Exhibit 10.8


 










[ * ] = Certain confidential
information contained in this document, marked by brackets, has been omitted
and filed separately with the Securities and Exchange Commission pursuant to
Rule 406 of the Securities Act of 1933, as amended.


 


 


CONTRACT RESEARCH AND DEVELOPMENT AGREEMENT


 


ON


 


INTERFERON-OMEGA
(IFN-OMEGA)


 





















 


TABLE OF CONTENTS


 


	
  1.

  	
  DEFINITIONS

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
  1.1

  	
  “Affiliate”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.2

  	
  “BioMedicines”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.3

  	
  “BI Pharma KG”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.4

  	
  “BioMedicines Confidential Information”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.5

  	
  “Cell Line(s)”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.6

  	
  “Certificate of Analysis”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.7

  	
  “Effective Date”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.8

  	
  “GMP”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.9

  	
  “License Agreement”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.10

  	
  “Master Cell Bank (MCB)”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.11

  	
  “Manufacturers Working Cell Bank(s) (MWCB)”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.12

  	
  “Phase I”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.13

  	
  “Phase II”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.14

  	
  “Process”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.15

  	
  “Product”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.16

  	
  “Project”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.17

  	
  “Project Fee”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.18

  	
  “Project Manager”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.19

  	
  “Project Team”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.20

  	
  “Start Date”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.21

  	
  “Sublicensee”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.22

  	
  “BI Pharma KG Confidential Information”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.23

  	
  “Specifications”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  2.

  	
  COOPERATION BETWEEN THE PARTIES IN THE
  COURSE OF THE PROJECT

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  2.1

  	
  Designation of Project Manager

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  2.2

  	
  Cooperation

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  3.

  	
  BIOMEDICINES RESPONSIBILITIES

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  3.1

  	
  General

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  3.2

  	
  Specific

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  4.

  	
  BI PHARMA KG RESPONSIBILITIES

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  4.1

  	
  Master Projectplan including Project
  Timeline

  	
   

  



 










[ * ] = CERTAIN CONFIDENTIAL INFORMATION CONTAINED
IN THIS DOCUMENT, MARKED BY BRACKETS, HAS BEEN OMITTED AND FILED SEPARATELY
WITH THE SECURITIES AND EXCHANGE COMMISSION PURSUANT TO RULE 406 OF THE
SECURITIES ACT OF 1933, AS AMENDED.


 


i





















 


	
   

  	
  4.2

  	
  Documentation

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  4.3

  	
  Additional Work

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  5.

  	
  PROJECT TO BE CONDUCTED ON FIXED-FEE BASIS

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  6.

  	
  PROJECT FEE

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  7.

  	
  PROGRESS TO PHASE II

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  7.1

  	
  Start of a Possible Phase II

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  8.

  	
  OWNERSHIP OF / LICENSE TO PROJECT DATA

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  8.1

  	
  Transfer of Project Data

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  8.2

  	
  Interim Reports

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  8.3

  	
  License for the Use of Project Data

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  9.

  	
  COMMERCIAL PRODUCTION AND SUPPLY

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  9.1

  	
  BI Pharma KG’s Right and Obligation to Commercial
  Production and Supply

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  9.2

  	
  Terms and Conditions

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  9.3

  	
  BI Pharma KG’s Inability to Manufacture

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  9.4

  	
  BioMedicines Forecast / Capacities /
  Exceeding Quantities

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  9.5

  	
  Pricing

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  10.

  	
  REPRESENTATIONS, WARRANTIES AND INDEMNIFICATION.

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  10.1

  	
  BioMedicines

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  10.2

  	
  BI Pharma KG

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  10.3

  	
  No Additional Warranty

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  11.

  	
  LIABILITY

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  11.1

  	
  Limitation of Liability

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  11.2

  	
  Special Limitation of Liability

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  11.3

  	
  Maximum Amount

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  12.

  	
  CONFIDENTIALITY

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  12.1

  	
  BI Pharma KG

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  12.2

  	
  BioMedicines

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  12.3

  	
  Exceptions to Confidentiality

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  12.4

  	
  Others

  	
   

  



 










[ * ] = CERTAIN CONFIDENTIAL INFORMATION
CONTAINED IN THIS DOCUMENT, MARKED BY BRACKETS, HAS BEEN OMITTED AND FILED
SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION PURSUANT TO RULE 406 OF
THE SECURITIES ACT OF 1933, AS AMENDED.


 


ii





















 


	
  13.

  	
  TERM AND TERMINATION

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  13.1

  	
  Term

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  13.2

  	
  Right to Terminate

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  13.3

  	
  Termination with Immediate Effect

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  13.4

  	
  Effect of Termination

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  14.

  	
  FORCE MAJEURE

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  15.

  	
  PUBLICITY

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  16.

  	
  NOTICES

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  17.

  	
  APPLICABLE LAW

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  18.

  	
  COMPLIANCE WITH LAWS

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  19.

  	
  INDEPENDENT CONTRACTORS

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  20.

  	
  WAIVER

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  21.

  	
  SEVERABILITY

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  22.

  	
  ENTIRETY

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  23.

  	
  ASSIGNMENT

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  APPENDICES

  	
   

  



 










[ * ] = CERTAIN CONFIDENTIAL INFORMATION
CONTAINED IN THIS DOCUMENT, MARKED BY BRACKETS, HAS BEEN OMITTED AND FILED
SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION PURSUANT TO RULE 406 OF
THE SECURITIES ACT OF 1933, AS AMENDED.


 


iii





















 


This Contract
Research And Development Agreement (“Agreement”) is
made effective as of 17 July, 1998 (“Effective Date”), by and among BioMedicines, Inc. (“BioMedicines),
a incorporated in the state of Delaware in the United States of America, having
its principal business offices at 909 Marina Village Parkway No. 583, Alameda,
CA 94501, and Boehringer
Ingelheim Pharma KG (“BI Pharma KG”) a German corporation having a
place of business at Birkendorfer Strabe 65, 88397
Biberach an der Riss, Federal Republic of Germany.


 


Background


 


BioMedicines has a license to certain proprietary rights in
INTERFERON-OMEGA (“IFN-OMEGA”) from Boehringer Ingelheim International GmbH (“BII”),
a German corporation, under a separate agreement dated 17 July, 1998 and which
is referenced in toto hereby.


 


BI Pharma KG owns all of the appropriate and specialized cell culture,
processing, protein purification aseptic filling and lyophilisation equipment,
as well as suitable packaging and labeling facilities that are necessary and
sufficient for the production of IFN-OMEGA, and, furthermore, employs personnel
who have the requisite experience, knowledge, and expertise in production of
proteins by cell culture and purification processes, as well as in the
development and registration of biopharmaceutical products.


 


BioMedicines desires to have BI Pharma KG personnel evaluate the
performance of the IFN-OMEGA production processes and sterile liquid filling of
the resulting product in BI Pharma KG’s facilities and according to the
provisions of this Agreement hereinafter to manufacture IFN-OMEGA for clinical
trial and commercial purposes.


 


Agreement


 


In
Consideration Of the mutual covenants set forth in
this Agreement, BI Pharma KG and BioMedicines hereby agree as follows:


 


1.             Definitions


 


1.1          “Affiliate” shall mean any
corporation or business entity controlled by, controlling or under common
control with either BI or B/M, as the case may be.  For this purpose, control shall mean any of
the following:


 


(a)           direct or indirect beneficial ownership
of more than fifty percent (50%) of the voting stock of such entity;


 


(b)           a fifty percent (50%) or greater
interest in the income of such entity;


 


(c)           a fifty percent (50%) or greater
management control over a joint venture; or


 


(d)           any other relationship that, in fact,
constitutes actual control.


