Document:

Nuvelo, Inc. 2004 Equity Incentive Plan, as amended

 Exhibit 10.41 
  
 NUVELO, INC. 
  
 2004 EQUITY INCENTIVE PLAN 

 TABLE OF CONTENTS 
  

							
	 	  	 	  	 	  	Page

	1.	  	Establishment, Purpose and Term of Plan	  	1
	 	  	1.1	  	 Establishment
	  	1
	 	  	1.2	  	 Purpose
	  	1
	 	  	1.3	  	 Term of Plan
	  	1
			
	2.	  	Definitions and Construction	  	1
	 	  	2.1	  	 Definitions
	  	1
	 	  	2.2	  	 Construction
	  	6
			
	3.	  	Administration	  	7
	 	  	3.1	  	 Administration by the Committee
	  	7
	 	  	3.2	  	 Authority of Officers
	  	7
	 	  	3.3	  	 Administration with Respect to Insiders
	  	7
	 	  	3.4	  	 Committee Complying with Section 162(m)
	  	7
	 	  	3.5	  	 Powers of the Committee
	  	7
	 	  	3.6	  	 No Repricing
	  	8
	 	  	3.7	  	 No Restricted Stock Award Acceleration
	  	9
	 	  	3.8	  	 Indemnification
	  	9
			
	4.	  	Shares Subject to Plan	  	9
	 	  	4.1	  	 Maximum Number of Shares Issuable
	  	9
	 	  	4.2	  	 Adjustments for Changes in Capital Structure
	  	10
			
	5.	  	Eligibility and Award Limitations	  	10
	 	  	5.1	  	 Persons Eligible for Awards
	  	10
	 	  	5.2	  	 Participation
	  	10
	 	  	5.3	  	 Incentive Stock Option Limitations
	  	11
	 	  	5.4	  	 Award Limits
	  	11
			
	6.	  	Terms and Conditions of Options	  	12
	 	  	6.1	  	 Exercise Price
	  	12
	 	  	6.2	  	 Exercisability and Term of Options
	  	12
	 	  	6.3	  	 Payment of Exercise Price
	  	13
	 	  	6.4	  	 Effect of Termination of Service
	  	14
	 	  	6.5	  	 Transferability of Options
	  	14
			
	7.	  	Terms and Conditions of Stock Appreciation Rights	  	14
	 	  	7.1	  	 Types of SARs Authorized
	  	14
	 	  	7.2	  	 Exercise Price
	  	14
	 	  	7.3	  	 Exercisability and Term of SARs
	  	14
	 	  	7.4	  	 Exercise of SARs
	  	15
	 	  	7.5	  	 Deemed Exercise of SARs
	  	15
	 	  	7.6	  	 Effect of Termination of Service
	  	15
	 	  	7.7	  	 Nontransferability of SARs
	  	15

  

 -i- 

 TABLE OF CONTENTS 
 (continued) 
  

							
	 	  	 	  	 	  	Page

	8.	  	Terms and Conditions of Restricted Stock Awards	  	15
	 	  	8.1	  	 Types of Restricted Stock Awards Authorized
	  	16
	 	  	8.2	  	 Purchase Price
	  	16
	 	  	8.3	  	 Purchase Period
	  	16
	 	  	8.4	  	 Payment of Purchase Price
	  	16
	 	  	8.5	  	 Vesting and Restrictions on Transfer
	  	17
	 	  	8.6	  	 Voting Rights; Dividends and Distributions
	  	17
	 	  	8.7	  	 Effect of Termination of Service
	  	17
	 	  	8.8	  	 Nontransferability of Restricted Stock Award Rights
	  	17
			
	9.	  	Terms and Conditions of Performance Awards	  	18
	 	  	9.1	  	 Types of Performance Awards Authorized
	  	18
	 	  	9.2	  	 Initial Value of Performance Shares and Performance Units
	  	18
	 	  	9.3	  	 Establishment of Performance Period, Performance Goals and Performance Award Formula
	  	18
	 	  	9.4	  	 Measurement of Performance Goals
	  	19
	 	  	9.5	  	 Settlement of Performance Awards
	  	20
	 	  	9.6	  	 Voting Rights; Dividend Equivalent Rights and Distributions
	  	21
	 	  	9.7	  	 Effect of Termination of Service
	  	21
	 	  	9.8	  	 Nontransferability of Performance Awards
	  	21
			
	10.	  	Terms and Conditions of Restricted Stock Unit Awards	  	22
	 	  	10.1	  	 Grant of Restricted Stock Unit Awards
	  	22
	 	  	10.2	  	 Purchase Price
	  	22
	 	  	10.3	  	 Vesting
	  	22
	 	  	10.4	  	 Voting Rights, Dividend Equivalent Rights and Distributions
	  	22
	 	  	10.5	  	 Effect of Termination of Service
	  	23
	 	  	10.6	  	 Settlement of Restricted Stock Unit Awards
	  	23
	 	  	10.7	  	 Nontransferability of Restricted Stock Unit Awards
	  	23
			
	11.	  	Deferred Stock Units	  	23
	 	  	11.1	  	 Establishment of Deferred Stock Unit Program
	  	23
	 	  	11.2	  	 Terms and Conditions of Deferred Stock Units
	  	24
			
	12.	  	Standard Forms of Award Agreement	  	25
	 	  	12.1	  	 Award Agreements
	  	25
	 	  	12.2	  	 Authority to Vary Terms
	  	25
			
	13.	  	Change in Control	  	25
	 	  	13.1	  	 Definitions
	  	25
	 	  	13.2	  	 Effect of Change in Control on Options and SARs
	  	26
	 	  	13.3	  	 Effect of Change in Control on Restricted Stock Awards
	  	27
	 	  	13.4	  	 Effect of Change in Control on Performance Awards
	  	27
	 	  	13.5	  	 Effect of Change in Control on Restricted Stock Unit Awards
	  	27
	 	  	13.6	  	 Effect of Change in Control on Deferred Stock Units
	  	28
			
	14.	  	Compliance with Securities Law	  	28

  

 -ii- 

 TABLE OF CONTENTS 
 (continued) 
  

							
	 	  	 	  	 	  	Page

	15.	  	Tax Withholding	  	28
	 	  	15.1	  	 Tax Withholding in General
	  	28
	 	  	15.2	  	 Withholding in Shares
	  	28
			
	16.	  	Amendment or Termination of Plan	  	29
			
	17.	  	Miscellaneous Provisions	  	29
	 	  	17.1	  	 Repurchase Rights
	  	29
	 	  	17.2	  	 Provision of Information
	  	29
	 	  	17.3	  	 Rights as Employee, Consultant or Director
	  	29
	 	  	17.4	  	 Rights as a Stockholder
	  	29
	 	  	17.5	  	 Fractional Shares
	  	30
	 	  	17.6	  	 Severability
	  	30
	 	  	17.7	  	 Beneficiary Designation
	  	30
	 	  	17.8	  	 Unfunded Obligation
	  	30

  

 -iii- 

 AMENDED AND RESTATED 
 NUVELO, INC. 
 2004 EQUITY INCENTIVE PLAN 
  
 1. ESTABLISHMENT, PURPOSE
AND TERM OF PLAN 
  
 1.1 Establishment. The Nuvelo, Inc. 2004 Equity Incentive Plan (the “Plan”) is
hereby established effective as of May 6, 2004, the date of its approval by the stockholders of the Company (the “Effective Date”). 
  
 1.2 Purpose. The purpose of the Plan is to advance the interests of the Participating Company Group
and its stockholders by providing an incentive to attract, retain and reward persons performing services for the Participating Company Group and by motivating such persons to contribute to the growth and profitability of the Participating Company
Group. The Plan seeks to achieve this purpose by providing for Awards in the form of Options, Indexed Options, Stock Appreciation Rights, Restricted Stock Purchase Rights, Restricted Stock Bonuses, Performance Shares, Performance Units, Restricted
Stock Units and Deferred Stock Units. After the Effective Date, the Company shall terminate, and no longer issue any awards from under, the Company’s 2002 Equity Incentive Plan, Director Stock Option Plan, Scientific Advisory Board/Consultants
Stock Option Plan, 1995 Stock Option Plan and the Variagenics 1997 Employee, Director & Consultant Stock Option Plan. 
  
 1.3 Term of Plan. The Plan shall continue in effect until the earlier of its termination by the Board or the date on which all of
the shares of Stock available for issuance under the Plan have been issued and all restrictions on such shares under the terms of the Plan and the agreements evidencing Awards granted under the Plan have lapsed. However, all Incentive Stock Options
shall be granted, if at all, within ten (10) years from the Effective Date. 
  
 2. DEFINITIONS AND CONSTRUCTION. 
  
 2.1 Definitions. Whenever used herein, the following terms shall have their respective meanings set forth below: 
  
 (a)
“Affiliate” means (i) an entity, other than a Parent Corporation, that directly, or indirectly through one or more intermediary entities, controls the Company or (ii) an entity, other than a
Subsidiary Corporation, that is controlled by the Company directly, or indirectly through one or more intermediary entities. For this purpose, the term “control” (including the term “controlled by”) means the possession, direct
or indirect, of the power to direct or cause the direction of the management and policies of the relevant entity, whether through the ownership of voting securities, by contract or otherwise; or shall have such other meaning assigned such term for
the purposes of registration on Form S-8 under the Securities Act. 
  

 1 

 (b) “Award” means any Option, Indexed
Option, SAR, Restricted Stock Purchase Right, Restricted Stock Bonus, Performance Share, Performance Unit, Restricted Stock Unit or Deferred Stock Unit granted under the Plan. 
  
 (c) “Award Agreement” means a written agreement between
the Company and a Participant setting forth the terms, conditions and restrictions of the Award granted to the Participant. An Award Agreement may be an “Option Agreement,” an “Indexed Option Agreement,” a “SAR
Agreement,” a “Restricted Stock Purchase Agreement,” a “Restricted Stock Bonus Agreement,” a “Performance Share Agreement,” a “Performance Unit Agreement,” a “Restricted Stock Unit Agreement,”
or a “Deferred Stock Unit Agreement.” 
  
 (d) “Board” means the Board of Directors of the Company. 
  
 (e) “Code” means the Internal Revenue Code of 1986, as amended, and any
applicable regulations promulgated thereunder. 
  
 (f) “Committee” means the Compensation Committee or other committee of the Board duly appointed to administer the Plan and having such powers as shall be specified by the Board. If
no committee of the Board has been appointed to administer the Plan, the Board shall exercise all of the powers of the Committee granted herein, and, in any event, the Board may in its discretion exercise any or all of such powers. 
  
 (g)
“Company” means Nuvelo, Inc., a Nevada corporation, or any successor corporation thereto. 
  
 (h) “Consultant” means a person engaged to provide consulting or advisory
services (other than as an Employee or a member of the Board) to a Participating Company, provided that the identity of such person, the nature of such services or the entity to which such services are provided would not preclude the Company from
offering or selling securities to such person pursuant to the Plan in reliance on a Form S-8 Registration Statement under the Securities Act. 
  
 (i) “Deferred Stock Unit” means a bookkeeping entry representing a right granted to a
Participant pursuant to Section 11 of the Plan to receive a share of Stock on a date determined in accordance with the provisions of Section 11 and the Participant’s Award Agreement. 
  
 (j)
“Director” means a member of the Board. 
  
 (k) “Disability” means the permanent and total disability of the Participant,
within the meaning of Section 22(e)(3) of the Code. 
  
 (l) “Dividend Equivalent” means a credit, made at the discretion of the Committee or as otherwise provided by the Plan, to the account of a Participant in an amount equal to the cash
dividends paid on one share of Stock for each share of Stock represented by an Award held by such Participant. 
  

 2 

 (m) “Employee” means any
person treated as an employee (including an Officer or a Director who is also treated as an employee) in the records of a Participating Company and, with respect to any Incentive Stock Option granted to such person, who is an employee for purposes
of Section 422 of the Code; provided, however, that neither service as a Director nor payment of a Director’s fee shall be sufficient to constitute employment for purposes of the Plan. The Company shall determine in good faith and in the
exercise of its discretion whether an individual has become or has ceased to be an Employee and the effective date of such individual’s employment or termination of employment, as the case may be. For purposes of an individual’s rights, if
any, under the Plan as of the time of the Company’s determination, all such determinations by the Company shall be final, binding and conclusive, notwithstanding that the Company or any court of law or governmental agency subsequently makes a
contrary determination. 
  
 (n)
“Exchange Act” means the Securities Exchange Act of 1934, as amended. 
  
 (o) “Fair Market Value” means, as of any date, the value of a share of Stock or
other property as determined by the Committee, in its discretion, or by the Company, in its discretion, if such determination is expressly allocated to the Company herein, subject to the following: 
  
 (i) If, on such date, the Stock is listed on a national or
regional securities exchange or market system, the Fair Market Value of a share of Stock shall, unless expressly determined otherwise by the Committee, in its discretion, be the average of the high and low price of a share of Stock on such date, as
quoted on the Nasdaq National Market, The Nasdaq SmallCap Market or such other national or regional securities exchange or market system constituting the primary market for the Stock, as reported in The Wall Street Journal or such other
source as the Company deems reliable. If the relevant date does not fall on a day on which the Stock has traded on such securities exchange or market system, the date on which the Fair Market Value shall be established shall be the last day on which
the Stock was so traded prior to the relevant date, or such other appropriate day as shall be determined by the Committee, in its discretion. 
  
 (ii) If, on such date, the Stock is not listed on a national or regional securities exchange or market system, the Fair Market Value of a
share of Stock shall be as determined by the Committee in good faith without regard to any restriction other than a restriction which, by its terms, will never lapse. 
  
 (p) “Incentive Stock Option” means an Option intended to
be (as set forth in the Award Agreement) and which qualifies as an incentive stock option within the meaning of Section 422(b) of the Code. 
  
 (q) “Indexed Option” means an Option with an exercise price which either increases by
a fixed percentage over time or changes by reference to a published index, as determined by the Committee and set forth in the Option Agreement. 
  

 3 

 (r) “Insider” means an Officer, a
Director or any other person whose transactions in Stock are subject to Section 16 of the Exchange Act. 
  
 (s) “Nonstatutory Stock Option” means an Option not intended to be (as set
forth in the Award Agreement) an incentive stock option within the meaning of Section 422(b) of the Code. 
  
 (t) “Officer” means any person designated by the Board as an officer of the Company.

  
 (u)
“Option” means the right to purchase Stock at a stated price for a specified period of time granted to a Participant pursuant to Section 6 of the Plan. An Option may be either an Incentive
Stock Option, a Nonstatutory Stock Option or an Indexed Option. 
  
 (v) “Parent Corporation” means any present or future “parent corporation” of the Company, as defined in Section 424(e) of the Code. 
  
 (w)
“Participant” means any eligible person who has been granted one or more Awards. 
  
 (x) “Participating Company” means the Company or any Parent Corporation,
Subsidiary Corporation or Affiliate. 
  
 (y)
“Participating Company Group” means, at any point in time, all entities collectively which are then Participating Companies. 
  
 (z) “Performance Award” means an Award of Performance
Shares or Performance Units. 
  
 (aa)
“Performance Award Formula” means, for any Performance Award, a formula or table established by the Committee pursuant to Section 9.3 of the Plan which provides the basis for computing the value of
a Performance Award at one or more threshold levels of attainment of the applicable Performance Goal(s) measured as of the end of the applicable Performance Period. 
  
 (bb) “Performance Goal” means a performance goal
established by the Committee pursuant to Section 9.3 of the Plan. 
  
 (cc) “Performance Period” means a period established by the Committee pursuant to Section 9.3 of the Plan at the end of which one or more Performance Goals are to be
measured. 
  
 (dd)
“Performance Share” means a bookkeeping entry representing a right granted to a Participant pursuant to Section 9 of the Plan to receive a payment equal to the value of a Performance Share, as
determined by the Committee, based on performance. 
  

 4 

 (ee) “Performance Unit” means a
bookkeeping entry representing a right granted to a Participant pursuant to Section 9 of the Plan to receive a payment equal to the value of a Performance Unit, as determined by the Committee, based upon performance. 
  
 (ff) “Prior Plan
Options” means any option or other award granted by the Company which is subject to vesting or repurchase by the Company, including specifically, all such options and awards granted pursuant to the Company’s 2002
Equity Incentive Plan, Director Stock Option Plan, Scientific Advisory Board/Consultants Stock Option Plan, 1995 Stock Option Plan and the Variagenics 1997 Employee, Director & Consultant Stock Option Plan which is outstanding on or after the
Effective Date.  
  
 (gg)
“Restricted Stock Award” means an Award of a Restricted Stock Bonus or a Restricted Stock Purchase Right. 
  

(hh) “Restricted Stock Bonus” means Stock granted to a Participant pursuant to
Section 8 of the Plan. 
  
 (ii)
“Restricted Stock Purchase Right” means a right to purchase Stock granted to a Participant pursuant to Section 8 of the Plan. 
  
 (jj) “Restricted Stock Unit” or
“Stock Unit” means a bookkeeping entry representing a right granted to a Participant pursuant to Section 10 of the Plan to receive a share of Stock on a date determined in accordance with the
provisions of Section 10 and the Participant’s Award Agreement. 
  
 (kk) “Restriction Period” means the period established in accordance with Section 8.5 of the Plan during which shares subject to a Restricted Stock Award are subject
to Vesting Conditions. 
  
 (ll)
“Retirement” means a Participant’s termination of Service, if as of the date of such termination, the Participant has reached the age of fifty-eight (58) and has completed eight (8) years of
continuous Service to the Participating Company Group. A Participant who terminates Service with the Participating Company Group and resumes Service more than six (6) months after his or her original termination date, will not have his or her
Service with the Participant Company Group prior to his or her original termination date count for purposes of determining Retirement. Notwithstanding the foregoing, the Board shall have the discretion to determine on a case by case basis whether
such prior Service with the Participant Company Group may be counted for purposes of Retirement. The Board will notify any rehired Participant if the Board has determined such prior Service will count towards Retirement, and in the absence of such
notification from the Board, such Service shall not be counted for purposes of Retirement. 
  
 (mm) “Rule 16b-3” means Rule 16b-3 under the Exchange Act, as amended from time to
time, or any successor rule or regulation. 
  
 (nn) “SAR” or “Stock Appreciation Right” means a bookkeeping entry representing, for each share of Stock subject to such SAR, a right
granted to a Participant pursuant to Section 7 of the Plan to receive payment of an amount equal to the excess, if any, of 

  

 5 

 
the Fair Market Value of a share of Stock on the date of exercise of the SAR over the exercise price. 
  
 (oo) “Section
162(m)” means Section 162(m) of the Code. 
  
 (pp) “Securities Act” means the Securities Act of 1933, as amended. 
  

(qq) “Service” means a Participant’s employment or service with the Participating Company
Group, whether in the capacity of an Employee, a Director or a Consultant. A Participant’s Service shall not be deemed to have terminated merely because of a change in the capacity in which the Participant renders such Service or a change in
the Participating Company for which the Participant renders such Service, provided that there is no interruption or termination of the Participant’s Service. Furthermore, a Participant’s Service shall not be deemed to have terminated if
the Participant takes any military leave, sick leave, or other bona fide leave of absence approved by the Company. However, if any such leave taken by a Participant exceeds ninety (90) days, then on the one hundred eighty-first (181st) day following
the commencement of such leave any Incentive Stock Option held by the Participant shall cease to be treated as an Incentive Stock Option and instead shall be treated thereafter as a Nonstatutory Stock Option, unless the Participant’s right to
return to Service with the Participating Company Group is guaranteed by statute or contract. Notwithstanding the foregoing, unless otherwise designated by the Company or required by law, a leave of absence shall not be treated as Service for
purposes of determining vesting under the Participant’s Award Agreement. A Participant’s Service shall be deemed to have terminated either upon an actual termination of Service or upon the entity for which the Participant performs Service
ceasing to be a Participating Company. In addition, a Participant’s Service shall be deemed to have terminated if, in the Committee’s sole discretion, the Participant’s employment relationship is transferred to an Affiliate or
Subsidiary Corporation and the Participant is offered a replacement equity award from the Affiliate or Subsidiary Corporation. Subject to the foregoing, the Company, in its discretion, shall determine whether the Participant’s Service has
terminated and the effective date of such termination. 
  
 (rr) “Stock” means the common stock of the Company, as adjusted from time to time in accordance with Section 4.2 of the Plan. 
  
 (ss) “Subsidiary
Corporation” means any present or future “subsidiary corporation” of the Company, as defined in Section 424(f) of the Code. 
  
 (tt) “Ten Percent Owner” means a Participant who, at the
time an Incentive Stock Option is granted to the Participant, owns stock possessing more than ten percent (10%) of the total combined voting power of all classes of stock of a Participating Company (other than an Affiliate) within the meaning of
Section 422(b)(6) of the Code. 
  
 (uu)
“Vesting Conditions” mean those conditions established in accordance with Section 8.5 or Section 10.3 of the Plan prior to the satisfaction of which shares subject to a Restricted Stock Award or
Restricted Stock Unit Award, respectively, remain subject to forfeiture or a repurchase option in favor of the Company upon the Participant’s termination of Service. 
  

 6 

 2.2 Construction. Captions and titles contained herein are for convenience only
and shall not affect the meaning or interpretation of any provision of the Plan. Except when otherwise indicated by the context, the singular shall include the plural and the plural shall include the singular. Use of the term “or” is not
intended to be exclusive, unless the context clearly requires otherwise. 
  
 3. ADMINISTRATION 
  
 3.1 Administration by the Committee. The Plan shall be administered by the Committee. All questions of interpretation of the Plan
or of any Award shall be determined by the Committee, and such determinations shall be final and binding upon all persons having an interest in the Plan or such Award. 
  
 3.2 Authority of Officers. Any Officer shall have the authority to act on behalf of the Company with
respect to any matter, right, obligation, determination or election which is the responsibility of or which is allocated to the Company herein, provided the Officer has apparent authority with respect to such matter, right, obligation, determination
or election. The Board may, in its discretion, delegate to a committee comprised of one or more Officers the authority to grant one or more Awards, without further approval of the Board or the Committee, to any Employee, other than a person who, at
the time of such grant, is an Insider; provided, however, that (a) such Awards shall not be granted for shares in excess of the maximum aggregate number of shares of Stock authorized for issuance pursuant to Section 4.1, (b) the exercise price per
share of each Option shall be not less than the Fair Market Value per share of the Stock on the effective date of grant (or, if the Stock has not traded on such date, on the last day preceding the effective date of grant on which the Stock was
traded), and (iii) each such Award shall be subject to the terms and conditions of the appropriate standard form of Award Agreement approved by the Board or the Committee and shall conform to the provisions of the Plan and such other guidelines as
shall be established from time to time by the Board or the Committee. 
  
 3.3 Administration with Respect to Insiders. With respect to participation by Insiders in the Plan, at any time that any class of equity security of the Company is registered pursuant to Section 12 of the
Exchange Act, the Plan shall be administered in compliance with the requirements, if any, of Rule 16b-3. 
  
 3.4 Committee Complying with Section 162(m). If the Company is a “publicly held corporation” within the meaning of
Section 162(m), the Board may establish a Committee of “outside directors” within the meaning of Section 162(m) to approve the grant of any Award which might reasonably be anticipated to result in the payment of employee remuneration that
would otherwise exceed the limit on employee remuneration deductible for income tax purposes pursuant to Section 162(m). 
  
 3.5 Powers of the Committee. In addition to any other powers set forth in the Plan and subject to the provisions of the Plan, the
Committee shall have the full and final power and authority, in its discretion: 
  
 (a) to determine the persons to whom, and the time or times at which, Awards shall be granted and the number of shares of Stock or units
to be subject to each Award; 
  

 7 

 (b) to determine the type of Award granted and to designate Options as Incentive Stock
Options, Nonstatutory Stock Options or Indexed Options; 
  
 (c) to determine the Fair Market Value of shares of Stock or other property; 
  
 (d) to determine the terms, conditions and restrictions applicable to each Award (which need not be identical) and any shares acquired
pursuant thereto, including, without limitation, (i) the exercise or purchase price of shares purchased pursuant to any Award, (ii) the method of payment for shares purchased pursuant to any Award, (iii) the method for satisfaction of any tax
withholding obligation arising in connection with Award, including by the withholding or delivery of shares of Stock, (iv) the timing, terms and conditions of the exercisability or vesting of any Award or any shares acquired pursuant thereto, (v)
the Performance Award Formula and Performance Goals applicable to any Award and the extent to which such Performance Goals have been attained, (vi) the time of the expiration of any Award, (vii) the effect of the Participant’s termination of
Service on any of the foregoing, and (viii) all other terms, conditions and restrictions applicable to any Award or shares acquired pursuant thereto not inconsistent with the terms of the Plan; 
  
 (e) to determine whether an Award of Restricted Stock Units,
SARs, Performance Shares or Performance Units will be settled in shares of Stock, cash, or in any combination thereof; 
  
 (f) to approve one or more forms of Award Agreement; 
  
 (g) to amend, modify, extend, cancel or renew any Award or to waive any restrictions or conditions
applicable to any Award or any shares acquired pursuant thereto; 
  
 (h) to accelerate, continue, extend or defer the exercisability or vesting of any Award or any shares acquired pursuant thereto, including with respect to the period following a Participant’s termination of
Service; 
  
 (i) to prescribe, amend or rescind
rules, guidelines and policies relating to the Plan, or to adopt sub-plans or supplements to, or alternative versions of, the Plan, including, without limitation, as the Committee deems necessary or desirable to comply with the laws or regulations
of or to accommodate the tax policy, accounting principles or custom of, foreign jurisdictions whose citizens may be granted Awards; 
  
 (j) to authorize, in conjunction with any applicable Company deferred compensation plan, that the receipt of cash or Stock subject to any
Award under this Plan, may be deferred under the terms and conditions of such Company deferred compensation plan; and 
  
 (k) to correct any defect, supply any omission or reconcile any inconsistency in the Plan or any Award Agreement and to make all other
determinations and take 

  

 8 

 
such other actions with respect to the Plan or any Award as the Committee may deem advisable to the extent not inconsistent with the provisions of the Plan
or applicable law. 
  
 3.6 No Repricing.
Without the affirmative vote of holders of a majority of the shares of Stock cast in person or by proxy at a meeting of the stockholders of the Company at which a quorum representing a majority of all outstanding shares of Stock is present or
represented by proxy, the Board shall not approve a program providing for either (a) the cancellation of outstanding Options and/or SARs and the grant in substitution therefore of any new Awards, including specifically any new Options and/or SARs
having a lower exercise price or (b) the amendment of outstanding Options and/or SARs to reduce the exercise price thereof. This paragraph shall not be construed to apply to “issuing or assuming a stock option in a transaction to which section
424(a) applies,” within the meaning of Section 424 of the Code. 
  
 3.7 No Restricted Stock Award Acceleration. Notwithstanding any provision of the Plan to the contrary, no Restricted Stock Award may be granted which provides, or subsequently amended to provide, for (i) any
acceleration of vesting for any reason other than upon a Change in Control or after the Participant’s death or Disability and (ii) vesting of one hundred percent (100%) of any such Restricted Stock Award prior to the passage of three (3) years
of Service (unless such Restricted Stock Award will vest in accordance with the satisfaction of any Performance Measure set forth in Section 9.4). 
  
 3.8 Indemnification. In addition to such other rights of indemnification as they may have as members of the Board or the Committee
or as officers or employees of the Participating Company Group, members of the Board or the Committee and any officers or employees of the Participating Company Group to whom authority to act for the Board, the Committee or the Company is delegated
shall be indemnified by the Company against all reasonable expenses, including attorneys’ fees, actually and necessarily incurred in connection with the defense of any action, suit or proceeding, or in connection with any appeal therein, to
which they or any of them may be a party by reason of any action taken or failure to act under or in connection with the Plan, or any right granted hereunder, and against all amounts paid by them in settlement thereof (provided such settlement is
approved by independent legal counsel selected by the Company) or paid by them in satisfaction of a judgment in any such action, suit or proceeding, except in relation to matters as to which it shall be adjudged in such action, suit or proceeding
that such person is liable for gross negligence, bad faith or intentional misconduct in duties; provided, however, that within sixty (60) days after the institution of such action, suit or proceeding, such person shall offer to the Company, in
writing, the opportunity at its own expense to handle and defend the same. 
  
 4. SHARES SUBJECT TO PLAN. 
  
 4.1 Maximum Number of Shares Issuable. Subject to adjustment as provided in Section 4.2, the maximum
aggregate number of shares of Stock that may be granted under the Plan shall be Seven Million Two Hundred and Four Thousand and Eighty-Five (7,204,085), reduced at any time by the number of shares subject to the Prior Plan Options (which as of the
Effective Date equaled approximately Two Million Four Hundred and Fifty-Four Thousand and Eighty-Five (2,454,085)). Such shares shall consist of authorized but unissued or reacquired shares of Stock or any combination thereof. If any
outstanding Award, 

  

 9 

 
including any Prior Plan Options, for any reason expires or is terminated or canceled without having been exercised or settled in full, or if shares of Stock
acquired pursuant to an Award subject to forfeiture or repurchase, including any Prior Plan Options, are forfeited or repurchased by the Company, the shares of Stock allocable to the terminated portion of such Award, including any Prior Plan
Options, or such forfeited or repurchased shares of Stock shall again be available for grant under the Plan. Shares of Stock shall not be deemed to have been granted pursuant to the Plan (a) with respect to any portion of an Award that is settled in
cash or (b) to the extent such shares are withheld in satisfaction of tax withholding obligations pursuant to Section 15.2. Upon payment in shares of Stock pursuant to the exercise of a SAR, the number of shares available for grant under the Plan
shall be reduced only by the number of shares actually issued in such payment. If the exercise price of an Option is paid by tender to the Company, or attestation to the ownership, of shares of Stock owned by the Participant, the number of shares
available for grant under the Plan shall be reduced by the net number of shares for which the Option is exercised. 
  
 4.2 Adjustments for Changes in Capital Structure. Subject to any required action by the stockholders of the Company, in the event
of any change in the Stock effected without receipt of consideration by the Company, whether through merger, consolidation, reorganization, reincorporation, recapitalization, reclassification, stock dividend, stock split, reverse stock split,
split-up, split-off, spin-off, combination of shares, exchange of shares, or similar change in the capital structure of the Company, or in the event of payment of a dividend or distribution to the stockholders of the Company in a form other than
Stock (excepting normal cash dividends) that has a material effect on the Fair Market Value of shares of Stock, appropriate adjustments shall be made in the number and class of shares subject to the Plan and to any outstanding Awards, and in the
exercise or purchase price per share under any outstanding Award in order to prevent dilution or enlargement of Participants’ rights under the Plan. For purposes of the foregoing, conversion of any convertible securities of the Company shall
not be treated as “effected without receipt of consideration by the Company.” Any fractional share resulting from an adjustment pursuant to this Section 4.2 shall be rounded down to the nearest whole number, and in no event may the
exercise or purchase price under any Award be decreased to an amount less than the par value, if any, of the stock subject to such Award. The adjustments determined by the Committee pursuant to this Section 4.2 shall be final, binding and
conclusive. 
  
 5. ELIGIBILITY
AND AWARD LIMITATIONS. 
  
 5.1 Persons Eligible for Awards. Awards may be granted only to Employees, Consultants and Directors. For purposes of the foregoing
sentence, “Employees,”“Consultants”and “Directors” shall include prospective Employees, prospective Consultants and prospective Directors to whom Awards are granted in connection with written offers of an employment or
other service relationship with the Participating Company Group; provided, however, that no Stock subject to any such Award shall vest, become exercisable or be issued prior to the date on which such person commences Service. 
  
 5.2 Participation. Awards are granted solely at the
discretion of the Committee. Eligible persons may be granted more than one (1) Award. However, eligibility in 

  

 10 

 
accordance with this Section shall not entitle any person to be granted an Award, or, having been granted an Award, to be granted an additional Award.

  
 5.3 Incentive Stock Option Limitations.

  
 (a) Persons Eligible. An
Incentive Stock Option may be granted only to a person who, on the effective date of grant, is an Employee of the Company, a Parent Corporation or a Subsidiary Corporation (each being an “ISO-Qualifying
Corporation”). Any person who is not an Employee of an ISO-Qualifying Corporation on the effective date of the grant of an Option to such person may be granted only a Nonstatutory Stock Option. An Incentive Stock
Option granted to a prospective Employee upon the condition that such person become an Employee of an ISO-Qualifying Corporation shall be deemed granted effective on the date such person commences Service with an ISO-Qualifying Corporation, with an
exercise price determined as of such date in accordance with Section 6.1. 
  
 (b) Fair Market Value Limitation. To the extent that options designated as Incentive Stock Options (granted under all stock option plans of the Participating Company Group, including the Plan) become
exercisable by a Participant for the first time during any calendar year for stock having a Fair Market Value greater than One Hundred Thousand dollars ($100,000), the portion of such options which exceeds such amount shall be treated as
Nonstatutory Stock Options. For purposes of this Section, options designated as Incentive Stock Options shall be taken into account in the order in which they were granted, and the Fair Market Value of stock shall be determined as of the time the
option with respect to such stock is granted. If the Code is amended to provide for a different limitation from that set forth in this Section, such different limitation shall be deemed incorporated herein effective as of the date and with respect
to such Options as required or permitted by such amendment to the Code. If an Option is treated as an Incentive Stock Option in part and as a Nonstatutory Stock Option in part by reason of the limitation set forth in this Section, the Participant
may designate which portion of such Option the Participant is exercising. In the absence of such designation, the Participant shall be deemed to have exercised the Incentive Stock Option portion of the Option first. Upon exercise, shares issued
pursuant to each such portion shall be separately identified. 
  
 5.4 Award Limits. 
  
 (a)
Aggregate Limit on Restricted Stock Awards and Performance Awards. Subject to adjustment as provided in Section 4.2, in no event shall more than One Million (1,000,000) shares of Stock in the aggregate be issued under the Plan pursuant
to the exercise or settlement of Restricted Stock Awards and Performance Awards. 
  
 (b) Section 162(m) Award Limits. The following limits shall apply to the grant of any Award if, at the time of grant, the
Company is a “publicly held corporation” within the meaning of Section 162(m). 
  
