Contract Research and Development Agreement – ImClone Systems Inc. and Boehringer Ingelheim Pharma KG
TABLE OF CONTENTS
1. DEFINITIONS
1.1 BI PHARMA KG
1.2 BI PHARMA KG Confidential Information
1.3 Cell Line
1.4 Certificate of Analysis
1.5 cGMP
1.6 C225
1.7 Effective Date
1.8 IMCLONE
1.9 IMCLONE Confidential Information
1.10 Master Cell Bank (MCB)
1.11 Manufacturer's Working Cell Bank (MWCB)
1.12 Phase I
1.13 Phase II
1.14 Phase III
1.15 Process
1.16 Product
1.17 Project
1.18 Project Fee
1.19 Project Manager
1.20 Project Team
1.21 Specifications
1.22 Start Date
2. COOPERATION BETWEEN THE PARTIES IN THE COURSE OF THE PROJECT
2.1 Designation of Project Manager
2.2 Project Team
2.3 Cooperation
2.4 Access to facilities
3. IMCLONE'S TASKS AND RESPONSIBILITIES
3.1 License to Use of IMCLONE Cell Line and Intellectual Property
3.2 Materials and Information to be Provided
3.3 Activities to be Performed
December 28, 1998
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4. BI PHARMA KG'S TASKS AND RESPONSIBILITIES
4.1 BI PHARMA KG's Tasks
4.2 Control of Cell Line
4.3 Quarantine and Testing
4.4 Phase I/II Development Program
4.5 Responsibility for Failed Fermentations and Downstream Operations
4.6 Materials and Information to be Delivered
4.7 Product to be Delivered
4.8 Prior Approval
4.9 Retention Samples
4.10 Additional Work
5. PHASE I/II TO BE CONDUCTED ON FIXED-FEE BASIS
6. PHASE I/II PROJECT FEE
7. ADDITIONAL WORK / FUTURE ACTIVITIES
7.1 Additional Work
7.2 Future Activities
7.3 Others
8. OWNERSHIP OF PROJECT DATA
8.1 General
8.2 Intellectual Property Rights solely covering the Product
8.3 All other Intellectual Property Rights
9. REPRESENTATIONS. WARRANTIES AND INDEMNIFICATION
9.1 IMCLONE
9.2 BI PHARMA KG
10. LIMITATION OF LIABILITY
10.1 No Warranty of Merchantability of Fitness
10.2 Limitation of Liability
10.3 Maximum Amount
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11. CONFIDENTIALITY
11.1 BI PHARMA KG
11.2 IMCLONE
11.3 Exceptions
11.4 Others
12. TERM AND TERMINATION
12.1 Term
12.2 Right to Terminate
12.3 Effect of Termination
13. MISCELLANEOUS
13.1 Force Majeure
13.2 Publicity
13.3 Notices
13.4 Applicable Law
13.5 Compliance with Laws
13.6 Independent Contractors
13.7 Waiver
13.8 Severability
13.9 Entirety
13.10 Assignment
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CONTRACT RESEARCH AND DEVELOPMENT AGREEMENT
(C225)
THIS CONTRACT RESEARCH AND DEVELOPMENT AGREEMENT ('Agreement') is made as of
April 30, 1999 by and among ImClone Systems Incorporated, ('IMCLONE'), having
its principal business offices at 180 Varick Street, New York, New York 10014,
U.S.A. and Boehringer Ingelheim Pharma KG ('BI PHARMA KG') a German corporation
having its principal place of business at Birkendorfer Stra(beta)e 65, 88397
Biberach an der Riss, Federal Republic of Germany.
BACKGROUND
----------
IMCLONE is the proprietor of a hybridoma cell line [ *** ] which produces a
monoclonal antibody C225 directed against Epidermal Growth Factor Receptor
(EGFR) as a result of stable transfection with a C225 expression construct, as
well as methods for the purification and analysis of C225.
BI PHARMA KG owns specialized cell culture, processing, protein purification and
Iyophilization facilities that may be suitable for production of C225, and
employs personnel who have experience in production of proteins by cell culture
and purification processes as well as in registration of biopharmaceuticals.
IMCLONE desires to have BI PHARMA KG personnel evaluate, further develop, supply
and scale-up the production process for C225 in BI PHARMA KG's facilities.
IMCLONE and Dr. Karl Thomae GmbH (as of 01.01.1998 and in this Agreement
substituted by BI Pharma KG as the contractual assignee of all rights and
obligations thereunder) have previously entered into a Material Transfer
Agreement for Evaluation dated November 10/24, 1997 to evaluate potential
production and supply of C225.
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AGREEMENT
---------
IN CONSIDERATION OF the mutual covenants set forth in this Agreement, BI PHARMA
KG and IMCLONE hereby agree as follows:
1. DEFINITIONS
1.1 'BI PHARMA KG'
shall mean Boehringer Ingelheim Pharma KG.
