License Agreement - Ann Arbor Stromal Inc. and the Regents of the University of Michigan
ATTACHMENT 1
RESEARCH AGREEMENT
UM/Ann Arbor Stromal
LICENSE AGREEMENT
By this Agreement, Ann Arbor Stromal, Inc. (hereinafter "Ann Arbor Stromal") and
the Regents of The University of Michigan, a constitutional corporation of the
State of Michigan (hereinafter "University") agree as follows:
1. INCORPORATION BY REFERENCE
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Incorporated by reference with full force and effect to the provisions,
definitions, terms and conditions of this License Agreement (hereinafter
"License") are the provisions, definitions, terms and conditions of the
Research Agreement to which this License is attached, including the Option
Agreement and its Appendices.
2. DEFINITIONS
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2.1 "Effective Date" of this License shall be the date of completed
execution by both Parties in accordance with the provisions of Article
9 entitled "License", in the abovementioned Research Agreement to which
this License is attached.
2.2 "Parties", in singular or plural usage as required by the context,
means Ann Arbor Stromal and/or University.
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2.3 "Territory" means all countries of the world.
2.4 "Licensed Technology" means all patentable inventions and Know-how for
the production of red blood cells, white blood cells, platelets and
bone marrow cells, which are either described in University Project
proposal, or conceived or reduced to practice as part of Project, or
conceived or reduced to practice, whether or not pursuant to or as
part of the Project, by Drs. Stephen G. Emerson, Michael F. Clarke or
Bernhard O. Palsson, or those working under their direction, during
the term of their participation in the Project and Ann Arbor Stromal's
funding of the Project.
2.5 "Licensed Patent(s)" means any and all pending patent applications(s)
included within Licensed Technology, whether now existing or hereafter
filed, both domestic and foreign, and any patents issuing therefrom.
2.6 "Valid Claim(s)" means any claim(s) pending in a patent application or
in an unexpired patent included within the Licensed Patents which has
not been held unenforceable, unpatentable, or invalid by a decision of
a court or other governmental agency of competent jurisdiction,
unappealable or unappealed within the time allowed for appeal, and
which has not been admitted to be invalid or unenforceable through
reissue or disclaimer. If in any country there should be two or more
such decisions conflicting with respect to the validity of the same
claim, the decision of the higher or highest tribunal shall thereafter
control;
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however, should the tribunals be of equal rank, then the decision or
decisions upholding the claim shall prevail when the conflicting
decisions are equal in number, and the majority of decisions shall
prevail when the conflicting decisions are unequal in number.
2.7 "Know-How" means (a) all information, data and knowledge contained in
patent applications or patents which are at anytime included in the
definition of Licensed Patents, and (b) any other methods, procedures,
processes, compositions of matter, biological materials, trade
secrets, experience, work products technical information, inventions,
discoveries, improvements, reports, data, results from experiments,
developmental efforts and demonstrations and subject matter related to
the Project, whether or not contained in Licensed Patents.
2.8 "Product(s)" means any red blood cells, white blood cells, platelets
and bone marrow cells as well as any components, by-products, progeny
or derivatives thereof and any factor, composition, substance,
equipment, mechanism, device or other property and combinations
thereof, the manufacture, use or sale of which would, but for this
License, comprise an infringement of one or more Valid Claims.
2.9 "Combination Sales" shall mean sales of Product by Ann Arbor Stromal,
its Affiliates or subsidiaries as a combined package comprised in part
of Product and in part of one or more other products or parts which
constitute either an
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active ingredient or a significant delivery system or mechanism and
which could readily be sold by Ann Arbor Stromal, its Affiliates or
subsidiaries and used for their intended purpose by their purchasers
without the incorporation or use of Product.
2.10 "Net Sales" means the sum, over the term of this License, of all
amounts of monies received and all other consideration received (when
in a form other than cash or its equivalent, the fair market value
thereof when received) by Ann Arbor Stromal, its Affiliates or
subsidiaries from purchasers or users from or by reason of the sale,
distribution or use of Product, less any amounts collected for taxes,
including sales and use taxes, customer charges, allowances (including
any allowance for bad debts), import and export duties and other
governmental charges, prompt payment or other customary trade
discounts allowed or taken, credits or refunds for goods returned and
transportation and delivery charges (including insurance premiums).
If Product is sold in Combination Sales, then Net Sales shall be
computed in the following manner: First, gross revenues from the
Combination Sales shall be reduced by any applicable deductions
itemized in the first paragraph of this definition in order to arrive
at "Combination Net Sales"; second, Net Sales shall be calculated by
employing the following formulas:
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C - p = Net Sales.
In the above formula, "p" is the fair market value of all other
products or parts which constitute an active ingredient or significant
delivery system or mechanism within the Combination Sale and C is
equal to Combination Net Sales.
All fair market value calculations made by Ann Arbor Stromal hereunder
shall be in good faith determined by Ann Arbor Stromal in the event no
market price is available. In the event the University disagrees with
any aspect of Ann Arbor Stromal's implementation of this definition,
University may request that such dispute be submitted to arbitration
as described in Article 17 and Ann Arbor Stromal hereby agrees to
promptly grant and fully cooperate with such request.
2.11 "Affiliate" shall mean any corporation, partnership, proprietorship or
other entity controlled by, controlling, or under common control with
Ann Arbor Stromal, and shall include any corporation, partnership,
proprietorship or other entity directly or indirectly owning, owned by
or under common ownership with the party in question to the
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extent of twenty-five percent (25%) or more of the equity or voting
shares, including shares owned beneficially by such party.
2.12 "Calendar Quarters" means the three (3) months ending on the last day
of March, June, September and December of each year.
3. GRANTS
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3.1 Subject to the conditions and provisions of this License, University
hereby grants to Ann Arbor Stromal an exclusive world-wide license,
without the right to grant sublicenses, except as described in
paragraph 3.2 below, under Licensed Patents and to use Know-How to
make, use, and sell Product(s), except that University hereby retains
the right to use Licensed Patents and Know-How solely for research
purposes, and except that to the extent funding from federal agencies
results in Licensed Technology or Licensed Patents in addition to
Project funding, the federal government may have its standard license
rights with respect to such Licensed Technology or Licensed Patents.
3.2 If at any time Ann Arbor Stromal wishes to grant sublicense rights
under its exclusive license rights granted herein, University and Ann
Arbor Stromal shall negotiate in good faith in order to allow Ann
Arbor Stromal to enter into such sublicensing arrangements with a
royalty return on Product(s) to University comparable to royalties
earned by
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University under this License. Subject only to this understanding and
the need to have any sublicensing arrangements reflect a fair market
value return to Ann Arbor Stromal as in an arms length transaction, it
is the understanding of the parties that Ann Arbor Stromal should be
able to make its own decisions as to the appropriate mechanisms,
including sublicensing, for exploiting the Licensed Technology.
3.3 The University and Ann Arbor Stromal hereby assert that, to the best of
their knowledge as of the date of execution of the Option Agreement,
there do not exist any University patents or pending patents, other
than the Licensed Patents of this License Agreement, which would be
infringed by the practice of the Licensed Patents of this License or
which would otherwise prevent the practice of any of the Valid Claims.
If, however, such University patents or patent applications are
subsequently found to have existed prior to the date of the Option
Agreement, University shall use reasonable efforts to grant to Ann
Arbor Stromal a nonexclusive license to such patents and/or patent
applications, to the extent necessary for the practice of the Licensed
Technology of this License.
4. ROYALTIES
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4.1 The license rights granted to Ann Arbor Stromal herein are subject to
Ann Arbor Stromal's payment of royalties to University according to the
provisions of this Section 4.
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4.2 For Product(s) defined in 2.8 herein, Ann Arbor Stromal will pay
University a royalty equal to two percent (2%) of Net Sales of such
Product(s) by Ann Arbor Stromal and Affiliates for the life of the last
to expire of Licensed Patents.
4.3 Where Net Sales form the basis upon which payment to University is
derived, the obligation to pay University under this Section 4 is
imposed only once with respect to the same unit of Product regardless
of the number of Valid Claims, Licensed Patents or items of Know-How
covering the same; however, for purposes of determination of payments
due hereunder, whenever the term Product may apply to a property during
various stages of manufacture, use or sale, Net Sales, as otherwise
defined shall be derived from the sale, distribution or use of such
Product by Ann Arbor Stromal and Affiliates at the stage of its highest
invoiced value to unrelated third parties.
4.4 If at any time or from time to time an unrelated third party in any
country shall, under right of a compulsory license granted or ordered
to be granted by a competent governmental authority, manufacture, use
or sell any Product with respect to which royalties shall be payable
pursuant to Paragraph 4.2 of this Section, then Ann Arbor Stromal, upon
notice to University and during the period such compulsory license
shall be effective, shall have the right to reduce such royalty on each
unit of Product sold
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in such country to an amount no greater than the amount payable by said
third party in consideration of its compulsory license.
5. REPORTS
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5.1 Within sixty (60) days after the close of each Calendar Quarter during
the term of this License (including the last day of any such Calendar
Quarter following any termination of this License), Ann Arbor Stromal
shall report to University all royalties accruing to University under
Section 4 during such Calendar Quarter. Such quarterly reports shall
indicate for each Calendar Quarter the gross sales and Net Sales of
Product; such reports shall also indicate Net Sales with respect to
which payments are due and the amount of such payments, as well as the
various calculations used to arrive at said amounts, including the
quantity, description (nomenclature and type designation), country of
sale and country of manufacture of Product(s). In case no payment is
due for any such period, Ann Arbor Stromal shall so report.
5.2 Ann Arbor Stromal covenants that it will promptly establish and
consistently employ a system of specific nomenclatures and type
designations for Product(s) so that the various types can be identified
and segregated, and Ann Arbor Stromal and Affiliates will consistently
employ such system when rendering invoices thereon and henceforth
agrees to inform University, or its auditors, when requested as to
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the details concerning such nomenclature system as well as to all
additions thereto and changes therein.