 (i) Options and SARs. Subject to adjustment as provided in Section 4.2, no Employee shall be granted within any fiscal year of the
Company one or more Options or Freestanding SARs which in the aggregate are for more than Seven Hundred and Fifty Thousand (750,000) shares of Stock, provided, however, that the Company may make an 

  

 11 

 
additional one-time grant to any newly-hired Employee of an Option and/or SAR for the purchase of up to an additional Five Hundred Thousand (500,000) shares
of Stock. An Option which is canceled (or a Freestanding SAR as to which the exercise price is reduced to reflect a reduction in the Fair Market Value of the Stock) in the same fiscal year of the Company in which it was granted shall continue to be
counted against such limit for such fiscal year. 
  
 (ii) Restricted Stock Awards and Restricted Stock Units. Subject to adjustment as provided in Section 4.2, no Employee shall be granted within any fiscal year of the Company one or more Restricted Stock Awards or Restricted Stock
Units, subject to Vesting Conditions based on the attainment of Performance Goals, for more than Four Hundred Thousand (400,000) shares of Stock, provided, however, that the Company may make an additional one-time grant to any newly-hired Employee
of a Restricted Stock Award or Restricted Stock Units of up to an additional One Hundred and Fifty Thousand (150,000) shares of Stock. 
  
 (iii) Performance Awards. Subject to adjustment as provided in Section 4.2, no Employee shall be granted (A) Performance Shares
which could result in such Employee receiving more than Four Hundred Thousand (400,000) shares of Stock for each full fiscal year of the Company contained in the Performance Period for such Award, or (B) Performance Units which could result in such
Employee receiving more than Two Million dollars ($2,000,000) for each full fiscal year of the Company contained in the Performance Period for such Award. No Participant may be granted more than one Performance Award for the same Performance Period.

  
 6. TERMS AND
CONDITIONS OF OPTIONS. 
  
 Options shall be evidenced by Award Agreements specifying the number of shares of Stock covered thereby, in such form as the Committee
shall from time to time establish. No Option or purported Option shall be a valid and binding obligation of the Company unless evidenced by a fully executed Award Agreement. Award Agreements evidencing Options may incorporate all or any of the terms
of the Plan by reference and shall comply with and be subject to the following terms and conditions: 
  
 6.1 Exercise Price. The exercise price for each Option shall be established in the discretion of the Committee; provided, however,
that (a) the exercise price per share shall be not less than the Fair Market Value of a share of Stock on the effective date of grant of the Option, (b) no Incentive Stock Option granted to a Ten Percent Owner shall have an exercise price per share
less than one hundred ten percent (110%) of the Fair Market Value of a share of Stock on the effective date of grant of the Option, and (c) notwithstanding anything to the contrary in this Section 6.1, in the case of an Indexed Option, the Committee
shall determine the exercise price of such Indexed Option and the terms and conditions that affect, if any, any adjustments to the exercise price of such Indexed Option. Notwithstanding the foregoing, an Option may be granted with an exercise price
lower than the minimum exercise price set forth above if such Option is granted pursuant to an assumption or substitution for another option in a manner qualifying under the provisions of Section 424(a) of the Code. 
  

 12 

 6.2 Exercisability and Term of Options. Options shall be exercisable at such time
or times, or upon such event or events, and subject to such terms, conditions, performance criteria and restrictions as shall be determined by the Committee and set forth in the Award Agreement evidencing such Option; provided, however, that (a) no
Option shall be exercisable after the expiration of ten (10) years after the effective date of grant of such Option, (b) no Incentive Stock Option granted to a Ten Percent Owner shall be exercisable after the expiration of five (5) years after the
effective date of grant of such Option, and (c) no Option granted to a prospective Employee, prospective Consultant or prospective Director may become exercisable prior to the date on which such person commences Service. Subject to the foregoing,
unless otherwise specified by the Committee in the grant of an Option, any Option granted hereunder shall terminate ten (10) years after the effective date of grant of the Option, unless earlier terminated in accordance with its provisions.

  
 6.3 Payment of Exercise Price. 
  
 (a) Forms of Consideration Authorized. Except
as otherwise provided below, payment of the exercise price for the number of shares of Stock being purchased pursuant to any Option shall be made (i) in cash, by check or in cash equivalent, (ii) by tender to the Company, or attestation to the
ownership, of shares of Stock owned by the Participant having a Fair Market Value not less than the exercise price, (iii) by delivery of a properly executed notice of exercise together with irrevocable instructions to a broker providing for the
assignment to the Company of the proceeds of a sale or loan with respect to some or all of the shares being acquired upon the exercise of the Option (including, without limitation, through an exercise complying with the provisions of Regulation T as
promulgated from time to time by the Board of Governors of the Federal Reserve System) (a “Cashless Exercise”), (iv) by such other consideration as may be approved by the Committee from time to
time to the extent permitted by applicable law, or (v) by any combination thereof. The Committee may at any time or from time to time grant Options which do not permit all of the foregoing forms of consideration to be used in payment of the exercise
price or which otherwise restrict one or more forms of consideration. 
  
 (b) Limitations on Forms of Consideration. 
  
 (i) Tender of Stock. Notwithstanding the foregoing, an Option may not be exercised by tender to the Company, or attestation to the
ownership, of shares of Stock to the extent such tender or attestation would constitute a violation of the provisions of any law, regulation or agreement restricting the redemption of the Company’s stock. Unless otherwise provided by the
Committee, an Option may not be exercised by tender to the Company, or attestation to the ownership, of shares of Stock unless such shares either have been owned by the Participant for more than six (6) months (and not used for another Option
exercise by attestation during such period) or were not acquired, directly or indirectly, from the Company. 
  
 (ii) Cashless Exercise. The Company reserves, at any and all times, the right, in the Company’s sole and absolute discretion,
to establish, decline to approve or terminate any program or procedures for the exercise of Options by means of a Cashless Exercise, including with respect to one or more Participants specified by the Company notwithstanding that such program or
procedures may be available to other Participants. 
  

 13 

 6.4 Effect of Termination of Service. An Option shall be exercisable after a
Participant’s termination of Service to such extent and during such period as determined by the Committee, in its discretion, and set forth in the Award Agreement evidencing such Option. 
  
 6.5 Transferability of Options. During the lifetime
of the Participant, an Option shall be exercisable only by the Participant or the Participant’s guardian or legal representative. Prior to the issuance of shares of Stock upon the exercise of an Option, the Option shall not be subject in any
manner to anticipation, alienation, sale, exchange, transfer, assignment, pledge, encumbrance, or garnishment by creditors of the Participant or the Participant’s beneficiary, except transfer by will or by the laws of descent and distribution.
Notwithstanding the foregoing, to the extent permitted by the Committee, in its discretion, and set forth in the Award Agreement evidencing such Option, a Nonstatutory Stock Option shall be assignable or transferable subject to the applicable
limitations, if any, described in the General Instructions to Form S-8 Registration Statement under the Securities Act. Notwithstanding any of the foregoing, the Board may permit further transferability of any Option, on a general or specific basis,
and may impose conditions and limitations on any permitted transferability. 
  
 7. TERMS AND CONDITIONS OF STOCK APPRECIATION RIGHTS. 
  
 Stock Appreciation Rights shall be evidenced by Award
Agreements specifying the number of shares of Stock subject to the Award, in such form as the Committee shall from time to time establish. No SAR or purported SAR shall be a valid and binding obligation of the Company unless evidenced by a fully
executed Award Agreement. Award Agreements evidencing SARs may incorporate all or any of the terms of the Plan by reference and shall comply with and be subject to the following terms and conditions: 
  
 7.1 Types of SARs Authorized. SARs may be granted in
tandem with all or any portion of a related Option (a “Tandem SAR”) or may be granted independently of any Option (a “Freestanding SAR”). A
Tandem SAR may be granted either concurrently with the grant of the related Option or at any time thereafter prior to the complete exercise, termination, expiration or cancellation of such related Option. 
  
 7.2 Exercise Price. The exercise price for each SAR
shall be established in the discretion of the Committee; provided, however, that (a) the exercise price per share subject to a Tandem SAR shall be the exercise price per share under the related Option and (b) the exercise price per share subject to
a Freestanding SAR shall be not less than the Fair Market Value of a share of Stock on the effective date of grant of the SAR. 
  
 7.3 Exercisability and Term of SARs. 
  
 (a) Tandem SARs. Tandem SARs shall be exercisable only at the time and to the extent, and only to the extent, that the
related Option is exercisable, subject to such provisions as the Committee may specify where the Tandem SAR is granted with respect to less than the full number of shares of Stock subject to the related Option. The Committee may, in its discretion,
provide in any Award Agreement evidencing a Tandem SAR that such SAR may not be exercised without the advance approval of the Company and, if such approval is not given, then the Option shall nevertheless remain exercisable in accordance with its
terms. A 

  

 14 

 
Tandem SAR shall terminate and cease to be exercisable no later than the date on which the related Option expires or is terminated or canceled. Upon the
exercise of a Tandem SAR with respect to some or all of the shares subject to such SAR, the related Option shall be canceled automatically as to the number of shares with respect to which the Tandem SAR was exercised. Upon the exercise of an Option
related to a Tandem SAR as to some or all of the shares subject to such Option, the related Tandem SAR shall be canceled automatically as to the number of shares with respect to which the related Option was exercised. 
  
 (b) Freestanding SARs. Freestanding SARs shall
be exercisable at such time or times, or upon such event or events, and subject to such terms, conditions, performance criteria and restrictions as shall be determined by the Committee and set forth in the Award Agreement evidencing such SAR;
provided, however, that no Freestanding SAR shall be exercisable after the expiration of ten (10) years after the effective date of grant of such SAR. 
  
 7.4 Exercise of SARs. Upon the exercise (or deemed exercise pursuant to Section 7.5) of a SAR, the Participant (or the
Participant’s legal representative or other person who acquired the right to exercise the SAR by reason of the Participant’s death) shall be entitled to receive payment of an amount for each share with respect to which the SAR is exercised
equal to the excess, if any, of the Fair Market Value of a share of Stock on the date of exercise of the SAR over the exercise price. Payment of such amount shall be made in cash, shares of Stock, or any combination thereof as determined by the
Committee. Unless otherwise provided in the Award Agreement evidencing such SAR, payment shall be made in a lump sum as soon as practicable following the date of exercise of the SAR. The Award Agreement evidencing any SAR may provide for deferred
payment in a lump sum or in installments. When payment is to be made in shares of Stock, the number of shares to be issued shall be determined on the basis of the Fair Market Value of a share of Stock on the date of exercise of the SAR. For purposes
of Section 7, a SAR shall be deemed exercised on the date on which the Company receives notice of exercise from the Participant. 
  
 7.5 Deemed Exercise of SARs. If, on the date on which a SAR would otherwise terminate or expire, the SAR by its terms remains
exercisable immediately prior to such termination or expiration and, if so exercised, would result in a payment to the holder of such SAR, then any portion of such SAR which has not previously been exercised shall automatically be deemed to be
exercised as of such date with respect to such portion. 
  
 7.6 Effect of Termination of Service. Subject to earlier termination of the SAR as otherwise provided herein a SAR shall be exercisable after a Participant’s termination of Service to such extent and
during such period as determined by the Committee, in its discretion, and set forth in the Award Agreement evidencing such SAR and thereafter shall terminate. 
  

7.7 Nontransferability of SARs. During the lifetime of the Participant, a SAR shall be exercisable only by the Participant or
the Participant’s guardian or legal representative. Prior to the exercise of a SAR, the SAR shall not be subject in any manner to anticipation, alienation, sale, exchange, transfer, assignment, pledge, encumbrance, or garnishment by creditors
of the Participant or the Participant’s beneficiary, except transfer by will or by the laws of descent and distribution. Notwithstanding any of the foregoing, the Board 

  

 15 

 
may permit further transferability of any SAR, on a general or specific basis, and may impose conditions and limitations on any permitted transferability.

  
 8. TERMS AND
CONDITIONS OF RESTRICTED STOCK AWARDS. 
  
 Restricted Stock Awards shall be evidenced by Award Agreements specifying whether the Award is a Restricted Stock Bonus or a Restricted
Stock Purchase Right and the number of shares of Stock subject to the Award, in such form as the Committee shall from time to time establish. No Restricted Stock Award or purported Restricted Stock Award shall be a valid and binding obligation of
the Company unless evidenced by a fully executed Award Agreement. Award Agreements evidencing Restricted Stock Awards may incorporate all or any of the terms of the Plan by reference and shall comply with and be subject to the following terms and
conditions: 
  
 8.1 Types of Restricted Stock
Awards Authorized. Restricted Stock Awards may be in the form of either a Restricted Stock Bonus or a Restricted Stock Purchase Right. Restricted Stock Awards may be granted upon such conditions as the Committee shall determine, including,
without limitation, upon the attainment of one or more Performance Goals described in Section 9.4. If either the grant of a Restricted Stock Award or the lapsing of the Restriction Period is to be contingent upon the attainment of one or more
Performance Goals, the Committee shall follow procedures substantially equivalent to those set forth in Sections 9.3. through 9.5(a). 
  
 8.2 Purchase Price. The purchase price for shares of Stock issuable under each Restricted Stock Purchase Right shall be established
by the Committee in its discretion. No monetary payment (other than applicable tax withholding) shall be required as a condition of receiving shares of Stock pursuant to a Restricted Stock Bonus, the consideration for which shall be services
actually rendered to a Participating Company or for its benefit. Notwithstanding the foregoing, the Participant shall furnish consideration in the form of cash or past services rendered to a Participating Company or for its benefit having a value
not less than the par value of the shares of Stock subject to such Restricted Stock Award. 
  
 8.3 Purchase Period. A Restricted Stock Purchase Right shall be exercisable within a period established by the Committee, which
shall in no event exceed thirty (30) days from the effective date of the grant of the Restricted Stock Purchase Right; provided, however, that no Restricted Stock Purchase Right granted to a prospective Employee, prospective Consultant or
prospective Director may become exercisable prior to the date on which such person commences Service. 
  
 8.4 Payment of Purchase Price. Except as otherwise provided below, payment of the purchase price for the number of shares of Stock
being purchased pursuant to any Restricted Stock Purchase Right shall be made (a) in cash, by check, or in cash equivalent, (b) by such other consideration as may be approved by the Committee from time to time to the extent permitted by applicable
law, or (iii) by any combination thereof. The Committee may at any time or from time to time grant Restricted Stock Purchase Rights which do not permit all of the foregoing forms of consideration to be used in payment of the purchase price or which
otherwise 

  

 16 

 
restrict one or more forms of consideration. Restricted Stock Bonuses shall be issued in consideration for past services actually rendered to a Participating
Company or for its benefit. 
  
 8.5 Vesting
and Restrictions on Transfer. Shares issued pursuant to any Restricted Stock Award may or may not be made subject to Vesting Conditions based upon the satisfaction of such Service requirements, conditions, restrictions or performance criteria,
including, without limitation, Performance Goals as described in Section 9.4, as shall be established by the Committee and set forth in the Award Agreement evidencing such Award. During any Restriction Period in which shares acquired pursuant to a
Restricted Stock Award remain subject to Vesting Conditions, such shares may not be sold, exchanged, transferred, pledged, assigned or otherwise disposed of other than pursuant to an Ownership Change Event, as defined in Section 13.1, or as provided
in Section 8.8. Upon request by the Company, each Participant shall execute any agreement evidencing such transfer restrictions prior to the receipt of shares of Stock hereunder and shall promptly present to the Company any and all certificates
representing shares of Stock acquired hereunder for the placement on such certificates of appropriate legends evidencing any such transfer restrictions. 
  
 8.6 Voting Rights; Dividends and Distributions. Except as provided in this Section, Section 8.5 and any Award Agreement, during the
Restriction Period applicable to shares subject to a Restricted Stock Award, the Participant shall have all of the rights of a stockholder of the Company holding shares of Stock, including the right to vote such shares and to receive all dividends
and other distributions paid with respect to such shares. However, in the event of a dividend or distribution paid in shares of Stock or any other adjustment made upon a change in the capital structure of the Company as described in Section 4.2,
then any and all new, substituted or additional securities or other property (other than normal cash dividends) to which the Participant is entitled by reason of the Participant’s Restricted Stock Award shall be immediately subject to the same
Vesting Conditions as the shares subject to the Restricted Stock Award with respect to which such dividends or distributions were paid or adjustments were made. 
  
 8.7 Effect of Termination of Service. Unless otherwise provided by the Committee in the grant of a
Restricted Stock Award and set forth in the Award Agreement, if a Participant’s Service terminates for any reason, whether voluntary or involuntary (including the Participant’s death or Disability), then (a) the Company shall have the
option to repurchase for the purchase price paid by the Participant any shares acquired by the Participant pursuant to a Restricted Stock Purchase Right which remain subject to Vesting Conditions as of the date of the Participant’s termination
of Service and (b) the Participant shall forfeit to the Company any shares acquired by the Participant pursuant to a Restricted Stock Bonus which remain subject to Vesting Conditions as of the date of the Participant’s termination of Service.
The Company shall have the right to assign at any time any repurchase right it may have, whether or not such right is then exercisable, to one or more persons as may be selected by the Company. 
  
 8.8 Nontransferability of Restricted Stock Award
Rights. Prior to the issuance of shares of Stock pursuant to a Restricted Stock Award, rights to acquire such shares shall not be subject in any manner to anticipation, alienation, sale, exchange, transfer, assignment, pledge, encumbrance or
garnishment by creditors of the Participant or the Participant’s beneficiary, except transfer by will or the laws of descent and distribution. All 

  

 17 

 
rights with respect to a Restricted Stock Award granted to a Participant hereunder shall be exercisable during his or her lifetime only by such Participant
or the Participant’s guardian or legal representative. 
  
 9. TERMS AND CONDITIONS OF PERFORMANCE AWARDS. 
  
 Performance Awards shall be evidenced by Award Agreements in such form as the Committee shall from time to
time establish. No Performance Award or purported Performance Award shall be a valid and binding obligation of the Company unless evidenced by a fully executed Award Agreement. Award Agreements evidencing Performance Awards may incorporate all or
any of the terms of the Plan by reference and shall comply with and be subject to the following terms and conditions: 
  
 9.1 Types of Performance Awards Authorized. Performance Awards may be in the form of either Performance Shares or Performance
Units. Each Award Agreement evidencing a Performance Award shall specify the number of Performance Shares or Performance Units subject thereto, the Performance Award Formula, the Performance Goal(s) and Performance Period applicable to the Award,
and the other terms, conditions and restrictions of the Award. 
  
 9.2 Initial Value of Performance Shares and Performance Units. Unless otherwise provided by the Committee in granting a Performance Award, each Performance Share shall have an initial value equal to the Fair
Market Value of one (1) share of Stock, subject to adjustment as provided in Section 4.2, on the effective date of grant of the Performance Share, and each Performance Unit shall have an initial value of one hundred dollars ($100). The final value
payable to the Participant in settlement of a Performance Award determined on the basis of the applicable Performance Award Formula will depend on the extent to which Performance Goals established by the Committee are attained within the applicable
Performance Period established by the Committee. 
  
 9.3 Establishment of Performance Period, Performance Goals and Performance Award Formula. In granting each Performance Award, the Committee shall establish in writing the applicable Performance Period, Performance Award Formula and
one or more Performance Goals which, when measured at the end of the Performance Period, shall determine on the basis of the Performance Award Formula the final value of the Performance Award to be paid to the Participant. Unless otherwise permitted
in compliance with the requirements under Section 162(m) with respect to “performance-based compensation,” the Committee shall establish the Performance Goal(s) and Performance Award Formula applicable to each Performance Award no later
than the earlier of (a) the date ninety (90) days after the commencement of the applicable Performance Period or (b) the date on which 25% of the Performance Period has elapsed, and, in any event, at a time when the outcome of the Performance Goals
remains substantially uncertain. Once established, the Performance Goals and Performance Award Formula shall not be changed during the Performance Period. The Company shall notify each Participant granted a Performance Award of the terms of such
Award, including the Performance Period, Performance Goal(s) and Performance Award Formula. 
  

 18 

 9.4 Measurement of Performance Goals. Performance Goals shall be established by
the Committee on the basis of targets to be attained (“Performance Targets”) with respect to one or more measures of business or financial performance (each, a “Performance
Measure”), subject to the following: 
  
 (a) Performance Measures. Performance Measures shall have the same meanings as used in the Company’s financial statements, or, if such terms are not used in the Company’s financial statements,
they shall have the meaning applied pursuant to generally accepted accounting principles, or as used generally in the Company’s industry. Performance Measures shall be calculated with respect to the Company and each Subsidiary Corporation
consolidated therewith for financial reporting purposes or such division or other business unit as may be selected by the Committee. For purposes of the Plan, the Performance Measures applicable to a Performance Award shall be calculated in
accordance with generally accepted accounting principles, but prior to the accrual or payment of any Performance Award for the same Performance Period and excluding the effect (whether positive or negative) of any change in accounting standards or
any extraordinary, unusual or nonrecurring item, as determined by the Committee, occurring after the establishment of the Performance Goals applicable to the Performance Award. Performance Measures may be one or more of the following, or a
combination of the any of the following, as determined by the Committee: 
  
 (i) revenue; 
 (ii) gross margin; 
 (iii) operating margin; 
 (iv) operating income; 
 (v) pre-tax profit; 
 (vi) earnings before interest, taxes and depreciation; 
 (vii) net income; 
 (viii) cash flow; 
 (ix) expenses; 
 (x) the market price of the Stock; 
 (xi) earnings per share; 
 (xii) return on stockholder equity; 
 (xiii) return on capital; 
 (xiv) return on net assets; 
 (xv) economic value added; 
 (xvi) number of customers; 
 (xvii) market share; 
 (xviii) return on investment 
 (xix) profit after tax 
 (xx) product approval; and 
 (xxi) customer satisfaction. 
  
 (b) Performance Targets. Performance Targets
may include a minimum, maximum, target level and intermediate levels of performance, with the final value of a Performance Award determined under the applicable Performance Award Formula by the level attained during the applicable Performance
Period. A Performance Target may be stated as an absolute value or as a value determined relative to a standard selected by the Committee. 
  

 19 

 9.5 Settlement of Performance Awards. 
  
 (a) Determination of Final Value. As soon as
practicable following the completion of the Performance Period applicable to a Performance Award, the Committee shall certify in writing the extent to which the applicable Performance Goals have been attained and the resulting final value of the
Award earned by the Participant and to be paid upon its settlement in accordance with the applicable Performance Award Formula. 
  
 (b) Discretionary Adjustment of Award Formula. In its discretion, the Committee may, either at the time it grants a
Performance Award or at any time thereafter, provide for the positive or negative adjustment of the Performance Award Formula applicable to a Performance Award granted to any Participant who is not a “covered employee” within the meaning
of Section 162(m) (a “Covered Employee”) to reflect such Participant’s individual performance in his or her position with the Company or such other factors as the Committee may determine. If
permitted under a Covered Employee’s Award Agreement, the Committee shall have the discretion, on the basis of such criteria as may be established by the Committee, to reduce some or all of the value of the Performance Award that would
otherwise be paid to the Covered Employee upon its settlement notwithstanding the attainment of any Performance Goal and the resulting value of the Performance Award determined in accordance with the Performance Award Formula. No such reduction may
result in an increase in the amount payable upon settlement of another Participant’s Performance Award. 
  
 (c) Effect of Leaves of Absence. Unless otherwise required by law, payment of the final value, if any, of a Performance
Award held by a Participant who has taken in excess of thirty (30) days in leaves of absence during a Performance Period shall be prorated on the basis of the number of days of the Participant’s Service during the Performance Period during
which the Participant was not on a leave of absence. 
  
 (d) Notice to Participants. As soon as practicable following the Committee’s determination and certification in accordance with Sections 9.5 (a) and (b), the Company shall notify each Participant of the determination of
the Committee. 
  
 (e) Payment in
Settlement of Performance Awards. As soon as practicable following the Committee’s determination and certification in accordance with Sections 9.5(a) and (b), payment shall be made to each eligible Participant (or such
Participant’s legal representative or other person who acquired the right to receive such payment by reason of the Participant’s death) of the final value of the Participant’s Performance Award. Payment of such amount shall be made in
cash, shares of Stock, or a combination thereof as determined by the Committee. Unless otherwise provided in the Award Agreement evidencing a Performance Award, payment shall be made in a lump sum. An Award Agreement may provide for deferred payment
in a lump sum or in installments. If any payment is to be made on a deferred basis, the Committee may, but shall not be obligated to, provide for the payment during the deferral period of Dividend Equivalents or interest. 
  
 (f) Provisions Applicable to Payment in
Shares. If payment is to be made in shares of Stock, the number of such shares shall be determined by dividing the final value of the Performance Award by the value of a share of Stock determined by the method 

  

 20 

 
specified in the Award Agreement. Such methods may include, without limitation, the closing market price on a specified date (such as the settlement date) or
an average of market prices over a series of trading days. Shares of Stock issued in payment of any Performance Award may be fully vested and freely transferable shares or may be shares of Stock subject to Vesting Conditions as provided in Section
8.5. Any shares subject to Vesting Conditions shall be evidenced by an appropriate Award Agreement and shall be subject to the provisions of Sections 8.5 through above. 
  
 9.6 Voting Rights; Dividend Equivalent Rights and Distributions. Participants shall have no voting
rights with respect to shares of Stock represented by Performance Share Awards until the date of the issuance of such shares, if any (as evidenced by the appropriate entry on the books of the Company or of a duly authorized transfer agent of the
Company). However, the Committee, in its discretion, may provide in the Award Agreement evidencing any Performance Share Award that the Participant shall be entitled to receive Dividend Equivalents with respect to the payment of cash dividends on
Stock having a record date prior to the date on which the Performance Shares are settled or forfeited. Such Dividend Equivalents, if any, shall be credited to the Participant in the form of additional whole Performance Shares as of the date of
payment of such cash dividends on Stock. The number of additional Performance Shares (rounded to the nearest whole number) to be so credited shall be determined by dividing (a) the amount of cash dividends paid on such date with respect to the
number of shares of Stock represented by the Performance Shares previously credited to the Participant by (b) the Fair Market Value per share of Stock on such date. Dividend Equivalents may be paid currently or may be accumulated and paid to the
extent that Performance Shares become nonforfeitable, as determined by the Committee. Settlement of Dividend Equivalents may be made in cash, shares of Stock, or a combination thereof as determined by the Committee, and may be paid on the same basis
as settlement of the related Performance Share as provided in Section 9.5. Dividend Equivalents shall not be paid with respect to Performance Units. In the event of a dividend or distribution paid in shares of Stock or any other adjustment made upon
a change in the capital structure of the Company as described in Section 4.2, appropriate adjustments shall be made in the Participant’s Performance Share Award so that it represents the right to receive upon settlement any and all new,
substituted or additional securities or other property (other than normal cash dividends) to which the Participant would entitled by reason of the shares of Stock issuable upon settlement of the Performance Share Award, and all such new, substituted
or additional securities or other property shall be immediately subject to the same Performance Goals as are applicable to the Award. 
  
 9.7 Effect of Termination of Service. The effect of a Participant’s termination of Service on the Performance Award shall be
determined by the Committee, in its discretion, and set forth in the Award Agreement evidencing such Performance Award. 
  
 9.8 Nontransferability of Performance Awards. Prior to settlement in accordance with the provisions of the Plan, no Performance
Award shall be subject in any manner to anticipation, alienation, sale, exchange, transfer, assignment, pledge, encumbrance, or garnishment by creditors of the Participant or the Participant’s beneficiary, except transfer by will or by the laws
of descent and distribution. All rights with respect to a Performance Award granted to a Participant hereunder shall be exercisable during his or her lifetime only by such Participant or the Participant’s guardian or legal representative.

  

 21 

 10. TERMS AND CONDITIONS OF
RESTRICTED STOCK UNIT AWARDS. 
  
 Restricted Stock Unit Awards shall be evidenced by Award Agreements specifying the number of Restricted Stock Units subject to the Award,
in such form as the Committee shall from time to time establish. No Restricted Stock Unit Award or purported Restricted Stock Unit Award shall be a valid and binding obligation of the Company unless evidenced by a fully executed Award Agreement.
Award Agreements evidencing Restricted Stock Units may incorporate all or any of the terms of the Plan by reference and shall comply with and be subject to the following terms and conditions: 
  
 10.1 Grant of Restricted Stock Unit Awards.
Restricted Stock Unit Awards may be granted upon such conditions as the Committee shall determine, including, without limitation, upon the attainment of one or more Performance Goals described in Section 9.4. If either the grant of a Restricted
Stock Unit Award or the Vesting Conditions with respect to such Award is to be contingent upon the attainment of one or more Performance Goals, the Committee shall follow procedures substantially equivalent to those set forth in Sections 9.3 through
9.5(a). 
  
 10.2 Purchase Price. No
monetary payment (other than applicable tax withholding, if any) shall be required as a condition of receiving a Restricted Stock Unit Award, the consideration for which shall be services actually rendered to a Participating Company or for its
benefit. 
  
 10.3 Vesting. Restricted
Stock Units may or may not be made subject to Vesting Conditions based upon the satisfaction of such Service requirements, conditions, restrictions or performance criteria, including, without limitation, Performance Goals as described in Section
9.4, as shall be established by the Committee and set forth in the Award Agreement evidencing such Award. 
  
 10.4 Voting Rights, Dividend Equivalent Rights and Distributions. Participants shall have no voting rights with respect to shares
of Stock represented by Restricted Stock Units until the date of the issuance of such shares (as evidenced by the appropriate entry on the books of the Company or of a duly authorized transfer agent of the Company). However, the Committee, in its
discretion, may provide in the Award Agreement evidencing any Restricted Stock Unit Award that the Participant shall be entitled to receive Dividend Equivalents with respect to the payment of cash dividends on Stock having a record date prior to
date on which Restricted Stock Units held by such Participant are settled. Such Dividend Equivalents, if any, shall be paid by crediting the Participant with additional whole Restricted Stock Units as of the date of payment of such cash dividends on
Stock. The number of additional Restricted Stock Units (rounded to the nearest whole number) to be so credited shall be determined by dividing (a) the amount of cash dividends paid on such date with respect to the number of shares of Stock
represented by the Restricted Stock Units previously credited to the Participant by (b) the Fair Market Value per share of Stock on such date. Such additional Restricted Stock Units shall be subject to the same terms and conditions and shall be
settled in the same manner and at the same time (or as soon thereafter as practicable) as the Restricted Stock Units originally subject to the Restricted Stock Unit Award. In the event of a dividend or distribution paid in shares of Stock or any
other adjustment made upon a change in the capital structure of the Company as described in 

  

 22 

 
Section 4.2, appropriate adjustments shall be made in the Participant’s Restricted Stock Unit Award so that it represents the right to receive
upon settlement any and all new, substituted or additional securities or other property (other than normal cash dividends) to which the Participant would entitled by reason of the shares of Stock issuable upon settlement of the Award, and all such
new, substituted or additional securities or other property shall be immediately subject to the same Vesting Conditions as are applicable to the Award. 
  
 10.5 Effect of Termination of Service. Unless otherwise provided by the Committee in the grant of a Restricted Stock Unit Award and
set forth in the Award Agreement, if a Participant’s Service terminates for any reason, whether voluntary or involuntary (including the Participant’s death or Disability), then the Participant shall forfeit to the Company any Restricted
Stock Units pursuant to the Award which remain subject to Vesting Conditions as of the date of the Participant’s termination of Service. 
  
 10.6 Settlement of Restricted Stock Unit Awards. The Company shall issue to a Participant on the date on which Restricted Stock
Units subject to the Participant’s Restricted Stock Unit Award vest or on such other date determined by the Committee, in its discretion, and set forth in the Award Agreement one (1) share of Stock (and/or any other new, substituted or
additional securities or other property pursuant to an adjustment described in Section 10.4) for each Restricted Stock Unit then becoming vested or otherwise to be settled on such date, subject to the withholding of applicable taxes.
Notwithstanding the foregoing, if permitted by the Committee and set forth in the Award Agreement, the Participant may elect in accordance with terms specified in the Award Agreement to defer receipt of all or any portion of the shares of Stock or
other property otherwise issuable to the Participant pursuant to this Section. 
  
 10.7 Nontransferability of Restricted Stock Unit Awards. Prior to the issuance of shares of Stock in settlement of a Restricted
Stock Unit Award, the Award shall not be subject in any manner to anticipation, alienation, sale, exchange, transfer, assignment, pledge, encumbrance, or garnishment by creditors of the Participant or the Participant’s beneficiary, except
transfer by will or by the laws of descent and distribution. All rights with respect to a Restricted Stock Unit Award granted to a Participant hereunder shall be exercisable during his or her lifetime only by such Participant or the
Participant’s guardian or legal representative. 
  
 11.
DEFERRED STOCK UNITS. 
  
 11.1 Establishment of Deferred Stock Unit Program. The Committee, in its discretion and upon such terms and conditions as it may
determine, may establish one or more programs pursuant to the Plan under which: 
  
 (a) Participants designated by the Committee who are Insiders or otherwise among a select group of highly compensated Employees may
irrevocably elect, prior to a date specified by the Committee, to reduce such Participant’s compensation otherwise payable in cash (subject to any minimum or maximum reductions imposed by the Committee) and to be granted automatically at such
time or times as specified by the Committee one or more Awards of Deferred Stock Units with respect to such numbers of shares of Stock as determined 

  

 23 

 
in accordance with the rules of the program established by the Committee and having such other terms and conditions as established by the Committee.

  
 (b) Participants designated by the Committee
who are Insiders or otherwise among a select group of highly compensated Employees may irrevocably elect, prior to a date specified by the Committee, to be granted automatically an Award of Deferred Stock Units with respect to such number of shares
of Stock and upon such other terms and conditions as established by the Committee in lieu of: 
  
 (i) shares of Stock otherwise issuable to such Participant upon the exercise of an Option; 
  
 (ii) cash or shares of Stock otherwise issuable to such
Participant upon the exercise of a SAR; or 
  
 (iii) cash or shares of Stock otherwise issuable to such Participant upon the settlement of a Performance Award. 
  
