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EXHIBIT 10.47
AGREEMENT FOR A DEVELOPMENT PROJECT
TO EXPRESS BR96 ANTIBODY IN
TRANSGENIC GOAT MILK
to be performed by
GENZYME TRANSGENICS CORPORATION
on behalf of
BRISTOL-MYERS SQUIBB COMPANY
2 MARCH 1995
CONFIDENTIAL MATERIALS OMITTED AND FILED SEPARATELY WITH THE
SECURITIES AND EXCHANGE COMMISSION. ASTERISKS DENOTE
SUCH OMISSIONS.
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AGREEMENT
THIS AGREEMENT (the "Agreement") is made on the date of signature below by and
between GENZYME TRANSGENICS CORPORATION ('GTC"), with offices at One Mountain
Road, Framingham, Massachusetts 01701-9322, and BRISTOL-MYERS SQUIBB COMPANY
("BMS"), with offices at Route 206 and Province Line Road, Princeton, New
Jersey 08543.
BACKGROUND
Bristol-Myers Squibb Company "BMS) is a company actively involved in the
development and production of monoclonal antibodies using mammalian cell culture
and other technologies.
BMS believes that some future therapeutic treatments of diseases including
cancers using monoclonal antibodies will be satisfied by recombinantly sourced
antibodies. Consequently, BMS is interested in evaluating technologies providing
recombinantly sourced antibodies, including transgenic technology.
Genzyme Transgenics Corporation (GTC) has expertise in developing transgenic
production processes, beginning with small mammal feasibility studies, and
leading potentially to full scale manufacturing. GTC has successfully expressed
a number of proteins in mice (including monoclonal antibodies) and some of these
in rabbits or goats.
BMS has a monoclonal antibody, BR96, which it conjugates to doxorubicin and the
resulting product, has indication as an anti-cancer tumor therapy, which is
currently in Phase I clinical trials. The antibody is currently produced in
myeloma cells, and was efficacious in animal trials.
BMS is interested in having GTC perform a development project to express the
BR96 monoclonal antibody ("BR96") in transgenic goat milk (the "Project"), nd
GTC is interested in performing such a Project, all in accordance with the terms
and conditions set forth herein.
OBJECTIVE
To produce a number of transgenic founder goats expressing fully processed,
functional BR96 in their milk, at levels which will be economically viable as
production animals and provide the basis for a commercial-scale manufacturing
process.
In this event, BMS will consider a pivotal switch to a transgenically produced
BR96 for continuing clinical trials and large scale manufacturing.
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The success criteria to the project will be met and the project concluded upon
demonstration that founder females, and female progeny of male founders, produce
in the ordinary course mil, containing fully processed, functional BR96 in
concentrations of not less than 0.1 g/l and delivery of reasonable quantities of
examples of such milk to BMS, provided that GTC uses all reasonable efforts to
achieve such criteria within the "Timeline" as hereinafter provided. GTC makes
no guarantee that such success criteria can be attained.
FACT FILE ON BR96
- - BR96 is a human or humanized antibody.
- - BMS can supply either gDNA or cDNA sequences for both heavy
and light chains.
- - BR96 requires correct processing and assembly, and must be
glycosylated to confer bioactivity.
- - The ultimate volume requirements will be in the range of
hundreds of kilograms of BR96 per annum.
- - The final BR96 product will have to be at least 95% pure, with no
single contaminant comprising more than 2% of the total impurity.
GOAT DEVELOPMENT PROJECT OUTLINE
GTC will provide personnel, facilities and resources as required to perform the
Project.
GTC agrees to engineer constructs using two gDNA or cDNA sequences supplied to
GTC by BMS, one sequence coding for the BR96 light chain, and the other for the
heavy chain. These should be supplied by BMS prepared for one step ligation into
GTC's expression vectors. The sequences will be checked and will be inserted
into GTC's B-casein expression vectors.
In the event that the genes supplied by BMS are not suitable for one step
ligation into GTC's expression vectors, GTC shall offer BMS the option of
either: (a) modifying the genes to meet GTC's specified requirement or (b)
having GTC modify the genes to meet GTC's specified requirement. In the event
BMS selects option (b), BMS agrees to pay GTC upon submission of invoices 150%
of GTC's full costs incurred in undertaking this additional work.