5.3 Ann Arbor Stromal shall keep and it shall cause its Affiliates to keep,
true and accurate records and books of account containing data
reasonably required for the computation and verification of payments to
be made as provided by this License, which records and books shall be
open for inspection upon reasonable notice during business hours by
inspectors selected by and at the expense of University for the purpose
of verifying the amount of payments due and payable. Said right of
inspection will exist for six (6) years from the date of origination of
any such record and this requirement and right of inspection shall
survive any termination of this License for a period of three (3) years
after such termination. However, in the event that such inspection
reveals an underpayment of royalties to University in excess of five
percent (5%), then said inspection shall be at Ann Arbor Stromal's
expense and such underpayment shall become immediately due and payable
to University.
5.4 The reports provided hereunder shall be certified by an authorized
representative of Ann Arbor Stromal to be correct to the best of Ann
Arbor Stromal's knowledge and information.
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6. TIMES AND CURRENCIES OF PAYMENTS
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6.1 Payments accrued at the close of each Calendar Quarter shall be due and
payable in Ann Arbor, Michigan on the date each quarterly report,
provided for under Section 5 above, is due and shall be paid in United
States dollars. Ann Arbor Stromal agrees to make all payments due
hereunder to University by check addressed to the University's
Intellectual Properties Office or by wire transfer to the bank account
designated by University with telephonic confirmation of receipt
thereof.
6.2 On all amounts outstanding and payable to University, interest shall
accrue from the date such amounts are due and payable at a rate of two
(2) points above the prime lending rate as established by the Chase
Manhattan Bank, N.A. in New York City, New York, or at such lower rate
as may be required by law.
6.3 Any United States currency payments hereunder shall be determined by
converting foreign currencies into their equivalent in United States
dollars at the exchange rate of such currency as reported (or if
erroneously reported, as subsequently corrected) in the Wall Street
Journal on the last business day of the Calendar Quarter during which
such payments accrue (or if not reported on that date, as quoted by the
Chase Manhattan Bank, N.A. in New York City, New York).
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7. COMMERCIALIZATION
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7.1 Ann Arbor Stromal agrees to use commercially reasonable efforts in
proceeding with the development, manufacture, marketing and sale of
Products to commercially exploit the Licensed Technology and in
creating a supply and demand for same; provided, however, Ann Arbor
Stromal shall be entitled to exercise prudent business judgment in
meeting its obligations hereunder.
7.2 Where Ann Arbor Stromal engages in continuing development with respect
to Product(s), Ann Arbor Stromal shall keep University informed of such
developments in writing. Ann Arbor Stromal shall promptly inform
University of any patent applications, or similar applications,
relating to Product(s) or improvements thereon, filed by or on behalf
of Ann Arbor Stromal or Affiliates anywhere in the world.
8. INFRINGEMENT
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8.1 In the event a third party is infringing a Valid Claim by making, using
or selling Product(s) as defined herein, Ann Arbor Stromal shall have
the right to bring suit in its own name. University agrees to use
reasonable efforts to cooperate in the prosecution of such suit. Ann
Arbor Stromal shall bear the expense of any such litigation and, except
as described in Paragraph 8.5 below, shall have full authority to
negotiate a settlement on such terms as Ann Arbor Stromal shall
determine. Ann Arbor Stromal shall
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share twenty-five percent (25%) of any resulting settlement payments or
recovery awarded, less reasonable and actual attorneys' fees paid and
unrecovered by Ann Arbor Stromal and University, with University.
8.2 In the event University, in its sole discretion determines that an
infringement of Valid Claims resulting from a third party's making, using
or selling of Product(s) is significant, University shall serve notice on
Ann Arbor Stromal and Ann Arbor Stromal shall, within sixty (60) days of
said notice, commence appropriate legal action. Ann Arbor Stromal shall
share twenty-five percent (25%) of any resulting settlement payments or
recovery awarded, less reasonable and actual attorneys' fees paid and
unrecovered by Ann Arbor Stromal and University, with University. If Ann
Arbor Stromal fails to commence such action, University may, at its option,
commence legal action. Ann Arbor Stromal shall use reasonable efforts to
cooperate in such action. University shall bear the expense of any such
litigation and, except as described in Paragraph 8.5 below, shall have full
authority to negotiate a settlement on such terms as University shall
determine. Provided that Ann Arbor Stromal has maintained the license
rights granted in 3.1 herein, University shall share twenty-five percent
(25%) of any resulting settlement payments or recovery awarded, less
reasonable and actual attorneys' fees paid and unrecovered by University
and Ann Arbor Stromal, with Ann Arbor Stromal.
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8.3 In the event that during the term hereof there be made against Ann
Arbor Stromal, any charge for infringement of any third-party patent by
reason of Ann Arbor Stromal's or Affiliate's manufacture or sale of a
Product or any customer's use of the Product which charge is grounded
essentially on an asserted domination by that third-party patent of the
manufacture, sale or use of such Product, Ann Arbor Stromal shall give
written notice thereof to University. Ann Arbor Stromal agrees to
effectuate, if possible, an acceptable change in the Product to avoid
such alleged infringement. If no such satisfactory change can be
effectuated, University and Ann Arbor Stromal agree to collaborate and
enter into discussions with said third party for the purposes of
negotiating a settlement. If no settlement can be agreed upon by Ann
Arbor Stromal, University and the third party, Ann Arbor Stromal shall
have the right, but not the obligation, to defend any suit for
infringement brought against it by the third party, and if required by
law or if requested by University, to join University as a party
defendant. If Ann Arbor Stromal shall elect not to defend such
infringement suit, Ann Arbor Stromal shall promptly notify University
to that effect and University shall thereafter have the obligation to
defend the suit provided Ann Arbor Stromal reimburses the University
within thirty (30) days of invoicing for all cost and expenses
(including reasonable attorney fees), and if required by law or if
requested by Ann Arbor Stromal, to join Ann Arbor Stromal as a party
defendant.
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8.4 Ann Arbor Stromal will bear the cost of defending claims of
infringement or pursuing infringers, except as allowed in Paragraph 8.2
above. However, Ann Arbor Stromal can be reimbursed for up to one-half
of the unrecovered amount of such actual and reasonable expenses in the
following manner: Ann Arbor Stromal can deduct from royalties otherwise
due and payable to University under the License, up to fifty percent
(50%) until such time as Ann Arbor Stromal has recovered one-half of
its actual, reasonable, and otherwise unrecovered expenses.
University's "obligation" of bearing one-half of Ann Arbor Stromal's
expenses shall not exceed the ability of the above-described mechanism
(i.e., a 50% reduction in royalty payments due and payable) to
reimburse such expenses and University royalty payments otherwise due
shall never be reduced by more than 50%. Ann Arbor Stromal will make an
accounting to University of all such expenses as part of its reporting
obligations under Section 5.
8.5 Neither University nor Ann Arbor Stromal shall compromise or settle any
claim or action in any manner that would affect the rights of the other
Party without the consent of said other Party.
9. TERMINATION
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9.1 With respect to any termination of this License, and except as provided
herein to the contrary, all rights and
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obligations of the Parties hereunder shall cease with respect thereto,
except as follows:
9.1.1 Obligations to pay royalties and other sums accruing hereunder up to
the day of such termination;
9.1.2 Obligations to pay royalties on Net Sales, subsequent to said date of
termination of Product(s) in Stock at the date of termination with
respect to which stock Ann Arbor Stromal shall have a reasonable time
to sell or liquidate in a reasonable manner as deemed necessary by
Ann Arbor Stromal under the circumstances;
9.1.3 Obligations for record keeping and accounting reports for so long as
Product(s) are sold pursuant to Paragraph 9.1.2 above. At such time
as there are no sales or other dispositions of Product(s) upon
termination of this License, Ann Arbor Stromal shall render a final
report and royalty payment;
9.1.4 University's rights to audit books and records as described in
Section 5 herein;
9.1.5 Obligations of indemnity under Section 18;
9.1.6 Any cause of action or claim of Ann Arbor Stromal or University
accrued or to accrue because of any breach or default by the other
Party hereunder;
9.2 This License will become effective on its Effective Date and, unless
terminated under another, specific provision of
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this License, will remain in effect until and terminate upon the
expiration of the later of Ann Arbor Stromal's obligation to pay
royalties under Paragraph 4.3 herein or the last to expire of Licensed
Patents. After such full-term termination of this License, Ann Arbor
Stromal shall have the right to make, use and sell Product(s) without
further payment to University hereunder.
9.3 If Ann Arbor Stromal shall at any time default in the payment of any
royalty or the making of any report hereunder, or shall commit any
material breach of any material covenant or promise herein contained,
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or shall make any false report and shall fail to remedy any such
default, material breach or report within sixty (60) days after written
notice thereof by University, University may, at its option, terminate
this License by notice in writing to such effect. In the event of such
termination, interest shall continue to accrue as described in
Paragraph 6.2 on any amounts outstanding and payable to University and
any such termination shall be without prejudice to University's other
legal rights for breach of this License.
9.4 In the event that Ann Arbor Stromal desires to terminate this License,
Ann Arbor Stromal shall serve upon University a notice of termination,
including a statement of reasons for such termination, at least six (6)
months before a termination date established by Ann Arbor Stromal. Such
notice shall be deemed by the parties to be final, and immediately upon
service of such notice of termination,
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University shall have the right to begin negotiations and enter into
agreements with others for the manufacture, sale and use of the
Product(s), and may, at its option, disclose to said others any and all
information related to Product(s) other than Confidential Information
generated or developed solely by Ann Arbor Stromal. During the period
of time from the notice of termination until termination pursuant to
this provision, Ann Arbor Stromal shall continue to commercialize
Product(s) and to make them reasonably available to the public at fair
market value.
10. ASSIGNMENT
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This License shall not be transferable or assignable by either Party without
the prior written consent of the other Party, which consent shall not be
unreasonably withheld; and any attempt to transfer or assign this License
without such consent shall be void from the beginning. No transfer or
assignment may be made by Ann Arbor Stromal unless and until the intended
transferee or assignee agrees in writing to accept all of the terms and
conditions of this License. For purposes of implementing this clause the
University's consent may only be withheld:
i) if the University reasonably believes that implementing the terms of
the proposed transfer or assignment could economically discriminate
against the University or its employees holding equity in Ann Arbor
Stromal as compared to any of the other shareholders or investors in
Ann Arbor Stromal or their principals; or
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ii) if the University reasonably believes that the proposed transfer
or assignment is to a third party which is not in a financial and
technical position at least equivalent to that of Ann Arbor
Stromal for purposes of exploiting and commercializing the
Licensed Technology.
