EXHIBIT 10.16
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LICENSE AGREEMENT
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THIS AGREEMENT is made on 25th March 1997 between:
1. AMRAD DEVELOPMENTS PTY LTD (ACN 000 000 000) incorporated in Victoria of
00-00 Xxxxxx Xxxx, Xxx, Xxxxxxxx, Xxxxxxxxx (AMRAD); and
2. XXXXXX INSTITUTE FOR CANCER RESEARCH incorporated in New York, United
States of America, having an office at 0000 Xxxxxx xx xxx Xxxxxxxx, Xxx
Xxxx, Xxx Xxxx, 0000: (XXXXXX); and
3. COLLATERAL THERAPEUTICS INC incorporated in California, United States of
America, having an office at 0000 Xxxxx Xxxxxx Xxxxx, Xxx Xxxxx,
Xxxxxxxxxx, 00000 (COLLATERAL).
RECITALS
A. Each of AMRAD Operations Pty Ltd and XXXXXX is the legal and beneficial
owner of certain intellectual property relating to the Technology and
Patent Rights (as defined in Clause 1.1. herein).
B. Pursuant to a Collaboration Agreement dated 6 December 1996 (Collaboration
Agreement); AMRAD and XXXXXX have agreed to collaborate in the
commercialization of the Technology and the Patent Rights in the manner
set out therein. AMRAD Operations Pty Ltd has subsequently licenced, with
the consent of XXXXXX, its rights under that Agreement and in respect of
the Patent Rights and Technology to AMRAD.
C. Pursuant to the Collaboration Agreement, AMRAD and XXXXXX may grant
licences to third parties to use and exploit the Technology and the Patent
Rights.
D. COLLATERAL is the exclusive licensee of a PCT patent application filed in
the name of The Regents of the University of California on 27 February
1996 under *** *** (which the University of California has internally
designated patent application *** *** ) covering an angiogenic
gene-containing adenovirus delivery system for use in in-vivo gene therapy
for cardiovascular disorders. COLLATERAL has conducted studies which in
its opinion support the possible therapeutic use of an angiogenic
gene-containing adenovirus for the treatment and prevention of
cardiovascular disorders.
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Confidential Treatment and filed separately with the Commission.
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E. COLLATERAL has entered into an agreement with Schering AG (Schering AG
Agreement) to develop gene therapy products using the technology
referred to in Recital D above, pursuant to which agreement COLLATERAL
shall receive milestone payments and royalties.
F. During the course of negotiations with AMRAD in relation to this
Agreement, COLLATERAL has represented to AMRAD that COLLATERAL shall
receive approximately thirty per cent (30%) of the milestone payments
payable to COLLATERAL pursuant to the Schering AG Agreement during the
product development phase of the Schering AG Agreement, and that the
remaining payments are to be paid to COLLATERAL following first
commercial sale of products. Further, during the course of those
negotiations, COLLATERAL has represented to AMRAD that COLLATERAL shall
use the majority of the total milestone payments it receives pursuant
to the Schering AG Agreement to fund ongoing research and development
of Licensed Products or, depending on the results of that research, an
alternative gene product.
G. COLLATERAL wishes to receive an exclusive licence to use and exploit the
Technology and Patent Rights to develop cardiovascular gene therapy
products using at first instance the technology referred to in Recital D
above. Each of AMRAD and XXXXXX is willing to grant COLLATERAL such a
licence on the terms and conditions contained in this Agreement.
IT IS AGREED as follows.
1. DEFINITIONS AND INTERPRETATION
1.1 Definitions
The following definitions apply unless the context requires otherwise.
Affiliate with respect to a corporation, means a corporation which owns,
is owned by or is under common ownership with the first-named corporation.
For the purposes of this definition, the term "owns" as used with respect
to any person means ownership (directly or indirectly) of at least
fifty-one per cent (51%) of the outstanding voting securities of a
corporation or a comparable equity interest in a corporation (or such
lesser percentage, being the maximum percentage of ownership allowed by
law in a particular jurisdiction).
Agreement means this Licence Agreement.
AMRAD Patent Application means the patent application described in
Schedule l.
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Benchmark means the benchmarks referred to in Clause 5.3 and/or described
in Schedule 3.
Collaboration Agreement means the Collaboration Agreement between AMRAD
Operations Pty Ltd and XXXXXX dated 6 December 1996.
Effective Date means the date of execution of this Agreement.
Field means gene therapy for the treatment and prevention of
cardiovascular disease but excludes the use of any product or technology
described or claimed within the Patent Rights for any purpose relating to
the treatment and prevention of malignant diseases or acute wounds or
other diseases (except as described above) and also excludes any product
or technology within the Patent Rights for the manufacture of recombinant
proteins (other than proteins produced in the human body as a result of
gene therapy) for any purpose and also excludes, for the avoidance of
doubt, any other use of the Patent Rights or Technology.
IND means investigational new drug, and a reference to the filing thereof
is a reference to the filing of an application with the United States of
America Food and Drug Administration to initiate clinical trials thereof.
Indication means any indications to be treated using Licensed Products as
described in the definition of Field including coronary artery disease,
congestive heart failure and peripheral vascular disease.
Licence Fee means any amount payable by COLLATERAL to AMRAD or XXXXXX
pursuant to this Agreement.
Licensed Product means any product including a nucleic acid sequence
encoding VRF/VEGF-B gene for use solely in the Field, the manufacture, use
or sale of which falls within the scope of one or more subsisting and
unexpired claims within the Patent Rights which has not been permanently
revoked, held unenforceable 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 or otherwise. For
the avoidance of doubt, Licenced Products excludes any protein, peptide or
receptors for VRF/VEGF-B.
LICENSOR means, collectively, AMRAD and XXXXXX.
XXXXXX Patent Applications means the patent applications described in
Schedule 2.
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Net Revenue means royalty payments received by COLLATERAL on Net Sales
made by Schering AG or other sub-licensees of COLLATERAL, less, if
the Licensed Products involve in any way whatsoever the technology
claimed in *** if payable to the Regents of the University of
California pursuant to an exclusive licence agreement between the said
Regents and COLLATERAL entitled *** dated 28 September 1995 as amended
***.
Net Sales means gross proceeds from sales of Licensed Products by a
sub-licensee or COLLATERAL less deductions for:
(a) transportation charges, including insurance relating thereto;
(b) sales and excise taxes or customs duties paid by the person selling
or distributing any Licensed Product or any other governmental
charges imposed upon the sale or distribution of any Licensed
Product;
(c) distributors' fees. rebates or allowances actually granted. allowed
or incurred:
(d) quantity discounts, cash discounts or chargebacks actually granted,
allowed or incurred in the ordinary course of business in connection
with the sale or distribution of any Licensed Product;
(e) allowances or credits to customers, not in excess of the selling
price of any Licensed Product, on account of governmental
requirements, rejection, outdating, recalls or returns of such
Licensed Product.
