THE INFORMATION MARKED BY * AND [ ] HAS BEEN OMITTED PURSUANT TO A REQUEST
FOR CONFIDENTIAL TREATMENT. THE OMITTED PORTIONS HAVE BEEN SEPARATELY FILED
WITH THE COMMISSION.
This Agreement made and entered into this 1st day of May 1997 by and between
Ohio University, having office at 105 Research and Technology Center, ▇▇▇▇▇▇,
▇▇▇▇ ▇▇▇▇▇, (hereinafter referred to as "Institution") and Progenitor, Inc.,
having offices at ▇▇▇▇ ▇▇▇▇▇▇▇▇ ▇▇▇▇, ▇▇▇▇▇▇▇▇, ▇▇▇▇ ▇▇▇▇▇-▇▇▇▇ (hereinafter
referred to as "Sponsor").
WHEREAS, the research program contemplated by this Agreement is of mutual
interest and benefit to Institution and to the Sponsor, and will further the
research objectives of the Institution in a manner consistent with its status as
a non-profit tax-exempt research institution,
NOW, THEREFORE the parties are as follows:
1. STATEMENT OF WORK. Institution agrees to use its best efforts to perform
the Research Plan outlined in the proposal dated 1 May 1997 and in general
conformance with the Proposal Budget and Research Plan which are
incorporated into this Agreement by reference and attached hereto as
Exhibit 1.
2. PRINCIPLE INVESTIGATOR. The research will be supervised by Dr. ▇▇▇▇▇▇
▇▇▇▇▇▇. If for any reason ▇▇. ▇▇▇▇▇▇ is unable to continue to serve as
principle investigator, and a successor acceptable to both Institute and
Sponsor is not available, this Agreement shall be terminated as mutually
agreed.
3. PERIOD OF PERFORMANCE. The research shall be conducted during the period 1
May 1997 to 30 April 1999.
4. CONSIDERATION. In consideration for the research to be conducted by the
Principle Investigator and Institution during the first year of this
Agreement, Sponsor will pay to Institution a total of [***]. Payment
shall be made to Institution in four installments. The first installment
shall equal [***] and shall be paid upon execution of this Agreement.
The second, third and fourth installments shall each equal [***] and
shall be paid on 1 August 1997, 1 November 1997 and 1 February 1998. In
consideration for the research to be conducted by the Principle
Investigator and Institution during the second and final year of this
Agreement, Sponsor will pay to Institution a total of [***]. Payment
shall be made to Institution in four installments. The first installment
shall equal [***] and shall be paid upon 1 May 1998. The second, third
and fourth installments shall each equal [***] and shall be paid on 1
August 1998, 1 November 1998 and 1 February 1999.
5. TERMINATION. Sponsor may terminate this Agreement upon material breach by
Institution or Principal Investigator of their obligations under this
Agreement, provided that the Institution and/or the Principal Investigator
has not cured the material breach within thirty (30) days after receipt of
written notice from Sponsor specifying such breach. In the event that
Institution or Principal Investigator has not cured such breach within such
thirty (30) day period, Sponsor, at Sponsor's sole discretion, may
terminate
1
this Agreement upon a second written notice to Institution and Principal
Investigator, such termination to be effective upon receipt of such second
written notice by Institution and Principal Investigator. Notwithstanding
any other terms and conditions hereunder, this Agreement may be terminated
by either party by written notification to the other party at least one-
hundred eighty (180) days prior to the desired effective date of the
termination. In the event of early termination by Sponsor for any reason
except for a material breach of this Agreement by Institution and Principal
Investigator, the Institution shall be entitled to payment of all
expenditures or encumbrances that cannot be canceled and which were incurred
prior to the termination date. Further, upon termination of this Agreement,
any materials provided to Institution by Sponsor under this Agreement shall
be destroyed or returned to Sponsor, at Sponsor's option.
6. PUBLICATIONS. Institution will be free to publish results under this
Agreement. A copy of each publication will be provided to the Sponsor
forty-five (45) days prior to submission for publication to allow adequate
time for the parties to identify and protect patentable subject matter.
Notwithstanding the above, publication will be delayed until patent
applications have been filed in the United States, provided the delay does
not exceed sixty (60) days from the date the publication is submitted to
the Sponsor.