11. REGISTRATION OR RECORDATION
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11.1 If the terms of this License, or any assignment or license under this
License are or become such as to require or make it appropriate that
the Agreement or license or any part thereof be registered with or
reported to a national or supranational agency of any area in which Ann
Arbor Stromal, or Affiliates would do business, Ann Arbor Stromal will,
at its expense, undertake such registration or report. Prompt notice
and appropriate verification of the act of registration or report of
any agency ruling resulting from it will be supplied by Ann Arbor
Stromal to University.
11.2 Any formal recordation of this Agreement or any license herein granted
which is required by the law of any country of the Territory as a
prerequisite to enforceability of the Agreement or license in the
courts of any such country or for other reasons shall also be carried
out by Ann Arbor Stromal at its expense, and appropriately verified
proof of recordation shall be promptly furnished to University.
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12. EXPORT LAWS AND REGULATIONS OF THE UNITED STATES
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12.1 The Export Regulations of the United States Department of Commerce
prohibit the exportation from the United States of certain types of
technical data and commodities (listed in the Export Administration
Regulations), unless the exporter (e.g., Ann Arbor Stromal or
Affiliates) has received the required General License or Validated
License, whichever is applicable. In addition, the exporter may be
required to obtain certain written assurances regarding re-export from
the foreign importer for certain types of technical data and
commodities. Prior to its engaging in any export activity, Ann Arbor
Stromal has advised University that it will receive a copy of the then
current Export Administration Regulations of the United States
Department of Commerce and will arrange for a subscription under which
it will receive Supplementary Bulletins from the United States
Department of Commerce upon their issuance. Ann Arbor Stromal hereby
agrees to comply with, and to require Affiliates to comply with, the
Export Administration Regulations of the United States Department of
Commerce; and Ann Arbor Stromal hereby gives University the assurances
called for in the Export Administration Regulations, including the
assurances called for in Part 379.4 and any successor provisions of
such regulations.
12.2 This License shall be subject to all United States Government laws and
regulations now or hereafter applicable to the subject matter of this
License.
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13. NOTICES
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Any notice, request, report, or payment required or permitted to
be given or made under this License by any Party shall be given
by sending such notice by prepaid certified mail, return receipt
requested, or by facsimile transmission to the address set forth
below or such other address as such party shall have specified by
written notice given in conformity herewith. Any notice not so
given shall not be valid unless and until actually received, and
any notice given in accordance with the provisions of this paragraph
shall be effective when mailed:
TO University: The University of Michigan
Intellectual Properties Office
475 East Jefferson, Room 2354
Ann Arbor, Michigan 48109-1248
Attention: File No. 433
TO Ann Arbor Stromal: Robert Kunze
General Partner
H&Q Life Science Technology Fund I
One Bush Street
San Francisco, California 94104
With copy provided to: Kenneth L. Guernsey
Attorney at Law
Cooley, Godward, Castro, Huddleson & Tatum
One Maritime Plaza, 20th Floor
San Francisco, CA 94111-3580
14. INVALIDITY
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In the event that any term, provision, or covenant of this License shall
be determined by a court of competent jurisdiction to be invalid, illegal,
or unenforceable, that term will be curtailed, limited, or deleted, but
only to the extent necessary
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to remove such invalidity, illegality, or unenforceability, and the
remaining terms, provisions, and covenants shall not in any way be affected
or impaired thereby. In the event that the time period of any covenant
shall be held unenforceable as a matter of law, said covenant will be
interpreted to be effective for an enforceable time period.
15. ENTIRE AGREEMENT AND AMENDMENT
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This License contains the entire understanding of the Parties with respect
to the matter contained herein, and supersedes all prior agreements, oral
or written, and all other communication between them relating to the
subject matter hereof. The Parties hereto may, from time to time during the
continuance of this License, modify, vary or alter any of the provisions of
this License, but only by an instrument duly executed by authorized
officials of both Parties hereto.
16. GOVERNING LAW
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This License and the relationships between the Parties shall be governed in
all respects by the law of the State of Michigan, the United States of
America, except that questions affecting the construction and effect of any
patent shall be determined by the law of the country in which the patent
has been granted.
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17. ARBITRATION AND DISPUTE RESOLUTION
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Any dispute relating to the interpretation or performance of this Agreement
or the grounds for the termination hereof shall be resolved at the request
of either party through final and binding arbitration by a single
arbitrator in accordance with the Commercial Arbitration rules of the
American Arbitration Association ("AAA"). Such arbitrator shall be selected
by the mutual agreement of the parties or, failing such agreement, shall be
selected according to the relevant AAA rules. The parties shall bear the
costs of such arbitrator and arbitration equally. The prevailing party in
any such arbitration shall be entitled to its reasonable attorney's fees
and costs solely at the discretion of the arbitrator in addition to any
other amount of recovery ordered by such arbitrator. The arbitrator or
court, as the case may be, shall determine which party is the "prevailing
party" for purposes of this section. If judicial enforcement or review of
such arbitrator's award is sought by either party, judgment may be entered
upon such award in any court of competent jurisdiction. Ann Arbor Stromal
hereby consents to venue and personal jurisdiction in Ann Arbor, Michigan
for any such arbitration proceeding and for any court proceeding. The duty
of the parties to arbitrate any dispute relating to the interpretation or
performance of this Agreement or the grounds for the termination thereof
shall survive any termination of this Agreement.
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18. INDEMNITY: INSURANCE
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18.1 Ann Arbor Stromal shall defend, indemnify and hold harmless and
shall require Affiliates to defend, indemnify and hold harmless
University, its fellows, officers, employees and agents, for and
against any and all claims, demands, damages, losses, and expenses
of any nature (including attorneys' fees and other litigation
expenses), resulting from, but not limited to, death, personal
injury, illness, property damage or products liability arising from
or in connection with, any of the following:
18.1.1 Any manufacture, use, sale or other disposition by
Ann Arbor Stromal, Affiliates, or other transferees of
Products;
18.1.2 The direct or indirect use of Products by any person;
18.1.3 The use by Ann Arbor Stromal or Affiliates of any invention,
discovery, data, information, product or process related to
Licensed Patents or Know-How.
18.2 University shall be entitled to participate at its option and expense
through counsel of its own selection, and may join in any legal
actions related to any such claims, demands, damages, losses and
expenses under Paragraph 18.1.
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19. NO WARRANTY: LIMITATIONS OF LIABILITY
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19.1 UNIVERSITY MAKES NO REPRESENTATIONS, EXTENDS NO WARRANTIES
OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING BUT NOT
LIMITED TO THE IMPLIED WARRANTIES OF MERCHANTABILITY OR
FITNESS FOR A PARTICULAR PURPOSE, AND ASSUMES NO
RESPONSIBILITIES WHATEVER WITH RESPECT TO DESIGN, DEVELOPMENT,
MANUFACTURE, USE, SALE OR OTHER DISPOSITION BY ANN ARBOR STROMAL
OR AFFILIATES OF PRODUCTS. Regardless of any testing which may
have been done at University, University makes no representations
regarding how Product can or should be used in any specific process.
19.2 THE ENTIRE RISK AS TO PERFORMANCE OF PRODUCTS IS ASSUMED BY ANN
ARBOR STROMAL AND AFFILIATES. Every user of Product must do its
own verification testing and define for itself any processes for
its use of Product. In no event shall University be responsible
or liable for any direct, indirect, special, incidental, or
consequential damages or lost profits to Ann Arbor Stromal,
Affiliates, users or any other individual or entity regardless of
legal theory. The above limitations on liability apply even though
University may have been advised of the possibility of such damage.
19.3 University represents that to the best of its knowledge and belief
it has the lawful right to grant the license set forth herein
without breaching the terms or conditions of any agreements with
any third parties.
25
<PAGE>
20. PUBLICITY
---------
Ann Arbor Stromal agrees to refrain from using and to require
Affiliates to refrain from using quotes or opinions attributed or
attributable to University or any employee of University in publicity,
advertising, or news releases without the prior written approval of an
authorized representative of University. Reports in scientific literature
and presentations of joint research and development work are not considered
publicity.
21. PRODUCT MARKING
---------------
Ann Arbor Stromal and Affiliates agree to mark Products with the
appropriate patent notice as approved by University.
22. NON-WAIVER
----------
No waiver, no matter how long continuing or how many times extended,
by either Party of a breach of any term or condition of this License
shall be considered as a permanent waiver or as an amendment to this
instrument.
23. ARTICLE HEADINGS
----------------
The Article headings herein are for purposes of convenient reference
only and shall not be used to construe or modify the terms written in
the text of this agreement.
26
<PAGE>
24. FORCE MAJEURE
-------------
Neither Party hereto shall be deemed to be in default of any provision of
this License, or for any failure in performance, resulting from acts or
events beyond the reasonable control of such Party. For purposes of this
License, such acts shall include, but not be limited to, acts of Good, acts
of civil or military authority, civil disturbance, war, strikes, fires,
power failures, other catastrophes, or other "force majeure" events beyond
the Parties' reasonable control.
25. NO AGENCY RELATIONSHIP
----------------------
Except as clearly and specifically provided under the terms and provisions
of this License, neither Party shall be deemed to be an agent of the
other in connection with the exercise of any rights hereunder, and neither
shall have any right or authority to assume or create any obligation or
responsibility on behalf of the other.
26. CONFIDENTIALITY PROVISIONS
--------------------------
26.1 University and Ann Arbor Stromal each agree not to disclose or use,
except as required by law or contemplated by this License and the
Research Agreement to which this License is attached, the following
("Confidential Information"): (i) any of the terms of this License
and the Exhibits hereto (except for disclosure of basic terms which
may be required under University policy), or (ii) except as otherwise
27
<PAGE>
provided for in the Research Agreement's Article 7 (Publications), any
Project related Know-How, data, process, technique, drawing, formula,
future development, or engineering or manufacturing development of either
party and any marketing, business plan, servicing, financial or personnel
matter relating to the other party, its present or future products, sales,
suppliers, customers, employees, investors or business except as Ann Arbor
Stromal finds reasonably necessary to conduct its business or raise
capital or (iii) any information received from the other party which is in
written form and marked "Confidential", "Proprietary", "Secret" or the
like.