Patent Rights means the AMRAD Patent Applications and the XXXXXX Patent
Applications and any patent subsequently issued thereon in any country
(including any additions, divisions, continuations, continuations-in-part,
reissues, registrations or extensions of the said patents or patent
applications and any special protection certificates issued in connection
with any of the said patents or patent applications).
Phase 3 Clinical Trials has the same meaning as that term has in the
United States of America Government's Food and Drug Code of Federal
Regulations (edition of 1 April 1993), 21CFR CH.1S 312.21.
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Confidential Treatment and filed separately with the Commission.
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Pig Studies means, for the purposes of this Agreement, in vivo studies
conducted in pigs to determine the efficacy of the use of the VRF/VEGF-B
gene (delivered by an adenoviral vector) in the establishment and
development of collateral circulation in the ameroid pig model of
myocardial ischaemia for the treatment and prevention of coronary artery
disease.
PLA means a product licence application to a regulatory authority
incorporating data and information for the purpose of obtaining
authorization to market the said product.
Schering AG means Schering AG, a company incorporated in Germany having
an office at 133342 Berlin, Germany.
Technology means any and all technical data, information, materials and
know-how related, directly or indirectly to the Patent Rights, which is
needed in the practice of the Patent Rights in the Field and includes the
Biological Materials described in Clause 4 hereof which have been provided
on a confidential basis.
Territory means the entire world.
Third Party means any person other than AMRAD, XXXXXX or COLLATERAL.
VRF/VEGF-B gene means nucleic acid sequences described and claimed in the
Patent Rights, but for the avoidance of doubt does not include recombinant
proteins manufactured by the expression of those nucleic acid sequences in
a host cell (other than proteins produced in the human body as a result of
gene therapy) and also excludes any protein, peptide or receptors for
VRF/VEGF-B.
1.2 Interpretation
Headings are for convenience only and do not affect interpretation. The
following rules apply unless the context requires otherwise.
(a) The singular includes the plural and conversely.
(b) A gender includes all genders.
(c) If a word or phrase is defined, its other grammatical forms have a
corresponding meaning.
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(d) A reference to a person, corporation trust, partnership,
unincorporated body or other entity includes any of them.
(e) A reference to a Clause or Schedule is a reference to a clause of or
a schedule to this Agreement.
(f) A reference to an agreement or document (including, without
limitation, a reference to this Agreement) is to the agreement or
document as amended, varied, supplemented, novated or replaced,
except to the extent prohibited by this Agreement or that other
agreement or document.
(g) A reference to a party to this Agreement or another agreement or
document includes the party's successors, permitted substitutes and
permitted assigns and, where applicable, the party's legal personal
representatives.
(h) A reference to legislation or to a provision of legislation includes
a modification or reenactment of it, a legislative provision
substituted for it and a regulation or statutory instrument issued
under it.
(i) A reference to conduct includes, without limitation, an omission,
statement or undertaking, whether or not in writing.
(j) A reference to an agreement includes any undertaking, deed,
agreement and legally enforceable arrangement, whether or not in
writing, and a reference to a document includes an agreement (as so
defined) in writing and any certificate, notice, instrument and
document of any kind.
(k) A reference to dollars and $ is to the currency of the United States
of America.
(l) A reference to a right or obligation of any two or more persons
confers that right, or imposes that obligation, as the case may be.
jointly and severally.
1.3 Consents or Approvals
If the doing of any act, matter or thing under this Agreement is dependent
on the consent or approval of a party or is within the discretion of a
party, the consent or approval may be given or the discretion may be
exercised conditionally or unconditionally or withheld by the party in its
absolute discretion unless express provision to the contrary has been
made.
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2. REPRESENTATIONS AND WARRANTIES
2.1 Authorisation
Each party to this Agreement warrants and represents to the others that it
has the legal rights and power to extend the rights and licences granted
in this Agreement, that each has the full right to enter into this
Agreement and to perform its obligations hereunder, and that it has not
made nor will make any commitments to others in conflict with or in
derogation of its rights and obligations under this Agreement. Each party
to this Agreement further represents to the other parties to this
Agreement that it is not aware of any legal obstacles, including patent
rights of others, which could prevent it from carrying out the provisions
of this Agreement.
2.2 Patent Validity
(a) Nothing in this Agreement shall be construed as a warranty or
representation by the LICENSOR as to the validity or scope of any
Patent Rights or that the exercise of any rights granted under this
Agreement will not infringe any Third Party rights.
(b) Subject to Clause 2.2(a), as at the Effective Date:
(i) AMRAD is not aware that the exercise of any rights granted
under this Agreement in respect of the AMRAD Patent
Applications will infringe any Third Party rights; and
(ii) XXXXXX is not aware that the exercise of any rights granted
under this Agreement in respect of the XXXXXX Patent
Applications will infringe any Third Party rights.
2.3 Warranties
(a) XXXXXX hereby warrants to COLLATERAL that the statements contained
in Recitals A, B and C to this Agreement are true and correct in
every particular.
(b) AMRAD hereby warrants to COLLATERAL that the statements contained in
Recitals A, B and C to this Agreement are true and correct in every
particular.
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(c) COLLATERAL hereby warrants to the LICENSOR that the statements
contained in Recitals D, E, F G, and H to this Agreement are true
and correct in every particular and that the representations
referred to in said Recital G are true and correct in every
particular.
3. LICENCE
3.1 Grant of Licence
(a) The LICENSOR hereby grants to COLLATERAL an exclusive licence under
the Patent Rights and the Technology to manufacture, have
manufactured, import, use, sell and offer for sale Licensed Product
for use in the Field throughout the Territory for the term of this
Agreement.
(b) COLLATERAL acknowledges that LICENSOR has represented that all of
the Patent Rights and the Technology are owned or controlled by the
LICENSOR or third parties who have granted licences to the LICENSOR
and that COLLATERAL's rights to the Technology are pursuant to this
Agreement and as a licensee only.
3.2 Acknowledgement by the Parties
The parties acknowledge that COLLATERAL is not seeking, and the
LICENSOR is not making, any warranties or representations as to the
merchantability or suitability for any particular purpose of the
Technology, the capacity of any of the Patent Rights to infringe any
Third Party Rights or the validity of any of the Patent Rights.
3.3 Right to Sub-license
(a) COLLATERAL may sub-license the rights granted under Clause 3.1 to
Schering AG or an Affiliate of Schering AG provided that COLLATERAL
procures that Schering AG or any Affiliate of Schering AG to whom
a sub-license is granted pursuant to this Clause 3.3(a) shall enter
into an agreement with COLLATERAL on terms which are consistent with
the terms of this Agreement.