7. REPORTS. The Institution will provide Sponsor with detailed annual written
reports within forty-five (45) days after 1 May in each calendar year or
after the date of termination. Reports will include a detailed review of
progress on the Research Plan and a detailed accounting of activities
during the preceding 12 months as they affect the achievement of project
milestones, as well as proposed revisions to the Research Plan and the
projected budget for next year. Institution and Sponsor acknowledge and
agree that such reports may not be sufficient to permit Sponsor to receive
full advantage of the work conducted under the Research Plan. Therefore,
Institution and Principle Investigator will meet periodically with Sponsor
to review the Research Plan and discuss the research progress. Such review
and discussion will be in sufficient detail to permit Sponsor to be
informed of research results and research progress as they affect the
achievement of project milestones. Failure of Institution and Principal
Investigator to provide such sufficient detail will be deemed a material
breach of this Agreement by Institution and Principal Investigator. If the
location of the meetings is outside of the Athens, Ohio area, Sponsor will
pay travel expenses actually incurred by Institution and Principle
Investigator. Nothing in this clause shall be construed as requiring
Institution or Principal Investigator to disclose to Sponsor, either in the
written reports or the reviews and discussions, any intellectual property
developed outside of the scope of work of this Agreement and owned either
exclusively by Institution or jointly by Institution and any other
sponsor(s) of research, or provided to Institution by any other provider(s)
of proprietary research materials or information.
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8. INTELLECTUAL PROPERTY. Title to any invention conceived or first reduced
to practice in the performance of the Research Plan solely by any person(s)
employed or otherwise appointed by Institution, or at any time by any
person(s) at Institution whose salary and benefits are paid through
financial support provided by Sponsor, shall remain with Institution.
Title to any invention conceived or first reduced to practice jointly by
Institution and by any employee(s) of Sponsor in the performance of the
Research Plan shall be jointly owned by Institution and Sponsor. Sponsor
shall have, and Institution hereby grants to Sponsor, a right of first
refusal to acquire an exclusive license to Institution's rights in any
invention conceived or first reduced to practice either (i) in the
performance of the Research Plan by any person(s) employed or otherwise
appointed by Institute, or (ii) at any time by any person(s) whose salary
and benefits are paid through financial support provided by Sponsor. The
terms and condition of such license shall be negotiated in good faith
between the parties and shall be consistent with the terms of license and
consideration which are incorporated into this Agreement by reference and
attached hereto as Exhibit 2. Sponsor may exercise such right of first
refusal at any time during a period of ninety (90) days after the date of
Sponsor's receipt of Institution's written notice describing an invention
in detail. After such ninety (90) day period, the right of first refusal
granted to Sponsor shall expire and Institution may grant rights to a third
party under Institution's rights in any such invention without obligation
to Sponsor.
9. USE OF NAMES. Neither party will use the name of the other in any
advertising or other form of publicity without the prior written permission
of the other.
10. CONFIDENTIAL INFORMATION. During the term of this Agreement both parties
will exchange certain proprietary Confidential Information in connection
therewith, either written or orally ("Information"). Both Sponsor and
Institution agree to keep such Information strictly confidential; will not
use such Information to reverse engineer or design around proprietary
projects or products; and will not disclose Information to others without
the express written permission of the other party; provided, however, they
will not be prevented from using or disclosing information which:
a) is now, or which hereafter, through no act or failure of the other
party, becomes generally known or available;
b) is known by the other party at the time of receiving such Information;
c) is hereafter furnished to the other party by a third party who did not
acquire such Information directly or indirectly from the other party;
or
d) is independently developed by the other party without knowledge of
Information, and the recipient party can demonstrate or prove truth
thereof.
11. NOTICES. Any notice to be given or which shall be given under this
Agreement shall be in writing delivered by first class mail addressed to
the parties as follows:
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Sponsor: Progenitor, Inc.
Vice President, Corporate Development
▇▇▇▇ ▇▇▇▇▇▇▇▇ ▇▇▇▇
▇▇▇▇▇▇▇▇, ▇▇▇▇ ▇▇▇▇▇-▇▇▇▇
Institution: Ohio University
Office of Research and Sponsored Programs
105 Research and Technology Center
▇▇▇▇▇▇, ▇▇▇▇ ▇▇▇▇▇
12. In the event notices, statements and payments required under this Agreement
are sent by certified or registered mail by one party to the other party at
its above address, they shall be deemed to have been given or made as of
the date so mailed, otherwise as of the date received.
