EXHIBIT 10.26
Xxxxx Xxxx and Westfield College
Research Agreement
This Agreement is made as of the 8th Day of June 1999 between Xxxxx Xxxx and
Xxxxxxxxx Xxxxxxx xx Xxxx Xxx Xxxx, Xxxxxx Xx 0XX ("College")and Bioenvision Inc
a Delaware Corporation of 00 Xxx Xxxxxxx Xxxx, Xxxxx, Xxxxxxxx 00000, XXX with
offices at Xxxxxxxxx Xxxxx, 00 Xxxxxxxx Xxxxx, Xxxxxx XX0X 0XX ("Bioenvision")
WHEREAS:
Stegram Pharmaceuticals Ltd of 00 Xxxxxxxxxx Xxxxx, Xxxxxxxxxxxxx, Xxxxxx
XX00 0XX ("Stegram")has secured certain rights in connection with a
substance known as Trilostane and as Modrenal and its use in
pharmaceutical preparations ("Products")
Stegram has granted Bioenvision a licence to manufacture and market
Products
The College has expertise in the evaluation of oestrogen receptors
The College has been conducting a programme of research in support of
Stegram's plans to develop and market Products ("Programme I")
Bioenvision wishes the College to continue and expand Programme I in
support of its plans to manufacture and market Products and wishes the
results from this further programme of research ("Programme II") to be
vested in Stegram
The College is willing to continue and expand Programme I in support of
Bioenvision's plans to manufacture and market Products
NOW IT IS HEREBY AGREED:
1. Definitions
1.1 Programme II means a programme of research in support of
Bioenvision's plans to manufacture and market Products which is
generally described in Appendix 1.
1.2 Foreground Intellectual Property means all intellectual property
and results arising from Programme II and Foreground Intellectual
Property includes any intellectual property arising from Programme
I and defined as Foreground Intellectual Property in the agreement
dated 4 July 1997 between the College and Stegram concerning
Programme I a copy of which is attached to this Agreement for
reference.
1.3 Background Intellectual Property means all intellectual property
existing at the time of this Agreement concerning the Products
other than intellectual property which has arisen from Programme I
and defined as Foreground Intellectual Property in the agreement
dated 4 July 1997 between the College and Stegram concerning
Programme I a copy of which is attached to this Agreement for
reference.
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2. Programme II
2.1 Programme II will be directed by Xxxxxxxxx X X Xxxxxx (Division of
Biomedical Sciences) who will be the College's representative for
all matters concerning Programme II.
2.2 Should Bioenvision wish to modify Programme II then the College will
endeavour to incorporate any modification that does not require
additional resources and should additional resources be required
then the College will endeavour to make these available subject to
suitably qualified staff being available and mutual agreement on the
charges for these resources.
2.3 Should Xxxxxxxxx X X Xxxxxx (Division of Biomedical Sciences) no
longer be willing to direct Programme II and/or be employed by the
College then the College will endeavour to appoint a suitably
qualified successor who is acceptable to Bioenvision and continue
with Programme II.
2.4 Should the College and Bioenvision be unable to agree on a successor
to Xxxxxxxxx X X Xxxxxx (Division of Biomedical Sciences) then the
College will endeavour to assist Bioenvision should it decide to
make alternative arrangements to continue with Programme II.
3. Payments to the College
3.1 Bioenvision undertakes to pay the College the following sums:
Commencing on signature of this Agreement the sum of (pound)25,000
in 4 (four) equal quarterly instalments in respect of consumables
and laboratory expenses in connection with Objective I of Programme
II.
Commencing on the date of appointment 12 (twelve) quarterly
instalments of (pound)18,750 for services of a Research Assistant
(Research Assistant I) which includes provision for (pound)2,500
per quarter for general laboratory services and consumables.
Commencing on the date of appointment 12 (twelve) quarterly
instalments of (pound)16,250 for services of a second Research
Assistant (Research Assistant II) which includes provision for
(pound)2,500 per quarter for general laboratory services and
consumables.
3.2 All payments will be due on presentation of the College's invoice
and the College reserves the right to add VAT if required to do so.
3.3 For the avoidance of doubt Bioenvision recognises that the sums
payable according to this Article 3 are only sufficient to meet the
estimated labour and direct material costs of Programme II.
3.4 Should the College become aware that the direct materials costs will
exceed those provided for in Article 3.1 then it will promptly
notify Bioenvision of this and the College undertakes not to incur
any such additional expenditure without the prior approval of
Bioenvision.
4. Reporting
4.1 The College will provide Bioenvision with quarterly written progress
reports and a full and complete written report at the end of
Programme II and Bioenvision agrees that at the request of Stegram
the College may provide copies of these reports to Stegram.
