificates or their equivalents in any country in the Territory with respect to a BMS Patent or
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     2.21 Data Exclusivity and Orange Book Listings. Subject to applicable terms of the
Pharmatop License Agreement: (i) with respect to data exclusivity periods in the Territory (such
as those periods listed in the FDA’s Orange Book (including any available pediatric extensions))
Cadence, as appropriate, shall use commercially reasonable efforts consistent with its obligations
under Applicable Law in the Territory to seek, maintain and enforce all such data exclusivity
periods available for Products, and (ii) with respect to filings in the FDA Orange Book for issued
patents for a Product, the appropriate Party shall, consistent with its obligations under
Applicable Law in the Territory, list (and update as appropriate) in a timely manner all applicable
Patents required to be filed by it, or that it is permitted to file, under such Applicable Law in
connection with such Product. At least [***] ([***])[***] prior to an anticipated deadline for the
filing of patent listing information for such Patents, the Party making such filing shall notify in
writing and consult with the other Party regarding the content of such filing. In the event of a
dispute between the Parties as to whether a particular Patent can be listed and/or the content of
the filing for such listing, the Parties shall take expedited steps to resolve the dispute as
promptly as possible, including seeking advice of an independent legal counsel to guide their
decision. The other Party shall provide, consistent with its obligations under Applicable Law in
the Territory, reasonable cooperation to the Party making such listing in filing and maintaining
such Orange Book (and foreign equivalent) listings.

     2.22 Notification of Patent Certifications. A Party receiving any allegation of
patent invalidity, unenforceability or non-infringement of a Pharmatop Patent or a BMS Patent
pursuant to a paragraph IV patent certification by a Third Party filing an Abbreviated New Drug
Application, an application under §505(b)(2) of the FDCA or other similar patent certification by a
Third Party, and/or any foreign equivalent thereof in connection with a Product in the Territory
shall notify the other Party and shall provide the other Party with copies of all such allegations.
Such notification and copies shall be provided to the other Party within five (5) days after
receipt of such certification. If and to the extent such allegation relates to a Pharmatop Patent,
and subject to the terms of the Pharmatop License Agreement, Cadence shall have the right (but not
the obligation) to contest such patent certification in the Territory and initiate and control
actions with respect thereto in accordance with Section 2.16, and upon request by Cadence, BMS shall
provide reasonable assistance and cooperation at Cadence’s expense in any actions reasonably
undertaken by Cadence to contest any such patent certification.

     2.23 Audit, Inspection and Review. BMS shall have the right [***] during business
hours and upon reasonable prior notice to enter, inspect and evaluate that part of any plant or
other facility that is engaged in the production, preparation, processing or storage of the
Products for compliance with applicable environmental, health and safety regulations, cGMP and
other Applicable Law in the Territory and for compliance with the terms of this Agreement; provided
that such inspections may not be made more than [***] in any [***]; and provided, further, that if
material corrective measures are necessary, BMS may [***] verify the implementation of such
corrective measures. In addition to the other rights of BMS set forth in this Agreement: (i) BMS
shall have the same right to inspect and review the activities of Cadence hereunder as Pharmatop
has with respect to BMS under the Pharmatop License Agreement, and (ii) BMS shall have the same
rights to audit Cadence’s (and any of its sublicensee’s) activities relevant to this

 

			
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Agreement, and
to inspect Cadence’s (and any sublicensee’s) facilities involved in the manufacture of Products, in
the same manner as Pharmatop has with respect to BMS’s activities and facilities under the
Pharmatop License Agreement. Cadence shall cause its sublicensees, suppliers, toll manufacturers
and other Third Parties involved in the production, preparation, processing or storage of the
Products to provide such access to BMS and shall include an appropriate provision in the applicable
contract with any such Third Party providing for such access and shall cause such sublicensees,
suppliers, toll manufacturers and other Third Parties to grant such access to BMS. Cadence shall
notify BMS within [***] ([***])[***] after receipt of any notice of any inquiry, inspection or
legal action by any Drug Regulatory Authority related to any aspect of the production of the
Products. Cadence shall provide to BMS, promptly after receipt by Cadence, a copy of the results
of any inspection reports and/or legal actions with or by any Drug Regulatory Authority in the
Territory relating to such matters. Cadence shall keep BMS informed on an on-going basis as to any
proposed responses regarding corrective or remedial actions to be taken as a result of any such
inquiry, inspection or legal action, including actions relating to plants and facilities of Third
Parties.

     2.24 [***] Covenant; [***] Covenant.

     (a) Certain Definitions. As used herein:

     “Available [***]” means, as of any date, [***] determined In Accordance With GAAP
[***].

     “[***]” means as of any date, [***] determined In Accordance with GAAP [***]:

     (1) (A) [***], or

     (B) [***], and

     (2) (A) [***], (B) [***] and (C) [***],

     but only to the extent any such items are not already included in [***].

     “[***]” means, as of any date [***] plus [***], in each case determined In Accordance
With GAAP.

     “[***]” means, as of any date, the [***].

     “[***]” means, as of any date, the [***].

     “[***]” means, as of any date, the [***].

     (b) [***] Covenant. Provided that neither [***]:

     (A) [***]; or

 

			
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          (B) [***].

          The foregoing covenant is referred to herein as the “[***] Covenant”. [***] shall be entitled
to temporary and permanent injunctive relief in order to restrain any violation of this Section
2.24(b).

          As used herein, the term “[***] Product” means (i) [***] and/or (ii) [***].

          (c) Termination of Covenant. If on [***] Covenant shall immediately terminate without
any action on the part of [***]. Each such date of such termination is referred to herein as a
“Covenant Termination Date”. In the event [***].

          During any period in which [***] shall have the right to (i) [***] and (ii) [***].

          (d) Permanent Termination of Covenant; [***]. If [***]

          (e) Reinstatement of [***]. As set forth in Section 2.1(c), if and when [***].

ARTICLE III – ADDITIONAL COVENANTS

     3.1 Annual Operating Plan. Not later than [***]([***])[***] prior to the beginning of
each Calendar Year, Cadence shall provide to BMS a written operating plan (each an “Annual
Operating Plan”) setting forth in reasonable detail Cadence’s plans for the continued development
(including plans for clinical and other studies and plans for obtaining any necessary Approvals in
the Territory) and commercialization of the Products for such Calendar Year, together with the
related budgets therefore and the estimated timelines for completion of key activities. The
initial Annual Operating Plan for 2006 is as Previously Disclosed. Each subsequent Annual
Operating Plan shall include a comparable level of information and detail as set forth in such
Previously Disclosed Annual Operating Plan (and following first commercial sale of the Product in
the Territory, shall include a line item for advertising and promotional expenses). Cadence shall
promptly notify BMS in writing of any material change in any such Annual Operating Plan or of any
material deviation from any Annual Operating Plan.

     3.2 Development, Commercialization and Financial Reports and Consultations.

          (a) Quarterly Development and Commercialization Reports. Cadence shall provide
quarterly written reports to BMS, within [***]([***])[***]) following the end of each Calendar
Quarter, presenting a summary in reasonable detail of the development and commercialization actions
taken by Cadence relating to the Products in the Territory and results obtained through the end of
such Calendar Quarter and a summary of any material changes to the Development Plan since the last
such quarterly report. The report with respect to commercialization activities shall include,
among other things, the number of full-time equivalent sales representatives assigned to each
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co-marketing partner or any Third Party with which
Cadence has any other arrangement for such Third Party to market, promote or sell any Product.

	 	(b)	 	[***] Reports. [***]:
	 
	 	(i)	 	[***].
	 
	 	(ii)	 	[***];
	 
	 	(iii)	 	[***].
	 
	 	(c)	 	[***] Statements. If [***] shall be In Accordance With GAAP [***].
	 
	 	(d)	 	Calculations, Notifications and Consultations concerning [***]. If [***]:
	 
	 	(i)	 	[***](A) [***] and (B) [***].
	 
	 	(ii)	 	[***].
	 
	 	(iii)	 	[***].
	 
	 	(e)	 	[***] Reports. If on the [***], if any:
	 
	 	(i)	 	[***], within [***]([***])[***]:

	 	(A)	 	[***],
	 
	 	(B)	 	[***],
	 
	 	(C)	 	[***],
	 
	 	(D)	 	[***],
	 
	 	(E)	 	[***],
	 
	 	(F)	 	[***] Section 3.2(b):

	 	(1)	 	the [***] In Accordance With GAAP.
	 
	 	(2)	 	a [***];

	 	(G)	 	a [***].

	 	(ii)	 	[***]:

	 	(A)	 	within [***]([***])[***]; and

 

			
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	 	(B)	 	not later than [***] ([***])[***].

          In the event [***].

          (f) Standards for Determining [***]. All projections used to determine [***] (i)
[***] (A) [***] and (B) [***] and (ii) [***]. If any calculation of [***].

          (g) Presentations concerning Development and Commercialization Activities. In
addition, on reasonable request by BMS, Cadence shall meet with BMS to make presentations
concerning the development and commercialization activities taken relating to the Products and
to permit BMS to ask reasonable questions and receive answers from Cadence with respect to
such matters (including advertising and promotional expenditures and measures of sales effort);
provided, however, that Cadence shall not be required to make more than [***] in any Calendar Year.
[***].

          (h) Date of NDA Approval. Cadence shall notify BMS in writing as soon as reasonably
practicable of the expected date of approval by the FDA of the NDA with respect to any Product in
the United States and shall notify BMS of any such Approval not later than [***]([***])[***]
following the date on which Cadence receives written notice of such approval or receives an
“approvable letter” from the FDA with respect to any such NDA.

          (i) Correspondence with Pharmatop. Each Party shall provide to the other Party copies
of all material correspondence and reports provided by it to Pharmatop or by Pharmatop to it after
the Effective Date with respect to the Products in the Territory.

     3.3 Development Responsibilities and Costs.

          (a) Cadence’s initial plan (current as of the Execution Date) for the development of the
Products, including the clinical and other studies it contemplates as of the date of this Agreement
in order to obtain Approval of the Products in the United States and related budgets and timelines
as of the Execution Date as the same may be amended from time to time in accordance with Section
3.3(c) (collectively, the “Development Plan”) has been Previously Disclosed.

          (b) Cadence shall have sole responsibility for, and shall bear the cost of the development and
commercialization of the Products in the Territory. Cadence shall develop and commercialize the
Products in compliance with all Applicable Law. Without limiting the foregoing, Cadence shall
cause all Products manufactured, labeled, advertised and sold by it and its Affiliated Companies
and sublicensees or on its or their behalf to comply in all material respects with Applicable Law.

          (c) Without limiting Cadence’s obligations under the Pharmatop License Agreement, Cadence
shall use reasonable commercial efforts to pursue, fund and complete the development of the
Products as set forth in the Development Plan as modified from time to time in accordance with this
Agreement (including obtaining all necessary Approvals in the

 

			
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Territory). In the event that the
results of clinical or other studies or communications from Drug Regulatory Authorities require a
material modification to the Development Plan, Cadence shall consult with BMS concerning such
results or communications and potential changes to the Development Plan that would offer a
reasonable prospect for obtaining Approvals on a reasonably expeditious basis. Any modification to
the Development Plan that involves [***]. No such consent by BMS shall relieve Cadence of any
obligation under the Pharmatop License Agreement.

     3.4 Obligations in respect of the Pharmatop License Agreement. Notwithstanding any
other provision of this Agreement, Cadence (i) hereby unconditionally assumes and agrees during the
term of this Agreement to perform as and when due all the obligations of BMS under the Pharmatop
License Agreement that relate to the Territory (except (A) to the extent such obligations were
required to be performed by BMS prior to the Effective Date and (B) for any obligation to indemnify
Pharmatop for any breach by BMS of any such obligations prior to the Effective Date), the BMS
Rights or the exercise of the rights sublicensed to Cadence under this Agreement and (ii) shall
comply with all the terms and conditions of the Pharmatop License Agreement that relate to the
Territory, the BMS Rights or the exercise of the rights sublicensed to Cadence under this
Agreement, it being understood that Cadence shall be obligated to perform such obligations and
comply with such terms and conditions in respect of its activities under this Agreement and the
Pharmatop License Agreement but shall not have any obligation to cause BMS to perform such
obligations or to cause BMS to comply with such terms and conditions. Without limiting the
foregoing, Cadence shall be obligated to perform and comply, but shall not have any liability with
respect to any failure by BMS (but not its own failure) to perform and comply, with Section 4.6(a),
Article 10 or Article 12 of the Pharmatop License Agreement. Without limiting any other right or
remedy of BMS under this Agreement and in order to prevent, ameliorate, mitigate or cure a breach
of the Pharmatop License Agreement, in the event that Cadence fails to perform any of such
obligations under the Pharmatop License Agreement (except to the extent that a breach by BMS of its
obligations under this Agreement or the Pharmatop License Agreement or any other act or omission by
BMS prevents such performance by Cadence or any of its Affiliated Companies, sublicensees,
contractors or agents), which failure is not cured within ninety (90) days after written notice
from BMS, BMS may perform such obligation on behalf of Cadence at Cadence’s expense, and Cadence
shall reimburse BMS for its fully burdened costs (including both its out-of-pocket costs and
internal costs) in connection with such performance; provided, however, that this Section 3.4 shall
not authorize BMS to control the conduct of any clinical trial or study under the Development Plan.
This Agreement sets forth the obligations of the Parties inter se, and nothing in this Agreement
(including any standard of effort set forth herein) shall limit or modify the obligations of the
Parties assumed under the Pharmatop License Agreement.

     3.5 Certain Rights and Obligations under the Pharmatop License Agreement.

          (a) BMS shall provide Cadence with copies of written communications received by BMS from
Pharmatop after the Effective Date pursuant to Section 2.2 of the Pharmatop License Agreement with
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performed by Pharmatop and concerning any
inventions or Know-How (as defined in the Pharmatop License Agreement) made by Pharmatop relating
to the Products.

          (b) If Pharmatop provides to BMS a copy of any application, filing or request for review and
comment by BMS, BMS shall provide a copy of each application, filing or request to Cadence promptly
after receipt thereof, and shall give reasonable consideration to any comments of Cadence in any
comments provided by BMS to Pharmatop.

          (c) If Pharmatop provides to BMS a quarterly written patent report pursuant to Section 5.1(d)
of the Pharmatop License Agreement, BMS shall provide a copy of such report to Cadence within a
reasonable period of time after receipt thereof, provided that BMS may redact information relating
to Patents outside the Territory.

          (d) To the extent that Pharmatop is obligated to indemnify sublicensees of BMS pursuant to
Section 12.1 of the Pharmatop License Agreement and Cadence desires to assert a claim for
indemnification pursuant to such section, Cadence shall have the right, to the extent permitted by
the Pharmatop License Agreement, to assert such claim for indemnification against Pharmatop. In
the event Cadence is not permitted by the Pharmatop License Agreement to assert such claim directly
against Pharmatop, BMS shall cooperate with Cadence (at Cadence’s expense and subject to Section
7.7 of this Agreement) to permit Cadence to assert such claim, including, if necessary, allowing
Cadence to bring such claim in the name of BMS, unless BMS has a reasonable objection to such
procedure; provided that Cadence shall give BMS written notice of any proposed settlement with
Pharmatop and a reasonable opportunity to review and comment on such proposed settlement, and
Cadence shall not enter into any settlement with Pharmatop that could adversely affect the rights
of BMS hereunder or under the Pharmatop License Agreement without the prior written consent of BMS
in its sole discretion.

          (e) To the extent that BMS is permitted to assert against Pharmatop a claim on behalf of
Cadence (as BMS’s sublicense) for (i) indemnification and defense pursuant to Section 3.2 of the
Pharmatop License Agreement based on any use made by Pharmatop, its Affiliated Companies or its or
their licensees of the Registrational Information or with respect to the breach of any
representation, warranty or covenant of Pharmatop contained in the Pharmatop License Agreement or
(ii) for specific performance of any covenant of Pharmatop contained in the Pharmatop License
Agreement, BMS shall use reasonable efforts to cooperate with Cadence
(at Cadence’s expense and subject to Section 7.7 of this Agreement) to permit Cadence to assert such claim or request for
specific performance by Pharmatop, including, if necessary, allowing Cadence to bring such claim in
the name of BMS, unless BMS has a reasonable objection to such procedure; provided that Cadence
shall give BMS written notice of any proposed settlement with Pharmatop and a reasonable
opportunity to review and comment on such proposed settlement, and Cadence shall not enter into any
settlement with Pharmatop that could adversely affect the rights of BMS hereunder or under the
Pharmatop License Agreement without the prior written consent of BMS in its sole discretion. BMS
makes no representation or warranty as to whether BMS is permitted to assert any such claim on
behalf of Cadence.

          (f) Whenever Cadence provides any report, notice or other communication to Pharmatop in
compliance with of any of the obligations under the Pharmatop License Agreement assumed by Cadence
pursuant to Section 3.4 (e.g., the obligation to provide quarterly updates

34

 

pursuant to Section 4.3
of the Pharmatop License Agreement), Cadence shall provide a copy of such report or notice to BMS
at least [***] ([***])[***] prior to the time such report, notice or communication is provided to
Pharmatop or, if it is impracticable to provide such copy at least
[***]([***])[***]) ahead of time, Cadence shall provide such copy to BMS as early as
practicable prior to the provision thereof to Pharmatop.

          (g) BMS agrees that it shall, if reasonably requested by Cadence and at Cadence’s expense,
take reasonable efforts to enforce the material obligations of Pharmatop under the Pharmatop
License Agreement as it relates to the Territory, including obligations under Article 5 of the
Pharmatop License Agreement.

          (h) BMS covenants that it shall not agree or consent to any amendment, supplement or other
modification to the Pharmatop License Agreement or exercise any other right of agreement or consent
thereunder, in each case as it relates to the Territory, unless Cadence has consented in its sole
discretion in writing to the same.

          (i) If Cadence is not in breach of any of its material obligations under this Agreement, BMS
shall not terminate the Pharmatop License Agreement (either unilaterally or by mutual agreement
with Pharmatop) with respect to any country in the Territory without the prior written consent of
Cadence, which consent may be given or withheld in Cadence’s sole discretion. If Cadence is in
breach of any of its material obligations under this Agreement, BMS may terminate the Pharmatop
License Agreement in its sole discretion. If BMS determines to terminate the Pharmatop Agreement,
BMS shall consult with Cadence in advance to the extent reasonably practical.

          (j) BMS shall not market a Competing Product (as defined in the Pharmatop License Agreement)
in any country in the Territory during the Pharmatop Royalty Term for such country without
obtaining a written waiver from Pharmatop of the consequences of such marketing under Section 7.4
of the Pharmatop License Agreement.

          (k) Cadence shall provide written notice to BMS of any use by Pharmatop of which Cadence is
aware of any Registrational Information of Cadence as to which BMS has the
right [***] from Pharmatop as contemplated by Sections 3.1 and 3.3 of the Pharmatop License Agreement, and, if
requested by Cadence, BMS shall thereafter request from Pharmatop [***] contemplated by Sections
3.1 and 3.3 of the Pharmatop License Agreement. If BMS [***] from Pharmatop for the use by
Pharmatop of any Cadence Registrational Information as contemplated by Section 3.1 and 3.3 of the
Pharmatop License Agreement, BMS shall [***] over to Cadence within [***]([***])[***] after the
receipt thereof.

     3.6 Conduct of Clinical Trials of Products by Cadence in Clinical Study Countries. In
the event (i) Cadence is unable (or reasonably believes that it will be unable) to recruit in the
Territory sufficient clinical study subjects to conduct clinical trials necessary for Approval of
the Products in the Territory due to US treatment parameters that would significantly delay or
impair Cadence’s ability to recruit patients or otherwise complete the study on a timely basis and
(ii) Cadence desires to conduct all or a portion of such clinical study in any of the Clinical
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Countries where BMS retains rights to commercialize the Product, then Cadence shall notify
BMS in writing and provide BMS with a copy of the clinical trial study design and protocol(s)
for the conduct of such clinical study in the Clinical Study Countries in which it plans to
conduct such study and a statement of the proposed number of patients proposed to be recruited in
each city in such Clinical Study Countries. Cadence shall not conduct any such study without the
prior written consent of BMS and the license provided for below, which consent and license shall
not be unreasonably withheld if: (i) such study design and protocols are reasonably satisfactory
to BMS (and its Affiliated Companies in the Clinical Study Countries) and (ii) such study is lawful
to conduct in the regulatory jurisdictions where such study will be conducted and meets prevailing
ethical standards and guidelines (including BMS internal policies) relating to the conduct of
clinical trials and the use of the Product. In the event BMS consents to the conduct of such study
in a Clinical Study Country, BMS shall cause its applicable Affiliated Companies to grant a limited
license or sublicense to Cadence’s Affiliated Company in such Clinical Study Country where the BMS
Affiliated Companies have rights to grant such license or sublicense solely for the purpose of
permitting such clinical study solely in accordance with such study design and protocol; provided
that (1) not later than [***] ([***])[***] after [***] during such clinical trial, Cadence shall
provide BMS with a written report of the number of vials of Product administered to patients in
such clinical study in each country outside the Territory where such study is conducted and [***],
and (2) such clinical study shall be subject to such reasonable limitations as may be reasonably
satisfactory to BMS to avoid undue concentration of study subjects in a particular city.

     Neither BMS nor any of its Affiliated Companies shall have any duties or responsibilities in
connection with such clinical trial, other than (to the extent applicable) the supply of Clinical
Testing Products pursuant to the Clinical Supply Agreement, except that this provision shall not
affect the obligations of BMS and Cadence to exchange safety information as provided in Section
2.15 and the Safety Data Exchange Agreement to be entered into pursuant to Section 2.15.

     In the event Cadence desires to conduct all or a portion of such clinical study in [***], then
Cadence may request that BMS consent to the inclusion of [***] as an additional Clinical Study
Country. In the event (i) Cadence is unable (or reasonably believes that it will be unable) to
recruit in the Territory and the Clinical Study Countries sufficient clinical study subjects to
conduct clinical trials necessary for Approval of the Products in the Territory due to treatment
parameters in the US and the Clinical Study Countries that would significantly delay or impair
Cadence’s ability to recruit patients or otherwise complete the study on a timely basis and (ii)
Cadence desires to conduct all or a portion of such clinical study in any of the other countries
where BMS retains rights to commercialize the Product, then Cadence may request that BMS consent to
the inclusion of up to [***]([***]) additional countries as Clinical Study Countries; provided that
Cadence may not request the inclusion of more [***]([***]) additional countries as Clinical Study
Countries, including [***], over the term of this Agreement. In the event Cadence makes such
request, BMS shall cause its Alliance Manager to use reasonable efforts to obtain the necessary
internal BMS consents and approvals of the applicable BMS Affiliated Company in the applicable
country to the inclusion of such country as a Clinical Study Country,

 

			
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which consents and approvals may be given or withheld in the sole discretion of such BMS
Affiliated Company. In the event such consents and approvals are obtained, the Parties shall amend
the list of Clinical Study Countries to include such country.

     Cadence acknowledges that as of the Effective Date, BMS does not commercialize, and has not
effected the registration of, Products in certain of the Clinical Study Countries and other
countries where Cadence may desire to conduct clinical trials or studies. Nothing in this
Agreement shall obligate BMS or any of its Affiliated Companies (i) to maintain, retain, obtain or
seek any rights in any Clinical Study Country or any other country where Cadence may desire to
conduct clinical trials or studies or (ii) to make, maintain, refile, renew or reinstate any
Regulatory Filing in any such country.

     3.7 Conduct of US or Canadian Clinical Trials of Products by BMS. In the event BMS is
unable (or reasonably believes that it will be unable) to recruit outside the Territory sufficient
clinical study subjects to conduct clinical trials necessary for Approval of the Products in any
jurisdiction outside the Territory due to local treatment parameters that would significantly
delay or impair BMS’s ability to recruit patients or otherwise complete the study on a timely basis
and BMS desires to conduct any clinical trials or studies of Products in the Territory, then BMS
shall notify Cadence in writing and provide Cadence with a copy of the clinical trial study design
and protocol(s) for the conduct of such clinical trial in the Territory and a statement of the
proposed number of patients proposed to be recruited in each city in the Territory. BMS shall not
conduct such study without the prior written consent of Cadence, which shall not be unreasonably
withheld if: (i) such study design and protocols are reasonably satisfactory to Cadence; and (ii)
such study is lawful to conduct in the country in the Territory where such study will be conducted
and meets prevailing ethical standards and guidelines (including Cadence internal policies)
relating to the conduct of clinical trials and the use of the Product. In the event Cadence
consents to the conduct of such study in the Territory, BMS may conduct such study solely in
accordance with such study design and protocol; provided that:

     (A) if such clinical trial or study will take place prior to the launch of the
Product by Cadence in the country where BMS proposes to conduct such clinical trial or
study, such study is subject to such reasonable limitations designed to avoid impairing
Cadence’s ability to recruit patients for its own contemporaneous clinical trials; or

     (B) if such clinical trial or study will take place after the launch of the
Product by Cadence in the country where BMS proposes to conduct such clinical trial or
study, then (1) not later than [***] ([***])[***] after [***] during such clinical trial,
BMS shall provide Cadence with a written report of the number of vials of Product
administered to patients in such clinical study in each country in the Territory where such
study is [***], and (2) such clinical study shall be subject to such reasonable limitations
as may be reasonably satisfactory to Cadence to avoid undue concentration of study subjects in a
particular city in the Territory.

     Neither Cadence nor any of its Affiliated Companies shall have any duties or responsibilities
in connection with such clinical trial by BMS or its Affiliated Companies, except

 

			
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that this
provision shall not affect the obligations of BMS and Cadence to exchange safety information as
provided in Section 2.15 and the Safety Data Exchange Agreement to be entered into pursuant to
Section 2.15.

     3.8 Existing BMS Suppliers. [***].

ARTICLE IV – FINANCIAL TERMS

     4.1 Payments to BMS. In partial consideration of the rights granted to Cadence
hereunder:

          (a) On the Effective Date, Cadence shall pay to BMS Twenty-Five Million Dollars ($25,000,000).

          (b) Within ten (10) Business Days following the [***], Cadence shall pay to BMS [***]([***]).
Such amount shall be paid only once, regardless of [***].

          (c) Within ten (10) Business Days after [***], Cadence shall pay to BMS an amount equal to
[***]([***])[***]; provided, however, that such payment shall not exceed [***]([***]).

          (d) Not later than [***]([***][***] following the [***] in which the [***], Cadence shall pay
to BMS [***]([***]); provided, however, if [***], Cadence shall pay such amount to BMS not later
than [***]([***])[***] following the [***].

          (e) In addition to the payment provided for in Section 4.1(d) above, not later than
[***]([***][***] following the [***] in which the [***], Cadence shall pay to BMS [***]([***]);
provided, however, if such [***], Cadence shall pay such amount to BMS not later than [***]([***])
[***].

          (f) During the Pharmatop Royalty Term, Cadence shall pay to BMS royalties calculated at the
rate of:

               (i) [***] of that portion of aggregate Net Sales in each Calendar Year that is [***],

               (ii) [***] of that portion of aggregate Net Sales in each Calendar Year that is [***] and up
to and including Net Sales of [***], and

               (iii) [***] of that portion of aggregate Net Sales in each Calendar Year that is [***],

with the aggregate amount of Royalties payable pursuant to clauses (i) – (iii) above [***] by the
amount of the [***] and any [***] and [***] of this Agreement and the terms of the Pharmatop
License Agreement (which [***] provided for in [***]). In the event the amount of [***] and any
[***] with respect to any [***].

 

			
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          In the event the royalties payable to Pharmatop are reduced in respect of any Combination
Product (as defined in the Pharmatop License Agreement) sold by Cadence or its Affiliated Companies
or sublicensees in the Territory, the Royalties payable to BMS pursuant to this Section 4.1(f) in
respect of such Combination Product shall be reduced (dollar-for-dollar) by the amount of the
reduction in such royalties payable to Pharmatop.

          [***].

          (g) During the BMS Patent Royalty Term, Cadence shall pay to BMS royalties calculated at the
rate of:

               (i) [***] of that portion of aggregate Net Sales of Products that are BMS Patent Products in
each Calendar Year that is [***],

               (ii) [***] of that portion of aggregate Net Sales of Products that are BMS Patent Products in
each Calendar Year that is in [***] and up to and including Net Sales of such Products of [***],
and

               (iii) [***] of that portion of aggregate Net Sales of Products that are BMS Patent Products in
each Calendar Year that is [***].

          [***].

          The Royalties payable by Cadence to BMS pursuant to this Section 4.1(g) shall be [***] for any
Calendar Quarter if:

          (i) [***]

          (ii) [***]

          (iii) [***]

but only to the extent such Royalties are [***] as of the date of such event.

          [***].

          (h) The royalties payable pursuant to Section 4.1(f) and Section 4.1(g) are referred to herein
as “Royalties”). Such Royalties shall be paid quarterly as provided in Section 4.7 of this
Agreement.

          (i) [***].

     4.2 Reduction of Certain Milestone Payments.

          (a) If (i) after the Effective Date, a Third Party claim or action challenging the Pharmatop
Patents succeeds so as to deprive Pharmatop (and therefore BMS and Cadence) of any of its rights
under the Pharmatop Patents in the United States or (ii) after the Effective Date, Pharmatop or BMS
is unable to maintain, or a material alteration of the scope or content occurs with respect to, any
of the claims under any of the Pharmatop Patents, in the United States, then

 

			
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(1) the payment
provided for in Section 4.1(b) shall, if not yet earned, be reduced to [[***] ([***]) and (2) the
payment provided for in Section 4.1(c) shall, if not yet earned, be reduced by [***].

          (b) If a Third Party should market in the United States after the Effective Date a
parenterally-administered liquid solution product, in a stable and readily injectible form, that
(i) contains paracetamol and one or more other analgesic ingredients, (ii) uses any of the
Technology contained within any issued claim of any Pharmatop Patent in such country or any
Pharmatop Know-How, and (iii) is not considered to infringe any Pharmatop Patent or BMS Patent in
such country (whether by judicial determination or settlement, by joint agreement of either BMS and
Pharmatop or BMS and Cadence or by the failure of Pharmatop, BMS and Cadence to prosecute such
Third Party for infringement under Section 6.5 of the Pharmatop License Agreement or Section 2.16
of this Agreement), then (1) the payment provided for in Section 4.1(b) shall, if not yet earned,
be reduced to [***]([***]) and (2) the payment provided for in Section 4.1(c) shall, if not yet
earned, be reduced by [***]; provided that (A) during the pendency of any legal action against such
Third Party with respect to the possible infringement of a Pharmatop Patent or BMS Patent the
amount of such reduction (the “Retained Sum”) shall be temporarily retained by Cadence until such
litigation ends, (B) if the outcome of the litigation is the invalidation of the Pharmatop Patents
so that the Third Party is free to sell such product in the United States, [***] and (C) if the
outcome of the litigation is not as described in clause (B) above, [***].

          (c) The reductions provided for in Sections 4.2(a) and 4.2(b) shall not be [***] and (i) the
aggregate amount of the reduction in the payment provided for in Section 4.1(b) shall not exceed
[***]([***]) and (ii) the aggregate amount of the reduction in the payment provided for in Section
4.1(c) shall not exceed [***].

          (d) Notwithstanding the foregoing Sections 4.2(a) and 4.2(b), if aggregate Net Sales during
any Calendar Year [***], then (i) for the [***] such Calendar Year Cadence shall pay to BMS
[***]([***]) of the aggregate amount of the reduction [***], (ii) for the [***] such Calendar Year
Cadence shall pay to BMS an [***]([***]) of the aggregate [***] and (iii) for the
[***] such Calendar Year Cadence shall pay to BMS an [***]([***]) of the aggregate [***].
Such [***] shall be made not later than [***]([***])[***] following the applicable Calendar Year.

     4.3 Payments by Cadence to Pharmatop. In partial consideration of the rights granted
to Cadence hereunder and without limiting any of the other obligations assumed by Cadence under the
Pharmatop License Agreement:

          (a) Within ten (10) business days (as such term is used in the Pharmatop License Agreement)
following the [***], Cadence shall pay to Pharmatop [***]([***]) in satisfaction of the obligation
set forth in Section 7.1(b) of the Pharmatop License Agreement.

 

			
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          (b) Cadence shall pay to Pharmatop all royalties payable to Pharmatop pursuant to the
Pharmatop License Agreement with respect to the Territory in the manner provided for in such
agreement.

          (c) If for any period a Guaranteed Payment is due under the Pharmatop License Agreement,
Cadence shall pay to Pharmatop the amount of such Guaranteed Payment in the manner provided for in
the Pharmatop License Agreement.

          (d) Cadence shall provide to BMS evidence reasonably satisfactory to BMS of each such payment.

          (e) The amount of the payments made to BMS under this Agreement shall be Confidential
Information of BMS and of Cadence. Cadence shall not disclose to Pharmatop in the reports provided
by Cadence to Pharmatop pursuant to the Pharmatop License Agreement or otherwise the amount of any
payments to BMS hereunder.