 


1.2          “BioMedicines” shall mean
BioMedicines Inc. as laid down first above.


 










[ * ] = CERTAIN CONFIDENTIAL INFORMATION
CONTAINED IN THIS DOCUMENT, MARKED BY BRACKETS, HAS BEEN OMITTED AND FILED
SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION PURSUANT TO RULE 406 OF
THE SECURITIES ACT OF 1933, AS AMENDED.


 


1





















 


1.3          “BI Pharma KG” shall mean
Boehringer Ingelheim Pharma KG as laid down first above.


 


1.4          “BioMedicines Confidential
Information” shall mean all technical and other
information relating to the Product that is disclosed or supplied to BI Pharma
KG by BioMedicines pursuant to this Agreement whether patented or unpatented,
including, without limitation, trade secrets, know-how, processes, concepts,
experimental methods and results and business, scientific plans and financial
information or data and shall retroactively include similar such BioMedicines
confidential information previously provided to BII under confidentiality
obligation that BII subsequently disclosed verbally or in writing to BI Pharma
KG.


 


1.5          “Cell Line(s)” shall mean a CHO DX B11-SS cell line
currently designated 2-1C4 (or any similar cell line designated differently)
and any other cell line(s) developed pursuant to this Agreement.


 


1.6          “Certificate of Analysis”
shall mean a document describing testing methods and results, the accuracy of
which has been certified by a party, to be agreed upon between the parties in
due time.


 


1.7          “Effective Date”
shall mean the date first above written, which shall be the effective date of
this Agreement.


 


1.8          “GMP” shall
mean the regulatory requirements for good manufacturing practices promulgated
by the United States Food and Drug Administration (FDA) under the Federal Food,
Drug and Cosmetic Act, as amended, 21 C.F.R, § 210 et seq.  and 21 C.F.R. § 600-610, as applicable, or
any manufacturing standards set now or in the future by the FDA or by the currently
applicable regulations, directives, or decisions of the European Union (as now
published in the Official Journal of the
European Community (EC) or its successor publication or directed
specifically to BI Pharma KG by the appropriate regulatory authorities.  Moreover, GMP shall be understood to be the
higher or more stringent of the FDA or EC standards as mutually agreed by BI
Pharma KG and BioMedicines.


 


1.9          “License Agreement”
Shall mean the License Agreement concluded between BioMedicines and BII
regarding IFN- OMEGA.


 


1.10        “Master Cell Bank (MCB)”
shall mean reference deposit or collection of ampoules of the Cell Line 2-1C4
(or other cell lines as described above in Section 1.5) and that has currently
been designated MCB 054 Th, and any successor or substantially similar but
differently designated cell line and cell lines created pursuant to the
Agreement.


 


1.11        “Manufacturers Working Cell Bank(s)
(MWCB)” shall mean BI Pharma KG’s collection of [*] serially subcultivated cells that will
be derived from the MCB. The MWCB’(s) will be used to establish seed cultures
of the Cell Line to initiate the Process.


 










[ * ] =
CERTAIN CONFIDENTIAL INFORMATION CONTAINED IN THIS DOCUMENT, MARKED BY
BRACKETS, HAS BEEN OMITTED AND FILED SEPARATELY WITH THE SECURITIES AND
EXCHANGE COMMISSION PURSUANT TO RULE 406 OF THE SECURITIES ACT OF 1933, AS
AMENDED.


 


2





















 


1.12        “Phase I” shall
mean all activities and work to be performed as laid down in the Master Project
plan attached hereto as Appendix 1 (“Master Project Plan Interferon Omega;
Proposed Development Plan”) which shall include manufacturing for purposes of
commercialisation.


 


1.13        “Phase II”
shall mean the future research and development activities and work to be performed
according to a future agreement of the parties hereto, but excluding
manufacturing for purposes of commercialisation.


 


1.14        “Process” shall
refer to a BI Pharma KG developed and owned process for using the Cell Line,
including defined procedures, equipment and analytical methodologies for
in-process control, release testing and Product characterization, that has been
used by BI Pharma KG to produce the Product at the [*] fermentation scale, or, if and when applicable, the
modified process after adaptation to serum-free production by BI Pharma KG.


 


1.15        “Product” shall
mean drug substance or final product of IFN-OMEGA produced by the Cell Line(s)
in accordance with the Process.


 


1.16        “Project” shall
mean the Phase I program described herein, in which BI Pharma KG will
establish, implement, upscale and evaluate the serum-free Process at the
respective fermentation scale in BI Pharma KG’s facility and equipment.  The primary objectives of the Project will be
to perform registration runs at commercial scale in the BI Pharma KG facility,
successfully demonstrate that equivalent Product (i. e. Product meeting the
Specifications) can be reproducibly manufactured in BI Pharma KG’s facilities,
and prepare the CMC part of a BLA registration dossier with all relevant data
generated in the Project.  A proposed
timeline for the Project is included in Appendix 1.


 


1.17        “Project Fee”
shall have the meaning specified in Section 6 hereof.


 


1.18        “Project Manager”
shall have the meaning specified in Section 2.1 hereof.


 


1.19        “Project Team”
shall have the meaning specified in Section 2.2 hereof.


 


1.20        “Start Date”
shall mean the date mutually agreed by BI Pharma KG and BioMedicines, which is
anticipated to be on or about 1 August 1998.


 


1.21        “Sublicensee”
shall mean a person or legal entity to which BioMedicines grants a sublicense
of some or all of the rights granted to BioMedicines according to the License
Agreement.


 


1.22        “BI Pharma KG Confidential
Information” shall mean all technical and other
information relating to the Cell Line, Process, Product and BI Pharma KG’s
facilities and associated technologies that is disclosed or supplied to, or
used on behalf of, BioMedicines by BI Pharma KG pursuant to this Agreement,
whether patented or unpatented, including, without limitation, trade secrets,
know-how, processes, concepts, experimental methods and results and business
and scientific plans.


 










[ * ] =
CERTAIN CONFIDENTIAL INFORMATION CONTAINED IN THIS DOCUMENT, MARKED BY
BRACKETS, HAS BEEN OMITTED AND FILED SEPARATELY WITH THE SECURITIES AND
EXCHANGE COMMISSION PURSUANT TO RULE 406 OF THE SECURITIES ACT OF 1933, AS
AMENDED.


 


3


















 


1.23        “Specifications”
shall mean the specifications for the Product and the respective test methods
for release of drug substance and drug product as mutually agreed by the
Project Team, as such specifications may be amended from time to time by mutual
agreement of BioMedicines and BI Pharma KG according to the further development
of the Process and Product.


 


2.             Cooperation between the Parties in the Course
of the Project


 


2.1          Designation
of Project Manager.  BI Pharma
KG and BioMedicines shall each identify a Project Manager who will be
responsible for communicating all instructions and information concerning the
Project to the other party.  Each Project
Manager will be available on an agreed upon regular basis for consultation at
pre-arranged times during the course of the Project.  In the absence of the Project Manager, a
substitute shall be appointed. 
Additional modes or methods of communication and decision making may be
implemented with the mutual consent of each party.


 


2.2          Cooperation.  In the course of the Project, BI Pharma KG
will at all times take into consideration and implement the recommendations of
BioMedicines as long as they do not unreasonably and adversely influence other
BI Pharma KG biotech operations; in the absence of explicit instructions from
BioMedicines, BI Pharma KG shall be entitled to employ its reasonable judgment
in carrying out the Project.  BI Pharma
KG shall be entitled to rely upon any instructions or directives provided by
any BioMedicines representative and BI Pharma KG shall not be responsible for
the failure to achieve any objective or the inability to adhere to any
guideline if such failure or inability is caused by events beyond the
reasonable control of BI Pharma KG or by instructions or directives provided by
BioMedicines, if any.


