EXHIBIT 10.25
Licence agreement
THIS AGREEMENT dated 11th March 1999 is between:
(1) UNIVERSITY COLLEGE LONDON, incorporated in the United Kingdom by Royal
Charter, acting through its Royal Free and University College Medical
School, whose address is ▇▇▇▇▇▇▇ ▇▇▇▇ ▇▇▇▇▇▇, ▇▇▇▇▇▇ ▇▇▇ ▇▇▇ ("Royal
Free"); and
(2) BIOENVISION, INC, incorporated in Delaware whose principal place of
business is at ▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇, ▇▇ ▇▇▇▇▇▇▇▇ Place, St James's, London SW
1Y 4AU] ("Bioenvision").
RECITALS:
A. Royal Free is the registered owner of Patents (as defined below) and has
developed technical information ("Know-how", as defined below) relating to
the development and uses of an eukaryotic gene expression cassette with
muscle element promotors and related technologies.
B. Bioenvision recognises that Royal Free owns inventions and intellectual
property useful in the conduct of Bioenvision's business.
C. Bioenvision also recognises that its anticipate business activity will
encompass the practice of technology that requires a license under patents
owned by Royal Free.
D. Bioenvision wishes to acquire rights under the Patents and to use the
Know-how for the development and commercialisation of Licensed Products in
the Field and in the Territory, in accordance with the provisions of this
Agreement.
IT IS AGREED as follows:
1 Definitions
In this Agreement, the following words shall have the following meanings:
Affiliate In relation to a Party, means any entity or person which
controls, is controlled by, or is under common control with
that Party. For the purposes of this definition, "control"
shall mean direct or indirect beneficial ownership of 50%
(or, outside a Party's home territory, such lesser
percentage as is the maximum, permitted level of foreign
investment) or more of the share capital, stock or other
participating interest carrying the right to vote or to
distribution of profits of that entity or person, as the
case may be.
Commencement Date The date of signature of this agreement (subject to the
terms of clause 2.1).
Delivered Items Has the meaning given in Clause 3.2.
Field means, and is limited to, the practice of the Invention and
Know-how embodied in the patent application referred to in
Schedule 1 and licensed hereunder for the treatment of
disorders associated with liver dysfunction, disease
conditions characterised by decreased production of liver
proteins e.g. albumin, cancer, and endocrine disorders that
may affect liver function in human and animal applications.
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Know-how Technical information in the Field:
(a) Developed in the Laboratory under the supervision of
the Principal Investigator prior to the
Commencement Date and relating directly to the
inventions claimed in the Patents; or
(b) Developed in the course of the Project (i) in the
Laboratory under the supervision of the Principal
Investigator or (ii) by Bioenvision.
Laboratory The laboratory of the Principal Investigator within Royal
Free's Department of Anatomy and Developmental Biology.
Licensed Products Any and all products that are manufactured, sold or
otherwise supplied by Bioenvision or its sub-licensees and
which (a) are within any Valid Claim of the Patents and/or
(b) incorporate, or their development made use of, any of
the Know-how.
Net Receipts The amounts received by Bioenvision or its Affiliates
from the grant of sub-licences under the Patents and
Know-how, less any Value Added Tax or other sales tax.
Net Sales Value The invoiced price of Licensed Products sold by Bioenvision
or its Affiliates to independent third parties in arm's
length transactions exclusively for money or, where the sale
is not at arm's length, the price that would have been so
invoiced if it had been at arm's length, after deduction of
normal trade discounts actually granted and any credits
actually given, and, provided the amounts are separately
charged on the relevant invoice any costs of packaging,
insurance, carriage and freight, any value added tax or
other sales tax, and any import duties or similar applicable
government levies.
Parties Royal Free and Bioenvision, and "Party" shall mean either of
them.
Patents Any and all of the patents and patent applications referred
to in Schedule 1, and any and all of the patents and patent
applications (if any) which may be made during the term of
this Agreement and which form part of the Project IPR,
including any continuations, continuations in part,
extensions, reissues, divisions, and any patents,
supplementary protection certificates and similar rights
that are based on or derive priority from the foregoing.
Principal
Investigator ▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇▇
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Project The further development by the Parties of the inventions and
developments described in the Patents and the Know-how. The
Parties anticipate that the Project shall be conducted in
accordance with the provisions of Schedule 3.
Project IPR Any and all inventions, know-how, data and other
developments made in the course of the Project, and any
patent applications, patents and other intellectual property
that may be generated in respect of such inventions,
know-how, data and developments during the term of this
Agreement.
Territory European Community, United States of America, Canada, Middle
East, Japan.
Valid Claim A claim of a patent or patent application that has not
expired or been held invalid or unenforceable by a court of
competent jurisdiction in a final and non-appealable
judgment.
2 Grant of rights
2.1 The parties agree to execute a Co-development agreement for the pursuit of
the Project to be executed within 30 days (or some other period agreed
between the parties) of the Commencement Date. If such a Co-development is
not executed, then this License Agreement will terminate.
2.1.1 Licences. Royal Free hereby grants to Bioenvision, subject to the
provisions of this Agreement:
2.1.2 an exclusive licence in the Field under the Patents, with the right to
sub-license, subject to clause 2.3 below, to develop, manufacture, have
manufactured, use and sell Licensed Products but only in the Field in
the Territory; and
2.1.3 an exclusive licence in the Field to use the Know-how, with the right
to sub-license, subject to clause 2.3 below, to develop, manufacture,
have manufactured, use and sell Licensed Products but only in the Field
in the Territory.