26.2 The parties hereto agree that the provisions of this Article 26 shall
survive, whether or not the other provisions hereof remain in full
force and effect, for a period of three (3) years after any termination
of this License.
26.3 Confidential Information shall not include and neither party shall be
obligated to hold in confidence or restrict the use of any information
(i) which is or becomes public knowledge without breach of this License,
(ii) which is or becomes available without a confidentiality restriction
and without breach of this License from a source other than a party
hereto, (iii) which is produced in response to a court order or government
action, (iv) which is disclosed with the other party's prior written
approval, (v) which is independently developed by the party receiving
the Confidential Information from the other party, or (vi) which is known
by other means to the party receiving the
28
<PAGE>
Confidential Information at the time of disclosure of same, and in the
case of (v) and (vi), can be established by documentary evidence.
IN WITNESS WHEREOF, each of the Parties hereto has caused this entire
agreement to be executed in duplicate originals by its duly authorized
officer or representative.
FOR THE REGENTS OF
FOR ANN ARBOR STROMAL, INC. THE UNIVERSITY OF MICHIGAN
By /s/ R. DOUGLAS ARMSTRONG By /s/ ROBERT F. GAVIN
--------------------------- ---------------------------
(authorized representative) (authorized representative)
Typed Name R. Douglas Armstrong Typed Name Robert F. Gavin
-------------------- ---------------
Title President and CEO Title Director, Intellectual Properties
----------------- ---------------------------------
Date 3/13/92 Date 3/13/92
------- -------
29
<PAGE>
FIRST AMENDMENT TO LICENSE AGREEMENT
This First Amendment to License Agreement is made as of March 13, 1992,
---------------
by and between Aastrom Biosciences, Inc. (formerly Ann Arbor Stromal, Inc.),
a Michigan corporation, (hereinafter "Aastrom") and the Regents of the
University of Michigan, a constitutional corporation of the State of Michigan
(hereinafter "University").
RECITATIONS
The following is a recital of facts underlying this Agreement:
A. On March 13, 1992 the parties hereto have executed a certain License
--------------
Agreement ("License Agreement") as contemplated by a certain Research
Agreement between the parties hereto which was executed by them during
August of 1989 (the "Research Agreement"). Defined terms not otherwise
defined in this First Amendment shall have the meanings set forth in the
License Agreement.
B. The parties now wish to amend the License Agreement in certain respects.
NOW, THEREFORE, in consideration of their mutual promises, the parties hereto
agree as follows:
1. The License Agreement is hereby amended as follows.
(a) Licensed Technology includes:
<PAGE>
i) all patent applications, including related foreign patent applications,
and patents issuing therefrom identified in Exhibit A attached hereto;
ii) all Know-How included in patents and patent applications of Exhibit A
and grant proposals, papers, abstracts and other documents described in
Exhibit B attached hereto; and
iii) all additional patentable inventions and Know-How for the production of
red blood cells, white blood cells, platelets and bone marrow cells, which
is either described in University Project proposal, or conceived or reduced
to practice as part of Project, or conceived or reduced to pratice, whether
or not pursuant to or as part of the Project, by Drs. Stephen G. Emerson,
Michael F. Clarke or Bernhard O. Palsson, or those working under their
direction, during the term of their participation in the Project and
Aastrom's funding of the Project.
(b) Section 3.2 of the License Agreement hereby is amended to read in its
entirety as follows:
3.2 Aastrom shall have the right to grant one or more sublicenses for
third parties to use the rights granted to Aastrom under its exclusive
2
<PAGE>
license rights granted in this License Agreement; and, subject to approval by
Aastrom, sub-sublicense agreements may also be granted by a third party
sublicensee. All sublicenses and sub-sublicenses, if any, shall provide that the
sublicensee and sub-sublicensee shall comply fully with all provisions of this
License Agreement, including without limitation, paying the same royalty to the
University as is specified in this License Agreement. Notwithstanding any such
sublicensing, Aastrom shall still remain fully responsible and liable for
compliance with all terms of this License Agreement, including compliance by any
and all sublicensees and sub-sublicensees. No consent from University is
required for any sublicense or sub-sublicense, as described above; however,
Aastrom shall provide timely notice of each sublicense hereunder along with
copies of all sublicense agreements. Should Aastrom propose to enter into a
sublicense which reduces any royalties payable to University, or which otherwise
modifies any of the rights of University under this License Agreement, then no
such sublicense can be entered into without the prior written consent of
University and any
3
<PAGE>
such sublicense entered into without prior written consent of
University shall be void from the beginning. For example, if the
proposed sublicensee is to issue stock to Aastrom in lieu of
royalties, or if a proposed sublicensee is to make a lump sum front-
end payment as a set-off against or in lieu of future royalties, then
there shall be negotiations between Aastrom and University for an
equitable allocation of said consideration in lieu of royalties, with
the mutual consent of Aastrom and University required for any such
non-conforming sublicense agreement.
2. Article 13 of the License Agreement, entitled "Notices", is amended as
follows:
i) Provision for notice to Robert Kunze and Kenneth Guernsey is hereby
deleted; and
ii) Notice to Aastrom shall be provided to:
Aastrom Biosciences, Inc.
President/CEO
P.O. Box 130469
Ann Arbor, Michigan 48113-0469
4
<PAGE>
3. As amended hereby, the License Agreement shall continue in full force
and effect.
IN WITNESS WHEREOF, the parties hereto have caused their duly authorized
representatives to execute and deliver this First Amendment as of the date
set forth above.
FOR THE REGENTS OF
FOR AASTROM BIOSCIENCES, INC. THE UNIVERSITY OF MICHIGAN
By /s/ R. DOUGLAS ARMSTRONG By /s/ ROBERT F. GAVIN
--------------------------- --------------------------
(authorized representative) (authorized representative)
Typed Name R. Douglas Armstrong Typed Name Robert F. Gavin
-------------------- ---------------
Title President and CEO Title Director, Intellectual Properties
----------------- ---------------------------------
5
<PAGE>
EXHIBIT A
License Agreement Amendment dated March 13, 1992
between UM and Aastrom Biosciences
DOCUMENTATION FOR LICENSE AMENDMENT AGREEMENT
1. The following U.S. patent applications and all related foreign applications:
A. U.S. APPLICATION, SER. #07/366,639, OSMMN REF. #2363-022-55
Methods, Compositions and Devices for Growing Cells.
Filed: 6/15/89
B. U.S. APPLICATION, SER. #07/628,343, OSMMN REF. #2363-023-55 CIP
Methods and Compositions for the Ex Vivo Replication of Stem Cells
and for the Optimization of Hematopoietic Progenitor Cell Cultures.
Filed: 12/17/90
E. U.S. APPLICATION, SER. #07/737,024, OSMMN REF. #2363-034-55
Methods and Compositions for the Ex Vivo Replication of Stem Cells,
for the Optimization of Hematopoietic Progenitor Cell Cultures,
and for Increasing the Metabolism, GM-CSF Secretion and/or IL-6
Secretion of Human Stromal Cells.
Filed: 7/29/91
F. U.S. APPLICATION, SER. #07/740,590, OSMN REF. #2363-035-55
Methods for Human Gene Therapy, Including Methods and Compositions
for the Ex Vivo Replication and Stable Genetic Transformation of Human
Stem Cells, for the Optimization of Human Hematopoietic Progenitor Cell
Cultures and Stable Genetic and/or IL-6 Secretion of Human Stromal
Cells.
Filed: 8/5/91
H. U.S. APPLICATION, SER. #07,815,513, OSMMN REF. #2363-036-55
Methods for Regulating the Specific Lineages of Cells Produced in
a Human Hematopoietic Cell Culture, Methods for Assaying the Effect
of Substances on Lineage-Specific Cell Production, and Cell Compositions
Produced by these Cultures.
Filed: 1/2/92
I. U.S. APPLICATION, SER. #07/822,136, OSMMN REF. #2363-055-55
Targeted Virus.
Filed: 1/17/92
J. PENDING U.S. APPLICATION, OSMMN REF. #2363-043-55
Methods, Compositions and Devices for Maintaining and Growing Human
Stem and/or Hematopoietic Cells.
Filed: 3/4/92
Page 1
2/4/92
<PAGE>
DESCRIPTION AUTHOR DATE
----------- ------ ----
2. Business Plan and Strategy AASTROM Biosciences, Inc. Dec., 1991
3. Research Plan AASTROM Biosciences, Inc. Sept., 1991
4. Goals, Science/Business, Ann Arbor Stromal, Inc. Undated
Personnel & Structure
5. Research Agreement Appendix C to Option 3/24/89
Agreement
6. SBIR Proposal: Hematopoietic R. Douglas Armstrong 12/12/91
Cell Expansion System
7. NRA-91-OSSA-18 Proposal: Bernard O. Palsson 11/25/91
Shear Sensitivities of Human
Bone Marrow Cultures
8. ACS Proposal: Hematopoietic Bernard O. Palsson 10/30/91
Bioreactor System to Improve
Bone Marrow Transplantation
for Treatment of Cancer
9. Aastrom System One (Version Bernard O. Palsson 10/19/91
1.00 - Draft)
10. NRA-91-OSSA-13 Proposal: Bernard O. Palsson 8/15/91
Reconstructing Human Bone
Marrow Ex Vivo
11. NSF Proposal: Optimal Growth Bernard O. Palsson 7/3/90
Factor Combinations for Human
Bone Marrow Cultures and Large-
Scale Cell Production
12. Naval Medical Command Proposal: Bernard O. Palsson 2/20/89
Ex vivo Bone Marrow:
Construction of a Perfusion
Device
13. SBIR Proposal: Bioreactor for R. Douglas Armstrong 12/12/91
Retrovirus Infection of hemato-
poietic Cells
14. Experiment (Clarke) Michael F. Clarke 1/9/92
15. NIH Proposal: In Vitro Stephen G. Emerson 1/16/92
Expanded Hematopoietic
Progenitors for ABMT
16. NIH Proposal: Stromal Cell Stephen G. Emerson 9/20/91
CSF Regulation and
Hematopoiesis
17. Aplastic Anemia Foundation Stephen G. Emerson 7/1/92 (beg.
of America (Postdoctoral date)
application): Leslie G.
