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EXHIBIT 10.3
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Portions of this Exhibit 10.3 have been redacted and are the subject of a
confidential treatment request filed with the Secretary of the Securities and
Exchange Commission.
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Exhibit 10.3
Conformed Copy
As Executed on March 5, 1993
COLLABORATIVE RESEARCH AGREEMENT
This COLLABORATIVE RESEARCH AGREEMENT is entered into as of January 4,
1993 by and between HOECHST AKTIENGESELLSCHAFT ("HOECHST"), a German company
with the address of Bruningstrasse 50, Postfach 80 03 20, D-6230 Frankfurt am
Main 80, Germany and ONCOGENE SCIENCE, INC. ("OSI"), a Delaware corporation
having an office at 106 Charles Lindbergh Boulevard, Uniondale, New York 11553.
WHEREAS, OSI was organized to develop, produce and market therapeutic
and diagnostic products for, among other things, the early detection, monitoring
and treatment of human disease; and
WHEREAS, HOECHST has the capability to undertake research for the
discovery and evaluation of agents for treatment of disease and also the
capability for clinical analysis, manufacturing and marketing of such agents;
and
WHEREAS, HOECHST and OSI wish to pursue the research described in this
Agreement;
NOW, THEREFORE, the parties agree as follows:
1. Definitions
Whenever used in this Agreement, the terms defined in this Section 1
shall have the meanings specified.
1.1 "Affiliate" means any entity of which the party in
question, directly or indirectly, owns thirty percent or more of the equity
capital. Unless the context otherwise
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requires, the rights granted under the Agreement shall extend to any Affiliate,
provided, however, that the other party hereto is notified in writing of the
identity and participation of such Affiliate and further provided that such
Affiliate shall observe the relevant provisions of this Agreement.
1.2 "Allocated Overhead" means the amount of overhead,
including general and administrative costs, determined in accordance with
generally accepted accounting principles, incurred by OSI and allocated to the
Sponsored Research Program in the same proportion that the total man-hours of
work performed in the Sponsored Research Program bears to the total man-hours of
work performed in all OSI research programs, or such other customary allocation
basis that may be agreed in writing between the parties.
1.3 "Annual Research Plan" means the written plan describing
the annual research and budgets concerning the Target Proteins to be carried out
during each Commitment Year by HOECHST and OSI pursuant to this Agreement,
including both the Annual Sponsored Research Plan to be carried out by OSI and
the specific Projects, timetables and technical goals to be pursued by HOECHST
and OSI.
1.4 "Annual Sponsored Research Plan" means the written plan
describing the research concerning the Target Proteins to be carried out during
each Commitment Year by OSI pursuant to this Agreement, including the specific
Projects, timetables and technical goals to be pursued by OSI.
1.5 "Base Program" means the Research Program as described in
the Annual Research Plan.
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1.6 "HOECHST Confidential Information" means all information
about any element of HOECHST Technology which is disclosed by HOECHST to OSI and
designated "Confidential" in writing by HOECHST at the time of disclosure to OSI
to the extent that such information as of the date of disclosure to OSI is not
(i) known to OSI other than by virtue of a prior confidential disclosure to OSI
by HOECHST, (ii) disclosed in the published literature, or otherwise generally
known to the public, or (iii) obtained from a third party free from any
obligation of secrecy; provided, however, that such third party has no
obligation of confidentiality to OSI.
1.7 "OSI Confidential Information" means all information about
any element of OSI Technology which is disclosed by OSI to HOECHST and
designated "Confidential" in writing by OSI at the time of disclosure to HOECHST
to the extent that such information as of the date of disclosure to HOECHST is
not (i) known to HOECHST other than by virtue of a prior confidential disclosure
to HOECHST by OSI, (ii) disclosed in the published literature, or otherwise
generally known to the public, or (iii) obtained from a third party free from
any obligation of secrecy; provided, however, that such third party has no
obligation or confidentiality to HOECHST.
1.8 "Commitment Year" means a twelve-month period terminating
on each anniversary of the Effective Date.
1.9 "Contract Period" means the period beginning on the
Effective Date and ending on the date on which this Agreement terminates.
1.10 "Effective Date" is January 4, 1993.
1.11 "Event of Termination" has the meaning set forth in
Section 8.3.
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1.12 "Funding Payments" has the meaning set forth in Section
3.
1.13 "Human Therapeutic Product" means any product for the
treatment or management of any disease state in a human patient or any other
human therapeutic indication derived from the Research Program in the course of
research concerning a Target Protein.
1.14 "Diagnostic Product" means any product useful for the
identification or quantification of the propensity toward or actual existence of
any disease state in a human patient or any other human diagnostic utility
identified in the course of the Research Program.
1.15 "Licensed Human Therapeutic Product" means a Human
Therapeutic Product that employs OSI Patent Rights, HOECHST Patent Rights, OSI
Technology or HOECHST Technology in its manufacture, use or sale.
1.16 "HOECHST Patent Rights" shall mean all applications for
letters patent, whether domestic or foreign, which are encompassed within
HOECHST Technology, including all continuations, continuations-in-part,
divisions, renewals and patents and additions thereof, all letters patent
granted thereon, and all reissues and extensions thereof.
1.17 "OSI Patent Rights" shall mean all applications for
letters patent, whether domestic or foreign, which are encompassed within OSI
Technology, including all continuations, continuations-in-part, divisions,
renewals and patents and additions thereof, all letters patent granted thereon,
and all reissues and extensions thereof.
1.18 "Person" means any individual, estate, trust,
partnership, joint venture, association, firm, corporation, company, or other
entity.
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1.19 "Project" means each of those projects set forth in the
table of contents of an Annual Research Plan adopted pursuant to this Agreement.
1.20 "Target Protein(s)" means each of those proteins
identified as a drug development target in the Annual Sponsored Research Plan
towards which research projects will be conducted to identify lead compounds
from which transcription based drugs may be developed or derived, including all
therapeutic indications identified in the course of such research projects.
1.21 "Technology" means and includes all technology and
technical information that pertains to the development of Human Therapeutic
Products and Diagnostic Products derived from the Research Program.
1.22 "HOECHST Technology" means Technology developed through
the use of OSI Technology that pertains to a Target Protein and relates to
specific chemical compounds or drugs or the therapeutic use(s) of such compounds
or drugs, that is or was:
(a) developed by employees of, or consultants to, HOECHST
alone or jointly with third parties including OSI; or
(b) acquired by purchase, license, assignment or other
means from third parties by HOECHST.