     4.4 Manner of Payment. All payments to be made to BMS or Cadence hereunder shall be
paid in Dollars by wire transfer of immediately available funds to a bank account designated in
writing by the payee not less than [***] ([***])[***] prior to the required payment date.

     4.5 Interest. Any payment by Cadence to BMS hereunder not made as and when due shall
bear interest at the rate of [***]([***]) per annum, compounded daily, from the due date to the
date of payment.

     4.6 Expenses; Taxes.

          (a) Expenses. Except as expressly set forth in this Agreement, all costs and expenses
incurred in connection with the preparation and negotiation of this Agreement and the other Transaction Documents and the transactions
contemplated hereby shall be paid by the Party incurring such expense. Each Party shall bear the
fees and expenses of any agent, broker, investment banker, finder or other Person engaged by it or
any of its Affiliated Companies in connection with the transactions contemplated by this Agreement
and the other Transaction Documents.

          (b) Transfer Taxes. Any Transfer Tax, if any, applicable to the transactions contemplated by
this Agreement shall be borne and paid by Cadence.

          (c) Tax Withholding. The withholding tax, duties, and other levies (if any) applied by a
government of any country of the Territory on payments made by Cadence to BMS hereunder shall be
borne by BMS. Cadence, its Affiliated Companies and sublicensees shall cooperate with BMS to
enable BMS to claim exemption therefrom under any double taxation or similar agreement in force,
shall provide to BMS proper evidence of payments of withholding tax, and shall assist BMS by
obtaining or providing in as far as possible the required documentation for the purpose of BMS’s
tax returns.

     4.7 Sales Reports and Royalty and Other Payments. The Royalties payable under Section
4.1 shall be calculated and will be payable quarterly for sales made in each Calendar

 

			
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Quarter in
the Royalty Term and the BMS Patent Royalty Term, as applicable. Cadence shall prepare and send to
BMS within [***] ([***])[***] after the end of each Calendar Quarter ([***]([***])[***] after the
last Calendar Quarter in a Calendar Year to allow for additional time to determine any adjustments
required to be made on an annual basis) a detailed statement, country by country and by dosage and
pharmaceutical form, of the Net Sales (and, during the BMS Patent Royalty Term, the Net Sales of
BMS Patent Products), the calculation of the Royalties payable under Section 4.1, the calculation
of any amounts payable to Pharmatop pursuant to the Pharmatop License Agreement with respect to the
Territory and the calculation of any reduction in the Royalties or other amounts deducted from the
payments to BMS as contemplated by Section 4.1 together with a description of any facts or
circumstances that Cadence believes entitles it to a reduction in, or deduction from, the Royalties
payable under this Agreement as contemplated by Section 4.1 and information reasonably satisfactory
to BMS to permit the calculation of any such reduction or deduction, accompanied by payment in
accordance with Section 4.4 of the Royalties due BMS. Cadence shall provide to BMS a copy of each
statement of Net Sales provided by Cadence to Pharmatop contemporaneously with the provision of
such statement to Pharmatop, which statements shall not disclose the Royalties or other amounts
payable to BMS under this Agreement.

     4.8 Sales Record Audit. Cadence shall keep, and shall cause each of its Affiliated
Companies, sublicensees, distributors and agents to keep, full and accurate books of accounting In
Accordance With GAAP containing all particulars that may be necessary for the purpose of
calculating all Royalties payable to BMS. Such books of accounting (including those of Cadence’s
Affiliated Companies, sublicensees, distributors and agents) shall be kept at their principal place
of business, together with all necessary supporting data. BMS may, on reasonable (but not less
than [***]([***])[***]) written notice to Cadence,
have the calculation of the Royalties payable under Section 4.1 and any calculation or
reconciliation statement provided pursuant to Section 4.7 audited at its own expense by an
accounting firm selected by BMS that is reasonably acceptable to Cadence and that is bound by a
written agreement of confidentiality to Cadence. The auditor’s assignment will be limited to
reviewing the accuracy of a calculation or reconciliation statement sent by Cadence, and to
disclosing only if there are any errors in payment and, if an error exists, the amount of such
error(s) and the calculation thereof, and no additional or any other information. If an audit
discloses that the amount of Royalties owed to BMS was understated by more than [***]([***][***],
then [***] must reimburse [***] for the cost of the audit, in addition to paying the additional
Royalties together with interest on the additional amounts, calculated from the date on which the
additional amount should have been paid, as provided in Section 4.5. Such audit rights may be
exercised only once in any given Calendar Year, and any such audit shall apply [***].

ARTICLE V – MUTUAL COVENANTS OF THE PARTIES

     5.1 Publicity. Neither Party shall issue any public release or announcement
concerning this Agreement or the transactions contemplated hereby without the prior consent of the
other Party, except to the extent required by Applicable Law or the rules or regulations of any

 

			
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United States or foreign securities exchange (or inter-dealer quotation system) or regulatory
commission (in which case such Party shall, to the extent practicable, allow the other Party
reasonable time to comment on such release or announcement in advance of such issuance); provided,
however, that prior to any such disclosure, such Party shall use reasonable efforts to give advance
notice to the other Party of the timing and content of such disclosure. Nothing contained in this
Section 5.1 shall prevent either Party from making internal announcements to its and its Affiliated
Companies’ employees.

     5.2 Confidentiality.

          (a) Confidentiality Obligations. Each Party recognizes that the other Party’s Confidential
Information constitutes highly valuable and proprietary confidential information and material.
Each Party agrees that until the date that is [***]([***])[***] after the date of disclosure to it
of any given item of Confidential

Information, it will keep confidential, and will cause its officers, employees, consultants,
agents, Affiliated Companies and sublicensees to keep confidential, such Confidential Information
disclosed to it by the other Party; provided that if the Pharmatop License Agreement requires a
longer period of confidentiality with respect to any Confidential Information of Pharmatop
disclosed to a Party, such Party shall also observe such longer period of confidentiality in
accordance with the Pharmatop License Agreement. Neither BMS nor Cadence nor any of their
respective employees, consultants, Affiliated Companies or sublicensees shall use Confidential
Information of the other Party for any purpose whatsoever except as otherwise expressly permitted
by this Agreement.

          (b) Limited Disclosure. Each Party agrees that any disclosure of the other Party’s
Confidential Information to any officer, employee, consultant, agent or Affiliated Company of such
Party, shall be made only if and to the extent necessary to carry out its obligations and
responsibilities, or to exercise its rights, under this Agreement, shall be limited to the maximum
extent possible consistent with such rights and responsibilities, and shall only be made to persons
who are bound by their employment (or other) contract (or, in the case of counsel or other licensed
professionals, by applicable rules of professional conduct) to maintain the confidentiality thereof
and not to use such Confidential Information except as expressly permitted by this Agreement. Each
Party further agrees not to disclose or transfer the other Party’s Confidential Information to any
Third Party under any circumstance without the prior written approval from the other Party (such
approval not to be unreasonably withheld, delayed or conditioned if such Confidential Information
is appropriately protected by the recipient), except as otherwise required by law, and except as
otherwise expressly permitted by this Agreement. Each Party shall take such action, and shall
cause its officers, employees, consultants, agents, Affiliated Companies and sublicensees to take
such action, to preserve the confidentiality of the other Party’s Confidential Information as it
would customarily take to preserve the confidentiality of its own Confidential Information, using a
level of care that shall not under any circumstances be less than reasonable care. Each of the
Receiving Party’s Affiliated Companies shall be bound by the confidentiality obligations set forth
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set forth in Section 5.2(a), including any entity that
becomes an Affiliated Company after the date of the relevant disclosure by the Disclosing Party,
whether or not such Affiliated Company ceases to be an Affiliated Company of the Receiving Party
during the term of the confidentiality obligations hereunder; and the Receiving Party shall be
responsible for any unauthorized disclosure of such Confidential Information by any of its
Affiliated Companies to which such Confidential Information is disclosed, including after such
company ceases to be an Affiliated Company.

          (c) Authorized Disclosure. The Receiving Party may disclose Confidential Information
belonging to the other Party to the extent (and only to the extent) such disclosure is reasonably
necessary in the following instances:

               (i) as reasonably necessary for filing or prosecuting Patents as contemplated by this
Agreement;

               (ii) as reasonably necessary for Regulatory Filings and other communications with Drug
Regulatory Authorities as contemplated by this Agreement;

               (iii) as reasonably necessary for prosecuting or defending litigation;

               (iv) subject to Section 5.2(e) of this Agreement, as reasonably necessary to comply
with Applicable Law (including the rules and regulations of the Securities and Exchange
Commission or any national securities exchange) and with judicial process, if in the
reasonable opinion of the Receiving Party’s counsel, such disclosure is necessary for such
compliance; and

               (v) in connection with the performance of this Agreement and solely on a “reasonable
need to know basis”, to Affiliated Companies, potential collaborators (including potential
co-marketing and co-promotion contractors), sublicensees, potential sublicensees, research
collaborators, potential investment bankers, lenders, investors, employees, consultants,
medical professionals participating in the conduct of clinical trials, or agents, each of
whom prior to disclosure must be bound by similar obligations of confidentiality and non-use
at least equivalent in scope to those set forth in this Section 5.2; provided, that in the
case of disclosure to academic researchers and academic institutions, the confidentiality
period hereunder shall be the longest such period as the applicable Party may reasonably
negotiate with such researchers or institutions; and provided, that the Receiving Party
shall remain responsible for any failure by any Person who receives Confidential Information
pursuant to this Section 5.2 to treat such Confidential Information as required under this
Section 5.2;

provided, however, that nothing in this Agreement shall limit or affect the Parties’
confidentiality obligations under the Pharmatop License Agreement.

          If and whenever any Confidential Information is disclosed in accordance with this Section 5.2,
such disclosure shall not cause any such information to cease to be Confidential Information except
to the extent that such disclosure results in a public disclosure of such information (otherwise
than by breach of this Agreement). With respect to disclosures under Sections 5.2(c)(iii) and
5.2(c)(iv), where reasonably possible, the Receiving Party shall notify the

44

 

Disclosing Party of the
Receiving Party’s intent to make such disclosure sufficiently prior to making such disclosure so as
to allow the Disclosing Party adequate time to take whatever action it may deem appropriate to
protect the confidentiality of the information, and the Receiving Party shall further reasonably
assist the Disclosing Party to obtain confidential treatment of such Confidential Information.

          The Parties acknowledge that the terms of this Agreement shall be treated as Confidential
Information of both Parties. For the avoidance of doubt, this Section 5.2 shall in no way prevent
a Party from disclosing the existence of this Agreement or any terms of this Agreement in order to
seek legal advice whenever deemed appropriate by such Party or to enforce such Party’s rights under
this Agreement, whether through arbitration proceedings, court proceedings or otherwise, or to
defend itself against allegations or claims relating to this Agreement, or to disclose such terms
as it may be advised in written opinion of outside counsel are required to be disclosed to comply
with Applicable Law (a copy of which opinion shall be provided to the other Party).

          (d) Employees and Consultants. Each Party hereby represents that all of its employees and any
consultants to such Party or its Affiliated Companies that will have access to the Confidential
Information of the other Party shall be bound by written obligations (or, in the case of counsel or
other licensed professionals, bound by rules of professional conduct) to maintain such information
in confidence consistent with the terms of this Agreement and not to use such information except as
expressly permitted herein. Each Party agrees to enforce confidentiality obligations to which its
employees and consultants (and those of its Affiliated Companies) are obligated with respect to any
such Confidential Information and agrees to be responsible for any breach or violation by such
Persons of any provisions of this Agreement or the Pharmatop License Agreement relating to the
confidentiality or non-use of any such Confidential Information by such Persons.

          (e) Securities Filings. In the event either Party proposes to file with the Securities and
Exchange Commission or the securities regulators of any state or other jurisdiction a registration
statement or any other disclosure document which describes or refers to this Agreement under the
Securities Act of 1933, as amended, the Exchange Act, or any other Applicable Law relating to
securities matters, that Party shall notify the other Party of such intention and shall provide
such other Party with a copy of relevant portions of the proposed filing not less than five (5)
Business Days prior to such filing (and any revisions to such portions of the proposed filing a
reasonable time prior to the filing thereof), including any exhibits thereto relating to this
Agreement, and shall use reasonable efforts to obtain confidential treatment of any information
concerning this Agreement that such other Party requests be kept confidential, and shall only
disclose Confidential Information which it is advised by counsel or the Securities and Exchange
Commission is legally required to be disclosed. No such notice shall be required under this
Section 5.2(e) if the substance of the description of or reference to this Agreement contained in
the proposed filing has been included in any previous filing made by either Party hereunder or
otherwise approved by the other Party.

          (f) Academic Publications. The Parties recognize that independent investigators have been
engaged, and will be engaged in the future, to conduct clinical trials and studies of the Products.
The Parties recognize that such investigators operate in an academic

45

 

environment and may release
information regarding such studies in a manner consistent with academic standards and as further
provided in this paragraph. In the event that any such independent investigator of a Party desires
to publish any abstract, manuscript or article or make any presentation (including verbal
presentations) or other publication that includes any Confidential Information of the other Party,
such Party shall (i) require such independent investigator to provide the other Party and its
patent counsel the opportunity to review any proposed abstract, manuscript, article, presentation
(including verbal presentations) or other publication at least thirty (30) days prior to its
intended submission for publication or such presentation and (ii) upon request of the other Party
not to submit any such abstract, article or manuscript for publication or not to make such
presentation for such additional reasonable period of time (but not to exceed an additional thirty
(30) days) to enable the other Party to secure patent protection for any material in such
publication which it believes to be patentable or to consider the implications of publication on
eventual commercialization.

          (g) Additional Confidentiality Obligations under the Pharmatop License Agreement. The
provisions of this Section 5.2 are in addition to and not in limitation of any applicable
obligation of confidentiality under the Pharmatop License Agreement.

     5.3 Restrictions Binding on Affiliated Companies and Investors. Each Party shall
require each of its Affiliated Companies and investors to which Confidential Information of the
other Party is disclosed as permitted hereunder to comply with the covenants and restrictions set
forth in Sections 5.1 and 5.2 as if each such Affiliated Company and each such investor were a
Party to this Agreement and shall be fully responsible for any breach of such covenants and
restrictions by any such Affiliated Company or investor.

     5.4 Alliance Management. Each of the Parties shall appoint one senior representative
who possesses a general understanding of development, regulatory and commercialization issues to
act as its Alliance Manager. The role of the Alliance Manager is to act as a single point of
contact between the Parties to assure a successful working relationship. Each Party may change its
designated Alliance Manager from time to time upon written notice to the other Party. Any Alliance
Manager may designate a substitute to temporarily perform the functions of that Alliance Manager.

     5.5 Liens.

          (a) Cadence shall not during the term of this Agreement (i) grant any Lien (excluding any
permitted sublicenses) with respect to this Agreement or any of the rights licensed or sublicensed
to it under this Agreement or (ii) permit such a lien, security interest or other encumbrance
(excluding any permitted sublicenses) to attach to this Agreement or any of such rights. For sake
of clarity, any breach of this Section 5.5(a) by Cadence that is not cured within ten (10) Business
Days after written notice thereof shall be deemed a material breach of this Agreement.

          (b) BMS shall not during the term of this Agreement (i) grant any Lien (excluding any
permitted sublicenses) with respect to any of the BMS Rights, BMS Patents or BMS Know-How that
would prevent BMS from granting the licenses hereunder or performing its obligations under this
Agreement, or (ii) permit such a Lien to attach to the BMS Rights,

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BMS Patents or BMS Know-How. For sake of clarity, any breach of this Section 5.5(b) by BMS that is not cured within ten (10) Business
Days after written notice thereof shall be deemed a material breach of this Agreement.

     5.6
BMS Confidential Disclosure Agreements. Promptly following the Effective Date, BMS shall assign to Cadence the Confidential Disclosure
Agreements executed by BMS and the other potential sublicensees considered by BMS in connection with the sublicense of the BMS Rights
contemplated hereby, to the extent assignable; provided, however, that if BMS is not permitted by the terms of such Confidential Disclosure
Agreements to so assign them, BMS shall request the other parties to such Confidential Disclosure Agreement to (i) return or destroy all the
confidential information of BMS relating to the Products and the BMS Rights provided to them by BMS in connection with such transaction and (ii)
certify to BMS that such confidential information has been returned or destroyed; provided, further, that BMS shall not have any obligation to
bring any suit or take any other action against any such other party to enforce the obligations thereunder. BMS shall provide to Cadence copies
of any such certifications received by BMS.

ARTICLE VI – REPRESENTATIONS AND WARRANTIES

     6.1 Mutual Representations and Warranties. Each of BMS and Cadence represents and
warrants to the other Party as follows:

          (a) Organization. Such Party is a corporation duly organized, validly existing and in good
standing (or subsisting) under the laws of the jurisdiction of its organization, is qualified to do
business and is in good standing (or subsisting) as a foreign corporation or company in each
jurisdiction in which the performance of its obligations under this Agreement requires such
qualification, and has full corporate or company power and authority and possesses all governmental
franchises, licenses, permits, authorizations and approvals (other than the termination or
expiration of any waiting periods under the HSR Act, if applicable) necessary to enable it to
perform its obligations under this Agreement, other than such franchises, licenses, permits,
authorizations and approvals the lack of which, individually or in the aggregate, could not
reasonably be expected to have a Material Adverse Effect.

          (b) Authorization. The execution, delivery and performance by such Party of this Agreement
have been duly authorized by all necessary corporate action and do not and will not require any
further consent or approval of its shareholders or members. Such Party has the power and authority
to execute and deliver this Agreement and to perform its obligations hereunder and to grant the
rights and licenses granted (or to be granted) by it in this Agreement.

          (c) Binding Agreement. Such Party has duly executed and delivered this Agreement, and this
Agreement (assuming the due authorization, execution and delivery by each other party thereto),
constitutes its legal, valid and binding obligation, enforceable against it in accordance with its
terms, subject to applicable bankruptcy, insolvency, fraudulent transfer, reorganization,
moratorium and similar laws and judicial decisions of general applicability relating to or
affecting creditors’ rights generally and to general principles of equity (regardless of whether
enforceability is sought in equity or at law).

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          (d) No Conflicts; Consents. The execution and delivery by such Party of this Agreement do
not, and the consummation of the transactions contemplated by this Agreement do not and will not,
conflict with, or result in any violation of or default (with or without notice or lapse of time,
or both) under, or give rise to a right of termination, cancellation or acceleration of any
obligation or to loss of a material benefit under, or to increased, additional or accelerated
rights or entitlements of any Third Party under, or result in the creation of any Lien upon any of
the assets of such Party under, any provision of (i) its Organizational Documents, (ii) any
Contract to which such Party is a party or by which any of its properties or assets is bound,
except for the rights of Pharmatop under the Pharmatop License Agreement or (iii) any judgment,
order or decree (collectively, “Judgments”) or any Applicable Law applicable to such Party or its
properties or
assets. No consent, approval, license, permit, order or authorization (collectively,
“Consent”) of, or registration, declaration or filing with, any Governmental Entity (other than any
filing under the HSR Act) or any other Third Party is required to be obtained or made by or with
respect to such Party in connection with the execution, delivery and performance of this Agreement
or the consummation of the transactions contemplated by this Agreement.

          (e) Litigation. There are no (a) outstanding Judgments against or affecting such Party, or
(b) claims, actions, suits, proceedings, arbitrations, investigations, inquiries, or hearings or
notices of hearings (collectively, “Proceedings”) pending or, to the knowledge of such Party,
threatened in writing against or affecting such Party, its Affiliated Companies, by or against any
Governmental Entity or any other Person, that in any manner challenges or seeks to prevent, enjoin,
materially alter or materially delay the transactions contemplated by this Agreement or that,
individually or in the aggregate, could reasonably be expected to have a Material Adverse Effect on
such Party or on the exploitation (including the import, use, manufacture, sale and offer for sale)
of the Products hereunder.

     6.2 Additional Representations of Cadence. Without limiting the generality of the
representations and warranties set forth in Section 6.1 above, Cadence represents and warrants to
BMS as follows:

(a) Financial Statements. True and complete copies of the audited balance sheet of Cadence as of
December 31, 2004, and the related statements of income, shareholders’ equity and cash flows for
the fiscal year ended on such date, together with the notes thereto and the unaudited consolidated
balance sheets of Cadence and its subsidiaries as of December 31, 2005, and the related statements
of income, shareholders’ equity and cash flows for the twelve (12) months ended on such date
(collectively, the “Financial Statements”) have been Previously Disclosed. The Financial
Statements are In Accordance With GAAP (as defined below). As used herein with respect to any
financial statements, “In Accordance With GAAP” means that such financial statements: (i) are in
accordance with the books and records of Cadence and its subsidiaries, if any, (ii) are true and
correct and fairly present in all material respects the financial position, results of operations,
shareholders’ equity and cash flows of Cadence and its subsidiaries, if any, on a consolidated
basis, if applicable, as of the dates and for the periods indicated, in each case in conformity
with United States generally accepted accounting principles consistently applied during the
applicable periods and (iii) if such financial statements are audited, include all required
footnotes and, if such financial statements are unaudited, include all required footnotes
concerning contingent liabilities, if any. The statements of income included

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in the Financial
Statements do not contain any items of special or nonrecurring income, revenue or expense and have
not been affected by the inclusion of transactions entered into otherwise than on normal commercial
terms or by any other factors rendering such profits for all or any of such periods exceptionally
high or low, except as expressly specified therein. Except as specified in the Financial
Statements or the notes thereto, the balance sheets included in the Financial Statements do not
reflect any write-up or revaluation increasing the book value of any assets. The books and
accounts of Cadence and its subsidiaries
are true and complete in all material respects and fully and fairly reflect all of the transactions
of Cadence and its subsidiaries.

          (b) Absence of Undisclosed Liabilities. To the knowledge of Cadence, Cadence and its
subsidiaries have no liability of any nature whatsoever (whether known or unknown, due or to become
due, accrued, absolute, contingent, existing, inchoate or otherwise) including any unfunded
obligation under any benefit plan (as defined in ERISA) or liabilities for Taxes, except for (i)
liabilities reflected or reserved against in the consolidated balance sheet of Cadence and its
subsidiaries as of December 31, 2005 (the “Balance Sheet Date”) included in the Financial
Statements (collectively, the “Balance Sheet”), or in the notes thereto, (ii) liabilities under the
Loan and Security Agreement among Cadence, Oxford Finance Corporation and Silicon Valley Bank dated
February 17, 2006 (the “Loan Agreement”), (iii) current liabilities incurred in the ordinary course
of business and consistent with past practice from the Balance Sheet Date to the Effective Date
which, individually and in the aggregate, do not exceed [***] and (iv) liabilities which
individually or in the aggregate would not have a Material Adverse Effect on Cadence. The
collateral pledged by Cadence pursuant to the Loan Agreement does not include any of Cadence’s
rights in, to or under this Agreement.

          (c) Absence of Material Adverse Effect. To the knowledge of Cadence, since the Balance Sheet
Date and through the Effective Date, Cadence and its subsidiaries have not experienced a Material
Adverse Effect and no event or circumstance has occurred or developed which is reasonably likely to
result in such a Material Adverse Effect or which has resulted, or is reasonably likely to result,
in any loss or liability to Cadence and its subsidiaries in excess of [***].

          Without limiting the foregoing, since the Balance Sheet Date there has not been, occurred or
arisen: (i) any declaration, setting aside or payment of any dividend or distribution (whether in
cash, stock or property) in respect of capital stock of Cadence or any of its subsidiaries, or any
direct or indirect redemption, purchase or other acquisition of shares of such capital stock or any
split, combination or reclassification of such capital stock (other than redemption of shares
issued pursuant to early-exercised options under Cadence’s 2004 Equity Incentive Award Plan), (ii)
any Lien on any of the assets or properties of Cadence and its subsidiaries (other than the pledge
of assets pursuant to the Loan Agreement); or (iii) any authorization, approval, agreement or
commitment to do any of the foregoing. The pledge of assets pursuant to the Loan Agreement does
not grant any Lien with respect to this Agreement or any of the rights licensed or sublicensed to
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          (d) Legal Matters. Since Cadence’s date of incorporation (May 26, 2004), there has not been
any, and there is no, claim, action, suit, litigation, investigation, inquiry, review or proceeding
(collectively, “Cadence Claims”) pending against Cadence or any of its subsidiaries relating to the
business or assets of Cadence or its subsidiaries before or by any court, arbitrator or

Governmental Entity; and to the knowledge of Cadence no such Cadence Claim has been threatened.
Neither Cadence nor any of its subsidiaries is subject to any judgment, decree, writ, injunction,
ruling, award or order of any Governmental Entity or any arbitrator relating to the business or
assets of Cadence and its subsidiaries.

          (e) Receipt of Financing; Restrictions. Between the Execution Date and the Effective Date,
Cadence will have received additional financing in an amount that is not less than $50 million from
the sale of equity securities. The holders of the equity securities of Cadence and its
subsidiaries do not have (by virtue of the terms of such equity securities, by contract or
otherwise) any right (mandatory or optional) to require the redemption of any of such equity
securities. On or before the Effective Date, Cadence will have entered into the Loan Agreement
obligating the lender or lenders thereunder to lend to Cadence not less than $7 million, subject to
the terms and conditions set forth therein. Cadence has provided to BMS true and complete copies
of the documents relating to such equity financing and such Loan Agreement.

     6.3 BMS Rights.

          (a) Pharmatop Patents. As of the Execution Date, BMS represents and warrants to
Cadence as follows with respect to the Pharmatop Patents and Pharmatop Know-How:

               (i) Schedule 6.3(a) sets forth a list of all the Pharmatop Patents. To the knowledge
of BMS’s in-house patent counsel after reasonable due diligence, (A) the most recent Patent report
provided to BMS pursuant to Section 5.1 of the Pharmatop License Agreement relating to the
Pharmatop Patents has been provided to Cadence, except for information that may have been redacted
relating to Patents outside the Territory, and (B) BMS has not received any written notices of
allowances for the Pharmatop Patents or written notices of interferences proceedings with respect
thereto, except as previously disclosed to Cadence.

               (ii) To the knowledge of BMS’s in-house patent counsel after reasonable due diligence, there
are no unpaid maintenance, annuity or renewal fees currently overdue for any of the Pharmatop
Patents.

               (iii) To the knowledge of BMS’s in-house patent counsel, BMS is the sole and exclusive
licensee of the Pharmatop Patents in the Territory.

               (iv) BMS has not sublicensed, granted any interest in or options to the Pharmatop Patents to
any Third Party in the Territory and covenants not do so prior to the expiration or termination of
this Agreement, except in the exercise of BMS’s retained rights pursuant to Section 2.2.

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          (b) To the knowledge of BMS’s in-house counsel, BMS is not, nor has it received any notice
that it is, in default (or that with the giving of notice or lapse of time or both it would be in
default) with respect to the BMS Rights under the Pharmatop License Agreement that would permit
Pharmatop to terminate, or exercise a right of rescission, revision or amendment of, the Pharmatop
License Agreement with respect to the Territory and covenants that it shall not take, and shall
cause its Affiliated Companies not to take, any action or omit to
take any action after the Execution Date that would permit Pharmatop to terminate, or exercise
a right of rescission, revision or amendment of, the Pharmatop License Agreement with respect to
the Territory, other than the omission of the performance of obligations assumed by Cadence
hereunder.

          (c) To the knowledge of BMS’s in-house patent counsel, BMS has not received written notice of
any claim, action, suit or litigation alleging that BMS’s exploitation (including the import, use,
manufacture, sale and offer for sale) of the BMS Rights for the Product interferes with, infringes,
or misappropriates any intellectual property rights of any Third Party (including written notice of
any claim, action, suit or litigation that BMS must license or refrain from using any intellectual
property rights of any Third Party in order to exploit(including the import, use, manufacture, sale
and offer for sale) any Products. To the knowledge of BMS’s in-house patent counsel, BMS has not
received written notice that any claim, action, suit or litigation is pending or threatened which
challenges the legality, validity, enforceability, use or ownership of any BMS Rights.

          (d) BMS represents and warrants to Cadence that a true and correct copy of the Pharmatop
License Agreement as of the Effective Date, including any and all amendments, supplements or other
modifications thereto, except for the redaction of certain financial information in Section 7.1
thereof, has been Previously Disclosed. A copy of the Licensor Confirmation provided by Pharmatop
with respect to certain intellectual property and other matters as of February 6, 2006, has been
Previously Disclosed.

          (e) To the knowledge of BMS, no circumstances or grounds exist that would entitle Pharmatop to
terminate or exercise a right of rescission, revision, or amendment of the Pharmatop License
Agreement with respect to the Territory, and the execution, delivery and performance of this
Agreement will not constitute such a circumstance or ground.

          (f) BMS has protected the Pharmatop Know-How in a manner not materially different from the
manner in which it customarily protects its other proprietary know-how of comparable commercial
value.

     6.4 BMS Patents and Know-How. As of the Execution Date, BMS represents and warrants
to Cadence with respect to the BMS Patents and BMS Know-How that to the knowledge of its in-house
patent counsel:

          (a) there are no unpaid maintenance, annuity or renewal fees currently overdue for any of the
BMS Patents; and

          (b) there are no claims, judgments or settlements against or owed by BMS and no litigation
pending or threatened in writing relating to the BMS Patents; and

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          (c) BMS has protected the BMS Know-How in a manner not materially different from the manner in
which it customarily protects its other proprietary know-how of comparable commercial value.

     6.5 DISCLAIMER.

          (a) EXCEPT FOR THE EXPRESS REPRESENTATIONS AND WARRANTIES SET FORTH IN THIS ARTICLE VI OR IN
SECTION 5.2(D), BMS MAKES NO REPRESENTATIONS OR WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED,
WITH RESPECT TO THE BMS RIGHTS, BMS PATENTS OR BMS KNOW-HOW, IMPROVEMENTS, REGISTRATIONAL
INFORMATION, REGULATORY FILINGS, APPROVALS, PRODUCT DATA, OTHER PRODUCT DATA OR REPORTS, STUDIES,
PATENTS, PROCESSES, FORMULATIONS, TECHNIQUES OR OTHER TRADE SECRETS OR CONFIDENTIAL INFORMATION
PROVIDED BY BMS TO CADENCE HEREUNDER OR ANY LICENSE GRANTED BY BMS HEREUNDER, OR WITH RESPECT TO
ANY COMPOUNDS OR PRODUCTS. WITHOUT LIMITING THE FOREGOING, BMS MAKES NO EXPRESS OR IMPLIED
WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, WITH RESPECT TO THE BMS RIGHTS,
BMS PATENTS OR BMS KNOW-HOW OR ANY LICENSE GRANTED BY BMS HEREUNDER, OR WITH RESPECT TO ANY
COMPOUNDS OR PRODUCTS. FURTHERMORE, NOTHING IN THIS AGREEMENT SHALL BE CONSTRUED AS A
REPRESENTATION OR WARRANTY BY BMS THAT ANY OF THE FOREGOING IS VALID OR ENFORCEABLE OR THAT
CADENCE’S USE THEREOF CONTEMPLATED HEREUNDER DOES NOT INFRINGE ANY PATENT RIGHTS OR OTHER
INTELLECTUAL PROPERTY RIGHTS OF ANY THIRD PARTY.

          (b) EXCEPT FOR THE EXPRESS REPRESENTATIONS AND WARRANTIES SET FORTH IN THIS ARTICLE VI OR IN
SECTION 5.2(D), CADENCE MAKES NO REPRESENTATIONS OR WARRANTIES OF ANY KIND, EITHER EXPRESS OR
IMPLIED, WITH RESPECT TO THE IMPROVEMENTS, REGISTRATIONAL INFORMATION, REGULATORY FILINGS,
APPROVALS, PRODUCT DATA, OTHER PRODUCT DATA OR REPORTS, STUDIES, PATENTS, PROCESSES, FORMULATIONS,
TECHNIQUES OR OTHER TRADE SECRETS OR CONFIDENTIAL INFORMATION PROVIDED BY CADENCE TO BMS HEREUNDER
OR ANY LICENSE GRANTED BY CADENCE HEREUNDER, OR WITH RESPECT TO ANY COMPOUNDS OR PRODUCTS. WITHOUT
LIMITING THE FOREGOING, CADENCE MAKES NO EXPRESS OR IMPLIED WARRANTIES OF MERCHANTABILITY OR
FITNESS FOR A PARTICULAR PURPOSE, WITH RESPECT TO ANY LICENSE GRANTED BY CADENCE HEREUNDER, OR WITH
RESPECT TO ANY COMPOUNDS OR PRODUCTS. FURTHERMORE, NOTHING IN THIS AGREEMENT SHALL BE CONSTRUED AS
A REPRESENTATION OR WARRANTY BY CADENCE THAT ANY OF THE FOREGOING IS VALID OR ENFORCEABLE OR THAT
BMS’S USE THEREOF CONTEMPLATED HEREUNDER DOES NOT INFRINGE ANY PATENT RIGHTS OR OTHER INTELLECTUAL
PROPERTY RIGHTS OF ANY THIRD PARTY.