These constructs will be either co-injected, or ligated and injected in tandem,
into suitable numbers of goat embryos which would normally be expected to yield
sixty live births, 10% of which GTC would reasonably expect to be transgenic.
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Therefore, GTC would expect to generate six founders transgenic for BR96.
The Project may be extended to include expression of alternative gene sequences
if deemed necessary.
GTC can give no guarantee of generating the desired number of founders, or any
founders at all in the event that the gene or protein derived from it proves to
have lethal or deleterious effects on the goats.
ADDITIONAL ACTIVITIES
As an additional study within this development project, GTC will use best
endeavors to purify BR96 expressed in transgenic goat milk, to greater than 90%
purity, providing that BR96 is successfully expressed in transgenic goat milk as
a result of this program. GTC will use the best technology currently available
to it as a result of its protein purification development work. For the
avoidance of doubt, GTC will not specifically undertake a purification process
development project for BR96 within the scope of this goat development program
and Agreement.
TIMELINE
ACTIVITY OBJECTIVE TIMING
-------- --------- ------
(weeks)
Collection of goat Achieve birth of viable 30
embryos, microinjection of offspring, identify
construct re-implantation transgenic kids.
to recipients, goat
husbandry, estrus to birth
of kids
Husbandry to sexual Pregnancy and birth to 26
maturity, and mating of stimulate production of
transgenic founders to milk in transgenic
non- transgenic mates females. Derive female
offspring from males.
Goat husbandry through Collection of transgenic 30
estrus to birth of milk from female
offspring from transgenic founders, identification
founders. Collection of of transgenic BR96 in
first lactation milk from milk, and determination
female founders. of expression level.
Identification of --
transgenic female 86
offspring from male lines. --
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ACTIVITY OBJECTIVE TIME
-------- --------- ----
(weeks)
Husbandry to sexual Pregnancy and birth to 26
maturity, and mating of stimulate production of
transgenic female milk to determine
offspring from male lines. expression level from
male lines.
Goat husbandry through Collection of transgenic 30
estrus to birth of milk from male line
offspring. Collection of offspring, identification
first lactation milk from of transgenic BR96 in ---
female offspring of male milk, and determination 142
lines. of expression level. ---
TO BE SUPPLIED BY BRISTOL-MYERS SQUIBB
- - gDNA and/or cDNA genes coding for the BR96 light and heavy chains as
determined by BMS, suitable for one step ligation into GTC's B-casein
vectors. Specifically, the genes should be prepared so that they can be
cloned as SalI or XhoI inserts into GTC's B-casein vectors. Also, the
genes should contain no internal SalI, XhoI or NotI sites.
- - Available sequence data and relevant proprietary background
information, for example, is the 5' region optional for high level
expression, or is there a Kozak sequence around the initiating ATG, and
no up stream ATG's.
- - A small amount of BR96 for use as standards in any assays.
- - Assay procedures and reagents useful to GTC for analysis of goat milk
to determine expression level and activity of BR96, as available. ELISA
and Western blotting are commonly used.
- - Any information related to expression of BR96 in tissue culture, and
any other relevant expression information.
CERTAIN RESTRICTIONS
GTC shall not use, nor shall it permit any third party to use, any gDNA, cDNA,
BR96 or other material provided by BMS, or any material derived herefrom, or any
male or female transgenic goat produced hereunder, for any purpose or otherwise
for its own or any third party's benefit, except as contemplated hereby solely
for BMS's benefit.
PAYMENT
In consideration of GTC conducting the Project, BMS will pay GTC as described
below:
(a) BMS will pay GTC a base fee of $ * in three payments
as follows:
(i) $ * upon execution of this Agreement by both
parties.
CONFIDENTIAL MATERIALS OMITTED AND FILED SEPARATELY WITH THE
SECURITIES AND EXCHANGE COMMISSION. ASTERISKS DENOTE SUCH OMISSIONS.
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(ii) $ * upon completion of the micro injection of a
suitable number of goat embryos which would normally be
expected to yield 60 live births, and transfer of such
embryos to recipient female goats.