(b) COLLATERAL may sub-license the rights granted under Clause 3.1 to a
Third Party other than Schering AG or an Affiliate of Schering AG
provided that:
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(i) COLLATERAL and the LICENSOR shall first negotiate and agree on
a fee to be paid by COLLATERAL to the LICENSOR upon the grant
of such sublicence:
(ii) COLLATERAL obtains the LICENSOR's prior written consent to any
such sub-licence;
(iii) COLLATERAL shall procure that any person to whom a sub-licence
is granted pursuant to this Clause 3.3 shall enter into an
agreement with COLLATERAL on terms which are consistent with
the terms of this Agreement;
(iv) any sub-licence granted to a person pursuant to this Clause
3.3 shall expressly prohibit any right to further sub-license
or to transfer or assign the sub-licence; and
(v) upon termination of this Agreements, all rights granted to any
person pursuant to this Clause 3.3 shall immediately cease.
(c) Notwithstanding the provisions of Clause 3.3(b) (i) the parties
agree that *** shall be payable by COLLATERAL to the LICENSOR with
respect to COLLATERAL's exercising its rights to grant a sub-licence
under Clause 3.3(b) to an Affiliate of COLLATERAL or to a Third
Party which has purchased all of the assets or capital stock of
COLLATERAL.
(d) For the avoidance of doubt, COLLATERAL shall procure that any person
to whom a sub-licence is granted pursuant to this Clause 3.3 shall
be bound by the terms and conditions of this Agreement.
COLLATERAL shall be liable to the LICENSOR for any failure of a
sub-licensed person to perform the obligations ascribed to
COLLATERAL under this Agreement. Any such failure shall be taken
to be a failure of COLLATERAL to perform the obligations ascribed
to COLLATERAL under this Agreement.
(e) Except as expressly permitted by this Clause 3.3, COLLATERAL shall
not sub-license any, or any part of, the rights under Clause 3.1 of
this Agreement.
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4. MATERIALS
The parties acknowledge that, pursuant to an Agreement to Provide
Biological Materials between AMRAD and COLLATERAL, effective on 7 October
1996, AMRAD has sent to COLLATERAL, and COLLATERAL has received, the
Biological Materials (as defined in that agreement) on the terms and
conditions stated in that agreement. Any further Biological Materials or
Technology to be supplied to COLLATERAL shall be supplied on terms and
conditions as shall be agreed between the parties from time to time.
5. PAYMENTS BY COLLATERAL
5.1 Method of Payment
All payments due by COLLATERAL to the LICENSOR pursuant to this Agreement
shall be:
(a) net payments and no deductions shall be made in respect of
withholding tax or other charges except in accordance with Clause
5.10;
(b) made by bank draft or telegraphic transfer and shall be paid as to
*** to AMRAD and as to *** to XXXXXX;
(c) non-refundable; and
(d) payable in the currency of the United States of America and paid
into such accounts as AMRAD and XXXXXX may direct.
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5.2 Licence Fees
COLLATERAL has agreed to pay licence fees as follows:
(a) Within five (5) working days of the Effective Date, COLLATERAL shall
pay to the LICENSOR the licence fee of $250,000; and
(b) On June 15, 1997 COLLATERAL shall pay to the LICENSOR a further
licence fee of $750,000
(c) On 30 October 1997, COLLATERAL shall pay to the LICENSOR a further
licence fee of $150,000
5.3 Licence Fee - Milestone Payments
(a) Within thirty (30) days of the date of the completion of any
Initial Public Offering for the purchase of any shares in
COLLATERAL being listed on any stock exchange in the United
States or the expiration of eighteen (18) months from the
Effective Date, whichever is the first to occur, COLLATERAL shall
forthwith pay to the LICENSOR a further licence fee of
$1,000,000. In the event that COLLATERAL fails to pay to LICENSOR
such fee within ten (10) days from when such fee is due and
payable this Agreement shall, subject to any agreement between
the parties to allow this Agreement to continue in full force and
fefect, be deemed to have terminated with immediate effect.
(b) Within *** of achievement of any of the following Benchmarks in
relation to any Indication, COLLATERAL shall pay to the LICENSOR a
*** as follows:
***
***
***
***
***
***
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***
***
***
***
it being understood however, that except as provided in Clause 5.4
with respect to an additional *** *** once a *** has been paid for
any Licensed Product, COLLATERAL's obligation to pay that *** shall
be extinguished, such that each of the above *** shall be due and
payable by COLLATERAL to the LICENSOR only once, irrespective of how
many Licensed Products may reach a *** has already been paid.
5.4 Licence Fee - Additional Indications
Within *** other than for an Indication in respect of which COLLATERAL
has paid the LICENSOR a Benchmark fee under Clause 5.3(b)(iv), COLLATERAL
shall pay to the LICENSOR a single one time licence fee of $1,000,000
for each such Indication.
5.5 Licence Fee - Annual Licence Fee
On 1 January 2002 and upon each successive anniversary of the Effective
Date thereafter, COLLATERAL shall pay to the LICENSOR a licence fee of
$1,500,000 such licence fees to be off-set against any amounts received
by the LICENSOR pursuant to Clause 5.6.
5.6 Licence Fee - Royalty
(a) In addition to the payments set out in Clauses 5.2 to 5..5,
COLLATERAL shall pay to the LICENSOR a royalty equal to ***
(b) The payments due by COLLATERAL to the LICENSOR pursuant to Clause
5.6(a) shall be made to the LICENSOR within *** of the end of each
calendar quarter, and each such payment shall be accompanied by a
written report signed by an officer of COLLATERAL and in a form
satisfactory to the LICENSOR containing the calculation of the
payment due to the LICENSOR for the said calendar quarter.
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(c) If COLLATERAL or any of its sub-licensees receives any cash or
non-cash benefit or otherwise derives any other cash or non-cash
benefit in connection with the exploitation of the Technology or
Licensed Products other than pursuant to an arm's length licence
agreement with a Third Party, for the purposes of calculating the
amount payable to the LICENSOR pursuant to this Clause 5.6,
COLLATERAL or its sub-licensees (as the case may be) shall be taken
to have received a royalty payment that would have been received on
an arm's length licence agreement.
(d) Without limiting Clause 5.6(c), if COLLATERAL sells any Licensed
Product to any Third Party then COLLATERAL shall pay the LICENSOR a
royalty on that sale, being an amount equal to the amount COLLATERAL
would have received from Schering AG pursuant to the Schering AG
Agreement had Schering AG sold such Licensed Product and paid
royalties to COLLATERAL in accordance with the terms and conditions
of the Schering AG Agreement.