     6.6 LIMITATION OF LIABILITY. NOTWITHSTANDING ANYTHING IN THIS AGREEMENT OR OTHERWISE,
(I) NEITHER PARTY SHALL BE LIABLE TO THE

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OTHER (OR TO ANY INDEMNIFIED PARTIES) WITH RESPECT TO ANY
SUBJECT MATTER OF THIS AGREEMENT, WHETHER UNDER ANY CONTRACT, NEGLIGENCE, STRICT LIABILITY OR OTHER
LEGAL OR EQUITABLE THEORY, FOR ANY INCIDENTAL,
INDIRECT, SPECIAL, EXEMPLARY, PUNITIVE, MULTIPLE, OR CONSEQUENTIAL DAMAGES (INCLUDING LOST
PROFITS, LOSS OF USE, DAMAGE TO GOODWILL, OR LOSS OF BUSINESS), EXCEPT THAT SUCH LIMITATION SHALL
NOT APPLY TO (A) PUNITIVE OR CONSEQUENTIAL DAMAGES PAID OR PAYABLE TO A THIRD PARTY BY AN
INDEMNIFIED PARTY FOR WHICH THE INDEMNIFIED PARTY IS ENTITLED TO INDEMNIFICATION HEREUNDER, (B) A
BREACH OF THE [***] COVENANT, (C) ANY FAILURE BY CADENCE OR ITS AFFILIATED COMPANIES TO (1) OBSERVE
OR COMPLY WITH THE TERMS OF THE PHARMATOP LICENSE AGREEMENT OR (2) PERFORM ANY OF THE OBLIGATIONS
UNDER THE PHARMATOP LICENSE AGREEMENT ASSUMED BY CADENCE HEREUNDER THAT, IN THE CASE OF EACH OF
PART (1) AND (2) OF THIS CLAUSE (C) RESULTS IN A TERMINATION OF THE PHARMATOP LICENSE AGREEMENT
WITH RESPECT TO ANY COUNTRY IN THE TERRITORY OR A TERMINATION OF THE PHARMATOP LICENSE AGREEMENT IN
ITS ENTIRETY, (D) ANY BREACH OF THE PHARMATOP LICENSE AGREEMENT BY BMS OR ITS AFFILIATED COMPANIES
(OTHER THAN WITH RESPECT TO ANY OBLIGATION TO BE PERFORMED BY CADENCE) THAT RESULTS IN A
TERMINATION OF THE PHARMATOP LICENSE AGREEMENT WITH RESPECT TO ANY COUNTRY IN THE TERRITORY OR A
TERMINATION OF THE PHARMATOP LICENSE AGREEMENT IN ITS ENTIRETY OR (E) ANY BREACH OF [***] OF THIS
AGREEMENT BY BMS OR ITS AFFILIATED COMPANIES OR OF [***] OF THIS AGREEMENT BY CADENCE OR ITS
AFFILIATED COMPANIES AS TO WHICH CADENCE OR BMS, AS THE CASE MAY BE, TERMINATES THIS AGREEMENT
PURSUANT TO SECTION 8.3(B) (IT BEING UNDERSTOOD THAT A BREACH OF ANY OF SUCH SECTIONS IS NOT
NECESSARILY A MATERIAL BREACH THAT WOULD PERMIT TERMINATION UNDER SECTION 8.3(B)), AND (II) EXCEPT
AS PROVIDED IN [***] ABOVE, BMS SHALL NOT BE LIABLE IN RESPECT OF ANY BREACH OF ANY REPRESENTATION
OR WARRANTY OF BMS CONTAINED IN THIS AGREEMENT IN AN AMOUNT GREATER THAN THE AMOUNTS PAID BY
CADENCE TO BMS UNDER SECTION 4.1 OF THIS AGREEMENT.

ARTICLE VII – INDEMNIFICATION; ARBITRATION

     7.1 Mutual Indemnification. Each Party (the “Indemnifying Party”) shall indemnify,
defend and hold harmless the other Party, its Affiliated Companies and their respective directors,
officers, employees, and agents and their respective successors, heirs and permitted assigns (the
“Indemnitees”), against any liability, damage, loss or expense (including reasonable attorneys’
fees and expenses of litigation) (collectively, but subject to Section 6.6 hereof, “Losses”)
incurred by or imposed upon the Indemnitees, or any one of them arising out of or resulting from
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               (i) any breach of any representation or warranty of the Indemnifying Party contained in this
Agreement; and

(ii) any breach of any covenant or agreement of the Indemnifying Party contained in this Agreement.

     7.2 Additional Indemnification Obligations of Cadence. Without limiting its
obligations under Section 7.1, Cadence further agrees to indemnify, defend and hold harmless BMS,
its Affiliated Companies and their respective directors, officers, employees, and agents and their
respective successors, heirs and assigns (the “BMS Indemnitees”), against any Losses payable by the
BMS Indemnitees, or any one of them, to any Third Party arising out of or resulting from (or
alleged to arise out of or result from) (A) any breach of the Pharmatop License Agreement (other
than a breach by Pharmatop) resulting from (i) any failure of Cadence or any of its Affiliated
Companies, sublicensees, contractors or agents to perform, observe or comply with any provision of
the Pharmatop License Agreement that relates to the Territory (except to the extent that a breach
by BMS of its obligations under this Agreement or the Pharmatop License Agreement or any other act
or omission by BMS prevents such performance, observance or compliance by Cadence or its Affiliated
Companies, sublicensees, contractors or agents) or (ii) the exercise by Cadence or its Affiliated
Companies, sublicensees, contractors or agents of the BMS Rights sublicensed to Cadence under this
Agreement, (B) the development of Products by or on behalf of Cadence or any of its Affiliated
Companies or sublicensees for the Territory or any other jurisdiction as to which Cadence or any of
its Affiliated Companies has or may acquire rights with respect to Products, (C) the marketing,
promotion, sale, use, consumption of, or exposure to, Products in the Territory or any such other
jurisdiction, (D) the manufacturing (other than pursuant to the Clinical Supply Agreement) of
Products for sale, use or consumption in the Territory or any such other jurisdiction, (E) the use
by Cadence and its Affiliated Companies or any of its or their sublicensees, contractors or agents
of BMS’s Product Data, Other Product Data or Regulatory Filings or other data, information,
records, filings or Confidential Information that BMS provides to Cadence pursuant to this
Agreement or (F) any failure by Cadence and its Affiliated Companies and its and their sublicensees
to comply with Applicable Law in connection with the development and commercialization (including
the manufacture, marketing, promotion and sale) of the Products hereunder.

7.3 Additional Indemnification Obligations of BMS. Without limiting its obligations under
Section 7.1, BMS further agrees to indemnify, defend and hold harmless Cadence, its Affiliated
Companies and their respective directors, officers, employees, and agents and their respective
successors, heirs and assigns (the “Cadence Indemnitees”), against any Losses payable by the
Cadence Indemnitees, or any one of them, to any Third Party arising out of or resulting from (or
alleged to arise out of or result from) (A) any breach of the Pharmatop License Agreement (other
than a breach by Pharmatop or a failure by Cadence or any of Cadence’s Affiliated Companies or any
of their sublicensees, contractors or agents to perform, observe or comply with any of the
provisions of the Pharmatop License Agreement, except to the extent that a breach by BMS of its
obligations under this Agreement or the Pharmatop License Agreement or any other act or omission by
BMS prevents such performance, observance or compliance by Cadence or its Affiliated Companies,
sublicensees, contractors or agents) resulting from (i) any
failure of BMS or any of its Affiliated Companies or its or their sublicensees (other than
Cadence), contractors or agents to perform, observe or comply with
any provision of the Pharmatop
License Agreement

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that relates to the Territory (except to the extent such failure results from any
act or omission of Cadence and its Affiliated Companies, sublicensees contractors and agents to
perform, observe or comply with any provision of the Pharmatop License Agreement that relates to
the Territory or with this Agreement), (B) any breach of the Pharmatop License Agreement by BMS or
any of its Affiliated Companies or its or their sublicensees (other than Cadence), contractors or
agents that arises out of activities of BMS or any of its Affiliated Companies or its or their
sublicensees (other than Cadence) outside the Territory, (C) the exploitation (including the
import, use, manufacture, sale and offer for sale) of the Products by BMS or any of its Affiliated
Companies or its or their sublicensees (other than Cadence), contractors or agents outside the
Territory or inside the Territory pursuant to the rights retained by BMS under this Agreement, (D)
the exploitation (including the import, use, manufacture, sale and offer for sale) of the Products
by BMS or any of its Affiliated Companies or its or their sublicensees (other than Cadence),
contractors or agents inside the Territory prior to the Effective Date or (E) the use by BMS and
its Affiliated Companies or any of its or their sublicensees (other than Cadence), contractors or
agents of Cadence’s Product Data, Other Product Data or Regulatory Filings or other data,
information, records, filings or Confidential Information that Cadence provides to BMS pursuant to
this Agreement.

     7.4 Conditions to Indemnification; Third Party Claims. Subject to Article 12 of the
Pharmatop License Agreement, to the extent applicable, a Party seeking indemnification under this
Article VII (the “Indemnified Party”) with respect to any claim brought by any Third Party shall
give prompt notice of the claim to the Indemnifying Party and, provided that the Indemnifying Party
is not contesting the indemnity obligation, shall permit the Indemnifying Party to control and
assume the defense of any litigation relating to such claim and disposition of any such claim
unless the Indemnifying Party is also a party (or likely to be named a party) to the proceeding in
which such claim is made and the Indemnified Party gives notice to the Indemnifying Party that it
may have defenses to such claim or proceeding that are in conflict with the interests of the
Indemnifying Party, in which case the Indemnifying Party shall not be so entitled to assume the
defense of the case. If the Indemnifying Party does assume the defense of any claim or proceeding,
it (i) shall act diligently and in good faith with respect to all matters relating to the
settlement or disposition of any claim as the settlement or disposition relates to Parties being
indemnified under this Article VII, (ii) shall cause such defense to be conducted by counsel
reasonably acceptable to the Indemnified Party and (iii) shall not settle or otherwise resolve any
claim without prior notice to the Indemnified Party and the consent of the Indemnified Party if
such settlement involves anything other than the payment of money by the Indemnifying Party. The
Indemnified Party shall cooperate with the Indemnifying Party in its defense of any claim for which
the Indemnifying Party has assumed the defense in accordance with this Section 7.4, and shall have
the right (at its own expense) to be present in person or through counsel at all legal proceedings
giving rise to the right of indemnification.

     7.5 Insurance. Cadence shall, beginning with the initiation of its first clinical
trial for a Product, maintain at all times thereafter during the term of
this Agreement, and until the later of (i) [***] ([***])[***] after termination or expiration
of this Agreement or (ii) the date that all statutes of limitation covering claims or suits that
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the sale or use of a Product have expired in all
countries in the Territory, comprehensive general liability insurance from a recognized,
creditworthy insurance company having an Excellent rating (A rating or above by A.M. Best), a
financial performance rating of at least Strong (A rating or above by A.M. Best) and an A.M. Best
Class Size of at least VIII, on a claims-made basis, with endorsements for contractual liability
and product liability, and with coverage limits of not less than [***] ([***]) per occurrence and,
[***], [***]([***])in the aggregate or, [***], [***]([***]) in the aggregate and which shall name
BMS as an “additional insured” thereunder. The minimum level of insurance set forth herein shall
not be construed to create a limit on Cadence’s liability hereunder. Within [***]([***])[***]
following written request from BMS, Cadence shall furnish to BMS a certificate of insurance
evidencing such coverage as of the date. Cadence shall provide BMS with not less than [***]([***])
days’ prior written notice of any modification or cancellation of coverage by Cadence and shall
provide written notice to BMS not less than [***]([***])[***] after receiving notice from its
insurer (or insurance broker) of any modification or cancellation of coverage by the insurer. In
the case of a modification or cancellation of such coverage, Cadence shall promptly provide BMS
with a new certificate of insurance evidencing that Cadence’s coverage meets the requirements in
the first sentence of this Section. The collection by BMS of any proceeds under any such insurance
policy shall not affect BMS’s right to obtain indemnification or other remedies under this
Agreement, except to the extent that the collection of such proceeds reduces BMS’s Losses, and the
assertion by BMS of a claim under any such insurance policy shall not impair BMS’s right to assert
a claim against Cadence or any other Person for indemnification or otherwise pursuant to this
Agreement.

     7.6 Arbitration. Except as set forth in Section 7.7, any controversy or claim arising
out of or relating to this Agreement or the validity, inducement or breach thereof (a “Dispute”)
shall be settled by binding arbitration as follows:

     (a) A Party may submit such Dispute to arbitration by notifying the other Party, in
writing, of such Dispute and demanding arbitration of such Dispute in accordance with this
Section 7.6. Any such Dispute shall, except as provided herein, be finally resolved under
the Rules of Arbitration of the International Chamber of Commerce (the “ICC”) before an
arbitration tribunal of three (3) arbitrators appointed and ruling in accordance with such
Rules of Arbitration (the “Rules”), except where the Rules conflict with this Section 7.6,
in which case this Section shall control. Each of the arbitrators shall be an attorney who
has at least fifteen (15) years of experience with a law firm or corporate law department of
over twenty-five (25) lawyers or a judge of a court of general jurisdiction. The governing
law set forth in Section 9.8 shall govern any such proceedings, unless otherwise required by
Section 7.7. The language of the arbitration shall be English.

     (b) Within thirty (30) days after the designation of the arbitrator, the arbitrator and
the Parties shall meet, and each Party shall provide to the arbitrator a written summary of
all disputed issues, such Party’s position on such disputed issues and such Party’s proposed
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     (c) The arbitrator shall set a date for a hearing, which shall be no later than thirty
(30) days after the submission of written proposals pursuant to Section 7.6(b), for the
presentation of evidence and legal argument concerning each of the issues identified by the
Parties. The Parties shall have the right to be represented by counsel.

     (d) The arbitrator shall use his or her best efforts to rule on each disputed issue
within thirty (30) days after completion of the hearing described in Section 7.6(c). The
determination of the arbitrator as to the resolution of any dispute shall be binding and
conclusive upon all Parties. All rulings of the arbitrator shall be in writing and shall be
delivered to the Parties except to the extent that the Rules provide otherwise. Nothing
contained herein shall be construed to permit the arbitrator to award punitive, exemplary or
any similar damages.

     (e) [***].

     (f) Any arbitration pursuant to this Section 7.6 shall be conducted in Chicago,
Illinois or, if such arbitration includes Pharmatop as contemplated by Section 7.7, Paris,
France. Any arbitration award may be entered in and enforced by any court with
jurisdiction.

     (g) The Parties acknowledge and agree that the breach by any Party of the provision of
this Agreement related to the protection of trade secrets or confidentiality would not be
fully compensable by money damages and would result in irreparable harm to the other Party.
Notwithstanding anything in this Article 7, each Party shall have the right to seek
injunctive or other equitable relief from a court of competent jurisdiction that may be
necessary to avoid irreparable harm, maintain the status quo or preserve the subject matter
of the arbitration, including any breach or threatened breach of Section 5.1 or 5.2.

     7.7 Pharmatop Arbitration. In the event of any controversy or claim between Pharmatop
and BMS relating to or affecting the rights thereunder with respect to the Territory arising out of
or relating to the Pharmatop License Agreement or the performance by Cadence of its obligations
under this Agreement or the Pharmatop License Agreement that is the subject of an arbitration
proceeding pursuant to Section 13.1 of the Pharmatop License Agreement, Cadence agrees that, if
requested by BMS (or if requested by Cadence to the extent such proceeding relates to the
Territory) and to the extent permitted by the Pharmatop License Agreement or by Pharmatop or the
arbitrators, (i) Cadence will (if requested by BMS) join in and participate in such proceeding;
(ii) if requested by Cadence with respect to any such proceeding that relates to the Territory, BMS
shall use reasonable efforts to seek to include Cadence in such proceeding, and (iii) if Cadence
participates or is included in such proceeding, any controversy or claim between BMS and
Cadence relating thereto shall be settled by arbitration in such proceeding to the extent possible
rather than in a proceeding under Section 7.6. In the event of any controversy or claim between
Pharmatop and Cadence arising out of or relating to the Pharmatop License Agreement or the
performance by Cadence of its obligations under this Agreement or the Pharmatop License Agreement
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pursuant to Section 13.1 of the Pharmatop License
Agreement or otherwise, BMS shall be entitled to participate in such proceeding, and to the extent
permitted by the Pharmatop License Agreement or by Pharmatop or the arbitrators, any controversy or
claim between BMS and Cadence relating thereto shall be settled by arbitration in such proceeding.
In the event BMS reasonably believes that the participation of Pharmatop in any arbitration
proceeding between BMS and Cadence pursuant to Section 7.6 would facilitate the orderly resolution
of such Dispute, BMS shall be entitled to have Pharmatop participate in such arbitration
proceeding.

ARTICLE VIII – TERM AND TERMINATION

     8.1 Term. This Agreement shall commence as of the Effective Date and, unless sooner
terminated in accordance with the terms hereof or by mutual written consent, shall expire in each
country in the Territory, on a country-by-country basis, upon the expiration of both the Royalty
Term and BMS Patent Royalty Term in such country.

     8.2 Automatic Termination. This Agreement shall terminate automatically in the event
of the termination of the Pharmatop License Agreement. In the event of a partial termination of
the Pharmatop License Agreement, this Agreement shall terminate in respect of the rights so
terminated under the Pharmatop License Agreement.

     8.3 Termination by Either Party. Either Party shall have the right to terminate this
Agreement on a country-by-country basis (except that any termination with respect to the United
States shall also apply to Canada), at its sole discretion, upon delivery of written notice to the
other Party, upon the occurrence of any of the following:

     (a) the Bankruptcy of the other Party; and

     (b) a material breach of this Agreement by the other Party with respect to any country
in the Territory (or, in the case of any covenant that is qualified by materiality, any
breach) that is not cured within the Specified Number of Days (as defined below) after
written notice of such breach is given; provided that such additional cure period shall not
apply to any breach of Section 5.5; and provided, further that the Parties acknowledge that
a series of breaches which are immaterial individually may, when considered in the
aggregate, result in a material breach and that such opportunity to cure shall run in
respect of each such immaterial breach from the date that the Party seeking to terminate has
given notice of such material breach.

          As used herein “Specified Number of Days” means ninety (90) days (or 180 days in the case of
a termination based on the second proviso of the first paragraph of this Section 8.3(b)), except
that:

          (i) if
[***]1 have not occurred:

               (A) [***],

 

			
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               (B)
[***]2 and

               (C) [***];

          (ii) if the [***] has occurred, the Specified Number of Days shall be
[***]([***])[***]; and

          (iii) if the [***] has occurred, the Specified Number of Days shall be
[***]([***])[***].

     8.4 Termination by BMS. BMS shall have the right to terminate this Agreement, at
BMS’s sole discretion, upon delivery of written notice to Cadence, upon the occurrence of any of
the following:

          (a) the failure of Cadence or any of its Affiliated Companies, sublicensees, contractors or
agents to perform, observe or comply with any provision of the Pharmatop License Agreement that
relates to the Territory, the BMS Rights or the exercise of the rights sublicensed or licensed to
Cadence under this Agreement or any other act or omission of Cadence or any of its Affiliated
Companies or any of their sublicensees, contractors or agents that results in a material breach of
the Pharmatop License Agreement or would permit Pharmatop to terminate, or exercise a right of
rescission with respect to, the Pharmatop License Agreement (except to the extent that a breach by
BMS of its obligations under this Agreement or any other act or omission by BMS prevents such
performance, observance or compliance by Cadence or its Affiliated Companies, sublicensees,
contractors or agents);

          (b) the failure of Cadence to deliver to BMS any of the reports, statements or other
information required to be delivered to BMS pursuant to Section 3.2(e) which failure is not cured
within the ten (10) Business Day period provided for in such Section.

     8.5 Termination by Cadence.

     (a) Upon the occurrence of any of the following, Cadence shall have the right to terminate
this Agreement on a country-by-country basis (except that, unless otherwise specifically provided
herein, any termination with respect to the United States shall also apply to
Canada), at Cadence’s sole discretion, upon delivery prior written notice to BMS of not less
than (A) thirty (30) days’ more notice than is required under the Pharmatop License Agreement or
(B) ninety (90) days if no notice period is specified under the Pharmatop License Agreement:

     (i) the occurrence after the Effective Date of an event that relates to the Territory
and would entitle BMS to terminate the Pharmatop License Agreement pursuant to Section 5.3,
6.2(a), 6.2(b), 6.3(a) or 6.3(b) thereof, whether or not BMS exercises such right of
termination; provided, however, that if such right of termination relates only to a specific
country in the Territory then the right of Cadence to terminate this Agreement shall apply
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event would permit a reduction
in the royalty payable to Pharmatop under the Pharmatop License Agreement and Cadence elects
to pay such reduced royalty, then Cadence shall not have any right to terminate this
Agreement as a result of such event; or

     (ii) a failure by Pharmatop to perform any of its material obligations under the
Pharmatop License Agreement with respect to the Territory that would permit BMS to terminate
the Pharmatop License Agreement with respect to the Territory and is not cured within any
cure period applicable under the Pharmatop License Agreement; provided that if such right of
termination relates only to a specific country in the Territory then the right of Cadence to
terminate this Agreement shall apply only to such country.

     (b) If
the [***]3 Date occurs, Cadence may terminate this Agreement upon
not less than ninety (90) days’ prior written notice to BMS.

     8.6 Scope of Termination. Except as otherwise provided in this Agreement, any
termination of this Agreement pursuant to this Article 8 shall be as to all countries in the
Territory and all Products, except that in the event of a termination at the election of a Party
the terminating Party may elect by written notice to the other Party to have such termination apply
in respect to one (but not both) of the countries in the Territory, as designated by such Party in
such notice, in which case the rights and obligations of the Parties as to the remaining country of
the Territory shall be unaffected by such termination as to the non-terminated country; provided,
however, that, except for a termination pursuant to Section 8.5(ii), any termination with respect
to the United States shall also apply to Canada.

     8.7 Effect of Termination. Upon termination of this Agreement with respect to any
country or all countries in the Territory:

          (a) All rights and licenses granted to Cadence in Article 2 and Sections 3.5, 3.6 and 3.7
shall terminate with respect to each terminated country and all rights of Cadence under the BMS
Rights and the Pharmatop License Agreement, the BMS Patents and BMS Know-How shall revert to BMS,
and Cadence shall cease all use of the BMS Rights, BMS Patents and BMS Know-How with respect to
each terminated country, provided that, to the extent permitted by the Pharmatop License Agreement
and unless this Agreement is terminated as a result of a breach or failure to comply by Cadence or
any of its Affiliated Companies or their
sublicensees, contractors or agents to comply with the terms and conditions of this Agreement
or the Pharmatop License Agreement, Cadence shall have the right for one hundred eighty (180) days
after such termination to sell off any Products already manufactured or ordered pursuant to
non-cancelable purchase orders. All Net Sales of such sold off Products shall be subject to the
Royalty payments provided for in Article IV.

          (b) Cadence shall assign to BMS or BMS’s designee free of charge all INDs, NDAs and other
Regulatory Filings, Product Data, Other Product Data and Approvals owned or Controlled by Cadence
relating to the Products (and all of Cadence’s right, title and interest therein and thereto) in
each terminated country, and Cadence shall provide to BMS or BMS’s

 

			
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designee free of charge one (1)
copy of all documents and filings contained in or referenced in any such filings, together with the
raw and summarized data for any preclinical and clinical studies of the Products. Cadence shall
take such actions with the applicable Drug Regulatory Authorities in each terminated country to
transfer ownership and control of such Regulatory Filings to BMS not later than five (5) days after
such termination.

          (c) Cadence shall transfer to BMS or BMS’s designee free of charge all Product Data, Other
Product Data and other data generated in connection with any preclinical studies, clinical trials
and other studies conducted by or on behalf of Cadence and its Affiliated Companies relating to the
Products and within forty-five (45) days after such termination shall transfer to BMS or BMS’s
designee copies of all Regulatory Filings with Drug Regulatory Authorities in the terminated
countries with respect to Products, rendered PDF copies of the applicable clinical study reports
(and the appendices, tables, listings and graphs therein), the SAS data sets containing the raw
data from the applicable clinical studies. If Cadence maintains such Product Data, Other Product
Data and other data in electronic form, Cadence shall provide it to BMS or BMS’s designee in
electronic form, but Cadence shall have no obligation to reformat or otherwise alter or modify any
materials or to create or recreate any such materials in electronic form in order to provide them
to BMS.

          (d) Cadence shall disclose to BMS in writing its manufacturing patents, processes, techniques
and trade secrets for making the Products and BMS shall automatically have a fully paid up,
exclusive, perpetual, worldwide, transferable, sublicensable right and license under know-how and
patents Controlled by Cadence and its Affiliated Companies relating to any composition,
formulation, method of use or manufacture of any Product solely for using, importing, making,
having made, selling and offering for sale Products outside the Territory and in each terminated
country.

          (e) Cadence shall assign (or, if applicable, cause its Affiliated Company to assign) to BMS or
BMS’s designee free of charge all of Cadence’s (and such Affiliated Companies’) right, title and
interest in and to any registered or unregistered trademark, trademark application, trade name or
internet domain name that is specific to a Product in each terminated country (it being understood
that the foregoing shall not include any trademarks or trade names that contain the name
“Cadence”).

          (f) Cadence shall assign to BMS or BMS’s designee free of charge all of Cadence’s right, title
and interest in any inventions owned by it pursuant to Section 2.7 (and any
patent applications filed thereon and patents issued thereon) pertaining to the composition of
matter or method of use or utility of any Product in each terminated country

          (g) BMS shall be entitled to retain all amounts previously paid to BMS by Cadence under this
Agreement.

          (h) Neither Party shall be relieved of any obligation that accrued prior to the effective date
of such termination or expiration, including any obligation of Cadence with respect to any amount
due or payable to BMS that accrued or that arises out of acts or events occurring prior to the
effective date of termination.

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          (i) Unless such termination was as a result of a breach of this Agreement by Cadence or any of
its Affiliated Companies, sublicensees, agents or contractors or a failure of Cadence or any of its
Affiliated Companies, sublicensees, agents or contractors to comply with or observe the terms of
the Pharmatop License Agreement or a termination by Cadence pursuant to Section 8.5, Cadence shall
have, unless the License has been terminated pursuant to Section 2.17(b), a fully paid up,
perpetual, noncancelable and non-exclusive license (A) under the BMS Know-How, with the right to
sublicense as provided in Section 2.4, to make and have made the Products anywhere in the world
solely for use and sale within the Territory, (B) under the BMS Patents, with the right to
sublicense as provided in Section 2.4, to import, use, sell and offer for sale Products in the
Territory and (C) under the BMS Patents, with the right to sublicense as provided in Section 2.4,
to make and have made the Products in the Territory solely for use and sale within the Territory;
provided, however, that the licenses granted in clauses (B) and (C) of this paragraph shall not
grant any right to the composition of matter of any Other Chemical Entity, or the right to make or
have made any Other Chemical Entity or to any use not claimed by the BMS Patents.

          (j) Notwithstanding the foregoing, in the event this Agreement terminates as the result of the
termination of the Pharmatop License Agreement as the result of a material breach of that agreement
by BMS (that is not the result of a breach of this Agreement by Cadence or any of its Affiliated
Companies, sublicensees, agents or contractors or a failure of Cadence or any of its Affiliated
Companies, sublicensees, agents or contractors to comply with or observe the terms of the Pharmatop
License Agreement), the assets to be transferred and information to be disclosed to BMS or its
designee pursuant to Sections 8.7(b), (c), (d), (e) and (f) shall not be transferred or disclosed
to BMS or its designee but shall, at on the written request of BMS, be transferred to Pharmatop;
provided, however, that (1) BMS shall have the right upon its request to have such assets
transferred, and such information disclosed, to it or its designee on terms to be agreed by BMS and
Cadence and (2) if Cadence obtains any damages or other remedy in respect of its cost of producing
or obtaining such assets and information, such assets shall be transferred, and such information
shall be disclosed, to BMS or its designee.

          (k) The Parties hereto recognize that the assets to be assigned and transferred to BMS or its
designee (or to Pharmatop or its designee) pursuant to this Section 8.7 are unique and are not
available on the open market and that any breach of the terms of this Section 8.7 would give rise
to irreparable harm for which money damages would not be an adequate remedy. Accordingly, the
Parties agree that, in addition to all other remedies available to it, BMS shall be entitled to
enforce the terms of this Section 8.7 by a decree of specific performance, without the
necessity of proving the inadequacy as a remedy of money damages. In the event of failure to
obtain such assignment, Cadence hereby consents and grants to BMS and its designee the right to
access and reference (without any further action required on the part of Cadence, whose
authorization to file this consent with any Regulatory Authority is hereby granted) any and all
such Regulatory Filings, Product Data, Other Product Data, information and Approvals for any
regulatory or other use or purpose in each terminated country.

     8.8 Transition. Upon termination of this Agreement with respect to any country or all
countries in the Territory, all actions then being controlled or undertaken by Cadence with respect
to the applicable terminated countries in the Territory shall revert to the control of BMS or its
designee, and Cadence and BMS (or BMS’s designee) shall cooperate and use

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commercially reasonable
efforts to effect an orderly transfer and transition of such activities to BMS or its designee, and
Cadence shall take any reasonable action requested by BMS to facilitate such transition. BMS and
Cadence shall endeavor to effect such transition as promptly as reasonably practicable.

     8.9 Survival. The following provisions shall survive termination or expiration of
this Agreement, as well as any other provisions which by their nature are intended to survive
termination or expiration: Section 2.8(c), BMS’s rights of use and reference set forth in Section
2.9, Section 2.15, Section 4.8, Section 5.1, Section 5.2, Section 5.3, Section 6.6, Article 7
(other than Section 7.5), Article 8 and Article 9.

     8.10 Bankruptcy. The Parties agree that in the event a Party becomes a debtor under
Title 11 of the U.S. Code (“Title 11”), this Agreement shall be deemed to be, for purposes of
Section 365(n) of Title 11, a license to rights to “intellectual property” as defined therein.
Each Party as a licensee hereunder shall have the rights and elections as specified in Title 11.
Any agreements supplemental hereto shall be deemed to be “agreements supplementary to” this
Agreement for purposes of Section 365(n) of Title 11.

ARTICLE IX – MISCELLANEOUS

     9.1 Amendments. This Agreement may be amended only by a writing signed by each of the
Parties, and any such amendment will be effective only to the extent specifically set forth in such
writing.

     9.2 Counterparts; Facsimile Execution. This Agreement may be executed in any number
of counterparts, and by each of the Parties on separate counterparts, each of which, when so
executed, will be deemed an original, but all of which will constitute but one and the same
instrument. Delivery of an executed counterpart of this Agreement by facsimile will be equally as
effective as delivery of a manually executed counterpart of this Agreement.

     9.3 Cumulative Remedies. The rights and remedies of the Parties under this Agreement
are cumulative and not exclusive of any rights or remedies which the Parties would otherwise have.
No single or partial exercise of any such
right or remedy by a Party, and no discontinuance of steps to enforce any such right or
remedy, will preclude any further exercise thereof or of any other right or remedy of such Party.

     9.4 Entire Agreement. This Agreement and the Clinical Supply Agreement contain the
entire agreement of the Parties with respect to the transactions contemplated hereby and supersedes
all prior written and oral agreements, and all contemporaneous oral agreements, relating to such
transactions.

     9.5 Schedules. The Schedules attached to in this Agreement are an integral part
hereof and all references to this Agreement include such Schedules.

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     9.6 Force Majeure.

          (a) General. No Party shall be liable for any failure to perform its obligations under this
Agreement (other than obligations to make payments of money) to the extent such performance has
been delayed, interfered with or prevented by an event of Force Majeure, except that Pharmatop
shall not be excused from performance of any obligation under the Pharmatop License Agreement
assumed by it unless such performance is excused under such agreement

          (b) Definition. As used in this Section, “Force Majeure” means any circumstances whatsoever
which are not within the reasonable control of the Party affected thereby, including an act of God,
an act of any Governmental Entity (including any Drug Regulatory Authority), war, insurrection,
riot, strike or labor dispute, shortage of materials, fire, explosion, flood, government
requisition or allocation, breakdown of or damage to plant, equipment or facilities, interruption
or delay in transportation, fuel supplies or electrical power, embargo, boycott, order or act of
civil or military authority. The Party who declares an event of Force Majeure shall give prompt
notice to the other Party of such declaration.

          (c) Duty to Mitigate. If the performance of any obligation has been delayed, interfered with
or prevented by an event of Force Majeure, then the Party affected by such event will take such
actions as are reasonably available to remove the event of Force Majeure or to mitigate the effect
of such occurrence, except that labor disputes will be settled at the sole discretion of the Party
affected thereby.

          (d) Suspension of Certain Obligations. If an event of Force Majeure occurs, the obligations
of the Parties under this Agreement (other than obligations to make payments of money) will be
suspended during, but not longer than, the continuance of the event of Force Majeure.

     9.7 Assignment.

          (a) BMS may, without Cadence’s consent, assign or transfer all of its rights and obligations
hereunder, in connection with any transfer of all of BMS’s rights under the Pharmatop License
Agreement with respect to the Territory to any Affiliated Company of BMS
or to any Third Party (including a successor in interest); provided, that such assignee or
transferee agrees in a writing provided to Cadence to be bound by the terms of this Agreement.