1.23 "OSI Technology" means all Technology that pertains to a
Target Protein and relates to transcriptional modulation of gene expression of
the gene encoding the Target Protein, including all improvements thereto and the
use of such Technology to develop transcription-based drugs, that is or was:
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(c) developed by employees of, or consultants to, OSI
alone or jointly with third parties including HOECHST; or
(d) acquired by purchase, license, assignment or other
means from third parties by OSI. OSI Technology shall include all such
Technology other than HOECHST Technology.
1.24 "Research Committee" has the meaning specified in Section
2.2.
1.25 "Research Program" is the collaborative research program
concerning the Target Proteins conducted by HOECHST and OSI.
1.26 "Sponsored Research Program" is that part of the Research
Program that is to be carried out by OSI.
1.27 "Valid Claim" means a claim within OSI Patent Rights or
HOECHST Patent Rights so long as such claim shall not have been disclaimed by
HOECHST or OSI, whichever is appropriate, or shall not have been held invalid in
a final decision rendered by a tribunal of competent jurisdiction from which no
appeal has been or can be taken.
1.28 "OSI Human Therapeutic Product" means any product for the
treatment or management of any disease state in a human patient developed as a
proprietary drug by OSI and derived from a HOECHST compound, in accordance with
Section 2.3.2(b).
2. Collaborative Research Program
2.1.1 Purpose. OSI and HOECHST shall conduct a collaborative
Research Program concerning the Target Proteins throughout the Contract Period.
The objectives of the Research Program are to discover Human Therapeutic
Products.
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2.1.2 Annual Research Plan. The Annual Research Plan for the
first Commitment Year is described in Appendix I hereto. For each Commitment
Year after the first Commitment Year, the Annual Research Plan shall be prepared
by the Research Committee for submission to, and approval by, HOECHST and OSI no
later than ninety (90) days before the end of the prior Commitment Year. If
HOECHST and OSI cannot agree on the Annual Research Plan or Annual Sponsored
Research Plan, OSI shall determine its content. The Annual Research Plan and the
Annual Sponsored Research Plan for each Commitment Year shall be appended to and
made part of this Agreement.
2.1.3 Exclusivity.
(a) OSI agrees that during the Contract Period neither OSI
nor any of its Affiliates shall conduct research itself or sponsor any other
research, or engage in any research sponsored by any Person not a party to this
Agreement, if the objectives of such research are the discovery and development
of novel Human Therapeutic Products against the Target Proteins unless agreed to
by the Research Committee. If OSI becomes aware during the Contract Period of an
opportunity to sponsor other research having any of the objectives of the
Research Program or to engage in such research sponsored by a Person that is not
a party to this Agreement, it shall promptly notify HOECHST of such opportunity.
HOECHST and OSI shall then negotiate in good faith for a period of one hundred
twenty (120) days an agreement by which such opportunity can be incorporated
into the Research Program or otherwise used to further the purposes of the
Research Program to their mutual advantage. If at the end of the one hundred
twenty (120) day period, the parties have not reached
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agreement, OSI shall be free to pursue such opportunity with a third party
without further obligation to HOECHST.
(b) HOECHST agrees that during the Contract Period neither
HOECHST nor any of its Affiliates shall sponsor any other research, or engage in
any research sponsored by any Person not a Party to this Agreement using the
gene transcription methods described in the Research Plan, if the objectives of
such research are the discovery of novel Human Therapeutic Products; provided,
however, that, if HOECHST becomes aware during the Contract Period of an
opportunity to sponsor other research having any of the objectives of the
Research Program or to engage in such research sponsored by a Person that is not
a party to this Agreement, it shall promptly notify OSI of such opportunity.
HOECHST and OSI shall then negotiate in good faith for period of one hundred
twenty (120) days an agreement by which such opportunity can be incorporated
into the Research Program or otherwise used to further the purposes of the
Research Program to their mutual advantage. If at the end of the one hundred
twenty (120) day period, the parties have not reached agreement, HOECHST shall
be free to pursue such opportunity with a third party without further obligation
to OSI.
2.2 Research Committee
2.2.1 Purpose. A research committee shall be established (the
"Research Committee") by HOECHST and OSI for the following purposes:
(a) to review and evaluate progress under each Annual
Research Plan;
(b) to prepare the Annual Research Plan for each Commitment
Year; and
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(c) to coordinate and monitor publication of research
results obtained from the exchange of information and materials that relate to
the Research Program.
(d) to make priority and program decisions.
2.2.2 Membership. HOECHST and OSI each shall appoint, in its
sole discretion, four members to the Research Committee. Substitutes may be
appointed at any time.
The initial members shall be:
OSI Appointees: ***
***
***
HOECHST Appointees: ***
***
2.2.3 Chair. The Research Committee shall be chaired by two
co-chairpersons, one appointed by HOECHST and the other appointed by OSI.
2.2.4 Meetings. The Research Committee shall meet at least
three times a year, at places and on dates selected by each party in turn. Other
representatives of HOECHST or OSI or both, in addition to the members of the
Research Committee, may attend such meetings at the invitation of both parties.
*** These portions deleted pursuant to a request for confidential treatment.
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2.2.5 Minutes. The Research Committee shall keep accurate
minutes of its deliberations which record all proposed decisions and all actions
recommended or taken. The minutes shall be delivered to all Research Committee
members within five working days after each meeting. The party hosting the
meeting shall be responsible for the preparation of the minutes. Draft minutes
shall be edited by the co-chairpersons and shall be issued in final form only
with their approval and agreement.
2.2.6 Decisions. Subject to the provisions of 2.1.2, all
technical decisions of the Research Committee shall be made by a majority of its
members.
2.2.7 Expenses. HOECHST and OSI shall each bear all expenses
of their respective members related to their participation on the Research
Committee.
2.3 Reports and Materials
2.3.1 Reports. During the Contract Period, HOECHST and OSI
each shall furnish to the Research Committee:
(a) summary reports within fifteen (15) days after the
end of each three-month period, commencing on the Effective Date, describing its
progress under the Annual Research Plan; and
(b) comprehensive written reports within thirty (30)
days after the end of each Commitment Year, describing in detail the work
accomplished by it under the Annual Research Plan during the Commitment Year and
discussing and evaluating the results of such work.
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2.3.2 Materials.
(a) OSI and HOECHST shall, during the Contract Period as
a matter of course as described in the Annual Research Plan or upon each other's
oral or written request, furnish to each other samples of biochemical,
biological or synthetic chemical materials which are part of either OSI or
HOECHST Technology and which are necessary for each party to carry out its
responsibilities under the Annual Research Plan. To the extent that the
quantities of materials requested by either party exceed the quantities set
forth in the Annual Research Plan, the requesting party shall reimburse the
other party for the reasonable costs of such materials if they are furnished.