5.7 CPI Adjustment
The Licence Fees set out in Clauses 5.3 and 5.4 shall be annually adjusted
in accordance with the increase in the United States of America Consumer
Price Index in the period from the first anniversary of the Effective Date
to the date on which the payment is made. For the purposes of this
Agreement, the Index at a particular time shall be the Index most recently
published by the United States Bureau of Economics and Statistics at that
time.
5.8 Records
COLLATERAL shall keep, and shall cause any person to whom it was granted a
sub-licence pursuant to Clause 3.3 to keep for a minimum of *** complete
records of all matters which are relevant for determining the Licence Fees
which are to be paid to the LICENSOR pursuant to this Agreement and shall
allow the authorised representatives of the LICENSOR reasonable access no
more than twice per year to examine and make copies of such records.
5.9 Default Interest
If COLLATERAL fails to make any payment due pursuant to this Agreement by
the due date, then it shall pay the LICENSOR interest on the amount due
from the date payment fell due until the amount is paid at the rate of:
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(a) *** per month for *** from the date payment fell due; and
(b) *** per month thereafter.
5.10 Withholding Taxes
Notwithstanding anything else contained in this Agreement if COLLATERAL is
required to pay withholding tax on any payments to be made hereunder it
shall forthwith provide the LICENSOR with documentary evidence that such
tax has been paid to an appropriate authority to enable the LICENSOR to
obtain the credit for such tax payment in its country of incorporation.
5.11 Prior Termination
Unless LICENSOR advises COLLATERAL in writing *** of the due date
otherwise in the event that any of the payments described in this clause 5
are not made by the due date this Agreement will terminate with immediate
effect on *** following such due date PROVIDED THAT such termination will
not effect the LICENSOR's right to receive the payments then owing
pursuant to this clause.
6. INTELLECTUAL PROPERTY
6.1 Infringement by Third Parties
(a) A party shall promptly notify the other parties in writing of any
alleged or threatened infringement within the Field of any patent
included within the Patent Rights of which such party becomes aware.
COLLATERAL shall have the right to bring and control any action or
proceeding with respect to such alleged or threatened infringement
within the Field (Proceeding) at its own expense and represented by
legal advisers of its own choice.
(b) In the event COLLATERAL brings a Proceeding, the LICENSOR shall
co-operate fully with COLLATERAL including, if required, undertaking
any action or agreeing to be joined as a party to such Proceeding,
the reasonable costs of which shall be at COLLATERAL's expense,
provided that:
(i) the LICENSOR shall retain the right to be represented by legal
advisers of its own choice at its expense;
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(ii) COLLATERAL shall keep the LICENSOR fully informed of the
status of such Proceeding on a regular basis or, as reasonably
requested by the LICENSOR, from time to time; and
(iii) the LICENSOR shall retain the right to become involved in any
negotiations, including without limitation any settlement
negotiations, in which the parties to such Proceeding may be
engaged from time to time.
(c) In the event COLLATERAL commences a Proceeding, any recovery
realised as a result of such Proceeding, after reimbursement of any
and all litigation expenses and reasonable costs of COLLATERAL,
shall be treated as Net Revenue under this Agreement.
(d) In the event the LICENSOR notifies COLLATERAL in writing of any
infringement referred to in Clause 6.1(a) and COLLATERAL fails to
commence a Proceeding within a reasonable time of being so notified
by the LICENSOR, provided that such time shall not, in any event,
exceed ninety (90) days, the LICENSOR may commence a Proceeding at
its own expense and may be represented by legal advisers of its own
choice. In the event the LICENSOR brings a Proceeding, COLLATERAL
shall provide all reasonable assistance to the LICENSOR in relation
to such Proceeding and on the terms as set out in Clause 6.1 (b) as
if COLLATERAL were the LICENSOR and the LICENSOR were COLLATERAL
(e) In the event the LICENSOR brings a Proceeding pursuant to Clause
6.1(d), the LICENSOR shall be entitled to any recovery realised as a
result of such Proceeding.
6.2 Infringement of Third Party Rights
Each party shall promptly notify the other parties in writing in the event
that any allegation of infringement of any Third Party patent is raised by
reason of the exercise by COLLATERAL or any of its sub-licencees of any
rights pursuant to Clause 3.1 or 3.3 (Alleged Third Party Patent Rights)
In the event that such an action is brought by a Third Party COLLATERAL,
or any sub-licensee of COLLATERAL, as may be determined by COLLATERAL,
shall have the right to control any defence of any such action at its own
expense and represented by legal advisers of its own choice and the
LICENSOR shall have the right, at its own expense, to be represented in
any such action by legal advisers of its own choice. In the event of any
infringement or alleged infringement of any Alleged Third Party Patent
Rights, the LICENSOR shall co-operate in good faith with
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COLLATERAL or any sub-licensee of COLLATERAL (as the case may be) on a
reasonable basis to negotiate and settle any dispute with a Third Party in
relation to such infringement or alleged infringement of any Alleged Third
Party Patent Rights and otherwise resolve any such infringement or alleged
infringement and secure COLLATERAL's continued rights to the Alleged Third
Party Patent Rights, if necessary or desirable.
6.3 Co-operation in Connection with Infringement Disputes
In any suit or dispute involving infringement or alleged infringement
within the Field by a Third Party of a patent included within the Patent
Rights, or infringement or alleged infringement by COLLATERAL of any
Alleged Third Party Patent Rights, the parties shall co-operate fully and,
upon the request and at the reasonable expense of COLLATERAL, the LICENSOR
shall make available to COLLATERAL or its sub-licensees at reasonable
times and under appropriate conditions all relevant personnel, records,
papers, information, samples, specimens and the like which are in its
possession or control provided however that the LICENSOR shall not be
obliged to provide such assistance if to do so would materially disrupt
its normal business activities.
6.4 Prosecution and Maintenance of Patent Rights
The LICENSOR shall make determinations with respect to, shall be solely
responsible for, and shall bear all of its reasonably incurred expenses
from and after the Effective Date in connection with prosecuting to
issuance patent applications, for filing and prosecuting all patent
re-issues and re-examinations, for applying for and obtaining any patent
term extensions, and for paying all maintenance fees on all patents.
relating to the Patent Rights; provided however that the LICENSOR shall
file and prosecute to issuance applications claiming the subject matter of
those applications described in Schedule 1 and Schedule 2 in the United
States of America, Australia, Canada, the European Patent Office and
Japan. The LICENSOR shall keep COLLATERAL reasonably informed of the
status of all such applications and patents.
7. OBLIGATIONS OF THE PARTIES
7.1 Best Endeavours
COLLATERAL and its sub-licensees shall use its commercially reasonable
efforts consistent with its best business and scientific judgement and
conduct itself according to international pharmaceutical industry
standards in attempting to develop and commercialise Licensed Products.