2.2 Formal licences. The Parties shall execute such formal licences as may be
necessary or appropriate for registration with Patent Offices and other
relevant authorities in particular territories. In the event of any
conflict in meaning between any such licence and the provisions of this
Agreement, the provisions of this Agreement shall prevail wherever
possible. Prior to the execution of the formal licence(s) (if any)
referred to above, the Parties shall so far as possible have the same
rights and obligations towards one another as if such licence(s) had been
granted. The Parties shall use reasonable endeavours to ensure that, to
the extent permitted by relevant authorities, this Agreement shall not
form part of any public record.
2.3 Sub-licensing. Bioenvision shall be entitled to grant sub-licences of its
rights under this Agreement to any person, provided that:
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2.3.1 the royalties and other consideration provided for in the sub-licence
shall be at an amount or rate which is not less than the amount or rate
provided for in this Agreement;
2.3.2 the sub-licence shall include obligations on the sub-licensee which are
equivalent to the obligations on Bioenvision under this Agreement;
2.3.3 the sub-licence shall terminate automatically on the termination of
this Agreement for any reason;
2.3.4 within 30 days of the grant of any sub-licence Bioenvision shall
provide to Royal Free a true copy of it; and
2.3.5 Bioenvision shall be responsible for any breach of the sub-licence by
the sub-licensee, as if the breach had been that of Bioenvision under
this Agreement, and Bioenvision shall indemnify Royal Free against any
loss, damages, costs, claims or expenses which are awarded against or
suffered by Royal Free as a result of any such breach by the
sub-licensee.
2.4 Reservation of rights. Royal Free reserves the non-exclusive right to use
the Know-how and the Patents in the Field for the purposes of academic
research and teaching. Royal Free shall have the exclusive, worldwide,
sub-licensable right to use, develop and commercialise Project IPR outside
the Field.
2.5 No other licence. It is acknowledged and agreed that no licence is granted
by Royal Free to Bioenvision other than the licence(s) expressly granted
by the provisions of this clause 2. Without prejudice to the generality of
the foregoing Royal Free reserves all rights under the Patents and
Know-how outside the Field.
2.6 Quality. Bioenvision shall ensure that all of the Licensed Products
marketed by it and its sub-licensees are of satisfactory quality and
comply with all applicable laws and regulations in each part of the
Territory.
3 Know-how and Confidential Information
3.1 Provision of Know-how. Upon Bioenvision's reasonable request, Royal Free
shall arrange for the Principal Investigator to supply Bioenvision with all
Know-how in his possession that Royal Free is at liberty to disclose and has not
previously been disclosed and which is reasonable necessary or desirable to
enable Bioenvision to undertake the further development of the Licensed
Products. The Know-how shall be subject to the confidentiality provisions of
Clause 3.5. The method of such supply shall be agreed between the Principal
Investigator and Bioenvision but shall not require the Principal Investigator to
undertake more than 2 man-days of work, unless otherwise agreed in writing
between the Parties. If it is agreed that the Principal Investigator shall
travel to Bioenvision's premises in connection with such supply, Bioenvision
shall reimburse all reasonable travel, accommodation and subsistence costs
incurred.
3.1 Status of Know-how. Bioenvision acknowledges that the Know-how is at an
early stage of development. Accordingly, specific results cannot be
guaranteed and any results, materials, information or other items,
including without limitation Know-how (together "Delivered Items")
provided under or in connection with this Agreement are provided "as is"
and without any express or implied warranties, representations or
undertakings. As examples, but without limiting the foregoing, Royal Free
does not give any warranty that Delivered Items are of merchantable or
satisfactory quality, are fit for any particular purpose, comply with any
sample or description, or are viable, uncontaminated, safe or non-toxic.
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3.2 Responsibility for development of Licensed Products. Bioenvision shall be
exclusively responsible for the technical and commercial development and
manufacture of Licensed Products and for incorporating any modifications
or developments thereto that may be necessary or desirable and for all
Licensed Products sold or supplied, and accordingly Bioenvision shall
indemnify Royal Free in the terms of Clause 7.3.
3.3 Use of Know-how. Bioenvision undertakes that for a period of 10 years from
the Commencement Date or for so long as any substantial part of the
Know-how remains subject to the obligations of confidence of Clause 3.5,
whichever is the shorter, it will not use the Know-how for any purpose
except as expressly licensed hereby and in accordance with the provisions
of this Agreement.
3.4 Confidentiality obligations. Each Party ("Receiving Party") undertakes:
3.4.1 to maintain as secret and confidential all Know-how and other technical
or commercial information obtained directly or indirectly from the
other Party ("Disclosing Party") in the course of or in anticipation of
this Agreement and to respect the Disclosing Party's rights therein,
3.4.2 to use the same exclusively for the purposes of this Agreement, and
3.4.3 to disclose the same only to those of its employees, contractors and
sub-licensees pursuant to this Agreement (if any) to whom and to the
extent that such disclosure is reasonably necessary for the purposes of
this Agreement.