(b) HOECHST agrees that OSI may test the compounds
furnished by HOECHST for screening in the Research Program against OSI's
proprietary drug assays, provided that OSI identifies such proprietary assays to
HOECHST and HOECHST gives its consent in writing which consent shall not
unreasonably be withheld, and OSI agrees to pay royalties or extend other rights
to HOECHST as hereinafter provided.
(c) OSI shall not analyze the test compounds provided by
HOECHST with respect to composition or structure without prior written consent
of HOECHST.
2.4 Laboratory Facilities and Personnel. OSI shall provide
suitable laboratory facilities, equipment and personnel for the work to be done
by OSI in carrying out the Annual Sponsored Research Plan.
2.5 Diligent Efforts. HOECHST and OSI each shall use
reasonably diligent efforts to achieve the objectives of the Research Program.
OSI will use reasonably diligent
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efforts to achieve the objectives listed in the Annual Research Plan (Appendix
I) and HOECHST will use reasonably diligent efforts to assist OSI in the pursuit
of those objectives. To achieve the objectives of the Research Program, HOECHST
will specifically use diligent efforts:
(a) to advance the pharmacological assessment of
compounds identified by OSI or HOECHST in order to select those worthy of
further investigation;
(b) to determine the chemical structure of the selected
compounds and to make related compounds to determine the relationship between
structure and activity and to identify potential development candidates;
(c) to select development candidates; and
(d) to develop manufacturing methods and pharmaceutical
formulations for those selected candidates.
Furthermore, HOECHST will try to assess safety and efficacy of the
selected development candidates in animals and in human patients under
conditions designed to yield data suitable for inclusion in approval
applications to be submitted to the U.S. Food and Drug Administration and
other appropriate authorities.
3. Funding of the Sponsored Research Program.
3.1 Base Funding Payments. The funding obligations of OSI
and HOECHST for each Commitment Year (the "Base Funding Payments") shall be as
follows:
(a) OSI agrees to pay for the fully-weighted costs of
the Base Program tasks assigned to it, which are expected to cost a total of
*** over the ***
***These portions deleted pursuant to a request for confidential treatment.
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*** of the program, plus any supplementary program or additional costs
which may be mutually agreed upon by HOECHST and OSI, including the extra costs
of screening more than *** assumed in the Base Program, in
accordance with Section 3.2 below. Additional HOECHST compounds will be screened
by OSI at a cost of ***.
(b) HOECHST agrees to make Base Funding Payments to
reimburse OSI for the Base Program in accordance with the following commitment
schedule (the "Funding Schedule"):
HOECHST TOTAL HOECHST
OSI HOECHST R&D REIMBURSEMENT PAYMENT
($millions) CONTRIBUTION SUPPORT TO OSI TO OSI
- ----------- ------------ ------- ------ ------
Year 1 *** *** *** ***
Year 2 *** *** *** ***
Year 3 *** $ *** $ *** $ ***
Year 4 *** *** *** ***
Year 5 *** *** *** ***
Year 6 *** *** *** ***
------- ------ -------- ---------
Total $ *** $ *** $ *** $ ***
- ------------------------------
* includes cost of screening ***
3.2 Supplementary Funding Payments. In addition to the Base
Funding Payments, HOECHST agrees to reimburse OSI for any supplementary program
or other additional amounts which may be mutually agreed upon in advance as
follows ("Supplementary Funding Payments"):
***These portions deleted pursuant to a request for confidential treatment.
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(a) HOECHST agrees to reimburse OSI for the fully-weighted
costs of screening compounds provided by HOECHST in excess of *** compounds;
and
(b) HOECHST agrees to reimburse OSI for the cost of work
performed on any additional Target Proteins or cell-lines (all of which must be
approved by OSI and HOECHST in advance) or other additional tasks as
contemplated by this Agreement or which may be recommended by the Research
Committee.
3.3 Timing of Payments.
3.3.1 Timing: Base Payments. All Base Funding Payments by
HOECHST for the Base Program shall be made in accordance with the Funding
Schedule shown in Section 3.1(b) at the beginning of the year set forth.
3.3.2 Timing: Supplementary Payments.
(a) All Supplementary Funding Payments by HOECHST for
supplementary programs or approved additional costs shall be made quarterly in
advance for work scheduled to be performed by OSI during the upcoming three (3)
month period, against OSI's invoice for such three (3) month period. Adjustments
as necessary to reflect the work actually performed by OSI shall be made at the
end of each three (3) month period and shall be reflected in OSI's invoice for
the next three (3) month period.
(b) The amount of any Supplementary Funding Payment for
each quarter shall be based on the work in progress pursuant to any applicable
supplementary research agreement and the annual budget associated therewith.
(c) Each Supplementary Funding Payment shall be paid on
the first day of the quarter or thirty (30) days after receipt of invoice,
whichever is later.
*** These portions deleted pursuant to a request for confidential treatment.
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3.4 Books and Records. OSI shall keep for three (3) years
from the expiration of this Agreement complete and accurate records of its
expenditures of Funding Payments received by it. The records shall conform to
good accounting principles as applied to a similar company similarly situated.
HOECHST shall have the right at its own expense during the term of this
Agreement and during the subsequent three-year period to appoint an independent
certified public accountant reasonably acceptable to OSI to inspect said records
to verify the accuracy of such expenditures, pursuant to each Annual Sponsored
Research Plan. OSI shall make its records available for inspection by the
independent certified public accountant during regular business hours at the
place or places where such records are customarily kept, upon reasonable notice
from HOECHST to the extent reasonably necessary to verify the accuracy of the
expenditures and required reports. This right of inspection shall not be
exercised more than once in any calendar year and not more than once with
respect to records covering any specific period of time. HOECHST agrees to hold
in strict confidence all information concerning such expenditures, other than
their total amounts, and all information learned in the course of any audit or
inspection, except to the extent that it is necessary for HOECHST to reveal the
information in order to enforce any rights it may have pursuant to this
Agreement or if disclosure is required by law. The failure of HOECHST to request
verification of any expenditures before or during the three-year period shall be
considered acceptance of the accuracy of such expenditures, and OSI shall have
no obligation to maintain any records pertaining to such report or statement
beyond the three-year period.
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4. Treatment of Confidential Information.
4.1.1 Confidentiality. HOECHST and OSI recognize that the OSI
and HOECHST Confidential Information constitutes highly valuable, proprietary,
confidential information. Subject to the terms and conditions of the Secrecy
Agreement dated June 28, 1991, the Supplementary Secrecy Agreement dated May 19,
1992, the disclosure obligations set forth in Section 4.3 and 4.4 hereof and the
publication rights set forth in Section 4.2 hereof, HOECHST and OSI each agree
that during the term of this Agreement and for five (5) years thereafter, they
will keep confidential, and will cause their Affiliates to keep confidential,
all Confidential Information that is disclosed to them or to any of their
Affiliates pursuant to this Agreement. Neither HOECHST nor OSI nor any of their
Affiliates shall use such Confidential Information except as expressly permitted
in this Agreement.