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7.2 Achievement of Benchmarks
(a) COLLATERAL shall achieve the Benchmarks described in Schedule 3 as
follows:
(i) in relation to completion of Pig Studies by October 30, 1997;
(ii) in relation to *** Provided That COLLATERAL shall be entitled
to extend the time to complete this Benchmark for no more than
two (2) periods of three (3) months by the payment of
$150,000 per each three month period.
Within *** of achieving a Benchmark, COLLATERAL shall notify the
LICENSOR that the said Benchmark has been achieved.
(b) If COLLATERAL fails to achieve a Benchmark within the time
stipulated in Clause 7.2(a)(i) and/or (ii) then this Agreement
shall, subject to any agreement between the parties to allow this
Agreement to continue in full force and effect, be deemed to have
terminated with effect from the day following the time stipulated in
Clause 7.2(a). Time is of the essence with respect to COLLATERAL's
compliance with the requirements stated in Clause 7.2(a).
7.3 Pig Studies
(a) The parties to this Agreement acknowledge that the Pig Studies are
being conducted to support a clinical development program for the
use of Licensed Products in the Field for the treatment and
prevention of coronary artery disease and COLLATERAL agrees that it
shall conduct the Pig Studies in accordance with this aim.
(b) COLLATERAL shall notify the LICENSOR of the completion of the Pig
Studies in accordance with Clause 7.2(a) and with such notification
shall provide a report containing the data and results of the Pig
Studies to the LICENSOR for its review.
(c) In the event that the Pig Studies have achieved all of the criteria
established under Schedule 4 and provided that COLLATERAL notify the
LICENSOR of their intention to continue with the development of the
Licensed Products this licence shall, subject to the terms and
conditions set out herein remain in full force and effect.
*** Portions of this page have been omitted pursuant to a request for
Confidential Treatment and filed separately with the Commission.
Page 18
(d) In the event that the Pig Studies fail to meet some or all of the
criteria established under Schedule 4, within *** of receiving the
report described in Clause 7.3 (b) and after consultation with
COLLATERAL, LICENSOR may elect at its total discretion to allow
further development of the Technology and/or Licenced Products as
provided for in Clause 7.3(e). In the event that the LICENSOR does
not exercise its discretion under this Clause 7.3(d) this Agreement
will be deemed to have terminated effective as of 30 October 1997.
(e) If the LICENSOR exercises its discretion pursuant to Clause 7.3(d)
then COLLATERAL shall be entitled to conduct further Pig Studies in
myocardial ischaemia or peripheral vascular disease and/or
congestive heart failure aimed at supporting a clinical development
program for the use of Licensed Products on the same terms and
conditions as contained in this Agreement provided that, prior to
COLLATERAL being entitled to conduct such studies, the LICENSOR and
COLLATERAL shall discuss and agree upon new benchmarks and dates for
the achievement of such benchmarks for the use of the VRF/VEGF-B
gene in these further studies.
(f) If the LICENSOR and COLLATERAL do not agree in relation to the
benchmarks under Clause 7.3(e), within thirty (30) days of the end
of the period commencing 30 October 1997, this Agreement shall,
subject to any agreement between the parties to allow this Agreement
to continue in full force and effect, be deemed to have terminated
with effect from 30 October 1997.
7.4 Reporting
Within *** of the conclusion of the period of *** after the Effective
Date, COLLATERAL shall submit a written report to the LICENSOR, which
report shall include reasonable details of such matters as the LICENSOR
may from time to time reasonably request including, but not limited to:
(a) current status of research and development conducted in relation to
the Technology, Patent Rights and Licensed Products;
(b) current status of exploitation of the Technology, Patent Rights and
Licensed Products;
(c) current status of any applications for regulatory approval in
relation to the Technology, Patent Rights and Licensed Products;
*** Portions of this page have been omitted pursuant to a request for
Confidential Treatment and filed separately with the Commission.
Page 19
(d) current status of any manufacturing being conducted by or on behalf
of COLLATERAL or by or on behalf of and of its sub-licensees in
relation to any exploitation of the Technology, Patent Rights and
Licensed Products;
(e) any sub-licences granted by COLLATERAL pursuant to Clause 3.3;
(f) marketing and sales in relation to any exploitation of the
Technology, Patent Rights and Licensed Products conducted during the
said period of six (6) calendar months;
(g) any manufacturing, marketing, sales plans or projections in relation
to any exploitation of the Technology, Patent Rights and Licensed
Products; to be conducted for the subsequent period of six (6)
calendar months and the remainder of the applicable calendar year;
and
Thereafter, COLLATERAL shall submit a written report to the LICENSOR,
which report shall include the above details, within ten (10) days of the
conclusion of each successive period of six (6) calendar months for the
remainder of the term of this Agreement and provide such other comments
and advice to the LICENSOR as reasonably requested by the LICENSOR from
time to time upon reasonable notice to COLLATERAL.
7.5 Assistance
If AMRAD agrees to assist COLLATERAL in relation to the planning and
review of development programs relating to the exploitation of the
Technology it shall do so on terms and conditions as shall be agreed
between the parties from time to time.
8. CONFIDENTIALITY
8.1 Obligations
Except as otherwise provided in this Clause 8, during the term of this
Agreement. and thereafter until the date of expiration of the last of any
patent within the Patent Rights both the LICENSOR and COLLATERAL shall
maintain in confidence and use only for the purposes of this Agreement
information and data resulting from or related to the use or development
of the Technology in the Field pursuant to this Agreement, or supplied by
the LICENSOR pursuant to this Agreement (Information).
Page 20
8.2 Permitted Disclosures
To the extent it is reasonably necessary to fulfil its obligations or
exercise its rights pursuant to this Agreement, COLLATERAL may disclose
Information it is otherwise obligated pursuant to this Clause 8 not to
disclose to an Affiliate, a permitted sub-licensee or a potential
sub-licensee of the Technology on a need-to-know basis on condition that
such person or persons (as the case may be) agree to keep the Information
confidential for the same time periods and to the same extent as
COLLATERAL is required to keep the Information confidential. COLLATERAL
may also disclose such information to government or other regulatory
authorities to the extent that such disclosure is reasonably necessary to
obtain a patent or authorization to conduct a clinical trial with or to
commercially market any product arising out of the Technology. The
obligation not to disclose Information shall not apply to any part of such
Information that:
(a) is or becomes patented, published or otherwise part of the public
domain other than by acts of the person obligated not to disclose
such Information in the contravention of this Agreement;
(b) is disclosed to the receiving party by a Third Party, provided such
Information was not obtained from such Third Party directly or
indirectly from the LICENSOR or COLLATERAL (as the case may be);
(c) prior to disclosure pursuant to this Agreement, was already in the
possession of the receiving party, provided such Information was not
obtained directly or indirectly from the LICENSOR or COLLATERAL (as
the case may be);
(d) is developed independently of the Information obtained from the
LICENSOR or COLLATERAL (as the case may be), as demonstrated by
written evidence; or
(e) is disclosed by either the LICENSOR or COLLATERAL with the prior
written consent of the other.