1.2 'BI PHARMA KG Confidential Information'
shall mean all technical and other information relating to BI PHARMA
KG's facilities and associated technologies that is disclosed or
supplied to, IMCLONE by BI PHARMA KG (except IMCLONE Confidential
Information) 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.
1.3 'Cell Line'
shall mean the IMCLONE cell line [ *** ] that expresses the Product.
1.4 'Certificate of Analysis'
shall mean a document to be established by mutual agreement describing
testing methods and results.
1.5 'cGMP'
shall mean the regulatory requirements for current good manufacturing
practices promulgated by the FDA under the Federal Food, Drug and
Cosmetic Act, as amended, 21 C.F.R. Section 210 et seq and 21 C.F.R.
Section 600-610, as applicable.
1.6 'C225'
shall mean a chimerized monoclonal antibody directed against EGFR
produced by the Cell Line.
1.7 'Effective Date'
shall mean the date first above written, which shall be the effective
date of this Agreement.
1.8 'IMCLONE'
shall mean ImClone Systems Incorporated or an affiliate of ImClone
Systems Incorporated.
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1.9 'IMCLONE Confidential Information'
shall mean the Cell Line, Process, Product and all technical,
scientific or business and other materials and information that are
disclosed or supplied to BI PHARMA KG by IMCLONE or developed on behalf
of IMCLONE by BI PHARMA KG (excluding BI PHARMA KG Confidential
Information) 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.
1.10 'Master Cell Bank (MCB)'
shall mean a cell bank established by BI PHARMA KG derived from a
suspension serum-free adapted cell line to be produced at BI PHARMA KG.
1.11 'Manufacturer's Working Cell Bank (MWCB)'
shall mean a cell bank established by BI PHARMA KG derived from the
MCB.
1.12 'Phase I'
shall refer to process transfer of the Process to a [ *** ] scale at BI
PHARMA KG, continued scale-up to a [ *** ] and [ *** ] pilot
fermentation scale and establishment of a downstream purification
process according to APPENDIX 1, all of which has been completed as of
the Effective Date.
1.13 'Phase II'
shall refer to demonstrating the process at small scale [ *** ],
performing Product equivalency testing and establishing a filling
process of the corresponding Product as well as the scale-up to [ *** ]
pilot scale and cGMP production of clinical grade material at that
scale to be undertaken by BI PHARMA KG pursuant to this Agreement and
according to the updated Master Projectplan (APPENDIX 1.1) dated
November 1998. The agreed upon process format for Phase II of the
project is given in APPENDIX 6. [ *** ].
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1.14 'Phase III'
shall refer to a second project, which may be implemented by separate
agreement between IMCLONE and BI PHARMA KG following completion of
Phase II activities, involving scaling the Process from the [ *** ]
fermentation scale implemented in Phase II to the [ *** ].
1.15 'Process'
shall refer to a proprietary IMCLONE 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 IMCLONE to produce the Product at the laboratory
scale, which shall be disclosed by IMCLONE to BI PHARMA KG to enable BI
PHARMA KG to carry out the Project or, if and when applicable, the
modified process after further development and scale up by BI PHARMA KG
to the [ *** ] fermentation scale.
1.16 'Product'
shall mean the biologically active C225 produced by the Cell Line in
accordance with the Process.
1.17 'Project'
shall mean the Phase I and Phase II contract research program described
herein, in which IMCLONE shall transfer the Process to BI PHARMA KG to
be implemented, scaled-up and evaluated at the [ *** ] fermentation
scale in and by BI PHARMA KG's facility and equipment. The primary
objectives of the Project will be to transfer, establish and scale up
the Process in the BI PHARMA KG facility, successfully demonstrate that
Product can be reproducibly manufactured in BI PHARMA KG's facilities
at [ *** ] scale, and generate a report compiling a summary of data
generated in the Project. The proposed workscopes and timelines for the
Project are laid down in the Master Projectplans attached hereto as
APPENDIX 1 and APPENDIX 1.1. Phase I has been completed as of the date
of this Agreement.
1.18 'Project Fee'
shall have the meaning specified in Section 6 hereof.
1.19 'Project Manager'
shall have the meaning specified in Section 2.1 hereof.
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1.20 'Project Team'
shall have the meaning specified in Section 2.2 hereof.
1.21 'Specifications'
shall mean the specifications for the Product and the respective test
methods attached hereto as APPENDIX 5 on the basis of the
specifications provided by IMCLONE and as such specifications may be
amended from time to time by mutual agreement of IMCLONE and BI PHARMA
KG according to further development of the Process and Product.
1.22 'Start Date'
shall mean February 1, 1998 (according to the Master Projectplan
APPENDIX 1).
2. COOPERATION BETWEEN THE PARTIES IN THE COURSE OF THE PROJECT
2.1 Designation of Project Manager.
BI PHARMA KG and IMCLONE shall each identify a Project Manager, and if
they choose, the supervisor of the Project Manager. The Project Manager
or the Project Manager's supervisor will be exclusively responsible for
communicating all instructions and information concerning the Project
to the other party and shall be the person or people to whom such
instructions and information are communicated by the other party. Each
Project Manager or the Project Manager's supervisor will be available
on a weekly basis for consultation at prearranged times during the
course of the Project or as may otherwise be reasonably required or
advisable. In the absence of the Project Manager or the Project
Manager's supervisor, 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 Project Team.