4.1.2 Disclosure of Confidential Information. HOECHST and OSI
acknowledge that the HOECHST and OSI Confidential Information is highly
valuable, proprietary, confidential information, and agree that any disclosure
of Confidential Information to any officer, employee or agent of the other or of
any of its Affiliates shall be made only if and to the extent necessary to carry
out its responsibilities under this Agreement and shall be limited to the
maximum extent possible consistent with such responsibilities. They agree not to
disclose the other's Confidential Information to any third parties under any
circumstance without written permission. Both parties shall take such action,
and shall cause its Affiliates to take such action, to preserve the
confidentiality of each other's Confidential Information as they would
customarily take to preserve the confidentiality of their own Confidential
Information. Each party, upon the other's request, will return all the
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Confidential Information disclosed pursuant to this Agreement including all
copies, and extracts, of documents within 60 days of the request after the
termination of this Agreement.
4.1.3 Employees and Consultants. OSI represents that all of
its employees participating in the Research Program who shall have access to
HOECHST Technology and HOECHST Confidential Information are bound by agreement
to maintain such information in confidence. Consultants will be similarly bound.
4.2 Publication. Section 4.1 to the contrary
notwithstanding, the results obtained in the course of the Research Program may
be submitted for publication following scientific review by the Research
Comittee and subsequent approval by the management of OSI and HOECHST,
respectively. After receipt of the proposed publication by both HOECHST's and
OSI's managements, written approval or disapproval shall be provided within 30
days for a manuscript, an abstract for presentation at, or inclusion in the
proceedings of, a scientific meeting, or a transcript of an oral presentation to
be given at a scientific meeting.
4.3 Publicity. Except as required by law, neither party may
disclose the existence of this Agreement or the research described in it without
the written consent of the other party, which consent shall not be unreasonably
withheld.
4.4 Disclosure of Inventions. Each party hereto shall
promptly inform the other about all inventions concerning the Target Proteins
that are conceived, made or developed in the course of carrying out the Research
Program by employees of, or consultants to, either of them, whether such
inventions were conceived, made or developed solely or jointly with employees
of, or consultants to, the other. This Agreement shall not be
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construed to obligate either party to disclose to the other any invention which
does not concern the Target Proteins.
4.5 Restrictions on Transferring Materials. HOECHST and OSI
recognize that the biological and biochemical materials which are part of OSI
Technology and HOECHST Technology represent valuable commercial assets.
Therefore, throughout the Contract Period and for five (5) years thereafter, OSI
and HOECHST each agree not to transfer to any third party any such compound or
material which constitutes Technology owned solely by the other party unless
agreed to by the Research Committee. Additionally, throughout the Contract
Period and for six (6) months thereafter, OSI and HOECHST each agree not to
transfer to any third party any such compound or material which constitutes
Technology owned solely by it, unless prior consent for any such transfer is
obtained from the other, which consent shall not be unreasonably withheld, and
unless such third party agrees as a condition of any such transfer not to
transfer the material further.
5. Intellectual Property Rights.
5.1 Ownership. All OSI Technology and OSI Patent Rights
shall be owned solely by OSI regardless of whether such OSI Technology or OSI
Patent Rights are developed, conceived, discovered, or invented by employees of,
or consultants to, OSI solely or jointly with employees of, or consultants to,
HOECHST. All HOECHST Technology and HOECHST Patent Rights shall be owned solely
by HOECHST regardless of whether such HOECHST Technology or HOECHST Patent
Rights are developed, conceived, discovered, or invented by employees of, or
consultants to, HOECHST solely or jointly with employees of, or consultants to,
OSI.
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5.2 Filing, Prosecution and Maintenance of Patent Rights.
Subject to Sections 5.3, 5.4 and 5.5 below, OSI shall have the exclusive right,
at its expense and in its sole discretion to file, prosecute, defend, enforce,
and maintain OSI Patent Rights. HOECHST shall have the exclusive right, at its
expense and in its sole discretion to file, prosecute, defend, enforce and
maintain HOECHST Patent Rights.
5.3 Filing, Prosection and Maintenance of Patents Resulting
from the Research Program. OSI and HOECHST will discuss and decide jointly,
which party will have the right and obligation to file patent applications on
behalf of OSI or HOECHST, as applicable, on any patentable invention developed
by either OSI or HOECHST during the Contract Period relating to the Target
Proteins. Both parties will consult with each other regarding countries in which
such patent applications should be filed. The filing party will file patent
applications in those countries where the other party requests to file patent
applications. The filing party will have to prosecute all patent applications
relating to Contract Period Inventions and to respond to oppositions filed by
third parties. The filing party will have to maintain in force any letters
patent relating to Contract Period Inventions. The filing party will notify the
other party in a timely manner of any decision to abandon a pending patent
application relating to a Contract Period Invention or an issued patent relating
to a Contract Period Invention. Thereafter the other party shall have the
option, at its expense, of continuing to prosecute any such pending patent
application or of keeping the issued patent in force.
5.4 Status Reports. The filing party shall provide to the
other party copies of all patent applications relating to Contract Period
Inventions immediately after filing. The
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filing party shall also provide to the other party copies of important documents
relating to prosecution of all such patent applications in a timely manner.
5.5 Reimbursement of Costs for Filing, Prosecuting and
Maintaining Certain Patents. The filing party will be reimbursed for the costs
of filing, prosecuting and maintaining all patent applications and all patents
which relate to Contract Period Inventions in countries where the other party
requests that such patent applications be filed, prosecuted and maintained, upon
receipt of invoices from the filing party. Such reimbursement shall be in
addition to Funding Payments and Supplementary Funding Payments pursuant to
Section 3 hereof. However, the other party may, upon 90 days advance written
notice, discontinue reimbursing the filing party for the cost of filing,
prosecuting or maintaining any patent application or any patent in any country.
The filing party shall pay all costs in those countries in which the other party
does not request that the filing party file, prosecute or maintain patent
applications and patents which relate to Contract Period Inventions, but in
which the filing party, at its option, elects to do so.
6. Other Rights of the Parties. During the Contract Period, OSI
and HOECHST shall promptly notify each other in writing of any and all
opportunities to acquire in any manner from third parties, technology or patents
which may be useful in, or may relate to, the Research Program. OSI and HOECHST
shall decide if such rights should be acquired and, if so, whether by OSI or
HOECHST. If acquired, such rights shall become OSI Technology or HOECHST
Technology, as appropriate.