13. ASSIGNMENT. This Agreement shall be binding upon and inure to the benefit
of the parties hereto and the successors to substantially the entire
business and assets hereto, provided the successor entity agrees in writing
to abide by all the terms of this Agreement.
14. GOVERNING LAW. The validity and interpretation of the Agreement and the
legal relation of the parties to it shall be governed by the laws of the
State of Ohio and the United States.
15. FORCE MAJEURE. Institution shall not be responsible to the Sponsor for
failure to perform any of the obligations imposed by the Agreement,
provided such failure shall be occasioned by fire, flood, explosion,
lightning, windstorm, earthquake, subsidence of soil, failure or
destruction, in whole or in part, of machinery or equipment, failure or
supply of materials, discontinuity in supply of power, governmental
interference, civil commotion, riot, war, labor disturbance, transportation
difficulties, labor shortage or any cause beyond the reasonable control of
Institution.
16. ENTIRE AGREEMENT. Unless otherwise specified, this Agreement embodies the
entire understanding between Institution and Sponsor for this project, any
prior or contemporaneous representations, either written or oral are hereby
superseded. No amendment or changes to this Agreement, including without
limitation, change in the statement of work, total estimated cost, and
period of performance, shall be effective unless made in writing and signed
by authorized representative of the parties.
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For Institution For Progenitor, Inc.
By: /s/▇▇▇▇▇ ▇. ▇▇▇▇ By: /s/ ▇▇▇▇▇▇▇ ▇. ▇▇▇▇▇▇▇▇
------------------------------ ------------------------------
Title: Associate Vice President for Title: V.P. Corporate Finance
---------------------------- ----------------------------
Research
----------------------------
Date: 04/21/97 Date: 04/21/97
----------------------------- ----------------------------
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EXHIBIT 1 - RESEARCH PLAN AND PROPOSAL BUDGET
WORK PLAN FOR CONTRACT WITH PROGENITOR, INC.
TO
ASSAY GENOMIC CODING SEQUENCES FOR GENE FUNCTION
A PROPOSAL BY THE OHIO UNIVERSITY EDISON INSTITUTE
The combination of the NIH Human Genome Project and the efforts of many
biotechnology companies focusing in the area of molecular genomics have already
sequenced many of the human genes and soon will have identified the sequence of
each human gene. Unfortunately, this information is of little useful scientific
value without some knowledge of the biological function of each of these known
sequences. The real challenge of genomics research will be this identification
of gene function, not, the more trivial, gene sequencing.
Identification of gene function requires the use of either a whole animal
or a multipotent or totipotent embryonic cellular assay system. Because of the
Edison Institute's foundation of, and long history in, the use of transgenic
models it is unusually well positioned to utilize these unique whole animal
systems to develop rapid assays for gene function to screen genomic sequences of
unknown function with a reasonably high throughput efficiency. Assays in two
different animal model systems are proposed.
HIGH LEVEL CONSTITUTIVE EXPRESSION OF GENOMIC CODING SEQUENCES OF UNKNOWN
FUNCTION DURING EMBRYONIC DEVELOPMENT
The scientific goal of studying gene function is to identify genes coding
for key factors important in initiating or directing critical biological
processes which, in turn, may involve many other gene products. This is true
since the products of these genes may function as important triggers for a
medically important cascade. An example is Erythropoietin which triggers the
rebuilding of the red blood cell population of cancer patients following
chemotherapy. Therefore, it is important to bias studies of gene function and
the use of gene function assays towards such dominant regulating factors.
