Exhibit 10.1


 


CONFIDENTIAL
TREATMENT REQUESTED


UNDER
17 C.F.R §§ 200.80(b)4, AND 240.24b-2


 


Execution Copy


 


FIRST
AMENDMENT


 


TO
COLLABORATION RESEARCH AND LICENSE AGREEMENT


 


THIS FIRST AMENDMENT TO COLLABORATION AND LICENSE
AGREEMENT (the “Amendment”) is made and entered into effective as of
July 27, 2010 (the “First Amendment Effective Date”) by and between
Bristol-Myers Squibb Company, a
Delaware corporation (“BMS”) and Isis
Pharmaceuticals, Inc., a Delaware Corporation (“Isis”).


 


WHEREAS, BMS and Isis entered into a Collaboration and
License Agreement effective May 8, 2007 (the “Collaboration Agreement”)
relating to the discovery, development and commercialization of ASOs targeting
PCSK9;


 


WHEREAS, the initial 3-year Research Term for the
conduct of the Research Program under the Collaboration Agreement ended
May 8, 2010; and


 


WHEREAS, the Parties now desire to amend the
Collaboration Agreement to extend the Research Term for the continuation of the
Research Program in accordance with and subject to the Collaboration Agreement
as amended by this Amendment.


 


NOW, THEREFORE in consideration of the foregoing and
the mutual covenants herein contained, the Parties do hereby agree as follows.


 


1.             Definitions. 
The terms in this Amendment with initial letters capitalized shall have
the meaning set forth in this Amendment and if not defined in this Amendment
shall have the meaning set forth in the Collaboration Agreement.  Unless stated otherwise, reference to a
Section refers to that Section in the Collaboration Agreement.


 


2.             Extension of the Research Program. 
The initial Research Term under the Collaboration ended May 8,
2010.  The Parties now desire to extend
the Research Term (and the Research Term is hereby extended) to continue from
May 8, 2010 for an additional period ending June 30, 2012 (such
period being the “Extended Research Term”).  BMS shall have the option to extend the
Research Term for [***] additional [***] after such 2-year period in accordance
with the provisions of Sections 3.2.1 and 3.2.2 as applied to such BMS option
to extend the Research Term.  The
Research Program to be carried out during the Extended Research Term is
referred to herein as the “Extended Research Program”).


 


3.             Research Plan for Extended Research
Program.  The Research Plan for the Extended Research
Program is attached hereto as Attachment A.


 


4.             FTE Funding and Research Program Cost
Payments by BMS for Conduct of Extended Research Program. 
BMS shall fund the number of Isis FTEs as set forth in Attachment A
hereto for the conduct of the Extended Research Program.  Such FTE funding payments shall be made in
accordance with Section 3.5.2 of the Collaboration Agreement, except that
the first such payment which is for the 3rd Calendar Quarter of 2010 (for [***]
Isis FTEs) shall be made within 30 days following the Amendment Effective
Date.  The budget for the Research
Program Costs for the Extended Research Program are set forth in Attachment A
hereto.  The FTE Rate during the Extended
Research Term shall be $[***] per FTE per year (i.e., without further
adjustment).


 

















 


5.             Success Compound. 
It is the objective of the Extended Research Program to identify one or
more Success Compounds.  “Success
Compound” means a Compound identified during the Extended Research Program
either (i) meeting both the Success Criteria and the [***] Criteria as
reasonably determined by BMS or (ii) for which [***] has been initiated by
BMS using [***] in accordance with [***] of the Collaboration Agreement.  “Success Criteria” has the meaning set
forth in Attachment A hereto.  BMS shall
act in good faith in its reasonable determination as to whether a Compound
meets the Success Criteria.


 


6.             [***]. 
“[***] Criteria” means a Compound which is or would be expected
to be [***]) by a [***] during the Extended Research Term and which would be
expected to have [***]).  In order to
meet the [***] Criteria a Compound must:


 


(1) [***]), and


 


(2) demonstrate in pre-clinical studies
[***].  For clarity, a Compound having a
[***], will satisfy the condition set forth in the foregoing clause (2).


 


If Isis disputes BMS’ determination that a Compound
has not met the [***] Criteria, Isis will provide BMS written notice
thereof, and, notwithstanding Section 13.4 of the Agreement, the Parties
will promptly refer the dispute to a mutually agreed [***] expert for
resolution, and the determination by such expert will be binding on the
Parties.