          (b) Upon [***] ([***])[***] advance written notice to BMS and subject to BMS’s (and, if
required by the Pharmatop License Agreement, Pharmatop’s) prior written approval, which approval
may be withheld or granted by BMS in its sole discretion (and by Pharmatop in accordance with the
Pharmatop License Agreement), Cadence may assign or transfer all of its rights and obligations
hereunder to a Third Party [***]; provided, that such Third Party shall have agreed prior to such
assignment or transfer to be bound by the terms of this Agreement in a writing provided to BMS and
Pharmatop. Cadence may assign or transfer all of its rights and obligations hereunder without such
consent to an Affiliated Company of Cadence (so long as such assignment or transfer includes all
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manufacturing assets relating to this Agreement, and all rights and
obligations under this Agreement); provided, that such Affiliated Company shall have agreed prior
to such assignment or transfer to be bound by the terms of this Agreement in a writing provided to
BMS; and provided, further, that all such rights and obligations automatically revert to Cadence
free of any Liens in the event such company ceases to be an Affiliated Company of Cadence. For the
purposes of clarification, transfers to a successor in interest by reason of merger, consolidation
or sale of substantially all of the assets of Cadence shall be governed by Section 9.7(c).

          (c) Cadence may assign or transfer all of its rights and obligations hereunder without such
consent to a successor in interest by reason of merger, consolidation or sale of substantially all
of the assets of Cadence (and so long as such assignment or transfer includes, without limitation,
all Approvals in the Territory, all manufacturing assets relating to this Agreement, and all rights
and obligations under this Agreement); provided, that such successor in interest shall have agreed
prior to such assignment or transfer to be bound by the terms of this Agreement in a writing
provided to BMS.

          (d) Subject to the foregoing, this Agreement shall inure to the benefit of and be binding on
the Parties’ successors and permitted assigns.

          (e) Any assignment or transfer in violation of the foregoing shall be null and void and wholly
invalid, the assignee or transferee in any such assignment or transfer shall acquire no rights
whatsoever, and the non-assigning non-transferring Party shall not be required to recognize, such
assignment or transfer.

          (f) No assignment by any Party of any of its rights or obligations under this Agreement shall
relieve such Party from any of its obligations hereunder and the assignor shall remain jointly and
severally liable with the assignee for the performance of the assigned obligations.

     9.8 Governing Law. This Agreement is a contract under the laws of the State of New
York and for all purposes will be governed by, and construed and enforced in accordance with, the
laws of said State, without giving effect to any internal conflict of law rules.

     9.9 Headings. All titles and headings in this Agreement are intended solely for
convenience of reference and will in no way limit or otherwise affect the interpretation of any of
the provisions hereof.

     9.10 Notices. All notices, consents, requests, demands and other communications
required or permitted under this Agreement: (a) will be in writing; (b) will be sent by messenger,
certified or registered U.S. mail, a reliable express delivery service or facsimile (with a copy
sent by one of the foregoing means), charges prepaid as applicable, to the appropriate address(es)
or fax number(s) set forth below; and (c) will be deemed to have been given on the date of receipt
by the addressee (or, if the date of receipt is not a Business Day, on the first Business Day after
the date of receipt), as evidenced by (i) a receipt executed by the addressee (or a responsible
person in his or her office), the records of the Person delivering such communication or a notice
to the effect that such addressee refused to claim or accept such communication, if sent by
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machine showing that such communication was sent to the appropriate number on a specified date, if
sent by facsimile. All such communications will be sent to the following addresses or numbers, or
to such other addresses or numbers as any Party may inform the others by giving five (5) Business
Days’ prior notice:

	 	 	 
	If to Cadence:

	 	With copies to:
	 
	 	 
	Cadence Pharmaceuticals, Inc.

	 	Cadence Pharmaceuticals, Inc.
	12730 High Bluff Drive, Suite 410

	 	12730 High Bluff Drive, Suite 410
	San Diego, CA 92130

	 	San Diego, CA 92130
	Attn: President & CEO

	 	Attn: Vice President, Business Development
	Fax No.: (858) 436-1401

	 	Fax No.: (858) 436-1401
	 
	 	 
	If to BMS:

	 	With a copy to:
	 
	 	 
	Bristol-Myers Squibb Company

	 	Bristol-Myers Squibb Company
	Route 206 & Province Line Road

	 	Route 206 & Province Line Road
	Princeton, NJ 08540

	 	Princeton, NJ 08540
	Attn: Senior Vice President –Corporate Business

          Development

	 	Attn: Vice President and SeniorCounsel, Licensing and
          Business Development
	Fax No.: (609) 252-7128

	 	Fax No.: (609) 252-4232

     9.11 Severability. Any provision of this Agreement which is prohibited or
unenforceable in any jurisdiction will, as to such jurisdiction, be ineffective to the extent of
such prohibition or unenforceability without invalidating the remaining portions hereof or
affecting the validity or enforceability of such provision in any other jurisdiction.

     9.12 No Third Party Beneficiaries. This Agreement is made solely for the benefit of
the Parties hereto and their successors and permitted assigns, and, except as specifically set
forth in this Agreement, no other Person has, or
is entitled to enforce, any rights, benefits or obligations under this Agreement. Nothing set
forth in this Agreement shall diminish, affect or impair the rights of Pharmatop under the
Pharmatop License Agreement.

     9.13 Waivers. The due performance or observance by the Parties of their respective
obligations under this Agreement will not be waived, and the rights and remedies of the Parties
hereunder will not be affected, by any course of dealing or performance or by any delay or failure
of any Party in exercising any such right or remedy. The due performance or observance by a Party
of any of its obligations under this Agreement may be waived only by a writing signed by the Party
against whom enforcement of such waiver is sought, and any such waiver will be effective only to
the extent specifically set forth in such writing.

     9.14 Documentary Conventions. As used in this Agreement, (a) whenever the context may
require, any pronoun shall include the corresponding masculine, feminine and neuter forms; (b) the
words “include,” “includes” and “including” shall be deemed to be followed by the phrase “without
limitation;” (c) the terms “hereof,” “herein,” “hereby,” “hereunder” and

66

 

derivative or similar
words refer to this entire Agreement and (d) unless otherwise specified, the terms “Section” or
“Exhibit” or “Schedule” refer to the specified Section, Exhibit or Schedule of or to this
Agreement. All references to generally accepted accounting principles shall refer to United States
generally accepted accounting principles, and all accounting terms not defined in any agreement or
instrument shall have the meanings determined by United States generally accepted accounting
principles as in effect from time to time. References to a Person are also to its permitted
successors and permitted assigns. Unless otherwise expressly provided herein, any reference to a
statute, instrument or other agreement in this Agreement means such statute, instrument or
agreement as it may from time to time be amended, modified or supplemented, including (in the case
of agreements or instruments) by waiver or consent and (in the case of statutes) by succession of
comparable successor statutes.

     9.15. Consents and Approvals. All consents or approvals of the Parties contemplated
hereunder shall not be unreasonably withheld, delayed or conditioned unless expressly stated as
otherwise.

     9.16. Absence of Presumption. Each of the Parties acknowledges and agrees that this
Agreement has been diligently reviewed by and negotiated by and between them, that in such
negotiations each of them has been represented by competent counsel and that the final agreement
contained herein, including the language whereby it has been expressed, represents the joint
efforts of the Parties hereto and their counsel. Accordingly, in interpreting this Agreement or
any provision hereof, no presumption shall apply against any Party hereto as being responsible for
the wording or drafting of this Agreement or any such provision, and ambiguities, if any, in this
Agreement shall not be construed against any Party, irrespective of which Party may be deemed to
have authored the ambiguous provision.

     9.17. Relationship of Parties. Nothing in this Agreement shall be construed to (i)
create or imply a general partnership or joint venture
between the Parties, (ii) make either Party the agent of the other for any purpose, (iii) give
either Party the right to bind the other, (iv) create any duties or obligations between the Parties
except as expressly set forth herein (other than the implied obligation of good faith), or (v)
grant any direct or implied licenses or any other right other than as expressly set forth herein.

[REMAINDER OF PAGE INTENTIONALLY LEFT BLANK]

67

 

SIGNATURE PAGE TO IV APAP AGREEMENT

     IN WITNESS WHEREOF, the Parties have duly executed this Agreement as of the Execution Date.

	 	 	 	 	 	 	 
	 	 	BRISTOL-MYERS SQUIBB COMPANY	 	 
	 
	 	 	 	 	 	 
	 

	 	By:
	 	/s/ Tamar Howson	 	 
	 

	 	 	 	 	 	 
	 

	 	Name:
	 	Tamar Howson	 	 
	 

	 	Title:
	 	SVP, Corporate & Business Development	 	 
	 
	 	 	 	 	 	 
	 	 	CADENCE PHARMACEUTICALS, INC.	 	 
	 
	 	 	 	 	 	 
	 

	 	By:
	 	/s/ Theodore R. Schroeder	 	 
	 

	 	 	 	 	 	 
	 

	 	Name:
	 	Theodore R. Schroeder	 	 
	 

	 	Title:
	 	President and CEO	 	 

 

 

SCHEDULE 1.1

BMS PATENTS

US Patent Nos. 6,593,331 and 6,511,982

Any US Patent that issues pursuant to [***]

and any continuations, continuations-in-part, divisions, reissues, re-examinations, extensions and
renewals of any of the foregoing.

 

			
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been omitted and filed separately with the Commission. Confidential treatment
has been requested with respect to the omitted portions.

 

 

SCHEDULE 6.3(a)

PHARMATOP PATENTS

U.S. Patent 6,992,218

Canadian Patent (application) 2 415 403

U.S. Patent 6,028,222

Canadian Patent (application) 2 233 924Exhibit 10.12

 

Exhibit
10.12

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.

PHARMATOP LICENSE AGREEMENT

E-1

 

 

License
Agreement

This agreement (the “Agreement”) is entered into as of the 23rd day of December, 2002 by and
among SCR Pharmatop, a civil law partnership organized under the laws of France, having its head
office’s address at 10, Square St. Florentin, 78150 Le Chesnay, France, recorded with the Register
of Commerce and Companies of Versailles under No. 407552702 (“PHARMATOP”), and Bristol-Myers Squibb
Company, a corporation organized under the laws of the State of Delaware, USA, having its head
office’s address at 345 Park Avenue, New York, New York 10154 USA (referred to hereafter as “BMS”).

W I T N E S S E T H

WHEREAS, PHARMATOP is the owner of certain patents, patent applications, and know-how relating to
parenteral paracetamol formulations;

WHEREAS, PHARMATOP has entered into a license agreement dated April 12, 1999 on these patents,
patent applications and know-how covering a certain number of countries in Europe, Africa, the
Middle East and Asia with UPSA S.A., a subsidiary of BMS; and

WHEREAS, BMS wishes to acquire an exclusive license under such patents, patent applications, and
know-how of PHARMATOP in the Territory (as defined below), and PHARMATOP is willing to grant BMS
such an exclusive license under the terms and conditions of this Agreement.

NOW, THEREFORE, in consideration of the above premises and the covenants contained herein, the
parties agree as follows:

Article 1—Definitions

The following definitions apply for the purposes of this Agreement:

	1.1	 	The term “Affiliated Companies” shall mean any entity that directly or indirectly controls,
is controlled by or is under common control with a Party to this Agreement, and

 

 

	 	 	for such purpose “control” shall mean the power to direct or cause the direction of the
management or the policies of the entity, whether through the ownership of voting
securities, by contract or otherwise.
	 
	1.2	 	The term “Advertising and Promotion” means customary activities that are reasonably incident
to the advertising and promotion of the Product in a country in the Territory (it being
understood that Phase IV clinical studies are not part of Advertising and Promotion). The
term “Advertising and Promotional Costs” means the out-of-pocket costs and expenses paid by
BMS or its Affiliates to a Third Party (and a reasonable charge for internal copying expenses
for promotional materials).
	 
	1.3	 	The term “Calendar Quarter” shall mean each of the periods of time from (a) January 1 through
March 31; (b) April 1 through June 30; (c) July 1 through September 30; and (d) October 1
through December 31.
	 
	1.4	 	The term “Competing Product” means any one or more non-opiate analgesic
parenterally-administered liquid solution products, in a stable and readily injectible form
for the treatment of post-operative pain (but which can not be another Injectible APAP
Product). For purposes of this Agreement, [***]
shall be deemed an opiate product, the marketing of which shall not be restricted by this
Agreement in any way.

	1.5	 	The term “Derivative” of paracetamol means any compound whose chemical structure is derived
from the chemical structure for paracetamol through structural modifications and/or chemical
changes that retain those portions of paracetamol’s chemical structure that are known to
contribute materially to the activity, specificity and selectivity of paracetamol.
	 
	1.6	 	The term “Diligent Efforts” means the carrying out of obligations or tasks in a sustained
manner consistent with the efforts that BMS devotes to a product or a research, development or
marketing project of similar market potential, profit potential or strategic value resulting
from its own research efforts, based on conditions then prevailing.

 

			
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	1.7	 	The term “FDA” shall mean the U.S. FDA or corresponding administrative body in Canada,
Mexico, or in any other country elsewhere in the Territory.
	 
	1.8	 	The term “Injectible APAP Product” means any parenterally administered dosage form of
paracetamol or propacetamol, or any Derivative thereof, whether alone or in combination with
one or more other drugs (as defined, as of the Effective Date, in Section 201 of the United
States Federal Food, Drug and Cosmetic Act).
	 
	1.9	 	The term “Licensed Know-how” refers to precautions and procedures required to enable the
manufacture of the liquid paracetamol solution, stable and ready for use by injection, that
are owned by, controlled by, or licensed (with right to sublicense) to PHARMATOP at any time
during the term of this Agreement, whether or not described in the Patent and in the Patent
Applications, and that represent Confidential Information of PHARMATOP. The current said
precautions and procedures are described in Appendix 5 attached hereto, and made a
part hereof.
	 
	1.10	 	The term “Licensed Patents” shall mean (a) the Patent, (b) the Patent Applications, (c) any
other patents granted and patent applications applied for in the Territory relating to the
manufacture, formulation, use or sale of the Products that are owned by, controlled by, or
licensed to PHARMATOP during the term of this Agreement, and (d) any continuations,
continuations-in-part, divisions, reissues, re-examinations, extensions, and renewals of any
of the patent applications and patents listed in (a)-(c), and all patents which may be granted
on any patent applications in (b)-(d) in the Territory.
	 
	1.11	 	The term “Licensed Rights” shall mean the Licensed Patents and the Licensed Know-How.
	 
	1.12	 	The term “Marketing Period” shall mean, for a given country in the Territory, the period
running from the first day on which Products are sold in such country until the end of the
Agreement with respect to such country.
	 
	1.13	 	The term “NDA” shall mean a new drug application submitted to the FDA seeking approval to
manufacture, promote, market, distribute, or sell a Product in a country in the Territory.

-3-

 

	1.14	 	The term “Net Sales” shall mean the total revenue invoiced by BMS, Affiliated Companies, or
sub-licensees from the sale of a Product to independent Third Parties less the following
amounts: (a) credits, allowances and rebates to, and chargebacks from the account of, such
customers for spoiled, damaged, out-dated and returned Product; (b) trade discounts, cash
discounts, quantity discounts, rebates and other price reduction programs, and other charge
back payments; (c) sales, value-added and other similar taxes (including duties or other
governmental charges levied on, absorbed or otherwise imposed on the sales of Products
including, without limitation, governmental charges otherwise measured by the billing amount);
(d) customs duties, surcharges and other governmental charges incurred in connection with the
exportation or importation of the Product; and (e) bad debts on Product sales written off in
accordance with generally accepted accounting principles, consistently applied. For the
purposes of this definition, samples distributed by BMS, its Affiliates, or sub-licensees to
their customers free of charge, and any Product used or provided for clinical or research
purposes, shall not be included in Net Sales.
	 
	1.15	 	The term “Patent” shall mean US patent No. 6,028,222 issued on 22nd February 2000,
a copy of which is attached hereto in Appendix 1 as Exhibit A and made a part
hereof, and any patent or supplementary protection certificate that PHARMATOP may obtain that
depends on such patent or that is granted based on the Patent Applications.
	 
	1.16	 	The term “Patent Applications” shall mean (a) international patent application PCT/FR
97/01452, filed on 5th August 1997, a copy of which is attached hereto in Appendix 1
as Exhibit B, (b) international patent application PCT/FR01/01749, filed on
6th June 2001, a copy of which is attached hereto in Appendix 1 as
Exhibit C, and (c) any other patent application that PHARMATOP may file that depends
on a Patent or is based on claims contained in the patent applications specified above.
	 
	1.17	 	The term “Presentation” shall mean dosage and pharmaceutical form.

-4-

 

	1.18	 	The term “Primary Detail Equivalent (PDE)” shall mean either [***] where

	 	(a)	 	a [***] means [***]; and
	 
	 	(b)	 	a [***] means [***]; and
	 
	 	(c)	 	a [***] means [***].

	 	 	All PDEs shall be [***] and shall be reported by BMS in accordance with [***].
	 
	1.19	 	The term “Product” shall mean any parenterally administered dosage form containing
paracetamol (or any Derivative thereof) alone or in combination with one or more drugs (as
defined, as of the execution of this Agreement, in Section 201 of the United States Federal
Food, Drug and Cosmetic Act), and for which the manufacture, use or sale in a country in the
Territory (x) would otherwise infringe the Licensed Patents but for the license rights granted
to BMS in Article 2 hereof and/or (y) incorporates or uses to any material extent any Know-How
licensed to BMS under Article 2 hereof.
	 
	1.20	 	The term “Royalty Term” means, with respect to a given country in the Territory, the date
commencing with the date of first commercial sale of a Product in such country, and
terminating upon the later of (a) the date that is ten (10) years after such first commercial
sale of a Product in such country, or (b) the date that the manufacture, use or sale of a
Product in such country is no longer covered by any Valid Claim of a Licensed Patent licensed
to BMS hereunder in such country.

 

			
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	1.21	 	The term “Target Product Profile” means the target Product profile attached as
Appendix 2 hereto.
	 
	1.22	 	The term “Tax” shall mean any tax, levy, impost, duty, charge, assessment or fee of any
nature (including interest, penalties and additions thereto) that is imposed by any government
or other taxing authority.
	 
	1.23	 	The term “Territory” shall mean the United States (including Puerto Rico and all U.S.
possessions and territories), Canada and Mexico.
	 
	1.24	 	The term “Third Party” means any person or entity other than PHARMATOP, BMS, and their
respective Affiliated Companies.
	 
	1.25	 	The term “U.S. FDA” shall mean the United States Food and Drug Administration and any
successors thereto.
	 
	1.26	 	The term “Valid Claim” shall mean a claim in any unexpired issued patent that has not been
held invalid or unenforceable by a non-appealed or unappealable decision by a court or other
appropriate body of competent jurisdiction, and which is not admitted to be invalid through
disclaimer, dedication to the public, and which has not been cancelled or abandoned in
accordance with or as permitted by the terms of this Agreement or by mutual written agreement.
	 
	1.27	 	The term “Year” means, as to a given country in the Territory, the period beginning on the
date of first commercial sale of Product in such country and ending on the first March 31,
June 30, September 30 or December 31 that is closest (before or after) to the date that is
twelve months following such first commercial sale, and each twelve (12) month period
thereafter during the Royalty Term.

-6-

 

Additional defined terms are as follows:

	 	 	 	 	 
	Defined Term	 	Section in Which Defined
	Affected Country
	 	 	6.2	(a)
	Combination Product
	 	 	7.2	(b)
	Confidential Information
	 	 	10.1	 
	Grace Period
	 	 	4.6	(c)
	Guaranteed Payments
	 	 	7.3	 
	ICC
	 	 	13.1	 
	Improvement
	 	 	8.1	 
	Inspection
	 	 	7.5	(b)
	Inventors
	 	 	6.1	(a)
	NewPharm
	 	 	6.1	(a)
	Registrational Information
	 	 	3.1	 
	Retained Sum
	 	 	6.5	(a)
	Transaction
	 	 	4.6	(c)
	Transaction Date
	 	 	4.6	(c)

Article 2—License 

	2.1	 	PHARMATOP hereby grants to BMS an exclusive, royalty-bearing license, with right to
sublicense, under the Licensed Rights, to import, use, sell and offer for sale, make and have
made, Products in the Territory. Furthermore, PHARMATOP also hereby grants to BMS the right
to make and have made the Products outside the Territory for use within the Territory, subject
to the consent of UPSA S.A. for the countries for which an exclusive manufacturing right has
been granted by PHARMATOP to UPSA S.A. Except as may be otherwise agreed in writing by
PHARMATOP in its sole discretion, the license granted to BMS shall only permit it to sell
Products that are packaged, finished products ready for use, and the license shall not extend
to any sales in bulk or of semi-finished products except to BMS sublicensee(s).
	 
	2.2	 	PHARMATOP does not promise or undertake to continue its research and development work in the
field of the Licensed Rights. If, however, at its sole discretion, PHARMATOP does continue
such work, it agrees to keep BMS fully informed on the results of its work, and if it makes
any inventions or develops any Know-How relating to the Product, such inventions and know-how
will be licensed to BMS pursuant to Section 2.1.

-7-

 

	2.3	 	PHARMATOP shall not itself use the Licensed Rights in any way, directly or indirectly,
including through licenses, for the manufacture, use, importation, and/or sale of Injectible
APAP Products in the Territory. PHARMATOP covenants and warrants that it shall not develop,
manufacture, or sell, or provide any assistance to any Third Party for the purpose of
developing, manufacturing or selling, any Injectible APAP Products for use in a country in the
Territory during the Marketing Period for such country. Notwithstanding the foregoing,
PHARMATOP shall have the right to use, manufacture, sell and license the Licensed Rights in
connection with other products other than Injectible APAP Products in the Territory or any
other country where PHARMATOP has granted to BMS or one of its Affiliated Companies exclusive
rights under any of its patents and know- how to sell such products in such country, and any
such use shall not violate the exclusivity provisions of this Agreement in respect of the
Licensed Rights granted to BMS hereunder; provided, however, that PHARMATOP
shall give to BMS a right of first refusal to license the right to use, manufacture and sell
such other products in the Territory under terms and conditions proposed by PHARMATOP.
	 
	2.4	 	PHARMATOP shall not assign or sell its rights under the Licensed Rights in the Territory to a
Third Party without (a) requiring the assignee or purchaser to assume all of PHARMATOP’s
obligations under this Agreement in its own name and (b) obtaining BMS’ prior consent in
writing, which may not be unreasonably withheld so long as PHARMATOP agrees to be jointly and
severally liable with the proposed assignee/purchaser for all obligations owed BMS under the
terms of this Agreement.
	 
	2.5	 	BMS may assign its rights under this Agreement to a Third Party, in whole or in part,
provided that (i) the assignee entity expressly assumes all of BMS’ obligations under this
Agreement, unconditionally and in writing, so that it becomes directly obligated towards
PHARMATOP, (ii) BMS remains jointly obligated with the assignee entity for all of its
obligations under this Agreement; and (iii) PHARMATOP has given its prior written consent to
such assignment, which consent shall not be unreasonably withheld or delayed. BMS may also
assign or otherwise transfer this Agreement and the license granted hereby to an Affiliated
Company or successor in connection with a merger, consolidation, reorganization, or sale or
other transfer of its entire business, provided, in

-8-

 

	 	 	such case, that any such assignee or transferee has agreed in writing to be bound by the
terms and provisions of this Agreement or is so bound by operation of law.
	 
	2.6	 	BMS may grant sub-licenses to Affiliated Companies and Third Parties provided that (a) BMS
provides PHARMATOP with advance notice in writing of each sub-license, (b) no sub-license
attempts to reduce or limit any of PHARMATOP’s rights under this Agreement, (c) BMS agrees to
be liable for the actions of any sub-licensee, and (d) PHARMATOP is given the same right to
supervise the activities of the sub-licensee as it has under the terms of this Agreement to
supervise BMS’ activities. BMS’ right to grant sub-licenses in accordance with this Section
shall include the right to delegate responsibility for marketing the Products in one or more
countries in the Territory.
	 
	2.7	 	If the Products are manufactured by a company other than BMS, whether an Affiliated Company
or not, BMS must provide PHARMATOP with the identity(ies) of the manufacturer(s), and provide
proof to PHARMATOP that (a) the manufacturer(s) has been informed in writing that the products
to be made are subject to the Licensed Patents held by PHARMATOP and (b) the manufacturer(s)
has agreed to manufacture the products only pursuant to agreement with BMS and solely for the
benefit of BMS and its sublicensees. The above restrictions do not apply to raw materials,
packaging items or other incidental articles from outside suppliers, or to the performance of
packing operations in accordance with customary practices in the pharmaceutical industry.
	 
	2.8	 	Any sub-licensee hereunder shall be required to assume all of the obligations of BMS under
this Agreement with respect to the rights sublicensed. BMS will indemnify and hold PHARMATOP
harmless from the failure of any sub-licensee to perform its obligations relating to Products
in the same manner as BMS is obligated to indemnify and hold PHARMATOP harmless under this
Agreement if BMS (rather than the sublicensee) had so failed to perform. PHARMATOP shall have
the same rights to audit any sub-licensee’s activities relevant to its sublicensing agreement,
and to inspect any sub-licensee’s facilities involved in the manufacture of Products, in the
same manner as PHARMATOP has with respect to BMS’ activities and facilities hereunder.

-9-

 

	2.9	 	In the event that BMS makes sales of Products to an Affiliated Company or sub-licensee,
then, notwithstanding anything to the contrary in Section 1.14 hereof, the calculation of Net
Sales for purposes of determining royalties owed to PHARMATOP under Section 7.2 hereof shall
be based on the greater of (x) [***]
and (y) [***] [***]
	 
	2.10	 	Nothing in this Agreement shall be construed to grant a Party any rights in any intellectual
property rights, information or data owned or controlled by any other Party or its Affiliates,
except as expressly set forth in this Agreement.
	 
	2.11	 	Within [***] after the execution of this Agreement, BMS will inform PHARMATOP whether, and in
what other countries of the world where BMS does not already possess such rights, BMS is interested
in obtaining rights to develop and market the Product. If BMS notifies PHARMATOP that BMS is
interested, then the Parties will use all reasonable efforts to conclude an agreement within [***]
thereafter in which PHARMATOP grants BMS the exclusive right in such countries in which BMS
indicated an interest; provided that the Parties can agree on mutually acceptable terms and
conditions during such [***] Should any such negotiations terminate without the grant of an
exclusive license to BMS in a given country, PHARMATOP shall be free thereafter to conduct
negotiations with any Third Party and grant licenses to the Product to any Third Party in such
country; provided, however, that BMS shall be entitled to exercise a right of first
refusal with respect to any such country as follows: Before PHARMATOP may accept an offer from, or
make an offer to, a Third Party on financial terms more favorable to the Third Party, when taken as
a whole, than those last offered by PHARMATOP to BMS to acquire such rights in such country,
PHARMATOP will inform BMS of such offer and shall allow BMS a period of [***] in which to elect
whether to acquire such rights under such terms as are offered to or by PHARMATOP with the Third
Party.

 

			
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Article 3—PHARMATOP’s Rights to Information 

	3.1	 	Subject to Section 3.3, PHARMATOP shall be entitled, for the protection and advancement of
its rights in the Licensed Rights outside the Territory, to either obtain from BMS, or have
the right to reference, all information and conclusions relating to or resulting from any
analytical, galenical, stability, toxicology or pharmacokinetic work and/or clinical studies
and clinical trials conducted by BMS relating to the Products and all materials in the NDA
submitted to the U.S. FDA for the Products (collectively, the “Registrational
Information”) for the purpose of developing, manufacturing, registering, seeking marketing
approval for and selling an Injectible APAP Product in any country outside the Territory where
BMS or any of its Affiliates have not been licensed rights under any PHARMATOP patent or
know-how under a separate agreement with PHARMATOP; provided, however, that
BMS has the reciprocal right (subject to payment by BMS in the same manner as PHARMATOP is
obligated under Section 3.3) to obtain and use any such similar registrational information
obtained by PHARMATOP’s licensees with respect to the development and marketing of any such
Injectible APAP Product in any such country. Subject to Section 3.3, BMS hereby expressly
permits PHARMATOP to use the Registrational Information to attempt to secure a licensee for
the sale and use of the Products outside the Territory in which BMS or any of its Affiliates
does not have exclusive license rights under any separate agreement with PHARMATOP, provided,
that the Registrational Information is treated as Confidential Information of BMS and is
disclosed to a potential licensee only pursuant to an appropriate confidentiality agreement as
set forth in Section 3.3 and that PHARMATOP remains responsible to BMS for any breach by such
potential licensee of its confidentiality and non-use obligations.
	 
	3.2	 	Subject to Section 3.3, PHARMATOP or the licensee shall be entitled to use the
Registrational Information as part of new drug applications out of the Territory and shall
not owe any compensation to BMS for same. BMS shall have no liability or responsibility for
any use made by PHARMATOP and its licensees of the Registrational Information, and, subject
to sections 12.3 and 12.4, PHARMATOP shall indemnify,

-11-

 

	 	 	defend and hold BMS and its Affiliates harmless from any use made by PHARMATOP, its
Affiliated Companies, or its or their licensees of the Registrational Information.
	 
	3.3	 	Before PHARMATOP shall have the right to access or use any of the Registrational Information
as provided in this Article 3 for purposes of any regulatory filing, [***]
shall reimburse [***] [***] of the [***] [***] to develop or obtain the Registrational
Information. [***] shall not be required to reimburse [***] for the purpose of sharing such
Registrational Information, under agreement of confidentiality, with a Third Party to the
extent reasonably required for such Third Party to determine its interest in licensing the
Product in any countries where BMS and its Affiliates do not have license rights;
provided, that the Registrational Information to be made available to the Third Party
shall not include the actual Investigational New Drug (IND) or NDA filing, any clinical trial
or adverse event database, or any study results which have not been made publicly available or
filed to the NDA. Such sharing may include such Third Party having reasonable access to such
Registrational Information at BMS, at PHARMATOP’s expense, in order to conduct reasonably
necessary due diligence. Such Third Party shall not have access to the Registrational
Information until it shall have executed a confidentiality agreement, in form and substance
acceptable to PHARMATOP and BMS, in which BMS either is a party to the confidentiality
agreement or is entitled to enforce such confidentiality as an express third party beneficiary
thereof under the terms of the confidentiality agreement and applicable law.

Article 4—Development and use obligations 

	4.1	 	BMS shall use its Diligent Efforts to obtain NDA approvals (and other regulatory
authorizations) required to develop and market the Products in each country in the Territory.
	 
	4.2	 	Neither Party warrants, represents or guarantees that the Products will obtain NDA approvals
in the Territory.

 

			
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	4.3	 	During the preparation and pendency of the various NDAs, BMS shall advise PHARMATOP in
writing on a confidential basis at least [***] as to actions taken, or to be taken, the likely
date of presentation of NDAs, any problems encountered, and the likely date of NDA approvals.
Within [***]
after the Effective Date and thereafter [***] until NDA Approval is received in a given
country, BMS will provide an estimate of the Product development timelines in such country and
for all studies that it is then undertaking or that it plans to undertake within the following
[***] in such country and will update such timelines on a [***] basis thereafter;
provided, that it is understood that, all forecasts are estimates for review by
PHARMATOP only, are not guaranteed or warranted and may not be relied upon in any way, and,
except as permitted by Article 10, may not be disclosed to Third Parties. PHARMATOP shall
submit to BMS in writing any comments on studies or applications conducted or submitted by
BMS. BMS must reply to any such comments in reasonable detail, so that PHARMATOP can make an
assessment of BMS’ performance of its obligations with respect to this Article 4; provided
that BMS shall remain solely responsible for the development and regulatory strategy for the
Product.
	 
	4.4	 	If any matter or issue (including, but not limited to, an unexpected safety issue,
manufacturing problems or significant additional studies are required by U.S. FDA) arises
which is likely to materially obstruct or significantly delay the issue of an NDA approval
in a given country by more than [***], particularly the U.S. NDA approval, BMS must inform
PHARMATOP immediately and the parties must then consult with each other to examine and
determine whether any corrective measures should be undertaken to supplement or amend the
NDA in such country. If the proposed corrective measures are not economically or
technically viable to implement, then BMS may elect to terminate this Agreement as to such
country (and if the affected country is the United States, then it may elect to do so either
as to all countries or just the U.S.), in which case [***] all licenses and rights granted
to BMS hereunder shall immediately terminate with respect to such country(ies), and
PHARMATOP shall recover its entire freedom with respect to the Licensed Rights in such
country(ies) [***]

 

			
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	 	 	[***] (and without BMS being liable to PHARMATOP in any manner on account of such
termination) and the terms of Section 9.3(b) shall apply.
	 