7. Option for License. Upon request of either party to this
Agreement, OSI and HOECHST will enter into negotiations with respect to a
license agreement pursuant to which
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HOECHST would acquire an exclusive, worldwide license, including the right to
grant sublicenses, to make, use and sell Licensed Human Therapeutic Products,
and OSI would acquire the exclusive, worldwide, perpetual license, including the
right to grant sublicenses, to make, use and sell Diagnostic Products, products
sold exclusively for research purposes and OSI Human Therapeutic Products
(derived from HOECHST compounds) under all HOECHST'S right, title and interest
in HOECHST Technology. The option hereinabove provided for will commence with
the Effective Date and expire four (4) years after the end of the Contract
Period unless such option is earlier terminated pursuant to Section 8.4.2 of
this Agreement. Such license agreement shall among other things provide for:
a) payments by HOECHST to OSI of a royalty of *** of Net Sales (as
defined therein) for each Human Therapeutic Product employing OSI Patent Rights
or HOECHST Patent Rights and *** on Net Sales for each Human Therapeutic Product
employing only OSI Technology, or HOECHST Technology;
b) payments by OSI of *** on Net Sales for any Diagnostic Product using
OSI Patent Rights, OSI Technology, HOECHST Patent Rights or HOECHST Technology;
c) OSI shall pay a royalty of *** on Net Sales for any OSI Human
Therapeutic Product derived from a HOECHST compound if OSI decides to market the
OSI Human Therapeutic Product itself. If OSI decides not to market the OSI Human
Therapeutic Product itself, it shall give HOECHST the first right to negotiate
for marketing rights;
d) if Patent Rights are involved, payments of the applicable royalty
will be made until the last valid patent claim expires;
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e) if Technology is involved and there are no valid patent claims,
payments of the applicable royalty will be made with respect to sales in a
Designated Country (as hereinafter defined) until ten (10) years after the first
commercial sale is made in such Designated Country. The Designated Countries are
USA, Canada, Germany, United Kingdom, France, Spain, Italy and Japan; and
(f) such other customary and other terms as are negotiated between the
parties.
8. Term, Extension, Termination and Disengagement.
8.1 Term. Unless sooner terminated or extended, this Agreement
shall expire six years after the Effective Date.
8.2 Extension. HOECHST, at least six months prior to the end of the
term, shall notify OSI in writing if it desires to extend the Sponsored Research
Program. If OSI is willing to extend the Sponsored Research Program, OSI must so
notify HOECHST within three (3) months after receipt of HOECHST's notice.
HOECHST and OSI shall thereafter promptly negotiate in good faith mutually
acceptable terms for any extension to this Agreement.
8.3 Events of Termination. The following events shall constitute
events of termination ("Events of Termination"):
(a) Any representation or warranty by OSI or HOECHST, or any of
its officers, under or in connection with this Agreement shall prove to have
been incorrect in any material respect when made.
(b) OSI or HOECHST shall fail in any material respect to
perform or observe any term, covenant or understanding contained in this
Agreement or in any of the
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other documents or instruments delivered pursuant to, or concurrently with, this
Agreement, and any such failure shall remain unremedied for 30 days after
written notice to the failing party.
(c) Either party shall be entitled to terminate this Agreement
by written notice to the other having immediate effect, if the other party is
acquired by or merged with or transfers all of its assets or an essential part
of such assets to, or if fifty percent or more of its voting stock is acquired
by, or otherwise comes under the control of, a person or an organization which
is a competitor of the terminating party, or if any such person or organization
obtains an option or preemption right to acquire fifty percent or more of the
voting stock or otherwise control of the other party, such party shall without
delay inform the party which is entitled to terminate, of such acquisition,
transfer, control, option or preemption right.
8.4 Termination.
8.4.1 Upon the occurrence of any Event of Termination, the
party not responsible may, by notice to the other party, terminate this
Agreement.
8.4.2 If HOECHST terminates this Agreement pursuant to Section
8.4.1, the option of HOECHST to negotiate a license provided for in Section 7
shall continue according to such Section. If OSI terminates this Agreement
pursuant to Section 8.4.1, the option of HOECHST to negotiate a license provided
for in Section 7 shall also terminate.
8.4.3 Upon termination of this Agreement, HOECHST will
reimburse OSI for any additional work done, or pending, within a six month
period following such termination.
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9. Representations and Warranties. OSI and HOECHST each
respectively represents and warrants as follows:
9.1 It is a corporation duly organized, validly existing and in
good standing under the laws of the State of Delaware and Germany, respectively,
and, is qualified to do business and is in good standing as a foreign
corporation in each jurisdiction in which the conduct of its business or the
ownership of its properties requires such qualification and has all requisite
power and authority, corporate or otherwise, to conduct it's business as now
being conducted, to own, lease and operate its properties and to execute,
deliver and perform this Agreement.
9.2 The execution, delivery and performance by it of this
Agreement have been duly authorized by all necessary corporate action and do not
and will not (a) require any consent or approval of its stockholders, (b)
violate any provision of any law, rule, regulation, order, writ, judgment,
injunction, decree, determination or award presently in effect having
applicability to it or any provision of its charter or by-laws or (c) result in
a breach of or constitute a default under any material agreement, mortgage,
lease, license, permit or other instrument or obligation to which it is a party
or by which it or its properties may be bound or affected.
9.3 This Agreement is a legal, valid and binding obligation of
it, enforceable against it in accordance with its terms and conditions, except
as such enforceability may be limited by applicable bankruptcy, insolvency,
moratorium, reorganization or similar laws, from time to time in effect,
affecting creditor's rights generally.
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9.4 It is not under any obligation to any person, contractual
or otherwise, that is conflicting or inconsistent in any respect with the terms
of this Agreement or that would impede the diligent and complete fulfillment of
its obligations.
9.5 It has good and marketable title to, or valid leases or
licenses for, all of its properties, rights and assets necessary for the
fulfillment of its responsibilities in the Research Program, subject to no claim
of any third party other than the relevant lessors or licensors.
10. Covenants of OSI.
10.1 Affirmative Covenants of OSI Other Than Reporting
Requirements. Throughout the Contract Period, OSI shall:
10.1.1 maintain and preserve its corporate existence, rights,
franchises and privileges in the jurisdiction of its incorporation, and qualify
and remain qualified as a foreign corporation in good standing in each
jurisdiction in which such qualification is from time to time necessary or
desirable in view of its business and operations or the ownership of its
properties.
10.1.2 comply in all material respects with the requirements of
all applicable laws, rules, regulations and orders of any government authority
to the extent necessary to conduct the Sponsored Research Program.