Blesecker
Documentation for License Amendment Agreement
Page 2
2/4/92
<PAGE>
DESCRIPTION AUTHOR DATE
----------- ------ ----
18. The Leukemia Society of Stephen G. Emerson 8/29/89
America (Scholarship
application): Stem Cell
Cytoadhesion Molecules in
Chronic Myelogenous Leukemia
19. The Leukemia Society of America Stephen G. Emerson 4/26/91
(Scholarship application -
continuation) Stem Cell
Cytoadhesion Molecules in Chronic
Myelogenous Leukemia
20. NIH Proposal: Optimization and Stephen G. Emerson 7/20/90
Manipulation of Human Marrow Cultures
21. NSF Proposal: (Research Experience Stephen G. Emerson 1/30/89
for Undergraduates) Effect of Serum
Concentration and Perfusion Rate on
Stromal Cell Metabolism
22. NSF Proposal: Contruction and Stephen G. Emerson 5/15/89
Maintenance of Functioning Bone
Marrow Tissue Ex Vivo
23. NSF Proposal: Construction of a Stephen G. Emerson 5/10/88
High Efficiency Ex Vivo Bone Marrow
24. NRA-88-OSSA-5 Proposal: Development Stephen G. Emerson 8/15/88
of a Device for the Large-Scale
Cultivation of Human Bone Marrow:
Space Flight Applications
25. Presidential Initiations Proposal: Stephen G. Emerson Undated
Development of an Artificial Bone
Marrow
26. Paper: In Vitro Myelopoiesis Schwartz RM, Emerson Blood,
Stimulated by Rapid Medium Exchange SG, Clarke MF, Palsson 78:12, pp
and Supplementation with hemato- BO 3155-3161,
poietic Growth Factors (12/15/91)
27. Paper: Can Dexter Cultures Support Varma A, El-Awar FY, Experi-
Stem Cell Proliferation? Palsson BO, Emerson SG, mental
Clarke MF Hematology,
20:87-91
(1992)
28. Paper: Rapid medium perfusion rate Schwartz RM, Palsson PNAS,
significantly increases the BO, Emerson SG 88:6760-
productivity and longevity of human 6764
bone marrow cultures (8/91)
29. Paper: The Construction of High Emerson SG, Palsson BO, J Cell.
Efficiency Human Bone Marrow Tissue Clarke MF Biochem
Ex Vivo 45:268-
272 (1991)
Documentation for License Amendment Agreement
Page 3
2/4/92
<PAGE>
DESCRIPTION AUTHOR DATE
----------- ------ ----
30. Paper: Culture Perfusion Schedules Caldwell J, J Cell Phys
Influence the Metabolic Activity and Palsson BO, 147:344-353
Granulocyte-Macrophage Colony- Locey B, (1991)
Stimulating Factor Production Rates Emerson SG
of Human Bone Marrow Stromal Cells
31. Paper: Influence of Medium Exchange Caldwell J, Biotechnol.
Schedules of Metabloic, Growth, and Locey B, Progress
GM-CSF Secretion Rates of Genetically Clarke MF, Vol. 7, No.1
Engineering NIH-3T3 Cells Emerson SG Jan/Feb, 1991
Palsson BO
32. Paper: The Influence of Extra-Cellular Schwartz RM, Submitted to
Matrix and Stroma Remodeling on the Caldwell J, Cytotechnology
Productivity of Long-Term Human Bone Clarke MF, Sept., 1991
Marrow Cultures Emerson SG,
Palsson BO
33. Advanced Technology Program Proposal: R. Douglas 9/24/91
ATP 91-01: Human Stem Cell and Armstrong
Hematopoietic Expansion Systems
34. Thesis: Optimization of Human Long- Richard M. 1991
Term Bone Marrow Cultures Schwartz
35. Chapter: The Role of Physiologic Caldwell J, Undated
Perfusion in the Metabolism and Palsson BO,
Genetic Regulation of Cytokine Clarke MF,
Production in Mesenchymal Stromal Cells Emerson SG
36. UM Disclosure #715 "Mouse Tyrosine Emerson SG Biotechnol
Kinare partial CDNA sequences A1,
A8, P4, P7, P21"
Documentation for License Amendment Agreement
Page 4
2/4/92
<PAGE>
SECOND AMENDMENT TO
LICENSE AGREEMENT
This Second Amendment to License Agreement is entered into as of October 8,
1993, by and between Aastrom Biosciences, Inc. (formerly Ann Arbor Stromal,
Inc., a Michigan corporation, hereinafter called "Aastrom"), and the Regents of
the University of Michigan, a constitutional corporation of the State of
Michigan (hereinafter called "University").
RECITATIONS
The following is a recital of facts underlying this Agreement.
A. In August, 1989, the parties hereto entered into a certain Research
Agreement (the "Research Agreement") pursuant to which Aastrom provided
funding to the University for the University to conduct a certain research
project. Pursuant to an Extension Agreement dated March 2, 1992, the
parties extended the term of the Research Agreement until June 30, 1993,
and extended the scope of the research projects and funding under the
Research Agreement. As used hereinafter, the term "Research Agreement"
shall include said Extension Agreement. Pursuant to the Research
Agreement, Aastrom is entitled to an exclusive license to utilize any and
all inventions, technology, and know-how (i) resulting from the research
projects funded by Aastrom at the University, or (ii) related to the
research projects (subject to certain qualifications).
B. On March 13, 1992, the parties entered into a certain License Agreement
(the "License Agreement"), as contemplated by the Research Agreement; and
on March 13, 1992, the parties also entered into that certain First
Amendment to License Agreement (the "First Amendment to License Agreement")
for the purpose of modifying and clarifying certain terms in the original
License Agreement. As used hereinafter, the term "License Agreement" shall
include said First Amendment.
C. Subsequent to entering into the First Amendment to License Agreement, some
additional patent rights, technology, know-how and other intellectual
property rights have been identified which are to be licensed to Aastrom
pursuant to the License Agreement. This Second Amendment is being entered
into for the purpose of identifying said additional rights.
NOW THEREFORE, in consideration of their mutual promises, the parties
hereto agree as follows:
1. LICENSED TECHNOLOGY. In addition to all other Licensed Technology (as
defined in the License Agreement) which is already identified as being
covered by the License Agreement, the Licensed Technology shall also
include the additional patent-
<PAGE>
related matters identified in Exhibit A attached hereto, as well as
the additional technology and know-how identified in the documents
described in Exhibits B (1) and B(2) attached hereto, which technology
and know-how have resulted from research pursuant to the Research
Agreement.
2. EFFECT. Excepting only as otherwise expressly set forth above, all
other terms and provisions of the License Agreement shall remain in
full force and effect.
IN WITNESS WHEREOF, the parties hereto have caused their duly authorized
representatives to execute and deliver this Second Amendment as of the date set
forth above.
FOR: FOR:
THE REGENTS OF
AASTROM BIOSCIENCES, INC. THE UNIVERSITY OF MICHIGAN
BY: /s/ R. DOUGLAS ARMSTRONG BY: /s/ ROBERT L. ROBB
--------------------------- -----------------------------------
R. DOUGLAS ARMSTRONG, PH.D.
PRESIDENT AND CEO ITS: Director Technology/Management
Office
-2-
<PAGE>
EXHIBIT A
PATENT MATTERS
All of the following patent applications and patent matters, including all
related foreign patent rights and all patents issued and patent rights related
thereto:
A. U.S. APPLICATION #07/990,299, CAMPBELL & FLORES REF.#P-UM 9380
Novel Embryonic Tyrosine Kinase Sequences and Uses Thereof
Biesecker, Leslie G.; Emerson, Stephen Gx.
filed: 12/8/92
B. PENDING U.S. APPLICATION, CAMPBELL & FLORES REF. #P-UM 9430
P53-Mediated Apoptosis for the Therapeutic Treatment of Diseases
Clarke, Michael F.
C. PENDING U.S. APPLICATION, CAMPBELL & FLORES REF. #P-AA 9609
Directed Motion of Gene-Transfer Vectors for Increased Infectivities
Palsson, Bernhard O.