 


BI Pharma KG shall permit BioMedicines, from time to time upon at least
thirty (30) days’ prior notice to BI Pharma KG to conduct audits at BI Pharma
KG’s facilities used for the Project during BI Pharma KG’s normal business
hours and at a reasonable frequency. 
While at any BI Pharma KG facility, BioMedicines personnel shall comply
with all applicable BI Pharma KG security and safety policies and procedures.


 


3.             BioMedicines Responsibilities.


 


3.1          General.  BioMedicines will periodically and
appropriately keep BI Pharma KG informed of the status of its activities around
the Product as long as the same facilitate the development and manufacture of
the Product according to this Agreement.


 


3.2          Specific.  As far as not specified herein the responsibilities
of BioMedicines are defined in the License Agreement and possibly other
separate agreements between BioMedicines and Boehringer Ingelheim International
GmbH (BII), BI Pharma KG, or other BII Affiliates as appropriate.


 


4.             BI Pharma KG Responsibilities


 


4.1          Master
Projectplan including Project Timeline.  In the course of this Agreement BI Pharma KG
shall perform the work and tasks as laid down and detailed in the Master


 










[ * ] =
CERTAIN CONFIDENTIAL INFORMATION CONTAINED IN THIS DOCUMENT, MARKED BY
BRACKETS, HAS BEEN OMITTED AND FILED SEPARATELY WITH THE SECURITIES AND
EXCHANGE COMMISSION PURSUANT TO RULE 406 OF THE SECURITIES ACT OF 1933, AS
AMENDED.


 


4





















 


Projectplan including Project Timeline, attached as Appendix 1
hereto.  Any third party contractors that
BI Pharma KG intends to hire for the Project need the approval of BioMedicines,
except for single quality control tasks. 
Such quality control tasks and vendors will be identified to BioMedicines.


 


4.2          Documentation.  As soon as the data and documents are
available to BI Pharma KG and needed for registration, as mutually agreed upon
in the project plan, BI Pharma KG shall provide BioMedicines with all CMC-parts
of a United States FDA Biologics License Application (BLA) or similar
document(s) for European Registration as may be required to enable and
facilitate regulatory approval(s) to market IFN-OMEGA: Such CMC-documents shall
be provided to BioMedicines in English, shall be complete and accurate, and
shall contain all data required to enable and facilitate regulatory
approval(s).  The format(s) for such
documents will be appropriate for the regulatory agency in question and
mutually agreed.


 


4.3          Additional
Work.  On request of
BioMedicines BI Pharma KG shall perform additional work to sustain the progress
of the Project on conditions in terms of money, time and scope to be subject to
mutual agreement of the parties hereto.


 


5.             Project to be Conducted on Fixed-Fee Basis


 


The Project shall be conducted by BI Pharma KG for BioMedicines on
fixed fee basis, in consideration of payment by BioMedicines of the Project Fee
according to the Master Projectplan as laid down in Appendix 1.


 


BioMedicines acknowledges that the Project is experimental in nature
and that no favorable or useful result can be assured by BI Pharma KG.
Accordingly, BI Pharma KG shall not be responsible to BioMedicines for any
failure of fermentations except for


 


contamination of (a) batch(es) due to BI Pharma KG’s mishandling or inability
to obtain useful yields (Definition) of Product


 


and the Project Fee shall be payable in full regardless of result
unless the Project is terminated prior to its scheduled completion pursuant to
Section 13 hereof.


 


6.             Project Fee


 


Subject to Section 5 above, BioMedicines shall pay BI Pharma KG a
Project Fee of [*] for the
services provided in carrying out the Project. 
This fee includes all fees for BI Pharma KG’s work according to Article
4 hereof.


 


Disposal of organic and hazardous waste is included in the Project
Fee.  The Project Fee shall be payable in
installments, each non-refundable when paid, as provided for in the Master
Projectplan (Appendix 1).


 


Each invoice shall be payable within 30 days following receipt thereof.


 










[ * ] =
CERTAIN CONFIDENTIAL INFORMATION CONTAINED IN THIS DOCUMENT, MARKED BY
BRACKETS, HAS BEEN OMITTED AND FILED SEPARATELY WITH THE SECURITIES AND
EXCHANGE COMMISSION PURSUANT TO RULE 406 OF THE SECURITIES ACT OF 1933, AS
AMENDED.


 


5





















 


7.             Progress to Phase II


 


7.1          Start
of a Possible Phase II.  If
BioMedicines decides to conduct a Phase II the parties will have to agree on
the conditions thereof (in terms of time and commercial conditions) in due time
depending on the then prevailing capacity of BI Pharma KG.


 


8.             Ownership of / License to Project Data


 


8.1          Transfer
of Project Data.  In
consideration of the Project Fee, BI Pharma KG shall execute the Project in a
timely manner (as further detailed in the Appendices) and shall make available
to BioMedicines in a timely manner all information, data, or materials obtained
or developed in the course of the Project necessary to evaluate, test, develop,
register, market, or sell the Product.


 


8.2          Interim
Reports.  BI Pharma KG agrees
to provide interim reports to BioMedicines on a reasonable basis (max.  quarterly basis).


 


8.3          License
for the Use of Project Data. 
BioMedicines, its Affiliates or Sublicensees shall have a worldwide,
royalty-free, exclusive license, with the right to sublicense, to
Product-specific information and a non-exclusive license to otherwise
non-Product-specific information (i.e., information that may also apply to
other projects/products) to use BI Pharma KG Confidential Information that is
used in carrying out the Process to evaluate, test, develop, register, market,
and sell the Product.  These licenses,
and sublicenses if any, shall expire automatically at the same time when the
License Agreement expires.


 


9.             Commercial Production and Supply


 


9.1          BI
Pharma KG’s Right and Obligation to Commercial Production and Supply.  The parties acknowledge and agree that, in
case BioMedicines decides to commercialize the Product, BI Pharma KG has an
exclusive right and obligation to produce and supply commercial quantities of
Product (in bulk drug, final product and/or finished product form) for
BioMedicines within the respective capacity of BI Pharma KG and the parties
shall negotiate in good faith and consummate a supply agreement at the earliest
reasonable opportunity for the supply by BI Pharma KG of commercial quantities
of the respective Product for the term of the License Agreement.


 


9.2          Terms
and Conditions.  Such supply
agreement shall contain terms and conditions customary for such a supply
agreement and shall be concluded between BioMedicines and BI Pharma KG or, at
the sole discretion of BI PHARMA KG, with BII or any other Affiliate of BI
Pharma KG as the case may be, provided however, that the main production
activities shall remain at BI Pharma KG.


 


9.3          BI
Pharma KG’s Inability to Manufacture.  Should BI Pharma KG be unable for any reason
to manufacture sufficient quantities of Product, BI Pharma KG will take all
necessary or desirable steps to facilitate the manufacture of Product by
BioMedicines or by a third party.


 










[ * ] =
CERTAIN CONFIDENTIAL INFORMATION CONTAINED IN THIS DOCUMENT, MARKED BY
BRACKETS, HAS BEEN OMITTED AND FILED SEPARATELY WITH THE SECURITIES AND
EXCHANGE COMMISSION PURSUANT TO RULE 406 OF THE SECURITIES ACT OF 1933, AS
AMENDED.