 11.2 Terms and Conditions of Deferred Stock Units. Deferred Stock Units granted pursuant to this Section 11 shall be evidenced by
Award Agreements in such form as the Committee shall from time to time establish. No such Deferred Stock Unit or purported Deferred Stock Unit shall be a valid and binding obligation of the Company unless evidenced by a fully executed Award
Agreement. Award Agreements evidencing Deferred Stock Units may incorporate all or any of the terms of the Plan by reference and shall comply with and be subject to the following terms and conditions: 
  
 (a) Vesting Conditions. Deferred Stock Units
shall not be subject to any vesting conditions. 
  
 (b) Terms and Conditions of Deferred Stock Units. 
  
 (i) Voting Rights; Dividend Equivalent Rights and Distributions. Participants shall have no voting rights with respect to shares of Stock represented by Deferred Stock Units until the date of the issuance of
such shares (as evidenced by the appropriate entry on the books of the Company or of a duly authorized transfer agent of the Company). However, a Participant shall be entitled to receive Dividend Equivalents with respect to the payment of cash
dividends on Stock having a record date prior to date on which Deferred Stock Units held by such Participant are settled. Such Dividend Equivalents shall be paid by crediting the Participant with additional whole and/or fractional Deferred Stock
Units as of the date of payment of such cash dividends on Stock. The method of determining the number of additional Deferred Stock Units to be so credited shall be specified by the Committee and set forth in the Award Agreement. Such additional
Deferred Stock Units shall be subject to the same terms and conditions and shall be settled in the same manner and at the same time (or as soon thereafter as practicable) as the Deferred Stock Units originally subject to the Deferred Stock Unit
Award. In the event of a dividend or distribution paid in shares of Stock or any other adjustment made upon a change in the capital structure of the Company as described in Section 4.2, appropriate adjustments shall be made in the Participant’s
Deferred Stock Unit Award so that it represent the right to receive upon settlement any and all new, substituted or 

  

 24 

 
additional securities or other property (other than normal cash dividends) to which the Participant would entitled by reason of the shares of Stock issuable
upon settlement of the Award. 
  
 (ii)
Settlement of Deferred Stock Unit Awards. A Participant electing to receive an Award of Deferred Stock Units pursuant to this Section 11, shall specify at the time of such election a settlement date with respect to such Award. The Company
shall issue to the Participant as soon as practicable following the earlier of the settlement date elected by the Participant or the date of termination of the Participant’s Service, a number of whole shares of Stock equal to the number of
whole Deferred Stock Units subject to the Deferred Stock Unit Award. Such shares of Stock shall be fully vested, and the Participant shall not be required to pay any additional consideration (other than applicable tax withholding) to acquire such
shares. Any fractional Deferred Stock Unit subject to the Deferred Stock Unit Award shall be settled by the Company by payment in cash of an amount equal to the Fair Market Value as of the payment date of such fractional share. 
  
 (iii) Nontransferability of Deferred Stock Unit
Awards. Prior to their settlement in accordance with the provision of the Plan, no Deferred Stock Unit Award shall be subject in any manner to anticipation, alienation, sale, exchange, transfer, assignment, pledge, encumbrance, or garnishment by
creditors of the Participant or the Participant’s beneficiary, except transfer by will or by the laws of descent and distribution. All rights with respect to a Deferred Stock Unit Award granted to a Participant hereunder shall be exercisable
during his or her lifetime only by such Participant or the Participant’s guardian or legal representative. 
  
 12. STANDARD FORMS OF AWARD
AGREEMENT. 
  
 12.1 Award Agreements. Each Award shall comply with and be subject to the terms and conditions set forth in the appropriate form of Award Agreement approved by the Committee and as amended from time to time.
Any Award Agreement may consist of an appropriate form of Notice of Grant and a form of Agreement incorporated therein by reference, or such other form or forms as the Committee may approve from time to time. 
  
 12.2 Authority to Vary Terms. The Committee shall
have the authority from time to time to vary the terms of any standard form of Award Agreement either in connection with the grant or amendment of an individual Award or in connection with the authorization of a new standard form or forms; provided,
however, that the terms and conditions of any such new, revised or amended standard form or forms of Award Agreement are not inconsistent with the terms of the Plan. 
  
 13. CHANGE IN
CONTROL. 
  
 13.1 Definitions. 
  
 (a) An “Ownership Change Event” shall be deemed to have occurred if any of the following occurs with respect to the Company: (i) the direct or indirect sale
or exchange in a single or series of related transactions by the stockholders of the Company of more than fifty percent (50%) of the voting stock of the Company; (ii) a merger or consolidation in 

  

 25 

 
which the Company is a party; (iii) the sale, exchange, or transfer of all or substantially all of the assets of the Company (other than a sale, exchange or
transfer to one or more subsidiaries of the Company); or (iv) a liquidation or dissolution of the Company. 
  
 (b) A “Change in Control” shall mean an Ownership Change Event or series of
related Ownership Change Events (collectively, a “Transaction”) in which the stockholders of the Company immediately before the Transaction do not retain immediately after the Transaction, in
substantially the same proportions as their ownership of shares of the Company’s voting stock immediately before the Transaction, direct or indirect beneficial ownership of more than fifty percent (50%) of the total combined voting power of the
outstanding voting securities of the Company or, in the case of an Ownership Change Event described in Section 13.1(a)(iii), the entity to which the assets of the Company were transferred (the
“Transferee”), as the case may be. For purposes of the preceding sentence, indirect beneficial ownership shall include, without limitation, an interest resulting from ownership of the voting
securities of one or more corporations or other business entities which own the Company or the Transferee, as the case may be, either directly or through one or more subsidiary corporations or other business entities. The Committee shall have the
right to determine whether multiple sales or exchanges of the voting securities of the Company or multiple Ownership Change Events are related, and its determination shall be final, binding and conclusive. 
  
 13.2 Effect of Change in Control on Options and SARs.

  
 (a) Accelerated Vesting.
Notwithstanding any other provision of the Plan to the contrary, the Committee, in its sole discretion, may provide in any Award Agreement or, in the event of a Change in Control, may take such actions as it deems appropriate to provide for the
acceleration of the exercisability and vesting in connection with such Change in Control of any or all outstanding Options and SARs and shares acquired upon the exercise of such Options and SARs upon such conditions and to such extent as the
Committee shall determine. 
  
 (b)
Assumption or Substitution. In the event of a Change in Control, the surviving, continuing, successor, or purchasing corporation or other business entity or parent corporation thereof, as the case may be (the
“Acquiring Corporation”), may, without the consent of the Participant, either assume the Company’s rights and obligations under outstanding Options and SARs or substitute for
outstanding Options and SARs substantially equivalent options and stock appreciation rights for the Acquiring Corporation’s stock. In the event that the Acquiring Corporation elects not to assume or substitute for outstanding Options and SARs
in connection with a Change in Control, or if the Acquiring Corporation is not a “publicly held corporation” within the meaning of Section 162(m), the exercisability and vesting of each such outstanding Option, SAR and any shares acquired
upon the exercise thereof held by a Participant whose Service has not terminated prior to such date shall be accelerated, effective as of the date ten (10) days prior to the date of the Change in Control. The exercise or vesting of any Option, SAR
and any shares acquired upon the exercise thereof that was permissible solely by reason of this Section 13.2 and the provisions of such applicable Award Agreement shall be conditioned upon the consummation of the Change in Control. Any Options and
SARs which are neither assumed or substituted for by the Acquiring Corporation in connection with the Change in Control nor exercised as of the date of the Change in Control shall terminate and cease to be outstanding effective as of the date of the
Change in Control. Notwithstanding the foregoing, 

  

 26 

 
shares acquired upon exercise of an Option or SAR prior to the Change in Control and any consideration received pursuant to the Change in Control with
respect to such shares shall continue to be subject to all applicable provisions of the applicable Award Agreement evidencing such Option or SAR except as otherwise provided in such applicable Award Agreement. Furthermore, notwithstanding the
foregoing, if the corporation the stock of which is subject to the outstanding Options and SARs immediately prior to an Ownership Change Event described in Section 13.1(a)(i) constituting a Change in Control is the surviving or continuing
corporation and immediately after such Ownership Change Event less than fifty percent (50%) of the total combined voting power of its voting stock is held by another corporation or by other corporations that are members of an affiliated group within
the meaning of Section 1504(a) of the Code without regard to the provisions of Section 1504(b) of the Code, the outstanding Options and SARs shall not terminate unless the Committee otherwise provides in its discretion. 
  
 (c) Cash-Out. The Committee may, in its sole
discretion and without the consent of any Participant, determine that, upon the occurrence of a Change in Control, each or any Option or SAR outstanding immediately prior to the Change in Control shall be canceled in exchange for a payment with
respect to each vested share of Stock subject to such canceled Option or SAR in (i) cash, (ii) stock of the Company or of a corporation or other business entity a party to the Change in Control, or (iii) other property which, in any such case, shall
be in an amount having a Fair Market Value equal to the excess of the Fair Market Value of the consideration to be paid per share of Stock in the Change in Control over the exercise price per share under such Option or SAR (the
“Spread”). In the event such determination is made by the Committee, the Spread (reduced by applicable withholding taxes, if any) shall be paid to Participants in respect of their canceled Options
and SARs as soon as practicable following the date of the Change in Control. 
  
 13.3 Effect of Change in Control on Restricted Stock Awards. The Committee may, in its discretion, provide in any Award Agreement evidencing a Restricted Stock Award that, in the event of a Change in Control,
the lapsing of the Restriction Period applicable to the shares subject to the Restricted Stock Award held by a Participant whose Service has not terminated prior to the Change in Control shall be accelerated effective immediately prior to the
consummation of the Change in Control to such extent as specified in such Award Agreement. Any acceleration of the lapsing of the Restriction Period that was permissible solely by reason of this Section 13.3 and the provisions of such Award
Agreement shall be conditioned upon the consummation of the Change in Control. 
  
 13.4 Effect of Change in Control on Performance Awards. The Committee may, in its discretion, provide in any Award Agreement
evidencing a Performance Award that, in the event of a Change in Control, the Performance Award held by a Participant whose Service has not terminated prior to the Change in Control shall become payable effective as of the date of the Change in
Control to such extent as specified in such Award Agreement. 
  
 13.5 Effect of Change in Control on Restricted Stock Unit Awards. The Committee may, in its discretion, provide in any Award Agreement evidencing a Restricted Stock Unit Award that, in the event of a Change in
Control, the Restricted Stock Unit Award held by a Participant whose Service has not terminated prior to such date shall be settled 

  

 27 

 
effective as of the date of the Change in Control to such extent as specified in such Award Agreement. 
  
 13.6 Effect of Change in Control on Deferred Stock
Units. The Committee may, in its discretion, provide in any Award Agreement evidencing a Deferred Stock Unit Award that, in the event of a Change in Control, the Deferred Stock Units pursuant to such Award shall be settled effective as of the
date of the Change in Control to such extent as specified in such Award Agreement. 
  
 14. COMPLIANCE WITH SECURITIES LAW. 
  
 The grant of Awards and the issuance of shares of Stock pursuant to any Award shall be subject to compliance
with all applicable requirements of federal, state and foreign law with respect to such securities and the requirements of any stock exchange or market system upon which the Stock may then be listed. In addition, no Award may be exercised or shares
issued pursuant to an Award unless (a) a registration statement under the Securities Act shall at the time of such exercise or issuance be in effect with respect to the shares issuable pursuant to the Award or (b) in the opinion of legal counsel to
the Company, the shares issuable pursuant to the Award may be issued in accordance with the terms of an applicable exemption from the registration requirements of the Securities Act. The inability of the Company to obtain from any regulatory body
having jurisdiction the authority, if any, deemed by the Company’s legal counsel to be necessary to the lawful issuance and sale of any shares hereunder shall relieve the Company of any liability in respect of the failure to issue or sell such
shares as to which such requisite authority shall not have been obtained. As a condition to issuance of any Stock, the Company may require the Participant to satisfy any qualifications that may be necessary or appropriate, to evidence compliance
with any applicable law or regulation and to make any representation or warranty with respect thereto as may be requested by the Company. 
  
 15. TAX WITHHOLDING. 
  
 15.1 Tax Withholding in General. The Company shall
have the right to deduct from any and all payments made under the Plan, or to require the Participant, through payroll withholding, cash payment or otherwise, including by means of a Cashless Exercise of an Option, to make adequate provision for,
the federal, state, local and foreign taxes, if any, required by law to be withheld by the Participating Company Group with respect to an Award or the shares acquired pursuant thereto. The Company shall have no obligation to deliver shares of Stock,
to release shares of Stock from an escrow established pursuant to an Award Agreement, or to make any payment in cash under the Plan until the Participating Company Group’s tax withholding obligations have been satisfied by the Participant.

  
 15.2 Withholding in Shares. The
Company shall have the right, but not the obligation, to deduct from the shares of Stock issuable to a Participant upon the exercise or settlement of an Award, or to accept from the Participant the tender of, a number of whole shares of Stock having
a Fair Market Value, as determined by the Company, equal to all or any part of the tax withholding obligations of the Participating Company Group. The Fair Market Value of any shares of Stock withheld or tendered to satisfy any such tax withholding
obligations shall not exceed the amount determined by the applicable minimum statutory withholding rates. 
  

 28 

 16. AMENDMENT OR TERMINATION OF
PLAN. 
  
 The Committee may amend, suspend or terminate the Plan at any time. However, without the approval of the Company’s stockholders, there shall be (a) no increase in the maximum aggregate number of shares of Stock
that may be issued under the Plan (except by operation of the provisions of Section 4.2, (b) no change in the class of persons eligible to receive Incentive Stock Options, (c) no Option and/or SAR repricing as described in Section 3.6, (d) no
amendment to permit the granting of Options (other than Indexed Options) with exercise prices less than Fair Market Value on the date of grant, and (e) no other amendment of the Plan that would require approval of the Company’s stockholders
under any applicable law, regulation or rule. No amendment, suspension or termination of the Plan shall affect any then outstanding Award unless expressly provided by the Committee. In any event, no amendment, suspension or termination of the Plan
may adversely affect any then outstanding Award without the consent of the Participant unless necessary to comply with any applicable law, regulation or rule. 
  

17. MISCELLANEOUS PROVISIONS. 
  
 17.1 Repurchase Rights. Shares issued under the Plan
may be subject to one or more repurchase options, or other conditions and restrictions as determined by the Committee in its discretion at the time the Award is granted. The Company shall have the right to assign at any time any repurchase right it
may have, whether or not such right is then exercisable, to one or more persons as may be selected by the Company. Upon request by the Company, each Participant shall execute any agreement evidencing such transfer restrictions prior to the receipt
of shares of Stock hereunder and shall promptly present to the Company any and all certificates representing shares of Stock acquired hereunder for the placement on such certificates of appropriate legends evidencing any such transfer restrictions.

  
 17.2 Provision of Information. Each
Participant shall be given access to information concerning the Company equivalent to that information generally made available to the Company’s common stockholders. 
  
 17.3 Rights as Employee, Consultant or Director. No person, even though eligible pursuant to Section
5, shall have a right to be selected as a Participant, or, having been so selected, to be selected again as a Participant. Nothing in the Plan or any Award granted under the Plan shall confer on any Participant a right to remain an Employee,
Consultant or Director or interfere with or limit in any way any right of a Participating Company to terminate the Participant’s Service at any time. To the extent that an Employee of a Participating Company other than the Company receives an
Award under the Plan, that Award shall in no event be understood or interpreted to mean that the Company is the Employee’s employer or that the Employee has an employment relationship with the Company. 
  
 17.4 Rights as a Stockholder. A Participant shall
have no rights as a stockholder with respect to any shares covered by an Award until the date of the issuance of such shares (as evidenced by the appropriate entry on the books of the Company or of a duly authorized transfer agent of the Company).
No adjustment shall be made for dividends, distributions or other rights for which the record date is prior to the date such shares are issued, except as provided in Section 4.2 or another provision of the Plan. 
  

 29 

 17.5 Fractional Shares. The Company shall not be required to issue fractional
shares upon the exercise or settlement of any Award. 
  
 17.6 Severability. If any one or more of the provisions (or any part thereof) of this Plan or of any Award Agreement issued hereunder, shall be held to be invalid, illegal or unenforceable in any respect, such provision shall be
modified so as to make it valid, legal and enforceable, and the validity, legality and enforceability of the remaining provisions (or any part thereof) of the Plan or of any Award Agreement shall not in any way be affected or impaired thereby. The
Company may, without the consent of any Participant, and in a manner determined necessary solely in the discretion of the Company, amend the Plan and any outstanding Award Agreement as the Company deems necessary to ensure the Plan and all Awards
remain valid, legal or enforceable in all respects. 
  
 17.7 Beneficiary Designation. Subject to local laws and procedures, each Participant may file with the Company a written designation of a beneficiary who is to receive any benefit under the Plan to which the Participant is entitled
in the event of such Participant’s death before he or she receives any or all of such benefit. Each designation will revoke all prior designations by the same Participant, shall be in a form prescribed by the Company, and will be effective only
when filed by the Participant in writing with the Company during the Participant’s lifetime. If a married Participant designates a beneficiary other than the Participant’s spouse, the effectiveness of such designation may be subject to the
consent of the Participant’s spouse. If a Participant dies without an effective designation of a beneficiary who is living at the time of the Participant’s death, the Company will pay any remaining unpaid benefits to the Participant’s
legal representative. 
  
 17.8 Unfunded
Obligation. Participants shall have the status of general unsecured creditors of the Company. Any amounts payable to Participants pursuant to the Plan shall be unfunded and unsecured obligations for all purposes, including, without limitation,
Title I of the Employee Retirement Income Security Act of 1974. No Participating Company shall be required to segregate any monies from its general funds, or to create any trusts, or establish any special accounts with respect to such obligations.
The Company shall retain at all times beneficial ownership of any investments, including trust investments, which the Company may make to fulfill its payment obligations hereunder. Any investments or the creation or maintenance of any trust or any
Participant account shall not create or constitute a trust or fiduciary relationship between the Committee or any Participating Company and a Participant, or otherwise create any vested or beneficial interest in any Participant or the
Participant’s creditors in any assets of any Participating Company. The Participants shall have no claim against any Participating Company for any changes in the value of any assets which may be invested or reinvested by the Company with
respect to the Plan. 
  

 30 

 PLAN HISTORY AND NOTES TO COMPANY 
  

			
	                    , 2004	  	Board adopts Plan with a reserve of Seven Million Two Hundred and Four Thousand and Eighty-Five (7,204,085), reduced at any time by the number of shares subject to the Prior Plan Options
(which as of the Effective Date equaled approximately Two Million Four Hundred and Fifty-Four Thousand and Eighty-Five (2,454,085)). Such shares shall consist of authorized but unissued or reacquired shares of Stock or any combination thereof. If
any outstanding Award, including any Prior Plan Options, for any reason expires or is terminated or canceled without having been exercised or settled in full, or if shares of Stock acquired pursuant to an Award subject to forfeiture or repurchase,
including any Prior Plan Options, are forfeited or repurchased by the Company, the shares of Stock allocable to the terminated portion of such Award, including any Prior Plan Options, or such forfeited or repurchases shares of Stock shall again be
available for issuance under the Plan
		
	                    , 2004	  	Stockholders approve Plan.
		
	IMPORTANT NOTE: Implementation of Section 11—Deferred Stock Units	  	The establishment of a Deferred Stock Unit program pursuant to Section Error! Reference source not found. requires that the Company determine whether such program will constitute a
“top-hat” pension plan under ERISA. If so, file notice with Dept. of Labor under ERISA Reg. 2520.104-23 within 120 days of adoption of resolutions by the Committee to establish the program to obtain exemption from reporting and disclosure
requirements of ERISA.Development and Validation Agreement

 EXHIBIT 10.55 
  
 THIS AGREEMENT is made by and between: 
  

	(1)	AVECIA LIMITED, acting through its Avecia Biotechnology business, with offices at Hexagon Tower, Blackley, Manchester, M9 8ZS, England (“Avecia”); and

  

	(2)	NUVELO, INC., a Delaware corporation with offices at 675 Almanor Avenue, Sunnyvale, CA 94085, USA (“Nuvelo”). 

  
 WHEREAS 
  

	A	Avecia has experience and knowledge with regard to process development, fermentation and manufacture of recombinant proteins. 

  

	B	Nuvelo is carrying out research and development in relation to the Product (as defined below). 

  

	C	In anticipation of entering into a definitive agreement to carry out a range of activities in relation to the Product (as defined in this Agreement), Avecia and Nuvelo entered into
an Interim Agreement on 21 January 2005 (the “Interim Agreement”) that set out the interim terms and conditions on which the following portions of the Project, consisting of (i) assessment and planning, (ii) transfer of process and
assays, (iii) purchase of certain capital equipment, (iv) replicate 15L fermentation and purification runs and (v) GMP consultancy preparatory to GMP manufacture, would be carried out before execution of the definitive agreement.

  

	D	Nuvelo now wishes Avecia to carry out activities in relation to the API (as defined below), including validation work in respect of the Process (as defined below).

  
 NOW IT IS HEREBY AGREED BY NUVELO AND AVECIA AS FOLLOWS:

  

	1.	Definitions: 

  

			
	Affiliate	  	Any corporation, association or other business entity which directly or indirectly controls, is controlled by or is under common control with Avecia or Nuvelo and “control,”
“controls” or “controlled” shall mean the legal power to direct or cause the direction of the general management and policies of such entity whether through the ownership of at least 50% of the voting securities or
voting capital stock of such business entity, or any other comparable controlling equity or controlling ownership interest with respect to a business entity other than a corporation.
		
	API	  	The polypeptide referred to by Nuvelo as alfimeprase is the Active Pharmaceutical Ingredient. In accordance with Annexe 18 of the EU Guide to Good Manufacturing Practice 2002, titled
“Good

  

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	 	  	Manufacturing Practice for Active Pharmaceutical Ingredients,” an Active Pharmaceutical Ingredient is any substance or mixture of substances intended to be used in the manufacture of a drug
(medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation,
treatment, or prevention of disease or to affect the structure and function of the body.
		
	API Specification	  	The specification for API attached to, and part of the Quality Agreement, which may be amended from time to time in accordance with the terms and conditions of this Agreement and the Quality
Agreement.
		
	Applicable Laws	  	All applicable supranational, national or local laws, rules and regulations, including without limitation the United States Federal Food, Drug and Cosmetic Act, the regulations promulgated
pursuant thereto, any applicable non-U.S. equivalents thereof, and any successor laws, rules or regulations thereto.
		
	Avecia Default	  	 Means:
  
 (a) A Failure by Avecia to use reasonable commercial endeavours to progress the Project;
  
 (b) A Failure by Avecia to manufacture any Development Batch or any Validation Batch in accordance with cGMP,
specifically including any failure to follow Avecia’s facilities’ Standard Operating Procedures that results in, or from which arises, a Defective Batch;
  
 (c) Solely with respect to the centrifuge trials, a failure by Avecia to conduct the centrifuge trials in accordance
with Avecia’s Standard Operating Procedures: (1) for the fermentation and harvest suite or suites which are applicable to the centrifuge trials in the reasonable determination of the Quality Team, a list of which shall be generated by the
Quality Team; and (2) for, as reasonably modified from time to time as a result of the work carried out under the Project, any equipment to be used in the centrifuge trials;
  
 (d) Solely with respect to the Development Batches:
  
 (1) A failure by Avecia personnel—including without limitation lack of appropriate training,
lack of attention to MBRs or Standard Operating

  

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	 	  	 Procedures, or lack of proper laboratory analysis—that results in, or from which arises, a Defective Batch;
  
 (2) A failure of Avecia documentation—including
without limitation inadequate Standard Operating Procedure or MBR documentation, improperly organized or lost documentation, or poor analysis of information incorporated into any such documentation—that results in, or from which arises, a
Defective Batch;
  
 (3)
Adulteration—including without limitation adulteration from cleaning agents and/or other contaminants, or adulteration from using reagents other than in the order specified in the Work Programme or the MBRs for the Process—that results in,
or from which arises, a Defective Batch;
  
 (4) A failure of Avecia equipment—including without limitation poor maintenance, age of the equipment, computer malfunction, software malfunction or controller malfunction, equipment being out of specification or not properly
calibrated, equipment not being validated for intended use, improper cleaning, improper cleaning cycles or failure to clean equipment—that results in, or from which arises, a Defective Batch;
  
 (5) A Failure of an Avecia facility—including
without limitation a cGMP violation in the facility, improper environmental controls, including HVAC system failure, poor construction or inadequate maintenance—that results in, or from which arises, a Defective Batch; or
  
 (6) A failure of Avecia raw materials—including
without limitation raw materials that are out of specification, quarantined, improperly tested, improperly processed or expired—that results in, or from which arises, a Defective Batch;
  
 (e) For the avoidance of doubt, a failure of a centrifuge trial or the
occurrence of a Defective Batch that is a Development Batch, that results from a factor—other than any of the factors listed in Clauses (a) through (d) above—which affects the Process or production of the API and was not known and could
not reasonably have been known by Avecia at the commencement of the applicable stage of the Project shall not be considered to be an Avecia default; such factors include, without limitation:
  
 (1) the Process does not perform as anticipated due
to a change of scale;

  

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	 	  	 (2) inability of the centrifuge to clarify the harvested broth to an acceptable level;
  
 (3) failure during a centrifuge run of the pH
control system to maintain a specified range; and
  
 (4) failure during a centrifuge run of the feed strategy to generate the expected product yield or quality; or
  
 (f) The occurrence of a Defective Batch during the Validation Campaign is, and is automatically deemed to be an Avecia Default, except upon the
occurrence of a Defective Batch which results from a factor—other than any of the factors listed in Clauses (a) through (d) above—which affects the Process or production of the API and was not known and could not reasonably have been known
by Avecia before the Defective Batch occurred, including, without limitation, a previously unknown factor not studied either as part of the Amgen programme transferred to Avecia or the Avecia laboratory work programme carried out pursuant to the
Project (the preceding in this Clause (f) referred to herein as a “Validation Process Failure”).

		
	Background Intellectual Property	  	 Any Intellectual Property owned by or Controlled by a Party (where “Controlled” means the ability to grant a license or sublicense to the
Intellectual Property):
  
 (a)    at the Commencement Date of this Agreement; or
  
 (b)    after the Commencement Date that is either: (1) acquired independently of the Project; or (2)
developed independently of the Project by any employee of that Party without use of or reference to any of the Confidential Information disclosed by the other Party.

		
	Batch	  	A quantity of API produced using the Process that (a) is expected to have uniform character and quality within specified limits, and (b) is produced according to a single manufacturing run
during the same cycle of the Process.
		
	Batch Dispute	  	The definition set forth in Clause 2.7(g).
		
	Cancellation Fee	  	A sum calculated in accordance with Schedule 4. The Cancellation Fee may include, as applicable as set forth in Schedule 4 and in accordance with the terms

  

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	 	  	and conditions of this Agreement, the Development Batch Fee and/or the Validation Campaign Fee.
		
	Certificate of Analysis	  	A document, the form of which is approved in advance by the Quality Team, that is prepared and issued by Avecia’s quality assurance department certifying analysis and cGMP manufacture of
the API and its compliance with the API Specification.
		
	cGMP	  	Current Good Manufacturing Practices required by Regulatory Authorities with respect to the development, manufacture, storage and supply of any Batch, including current good manufacturing
practices as incorporated in Annexe 18 of the EU Guide to Good Manufacturing Practice 2002, titled “Good Manufacturing Practice for Active Pharmaceutical Ingredients” (formerly ICH Q7A) and as interpreted in the USA Federal Register Vol 66
No. 186 (formerly ICH Q7A), and subject to any arrangements, additions or clarifications agreed in writing from time to time between the Parties in the Quality Agreement.
		
	Commencement Date	  	21st January 2005.
		
	Completion	  	Completion of the Project as set out in Clause 4.
		
	Confidential Information	  	Shall have the meaning given in the Confidentiality Agreement, subject to Clause 7. New Intellectual Property shall be deemed to be Confidential Information disclosed by Nuvelo.
		
	Confidentiality Agreement	  	The confidentiality agreement entered into between the Parties and dated 21st September 2004, attached hereto as Schedule 7.
		
	Defective Batch	  	 Either:
  
 (a)    A Batch that has not been produced in accordance with cGMP, specifically including all Standard
Operating Procedures for Avecia’s facility and the Master Batch Records for the Process, and for which any non-conformances from the SOPs or the MBRs cannot be closed-out in accordance with the procedures for close-out of non-conformances set
forth in the Quality Agreement; or
  
 (b)    A Batch, other than the first Development Batch or the Engineering Batch, which cannot be Released.

  

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	Development Batch or cGMP Development Batch	  	A Batch manufactured during Development Batch Manufacture, specifically including the Engineering Batch.
		
	Development Batch Manufacture	  	The work to manufacture the development Batches and the Engineering Batch in accordance with Clause 2.3 and the Work Programme.
		
	Engineering Batch	  	A Batch manufactured immediately prior to the Validation Campaign for the purpose of re-testing the Process before commencement of the Validation Campaign.
		
	Equipment	  	Any equipment (such as, without limitation, columns, freezers, filtration skids, cassette holders, ammonia feed tanks) which is required to be purchased in order for Avecia to carry out the
Project and which is set forth in Schedule 6 to this Agreement or set forth in the Work Programme or any Programme Amendment Order.
		
	Executive Committee or EC	  	The executive committee established pursuant to Clause 2.7.
		
	Expenditure	  	An amount paid or due and payable to a Third Party for the purchase of subcontractor services directly from the Third Party in accordance with Clause 13.2 or for the purchase of goods or
materials directly from the Third Party.
		
	Force Majeure	  	Any cause beyond the reasonable control of the Party in question, which for the avoidance of doubt and without prejudice to the generality of the foregoing, may include governmental actions,
war, riots, terrorism, civil commotion, fire, flood, epidemic, labour disputes (excluding labour disputes involving the work force or any part thereof of the Party in question), restraints or delays affecting shipping or carriers, inability or delay
in obtaining supplies of adequate or suitable materials, and act of God, but shall not include failure of the Product in clinical trials or failure of the Product to gain regulatory approval.
		
	Handling Fee	  	A sum equivalent to 8% of the actual Expenditure for the Equipment or consumables purchased under Clauses 3.2(a)(1), 3.2(a)(3) and 3.3.
		
	Hold Time	  	Any period of time during Development Batch Manufacture or the Validation Campaign during which Batches are not being manufactured, whether by

  

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	 	  	agreement so that modifications to procedures, processes and/or facilities or review thereof can be undertaken or as a result of a Nuvelo Delay or an Avecia Default.
		
	Intellectual Property	  	Any Patent, trade secret, copyright or other industrial or intellectual property right.
		
	Invention	  	Any invention, innovation, improvement, development, discovery, computer program, device, method, know-how, process, technique or the like, whether or not written or otherwise fixed in any form
or medium, regardless of the media on which contained and whether or not patentable or copyrightable.
		
	New Intellectual Property or New IP	  	Any Intellectual Property that claims or covers any New Invention.
		
	New Invention	  	Any Invention directly resulting from or directly arising out of Avecia’s performance of the Project.
		
	Non-Manufacturing Delay	  	A delay resulting from a decision by Nuvelo to delay the Project for reasons unrelated to: the Project; manufacture of the API under the Agreement; any Avecia Default; or any Process Failure.
Non-Manufacturing Delay may include, without limitation, decisions made in response to the outcome of clinical trials of the API.
		
	Nuvelo Delay	  	Any delay in the Development Batch Manufacture or the Validation Campaign which is caused by Nuvelo including, without limitation, unreasonable refusal to agree to any matter requiring mutual
agreement under this Agreement in a timely manner; but, each of the following is not, and shall not be deemed to be, a Nuvelo Delay: (i) any delay or refusal by Nuvelo to agree based upon or resulting from an Avecia Default; and (ii) any delay
resulting from Nuvelo’s refusal to take a license under a Patented, Licensed Avecia Invention under Clause 5.2(c).
		
	Master Batch Record or MBR	  	A written description of the procedure to be followed for manufacturing a Batch of the API, including but not limited to the history of a Batch from the raw material stage up through and until
completion of the Batch, a complete list of all active and inactive ingredients, components, weights and measures, descriptions of drug product containers, closures, packaging materials, and labelling and complete specifications for each, within the
meaning of 21 Code of Federal Regulations 211.186, or its successor as in effect from

  

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	 	  	time to time, and also in compliance with Annexe 18 of the EU Guide to Good Manufacturing Practice 2002, titled “Good Manufacturing Practice for Active Pharmaceutical Ingredients”
(formerly ICH Q7A), or its successor as in effect from time to time.
		
	Party or Parties	  	Avecia and Nuvelo are referred to individually herein as a “Party”, and collectively as the “Parties”.
		
	Patent	  	Any: (a) patent, including without limitation any inventor’s certificate or design patent, and any substitution, extension, registration, confirmation, reissue, re-examination or any like
filing thereof related to a patent; and (b) any pending patent application, including without limitation any continuation, division or continuation-in-part thereof and any provisional application.
		
	Process	  	The process for the manufacture of API communicated to Avecia by, or on behalf of, Nuvelo and subsequently scaled-up by Avecia under and in accordance with this Agreement.
		
	Process Assumptions	  	The following: (a) requirements set forth in the Master Batch Records for the Process, (b) requirements set forth in Avecia’s Standard Operating Procedures, and (c) raw materials and
consumables requirements and specifications. Any amounts of time necessary to conduct a particular part of the Process, also referred to as cycle times, are expressly excluded from Process Assumptions, irregardless of any statements to the contrary
set forth in the Work Programme.
		
	Product	  	Any product that incorporates or contains the API.
		
	Programme Amendment Order	  	A document in the form set out in Schedule 3 detailing changes to the Project agreed upon and signed by both Parties.
		
	Project	  	The range of activities to be carried out under this Agreement in accordance with the Work Programme, the details of which are more fully set out in the Work Programme, and any additional or
alternative work not set forth in the Work Programme that may be agreed in a Programme Amendment Order.
		
	Project Steering Committee or PSC	  	The Project steering committee established pursuant to Clause 2.7.