-3-
<PAGE>
EXHIBIT B (1)
Know-how and Technology Items
All of the following and attached grant proposals, papers, abstracts and other
documents, together with all inventions, know-how and/or technology described
therein or resulting therefrom:
DESCRIPTION AUTHOR DATE
1. PAPER: BONE MARROW GUBA, SC; SARTOR, BLOOD
STROMAL FIBROBLASTS SECRETE CL; GOTTSCHALK, LR; 80(5):1190-1198
INTERLEUKIN-6 AND YE-HE,J; SEPT., 1992)
GRANULOCYTE-MACROPHAGE MULLIGAN,T;
COLONY-STIMULATING FACTOR EMERSON,SG
IN THE ABSENCE OF
INFLAMMATORY STIMULATION:
DEMONSTRATION BY SERUM-FREE
BIOASSAY, ENZYME-LINKED
IMMUNOSORBENT ASSAY, AND
REVERSE TRANSCRIPTASE
POLYMERASE CHAIN REACTION
2. ABSTRACT: MOLECULAR GOTTSCHALK, LR; ASH, 1992
REGULATION OF THE HUMAN GIANNOLA, DM;
IL-3 GENE IN T-CELLS: EMERSON, SG
EXPRESSION REQUIRES AN
INTACT AP-1 AND ELF-1
NUCLEAR PROTEIN BINDING SITE
3. ABSTRACT: EX VIVO PALSSON, BO; ASH, 1992
EXPANSION OF HEMATOPOIETIC SCHWARTZ, RM;
PROGENITOR CELLS AND LTCIC PALSSON, M;
BY CONTINUOUS PERFUSION ARMSTRONG, RD;
CULTURE CLARKE, MF;
EMERSON, SG
4. ABSTRACT: IL-1 ALPHA CALDWELL, J; ASH, 1992
AND TNF-ALPHA ACT EMERSON, SG
SYNERGISTICALLY TO
STIMULATE PRODUCTION OF
MYELOID COLONY-STIMULATING
FACTORS BY CULTURED HUMAN
BONE MARROW STROMAL CELLS
AND CLONED STROMAL CELL
STRAINS
5. ABSTRACT: THE CLONING BIESECKER, LG; ASH, 1992
OF 5 NOVEL TYROSINE KINASE GOTTSCHALK, LR;
PARTIAL CDNAS ENCODING EMERSON, SG
CANDIDATE STEM CELL
CYTOKINE RECEPTORS
6. PAPER: IDENTIFICATION BIESECKER, L.G., ET AL PNAS
OF FOUR MURINE CDNAS 90, 7044-7048
ENCODING PUTATIVE PROTEIN (1993)
KINASES FROM PRIMITIVE
EMBRYONIC STEM CELLS
DIFFERENTIATED IN VITRO
-4-
<PAGE>
7. PAPER: INTERLEUKIN 6 IS A BIESECKER, LG; EXPERIMENTAL
COMPONENT OF HUMAN UMBILICAL EMERSON, SG HEMATOLOGY,
CORD SERUM AND STIMULATES 21:774-778
HEMATOPOIESIS IN EMBRYONIC STEM 1993
CELLS IN VITRO
8. PAPER: MOLECULAR REGULATION GOTTSCHALK, LR; JOURNAL OF
OF THE HUMAN IL-3 GENE: GIANNOLA, DM; EXPERIMENTAL
INDUCIBLE T-CELL RESTRICTED EMERSON, SG MEDICINE
EXPRESSION REQUIRES INTACT AP-1 IN PRESS
AND ELF-1 NUCLEAR PROTEIN NOV., 1993
BINDING SITES
9. PAPER: IL-1 ALPHA AND CALDWELL, J; JOURNAL OF
TNF-ALPHA ACT SYNERGISTICALLY TO EMERSON, SG CELLULAR
STIMULATE PRODUCTION OF MYELOID PHYSIOLOGY
COLONY-STIMULATING FACTORS BY ACCEPTED
CULTURED HUMAN BONE MARROW 1994
STROMAL CELLS AND CLONED STROMAL
CELL STRAINS
10. ABSTRACT: PHASE I SILVER, SM; ASH, 1993
EVALUATION OF EX VIVO EXPANDED ADAMS, PT;
HEMATOPOIETIC CELLS PRODUCED BY HUTCHINSON, RJ;
PERFUSION CULTURES IN AUTOLOGOUS DOUVILLE, JW;
BONE MARROW TRANSPLANTATION PAUL, LA; CLARKE,
(BMT). MF; PALSSON, BO;
EMERSON, SG
11. ABSTRACT: EXPANSION IN VAN ZANT, G; ASH, 1993
BIOREACTORS OF HUMAN PROGENITOR LARSON, DB;
POPULATIONS FROM CORD BLOOD AND DRUBACHEVSKY, I;
MOBILIZED PERIPHERAL BLOOD PALSSON, M;
EMERSON, SG
12. ABSTRACT: CLINICAL SCALE ARMSTRONG, RD; ASH, 1993
PRODUCTION OF STEM AND KOLLER, MR; PAUL,
HEMATOPOIETIC CELLS EX VIVO L; DOUVILLE, J;
MALUTA, J; FISH,
R; PALSSON, BO;
VAN ZANT, G;
EMERSON,SG
13. ABSTRACT: EXPANSION OF RUMMEL, SA; ASH, 1993
HUMAN HEMATOPOIETIC EMERSON, SG; VAN
STEM/PROGENITOR CELLS RESISTANT ZANT, G
TO TREATMENT WITH
4-HYDROPEROXYCYCLOPHOSPHAMIDE
14. ABSTRACT: BIOREACTOR KOLLER, MR; ASH, 1993
EXPANSION OF WHOLE, NEWSOM, B; VAN
DENSITY-SEPARATED, AND ZANT, G; EMERSON,
CD34-ENRICHED HUMAN BONE MARROW SG, PALSSON, BO
15. SEMINAR: PROGRESS REPORT PETER G. EIPERS 10/19/92
16. PAPER: MEL CELLS, THE CLARKE, MF SUBMITTED TO
ONCOGENE C-MYB NATURE 1/93
-5-
<PAGE>
17. PAPER: CELL CYCLE ANALYSIS RYAN, JJ; RIZWAN, MOLECULAR AND
OF P53-INDUCED CELL DEATH IN D; GOTTLIEB, CA; CELLULAR BIOLOGY
MURINE ERYTHROLEUKEMIA CELLS CLARKE, MF 13(1)
(JAN, 1993)
18. SEMINAR: MY PRIMARY OBJECT.. ALICE CURRY 1/25/93
19. SEMINAR: PROGRESS REPORT, PETER G. EIPERS 3/8/93
FEB. 1993
20. SEMINAR: CONSTRUCTION OF A FAISAL EL-AWAR 4/19/93
RETROVIRUS PACKAGING CELL LINE
21. SEMINAR: FIRST CD 18 PETER G. EIPERS 6/14/93
INFECTION........................
22. SEMINAR: GENERATION OF AN ALICE M. CURRY 7/26/93
HIV-BASED PACKAGING LINE
23. PROGRESS REPORTS ALICE M. CURRY JAN., APR., MAY,
JULY, 1993
24. PAPER: EFFECT OF STROMAL AGE EL-AWAR, FY; SUBMITTED TO
ON HEMATOPOIESIS IN HUMAN EMERSON, SG; EXP. HEMATOLOGY
LONG-TERM BONE MARROW CULTURES CLARKE, MF
25. ABSTRACT: EIPERS, PG; ASH, 1993
RETROVIRUS-MEDIATED GENE KRAUSS, JC; TODD,
TRANSFER IN HUMAN BONE MARROW RF; EMERSON, SG;
MONONUCLEAR CELLS GROWN IN PALSSON, BO;
CONTINUOUS PERFUSION CULTURES CLARKE, MF
26. NIH GRANT APPLICATION: MICHAEL F. CLARKE 9/30/93
ANALYSIS OF THE KINETICS OF
HEMATOPOIETIC CELL DIVISION BY
RETROVIRUS TAGGING
27. ABSTRACT: FLOW CYTOMETRIC ROGERS, CE; ASH, 1993
ANALYSIS OF BIOREACTOR EXPANDED BRADLEY, MS;
HUMAN BONE MARROW; ERYTHROID PALSSON, BO;
DEVELOPMENT AND CORRELATION WITH KOLLER, MR
BURST-FORMING UNIT-ERYTHROID
(BFU-E).
28. ABSTRACT: EXTENDED GROWTH OH, DJ; KOLLER, ASH, 1993
OF STEM AND PROGENITOR CELLS MR; PALSSON, BO
FROM ADULT HUMAN BONE MARROW IN
SEQUENTIAL BIOREACTOR CULTURES
29. ABSTRACT: GROWTH FACTOR PALSSON, BO; ASH, 1993
CONSUMPTION AND PRODUCTION IN EX BRADLEY, MS;
VIVO PERFUSION CULTURES OF HUMAN KOLLER, MR
BONE MARROW
30. SEMINAR: INTRO TO MINETTE LEVEE 10/13/92
MICROENCAPSULATION
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<PAGE>
31. SEMINAR: FLOW CYTOMETRY & CLARE ROGERS 11/30/92
HUMAN MARROW
32. SEMINAR: CULTIVATION OF DUK JAE OH 1/18/93
BONE MAROW CELLS IN HEMOGEN 107
(DIAMOND SHAPE) REACTORS
33. SEMINAR: ENCAPSULATED BONE LEVEE, MG; LEE, 3/29/93
MARROW CULTURES AS A POTENTIAL GM; PAEK, SH;
ASSAY FOR HUMAN HEMATOPOIETIC PALSSON, BO
PROGENITORS
34. SEMINAR: FLOW CYTOMETRIC ROGERS, CE; 3/29/93
ANALYSIS OF HUMAN MYELOID BRADLEY, S;
LINEAGE DEVELOPMENT IN KOLLER, MR;
HEMATOPOIETIC BIOREACTOR SYSTEMS PALSSON, BO
35. SEMINAR: OXYGEN TRANSPORT PENG, CA; 4/5/93
IN THE HEMOGEN BIOREACTORS PALSSON, BO
36. SEMINAR: TISSUE ENGINEERING BERNHARD O. 4/12/93
PALSSON
37. SEMINAR: DYNAMICS OF CELL PENG, CA; ROGERS, 6/7/93
GROWTH AND DIFFERENTIATION IN C; OH, DJ;
HEMOGENS BRADLEY, S;
PALSSON, BO
38. SEMINAR: METABOLIC STUDY IN DUK JAE OH 8/23/93
BONE MARROW CULTURE
39. MINUTES & NOTES, GENE BERNHARD O. 6/21/93 THRU
THERAPY PROJECT MEETINGS PALSSON ET AL 9/28/93
40. SBIR GRANT APPLICATION: A MANFRED R. KOLLER 8/14/92
CLONAL HEMATOPOIETIC PROGENITOR
CELL ASSAY
41. SBIR GRANT APPLICATON: HIGH R. DOUGLAS 8/14/92
TITER RETROVIRAL SUPERNATANTS ARMSTRONG
-7-
<PAGE>
DESCRIPTION AUTHOR DATE
----------- ------ ----
PROPOSALS:
1. American Cancer Society - Development Bernhard O. Palsson 10/15/92
of a Clinical Hematopoietic Bioreactor
System to Improve Bone Marrow Transplan-
tation
2. National Science Foundation - Bernhard O. Palsson 1/27/93
Hematopoietic Bioengineering and
Biotechnology
3. NIH - Bernhard O. Palsson 1/28/93
Hematopoietic Tissue Engineering
4. NIH - Bernhard O. Palsson 5/27/93
Human Hematopoietic Differentiation
and Lineage Development Ex Vivo
PAPERS:
5. The Influence of Extra-Cellular Matrix Schwartz, R.M., Cytotechnology
and Stroma Remodeling on the Productivity Caldwell, J., Clarke, 10:217-224
of Long-Term Human Bone Marrow Cultures M.F., Emerson, S.G., (1993)
and Palsson, B.O.