11. Dispute Resolution.
11.1 Any dispute which cannot be resolved by discussion between
the parties under this Agreement shall be resolved by binding arbitration in
accordance with the rules then obtaining of the American Arbitration
Association. The arbitrators shall have the power
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to award specific performance or injunctive relief and reasonable attorney's
fees and expenses to any party in such arbitration, except that the arbitrators
shall not have the power to reform this Agreement. Such arbitration shall be
held in the main office of the American Arbitration Association in the City of
New York.
11.2 The arbitration award rendered shall be final and binding
upon the parties and judgement thereon may be entered in any court of competent
jurisdiction.
12. Notices. All notices shall be mailed via certified mail, return
receipt requested, or courier, addressed as follows, or to such other address as
may be designated from time to time:
If to HOECHST: at its address set forth at the beginning of this
Agreement
Attention: Dr. Jessen
HOECHST AG
General Pharma Research
Postfach 80 03 20, D-6230
Frankfurt am Main 80, Germany
If to OSI: at its address set forth at the beginning of this
Agreement
Attention: Chief Executive Officer
Notices shall be deemed given as of the date of receipt.
13. Governing Law. This Agreement shall be construed in accordance
with the laws of the State of New York.
14. Miscellaneous.
14.1 Binding Effect. This Agreement shall be binding upon and
inure to the benefit of the parties and their respective legal representatives,
successors and permitted assigns.
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14.2 Headings. Paragraph headings are inserted for convenience
of reference only and do not form a part of this Agreement.
14.3 Counterparts. This Agreement may be executed
simultaneously in two or more counterparts, each of which shall be deemed an
original.
14.4 Amendment; Waiver; etc. This Agreement may be amended,
modified, superseded or cancelled, and any of the terms may be waived, only by a
written instrument executed by each party or, in the case of waiver, by the
party or parties waiving compliance. The delay or failure of any party at any
time or times to require performance of any provision shall in no manner affect
the rights at a later time to enforce the same.
14.5 No Third Party Beneficiaries. No Person not a party to
this Agreement, including any employee of any party to this Agreement, shall
have or acquire any rights by reason of this Agreement. Nothing contained in
this Agreement shall be deemed to constitute the parties partners with each
other or any Person.
14.6 Assignment and Successors. This Agreement may not be
assigned by either party, except that each party may assign this Agreement and
its rights and interests hereunder, in whole or in part, to any of its
Affiliates, any purchaser of all or substantially
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all of its assets or to any successor corporation resulting from any merger or
consolidation with or into such corporation.
IN WITNESS WHEREOF, the parties have caused this Agreement to be
executed by their duly authorized representatives.
HOECHST AKTIENGESELLSCHAFT ONCOGENE SCIENCE, INC.
By /s/ DR. GERT CASPRITZ By /s/ GARY E. FRASHIER
----------------------------- ---------------------------
Title: Manager Title: President and
Cooperation and Licensing Chief Executive Officer
By /s/ JORGEN REDEN, PH.D.
-----------------------------
Title: Member of Management
Board Pharma
Head of Research
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THE RESEARCH PLAN INCORPORATING THE ANNUAL SPONSORED
RESEARCH PLAN FOR THE COLLABORATION BETWEEN
ONCOGENE SCIENCE INC AND HOECHST AG
APPENDIX 1
Revised 12/11/92
31
Executive Summary
Oncogene Science has developed a proprietary drug discovery technology
designed to identify compounds which affect the transcription of specific target
genes. A review on the development of this technology at Oncogene and the
advantages of transcription as an approach to drug discovery can be found in
Supplement 1. The immediate goal of the proposed collaboration with Hoechst AG
is to exploit this technology ***. The primary screening system employs live,
genetically engineered transcription-reporter cells and state-of-the-art
robotics which will enable screening of ***.
Compounds of interest identified by the primary screen will be
evaluated in secondary screens ***. Thus, the later
stages of the drug development pathway and clinical trial strategies are not
discussed in this document.
The collaboration between Hoechst AG and Oncogene Science can be
divided into three phases:
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initiation of the collaboration, and will be associated with the program for the
duration of the collaboration. During the screening phase additional manning ***
will be allocated from the core screening group at Oncogene.
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MOLECULAR TARGETS
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SUPPLEMENT 1
TRANSCRIPTION AND DRUG DISCOVERY
ONCOGENE SCIENCE'S GENE EXPRESSION TECHNOLOGY
Introduction
Over the last five years Oncogene Science has carried out a major
research effort focused on gene transcription as a novel approach to drug
discovery. Extensive patents have been filed covering both the method of drug
discovery and the resulting drugs identified by this technology. The goal is to
identify small molecular weight compounds which specifically modulate the
expression of a target gene of interest, thereby either increasing or decreasing
the concentration of the corresponding protein product. The unique screening
system employs live genetically engineered cells and state-of-the-art robotics,
which enables up to 100,000 compounds to be screened in a single year against
multiple target genes simultaneously. This approach can be used to identify lead
compounds in almost every therapeutic area. Transcriptional modulation not only
provides a potential means to replace recombinant protein based drugs, but also
provides a novel approach to manipulate key therapeutic targets in the body.
Traditional Drug Discovery Approaches
Until recently, a major focus of the pharmaceutical industry had
remained centered around improving either the efficacy or safety of existing
drugs, agents whose detailed mechanism of action was often unknown. The
chemistry effort to support this approach during this century has been prolific,
and more than 3 million unique chemical structures have now been cataloged.
Within the last decade, however, molecular biologists have begun to
unravel the detailed molecular aspects of normal cellular physiology and the
abnormalities associated with various disease processes. To date, the
application of molecular biology to drug discovery has taken three basic
directions; (i) the discovery of protein factors which act directly as
pharmaceutical agents; (ii) the combination of X-ray crystallography and
computer modelling to design organic compounds based upon a detailed
understanding of protein structure; or (iii) the use of recombinant proteins in
in vitro assays, in order to screen several thousand natural
products extracts or synthetic organic compounds. Each of these approaches,
however, suffers from significant limitations.
The development of protein-based pharmaceuticals is perhaps the best
known application of molecular biology to the drug industry. Major successes
have included growth hormone for the treatment of pituitary dwarfism, tissue
plasminogen activator to treat myocardial infarction, insulin for diabetes, and
erythropoietin and G-CSF for the treatment of anemia and neutropenia,
respectively. All of these agents, however, possess a number of major
limitations characteristic of protein-based therapeutants. These include the
route of administration, cost of manufacture,
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formulation, stability and the relative complexity of patenting recombinant
biologicals. Furthermore, the use of proteins as drugs is restricted to diseases
or physiological states that can be influenced by serum borne factors. These
problems, as well as a number of other major limitations, also apply to
therapeutic approaches based upon the use of monoclonal antibodies.