  

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	Quality Agreement	  	 The document, a copy of which is attached as Schedule 2, that sets forth, amongst other things:
  
 (a)    the mutually agreed
quality standards applicable for the manufacture of the API under the Agreement in accordance with cGMP; and
  
 (b)    the roles and responsibilities of each Party’s personnel in relation to quality assurance matters
under this Agreement; and
  
 (c)    the API Specifications.

		
	Quality Team	  	The Avecia Quality Unit together with the Nuvelo Quality Unit, as further set forth in the Quality Agreement.
		
	Regulatory Authority or Regulatory Authorities	  	The U.S. Food and Drug Administration, the European Agency for the Evaluation of Medicinal Products, and any equivalent governmental regulatory body in any territory in the world, and any
successor entity or entities to any of the preceding.
		
	Regulatory Filing	  	Any and all correspondence or petitions to Regulatory Authorities for the purpose of registering the Product or the Process, or modifying or supplementing existing filings and subsequent
amendments and supplements thereto, as required by Applicable Laws, in order to develop, manufacture, test, sell or distribute Product or the API under this Agreement.
		
	Release or Released	  	 The process by which, in respect of each Batch:
  
 (a)    Avecia’s Quality Unit:
  
 (1)    reviews and approves completed Batch records;
  
 (2)    reviews and approves all
campaign Batch records and buffer Batch records;
  
 (3)    closes out all non-conformances;
  
 (4)    closes out all change controls;
  
 (5)    issues a Certificate of Analysis;
  
 (6)    Issues a Certificate of
Compliance; and
  
 (b)    Nuvelo’s Quality Unit:
  
 (1)    Reviews, and, if appropriate, accepts all Batch related manufacturing documentation;

  

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	 	  	 (2)    Reviews, and, if appropriate, accepts QC Batch related analyses; and

 
 (3)    Reviews, and, if
appropriate, accepts the Certificate of Analysis.
  
 For the purpose of this
definition, “Accepts” means Avecia has received written notification from Nuvelo that Nuvelo accepts the documents referred to in Clause (b) above. In the absence of such written notification that Nuvelo does or does not accept such
documents, upon the expiration of 30 calendar days from the date on which Nuvelo receives Avecia’s written notification of Avecia’s completion of the tasks referred to in Clause (a) above, Nuvelo is deemed to have accepted the documents
referred to in Clause (b) above. A Batch that has been Released may be referred to as a “Released Batch”. A Released Batch, or set of Released Batches, may also be referred to as “Released API”. If Nuvelo rejects
the documents referred to in Clause (b) above, the matter will be addressed in accordance with Clause 2.7(g).

		
	Standard Operating Procedures or SOPs	  	Written procedures requiring uniform performance of specific functions, or uniform use of specific equipment or resources to ensure data, analysis and manufacturing quality and
uniformity.
		
	Third Party	  	Any person or entity other than the Parties or their respective Affiliates.
		
	Unremedied Breach	  	A material breach of this Agreement which is not remedied within 30 calendar days after receipt of written notice from the non-breaching Party requiring rectification of the
breach.
		
	Validation Batch	  	A Batch manufactured by Avecia as part of the Validation Campaign.
		
	Validation Campaign	  	The campaign carried out by Avecia to manufacture three (3) consecutive Validation Batches that can be Released out of up to five (5) anticipated Validation Batches, intended to demonstrate to
Regulatory Authorities a high degree of assurance that the Process will consistently produce Batches meeting pre-determined acceptance criteria necessary for Release, as set out in more detail in Schedule 1 and the Quality
Agreement.
		
	Validation Master Plan	  	A validation project plan developed by Avecia and reviewed, and if acceptable, approved by Nuvelo in writing which contains all of the validation activities for

  

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	 	  	the Validation Campaign, including validation steps, deliverables, a time schedule and responsibilities.
		
	Valid Claim	  	A claim of a Patent that: (a) in the case of a pending claim, is being prosecuted, has been pending for no more than 6 years and has not been abandoned or permitted to lapse, and (b) in the
case of an issued claim, has not expired or been held invalid or unenforceable in a final binding court decision from which no appeal can be or is taken.
		
	Work Programme	  	The protocol for the performance of the Project by Avecia, agreed upon by the Parties and attached as Schedule 1 of this Agreement. The Work Programme sets forth the timing and requirements
for the activities to be carried out under the Project, including the Work Programme Timeline, attached to the Work Programme as Appendix 2.

  

	 	1.2	Interpretation. References in this Agreement to “Schedules” refer to the Schedules incorporated into this Agreement, specifically including, without
limitation, the Confidentiality Agreement, the Quality Agreement, and the Work Programme. To the extent that there is conflict between or ambiguity relating to, on the one hand, any or all of the Schedules and, on the other, the remainder of this
Agreement, the wording of the remainder of this Agreement shall prevail. 

  

	2.	Performance of Project 

  

	 	2.1	General. 

  

	 	(a)	Avecia shall carry out the Project in accordance with the terms and conditions of this Agreement and the Quality Agreement with reasonable skill and care and no less than the level
of skill and care to be reasonably expected of a professional provider of such services. Avecia also shall perform the Project in compliance with all relevant professional standards, all Applicable Laws and cGMP. 

  

	 	(b)	The Parties acknowledge that, having regard to the fact that the work to be performed hereunder is by its nature developmental, Avecia does not guarantee to Nuvelo the achievement
of a successful outcome for the Project, but will use reasonable commercial endeavours to ensure timely success. 

  

	 	2.2	Laboratory work and scale-up activities 

  

	 	(a)	 Following the Commencement Date, Avecia shall carry out, and has carried out with respect to a portion thereof as set forth in the Interim Agreement, a range of
activities, including 

  

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data acquisition and assessment, process transfer, replicate 15L runs, process characterisation, fermentation and downstream process, assay validation,
process transfer and prep for large scale manufacture, laboratory based cleaning studies and centrifuge trials on two (2) 3000 litre Batches of the API, all as set out in more detail in the Work Programme. 

  

	 	(b)	Centrifuge Trials. 

  

	 	(1)	Obligations and Timing. Avecia shall carry out production of two (2) centrifuge trials on two (2) 3000 litre Batches of the API in accordance with its ABC5000 facilities’
Standard Operating Procedures, the Master Batch Records for the Process, all Applicable Laws and the terms and conditions of this Agreement. Avecia shall commence modifications of its ABC5000 facility for the centrifuge trials no later than week
commencing July 4, 2005, Pacific Standard Time. If Avecia fails to commence the modifications of its ABC5000 facility necessary for the centrifuge trials before the expiration of the week commencing July 4, 2005, Pacific Standard Time, then Nuvelo
is entitled to terminate this Agreement in accordance with Section 8.2 upon 10 calendar days written notice to Avecia, without payment of any Cancellation Fees if Avecia has not commenced the modifications before the expiration of the 10 calendar
day period. 

  

	 	(2)	Process Failures; Additional Centrifuge Work. If neither of the two centrifuge trials is successful for any reason other than an Avecia Default, then the Parties shall meet to agree
to an additional phase of process development work, to include the performance of further centrifuge trials (all such work referred to herein as “Additional Centrifuge Work”) and commercially reasonable terms for the performance of
the Additional Centrifuge Work. The Additional Centrifuge Work shall be set forth in a Programme Amendment Order, such Programme Amendment Order to include revised timings for Development Batch Manufacture and Validation Campaign, as appropriate.
If, other than as a result of an Avecia Default, the Additional Centrifuge Work does not result in at least one successful centrifuge trial and Development Batch Manufacture has not commenced before the expiration of December 31, 2005, Pacific
Standard Time, then Nuvelo may either terminate the Agreement in accordance with Clause 8.2 upon a date that is 30 calendar days after December 31, 2005, Pacific Standard Time or call an Urgent Meeting of the PSC to discuss whether further
Additional Centrifuge Work should be conducted. 

  

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	 	(3)	Centrifuge Trials; Avecia Default. If neither of the two centrifuge trials is successful as a result of Avecia Default(s), Avecia shall promptly reprocess, rework if pre-approved in
writing by an authorized representative of Nuvelo or re-perform, the centrifuge trials at Avecia’s cost and expense until either (i) one of the centrifuge trials is successful or; (ii) the centrifuge trials are unsuccessful other than as a
result of an Avecia Default, at which time Clause 2.2(b)(2) will apply. 

  

	 	2.3	Development Batch Manufacture 

  

	 	(a)	Batch Production. Avecia shall carry out production of two (2) Development Batches (in accordance with the terms set forth below) in its ABC5000 facility in accordance with the
terms and conditions of this Agreement, cGMP, Applicable Laws and the Work Programme, with the primary aim of testing and improving Batch records and operating procedures, clarifying any scale-up issues and ensuring operator familiarity with the
Process. Avecia also shall carry out an Engineering Batch in accordance with Clause 2.3(e). Whilst Development Batch Manufacture is intended to produce Development Batches which can be Released, it is recognised that problems related to the Process
that are not Avecia Defaults may preclude this. 

  

	 	(b)	Development Batch Failure. If the Quality Team is in agreement that neither of the two (2) Development Batches manufactured under Clause 2.3(a) can be Released, Avecia shall, at the
direction and option of Nuvelo, either: 

  

	 	(1)	reprocess one of the two (2) Development Batches produced during Development Batch Manufacture in accordance with cGMP; 

  

	 	(2)	if pre-approved in writing by an authorized representative of Nuvelo, rework one of the two (2) Development Batches produced during Development Batch Manufacture in accordance with
cGMP; 

  

	 	(3)	manufacture another Development Batch; or 

  

	 	(4)	immediately stop all work, as a result of a decision by Nuvelo to terminate the Agreement in accordance with Clause 8. 

  

	 	(c)	Next Actions Upon Development Batch Failure. 

  

	 	(1)	 Avecia Default. In the event that the Quality Team is in agreement that the second Development Batch or both of the two (2) Development Batches manufactured under
Clause 2.3(a) are Defective Batches as a result of an Avecia Default, Avecia shall rework, reprocess or 

  

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manufacture in accordance with Clause 2.3(b)—within 10 business days after the Quality Team notified the PSC of the Quality Team’s determination if
the Avecia Default is of a nature that can be promptly corrected, otherwise, as soon as reasonably practicable thereafter—at Avecia’s cost and expense, until such time as Avecia generates a Development Batch that can be Released (or could
have been Released but for an issue that is not an Avecia Default); but if, as a result of Avecia Default(s), Avecia fails to generate a Development Batch which can be Released within 3 months from commencement of such rework, reprocessing or
further manufacture, then the PSC shall hold an Urgent Meeting to discuss whether or not yet another Development Batch should be generated. Nuvelo is entitled to terminate the Agreement, without payment of any Cancellation Fees, if Development
Batches cannot be Released as a result of Avecia Default(s) before the expiration of the 3 month cure period provided in this Clause 2.3(c)(1). Nuvelo may terminate the Agreement during the 3 month cure period for Unremedied Breach if Avecia fails
to generate a Development Batch that can be Released as a result of Avecia Default(s) and is not using commercially reasonable efforts to generate at least one Development Batch that can be Released per month during the three month cure period.

  

	 	(2)	Process Failure. If the first 2 Development Batches cannot be Released for a reason other than Avecia Default, at the request of Nuvelo, Avecia shall rework, reprocess or
manufacture Development Batches at a time and at a cost to Nuvelo to be agreed by the Parties in good faith and recorded in a Programme Amendment Order. If the rework, reprocessing or further manufacture results in another Development Batch which is
a Defective Batch for a reason other than Avecia Default, then the PSC shall hold an Urgent Meeting to discuss whether or not yet another Development Batch should be generated. If and at such time as Avecia and Nuvelo agree that Process scale-up
problems causing the Defective Batches in accordance with this Clause 2.3(c)(2) are or will be satisfactorily resolved, unless the Agreement is terminated by one the Parties, the Parties will agree to a revised timetable for manufacture of a number
of Development Batches to be determined, upon commercially reasonable terms, in a Programme Amendment Order. 

  

	 	(d)	 Successful Development Batch Release: Pre-Validation Campaign Review. If at least one (1) of the two (2) 

  

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Development Batches manufactured under Clause 2.3(a) can be Released or if rework, reprocessing or further manufacture carried out in accordance with Clause
2.3(b) results in a Development Batch which can be Released, the Project Steering Committee shall review the activities carried out to date, solely to evaluate operability of the Process and Avecia’s cGMP compliance in order to ensure that both
Parties are confident of success in the Validation Campaign (“the Pre-Validation Campaign Review”). During the Pre-Validation Campaign Review, the PSC, with input from the Quality Team, shall discuss readiness to carry out the
Validation Campaign, potential timing for its conduct and any other issues concerning the Process operability or cGMP compliance. This discussion will include a review and analysis of the actual performance of the Development Batches compared to the
Process Assumptions, and an attempt by the PSC to reach agreement with respect to whether the Validation Campaign shall be delayed, not be delayed, or not be carried out at all. If during the Pre-Validation Campaign Review, the EC, after referral of
the matter to it by the Project Steering Committee, is unable to reach a final decision in accordance with the terms of Clause 2.7(f) as to whether the Validation Campaign shall be delayed, not be delayed, or not be carried out at all—solely
due to Process operability or Avecia cGMP compliance issues, or any other concerns which resulted in a Development Batch being a Defective Batch— then either Party may terminate this Agreement in accordance with and subject to the terms
provided for termination set forth in this Agreement, including the possibility that the Parties may mutually agree to terminate the Agreement under Clause 8.4. 

  

	 	(e)	Proceeding to Validation Campaign. If at least one (1) Development Batch is Released, then following completion of, and subject to either agreement by the PSC or a determination
made by the EC in the Pre-Validation Campaign Review, Avecia shall carry out an Engineering Batch and shall proceed to and shall carry out the Validation Campaign in accordance with the terms and conditions of this Agreement for the performance of
the Project in accordance with Clause 2.1, the Work Programme and any revised timetable for performance of the Engineering Batch and the Validation Campaign resulting from Pre-Validation Campaign Review. Development Batch Manufacture shall be deemed
to be complete when: (1) the Quality Team has completed Release of at least one Development Batch, and that Batch’s associated documentation has been delivered to Nuvelo; and (2) Avecia has completed manufacture of an Engineering Batch that is
not a Defective Batch, and the Engineering Batch’s associated documentation has been delivered to Nuvelo.  

  

 15 

	 	(f)	Delivery of Defective Batches. In the event that during Development Batch Manufacture it is determined by the Quality Team that a Development Batch is a Defective Batch, the
Defective Batch shall not be delivered to Nuvelo, unless Nuvelo requests it. If Nuvelo requests delivery of the Defective Batch, Avecia shall deliver such Defective Batch in accordance with Clause 4.2 and such Defective Batch may be used in research
or development internally, labelled for non-human use or destroyed. 

  

	 	(g)	Quality Team Disagreement. If the Quality Team cannot reach agreement with respect to whether or not a Development Batch is a Defective Batch, or whether or not a Defective Batch
resulted from an Avecia Default, the disagreement will be resolved in accordance with Clause 2.7(g). 

  

	 	2.4	Validation Campaign 

  

	 	(a)	cGMP Preparation 

  

	 	(1)	Avecia shall carry out cGMP preparation work following the decision that Avecia shall carry out the Validation Campaign under and in accordance with Clause 2.3(e) above. Such cGMP
preparation work shall include the work identified in the Work Programme, the Quality Agreement and any additional work agreed under a Program Amendment Order pursuant to Clause 2.3(c)(2) or otherwise. 

  

	 	(2)	Avecia shall produce a Validation Master Plan for review, comment and approval by Nuvelo before the start of the Validation Campaign. 

  

	 	(3)	Avecia shall conduct the Validation Campaign in accordance with the terms and conditions of this Agreement and the Quality Agreement. The Quality Agreement sets forth how the
Parties’ Quality Units will jointly review non-conformances, determine severity, assess their level of impact on the API and agree on actions which may include accepting a Validation Batch, failing a Validation Batch or declaring a Validation
Batch to be a Defective Batch, disqualifying a Validation Batch from the series of three (3) consecutive Batches or passing or failing the entire Validation Campaign. 

  

	 	(b)	Manufacture of Validation Batches 

  

	 	(1)	 Commencement of Validation Campaign. Avecia shall commence manufacture of Validation Batches following confirmation by the Quality Team that the 

  

 16 

	 	 
preparation work set forth in Clauses 2.4(a)(1) and 2.4(a)(2) has been completed and the Master Batch Records have been approved in accordance with the
Quality Agreement. If the Quality Team is unable to reach agreement on such confirmation and approval, the matter shall be referred to the PSC for resolution. 

  

	 	(2)	Number of Validation Batches. Subject to Clause 2.4(b)(3) below, the Validation Campaign shall consist of up to five (5) Validation Batches with an expectation of producing three
(3) Released consecutive successful production Batches and thus constitute a formal Validation Campaign. Avecia will ensure that sufficient time is scheduled in its ABC5000 facility to complete a Validation Campaign of up to five (5) Validation
Batches. 

  

	 	(3)	5th Validation Batch. In the event that the
Quality Team determines that a fifth (5th) Validation Batch is required, other than as a result of an Avecia
Default, in order to increase the chances of successful completion of the Validation Campaign, Avecia shall carry out manufacture of a fifth (5th) Validation Batch on the basis that Avecia will meet the costs of operating its ABC 5000 facility and Nuvelo shall pay to Avecia, as an additional technical consultancy fee, the actual Expenditures
for any additional raw materials or consumables required to be purchased in order to manufacture such fifth (5th)
Validation Batch, plus the Handling Fee, in accordance with Clause 3.2(b). 

  

	 	(4)	Documentation Review. During the Validation Campaign, the Parties shall carry out review of the Master Batch Records, campaign Batch records and other relevant documentation
relating to each Validation Batch as it is manufactured. This review and assessment will involve the Nuvelo Quality Unit and such other of Nuvelo’s staff as Nuvelo directs, in Nuvelo’s discretion. 

  

	 	(5)	Completion of Validation Campaign. The Validation Campaign shall be deemed to be complete when the Quality Team determines that the Validation Campaign has completed three (3)
Validation Batches that can be designated consecutive successful production Batches that have completed Release, and all associated documentation and a validation summary report have been delivered to Nuvelo in accordance with Clause 4.2.

  

 17 

	 	(c)	Quality Unit Determination 

  

	 	(1)	Determination of Validation Success or Failure. The Quality Team shall determine in accordance with the Quality Agreement and by reference to cGMP whether the Validation Campaign
has been successful. In the event that the Quality Team determines that the Validation Campaign has not been successful, then, as set forth in and in accordance with Clauses 2.4(c)(2) and 2.4(c)(3) below, Avecia shall repeat the Validation Campaign
or Validation Batches (as appropriate) within 10 business days after the Quality Team notified the PSC of the Quality Team’s determination, if the cause of the failure of the Validation Campaign is of a nature that can be promptly corrected,
otherwise, as soon as reasonably practicable thereafter. In the event of any dispute arising amongst the Quality Team, the matter will be resolved in accordance with Clause 2.7(g).  

  

	 	(2)	Avecia Default. If the Validation Campaign is determined not to be successful as a result of an Avecia Default, then the repeated Validation Campaign or Validation Batches (as
appropriate) shall be promptly carried out by Avecia at Avecia’s cost and expense; but if the repeated Validation Campaign or Validation Batches (as appropriate) does not result in a successful Validation Campaign as a result of an Avecia
Default within 3 months of commencement of such repeated Validation Campaign or Validation Batches (as appropriate), then the PSC shall hold an Urgent Meeting to discuss whether or not the Validation Campaign or Validation Batches (as appropriate)
shall be repeated again. Nuvelo is entitled to terminate the Agreement, without payment of any Cancellation Fees, if, as a result of Avecia Default, the repeated Validation Campaign or Validation Batches (as appropriate) does not result in a
successful Validation Campaign before the expiration of the 3 month cure period provided in this Clause 2.4(c)(2). Nuvelo may terminate the Agreement during the 3 month cure period for Unremedied Breach if Avecia fails to generate a successful
Validation Campaign and is not using commercially reasonable efforts to generate at least 5 Validation Batches that could lead to a successful Validation Campaign during the three month cure period. 

  

	 	(3)	 Validation Process Failure. If the Validation Campaign is determined not to be successful because of a Validation Process Failure, then, if requested in writing by
Nuvelo, a repeated Validation Campaign or Validation Batches (as appropriate) shall be carried out by Avecia at a commercially reasonable cost to Nuvelo to be agreed in good faith by the Parties and set out in 

  

 18 

	 	 
a Programme Amendment Order. In the event that a repeated Validation Campaign carried out under this Clause is determined not to be successful, then the
Parties shall meet to discuss what action should be taken. 

  

	 	(d)	Quality Team Disagreement. If the Quality Team cannot reach agreement with respect to whether or not a Validation Batch is a Defective Batch, or whether or not a Defective Batch
resulted from an Avecia Default, the disagreement will be resolved in accordance with Clause 2.7(g). 

  

	 	2.5	Delays and Cancellations. Nuvelo shall have an option to, and otherwise may as a result of an Avecia Default, delay commencement of, or cancel Development Batch Manufacture
or the Validation Campaign. The Parties also acknowledge that delays may occur as a result of Process Failures, as set forth below. In the event that Nuvelo decides to exercise such option or take such action, the following provisions shall apply:

  

	 	(a)	Notice. Nuvelo shall give written notice to Avecia of its intention to delay or cancel Development Batch Manufacture or the Validation Campaign (as appropriate), and, in the case of
delay, setting out the estimated length, or circumstances that would dictate the length, of the delay. Notice is deemed given at such time as either Party notifies the other Party in writing that the Validation Campaign will be delayed as a result
of a Process Failure, and in such case, the PSC shall determine the estimated length of the delay. 

  

	 	(b)	Cancellation Fees; Non-Manufacturing Delays or Cancellation. With respect to any cancellation or Non-Manufacturing Delay, Nuvelo shall pay to Avecia the Cancellation Fees in
consideration for technical consultancy into the effect of such Non-Manufacturing Delay or cancellation on the Project. 

  

	 	(c)	 Process Failure Delay Fee. With respect to any delay of the Validation Campaign resulting from a Process Failure that results in a delay of the completion of the
usage of Avecia’s manufacturing facilities for the Validation Campaign by more than two weeks after August 16, 2006, Nuvelo shall pay to Avecia, in consideration for technical consultancy into the effect of such delay on the Project, the sum of
£212,470 pounds per week (the “Process Failure Delay Fee”) for each week beyond the expiration of two weeks after August 16, 2006, during which the completion continues to be delayed, until such time as Nuvelo has paid to
Avecia an amount in Process Failure Delay Fees that is equal to the lesser of: £2,550,000 pounds; or the amount Nuvelo would have paid to Avecia in Cancellation Fees if notice had been given regarding a Non-Manufacturing Delay instead of a
delay 

  

 19 

	 	 
resulting from a Process Failure. Avecia shall make commercially reasonable endeavours to raise revenue by utilising the production facility during the
period during which the Validation Campaign was intended to take place but for the delay. Avecia shall refund to Nuvelo a sum equivalent to the revenue (net of raw materials and consumables Expenditure) raised as a result of such alternative use up
to a maximum of 80% of the technical consultancy fee paid under this Clause 2.5(c). For the purposes of this Clause 2.5(c), “Process Failure” means the occurrence of a Defective Batch that results from a factor—other than any
of the factors listed in paragraphs (a) through (d) of the definition of Avecia Default—which affects the Process or production of the API and was not known and could not reasonably have been known by Avecia prior to the time at which the
factor became known, including, without limitation, a previously unknown factor not studied either as part of the Amgen programme transferred to Avecia or the Avecia laboratory work programme carried out pursuant to the Project.

  

	 	(d)	Delay. The Parties shall meet to discuss availability of Avecia’s manufacturing facility for the delayed Development Batch Manufacture or the Validation Campaign (as
appropriate) in accordance with Clause 2.3 and 2.4 and, except with respect to any delay resulting from or arising out of an Avecia Default, Nuvelo’s refusal to take a license under a Patented, Licensed Avecia Invention under Clause 5.2(c) or
failure of the centrifuge trials, if the delay is in excess of six (6) months, a commercially reasonable amount payable by Nuvelo to Avecia in respect of such later commencement of Development Batch Manufacture or the Validation Campaign (as
appropriate). 

  

	 	(e)	Effect of Delay on Project. Except with respect to a delay resulting from or arising out of an Avecia Default or Nuvelo’s refusal to take a license under a Patented, Licensed
Avecia Invention under Clause 5.2(c), Avecia shall not be obliged to carry out the delayed Development Batch Manufacture or the Validation Campaign (as appropriate) until the Parties have reached agreement on the later commencement thereof, but will
use reasonable commercial endeavours to reschedule the availability of its facility and appropriate personnel. In the case of a delay resulting from an Avecia default, if Nuvelo decides to have Avecia proceed with Development Batch Manufacture
and/or the Validation Campaign, Avecia shall carry out the delayed Development Batch Manufacture or Validation Campaign in accordance with the terms and conditions set forth in Clauses 2.3 and 2.4. 

  

	 	(f)	 Effect of Cancellation. Where Nuvelo elects to cancel Development Batch Manufacture, Avecia shall not be obliged to carry out the Validation Campaign, and except
with respect 

  

 20 

	 	 
to any cancellation resulting from or arising out of an Avecia Default or failure of the centrifuge trials, the Validation Campaign shall also be deemed
cancelled with effect from the date of notice of Nuvelo’s intention to cancel Development Batches Manufacture and the Validation Campaign. 

  

	 	2.6	Nuvelo Delay. 

  

	 	(a)	In the event of a Nuvelo Delay, Avecia and Nuvelo will use reasonable commercial endeavours to minimize such Nuvelo Delay or, subject to agreement by both Parties, to adjust the
Development Batch Manufacture or the Validation Campaign schedule to accommodate such delay. Any Nuvelo Delay which cannot be avoided shall be considered to be Hold Time in respect of the affected Batch. 

  

	 	(b)	In the event that a Nuvelo Delay results in an inability for Avecia to carry out the Development Batch Manufacture or the Validation Campaign in accordance with the mutually agreed
schedule therefor, then the Parties shall meet to discuss availability of Avecia’s manufacturing facility for the delayed Development Batch Manufacture or the Validation Campaign (as appropriate), and a commercially reasonable amount payable by
Nuvelo to Avecia in respect of such later commencement of Development Batch Manufacture or the Validation Campaign (as appropriate). 

  

	 	2.7	Project Steering Committee, or PSC, Executive Committee, or EC, and Resolution of Batch Disputes. 

  

	 	(a)	Membership. 

  

	 	(1)	PSC Membership. The PSC shall have at least 6 and up to 8 members, within any case, an equal number of members appointed by each Party. Each Party’s initial membership on the
PSC shall be as set forth in Schedule 5. Each Party may replace its PSC representatives at any time upon written notice to the other Party, provided that each Party shall appoint and maintain for the duration of the term of this Agreement
representatives on the PSC of equivalent or higher position within that Party as the original representative(s) set forth on Schedule 5. The PSC shall keep minutes of its meetings and submit its meeting minutes to the EC members for EC and Party
review. The host Party at each in-person meeting shall prepare the minutes for that meeting, otherwise, minute taking will alternate between the Parties for each meeting. 

  

	 	(2)	 EC membership. The EC shall be composed of 2 members, 1 representative of each Party. Each EC 

  

 21 

	 	 
member shall not be a member of the PSC, shall have obtained, and maintain, the level of vice president (or comparable title) or above, and shall be duly
authorized by the Party it represents to resolve any and all disagreements of the PSC. The EC representatives are set forth on Schedule 5. Each Party may replace its EC representative with another qualifying individual at any time upon written
notice to the other Party. The EC shall keep minutes of its meetings and prepare a report for Party review. Minute taking will alternate between the Parties for each meeting. 

  

	 	(b)	Power and Responsibilities. 

  

	 	(1)	PSC Powers and Responsibilities. The PSC shall have the following specific responsibilities and authority: 

  

	 	(i)	to review and approve the overall plan for process development, characterization, manufacturing and Release of Batches of Product; 

  

	 	(ii)	to review and approve resources and timelines for the Project, and any changes for the Project; 

  

	 	(iii)	to evaluate and manage any changes or other incidents that may occur during the course of the Project; 

  

	 	(iv)	to serve as a forum for the sharing of information between the Parties with respect to Project activities and Project progress; and 

  

	 	(v)	to evaluate Batch Disputes that arise at the Quality Team level in accordance with Clause 2.7(g). 

  

	 	(2)	EC Powers and Responsibilities. The EC shall support the PSC in decision-making and support the overall strategy for the Project. The EC shall have the following specific
responsibilities and authority: 

  

	 	(i)	to resolve any disagreements of the PSC, but excluding Batch Disputes, in accordance with Clause 2.7(f); 

  

	 	(ii)	to review PSC meeting minutes and evaluate the effectiveness and composition of the PSC, providing any comments thereon back to the PSC for consideration; and

  

	 	(iii)	to serve as a forum for information sharing between senior management of the Parties. 

  

 22 

	 	(c)	Limitations on PSC and EC. The PSC and the EC shall have no power to amend or waive compliance with this Agreement. Any amendments that alter the terms of this Agreement
shall be implemented, if at all, pursuant to Clause 14 below. The PSC and EC shall have only the responsibility explicitly provided for them in Clause 2.7(b), and shall not have any other powers or responsibilities. 

  

	 	(d)	Regular Meetings. The Parties shall endeavour to schedule regular meetings of the PSC and EC at least 30 calendar days in advance. The PSC shall meet at least once a calendar
quarter, and at least 2 regular meetings per year will be held in person. The EC shall meet twice a year, and shall decide whether or not it will meet in person, by teleconference or videoconference. Committee meetings held in person will alternate
between sites designated by each Party and each Party shall be responsible for all of its own expenses of participating in PSC and EC meetings. With the consent of the representatives of each Party serving on the PSC, other representatives of each
Party may attend meetings of the PSC. With the consent of each EC member, other representatives of each Party may attend meetings of the EC, or portions thereof. 

  

	 	(e)	Additional & Urgent Meetings. Upon mutual agreement of the PSC or EC, not to be unreasonably withheld, the Parties may schedule additional meetings of the PSC or EC as
necessary to appropriately conduct the Project, and any such additional PSC or EC meetings will be held by teleconference or videoconference and will be held no later than 15 calendar days after reasonably requested by a Party. A meeting of the PSC
may be requested on an urgent basis (“Urgent Meeting”) for the following reasons: Batch failure, excessive downtime in the facility being used to develop or manufacture Product, notice of a Batch Dispute, significant cGMP or
Applicable Law violation or significant adulteration of Product or a Batch. An Urgent Meeting shall be held no later than 3 business days after requested by a Party. Urgent meetings may be held in-person, by teleconference or by videoconference. If
the PSC cannot come to agreement on a matter before it at an Urgent Meeting, except with respect to a Batch Dispute, the matter shall be immediately referred to the EC for resolution. 

  

	 	(f)	 Decision Making & Dispute Resolution. The PSC and EC will reasonably discuss all matters that come before them. Decisions of the PSC and EC will be made
by unanimous agreement, with each Party having one vote on the PSC and one vote on the EC. If the PSC cannot come to agreement on an issue at the applicable PSC meeting, other than with 

  

 23 

	 	 
respect to a Batch Dispute, the PSC shall promptly refer the matter to the EC. The EC shall meet no later than 15 calendar days after referral of a matter to
it by the PSC. The EC shall have 15 calendar days after meeting to resolve the matter. If the EC cannot mutually agree on a resolution of the matter before the expiration of the 15 day period, then Nuvelo is entitled to make the final decision for
the EC on the matter, which Nuvelo decision shall not be unreasonable, with the exception of the following matters, which shall only be resolved by mutual agreement of the EC, Avecia’s agreement to such matters not be unreasonably withheld: (1)
any matter which would require execution of a Programme Amendment Order; (2) any matter which would, other than as a result of an Avecia Default, adversely effect a manufacturing schedule— which schedule is not in conflict with the Project
timeline set forth in the Work Program Timeline—established for a third party by Avecia, for use of Avecia’s facilities; or (3) materially change the Project timeline set forth in the Work Program Timeline. The decisions of the EC, whether
determined by final decision of Nuvelo or mutual decision, in accordance with the preceding sentence, shall bind both of the Parties, except that: Avecia may refer a matter upon which Nuvelo made a final decision to dispute resolution in accordance
with Clause 19.2 if in Avecia’s reasonable, good faith judgement, Nuvelo’s decision would (1) violate the express terms of this Agreement; or (2) result in a breach of Applicable Law. 

  

	 	(g)	Dispute Resolution for Batch Disputes. If a dispute arises amongst the Quality Team relating to whether or not a Batch of the API is a Defective Batch, or whether or not a
Defective Batch results from or arises out of an Avecia Default (each of the preceding a “Batch Dispute”), such Batch Dispute shall be resolved as follows. 

  

	 	(1)	The Quality Team shall immediately notify the Project Steering Committee (PSC) in writing (the “Batch Dispute Notice”) that a Batch Dispute exists amongst
the Quality Team. The Quality Team will discuss the Batch Dispute in good faith to attempt to reach agreement on: (i) whether a Batch is a Defective Batch and, if so, what course of action shall be taken to address it; and (ii) whether or not a
Defective Batch resulted from or arose out of an Avecia Default. 

  

	 	(2)	 In the event that the Quality Team fails to reach agreement on a Batch Dispute within 15 calendar days after sending the Batch Dispute Notice to the PSC, the
Quality Team shall immediately refer the Batch Dispute to the PSC for discussion, by written notice to the PSC. Once the Batch Dispute has been referred to the PSC, the PSC has 5 business days from receipt of the referral notice to either resolve
the Batch Dispute or 

  

 24 

	 	 
refer the Batch Dispute to an independent expert or laboratory, with the expertise necessary to reasonably resolve the Batch Dispute.