	4.5	 	Once an NDA approval has been obtained, along with any other necessary approvals, BMS shall
use Diligent Efforts to market the Products in the country in which approval has been
obtained. BMS shall, at least [***],
provide to PHARMATOP a written report on the means and operations used by it to promote the
Products. Within [***] [***] [***] and thereafter [***] until the end of the Royalty Term for
a given country, BMS will provide its sales forecast for the following [***] and will update
such forecast (and provide actual sales performance results by Presentation) on a [***] basis
thereafter; provided, that it is understood that all sales forecasts are estimates for
review by PHARMATOP only, are not guaranteed or warranted and may not be relied upon in any
way, and may not be disclosed to Third Parties. On receiving these reports, PHARMATOP may ask
BMS in writing for reasonable further information and/or clarifications that directly concerns
the Product and that BMS may lawfully provide so as to enable PHARMATOP to assess BMS’
performance of its obligations under this Section.
	 
	4.6	 	 

	 	(a)	 	Except as provided in section 4.6(c), BMS agrees that, during the Marketing
Period for a given country in the Territory, it will not sell and/or market any
Injectible APAP Product other than the Product. BMS represents that it currently
has no intention of developing and/or marketing other Injectible APAP Product for
use in the Territory. For any country in the Territory where BMS is already
marketing a propacetamol product on the Effective Date of this Agreement, BMS agrees
that, subject to any legal commitments it may have to Third Parties as of the
Effective Date and consistent with any requirements of applicable law, BMS will (1)
upon launch of the Product in such country, cease active promotion and marketing of
the propacetamol product in such country and transition customers of the
propacetamol product over to the Product in a manner that does not unduly

 

			
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	 	 	 	jeopardize BMS’ customer relationships and allows for BMS’ inventory of
propacetamol products to be appropriately worked down; and (2) not sell or license
its rights to the propacetamol product to any Third Party for sale or use in such
country.
	 
	 	(b)	 	Subject to Section 7.4, nothing in this Agreement shall restrict or affect BMS’
ability to develop and market at any time during the term of this Agreement, in any
country in the Territory, one or more parenterally-administered products containing an
analgesic or an opiod (as long as such product is not another Injectible APAP Product).
BMS shall inform PHARMATOP promptly of any decision to market any parenteral opiate or
non-opiate product for the treatment of post-operative pain.
	 
	 	(c)	 	Nothing in any provision of this Agreement shall, expressly or impliedly, preclude or
restrict BMS (or any of its Affiliated Companies) in any way from (1) acquiring the voting
stock or other securities, or the assets, of any Third Party, (2) selling voting stock or
other securities, or any of their assets, to any Third Party, or (3) merging, amalgamating,
taking over or consolidating (or engaging in any similar transaction) with any Third Party
(any of the foregoing a “Transaction”), where such Third Party is developing or
marketing its own Injectible APAP Product, subject to the following: If such Third Party
becomes an Affiliated Company of BMS by reason of such Transaction and is then marketing its
own Injectible APAP Product in a country in the Territory, then BMS shall inform PHARMATOP in
writing, within [***]
after the consummation of such Transaction has been publicly announced
(“Transaction Date”), whether BMS will divest or cause the divestiture of
the competing Injectible APAP Product in such country(ies). If BMS informs
PHARMATOP that it plans to so divest, then BMS shall use commercially reasonable
efforts to divest itself of such competing Injectible APAP Product in a manner
consistent with its reasonable business judgement and to complete such divestiture
of the competing Injectible APAP Product as promptly as practicable following
notification by BMS to PHARMATOP of the decision to divest. BMS shall have

 

			
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	 	 	 	until the date that is [***] after the applicable Transaction Date to complete
such divestiture (the “Grace Period”); provided, that, so long as
BMS demonstrates to PHARMATOP’s reasonable satisfaction that BMS used commercially
reasonable efforts to effect such divestiture within such [***] Grace Period, but
was unable reasonably to effect such divestiture, then such [***] Grace Period shall
be extended for such additional [***] periods thereafter as is necessary to enable
such competing Injectible APAP Product to be in fact divested, so long as BMS
continues to demonstrate to PHARMATOP’s reasonable satisfaction that BMS is using
commercially reasonable efforts to effect such divestiture within such period, and
provided further that in no event shall the aggregate Grace Period exceed [***] BMS
shall keep PHARMATOP reasonably informed of its efforts and progress in effecting
such divestiture until it is completed. The sale, promotion or marketing of any
such competing Injectible APAP Product by BMS or any of its Affiliated Companies
within the Territory during such Grace Period pursuant to this Section 4.6(c) shall
not be grounds for termination of this Agreement under Section 4.6(a). Nothing in
this Paragraph is intended to affect BMS’ obligation to use Diligent Efforts to
market the Product during the Grace Period.
	 
	 	 	 	If BMS notifies PHARMATOP that BMS does not plan to divest the competing Injectible APAP
Product, then, BMS shall have [***] after the Transaction Date in which to sublicense or sell
the rights to the Product to a Third Party, and if BMS is unable to do so within such [***],
then PHARMATOP may terminate this Agreement with respect to the affected country(ies) at any
time thereafter upon not less than [***]
written notice to BMS and the terms of Section 9.3(b) shall apply.

	4.7	 	All INDs and NDAs for any Product shall be owned solely by BMS, and BMS shall be responsible
for all regulatory filings to be made thereto.

 

			
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Article 5—Patent Application Examination 

	5.1	 	PHARMATOP shall use its best efforts to diligently prosecute the Patent Applications and to
have the Patent Applications granted by the patent offices concerned, within the customary
timeframes. PHARMATOP agrees to keep BMS informed on the progress of the examination of the
applications; to reply diligently in consultation with BMS to comments made by the examiners
(and Third Parties where appropriate); and, to take other reasonable and customary actions to
avoid delays with the issuance of the patents or a reduction to the scope thereof.

	 	(a)	 	PHARMATOP will promptly notify BMS in writing after each Notice of Allowance
and patent issuance in the Territory. The parties will cooperate to ensure a timely
filing in the Orange Book with respect to an issued patent.
	 
	 	(b)	 	PHARMATOP and BMS will cooperate to ensure timely filings for any available
Patent Term Restoration on the Product (currently, filings must be made within 60 days
after NDA Approval).
	 
	 	(c)	 	With respect to any Patent Right filed, prosecuted or maintained by PHARMATOP,
each patent application, office action, response to office action, request for terminal
disclaimer, voluntary amendment, interference proceeding filing or action, and request
for reissue or re-examination of any patent issuing from such application shall be
provided by PHARMATOP to BMS sufficiently prior to any such application, filing or
request to allow reasonable time for adequate review and comment by BMS. PHARMATOP
will also provide BMS copies of all correspondence and other material documents
received or prepared by PHARMATOP in the prosecution, maintenance, and enforcement of
the Licensed Patent Rights.
	 
	 	(d)	 	PHARMATOP shall provide to BMS, on a quarterly basis, a written patent report
that includes the serial number, docket number and status of each Licensed Patent.

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	 	(e)	 	Within 90 days after execution of this Agreement, PHARMATOP will also ensure
that a signed and duly notarized Assignment Document, assigning the entire right,
title and interest in US Patent No. 6,028,222 from Francois Dietlin and Daniele
Fredj to SCR Pharmatop, is filed in the United States Patent and Trademark Office.
	 
	 	(f)	 	PHARMATOP will ensure that Patent Applications filed in the Territory will
include at least the same claims as filed in the PCT Applications as of the Effective
Date.

	5.2	 	PHARMATOP will, to the greatest extent practicable, prosecute the Patent Applications as
currently filed (or that will be filed in the Territory pursuant to section 5.1(f)), and
agrees not to alter the terms so as to materially narrow the scope thereof or abandon any
material pending claims unless consented to by BMS, or as otherwise is reasonable in light of
the prosecution of the Patent Applications. PHARMATOP does not guarantee to BMS that the
patents will be issued in terms similar to those of the Patent Applications. PHARMATOP will
not abandon any issued claims or admit that any such issued claims of the Patents are
unenforceable by disclaimer or otherwise, without BMS’ prior written consent.
	 
	5.3	 	During the entire period of examination of the Patent Applications, BMS will comply with all
its obligations towards PHARMATOP, including, but not limited to its financial obligations,
and shall not be entitled to suspend them on the ground that the examiners or Third Parties
have commented on or challenged the filed Patent Applications. BMS will be entitled to
terminate this Agreement with respect to a particular country, or obtain a reduction in the
royalty rate for sales therein, in accordance with Sections 6.2 and 6.3 below, as a result of
a final patent office decision that definitively rejects a Patent Application in such
country(ies).
	 
	5.4	 	 

	 	(a)	 	PHARMATOP shall pay the annual fees due to the patent offices in a timely manner to maintain
the Patents in force until their expiry. [***]
will reimburse

 

			
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	 	 	 	[***], commencing from and after the [***] of the Effective Date of this Agreement,
for its payment of the annual maintenance fees in any country in the Territory where
no Products have been sold as of the time of such payment, provided that
[***] provides proof of such payment and requests such reimbursement. For budgeting
purposes, [***] shall provide to [***], on February 1 and August 1 of each Year, a
reasonably detailed estimate of the out-of-pocket expenses it expects to incur, in
the next six (6) months, with respect to Licensed Patents.
	 
	 	(b)	 	If PHARMATOP files for and obtains new Patents in a country in the Territory
based on Inventions made after the Effective Date of this Agreement that is likely to
have the effect of extending BMS’ period of marketing exclusivity, [***] will reimburse
[***] for [***] of its costs of filing and prosecuting the corresponding patent
applications in such country, including [***] reasonable out-of-pocket legal fees and
expenses, on presentation of appropriate supporting documents; provided,
however, that (a) [***] shall not be obligated to make any such reimbursement
to [***] prior to the [***] of the Marketing Period in such country or in any year in
which an Injectible APAP Product is marketed by a Third Party in such country, and (b)
any such reimbursement paid by [***] for a given country will be returned to [***] if,
prior to the [***] of the Marketing Period in such country, an Injectible APAP Product
which does not infringe the Patents is marketed in such country.

Article 6—Additional Provisions Affecting the Patents 

	6.1	 	 

	 	(a)	 	PHARMATOP represents and warrants that Francois Dietlin and Daniele Fredj (the
“Inventors”) solely discovered or derived the inventions covered by the
Patents, as well as the Know-How embodied in the formulation of the Product, through
their own research and efforts and without misappropriating the trade secrets or
confidential information of any Third Party, and that the Inventors have

 

			
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	 	 	 	never been employed by or provided services to Fresenius. It further represents
that the portion of the inventions covered by U.S. patent No. 6,028,222 was duly
assigned by the Inventors to Newpharm, a company organized under the laws of France
having its head office’s address at 10, square St. Florentin, 78150 Le Chesnay,
France (“Newpharm”) which obtained French patent No. 2.751.875 and that
Newpharm subsequently assigned the associated ongoing research and priority rights
to PHARMATOP as set forth in the agreement attached as Exhibit D and
confirmed by Newpharm in the letter attached hereto as Exhibit E. PHARMATOP
also represents that it is the sole owner of the Licensed Rights, and otherwise has
the sole right to exclusively license and grant rights to them, and that, to the
best of its knowledge, each invention is patentable.
	 
	 	(b)	 	BMS represents that, to its knowledge as of the Effective Date, and having
examined the Patent and the Patent Applications, it has not identified, and otherwise
has no knowledge of, any reasons why the Patent might be invalid or why the Patent
Applications could not be granted under conditions enabling the license herein to be
effectively implemented.
	 
	 	(c)	 	PHARMATOP represents and warrants to BMS that: (i) there is no action, suit or
proceeding pending or threatened in writing as of the Effective Date by any Third Party
against PHARMATOP, its Affiliated Companies, or any of the Inventors named in the
Patents which, if adversely determined, would have a material adverse effect upon the
issued claims of the Patents in the Territory as of the Effective Date or upon the
issuance of any claims of the Patent Applications in the Territory as of the Effective
Date; (ii) the issued claims of the Patent in the Territory which cover the
manufacture, use, importation or sale of Product are not dominated by any issued
patents of any Third Party in the Territory; and (iii) except as disclosed in
Appendix 3 (re Fresenius), it is not aware of any infringement by any Third
Party as of the Effective Date of any of the Patents in the Territory.

	6.2	 	 

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	 	(a)	 	If PHARMATOP is:

	 	(i)	 	unable to obtain, without material alteration or restriction as
to scope and content, issuance in the Territory of the claims being prosecuted
as of the Effective Date on the PCT Patent Applications filed as of the
Effective Date; or
	 
	 	(ii)	 	unable to maintain, or a material alteration of the scope or
content occurs with respect to, any of the claims under any of the Patents
issued as of the Effective Date or on any patents issued on Patent Applications
filed as of the Effective Date;

	 	 	 	then BMS may at its option terminate this Agreement for any of the countries so affected (an
“Affected Country”), or, if the affected country is the United States, then either as to the
United States or as to all countries in the Territory. Any such termination shall require (A)
not less than [***]
prior written notice, if after [***] in the [***] or (B) not less than
[***] [***] prior written notice, if [***] in the [***].
	 
	 	(b)	 	If a Third Party should market in any country in the Territory a
parenterally-administered liquid solution product, in a stable and readily injectible
form, that (x) contains paracetamol and one or more other analgesic ingredients, (y)
uses any of the technology contained within any issued claim of any Licensed Patent in
such country or any Licensed Know-How, and (z) is not considered to infringe any Patent
within the Licensed Rights in such country (whether by judicial determination or
settlement, by joint agreement of PHARMATOP and BMS, or by both Parties failure to
prosecute such Third Party for infringement under Section 6.5), then BMS may elect to
terminate this Agreement pursuant to Section 9.3(a) for any such Affected Country, or,
if the Affected Country is the United States, then as to all countries in the
Territory.
	 
	 	(c)	 	If BMS opts to terminate this Agreement pursuant to section 6.2(a) or section
6.2(b) with respect to one or more Affected Countries, it shall be under the terms and
conditions of section 9.3(b). BMS shall not be entitled to obtain from PHARMATOP the
return of any sums paid to PHARMATOP before the date of said termination unless BMS can
establish that the refusal to issue the patent (or

 

			
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	 	 	 	the withdrawal thereof) is due to a knowingly inaccurate representation made by
PHARMATOP in Section 6.1 of this Agreement. BMS shall be permitted thereafter to
sell Products already manufactured by such termination date, provided that it pays
PHARMATOP the contractual royalties on such sales provided for in Article 7. BMS
shall not be restricted in any way thereafter from manufacturing and selling another
Injectible APAP Product in such terminated country(ies) for which the manufacture or
sale in such country (x) does not infringe the Licensed Patents and (y) does not use
to any material extent any Licensed Know-How.
	 
	 	(d)	 	In the event that BMS opts to maintain the Agreement in effect in an Affected
Country under section 6.2(a) or 6.2(b), then:

	 	(i)	 	if such Affected Country is [***], the Guaranteed Payment
provision (section 7.3) shall be [***] thereafter effective as of the [***] in
which BMS elected to maintain the Agreement and each [***]thereafter; and
	 
	 	(ii)	 	the royalty rate on all Net Sales in such country for any
quarter in a given Year will be reduced by [***] for each such quarter in
which:
	 
	 	 	 	[***]

 

			
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[***]

	6.3	 	 

	 	(a)	 	Should the Patents (or their inventorship) be the subject of an administrative
or judicial challenge by a Third Party, PHARMATOP will undertake at its expense, in
consultation and liaison with BMS, to take all appropriate measures to oppose the
challenge by the Third Party. Subject to Sections 12.3 and 12.4, PHARMATOP shall
defend, indemnify and hold harmless BMS from any liabilities, losses, costs or damages,
which shall include costs or judgements whether for money or equitable relief, and
reasonable legal expenses and reasonable attorney’s fees, arising out of any such
claims, suits or challenges. PHARMATOP shall not enter into a settlement agreement
with such Third Party without the written consent of BMS, which shall not be
unreasonably withheld. PHARMATOP shall not enter into a settlement agreement with such
Third Party without the written consent of BMS, which shall not be unreasonably
withheld. BMS shall have the right to participate and be represented in any such suit
by its own counsel at its own expense. The pendency of any administrative or judicial
claim or action by a Third Party challenging the Patents will not permit BMS to cease
or suspend its performance of its obligations under this Agreement, including its
financial obligations. If the Third Party’s claim or action succeeds so as to deprive
PHARMATOP of any of its rights on Licensed Patents in a country in the Territory, then
BMS may terminate this Agreement as to such country in the same manner as it would have
been entitled to terminate pursuant to Section 6.2(a)(ii) and 6.2(c) (with BMS
providing the same written notice of termination required thereby unless the outcome of
such Third Party’s claim or action would require BMS to cease marketing of the Product
prior to the end of the notice period) or to continue to market the Product subject to
Section 6.2(d).
	 
	 	(b)	 	In the event that PHARMATOP fails or elects not to defend any such action, suit,
or challenge, then BMS may defend such action, suit or proceeding at its own
expense, in its own name and the name of PHARMATOP, and entirely under

 

			
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	 	 	 	BMS’ own direction and control. PHARMATOP will reasonably assist BMS (at BMS’
expense) in any action or proceeding being prosecuted or defended by BMS, if so
requested by BMS or required by law. PHARMATOP shall have the right to participate
and be represented in any such suit by its own counsel at its own expense. No
settlement of any such action or defense which restricts the scope or affects the
enforceability of a Licensed Patent may be entered into by BMS without the prior
consent of PHARMATOP, which consent shall not be unreasonably withheld. If the
Third Party’s claim or action succeeds so as to deprive PHARMATOP of any of its
rights on Licensed Patents in a country in the Territory, then BMS may terminate
this Agreement as to such country in the same manner as it would have been entitled
to terminate pursuant to Section 6.2(a)(ii) and 6.2(c) (with BMS providing the same
written notice of termination required thereby unless the outcome of such Third
Party’s claim or action would require BMS to cease marketing of the Product prior to
the end of the notice period) or to continue to market the Product subject to
Section 6.2(d).

	6.4	 	PHARMATOP represents that, to its knowledge, the manufacture and sale of the Products in
Territory will not infringe any intellectual property right of any Third Parties and, subject
to sections 12.3 and 12.4, PHARMATOP will hold BMS harmless against any Third Party action or
claim asserting an infringement of such rights. In the event such an action or claim is
brought by a Third Party, then, subject to section 6.3, BMS will be obligated to continue to
perform its obligations under this Agreement, including its financial obligations.
	 
	6.5	 	 

	 	(a)	 	In the event that a Third Party is manufacturing and/or marketing anywhere in
the Territory an Injectible APAP Product for which the manufacture, use or sale
thereof infringes a Valid Claim under the Licensed Patents, the Parties shall
consult with each other in order to attempt to end such infringement, and shall take
all appropriate action to do so. BMS shall have the right in the first instance,
but not the obligation, to initiate legal action against an infringing party under
its

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	 	 	 	own direction and control. PHARMATOP will reasonably assist BMS ([***])
in any action or proceeding being prosecuted if so requested, and will
lend its name to such actions or proceedings if requested by BMS or required by law.
No settlement of any such action which restricts the scope, or adversely affects
the enforceability, of a Licensed Patent may be entered into by BMS without the
prior written consent of PHARMATOP, which consent shall not be unreasonably
withheld.
	 
	 	(b)	 	If BMS elects not to bring any action for infringement described in Section
6.5(a) and so notifies PHARMATOP in writing, then PHARMATOP may bring such action at
its own expense, in its own name and entirely under its own direction and control. BMS
will reasonably assist PHARMATOP ([***]) in any action or proceeding being prosecuted
if so requested, and will lend its name to such actions or proceedings if requested by
PHARMATOP or required by law. No settlement of any such action which restricts the
scope, or adversely affects the enforceability, of any Licensed Patent may be entered
into by PHARMATOP without the prior written consent of BMS, which consent shall not be
unreasonably withheld.
	 
	 	(c)	 	If either Party brings such an action or defends such a proceeding under this
Section 6.5 and subsequently ceases to pursue or withdraws from such action or
proceeding, it shall promptly notify the other Party and the other Party may substitute
itself for the withdrawing Party under the terms of this Section 6.5.
	 
	 	(d)	 	In the event either Party exercises the rights conferred in this Section 6.5 and
recovers any damages or other sums in such action, suit or proceeding or in
settlement thereof, such damages or other sums recovered shall first be applied to
all out-of-pocket costs and expenses incurred by the Parties in connection
therewith, including attorneys fees. If such recovery is insufficient to cover all
such costs and expenses of both Parties, it shall be shared in proportion to the
total of such costs and expenses incurred by each Party. If after such
reimbursement any funds shall remain from such damages or other sums recovered, such
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	 	 	 	shall be retained by [***];
provided, [***].

	 	(e)	 	BMS will be obliged to continue performing its obligations towards PHARMATOP
during the pendency of any legal action against a Third Party; provided,
however, that, during such period of time [***] shall pay [***] [***] of the
royalties contractually due on Net Sales in the country where the infringing injectible
APAP Product is being marketed, with the balance (the “Retained Sums”)
temporarily retained by [***] If the outcome of the litigation is the invalidation of
a Patent, the provisions of Section 6.2 will be applicable, and, if [***] elects to
continue as provided in Section 6.2(c), [***](f) Any infringement of the Patents by an
Affiliated Company of BMS whom BMS has not sublicensed shall be deemed to be a breach
of Agreement by BMS.

	6.6	 	PHARMATOP does not make any representations of warranties with respect to the Patents other
than those expressly stated in this Article 6.
	 
	6.7	 	BMS will have sole liability to Third Parties for any injuries or death caused to any person
by reasons of the manufacture, use or sale of the Products manufactured or sold pursuant to
this Agreement, and will indemnify PHARMATOP against claims by Third Parties based on product
liability as provided for in Section 12.2.
	 
	6.8	 	In the event that BMS reasonably believes after consultation with PHARMATOP that it is required
to obtain a license from a Third Party in order to practice the Licensed Patents and Know-how, then
any license fees or other royalties payable by BMS to such Third Party with respect to same shall
be [***].

 

			
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Article 7—License Fees and Royalties 

	7.1	 	BMS shall make the following lump sum, non-refundable (except as provided in section 12.3 or
as may be otherwise expressly provided in this Agreement) payments to PHARMATOP:

	 	(a)	 	Within fifteen (15) business days following execution of this Agreement, the sum of [***].
	 
	 	(b)	 	Within ten (10) business days [***], the sum of [***] This amount will be paid
only [***], [***]

	7.2	 	 

	 	(a)	 	Subject to the Guaranteed Payments provided for in Section 7.3 and to sections
6.2, 6.5(e), 6.8, 7.2(b), 7.2(c) and 12.3 hereof, BMS shall make the following royalty
payments to PHARMATOP:

	 	i.	 	[***] percent ([***]%) of the Net Sales of Products during
the [***] and [***] [***] in a given country;
	 
	 	ii.	 	[***] percent ([***]%) of the Net Sales of Products during the
[***] in a given country;
	 
	 	iii.	 	[***] percent ([***]%) of the Net Sales of Products during the
[***] in a given country; and
	 
	 	iv.	 	[***] percent ([***]%) of Net Sales of Products during the
[***], and all subsequent [***] of the Royalty Term thereafter in a given
country, unless this Agreement is sooner terminated in such country.

	 	 	 	Upon payment of all royalties due PHARMATOP in a given country through the end of
the Royalty Term for such country, BMS shall have a fully paid-up license under Section
2.1 to use the Licensed Rights in such country to develop, make, use and sell the
Products.

 

			
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	 	(b)	 	[***] then the effective royalty rate for sales of such Combination Products shall be
[***] [***]
of the royalty rate paid by BMS to such Third Party for the Combination
Product, subject to a [***] of the royalty payable to PHARMATOP of [***] BMS will
provide evidence, reasonably satisfactory to PHARMATOP, of any [***](c) [***] [***]
[***]. [***]

	7.3	 	Subject to Section 12.3 hereof, during each of the first [***] of the Marketing Period
in the United States, BMS shall pay royalties to PHARMATOP equal to the greater of (i) [***]
or (ii) the [***]do not conform in all respects [***]Further, in any quarter in any Year in
[***]

 

			
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	 	 	[***]
be multiplied by a fraction the numerator of which is [***]and the denominator of which
is the sum of the numerator plus [***]using a mutually agreed upon methodology for
calculating [***]during such quarter[***]The Parties will review the procedures[***]from
time to time to ensure that they are fair and equitable to both Parties.
	 
	7.4	 	 

	 	(a)	 	In the event that BMS markets a Competing Product in a country in the Territory
during the Royalty Term for such country, BMS agrees that:

	 	(i)	 	During the [***] period following the launch of such Competing
Product (commencing with the [***] of the [***] following such launch), BMS
will continue to provide for the Product at least [***] of the Primary Detail
Equivalents (PDEs) and will continue to spend on the Product at least [***] of
the Advertising and Promotional Costs that it spent, as determined on an [***]
for the Product during the [***] period preceding such Competing Product
launch; and
	 
	 	(ii)	 	During the [***] period following the launch of such Competing
Product, BMS will continue to provide for the Product at least [***] of the
Primary Detail Equivalents (PDEs) and will continue to spend on the Product at
least [***] of the Advertising and Promotional Costs that it spent, as
determined on an [***] for the Product during the [***] period preceding such
Competing Product launch and the [***] period following such Competing Product
launch; and
	 
	 	(iii)	 	During the [***] period following the launch of such Competing
Product, BMS will continue to provide for the Product at least [***] of the
Primary Detail Equivalents (PDEs) and will continue to spend on the Product
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	 	 	 	Advertising and Promotional Costs that it spent, as determined on an [***]
for the Product during the [***] period following such Competing
Product launch.

	 	 	 	Notwithstanding the foregoing, in the event that such Competing Product is launched
during the period that Guaranteed Payments under Section 7.3 are payable, then
subsections 7.4(a)(i)-(iii) shall not apply except with respect to those full [***]
periods following such Competing Product launch that occur after the expiration of
the payment of such Guaranteed Payments during such [***].
	 
	 	 	 	Further, this Section 7.4(a) shall only apply to the [***] Competing Product that
BMS may launch within each country in the Territory
	 
	 	(b)	 	BMS will provide PHARMATOP, within [***] [***] after the end of each [***]
period following such Competing Product launch with sufficient information regarding
BMS’ PDE detailing and Advertising and Promotional spending to enable PHARMATOP to make
a reasonable, competent assessment as to whether BMS has fulfilled its obligations
under Section 7.4(a) above.
	 
	 	(c)	 	In the event that BMS fails to fulfill any of (i), (ii) or (iii) under section 7.4(a) above,
then PHARMATOP may, upon ninety days written notice to BMS, terminate this Agreement at any
time within thirty days after PHARMATOP receives the information from BMS required for
PHARMATOP to determine that BMS has failed to fulfill such obligations, in which event [***],
all licenses and rights granted to BMS hereunder shall immediately terminate, and PHARMATOP
shall recover its entire freedom with respect to the Licensed Rights in such country [***] and
the terms of Section 9.3(b) shall apply. If PHARMATOP elects to terminate BMS’ rights, such
termination shall be PHARMATOP’s sole remedy and BMS shall not be liable for any additional
damages to PHARMATOP with respect to such failure.

 

			
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	7.5	 	 

	 	(a)	 	The contractual royalties will be calculated and will be payable quarterly for sales made in
each Calendar Quarter in the Royalty Term. A detailed statement, country by country and by
Presentation, will be prepared and sent by BMS to PHARMATOP within [***] of the end of each
Calendar Quarter ([***] [***] after the last quarter in an Agreement Year to allow for
additional time to determine any adjustments required to be made on an annual basis),
accompanied by payment of the royalties due PHARMATOP. If the annual reconciliation shows an
amount due by either Party to the other, the amount due shall be paid as follows: BMS shall
pay any amount due by it at the same time as it provides the reconciliation to PHARMATOP.
PHARMATOP shall repay any amount due by it to BMS within [***]
after the receipt by it of such reconciliation report.
	 
	 	(b)	 	PHARMATOP may, on reasonable (but not less than [***]) written notice to BMS, have a
calculation statement audited at its own expense by an accounting firm selected by PHARMATOP
that is reasonably acceptable to BMS and that is bound by a written agreement of
confidentiality to BMS. The, auditor’s assignment will be limited to reviewing the accuracy
of a calculation statement sent by BMS (the “Inspection”), and to disclosing only if
there are any errors in payment and, if an error exists, the amount of such error(s) and the
calculation thereof, and no additional or any other information. If an audit discloses that
the amount of royalties owed to PHARMATOP was understated by more than [***] [***], then [***]
must reimburse [***] for the cost of the audit, in addition to paying the additional royalties
together with interest on the additional amounts, calculated from the date on which the
additional amount should have been paid, as provided in section 7.7. Such audit rights may be
exercised [***], and any such audit shall apply [***].

 

			
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	7.6	 	BMS shall make all payments to PHARMATOP in United States Dollars by electronic funds
deposit, to a French bank and account number designated in writing by the Gerant of
PHARMATOP. Each Party shall bear its own expenses with respect to any such electronic funds
transfer. When products are sold for monies other than United States dollars, the monies
due will first be determined in the foreign currency of the country in which such products
were sold and then converted into equivalent United States currency, on a monthly basis,
using the applicable U.S. Federal Reserve rate in effect on the last business day of each
calendar month. Each quarterly Royalty Payment shall cover three (3) such monthly
conversions. PHARMATOP agrees that it will be solely responsible for all payments owed to
Newpharm or the Inventors.
	 
	7.7	 	Any amounts not paid on its due date by BMS to PHARMATOP will bear simple interest on the
outstanding balance at the [***]
the applicable period, calculated from the contractual due date until the date of payment,
without the need for a formal notice to pay or any other notice.
	 
	7.8	 	Neither the payment of interest by BMS nor the acceptance of the same by PHARMATOP shall
effect a waiver of any of PHARMATOP’s rights or remedies under this Agreement.
	 
	7.9	 	BMS shall pay any and all excise, sales, use, value added, and other similar Taxes solely
arising as a result of Product sales under this Agreement. Where required to withhold any tax
in connection with any payment hereunder to PHARMATOP due to applicable law, treaty, rule or
order of a governmental body, BMS shall deposit such taxes with the appropriate tax or revenue
authorities as a deduction from such royalty or other payment, and shall notify PHARMATOP and,
upon request of PHARMATOP, BMS shall furnish satisfactory evidence of such withholding and
payment. [***] shall not be required to gross up or reimburse [***] for any such
withholdings. BMS shall reasonably cooperate with PHARMATOP in obtaining exemption from
withholding taxes where available under applicable law. PHARMATOP shall be solely responsible
for all taxes levied on PHARMATOP’s revenues, profits or income arising out of this Agreement.

 

			
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	7.10.	 	BMS agrees that it will not engage in any fraudulent transactions relating to sales of the
Products that are specifically designed to reduce or avoid royalty payments to PHARMATOP.

Article 8—Improvements made by BMS 

BMS shall promptly inform PHARMATOP of any adaptation, improvement, enhancement or upgrade
(collectively, an “Improvement”) BMS makes with respect to the formulation and/or manufacture
of the Products, whether such Improvement can be protected by patent or not. BMS will remain
the owner of any such Improvement that it makes to the Products; provided, however, that BMS
must grant to PHARMATOP, upon request, a non-exclusive, [***]
license to practice and use the Improvement, including the right to grant sublicenses,
outside of the Territory solely in connection with the manufacture, use or sale of the Products;
provided, that any sub-licensee of such rights shall have granted reciprocal rights to PHARMATOP
which can be sublicensed to BMS.

Article 9—Term / Termination

	9.1	 	Unless terminated earlier pursuant to the terms of this Agreement, the term of this Agreement
shall run on a country-by-country basis until the end of the Marketing Period. Upon the
expiration of this Agreement in a country, BMS will have no further financial obligations
towards PHARMATOP for sales made in such country after such expiration.
	 
	9.2	 	Should either Party fail to perform any of material obligations of this Agreement, and fail
to cure such breach or default within ninety (90) days alter receiving a written notice from
the non-breaching Party specifying the breach and demanding that it be cured, then the
non-breaching Party shall have the right to terminate this Agreement; provided, that
if the material breach is restricted to a given country, termination shall be as to such
country only.
	 
	9.3	 	 

 

			
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	 	(a)	 	BMS may, in its sole discretion, terminate this Agreement at any time during the Marketing
Period with respect to a given country at any time, provided that (i) it gives written notice
at least twelve (12) months in advance, and (ii) BMS has paid all amounts due under this
Agreement as of the date of such notice. If BMS terminates this Agreement pursuant this
section 9.3(a), then BMS agrees not to market any other Injectible APAP Product in such
country for a period of [***]
following termination; provided, that this section 9.3(a) shall not apply to
any Injectible APAP product marketed by BMS (x) that is thereafter acquired by BMS or
any of its Affiliates as a result of a Transaction (as such term is defined in section
4.6(c)) that occurs following the giving of such notice of termination and which was a
marketed product of the Third Party at the Transaction Date or (y) that is marketed by
BMS in accordance with the last sentence of section 6.2(c) as a result of a termination
by BMS pursuant to section 6.2(c) or 6.3(a).
	 