BI PHARMA KG and IMCLONE shall each name representatives to a Project
Team, which shall consist of knowledgeable specialists in appropriate
disciplines who shall be responsible for planning and executing the
Project and any subsequent interactions between the parties. At regular
intervals, the Project Managers shall schedule meetings between each
company's representatives for the purpose of communicating Project
updates and providing a forum for strategic decision making and rapid
resolution of issues.
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Joint Project meetings shall be conducted by telephone-conference,
video-conference and face to face meetings. Meeting minutes shall be
prepared jointly by the Project Managers to record all issues discussed
and decisions made, subject to final approval of such minutes by both
parties. Such minutes are considered to be accepted by a party when
there is no objection made by such a party within a period of 7 (seven)
days after such minutes have been received by the respective party.
The present list of the members of the Project Team is attached hereto
as APPENDIX 2.
2.3 Cooperation.
BI PHARMA KG and IMCLONE each agree to work together collaboratively on
the Project as reasonably expeditiously as possible, with the objective
of completing the Project according to the mutual agreed timelines (see
APPENDIX 1 and APPENDIX 1.1).
In the course of the Project, BI PHARMA KG will at all times take into
consideration and implement the recommendations of IMCLONE as long as
they do not negatively influence other BI PHARMA KG biotech operations
and are agreed upon by the Project Team. In the absence of explicit
instructions from IMCLONE, 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 the
IMCLONE Project Manager or the IMCLONE Project Manager's supervisor
and, subject to Sections 4.5 and 4.7 below shall not be responsible for
failure to achieve any objective or the inability to adhere to any
guideline due to technical failures, incomplete direction or
documentation of Process variables, or other causes beyond the control
of BI PHARMA KG.
2.4 Access to facilities.
IMCLONE shall permit personnel of BI PHARMA KG, upon reasonable prior
written notice to IMCLONE, to visit its facilities during appropriate
times to observe the Process and certain analytical procedures for C225
as conducted by IMCLONE. BI PHARMA KG shall permit IMCLONE, upon
reasonable prior notice to BI PHARMA KG, to review the originals of all
batch records and other primary documents at its facilities and shall
allow IMCLONE personnel to be present in its facilities at appropriate
times (e.g. to observe the implementation of the Process). While
visiting the facility of the other party, personnel of BI PHARMA KG and
IMCLONE shall comply with all security and safety policies and
procedures of the other party.
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3. IMCLONE'S TASKS AND RESPONSIBILITIES
3.1 License to Use of IMCLONE Cell Line and Intellectual Property.
IMCLONE hereby grants to BI PHARMA KG a limited, non-exclusive right
and license, without the right to sublicense, to use IMCLONE
Confidential Information, including but not limited to the Cell Line
and Process, solely for the purpose of enabling BI PHARMA KG to carry
out its tasks and responsibilities under this Agreement with respect to
the Project.
3.2 Materials and Information to be Provided.
To enable BI PHARMA KG to begin the Project, IMCLONE shall provide:
(a) 10 vials of the MCB and/or MWCB for Project start, additional
quantities may be requested.
(b) a description of IMCLONE's methods for testing of the Cell Line
and its progenitor cell line.
(c) documentation describing the exact composition of the [ *** ] and
a sufficient quantity of actual medium to enable BI PHARMA KG to
begin to culture the Cell Line upon receipt from IMCLONE;
(d) a description of the Cell Line and of genetic construct used for
expression of the Product (for registration according to German
gene technology law ('Gentechnikgesetz')), and
(e) at BI PHARMA KG's reasonable request any additional information
concerning the Process, analytical test methods, reference
materials, and any critical reagents to facilitate the Project.
3.3 Activities to be Performed. As the Project is carried out, IMCLONE
shall:
(a) use reasonable efforts to perform the work and tasks as set forth
and detailed in APPENDIX 3.
(b) at BI PHARMA KG's request and subject to Section 2.4 above,
arrange for BI PHARMA KG personnel to visit IMCLONE's production
facility to observe and record the Process as carried out by
IMCLONE in its facility. Any such records shall be considered
IMCLONE Confidential Information.
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4. BI PHARMA KG'S TASKS AND RESPONSIBILITIES
4.1 BI PHARMA KG's Tasks.
In the course of this Agreement BI PHARMA KG shall perform the work and
tasks as laid down and detailed in APPENDIX 4 hereto.
4.2 Control of Cell Line.
BI PHARMA KG shall maintain (for safety reasons in two different
buildings) the Cell Line in safe and secure storage under its control
in its facilities and shall not permit the transfer of the Cell Line to
any third party that is not specifically authorized in writing by
IMCLONE (except to a contract laboratory used for the characterization
of the MCB or MWCB under substantially the same requirement of
confidentiality). BI PHARMA KG shall comply with all applicable
regulatory requirements relating to general safety and biosafety in
handling the Cell Line and any raw materials used in the Project.