  

	 	(3)	If the PSC cannot resolve the Batch Dispute or agree upon an independent expert or laboratory to resolve the Batch Dispute before the expiration of 5 business days after receiving
the referral notice, the PSC shall immediately notify the EC of its failure in writing. Within no later than 2 business days after receiving notice of the failure from the PSC, each EC member shall nominate an independent expert who shall not: be a
current or former employee, consultant or agent of a Party; have an immediate family member who is an employee, consultant or agent of a Party; or have any financial interest in a Party. Promptly thereafter, those two independent experts shall agree
on a third independent expert who shall use any reasonable information, materials and data provided to him or her by the other two experts within 10 business days after his or her agreement to act as the third independent expert, to either promptly
resolve the Batch Dispute or determine which independent Third Party laboratory will conduct the work necessary to promptly resolve the Batch Dispute. Such referral shall be solely for the purpose of establishing whether or not the applicable Batch
is a Defective Batch and whether or not any Defective Batch results from or arises out of an Avecia Default. The decision of the independent expert, or independent laboratory, shall be made in writing and shall be binding upon the Parties. Whichever
Party failed to accurately assess whether the Batch was or was not a Defective Batch, or whether or not a Defective Batch resulted from or arose out of an Avecia Default, shall bear the full cost and expense associated with the hiring and
performance of the independent experts and/or laboratory. 

  

	 	2.8	Programme Amendment Orders. The Parties may agree to vary the Project and sums to be paid under Clause 3 as a result of a Project variation, so long as such variation is made
in writing in a Programme Amendment Order. The Parties recognize that any of the following will require changes to the Work Programme that may cause a change in payments set out in Clause 3: 

  

	 	(a)	Nuvelo requires Avecia to carry out additional or different work to that specified in the Work Programme set forth in Schedule 1; or 

  

	 	(b)	the actual circumstances encountered in carrying out the Project differ from the then current Process Assumptions; or 

  

 25 

	 	(c)	in the event that there is a delay to the Project for any reason other than Avecia Default or Nuvelo’s refusal to take a license under a Patented, Licensed Avecia Invention,
including a Nuvelo Delay; or 

  

	 	(d)	in the event that Additional Centrifuge Work is required as a result of a failure, other than one attributable to an Avecia Default, of the centrifuge trials pursuant to Clause
2.2(b); or 

  

	 	(e)	Hold Time, but excluding Hold Time resulting from or arising out of: (1) an Avecia Default or (2) Nuvelo’s refusal to take a license under a Patented, Licensed Avecia
Invention. 

  

	 	2.9	Regulatory Matters and Regulatory Assistance.  

  

	 	(a)	During the Project and following Completion, Avecia will provide reasonable assistance to Nuvelo in respect of Nuvelo’s Regulatory Filing activities for the Product and the
Process, including preparatory to and during Pre-Approval Inspection (PAI) and related quality unit support, as further set forth below. 

  

	 	(b)	At no additional cost to Nuvelo, Avecia shall: provide Nuvelo with any and all requested data created in connection with the development and manufacture of the API under this
Agreement which is reasonably necessary to support submissions for regulatory approvals to Regulatory Authorities; and take all actions necessary to recreate or modify as reasonably necessary any documentation or materials provided by Avecia to
Nuvelo for submission to Regulatory Authorities that were not provided to Nuvelo in a form or format reasonably acceptable to the applicable Regulatory Authority. Nuvelo shall advise Avecia on the form or format Nuvelo, or the Regulatory Authority,
to the extent Nuvelo is aware of the Regulatory Authority’s requirements, may require prior to provision of such documentation or materials by Avecia.  

  

	 	(c)	Subject to payment by Nuvelo of a reasonable commercial rate for such assistance and Avecia’s reasonable expenses, Avecia shall develop any data requested by Nuvelo concerning
the development, manufacture or quality assurance testing of the API which is necessary to support submissions for regulatory approvals to Regulatory Authorities, which data was not anticipated to be developed as part of the Project under the Work
Programme or the Quality Agreement. 

  

	 	(d)	 Nuvelo shall be responsible for preparing and filing all submissions for regulatory approvals of Product. Nuvelo will confirm Nuvelo interpretations of Avecia data
in the Chemistry, Manufacturing and Controls (CMC) section of any 

  

 26 

	 	 
submissions to Regulatory Authorities with Avecia before submission to Regulatory Authorities. Nuvelo owns and shall own all Regulatory Filings related to
the Product and the API. 

  

	 	(e)	At no additional cost to Nuvelo, to the extent Nuvelo needs to submit and make available any Master Batch Record in connection with obtaining any regulatory approvals from any
Regulatory Authority, to the fullest extent permissible under Applicable Laws, Avecia shall provide Nuvelo with any and all information necessary for Nuvelo to make the Master Batch Record available to the applicable Regulatory Authority.

  

	 	(f)	At no additional cost or expense to Nuvelo, Nuvelo shall have full access to and the right to use and reference, any correspondence, facility and engineering records and diagrams,
validation documentation, Batch records, reports, analyses, regulatory requirements and any other data and documentation generated in connection with the Project, and Avecia shall provide Nuvelo with 1 full set of the foregoing documentation upon
request. 

  

	 	(g)	Avecia will handle all waste resulting from or arising out of the Project in accordance with Applicable Laws. 

  

	 	(h)	The provision of data, information or copies of records from Avecia’s work is included in the fees set out in Clause 3. In the event that Avecia needs to generate additional
information under paragraph (c) above or re-analyze data in an unanticipated way in response to a Regulatory Authority request, then that information and data shall be provided subject to agreement of a reasonable commercial rate based on the
time/effort required. 

  

	 	2.10	Quality Audits by Nuvelo & SCAR Reporting. 

  

	 	(a)	Nuvelo reserves the right to conduct, twice-a-year, comprehensive quality audits of Avecia’s facilities, which may include a site tour, questioning of employees in work areas
and review of quality system documentation to the appropriate quality standards. Avecia will be notified in advance of the intention to conduct an audit and the audit’s scope, and a mutually convenient date will be selected. During the audit,
any non-conformances will be noted and documented in a report issued by Nuvelo within thirty (30) business days. Avecia will be requested to submit a written response and corrective action plan within thirty (30) business days of receipt of the
report. Avecia will close all corrective actions that can be closed within 90 business days to the satisfaction of Nuvelo. Corrective actions that cannot be closed out within 90 business days will have a timeline for closure agreed with Nuvelo.

  

 27 

	 	(b)	Supplier performance issues or non-conformances in the API will be indicated to Avecia, in addition to any notifications through the PSC or EC, in the form of a Nuvelo Supplier
Corrective Action Report (SCAR)/Memo. Avecia will be requested to respond to the SCAR/Memo usually within thirty (30) business days post receipt.  

  

	3.	Payments  

  

	 	3.1	Consideration. In consideration of Avecia carrying out the technical consultancy activities pursuant to the Project in accordance with the terms and conditions of this
Agreement and in consideration for sale and delivery of API in accordance with the terms and conditions of this Agreement, Nuvelo shall pay to Avecia a sum of ten million pounds (£10,000,000), to be paid, as follows, if and only if the
following terms and conditions set forth below are met: 

  

							
	 Milestone
 Number

	  	 Anticipated/Approximate
Completion Date
 Of Milestone

	  	 Milestone/Invoice Trigger

	  	Amount
Triggered by
Milestone (£)

	 1
	  	Done and paid in full before the signature date of this Agreement	  	In consideration for technical consultancy in relation to assessment and planning, paid on the Commencement Date	  	105,000
				
	 2
	  	Done and paid in full before the signature date of this Agreement	  	In consideration for Avecia carrying out technical consultancy preparatory to GMP manufacture, paid on the Commencement Date	  	50,000
				
	 3
	  	Done and paid in full before the signature date of this Agreement	  	In consideration for technical consultancy pursuant to commencement of the Project, paid on 28th February 2005	  	300,000
				
	 4
	  	Signature of this Agreement	  	In consideration for Avecia carrying out technical consultancy in relation to transfer of process and assays, payable on completion of transfer of process and analytical methods	  	105,000
				
	 5
	  	Signature of this Agreement	  	In consideration for technical consultancy pursuant to Process characterisation in the laboratory (Experimental set 1, based on RPN analysis), payable on commencement of the Process
characterisation	  	136,250
				
	 6
	  	Signature of this Agreement	  	In consideration for technical consultancy pursuant to assay validation, payable on commencement of assay validation	  	358,750
				
	 7
	  	Signature of this Agreement	  	In consideration for technical consultancy pursuant to preparation of the Project plan, payable on agreement of the Project plan, including the manufacturing schedule by the PSC	  	50,000

  

 28 

							
	 8
	  	Signature of this Agreement	  	In consideration for technical consultancy pursuant to modification of ABC5000 facility modifications for centrifuge trials, payable on commencement of modifications	  	350,000
				
	 9
	  	18-Jul-05	  	In consideration for technical consultancy pursuant to preparation of a cleaning study, payable on completion of the cleaning study and delivery of a report on such study	  	10,000
				
	 10
	  	08-Aug-05	  	In consideration for technical consultancy pursuant to preparation of Batch records for centrifuge trials, payable on completion of such Batch records	  	160,000
				
	 11
	  	14-Aug-05	  	In consideration for technical consultancy pursuant to preparation for Development Batch Manufacture, payable three (3) months prior to commencement of manufacture of the first Development
Batch	  	420,000
				
	 12
	  	18-Aug-05	  	In consideration for technical consultancy pursuant to the replicate 15L fermentation runs, payable on completion of the runs and delivery of the associated technical report	  	54,500
				
	 13
	  	22-Aug-05	  	In consideration for technical consultancy in performance of the centrifuge runs, payable on commencement of the first centrifuge run	  	200,000
				
	 14
	  	01-Sep-05	  	In consideration for technical consultancy pursuant to the centrifuge runs, payable on completion of the first centrifuge run	  	250,000
				
	 15
	  	07-Sep-05	  	In consideration for technical consultancy pursuant to the replicate purification runs, payable on completion of the runs and delivery of the associated technical report	  	54,500
				
	 16
	  	26-Sep-05	  	In consideration for technical consultancy pursuant to 100L labscale purification, payable on completion thereof	  	44,000
				
	 17
	  	26-Sep-05	  	In consideration for technical consultancy pursuant to preparation of Batch records, payable on commencement of Batch record writing (approval of Process Specification for GMP Development
Batches)	  	88,500

  

 29 

							
	 18
	  	28-Oct-05	  	In consideration for technical consultancy pursuant to preparation for Development Batch Manufacture, payable on completion of the plant report for centrifuge runs	  	200,000
				
	 19
	  	14-Nov-05	  	In consideration for technical consultancy pursuant to preparation for Development Batch Manufacture, payable on completion of the Batch records for Development Batch Manufacture	  	88,500
				
	 20
	  	14-Nov-05	  	In consideration for technical consultancy pursuant to performance of Development Batch Manufacture, payable on commencement of Development Batch Manufacture	  	751,250
				
	 21
	  	18-Nov-05	  	In consideration for technical consultancy pursuant to assay validation, payable upon completion of assay validation for the first 10 assays to be validated	  	291,250
				
	 22
	  	21-Nov-05	  	 In consideration for technical consultancy pursuant to characterisation of the Process in the laboratory (Experimental Set 1) payable on delivery
of the fermentation technical report
 and purification technical report
	  	136,250
				
	 23
	  	01-Dec-05	  	As a first stage payment in consideration for sale and delivery of a Released Batch of API, payable on commencement of manufacture of the second Development Batch	  	251,250
				
	 24
	  	20-Jan-06	  	In consideration for technical consultancy pursuant to assay validation, payable upon completion of assay validation for the remainder of the assays to be validated	  	417,000
				
	 25
	  	01-Mar-06	  	As a final stage payment in consideration for sale and delivery of Released Development Batch(es), payable on Release of at least one Development Batch during Development Batch
Manufacture	  	510,000
				
	 26
	  	12-Apr-06	  	In consideration for technical consultancy during performance of Engineering Batch manufacture, payable on commencement of manufacture of the Engineering Batch	  	424,940

  

 30 

							
	 27
	  	12-Apr-06	  	In consideration for technical consultancy in preparation of Batch records for the Validation Campaign, payable on completion of such Batch records	  	120,600
				
	 28
	  	26-Apr-06	  	In consideration for technical consultancy during Engineering Batch manufacture, payable on completion of manufacture of the Engineering Batch, as evidenced by commencement of post-Batch
cleaning of the facility	  	424,940
				
	 29
	  	26-Apr-06	  	As a first stage payment in consideration for sale and delivery of Released API produced during the Validation Campaign, payable on commencement of manufacture of the first Validation
Batch	  	424,940
				
	 30
	  	26-Apr-06	  	In consideration for technical consultancy pursuant to preparation of the Validation Master Plan under clause 2.4(a)(ii) of the Work Programme, payable on completion of Validation Master
Plan	  	50,000
				
	 31
	  	26-Apr-06	  	In consideration for technical consultancy pursuant to preparation of the Validation Master Plan, payable on execution of the Validation Master Plan	  	99,000
				
	 32
	  	12-May-06	  	As a second stage payment in consideration for sale and delivery of Released API produced during the Validation Campaign, payable on commencement of manufacture of the second Validation
Batch	  	424,940
				
	 33
	  	29-May-06	  	As a third stage payment in consideration for sale and delivery of Released API produced during the Validation Campaign, payable on commencement of manufacture of the third Validation
Batch	  	424,940
				
	 34
	  	12-Jun-06	  	As a fourth stage payment in consideration for sale and delivery of Released API produced during the Validation Campaign, payable on commencement of manufacture of the fourth Validation
Batch	  	424,940

  

 31 

							
	 35
	 	 26-Jun-06
	  	As a fifth stage payment in consideration for sale and delivery of Released API produced during the Validation Campaign, payable on commencement of manufacture of the fifth Validation Batch,
if agreed under Clause 2.4(b)(3)	 	Payment in accordance with
Clause 2.4(b)(3)
				
	 36
	 	 16-Aug-06
	  	As a sixth stage payment in consideration for sale and delivery of Released API produced during the Validation Campaign, payable on Release of the first Validation Batch	 	424,940
				
	 37
	 	 01-Sep-06
	  	As a seventh stage payment in consideration for sale and delivery of Released API produced during the Validation Campaign, payable on Release of the second Validation Batch	 	424,940
				
	 38
	 	 18-Sep-06
	  	As an eighth stage payment in consideration for sale and delivery of Released API produced during the Validation Campaign, payable on Release of the third Validation Batch	 	424,940
				
	 39
	 	 02-Oct-06
	  	As a ninth stage payment in consideration for sale and delivery of Released API produced during the Validation Campaign, payable on Release of the fourth Validation Batch, such stage payment
to be the final stage payment for sale and delivery of API produced during the Validation Campaign, in the event that the PSC determines that a fifth Validation Batch is not required.	 	424,940
				
	 40
	 	 18-Oct-06
	  	As final stage payment in consideration for sale and delivery of Released API produced during the Validation Campaign, payable on Release of the fifth Validation Batch, in the event
that the PSC determines that a fifth Validation Batch is not required	 	Payment in accordance with
Clause 2.4(b)(3)
				
	 41
	 	 01-Dec-06
	  	In consideration for technical consultancy pursuant to preparation of validation reports, payable on delivery of such reports	 	99,000

  

	 	3.2	Excluded Items. 

  

	 	(a)	The sums set out in Clause 3.1 above do not include: 

  

	 	(1)	 Expenditure actually incurred by Avecia for major consumable items (including, without limitation, Expenditure associated with chromatography resins and filtration
membranes) intended to be used and not reasonably usable for other purposes by Avecia, or 

  

 32 

	 	 
actually used for cGMP Batches (including centrifuge trials conducted under Clause 2.2, Development Batch Manufacture and the Validation Campaign); or

  

	 	(2)	Expenditures actually incurred by Avecia for work conducted by subcontractors, subcontracted by Avecia in accordance with Clause 13.2, for the performance of the following assays,
which assays are discussed in more detail in the Work Programme: (i) intact MS, (ii) DNA or equivalent, (iii) USP/EP Pyrogen, (iv) EPA Copper and Zinc, and (v) DNA sequence for cell bank; or  

  

	 	(3)	Expenditure actually incurred by Avecia in respect of other consumable items purchased for use in the Project (including, without limitation, disposable bags, tubing, hoses and
chemical raw material costs), or actually used for cGMP Batches (including centrifuge trials conducted under Clause 2.2, Development Batch Manufacture and the Validation Campaign). 

  

	 	(b)	Avecia shall notify Nuvelo of the Expenditure incurred in respect of Clause 3.2(a)(3) and Avecia shall obtain Nuvelo’s approval in writing prior to incurring such Expenditure
in Clause 3.2(a)(1) or 3.2(a)(2) and, subject to approval in respect of Expenditure under Clauses 3.2(a)(1) or 3.2(a)(2), such Expenditure shall thereupon form part of the consideration for the provision of the technical consultancy services
(including qualification, quality assurance and quality control activities) by Avecia and Avecia shall invoice Nuvelo for: (1) such amounts; and (2) in the case of Expenditure incurred under Clauses 3.2(a)(1) and 3.2(a)(3), the Handling Fee. Upon
any termination of this Agreement, all consumable items purchased by Avecia for the Project that are not consumed or otherwise worn beyond further use by their use in the Project shall, upon Nuvelo’s request, be sold to Nuvelo or Nuvelo’s
designee for the sum total of £1 and delivered by Avecia, ready for shipment, into the custody of a shipper reasonably acceptable to Nuvelo or Nuvelo’s designee, the cost of shipment to be at Nuvelo’s cost and expense, for
Nuvelo’s or its designee’s use and disposal, in its discretion.  

  

	 	3.3	Equipment. In order for Avecia to provide technical consultancy services work under this Agreement, it will be necessary for certain items of Equipment to be purchased by
Avecia. Avecia will be authorised to proceed with the relevant services for which the Equipment is required on the following terms: 

  

	 	(a)	 Avecia shall obtain, from an independent Third Party, at least 2 quotations for each item of Equipment and send a copy of the quotations by fax or email to Nuvelo
and Nuvelo shall inform Avecia within 5 business days of receipt which 

  

 33 

	 	 
quotation Nuvelo approves and whether it authorises Avecia to proceed with the services for which the item of Equipment is required. In the absence of such
approval, Avecia shall not proceed with the relevant services. 

  

	 	(b)	If Nuvelo gives its approval to the relevant quotation, Avecia shall be considered authorised to proceed with the relevant services set forth under the Work Programme or agreed upon
Program Amendment Order and shall purchase the item of Equipment for such purpose. Any Equipment purchased by Avecia shall be dedicated to the Project, and shall not be used for any other use or purpose. Avecia shall keep the Equipment in good
working order. The purchase price of the item of Equipment per the approved quotation shall thereupon form part of the consideration for the provision of the technical consultancy services (including qualification, quality assurance and quality
control activities) by Avecia and Avecia shall invoice Nuvelo for: (i) such amount; and (ii) the Handling Fee. 

  

	 	(c)	Following completion or termination of the Project, whichever occurs first, at any time within 12 months following such completion or termination, Nuvelo shall be entitled to
purchase all or any portion of the Equipment from Avecia for the sum total of £1.00 in its or their then current, good working condition, subject to payment of any outstanding and undisputed fees by Nuvelo to Avecia for work carried out under
this Agreement in accordance with the terms and conditions of this Agreement and the Work Programme.  

  

	 	(d)	Nuvelo shall provide to Avecia reasonable prior written notice of its wish to purchase the Equipment so as to minimize any unplanned facility downtime and Nuvelo shall be
responsible for all commercially reasonable removal costs and expenses. If the removal of any Equipment is performed by Nuvelo personnel, Nuvelo agrees to pay for the making good of any damage caused to Avecia’s facility as a result of such
removal. If the removal is performed by Avecia personnel, Avecia agrees to pay for the making good of any damage caused to the Equipment being removed as a result of such removal. 

  

	 	3.4	 Invoices and Timing of Payments. Avecia shall promptly issue invoices for the sums set out in Clauses 3.1, 3.2 and 3.3 once such sums become payable in
accordance with Clauses 3.1, 3.2 and 3.3. In respect of invoices in respect of sums set out in Clause 3.1, Nuvelo shall pay invoices received by Nuvelo on or before the 15th day of each month by the end of that month and shall pay invoices received by Nuvelo after the 15th day of each month by the end of the following month. In respect of invoices in respect of sums set out in Clause 3.2, Nuvelo shall pay such sums within 30
calendar days after Nuvelo’s receipt of the relevant invoice. In respect of 

  

 34 

	 	 
invoices in respect of sums set out in Clause 3.3, Nuvelo shall pay such invoices within ten (10) business days after receipt of the relevant invoice.
Payments shall be made in Pounds Sterling. 

  

	 	3.5	Bank Account Details. All amounts payable to Avecia under this Agreement shall be paid by wire transfer, quoting invoice numbers of payment, to an account number specified in
writing by Avecia. 

  

	 	3.6	Taxes. Any payment under this Agreement is stated exclusive of any Value Added Tax. It is the understanding of both Parties that the technical consultancy services being
provided under this Agreement are outside the scope of UK VAT. However, in the event that UK VAT does become payable, the UK VAT shall be for the account of Nuvelo and Avecia shall use best efforts to assist Nuvelo in seeking recovery of such tax
paid from the UK HM Customs and Excise. If Nuvelo is otherwise required to withhold tax applicable to any payment under this Agreement, Nuvelo shall promptly provide Avecia with the official receipts and such other evidence of payment as Avecia may
reasonably request and Nuvelo shall render Avecia reasonable assistance in order to allow Avecia to obtain the benefit of any relevant present or future double taxation treaty. 

  

	 	3.7	Financial Tracking; Reporting. The PSC and Nuvelo’s financial team representatives will review and measure the growth in value of the Project by tracking resources used
versus progress against the deliverables set out in the Work Programme. In respect of consumables, raw materials and any other items purchased by Avecia under Clause 3.2, Avecia will provide a breakdown by item and include copies of invoices for
those items of an individual price of greater than £5,000, to the PSC and Nuvelo’s financial team representatives. Within 3 business days after the end of each month, Avecia will provide a financial ‘Earned Value Analysis’
report for that month to Nuvelo. Utilizing the Payment Schedule set forth in Clause 3.1, the report will summarize the approximate value of services provided to Nuvelo for each Project stage that Avecia actively performed during that month. Upon
written request by Nuvelo, Avecia shall provide, within thirty days of receipt of Nuvelo’s written notice, documented proof of purchase for all Expenditures and Equipment, or for specified Expenditures and Equipment, passed through to Nuvelo in
accordance with Sections 3.2, 3.3 and 3.4. Avecia will provide Nuvelo with a quarterly written report at each regular PSC meeting setting forth the activity status of its manufacturing suite(s) that are intended to be used or could be used for the
Project, for the six months following the date of submission of the report to Nuvelo. The report will set forth the times when Avecia’s suites are available and when they are committed to other projects. 

  

 35 

	4.	Completion of the Project 

  

	 	4.1	Completion. Completion of the Project will be deemed to have occurred when the Development Batch Manufacture, the Validation Campaign and any additional or alternative work
agreed in a Programme Amendment Order have been completed. 

  

	 	4.2	Packaging, Shipping and Delivery. Deliveries of all material, including documentation, returned consumable items or Equipment under Clauses 3.2 or 3.3, and API will be made
Ex Works, Avecia’s Billingham facility (Incoterms 2000), subject to the following. Avecia is responsible for packaging and labelling the API in anticipation of shipment. Avecia also shall employ a shipper, reasonably acceptable to Nuvelo, for
the shipment of all Released API and any Defective Batch. Avecia will package the Released API or Defective Batch in validated containers under validated shipping conditions. Until the shipping conditions have been validated, Avecia will package the
Released API or Defective Batch with temperature monitoring devices that are able to function properly during the shipping process, as further set forth in the Quality Agreement. Risk of loss for all Released API or Defective Batch shall transfer to
Nuvelo after delivery of the Released API or Defective Batch to the Nuvelo-approved shipper by Avecia, except with respect to any loss resulting from a failure of Avecia to properly package and label the API for shipment. Nuvelo will purchase
insurance to cover any loss to the Released API or Defective Batch once it is delivered to the shipper. Nuvelo agrees that it shall export the API sold to it promptly and in any case within 3 months of the final stage payment for the API and shall
provide evidence of such export within 3 months thereof.  

  

	 	4.3	Payment on Completion. Nuvelo shall pay to Avecia within thirty (30) calendar days after Completion any sums required to be paid pursuant to Clause 3.2 above which may remain
outstanding at Completion. Upon Completion, Nuvelo shall pay any sums for milestones triggered pursuant to Clause 3.1 in accordance with the payment terms set forth in Section 3.4. 

  

	 	4.4	Irrevocable Option for Future Manufacturing Period. 

  

	 	(a)	 Avecia hereby grants Nuvelo an irrevocable option (the “Manufacturing Option”) to purchase, upon commercially reasonable terms to be agreed under
Clause 4.4(c) below, 3 kilograms of Released API (“the Manufacturing Quantity”), to be manufactured in the stream in Avecia’s ABC5000 facility 

  

 36 

	 	 
in which the Process was validated under this Agreement, during the period commencing April 1, 2007 and expiring October 31, 2008 (“the Manufacturing
Option Period”). 

  

	 	(b)	Following signature of this Agreement and whilst this Agreement remains in force, Nuvelo shall use reasonable commercial endeavours to provide Avecia with an estimate regarding the
potential timing of the Manufacturing Quantity during the Manufacturing Option Period. The obligation to provide the estimate will commence on Release of the first Validation Batch and the forecast will be updated at each PSC meeting or on Nuvelo
becoming aware of a change in its timeline if earlier. To exercise the Manufacturing Option, Nuvelo shall give Avecia written notice of its exercise not later than 1 calendar year before the date that Nuvelo expects Avecia to deliver the
Manufacturing Quantity to Nuvelo. In the absence of providing Avecia with timely written election, the option in Clause 4.4(a) shall lapse. 

  

	 	(c)	No later than 30 calendar days after commencement of the Validation Campaign, Avecia and Nuvelo shall promptly commence negotiations in good faith for the supply of the API by
Avecia to Nuvelo upon commercially reasonable terms (“Supply Agreement”). The Supply Agreement is anticipated to contain provisions related to anticipated volumes, pricing, forecasting mechanisms and quality control provisions, and
such other commercially reasonable provisions. The Parties shall use reasonable commercial efforts to commence discussions regarding possible key principles of any Supply Agreement after the first successful Release of a Development Batch. Nuvelo
shall have no obligation to enter into the Supply Agreement and may immediately halt negotiations at any time, as a result of an Avecia Default.  

  

	5.	Intellectual Property & Confidential Information 

  

	 	5.1	Background Intellectual Property. Except with respect to the licenses granted in this Clause 5, nothing in this Agreement shall be deemed to imply any license to a Party to
use the other Party’s Background Intellectual Property. Nothing in this Agreement shall affect the ownership by either Party of any of its Background Intellectual Property. 

  

	 	5.2	Non-exclusive Licenses under Background Intellectual Property and New Intellectual Property. 

  

	 	(a)	 Project Use License. Subject to the terms and conditions of this Agreement, Nuvelo grants to Avecia: (1) a royalty free, non-exclusive licence, without the right to
sublicense, under its Background Intellectual Property solely to perform and otherwise carry out the Project, and for no other use or 

  

 37 

	 	 
purpose; and (2) a royalty free, non-exclusive license, without the right to sublicense without Nuvelo’s prior written approval, under the New
Intellectual Property solely to perform and otherwise carry out the Project. 

  

	 	(b)	Nuvelo Commercial License. Subject to the terms and conditions of this Agreement, specifically including Clause 5.2(c), Avecia hereby grants Nuvelo a royalty-free, irrevocable,
non-exclusive, world-wide license, with power to sub-license through multiple levels of sublicensees, under any of Avecia’s Background Intellectual Property that is incorporated into the Process during the Project, to make, have made, use,
sell, offer for sale and import the Product or the API or any form, including any filled or finished form, of the Product or API. 

  

	 	(c)	Royalty-Bearing License. If Avecia believes in good faith that the Process would be materially improved by the utilization in the Process of an Invention or Inventions covered by a
Valid Claim or Valid Claims within Avecia’s Background IP, then if and only if Avecia has previously, and continues to only grant access to such Inventions to Third Parties under a royalty-bearing license (each such Invention a “Patented,
Licensed Avecia Invention”), Avecia shall notify Nuvelo in writing regarding Avecia’s proposal to incorporate any Patented, Licensed Avecia Invention into the Process, and shall propose commercially reasonable terms for a license to the
Patent or Patents containing the Valid Claim or Valid Claims covering the Patented, Licensed Avecia Invention(s). Nuvelo has no obligation whatsoever to agree to the utilization of any Patented, Licensed Avecia Invention in the Process, and Avecia
shall not delay or discontinue the Project as a result of a decision by Nuvelo not to incorporate any Patented, Licensed Avecia Invention in the Process. If a duly authorized representative of Nuvelo agrees in writing to the utilization of a
Patented, Licensed Avecia Invention in the Process, then Avecia shall grant Nuvelo a worldwide license under the Patent(s) containing the Valid Claim(s) that cover the Patented, Licensed Avecia Invention(s) to make, have made, use, sell, offer for
sale and import the Product or the API or any form, including any filled or finished form, of the Product or API, subject to agreement upon commercially reasonable terms. 

  

	 	5.3	 Ownership & Protection of New Intellectual Property. Any and all New Inventions, and any and all New Intellectual Property, shall belong to Nuvelo.
Avecia shall, and shall ensure that its employees shall, at Nuvelo’s expense, perform all acts and execute all instruments necessary to assign to Nuvelo all right, title and interest in and to any and all New Invention and New Intellectual
Property. Nuvelo is entitled to, but has no obligation, to file, prosecute, maintain, register, enforce or defend any and all New Intellectual 

  

 38 

	 	 
Property. All fees, costs and expenses connected with Nuvelo’s filing, prosecution, maintenance, enforcement or defense of New Intellectual Property
shall be borne and paid by Nuvelo. 

  

	 	5.4	Non-exclusive license under New Intellectual Property. Subject to the terms and conditions of this Agreement, Nuvelo hereby grants to Avecia a royalty-free, irrevocable,
non-exclusive, world-wide license, with power to sub-license, but without the ability to grant Avecia’s sublicensees the ability to grant sublicenses, under the New Intellectual Property for any use other than to make, have made, use, sell,
offer for sale or import, keep or otherwise deal in Product or the API or any form, including any filled or finished form, of Product or API. 

  

	 	5.5	Provision of Technical Assistance and Process Transfer. If following Completion or following termination of this Agreement for any reason, Nuvelo requires Avecia’s
technical assistance for the transfer of all or any portion of the Process to Nuvelo or a Third Party designee of Nuvelo, or other technical assistance, then Avecia shall promptly provide Nuvelo with all reasonable assistance necessary to transfer
the Process to Nuvelo or Nuvelo’s Third Party designee, and Nuvelo will pay for Avecia’s reasonable, actual costs and expenses associated with transfer of the Process, except that if Nuvelo terminates for Avecia’s Unremedied Breach,
Nuvelo shall only pay Avecia for one-third of Avecia’s actual costs and expenses associated with such assistance notwithstanding the provisions of Clause 9.1(b). 

  

	 	5.6	Limitation. Avecia shall not, and shall not use the Process to, make, have made, use, sell, offer for sale or import API or Product for any entity, other than Nuvelo, in any
territory, without the prior written consent of a duly authorized representative of Nuvelo. 

  

	6.	Warranties, Liability and Indemnity 

  

	 	6.1	Warranties. 

  

	 	(a)	Each Party warrants to the other that: 

  

	 	(1)	it has the necessary right and authority to enter into this Agreement; and 

  

	 	(2)	to its knowledge as of the signature date of this Agreement, the use of its Background Intellectual Property pursuant to this Agreement for the purposes set out in this Agreement
will not infringe the Intellectual Property of a Third Party. 

  

	 	(b)	 Avecia represents and warrants that it has not been debarred, nor does it intend to use for the Project any individual who has been debarred, under Section 306 of
the Federal Food, Drug, 

  

 39 

	 	 
and Cosmetic Act, 21 U.S.C. §335a(a) or (b). In the event that Avecia becomes debarred, Avecia shall notify Nuvelo immediately.

  

	 	6.2	Nuvelo Indemnity to Avecia. 

  

	 	(a)	Except as otherwise provided below in Clause 6.2(b), Nuvelo shall indemnify, defend and hold harmless Avecia, its Affiliates and their directors, officers, employees and agents (the
“Avecia Indemnitees”) from and against any loss, claim, suit, liability, damage or expense, of whatsoever kind or nature (“Loss”), resulting from or arising out of: 

  

	 	(1)	actual or suspected infringement of the Intellectual Property of any Third Party arising from the Avecia Indemnitees’ application of Nuvelo’s Background IP or information
provided to the Avecia Indemnitees by Nuvelo, in the performance of the Project; 

  

	 	(2)	Nuvelo or its Affiliates, or their directors, officers, employees or agent’s use of any results of the Project performed by the Avecia Indemnitees hereunder (including without
limitation API or other materials manufactured); or 

  

	 	(3)	the negligence, wilful misconduct or breach of any Applicable Laws by Nuvelo or its Affiliates, or their directors, officers, employees or agents; 

  

	 	(b)	Nuvelo has no obligation to indemnify, defend or hold harmless the Avecia Indemnitees for any Loss to the extent resulting from or arising out of: 

  

	 	(1)	the actual or suspected infringement of the Intellectual Property of any Third Party arising from any of the Avecia Indemnitees’ application of Avecia’s Background IP or
information not provided to the Avecia Indemnitees by Nuvelo or its Affiliates, or their officers, directors, employees or agents, in the performance of the Project; 

  

	 	(2)	the negligence or wilful misconduct of any of the Avecia Indemnitees; 

  

	 	(3)	any breach of this Agreement by any of the Avecia Indemnitees; 

  

	 	(4)	any failure by any of the Avecia Indemnitees to comply with Applicable Laws; or 

  

	 	(5)	 in respect of the indemnity under paragraph (a)(2) of this Clause 6.2, Avecia’s continuing use of Nuvelo’s 

  

 40 

	 	 
Background IP, following Avecia receiving written notice, and supporting documentation, from Nuvelo that use of any of such Background IP results in the
actual or suspected infringement of the intellectual property of any Third Party and instructing Avecia to cease use of that part of Nuvelo’s Background IP which results in such actual or suspected infringement. 