(iii) $ * upon birth and identification of the first
goat kid transgenic for both heavy and light chain of
BR96 antibody born from the successful transfer of all
embryos injected with BR96 constructs.
(b) in addition, and if applicable, BMS will pay GTC a success
fee as set forth below within thirty (30) days after GTC
demonstrates to BMS the successful coexpression of the
injected BR96 constructs, as follows:
(i) $ * for an expression level equal to or greater
than * , but less than * g/l; or
(ii) $ * for an expression level equal to or greater
than * , but less than * g/l; or
(iii) $ * for an expression level equal to or greater
than * g/l.
For avoidance of doubt, BMS's payment of such success fee is one time only,
under clause A., B., or C., whichever first is demonstrated to be applicable;
"g/l" refers to concentration of fully processed, functional BR96 contained in
milk produced by one or more goats in the ordinary course, as BMS can
independently verify by assaying milk samples provided by GTC.
COMMENCEMENT AND DURATION
At the date of issue of this agreement, GTC would be able to undertake this
Project following signature of the agreement, and beginning in March 1995.
Liter volumes of milk from each founder would be available and supplied to BMS
from approximately 20 months through to 32 months later.
A final report and recommendation of which germ line to pursue for herd
development would be available after 32 months maximum.
GTC shall provide BMS with written interim reports, not less frequently than
semi-annually, on the progress and status of the project hereunder. Upon
reasonable inquiries from time to time, GTC shall also provide oral progress
updates to BMS.
CONFIDENTIAL MATERIALS OMITTED AND FILED SEPARATELY WITH THE SECURITIES AND
EXCHANGE COMMISSION. ASTERISKS DENOTE SUCH OMISSIONS.
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CONFIDENTIALITY
(a) For a period of ten (10) years from the date below, any
Confidential Information (as defined below) disclosed by the
disclosing party, directly or indirectly, to the receiving
party, or developed by GTC in the course of the project
hereunder (with respect to which GTC will be deemed to be
the receiving party) shall be deemed confidential, and shall
not be disclosed by the receiving party to third parties,
except as set forth below. Access to such Confidential
Information will be limited to employees, agents, Affiliates
(as defined below), consultants or contractors of the
receiving party who reasonably require such Confidential
Information for the purpose of this Agreement and who are
bound to the receiving party by similar obligations in
respect of confidentiality and use. The receiving party
will use such Confidential Information only to carry out its
obligations or to exercise its rights hereunder and will not
use such Confidential Information for its own benefit or for
the benefit of others or in any way inconsistent with this
Agreement.
(b) Nothing contained herein will in any way restrict or impair each
party's right to use, disclose or otherwise deal with any Confidential
Information which:
(i) at the time of disclosure, is in the public domain;
(ii) after disclosure, becomes part of the public domain by
publication or otherwise, except by breach of this
Agreement by the receiving party;
(iii) was demonstrably in the receiving party's possession at the
time of such disclosure, and which was not acquired, directly
or indirectly, from the disclosing party;
(iv) the receiving party receives from third parties, provided such
Confidential Information was not obtained by such third
parties, directly or indirectly, from the disclosing party on
a confidential basis;
(v) results from research and development of the receiving
party demonstrably independent of such disclosure;
(vi) is required to be disclosed by legal process; provided,
however, in each case the party so disclosing Confidential
Information timely informs the other party and uses its best
efforts to limit the disclosure and maintain confidentiality
to the extent possible and permits the other party to attempt
by appropriate legal means to limit such disclosure; and
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(vii) the disclosing party identifies in writing as being for public
disclosure.
(c) For purposes of this Agreement, the term "Confidential Information"
shall mean all of the data,information, technology, samples, gDNA,
cDNA, specimens, material and any other information affecting the
business operations of the disclosing party received by the receiving
party from the disclosing party and data, results and information
developed by GTC in the course of the project hereunder.
(d) For purposes of this Agreement, the term "Affiliate" shall mean any
corporation which controls, is controlled by or is under common control
with a party hereto.