4.3 Quarantine and Testing.
BI PHARMA KG will quarantine and test samples of the Cell Line already
provided to it in order to verify that the Cell Line is suitable for
introduction into BI PHARMA KG's facilities. The quarantine and testing
time is estimated to be about 2 (two) months.
4.4 Phase I/II Development Program.
Following quarantine testing of the MWCB (see APPENDIX 4) BI PHARMA KG
will transfer and establish the production process at laboratory scale
( [ *** ] fermentation scale) on the basis of Process information
supplied by IMCLONE. The agreed upon process format for Phase II of the
Project is given in APPENDIX 6. Material derived from such a process
will be tested for analytical equivalence with reference material from
IMCLONE. Remaining quantities may be used by IMCLONE at its discretion.
A scale-up will then be performed to the [ *** ] fermentation scale and
cGMP material [ *** ] for clinical trials will be produced at this
scale. The workscopes and timelines for such a program are given in the
Master Projectplans (see APPENDIX 1 and APPENDIX 1.1). The production
of further clinical material at [ *** ] fermentation scale, if required
by IMCLONE, has to be agreed upon separately in writing, and shall be
reflected in an amendment to this Agreement in accordance within the
terms set forth herein.
4.5 Responsibility for Failed Fermentations and Downstream Operations.
Responsibility for Failed Fermentations and Downstream Operations.
(a) IMCLONE acknowledges that the Project is experimental in nature
and that no favorable or useful result can be assured by BI PHARMA
KG.
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Accordingly, subject to the provisions of this Section 4.5, BI
PHARMA KG shall not be responsible to IMCLONE for any failure of
fermentations or downstream operations including, but not limited
to, purification, or inability to obtain useful yields of Product
or the success of the shift to the protein A process for reasons
not under BI PHARMA KG's control, 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
12 hereof.
(b) BI PHARMA KG shall be responsible for all bioreactor fermentations
and downstream operations including, but not limited to,
purification that fail for reasons under BI PHARMA KG's control
including, but not limited to, operator error, mechanical failure,
or contamination and BI PHARMA KG shall repeat any such failed
fermentations and downstream operations at its expense to complete
the workscopes to be performed during the Project according to
Section 4.4 above.
4.6 Materials and Information to be Delivered.
BI PHARMA KG will provide IMCLONE with the following materials and
information at the times indicated:
(a) a summary of the test results generated during the 2 (two) months
quarantine period within 30 (thirty) days following the end of
such period;
(b) within 2 (two) months following completion of each Phase of the
Project (Phase I and Phase II), a report to IMCLONE, as laid down
detailed in APPENDIX 7 including, a summary of the data BI PHARMA
KG collects in the course of the Project and Certificates of
Analysis for release of Product for clinical use, if any;
(c) other interim results as reasonable in appropriate time periods or
requested by IMCLONE, as mutually agreed by the Project Team.
4.7 Product to be Delivered.
BI PHARMA KG shall supply Product to IMCLONE from the [ *** ] pilot
scale and all purified Product (cGMP grade) from the [ *** ] scale runs
performed by BI PHARMA KG. BI PHARMA KG shall also provide IMCLONE with
samples of vialed Product that is produced by it. All Product
delivered, if any, shall conform with the Specifications which have to
be mutually agreed upon as laid down in APPENDIX 5 and BI PHARMA KG
shall issue a Certificate of Analysis covering such Specifications.
If the Product is asserted by IMCLONE not to meet the Specifications,
both parties shall re-test the Product. If IMCLONE and BI PHARMA KG are
not able to agree, whether the Product meets the Specifications or
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not and the parties are unable to resolve their differences, then
either party may refer the matter to an independent specialized
institution of international reputation agreeable to both parties for
final analysis, which shall be binding on both parties hereto.
All Product produced in the course of the Project shall be retained by
BI PHARMA KG and stored under conditions specified by IMCLONE (and
reasonably acceptable to BI PHARMA KG) not longer than 1 (one) year,
and delivered to IMCLONE as instructed by IMCLONE and at the cost and
risk of IMCLONE.
4.8 Prior Approval.
Prior to implementing any deviation from the Project, BI PHARMA KG
shall notify IMCLONE and obtain the written approval of the Project
Manager of IMCLONE or other person designated in writing by IMCLONE.
4.9 Retention Samples.
According to a sampling plan to be agreed upon by the Project Team, BI
PHARMA KG shall isolate, identify and retain samples of raw materials
used in fermentations carried out in the course of the Project, of
Process media at appropriate time points in each fermentation, and of
Product at each stage of purification. Retention samples shall be
provided promptly to IMCLONE at its request. Shipment shall be at the
cost and risk of IMCLONE.
4.10 Additional Work.
On request of IMCLONE, BI PHARMA KG shall perform additional
development 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 and defined in an amendment to the Master
Projectplans attached hereto as APPENDIX 1 and APPENDIX 1.1.
