LICENSE AGREEMENT
THIS AGREEMENT dated 11 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 Trafalgar House, ▇▇ ▇▇▇▇▇▇▇▇ ▇▇▇▇▇, ▇▇. ▇▇▇▇▇'▇, ▇▇▇▇▇▇ ▇▇▇▇
▇▇▇ ("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 recognizes that Royal Free owns inventions and intellectual
property useful in the conduct of Bioenvision's business.
C. Bioenvision also recognizes 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 commercialization 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).
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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 characterized by decreased production of liver
proteins e.g. albumin, cancer, and endocrine disorders that
may affect liver function in human and animal applications.
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-licenses 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 arc 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
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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 ▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇▇
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
development 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 Licenses. Royal Free hereby grants to Bioenvision, subject to
the provisions of this Agreement:
2.1.2 an exclusive license 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 license 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 licenses. The Parties shall execute such formal licenses as may
be necessary or appropriate for registration with Patent Offices and
other relevant authorities in particular
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territories. In the event of any conflict in meaning between any such
license and the provisions of this Agreement, the provisions of this
Agreement shall prevail wherever possible. Prior to the execution of
the formal license(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 license(s) had been granted. The Parties shall use
reasonable endeavors to ensure that, to the extent permitted by
relevant authorities, tills Agreement shall not form part of any public
record.
2.3 Sub-licensing. Bioenvision shall be entitled to grant sub-licenses of
its rights under tills Agreement to any person, provided that:
2.3.1 the royalties and other consideration provided for in the
sub-license 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-license shall include obligations on the sub-licensee
which are equivalent to the obligations on Bioenvision under
this Agreement;
2.3.3 the sub-license shall terminate automatically on the
termination of this Agreement for any reason;
2.3.4 within 30 days of the grant of any sub-license 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-license 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 sublicensee.
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 commercialize
Project IPR outside the Field,
2.5 No other license. It is acknowledged and agreed that no license is
granted by Royal Free to Bioenvision other than the license(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 sublicensees are of satisfactory quality and
comply with all applicable laws and regulations in each part of the
Territory.
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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 mid subsistence
costs incurred.
3.1 Status of Know-now. Bioenivision 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")
produced 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.
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
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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-.
3.5.4 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
3.5.5 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
3.5.6 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
3.5.7 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 its 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
3.5.8 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.
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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 ~20,000
(pounds sterling) which shall be the first installment 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 Bioenivision 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
4.3.2 6 percent in the case of Licensed Products which incorporate
or whose development made use of any of the Know-how.
4.4 Combination Product. If any 1icensed Products are incorporated in any
other product ("Combination Product") supplied by the Bioenivision 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.]
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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 licenses 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 license from any third
party ("Third Party License") 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 License provided
that the amount of royalty payable by Bioenvislon 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 ally remaining
unpaid balance of carried 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;
4.8.2 shall be paid in pound 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;
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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 endeavors 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 acCOL111tS showing the
quantity, description and value of Licensed Products sold by
it, and the amount of sub-licensing 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.
4.11.2 Bioenvison 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
9
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 COMMERCIALIZATION
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 maximize 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 licenses
granted to Bioenvision under Clause 2.
6 INTELLECTUAL PROPERTY
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6.1 Obtain and maintain the Patents.
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 endeavor 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 oil 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 arc 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
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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.
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
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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 tills Agreement, it does not do so in reliance
oil 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.
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.
13
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 a 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 ail 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, Mid die
licenses 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:
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 licenses granted
hereunder shall terminate automatically by expiry.
8.2 Early termination.
8.2.1 Bioenvision may terminate this Agreement at anytime on 90 days
notice in writing to Royal Free.
8.2.2 Without prejudice to any other fight 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
14
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;
8.3.2.2 subject to paragraph (a) above, Bioenvision shall no longer be
licensed to use or otherwise exploit 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 license 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 licenses,
pricing approvals and other permits and applications
transferred into the name of Royal Free or its nominee;
15
8.3.3.3 grant Royal Free an exclusive, worldwide license, with the
rights to grant sub-licenses, 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
labor 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
authorized representatives of Royal Free and Bioenvision.
9.3 Agreement 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 for all [or party] 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.
16
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 fights 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 Lit 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 7510.
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 message, 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
17
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 &
Head of Administration CEO
------------------------- -------------------------
Title Title
1/3/99 24/2/99
------------------------- -------------------------
date date
18
Schedule 1
The Patent
1) Patent number (published as) - WO 98/4933
(international application number)
- PCT/GB98/01198
Priority date 25 April 27
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
19
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.
20
Schedule 3
Summary of Development programme
DESCRIPTION OF PROJECT
DRAFT TIMETABLE
21
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 dearninase (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- I (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 spongiforin 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 t he 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 fOL111d that the use of a muscle specific
promoter provides a steady constitutive level of expression which allows an
effective amount of protein to be produced.
22
THE PROPOSED 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 VII, VIII 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
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