A corporation shall be regarded as in control of another corporation if
it owns or directly or indirectly controls at least fifty-one percent
(51%) of the voting stock of the other corporation, or in the absence
of the ownership of at least fifty-one percent (51%) of the voting
stock, if it possesses, directly or indirectly, the power to direct or
cause the direction of the management and policies of the corporation.
(e) The receiving party hereunder will obtain no right or license of any
other intellectual property rights by reason of this Agreement except
as otherwise expressly set forth in this Agreement.
(f) Upon execution of this Agreement, any existing Confidentiality
Agreement between the parties shall be superseded by this
Confidentiality clause.
PUBLICATION
Any publication arising from this Project would be only to the extent agreed
between the parties. Consent not to be unreasonably withheld.
GTC agrees that no publication or presentation shall contain Confidential
Information with respect to which it has confidentiality obligations pursuant to
the Confidentiality clause of this Agreement.
OWNERSHIP OF INTELLECTUAL PROPERTY
(a) BMS shall own the transgenic founder goats which express BR96 in their
milk, together with the transgenic male goats, and which may at BMS
option and expense; continue to be maintained by GTC or; may be
delivered to BMS by GTC as well as the milk produced by such goats, and
BMS may only use such goats and the milk produced from such goats in
any continued production development program, and not for commercial
proposes, unless BMS negotiates a license to GTC's proprietary
technology
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outwith this Agreement. BMS shall also continue to own all information
and materials delivered by BMS to GTC, and may use such information and
materials for any purpose whatsoever, and GTC shall have no rights to
use such information and materials outside of this Project.
(b) GTC shall retain ownership of the GTC B-casein expression vectors and
GTC's intellectual property relating to production of proteins in
transgenic animals.
TERMINATION
Either party may terminate this collaboration in the event of a material breach
by the other party of the terms of this agreement, provided the nondefaulting
party gives written notice of the proposed termination to the defaulting party,
specifying the grounds, and the defaulting party will have thirty (30) days to
cure the breach, or this agreement will terminate on the thirtieth day. In this
event, invoices will be issued for work undertaken up to the termination date,
not already paid for. Such invoices will be settled under the normal terms. BMS
may also at any time, upon thirty (30) days' written notice to GTC, terminate
this Agreement. Upon receipt of such notice, GTC shall immediately cease
incurring, to the extent practicable, any additional cost or expense in
connection with the project hereunder.
Upon any termination (other than termination by GTC by reason of BMS's breach
hereof), GTC shall refund to BMS any amount theretofore received from BMS to the
extent in excess of a reasonably prorated fee for the amount of work performed
by GTC through the time of termination. In the event of termination in all
cases, GTC will return all material belonging to BMS.
FURTHER DEVELOPMENT PROJECTS AND OBLIGATIONS
GTC may have the ultimate objective of manufacturing BR96 for BMS in large
animals in some form of supply agreement, the terms and conditions of which
would be worked out. If the Project is deemed successful, and BMS decides to
continue with the development of a transgenic animal manufacturing process for
BR96, the parties agree to commence in good faith negotiations in an effort to
reach agreement for GTC to manufacture BR96 and supply it to BMS at agreed
specifications and price. GTC and BMS undertake to use good faith efforts to
reach fair and reasonable terms for such an agreement, it being understood that
neither party shall be obligated to enter into such an agreement.
INFRINGEMENT OF THIRD-PARTY PATENTS
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(a) GTC warrants that it shall not knowingly infringe any existing
third-party patents or other intellectual property rights of any third
party relating to the transgenic expression vectors and the process
used in connection with the Project.
(b) BMS warrants that it shall not knowingly infringe any existing
third-party patents or other intellectual property rights of any third
party relating to the BR96 genes supplied by BMS hereunder and used in
connection with the Project.
INDEMNIFICATION
(a) Subject to compliance by the applicable Indemnitee as defined below
with its obligations set forth in Sections (d) and (e) hereof, GTC
shall defend, indemnify and hold BMS and its affiliates and the
respective directors, officers, employees and agents of BMS and its
affiliates,harmless from and against any and all damages, losses,
liabilities, claims, costs and expenses, including reasonable
attorneys' fees (collectively the "Losses"), arising out of, relating
to or resulting from the breach by GTC of any of its representations,
warranties and covenants contained within this Agreement.