6. Expansion of Human Bone Marrow Progenitor Palsson, B.O., et al Bio/Technology
Cells in a High Cell Density Continuous 11,368-372
Perfusion System (1993)
7. Large-Scale Expansion of Human Stem and Koller, M.R., Emerson, Blood
Progenitor Cells from Bone Marrow Mono- S.G., and Palsson, B.O. 82,378-384
nuclear Cells in Continuous Perfusion (1993)
Cultures
8. Retroviral Gene Transfer into Human Clarke, M.F., et al The Cancer Bulletin
Hematopoietic Cells Using Rapidly 45:2, 153-158
Perfused Long-Term Bone Marrow Cultures (1993)
9. Tissue Engineering: Reconstitution of Koller, M.R. and Biotechnology &
Human Hematopoiesis Ex Vivo Palsson, B.O. Bioengineering 42,
in press (1993)
7(a)
<PAGE>
DESCRIPTION AUTHOR DATE
----------- ------ ----
10. Kinetics of Retroviral Production from Shen, B.O., Clarke, M.F., Biotechnology & Bioengineering
the Amphotropic VCRIP Murine Producer Palsson, B.O. Accepted with revisions
Cell Line
11. Microencapsulated Bone Marrow Cultures Levee, M.G., Lee, G-M., Biotechnology & Bioengineering
as a Potential Assay for Human Hemato- Paek, S-H., Submitted
poietic Progenitor Cells
12. Unilineage Model of Hematopoiesis Peng, C-A., Koller, M.R., Biotechnology & Bioengineering
Predicts Self-Renewal of Stem and and Palsson, B.O. Submitted
Progenitor Cells from Observed Ex Vivo
Growth Patterns
13. Extended Growth of Adult Mononuclear Oh, D.J., Koller, M.F. To be submitted
Human Bone Marrow Cells Through and Palsson, B.O.
Repeated Harvesting and Replating
REPORTS:
14. Development of the HemoGen 106 Bone B.O. Palsson and S-H Paek April 15, 1992
Marrow Expansion System
15. Research and Development Program for B.O. Palsson September 22, 1992
the HemoGen 106 Bioreactor System
(Unfinished document)
16. The HemoGen 107/108 Series: Progress R.M. Schwartz and B.O. October 27, 1992
Report Palsson
17. Progress Report on Residence Time C-A. Peng and B.O. Palsson December 17, 1992
Distribution
18. Partial Cell Harvesting and Replating D.J. Oh and B.O. Palsson December 17, 1992
Experiments
19. Oxygen Transport in the HemoGen C-A. Peng and B.O. Palsson April 5, 1993
Bioreactors
20. Growth Factor Delivery in the HemoGen B.O. Palsson and C-A. Peng May 21, 1993
Bioreactors:
21. Slides to accompany 16 above B.O. Palsson April 12, 1993
22. Dynamics of Cell Growth and B.O. Palsson June 7, 1993
Differentiation in HemoGens
BD
7/20/93
7(b)
<PAGE>
Additionally, as specified in the Research Agreement, University hereby licenses
to Aastrom, pursuant to the terms of the License Agreement, all of the
inventions, technology and know-how which are either (i) described in the
Research Projects referenced in the Research Agreement, or (ii) conceived or
reduced to practice as part of said Research Projects, or (iii) conceived or
reduced to practice, whether or not pursuant to or as part of said Research
Projects, by Drs. Stephen G. Emerson, Michael F. Clarke or Bernhard O. Palsson,
or those working under their direction (including without limitation, research
scientists, technicians, and/or post-doctoral training fellows), during the term
of their participation in the Research Projects and Company's funding of the
Research Projects, provided that such inventions, technology and know-how are
related to the work described in said Research Projects. Further, the parties
hereby acknowledge that Drs. Emerson, Clarke and Palsson serve as consultants to
Company, as well as employees of University, and that inventions, know-how and
technology conceived, reduced to practice or developed by these scientists in
the course of their consulting work for Company shall be included in
subparagraph (iii) above, such that they shall be covered by this License
Agreement as Licensed Technology.
-8-
<PAGE>
THIRD AMENDMENT TO
LICENSE AGREEMENT
This Third Amendment to License Agreement is entered into as of June 21, 1995,
by and between Aastrom Biosciences, Inc. (formerly Ann Arbor Stromal, Inc., a
Michigan corporation, hereinafter called "Aastrom"), and the Regents of the
University of Michigan, a constitutional corporation of the State of Michigan
(hereinafter called "University").
RECITATIONS
The following is a recital of facts underlying this Agreement.
A. In August, 1989, the parties hereto entered into a certain Research
Agreement (the "Research Agreement") pursuant to which Aastrom provided
funding to the University for the University to conduct a certain research
project. On March 2, 1992, the parties extended the term of the Research
Agreement until June 30, 1993. Pursuant to a further Extension Agreement
dated October 20, 1993, and Request Letter dated June 13, 1994, the term of
the Agreement was further extended to June 30, 1994, and December 31, 1994,
respectively, and the scope of the research projects and funding under the
Research Agreement extended accordingly. As used hereinafter, the term
"Research Agreement" shall include said Extension Agreements and Letter.
Pursuant to the Research Agreement, Aastrom is entitled to an exclusive
license to utilize any and all inventions, technology, and know-how (i)
resulting from the research projects funded by Aastrom at the University,
or (ii) related to the research projects (subject to certain
qualifications).
B. On March 13, 1992, the parties entered into a certain License Agreement
(the "License Agreement"), as contemplated by the Research Agreement; and
on March 13, 1992, the parties also entered into that certain First
Amendment to License Agreement (the "First Amendment to License Agreement")
for the purpose of modifying and clarifying certain terms in the original
License Agreement. On October 8, 1993, the parties entered into a Second
Amendment to License Agreement. As used hereinafter, the term "License
Agreement" shall include said First and Second Amendments and this Third
Amendment.
C. Subsequent to entering into the First and Second Amendments to License
Agreement, some additional patent rights, technology, know-how and other
intellectual property rights have been identified which are to be licensed
to Aastrom pursuant to the License Agreement. This Third Amendment is
being entered into for the purpose of identifying said additional rights.
NOW THEREFORE, in consideration of their mutual promises, the parties
hereto agree as follows:
<PAGE>
1. LICENSED TECHNOLOGY. In addition to all other Licensed Technology (as
defined in the License Agreement) which is already identified as being
covered by the License Agreement, the Licensed Technology shall also
include the additional patent-related matters identified in Exhibit A
attached hereto, as well as the additional technology and know-how
identified in the documents described in Exhibits B (1) and B(2)
attached hereto, to the extent such technology and know-how are
described by Section E of the Extension Agreement.
2. EFFECT. Excepting only as otherwise expressly set forth above, all
other terms and provisions of the License Agreement shall remain in
full force and effect.
IN WITNESS WHEREOF, the parties hereto have caused their duly authorized
representatives to execute and deliver this Third Amendment as of the date set
forth above.
FOR: FOR:
THE REGENTS OF
AASTROM BIOSCIENCES, INC. THE UNIVERSITY OF MICHIGAN
BY: /s/ R. DOUGLAS ARMSTRONG BY: /s/ ROBERT L. ROBB
------------------------------ ---------------------------------
R. Douglas Armstrong, Ph.D.
President and CEO ITS: Director, Technology Management
Office
-2-
<PAGE>
EXHIBIT A
Patent Matters
All of the following patent applications and patent matters, including all
related foreign patent rights and all patents issued and patent rights related
thereto:
A. U.S. APPLICATION NO. 08/100,337
Filed: 7/30/93; (Continuation to U.S. App. #07/628,343)
B. U.S. APPLICATION NO. 08/164,779
Filed: 12/10/93; (Continuation to U.S. App. #07/737,024)
Amendment filed: 8/1/94
C. AMENDMENT TO U.S. APP. #07/740,590
Filed: 8/9/94
D. U.S. APP. NO. 08/178,433
Filed: 1/6/94 (Continuation to U.S. App. #07/845,969)
E. U.S. APPLICATION, SER. #08/143,751
Methods and Compositions for the ex vivo Replication of Stem Cells, for the
Optimization of Hematopoietic Progenitor Cell Cultures, and for Increasing
the Metabolism, GM-CSF Secretion and/or IL-6 Secretion of Human Stromal
Cells
Filed: 11/1/93 as a divisional of 07/845,969 (ex vivo mitotic stem cells)
------
F. U.S. APPLICATION, SER. #08/187,509
Methods and Compositions for the ex vivo Replication of Stem Cells, for the
Optimization of Hematopoietic Progenitor Cell Cultures, and for Increasing
the Metabolism, GM-CSF Secretion and/or IL-6 Secretion of Human Stromal
Cells
Filed: 1/28/94 as a continuation of 8/100,337, 7/628,343, 7/366,639; to
------
declare interference with Gillis et al patents.
G. U.S. APPLICATION, SER. #08/307,862
Stabilized Virus for Gene Therapy
Filed: 9/15/94
------
H. U.S. APPLICATION, SER. #08/353,531
Methods, Compositions and Apparatus for Cell Transfection
Filed: 12/9/94
------
-3-
<PAGE>
EXHIBIT B (1)
KNOW-HOW AND TECHNOLOGY ITEMS
ALL OF THE FOLLOWING AND ATTACHED GRANT PROPOSALS, PAPERS, ABSTRACTS AND OTHER
DOCUMENTS, TOGETHER WITH ALL INVENTIONS, KNOW-HOW AND/OR TECHNOLOGY DESCRIBED
THEREIN TO THE EXTENT DESCRIBED BY SECTION E OF THE EXTENSION AGREEMENT:
DESCRIPTION AUTHOR DATE
1. NIH GRANT APPLICATION: MICHAEL F. CLARKE 1/11/94
ANALYSIS OF HEMATOPOIETIC
CELL DIVISION BY RETROVIRUS
TAGGING*
2. PAPER: EIPERS,P; KRAUSS,J; REC'D. 8/1/94
RETROVIRAL-MEDIATED GENE PALSSON,B; EMERSON,S; TODD,R;
TRANSFER IN HUMAN BONE CLARKE, M.