5. PHASE I/II TO BE CONDUCTED ON FIXED-FEE BASIS
The Project shall be conducted by BI PHARMA KG for IMCLONE on a fixed
fee basis, in consideration of payment by IMCLONE of the Project Fee.
The estimated duration of the Project shall be 21 (twenty-one) months
from the Start Date as outlined in APPENDIX 1 and APPENDIX 1.1. Phase I
of the Project has been completed as of the Effective Date.
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6. PHASE I/II PROJECT FEE
IMCLONE shall pay BI PHARMA KG a Project Fee of DM 8, 950,000
(eightmillionninehundredandfiftythousand Deutsche Mark) for the
services provided in carrying out the Project as defined in APPENDIX 1
and APPENDIX 1.1, regardless of the favorability or usefulness of the
results (see Section 4.5 above). Of this amount to date DM 3,130,000
has been paid for the completion of Phase I.
This fee includes all fees for BI PHARMA KG's services under the
Master Projectplans for Phase I and Phase II, including but not limited
to, fees for Cell Line validation, facility use, raw material testing,
in-process testing services including bulk and finished product
testing, environmental monitoring as appropriate, and other calibration
and validation activities required to facilitate the successful
completion of the technology transfer and production of the clinical
grade material at the [ *** ] fermentation scale.
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 described in APPENDIX 1 and APPENDIX 1.1. To the extent
BI PHARMA KG is required to repeat any fermentations or downstream
operations pursuant to Section 4.5 (b) above, any installment related
to the completion of the fermentation or downstream operation or
delivery of the Product, as the case may be, shall not be payable until
such fermentation or downstream operation or delivery of Product, as
the case may be, has been completed.
The cost of commercially available materials purchased by IMCLONE for
use at BI PHARMA KG to support development in GLP and cGMP shall be
creditable to the applicable invoice.
Each invoice shall be payable within 30 (thirty) days following receipt
thereof.
7. ADDITIONAL WORK / FUTURE ACTIVITIES
7.1 Additional Work.
BI PHARMA KG and IMCLONE may confer to determine if additional work
relating to Phase I or Phase II should be undertaken pursuant to
subsequent agreement between BI PHARMA KG and IMCLONE. Neither party
shall be obligated to conduct any further undertakings on behalf of the
other except as may be mutually agreed and set forth in a subsequent
written agreement.
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7.2 Future Activities.
In the event IMCLONE requires additional Product for the conduct of
clinical Phase III and/or for commercial supply and IMCLONE determines
in its sole discretion not to be the producer of that additional
quantities of Product, then IMCLONE and BI PHARMA KG shall engage in
good faith negotiations with respect to an agreement(s) for such
additional supply to contain usual and customary terms for similar
agreements under comparable circumstances. If the parties are unable to
agree to terms (including, but not limited to terms regarding quantity
of Product) within 120 (onehundredtwenty) days after BI PHARMA KG is
informed of IMCLONE's detailed request in writing, then IMCLONE may
engage in negotiations for such supply with other third parties;
provided, however, that IMCLONE shall not consummate any such agreement
with any third parties on terms that are in the aggregate more
favorable than those terms offered by BI PHARMA KG to IMCLONE without
first giving BI PHARMA KG an opportunity to accept the agreement(s) on
the terms offered to such third parties.
In case BI PHARMA KG will not exercise its right to enter into
negotiations with IMCLONE regarding an agreement to govern clinical
Phase III and/or commercial supply within 30 (thirty) days after the
written request of IMCLONE or if the parties are not able to conclude
such final agreement within 120 (onehundredtwenty) days after BI PHARMA
KG has received the written request of IMCLONE or if BI PHARMA KG has
not accepted the agreement(s) on the third party terms, then BI PHARMA
KG shall be deemed to have waived its rights granted under this Section
7.2.
7.3 Others.
IMCLONE shall not assert any right to use BI PHARMA KG facilities at
any future date as a result of its use of BI PHARMA KG facilities
pursuant to this Agreement, nor shall BI PHARMA KG assert any right to
use or have access to the Cell Line, Process, Product, MCB or MWCB as a
result of its activities pursuant to this Agreement.
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8. OWNERSHIP OF PROJECT DATA
8.1 General.
All information and intellectual property rights relating to the
transfer of information under Section 4.6 above, with the exception of
BI PHARMA KG Confidential Information, shall be the sole and exclusive
property of IMCLONE and IMCLONE shall have the right to use such
information for any purpose without further obligation to BI PHARMA KG.
For the purpose of this Agreement all information regarding BI PHARMA
KG's facility and technical equipment shall be considered BI PHARMA
KG'S Confidential Information.
8.2 Intellectual Property Rights solely covering the Product.
Any and all intellectual property rights solely covering the Product,
including, but not limited to, patents and patent applications arising
out of the activities performed under this Agreement shall be the sole
and exclusive property of IMCLONE, which shall have the sole right to
file such applications and will meet all costs in relation thereto.