  

	 	6.3	Avecia Indemnity to Nuvelo. 

  

	 	(a)	Except as otherwise provided below in Clause 6.3(b), Avecia shall indemnify, defend and hold harmless Nuvelo and its Affiliates, and their officers, directors, employees and agents
(“Nuvelo Indemnitees”) from and against any Loss resulting from or arising out of: 

  

	 	(1)	actual or suspected infringement of the Intellectual Property of any Third Party by any of the Avecia Indemnitees’ or Avecia subcontractor’s application of Avecia’s
Background IP during the performance of the Project; 

  

	 	(2)	any of the Nuvelo Indemnitees’ use of any Avecia Background IP or any results of the Project generated by any of the Avecia Indemnitees, or any Avecia subcontractors, hereunder
(including without limitation API or other materials manufactured) to the extent any of the Nuvelo Indemnitees’ use of the Avecia Background IP or any results of the Project results in the actual or suspected infringement of the Intellectual
Property of any Third Party, but with respect to any results of the Project, solely to the extent such results were generated through any of the Avecia Indemnitees’ application of Avecia’s Background IP in the performance of the Project;
or 

  

	 	(3)	the negligence, wilful misconduct or breach of any Applicable Laws by any of the Avecia Indemnitees; 

  

	 	(b)	Avecia has no obligation to indemnify, defend or hold harmless the Nuvelo Indemnitees for any Loss to the extent resulting from or arising out of: 

  

	 	(1)	the negligence or wilful misconduct of any of the Nuvelo Indemnitees; 

  

	 	(2)	any breach of this Agreement by any of the Nuvelo Indemnitees; 

  

	 	(3)	any failure by any of the Nuvelo Indemnitees to comply with Applicable Laws; or 

  

 41 

	 	(4)	in respect of the indemnity under paragraph (a)(2) of this Clause 6.3, Nuvelo’s continuing use of any results of the Project, following Nuvelo receiving written notice from
Avecia, and supporting documentation, that use of such results of the Project results in the actual or suspected infringement of the intellectual property of any Third Party. 

  

	 	6.4	Indirect, Consequential and Special Damages Excluded. Except with respect to indemnity under Clauses 6.2 and 6.3 above or any breach of intellectual property or
confidentiality provisions in accordance with Clauses 5 and 7, in no event shall either Party be liable for any special, incidental, consequential or indirect damages arising in any way out of or relating to this Agreement, however caused and on any
theory of liability. This limitation will apply even if the other Party has been advised of the possibility of such damages. 

  

	 	6.5	Limitation. Neither Party’s liability under this Agreement will exceed the total amount that would be due to Avecia if the Project was fully completed, except with
respect to any liability of Avecia arising under Clause 9.1(c). 

  

	 	6.6	Insurance. Each Party shall secure and maintain in full force and effect during the term of this Agreement policies of insurance providing coverage for (a) employer’s
liability and (b) public and products liability having policy limits, deductibles and other terms appropriate to the conduct of that Party’s business. Evidence of such insurance in the form of a broker’s letter will be made available for
examination upon request of the other Party. 

  

	 	6.7	General Conditions of Indemnification. Each Party’s agreement to indemnify, defend and hold the other harmless in accordance with Clauses 6.2 and 6.3 is conditioned on
the indemnified Party: (a) providing prompt written notice to the indemnifying Party of any claim or lawsuit with potential for a Loss no more than ten (10) business days after the indemnified Party has knowledge of such claim or lawsuit, but the
ten (10) day time period shall not preclude indemnity hereunder so long as the delay has not materially prejudiced defense of the claim or suit; (b) permitting the indemnifying Party to have full conduct and control to investigate, prepare for,
defend against and settle any such claim or lawsuit; (c) providing the indemnifying Party, at the indemnifying Party’s reasonable expense, with the full cooperation and assistance in the investigation of, preparation for and defense of any such
claim or lawsuit; and (d) not agreeing to any compromise or settlement materially adverse to the rights of the indemnified Party under this Agreement without the indemnifying Party’s prior written consent. This Clause 6.7 survives termination
of this Agreement with respect to any Loss arising from the Parties’ performance during the term of this Agreement and with respect to any conditions and obligations that survive the termination or expiration of this Agreement.

  

 42 

	7.	Confidentiality 

  

	 	7.1	The provisions of the Confidentiality Agreement shall remain in full force and effect, except to the extent modified by the terms and conditions of this Agreement.

  

	 	7.2	The obligations of confidentiality and non-disclosure set forth in the Confidentiality Agreement will continue for seven (7) years after the expiration or termination of this
Agreement, and the Confidentiality Agreement shall not terminate or expire before the termination of this Agreement. 

  

	 	7.3	Avecia may use the Confidential Information solely for the purpose of the performance of the Project, except that Avecia may use New IP in accordance with the license set forth in
Clause 5.4, subject to entry of any relevant Third Party customer or supplier into confidentiality obligations to protect the confidentiality of such New IP, which obligations are no less onerous than those contained in this Agreement.

  

	 	7.4	The Confidentiality Agreement shall, with effect from the date hereof, be deemed to be extended to cover disclosures of information by either Party, together with any information
acquired by, or otherwise exposed to, either Party as a result of site visits, in each case pursuant to and subject to this Agreement. 

  

	8.	Duration and Termination 

  

	 	8.1	Commencement and Duration. This Agreement and the Project shall commence on the Commencement Date and shall continue (unless terminated in accordance with the provisions of
Clauses 8.2, 8.3 or 8.4) until Completion. 

  

	 	8.2	Termination by Nuvelo. Subject to Clause 9, Nuvelo may terminate this Agreement at any time with or without cause, cause including Unremedied Breach, effective immediately
upon written notice to Avecia. 

  

	 	8.3	Termination by Avecia. Avecia may terminate this Agreement immediately upon notice to Nuvelo in respect of an Unremedied Breach by Nuvelo, where material breach includes a
failure by Nuvelo to pay an amount owed to Avecia under this Agreement within 10 business days of when it is due. 

  

	 	8.4	Termination by Agreement. Subject to Clause 9, this Agreement may be terminated by mutual agreement at any time prior to Completion. 

  

 43 

	9.	Consequences of Termination 

  

	 	9.1	General. In the event of termination by either Party under Clause 8 above: 

  

	 	(a)	Termination other than for Unremedied Breach. Upon termination of this Agreement, other than for termination by Nuvelo in connection with an Unremedied Breach by Avecia, Nuvelo will
pay Avecia: 

  

	 	(1)	all sums due and payable up to the date of termination but not yet paid, but excluding any payments (other than the Handling Fee) due in respect of subcontractors appointed under
Clause 13.2 or consumable items or Equipment purchased under Clauses 3.2 and 3.3: (i) that can be returned; or (ii) the ordering of or contract for which can be cancelled; 

  

	 	(2)	all reasonable costs already incurred by Avecia up to the date of termination in accordance with the terms and conditions of this Agreement and uncancellable expenses incurred by
Avecia after termination which could not reasonably be avoided after a reasonable attempt by Avecia to mitigate such costs, including reasonable cancellation charges payable by Avecia to a subcontractor appointed under Clause 13.2 or the seller of
consumables or Equipment in respect of consumables or Equipment (i) that has been returned to the seller, or (ii) the order of or contract for which has been cancelled; and 

  

	 	(3)	the Cancellation Fee in consideration for technical consultancy services performed up to date of termination and in winding down and cancelling the Project, if and only if the
Agreement is terminated by: (i) Avecia under Clause 8.3; or (ii) by Nuvelo in accordance with Clause 8.2, but excluding termination by Nuvelo (A) for Unremedied Breach; (B) due to Force Majeure affecting Avecia; or (C) in accordance with Clause
2.2(b). 

  

	 	(4)	Fifty percent (50%) of the Development Batch Fee that otherwise would have been due and payable, as calculated in accordance with Schedule 4, in consideration for technical
consultancy services performed up to the date of termination and in winding down and cancelling the Project, if and only if, other than as a result of an Avecia Default, Nuvelo terminates the Agreement under Clause 8.2 as a result of a failure of
the centrifuge trials and a failure by Avecia to commence Development Batch Manufacture before the expiration of December 31, 2005, Pacific Standard Time, in accordance with Section 2.2(b)(2). 

  

 44 

	 	(b)	Termination for Unremedied Breach; Avecia Default. If Nuvelo terminates for Avecia’s Unremedied Breach, no later than 5 days after the effective date of Nuvelo’s
termination, Avecia shall pay to Nuvelo, as compensation for Nuvelo’s loss of monies paid to Avecia for work not performed in accordance with the terms and conditions of this Agreement, a sum equivalent to any and all monies paid to Avecia
under this Agreement, less amounts paid for technical consultancy work completed by Avecia in accordance with the terms and conditions of this Agreement and not affected by the breach. In the event of an Avecia Default in the performance of any
portion of the Project, Nuvelo is entitled to request Avecia to: (i) promptly repeat the applicable portion of the Project at Avecia’s own cost or (ii) reimburse Nuvelo for the price for that particular portion of the Project. Failure by Avecia
to timely cure an Avecia Default results in an Unremedied Breach of the Agreement. 

  

	 	(c)	Currency Exchange Rate Losses. If Nuvelo terminates this Agreement for Unremedied Breach by Avecia, Avecia shall be liable for any currency exchange rate losses incurred by Nuvelo
up through and until January 1, 2007, as a result of commitments made by Nuvelo to enable Nuvelo to pay Avecia the payments set forth in Clause 3.1 in British pounds sterling. Within 5 business days after the effective date of termination of the
Agreement for Avecia’s Unremedied Breach, Nuvelo shall arrange to sell all British pounds sterling purchased by Nuvelo in anticipation of its obligation to make future payments under this Agreement, and Nuvelo shall also arrange to sell all
contracts to purchase British pounds sterling purchased by Nuvelo in anticipation of its obligations to make future payments under this Agreement. Avecia shall pay to Nuvelo an amount equal to any currency exchange losses actually incurred by Nuvelo
in connection with such sales, as reduced by any amounts owed by Nuvelo to Avecia as of the effective date of termination on account of services completed by Avecia in compliance with and prior to termination of this Agreement. Avecia will pay any
undisputed amounts owed to Nuvelo under this Clause 9.1(c) within five (5) business days of its receipt of an invoice for such amounts from Nuvelo. All payments to Nuvelo under and in accordance with this Clause 9.1(c) will be made in United States
dollars. 

  

	 	(d)	Subject to Section 6.5, the rights and remedies set out in this Clause 9.1 in respect of the consequences of termination do not limit any other remedies or damages to which a Party
may be entitled in law or in equity. 

  

	 	9.2	 Acquired Rights. Termination or expiry of this Agreement, for whatever reason, shall not prejudice the rights of either Party 

  

 45 

	 	 
acquired before such termination or expiry, including the right to payment for services actually performed under the Project in accordance with the terms and
conditions of this Agreement, pursuant to Clause 3. 

  

	 	9.3	Survival. The provisions of Clauses 1.2, 2.9, 2.10(a), 3.3(c), 3.3(d), 3.5, 3.6, 3.7, 5, 6.2 through 6.5, 6.7 and 7 through 20 shall survive the termination or expiry of this
Agreement for the term set forth in the applicable Clause, or if no period is specified, the earlier of perpetuity of the maximum amount of time permitted under Delaware law. 

  

	10.	Independent Contractor 

  
 Nothing in this Agreement shall create, or be deemed to create, a partnership or the relationship of principal and agent or employer and employee between
the Parties. Each Party agrees to perform under this Agreement solely as an independent contractor. 
  

	11.	Entire Agreement 

  
 This Agreement and with the Schedules attached hereto contain the entire agreement between the Parties with respect to the subject matter set forth
therein and supersedes any previous agreements relating to the Project (including the Interim Agreement) and any understandings between the Parties with respect thereto. 
  

	12.	Announcements And Publicity 

  
 Subject to the prior written approval of the other Party, a Party may make an official press release, announcement or other formal publicity relating to
the transactions which are the subject of this Agreement. The Party wishing to make such release, announcement or publicity shall provide a copy of the text thereof to the other Party for its review, revision and approval, not to be unreasonably
withheld or delayed. Nothing in this Clause 12 shall preclude disclosure of the terms of this Agreement as required by Applicable Laws, including without limitation the regulations of the United States Securities and Exchange Commission. 

 

	13.	Assignment and Subcontracting 

  

	 	13.1	This Agreement shall be binding upon and inure to the benefit of the Parties hereto and their respective legal successors but shall not otherwise be assignable by either Party,
without the prior written consent of the other Party, which consent shall not be unreasonably withheld or delayed, except that either Party may assign this Agreement without consent to an Affiliate or a purchaser or acquirer of a Party, or of the
part of a Party’s business to which this Agreement relates. 

  

 46 

	 	13.2	With Nuvelo’s prior written consent as to the ability to subcontract particular work and as to the identity of each subcontractor, Avecia may subcontract certain analytical
work under the Project in accordance with the Quality Agreement, subject to inclusion in such subcontract of confidentiality and intellectual property provisions no less onerous than those contained herein, and commercially reasonable cancellation
provisions. Except as provided otherwise in Section 3.2(a)(2) or in a Programme Amendment Order, Avecia is responsible for all costs, fees and Expenditures associated with any subcontracted work, and shall not pass any such costs, fees or
Expenditures through to Nuvelo. Avecia shall be liable for any acts or omissions of any subcontractor as if such acts or omissions were Avecia’s own. 

  

	14.	Variation 

  
 No variation, modification or amendment of this Agreement shall bind either Party unless made in writing in the English language and agreed to in writing
by duly authorized officers of both Parties. 
  

	15.	Illegality 

  
 If any provision of this Agreement is agreed by the Parties to be illegal, void or unenforceable under any law that is applicable hereto or if any court
of competent jurisdiction in a final decision so determines, this Agreement shall continue in force and effect except that the illegal, void or unenforceable provision shall be deemed to be excised herefrom with effect from the date of such
agreement or judicial decision or such earlier date as the Parties may agree. 
  

	16.	Waiver 

  
 A failure by either Party hereto to exercise or enforce any rights conferred upon it by this Agreement shall not be deemed to be a waiver of any such
rights or operate so as to bar the exercise or enforcement thereof at any subsequent time or times. 
  

	17.	Notices 

  

	 	17.1	Formal Notices. Any formal notice required or permitted under this Agreement shall be in writing which may take the form of a letter or facsimile and shall be sent by prepaid
post, facsimile, or hand delivery (including messenger service). The addresses for any such notice or other communication shall be those stated on the first page of this Agreement. 

  

 47 

	 	17.2	Other Communications. In addition to the methods set out in Clause 17.1, any communications other than formal notices between the Parties may be made by telephone or by
email. 

  

	 	17.3	Change of Address. Any Party may, at any time by written notice to the other Party, change the address or the facsimile numbers to which notices or other communications shall
be sent. All notices and other communications shall have been duly given or made (i) when delivered by hand (including by messenger service) upon delivery or (ii) when delivered by post upon delivery or (iii) when faxed upon receipt of a legible
copy by recipient and production of a satisfactory transmission report by sender confirming transmission of the fax in full to the appropriate number by the fax machine which sent the fax. 

  

	18.	Force Majeure 

  
 Neither Party shall be liable to the other Party in any manner whatsoever for any failure or delay in performing its obligations under this Agreement if
and to the extent, and for the duration, that such is due to Force Majeure. Without prejudice to Clause 8, any said failure or delay shall not give either Party the right to terminate this Agreement except, and to the extent that such Force Majeure
continues for a period exceeding three (3) months. Termination as a result of Force Majeure shall take effect as if the Agreement had been terminated by mutual agreement under Clause 8.4. 
  

	19.	Law and Jurisdiction 

  

	 	19.1	Law. This Agreement is governed by and shall be construed and interpreted in accordance with the laws of the State of Delaware, United States of America. Any proceedings
between the Parties shall be conducted in the English language. 

  

	 	19.2	Referral to Senior Managers. Prior to any dispute, difference or disagreement concerning this Agreement proceeding to litigation pursuant to Clauses 19.1 and 19.4, the
Parties shall seek to resolve the matter within thirty (30) calendar days by referring it to the CFO of Avecia and the CEO of Nuvelo, each of which shall have the authority necessary to fully resolve the dispute.  

  

	 	19.3	Interim Steps. Neither of the Parties shall be deemed to be precluded from taking such interim formal steps as may be considered necessary to protect such Party’s
position while the procedures referred to in Clause 19.2 are pursued. 

  

	 	19.4	Jurisdiction. Except as provided for in Clause 19.2, in relation to any legal action or proceedings to enforce this Agreement or arising out of or in connection with this
Agreement each of the Parties irrevocably consents and submits to the exclusive jurisdiction and venue of the federal and state courts located in the State of Delaware. 

  

 48 

	20.	General 

  

	 	20.1	Headings. The headings for each Clause or Paragraph or Section in this Agreement, and in the Schedules, have been inserted for convenience of reference only and are not
intended to limit or expand on the meaning of the language contained in the particular clause, paragraph or section. 

  

	 	20.2	Ambiguities. 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. 

  

	 	20.3	Counterparts. This Agreement may be executed in two or more counterparts, including facsimile counterparts, each of which shall be deemed an original, but all of which
together shall constitute one and the same instrument. 

  

 49 

 IN WITNESS WHEREOF, the authorized representatives of the Parties have executed this Agreement as of the last date set
forth below, and upon its execution, this Agreement becomes effective as of the Commencement Date. 
  

									
	 For and on behalf of AVECIA LIMITED
	 	 	 	 
					
	Signature	 	 /s/ Kevin Cox
	 	 	 	 	 	 
	 Name
	 	 Kevin Cox
	 	 	 	 	 	 
	 Position
	 	 VP Biotechnology
	 	 	 	 	 	 
	 Date
	 	 30 June 2005
	 	 	 	 	 	 

  

									
	 For and on behalf of NUVELO INC.
	 	 	 	 
					
	Signature	 	 /s/ Lee Bendekgey
	 	 	 	Signature	 	 /s/ Michael Levy

	 Name
	 	 Lee Bendekgey
	 	 	 	 Name
	 	 Michael Levy

	 Position
	 	 CFO
	 	 	 	 Position
	 	 SVP R&D

	 Date
	 	 30 June 2005
	 	 	 	 Date
	 	 30 June 2005

  

 50 

  
 Schedule 1

  
 The Work Programme 
  

 51 

  
 Schedule 2

  
 Quality Agreement 
  

 52 

  
 Schedule 3

  
 Programme Amendment Order 
  

					
	 (1)    Project Title & Number
	 	 (2)    Date Project Started
	 	 (3)    P.A.O. Number

	
	 (4)    Reason for P.A.O.

	
	 (5)    Amendment required and new milestones

	
	 (6)    Impact on price, time frame, resources

	
	 (7)    Amended payment schedule (if required)

  

 53 

					
	 Authorisation
	 	 	 	 
			
	  	 	 	 	  
	 for Avecia
	 	 	 	 for customer

  

 54 

 Schedule 4 
  
 The Cancellation Fee 
  

	A.	The Cancellation Fee shall be a percentage of: 

  

	 	(1)	in the case of Development Batch Manufacture, the total payment to be made in respect of Development Batch Manufacture for completion of milestones 11, 17, 19, 20, 23 and 25 under
Clause 3.1, being £2,109,500 (“Development Batch Fee”) less any sums already received for milestones 11, 17, 19, 20, 23 and 25 under this Agreement in respect of Development Batch Manufacture at the date on which notice is given of
termination, cancellation or Non-Manufacturing Delay. 

  

	 	(2)	in the case of the Validation Campaign, the total payment to be made in respect of the Validation Campaign for completion of milestones 26, 27, 28, 29, 30, 31, 32, 33, 34, 36, 37,
38, 39 and 41 under Clause 3.1, including manufacture of the Engineering Batch (or as otherwise agreed in writing), being £4,618,000 (“the Validation Campaign Fee”) less any sums already received for milestones 26, 27, 28, 29, 30,
31, 32, 33, 34, 36, 37, 38, 39 and 41 under this Agreement in respect of the Validation Campaign and the Engineering Batch under Clause 3.1 at the date on which notice is given of termination, cancellation or Non-Manufacturing Delay.

  

	B.	The applicable percentage shall be dependent on the amount of notice of termination, cancellation or Non-Manufacturing Delay given by Nuvelo prior to the date for commencement of
Development Batch Manufacture or the Validation Campaign (as appropriate). 

  

	C.	The Cancellation Fee shall be calculated as follows: 

  

				
	 Notice Period

	  	Percentage of Validation Campaign Fee
or Development Batch Fee (as
appropriate)

	 
	 Nine months or more
	  	0	%
	 Fewer than nine months but more than six months
	  	50	%
	 Six months or fewer but more than four months
	  	70	%
	 Four months or fewer but more than one month
	  	90	%
	 One month or less
	  	100	%

  

	D.	 Avecia shall make commercially reasonable endeavours to raise revenue by utilising the production facility during the period during which 

  

 55 

	 	 
Development Batch Manufacture or the Validation Campaign (as appropriate) was intended to take place but for termination, cancellation on Non-Manufacturing
Delay by Nuvelo. Avecia shall refund to Nuvelo a sum equivalent to the revenue (net of raw materials and consumables Expenditure) raised as a result of such alternative use up to a maximum of 80% of the Cancellation Fee paid.

  

	E.	Where the Cancellation Fee is less than the amount already paid to Avecia by Nuvelo under this Agreement in consideration for Development Batch Manufacture or the Validation
Campaign (as appropriate), Avecia shall pay to Nuvelo the difference between the applicable Cancellation Fee and the amount already paid in consideration for the Development Batch Manufacture or the Validation Campaign (as appropriate).

  

 56 

 Schedule 5 
  
 Committee Members 
  
 Project Steering Committee Members 
  

			
	 Nuvelo

	  	 Avecia

	 Simon Allen, VP Business Development
 Leslie Barnes, Director, R&D Finance
 Dr. Kirk Hayenga, Senior Director, PSM
 Dr. Brian Kersten, Senior Director,
 Regulatory
and QA
	  	 Dr Stephen Taylor, Business General
 Manager, Biologics
 Steve Bagshaw, Head of Business
 Planning
 Dr Mark Carver, Head of R&D
 Dr Klaus Neurohr, Head of Quality &
 Regulatory Affairs

  
 Executive Committee
Members 
  

			
	 Nuvelo

	  	 Avecia

	 Dr. Michael Levy
 Senior Vice President,
 Research and Development
	  	 Dr Kevin Cox, Senior Vice-President,
 Avecia Biotechnology

  

 57 

 Schedule 6 
  
 The Equipment 
  

	
	 Liquid Nitrogen Dewars (x2) and Data Logger

	 Depth Filtration System

	 1000L jacketed bag holder

	 Delipid filter skid

	 2x1000mm chromatography columns, hydraulic skid and spares

	 2 x Freezers (-30°C & - 70°C)

  

 58 

 Schedule 7 
  
 The Confidentiality Agreement 
  
 See attached 
  

 59 

 Schedule 1 Work Programme 
  
 B2422 Work Programme 
  
 Scope Statement 
  
 Program to carry out technology transfer of the alfimeprase Process, Process characterization and validation of in-process and bulk API assays by Avecia and manufacture of two (2) cGMP Development Batches, one (1)
Engineering Batch and up to five (5) Validation Batches of alfimeprase in Avecia’s ABC 5000 facility. 
  
 Contents 
  

			
	Stage 1.	  	 Data Acquisition and Assessment

	Stage 2.	  	 Process Transfer & Fit

	Stage 3.	  	 Capital Equipment Specification and Procurement

	Stage 4.	  	 15L Fermentation Runs

	Stage 5.	  	 Laboratory Scale Purification Runs

	Stage 6.	  	 Assay Transfer of Validated Methods

	Stage 7.	  	 Assay Transfer

	Stage 8.	  	 Assay Validation

	Stage 9.	  	 Laboratory Process Characterisation (LPC)

	Stage 10.	  	 Fermentation Scale-Up and Centrifuge Trials at 3000L scale

	Stage 11.	  	 cGMP Preparation at 3000L scale

	Stage 12.	  	 Two (2) cGMP Development Batches at 3000L scale

	Stage 13.	  	 Validation Documentation

	Stage 14.	  	 One (1) Engineering Batch at 3000L scale

	Stage 15.	  	 Up to Five (5) Validation Batches at 3000L scale

	Appendix 1	  	 Process Assumptions

	Appendix 2	  	 B2422 Work Programme Timeline (see attachment)

  
 Detailed Work Programme

  
 Stage 1. Data Acquisition and Assessment 
  

	 	1.1.	Objectives 

  

	 	1.1.1.	To perform systematic review and gap analysis of Amgen technical information regarding the fermentation, harvest and purification steps for the alfimeprase Process.

  

	 	1.1.2.	To perform systematic review and gap analysis of Amgen technical information regarding the analytical testing for the alfimeprase Process. 

  

	 	1.1.3.	To perform systematic review and gap analysis of Amgen technical information regarding the genetically modified organism (GMO; Pichia) for alfimeprase. 

  

	 	1.2.	Activities 

  

	 	1.2.1.	Review and evaluate all Amgen technical reports, laboratory notebooks, laboratory reports and previous process batch records to define the alfimeprase Process.

  

 Page 1 of 11 

 Schedule 1    Work Programme 
  

	 	1.2.2.	Review the analytical methods listed below. 

  

					
	 Method number

	  	 Assay

	  	 Characteristic

	 A0819
	  	 Genotypic Verification (V)
	  	MCB and WCB Identity
	 A0662
	  	 Microbial Contaminants (V)
	  	Safety
	 A0359
	  	 Viable Cell Count (V)
	  	MCB and WCB Quality
	 A01382
	  	 AEX-Quant (V)
	  	Strength
	 A0848
	  	 Clot Lysis (validated)
	  	Potency
	 A0120
	  	 Absorbance at 280nm (validated)
	  	Strength
	 A0829
	  	 SEC (V)
	  	Purity
	 A0874
	  	 RP HPLC in-process (V)
	  	Purity
	 A0831
	  	 AEX-Qual (V)
	  	Purity
	 A0830
	  	 RP HPLC (V)
	  	Purity
	 A0815
	  	 SDS PAGE Coomassie (V)
	  	Purity, Identity
	 A0815
	  	 SDS PAGE Silver
	  	Purity
	 A0847
	  	 Peptide map (V)
	  	Identity
	 A0924
	  	 Intact MS OUTSOURCED (V)
	  	Identity
	 A0862
	  	 Anti Pichia EIA (V)
	  	Impurities
	 A01339
	  	 DNA or equivalent OUTSOURCED (V)
	  	Impurities
	 A0221
	  	 Appearance (V)
	  	Quality
	 	  	 USP/EP Pyrogen (rabbit) OUTSOURCED
	  	Safety
	 A0736
	  	 Bioburden (V)
	  	Safety
	 A0857
	  	 MES (V)
	  	Process clearance
	 A0837
	  	 Imidazole (V)
	  	Process clearance
	 A01102
	  	 EPA Copper and Zinc OUTSOURCED
	  	Buffer Monitoring
	 A0442
	  	 DNA sequence for cell bank OUTSOURCED (V)
	  	MCB and WCB Safety
	 A0719
	  	 Cell bank contamination (V)
	  	MCB and WCB Safety
	 A0404
	  	 Polysorbate 80 (V)
	  	Buffer monitoring
	 A0410
	  	 Sucrose and Mannitol (V)
	  	Buffer monitoring
	 A0225
	  	 Citrate (V)
	  	Buffer monitoring
	 A0302
	  	 Sulphate (V)
	  	Buffer monitoring
	 A0986
	  	 Tris (V)
	  	Buffer monitoring
	 	  	 EP Osmolality
	  	Quality
	 	  	 USP/EP pH
	  	Quality
	 	  	 USP/EP Conductivity
	  	Quality

  

	 	(V)	denotes analytical methods that require some validation work. 

  

	 	1.2.3.	Generate a GMO assessment to work with alfimeprase at Avecia. 

  

	 	1.3.	Deliverables 

  

	 	1.3.1.	Definition of a detailed work programme 

  

	 	1.3.2.	Project timeline 

  

 Page 2 of 11 

 Schedule 1    Work Programme 
  

 Stage 2. Process Transfer & Fit 
  

	 	2.1.	Objective 

  

	 	2.1.1.	To perform a gap analysis to identify new facility equipment required to manufacture alfimeprase. 

  

	 	2.2.	Activities 

  

	 	2.2.1.	Based on the technical data review (Stage 1), Avecia to highlight the requirements for new equipment purchases to support manufacture of alfimeprase. 

  

	 	2.3.	Deliverables 

  

	 	2.3.1.	Scope of equipment requirements 

  
 Stage 3. Capital Equipment Specification and Procurement 
  

	 	3.1.	Objectives 

  

	 	3.1.1.	To purchase Equipment for use during Centrifuge Trials 

  

	 	3.1.2.	To purchase Equipment for use during cGMP manufacture 

  

	 	3.2.	Activities 

  

	 	3.2.1.	Generate a user requirement specification (URS) for all new Equipment. 

  

	 	3.2.2.	Obtain vendor quotes and generate bid comparisons (as appropriate) for all new Equipment for Nuvelo to review. 

  

	 	3.2.3.	Upon receiving Nuvelo confirmation, place relevant order to purchase new Equipment and management of supplier regarding factory acceptance testing and delivery.

  

			
	 New Equipment for Centrifuge Trials

	  	Estimated cost
£000s

	 Liquid Nitrogen Dewars (x2) and Data Logger
	  	8.752
	 	  	

	 Total
	  	8.752
	 	  	

  

			
	 New Equipment for GMP manufacture

	  	Estimated cost
£000s

	 Depth Filtration System
	  	120
	 1000L jacketed bag holder
	  	30
	 Delipid filter skid
	  	10
	 2x1000mm chromatography columns, hydraulic skid and spares
	  	303
	 2 x Freezers (-30°C & - 70°C)
	  	6
	 	  	

	 Total
	  	469
	 	  	

  

 Page 3 of 11 

 Schedule 1    Work Programme 
  

	 	3.2.4.	In addition Avecia would need to make certain plant modifications to ABC5000 stream 2 facility and provide items of a generic nature at Avecia cost. 

  

	
	 Modification to fermenter control software

	 Trace heating on glucose line

	 Ammonia feed tank

	 Various tankage

	 0.2 μm filtration skid

	 Small UF rig (Sartorius Beta)

  

	 	3.3.	Deliverables 

  

	 	3.3.1.	URS for each new Equipment purchase. 

  

	 	3.3.2.	Installed and qualified new Equipment fit for purpose. 

  
 Stage 4. 15L Fermentation Runs 
  

	 	4.1.	Objectives 

  

	 	4.1.1.	To demonstrate robustness and reproducibility of the fermentation Process at laboratory scale within Avecia (familiarisation). 

  

	 	4.1.2.	To demonstrate the fermentation Process comparability after substitution of several raw materials (comparability). 

  

	 	4.2.	Activities 

  

	 	4.2.1.	Receive alfimeprase working cell bank (WCB) vials. 

  

	 	4.2.2.	Generate and ensure technical approval of laboratory protocols with Nuvelo. 

  

	 	4.2.3.	Perform four (4) fermentation runs at 15L using Avecia preferred supplier raw materials. Presentation of familiarisation data set to Nuvelo. 

  

	 	4.2.4.	Receive the original alfimeprase raw material list and specifications from Nuvelo. 

  

	 	4.2.5.	Review and technical approval of a comparability procedure drafted by Nuvelo. 

  

	 	4.2.6.	Perform four (4) fermentation runs at 15L for comparability, two (2) using the original alfimeprase Process raw materials and two (2) using Avecia preferred supplier raw materials.
Presentation of comparability data set to Nuvelo. 

  

	 	4.2.7.	Generate familiarisation and comparability technical reports. 

  

	 	4.3.	Deliverables 

  

	 	4.3.1.	Interim fermentation familiarisation technical report. 

  

	 	4.3.2.	Final fermentation comparability technical report. 

  

	 	4.3.3.	QA review of limited data from familiarization and comparability technical reports for Nuvelo. 

  
 Stage 5. Laboratory Scale Purification Runs 
  

	 	5.1.	Objectives 

  

	 	5.1.1.	To demonstrate robustness and reproducibility of the purification Process at 15L laboratory scale within Avecia (familiarisation). 

  

	 	5.1.2.	To demonstrate the purification Process comparability after substitution of several fermentation and purification raw materials (comparability). 

  

 Page 4 of 11 

 Schedule 1    Work Programme 
  

	 	5.1.3.	To demonstrate cleanability of alfimeprase in relation to proteins used in cleaning validation studies. 

  

	 	5.2.	Activities 

  

	 	5.2.1.	Receive the alfimeprase fermentation diafiltered, concentrated, clarified broth (DCCB) from Nuvelo. 

  

	 	5.2.2.	Perform two (2) purification runs through to final Product using Nuvelo DCCB. 

  

	 	5.2.3.	Perform analytical testing of the purification Process using ‘Nuvelo DCCB’. 

  

	 	5.2.4.	Receive the first 2 x 15L Avecia fermentation broth from Stage 4 familiarisation. Create DCCB and purify 2 x 15L to final Product. 

  

	 	5.2.5.	Perform analytical testing of purification Process using Avecia DCCB. 

  

	 	5.2.6.	Receive the second 2 x 15L Avecia fermentation broth from Stage 4 familiarisation. Create DCCB and purify 1 x 15L to final Product. 

  

	 	5.2.7.	Perform analytical testing of Avecia DCCB purification Process. 

  

	 	5.2.8.	Presentation of familiarisation data set to Nuvelo. 

  

	 	5.2.9.	Generate interim familiarisation technical report. 

  

	 	5.2.10.	Perform cleanability studies. 

  

	 	5.2.11.	Review and technical approval of a comparability procedure drafted by Nuvelo. 

  

	 	5.2.12.	Receive the next 4 x 15L Avecia fermentation broth from Stage 4 comparability. Create DCCB and purify 2 x 15L (one from each preferred raw material supplier) to final Product.