 


6





















 


9.4          BioMedicines
Forecast / Capacities / Exceeding Quantities.  In Appendix 2 BioMedicines has laid down its
present forecast estimation of its, its Affiliates and Sublicensees total
requirements of Product.  This forecast
is non-binding; however, BI Pharma KG’s capacity planning for commercial supply
is based on and limited by BioMedicines’s forecast.


 


If, for good reason, BI Pharma KG cannot produce and supply all
requested commercial quantities of Product as outlined in BioMedicines forecast
referenced above for whatever reason, BioMedicines will have the right to have
the missing quantities, as long as BI Pharma KG is not able to produce and
supply the respective quantities, produced elsewhere.


 


Moreover, the supply agreement shall provide for minimum quantities as
follows:


 


	
  per order for commercial supplies:

  	
   

  	
  [*] of Product and

  
	
   

  	
   

  	
   

  
	
  Per calendar year:

  	
   

  	
  [*] of Product (to
  be agreed upon between the parties at a later stage of the cooperation at the
  earliest reasonable opportunity and depending on BioMedicines’s forecast for
  commercial supply and BI Pharma KG’s capacity planning resulting therefrom.

  



 


BI Pharma KG’s will provide a reserved capacity for BioMedicines for a
certain amount of Product per calendar year based on the product
assumptions.  This capacity may be
increased by mutual agreement between the parties with a lead time of no more
than [*].


 


9.5          Pricing.  The pricing for the Product manufactured and
supplied under the supply agreement to be concluded (see Section 9.1 above)
shall take place in accordance with the License Agreement.


 


10.          Representations, Warranties and
Indemnification.


 


10.1        BioMedicines.  BioMedicines hereby represents, warrants and
agrees that:


 


(a)           BioMedicines has full corporate
authority to enter into this Agreement and this Agreement is binding upon
BioMedicines in accordance with its terms; and


 


(b)           BioMedicines shall indemnify, defend and
hold BI Pharma KG, its affiliates, and their respective officers, employees and
agents harmless from and against all losses, damages, costs and expenses
(including, without limitation, reasonable attorneys’ fees), including injury
to persons or damage to property resulting from any breach of the
representations and warranties made by BioMedicines under this Section, or as a
result of any claim, except for willful or knowing violation of third party
intellectual property rights by BI Pharma KG, of infringement of the
intellectual property rights of a third party based upon BI Pharma KG’s
activities


 










[ * ] =
CERTAIN CONFIDENTIAL INFORMATION CONTAINED IN THIS DOCUMENT, MARKED BY
BRACKETS, HAS BEEN OMITTED AND FILED SEPARATELY WITH THE SECURITIES AND
EXCHANGE COMMISSION PURSUANT TO RULE 406 OF THE SECURITIES ACT OF 1933, AS
AMENDED.


 


7





















 


in implementing the Process or producing the Product in accordance with
the instructions and documentation provided by BioMedicines or developed in the
course of the Project.


 


10.2        BI
Pharma KG.  BI Pharma KG
hereby represents, warrants and agrees that:


 


(a)           BI Pharma KG is the owner of the
facilities and BI Pharma KG Confidential Information to be used for purposes
set forth in this Agreement;


 


(b)           BI Pharma KG is not aware of any special
or unusual hazards that would arise as a result of its carrying out of the
Project as planned;


 


(c)           BI Pharma KG has full corporate
authority to enter into this Agreement and this Agreement is binding upon BI
Pharma KG in accordance with its terms; and


 


(d)           BI Pharma KG shall indemnify, defend and
hold BioMedicines and its officers, employees and agents harmless from and
against all losses, damages, costs and expenses (including, without limitation,
reasonable attorneys’ fees), including injury to persons or damage to property,
resulting from any breach of the representations and warranties made by BI
Pharma KG under this Section, or as a result of any claim that BI Pharma KG has
violated any local law, ordinance, or guideline in carrying out its
biotechnical manufacturing responsibilities under this Agreement or as a result
deliberate misconduct or gross negligence in the duties of BI Pharma KG under
the terms of the Agreement.


 


(e)           BI Pharma KG will not knowingly infringe
upon the intellectual property rights of BioMedicines or any third party.


 


(f)            BI Pharma KG will conduct all
manufacture of Product for clinical phase III trials according to manufacturing
standards set by the currently applicable regulations, directives or decisions
of the European Union (as now published in the Official Journal of the European
Community or its successor publication).


 


(g)           BI Pharma KG has conducted the positive
preliminary work with regard to the serum-free process.


 


(h)           BI Pharma KG will conduct the Project as
described to BioMedicines and that any documentation of Project results or
procedures provided to BioMedicines by BI Pharma KG shall be accurate in all
material respects.


 


10.3        No
Additional Warranty.  BI
Pharma KG shall provide the results of the Project to BioMedicines without any
additional warranty of any kind, express or implied, including, without
limitation, any warranties of merchantability or fitness for a particular
purpose.


 


11.          Liability


 


11.1        Limitation
of Liability.  Other than BI
Pharma KG generally knowing that BioMedicines will be using the Product in
clinical trials, BI Pharma KG has no


 










[ * ] =
CERTAIN CONFIDENTIAL INFORMATION CONTAINED IN THIS DOCUMENT, MARKED BY
BRACKETS, HAS BEEN OMITTED AND FILED SEPARATELY WITH THE SECURITIES AND
EXCHANGE COMMISSION PURSUANT TO RULE 406 OF THE SECURITIES ACT OF 1933, AS
AMENDED.


 


8





















 


knowledge or awareness of or control over the manner in which
BioMedicines intends to use any Product or results obtained in the
Project.  BI Pharma KG shall not be
liable to BioMedicines for any losses, damages, costs or expenses of any nature
incurred or suffered by BioMedicines or by a third party, arising out of any
dispute or other claims or proceedings made by or brought against BioMedicines
in respect of the results of the Project, or the use of any Product by
BioMedicines or by a third party (including, without limitation, product
liability claims and claims by a third party alleging infringement of its
intellectual property rights), nor shall BI Pharma KG be responsible in any way
for dealing with any such disputes, claims or proceedings except insofar as
such losses, damages, costs, expenses, claims or dealings shall be the result
of actions by BI Pharma KG, its personnel, or its agents that represent
deliberate misconduct or constitute gross negligence.


 


Notwithstanding the foregoing, BI Pharma KG shall remain liable for its
actions and the consequences thereof in the event that BI Pharma KG knowingly
infringes upon the intellectual property rights of BioMedicines or any third
party.


 


BioMedicines shall indemnify, defend and hold BI Pharma KG, its
Affiliates and their respective officers, employees and agents harmless from
and against all such losses, damages, costs and expenses (including, without
limitation, reasonable attorneys’ fees) except insofar as such losses, damages,
costs, expenses, claims or dealings shall be the result of actions by BI Pharma
KG, its personnel, or its agents that represent deliberate misconduct or
constitute gross negligence.


 


11.2        Special
Limitation of Liability. 
Notwithstanding Art. 10.2/10.3 above, BI Pharma KG shall in no way be
liable for the correctness, usefulness and operatability of material and data
(such as cellbanks, reagents etc.) received from BioMedicines, if any.


 


11.3        Maximum
Amount.  BI Pharma KG
undertakes to use its best efforts to perform the Project under the Master
Projectplan and to meet the target dates set forth in Appendix 1 hereto.  However, due to the biological nature of the
work to be performed hereunder BI Pharma KG’s liability under this Agreement
shall in no event amount to more than [*]
of the Project Fee due for the entire Project according to Articles 5 and 6
above.  The maximum of [*] shall not apply to liabilities
resulting from deliberate misconduct by BI Pharma KG.