Upon request of IMCLONE, BI PHARMA KG will assign any and all rights as
necessary to vest such ownership in IMCLONE.
8.3 All other Intellectual Property Rights.
All other intellectual property rights that arise out of the activities
performed under this Agreement, and that do not cover solely the
Product shall be the sole and exclusive property of BI PHARMA KG and
IMCLONE shall be granted a non-exclusive, royalty-free and worldwide
license solely for use to the Product.
9. REPRESENTATIONS. WARRANTIES AND INDEMNIFICATION
9.1 IMCLONE.
IMCLONE hereby represents, warrants and agrees that:
(a) IMCLONE is free to supply the Cell Line and IMCLONE Confidential
Information to BI PHARMA KG;
(b) IMCLONE is not aware of any special or unusual hazards involved in
handling the Cell Line or Product;
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(c) IMCLONE has full corporate authority to enter into this Agreement
and this Agreement is binding upon IMCLONE in accordance with its
terms; and
(d) IMCLONE shall indemnify, defend and hold BI PHARMA KG, its
affiliates, and their respective officers, employees and agents
harmless from and against all third party losses, damages, costs
and expenses (including, without limitation, reasonable attorneys'
fees), including injury to persons or damage to property resulting
from (i) any breach of the representations and warranties made by
IMCLONE under this Section, or (ii) any claim of infringement of
the intellectual property rights of a third party based upon BI
PHARMA KG's activities using the Cell Line or in implementing or
using the Process or producing the Product in accordance with the
instructions and documentation provided by IMCLONE or developed in
the course of the Project, except those which result from the
gross negligence or willful misconduct of an indemnified person or
entity and those for which BI PHARMA KG would have been liable if
BI PHARMA KG had used cell lines or processes other than Cell
Lines or Processes, or produced products other than Products.
9.2 BI PHARMA KG.
BI PHARMA KG hereby represents, warrants and agrees that:
(a) BI PHARMA KG has the lawful right to use 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 IMCLONE its
affiliates and their respective officers, employees and agents
harmless from and against all third party losses, damages, costs
and expenses (including, without limitation, reasonable attorneys'
fees), including injury to persons or damage to property,
resulting from (i) any breach of the representations and
warranties made by BI PHARMA KG under this Section, or (ii) any
claim that BI PHARMA KG has violated any applicable local law or
ordinance in carrying out
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its manufacturing responsibilities under this Agreement or (iii)
any claim of infringement of the intellectual property rights of a
third party, except those which result from gross negligence or
willful misconduct of an indemnified person or entity and those
based on BI PHARMA KG activities using the Cell Line or in
implementing or using the Process or producing the Product in
accordance with the instructions and documentation provided by
IMCLONE or developed in the course of the Project.
(e) BI PHARMA KG warrants that the Project shall be conducted as laid
down in APPENDIX 1 and APPENDIX 1.1 and in accordance with this
Agreement and, when appropriate, in compliance with cGMP, and that
any documentation of Project results or procedures provided to
IMCLONE by BI PHARMA KG shall be accurate in all material
respects. With regard to the results see Section 4.5 above.
10. LIMITATION OF LIABILITY
10.1 No Warranty of Merchantability or Fitness.
Subject to Section 9.2 above, BI PHARMA KG shall provide the results of
the Project to IMCLONE without any warranty of any kind, express or
implied, including, without limitation, any warranties of
merchantability or fitness for a particular purpose.
10.2 Limitation of Liability.
IMCLONE acknowledges that BI PHARMA KG has no control over the manner
in which IMCLONE intends to use any Product or results obtained in the
Project.
BI PHARMA KG shall not be liable to IMCLONE for any losses, damages,
costs or expenses of any nature incurred or suffered by IMCLONE or by a
third party, arising out of any dispute or other claims or proceedings
made by or brought against IMCLONE with respect to use of the results
of the Project, or the use of any Product by IMCLONE or by a third
party (including, without limitation, product liability claims and
claims by a third party alleging infringement of its intellectual
property rights), except as to those under Section 9.2 (d) above, nor
shall BI PHARMA KG be responsible in any way for dealing with any such
disputes, claims or proceedings; provided that it shall cooperate with
IMCLONE with respect to any such disputes or claims to the extent of
providing necessary or advisable information in connection with
IMCLONE's defense.
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10.3 Maximum Amount.
BI PHARMA KG undertakes to use its best efforts to perform the Project
under the Master Projectplans and to meet the target dates set forth in
APPENDIX 1 and APPENDIX 1.1 hereto. However, due to the biological
nature of the work to be performed hereunder BI PHARMA KG's liability
under this Agreement and its indemnification and hold harmless
obligations shall in no event amount to more than 10% (ten percent) of
the Project Fee. This limitation does not apply to willful breach or
misconduct of BI PHARMA KG or its officers, employees or agents.
11. CONFIDENTIALITY
11.1 BI PHARMA KG.
BI PHARMA KG shall not disclose IMCLONE Confidential Information to any
person other than its employees or employees of affiliated companies of
the Boehringer Ingelheim group who are bound by similar obligations of
confidentiality and who have a need to know such information in order
to perform their duties in carrying out the Project hereunder.