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4.2 The College and Bioenvision may discuss experimental results and
progress of Programme II at reasonable intervals at the request of
either the College or Bioenvision.
4.3 At the request of Bioenvision and/or Stegram the College and Stegram
may discuss experimental results and progress of Programme II at
reasonable intervals and may do so without reference to Bioenvision.
5. Foreground Intellectual Property
5.1 Bioenvision recognises and understands that under the terms and
conditions of a separate agreement between the College and Stegram
all Foreground Intellectual Property is vested Stegram.
6. Background Intellectual Property
6.1 The College has no interest in intellectual property owned and
possessed by Bioenvision.
6.2 Except where stated in this Agreement Bioenvision has no interest in
any intellectual property owned and possessed by the College.
7. Publications
7.1 Bioenvision recognises that the College has a statutory duty to
freely disseminate results of its research and shall not prevent any
publication of results arising from Programme II in accordance with
this duty.
7.2 Notwithstanding the provisions of Article 7.1 the College undertakes
to provide Bioenvision and Stegram with a copy of any proposed
publication and Bioenvision and/or Stegram may require the College
to delay publication for a period not exceeding six (6) months in
order to provide adequate time for consideration and protection of
any intellectual property.
7.3 No delay required by Bioenvision and/or Stegram according to Article
7.2 shall prevent Research Assistant II from submitting a thesis for
examination in accordance with procedures for examination for a
higher degree of the University of London.
8. Use of Results and College Name
8.1 Except where the information has already been placed in the public
domain Bioenvision undertakes not to use or publish or authorise
others to use or publish any information provided by the College
hereunder or any abstract therefrom in any scientific or
promotional or marketing or other material in connection with the
Products without the prior written permission of the College.
8.2 The College undertakes not to refuse permission according to
Article 8.1 where the publication as a whole does not distort or
misrepresent results or views expressed in the original material
provided to Bioenvision.
8.3 Nothing in this Agreement shall be interpreted as the College
endorsing the Products in any way whatsoever.
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8.4 Nothing in this Agreement shall be interpreted as giving Bioenvision
or any other party any right or permission to use or to authorise
others to use the name of the College or its emblem in any way
whatsoever.
8.5 Nothing in this Agreement shall be interpreted as giving the College
or any other party any right or permission to use or to authorise
others to use the name of Bioenvision or its emblem in any way
whatsoever.
9. Testing of Substances
9.1 No College employee may authorise the use of any substance in
clinical trials or any procedures requiring or normally requiring
ethical or regulatory approval unless specifically stated in writing
and in accordance with the College's procedures for such approval.
10. Warranties and Liabilities
10.1 Bioenvision warrants that at the time of this Agreement it is the
lawful owner of rights in respect of Products and Background
Intellectual Property and has permission from Stegram to enter into
this Agreement.
10.2 In entering into this Agreement the parties to this Agreement
recognise and agree that the College is not a party to any agreement
between Stegram and Bioenvision concerning the subject matter of
this Agreement.
10.3 The College will endeavour to undertake Programme II in a
professional and diligent manner but except in the case of death or
personal injury arising from negligence of the College accepts no
liability for any costs or expenses arising from any interpretation
or reliance that Bioenvision or other parties may place on any part
of the work product nor offers any warranty that it will solve any
particular problem.
10.4 Bioenvision undertakes to indemnify and keep the College indemnified
against any costs or expenses arising from claims made against the
College in connection with this Agreement including but not limited
to any dispute with Stegram or the infringement of any rights of
others.
11. Duration and Termination
11.1 This Agreement shall commence on the date of signature and shall
terminate three years after the date of the last appointment
according to Article 3 unless terminated earlier by mutual
agreement of the parties to this Agreement.
11.2 Bioenvision recognises that should Research Assistant II register
for a higher degree of the University of London then the College
will not agree to any termination that releases Bioenvision from
its obligations according to Article 3 in respect of Research
Assistant II.
11.3 Either Bioenvision or the College may terminate this Agreement
without further notice should the other party fail to meet its
obligations under this Agreement and does not remedy any such
failure within 2 (two) months of receipt of a written request from
the other party to remedy any such failure.
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11.4 No termination of this Agreement shall release Bioenvision or the
College from their obligations according to Articles 5, 7, 8 and 10.
11.5 No termination of this Agreement shall affect the rights of
Bioenvision or the College accrued up to up to the date of such
termination including nor shall release Bioenvision from the
obligation to make payments according to Article 3 for work carried
out and/or reasonable commitments made up to the date of such
termination.