 


7.             Additional Milestone Payments for First
Success Compound.  The following milestone payments would be
payable by BMS for the first Success Compound to achieve the milestone:


 


	
  $[***]

  	
   

  	
  [***]);

  
	
   

  	
   

  	
   

  
	
  $[***]

  	
   

  	
  [***];

  
	
   

  	
   

  	
   

  
	
  $[***]

  	
   

  	
  [***].

  



 


The milestone payments set forth above shall be
payable by BMS within 60 days following the achievement of such milestone event
(subject to Section 8 below).


 


For clarity, in addition to the milestones set forth
above, Compounds (including without limitation any Success Compound(s))
resulting from the Extended Research Program will be subject to the milestone
and royalty obligations (under Article 5 of the Collaboration Agreement),
and other terms and conditions, as set forth in the Collaboration Agreement.


 


8.             Termination.


 


8.1           BMS Right to Terminate Agreement at Time
First Compound First Demonstrated to be Success Compound. 
At the time that the first Compound is demonstrated to achieve the
Success Milestone, BMS shall have the right to elect to pay the Success
Milestone payment (as set forth in Section 7 above) with the Collaboration
Agreement continuing in effect in accordance with its terms as amended by this
Amendment, or alternatively, BMS may elect at its discretion to terminate the
Collaboration Agreement in its entirety by providing Isis with written notice
of such termination within [***] days following such first achievement of the
Success Milestone.  Such termination of
the Agreement shall be effective upon such written notice and Sections 9.5,
9.6.1 and 10.1 shall apply following such termination, provided however, that BMS shall have no
obligation to pay the Success Milestone payment following such termination of
the Agreement by BMS.


 


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8.2           Reduction or Termination of Research
Program Upon Payment of Success Milestone Payment. 
BMS shall have the right to reduce the scope of or terminate the Research
Program, and accordingly reduce or terminate the further funding of Isis FTEs
by BMS under Section 4 above, effective upon the [***]th day following written notice being given by
BMS to Isis, which written notice by BMS may be given at any time following the
first Compound becoming a Success Compound. 
In addition, Section 3.5 of the Collaboration Agreement shall apply
to each Research Year during the Extended Research Term, with the “Research
Year” during the Extended Research Term being the 12 month period beginning
on July 1, and each such Research Year being deemed to be a “1 year
extension of the Research Term” for purposes of Section 3.5.  In addition, without limiting
Section 3.5, the Parties may mutually agree in writing to reduce or change
the scope of or terminate the Research Program (and accordingly reduce or
terminate the further funding of Isis FTEs by BMS under Section 4 above).


 


8.3           For clarity, upon termination of the
Collaboration Agreement pursuant to Article 9 of the Collaboration Agreement,
BMS shall only be obligated to fund Isis FTEs under Section 4 above for
the period prior to such termination (and shall have no obligation to fund Isis
FTEs for the period thereafter).


 


9.             No Other Amendment; Continuation of the Collaboration
Agreement.  This Amendment does not and shall not amend
or modify the covenants, terms, conditions, rights and obligations of the
Parties under the Collaboration Agreement except as specifically set forth
herein.  The Collaboration Agreement
shall continue in full force and effect in accordance with its terms as amended
by this Amendment.


 


10.           Counterparts. 
This Amendment may be executed simultaneously in two or more
counterparts, any one of which need not contain the signature of more than one
party, but all such counterparts taken together shall constitute one and the
same instrument, and may be executed and delivered through the use of email of
pdf copies of the executed Amendment.


 


*   *  
*   signature
page follows  *   *   *


 


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IN WITNESS WHEREOF, the Parties hereto intending to be
legally bound have caused this Amendment to be executed by their duly
authorized representatives.


 


 


	
  BRISTOL-MYERS
  SQUIBB COMPANY

  	
   

  
	
   

  	
   

  	
   

  
	
  By:

  	
  /s/ Arthur H. Bertelsen

  	
   

  
	
   

  	
   

  	
   

  
	
  Name:

  	
  Arthur H. Bertelsen

  	
   

  
	
   

  	
   

  	
   

  
	
  Title:

  	
  VP Research Collaborations

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
  ISIS
  PHARMACEUTICALS, INC.

  	
   

  
	
   

  	
   

  	
   

  
	
  By:

  	
  /s/ B. Lynne Parshall

  	
   

  
	
   

  	
   

  	
   

  
	
  Name:

  	
  B. Lynne Parshall

  	
   

  
	
   

  	
   

  	
   

  
	
  Title:

  	
  Chief Operating Officer and CFO

  	
   

  



 


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Attachment A


 


Research Plan for
Extended Research Program


 


[***]


 


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