11.2 IMCLONE.
IMCLONE shall not disclose any BI PHARMA KG Confidential Information to
any person other than:
(a) its employees or consultants who are bound by substantially
similar obligations of confidentiality and who have a need to know
such information in order to provide direction to BI PHARMA KG or
evaluate the results of the Project; or
(b) regulatory authorities, for example, the FDA, that require such
information in order to review an IND or other regulatory filing.
11.3 Exceptions.
The obligations of confidentiality applicable to IMCLONE 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;
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(c) developed by the recipient independently of information obtained
from the disclosing party as evidenced by prior written records of
the recipient;
(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; provided that the recipient
notifies the disclosing party immediately upon receipt at any such
order or becoming aware of any such law or regulation, or released
with the prior written consent of the disclosing party.
11.4 Others.
No right or license under any patent or proprietary right is granted
hereunder by virtue of the disclosure of IMCLONE Confidential
Information or BI PHARMA KG Confidential Information except as
expressly provided herein. The obligations of both parties under this
Section 11 shall survive the expiration or termination of this
Agreement.
Both IMCLONE and BI PHARMA KG shall use reasonable and customary
precautions to safeguard IMCLONE Confidential Information and BI
PHARMA KG Confidential Information, including ensuring that all
employees or consultants 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.
12. TERM AND TERMINATION
12.1 Term.
This Agreement shall come into force as of the date first above written
and commence retroactively as of the Start Date and, unless terminated
earlier as provided herein, shall terminate 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 unless specifically extended by further written agreement.
12.2 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 (as described in
Section 13 below), the parties shall permit 30 (thirty) business days
for discussion to
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resolve, if possible, the scientific or technical issue giving rise to
the problem. If the parties fail to resolve the problem within this 30
(thirty) day period, either party shall have the right to terminate
this Agreement, effective upon written notice to the other.
In the event of such a termination initiated by IMCLONE, the amount due
to BI PHARMA KG hereunder shall equal all expenses reasonably incurred
by BI PHARMA KG prior to such termination in respect of the purchase of
supplies or raw materials plus an allocation of the balance of the
Project for the period prior to such termination and for a period of 8
(eight) weeks thereafter. BI PHARMA KG shall cease all work following
notice by IMCLONE of termination, and shall attempt in good faith to
minimize expenses hereunder by, for example, canceling any orders that
can be canceled.
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 (thirty) days after the receipt of
notice identifying the breach, requiring its remedy and stating
the intent of the party to terminate in the absence of 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.
12.3 Effect of Termination.
Upon the expiration or termination of this Agreement:
(a) At the request of IMCLONE, BI PHARMA KG shall deliver at the cost
and risk of IMCLONE all vials of the Cell Line, the MCB and the
MWCB, as well as description of all methods relating thereto to
IMCLONE or its designee and shall promptly return all IMCLONE
Confidential Information to IMCLONE; except for a single copy
and/or sample for documentation purposes only and
(b) IMCLONE 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.
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The respective rights of BI PHARMA KG and IMCLONE to
indemnification as set forth in Sections 9 and 10 above 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 IMCLONE in connection with the
Project that occur prior to termination.
13. MISCELLANEOUS
13.1 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 incurred hereunder prior to Force Majeure) 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.
13.2 Publicity.
Except as required by law (e.g. SEC-requirements), no press release or
other form of publicity regarding the Project or this Agreement shall
be permitted to be published unless both parties have indicated their
consent to the form of the release. Notwithstanding the foregoing,
IMCLONE may elect to issue a press release or other form of publicity
regarding the Project at any time, but shall first notify BI PHARMA KG
of such issuance and provide BI PHARMA KG with an opportunity to
comment thereon. Nothing in this Section 13.2 shall prevent the parties
from disclosing this Agreement as required by applicable laws, rules or
regulations.
13.3. Notices.
Any notice required or permitted to be given hereunder by either party
shall be in writing and shall be (i) delivered personally, (ii) sent
by registered mail, return receipt requested, postage prepaid or (iii)
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 Strasse 65
D-88397 Biberach an der Riss
Federal Republic of Germany
Attention: Dr. Wolfram Carius
Fax: + 0049 73 51/54-98049
Phone + 0049 73 51/54-9421
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If to IMCLONE: ImClone Systems Incorporated
180 Varick Street, 7th Floor
New York, New York 10014
Attention: Mr. John B. Landes,
Vice President,
Business Development and General Counsel
Fax: 001 212 645 1405
Phone: 001 212 645 2054
Each notice shall be deemed given (i) on the date it is received if it
is delivered personally, (ii) 1 (one) day after the date it is
postmarked if it is sent by certified United States mail, return
receipt requested, postage prepaid or (iii) on the date it is received
if it is sent by facsimile with immediate telephonic confirmation of
receipt.