 


12.          Confidentiality


 


12.1        BI
Pharma KG.  BI Pharma KG shall
not disclose BioMedicines Confidential Information to any person other than its
employees or employees of its Affiliates who have a need to know such
information in order to perform their duties in carrying out the Project
hereunder.  All other disclosures need
the prior approval of BioMedicines.


 


12.2        BioMedicines.  BioMedicines shall not disclose any BI Pharma
KG Confidential Information to any person other than its employees, directors,
or consultants who are bound by similar obligations of confidentiality and who
have a need to know such


 










[ * ] =
CERTAIN CONFIDENTIAL INFORMATION CONTAINED IN THIS DOCUMENT, MARKED BY
BRACKETS, HAS BEEN OMITTED AND FILED SEPARATELY WITH THE SECURITIES AND
EXCHANGE COMMISSION PURSUANT TO RULE 406 OF THE SECURITIES ACT OF 1933, AS
AMENDED.


 


9





















 


information in order to provide direction to
BI Pharma KG or evaluate the results of the Project.


 


12.3        Exceptions
to Confidentiality.  The
obligations of confidentiality applicable to BioMedicines Confidential
Information and BI Pharma KG Confidential Information shall not apply to any
information that is:


 


(a)           known publicly or becomes known publicly
through no fault of the recipient;


 


(b)           learned by the recipient from a third
party entitled to disclose it;


 


(c)           developed by the recipient independently
of information obtained from the disclosing party;


 


(d)           already known to the recipient before
receipt from the disclosing party, as shown by its prior written records;


 


(e)           required to be disclosed by law,
regulation or the order of a judicial or administrative authority (e.g. regulatory authorities, for example,
the FDA, that require such information in order to review an IND or other
regulatory filing); or


 


(f)            released with the prior written consent
of the disclosing party.


 


12.4        Others.
 No right or license, either
express or implied, under any patent or proprietary right is granted hereunder
by virtue of the disclosure of BioMedicines Confidential Information or BI
Pharma KG Confidential Information. 
Either party shall be entitled to injunctive relief in the event of a
breach of this Agreement by the other party. 
The obligations of both parties under this Section 11 shall survive the
expiration or termination of this Agreement. 
Both BioMedicines and BI Pharma KG shall use reasonable and customary
precautions to safeguard BioMedicines Confidential Information and BI Pharma KG
Confidential Information, including ensuring that all employees, consultants,
directors, agents, or the like who are provided access to such information are
informed of the confidential and proprietary nature of such information and
understand that all such information is required to be maintained confidential.


 


13.          Term and Termination


 


13.1        Term.  This Agreement shall, unless terminated
earlier, commence as of the Effective Date and shall expire upon the date of
payment of the last sum due hereunder, or upon the date when the last services required
to be performed hereunder are performed, whichever date shall last occur.


 










[ * ] =
CERTAIN CONFIDENTIAL INFORMATION CONTAINED IN THIS DOCUMENT, MARKED BY
BRACKETS, HAS BEEN OMITTED AND FILED SEPARATELY WITH THE SECURITIES AND
EXCHANGE COMMISSION PURSUANT TO RULE 406 OF THE SECURITIES ACT OF 1933, AS
AMENDED.


 


10





















 


13.2        Right
to Terminate.  If it becomes
apparent to either party at any stage of the Project that it will not be
possible to carry out the Project for scientific or technical reasons or as a
result of Force Majeure, the parties shall permit thirty (30) days for
discussion to resolve, if possible, the scientific or technical issue giving
rise to the problem.  If the parties fail
to resolve the problem, either party shall have the right to terminate this
Agreement, effective upon written notice to the other.  In the event of such termination, the amount
due to BI Pharma KG hereunder shall include all expenses reasonably incurred by
BI Pharma KG prior to such termination in respect of the purchase of supplies
or raw materials, and an allocation of the balance of the Project Fee for the
period prior to receipt of such termination by BI Pharma KG and for a period of
[*] weeks thereafter.  The amount to be paid per week in this case
shall be calculated separately Phase by Phase by dividing the amount to be paid
by BioMedicines for the respective entire Phase by the number of weeks of the
respective Phase.  Such the amount per
week may vary if the six week period reaches into the next Phase.  However, under no circumstances BioMedicines
shall be obliged to pay more than the amount that would have been due
ordinarily for the respective Phase.


 


13.3        Termination
with Immediate Effect.  Either
party may terminate this Agreement effective upon written notice if either of
the following events occurs.


 


(a)           The other party commits a breach of this
Agreement and the breach is not remedied within 30 days after the receipt of
notice identifying the breach and requiring its remedy; or


 


(b)           The other party (I) becomes unable to
pay its debts as they become due, (II) suspends payment of its debts, (III)
enters into or becomes subject to corporate rehabilitation or bankruptcy
proceedings or liquidation or dissolution, (IV) makes an assignment for the
benefit of its creditors or (V) seeks relief under any similar laws for debtor’s
relief.


 


(c)           If the License Agreement terminates for
whatsoever reason.


 


13.4        Effect
of Termination.  Upon the
expiration or termination of this Agreement:


 


(a)           At the request of BioMedicines, BI
Pharma KG shall promptly return all BioMedicines Confidential Information to
BioMedicines; except for a single copy and/or sample of each material for
documentation purposes only.  BI Pharma
KG’s responsibility to keep and store the Cell Line and any other material
shall terminate 6 (six) months after expiration or termination of this
Agreement; and


 


(b)           BioMedicines shall promptly return all
BI Pharma KG Confidential Information to BI Pharma KG, except for a single copy
and/or sample for documentation purposes only.


 


The respective rights of BI Pharma KG and BioMedicines to
indemnification as set forth in Section 9 hereof shall survive termination of
this Agreement with respect to any claims that relate to or derive from the
Project, or any acts or failures to act, of either BI Pharma KG or BioMedicines
in connection with the Project that occur prior to termination.


 










[ * ] =
CERTAIN CONFIDENTIAL INFORMATION CONTAINED IN THIS DOCUMENT, MARKED BY BRACKETS,
HAS BEEN OMITTED AND FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE
COMMISSION PURSUANT TO RULE 406 OF THE SECURITIES ACT OF 1933, AS AMENDED.


 


11


















 


14.          Force
Majeure.  Neither party shall
be in breach of this Agreement if there is any failure of performance under
this Agreement (except for payment of any amounts due hereunder) occasioned by
any act of God, fire, act of government or state, war, civil commotion,
insurrection, embargo, prevention from or hindrance in obtaining energy or
other utilities, labor disputes of whatever nature or any other reason beyond
the control of either party.


 


15.          Publicity.
 No press release or other form of
publicity regarding the Project or this Agreement shall be permitted by either
party to be published unless both parties have indicated their consent to the
form of the release in writing.


 


16.          Notices.  Any notice required or permitted to be given
hereunder by either party shall be in writing and shall be (a) delivered
personally, (b) sent by registered mail, return receipt requested, postage
prepaid or (c) delivered by facsimile with immediate telephonic confirmation of
receipt, to the addresses or facsimile numbers set forth below:


 


	
  If to BI Pharma KG:

  	
  Boehringer Ingelheim Pharma KG

  
	
   

  	
  Birkendorfer Straβe 65

  
	
   

  	
  88397 Biberach an der Riss

  
	
   

  	
  Federal Republic of Germany

  
	
   

  	
  Attention: Prof. Dr. Rolf G. Werner

  
	
   

  	
  Fax: 0 73 51/54-51 31

  
	
   

  	
  Phone 0 73 51/54-48 00

  
	
   

  	
   

  
	
  If to BioMedicines:

  	
  BioMedicines, Inc.