3.5 Exceptions to obligations. The provisions of Clause 3.5 shall not apply to
Know-how and other information which the Receiving Party can demonstrate
by reasonable, written evidence:
3.5.1 was, prior to its receipt by the Receiving Party from the Disclosing
Party, in the possession of the Receiving Party and at its free
disposal; or
3.5.2 is subsequently disclosed to the Receiving Party without any
obligations of confidence by a third party who has not derived it
directly or indirectly from the Disclosing Party; or
3.5.3 is or becomes generally available to the public through no act or
default of the Receiving Party or its agents, employees, Affiliates or
sub-licensees; or
3.5.4 the Receiving Party is required to disclose to the courts of any
competent jurisdiction, or to any government regulatory agency or
financial authority, provided that the Receiving Party shall (i) inform
the Disclosing Party as soon as is reasonably practicable, and (ii) at
the Disclosing Party's request seek to persuade the court, agency or
authority to have the information treated in a confidential manner,
where this is possible under the court, agency or authority's
procedures; or
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3.5.5 in the case of information disclosed by Royal Free to Bioenvision, is
disclosed to actual or potential customers for Licensed Products in so
far as such disclosure is reasonably necessary to promote the sale or
use of Licensed Products, provided that the customers sign a written
confidentiality undertaking at least as restrictive as Clauses 3.5 and
3.6.
3.6 Disclosure to employees. The Receiving Party shall procure that all of its
employees, contractors and sub-licensees pursuant to this Agreement (if
any) who have access to any of the Disclosing Party's information to which
Clause 3.5 applies, shall be made aware of and subject to these
obligations and shall have entered into written undertakings of
confidentiality at least as restrictive as Clauses 3.5 and 3.6 and which
apply to the Disclosing Party's information.
3.7 The fact that some or all of the Know-how becomes public knowledge shall
not affect the financial obligations for use of the Know-how licensed
under this Agreement if such Know-how was used or usable in the discovery,
development, manufacture, or approval for sale of Licensed Products within
the Field.
4 Payments
4.1 Payments for development work and clinical trials.
4.1.1 Bioenvision shall pay the costs of any further pre-clinical development
work deemed necessary prior to commencing clinical trials for the
Project, and this shall include the development of Licensed Products
for other therapeutic applications, the use of different formulations
and preparations of Licensed Products.
4.1.2 Bioenvision shall pay the costs of clinical trials of Licensed
Products. The costs of such development will not exceed $3 million
(three million U.S. dollars).
4.1.3 Bioenvision shall pay the cost of prosecuting, filing and maintaining
patents and defending revocation proceedings on patents and patent
applications, on the Licensed Products within the Territory that shall
become due after the date of this Agreement.
4.1.4 Bioenvision shall pay to Royal Free a milestone payment of
(pound)200,000 in addition to any royalty or other payments on
successful completion of the first Phase III trial for the first of
the Licensed Products developed under this Agreement.
4.2 Initial payment. Within 30 days of the Commencement Date, the Bioenvision
shall pay to Royal Free the non-refundable, sum of (pound)20,000 (pounds
sterling) which shall be the first instalment of the monies due under
Clause 4.1 (a)
4.3 Royalties. Bioenvision shall pay to Royal Free a royalty being a
percentage of the Net Sales Value of all Licensed Products or any part
thereof sold by Bioenvision or its sub-licensees. The percentage shall be
the higher of the following alternative percentages which applies to the
Licensed Product in question:
4.3.1 6 per cent in the case of Licensed Products which are within a Valid
Claim of a Patent in the country of manufacture or sale; or
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4.3.2 6 per cent in the case of Licensed Products which incorporate, or whose
development made use of, any of the Know-how.
4.4 Combination Products. If any Licensed Products are incorporated in any
other product ("Combination Product") supplied by the Bioenvision or its
sub-licensees and the Licensed Product is not priced separately from the
Combination Product, the Net Sales Value of such Licensed Product shall be
deemed to be that proportion of the Net Sales Value of the Combination
Product which is attributable to the Licensed Product, comparing the
manufacturing cost of the Licensed Product with that of the Combination
Product, as in the following formula: Net Sales Value of Licensed Product
= (manufacturing cost of Licensed Product divided by total manufacturing
cost of Combination Product) x Net Sales Value of Combination Product.]
4.5 Minimum royalties. If the royalties payable under Clause 4.3 are less than
$3,000 (USD) ("Minimum Royalty") in any calendar year after year three of
this agreement, Bioenvision shall pay to Royal Free the amount by which
the said royalties are less than the Minimum Royalty within 60 days of the
end of such calendar year, failing which Royal Free shall be entitled to
terminate this Agreement and all licences granted under this Agreement by
notice in writing to the Bioenvision given at any time after the expiry of
the said 60 day period. If this Agreement ends on any day other than the
end of a calendar year (ie December 31st), the Minimum Royalty due for
that year shall be reduced, pro-rata, ie the minimum amount due shall be
the Minimum Royalty for a complete year multiplied by the number of days
of the final calendar year during which this Agreement was in force, and
divided by 365 days.
4.6 Third party royalties. If, during the continuation of this Agreement,
Bioenvision considers it necessary to obtain a licence from any third
party ("Third Party Licence") in order to avoid infringing such third
party's patent(s) in the course of manufacture or sale of Licensed
Products, the royalties payable under this Agreement shall be reduced by
the amount of royalties paid under the Third Party Licence provided that
the amount of royalty payable by Bioenvision to Royal Free in any
quarterly period shall not be reduced by more than 50% of the amount which
would have been payable in the absence of this clause 4.6.
4.7 Payment dates.
4.7.1 Royalties due under this Agreement shall be paid within 60 days of the
end of each quarter ending on 31 March, 30 June, 30 September and 31
December, in respect of sales of Licensed Products made during such
quarter and within 60 days of the termination of this Agreement;
4.7.2 If this Agreement is for any reason terminated before all the earned
royalties herein provided for have been paid, Bioenvision shall
immediately pay to Royal Free any remaining unpaid balance of earned
royalties even though the due date provided in Clause 4.2 has not been
reached.