It is the belief of the molecular and developmental biologists at the
Edison Institute, in consultation with other experts in this field, and based
upon observation of non-viable transgenic embryos over expressing such genes
(e.g., Del I) that the constitutive over expression of dominant regulatory
factors specifically alters and disrupts the normal development of the cellular
lineages which respond to these factors. Therefore we propose inserting genomic
coding sequences of unknown function into expression cassettes driven by strong
constitutive promoters and injecting these genetic constructs into the
fertilized eggs to generate transgenic embryos. These embryos will then be
assayed by microscopic observation at time periods during early development to
identify specific aberrations or defects in development. When developmental
defects or abnormalities are observed in a reasonable percentage of the embryos
over expressing any particular gene, a more detailed histological examination of
these abnormalities at the
1
cellular level will be undertaken to determine the exact nature of the defect or
abnormality. Identification of such specific defects or abnormalities in
specific cellular lineages during embryonic development will strongly suggest
specific dominant gene function.
We propose performing this assay in two different animal model systems:
the zebra fish and the mouse. In the zebra fish, eggs will be injected by
methods well established by experts in transgenic fish biology at the Edison
Institute. Lineage commitment and substantial development of all organ systems
within the zebra fish embryo is complete within 24 hours following fertilization
and, since the zebra fish embryo is a very clear, transparent, embryo which can
be microscopically observed during its development in saline solution, the
initial assay can be completed within a 24- to 72 hour period.
While the mouse system is more complex because development takes place
within the uterine environment of the mother, this assay can also be performed
quite rapidly. Fertilized mouse eggs will be injected with the genetic
constructions and transplanted into recipient female mice. These recipients
will be sacrificed at timed intervals during the first 12 days of gestation,
before which most development has already occurred, and observed
microscopically.
Both the mouse embryo microsurgeon and the fish embryo microsurgeon can
inject approximately 200 to 400 eggs per day. This number should provide a
large enough sample to show any dominant effect. This proposal would allow for
up to 6 gene constructs to be assayed per month in either system.
PERSONNEL REQUIREMENTS FOR THE PROPOSED GENE FUNCTION ASSAYS
(see attached budget)
- Zebra Fish Laboratory:
- Fish embryo microsurgeon/ technician (embryo production and culture
egg microinjection, microscopic embryo assay)
- Consulting zebra fish embryologist (see following page)
- Mouse Embryo Laboratory:
- Mouse embryo microsurgeon/ embryologist (egg microinjection, histology
and overall management)
- Mouse embryology/ histology technician (microscopic embryo assay,
histological assays)
- Mouse technician (breeding and care of embryo donor and recipient
mice)
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- Genetic Construction Laboratory
- Molecular Biologist (▇▇▇▇ ▇▇▇▇ - design and direct the construction of
over expression genetic materials)
- Molecular Biology technician (construction of over expression genetic
materials)
CONSULTING ZEBRA FISH EMBRYOLOGIST (▇▇▇▇▇ ▇. ▇▇▇▇)
▇▇▇▇▇ ▇. ▇▇▇▇, Ph.D., Associate Professor, Department of Biological
Sciences, Ohio University, has agreed to participate in this project as a
consultant on zebra fish development, particularly in cases where neural
development is affected by over expression of a transgene. She will devote the
equivalent of 8% effort to the project and her involvement will be as follows:
1. TRAINING EDISON CENTER WORKERS - She will train members of the Edison
Institute staff in the use of morphological criteria to make initial screens of
transgenic embryos. She will also provide training in standard histology and
immunochemical techniques and their application to zebra fish embryos. ▇▇. ▇▇▇▇
assumes that Progenitor will want to begin making transgenic animals as soon as
possible once the contract goes into effect, therefore she would like to conduct
this training in April or May 1997 so that workers are prepared when genetic
material is received in July (assuming a July 1 start date).
2. INITIAL SCREEN - The Edison Institute will perform the initial screen for
gross morphological abnormalities, according to the criteria they learn from
training provided by ▇▇. ▇▇▇▇ (described above). Embryos will be screened with
vital dyes and a staging series to document changes in the normal patterns of
development of the major systems of the body. Embryos will be observed with
Nomarski optics at the follow stages: shield stage of the gastrula (6 hrs.
postfertilization (pf.)), 2-4 somite stage (10-12 hrs. pf.), early pharyngula
(24 hrs. pf.), late pharyngula (48 hrs. pf.) and late hatchling (72 hrs. pf.).
If embryos are judged to have abnormal developmental patterns, sample embryos at
each age as well as control embryos will be fixed and prepared for routine
histology and immunocytochemistry and reserved for my further analysis. ▇▇.