  

	 	5.2.13.	Perform analytical testing. 

  

	 	5.2.14.	Generate comparability technical report. 

  

	 	5.3.	Deliverables 

  

	 	5.3.1.	Interim purification familiarisation technical report. 

  

	 	5.3.2.	Final purification comparability technical report. 

  

	 	5.3.3.	Cleanability technical report. 

  

	 	5.3.4.	QA review of limited data from familiarization and comparability technical reports for Nuvelo. 

  
 Stage 6. Assay Transfer of Validated Methods 
  

	 	6.1.	Objectives 

  

	 	6.1.1.	To transfer the validated clot lysis and appearance analytical methods to Avecia QC. 

  

	 	6.2.	Activities 

  

	 	6.2.1.	Receive appropriate samples, historical data and reference standard from Nuvelo. 

  

	 	6.2.2.	Jointly review and ensure QA approval of analytical transfer protocols with Nuvelo for the clot lysis and appearance assays. 

  

	 	6.2.3.	Execute protocols and report data. 

  

	 	6.2.4.	Generate validation reports. 

  

	 	6.3.	Deliverables 

  

	 	6.3.1.	Validated method transfer reports. 

  

 Page 5 of 11 

 Schedule 1    Work Programme 
  

 Stage 7. Assay Transfer 
  

	 	7.1.	Objectives 

  

	 	7.1.1.	To transfer the non-validated Amgen analytical methods to Avecia. 

  

	 	7.1.2.	To transfer the non-validated Amgen analytical methods identified to be outsourced in Stage 1.2.2 to Avecia approved outsourced testing houses. 

  

	 	7.2.	Activities 

  

	 	7.2.1.	Receive appropriate samples, historical data and reference standard from Nuvelo. 

  

	 	7.2.2.	Jointly review and ensure QA approval of analytical transfer protocols with Nuvelo for non-validated assays defined in stage 1.2.2. 

  

	 	7.2.3.	Jointly review additional work required on assays to prepare for assay validation. 

  

	 	7.2.4.	Execute transfer protocols and report data. 

  

	 	7.2.5.	Generate transfer reports as determined by Nuvelo. 

  
 7.3. Deliverables 
  

	 	7.3.1.	Method transfer data and reports (if required) for each assay. 

  
 Stage 8. Assay Validation 
  

	 	8.1.	Objective 

  

	 	8.1.1.	To ensure validation of all the analytical methods identified by (V) in analytical table from Stage 1.2.2 of the work programme, for API Release testing during the validation
batches. 

  

	 	8.2.	Activities 

  

	 	8.2.1.	Generate validation sub-plan for analytical assays 

  

	 	8.2.2.	Jointly review and ensure QA approval of analytical validation protocols with Nuvelo for non-validated assays identified by (V) in the analytical table from Stage 1.2.2 of the work
programme. 

  

	 	8.2.3.	Execute validation protocols in accordance with ICH Q2A and Q2B and report data. 

  

	 	8.2.4.	Generate validation reports. 

  

	 	8.3.	Deliverables 

  

	 	8.3.1.	Method validation data and reports for each assay. 

  
 Stage 9. Laboratory Process Characterisation (LPC) 
  

	 	9.1.	Objective 

  

	 	9.1.1.	To evaluate key operational parameters and ranges for critical Process steps. 

  

	 	9.2.	Activities for LPC experimental set #1 

  

	 	9.2.1.	Review and evaluate all Amgen technical reports and data from previous LPC studies. 

  

	 	9.2.2.	Perform a RPN analysis. 

  

	 	9.2.3.	Perform Fermentation Studies 

  

	 	9.2.3.1.	Investigate degradation of seed fermenter media on sterilisation. 

  

	 	9.2.3.2.	Investigate the addition of antifoam (heating to filter sterilise) for addition to fermenter. 

  

	 	9.2.3.3.	Investigate seed fermenter inoculum volume. 

  

 Page 6 of 11 

 Schedule 1    Work Programme 
  

	 	9.2.3.4.	Investigate the change over to time triggers at a specified feed flow rate. 

  

	 	9.2.4.	Perform Purification Studies 

  

	 	9.2.4.1.	Investigate the SPHP step to determine the optimum UV cut-off range. 

  

	 	9.2.4.2.	Investigate the SPHP step and reduction in gradient range during elution. 

  

	 	9.2.4.3.	Investigate the temperature of operation during the IMAC step. 

  

	 	9.2.4.4.	Investigate the requirement for wash step #2 during the IMAC step. 

  

	 	9.2.4.5.	Investigate the pH of the load and buffer material during the IMAC step. 

  

	 	9.3.	Deliverables 

  

	 	9.3.1.	RPN analysis report 

  

	 	9.3.2.	LPC Experimental set 1 Fermentation technical report 

  

	 	9.3.3.	LPC Experimental set 1 Purification technical report 

  
 Stage 10. Fermentation Scale-Up and Centrifuge Trials at 3000L scale 
  

	 	10.1.	Objectives 

  

	 	10.1.1.	Release of working cell bank (WCB) for cGMP use 

  

	 	10.1.2.	To provide the first data on fermentation performance at 3000L scale 

  

	 	10.1.3.	To provide early definition of centrifuge operating conditions which can only be determined empirically 

  

	 	10.1.4.	To allow greater chance that the first cGMP Development batch would make useful Product and de-risk that stage of the programme. 

  

	 	10.2.	Activities 

  

	 	10.2.1.	Perform QC identity and purity testing of WCB and generate a Release Certificate of Analysis (CofA), approved by QA for the WCB. 

  

	 	10.2.2.	Order all raw materials and consumables. 

  

	 	10.2.3.	Generate draft manufacturing batch records. 

  

	 	10.2.4.	Review and technical approval of a comparability procedure drafted by Nuvelo. 

  

	 	10.2.5.	Carry out first 3000L fermentation and centrifuge trial. Analyse centrifuge performance data. 

  

	 	10.2.6.	Carry out the second fermentation and centrifuge trial with parameters to mimic the operation of the first cGMP Development batch or with refined parameters based on failure of
batch 1, if necessary. 

  

	 	10.2.7.	Supply 4 x 50 L fermentation broth for lab-scale purification. Store 2 x 50L of fermentation broth for future purifications. 

  

	 	10.2.8.	Perform 2 x 50L purification using broth from centrifuge trials to supply research grade material to Nuvelo. 

  

	 	10.2.9.	Generate manufacturing trial summary report. 

  

	 	10.3.	Deliverables 

  

	 	10.3.1.	QC document for cell bank testing. 

  

	 	10.3.2.	Release CofA for the WCB. 

  

	 	10.3.3.	Draft manufacturing batch records. 

  

	 	10.3.4.	Research grade material. 

  

 Page 7 of 11 

 Schedule 1    Work Programme 
  

	 	10.3.5.	Manufacturing batch summary report. 

  

	 	10.3.6.	Comparability report. 

  
 Stage 11. cGMP Preparation at 3000L scale 
  

	 	11.1.	Objectives 

  

	 	11.1.1.	To prepare for cGMP manufacture. 

  

	 	11.2.	Activities 

  

	 	11.2.1.	Generate a Process specification document. 

  

	 	11.2.2.	Generate cGMP manufacturing batch records. 

  

	 	11.2.3.	Generate QC document detailing the Release Product Specification (refer to Appendix 2). 

  

	 	11.2.4.	Order all raw materials and consumables. 

  

	 	11.2.5.	Review and technical approval of a comparability procedure drafted by Nuvelo. 

  

	 	11.3.	Deliverables 

  

	 	11.3.1.	Avecia QA approved Process specification document. 

  

	 	11.3.2.	Avecia QA approved cGMP manufacturing batch records. 

  

	 	11.3.3.	Avecia QA approved QC Document (Product Specification). 

  
 Stage 12. Two (2) cGMP Development Batches at 3000L scale 
  

	 	12.1.	Objectives 

  

	 	12.1.1.	To perform two (2) cGMP batches at 3000L scale 

  

	 	12.1.2.	To supply cGMP Product from at least 1 x 3000L Batch for clinical use. 

  

	 	12.2.	Activities 

  

	 	12.2.1.	Run the first cGMP Development batch at 3000L scale. 

  

	 	12.2.2.	Perform limited analytical testing according to Appendix 7 of the Quality Agreement. 

  

	 	12.2.3.	Perform full analytical testing for API Release of the first batch (to be jointly agreed and conditional on all limited testing performed in stage 12.2.2 being completed
successfully). 

  

	 	12.2.4.	Perform QA batch disposition for API Release of first batch if all Release testing was performed. 

  

	 	12.2.5.	Run the second cGMP Development batch at 3000L scale. 

  

	 	12.2.6.	Perform limited analytical testing according to Appendix 7 of the Quality Agreement. 

  

	 	12.2.7.	Perform full analytical testing for API Release of the second batch (to be jointly agreed and conditional on all limited testing performed in stage 12.2.6 being completed
successfully). 

  

	 	12.2.8.	Perform QA batch disposition for API Release of second batch. 

  

	 	12.2.9.	Generate manufacturing batch summary reports 

  

	 	12.2.10.	Review the Process assumptions and cycle times as part of pre-validation review. 

  

	 	12.3.	Deliverables 

  

	 	12.3.1.	Released cGMP API from at least 1 cGMP Development Batch to be supplied for clinical use. 

  

	 	12.3.2.	Any material not Released for clinical use will be made available to Nuvelo for research purposes. 

  

	 	12.3.3.	Manufacturing batch summary reports. 

  

 Page 8 of 11 

 Schedule 1    Work Programme 
  

 Stage 13. Validation Documentation 
  

	 	13.1.	Objective 

  

	 	13.1.1.	To generate and QA approval of validation documentation to support successful validation campaign. 

  

	 	13.2.	Activities 

  

	 	13.2.1.	Generate and approve the validation documentation shown below. 

  

							
	 Document

	  	 Purpose

	  	 Accountable
 Function

	  	 Approving
 Functions
 (Final formal Release by QA)

	Validation Master Plan	  	Defines overview Validation strategy for Product	  	QA	  	QA,QC, M, R&D
				
	Validation Sub Plans	  	 Defines specific Validation plans for Project relating to Equipment Qualification
 Cleaning Validation
 Analytical Validation
 Process Validation
 Electronic systems
 Training
	  	Various	  	QA,QC, M, R&D
				
	Process Validation Sub Plan	  	 Defines specific activities to be undertaken in Process Validation programme
 And links these to relevant technical reports and the Development Report
	  	R&D	  	QA,QC, M, R&D
				
	Process Validation Protocol	  	 Document listing:
 Runs to be undertaken in the
manufacturing campaign, the expected specification of material produced (and the acceptances ranges for this). Critical process control parameters and acceptance ranges.
 The results derived from the Process Validation Campaign shall be recorded in this document
	  	R&D	  	QA,QC, M, R&D
				
	Process Validation Sub Plan Report	  	Report detailing and analysing the outcome and data derived from the Process Validation Campaign	  	R&D	  	QA,QC, M, R&D
				
	Validation Summary Report	  	Summary document reviewing output from Validation Programme and formally closing it.	  	QA	  	QA,QC, M, R&D

  

 Page 9 of 11 

 Schedule 1    Work Programme 
  

	 	13.3.	Deliverables 

  

	 	13.3.1.	Avecia QA approved validation documentation as listed above. 

  
 Stage 14. One (1) Engineering Batch at 3000L scale 
  

	 	14.1.	Objectives 

  

	 	14.1.1.	To re-familiarise with the Process after the extended hold period. 

  

	 	14.1.2.	To de-risk the validation batches. 

  

	 	14.2.	Activities 

  

	 	14.2.1.	Order all raw materials and consumables. 

  

	 	14.2.2.	Run one (1) engineering batch. 

  

	 	14.2.3.	Perform limited analytical testing according to Appendix 4. 

  

	 	14.3.	Deliverables 

  

	 	14.3.1.	Manufacturing batch summary report. 

  
 Stage 15. Up to Five (5) Validation Batches at 3000L scale 
  

	 	15.1.	Objective 

  

	 	15.1.1.	To demonstrate consistent successful cGMP manufacture by performing up to five (5) consecutive batches with at least 3 consecutive batches conforming to approved validation
documentation. 

  

	 	15.1.2.	Perform Release Testing during validation batches. 

  

	 	15.2.	Activities 

  

	 	15.2.1.	Run up to five (5) consecutive cGMP manufacturing batches as per the approved validation documentation. 

  

	 	15.2.2.	Justify both Process and Product quality conformance for three (3) consecutive batches as per the validation documentation. 

  

	 	15.2.3.	Perform QA batch disposition for API Release of all acceptable Batches. 

  

	 	15.3.	Deliverables 

  

	 	15.3.1.	Released cGMP API, from 3 consecutive batches, to be supplied for clinical use. 

  

	 	15.3.2.	Validation summary report. 

  

 Page 10 of 11 

 Schedule 1    Work Programme 
  

 Appendix 1 Process Assumptions 
  
 Cycle Times 
  
 Fermentation & Harvest 
 The fermentation Process (from inoculation of the
production vessel through to harvesting of the last of the culture) is estimated to be completed in no more than seven (7) days (168 hours). Occupation of any one (1) inoculum vessel is also required for no more than one (1) day (24 hours).

  
 Purification 
 The Process is estimated to require no more than six (6) days (144 hours) occupation of the purification area for the process of each complete fermentation batch (including dispensing into final bulk containers).

  
 The total cycle time for each Batch is estimated to be no more than fourteen
(14) days in the ABC 5000 facility. 
  
 Occupancy times include time required for
key in process control tests to be completed. 
  
 Appendix 2 B2422 Work
Programme Timeline (see attachment) 
  

 Page 11 of 11 

 

 
 B2422 Work Programme Timeline Wed 29/06/05 ID Task Name Duration Start Finish Predecessors

  
 1 LOI signed 0 wks Fri 21/01/05 Fri 21/01/05 2
Stage 1 Data Review 9 wks Mon 20/12/04 Mon 21/02/05 
  
 12 Stage 1A Shipments to Avecia 8.57 wks Fri 21/01/05 Tue 22/03/05 18 Stage 2 Process Transfer & Fit 10 wks Mon 10/01/05 Mon 21/03/05 
  
 22 Regulatory Submission Reports 64.86 wks Mon 06/06/05 Sun 03/09/06 23 15L Familiarisation 2.29 wks Mon 11/07/05 Wed 27/07/05 

 
 30 15L Comparability 16.29 wks Mon 06/06/05 Wed 28/09/05
43 Centrifuge Trials 17.14 wks Mon 18/07/05 Tue 15/11/05 
  
 57 LPC#1 2.57 wks Fri 25/11/05 Tue 13/12/05 65 GMP Runs 24.57 wks Mon 10/10/05 Fri 31/03/06 
  
 78 LPC#2 2.57 wks Wed 10/05/06 Sun 28/05/06 86 Validation Campaign 19.57 wks Wed 19/04/06 Sun 03/09/06 
  
 100 Stage 3 Capital Specification and Procurement 28.4 wks
Mon 21/03/05 Wed 05/10/05 101 Stage 3A Specification 7 wks Mon 21/03/05 Mon 09/05/05 
  
 118 Stage 3B Quotes / Order 25.83 wks Fri 08/04/05 Wed 05/10/05 135 Stage 4 15L Fermentation 22.79 wks Tue 08/03/05 Mon 15/08/05 
  
 136 Agreed scope of work with Nuvelo 0 wks Tue 15/03/05 Tue 15/03/05 7FF+6.2 wks 137 Receive R&D WCB
vials 0 wks Mon 14/03/05 Mon 14/03/05 16 
  
 138
Receive RM CofA’s 0 wks Tue 08/03/05 Tue 08/03/05 9FS+3.5 wks 139 Order Av RM’s 1 wk Tue 15/03/05 Tue 22/03/05 136SS 
  
 140 Order Am RM’s 0 wks Mon 25/04/05 Mon 25/04/05 141 15L Fermentations #1a/b (Avecia media) 5 days Tue 05/04/05 Sun 10/04/05
11,137FS+22 days 
  
 142 Supply 15L #1 feedstock
to DSP 0 wks Sun 10/04/05 Sun 10/04/05 141 143 15L #2a/b Fermentations (Avecia media) 5 days Tue 19/04/05 Sun 24/04/05 141FS+9 days 
  
 144 Supply 15L #2 feedstock to DSP 0 wks Sun 24/04/05 Sun 24/04/05 143 145 Interim Familiarisation Technical Data 7 wks Mon 25/04/05 Mon
13/06/05 144FS+1 day 
  
 146 15L #3a Comparability
Fermentation (Avecia media) 2 wks Mon 11/07/05 Mon 25/07/05 140FS+11 wks 147 Supply 15L #3 feedstock to DSP 0 wks Mon 25/07/05 Mon 25/07/05 146 
  
 148 15L #3b Comparability Fermentation (Amgen media) 2 wks Mon 25/07/05 Mon 08/08/05 146 149 Supply 15L #3 feedstock to DSP 0 wks Mon
08/08/05 Mon 08/08/05 148 
  
 150 Review Data with
Nuvelo 0 wks Mon 01/08/05 Mon 01/08/05 147FS+1 wk 151 Technical Report 2 wks Mon 01/08/05 Mon 15/08/05 150 
  
 152 Cleaning studies 3 wks Mon 16/05/05 Mon 06/06/05 143FS+3.2 wks 153 Stage 5 Purification runs 26.8 wks Tue 08/03/05 Mon 12/09/05

  
 154 Agreed scope of work with Nuvelo 0 wks Tue
15/03/05 Tue 15/03/05 136 155 Order raw materials 2 wks Tue 08/03/05 Tue 22/03/05 154SS-1 wk 
  
 156 Receive DCCB material from Amgen 0 wks Tue 22/03/05 Tue 22/03/05 155 157 Conduct Amgen DCCB experiments 10 days Tue 29/03/05 Fri 08/04/05 
  
 158 15L #1a processing and analysis 3 wks Mon 11/04/05 Mon
02/05/05 142FS+1 day 159 15L #1b processing and analysis 3 wks Mon 18/04/05 Mon 09/05/05 158SS+1 wk 
  
 160 15L #2a processing and analysis (#2b held in reserve) 3 wks Mon 25/04/05 Mon 16/05/05 144FS+1 day 161 Interim Familiarisation Report 5
wks Mon 16/05/05 Mon 20/06/05 160 
  
 162 15L #3a
processing 1 wk Mon 25/07/05 Mon 01/08/05 147SS 163 15L #3b processing 1 wk Mon 08/08/05 Mon 15/08/05 149 
  
 164 15L #3b analysis (comparability testing)—external time?? 2 wks Mon 15/08/05 Mon 29/08/05 163 165 Review Data with Nuvelo 1 wk Mon
29/08/05 Mon 05/09/05 164 
  
 166 Technical Report
2 wks Mon 29/08/05 Mon 12/09/05 164 167 Cleaning Report 2 wks Mon 06/06/05 Mon 20/06/05 152 
  
 168 Stage 6 Assay Transfer of Validated Methods 28.5 wks Fri 21/01/05 Mon 08/08/05 169 Agreed scope of work with Nuvelo 0 wks Fri 21/01/05 Fri 21/01/05 8FF 
  
 170 Avecia receives samples 0 wks Fri 04/03/05 Fri 04/03/05
171 Avecia receives Ref Std 0 wks Fri 25/03/05 Fri 25/03/05 170FF+3 wks 
  
 172 A0848 Clot Lysis 8 wks Wed 25/05/05 Wed 20/07/05 186SS+10 wks 
  
 1st Quarter 2nd Quarter 3rd Quarter 4th Quarter 1st Quarter 2nd Quarter 3rd Quarter 4th Quarter 1st Quarter Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov
Dec Jan Feb 
  
 21/01 
  
 15/03 14/03 08/03 15/03 22/03 
  
 25/04 05/04 10/04 10/04 19/04 24/04 24/04 
  
 25/04 13/06 
  
 11/07 25/07 25/07 25/07 08/08 08/08 01/08 01/08 15/08 16/05
06/06 
  
 15/03 08/03 22/03 22/03 29/03 08/04
11/04 02/05 18/04 09/05 25/04 16/05 16/05 20/06 
  
 25/07 01/08 08/08 15/08 15/08 29/08 29/08 05/09 29/08 12/09 06/06 20/06 
  
 21/01 
  
 04/03 25/03 
  
 25/05 20/07

  
 1 of 3 Schedule 1 (Appendix 2) 

 

 
  
 B2422 Work Programme
Timeline Wed 29/06/05 ID Task Name Duration Start Finish 
  
 173 A0221 Appearance 5 wks Wed 25/05/05 Wed 29/06/05 174 A0120 Protein Concentration 20.7 wks Wed 16/03/05 Mon 08/08/05 
  
 184 Stage 7 Assay Transfer to Avecia 33.99 wks Wed 16/03/05 Wed 09/11/05 185 A01382 AEX-Quant 20.7 wks Wed 16/03/05 Mon 08/08/05

  
 195 A0874 RP HPLC in-process 20.7 wks Wed
16/03/05 Mon 08/08/05 205 A0831 AEX-Qual 20.7 wks Wed 16/03/05 Mon 08/08/05 
  
 215 A0830 RP HPLC 20.7 wks Wed 16/03/05 Mon 08/08/05 225 A0829 SEC-HPLC 20.7 wks Wed 16/03/05 Mon 08/08/05 
  
 235 A0815 SDS PAGE Coomassie 19.7 wks Wed 16/03/05 Mon 01/08/05 245 A0110 SDS PAGE Silver Stain (not going to QC) 17.7 wks Wed 16/03/05
Mon 18/07/05 
  
 252 A0862 Anti Pichia EIA 10 wks
Mon 20/06/05 Mon 29/08/05 262 A0847 Peptide map 10 wks Mon 04/07/05 Mon 12/09/05 
  
 272 A0404 Polysorbate 80 8.29 wks Mon 20/06/05 Wed 17/08/05 282 A0857 MES 9.29 wks Mon 08/08/05 Wed 12/10/05 
  
 292 A0837 Imidazole 9.29 wks Mon 08/08/05 Wed 12/10/05 302 A0410 Sucrose/Mannitol 13.29 wks Mon 08/08/05 Wed 09/11/05 
  
 312 A0225 Citrate 8.29 wks Mon 08/08/05 Wed 05/10/05 322
A0986 Tris 8.29 wks Mon 08/08/05 Wed 05/10/05 
  
 332 A0302 Sulphate 11.29 wks Mon 08/08/05 Wed 26/10/05 342 A0819 Genotypic Verification (direct to QC) 4 wks Mon 04/04/05 Mon 02/05/05 
  
 343 A0662 Microbial Contaminants (ditrect to QC) 4 wks Mon 04/04/05 Mon 02/05/05 344 A0719 Microbial Contaminants (Cell Bank) (ditrect to
QC) 4 wks Mon 04/04/05 Mon 02/05/05 
  
 345 A0359
Viable Cell Count (direct to QC?) 4 wks Mon 08/08/05 Mon 05/09/05 346 A0736 Bioburden (direct to QC) 4 wks Mon 04/04/05 Mon 02/05/05 
  
 347 Stage 8 Assay Validation 43.71 wks Wed 29/06/05 Mon 01/05/06 348 A01382 AEX-Quant 9 wks Mon 18/07/05 Mon 19/09/05 
  
 353 A0874 RP HPLC in-process 9 wks Mon 18/07/05 Mon 19/09/05
358 A0831 AEX-Qual 9 wks Mon 18/07/05 Mon 19/09/05 
  
 363 A0830 RP HPLC 7 wks Mon 18/07/05 Mon 05/09/05 
  
 368 A0829 SEC-HPLC 9 wks Mon 18/07/05 Mon 19/09/05 373 A0815 SDS PAGE Coomassie 9 wks Mon 11/07/05 Mon 12/09/05 
  
 378 A0862 Anti Pichia EIA 9 wks Mon 08/08/05 Mon 10/10/05 383 A0847 Peptide map 9 wks Mon 15/08/05 Mon 17/10/05 
  
 388 A0404 Polysorbate 80 9 wks Wed 27/07/05 Wed 28/09/05 393
A0736 Bioburden 9 wks Mon 14/11/05 Mon 16/01/06 
  
 398 A0857 MES 9 wks Wed 14/09/05 Wed 16/11/05 403 A0837 Imidazole 9 wks Wed 14/09/05 Wed 16/11/05 
  
 408 A0410 Sucrose/Mannitol 9 wks Wed 19/10/05 Wed 21/12/05 413 A0225 Citrate 9 wks Wed 14/09/05 Wed 16/11/05 
  
 418 A0986 Tris 9 wks Wed 21/09/05 Wed 23/11/05 423 A0302
Sulphate 9 wks Wed 28/09/05 Wed 30/11/05 
  
 428
A0662 Microbial Contaminants 9 wks Mon 21/11/05 Mon 23/01/06 433 A0819 Genotypic Verification (Cell Bank) 9 wks Mon 02/01/06 Mon 06/03/06 
  
 438 A0719 Microbial Contaminants (Cell Bank) 9 wks Mon 02/01/06 Mon 06/03/06 443 A0442 DNA Sequence Analysis (Cell Bank) (Outsourced) 17
wks Mon 02/01/06 Mon 01/05/06 
  
 457 A0359 Viable
Cell Count (Cell Bank) 9 wks Mon 02/01/06 Mon 06/03/06 462 A0924 Intact MS (Outsourced) 18 wks Wed 29/06/05 Wed 02/11/05 
  
 476 A01339 DNA (Outsourced) 18 wks Wed 29/06/05 Wed 02/11/05 490 USP/EP Pyrogen (Outsourced) 12 wks Wed 29/06/05 Wed 21/09/05 

 
 496 A01102 Zinc (Outsourced) 9 wks Mon 10/10/05 Mon
12/12/05 501 EPA 200.7 Copper (Outsourced) 9 wks Mon 10/10/05 Mon 12/12/05 
  
 506 Stage 9 Laboratory Process Characterisation 57.71 wks Fri 04/03/05 Wed 12/04/06 507 LPC reports received from Amgen 0 wks Fri 04/03/05 Fri 04/03/05 
  
 1st Quarter 2nd Quarter 3rd Quarter 4th Quarter 1st Quarter
2nd Quarter 3rd Quarter 4th Quarter 1st Quarter Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb 
  
 25/05 29/06 
  
 04/04 02/05 04/04 02/05 04/04 02/05 
  
 08/08 05/09 04/04 02/05 
  
 04/03 
  
 2 of 3 Schedule 1 (Appendix 2) 

 

 
  
 B2422 Work Programme
Timeline Wed 29/06/05 ID Task Name Duration Start Finish Predecessors 
  
 508 Avecia review of reports 3 days Fri 04/03/05 Mon 07/03/05 507 509 Avecia/Nuvelo/Amgen LPC meeting 4 days Mon 07/03/05 Fri 11/03/05 508 
  
 510 Agreed scope of work with Nuvelo 0 wks Mon 16/05/05 Mon 16/05/05 508FS+10 wks 511 Order materials 2 wks
Mon 02/05/05 Mon 16/05/05 510FF 
  
 512
Fermentation 4 wks Fri 16/09/05 Fri 14/10/05 511FS+3 wks,14416/004/10 513 Purification (pre-work & IMAC) #1 7 wks Mon 16/05/05 Mon 04/07/05 511 
  
 514 Purification (SPHP) #1 2 wks Fri 14/10/05 Fri 28/10/05 536 515 Technical Report #1 4 wks Fri 28/10/05 Fri 25/11/05 514 
  
 516 Experimental set #2 (scope to be defined after GMP
batches) 8 wks Wed 15/02/06 Wed 12/04/06 517 Stage 10 ABC5000 Fermentation and Centrifuge trials 32.37 wks Tue 15/03/05 Fri 28/10/05 
  
 518 Agreed scope of work with Nuvelo 0 wks Tue 15/03/05 Tue 15/03/05 136 519 Raw Materials Delivery 6 wks Mon 23/05/05 Mon 04/07/05

  
 520 Installation/Qualification of liquid N2
dewars 4 wks Fri 01/07/05 Fri 29/07/05 120FS+12 wks 521 Receive GMP WCB 0 wks Fri 29/07/05 Fri 29/07/05 520 
  
 522 Complete cell bank testing (excl. DNA sequence) 2 wks Fri 29/07/05 Fri 12/08/05 521 523 Facility handover to Nuvelo 0 wks Mon 04/07/05
Mon 04/07/05 
  
 524 Completion of draft
manufacturing batch records 0 wks Mon 22/08/05 Mon 22/08/05 526SS 525 Installation and Commissioning of new systems (estimated) 7 wks Mon 04/07/05 Mon 22/08/05 523 
  
 526 Inoculum + Seed 2.5 days Mon 22/08/05 Wed 24/08/05 525 527 Fermentation 1 5 days Wed 24/08/05 Mon
29/08/05 518,519,526 
  
 528 Large scale
centrifuge trial 1 2 days Mon 29/08/05 Wed 31/08/05 527 529 Inoculum + Seed 2.5 days Wed 31/08/05 Sat 03/09/05 528 
  
 530 Fermentation 2 5 days Sat 03/09/05 Thu 08/09/05 529 531 Large scale centrifuge trial 2 1 day Thu 08/09/05 Fri 09/09/05 530 

 
 532 Lab-scale purification (2 x 50L) 3 wks Fri 09/09/05
Fri 30/09/05 531 533 Plant Report 4 wks Fri 30/09/05 Fri 28/10/05 532 
  
 534 Stage 11 GMP Preparation 9.43 wks Fri 09/09/05 Mon 14/11/05 535 Documentation 9.43 wks Fri 09/09/05 Mon 14/11/05 
  
 541 Equipment Qualification (upstream) 5 wks Mon 19/09/05 Mon 24/10/05 531,130 542 Equipment Qualification (downstream) 6 wks Mon 03/10/05
Mon 14/11/05 541SS+2 wks 
  
 543 Column
Qualification 2 wks Wed 05/10/05 Wed 19/10/05 128 544 Stage 12 GMP Production 17.29 wks Mon 14/11/05 Wed 15/03/06 545 Batch 1 17.14 wks Mon 14/11/05 Tue 14/03/06 546 Manufacture 2 wks Mon 14/11/05 Mon 28/11/05 535,541,539,543,5 
  
 547 Pack-off 1 day Mon 28/11/05 Tue 29/11/05 546 548 QC
limited testing 1 wk Tue 29/11/05 Tue 06/12/05 547 549 QC testing (estimated) 5 wks Tue 06/12/05 Tue 10/01/06 548 550 QA Disposition (estimated) 9 wks Tue 10/01/06 Tue 14/03/06 549 
  
 551 Batch 2 14.14 wks Tue 06/12/05 Wed 15/03/06 552 Manufacture 2 wks Tue 06/12/05 Tue 20/12/05 548 553
Pack-off 1 day Tue 20/12/05 Wed 21/12/05 552 554 QC limited testing 1 wk Wed 21/12/05 Wed 28/12/05 553 
  
 555 QC testing (estimated) 5 wks Wed 28/12/05 Wed 01/02/06 554 556 QA Disposition (estimated) 11 wks Wed 28/12/05 Wed 15/03/06 555SS

  
 557 Manufacturing Summary Report 4 wks Wed
15/02/06 Wed 15/03/06 556FF 558 Fill Finish & Stability Trials (Nuvelo) 112 wks Wed 25/01/06 Wed 19/03/08 
  
 562 Stage 13 Validation Documentation 8 wks Wed 15/03/06 Wed 10/05/06 557 563 Stage 14 Pre-Validation Batch 2 wks Wed 10/05/06 Wed
24/05/06 562 564 Stage 15 Process Validation Campaign 12 wks Wed 24/05/06 Wed 16/08/06 563 
  
 1st Quarter 2nd Quarter 3rd Quarter 4th Quarter 1st Quarter 2nd Quarter 3rd Quarter 4th Quarter 1st Quarter Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov
Dec Jan Feb 
  
 04/03 07/03 07/03 11/03 16/05
02/05 16/05 16/09 14/10 16/05 04/07 14/10 28/10 28/10 25/11 15/02 12/04 15/03 
  
 23/05 04/07 01/07 29/07 29/07 29/07 12/08 04/07 22/08 04/07 22/08 22/08 24/08 24/08 29/08 29/08 31/08 31/08 03/09 03/09 08/09 08/09 09/09 09/09 30/09 30/09 28/10 
  
 19/09 24/10 03/10 14/11 05/10 19/10 14/11 28/11 28/11 29/11
29/11 06/12 06/12 10/01 10/01 14/03 
  
 06/12
20/12 20/12 21/12 21/12 28/12 28/12 01/02 28/12 15/03 15/02 15/03 15/03 10/05 10/05 24/05 24/05 16/08 
  
 3 of 3 Schedule 1 (Appendix 2) 

 QUALITY AGREEMENT 
  
 Nuvelo, Inc. 
 675 Almanor Avenue 
 Sunnyvale, CA 94085 
  
 and 
  
 Avecia Biotechnology 
 Biologics
Business 
 PO Box 2 
 Belasis Avenue 
 Billingham 
 Cleveland 
 TS23 1YN 
  

									
					
	Name 	 	 	 	 	 	Name 	 	 
			
	Klaus J Neurohr	 	 	 	Brian S Kersten
	Head of Quality and Regulatory Affairs	 	 	 	Sr. Director RA/QA
					
	Date 	 	 	 	 	 	Date 	 	 

  

					
	Date    30 Jun 05	  	Modification 0	  	Page 1 of 19

 Index 
  

							
	1.	  	Quality Agreement	  	4
				
	 	  	1.1	  	 Purpose
	  	4
				
	 	  	1.2	  	 Duration of Agreement
	  	4
				
	 	  	1.3	  	 API
	  	4
				
	 	  	1.4	  	 Regulatory Compliance
	  	4
			
	2.	  	Manufacturing cGMP Compliance	  	5
				
	 	  	2.1	  	 Materials
	  	5
				
	 	  	2.2	  	 Documentation
	  	5
				
	 	  	2.3	  	 Change Control
	  	6
				
	 	  	2.4	  	 Process Control
	  	7
				
	 	  	2.5	  	 Training
	  	7
				
	 	  	2.6	  	 Calibration
	  	8
			
	3.	  	Quality Control	  	8
			
	4.	  	Stability	  	8
			
	5.	  	Quality Assurance	  	9
				
	 	  	5.1	  	 Documentation
	  	9
				
	 	  	5.2	  	 Batch Disposition
	  	9
				
	 	  	5.3	  	 Internal Audits
	  	10
				
	 	  	5.4	  	 Audits by Nuvelo
	  	10
				
	 	  	5.5	  	 Regulatory Actions
	  	10
			
	6.	  	Dispute Resolution	  	11
			
	7.	  	Qualification	  	11
				
	 	  	7.1	  	 Equipment Computer Facility and Utility Qualification
	  	12
				
	 	  	7.2	  	 Laboratory Qualification
	  	12
				
	 	  	7.3	  	 Cleaning Verification and Validation
	  	12

  

					
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	 8.
	  	 Revisions
	  	12
			
	 Appendix 1
	  	 Glossary of terms
	  	 
			
	 Appendix 2
	  	 Responsibilities
	  	 
			
	 Appendix 3
	  	 List of Contacts
	  	 
			
	 Appendix 4
	  	 Batch Disposition Roles and Responsibilities
	  	 
			
	 Appendix 5
	  	 Responsibilities for Shipment of the Manufactured API
	  	 
			
	 Appendix 6
	  	 Draft Release Testing Specification and Criteria for Acceptance for Bulk Alfimeprase API
	  	 
			
	 Appendix 7
	  	Draft Limited Testing and Criteria for Acceptance to Demonstrate Acceptability of Process Performance for Bulk Alfimeprase API	  	 

  

					
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	1.	Quality Agreement 

  

	1.1	Purpose 

  

	 	1.1.1	This agreement defines the roles and responsibilities for both Avecia and Nuvelo with respect to quality assurance and regulatory compliance matters. 