  
	
   

  	
  909 Marina Village Parkway, No. 583

  
	
   

  	
  Alameda, CA 94501 USA

  
	
   

  	
  Fax:                                    

  
	
   

  	
  Phone:                                

  



 


Each notice shall be deemed given (a) on the
date it is received if it is delivered personally, (b) 1 day after the date it
is postmarked if it is sent by certified United States mail, return receipt
requested, postage prepaid or by other commercial carrier such as DHL (c) on
the date it is received if it is sent by facsimile with immediate telephonic
confirmation of receipt.  Notice to
BioMedicines shall be deemed to constitute notice to and for purposes of this
Agreement.


 


17.          APPLICABLE
LAW


 


This Agreement shall be governed by and
construed in accordance with the laws of the place of domicile of BI Pharma KG
and the courts of the place of domicile of BI Pharma KG shall have exclusive
jurisdiction over all legal matters and proceedings hereunder.


 


18.          COMPLIANCE
WITH LAWS


 


BI Pharma KG shall perform the work hereunder
in conformance with GMP, as applicable, and all German laws, ordinances and
governmental rules or regulations pertaining thereto.


 










[ * ] = CERTAIN CONFIDENTIAL INFORMATION
CONTAINED IN THIS DOCUMENT, MARKED BY BRACKETS, HAS BEEN OMITTED AND FILED
SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION PURSUANT TO RULE 406 OF
THE SECURITIES ACT OF 1933, AS AMENDED.


 


12





















 


19.          INDEPENDENT
CONTRACTORS


 


Each of the parties hereto is an independent
contractor and nothing herein contained shall be deemed to constitute the
relationship of partners, joint ventures, nor of principal and agent between
the parties hereto.  Neither party shall
hold itself out to third persons as purporting to act on behalf of, or serving
as the agent of, the other party.


 


20.          WAIVER


 


No waiver of any term, provision or condition
of this Agreement whether by conduct or otherwise in any one or more instances
shall be deemed to be or construed as a further or continuing waiver of any
such term, provision or condition or of any other term, provision or condition
of this Agreement.


 


21.          SEVERABILITY


 


If any provision of this Agreement is held to
be invalid or unenforceable by a court of competent jurisdiction all other
provisions shall continue in full force and effect.


 


22.          ENTIRETY


 


This Agreement, including any exhibits and
appendices attached hereto and referenced herein, constitutes the full
understanding of the parties and a complete and exclusive statement of the
terms of their agreement, and no terms, conditions, understandings or
agreements purporting to modify or vary the terms thereof shall be binding
unless it is hereafter made in writing and signed by both parties.


 


23.          ASSIGNMENT


 


This Agreement shall be binding upon the
successors and assigns of the parties and the name of a party appearing herein
shall be deemed to include the names of its successors and assigns provided
always that nothing herein shall permit any assignment by either party.  However, BI Pharma KG may assign this
Agreement to any suitably qualified Affiliate of BII.


 










[ * ] = CERTAIN CONFIDENTIAL INFORMATION
CONTAINED IN THIS DOCUMENT, MARKED BY BRACKETS, HAS BEEN OMITTED AND FILED
SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION PURSUANT TO RULE 406 OF
THE SECURITIES ACT OF 1933, AS AMENDED.


 


13





















 


IN WITNESS WHEREOF,
the parties have caused this Agreement to be executed as of the Effective Date.


 


	
  BIOMEDICINES, INC.

  	
  BOEHRINGER INGELHEIM PHARMA KG

  
	
   

  
	
  By:

  	
  /s/ S. M. Moran

  	
   

  	
  ppa.

  	
  ppa.

  
	
   

  	
  /s/ Rolf Werner

  	
   

  	
  /s/ Michelberger

  	
   

  
	
  Title:

  	
   

  	
  S.M. Moran, M.D.

  	
   

  	
   

  
	
   

  	
  Chief Executive Officer

  	
  Prof. Dr. Rolf G. Werner 

  	
  Dr. Michelberger

  
	
   

  	
   

  	
  (Head of Biotechnical

  Manufacture)

  	
  (Head of Legal Dept)

  
	
   

  
	
  Date

  	
  23 July 1998

  	
  Date

  	
  July 17, 1998

  	
   

  
										



 


 


Appendices:


Appendix 1            Master
Projectplan including Project Timeline


Appendix 2            BioMedicines
present forecast estimation of its Affiliates and Sublicensees total
requirements of Product


 










[ * ] = CERTAIN CONFIDENTIAL INFORMATION
CONTAINED IN THIS DOCUMENT, MARKED BY BRACKETS, HAS BEEN OMITTED AND FILED
SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION PURSUANT TO RULE 406 OF
THE SECURITIES ACT OF 1933, AS AMENDED.


 


14





















 





 


Appendix
1


 


Cost estimate of the Master Project Plan
Interferon Omega


 


	
  Establishing and Testing [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  –,–

  
	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  
	
  Total amount

  	
   

  	
  [*]

  



 










[ * ] = CERTAIN CONFIDENTIAL INFORMATION
CONTAINED IN THIS DOCUMENT, MARKED BY BRACKETS, HAS BEEN OMITTED AND FILED
SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION PURSUANT TO RULE 406 OF
THE SECURITIES ACT OF 1933, AS AMENDED.


 


15





















 


[*]


 










[ * ] = CERTAIN CONFIDENTIAL INFORMATION
CONTAINED IN THIS DOCUMENT, MARKED BY BRACKETS, HAS BEEN OMITTED AND FILED
SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION PURSUANT TO RULE 406 OF
THE SECURITIES ACT OF 1933, AS AMENDED.


 





















 


[*]


 










[ * ] = CERTAIN CONFIDENTIAL INFORMATION
CONTAINED IN THIS DOCUMENT, MARKED BY BRACKETS, HAS BEEN OMITTED AND FILED
SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION PURSUANT TO RULE 406 OF
THE SECURITIES ACT OF 1933, AS AMENDED.


 





















 





 


Appendix
2


 


BioMedicines present forecast estimation of
its, its Affiliates and

Sublicensees total requirements of Product


 


	
  1.

  	
   

  	
  [*] μg/[*] 

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  2.

  	
   

  	
  [*] per week per [*]-week treatment cycle

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  3.

  	
   

  	
  [*] cycle per year
  per patient

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  4.

  	
   

  	
  year 1:

  	
   

  	
  [*] patients

  	
   

  	
  =

  	
   

  	
  [*] cycles

  	
   

  	
  =

  	
   

  	
  [*]

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  5.

  	
   

  	
  year 2:

  	
   

  	
  [*] patients

  	
   

  	
  =

  	
   

  	
  [*] cycles

  	
   

  	
  =

  	
   

  	
  [*]

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  6.

  	
   

  	
  year 3:

  	
   

  	
  [*] patients

  	
   

  	
  =

  	
   

  	
  [*] cycles

  	
   

  	
  =

  	
   

  	
  [*]

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  7.

  	
   

  	
  In year 1, an additional

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  [*]

  
	
   

  	
   

  	
  will be needed to provide a reserve of drug
  in the pharmacies; 

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  in year 2 an additional

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  [*]

  
	
   

  	
   

  	
  will be needed to provide a reserve of drug
  in the pharmacies; and 

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  in year 3 an additional

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  [*]

  
	
   

  	
   

  	
  will be needed to provide a reserve of drug
  in the pharmacies 

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  8.