12. Assignment
12.1 Bioenvision shall not assign all or part of its rights or
obligations under this Agreement to Stegram or any other third party
without the prior written approval of the College, such approval not
being unreasonably withheld where the transferee is a properly
organised and competent body that agrees to accept all of
Bioenvision's obligations to the College under this Agreement.
11.2 The College shall not assign all or part of its rights or
obligations under this Agreement to any third party without the
prior written approval of Bioenvision, such approval not being
unreasonably withheld where the transferee is a properly organised
and competent body that agrees to accept all of the College's
obligations to Bioenvision.
12. General
12.1 No variation to this Agreement shall be recognised unless agreed to
in writing by the parties to this Agreement.
12.2 The parties to this Agreement agree that this Agreement is the sole
agreement between the parties in connection with the subject matter
and that this Agreement replaces and supercedes all previous
agreements and understandings between the parties.
12.3 This Agreement shall be governed by the laws of England and be
subject solely to the jurisdiction of English Courts.
AGREED:
Name: Xx XX Xxxx Xx X X Xxxxxxxx
Position: CEO Manager Research Grants and Contracts
-------------------------
Signature: /s/ Xx XX Xxxx /s/ Xx X X Xxxxxxxx
------------------------- -------------------------------------
On behalf of: Bioenvision Inc Xxxxx Xxxx and Westfield College
Date: 14/6/99 7/6/99
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I accept my obligations under this Agreement:
Name: Xxxxxxxxx X X Xxxxxx
Signature: /s/ X X Xxxxxx
---------------------------------
Division of Biomedical Sciences
Xxxxx Xxxx and Westfield College
Date 7 June 1999
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Appendix 1
Research Programme
Programme II
Aim: to provide rigorous elucidation of the mode of action of trilostane, and
analogues, on oestrogen receptor function at the molecular/cellular level.
Objectives: (in order of priority)
1. To establish interactions of trilostane with specific oestrogen receptor
isoforms.
Methods:
(a)Continue IEF separation of receptor isoforms with quantitation of
tritiated oestradiol binding in the presence and absence of
trilostane. This will be performed on breast tumour samples now
available, otherwise rat uterus.
(b)Confirm actions of trilostane on affinity of oestradiol binding to
receptor complement, using Scatchard analysis, in presence and
absence of trilostane, on breast tumour cytosol preparations.
2. To establish directly whether the interactions observed in objective I
affect receptor function.
Method:
Using an in vitro reporter system, the effect of trilostane on oestrogen
receptor activity will be measured. Reporter constructs containing either
the classical estrogen response element or an AP1 site will be incubated
with oestrogen receptors in the presence or absence of trilostane,
tamoxifen or both. Transcriptional activity will be assayed to determine
whether trilostane has its effect at the nuclear level.
3. To determine the actions of trilostane on breast cancer cell
proliferation, in the presence and absence of tamoxifen.
Methods:
(a)In vitro. Breast cancer cell lines, e.g. MCF 7, ZR 75, etc., will be
used in culture to establish the effects of trilostane on oestradiol
induced proliferation in the presence and absence of tamoxifen.
(b)In vitro. Epithelial cells isolated from primary breast tumours will
be grown in culture in the presence and absence of trilostane, as for
(a).
(c)In vitro. MCF-7 cells in culture will be cultured in the presence of
tamoxifen to obtain by selection a tamoxifen resistant cell line. Use
of these cells in culture in the presence or absence of trilostane
will determine its effects in a situation that replicates that of
patients who fail to respond to tamoxifen treatment.
(d)In vivo. Primary breast tumour cells from patients will be
transplanted into immunodeficient mice. The effects of trilostane on
tumour growth in the presence and absence of tamoxifen will be
determined.
4. To establish the precise nature of trilostane interaction with oestrogen
receptor isoforms in the absence of oestrogen, showing more directly to
which isoforms trilostane binds, and with what affinity.
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Method:
Using tritiated trilostane in IEF and Scatchard analysis of binding
characteristics. By then competing with unlabelled oestradiol this method will
also determine whether trilostane binding is competitive, or allosteric. If the
latter, this would suggest that results obtained under Objective 1 may not
reveal the full extent of trilostane interactions with the receptor, and may
underestimate its possible effects on oestrogen action.
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This Agreement is made this 6th Day of July 1997 between Xxxxx Xxxx and
Xxxxxxxxx Xxxxxxx xx Xxxx Xxx Xxxx, Xxxxxx Xx 0XX ("College") and Stegram
Pharmaceuticals Ltd of 00 Xxxxxxxxxx Xxxxx, Xxxxxxxxxxxxx, Xxxxxx XX00 0XX
("Stegram")
WHEREAS
Stegram has secured certain rights in connection with a substance known as
Trilostane and as Modrenal its use in pharmaceutical preparations ("Products").