▇▇▇▇ will train workers at the Edison Institute in the application of these
methods, and they will prepare the embryos for her analysis.
3. DETAILED SCREEN - Once Edison Institute workers have isolated embryos with
altered developmental patterns, ▇▇. ▇▇▇▇ will further analyze each group of
transgenic animals for a more precise spatial and temporal description of
abnormalities. To make this analysis, she will use comparisons of the
transgenic embryos with the control embryos and material from her own research.
These detailed analyses will be made in ▇▇. ▇▇▇▇' laboratory in ▇▇▇▇▇▇ ▇▇▇▇
on the Ohio University campus. To document the alterations she will make
digital images of control and transgenic animals. These images can be sent by
e-mail to scientists at the
3
Edison Institute or Progenitor to help them make decisions regarding direction
of future analysis efforts.
If interesting or promising patterns are found, ▇▇. ▇▇▇▇ plans to use more
sophisticated anatomical or immunochemical methods to explore the basis of
observed abnormalities. For example, if segmentation of the neural tube seems
to be altered, cell injection and time lapse techniques can be used to document
the divisions of individual cells and the dispersion of the progeny of the
injected cell; the patterns observed in transgenic animals can be compared with
patterns of similar cells in control animals.
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Proposal Budget
Progenitor - Embryonic Development
Period of Performance: July 1, 1997 through June 30, 1999
Principal Investigator: Dr. ▇▇▇▇▇▇ ▇▇▇▇▇▇
Edison Biotechnology Institute
Ohio University
Year 1 Year 2 Summary
I. Personnel
Salaries [***] [***] [***]
Benefits [***] [***] [***]
--------- --------- ----------
Total [***] [***] [***]
II. Operations
Lab Supplies [***] [***] [***]
Animal Care Costs (LARS) [***] [***] [***]
Photocopy, Postage, Phone, misc. [***] [***] [***]
Publication/Page Charges [***] [***] [***]
Computer Software [***] [***] [***]
Lab Equipment (under $500) [***] [***] [***]
Subcontracts [***] [***] [***]
Tuition [***] [***] [***]
--------- --------- ---------
Total [***] [***] [***]
III. Travel
Domestic [***] [***] [***]
Foreign [***] [***] [***]
--------- --------- ---------
Total [***] [***] [***]
IV. Capital Equipment [***] [***] [***]
V. Total Direct Costs [***] [***] [***]
VI. Indirect Costs (45% x MTDC) [***] [***] [***]
--------- --------- ---------
VII. Total Project Costs [***] [***] [***]
EXHIBIT 2 - TERM SHEET
LICENSE TERMS:
Grant: Worldwide, exclusive right and license, with
the right to grant sublicenses, under any and
all intellectual property conceived and/or
reduced to practice to make, use, offer to
sell, sell and import inventions made
relating to products and uses of gene
sequences (full or partial), protein
sequences (full or partial), antibodies,
expression systems, DNA, RNA and antisense.
Field: All fields without restriction.
Term: Expires on last to expire of valid patent
claims.
Intellectual Property: Filing, prosecution, enforcement, and defense
responsibility of Progenitor. Patent
applications to be filed in major market
countries and prosecuted to obtain broad
protection consistent with sound, prudent
patent practice. Progenitor will provide
Institution with copies of filings and
correspondence relating to, and will consult
with Institution on, prosecution activities
Diligence: Commercially reasonable efforts to achieve
objective milestones leading to
commercialization..
Termination: By Institution: For breach by Progenitor
By Progenitor: For breach by Institution of
upon 60-day notice.
Grant-back: Patent applications and data revert to
Institution upon termination of the license
agreement by Progenitor.
For a period of 1 year after the effective
date of reversion of rights to Institution,
Progenitor shall have a right of first
refusal on third-party
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grant-backs of joint intellectual property to
Institution.
FINANCIAL TERMS:
Intellectual property costs and Borne by Progenitor
expenses:
Consideration: Joint Intellectual Property: Progenitor to
pay to Institution [***] of any fees,
royalties or other cash consideration actually
received by Progenitor, excluding research and
development support and equity investments.
Institutional Intellectual Property:
Progenitor to pay to Institution [***] of any
fees, royalties or other cash consideration
actually received by Progenitor, excluding
research and development support and equity
investments.
2