  	
   

  	
  phase IV testing will require an additional
  [*] per year

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  



 










[ * ] = CERTAIN CONFIDENTIAL INFORMATION
CONTAINED IN THIS DOCUMENT, MARKED BY BRACKETS, HAS BEEN OMITTED AND FILED
SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION PURSUANT TO RULE 406 OF
THE SECURITIES ACT OF 1933, AS AMENDED.


 





















 


Amendment No. 1


 


to the Contract Research and Development
Agreement


on Interferon-Omega


dated July 17th/23rd,
1998


 


(hereinafter referred to as the “R&D-Agreement”)


 


 


between


 


BioMedicines,
Inc.


2000 Powell Street, Suite 1640


Emeryville, CA 94541


 


U.S.A.


 


	
   

  	
   

  	
  (hereinafter referred to as “BioMedicines”)

  



 


and


 


Boehringer Ingelheim Pharma GmbH & Co. KG


Birkendorfer Straβe 65


D-88397 Biberach an der Riss


 


Federal Republic of Germany


 


	
   

  	
   

  	
  (hereinafter
  referred to as “BI Pharma”)

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
  (hereinafter
  individually and/or collectively referred

  to as the “Party/Parties”)

  



 


PREAMBLE


 


Whereas, the R&D-Agreement
has been concluded between BioMedicines and BI Pharma (formerly doing business
as “Boehringer Ingelheim Pharma KG”) and which has been updated as regards the
Project by letter agreement of the Parties; and


 










[ * ] = CERTAIN CONFIDENTIAL INFORMATION
CONTAINED IN THIS DOCUMENT, MARKED BY BRACKETS, HAS BEEN OMITTED AND FILED
SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION PURSUANT TO RULE 406 OF
THE SECURITIES ACT OF 1933, AS AMENDED.


 










 










 


Whereas, the BioMedicines wishes
BI Pharma to supply certain quantities of drug substance to BioMedicines for
non-commercial development purposes before having a supply agreement in place
as intended by the License Agreement (as defined); and


 


Whereas, BI Pharma is willing to
supply BioMedicines with such quantities under the additional conditions laid
down hereinafter.


 


Now Therefore, the Parties agree
as follows.


 


1.              General


 


All
capitalized terms in this Agreement shall have the meaning laid down in the
R&D-Agreement unless otherwise defined in this Amendment No.1 or in the
Appendices hereto.


 


2.              Section 1
(Definitions)


 


In Section 1
of the R&D-Agreement a new Section 1.24 is added to read as follows:


 


“1.24                      Agreement on
Release Responsibility


shall mean the special agreement between the Parties with regard to
certain quantities of the drug substance in a certain form to be provided by BI
Pharma to BioMedicines for non-commercial development purposes at certain
conditions agreed upon by the Parties in that Agreement on Release
Responsibility.”


 


3.              Section 4


 


(1)                                      The existing Section 4.3 is made
Section 4.4.


 


(2)                                      A new Section 4.3 is inserted to
read as follows:


 


“4.3                            Agreement on
Release Responsibility


The Parties have agreed on the Agreement on Release Responsibility
attached hereto as Appendix Amend- No.1 — 1, according to which
drug substance in a certain form will be provided by BI Pharma to BioMedicines
for non-commercial development purposes at certain conditions agreed upon by
the Parties in that Agreement on Release Responsibility. The quantities itself
and the price for such quantities shall be agreed upon by the Parties in due
time in good faith negotiations before the respective order.”


 


4.              Section 4


This Amendment
No. 1 shall be effective as of the last signature hereto.


 










[ * ] =
CERTAIN CONFIDENTIAL INFORMATION CONTAINED IN THIS DOCUMENT, MARKED BY
BRACKETS, HAS BEEN OMITTED AND FILED SEPARATELY WITH THE SECURITIES AND
EXCHANGE COMMISSION PURSUANT TO RULE 406 OF THE SECURITIES ACT OF 1933, AS AMENDED.


 





















 


5.              Validity of the
R&D-Agreement


 


As far as not amended herein,
the R&D-Agreement shall remain in full force and effect.


 


IN WITNESS HEREOF, the parties
hereto have executed this Amendment No.1 as of the last day and year written
below.


 


 


	
  Biberach, 19. December 2003

  	
   

  	
  Emeryville, 22 March 2004

  
	
   

  	
   

  	
   

  
	
  Boehringer Ingelheim

  	
   

  	
  BioMedicines,
  Inc.

  
	
   

  	
   

  	
   

  
	
  Pharma GmBH & Co. KG

  	
   

  	
   

  
	
   

  	
   

  	
  ppa.

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
  Dr. Wolfram Carius

  	
   

  	
  Dr. H. Michelberger

  	
   

  	
  Thomas A. Alessi

  



 


 


Appendix:


 


Appendix Amend- No.1 – 1:                                            Agreement on Release Responsibility
(including Appendices)


 










[ * ] =
CERTAIN CONFIDENTIAL INFORMATION CONTAINED IN THIS DOCUMENT, MARKED BY
BRACKETS, HAS BEEN OMITTED AND FILED SEPARATELY WITH THE SECURITIES AND
EXCHANGE COMMISSION PURSUANT TO RULE 406 OF THE SECURITIES ACT OF 1933, AS
AMENDED.


 





















 


APPENDIX AMEND- NO.1 — 1: 


Agreement on Release Responsibility (including
Appendices)


 


Agreement on Release Responsibility


 


(including Release Procedure and Definition of Responsibilities for

Product Release

between


BioMedicines and BI Pharma)


 


TABLE OF CONTENTS


 


	
  1.

  	
  DEFINITIONS

  	
   

  
	
   

  	
   

  	
   

  
	
  2.

  	
  ORDER

  	
   

  
	
   

  	
   

  	
   

  
	
  3.

  	
  SPECIFICATIONS

  	
   

  
	
   

  	
   

  	
   

  
	
  4.

  	
  LABELLING

  	
   

  
	
   

  	
   

  	
   

  
	
  5.

  	
  DOCUMENTATION

  	
   

  
	
   

  	
   

  	
   

  
	
  6.

  	
  RESPONSIBILITIES

  	
   

  
	
   

  	
   

  	
   

  
	
  7.

  	
  LIABILITY

  	
   

  



 










[ * ] =
CERTAIN CONFIDENTIAL INFORMATION CONTAINED IN THIS DOCUMENT, MARKED BY
BRACKETS, HAS BEEN OMITTED AND FILED SEPARATELY WITH THE SECURITIES AND
EXCHANGE COMMISSION PURSUANT TO RULE 406 OF THE SECURITIES ACT OF 1933, AS
AMENDED.


 





















 


1.                                      Definitions


 


	
  “Bulk Drug Substance”:

  	
   

  	
  means under cGMP produced Interferon Omega
  processed to the bulk step;

  
	
   

  	
   

  	
   

  
	
  “Drug Product”

  	
   

  	
  means Bulk Drug Substance formulated and
  aseptically filled [*].
  Labelling will occur on the packaging boxes for shipment and storage;

  
	
   

  	
   

  	
   

  
	
  “Finished Product”

  	
   

  	
  means Drug Product after labelling of
  individual [*] and final
  release;

  
	
   

  	
   

  	
   

  
	
  “Certificate
  of Analysis”

  	
   

  	
  or
  “CoA” means a batch specific document, signed by an authorized representative
  of BI Pharma, describing specifications and testing methods and the results
  thereof for Bulk Drug Substance, Drug Product and Finished Product, as the
  case may be;

  
	
   

  	
   

  	
   

  
	
  “Certificate
  of Compliance”

  	
   

  	
  means
  a batch specific document, signed by an authorized representative of BI
  Pharma, confirming GMP compliance of production of a given batch signed by a
  Qualified Person.