4.8 Payment terms. All sums due under this Agreement:-
4.8.1 are exclusive of Value Added Tax which where applicable will be paid by
Bioenvision to Royal Free in addition;
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4.8.2 shall be paid in pounds sterling by irrevocable, confirmed letter of
credit drawn on a London bank, and in the case of sales or sub-license
income received by Bioenvision in a currency other than pounds
sterling, the royalty shall be calculated in the other currency and
then converted into equivalent pounds sterling at the buying rate of
such other currency as quoted by Barclays Bank plc in London as at the
close of business on the last business day of the quarterly period with
respect to which the payment is made;
4.8.3 shall be made without deduction of income tax or other taxes charges or
duties that may be imposed, except insofar as Bioenvision is required
to deduct the same to comply with applicable laws. The Parties shall
cooperate and take all steps reasonably and lawfully available to them,
at the expense of Royal Free, to avoid deducting such taxes and to
obtain double taxation relief. If Bioenvision is required to make any
such deduction it shall provide Royal Free with such certificates or
other documents as it can reasonably obtain to enable Royal Free to
obtain appropriate relief from double taxation of the payment in
question; and
4.8.4 shall be made by the due date, failing which Royal Free may charge
interest on any outstanding amount on a daily basis at a rate
equivalent to 3% above the Bank of England base lending rate then in
force.
4.9 Exchange controls, etc. If at any time during the continuation of this
Agreement Bioenvision is prohibited from making any of the payments
required hereunder by a governmental authority in any country then
Bioenvision will within the prescribed period for making the said payments
in the appropriate manner use its best endeavours to secure from the
proper authority in the relevant country permission to make the said
payments and will make them within 7 days of receiving such permission. If
such permission is not received within 30 (thirty) days of Bioenvision
making a request for such permission then, at the option of Royal Free,
Bioenvision shall deposit the royalty payments due in the currency of the
relevant country either in a bank account designated by Royal Free within
such country or such royalty payments shall be made to an associated
company of Royal Free designated by Royal Free and having offices in the
relevant country designated by Royal Free.
4.10 Royalty statements. Bioenvision shall send to Royal Free at the same time
as each royalty payment is made in accordance with clause 4.3 a statement
setting out, in respect of each territory or region in which Licensed
Products are sold, the types of Licensed Product sold, the quantity of
each type sold, and the total Net Sales Value in respect of each type,
expressed both in local currency and pounds sterling and showing the
conversion rates used, during the period to which the royalty payment
relates.
4.11 Records
4.11.1 Bioenvision shall keep at its normal place of business detailed and up
to date records and accounts showing the quantity, description and
value of Licensed Products sold by it, and the amount of sublicensing
revenues received by it in respect of Licensed Products, on a country
by country basis, and being sufficient to ascertain the royalties due
under this Agreement.
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4.11.2 Bioenvision shall make such records and accounts available, on
reasonable notice, for inspection during business hours by an
independent chartered accountant nominated by Royal Free for the
purpose of verifying the accuracy of any statement or report given by
Bioenvision to Royal Free under this Clause 4. The accountant shall be
required to keep confidential all information learnt during any such
inspection, and to disclose to Royal Free only such details as may be
necessary to report on the accuracy of Bioenvision's statement or
report. Royal Free shall be responsible for the accountant's charges
unless the accountant certifies that there is an inaccuracy of more
than 5 per cent in any royalty statement, in which case Bioenvision
shall pay his charges in respect of that inspection.
4.11.3 Bioenvision shall ensure that Royal Free has the same rights as those
set out in this Clause 4.12 in respect of any sub-licensee of
Bioenvision which is sub-licensed under the Patents or Know-how
pursuant to this Agreement.
5 Commercialisation
5.1 Bioenvision shall diligently proceed to develop and commercially exploit
Licensed Products to the maximum extent worldwide.
5.2 Without prejudice to the generality of Bioenvision's obligations under
Clause 5.1, Bioenvision shall provide at least annually to Royal Free an
updated, written Development Plan, showing all past, current and projected
activities taken or to be taken by Bioenvision to bring Licensed Products
to market and maximise the sale of Licensed Products worldwide. Royal
Free's receipt or approval of any such plan shall not be taken to waive or
qualify Bioenvision's obligations under Clause 5.1.
5.3 If Royal Free considers at any time during the period of this Agreement
that Bioenvision has without legitimate reason failed to proceed
diligently to develop and commercially exploit Licensed Products, Royal
Free shall be entitled to refer to an independent expert the following
questions:
5.3.1 whether Bioenvision has acted diligently; and if not
5.3.2 what specific action Bioenvision should have taken ("Specific Action")
in order to have acted diligently.
5.4 The independent expert shall be appointed in accordance with the
provisions of Schedule 2 and his decision shall be final and binding on
the Parties.
5.5 If the expert determines that Bioenvision has failed to comply with its
obligations, under this Clause 5, and if Bioenvision fails to take the
Specific Action within 6 months of the expert giving his decision in
accordance with Schedule 2, Royal Free shall be entitled, by giving, at
any time within 3 months after the end of that 6 month period, not less
than 3 months' notice to terminate this Agreement and the licences granted
to Bioenvision under Clause 2.