The second approach to drug discovery is contingent upon a detailed
knowledge of specific protein structure. Interactive computing theoretically
allows the design of small molecular weight compounds that are predicted to bind
to specific sites on the target protein. This approach requires that the three
dimensional structure of the target protein be known at very high resolution,
while modelling of the detailed interactions with compounds often necessitates
the use of modern supercomputers. An additional complication is that the
structure of the protein as determined by crystallography, may not reflect the
native conformation of the protein within the cell. As more protein structures
are solved, and as modelling programs become more powerful, rational drug design
may begin to make an important contribution to the drug discovery. To date,
however, there are no drugs on the market which have been developed de
novo using this technology.
The third traditional method has involved the screening of several
thousand fermentation broths, natural product extracts or synthetic organic
compounds, for their ability to influence the function of a purified or
partially purified protein, typically a hormone receptor or an enzyme. In many
instances, however, it can prove to be technically difficult to isolate a
complex protein with retention of its activity. In addition, the critical
biochemical activity of many disease targets may be unknown, thereby preventing
the design of an appropriate screen. In other cases, the key target may be a
member of a gene family where the corresponding polypeptides are almost
identical, and an effective drug must be able to selectively target one specific
member. Another major limitation of in vitro screening is that following a
considerable effort to generate interesting compounds, many leads ultimately
fail to be developed due to metabolism, cytotoxicity or lack of cell
permeability. Finally, it is becoming increasingly apparent that many diseases,
such as atherosclerosis, cancer and many neurological disorders, are
multifactorial in origin, and may ultimately require the simultaneous modulation
of multiple targets to achieve an effective control.
Oncogene Science believes that gene transcription provides a unique
approach to drug discovery, which has the potential to overcome many of the
limitations of conventional drugs and could lead to the development of novel
pharmaceuticals targeting most of the major therapeutic markets.
Gene Transcription As A Novel Target For Drug Discovery
At Oncogene Science, a proprietary drug discovery approach has been
developed which is designed specifically to identify compounds which affect the
transcription of target genes. The screen utilizes genetically engineered live
cells lines. Thus, once a particular gene has been chosen as a target, the first
step of the process is to clone the regions of DNA which regulate expression of
that gene. These sequences are then fused to a highly sensitive reporter gene
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which generates a readily measurable signal in response to changes in
transcription of the target gene. This genetically engineered DNA construct is
then introduced into an appropriate human cell type and stable lines isolated.
Such cell lines will then generate a signal which reflects a change in gene
expression when an appropriate compound is added to the tissue culture media.
Oncogene's approach is based upon a philosophy of very high-throughput drug
screening, ie., screening up to 100,000 compounds or fermentation broths against
each gene target in a single year. To achieve this, a proprietary screening
technology has been developed, which has been fully automated using
state-of-the-art robotics. Complete automation not only allows the primary
screen to be cost effective, but has proved essential to obtain highly
quantitative, reproducible data from high-throughput cell based screens.
Each robotic system can analyze several thousand samples per week
against multiple target genes simultaneously. By using multiple targets in the
primary screen, efficacy, cytotoxicity, and initial specificity are rapidly
evaluated. For example, the presence of a chemical which activates transcription
of the human growth hormone gene would be readily detected by an increase in the
reporter signal only in the cell target which employed a growth hormone fusion
construct. This technology is not only highly quantitative but is of sufficient
sensitivity to allow the detection of fewer than twenty five molecules of the
reporter per cell. This provides both a number of major technical advantages
while enabling the screen to detect initial lead compounds with apparent limited
activity, eg. potent compounds present at low concentrations in fermentation
broths. Automated on-line data reduction and statistical analysis allows rapid
quantitative determination to identify the initial lead compounds. Compounds of
interest identified by the primary screen are then further evaluated in
secondary screens (eg. by quantitative PCR, protein based assays, etc.) for
their ability to regulate the native endogenous gene in a similar fashion. A
variety of appropriate tertiary assays and animal models can then be employed
for the final stages of lead development.
Modulating gene transcription using drugs
Over the last few years it has become apparent that many of the body's
normal physiological pathways, as well as the response to disease states,
involve changes in gene transcription. For example, the amount of growth hormone
produced by the pituitary, or the levels of blood cell growth factors, such as
G-CSF and erythropoietin (Epo), are tightly controlled at the level of gene
transcription. The Epo gene is specifically activated in response to anoxia (low
oxygen). The growth hormone gene is transcriptionally activated by the binding
of a second hormone (termed GHRF) to a receptor on the plasma membrane. The goal
of Oncogene Science's transcription technology is to use small molecular weight
drugs to maximize such physiological responses to produce the desired
pharmacological endpoint.
In addition to the physiological evidence which clearly demonstrates
highly specific regulation at the level of gene transcription, there are already
a number of genes which are known to be subject to pharmaceutical intervention
by small molecular weight compounds. Steroid hormone receptors are themselves
transcription factors. Nolvadex (Tamoxifen), for example, regulates the
expression of estrogen responsive genes to control breast cancer, while
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Eulexin (flutamide) demonstrates dramatic palliative efficacy in the treatment
of prostate cancer by blocking the action of the testosterone receptor.
Similarly, steroid receptors are the target of drugs used as anti-inflammatory
agents, contraceptives, etc.
It has also become apparent that a number of drugs, whose mechanism was
previously unknown, act by specifically modulating the expression of various
target genes. One recent example of note is aspirin, which has been shown to
mediate its anti-inflammatory effects by inhibiting transcriptional activation
of prostaglandin synthesis by interleukin-1. Other examples include the
immunosuppressive agents cyclosporin A and FK506, which inhibit the
transcription of several genes involved in T cell activation, particularly
interleukin 2 (IL-2) and its receptor. Cyclosporin A and FK506, both bind to
proteins which regulate the activity of a transcription factor, which in turn
inhibits the expression of IL-2. Similarly, lovastatin indirectly up-regulates
the hepatic LDL receptor by lowering serum cholesterol. Such examples of
indirect regulatory effects stress the utility of a cell-based promoter-reporter
technology as a means to identify lead compounds with the potential to modulate
transcription at a variety of levels. Thus, compounds identified by the primary
screen do not have to bind directly to a transcription factor.
Advantages of targeting gene transcription
- Replacement of recombinant proteins as therapeutic agents, e.g.,
replace erythropoietin or growth hormone with a small molecular
weight pharmaceutical to increase the expression of the
endogenous gene. This could potentially overcome the major
limitations associated with the use of biologicals, eg. patents,
costs of production, formulation, route of administration, etc.
- Transcriptional modulation can act to affect either intracellular
or extracellular targets. In contrast, both recombinant
biologicals and monoclonal antibodies require a target to be
either present in the circulation or on the surface of cells.