Stegram wishes the College to undertake a programme of research in support of
its plans to develop market Products (Programme").
The College has expertise in the evaluation of oestrogen receptors.
The College is willing to undertake a programme of research in support of
Stegram's plans.
NOW IT IS HEREBY AGREED
1. Programme
1.1 The Programme will be directed by Xxxxxxxxx X X Xxxxxx (Department
of Biochemistry) who will be the College's representative for all
matters concerning the Programme.
1.2 The Programme has been agreed with Stegram and for the avoidance of
doubt is generally described in Appendix 1.
1.3 The Programme is expected to be completed by the end of May 1998.
2. Payment
2.1 Stegram undertakes to pay the College the sum of (pound) 10,000 as a
contribution towards the expenses of the Programme.
2.2 The payment will be due on signature of this Agreement on
presentation of the College's invoice and the College reserves the
right to add VAT if required to do so.
2.3 Stegram recognises that this sum does not represent the true cost
of the Programme and that additional costs will be met from other
College funds.
3. Reporting
3.l The College will provide a written report and commentary on
experimental results at the end of the Programme.
3.2 The College and Stegram may discuss experimental results and the
Programme at reasonable intervals.
4. Results, Discoveries and Inventions
4.l In the first instance the College shall own all intellectual
property arising from this Programme ("Foreground Intellectual
Property") and the College undertakes not to enter into any
arrangements with third parties in connection with this that are not
foreseen by this Agreement.
4.2 The College shall be responsible for making its staff aware of the
need for confidentiality and delaying disclosure of results in order
to apply for such protection of Foreground Intellectual Property
that it deems necessary and ensuring that the names of inventors and
claims to invention are properly registered.
4.3 Should the College decide not to apply for any specific protection
of Foreground Intellectual Property then it will inform Stegram and
Stegram may do so in conjunction with the College or otherwise and
the College will endeavour to assist Stegram in this matter through
supply of information in its possession, authorising the signing of
documents, continuing to maintain confidentiality and delaying
publication.
4.4 Should Stegram or the College believe Foreground Intellectual
Property might be used commercially then it will advise the other
party and the parties will meet to determine the most appropriate
way to proceed and the contributions of Stegram the College and any
third party(ies).
4.5 After reimbursing the College and/or Stegram for expenses incurred
under Articles 4.2 and/or 4.3 any remaining proceeds shall be
distributed as follows
Third party(ies) )
Stegram ) according to contribution
College )
4.6 The College shall be responsible for distributions to its staff and
students according to its published policy.
4.7 The College and Stegram will endeavour to reach mutual agreement
under Articles 4.4 and 4.5 and shall first refer any dispute to a
mutually acceptable party and failing resolution shall refer the
dispute to an arbitrator appointed by the President for the time
being of the Royal Society of Chemistry whose decision shall be
binding on both parties.
5. Background Intellectual Property
5.1 At the commencement of this Agreement Stegram shall be deemed to be
the owner of all existing intellectual property concerning the
Products and applications concerning breast cancer ("Background
Intellectual Property").
5.2 Should Stegram enter into negotiations with third parties with a
view to sale or transfer of its interest in or to granting a licence
for use of part or all of Background Intellectual Property then
Stegram will promptly advise the College of any such negotiations
and keep the College informed as to their progress.
5.3 Before Stegram concludes any negotiations it will meet with the
College and determine the contribution, to that date, of Stegram and
the College to any enhancement of the value of the Products and
Background Intellectual Property brought about by access to
Foreground Intellectual Property.
5.4 The parties recognise and accept that Stegrams obligations under
Articles 5.2 and 5.3 shall exclude negotiations with any third party
already having a licence from Stegram in connection with the
Products unless these involve Foreground Intellectual Property and
use of the Products in connection with breast cancer.
5.5 The enhancement in value shall be divided between the College and
Stegram by reference to the respective contributions agreed
according to Article 5.3.
5.6 The College shall be responsible for distribution of its share of
any enhancement in value to its staff according to its published
policy.
5.7 The College and Stegram will endeavour to reach mutual agreement
under Articles 5.3 and 5.4 and shall first refer any dispute to a
mutually acceptable party and still failing resolution shall refer
the dispute to an arbitrator to be appointed by the President for
the time being of the Royal Society of Chemistry whose decision
shall be binding on both parties.