8.3 Terms of this Agreement
The LICENSOR and COLLATERAL agree not to disclose any financial terms or
conditions of this Agreement to any Third Party without the prior written
consent of the other, except as required by applicable law or to persons
with whom the LICENSOR or COLLATERAL (as the case may be) has entered into
or proposes to enter into a business relationship provided that Third
Party is bound by confidentiality obligations. Notwithstanding the
foregoing:
Page 21
(a) COLLATERAL shall be permitted to disclose the material financial
terms of this Agreement to any potential acquirer, merger partner or
other bona fide potential strategic partner of COLLATERAL provided
that any such potential acquirer, merger, partner or other bona fide
strategic partner is bound by confidentiality obligations consistent
with this Agreement and further provided that the LICENSOR is
advised of the existence but not the identity of such potential
acquirer, merger partner or other bona fide strategic partner and
the nature of the disclosure to be made by COLLATERAL prior to such
disclosure being made; and
(b) the LICENSOR and COLLATERAL shall be permitted to disclose the terms
or conditions of this Agreement in accordance with the requirements
of the rules of any stock exchange or securities body without the
prior written consent of the other but only to the extent required
by such rules.
8.4 Public Comment
Notwithstanding anything contained in this Clause 8, COLLATERAL shall not
make any public comment either verbally or in writing concerning or
arising from this Agreement without first providing the other parties with
*** to review, and provide their approval for such announcement. The other
parties shall have the right to not unreasonably withhold approval of such
announcement provided that if no comments are provided to COLLATERAL
within *** the announcement will be deemed to be approved.
8.5 Survival of Obligations
This Clause 8 survives the termination of this Agreement.
9. LIMITATION OF LIABILITY AND INDEMNITY
(a) To the extent permitted by law, *** and any of their respective
servants, agents, sub-contractors or nominees are not liable for any
liabilities, losses, damages, charges, claims, actions, costs and
expenses suffered or incurred by *** ***.
*** Portions of this page have been omitted pursuant to a request for
Confidential Treatment and filed separately with the Commission.
Page 22
(b) Without limiting Clause 9(a), *** and any of their respective
servants. agents, sub-contractors or nominees are not liable for any
form of special, indirect, incidental or consequential loss or
damage (including loss of profits and loss or damage that was, or
may reasonably be supposed to have been, in the contemplation of the
parties as at the date of this Agreement as a probable result of any
such act or omission) *** ***.
(c) *** hereby indemnifies and shall keep indemnified and agrees to
defend *** and *** and any of their respective servants, agents,
sub-contractors or nominees against all liabilities, losses,
damages, charges, claims, actions, costs and expenses (including
without limitation legal fees calculated on a solicitor/client
basis) of any kind whatsoever suffered or incurred by any of them as
a result of or in connection with *** ***.
10. INSURANCE
(a) COLLATERAL shall maintain public and product liability insurance
with respect to the use and exploitation of the Patent Rights and
the production and distribution of any Licensed Products in such
amount as is customarily maintained in accordance with good practice
for the pharmaceutical industry. COLLATERAL shall maintain such
insurance for so long as it continues to use and exploit any of the
Patent Rights or produce or distribute any Licensed Products, and
thereafter for so long as COLLATERAL maintains insurance for itself
covering supply of such product.
(b) COLLATERAL shall, upon the request of the LICENSOR:
(i) produce evidence of the currency of such insurance; and
(ii) note the interest of the LICENSOR in the manner directed by
the LICENSOR on the policy in respect of such insurance.
*** Portions of this page have been omitted pursuant to a request for
Confidential Treatment and filed separately with the Commission.
Page 23
11. TERM AND EARLY TERMINATION
11.1 Term
Unless terminated earlier pursuant to Clauses 5.11, 7.2 or 7.3, or l1.3
this Agreement shall continue until the date of expiration of the last to
expire of any patent within the Patent Rights.
11.2 Effect of Termination
Upon termination of this Agreement for any reason whatsoever by either
party:
(a) all licences granted pursuant to this Agreement shall immediately
cease and COLLATERAL shall cease to make any use of the Technology
and the Patent Rights; and
(b) COLLATERAL shall immediately:
(i) return to the LICENSOR any materials provided to COLLATERAL
pursuant to Clause 4;
(ii) supply to the LICENSOR all documents, reports, notes,
memoranda, computer media or other materials which record,
contain or relate in any way to the Patent Rights or the
Technology and which were provided to or obtained by
COLLATERAL or prepared or made by or for or on behalf of
COLLATERAL except certain notes, documents and other materials
that are considered to be privileged or confidential or that
must be maintained to comply with regulatory requirements;
(iii) despite anything else in this Agreement, cease to make use of
anything subject to the confidentiality obligations in Clause
8,
and shall confirm in writing to the LICENSOR promptly when it has
complied with these obligations.
Page 24
(c) LICENSOR acknowledges that in respect of materials supplied in
clause 11.2 (b) arising from human clinical trials of Licensed
Products that it shall not be entitled to utilise such materials for
regulatory submissions seeking marketing approval of Licensed
Products in the Field, without the consent of COLLATERAL where such
consent is not to be unreasonably withheld. For the avoidance of
doubt the parties acknowledge that the LICENSOR can utilise any
other material supplied pursuant to clause 11.2(b) for regulatory
submission purposes.
11.3 Early Termination
(a) In addition to any rights it may have hereunder the LICENSOR may
terminate this Agreement with immediate effect upon the occurrence
of any of the following:
(i) upon or after the bankruptcy, insolvency, dissolution or
winding up of COLLATERAL (other than dissolution or winding up
for the purposes of a solvent reconstruction or amalgamation);
or
(ii) upon or after the breach of any material provision of this
Agreement by COLLATERAL, if COLLATERAL has not remedied the
breach within thirty (30) days after written notice thereof by
the LICENSOR.
(b) COLLATERAL may terminate this Agreement at any time on thirty (30)
days' notice to the LICENSOR provided that COLLATERAL shall not
terminate this Agreement for any reason whatsoever prior to the
completion of the Pig Studies or 30 October 1997, whichever is the
latter.
11.4 Survival of Accrued Obligations
Expiration or termination of this Agreement shall not relieve the parties
of any obligation accruing prior to such expiration or termination.