	 	(b)	 	Upon the effective date of a termination by BMS pursuant to this Section 9.3,
BMS will transfer to PHARMATOP, at PHARMATOP’s expense, the NDA approvals, so that
PHARMATOP may take over, in the affected country(ies) in the Territory, the marketing
of the Products (directly or through any Third Parties of its choice). The Parties
shall in good faith consult on the procedures for this transfer of the marketing
information and contracts (covering stocks, current orders, official records, etc),
endeavoring to ensure that the marketing is disturbed, as little as possible, by the
transfer and that each Party continues to comply with its obligations under applicable
law. BMS shall also license or assign to PHARMATOP without charge any
trademark/tradename used by BMS that is specific to the Products; however, no rights
will be assigned or licensed to PHARMATOP under any names, marks, or logos used by BMS
and its Affiliates on the Product that are also used on their other products (e.g., the
Bristol-Myers Squibb name). At its option, PHARMATOP may commence marketing the
Products (directly or indirectly) at any time after its receipt of the termination
notice. The Parties agree to negotiate in good faith a smooth transition of marketing
for the Product as well as an orderly disposition of BMS’ Product inventory during the
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	9.4	 	PHARMATOP shall have the right to terminate this Agreement on ninety (90) days’ written
notice if BMS either opposes any of the Patent Applications or challenges or contests the
validity or enforceability of any of the Licensed Patents.
	 
	9.5	 	In the event that this Agreement is terminated or rejected by a Party or its receiver or
trustee under applicable bankruptcy laws due to such Party’s bankruptcy, then all rights and
licenses granted under or pursuant to this Agreement by such Party to the other Party are, and
shall otherwise be deemed to be, for purposes of Section 365(n) of Title 11 of the United
States Bankruptcy Code and any similar law or regulation in any other country, licenses of
rights to “intellectual property” as defined under Section 101(35A) of Title 11 of the
Bankruptcy Code. The Parties agree that all intellectual property rights licensed hereunder,
including without limitation any patents or patent applications in any country of a Party
covered by the license grants under this Agreement, are part of the “intellectual
property” as defined under Section 101(35A) of the Bankruptcy Code subject to the
protections afforded the non-terminating Party under Section 365(n) of the U.S. Bankruptcy
Code, and any similar law or regulation in any other country.

Article 10—Confidentiality and Publicity

	10.1	 	All information of a proprietary or confidential nature disclosed by one Party to the other
or developed by the other Party under this Agreement (“Confidential Information”)
shall be maintained in confidence, not disclosed to any Third Party, and used only for the
purposes of this Agreement. Each Party may disclose the other Party’s Confidential
Information to Affiliated Companies, agents, legal and financial representatives, or
consultants under obligations of confidentiality, non-disclosure and non-use at least
equivalent to the obligations set forth in this Article. The obligations of confidentiality,
non-disclosure and non-use set forth in this Agreement shall expire five (5) years after the
date of termination or expiration of this Agreement.
	 
	10.2	 	The obligations of confidentiality, non-disclosure and non-use set forth shall not
apply to information: (a) that was previously known to the receiving Party or any of its
Affiliated Companies free of restriction as evidenced by the records of such Party; (b) that
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	 	 	becomes generally available to the public through no fault of the receiving Party; (c) that
is acquired in good faith by the receiving Party or any of its Affiliated Companies from a
Third Party not under an obligation of secrecy to the disclosing Party with respect to such
information; or (d) that is independently developed by employees or agents of the receiving
Party or any of the Affiliated Companies without reliance on Confidential Information
disclosed under this Agreement.
	 
	10.3	 	Notwithstanding the obligations of confidentiality, non-disclosure, and non-use set forth
herein, a Party may:

	 	(a)	 	disclose Confidential Information to a regulatory agency that is necessary to
obtain regulatory approval in a particular jurisdiction or as otherwise required by law
or judicial process;
	 
	 	(b)	 	disclose Confidential Information to a government official or agency if the
disclosure is necessary to protect the health and safety of a Party’s workers or the
public or as required by law or for defending, enforcing, or prosecuting patent
applications and patents; and
	 
	 	(c)	 	disclose Confidential Information reasonably required in connection with the
development, manufacture, use, sale, external testing, or marketing of Products in the
Territory in accordance with the terms of this Agreement.

	10.4	 	Except as set forth in this section, neither Party shall disclose the nature or
existence of this Agreement to any Third Party, or the relationship between the parties
hereunder, without the prior written consent of the other Party, except that each Party
shall be permitted, without the prior permission of the other Party, to disclose the
existence of this Agreement and the nature of the licenses granted hereunder as required by
law or judicial process and to its accountants and attorneys. PHARMATOP shall be permitted,
without the prior permission of BMS, to disclose the existence of this Agreement and the
nature of the licenses granted hereunder on a confidential basis to a) potential licensees
pursuant the provisions of section 3.1, but not other terms and conditions; and b) as to the
terms of this Agreement, its existing or potential investors and commercial bankers. BMS
shall be

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	 	 	permitted, without the prior permission of PHARMATOP, to disclose the existence and
terms of this Agreement on a confidential basis to potential sublicensees, copromotion
partners, merger and acquisition candidates and collaborators.
	 
	10.5	 	The provisions of this Article shall govern the exchange of Confidential Information between
the parties on or after the execution of this Agreement. The rights and obligations of this
Article shall survive termination of this Agreement.

Article 11—Warranties, Representations and Acknowledgements

	11.1	 	PHARMATOP warrants and represents that it is a partnership duly organized and validly
existing under the laws of France, and has all power and authority to carry on its business as
now being conducted and to own its properties and is duly licensed or qualified in each
jurisdiction in which its failure to qualify would have a material adverse effect on its
business, financial condition or operations. PHARMATOP represents that, as of the Effective
Date, the assets of PHARMATOP, excluding the Patents and Patent Applications, are valued at
less than [***]
and that its revenues for calendar year 2002 will be less than [***].
	 
	11.2	 	PHARMATOP warrants and represents that it has full legal power and authority to enter into
this Agreement and to consummate the transactions contemplated hereby; that the execution,
delivery and performance of this Agreement by it has been duly authorized by all requisite
legal action; and that this Agreement has been duly executed and delivered by it and
constitutes a valid and binding obligation enforceable in accordance with its terms, subject,
as to enforcement, to applicable bankruptcy, reorganization, insolvency, moratorium, and other
laws affecting creditors’ rights generally from time to time in effect.
	 
	11.3	 	PHARMATOP represents and warrants that neither PHARMATOP nor any of its respective
Affiliated Companies is a party to, subject to or bound by any agreement or any judgment,
award, order, writ, injunction or decree of any court, governmental body or arbitrator that
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	 	 	performance of this Agreement by it or that could prevent the carrying out of this
Agreement.
	 
	11.4	 	PHARMATOP represents and warrants that to the best of its knowledge there is no (i) action,
suit, dispute, or governmental, administrative, arbitration, or regulatory proceeding pending
or threatened in writing or (ii) any investigation pending or threatened in writing against or
relating to PHARMATOP, its Affiliated Companies, or their officers, general partners, and
stockholders that, in either case could prevent the carrying out of this Agreement.
	 
	11.5	 	PHARMATOP warrants and represents that it exclusively owns or controls by agreement or
license all right, title and interest in and to the Licensed Rights as defined herein and that
it has the full right and authority to enter into this Agreement and to carry out the
transactions contemplated herein.
	 
	11.6	 	PHARMATOP warrants and represents that it has no outstanding encumbrances or agreements,
either written or oral, relating to the use of the Licensed Rights in the Territory, and that
it has not granted nor will grant during the term of this Agreement or any renewal hereof, any
similar rights, license, consent, or privilege in the Territory to any Third Party with
respect to the rights granted herein.
	 
	11.7	 	BMS represents and warrants that BMS is a corporation duly organized, validly existing and in
good standing under the laws of the State of Delaware.
	 
	11.8	 	BMS represents and warrants that it has full corporate power and authority to enter into this
Agreement and to consummate the transactions contemplated hereby; that the execution, delivery
and performance of this Agreement have been duly authorized by all requisite corporate action;
and that this Agreement has been duly executed and delivered by BMS and constitutes a valid
and binding obligation of BMS, enforceable in accordance with its terms, subject, as to
enforcement, to applicable bankruptcy, reorganization, insolvency, moratorium, and other laws
affecting creditors’ rights generally from time to time in effect.

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	11.9	 	BMS represents and warrants that neither it nor any of its Affiliated Companies, is a party
to, subject to or bound by any agreement or any judgment, award, order, writ, injunction or
decree of any court, governmental body or arbitrator, which would conflict with or be breached
by the execution, delivery or performance of this Agreement by BMS or which could prevent the
carrying out of this Agreement.
	 
	11.10	 	BMS represents and warrants that to the best of its knowledge there is no (i) action, suit,
dispute, or governmental, administrative, arbitration, or regulatory proceeding pending or
threatened in writing or (ii) any investigation pending or threatened in writing against or
relating to BMS, its Affiliated Companies, or their officers and stockholders that, in either
case could prevent the carrying out of this Agreement.
	 
	11.11	 	BMS represents and warrants that all consents of Third Parties, including, without
limitation, governmental authorities and non-governmental self-regulatory agencies which
regulate the business of BMS, necessary to the execution and delivery of this Agreement by BMS
or to its performance as of the Effective Date of the transactions contemplated hereby have
been obtained and all filings with and notifications to such governmental authorities
(including non-governmental self-regulatory agencies), regulatory agencies or other entities
have been effected.
	 
	11.12	 	BMS covenants that it will use its commercially reasonable efforts such that all Products
manufactured, labeled, advertised, and sold by or on behalf of BMS under this Agreement shall
comply in all material respects with all applicable requirements of the U.S. Food, Drug and
Cosmetic Act and all other laws and regulations applicable thereto.
	 
	11.13	 	Except as disclosed in Appendix 3 (re Fresenius), PHARMATOP represents that, as of
the date of full execution of this Agreement, there are, to the best of its knowledge, no
Third Party patents that would materially affect BMS’ ability to sell Products or PHARMATOP’s
ability to obtain patent protection for Licensed Rights.
	 
	11.14	 	The representations and warranties of the parties set forth in this Article and in Section
6.1 shall survive the termination, cancellation or expiration of this Agreement without
limitation.

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Article 12—Indemnification; Limitation on Liability 

	12.1	 	Subject to Sections 12.3 and 12.4, each Party hereby agrees to indemnify, defend and hold the
other Party, its Affiliates, its licensees, and its and their officers, directors, employees,
consultants, contractors, sublicensees and agents (collectively, the “Indemnitees”)
harmless from and against any and all damages or other amounts payable to a Third Party
claimant (by enforceable judgement, settlement or otherwise), as well as any reasonable
attorneys’ fees and costs of litigation incurred by such Indemnitee as to any such Claim (as
defined in this Section 12.1) until the indemnifying Party has acknowledged that it will
provide indemnification hereunder with respect to such Claim as provided below, (collectively,
“Damages”) resulting from claims, suits, proceedings or causes of action
(“Claims”) brought by such Third Party against such Indemnitee based on: (a) a breach
of a representation or warranty by the indemnifying Party contained in this Agreement; (b)
breach of this Agreement or applicable law by such indemnifying Party; (c) negligence or
willful misconduct of a Party, its Affiliates or (sub)licensees, or their respective
employees, contractors or agents in the performance of this Agreement; and/or (d) breach of a
contractual or fiduciary obligation owed by it to a Third Party (including without limitation
misappropriation of trade secrets).
	 
	12.2	 	Subject to Section 12.4, BMS hereby agrees to indemnify, defend and hold harmless
PHARMATOP and its directors, agents and employees from and against any and all damages and
other amounts payable to a Third Party claimant (by enforceable judgement, settlement or
otherwise), as well as any reasonable attorneys’ fees and costs of litigation incurred by
such PHARMATOP indemnitee as to any Claim (as defined below) until BMS has acknowledged that
it will provide indemnification hereunder with respect to such Claim, as a result of any
suits, claims, actions, and demands (“Claims”) made by such Third Party against such
PHARMATOP Indemnitee that are based, directly or indirectly, on the manufacture, use, or
sale of any Products by BMS or its Affiliates, agents or sublicensees, except to the extent
such Claims result from (a) a breach of a representation or warranty by PHARMATOP contained
in this Agreement; (b) breach of this Agreement or applicable law by PHARMATOP; (c)
negligence, fraud, or willful misconduct by PHARMATOP or its employees, contractors or
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		 	of a contractual or fiduciary obligation owed by PHARMATOP or an of its employees or
shareholders to a Third Party (including without limitation misappropriation of trade
secrets), or as provided in section 6.3(a).
	 
	12.3	 	In the event that PHARMATOP is obligated to indemnify BMS as to a given amount for a given
Claim under this Agreement or is obligated to BMS for any damages of any character for any
breach of this Agreement (such damages and Claims, together, a “PHARMATOP Payment
Obligation”), BMS shall only be entitled to recover from PHARMATOP with respect to such
PHARMATOP Payment Obligation as follows:

	 	(a)	 	If such PHARMATOP Payment Obligation relates to a breach by PHARMATOP of any of
its representations or warranties under this Agreement, BMS may recover directly from
PHARMATOP (or, if PHARMATOP fails to meet its obligations, from its general partners)
damages with respect to such PHARMATOP Payment Obligation up to an amount that does not
exceed [***] of all amounts then paid to PHARMATOP by BMS pursuant to sections [***]
and [***], less all amounts previously paid directly by PHARMATOP to BMS (i.e., other
than by royalty offset) with respect to any other PHARMATOP Payment Obligations
pursuant to this subsection (a) and pursuant to section 12.3(b). To the extent that
such amount is not sufficient to cover the entire amount due BMS, BMS may recover any
remaining amount due it only by offsetting and withholding the amount due against any
future royalties due BMS under section 7.2 or 7.3 until such amount is paid.
	 
	 	(b)	 	If such PHARMATOP Payment Obligation relates to a breach by PHARMATOP of any provisions of
this Agreement other than its representations and warranties under this Agreement, BMS may
recover directly from PHARMATOP (or, if PHARMATOP fails to meet its obligations, from its
general partners) damages with respect to such PHARMATOP Payment Obligation up to an amount
that does not exceed [***]
of all amounts then paid to PHARMATOP by BMS pursuant to section [***] and
[***], less all amounts previously paid directly by PHARMATOP to BMS (i.e., other
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	 		 	other PHARMATOP Payment Obligations pursuant to this subsection (b) and, to the extent
relating to amounts previously paid by BMS pursuant to sections [***] and [***], with respect
to any other PHARMATOP Payment Obligations previously paid directly by PHARMATOP to BMS
pursuant to section [***] To the extent that such amount is not sufficient to cover the
entire amount due BMS, BMS may recover any remaining amount due it only by offsetting and
withholding the amount due against any future royalties due BMS under section [***]
or [***] until such amount is paid.

	 	 	For the avoidance of doubt, it is expressly agreed between the Parties that these
limitations are intended to be cumulative to cover all PHARMATOP Payment Obligations. In
other words, if monies are paid or deducted under 12.3(a) (from amounts other than payments
under section 7.1), such payments or deductions reduce monies available for payment or
deduction under 12.3(b), and vice-a-versa.
	 
	12.4	 	As used in this section 12.4, “Indemnitee” shall mean a party entitled to indemnification
under the terms of Section 12.1 or 12.2. It shall be a condition precedent to an Indemnitee’s
right to seek indemnification under such Section 12.1 or 12.2:

	 	(a)	 	shall inform the indemnifying Party under such applicable Section of a Claim as
soon as reasonably practicable after it receives notice of the Claim;
	 
	 	(b)	 	shall, if the indemnifying Party acknowledges that such Claim falls within the
scope of its indemnification obligations hereunder, permit the indemnifying Party to
assume direction and control of the defense, litigation, settlement, appeal or other
disposition of the Claim (including the right to settle the claim solely for monetary
consideration); provided, that the indemnifying Party shall seek the prior
written consent (not to be unreasonably withheld or delayed) of any such Indemnitee as
to any settlement which would materially diminish or materially adversely affect the
scope, exclusivity or duration of any Patents licensed under this Agreement, would
require any payment by such Indemnitee, would require an admission of legal wrongdoing
in any way on the part of an Indemnitee, or would amend this Agreement; and

 

			
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	 	(c)	 	shall fully cooperate (including providing access to and copies of pertinent
records and making available for testimony relevant individuals subject to its control)
as reasonably requested by, and at the expense of, the indemnifying Party in the
defense of the Claim.

	 	 	Provided that an Indemnitee has complied with the foregoing, the indemnifying Party shall
provide attorneys reasonably acceptable to the Indemnitee to defend against any such Claim.
Subject to the foregoing, an Indemnitee may participate in any proceedings involving such
Claim using attorneys of its/his/her choice and at its/his/her expense. In no event may an
Indemnitee settle or compromise any Claim for which it/he/she intends to seek
indemnification from the indemnifying Party hereunder without the prior written consent of
the indemnifying Party, or the indemnification provided under such Section 12.1 or 12.2 as
to such Claim shall be null and void.
	 
	12.5	 	PHARMATOP represents and warrants that it is a general partnership under French law, that its
general partners are Daniele Fredj and Francois Dietlin, and that under French law, each of
the general partners are responsible for the liabilities of PHARMATOP.
	 
	12.6	 	The liability, limitation of liability, and indemnification provisions set forth in this
Section 12 shall survive the termination, cancellation or expiration of this Agreement [***]

Article 13—Arbitration

	13.1	 	Any controversy or claim arising out of or relating to this Agreement or the validity,
inducement, or breach thereof, shall be settled by arbitration before a arbitration tribunal
of three (3) arbitrators appointed and ruling in accordance with the Arbitration Rules of
the International Chamber of Commerce Arbitration Association (“ICC”) then
pertaining, except where those rules conflict with this provision, in which case this
provision controls. Any court with jurisdiction shall enforce this clause and enter
judgment on any award. The arbitrators shall be attorneys who have at least fifteen (15)
years of experience with a law firm or corporate law department of over twenty five (25)
lawyers or who were a judge of a court of general jurisdiction. They shall not be a citizen
of 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-

 

	 	 	United States, Mexico, Canada, or France and shall not have its usual professional
office in one of these countries. They shall be selected within ten (10) days of
commencement of the arbitration by common consent of Parties or if Parties fall to agree in
the stated time, through selection procedures administered by the ICC. The arbitration
shall be held in the city of Paris, France. Within forty-five (45) days of initiation of
arbitration, the parties shall reach agreement upon and thereafter follow procedures
assuring that the arbitration will be concluded and the award rendered within no more than
six months from selection of the arbitrator. Failing such agreement, the ICC will design
and the parties will follow procedures that meet such a time schedule.
	 
	13.2	 	All proceedings shall be conducted, and all documents submitted, in the English language.
[***].
	 
	13.3	 	Each Party has the right prior to the commencement of an arbitration and, if the
arbitrators cannot hear the matter within an acceptable period or can not award effective
relief, during the arbitration, to seek and obtain from an appropriate court provisional
remedies such as attachment, preliminary injunction, or replevin, to avoid irreparable harm,
maintain the status quo or preserve the subject matter of the arbitration.

Article 14—General provisions

	14.1	 	Any delays in or failures of performance by a Party under this Agreement 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; acts,
regulations or laws of any government; strikes or other concerted acts of workers; fires;
floods; explosions; riots; wars; rebellions; and sabotage.
	 
	14.2	 	BMS shall obtain any and all governmental approvals required to authorize, implement or
enforce this Agreement or any of the terms and conditions hereof.

 

			
	***	 	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-

 

	14.3	 	No change in, addition to or waiver of any of the provisions of this Agreement shall be
valid or binding unless in writing and duly executed by the Party against whom enforcement
of the change, addition or waiver is sought. Any such waiver shall constitute a waiver only
with respect to the specific matter described in such writing and shall in no way impair the
rights of the Party granting such waiver in any other respect or at any other time.
	 
	14.4	 	Neither the waiver by any of the parties hereto of a breach of or a default under any of the
provisions of this Agreement, nor the failure by any of the parties, on one or more occasions,
to enforce any of the provisions of this Agreement or to exercise any right or privilege
hereunder, shall be construed as a waiver of any other breach or default of a similar nature,
or as a waiver of any of such provisions, rights or privileges hereunder.
	 
	14.5	 	Headings herein are for the parties’ convenience only, and shall not be used to interpret
this Agreement.
	 
	14.6	 	Except to the extent otherwise provided herein, each Party, shall bear its own expenses and
costs in connection with the transactions contemplated hereby, including the preparation,
execution and delivery of this Agreement and compliance herewith.
	 
	14.7	 	All matters affecting the interpretation, validity, performance and enforcement of this
Agreement shall be governed by the laws of the state of New York (USA), without regard or
giving effect to its choice or conflict of law principles other than Section 5-1401 of the New
York General Obligations Law.
	 
	14.8	 	If any provision of this Agreement is invalid or unenforceable in any jurisdiction, the
remaining provisions hereof shall remain in effect and such invalidity or unenforceability
shall not affect the validity or enforceability of such provision in any other jurisdiction.
The parties shall replace such ineffective provision for such jurisdiction with a valid and
enforceable provision which most closely approaches the purpose of this Agreement, and in
particular, the provision to be replaced.
	 
	14.9	 	PHARMATOP and BMS are independent contractors and shall not be deemed to be partners,
joint venturers or each other’s agents, and neither shall have the right to act on

-45-

 

	 	 	behalf of the other except as expressly provided hereunder or otherwise expressly agreed to
in writing.
	 
	14.10	 	The parties have incorporated in this Agreement all representations, warranties, covenants,
commitments and understandings on which they have relied in entering into this Agreement and,
except as provided for herein, neither Party has made any covenant or other commitment to the
other concerning its future action. Accordingly, this Agreement, together with the appendixes
and exhibits attached hereto, (i) constitute the entire agreement and understanding between
the parties with respect to the matters contained herein, and there are no promises,
representations, conditions, provisions or terms related thereto other than those set forth in
this Agreement, and (ii) supersede all previous understandings, agreements and representations
between the parties, written or oral relating to the subject matter hereof.
	 
	14.11	 	All communications, reports, payments and notices required by this Agreement shall be made
in writing and addressed to the parties at their respective addresses set forth below or to
such other address as requested by a Party by notice in writing to the other parties:

          If to PHARMATOP:

SCR Pharmatop

10, square St. Florentin

78150 Le Chesnay

FRANCE

Attention: Gerant

Phone: 33-1-39-545577

          If to BMS:

Bristol-Myers Squibb Company

Route 206 and Province Line Road

Princeton, New Jersey 08540-4000

Attn: President for Consumer Medicines

-46-

 

	 	 	with a copy to the Vice President and Senior Counsel, BMS Consumer Medicines, at the same
address.
	 
	 	 	All such notices, reports, payments and communications shall be deemed given or made and
effective (i) when delivered personally; or (ii) when received, if sent by recognized
overnight courier or by registered or certified mail, return receipt requested and postage
prepaid.
	 
	14.12	 	In order to insure that this license can be used validly against Third Parties, extracts of
this Agreement will be registered on the patent offices’ registers by BMS as deemed necessary
by BMS, at its expense.

[The next page is the signature page]

-47-

 

IN WITNESS WHEREOF, and intending to be legally bound, the parties hereto have caused this
Agreement to be executed in triplicates by their duly authorized representatives as of the 23rd day
of December 2002.

	 	 	 
	SCR PHARMATOP

	 	BRISTOL-MYERS SQUIBB COMPANY
	 
	 	 
	By:
/s/ Daniele Fredj

	 	By: /s/ [ illegible ]
	Name: Daniele Fredj

	 	Name:
	Title: Gerant

	 	Title:
	 
	 	 
	By:
/s/ Francois Dietlin
	 	 
	Name: Francois Dietlin
	 	 
	Title: Gerant
	 	 

 

APPENDICES AND EXHIBITS

	 	 	 
	Appendix 1 :

	 	Patent Related Disclosures and Documents

	 	 	 	 	 
	 

	 	Exhibit A:
	 	US Patent No. 6,028,222 issued on 22nd February 2000
	 
	 	 	 	 
	 

	 	Exhibit B:
	 	International Patent Application PCT/FR 97101452, filed on 5th
August 1997
	 
	 	 	 	 
	 

	 	Exhibit C:
	 	International Patent Application
PCT/FR01/01749, filed on 6th June
2001
	 
	 	 	 	 
	 

	 	Exhibit D:
	 	D-1: Assignment Document covering the portion of the inventions covered by U.S.
patent No. 6,028,222 assigned by the Inventors to Newpharm for all other countries of
the world (which obtained French patent No. 2.75 1.875) and as to which Newpharm
subsequently assigned the associated ongoing research and priority rights to PHARMATOP.
	 
	 	 	 	 
	 

	 	 	 	D-2: Assignment of inventions covering U.S. patent No. 6,028,222
assigned by the Inventors to PHARMATOP for the United States
	 
	 	 	 	 
	 

	 	Exhibit E:
	 	Letter from NewPharm confirming the assignment in Exhibit D

	 	 	 
	Appendix 2:

	 	Target Product Profile
	 
	 	 
	Appendix 3:

	 	Exceptions to PHARMATOP Representations and Warranties
	 
	 	 
	Appendix 4:

	 	Guaranteed Payment Schedule
	 
	 	 
	Appendix 5:

	 	Description of Licensed Know-How

 

 

			
	Exhibit A
	 	Appendix 1
	 
	 	
	 
	 	US006028222A

	 	 	 	 	 	 	 	 	 
	United States Patent           [19]

	 	[11]
	 	Patent Number:
	 	 	 	6,028,222
	Dietlin et al.

	 	[45]
	 	Date of Patent:
	 	Feb. 22, 2000

	 	 	 	 	 
	[54]	 	STABLE LIQUID PARACETAMOL COMPOSITIONS, AND METHOD FOR

PREPARING SAME
	 
	 	 	 	 
	[75]	 	Inventors: Francois Dietlin, Le Pecq.; Daniele Fredj,
Gif-sur-Yvette, both of France
	 
	 	 	 	 
	[73]	 	Assignee: SCR Pharmatop, France
	 
	 	 	 	 
	[21]

	 	Appl. No.:
	 	09/051,246
	 
	 	 	 	 
	[22]

	 	PCT Filed:
	 	Aug. 5, 1997
	 
	 	 	 	 
	[86]

	 	PCT No.:
	 	PCT/FR97/01452
	 
	 	 	 	 
	 

	 	§ 371 Date:
	 	Jun. 5, 1998
	 
	 	 	 	 
	 

	 	§ 102(e) Date:
	 	Jun. 5, 1998
	 
	 	 	 	 
	[87]

	 	PCT Pub. No.:
	 	WO98/05314
	 
	 	 	 	 
	 

	 	PTC Pub. Date:
	 	Feb. 12, 1998
	 
	 	 	 	 
	[30]	 	     Foreign Application Priority Date

	 	 	 	 	 
	   Aug 05, 1996 [FR] France	 	96 09858
	[51]

	 	Int. Cl.7
	 	CO7C 209/90
	 
	 	 	 	 
	[52]

	 	U.S. Cl.
	 	564/4; 514/617, 564/2;
	 

	 	 	 	564/5; 564/6; 564/7; 564/223
	 
	 	 	 	 
	[58]

	 	Field of Search
	 	564/4,5,6,7,
	 

	 	 	 	564/2,223 514/617
	 
	 	 	 	 
	[56]	 	References Cited

U.S. PATENT DOCUMENTS

	 	 	 	 	 	 	 	 	 	 	 
	 

	 	 	4,727,064	 	 	2/1988
	 	Pitha
	 	514/58
	 

	 	 	4,855,326	 	 	8/1989
	 	Fuisz
	 	514/777
	 

	 	 	5,658,919	 	 	8/1997
	 	Ratnaraj et al
	 	514/269

FOREIGN PATENT DOCUMENTS

     952395       9/1995       WIPO

OTHER PUBLICATIONS

XP 002045737, 1995

XP 002045739, 1985

XP 002045740, 1983

XP 002030816, 1986

Primary Examiner—Shailendra Kumar

Attorney, Agent, or Firm—Bierman, Muserlian and Lucas

[57] ABSTRACT

Novel stable paracetamol compositions for use in therapeutic chemistry and specifically galenic
pharmacy are disclosed. The compositions contain a solution of paracetamol in an aqueous solvent
combined with a buffer having a pH of 4 to 8, and a free radical capturing agent. A water-insoluble
inert gas is carefully bubbled through the aqueous solvent to remove oxygen from the medium. Said
compositions may also be combined with a centrally or peripherally acting analgesic agent, and are
provided as injectable compositions for relieving pain.

28 Claims, No Drawings

 

 

6,028,222

STABLE LIQUID PARACETAMOL

COMPOSITIONS, AND METHOD FOR

PREPARING SAME

     This application is a 371 of PCT/FR97/01452, filed Aug. 5, 1997.

FIELD OF THE INVENTION

     The present invention relates to novel stable, liquid, analgesic formulations, containing
paracetamol as main active ingredient, either in combination or not, with an analgesic derivative.

DISCUSSION OF THE PRIOR ART

     It has been known for many years and notably from a paper of FAIRBROTHER J. E. entitled:
Acetaminophen, published in Analytical Profiles of Drug Substances (1974), volume 3, pp. 1-109,
that paracetamol in the presence of moisture, and all the more in aqueous solution, may be
hydrolysed to yield p-aminophenol, which compound may itself be broken down into quinone-imine. The
rate of decomposition of paracetamol is enhanced as the temperature is increased and upon exposure
to light.

     In addition, the instability of paracetamol in aqueous solution as a function of the
solution’s pH has been extensively described. Thus, according to a paper entitled “Stability of
aqueous solution of N-acetyl-p-aminophenol” (KOSHY K. T. and LACH J.I.J. Pharm. Sci., 50 (1961),
pp. 113-118), paracetamol in aqueous solution is unstable, a fact which primarily correlates with
hydrolysis both in acidic and basic environment. This breakdown process is minimal at a pH close to
6, the half-life of the product thus degraded namely being as high as 21.8 years at 25° C.

     According to Arrhenium law and knowing the specific reaction constant as determined by these
authors, the time needed to observe a 5% decrease in paracetamol concentration of an aqueous
solution stored at 25° C. at the optimal pH as been predicted to be 19 months. Besides hydrolysis,
the paracetamol molecule separately undergoes another kind of decomposition that involves formation
of a quinone-imine that may readily polymerize with generation of nitrogen-containing polymers.

     These polymers and in particular those stemming from N-acetyl-p-benzoquinone-imine have been
further described as being the toxic metabolite of paracetamol, which is endowed notably with
cytotoxic and hemolytic effect. The decomposition of this metabolite in aqueous medium is still
more complex and gives rise to p-benzoquinone and hydroquinone (D. DAHLIN, J. Med. Chem., 25
(1982), 885-886).

     In the current state of the art and in view of the quality control requirements specific to
pharmaceutical practice regulations, the stability of paracetamol in aqueous solutions is thus
insufficient and does not allow the formulation of liquid pharmaceutical compositions for
injection. As a result, the successful preparation of liquid pharmaceutical formulations for
parenteral administration, based on paracetamol, has not been achieved.

     A number of trials has been undertaken to slow down the decomposition of paracetamol in
aqueous solution. Thus, in a paper entitled: Stabilization by ethylenediamine tetraacetic acid of
amide and other groups in drug compound, (FOGG Q. G. and SUMMAN, A. M., J. Clin. Pharm. Ther., 17:
(1992), 107-109), it is stated that a 0.1% aqueous solution of paracetamol has a p-aminophen
content resulting from hydrolysis of paracetamol, approximating 19,8% of the initial concentration
of paracetamol, as observed after storage in the dark during 120 days. Addition of EDTA at a rate
de 0.0075% brings down the decomposition rate to 7%. On the other hand, distilling an alkaline
solution of paracetamol results in an ammonia concentration of 14%, in presence or not of 1000 ppm
of ascorbic acid. Owing to its properties, ascorbic acid is indeed quite adapted to such
stabilization. However, upon exposure to bright light, a paracetamol solution containing 1000 ppm
of ascorbic acid does after all generate ammonia with a yield of 98%. In contrast, addition of EDTA
(0.0075%) to such a solution cuts down decomposition rate, with an ammonia yield not higher than
14%.

     Despite of such efforts, it has not been possible to prepare aqueous liquid solutions of
paracetamol. In particular solutions for injection, having a guaranteed stability.

SUMMARY OF THE INVENTION

     The present invention is aimed at solving the above stated problem in an appropriate manner.
It is directed to stable pharmaceutical compositions of paracetamol in an aqueous solvent having
added thereto a free radical antagonist. The aqueous solvent may be water or else aqueous mixtures
containing water and a polyhydric compound such as polyethylene-glycol (PEG) 300, 400, 1000, 1540,
4000 or 8000, propylene glycol or tetraglycol. A water-soluble alcanol such as for example ethanol
may also be used.

DETAILED DESCRIPTION OF THE

INVENTION

     Stability of the aqueous solutions mentioned above does not solely depend on the choice of a
given carrier. It also depends on other variables, such as careful adjustment of pH, removal of
oxygen dissolved in the carrier and addition of a free radical antagonist or a free radical
scavenger.

     Removal of dissolved oxygen is readily accomplished by bubbling an inert gas and preferably by
bubbling nitrogen.