13.4. Applicable Law.
This Agreement shall be governed by and construed in accordance with
the laws of Germany without regard to its choice of law principles. The
courts of the place of domicile of BI PHARMA KG shall have exclusive
jurisdiction over all legal matters and proceedings hereunder.
13.5 Compliance with Laws.
BI PHARMA KG shall perform the work hereunder in conformance with
GLP/cGMP, as applicable, and all German and/or EU laws, ordinances and
governmental rules or regulations pertaining thereto.
13.6. 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 venturers, 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.
13.7. 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.
13.8 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. The parties hereby
agree to attempt to substitute for
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any invalid or unenforceable provision a valid or enforceable provision
which achieves to the greatest extent possible the economic legal and
commercial objectives of the invalid or unenforceable provision.
13.9 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.
13.10 Assignment.
Neither party may assign this Agreement to a third party, except an
affiliate (including a subsidiary or division), and either IMCLONE or
BI PHARMA KG may assign this Agreement in connection with the sale of
all or substantially all of such party's assets or similar transaction.
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.
IN WITNESS WHEREOF, the parties have caused this Agreement to be executed as of
the Effective Date.
Biberach, ...............1999 New York, April 30, 1999
BOEHRINGER INGELHEIM PHARMA KG IMCLONE SYSTEMS INCORPORATED
ppa.
Dr. Jacob Prof. R. G. Werner By: John B. Landes
Member of the Board Head of Industrial
Biopharmaceuticals Title: VP, General Counsel
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APPENDICES:
-----------
Appendix 1: Master Projectplan including Project Timeline
Appendix 1.1: Updated Master Projectplan including Project timeline
Appendix 2: Project Team
Appendix 3: IMCLONE's Tasks in Detail
Appendix 4: BI PHARMA KG's Tasks in Detail
Appendix 5: Test Methods and Specifications for C225
Appendix 6: Protein A Process Format
Appendix 7: Summary Data Reports for Phase I and Phase II
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Appendix 1 Page 1 of 2
-------------------------------------------------------------------------------
Master Projectplan: C225
ImClone Systems, Inc./BI Pharma KG
Forecast of proposed Workscope and Cost Estimate
-------------------------------------------------------------------------------
[ ***]
Appendix 1.1 Page 1 of 4
-------------------------------------------------------------------------------
Update May 1999 Master Projectplan: C225
ImClone Systems, Inc./BI Pharma KG
Forecast of proposed Workscope and Cost Estimate
-------------------------------------------------------------------------------
[ ***]
Appendix 2
-------------------------------------------------------------------------------------------------------------
Function Boehringer Ingelheim ImClone
-------------------------------------------------------------------------------------------------------------
Project Team Leader Dr. Helmut Hoffmann Mr. Ronald Martell (?)
Ms. Martie Bohn
-------------------------------------------------------------------------------------------------------------
Head of Process Development Dr. Helmut Hoffmann (?)
-------------------------------------------------------------------------------------------------------------
Cell Banking and Characterization, Dr. Stefanos Grammatikos Ms. Betsy Hornberger
Virus Testing Dr. Daniel Velez
Dr. S. Joseph Tarnowski
-------------------------------------------------------------------------------------------------------------
Small Scale Cell Culture Labs Dr. Wolfgang Noe Mr. Joel Goldstein
Mr. Rajeew Gupta
Dr. Daniel Velez
Dr. S. Joseph Tarnowski
-------------------------------------------------------------------------------------------------------------
Fermentation Pilot Plant Dr. Ralph Kempken Mr. Joel Goldstein
Mr. Rajeew Gupta
-------------------------------------------------------------------------------------------------------------
Downstream Processing Dr. Joachim Walter Dr. Daniel Velez
Mr. Joel Goldstein
Dr. S. Joseph Tarnowski
-------------------------------------------------------------------------------------------------------------
Protein Analytical Chemistry Dr. Michael Schluter Ms. Betsy Hornberger
-------------------------------------------------------------------------------------------------------------
Process Validation Mr. Norbert Hentschel Mr. Glen Noonan
-------------------------------------------------------------------------------------------------------------
Filling Mr. Hans Hormann Mr. Edward Patten
-------------------------------------------------------------------------------------------------------------
Regulatory Dr. Uwe Bucheler Ms. Gretchen Toolan
-------------------------------------------------------------------------------------------------------------
Documentation Dr. Uwe Bucheler Mr. Edward Patten
-------------------------------------------------------------------------------------------------------------
Quality Assurance Mrs. Bettina Schulz
-------------------------------------------------------------------------------------------------------------
Contract Mrs. Kipping
-------------------------------------------------------------------------------------------------------------
APPENDIX 3
IMCLONE'S TASKS IN DETAILS
[ *** ]
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APPENDIX 4
BI PHARMA KG's Tasks in Detail
[ *** ]
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APPENDIX 5: TEST METHODS AND SPECIFICATIONS FOR C225
[ *** ]
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APPENDIX 6
[ *** ] A Process Format
[***]
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APPENDIX 7
SUMMARY DATA REPORTS FOR PHASE I AND PHASE II
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