Page 25
12. RESOLUTION OF DISPUTES
12.1 Disputes Committee
If any dispute or difference shall arise between the LICENSOR and
COLLATERAL pursuant to this Agreement then, prior to either party taking
any further action as by referring the matter to arbitration or commencing
legal proceedings, the matter in dispute shall be referred to a disputes
committee which shall consist of the respective chief executives of AMRAD,
XXXXXX and COLLATERAL (Disputes Committee). The chief executives shall
confer together in an endeavour to settle the dispute on some fair and
equitable commercial basis with regard to the basic legal rights of AMRAD,
XXXXXX and COLLATERAL. Any discussions or proceedings of the Disputes
Committee shall be on a without prejudice basis.
12.2 Use of Expert
Subject to agreement of all members of the Disputes Committee, the
Disputes Committee may, at its option, refer any dispute or difference to
an independent Third Park to act as an expert and not as an arbitrator in
settling the same, on terms that the decision of such independent Third
Party shall be binding on AMRAD, XXXXXX and COLLATERAL.
13. NOTICES
Any notice, demand, consent or other communication (Notice) given or made
under this Agreement:
(a) must be in writing and signed by a person duly authorised by the
sender;
(b) must either be delivered to the intended recipient by prepaid post
(if posted to an address in another country, by airmail) or by hand
or fax to the address or fax number below or the address or fax
number last notified by the intended recipient to the sender:
Page 26
(i) to XXXXXX institute
of Cancer Research: 0000 Xxxxxx xx xxx Xxxxxxxx
Xxx Xxxx, Xxx Xxxx,
Xxxxxx Xxxxxx of America 1015
Attention: President
Fax No: (000) 000 0000
with a copy to its London Office:
Fax No: (000) 000 0000
(ii) to Collateral
Therapeutics Inc: 0000 Xxxxx Xxxxxx Xxxxx
Xxx Xxxxx, Xxxxxxxxxx
Xxxxxx Xxxxxx of America 92121
Attention: President
Fax No: (000) 000 0000
(iii) to AMRAD Development
Pty Ltd: 000 Xxxx Xxxxxx
Xxxxxxx, Xxxxxxxx, 0000
Attention: Managing Director
Fax No: (000) 00000000
(c) will be taken to be duly given or made:
(i) in the case of delivery in person, when delivered:
(ii) in the case of delivery by post, five business days after the
date of posting (if posted to an address in the same country)
or fourteen business days after the date of posting (if posted
to an address in another country); and
(iii) in the case of fax, on receipt by the sender of a transmission
control report from the despatching machine showing the
relevant number of pages and the correct destination fax
machine number or name of recipient and indicating that the
transmission has been made without error,
but if the result is that a Notice would be taken to be given or
made on a day that is not a business day in the place to which the
Notice is sent or is later than 4:00pm (local time) it will be taken
to have been duly given or made at the commencement of business on
the next business day in that place.
14. ENTIRE AGREEMENT
This Agreement contains the entire agreement between the parties with
respect to its subject matter and supersedes all prior agreements and
understandings between the parties in connection with it.
Page 27
15. AMENDMENT
No amendment or variation of this Agreement is valid or binding on a party
unless made in writing executed by all parties.
16. ASSIGNMENT
16.1 No Assignment Without Consent
Neither party may assign or otherwise transfer this Agreement or any of
its rights or obligation herein without the prior written consent of the
other party, which consent shall not be unreasonably withheld.
16.2 Permitted Assignments
(a) Notwithstanding Clause 16.1, COLLATERAL may assign this Agreement:
(i) subject to Clause 16.3, to Schering AG on written notice to the
LICENSOR but without the prior written consent of the LICENSOR
provided that Schering AG undertakes in writing to the LICENSOR
to be bound by all of the terms and conditions of this Agreement
prior to any such assignment and LICENSOR is notified within five
(5) days of such assignment taking place;
(ii) without the prior written consent of the LICENSOR in connection
with the sale of all or substantially all of the assets of
COLLATERAL to an Affiliate of COLLATERAL in connection with a
corporate reorganisation, provided that such Affiliate undertakes
in writing to be bound by all the terms and conditions in this
Agreement and LICENSOR is notified within five (5) days of such
assignment taking place; and
(b) Notwithstanding Clause 16.1 AMRAD or XXXXXX may assign this
Agreement to an Affiliate provided that such Affiliate undertakes
to be bound by the terms and conditions of this Agreement.
16.3 Assignment to Schering AG
In the event that COLLATERAL assigns this Agreement to Schering AG
pursuant to Clause 16.2(a), the following amendments to this Agreement
shall be made:
Page 28
(a) in Clause 1.1, substitute for the definition of Net Revenue:
"Net Revenue means the prescribed percentage (as defined in
Clause 5.6(d)) of Net Sales made by Schering AG or royalty
payments received by Schering AG on Net Sales made by any
permitted sub-licensees less, in the event the exclusive
licence agreement between the Regents of the University of
California and COLLATERAL entitled *** dated 28 September
1995 as amended *** *** has been assigned to Schering AG
and the Licensed Products involve in any way whatsoever the
technology claimed in *** *** if payable to the said
Regents pursuant to the said exclusive licence agreement";
(b) in Clause 1.1, substitute for the definition of Net Sales:
"Net Sales" means gross proceeds from sales of Licensed
Products by Schering AG or by any permitted sub-licensees
less deductions for:
(a) transportation charges, including insurance relating
thereto;
(b) sales and excise taxes or customs duties paid by the
person selling or distributing any Licensed Product or
any other governmental charges imposed upon the sale or
distribution of any Licensed Product;
(c) distributors' fees, rebates or allowances actually
granted, allowed or incurred;
(d) quantity discounts, cash discounts or chargebacks
actually granted, allowed or incurred in the ordinary
course of business in connection with the sale or
distribution of any Licensed Product;
(e) allowances or credits to customers not in excess of the
selling price of any Licensed Product, on account of
governmental requirements, rejection, outdating, recalls
or returns of such Licensed Product.";
(c) substitute for Clause 5.6(c):
*** Portions of this page have been omitted pursuant to a request for
Confidential Treatment and filed separately with the Commission.
Page 29
"If Schering AG or any of its sub-licensees receives any
non-cash benefit or otherwise derives any non-cash
commercial benefit in connection with the exploitation of
the Technology other than pursuant to an arm's length sale
agreement with a Third Party, for the purposes of
calculating the amount payable to Schering AG pursuant to
this Clause 5.7, Schering AG or its sublicensees (as the
case may be) shall be taken to have received revenue that
would have been received on an arm's length sale
agreement."; and
(d) substitute for Clause 5.6(d):
"For the purposes of the definition of Net Revenue in Clause
1.1, the prescribed percentage referred to therein shall be
the percentage royalty on Net Sales which COLLATERAL had paid
to LICENSOR prior to the assignment of this Agreement to
Schering AG. Upon assignment of this Agreement to Schering AG,
Schering AG shall notify the LICENSOR of the prescribed
percentage."