     The appropriate free radical antagonist is chosen among the derivatives of ascorbic acid,
those derivatives bearing at least a thiol functional group and straight chain or cyclic polyhydric
compounds.

     Preferred ascorbic acid derivatives are D- or L-ascorbic acid, an alkali metal ascorbate, an
alkaline earth metal ascorbate or even still an aqueous medium-soluble ascorbic acid ester.

     Free radical scavengers, bearing a thiol functional group may be an organic compound
substituted by one or more thiol functional groups, of the aliphatic series such as cystein,
acetylcystein, thioglycollic acid and salts thereof, thiolactic acid and salts thereof,
dithlothreltol, reduced glutathion, thiourea, thioglycerol, methionine and mercaptoethane sulfonic
acid.

     The polyol used as a free radical scavenger is preferably a straight chain or a cyclic,
polyhydroxy alcohol such as mannitol, sorbitol, inositol, isosorbide, glycerol, glucose and
propylene-glycols.

     Among free radical scavengers required pour stabilizing paracetamol, the ascorbic acid
derivative currently preferred is sodium ascorbate. Preferred thiol functional group substituted
derivatives are cystein, reduced-slate glutathion, N-acetylcystein and mercaptoethane sulfonic
acid.

     It may appear as convenient to combine several free radical scavengers as far as they are
water-soluble and mutually compatible. Especially convenient free radical scavengers are mannitol,
glucose, sorbitol or even glycerol.

 

 

6,028,222

These may be readily combined.

     It may appear as convenient to add to the preparation one or a number of complexing agents to
improve stability of the molecule since the active ingredient is sensitive to the presence of trace
metals that eventually speed up its decay.

     Complexing agents are exemplified by nitrilotriacetic acid, ethylene diamino tetraacetic acid,
ethylene diamino, N, N’-diacetic-N, N’-dipropionic acid, ethylene diamino tetraphosphonic acid,
2,2’-(ethylene diamino)dibutyric acid, or ethylene-glycol bis(diaminoethyl ether)
N,N,N’,N’-tetraacetic acid and sodium or calcium salts thereof.

     The complexing agent also acts to complex bivalent ions (copper, zinc, calcium) that may be
present and that have a negative influence of the aging of the formulation throughout storage.

     The gas that is bubbled into the solution to drive out oxygen, may be nitrogen or carbon
dioxide or still an inert gas. Nitrogen is favoured.

     Isotonicity of the preparation may be achieved by adding an appropriate quantity of sodium
chloride, glucose, levulose or postassium chloride, or calcium chloride, or calcium
gluconoglucoheptonate, or mixtures thereof. The preferred isotonizing agent is sodium chloride.

     The buffer used is a buffer compatible with parenteral administration in humans, the pH of
which may be adjusted between 4 and 8. Preferred buffers are based on alkali metal ou alkaline
earth metal acetates or phosphates. A more preferred buffer is sodium acetate/hydrogene phosphate
adjusted to the required pH with hydrochloric acid or sodium hydroxide. The concentration of such a
buffer may be comprised between 0.1 and 10 mg/ml. The preferred concentration is confined in the
range of 0.25 to 5 mg/ml.

     On the other hand, preparations for injection have to be sterile and should lend themselves to
heat treatment sterilization. It is known that in certain conditions, antioxidants such as
glutathion are broken down ]FIALAIRC A. et al., J. Pharm. Biomed. Anal., vol. 10, No 6, pp. 457-460
(1992)]. The breakdown of reduced glutathion during heat treatment sterilization ranges from 40 to
77% depending on the selected temperature conditions. During such sterilization procedures, it is
convenient to employ means capable of preserving the integrity of these antioxidants. Addition of
complexing agents to aqueous solutions inhibits thermal decomposition of thiol derivatives, such as
glutathion.

     Liquid pharmaceutical compositions according to the invention are preferably compositions
intended for injection. The paracetamol content of the solution may range from 2 mg/ml to 50 mg/ml
in case of so called dilute solutions, i.e. that can be directly infused by intravenous route and
from 60 mg/ml to 350 mg/ml where so-called concentrated solution are considered, i.e. either
intended for direct injection by intravenous or intramuscular route, or intended to be diluted
prior to slow infusion administration. The preferred concentrations are comprised between 5 and 20
mg/ml for dilute solutions and between 100 and 250 mg/ml for concentrated solutions.

     Pharmaceutical compositions according to the invention may further contain another active
ingredient that enhances the specific effect of paracetamol.

     In particular, the pharmaceutical compositions according to the invention may contain a
CNS-acting analgesic such as for example a morphinic analgesic.

     The morphinic analgesic is selected among the morphinic derivatives of natural, semi-synthetic
or synthetic origin and piperidine derivatives selected from the following list, which is no way
intended to be exhaustive: buprenorphine, dramadol, codeine, dextromoramide, dextropropoxyphene,
hydrocodone, hydromorphone, ketobemidone, levomethadone, levorphanol, meptazinol, methadone,
morphine, nalbuphine, nicomorphine, dizocine, diamorphine, dihydrocodeine, dipipanone, methorphane,
dextromethorphane.

     Preferred morphinic derivatives are codeine sulfate or morphine hydrochloride.

     The codeine or codeine derivative concentration, expressed in terms of codeine base, is
comprised between 0.2% and 25% in relation to the paracetamol content. The preferred codeine
derivative is codeine sulfate. The concentration thereof is set between 0.5 and 15% in relation to
the paracetamol content.

     The morphine or morphine derivative concentration, expressed in terms of morphine base, is
comprised between 0.05 and 5% in relation to the paracetamol content. The preferred morphine
derivative is morphine hydrochloride the concentration of which is preferably set between 0.5 and
15% in relation to paracetamol content.

     The compositions according to the invention may further have added thereto an
anti-inflammatory agent such as of the of AINS type and in particular a phenylacetic acid compound.
Such agents are exemplified by ketoprofen, flurbiprofen, tiaprofenic acid, niflumic acid,
diclofenac or naproxen.

     Compositions according to the invention may in addition incorporate an antiemetic either a
CNS-acting neuroleptic such as haloperidol or chlorpromazine or metopimazine or of the
gastrokinetic-mediated type such as metochlopramide or domperidone or even a serotoninergic agent.

     Compositions in accordance with the invention may further incorporate an anti-epileptic drug
such as sodium valproate, clonazepam, carbamazepine or phenytoin.

     It may also be possible to combine paracetamol with a corticosteroid such as for example
prednisone, prednisolone, methyl prednisone, dexamethasone, betametasone or an ester thereof.

     Paracetamol can further be combined with a tricyclic antidepressant such as amitriptiline,
imipramine, clomipramine.

     Anti-inflammatory agents may be included in concentrations ranging from 0.100 g to 0.500 g per
1000 ml of formulated product.

In Case of Concentrated Solutions

     The water content expressed in percentage is preferably in excess of 5% of the total volume
and more preferably comprised between 10 and 65%.

     The quantity of propylene glycol formulated in percentage is preferably in excess of 5% and
more preferably comprised between 20 and 50%.

     The PEG used is preferably PEG 300, PEG 400, PEG 1000, PEG 1540 or PEG 4000. Concentrations
used are comprised between 10 and 60% in weight. PEG 300 and PEG 400 are further preferred.
Preferred concentrations range from 20 to 60%.

     Ethanol concentrations range from 0 to 30% of total volume and preferably range from 0 to 20%.

     Tetraglycol concentrations used do not exceed 15% to allow for maximal quantities that can
daily be received by parenteral administration viz 0.7 ml/kg of body weight.

 

 

6,028,222

     Glycerol concentration varies from 0.5 to 5% as a function of the viscosity of the medium
suitable for use depending on the administrative route.

In Case of Dilute Solutions

     The quantity of water used given in percentage is preferably in excess of 20% of the total
volume and preferably is comprised between 25 and 100%.

     The quantity of propylene-glycol employed given in percentage is preferably comprised between
0 and 10%.

     The PEG used is preferably PEG 300, PEG 400, or PEG 4000 with PEG 4000 being most preferred.
Preferred concentrations range from 0 to 10%. Tetraglycol concentrations used do not exceed 5%. In
preference, they are comprised between 0 and 4%.

     The ascorbic acid or ascorbic acid derivative concentration which is used is preferably more
than 0.05 mg/ml and more desirably, comprised between 0.15 mg/ml and 5 mg/ml. Higher quantities may
indeed be used, without exceeding the solubility limits. Higher ascorbic acid or ascorbic acid
derivative concentration are administered to human beings for prophylactic or therapeutic purposes.

     Thiol derivative concentration is comprised between 0.001% and 30% and more desirably,
comprised between 0.005% and 0.5% for dilute solutions, and between 0.1% and 20% for concentrated
solutions.

     The pH of the solution is desirably adjusted taking into consideration the optimal stability
of paracetamol in aqueous solution, i.e. at a pH around 6.0.

     The thus prepared composition may be packaged in glass sealed vials, or in stoppered glass
vials or in bottles made of a polymer material such as polyethylene, or in soft material bags made
from polyethylene, polyvinyl chloride or polypropylene.

     The composition may be sterilized by heat treatment, for example at 121° C. during 20 minutes
or else by sterile filtration.

     Currently preferred compositions in accordance with the invention have the following
ingredients:

     Concentrated solutions

	 	 	 	 	 	 	 	 	 
	 	 	Injection	 	Injection solution of
	 	 	solution of	 	paracetamol associated to a
	 	 	paracetamol	 	morphinic compound
	 	 	alone	 	(per ml)
	Ingredient	 	(per ml)	 	Codeine	 	Morphine
	 
	paracetamol

	 	0.160 g
	 	0.160 g
	 	0.160 g
	Codein sulfate.3H2O

	 	—
	 	0.0036 g
	 	—
	Morphine

	 	—
	 	—
	 	0.00037
	hydrochloride.3H.2O
	 	 	 	 	 	 	 	 
	Propylene glycol

	 	0.270 ml
	 	0.270 ml
	 	0.270 ml

	PEG 400

	 	0.360 ml
	 	0.360 ml
	 	0.360 ml

	Sodium acetate

	 	0.002 g
	 	0.002 g
	 	0.002 g
	Reduced glutathion

	 	0.002 g
	 	0.002 g
	 	0.002 g
	Hydrochloric acid
1 N

	 	q.s. pH 6.0*
	 	q.s. pH 6.0*
	 	q.s. pH 6.0*

	Water for injection

	 	q.s. 1000 ml
	 	q.s. 1000 ml
	 	q.s. 1000 ml

	Nitrogen

	 	q.s.f. bubbling
	 	q.s.f. bubbling
	 	q.s.f. bubbling

     The pH specified above is the actual pH that has been measured by a pH-meter after
obtaining a 5 fold dilution of the solution with distilled water. It will be noted that the
apparent pH of the pure solution is different.

     Using this solution composed of a solvent mixture constituted by 30% of propylene-glycol, by
40% of polyethylene-glycol 400 and by 30% of water (solution no 20), it is possible to dissolve
about 200 mg/ml of paracetamol at 20° C. Choosing a concentration of 160 mg/ml allows one to be
sure that no recristallization will occur, notably at low temperatures. In such situations, a
volume of 6,25 ml of said solution contains 1000 mg of paracetamol.

Dilute solutions

	 	 	 	 	 	 	 
	 	 	 	 	solution of paracetamol
	 	 	 	 	associated to codein (per ml)
	 	 	Injection	 	Such	 	Such
	 	 	solution of	 	morphinic	 	morphinic
	 	 	paracetamol	 	compound is	 	compound is
	Ingredient	 	alone (per ml)	 	codein	 	morphine
	 
	paracetamol

	 	0.0125 g
	 	0.125 g
	 	0.125 g
	Codein
sulfate.
3H.2O

	 	—
	 	0.00018 g
	 	—
	Morphine hydrochloride.
3H2O

	 	—
	 	—
	 	0.000019 g
	Mannitol

	 	0.025 g
	 	0.025 g
	 	0.025 g
	Sodium hydrogen phosphate dihydrate

	 	0.0025 g
	 	0.00025 g
	 	000025 g
	Sodium chloride

	 	0.002 g
	 	0.002 g
	 	0002 g
	Disodium ethylene diamino
tetraacetate

	 	0.0001 g
	 	0.0001 g
	 	0.0001 g
	Hydrochloric acid
or sodium hydroxide

	 	q.s. pH 5.5
	 	q.s. pH 5.5
	 	q.s. pH 5.5
	Water for injection

	 	q.s.f. 1000 ml
	 	q.s.f. 1000 ml
	 	q.s.f. 1000 ml
	Nitrogen

	 	q.s.f. bubbling
	 	q.s.f. bubbling
	 	q.s.f. bubbling

     The compositions according to the invention find therapeutic applications as pain relief
drugs. For moderate pain, the solutions merely contain paracetamol. For acute pain, the solutions
further contain a morphinic analgesic. Furthermore, the paracetamol solutions exert antipyretic
activity.

     The following examples are given by way of illustration and not by limitation.

EXAMPLE I

Determination of the Optimal Solvent Mixture

1.1 Concentrated solutions

     Increasing quantities of paracetamol were introduced in the solvent mixtures. The dissolution
rate of paracetamol increases with rise in temperature, so that the solubility tests in the
individual media were run by heating the solvent mixture to 60° C. After dissolution was judged
complete, the solutions were stored for 72 hours either at 25° C. or 4° C.

     The solubility values are listed in the following table:

	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 	 	 	 	Propylene	 	PEG	 	 	 	 	 	Solubility	 	Solubility
	Test	 	Water	 	glycol	 	400	 	 	 	Tetraglycol	 	at +4° C.	 	at +25° C.
	a*	 	(ml)	 	(ml)	 	(ml)	 	Ethanol	 	(ml)	 	(mg/ml)	 	(mg/ml)
	 
	1
	 	0.3
	 	0.4
	 	0.3
	 	—
	 	—
	 	110
	 	130
	2
	 	0.4
	 	0.3
	 	0.3
	 	—
	 	—
	 	110
	 	130
	3
	 	0.16
	 	0.3
	 	0.4
	 	—
	 	0.15
	 	190
	 	230
	4
	 	0.5
	 	—
	 	0.5
	 	—
	 	—
	 	110
	 	150
	5
	 	0.4
	 	0.3
	 	0.2
	 	0.1
	 	—
	 	<110
	 	120
	6
	 	0.5
	 	0.3
	 	0.1
	 	0.1
	 	—
	 	<100
	 	130
	7
	 	0.4
	 	0.4
	 	0.1
	 	0.1
	 	—
	 	<100
	 	150
	8
	 	0.5
	 	0.3
	 	0.2
	 	—
	 	—
	 	<100
	 	120
	9
	 	0.6
	 	0.3
	 	0.2
	 	—
	 	—
	 	<100
	 	<100
	10
	 	0.5
	 	0.4
	 	0.1
	 	—
	 	—
	 	<100
	 	<100
	11
	 	0.55
	 	0.3
	 	0.05
	 	0.1
	 	—
	 	<100
	 	<100
	12
	 	0.45
	 	0.4
	 	0.05
	 	0.1
	 	—
	 	<100
	 	120
	13
	 	0.65
	 	0.3
	 	0.05
	 	—
	 	—
	 	<100
	 	<100
	14
	 	0.55
	 	0.3
	 	0.05
	 	—
	 	—
	 	<100
	 	<100
	15
	 	0.4
	 	0.4
	 	0.2
	 	—
	 	—
	 	<100
	 	<150
	16
	 	0.45
	 	0.45
	 	0.1
	 	—
	 	—
	 	<100
	 	<100
	17
	 	0.4
	 	0.2
	 	0.4
	 	—
	 	—
	 	160
	 	200
	18
	 	0.5
	 	0.2
	 	0.3
	 	—
	 	—
	 	160
	 	160
	19
	 	0.5
	 	0.1
	 	0.3
	 	—
	 	—
	 	100
	 	190
	20
	 	0.3
	 	0.3
	 	0.4
	 	—
	 	—
	 	190
	 	200
	21
	 	0.3
	 	0.3
	 	0.35
	 	—
	 	0.15
	 	160
	 	210
	22
	 	0.25
	 	0.25
	 	0.35
	 	—
	 	0.15
	 	170
	 	220

 

 

6,028,222

     The solubility values of the solvent mixtures do not increase in a consistent manner with
increasing temperature. Solubility is not enhanced if ethanol is added.

     In addition, due to oversaturation phenomena which are observed in such solutions, notably in
media containing PEG, a delayed recristallization was noted subsequent to cooling. In these
conditions, the solutions under study were kept for 14 days at 20° C., then there was added, to the
solutions displaying no cristals following this time interval, a paracetamol germ cristal in order
to elicit cristallization of potentially oversaturated solutions. Finally, it was found that
solutions no 20 and no 3 have the highest solubility with respect to paracetamol, which threshold
was comprised between 160 mg/ml and 170 mg/ml depending on temperature.

     1.2 Dilute solutions

     Paracetamol is quantities well exceeding the solubility threshold was introduced in the
solvent mixtures previously warmed to 30° C. After stirring and cooling at 20° C., the solutions
were filtered. The paracetamol content of these solutions was determined by reading the absorbance
at 240 nm of a 1:200 dilution of the filtrate.

     The results are recorded in the following tables.

	 	 	 	 	 
	 	 	concentration of
	 	 	paracetamol
	 	 	(mg/50 ml)
	 
	Water
	 	 	720	 
	5% Glucose
	 	 	710	 
	4.82% levulose
	 	 	730	 
	7% mannitol
	 	 	680	 
	5% sorbital
	 	 	685	 
	0.9% sodium chloride
	 	 	615	 
	10% Calcium gluconoglucoheptonate
	 	 	670	 
	Lestradet’s solution (5% glucose, 0.2% sodium chloride, 0.15% potassium chloride, 1.1% calcium
gluconoglucoheptonate)
	 	 	730	 
	Ringer’s solution (0.7% sodium chloride, 0.1% potassium chloride, 0.1% sodium chloride)
	 	 	730	 
	Ringer’s solution-Phosphate (0.7% sodium chloride, 0.182% monopotassium phosphate,
0.182% calcium chloride)
	 	 	710	 
	Ringer’s solution-acetate (0.7% sodium chloride, 0.131% potassium acetate 0.013% calcium
chloride)
	 	 	715	 
	Urea 0.3 M
	 	 	725	 
	Type of solution (the following
solutions were prepared in Ringer’s
solution)
	 	 	 	 
	 
	 	 	 	 
	Pure Ringer’s solution
	 	 	735	 
	4.0% PEG 4000 + 1.0% propylene-glycol + 0.5% ethanol
	 	 	905	 
	4.0% PEG 4000 + 1.0% propylene-glycol + 1.0% ethanol
	 	 	905	 
	4.0% PEG 4000 + 1.0% propylene-glycol + 2.0% ethanol
	 	 	930	 
	Type of solution (the following solutions were prepared
in 0.9% sodium chloride solution)
	 	 	 	 
	 
	 	 	 	 
	0.9% sodium chloride
	 	 	615	 
	+0.6% tetraglycol
	 	 	640	 
	+1.2% tetraglycol
	 	 	680	 
	+3.0% tetraglycol
	 	 	720	 
	1.0% PEG 4000
	 	 	630	 
	1.0% PEG 4000 + 0.6% tetraglycol
	 	 	660	 
	1.0% PEG 4000 + 1.2% tetraglycol
	 	 	710	 
	3.0% PEG 4000 + 2.0% tetraglycol
	 	 	950	 

     Paracetamol solubility is increased by the presence of PEG.

     Solubilities of paracetamol in mixtures of PEG 4000 and 0.9% sodium chloride solutions were
determined in distilled water, at concentrations ranging from 0 to 7%, as a function of
temperature.

     The results are given in the following table:

	 	 	 	 	 	 	 	 	 	 	 
	 	 	Solvent volume (ml) required to
	PEG 4000 concentration	 	dissolve 1000 mg of paracetamol as
	(%/vol.) in 0.9% sodium	 	a function of temperature
	chloride solution	 	4° C.	 	17° C.	 	22° C.	 	30° C.	 	42° C.
	 
	0%
	 	130  
	 	92
	 	80
	 	65
	 	42
	1%
	 	99
	 	78
	 	67
	 	63
	 	47
	2%
	 	91
	 	72
	 	63
	 	59
	 	45
	3%
	 	80
	 	64
	 	56
	 	54
	 	41
	4%
	 	82
	 	62
	 	57
	 	49
	 	36
	5%
	 	79
	 	59
	 	51
	 	46
	 	34
	7%
	 	78
	 	61
	 	48
	 	42
	 	30

4.1 Concentrated solution

	 	 	 	 	 
	 	 	Quantity
	 	 	Solution without	 	Solution subjected to
	Ingredient	 	nitrogen bubbling	 	nitrogen bubbling
	 
	Paracetamol

	 	0.160 g
	 	0.160 g
	Propylene-glycol

	 	0.270 ml
	 	0.270 ml
	PEG 400

	 	0.360 ml
	 	0.360 ml
	Sodium hydroxide
or HCl 1N

	 	q.s. pH 6.0
	 	q.s. pH 6.0
	Nitrogen

	 	none
	 	q.s.f. purging and filling
	Water for injection

	 	q.s.f 1000 ml
	 	q.s.f. 1000 ml

     Solution 20 containing paracetamol in a quantity of 160 mg/ml, adjusted to pH 6.0 by
sodium hydroxide or hydrochloric acid 1N, was either subjected or not subjected to nitrogen gas
bubbling. Tightly stoppered and capped vials packed by dispensing 10 ml of such solutions under
nitrogen atmosphere or air, were sterilized by autoclaving at 121° C. during 20 minutes. The
percentage of secondary peaks was then measured by liquid chromatography with respect to the main
peak of paracetamol, as well as was the pink color strength by reading the solution absorbance by
absorption spectrophotometry at peak absorbance wavelength, that is 500 nm.

Results

	 	 	 	 	 	 	 	 	 
	 	 	Secondary peaks	 	 
	 	 	in % of main	 	absorbance of the
	 	 	peak of	 	solution at 500
	Solution tested	 	paracetamol	 	nm
	 
	Autoclaved solution
packed without nitrogen

	 	 	0.054	 	 	 	0.08	 
	Autoclaved solution
packed under nitrogen

	 	 	0.036	 	 	 	0.03	 

 

 

6,028,222

     It is therefore seen that the difference in color of the solution packed under nitrogen is
very striking.

     In order to check if 0% and 1% PEG-paracetamol solutions remain clear under cold storage, the
following solutions ere prepared:

	 	 	 	 	 	 	 	 	 
	 	 	Solution without	 	Solution with PEG
	Ingredient	 	PEG	 	added
	 
	Paracetamol

	 	 	1 g	 	 	 	1 g	 
	PEG 4000

	 	 	—	 	 	 	1 g	 
	0.9% Sodium chloride solution in water for injection

	 	 	0.036	 	 	 	0.03	 
	

	 	q.s. 125 ml
	 	q.s. 100 ml

     After storage of these solutions at 4° C. during 10 days, none of the vials tested showed
cristallization. Presence of PEG is therefore not mandatory if the solutions are to remain clear
throughout the time interval studied.

EXAMPLE II

Tests
Conducted for Characterizing Paracetamol 
Breakdown in Solution

     2.1 Demonstrating paracetamol instability in solution

     A paracetamol solution in water or in solution no 20 shows rapidly a pink color upon exposure
to light or storage at high temperature. At 50° C., color development occurs in 2 weeks time.
Appearance of such color tinge correlates with an increase in solution absorbance at a peak
absorbance wavelength of 500 nm. According to the paper of Fairbrother mentioned above, exposure of
paracetamol to moisture can result in hydrolysis with formation of para-aminophenol, followed by
oxydation, with appearance of a pink color, typical of the production of quinoneimine.

     2.2 Identifying the breakdown products of paracetamol

     In aqueous or partially aqueous solutions, p-aminophenol is not detected during storage. Rapid
production of colored products having a pink tinge is noted, the reaction rate being a function of
temperature and light. In course of time, such derivatives are increasingly dark and evolutes to
brown color.

     All occurs as if, in contrast to what has been reported in the literature, the breakdown of
paracetamol first involves an oxydative process followed by hydrolysis. According to this theory,
paracetamol may react with an oxidant present in solution, for example oxygen dissolved in the
aqueous layer. This mechanism may involve the production of free radicals resulting in molecular
coupling, a fact that may account for the production of colored derivatives evoluting in color from
pink to brown.

     2.3 Tests for demonstrating inhibition of free radical production

     A typical reaction involving the production of free radicals involves adding a 30% aqueous
solution of hydrogen peroxide and a copper pentahydrate solution at a concentration of 62.5 mg/ml,
to a 1.25% aqueous solution of paracetamol. In a matter of minutes, there develops a color reaction
resulting in a color shift from yellow to dark brown. The color intensity observed decreases if
free radical scavengers or glycerol are prior added to the paracetamol solution. Color intensity is
a function of type of the type of free radical scavenger added, in the following decreasing order
as judged by color intensity.

     Paracetamolalone>paracetamol+N-acetylcystein>paracetamol+cystein>paracetamol+sorbitol>paracetamol+mannitol>
paracetamol+glycerol.

EXAMPLE III

Stabilizing paracetamol solution by selecting the

pH that allows maximal stability

     3.1 Concentrated solution

	 	 	 
	Ingredient	 	Quantity
	 
	Paracetamol

	 	0.160 g
	Propylene-glycol

	 	0.270 ml
	PEG 400

	 	0.360 ml
	Sodium
hydroxide 1N or Hydrochloric acid 1N q.s.f.

	 	pH 7.0-8.0-9.0-9.5-10.0
corresponding to actual pH: pH 5.8-6.7-7.1-7.5-8.0-8.5
	
Nitrogen q.s.f.

	 	purging and filling 
	
Water for injection

	 	q.s. 1000 ml

     Solution 20 containing paracetamol in a concentration of 160 mg/ml was adjusted to different
pH’s: the apparent pH is given in comparison to actual pH (between parenthesis) after a 5
fold-dilution: 7,0 (5,8)-8,0 (8,7)-8,5 (7,1)-9,0 (97,5)-9,5 (8,0)-10.0 (8,5) using a sodium
hydroxide or normal hydrochloric acid solution. Vials that had been filled under nitrogen
atmosphere by dispensing 10 ml of such solutions, tightly stoppered and capped, were sterilized by
autoclaving at 121° C. for 20 minutes, and then in every case exposed, either to a temperature of
105° C. in the dark for 72 hours, or to a radiation of an actinic light at 5000° K. and 25° C.
during 264 hours.

     Results

     After autoclaving, only the solution adjusted to pH 10 shows a pink tinge. After storage at
105° C. for 72 hours, absorbance at 500 nm as well as the concentration of breakdown products of
paracetamol were minimal in the pH range from 7,5 to 9,5. Upon storage in the presence of light,
the color strength is enhanced as the pH is increased. Color development is extremely weak at pH
7,0 (actual pH 5,8). Neither the paracetamol content, nor the breakdown products are affected by
pH.

     3.2 Diluted solution

	 	 	 
	Ingredient	 	Quantity
	 
	Paracetamol

	 	0.008 g
	Sodium chloride

	 	0.0067 g
	Disodium phosphate dihydrate

	 	0.0012 g
	5% Citric acid q.s.f.

	 	pH 5.0-6.0-7.0
	Nitrogen q.s.f.

	 	bubbling and filling
	Water for injection

	 	q.s.f. 1000 ml

     The aqueous solution diluted and buffered having a paracetamol content of 8 mg/ml was adjusted
to different pH values: pH 5,0-7,0 using a citric acid solution.

     Vials that had been packed under nitrogen atmosphere by dispensing 10 ml of such solution, were
tightly stoppered and capped, sterilized by autoclaving at 121° C.

 

 

6,028,222

for 20 minutes, and then in every case exposed to 70° C. in the dark during 231 hours.

Results

     Following autoclaving, only the solution adjusted to pH 7 shows a pink color. After storage,
this same solution displays the brightest pink color. At pH 6,0 and 5,0 the solutions are faintly
colored.

EXAMPLE IV

Stabilization of Paracetamol in Solution by Oxygen Removal Through Nitrogen Bubbling

     4.2 Diluted solution

     Solution Tested

	 	 	 	 	 
	 	 	Quantity
	 	 	Solution without	 	Solution subjected to
	Ingredient	 	nitrogen bubbling	 	nitrogen bubbling
	Paracetamol
	 	0.008 g	 	0.008 g
	Sodium chloride
	 	0.008 g	 	0.008 g
	Disodium phosphate
dihydrate
	 	000.1 g	 	0.001 q
	5% Citric acid
	 	q.s.f. pH 6.0	 	q.s.f. pH 6.0
	Nitrogen
	 	none	 	q.s.f. purging and filling
	Water for injection
	 	q.s.f. 1000 ml	 	q.s.f. 1000 ml
	 
	 	 	 	 

     The diluted aqueous solution containing paracetamol is adjusted to pH 6,0 by means of a
citric acid solution.

     Vials that had been filled under a nitrogen atmosphere by dispensing 10 ml of such solutions,
were tightly stoppered and capped and then stored inside an incubator at 98° C. for 15 hours.

     The percentage of secondary peaks in relation to the main peak of paracetamol was measured by
liquid chromatography, so was the pink color strength by reading the solution absorbance by
absorbance spectrophotometry at a peak absorption wavelength, that is 500 nm.

Results

	 	 	 	 	 	 	 	 	 
	 	 	Secondary peaks in	 	Solution
	 	 	% of paracetamol	 	absorbance
	Solution tested	 	main peak	 	at 500nm
	Solution packed without
nitrogen atmosphere
	 	 	1.57	 	 	 	0.036	 
	solution packed under
nitrogen atmosphere
	 	 	0.44	 	 	 	0.016	 

     The pink color of the solution packed under nitrogen atmosphere is considerably tainter
than that observed for the solution obtained after sterilization under nitrogen of the solution
packed without nitrogen.

EXAMPLE V

Stabilizing Solutions of Paracetamol by Adding
Free Radical Antagonists

     5.1 Concentrated solution

	 	 	 
	Ingredient	 	Quantity
	Paracetamol

	 	0.160 g
	Propylene-glycol

	 	0.270 ml
	PEG 400

	 	0.360 ml
	Hydrochloric acid 1N
Or NaOH 1N q.s.f.

	 	pH 6.0
	Free radical scavenger (see
quantitative results)

	 	q.s.f. (see quantitative results)
	Nitrogen q.s.f.

	 	purging and filling
	Water for injection

	 	q.s.f 1000 ml

     The solutions thus prepared are divided in 10 ml capacity vials, stoppered with a
Bromobutyl stopper and capped with an aluminium cap. After autoclaving at 121° C. for 20 minutes,
the vials were stored for 48 hours, either in the presence of actinic light at 5500° K. at room
temperature or at 70° C. in the dark. The preparation was examined for any change in color.

Results

	 	 	 	 	 	 	 	 	 	 	 	 	 
	 	 	 	 	 	 	Appearance	 	Appearance
	 	 	 	 	 	 	of the solution	 	of solution
	 	 	 	 	 	 	upon exposure	 	at 70° C.
	Free radical	 	 	 	 	 	to light	 	Color
	scavenger	 	Concentration	 	Color intensity	 	intensity
	No scavenger
	 	 	—	 	 	pink (+)	 	pink (++)
	Sodium disulfite
	 	0.295 mg/ml	 	colorless	 	Colorless
	Sodium ascorbate
	 	1.0 mg/ml	 	yellow (+)	 	yellow (+)
	Reduced glutathion
	 	1 mg/ml	 	colorless	 	colorless
	Reduced glutathion
	 	8 mg/ml	 	colorless	 	colorless
	Cystein
hydrochloride
	 	1 mg/ml	 	cloudy	 	cloudy
	a-monothioglycerol
	 	1 mg/ml	 	colorless	 	colorless
	Dithiothreitol
	 	1 mg/ml	 	colorless	 	colorless
	Mannitol
	 	50 mg/ml	 	colorless	 	colorless

5.2 Dilute solution

Solutions tested

	 	 	 	 	 	 	 
	 	 	Quantity
	 	 	Formulation A	 	Formulation B	 	Formulation C
	Paracetamol

	 	0.008 g
	 	0.01 g
	 	0.0125 g
	Sodium chloride

	 	0.008 g
	 	0.008 g
	 	0.00486 g
	Disodium phosphate
dihydrate or sodium
acetate

	 	0.001 g
	 	0.001 g
	 	0.00125 g
	Hydrochloric acid

	 	q.s. pH 6.0
	 	q.s. pH 6.0
	 	q.s pH 5.5
	C.R.L.	 	q.s (see quantitative results)

	Nitrogen q.s.f.	 	purging and filling

	Water	 	q.s.f. 1000 ml

     The solutions thus prepared were divided in 10 ml, 100 ml or 80 ml capacity vials,
stoppered with a Bromobutyl stopper and capped with an aluminium cap. The preparation was examined
for any pink color development.

     After autoclaving at 121° C. for 20 minutes, the vials were stored for 48 hours, either in the
presence of actinic light at 5500° K. at room temperature or at 70° C. in the dark (formula A).

     After autoclaving at 124° C. for 7 minutes, the vials were stored for 48 hours at room
temperature in the dark (formulation B and C). The preparation was examined for any pink shift and
the paracetamol as well as CRL were measured where a thiol derivative was used.