MARROW CELLS GROWN IN
CONTINUOUS PERFUSION
CULTURE VESSEL*
3. PAPER: TISSUE BERNHARD PALSSON REC'D. 11/21/93
ENGINEERING: ENGINEERING
CHALLENGES
4. PAPER: GROWTH FACTOR BERNHARD PALSSON 1/20/94
CONSUMPTION AND PRODUCTION
IN AASTROM'S PERFUSION
BIOREACTOR SYSTEMS
5. MANUSCRIPT: KINETICS OF ANDREADIS, STYLIANOS; 7/8/94
RETROVIRAL INFECTION AND PALSSON, BERNHARD O.
THE INFLUENCE OF CELL
CYCLE: IMPLICATIONS FOR
GENE THERAPY
6. FOLDER: ALICE CURRY ALICE CURRY 5/31/94
NOTES (75 PAGES)
7. PROGRESS REPORTS ALICE M. CURRY NOV, 1993;
JAN. & FEB,
1994
8. ABSTRACT: LTC-IC KOLLER,M.R.; PALSSON, M.A.; ASH, 1994
EXPANSION REQUIRES RAPID MANCHEL,I; NEWSOM,B.S.;
MEDIUM EXCHANGE COMBINED PALSSON, BERNHARD O.
WITH THE PRESENCE OF
STROMAL AND OTHER ACCESSORY
CELLS
9. ABSTRACT: EXPANSION KOLLER,M.R.; MANCHEL, I; ASH, 1994
POTENTIAL OF CD34+ CELLS PALSSON, M.A.; BROTT,D.A.;
FROM PATIENTS IS LOWER AND SILVER,S.M.; PALSSON,B.O.
MORE STROMAL-DEPENDENT THAN
FROM NORMAL DONORS
*These materials especially may include some inventions, know-how and technology
not described by Section E of the Extension Agreement (and thus not included in
Licensed Technology); including inventions, know-how and technology developed by
or under the direction of Dr. Robert Todd related to leukocyte adhesion
deficiency disease.
-4-
<PAGE>
10. SBIR GRANT APPLICATION: BERNHARD O. PALSSON 4/14/94
NOVEL APPROACHES TO (PHASE I)
ENHANCING RETROVIRAL
STABILITY
11. SBIR GRANT APPLICATION: BERNHARD O. PALSSON 4/14/94
HEMATOPOIETIC CELL (PHASE II)
EXPANSION SYSTEM
12. ATP GRANT APPLICATION: R. DOUGLAS ARMSTRONG 6/21/94
GENE TRANSFER SYSTEM FOR
ENABLEMENT OF HUMAN GENE
THERAPY
13. SEMINAR: CD18 CELL PETER EIPERS 10/25/93
EXPANSION*
14. THESIS: MEETING ALICE CHUCK 6/29/94
PRESENTATION
15. THESIS: MEETING ALICE CHUCK 9/28/93
PRESENTATION
16. PAPER: GROWTH FACTOR M.R.KOLLER, M.S. SUBMITTED TO EXP.
CONSUMPTION AND PRODUCTION BRADLEY, B.O.PALSSON HEMATOLOGY, 9/28/94
IN PERFUSION BIOREACTOR
CULTURES OF HUMAN BONE
MARROW CORRELATES WITH
SPECIFIC CELL PRODUCTION
17. ABSTRACT: M.R.KOLLER, B.NEWSOM, KEYSTONE CONFERENCE,
CHARACTERIZATION OF HUMAN C.E.ROGERS, G.VAN TAOS, NM, 2/94
STEM AND PROGENITOR CELL ZANT, S.G.EMERSON,
EXPANSION IN BIOREACTORS B.O.PALSSON
18. PAPER: GROWTH FACTOR M.R.KOLLER, B.O.PALSSON 6/13/94
CONSUMPTION AND PRODUCTION
IN PERFUSION BIOREACTOR
CULTURES OF HUMAN BONE
MARROW
19. INTERNAL REPORT: TIMOTHY M. EISFELD 8/29/94; REVISED
RETROVIRUS PRODUCTION AND 8/30/94
CONCENTRATION PROJECT:
EXPERIENCE WITH THE
OPTICELL SYSTEM; FILE NO.
4.3.1-001
20. INTERNAL REPORT: TIMOTHY M. EISFELD 8/22/94
SUMMARY REPORT ON VIRUS
STABILIZATION PROJECT:
JANUARY 1994 TO PRESENT;
FILE NO. 4.3.2-001
21. PAPER: BIOREACTOR KOLLER,M.R. SUBMITTED TO BLOOD,
EXPANSION OF HUMAN BONE 1994 (MANUSCRIPT NO.
MARROW: COMPARISON OF 1-94-5-192)
UNPROCESSED,
DENSITY-SEPARATED, AND
CD34-ENRICHED CELLS
*These materials especially may include some inventions, know-how and technology
not described by Section E of the Extension Agreement (and thus not included in
Licensed Technology); including inventions, know-how and technology developed by
or under the direction of Dr. Robert Todd related to leukocyte adhesion
deficiency disease.
-5-
<PAGE>
22. PAPER: IL-1A REGULATES JERRY CALDWELL, BLOOD 84 (10),
EXPRESSION OF THE 75 KDA STEPHEN G. EMERSON SUPPLEMENT 1,
BUT NOT THE 55 KDA TNF 11/15/94
RECEPTOR BY CDCL STROMAL (NO. 1109)
CELLS: IMPLICATIONS FOR
IL-1/TNF SYNERGY.
*These materials especially may include some inventions, know-how and technology
not described by Section E of the Extension Agreement (and thus not included in
Licensed Technology); including inventions, know-how and technology developed by
or under the direction of Dr. Robert Todd related to leukocyte adhesion
deficiency disease.
-6-
<PAGE>
EXHIBIT B(2)
DESCRIPTION AUTHOR DATE
----------- ------ ----
PEER-REVIEWED PAPERS:
2. Microencapsulated Human Bone Marrow Cultures: A M. Levee, G.M. Lee, S.H. Paek, Biotechnology & Bioengineering
Potential Culture System for the Clonal Outgrowth B.O. Palsson 43, 734-739 (1994)
of Hemalopoietic Progenitor Cells
3. Retroviral Infection is Limited by Brownian Motion A.S. Chuck, C.A. Peng, M.F. Clarke Submitted to Science Dec. 1993
B.O. Palsson
4. Frequent Harvesting from Perfused Bone Marrow D.J. Oh, M.R. Koller, B.O. Palsson Biotechnology & Bioengineering
Cultures Results in Increased Overall Cell and 44, 609-616 (1994)
Progenitor Expansion
5. Replating of Bioreactor-Expanded Human Bone Marrow D.J. Oh, B.O. Palsson, M.R. Koller Submitted to Experimental
Results in Extended Growth of Primitive and Mature Hematology
Cells May 1994
6. Bioreactor Expansion of Human Bone Marrow: M.R. Koller, I. Manchel et al Submitted to J. Hematotherapy
Comparison of Unprocessed, Density-Separated 9/6/94
and CD34-enriched Cells
7. Unilineage Model of Hematopoiesis Predicts Self- C.A. Peng, M.R. Koller, and Submitted to Biotechnology &
Renewal of Stem and Progenitor Cells from Observed B.O. Palsson Bioengineering 9/93
ex vivo Growth Patterns
-7-
<PAGE>
EXHIBIT B(2)
DESCRIPTION AUTHOR DATE
----------- ------ ----
CHAPTERS IN BOOKS:
8. The Role of Physiological Perfusion in the J. Caldwell, B.O. Palsson, M.F. Clarke, Johns Hopkins University Press
Metabolism and Genetic Regulation of Cytokine and S.G. Emerson 1993 Baltimore
Production in Mesenchymal Stromal Cells
in The Hematopietic Microenvironment: Eds. M. W. Long and M.S. Wicha
The Functional and Structural Basis of Blood
Cell Development
ABSTRACTS:
9. Biomedical Expansion of Human Stem and Progenitor M.R. Koller, B. Newsom, G. Van NIH Workshop on Hematopoletic
Cells is More Efficient with Mononuclear Cells Zant, S.G. Emerson, B.O. Palsson Stem Cell Purification and
Than with CD34-Enriched Cells Biology, Rockville, MD.,
9/21/1993
10. Growth Factor Consumption and Production in ex B.O. Palsson, M.S. Bradley, and ASH Meeting, St. Louis, MO
vivo Perfusion Cultures of Human Bone Marrow M.R. Koller Dec. 1993
11. Extended Growth of Stem and Progenitor Cells from B.O. Palsson, D.J. Oh, and M.R. ASH Meeting, St. Louis, MO
Adult Human Bone Marrow in Sequential Bioreactor Koller Dec. 1993
Cultures
12. Bioreactor Expansion of Whole, Density-Separated, M.R. Koller, B. Newsom, G. Van ASH Meeting, St. Louis, MO
and CD34-Enriched Human Bone Marrow Zant, S.G. Emerson, B.O. Palsson Dec. 1993
13. Flow Cytometric Analysis of Bioreactor Expanded C.E. Rogers, M.S. Bradley, B.O. ASH Meeting, St. Louis, MO
Human Bone Marrow: Erythroid Development and Palsson, and M.R. Koller Dec. 1993
Correlation with Burst-Forming Unit-Erythroid
(BFU-E)
14. Clinical Scale Production of Stem and Hemato- R.D. Armstrong, M.R. Koller, L. ASH Meeting, St. Louis, MO
poietic Cells Ex Vivo Paul, J. Douville, J. Maluta, R. Fish, Dec. 1993
B.O. Palsson, G. Van Zant, S.G. Emerson
-8-
<PAGE>
EXHIBIT B(2)
DESCRIPTION AUTHORS DATE
----------- ------- ----
15. Hematopoletic Bioreactor Engineering for B.O. Palsson Engineering Foundation Conference:
Transplantation Rapid Detection and Control Cell Culture Engineering IV, San Diego,
of Progenitor Cell Production CA, March 7-12, 1994
16. Growth Factor Consumption and Production in B.O. Palsson and M.R. Koller American Chemical Soc. Spring
Ex Vivo Perfusion Cultures of Human Bone National Meeting, San Diego, CA
Marrow March 7-12, 1994
Prepared by
Barbara Dunn
8/10/94
-9-