6 Intellectual Property
6.1 Obtain and maintain the Patents.
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6.1.1 Bioenvision shall at its own cost and expense:
6.1.1.1 co-operate with Royal Free and its partners outside the Field (if any)
and endeavour to obtain valid Patents in the Field so as to secure the
broadest monopoly reasonably available; and
6.1.1.2 pay all renewal fees in respect of the Patents as and when due;
provided that if Bioenvision wishes to abandon any such
application or not to maintain any such Patent (or to cease
funding such application or Patent) it shall give 3 months
prior written notice to Royal Free and on the expiry of such
notice period Bioenvision shall cease to be licensed under the
patent application or patent identified in the notice.
6.1.2 Without prejudice to the provisions of Clause 6.2.(a), the Parties
agree that all Project IPR shall be jointly owned by the Parties as
beneficial owners in common, subject to the provisions of this
Agreement.
6.2 Infringement of the Patents
6.2.1 Each Party shall inform the other Party promptly if it becomes aware of
any infringement or potential infringement of any of the Patents in the
Field, and the Parties shall consult with each other to decide the best
way to respond to such infringement.
6.2.2 If the Parties fail to agree on a joint programme of action, including
how the costs of any such action are to be borne and how any damages or
other sums received from such action are to be distributed, then
Bioenvision shall be entitled to take action against the third party at
its sole expense and it shall be entitled to all damages or other sums
received from such action, after reimbursing Royal Free for any
reasonable expenses incurred in assisting it in such action. Royal Free
shall agree to be joined in any suit to enforce such rights subject to
being indemnified and secured in a reasonable manner as to any costs,
damages, expenses or other liability and shall have the right to be
separately represented by its own counsel at its own expense. If the
alleged infringement is both within and outside the Field, the Parties
shall also co-operate with Royal Free's other partners (if any) in
relation to any such action.
6.3 Infringement of third party rights
6.3.1 If any warning letter or other notice of infringement is received by a
Party, or legal suit or other action is brought against a Party,
alleging infringement of third party rights in the manufacture, use or
sale of any Licensed Product or use of any Patents, that Party shall
promptly provide full details to the other Party, and the Parties shall
discuss the best way to respond.
6.3.2 Bioenvision shall have the right but not the obligation to defend such
suit and shall have the right to settle with such third party, provided
that if any action or proposed settlement involves the making of any
statement, express or implied, concerning the validity of any Patent,
the consent of Royal Free must be obtained before taking such action or
making such settlement.
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6.3.3 Royal Free shall have the right to participate and be represented in
any such claims by a third party by its own legal representation, the
cost to be borne by Royal Free.
6.3.4 In the event, by way of counterclaim or otherwise, either Party or both
Parties recover any damages or other sums in any action, suit, or
proceedings involving a claim by a third party, or in settlement
thereof, such recovery shall be applied and shared as mutually agreed.
6.4 Revocation proceedings.
6.4.1 In the event either Party becomes aware of the institution by a third
party of any proceedings for the revocation of any Patent, patents [or
Improvements] in any country in the Territory licensed hereunder to
Bioenvision, such Party shall notify the other Party promptly.
Bioenvision shall defend any such proceedings at its own expense, in
its own name.
6.4.2 Royal Free shall have the right to participate in such revocation
proceedings at Bioenvision's expense, and will lend its name to such
proceedings if requested by Bioenvision or required by law.
Sub-licensees of Bioenvision shall also have the right to participate
in such revocation proceedings.
6.4.3 Settlement of any revocation proceedings shall be subject to the
approval of Royal Free; such approval shall not be unreasonably
withheld.
7 Warranties and liability
7.1 Warranties by Royal Free. Royal Free warrants, represents and undertakes
as follows:-
7.1.1 subject to Clause 7.3, it is the absolute and unencumbered owner of the
Patents and has caused its directors and employees to execute such
assignments of the Patents as may be necessary to give title to the
Patents to Royal Free; and
7.1.2 it has not done, and will not do nor agree to do during the
continuation of this Agreement, any of the following things if to do so
would be inconsistent with the exercise by Bioenvision of the rights
granted to it under this Agreement, namely:
7.1.2.1 grant or agree to grant any rights in the Patents or any improvements
thereto; or
7.1.2.2 assign, mortgage, charge or otherwise transfer any of the Patents or
(subject to clause 9.3 below) any of its rights or obligations under
this Agreement.
7.2 No other warranties
7.2.1 Each of Bioenvision and Royal Free acknowledges that, in entering into
this Agreement, it does not do so in reliance on any representation,
warranty or other provision except as expressly provided in this
Agreement, and any conditions, warranties or other terms implied by
statute or common law are excluded from this Agreement to the fullest
extent permitted by law.
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7.2.2 Without limiting the scope of Clause 7.2.(a), Royal Free does not give
any warranty, representation or undertaking:-
7.2.2.1 as to the efficacy or usefulness of the Patents or Know-how; or
7.2.2.2 that any of the Patents is or will be valid or subsisting or (in the
case of an application) will proceed to grant; or
7.2.2.3 that the use of any of the Patents or Know-how, the manufacture, sale
or use of the Licensed Products or the exercise of any of the rights
granted under this Agreement will not infringe any other intellectual
property or other rights of any other person; or
7.2.2.4 as imposing any obligation on Royal Free to bring or prosecute actions
or proceedings against third parties for infringement or to defend any
action or proceedings for revocation of any of the Patents; or
7.2.2.5 as imposing any liability on Royal Free in the event that any third
party supplies Licensed Products to customers located in the Territory.
7.3 Indemnity.
7.3.1 Bioenvision shall indemnify and hold harmless Royal Free, Royal Free
and their respective officers, employees, consultants, agents and
representatives (the "Indemnitees") against all third party Claims
which may be asserted against or suffered by any of the Indemnitees and
which relate to:-
(a) the use of any Delivered Items, or
(b) the manufacture, distribution, sale, supply or use of any
Licensed Products or any other products or services which
incorporate any Delivered Items,
by or on behalf of Bioenvision, its Affiliates or sub-licensees, or
subsequently by any third party, including without limitation claims
based on product liability laws.