  

	 	1.1.2	This Quality agreement also defines how Avecia Quality Unit and Nuvelo Quality Unit will interact with each other over Quality related issues. 

  

	 	1.1.3	This Quality agreement shall be incorporated with and constitute a part of the Commercial Agreement between Avecia and Nuvelo. 

  

	1.2	Duration of Agreement 

  

	 	1.2.1	The Quality agreement will be effective as of the Commencement Date of the Commercial Agreement and will expire with the termination of the Commercial Agreement.

  

	 	1.2.2	Avecia QA will review, and up-date the Quality Agreement accordingly, in agreement with Nuvelo QA on completion of the centrifuge trial runs, GMP runs and prior to the Validation
runs. 

  

	1.3	API 

  

	 	1.3.1	Avecia will manufacture all bulk Active Pharmaceutical Ingredient (API) in accordance with cGMP regulations. 

  

	1.4	Regulatory Compliance 

  

	 	1.4.1	Avecia will manufacture the API in compliance with all applicable EU regulations including the Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2002 Annexe 18
GMP for API in the EU. 

  

	 	1.4.2	Avecia will manufacture the API in compliance with ICHQ7A, as incorporated in the Federal Register Vol 66 No186 (formerly ICHQ7A) and those sections applicable within the FDA
regulations 210, 211, 600, 601 and 610. 

  

	 	1.4.3	Avecia will maintain all licenses and approvals necessary to manufacture the API and comply with all FDA regulations applicable to a manufacturer. 

  

	 	1.4.4	Avecia will test and release the API using validated analytical methods in compliance with FDA regulations and the most current versions of ICH guidance, including ICHQ2A,
“Text on Validation of Analytical Procedures and ICHQ2B, “ Validation of Analytical Procedures: Methodology”. The analytical methods will be validated by Avecia prior to the execution of the validation lots. 

 

	 	1.4.5	Avecia will ensure that it is in compliance with all computer and software validation requirements in accordance to 21 CFR Part 11. 

  

					
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	 	1.4.6	Avecia will identify to Nuvelo in writing all raw materials in the product of direct or indirect animal origin. Avecia will source these materials from countries which are not
listed in 9 CFR section 94.18 and further, the materials must have supporting Certificates of Compliance as required by the European Union Directive R 999/2001. 

  

	2.	Manufacturing cGMP Compliance 

  

	2.1	Materials 

  

	 	2.1.1	Avecia will use raw materials, packaging and labelling components that are acceptable to Nuvelo and sampled, tested via methods approved by Avecia and stored in accordance with
Avecia documentation and procedures. 

  

	 	2.1.2	Avecia is responsible for ensuring that all materials procured by Avecia for use in the API are in compliance with specifications for such raw materials. Avecia are also responsible
for ensuring the raw materials are acceptable to Nuvelo for use in the manufacture of the API. Nuvelo shall confirm to Avecia the acceptability of the raw materials in writing. Raw materials are given an expiration date upon the satisfactory
completion of all initial tests. Avecia will hold the relevant Certificates of Analysis for the materials. 

  

	 	2.1.3	Avecia will purchase raw materials from suppliers that are acceptable to Nuvelo and approved by Avecia. Nuvelo shall confirm to Avecia the acceptability of the suppliers in writing.

  

	 	2.1.4	Avecia and Nuvelo will jointly agree to a list of key suppliers who will be audited by Avecia to ensure that they are in compliance with the FDA and EU regulations.

  

	2.2	Documentation 

  

	 	2.2.1	Avecia will prepare the necessary documentation for each lot of API in its standard format as evidence that the API was manufactured in compliance with current GMP.

  

	 	2.2.2	Avecia will retain batch documentation for at least one year after the expiry date of the batch, five years after the records of manufacture have been completed, or three years
after the distribution of the batch whichever is the larger. Before disposing of batch documentation, Avecia will give advanced written warning of 3 months to Nuvelo. 

  

	 	2.2.3	Avecia will store the API under conditions approved by Nuvelo. Avecia will hold records of storage conditions according to Avecia’s Standard Operating Procedures.

  

	 	2.2.4	Avecia and Nuvelo will agree on storage conditions, containers and delivery configuration. Avecia is responsible for packaging and labelling the API for shipment, and delivery of
the API. Avecia will co-operate with Nuvelo for shipping arrangements. Avecia will deliver the API in validated shipping containers under validated shipping conditions. Until the shipping conditions have been validated, Avecia will deliver the API
with temperature monitoring devices ready and capable of proper monitoring during shipment. Down loaded data from the temperature monitoring devices shall be sent to Nuvelo within 3 business days of the return of the Temp Tale.(see Appendix 5)

  

	 	2.2.5	Delivery of API - Nuvelo will authorise Avecia to deliver upon submission of a Nuvelo delivery request form, to a location designated by Nuvelo. Delivery records, etc., will be
documented and maintained by Avecia. 

  

					
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	 	2.2.6	Avecia will deliver samples upon the submission of a Nuvelo sample request form, and Avecia will co-operate with Nuvelo for transit arrangements. 

  

	2.3	Change Control 

  
 These change activities will be documented in accordance with cGMP and shall be considered by Avecia to be records of the quality system, available for
review and audit. 
  

	 	2.3.1	Equipment 

  
 Avecia shall provide Nuvelo written notice of any proposed changes to the processing equipment used to manufacture the API, including: 
  
 a) Design changes to process equipment. 
  
 b) Major repairs to process equipment, excluding routine preventative
maintenance/repair activities. Replacement of equipment with identical equipment will be considered a major repair for the purposes of this agreement. 
  
 c) Scale up of lot size for manufacture of the component that does not involve use of alternative equipment. 
  

	 	2.3.2	Components 

  
 Avecia shall purchase components used to manufacture and package Nuvelo APIs in accordance with Nuvelo’s requirements. Avecia shall provide Nuvelo
written notice of any proposed changes, including changes to the sources of, and processes for the manufacture for the raw materials, including packaging changes, to the specified raw materials or components used in the manufacture of the API.
Avecia shall implement and maintain an appropriate quality agreement and purchasing controls with each raw material supplier, to ensure that Avecia is informed in advance of any such changes by its suppliers to raw material composition or
manufacturing processes. 
  

	 	2.3.3	Processes 

  
 Avecia shall notify Nuvelo of planned process changes in writing, prior to implementation and subject to Nuvelo’s Quality Assurance (QA) and Process
Sciences Manufacturing (PSM) groups’ approvals. 
  
 Prior to
any change being implemented, Nuvelo shall be given the opportunity to purchase components and API made by the existing process as assurance of continuity of supply. 
  

	 	2.3.4	Other Activities 

  
 Other activities, listed below, shall be documented in accordance with cGMP and shall be considered by Avecia to be records of the quality system,
available for review and audit. 
  

					
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 a) Adjustments necessary to operate equipment efficiently and safely for the manufacture of the API.
These may be recorded on quality documents; however, such documentation is only a requirement where it is specified on the Standard Operating Procedures used in that part of the processing. 
  
 b) Changes to lots of raw materials to make the API. These will be recorded
as required by the quality system. 
  

	2.4	Process Control 

  

	 	2.4.1	Inspections 

  
 a) Raw materials, intermediates, components, containers, and container closures for the API manufactured will be inspected upon receipt per requirements
of Avecia quality system. Documentation of those inspections will be retained in the batch record and appropriate samples will be maintained by Avecia. 
  
 b) Avecia and Nuvelo will work together to determine the required in-process inspections. In-process inspections may occur during the manufacture of the
API. These inspection activities will be documented in lab notebooks, Batch Sheets and /or Test Sheets, whichever is appropriate. A copy will be retained in the batch record. 
  
 c) Cleanliness : The API will be manufactured in an environment that is clean and meets current Avecia facility, regulatory
and safety standards, specifically including cGMP. The facility will be monitored on a regular basis during manufacturing according to Avecia approved procedures. 
  
 d) Identification and Traceability Criteria: All materials for making the API must be properly identified and traceable.
Identification shall include part number and lot number as a minimum. The quality status of each of these must also be identified. The quality status may be identified electronically, marked on the container or referenced to a lab notebook.

  
 e) Acceptance Criteria: Acceptance of the API is based on
achievement of the acceptance criteria in the API Specification identified by Nuvelo requirements. A draft Specification is attached to this Quality Agreement as Appendix 6. 
  
 f) The specification will be jointly approved by Avecia and Nuvelo QA prior to use in manufacturing cGMP API lots and the
approved specification will be held in a separate QC document. In the cGMP Development Batches and the Engineering Batch identified in the Work Programme, a limited set of release tests to demonstrate the suitability of the API for full release will
be performed prior to performance of all required release testing. A draft of the proposed limited testing for these batches is attached to this Quality Agreement in Appendix 7. 
  

	2.5	Training 

  
 Personnel manufacturing and/or testing the API must be trained appropriately on the equipment and methods used. This training must be documented in a
training record. The training records will be maintained by Avecia for inspection. 
  

					
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	2.6	Calibration 

  
 All equipment used to manufacture, test or store raw or intermediate materials or final APIs will be calibrated to meet the requirements of NIST
standards. 
  

	3.	Quality Control 

  

	3.1	All analytical methods will be validated prior to the execution of the validation lots in accordance with FDA regulation and ICH guidelines. 

  

	3.2	The testing activities for the API that are to be performed by Avecia QC will be in accordance with the specifications agreed upon by Avecia and Nuvelo. Avecia will not sub contract
any testing without prior written approval from Nuvelo. All sub contractor analytical laboratories will be audited by Avecia. Avecia warrants that all sub contractors used will be FDA and EU GMP compliant. 

  

	3.3	Avecia will notify Nuvelo of any critical or major investigations and Out of Specification (OOS), Out of Trend (OOT) results related to the In process testing and final testing of
the API within 72 hours or next working day (Monday-Friday). Nuvelo approval of such documentation is required and will be shown by sign-off on the back-page of the copy of the original investigation/OOS/OOT form faxed by Avecia QA to Nuvelo QA.
Notification will be provided for minor investigations, OOS and OOT results on a weekly basis and no approval by Nuvelo QA is required. 

  

	3.4	Avecia QC will retain sufficient samples of raw materials and the API from each batch to allow at least twice the quantity necessary to determine whether it meets the API
Specifications, a draft of which is attached hereto as Appendix 6, excluding bioburden and endotoxin testing. 

  

	3.5	Avecia QC will retain samples for at least 1 year after the expiration date of the last lot of drug API containing the API. Avecia will inform Nuvelo of this date and give advanced
written warning of expiration of 3 months to Nuvelo. 

  

	3.6	Avecia QC will produce a Certificate of Analysis for each batch of API confirming that the API has been tested via approved methods in accordance with the Specification in the
jointly approved QC document. Avecia will perform release testing for the API within 30 calendar days after the last day of manufacture. Avecia will ship the API to Nuvelo/Nuvelo designated site within 90 calendar days of API release.

  

	3.7	Avecia QA will target a bioburden level of £10 CFU/100mL.

  

	4.	Stability 

  

	4.1	Nuvelo is responsible, where appropriate, for determining that a routine stability monitoring program is implemented. 

  

	4.2	Avecia will provide Nuvelo or its designee with stability samples within two weeks of the last day of manufacture of each Batch and of each validation lot. 

 

					
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	5.	Quality Assurance 

  

	5.1	Documentation 

  

	 	5.1.1	Avecia QA is responsible for ensuring creation of the Nuvelo API specific manufacturing master documentation. Avecia QA and Nuvelo QA will approve the batch documentation before
commencement of manufacturing. Nuvelo QA are responsible for ensuring that the batch manufacturing records issued by Avecia QA for approval are done so within 2 business days of receipt of the final draft. 

  

	 	5.1.2	Avecia QA will approve Standard Operating Procedures required for the manufacture of the API. 

  

	 	5.1.3	Avecia QA will inform Nuvelo of any major and critical Non Conformance Reports generated during the manufacture of each batch of API within 2 business days. Nuvelo sign-off is
required on each critical or major non-conformance reports before closure of investigation. Notification will be provided for all minor non-conformances on a weekly basis. 

  

	 	5.1.4	Avecia QA will inform Nuvelo of any changes to the master batch records, bills of material specification and equipment. 

  

	 	5.1.5	Avecia QA will notify on a weekly basis via e-mail or e-room all Change Controls raised. All major and critical change controls raised will require Nuvelo sign off prior to
implementation. 

  

	5.2	Batch Disposition 

  

	 	5.2.1	For each batch of API, Avecia QA will provide to Nuvelo copies of the release, executed batch record, Certificate of Analysis, Certificate of Conformance, any deviation/change
control reports. Nuvelo will review and approve, as appropriate, the batch record and then accordingly forward a signed-off copy of the API disposition form to Avecia as confirmation of Nuvelo’s acceptance of the batch.

  

	 	5.2.2	Avecia QA is responsible for ensuring that the API has been manufactured according to the Specifications attached hereto as Appendix 6, Standard Operating Procedures, Master Batch
Records and cGMP. 

  

	 	5.2.3	Reprocess/Rework: Avecia QA will not internally authorise any rework without written prior approval from Nuvelo. Reprocessing may be performed at Avecia with internal approval. The
details of the reprocessing will be included in the batch record. Approval from Regulatory Affairs (RA), QA and PSM management will be required for any rework activities. 

  

	 	5.2.4	Nuvelo QA must respond within 2 business days to any Avecia QA issues reported during batch disposition. 

  

	 	5.2.5	The release of the API ready for shipping is the responsibility of Avecia QA. 

  

	 	5.2.6	Avecia QA will be responsible for ensuring that appropriate Batch Records are copied and dispatched to Nuvelo QA within 10 business days after final disposition.

  

					
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	 	5.2.7	Responsibilities for shipment of the API are detailed in Appendix 5. 

  

	 	5.2.8	Batch Disposition roles and responsibilities are detailed in (Appendix 4). 

  

	5.3	Internal Audits 

  

	 	5.3.1	Avecia QA will carry out routine internal audits for GMP compliance according to approved schedules developed as part of the Avecia Quality System. 

  

	5.4	Audits by Nuvelo 

  

	 	5.4.1	Nuvelo reserves the right to conduct twice-a-year, comprehensive quality audits of Avecia’s facilities, which may include a site tour, questioning of employees in work areas
and review of quality system documentation to the appropriate quality standards. Avecia will be notified in advance of the intention to conduct an audit and the audit’s scope, and a mutually convenient date will be selected. During the audit,
any non-conformances will be noted and documented in a report issued by Nuvelo within thirty (30) business days. Avecia will be requested to submit an acceptable written response and corrective action plan within thirty (30) business days of receipt
of the report. Avecia will close all corrective actions that can be closed within 90 business days to the satisfaction of Nuvelo. Corrective actions that cannot practically be closed out within 90 business days will have a timeline for closure
agreed with Nuvelo. 

  

	 	5.4.2	Supplier performance issues or non-conformances in the API will be indicated to Avecia in the form of a Nuvelo Supplier Corrective Action Report (SCAR)/Memo. Avecia will be
requested to respond to the SCAR/Memo usually within thirty (30) business days post receipt. 

  

	5.5	Regulatory Actions 

  

	 	5.5.1	Avecia QA will provide Nuvelo information and support for any Nuvelo regulatory submission (e.g., CMC) upon request. Nuvelo RA will supply Avecia with copies of the submitted
information that relates to manufacture by Avecia. 

  

	 	5.5.2	Nuvelo will inform Avecia QA of any pertinent changes in the CMC section of its regulatory document. 

  

	 	5.5.3	Avecia QA will inform Nuvelo in writing of any change of any kind to the Process that may impact Nuvelo regulatory submissions. Avecia shall not make any change to the Process
without Nuvelo’s written prior approval of the change. 

  

	 	5.5.4	Avecia QA will provide Nuvelo with advanced written notice of any FDA/MHRA regulatory inspections where possible. 

  

	 	5.5.5	Avecia will also allow Nuvelo representatives to be present at site during any FDA/regulatory audits relating to Nuvelo’s API. All responses to any FDA/MHRA findings must be
reviewed and approved by Nuvelo prior to submission. 

  

	 	5.5.6	During other regulatory audits (for non-Nuvelo APIs), if any findings are identified, Avecia will inform Nuvelo where their API is potentially affected. 

  

					
	Date    30 Jun 05	  	Modification 0	  	Page 10 of 19

	 	5.5.7	Avecia will confirm Nuvelo interpretations of Avecia data in the CMC section before Nuvelo’s submission to Regulatory Agencies. 

  

	6.	Dispute Resolution 

  
 If a dispute arises amongst the Quality Team relating to whether or not a Batch of the API is a Defective Batch, or whether or not a Defective Batch
results from or arises out of an Avecia Default (each of the preceding a “Batch Dispute”), such Batch Dispute shall be resolved as follows. 
  
 (1) The Quality Team shall immediately notify the Project Steering Committee (PSC) in writing (the “Batch Dispute Notice”) that a Batch Dispute
exists amongst the Quality Team. The Quality Team will discuss the Batch Dispute in good faith to attempt to reach agreement on: (i) whether a Batch is a Defective Batch and, if so, what course of action shall be taken to address it; and (ii)
whether or not a Defective Batch resulted from or arose out of an Avecia Default. 
  
 (2) In the event that the Quality Team fails to reach agreement on a Batch Dispute within 15 days after sending the Batch Dispute Notice to the PSC, the Quality Team shall immediately refer the Batch Dispute to the
PSC for discussion, by written notice to the PSC. Once the Batch Dispute has been referred to the PSC, the PSC has 5 business days from receipt of the referral notice to either resolve the Batch Dispute or refer the Batch Dispute to an independent
expert or laboratory, with the expertise necessary to reasonably resolve the Batch Dispute. 
  
 (3) If the PSC cannot resolve the Batch Dispute or agree upon an independent expert or laboratory to resolve the Batch Dispute before the expiration of 5 business days after receiving the referral notice, the PSC
shall immediately notify the EC of its failure in writing. Within no later than 2 business days after receiving notice of the failure from the PSC, each EC member shall nominate an independent expert who shall not: be a current or former employee,
consultant or agent of a Party; have an immediate family member who is an employee, consultant or agent of a Party; or have any financial interest in a Party. Promptly thereafter, those two independent experts shall agree on a third independent
expert who shall use any reasonable information, materials and data provided to him or her by the other two experts within 10 business days after his or her agreement to act as the third independent expert, to either promptly resolve the Batch
Dispute or determine which independent Third Party laboratory will conduct the work necessary to promptly resolve the Batch Dispute. Such referral shall be solely for the purpose of establishing whether or not the applicable Batch is a Defective
Batch and whether or not any Defective Batch results from or arises out of an Avecia Default. The decision of the independent expert, or independent laboratory, shall be made in writing and shall be binding upon the Parties. Whichever Party failed
to accurately assess whether the Batch was or was not a Defective Batch, or whether or not a Defective Batch resulted from or arose out of an Avecia Default, shall bear the full cost and expense associated with the hiring and performance of the
independent experts and/or laboratory. . 
  

	7.	Qualification 

  
 Avecia will generate the Validation Master Plan which contains the Validation Strategy. Avecia QA, Nuvelo QA and Nuvelo Process Sciences and Manufacturing
will jointly approve the Validation Master Plan which contains appropriate validation sub plans for the project which will be approved by Avecia QA. 
  

					
	Date    30 Jun 05	  	Modification 0	  	Page 11 of 19

	7.1	Equipment, Computer Facility and Utility Qualification 

  

	 	7.1.1 	Avecia is responsible for ensuring that equipment, computer, facility, utility and support systems for the manufacture of Nuvelo API are qualified according to regulatory
requirements including 21 CFR Part 11. Avecia will perform required Installation Qualification (IQ)/Operational Qualification (OQ)/Performance Qualification (PQ)/calibration activities. 

  

	7.2	Laboratory Qualification 

  

	 	7.2.1 	Avecia is responsible for ensuring that all QC laboratories are in compliance with FDA cGMP regulations and are appropriately qualified in all of the methodology associated with
Nuvelo’s APIs. 

  

	 	7.2.2 	Validation methodology will be developed in compliance with ICH Q2A Text on Validation of Analytical Procedures and ICH Q2B Validation of Analytical Procedures; Methodology. The
degree of validation of methods will be agreed with Nuvelo according to the status of the API. 

  

	7.3	Cleaning Validation and Verification 

  

	 	7.3.1 	Avecia is responsible for ensuring that a cleaning verification is conducted, and documented in accordance with cGMP and that a cleaning verification of API contact parts used in
the manufacture of Nuvelo API is carried out between batches of different APIs to prevent cross-contamination. 

  

	 	7.3.2 	Nuvelo will provide information (solubility, toxicity, dose, etc.) to establish cleaning limits. 

  

	8.0	REVISIONS 

  

							
	 Mod.
 No.

	  	DATE

	  	 REVISION DETAILS

	  	BY

	 0
	  	30 Jun 05	  	New Agreement	  	DH

  

					
	Date    30 Jun 05	  	Modification 0	  	Page 12 of 19

 Appendix 1 
  
 Glossary of Terms 
  
 API: Active Pharmaceutical Ingredient. 
  
 cGMP: Current Good Manufacturing Practice. 
  
 ICH: International Conference on Harmonization. 
  
 Certificate of Analysis: A compilation of the analytical test methods applied, specifications for each test and test results for a particular intermediate/finished API
lot. The certificate should be reviewed and approved by QA management. 
  
 Certificate of Conformance: Certification confirming that an intermediate or finished API has been manufactured in compliance to the cGMP’s and that quality records associated have been reviewed and approved by QA management.

  
 Commercial Agreement: the Agreement effective 21 January 2005 for the
manufacture of the API by and between Avecia and Nuvelo. 
  
 Approved Suppliers:
Suppliers approved within Avecia’s quality system and qualified using FDA/EU guidelines, and approved by Nuvelo. 
  
 Key Suppliers: Suppliers that supply key ingredients for the manufacture of the API. Change to these Suppliers would impact the API quality. 
  
 OOS: Out of Specification. 
  
 OOT: Out of Trend. 
  
 NIST: National Institute of Standards. 
  
 In-Process Control: Checks performed during production to monitor and if appropriate, to adjust the process and/or to ensure that the API conforms to the specifications
attached to the QA Agreement as Appendix 6. 
  
 Critical Non-conformance: A
non-conformance which would impact API quality. 
  
 Major Non-conformance: A
non-conformance which has a potential to impact API quality and requires an investigation to assess the impact on API quality. 
  
 Minor Non-conformance: A non-conformance which has no impact on API quality 
  
 Reprocess: Reprocess is defined as repeat processing of a manufacturing step that does not affect the disposition of the API. For example: a 0.22 micron filtration when
the filter integrity failed. 
  
 Rework: Upon prior written approval of Nuvelo,
rework may occur on identification of a non-conformance associated with the finished API (this applies to intermediate stages of API also) that may affect the API quality. Rework is only performed upon the prior written approval of Nuvelo as a
result of an investigation through the non-conformance reporting process or as a result of a change that occurred in the drug master file (ex: expiration date). For example: Relabeling of vials due to incorrect sample lot #. This would lead to an
non-conformance and then the change would be approved by Nuvelo before commencement of the rework . 
  

					
	Date    30 Jun 05	  	Modification 0	  	Page 13 of 19

 Appendix 2 
  
 Responsibilities 
  

					
	 Responsibility

	  	Avecia

	  	Nuvelo

	 Formula
	  	 	  	ü
	 API Method
	  	ü	  	 
	 Scale-up Procedure
	  	ü	  	 
	 Qualification Procedures
	  	ü	  	ü
	 Stability Programme
	  	 	  	ü
	 Raw Material Selection
	  	ü	  	ü
	 Documentation for TSE risk
	  	ü	  	 
	 Specific API Information (safety, transport etc)
	  	 	  	ü
	 API ready for shipping
	  	ü	  	 
	 API Storage
	  	ü	  	 
	 API Specification
	  	ü	  	ü
	 Method of Analysis
	  	ü	  	 
	 Method of Analysis verification
	  	ü	  	ü
	 Analysis + Release
	  	ü	  	ü
	 Storage of API QC Samples
	  	ü	  	 
			
	 Manufacture of API
	  	ü	  	 
	 Batch Number Assignment
	  	ü	  	 
	 Expiry Date Assignment
	  	ü	  	ü
	 Manufacturing Documentation
	  	ü	  	 
	 In Process Controls
	  	ü	  	 
			
	 Audit of API Manufacturer
	  	 	  	ü
	 Deviation Management
	  	ü	  	ü
	 Change Management
	  	ü	  	ü
	 Retention of Records
	  	ü	  	 
			
	 Shipping Study
	  	 	  	ü

  

					
	Date    30 Jun 05	  	Modification 0	  	Page 14 of 19

 Appendix 3 
  
 List of Contacts 
  

					
	Area of Responsibility	  	 AVECIA
 Main
Phone:
 +44 (0) 1642 363511
	  	 NUVELO
 Main
Phone: 408-215-4000

			
	QA	  	 Ian Snowball
 +44 (0) 1642 364476
 ian.snowball@avecia.com
	  	 Wendy van der Linden
 Ph: 408-215-4348
 wvanderlinden@nuvelo.com

			
	PSM	  	N/A	  	 Kirk Hayenga
 Ph: 408-215-4344
 khayenga@nuvelo.com
 Mike Berry
 Ph: 408-215-4581
 mberry@nuvelo.com

			
	RA	  	 Dave Theakston
 +44 (0) 1642 364034
 dave.theakston@avecia.com
	  	 Brian S. Kersten
 Ph: 408-215-4401
 bkersten@nuvelo.com

			
	QC	  	 Helen Bickley
 +44 (0) 1642 364483
 helen.bickley@avecia.com
	  	 Katie Reid
 Ph: 408-215-4544
 kreid@nuvelo.com

  

					
	Date    30 Jun 05	  	Modification 0	  	Page 15 of 19

 Appendix 4 
  
 Batch Disposition Roles and Responsibilities. 
  

							
	 Responsibilities for API Batch Disposition

	  	Avecia
QC

	  	Avecia
QA

	  	Nuvelo

	 Final Review of all batch related manufacturing documentation
	  	 	  	Ö	  	 
	 Review of QC batch related analyses
	  	Ö	  	 	  	 
	 Final Review of QC batch related analyses
	  	 	  	Ö	  	 
	 Generation of Certificate of Analysis (C of A)
	  	Ö	  	 	  	 
	 Final Review of C of A
	  	 	  	Ö	  	 
	 Final review of batch record and acceptance of the batch
	  	 	  	 	  	Ö
	 Generation of Water and Environmental (WESRs)
	  	Ö	  	 	  	 
	 Summary Reports for Manufacturing Period
	  	Ö	  	 	  	 
	 Final Review of WESRs
	  	 	  	Ö	  	 
	 BSE free statement for the batch
	  	 	  	Ö	  	 
	 Review of completed Non Conformance Reports
	  	 	  	 	  	Ö
	 Review of completed Change Control Reports
	  	 	  	 	  	Ö
	 Review and Client Approval of Major/Critical NCRs, investigations, OOS and OOT results
	  	 	  	 	  	Ö
	 Review and Client Approval of Major/Critical Change Control Reports
	  	 	  	 	  	Ö
	 Final Approval of all Non Conformance Reports
	  	 	  	Ö	  	 
	 Final Approval of all Change Control Reports
	  	 	  	Ö	  	 
	 Final approval of Lab investigations
	  	 	  	Ö	  	 
	 Notification of Minor, Changes, NCRs, investigations, OOS and OOT results to Nuvelo
	  	 	  	Ö	  	 
	 Compliance check against Avecia batch disposition procedure
	  	 	  	Ö	  	 
	 Batch Disposition
	  	 	  	Ö	  	 
	 Dispatch Instruction
	  	 	  	 	  	Ö
	 Copies of all batch documentation to Customer
	  	 	  	Ö	  	 

  

					
	Date    30 Jun 05	  	Modification 0	  	Page 16 of 19

 Appendix 5 
  
 Responsibilities for Delivery/Shipment of the Manufactured API 
  

							
	 Responsibilities

	  	Avecia

	  	Avecia
QA

	  	Nuvelo

	Provide Avecia with completed dispatch request form for shipment. Including, Batch number, quantity, reason for delivery, delivery contact and address.	  	 	  	 	  	ü
	Approve dispatch request form.	  	 	  	ü	  	 
	Agree dispatch time and date.	  	ü	  	ü	  	ü
	Generate shipping documentation†	  	ü	  	 	  	ü
	Send documentation to courier for checks (if applicable).	  	ü	  	 	  	 
	Provide all documentation to Avecia QA prior to shipment.	  	ü	  	 	  	 
	Arrange transport, packaging conditions/configuration and temperature monitoring devices and downloaded data.	  	ü	  	 	  	ü
	Arrange insurance cover for shipment (if required)	  	 	  	 	  	ü
	Check dispatch batch records & shipping documentation.	  	 	  	ü	  	 
	Execute dispatch batch record	  	 	  	ü	  	 
	Inform recipient of shipment.	  	ü	  	 	  	ü
	Return of confirmation receipts from recipient to Avecia QA.	  	ü	  	 	  	 
	Complete Final Product Log (SP3703)	  	 	  	ü	  	 
	Arrange customer invoice if using Avecia’s courier account.	  	ü	  	 	  	 

  

	†	Documentation includes: 

  

	 	a.	Cover letter (3 copies) 

  

	 	b.	MSDS (3 copies) 

  

	 	c.	CofA (3 copies) 

  

	 	d.	A signed statement of identity which details the quantity, container sizes, an accurate description of the material and the usage of the material. 

  

	 	e.	Customs invoice for shipments in EU. 

  

	 	f.	For deliveries to the United States. 

  

	 	i.	A signed US Customs declaration, indicating that the material is produced by recombinant microbial fermentation (including the strain) and stating the material does not contain any
animal or cell culture derived products or additives such as albumin or serum. 

  

	 	ii.	For material that does contain any animal or cell culture derived products or additives such as albumin or serum, a USDA permit is required for US customs clearance. Obtaining a
USDA permit is the responsibility of the customer. 

  

	 	iii.	A signed US Customs invoice stating the declared value of the shipment. 

  

	 	g.	Avecia finance department will confirm the type of commercial agreement, as either technical consultancy or sale of product. 

  

	 	i.	For ‘technical consultancy’ contracts, the declared value for all delivered material will be zero (0). 

  

	 	ii.	For ‘sale of product’ contracts the declared value for delivered material will be the cost of replacement. 

  

					
	Date    30 Jun 05	  	Modification 0	  	Page 17 of 19

 Appendix 6 
  

Draft Release Testing Specification and 
 Criteria for Acceptance for Bulk Alfimeprase API 
  

					
	 Parameter

	  	 Method Type

	  	 Acceptance Criterion

			
	Appearance	  	Appearance	  	Clear, colorless liquid
practically free of particulates
			
	Purity	  	Bioburden	  	Report result
	  	SDS-PAGE, Coomassie Stain	  	Report % main band; main band same position as standard
	  	SE-HPLC	  	Main Peak 3 95%
	  	RP-HPLC	  	Main Peak 3 88%
	  	AE-HPLC	  	Main Peak 3 93%
			
	Impurities	  	Pyrogenicity	  	Absence of pyrogens (dose level of 10 mL/kg)
	  	Nucleic Acid Content	  	£ 10 pg/1 mg alfimeprase
	  	Yeast Contaminant Immunoassay	  	£0.01% (w/w)
			
	Potency	  	Clot Lysis Activity	  	3 70% of standard activity
			
	Identity	  	Molecular Weight	  	22570 - 22583 Da
	  	Peptide map	  	Conforms to standard
			
	Quantity	  	Protein Concentration	  	9.0 to 11.0 mg/mL
			
	Excipients / Chemical Composition	  	PH	  	7.9 ± 0.4
	  	Osmolality	  	315 to 455 mOsm/kg
	  	Zn Content	  	0.43 to 0.65 mM
	  	Polysorbate 80	  	0.005 to 0.015% (w/v)

  

					
	Date    30 Jun 05	  	Modification 0	  	Page 18 of 19

 Appendix 7 
  

Draft Limited Testing and Criteria for Acceptance to Demonstrate Acceptability of Process Performance for Bulk Alfimeprase API 
  

					
	 Parameter

	  	 Method Type

	  	 Acceptance Criterion

			
	Purity	  	Bioburden	  	Report result
	  	RP-HPLC	  	Main Peak 3 88%
	  	AE-HPLC	  	Main Peak 3 93%
			
	Impurities	  	Yeast Contaminant
Immunoassay	  	£0.01% (w/w)
			
	Potency	  	Clot Lysis Activity	  	3 70% of standard activity
			
	Quantity	  	Protein Concentration	  	9.0 to 11.0 mg/mL
			
	Excipients / Chemical Composition	  	Osmolality	  	315 to 455 mOsm/kg

  

					
	Date    30 Jun 05	  	Modification 0	  	Page 19 of 19

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