(b) Subject to compliance by the applicable Indemnitee as defined below
with its obligations set forth in Sections (d) and (e) hereof, BMS
shall defend, indemnify and hold GTC, its affiliates and the respective
directors, officers, employees and agents of GTC and its affiliates,
harmless from and against any and all losses arising out of, relating
to or resulting from the breach by BMS of any of its representations,
warranties and covenants contained within this Agreement.
(c) "Indemnitor" means GTC with respect to Section (a) hereof and BMS with
respect to Section (b) hereof. "Indemnitee" means any of BMS and its
affiliates and the respective directors, officers, employees and agents
of BMS with respect to Section (a) hereof and any of GTC and the
respective directors, and agents of GTC and its affiliates with respect
to Section (b) hereof.
(d) Notice, Promptly after receipt by an Indemnitee of written notice of
the commencement of any suit, audit, demand, judgment, action,
investigation or proceeding relating to a Loss (a "Third Party
Action"), or promptly after an Indemnitee incurs a Loss or has
knowledge of the existence of a Loss, such Indemnitee will, if a claim
with respect thereto is to be made against Indemnitor due to
Indemnitor's obligation to provide indemnification hereunder, give
Indemnitor written notice of such Loss or the commencement of such
Third Party Action; provided, however, the failure to provide such
notice within a reasonable period of time shall not relieve Indemnitor
of any of its obligations hereunder except to he extent it is
prejudiced by such failure.
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(e) Defense. Indemnitor shall control the defense and settlement of a Third
Party Action, except that the applicable Indemnitee may assume such
defense provided that the obligation of Indemnitor to pay the
attorney's fees of such Indemnitee shall cease upon such election.
Indemnitor shall not enter into any resolution or other compromise of
such Third Party Action unless it (i) pays in cash or posts an adequate
bond for the payment of the amount of such resolution or other
compromise and obtains a complete release of the Indemnitee or (ii)
obtains the prior written consent of the Indemnitee, which shall not be
unreasonably withheld or delayed. If the Indemnitee defends such Third
Party Action, such Indemnitee shall not enter into any resolution or
other compromise of such Third Party Action unless such Indemnitee
obtains the prior written consent of Indemnitor, which shall not be
unreasonably withheld or delayed. The party defending the Third Party
Action shall keep the other party informed on an ongoing basis of the
status of such Third Party Action and shall deliver to such other party
copies of all documents relating to the Third Party Action as the other
party may reasonably request. The party assuming such defense shall
receive from the other party all necessary and reasonable cooperation
in the defense of a Third Party Action, including, but not limited to,
the services of employees of such other party who are familiar with the
events or circumstances out of which any such Third Party Action may
have arisen.
GOOD LABORATORY PRACTICES
GTC shall conduct the Project in conformance with the current state of
laboratory research art and in compliance with all laws, ordinances and
governmental rules or regulations pertaining thereto.
ASSIGNABILITY
Neither this Agreement nor any right or obligation hereunder shall be assignable
by GTC without the prior written consent of BMS, and any purported assignment
without such consent shall be void.
INDEPENDENT CONTRACTORS
The relationship of the parties hereto is that of independent contractors and
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.
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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.
CONTINUING OBLIGATION
The termination or expiration of this Agreement shall not relieve either party
of its obligations to the other party in respect of (a) the confidentiality or
use of Confidential Information, (b) the parties' respective indemnification
obligations described hereof and (c) any publication or presentation relating to
the Project described hereof.
TERMS OF CONDITIONS
GTC will be bound to the terms of this proposal, including the cost to BMS for a
period t least up until 20 March 1995. Both parties cause this Agreement to be
executed in duplicate by their representatives duly authorized as of the date
below.
Accepted on behalf of Bristol-Myers Squibb
Name /s/ MARILYN HARTIG Date 28-3-95
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Designation VP-External Science and Technology
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Accepted on behalf of Genzyme Transgenics Corporation
Name /s/ Steve Parkinson Date 10-3-95
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Designation Commercial Director
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