7.4 For the purpose of this clause 7.3, "Claims" shall mean all demands,
claims and liability (whether criminal or civil, in contract, tort or
otherwise) for losses, damages, legal costs and other expenses of any
nature whatsoever, and all costs and expenses incurred in connection
therewith.
7.5 Liability. Notwithstanding any other provision of this Agreement, no Party
shall be liable to any other Party to this Agreement in contract, tort,
negligence, breach of statutory duty or otherwise for any loss, damage,
costs or expenses of any nature whatsoever incurred or suffered by that
other party or its Affiliates of an indirect or consequential nature
including without limitation any economic loss or other loss of turnover,
profits, business or goodwill.
8 Duration and Termination
8.1 Commencement and Termination by Expiry. This Agreement, and the licences
granted hereunder, shall come into effect on the Commencement Date and,
unless terminated earlier in accordance with this Clause 8, shall continue
in force on a country by country basis until the later of:
Page 12 of 20
8.1.1 the date on which all the Patents have expired or been revoked without
a right of further appeal, and
8.1.2 the tenth anniversary of the Commencement Date;
and on such date this Agreement and the licences granted hereunder
shall terminate automatically by expiry.
8.2 Early termination
8.2.1 Bioenvision may terminate this Agreement at any time on 90 days notice
in writing to Royal Free.
8.2.2 Without prejudice to any other right or remedy, either Party may
terminate this Agreement at any time by notice in writing to the other
Party ("Other Party"), such notice to take effect as specified in the
notice:-
8.2.2.1 if the Other Party is in breach of this Agreement and, in the case of a
breach capable of remedy within 90 days, the breach is not remedied
within 90 days of the Other Party receiving notice specifying the
breach and requiring its remedy; or
8.2.2.2 if the Other Party becomes insolvent, or if an order is made or a
resolution is passed for the winding up of the Other Party (other than
voluntarily for the purpose of solvent amalgamation or reconstruction),
or if an administrator, administrative receiver or receiver is
appointed in respect of the whole or any part of the Other Party's
assets or business, or if the Other Party makes any composition with
its creditors or takes or suffers any similar or analogous action in
consequence of debt.
8.2.3 Royal Free may forthwith terminate this Agreement by giving written
notice to Bioenvision if Bioenvision or its Affiliate or sub-licensee
commences legal proceedings, or assists any third party to commence
legal proceedings, to challenge the validity or ownership of any of the
Patents.
8.3 Consequences of termination
8.3.1 Upon termination of this Agreement by expiry under clause 8.1 above,
Bioenvision shall have the non-exclusive right to use the Know-how
without charge or other obligation to Royal Free.
8.3.2 Upon termination of this Agreement for any reason otherwise than in
accordance with Clause 8.1:
8.3.2.1 Bioenvision and its sub-licensees shall be entitled to sell, use or
otherwise dispose of (subject to payment of royalties under clause 4)
any unsold or unused stocks of the Licensed Products for a period of 6
months following the date of termination;
Page 13 of 20
8.3.2.2 subject to paragraph (a) above, Bioenvision shall no longer be licensed
to use or otherwise exploit in any way, either directly or indirectly,
the Patents, in so far and for as long as any of the Patents remains in
force or the Know-how;
8.3.2.3 subject to paragraph (a) above, Bioenvision shall consent to the
cancellation of any formal licence granted to it, or of any
registration of it in any register, in relation to any of the Patents;
8.3.2.4 the provisions of certain clauses shall continue in force, to be
defined; and
8.3.2.5 subject as provided in this Clause 8.3.(b) and 8.3.(c) and 8.3.(d), and
except in respect of any accrued rights, neither party shall be under
any further obligation to the other.
8.3.3 Upon termination of this Agreement for any reason otherwise than
in accordance with Clause 8.1, and at Royal Free' request, the Parties
shall negotiate in good faith the terms of an agreement between them on
reasonable commercial terms under which Bioenvision would:
8.3.3.1 transfer to Royal Free exclusively all clinical and other data relating
to the development of Licensed Products;
8.3.3.2 to the extent possible, seek to have any product licences, pricing
approvals and other permits and applications transferred into the name
of Royal Free or its nominee;
8.3.3.3 grant Royal Free an exclusive, worldwide licence, with the rights to
grant sub-licences, under any improvements and other intellectual
property owned or controlled by Bioenvision relating to the Licensed
Products; and
8.3.3.4 grant Royal Free or its nominee the right to continue to use any
product name that had been applied to the Licensed Products prior to
termination of this Agreement.
8.3.4 If the Parties are unable to agree the terms of an agreement as
described in Clause 8.3.(c) within 90 days of Royal Free requesting the
negotiation of such an agreement, either Party may refer the terms for
settlement by an independent expert who shall be appointed in
accordance with the provisions of Schedule 2 and whose decision shall
be final and binding on the Parties. The Parties shall promptly execute
an agreement on the terms agreed between them or settled by the expert.
9 General
9.1 Force majeure. Neither Party shall have any liability or be deemed to be
in breach of this Agreement for any delays or failures in performance of
this Agreement which result from circumstances beyond the reasonable
control of that Party, including without limitation labour disputes
involving that Party. The Party affected by such circumstances shall
promptly notify the other Party in writing when such circumstances cause a
delay or failure in performance and when they cease to do so.