- The ability to modulate the level of a protein which cannot be
readily targeted by other means, e.g. intrinsic membrane proteins
such as the glucose transport proteins in diabetes, or the
macrophage scavenger receptor and the LDL receptor in the
treatment of atherosclerosis.
- Most traditional drugs have acted as either receptor antagonists
or enzyme inhibitors. Transcription-based pharmaceuticals allow
the absolute concentration of a target protein to be either
increased or decreased. This also represents a significant
advantage compared to antisense based approaches. Antisense
molecules are also inactive orally, expensive, and act only to
decrease protein levels.
- The biochemical activity of the protein encoded by a target gene
may be unknown, thereby preventing an effective in vitro
screening approach to be implemented. This technology employs a
cell-based transcription screen to target
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the gene and not its product, therefore a detailed knowledge of
protein function is not essential.
- Oncogene's primary screens are cell-based. This provides screens
which are considerably more physiological than using purified in
vitro assays, yet avoids the technical complexity and ethical
issues associated with animal based screens. The cell-based
approach also provides multiple target sites within the cell for
pharmacological intervention. In addition, compounds which either
fail to interact with the cell in a functional manner, or are
highly cytotoxic, are readily excluded.
- Targeting the specific expression of a gene in a multigene
family, rather than the corresponding polypeptide, provides a
means to facilitate specific intervention. Modulating the
activity of an entire family of structurally related proteins
could be deleterious to the organism, while modulation of a
specific member of a group of highly homologous proteins can be
difficult to achieve pharmacologically. One example would be the
specific transcriptional modulation of a CNS receptor where
although the family of polypeptides may exhibit a high degree of
homology, the regulatory regions (and the corresponding
transcription factors of the gene families which bind to these
regions) are typically distinct to allow cell type specific
expression.
- The possibility of tissue specific regulation of a target gene.
It is becoming increasingly apparent that the mechanisms regulate
any one gene at the transcriptional level vary between different
tissues. Thus, this approach has the potential to identify drugs
which modulate the expression of a target gene in a
tissue-specific manner. Again, this is not possible with
antisense approaches.
- It is now well documented that coordinated changes in gene
expression regulate a large number of metabolic processes in the
body. Thus, it may be possible to use a single drug to regulate
the transcription of small groups of genes simultaneously, rather
than using a conventional pharmaceutical to simply target one
specific enzyme or receptor. Given that many major diseases are
multifactorial in origin, such as atherosclerosis, Alzheimers,
and cancer, this approach may ultimately prove essential to
develop truly effective drugs in these areas.
- Oncogene Science's technology is unique. Gene transcription has
not been previously exploited. It is also apparent that very few
pharmaceutical companies have had the technology in place to
enable the screening over 100,000 compounds against a single
target, ie. typically most previous drug screens have evaluated
between 1,000-10,000 compounds. Thus, it can be anticipated that
a high-throughput screening approach based upon gene
transcription will result in the identification of novel drug
structures.
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- Over the last five years, Oncogene Science has established the
leading position in the field of gene transcription as an
approach to drug discovery. The original reason for focusing in
this area was that in unraveling the normal function of oncogenes
and anti-oncogenes, it had become apparent that the primary
function of many such genes is to modulate gene transcription,
either directly by binding to regulatory sequences on the DNA, or
indirectly by controlling key steps in the signal transduction
machinery.
- Oncogene Science has filed broad patent applications on
transcription based approaches, including claims on the methods
of discovery, the robotic technology, and the use of compounds
which specifically modulate gene transcription.
ONCOGENE SCIENCE'S SCREENING TECHNOLOGY
In order to facilitate the screening of large numbers of test samples,
Oncogene Science has invested extensively on the development of proprietary
robotics systems. In addition to carrying out cell-based transcription assays,
these systems are now able to run virtually any cell based or in-vitro screening
assays in a microplate format.
The robotic systems handle every step in the assay procedure. This
includes on-line cell incubation facilities, liquid handling systems for
dilutions and additions of test samples, and an array of units for manipulations
in an assay loop. Two robotic arm assemblies are employed to shuttle microplates
and microplate trays through the assay cycles. The transcription assays
culminate with a read-out from a 96 well luminometer. Data are captured
automatically into a processing network which performs quality controls on each
individual microplate assay well and carries out a rapid data reduction and
analysis. Each of the robotic systems has a capacity in excess of 100,000 assays
per week. This translates to approximately 100,000 compounds per year, with
follow-up, against multiple target genes.
Automation on this scale has proven to be essential for producing high
quality data from cell based screens, however it also provides a number of
additional advantages over other approaches to screening:
(i) Cost Effectiveness : Support for each robotic system requires
only a three person team. This includes the manning for all
tissue culture, robotic maintenance, robotic operation, data
analysis, database searching and report preparation, as well as
initial potency and cytotoxicity follow-up studies on
high-throughput screen leads.
(ii) High-Throughput : Each system has a capacity for up to 125,000
reporter assays per week. A practical, routine weekly throughput
is approximately 75% of this capacity. These assays can be
divided amongst replicate assays of individual samples, positive
and negative controls, and multiple test cell lines, as is
appropriate for a particular screening program. For example, in
the first 12
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month period employing the original system, over 125,000
compounds were screened against 3 cell lines with triplicate
determinations on each compound, and multiple controls on each
microplate assayed.
(iii) Accuracy : Automation has proven to be very effective in terms of
removing protocol errors and in more accurately controlling and
synchronizing procedures. This has resulted in running multiple
cellbased screens with a typical coefficient of variation across
each plate being less than 15%.
The systems have been designed with flexibility as a key consideration.
Thus, by interchanging the measurement device in place of a luminometer and
conversion of these instruments to a robot compatible format, it is possible to
utilize multiple read-outs suitable for various assay formats. For example,
Oncogene Science has now also developed microplate readers for the determination
of UV absorbance, fluorescence, and radioactivity, enabling almost any assay
configuration to be employed. All the software for running the robots, the
liquid sampling processor, data capture, and data processing has been developed
at Oncogene Science and is readily converted to suit alternate assay needs. This
technology is currently employed in both transcriptional reporter assays and
cell-based immunoassays.
Preparation of Compounds and Samples for High-throughput Screening
Oncogene Science has now incorporated into the robotic system the
capacity to operate in a mode which enables the rapid preparation of large
compound libraries (50-200,000 samples) in a 96-well format suitable for
screening. This approach also offers the possibility of archiving sets of master
compound plates for future screening needs. This procedure also makes maximum
use of the original compound allocation, with 1 mg of compound potentially
serving for 50-100 high-throughput screens against individual target assays.
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