     Results (CRL=free radical scavenger)

 

 

6,028,222

	 	 	 	 	 	 	 	 	 	 	 
	 	 	 	 	Solution	 	 
	 	 	 	 	appearance	 	 
	 	 	 	 	upon exposure	 	Solution appearance
	 	 	 	 	to light	 	at 70°
	C.R.L used	 	Concentration	 	color	 	strength	 	Color	 	strength
	No C.R.L

	 	—
	 	pink
	 	(+)
	 	pink
	 	(++)
	Thiourea

	 	0.5 mg/ml
	 	colorless
	 	 	 	colorless	 	 
	Dithiothreitol

	 	1 mg/ml
	 	colorless
	 	 	 	colorless	 	 
	a-monothio-glycerol

	 	1 mg/ml
	 	colorless
	 	 	 	colorless	 	 
	gluthathion

	 	1 mg/ml
	 	colorless
	 	 	 	colorless	 	 
	Sodium

	 	0.2 mg/ml
	 	pink
	 	(+)
	 	pink
	 	(+)
	ascorbate

	 	0.4 mg/ml
	 	colorless
	 	 	 	yellow
	 	(+)
	 

	 	0.6 mg/ml
	 	pink
	 	(+)
	 	yellow
	 	(+)
	 

	 	1.0 mg/ml
	 	colorless
	 	 	 	yellow
	 	(+)
	Cystein

	 	0.05 mg/ml
	 	colorless
	 	 	 	colorless	 	 
	hydrochloride

	 	0.1 mg/ml
	 	colorless
	 	 	 	colorless	 	 
	 

	 	0.25 mg/ml
	 	colorless
	 	 	 	colorless	 	 
	 

	 	0.5 mg/ml
	 	colorless
	 	 	 	colorless	 	 
	 

	 	0.75 mg/ml
	 	colorless
	 	 	 	colorless	 	 
	 

	 	1 mg/ml
	 	colorless
	 	 	 	colorless	 	 
	 

	 	2 mg/ml
	 	colorless
	 	 	 	colorless	 	 
	 

	 	5 mg/ml
	 	colorless
	 	 	 	colorless	 	 

	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	Dosage (in % of
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	theoretical
	 	 	 	 	 	 	Solution appearance	 	volume
	 	 	Concen-	 	 	 	 	 	 	 	 	 	 	 	 	 	parace-
	C.R.L. used	 	tration	 	color	 	strength	 	C.R.L.	 	tamol
	Cystein
hydrochloride
monohydrate
	 	0.2 mg/ml	 	colorless	 	 	 	 	 	 	80	%	 	 	99.2	%
	Cystein
hydrochloride
monohydrate
	 	0.5 mg/ml	 	colorless	 	 	 	 	 	 	95	%	 	 	99.6	%
	N-acetylcystein
	 	0.2 mg/ml	 	colorless	 	 	 	 	 	 	88	%	 	 	99.2	%
	Mannitol
	 	20 mg/ml	 	colorless	 	 	 	 	 	 	 	 	 	 	 	 
	Mannitol
	 	40 mg/ml	 	Colorless	 	 	 	 	 	 	 	 	 	 	 	 
	Mannitol
	 	50 mg/ml	 	Colorless	 	 	 	 	 	 	 	 	 	 	 	 
	Glucose
	 	50 mg/ml	 	Colorless	 	 	 	 	 	 	 	 	 	 	 	 

EXAMPLE VI

Stabilization of Solutions of Paracetamol
Containing a Morphinic Compound by Addition of
a Free Radical Scavenger

6.1 Concentrated solution

Solutions tested

	 	 	 
	Ingredient	 	Quantity
	Paracetamol

	 	0.160 g
	Codein phosphate

	 	0.008 g
	Propylene-glycol

	 	0.270 ml
	PEG 400

	 	0.360 ml
	Hydrochloric acid 1N q.s.

	 	q.s. pH 6.0
	Free radical scavenger

	 	q.s. (see quantitative results)
	Water for injection

	 	q.s.f. 1000 ml

     The solutions thus prepared were divided in 10 ml capacity vials, stoppered with a
Bromobutyl stopper and capped with a removable aluminium cap. After autoclaving at 121° C. for 20
minutes, the vials were stored for 48 hours either under actinic light at 5500° K. at room
temperature, or at 70° C. in the dark. The preparation was inspected for any change in color.

Results

	 	 	 	 	 	 	 	 	 	 	 
	 	 	 	 	Solution apperance upon	 	Solution apperance
	Free radical	 	 	 	exposure to light	 	70° C
	scavenger	 	Concentration	 	color	 	strength	 	color	 	strength
	No free radical scavenger

	 	—
	 	pink
	 	(+)
	 	pink
	 	(++)
	Sodium disulfite

	 	0.295 mg/ml
	 	yellow
	 	(+)
	 	yellow
	 	(++)
	Sodium ascorbate

	 	1.0 mg/ml
	 	yellow
	 	(++)
	 	yellow
	 	(+++)
	reduced glutathion

	 	1 mg/ml
	 	yellow
	 	 	 	amber yellow
	 	(+++)
	 

	 	8 mg/ml
	 	colorless
	 	 	 	yellow
	 	(++)
	 

	 	16 mg/ml
	 	colorless
	 	(+)
	 	yellow
	 	(+)
	Dithio-threitol
sodium hypo-phosphite

	 	1 mg/ml
	 	violet pink
	 	(+++)
	 	violet pink
	 	(++++)
	 

	 	5mg/ml
	 	pink
	 	(+)
	 	pink
	 	(++)

6.2 Dilute solutions

Solutions tested

	 	 	 
	Ingredient	 	Quantity
	Paracetamol

	 	0.008 g
	Codein phosphate

	 	0.0004 g
	Sodium chloride

	 	0.008 g
	Disodium phosphate dihydrate

	 	0.0015 g
	Hydrochloric acid

	 	q.s.f. pH 6.0
	Free radical scavenger

	 	q.s. (see results)
	Nitrogen q.s.f.

	 	purging and filling
	Water for injection

	 	q.s.f. 1000 ml

     The solutions thus prepared were divided in 10 ml capacity vials, stoppered with a
Bromobutyl stopper and capped with an aluminium cap. After autoclaving at 121° C. for 20 minutes,
the vials were stored for 48 hours, either under actinic light at 5500° C. at room temperature, or
at 70° C. in the dark. The preparation was examined for any change in color.

     For the solution not containing any free radical scavenger and for the solution containing 0.5
mg/ml of cystein hydrochloride as free radical antagonist, paracetamol as well as codein are
measured by high performance liquid chromatography, immediately after autoclaving, in comparison
with identical solutions not subjected to autoclaving.

     Appearence scoring of the solutions

	 	 	 	 	 	 	 	 	 	 	 
	 	 	 	 	Solution apperance upon	 	Solution apperance
	Free radical	 	 	 	exposure to light	 	70° C
	scavenger	 	Concentration	 	color	 	strength	 	color	 	strength
	No free radical scavenger

	 	—
	 	pink
	 	(+)
	 	pink
	 	(+)
	Sodium disulfite

	 	0.295 mg/ml
	 	colorless
	 	 	 	colorless	 	 
	Dithio-threitol

	 	0.5 mg/ml
	 	colorless
	 	 	 	colorless	 	 
	Monothio-glycerol

	 	0.5 mg/ml
	 	grey
	 	 	 	grey	 	 
	Reduced glutathion

	 	2.0 mg/ml
	 	colorless
	 	 	 	colorless	 	 
	N-acetylcystein

	 	2.0 mg/ml
	 	grey
	 	(+)
	 	grey
	 	(+)
	Cystein hydro-chloride

	 	0.05 mg/ml
	 	colorless
	 	 	 	pink	 	 
	 

	 	0.1 mg/ml
	 	colorless
	 	 	 	colorless	 	 
	 

	 	0.25 mg/ml
	 	colorless
	 	 	 	colorless	 	 
	 

	 	0.5 mg/ml
	 	colorless
	 	 	 	colorless	 	 
	 

	 	0.75 mg/ml
	 	colorless
	 	 	 	colorless	 	 
	 

	 	1.0 mg/ml
	 	colorless
	 	 	 	colorless	 	 
	 

	 	2.0 mg/ml
	 	colorless
	 	 	 	colorless	 	 
	 

	 	5.0 mg/ml
	 	colorless
	 	 	 	colorless
	 	(+)

     Assay results of paracetamol and codein

	 	 	 	 	 	 	 
	Solution tested	 	Ingredient assayed	 	non sterilized solution	after sterilization
	Solutions with no
free radical
scavenger added

	 	paracetamol
codein
	 	0.0078 g/ml
	 	0.0077 g/ml
	 

	 	 	 	0.00043 g/ml
	 	0.00042 g/ml
	Solution containing
0.5 mg/ml of
cystein
hydrochloride

	 	paracetamol
codein
	 	0.0082 g/ml
	 	0.0081 g/ml
	 

	 	 	 	0.00042 g/ml
	 	0.00042 g/ml

There is noted the lack of color development one one hand and excellent preservation of the
active ingredients after heat treatment sterilization on the other hand.

 

 

6,028,222

EXAMPLE VII

Biological Tolerance to the Preparation

7.1 Hematological tolerance

Tested solutions

	 	 	 
	Ingredient	 	Quantity
	Paracetamol

	 	0.160 g
	Propylene-glycol

	 	0.270 ml
	PEC 400

	 	0.360 ml
	Nitrogen q.s.f.

	 	purging and filling
	Water for injection

	 	q.s.f. 1000 ml

     The solution pH was not adjusted. The apparent pH is 7.6, corresponding to an actual pH of
6.5.

     Whole human blood is incubated with the solution under study, in equal proportions by volume.
2 ml were drawn at 10 minutes intervals and centrifuged for 5 minutes at 5000 rpm. 100 .mu.l of the
supernatant were diluted in 1 ml of distilled water. The absorbance of this solution was determined
against a water blank at 540 nm, peak absorption wavelength of hemoglobin.

     The study was run in comparison with a negative control (physiological saline) and a positive
control (pure water for injection).

Results

     The absorbances of the individual solutions after different incubation periods are provided in
the following table.

	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Solution	 	TO	 	10 min	 	20 min	 	30 min	 	40 min	 	50 min	 	60 min
	Water p.p.i
	 	 	2.23	 	 	 	2.52	 	 	 	2.30	 	 	 	2.37	 	 	 	2.38	 	 	 	2.33	 	 	 	2.36	 
	Physio-logical
saline
	 	 	0.04	 	 	 	0.05	 	 	 	0.05	 	 	 	0.05	 	 	 	0.04	 	 	 	0.05	 	 	 	0.04	 
	Sol. Tested
	 	 	0.09	 	 	 	0.19	 	 	 	0.27	 	 	 	0.25	 	 	 	0.24	 	 	 	0.24	 	 	 	0.25	 

7.2 Muscular tolerance

Solution tested

	 	 	 
	Ingredient	 	Quantity
	Paracetamol

	 	0.160 g
	Propylene-glycol

	 	0.270 ml
	PEG 400

	 	0.360 ml
	Nitrogen q.s.f.

	 	purging and filling
	Water for injection

	 	q.s.f. 1000 ml

     The pH of this solution was not adjusted. Apparent pH is equal to 7,6.

     Sprague-Dawley rats, weighing between 260 g and 450 g were anesthesized with an i.p. injection
of ethyl carbamate (2 ml/kg of a 50% aqueous solution). The extensor digitorum longus muscle was
dissected from the right or left hind leg, and placed in buffer medium having the following
composition:

	 	 	 
	Ingredient	 	Quantity
	Sodium chloride

	 	6.8 g
	Potassium chloride

	 	0.4 g
	Dextrose

	 	1.0 g
	Sodium bicarbonate

	 	2.2 g
	Phenol red (sodium salt)

	 	0.005 g
	Distilled water q.s.f.

	 	1 liter
	Hydrochloric acid 1N q.s.f.

	 	pH 7.4

     The muscle is transiently fixed to a board and maintained in position by tendons. The test
product was injected in an amount of 15 .mu.l by means of a 25 .mu.l-capacity Hamilton seringe no
702. The muscle is then placed over a grit and immersed in the buffer solution kept at 37° C. with
carbogen bubbling throughout the incubation period. At 30 minutes intervals, the muscles were
introduced in a tube containing fresh buffer at 37° C. The procedure was repeated 4 times. The
buffer solution hence incubated is assayed for creatine kinase activity.

The study was run in parallel with:

muscle alone not subjected to injection (blank)

needle alone (introducing the needle without product injection)

physiological saline

Triton X-100 solution (negative controls)

solution 20

solution 20+paracetamol 160 mg/ml.

     Creatine kinase was measured using a Hitachi 704 model analyzer in conjunction with a reagent
kit sold under tradename high performance Enzyline CK NAC 10 (Biomerieux).

Results

     The creatine kinase activity (IU/l) of the individual solutions after variable incubation
periods are provided in the table given hereinafter:

	 	 	 	 	 	 	 	 	 	 	 	 	 
	Solution tested	 	30 min	 	60 min	 	90 min	 	120 min	 	Total
	Muscle alone

	 	23 .±. 6
	 	24 .±. 12
	 	15 .±. 7
	 	13 .±. 5
	 	 	75	 
	Needle alone

	 	35 .±. 6
	 	33 .±. 10
	 	20 .±. 4
	 	18 .±. 7
	 	 	106	 
	Physiological saline

	 	30 .±. 6
	 	10 .±. 12
	 	17 .±. 6
	 	23 .±. 4
	 	 	100	 
	Triton-X

	 	1802 .±. 2114
	 	1716 .±. 978
	 	155 .±. 89
	 	289 .±. 251
	 	 	14962	 
	Solution 20
(excipients)

	 	71 .±. 24
	 	89 .±. 40
	 	39 .±. 27
	 	62 .±. 39
	 	 	261	 
	Solution 20 +
paracetamol

	 	141 .±. 40
	 	150 .±. 60
	 	68 .±. 63
	 	34 .±. 24
	 	 	393	 

     No necrosis signs were recorded using the composition according to the invention as no
significant difference between the results of test and excipient solutions was noted.

     What is claimed is:

     1. A stable, liquid formulation consisting essentially of acetaminophen dispersed in an
aqueous medium containing a buffering agent and at least one member of the group consisting of a
free radical scavenger and a radical antagonist.

     2. The formulation of claim 1 wherein the aqueous medium has been deoxygenated by bubbling a
water-insoluble inert gas.

     3. The formulation of claim 1 wherein the aqueous medium is buffered at a pH of 4 to 8.

     4. The formulation of claim 3 wherein the aqueous medium is buffered at a pH of 5.5 to 6.

     5. The formulation of claim 1 containing a free radical antagonist selected from the group
consisting of ascorbic acid ascorbic acid derivatives, organic compounds having at least one thiol
and a alkyl polyhydroxylated and cycloalkyl polyhydroxylated compounds.

     6. The formulation of claim 5 wherein the ascorbic acid derivatives are selected from the
group consisting of D-ascorbic acid, L-ascorbic acid, alkali metal ascorbates, alkaline earth metal
ascorbates and water-soluble ascorbic acid esters.

 

 

6,028,222

     7. The formulation of claim 5 wherein the organic compound having at least one thiol is
aliphatic or cycloaliphatic.

     8. The formulation of claim 1 containing a free radical scavenger containing at least one
thiol is selected from the group consisting of thiolglycolic acid, thiolacetic acid,
dithiothreitol, reduced glutathion, thiourea,
a-thioglycerol, cystein, acetlcystein and
mercaptoethane sulfonic acid.

     9. The formulation of claim 1 wherein the free radical scavenger is an aliphatic polyhydroxy
alkanol of 2 to 10 carbon atoms.

     10. The formulation of claim 9 wherein the polyhydroxy alkanol is a cyclic glucitol or a
straight chain glucitol of 6 to 10 carbon atoms.

     11. The formulation of claim 9 wherein the polyhydroxy alkanol is glycerol or propylene
glycol.

     12. The formulation of claim 10 wherein the cyclic glucitol is selected from the group
consisting of mannitol, sorbitol, inositol, glucose and levulose.

     13. The formulation of claim 1 also containing at least one complexing agent.

     14. The formulation of claim 1 wherein the acetaminophen has a concentration of 2 to 350
mg/ml.

     15. The formulation of claim 14 wherein the concentration is 60 is 350 mg/ml.

     16. The formulation of claim 14 diluted to a concentration of 2 to 50 mg/ml.

     17. The formulation of claim 1 also containing an isotonizing agent in an amount to obtain
isotonicity.

     18. The formulation of claim 1 sterilized by heat treatment.

     19. The formulation of claim 1 further containing an effective amount of an analgetic agent.

     20. The formulation of claim 19 the analgetic agent is a morphine analgetic selected from the
group consisting of natural morphines, semi-synthetic morphines, synthetic morphines,
phenylpiperidines, nipecotic acid compounds, phenylcyclohexanol compounds and phenylazepine
compounds.

     21. The formulation of claim 20 having a concentration of acetaminophen is 0.05 to 5% by
weight when morphine is present.

     22. The formulation of claim 20 having an acetaminophen concentration of 0.2 to 2.5% by
weight when codeine is present.

     23. The formulation of claim 1 further containing an anti-inflammatory agent of the
phenylacetic acid type.

     24. The formulation of claim 23 wherein the anti-inflammatory agent is ketoprofen.

     25. The formulation of claim 1 further containing an antiemetic agent.

     26. The formulation of claim 1 further containing an antipileptic agent.

     27. The formulation of claim 1 further containing a corticosteroid.

     28. The formulation of claim 1 further containing a tricyclic antidepressant.

 

 

Appendix 1

Exhibit B

SUMMARY OF INTERNATIONAL PATENT APPLICATION PCT/FR97/01452, FILED ON
 5th AUGUST 1997

This international patent application (PCT/FR97/01452) was filed on August 5, 1997. The
invention relates to novel stable paracetamol compositions for use in therapeutic chemistry and
specifically galenic pharmacy. The compositions contain a solution of paracetamol in an aqueous
solvent combined with a buffer having a pH of 4 to 8, and a free radical capturing agent. A
water-insoluble inert gas is carefully bubbled through the aqueous solvent to remove oxygen from
the medium. Said compositions may also be combined with a centrally or peripherally acting
analgesic agent, and are provided as injectable compositions for relieving pain.

 

 

Appendix 1

Exhibit C

SUMMARY OF INTERNATIONAL PATENT APPLICATION PCT/FR01/01749, FILED ON
 6th JUNE 2001

This international patent application (PCT/FR01/01749) was filed on June 6, 2001. The
invention concerns the field of organic chemistry and more particularly that of therapeutic
chemistry. More precisely, it concerns a method for obtaining aqueous formulations of easily
oxidizable active principles, in particular phenols, stable over a prolonged
period, which consists in advanced bubbling deoxygenation with an inert gas and or vacuumizing
them, while protecting them against possible oxygen uptake by maintaining them under inert gas
atmosphere, by filling under inert gas into bottles previously made air-free by inert gas blowing,
then in subjecting them when they are being closed to a vacuum so as to obtain in the bottle a
pressure of not more than 65.000 Pa, thereby obtaining solutes having a residual oxygen
concentration in the solution, less than 2 ppm, and preferably of the order of 1 ppm and
even 0.5 ppm. The invention is useful in particular for preparing injection preparations having an
oxygen content in the solution, less than 2 ppm.

 

 

 

Appendix I

Exhibit D-1

AGREEMENT FOR ASSIGNMENT OF PRIORITY RIGHT 

between

NEWPHARM, Société Civile de Recherche, registered at the National Trade Book under the serial
number 344 260 161 and the place of incorporation of which is situated at 5 rue d’Angiviller 78000
Versailles, represented by Mr DIETLIN François as its manager

Hereinafter designer as the “assignor” on one part,

and

PHARMATOP, Société Civile de Recherche, registered at the National Trade Book under the serial
number 407 552 702 and the place of incorporation of which is situated at 5 rue d’Angiviller 78000
Versailles, represented by Mrs FREDJ Danièle as its manager

Hereinafter designer as the “assignee” on the other part.

As the performance of a convention intervened this day between the same parties, it has been
set and agreed that follows: 

Article 1: Definitions

“Patent” means the French patent application filed on August 5, 1996 with the n°96-09858 under the
title “Novel stable liquid formulations based on Paracetamol and their mode of preparation”.

“Priority right” means the Unionist priority right stemming from the filing of the said “Patent” in
accordance with article 4 of the Convention of Union of Paris dated March 20, 1883.

Article 1: Assignment

The assignor assigns through the present to the assignee which agrees, the full and entire
ownership of the priority right.

 

 

Article 2 : Applicable law

The law which is applicable for this agreement is the French law.

Article 3 : Advertising

All powers are given to the bearer of an original of these documents for requesting or performing
all formalities, registrations, publications, filing and mentioning everywhere and in every
administration where need will be.

Made at Versailles in three originals, February 15, 1997.

	 	 	 	 	 
	 	 	 	 	 
	NEWPHARM

	 	 	 	PHARMATOP
	Represented by François DIETLIN

	 	 	 	Represented by Danièle FREDJ

 

 

 

Appendix 1

GEI-062

Exhibit D-2

ASSIGNMENT OF APPLICATION FOR PATENT

     WHEREAS, WE, Francois Dietlin & Daniele Fredj
citizens of France and residents of France for which Application PCT/FR97/01452 has been
filed on 8/5/97 in which the United States has been named as a Designated State, and an
app1ication for Letters Patent of the United States thus entitled has been made, said
app1ication having been executed on even date herewith and the French priority date
of August 5, 1996 of Application Serial No. 96/09858 is hereby claimed.

     WHEREAS, SCR Pharmatop a corporation duly organized and existing under the laws of France
and having a place of business at 5, rue d’Angiville F-78000 Versailles, France is
desirous of acquiring the entire right, title and interest in and to said invention, application
and any Letters Patent which may issue thereon;

     NOW, THEREFORE, to all whom it may concern, be it known that we, the said
François Dietlin & Daniele Fredj for and in
consideration of the sum of ONE DOLLAR ($1.00) to us in hand paid by the said
SCR Pharmatop and for other good
and valuable considerations, the receipt of all of which is hereby acknowledged, do hereby
sell, assign, transfer and set over unto the said SCR Pharmatop its
successors and assigns, the entire right, title and interest in and to said invention, said
application and any Letters Patent that may issue thereon in the United States together with
any division or divisions, extension or extensions, reissue or reissues thereof;

     AND, we hereby authorize and request the Commissioner of Patents and Trademarks
to issue any and all Letters Patent which may issue upon said invention to said SCR
Pharmatop as assignee of the entire right, title and interest in and to said
invention, application and any Letters Patent that may issue thereupon.

 

GEI—061

     IN WITNESS WHEREOF, We have hereunto set our hands as of the following
date:

	 	 	 	 	 	 	 	 	 
	 

	 	 	 	Date:	 	 	 	 
	 

FRANCOIS DIETLIN

	 	 	 	 	 	 

	 	 
	 
	 	 	 	 	 	 	 	 
	 

	 	 	 	Date:	 	 	 	 
	 

DANIELE FREDJ

	 	 	 	 	 	 

	 	 
	 
	 	 	 	 	 	 	 	 
	 

	 	 	 	 	 	 

	 	 
	 
	 	 	 	 	 	 	 	 
	 

	 	 	 	Date:	 	 	 	 
	 

	 	 	 	 	 	 

	 	 
	 
	 	 	 	 	 	 	 	 
	 

	 	 	 	Date:	 	 	 	 
	 

	 	 	 	 	 	 

	 	 
	 
	 	 	 	 	 	 	 	 
	 

	 	 	 	Date:	 	 	 	 
	 

	 	 	 	 	 	 

	 	 

	 	 	 	 	 
	 

	 	:	 	 
	 

	 	:
	 	ss:
	 

	 	:	 	 

     On this                     day of                                          before me personally came
                                                                                 to
me know and known to me to be the
individuals described in and who executed the foregoing instrument and fully acknowledged that they
executed the same.

	 	 	 	 	 	 	 	 	 
	 

	 	 	 	 
	 	 

	 	 

 

	 	 	 	 	 
		 	UNITED STATES DEPARTMENT OF COMMERCE

Patent and Trademark Office

ASSISTANT SECRETARY AND COMMISSIONER

	April 19, 1999

	 	PTAS
	 	PF PATENTS AND TRADEMARKS

Washington, D.C. 20231
	 
	 	 	 	 
	BIERMAN,
MUSERLIAN AND LUCAS
CHARLES A. MUSERLIAN
600 THIRD AVENUE
NEW YORK, NY 10016	 	
	 
	 	 
	 	 

UNITED STATES PATENT AND TRADEMARK OFFICE

NOTICE OF RECORDATION OF ASSIGNMENT DOCUMENT

THE ENCLOSED DOCUMENT HAS BEEN RECORDED BY THE ASSIGNMENT DIVISION OF THE U.S. PATENT AND TRADEMARK
OFFICE. A COMPLETE MICROFILM COPY IS AVAILABLE AT THE ASSIGNMENT SEARCH ROOM ON THE REEL AND FRAME
NUMBER REFERENCED BELOW.

PLEASE REVIEW ALL INFORMATION CONTAINED ON THIS NOTICE. THE INFORMATION CONTAINED ON THIS
RECORDATION NOTICE REFLECTS THE DATA PRESENT IN THE PATENT AND TRADEMARK ASSIGNMENT SYSTEM. IF YOU
SHOULD FIND ANY ERRORS OR HAVE QUESTIONS CONCERNING THIS NOTICE, YOU MAY CONTACT THE EMPLOYEE WHOSE
NAME APPEARS ON THIS NOTICE AT 703-308-9723. PLEASE SEND REQUEST FOR CORRECTION TO: U.S. PATENT
AND TRADEMARK OFFICE, ASSIGNMENT DIVISION, BOX ASSIGNMENTS, CG-4, 1213 JEFFERSON DAVIS HWY, SUITE
320, WASHINGTON, D.C. 20231.

	 	 	 
	RECORDATION DATE: 07/15/1998
	 	REEL/FRAME:  9706/0031
	 
	 	NUMBER OF PAGES:  3
	 
	 	 
	BRIEF: ASSIGNMENT OF ASSIGNOR’S INTEREST (SEE DOCUMENT FOR DETAILS).
	 
	 	 
	ASSIGNOR:
	 	 
	DIETLIN, FRANCOIS
	 	DOC DATE:  04/20/1998
	 
	 	 
	ASSIGNOR:
	 	 
	FREDJ, DANIELE
	 	DOC DATE:  04/20/1998
	 
	 	 
	ASSIGNEE:
	 	 
	SCR PHARMATOP
	 	 
	5, RUE D’ANGIVILLE
	 	 
	F-78000 VERSAILLES, FRANCE
	 	 

 

 

	 	 	 
	SERIAL NUMBER: 09051246
	 	FILING DATE: 06/05/1998
	PATENT NUMBER:
	 	ISSUE DATE:
	 
	 	 
	KIMBERLY WHITE, EXAMINER
	 	 
	ASSIGNMENT DIVISION
	 	 
	OFFICE OP PUBLIC RECORDS
	 	 

 

 

Appendix 1

Exhibit E

Newpharm

Résidence
Concorde — 10, square Saint-Florentin 7815 Le Chesnay

BRISTOL MYERS SQUIBB COMPANY

345 Park Avenue

New York NY 10154

USA

Paris, 20 December 2002

Dear Sirs,

We, SCR
NEWPHARM, are the owner of the French patent filed on 5
August 1996 under n°96.
09858 and issued under n°2.751.875.

We hereby represent to BMS

	 	•	 	that Mrs Danièle FREDJ and Mr François DIETLIN, inventors, have assigned to us,
except for the USA, all their rights,
	 
	 	•	 	that they have assigned their rights for the USA directly to PHARMATOP on 20
April 1998,
	 
	 	•	 	and that we have assigned to SCR PHARMATOP, an affiliated partnership, all
priority rights for all countries listed in international patent application PCT/FR97/01452
except USA on 15 February 1997.

We covenant that we will never contest or challenge the rights of PHARMATOP

	 	•	 	on US patent n°6.028.222 issued on 22 February 2000,
	 
	 	•	 	PCT/FR01/01749 filed on 6 June 2001,
	 
	 	•	 	and on any patent or supplementary protection certificate that PHARMATOP may
obtain that depends on hereabove stated patent or that is granted based on the hereabove
stated patent applications,

in the United States (including Puerto Rico and all US possessions and territories), Canada and
Mexico.

 

 

We agree that PHARMATOP will be solely and fully responsible for all and any payments owed by it to
us based on said rights and that we shall never claim to you whatsoever amount on these concerns.

Sincerely yours.

	 	 	 
	Danièle Fredj
	 	François Dietlin
	 	 	 
	
	 	

Société Civile de Recherche

Capital 1,341,551.35 € — Siret D 344 260 161 00023

Tel. : 33 1 39 54 55 77 — Telecopy : 33 1 39 66 91 85

 

 

APPENDIX 2

TARGET PRODUCT PROFILE

	A.	 	Indications at Launch 

     (a) PRODUCT is indicated for the treatment of post-operative acute pain in adults.

     (b) PRODUCT may be administered for up to 3 days.

     (a) PRODUCT may be administered concomitantly with morphine.

	B.	 	Supporting Clinical Data available for promotion at Launch

     (a) Single dose analgesic efficacy in oral surgery pain model. Onset of analgesia: less
than 10 minutes. Duration of analgesia: 4 to 6 hours.

     (b) Multiple dose analgesic efficacy confirmed in two different pain models:
orthopaedic surgery and lower abdominal surgery. Efficacy of proposed dosing regimen, p.r.n.
or fixed time, clearly demonstrated. Efficacy in combination with PCA morphine demonstrated.

	C.	 	Safety at LAUNCH

     (i) No clinically significant drug/drug interactions.

     (ii) PRODUCT has comparable tolerance to placebo at the injection site.

     (iii) PRODUCT carries no black box warnings.

     (iv) PRODUCT has gastrointestinal safety profile comparable to placebo.

     (v) PRODUCT has CNS safety profile comparable to placebo.

     (vi) PRODUCT has cardiovascular safety profile comparable to placebo.

     (vii) In cases of creatinine clearance <10 ml/min, due to the lack of data, infusion should
be used with caution.

	D.	 	Dosing at LAUNCH

     (i) PRODUCT is administered as a 15-minute intravenous infusion of 1gram. May be used every 4
to 6 hours, or up to 4 times per day. Maximum daily dose must not exceed 4 grams.

 

			
	 	 	Assumes conduct of 2 new clinical trials prior to NDA submission

 

 

APPENDIX 3

Exceptions to PHARMATOP Representations and Warranties

	–	 	international patent application PCT/W002/072080 A2 filed by FRESENIUS KABI DEUTSCHLAND GMBH, a
copy of which is attached.

SUMMARY OF INTERNATIONAL PATENT APPLICATION PCT/WO02/072080 A2,
 FILED BY FRESENIUS KABI DEUTSCHLAND

GMBH

This international patent application (PCT/WO02/072080 A2) was filed on March 12, 2002 by
Fresenius Kabi Deutschland GmbH. The invention relates to parenterally administrable, especially
infusible, aqueous paracetamol solutions which are stable in storage and free of particles and
discoloration. Said solutions contain a mixture of: a) between 1 and 17 grams of paracetamol per
liter, and b) between 0.01 and 0.17 grams of at least one physiologically compatible antioxidant
per liter, selected from the group comprising ascorbic acid, N-acetyl-L-cysteine and stabilizer
compounds containing SII groups which are different from N-acetyl-L-cysteine. The aqueous solution
is free of organic solvents and has a pH value of between 5.5 and 6.5 and an oxygen content of less than
0.5 milligrams per liter. The invention also relates to a method for producing such solutions, and
glass or plastic containers containing said solutions.

 

 

 

APPENDIX 4

GUARANTEED PAYMENTS (in US$ millions)

	 	 	 	 	 	 	 	 	 
	Year 1	 	Year 2	 	Year 3	 	Year 4	 	Year 5
	$[***]
	 	$[***]
	 	$[***]
	 	$[***]
	 	$[***]

Guaranteed Payment amounts shall be payable subject to applicable terms and conditions of the
Agreement, shall be payable (when applicable) on a quarterly basis, and shall be due at the same
time as a royalty payment would otherwise have been due and payable for such quarter.

 

			
	***	 	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.
 

 

 

Appendix 5

	 	 	 
	[Translation]

	 	ANNEX 2: PROCEDURES AND PRECAUTIONS RELATING TO THE MANUFACTURE
 OF THE FORMULATION PMC 0397

These procedures and precautions were established starting from the methods implemented during
successive manufacture, at the Delmas Laboratories, of the pilot batches of Perfalgan® whose
compositions, dates of manufacture and volumes implemented are indicated hereafter:

[* * *]

 

***   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.

 

 

[* * *]

 

***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.

 

 

[* * *]

 

***  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.

 

 

[***]

 

			
	***	 	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.

 

 

[***]

 

 

 

			
	***	 	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.

 

 

[***]

 

 

 

			
	***	 	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.

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