9.2 Amendment. This Agreement may only be amended in writing signed by duly
authorised representatives of Royal Free and Bioenvision.
Page 14 of 20
9.3 Assignment and third party rights.
9.3.1 Subject to clause 9.3.(b) below, neither Party shall assign, mortgage,
charge or otherwise transfer any rights or obligations under this
Agreement, nor any of the Patents or rights under the Patents, without
the prior written consent of the other Party.
9.3.2 Either Party may assign all its rights and obligations under this
Agreement together with its rights in the Patents to any company to
which it transfers all [or part] of its assets or business, PROVIDED
that the assignee undertakes to the other Party to be bound by and
perform the obligations of the assignor under this Agreement. However a
Party shall not have such a right to assign this Agreement if it is
insolvent or any other circumstance described in Clause 8.2.(b) applies
to it.
9.4 Waiver. No failure or delay on the part of either Party to exercise any
right or remedy under this Agreement shall be construed or operate as a
waiver thereof, nor shall any single or partial exercise of any right
or remedy preclude the further exercise of such right or remedy.
9.5 Invalid clauses. If any provision or part of this Agreement is held to
be invalid, amendments to this Agreement may be made by the addition or
deletion of wording as appropriate to remove the invalid part or
provision but other wise retain the provision and the other provisions
of this Agreement to the maximum extent permissible under applicable
law.
9.6 No Agency. Neither Party shall act or describe itself as the agent of
the other, nor shall it make or represent that it has authority to make
any commitments on the other's behalf.
9.7 Interpretation. In this Agreement:
9.7.1 the headings are used for convenience only and shall not affect its
interpretation;
9.7.2 references to persons shall include incorporated and unincorporated
persons; references to the singular include the plural and vice versa;
and references to the masculine include the feminine;
9.7.3 references to Clauses and Schedules mean clauses of, and schedules to,
this Agreement; and
9.7.4 references to the grant of "exclusive" rights shall mean that the
person granting the rights shall neither grant the same rights (in the
same Field and Territory) to any other person, nor exercise those
rights directly to the extent that and for as long as the Licensed
Products are within Valid Claims of unexpired Patents.
9.8 Notices
9.8.1 Any notice to be given under this Agreement shall be in writing and
shall be sent by first class mail or air mail, or by fax (confirmed by
first class mail or air mail) to the address of the relevant Party set
out at the head of this Agreement, or to the relevant fax number set
out below, or such other address or fax number as that Party may from
time to time notify to the other Party in accordance with this Clause
9.8. The fax numbers of the Parties are as follows: Royal Free - 44 -
171 794 3505; Bioenvision - 44 - 171 839 7570
Page 15 of 20
9.8.2 Notices sent as above shall be deemed to have been received three
working days after the day of posting (in the case of inland first
class mail), or seven working days after the date of posting (in the
case of air mail), or on the next working day after transmission (in
the case of fax messages, but only if a transmission report is
generated by the sender's fax machine recording a message from the
recipient's fax machine, confirming that the fax was sent to the number
indicated above and confirming that all pages were successfully
transmitted).
9.9 Law and Jurisdiction. The validity, construction and performance of this
Agreement shall be governed by English law and shall be subject to the
exclusive jurisdiction of the English courts to which the parties hereby
submit, except that a Party may seek an interim injunction in any court of
competent jurisdiction.
9.10 Further action. Each Party agrees to execute, acknowledge and deliver such
further instruments, and do all further similar acts, as may be necessary
or appropriate to carry out the purposes and intent of this Agreement.
9.11 Announcements. Neither Party shall make any press or other public
announcement concerning any aspect of this Agreement, or make any use of
the name of the other Party in connection with or in consequence of this
Agreement, without the prior written consent of the other Party.
9.12 Entire agreement. This Agreement, including its Schedules, sets out the
entire agreement between the Parties relating to its subject matter and
supersedes all prior oral or written agreements, arrangements or
understandings between them relating to such subject matter. The Parties
acknowledge that they are not relying on any representation, agreement,
term or condition which is not set out in this Agreement.
AGREED by the parties through their authorised signatories:-
For and on behalf of For and on behalf of
UNIVERSITY COLLEGE LONDON BIOENVISION, INC
/s/ C. A. TARHAN /s/ ▇.▇. ▇▇▇▇
--------------------------- -------------------------------
signed signed
C. A. TARHAN ▇.▇. ▇▇▇▇
--------------------------- -------------------------------
print name print name
Finance Director and Head of Adminstration CEO
------------------------------------------ -------------------------------
Title title
1/3/99 24/2/99
--------------------------- -------------------------------
Date date
Page 16 of 20
Schedule 1
The Patent
1) Patent number - (published as) WO 98/49333
(international application number) - PCT/GB98/01198
Priority date - 25 April 1997
Territories designated - Japan, USA, Europe (all territories)
2) Patent number - 07/500,375
Derived from PCT/GB 94/01114
Priority date - 20 May 1993
Territory designated - Japan
Page 17 of 20
Schedule 2
Appointment of expert
1. Pursuant to Clause 5.3, Royal Free may serve notice on Bioenvision ("Referral
Notice") that it wishes to refer to an expert (the "Expert") the questions set
out in that Clause.
2. The parties shall agree the identity of a single independent, impartial
expert to determine such questions. In the absence of such agreement within 30
days of the Referral Notice, the questions shall be referred to an expert
appointed by the President of Law Society of England and Wales.