  



 


2.                                      ORDER


 


BioMedicines
shall deliver to BI Pharma, in writing, a binding purchase to order for Bulk
Drug Substance or Drug Product. Such a purchase order will be based on an
agreed-upon planning basis for manufacturing of Bulk Drug Substance and Drug
Product considering the lead time for manufacturing at BI Pharma (3[*] months for Bulk Drug Substance and [*] months for Drug Product).


 


Delivery shall
take place by BI Pharma on the base of EXW (Incoterms 2000). Further delivery
terms (i.e. primary container, detailed quantities, shipment address, etc.)
will be agreed upon by the parties on a case by case basis and are subject to a
purchase order.


 


Bulk Drug
Product or Drug Product will be delivered to BioMedicines and will be shipped
based on BI Release


 


3.                                      SPECIFICATIONS


 


All Bulk Drug Substance or Drug Product supplied to BioMedicines
hereunder will comply with the specifications shown in Appendix 1 or 2
to this Release Procedure at


 










[ * ] =
CERTAIN CONFIDENTIAL INFORMATION CONTAINED IN THIS DOCUMENT, MARKED BY
BRACKETS, HAS BEEN OMITTED AND FILED SEPARATELY WITH THE SECURITIES AND
EXCHANGE COMMISSION PURSUANT TO RULE 406 OF THE SECURITIES ACT OF 1933, AS
AMENDED.


 





















 


the time of manufacture and be
in accordance with the current batch record and cGMP.


 


4.                                      LABELLING


 


The labels for the Bulk Drug Substance or Drug Product shipment
containers should contain at least the following:


•                                          name
of the Bulk Drug Substance or Drug Product;


•                                          batch
number;


•                                          manufacturer;


•                                          amount
of the Bulk Drug Substance or Drug Product;


•                                          storage
instructions;


•                                          manufacturing
date;


 


5.                                      DOCUMENTATION


 


Each delivery
of the Bulk Drug Substance or Drug Product to BioMedicines will be accompanied by a CoC and CoA, provided by
the competent Quality and Compliance department of BI Pharma.


 


6.                                      RESPONSIBILITIES


 


6.1                                 General:


 


BI Pharma will
be responsible for manufacturing, manufacturer’s release and stability testing
of Bulk Drug Substance, Drug Product and Finished Product, as the case may be.


 


6.2                                 Only
Bulk Drug Substance Shipped:


 


If only Bulk Drug Substance is shipped to BioMedicines, BI Pharma will
be responsible for manufacturing of Bulk Drug Substance, manufacturer’s release
and stability testing of Bulk Drug Substance. BioMedicines will be responsible
for manufacturing, final release for clinics and/or market supplies and
stability testing of Drug Product and Finished Product.


 


7.                                      LIABILITY


 


7.1                                 No
Warranty of Merchantability or Fitness. 


 


BI Pharma makes no warranty that the Bulk Drug Substance/Drug
Product/Finished Product (the “Product”) will be merchantable or fit for any
particular purpose, nor does BI Pharma make any other warranties with respect
to the Product, except as expressly stated in this Agreement.


 










[ * ] =
CERTAIN CONFIDENTIAL INFORMATION CONTAINED IN THIS DOCUMENT, MARKED BY
BRACKETS, HAS BEEN OMITTED AND FILED SEPARATELY WITH THE SECURITIES AND
EXCHANGE COMMISSION PURSUANT TO RULE 406 OF THE SECURITIES ACT OF 1933, AS
AMENDED.


 





















 


7.2                                 Limitation
of Liability as regards Amount and Consequential Damages


 


BI Pharma undertakes to use commercially reasonable efforts to provide
the Product as foreseen in this Agreement. However, due to [*] BI Pharma’s liability under this
Agreement shall in no event exceed the amount to be paid by BioMedicines for
the respective delivery.  Any liability
of BI Pharma for consequential damages is excluded.


 


7.3                                 Limitation
of Liability regarding Use of Product/any Formulations thereof


 


As BI Pharma has no knowledge or awareness of or control over the manner
in which BioMedicines intends to use any Product obtained according to this
Agreement and in particular does not know or control how BioMedicines intends
to use such Product or results in pre-clinical or clinical studies or
commercially, BI Pharma shall not be liable to BioMedicines for any losses,
damages, costs or expenses of any nature incurred or suffered by BioMedicines
or by a third party, arising out of any dispute or other claims or proceedings
made by or brought against BioMedicines in respect of the use of the Product by
BioMedicines or by a third party (including, without limitation, product
liability claims), nor shall BI Pharma be responsible in any way for dealing
with any such disputes, claims or proceedings.


 


BioMedicines shall indemnify, defend and hold BI Pharma, its affiliates
and their respective officers, employees and agents harmless from and against
all such losses, damages costs and expenses (including, without limitation,
reasonable attorneys’ fees).


 


Appendices:


 


Appendix 1:                                           Release
relevant Analytical Methods and Specifications for Interferon Omega Bulk Drug Substance at BI Pharma:


 


Appendix 2:                                           Release
relevant Analytical Methods and Specifications for Interferon Omega Drug Product at BI Pharma:


 










[ * ] =
CERTAIN CONFIDENTIAL INFORMATION CONTAINED IN THIS DOCUMENT, MARKED BY
BRACKETS, HAS BEEN OMITTED AND FILED SEPARATELY WITH THE SECURITIES AND
EXCHANGE COMMISSION PURSUANT TO RULE 406 OF THE SECURITIES ACT OF 1933, AS
AMENDED.


 





















 


Appendix
1


 


to the
Agreement on Release Responsibility


by and between
BioMedicines and BI Pharma:


 


Release relevant Analytical
Methods and Specifications for Interferon Omega Bulk Drug Substance at BI
Pharma:


 


BuIk Drug
Substance:


 


In-process
Specifications for Bulk Drug Substance


 


	
  Test

  	
   

  	
  Specification

  	
   

  	
  Process Step

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  



 


Release
Specifications for Bulk Drug Substance


 


Concentration [*] mg/mL and [*]
mg/mL


 


	
  Test

  	
   

  	
  Doc.-No.

  	
   

  	
  Specification

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  



 










[ * ] =
CERTAIN CONFIDENTIAL INFORMATION CONTAINED IN THIS DOCUMENT, MARKED BY
BRACKETS, HAS BEEN OMITTED AND FILED SEPARATELY WITH THE SECURITIES AND
EXCHANGE COMMISSION PURSUANT TO RULE 406 OF THE SECURITIES ACT OF 1933, AS
AMENDED.


 





















 


Final
formulated bulk after sterile filtration


 


	
  Test

  	
   

  	
  Doc.-No.

  	
   

  	
  Specification

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  



 


Appendix
2


 


to the
Agreement on Release Responsibility


by and between BioMedicines
and BI Pharma:


 


Release relevant Analytical
Methods and Specifications for Interferon Omega Drug Product at BI Pharma:


 


Drug Product:


 


	
  Test

  	
   

  	
  Doc.-No.

  	
   

  	
  Specification

  
	
  [*]

  	
   

  	
   

  	
   

  	
   

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
   

  	
   

  	
   

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  



 


[*]


 










[ * ] =
CERTAIN CONFIDENTIAL INFORMATION CONTAINED IN THIS DOCUMENT, MARKED BY
BRACKETS, HAS BEEN OMITTED AND FILED SEPARATELY WITH THE SECURITIES AND
EXCHANGE COMMISSION PURSUANT TO RULE 406 OF THE SECURITIES ACT OF 1933, AS
AMENDED.