17. NO WAIVER
No failure to exercise nor any delay in exercising any right, power or
remedy by a party operates as a continuing waiver. A single or partial
exercise of any right, power or remedy does not preclude any other or
further exercise of that or any other right, power or remedy. A waiver is
not valid or binding on the party granting that waiver unless made in
writing.
18. FURTHER ASSURANCES
Each party agrees to do all things and execute all deeds, instruments,
transfers or other documents as may be necessary or desirable to give full
effect to the provisions of this Agreement and the transactions
contemplated by it.
19. RELATIONSHIP OF THE PARTIES
This Agreement does not set up or create an employer/employee
relationship, partnership of any kind, an association or trust between the
parties, each party being individually responsible only for its
obligations as set out in this Agreement and in addition the parties agree
that their relationship is one of independent contractors. COLLATERAL is
not authorised or empowered to act as agent on behalf of AMRAD or XXXXXX
and COLLATERAL shall not on behalf of AMRAD or XXXXXX
Page 30
enter into any contract, warranty or representation as to any matter.
AMRAD or XXXXXX shall not be bound by the acts or conduct of COLLATERAL.
None of AMRAD, or XXXXXX are authorised or empowered separately or
together, to act as agent on behalf of COLLATERAL and none of AMRAD or
XXXXXX, separately or together, may enter any contract, warranty or
representations as to any matter on behalf of COLLATERAL. COLLATERAL shall
not be bound by the acts or conduct of any of AMRAD or XXXXXX, whether
acting alone or together.
20. COSTS AND STAMP DUTY
Each party shall bear its own costs arising out of the negotiation,
preparation and execution of this Agreement.
21. GOVERNING LAW AND JURISDICTION
This Agreement is governed by the laws of England. Subject to Clause 13,
each party submits to the non-exclusive jurisdiction of courts
exercising jurisdiction there in connection with matters concerning
this Agreement.
22. COUNTERPARTS
This Agreement may be executed in any number of counterparts. All
counterparts together will be taken to constitute one instrument.
Page 31
-------------------------------------------------------------------------------
SCHEDULE 1
-------------------------------------------------------------------------------
AMRAD Patent Applications
Patent Applications filed by AMRAD
***
Inventors: Xxxxxxx, N.;
Xxxxx, G;
Grimmond, S.;
Nordenskjold, M;
Larsson, C.
Claiming priority from:
***
***
***
*** Portions of this page have been omitted pursuant to a request for
Confidential Treatment and filed separately with the Commission.
Page 32
-------------------------------------------------------------------------------
SCHEDULE 2
-------------------------------------------------------------------------------
XXXXXX Patent Applications
US Patent Applications filed by XXXXXX
*** ***
Inventors: Xxx Xxxxxxxx and Xxxxxxxx Xxxxxxxx (Stockholm Branch, LICR).
*** ***
Inventors: Xxx Xxxxxxxx and Xxxxxxxx Xxxxxxxx of the Stockholm Branch,
LICR and Xxxxx Xxxxxxxx and Xxxx Xxxxxxx (University of
Helsinki).
*** ***
Inventors: Xxx Xxxxxxxx and Xxxxxxxx Xxxxxxxx of the Stockholm Branch,
LICR and Katri Pajusolo and Xxxx Xxxxxxx (University of
Helsinki).
*** ***
***
Inventors: Xxx Xxxxxxxx and Xxxxxxxx Xxxxxxxx of the Stockholm Branch,
LICR and Xxxxx Xxxxxxxx and Xxxx Xxxxxxx (University of
Helsinki).
*** Portions of this page have been omitted pursuant to a request for
Confidential Treatment and filed separately with the Commission.
Page 33
-------------------------------------------------------------------------------
SCHEDULE 3
-------------------------------------------------------------------------------
Benchmarks
Completion of Pig Studies in the ameroid pig model of
myocardial ischaemia 30 October 1997
*** ***
*** Portions of this page have been omitted pursuant to a request for
Confidential Treatment and filed separately with the Commission.
Page 34
-------------------------------------------------------------------------------
SCHEDULE 4
-------------------------------------------------------------------------------
CRITERIA FOR GENE EFFICACY IN PIG MYOCARDIAL ISCHEMIA MODEL
(1) Efficacy in the pig chronic myocardial ischemia model
o Documented selective transgene expression in the heart at 2 weeks
after gene transfer: Method and Criteria: PCR ( ~ ) for gene in
cardiac tissue.
o Statistically significant (p lesser than 0.05) improvement in
Function (systolic wall thickening assessed by transthoracic
echocardiography) and Perfusion (contrast echocardiography)
2 weeks following gene transfer:
Criteria:
(1) Improvement in both Perfusion and Function during pacing
induced stress compared to stress prior to gene transfer in
the same animal.
Improved Function and Performance will be:
(1) statistically significant (p lesser than 0 05), and
(2) improved from pre-gene-transfer stress by at least
50(degree)'~ relative to the baseline stress. Data will be the
mean of between 5 and ~ pigs instrumented and injected
essentially as described in Nature Medicine, 2: 534-534, 1996.
(2) Acceptable safety profile
No evidence of significant inflammation using histologic and
immunocytochemical criteria in the heart and in other tissues.
Page 35
EXECUTED as an agreement.
THE COMMON SEAL of AMRAD )
DEVELOPMENT PTY LTD was duly affixed in ) [SEAL]
the presence of: )
/s/ Xxxx Xxxxx /s/ Xxxxxx X. Klupais
----------------------------------- ----------------------------------
Director Secretary
Xxxx Xxxxx Xxxxxx Klupais
----------------------------------- ----------------------------------
Print Name Print Name
SIGNED SEALED AND DELIVERED by )
)
a duly authorised officer of XXXXXX )
INSTITUTE OF CANCER RESEARCH in the )
presence of: )
/s/ Xxxxx Xxxx Lenthau /s/ RDJ Xxxxxx
----------------------------------- /s/ Xxxxxx X. XxXxxxxxx Xx
Witness ----------------------------------
Duly Authorised Officer
Xxxxx Xxxx Lenthau Xxxxxx X. XxXxxxxxx Xx.
----------------------------------- Xxxxxxx XX Xxxxxx
Print Name ----------------------------------
Print Name
SIGNED SEALED AND DELIVERED by )
)
a duly authorised officer of COLLATERAL )
THERAPEUTICS INC in the presence of: )
)
/s/ H Xxxx Xxxxxxx MD /s/ Xxxx X. Xxxxx, Ph.D.
----------------------------------- ----------------------------------
Witness Duly Authorised Officer
H. Xxxx Xxxxxxx, MD Xxxx X. Xxxxx, Ph.D.
----------------------------------- ----------------------------------
Print Name Print Name