3. 60 days after the giving of a Referral Notice, both parties shall exchange
simultaneously statements of case in no more than 10,000 words, in total, and
each side shall simultaneously send a copy of its statement of case to the
Expert.
4. Each party may, within 30 days of the date of exchange of statement of case
pursuant to paragraph 3 above, serve a reply to the other side's statement of
case of not more than 10,000 words. A copy of any such reply shall be
simultaneously sent to the Expert.
5. The Expert shall make his decision on the said questions on the basis of
written statements and supporting documentation only and there shall be no oral
hearing. The Expert shall issue his decision in writing within 30 days of the
date of service of the last reply pursuant to paragraph 4 above or, in the
absence of receipt of any replies, within 60 days of the date of exchange
pursuant to paragraph 3 above.
6. The Expert's decision shall be final and binding on the parties.
7. The Expert's charges shall be borne equally by the parties.
Page 18 of 20
Schedule 3
Summary of Development programme
Description of project
Draft Timetable
Page 19 of 20
BioEnvision draft 28.1.99
GENE TRANSFER FOR THE TREATMENT OF LIVER DYSFUNCTION
Rationale. Methods of treating specific genetic diseases by gene therapy have
been proposed. Genetic diseases which have been the subject of preliminary
clinical trials include cystic fibrosis (CF) and adenosine deaminase (ADA)
deficiency. This programme is not concerned with a genetic condition but gene
transfer to treat patients with liver damage and who have undergone partial
hepatectomy or who have extensive liver damage from other causes. This is based
on the finding that a single intramuscular injection of cDNA in a suitable
vector, can be use to introduce proteins such as blood clotting factors, growth
factors and serum albumen which are normally produced by the healthy liver.
These can be expressed systemically until the liver recovers or throughout life.
The common clinical problems due to chronic hepatic insufficiency following
liver disease, damage and resection result in hypoalbuminaemia and deficiency of
certain factors such as growth and blood clotting factors. Factor VIII is
produced by the normal liver and inadequate supplies result haemophilia A which
is a life threatening condition. Sufferers from haemophilia are unable to clot
blood properly at the site of wounds. In addition to the dangers this poses for
the treatment of open cuts, the inability to clot blood properly causes damage
to joints and to internal tissues, e.g. muscle Liver also produces growth
factors such as insulin like growth factor-1 (IGF-1) which is required for the
repair and protection of tissues including the heart. It is also required for
the repair of the damaged liver. Hence its introduction will enhance the ability
of the liver to recover.
Treatment of hypoalbuminaemia can in theory be achieved by infusing serum
albumen but this has to be of high purity and it has a short half life.
Treatment of haemophilia A is possible by the administration of Factor VIII.
Until recently, albumen and factors such as Factor VIII had to be prepared by
concentration of blood donations which is problematic in that the preparations
could be contaminated with infectious agents such as Hepatitis B virus,
Hepatitis C virus HIV and prions which cause spongiform encephalopathies. The
gene for albumen and Factor VIII has been cloned and this has allowed the
production of recombinant Factor VIII that are of higher purity than blood
concentrates. However the administration of exogenous Factor VIII peptide to a
patient is very expensive and repeated doses are required every few days.
It has been reported that plasmid DNA injected into the muscle of rodents and
other mammals is taken up by the cells of such animals but the injected DNA does
not integrate into the cells. The direct transfer of DNA into muscle cells in
this manner has been proposed as a means of somatic gene transfer (▇▇▇▇▇ and
Goldspink, FEBS Letters 1992, 306;203-205). In order to develop this for use in
supplementing liver function a number of practical difficulties still remain.
Encouraging results have been obtained for expressing albumen as well as
clotting factors systemically by injecting their cDNA in a plasmid vector under
the control of our myosin regulatory elements. We have, somewhat surprisingly,
found that this enables the functional protein to be exported from the muscle
cell, thus permitting delivery of the protein, via the bloodstream, to a desired
site of action. Furthermore, we have found that the use of a muscle specific
promoter provides a steady constitutive level of expression which allows an
BioEnvision draft 28.1.99
effective amount of protein to be produced.
The propose work involves
1) Making different plasmid constructs which include the appropriate muscle
specific gene regulatory elements in order to obtain appropriate levels of
systemic expression. This includes multimerization of promoter and enhancer
elements to increase expression levels where required.
2) Constructing and testing other types of vectors including the adeno associate
vectors (AAVs) into which our regulatory elements as well as the appropriate
cDNAs will be included.
3) Expression of albumen, clotting factors V11, V111 and XI and IGF will be
assessed in skeletal muscle, blood, liver and germ cells for the different types
of constructs in nude and normal mice that have been subjected to partial
hepatectomy
4) The determination of the duration of expression of the different vectors over
a period of time up to one year and to assess any immune reaction to the vectors
as well as the engineered gene product in normal as well as nude (immune
incompetent) mice.
The duration of the about investigations is expected to be three years after it
should be appropriate to carry out clinical trials using the constructs deemed
most suitable for the treatment of liver dysfunction.
Budget
Year 1 Year 2 Year 3 Total:
Postdoctoral Molecular Biologist 29,824 30,928 32,078 93,830.00
Level 2.
University Technician, Grade C 17,855 17,855 17,855 53,565.00
Materials & Consumables: 8,900 8,767 8,383 26,050.00
Animals & Food 2,000 2,900 2,000 6,900.00
--------
200 male nude mice (MF-1) @
(pound)26.50/mouse.
Maintenance for 10 weeks
average @ 80p/week/mouse
180,345.00
Overheads @ 50% 90,172.50
---------