6. Publications
6.1 Stegram recognises that the College has a statutory duty to freely
disseminate results of its research and shall not prevent any
publication of results arising from this Programme in accordance
with this duty.
6.2 Notwithstanding the provisions of Article 6.1 the College undertakes
to provide Stegram with a copy of any proposed publication and
Stegram may require the College to delay publication for a period
not exceeding six (6) months in order to provide adequate time for
consideration and protection of any intellectual property.
7. Use of Results and College Name
7.1 Stegram undertakes not to use or publish or authorise others to use
or publish any information or results provided by the College
hereunder or any abstract therefrom in any scientific or promotional
or marketing or other material in connection with the Products
without the prior written permission of the College.
7.2 The College undertakes not to refuse permission where the
publication as a whole does not distort or misrepresent results or
views expressed in the original material provided to Stegram.
7.3 Nothing in this Agreement shall be interpreted as the College
endorsing or being associated with the Products in any way
whatsoever.
7.4 Nothing in this Agreement shall be interpreted as giving Stegram any
right or permission to use or to authorise others to use the name of
the College or its emblem in any way whatsoever.
8. Testing of Substances
8.l No College employee may authorise the use of any substance in
clinical trials or any procedures requiring or normally requiring
ethical or regulatory approval unless specifically stated in writing
and in accordance with the College's procedures for ethical
approval.
9. Warranties and Liabilities
9.1 The College will endeavour to undertake the Programme in a
professional and diligent manner but accepts no liability for any
costs or expenses arising from any interpretation or reliance that
Stegram or other parties may place on the work product nor offers
any warranty that it will solve any particular problem.
9.2 Stegram undertakes to indemnify the College against any costs or
expenses arising from this Agreement including but not limited to
any dispute concerned with Stegram's rights in the Products or the
infringement or any rights of others.
10. General
10.1 This Agreement shall be governed by the laws ot England and be
subject solely to the jurisdiction of English Courts.
AGREED
Name: G Xxxxxxxx Xx X X Xxxxxxxx
------------------------------
Signature: /s/ G Xxxxxxxx /s/ Xx X X Xxxxxxxx
------------------------------ --------------------------------
On behalf of Stegram Pharmaceuticals Ltd Xxxxx Xxxx and Westfield College
Date 9/7/97 4/7/97
------------------------------ --------------------------------
I accept my obligations under this Agreement
Name: Xxxxxxxxx X X Xxxxxx
-----------------------------
Signature: /s/ X X Xxxxxx
-----------------------------
Department of Biochemistry
Xxxxx Xxxx and Westfield College
Date 7 July 1997
-----------------------------------
Appendix 1
Research Programme
Purpose
To determine the interactions of trilostane (Modrenal) with oestrogen
receptor isoforms in the uterus and in breast tumours.
Objectives
We will use ligand binding and gel electrophoretic fractionation, as
appropriate, to characterise oestrogen receptor proteins in human uterus,
and breast tumours.
We will use breast tissue obtained at operation, and endometrial samples
from women of known reproductive status and stage of the menstrual cycle,
undergoing hysterectomy for benign conditions.
Cytosols from these tissues will be prepared as described in our
publications*, incubated with radioactively labelled oestradiol, and
specifically bound fractions will be separated on isoelectric focusing
gels to separate the four oestrogen receptor subtypes. Quantitation of
radiolabelled oestrogen bound to each isoform will be by liquid
scintillation counting of gel slices.
Ten samples of each tissue type will be used, and in each case,
specifically labelled oestradiol will be "competed" with (i) unlabelled
oestradiol (ii) tamoxifen (iii) Modrenal at varying concentrations.
Expected Results
The data are expected to show the relative affinities of the oestrogen
isoforms present in the two tissue types for oestradiol, tamoxifen and
Modrenal. In particular they are expected to reveal whether the
anti-cancer efficacy of Modrenal may be associated with binding to one or
more of the 4 oestrogen receptor subtypes that may be present.
*V.A. Xxxxx, J.R. Puddefoot, X. Xxxxxxxxxxxx, X. Xxxxxx, X.X. Xxxxx and X.
X. Xxxxxx, (1992). Oestrogen receptor isoforms, their distribution and
relation to progesterone receptor levels in breast cancer samples. Brit.
J. Cancer. 66. 1083-1087.
J.R. Puddefoot, V.A. Xxxxx, B. Bakkers, X. Xxxxxxxxxxxx, X. Xxxxxx, X.
Xxxxxx, X.X. Xxxxx, X. Xxxxxxxxx and X.X. Xxxxxx, (1993). The nature
and significance of multiple isoforms of the oestrogen receptor in breast
tumours. J. mol. endocr., II. 83-90.
