Exhibit 4.2
[***] - INDICATES MATERIAL THAT HAS BEEN OMITTED AND FOR WHICH CONFIDENTIAL
TREATMENT HAS BEEN REQUESTED. ALL SUCH OMITTED MATERIAL HAS BEEN FILED WITH THE
COMMISSION PURSUANT TO RULE 24B-2 PROMULGATED UNDER THE SECURITIES AND EXCHANGE
ACT OF 1934, AS AMENDED.
PSIONCOLOGY PTE. LTD.
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SINGAPORE GENERAL HOSPITAL PTE. LTD.
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SGH TECHNOLOGY VENTURES PTE. LTD
================================================================
COLLABORATION AGREEMENT
================================================================
THIS AGREEMENT is made as of the 24th day of July 2002
BETWEEN:
1 PSIONCOLOGY PTE. LTD. a company incorporated under the laws of Singapore
and whose registered office is at 80 Robinson Rd, #17-02, Singapore,
068898. ("PSIONCO"); and
2 SINGAPORE GENERAL HOSPITAL PTE LIMITED a company incorporated under the
laws of Singapore and whose registered office is at 11 Third Hospital
Avenue, #07-00 SNEC Building, Singapore 168751 ("SGH"); and
3 SGH TECHNOLOGY VENTURES PTE LIMITED a company incorporated under the laws
of Singapore with registration number 200205889D and whose registered
office is at 11 Third Hospital Avenue, #07-00 SNEC Building, Singapore
168751 ("SGHT").
PRELIMINARY
(1) By a Subscription and Shareholders Agreement between SGHT, pSiMedica
Limited (a company incorporated under the name of Forceglass Limited on 5
July, 2000 with a registered number 4027099 and whose registered office is
at One, St. Paul's Churchyard, London EC4M 8SH) ("PSIMEDICA"), Biotech
Research Ventures Pte Ltd (a company incorporated under the laws of
Singapore under number 200101402W of registered office, 24a Duxton Hill,
Singapore 089607 ("BRV")) and pSiOnco, of even date (the "SHARE
SUBSCRIPTION AGREEMENT"), it was agreed that SGHT and pSiOnco, together
with SGH would execute this Agreement upon its terms and conditions.
(2) By a Patent and Know-how Licence Agreement between (1) pSiMedica and (2)
pSiOnco of even date, pSiMedica granted pSiOnco a limited licence under
the pSiOnco Patents and pSiOnco Know-how to research, discover, develop,
manufacture, have manufactured, use market and sell within the Field the
pSiOnco Materials together with the right to grant sub-licences within the
Field (the "PATENT AND KNOW-HOW LICENCE")
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NOW IT IS HEREBY AGREED AS FOLLOWS:
1. DEFINITIONS AND INTERPRETATION
1.1 In this Agreement and in the Schedules to this Agreement the
following words and phrases shall have the following meanings unless
the context requires otherwise:
"Agreement" the terms and conditions set out in this document
and any and all Schedules and Appendices attached
to it as the same may be varied from time to time
in accordance with the Change of Research
Programme Procedure;
"Board" the board of directors for the time being of
psiOnco;
"Business
Day" a day other than a Saturday, Sunday, or public
holiday in Singapore;
"Chairman" the chairman of the Joint Research Committee,
appointed in accordance with the Share
Subscription Agreement;
"Change" a change to the Research Programme or the services
provided in accordance with this Agreement to
which the Change of Research Programme Procedure
applies;
"Change of
Research
Programme
Procedure" the procedure set out in Clause 14.1 to 14.3;
"Chemotherapy
Agents" Generic Chlorambucil or its generic variants and
generic 5-Flourouracil (5FU) or its generic
variants and/or such other chemotherapy agents as
agreed with pSiOnco from time to time in
accordance with the Change of Research Programme
Procedure;
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"Commencement
Date" the date first written above;
"Competent
Authority" any local or national agency, authority,
department, inspectorate, minister, ministry
official or public or statutory person (whether
autonomous or not) of any country or of any
government of any country having jurisdiction over
the Agreement or any of the Parties or over the
development or manufacture or marketing of
medicinal products including but not limited to
the Health Sciences Authority of Singapore;
"Documents" paper, notebooks, books, files, ledgers, records,
tapes, discs, diskettes, CD-ROM and any other
media on which Know How can be permanently stored;
"Field" intra-tumoural radiotherapy using the Radiotherapy
Agents and chemotherapy using the Chemotherapy
Agents where the therapy is applied interstitially
within the tumour (and not in any other matter
parenterally or otherwise) which for the avoidance
of doubt avoids introduction via the vasculature;
"Force
Majeure" in relation to any Party any event or circumstance
which is beyond the reasonable control of that
Party, which that Party could not reasonably be
expected to have taken into account at the
Commencement Date and which results in or causes
the failure of that Party to perform any or all of
its obligations under this Agreement including an
act of God, lightning, fire, storm, flood,
earthquake, accumulation of snow or ice, lack of
water arising from weather or environmental
problems, strike, lockout or other industrial
disturbance arising in relation to the work force
of a Third Party, war, terrorist act, blockade,
revolution, riot insurrection, civil commotion,
public demonstration, sabotage, act of vandalism,
prevention from or hindrance in obtaining in any
way materials, energy or other supplies,
explosion, fault or failure of plant or machinery,
governmental restraint, act of legislature and
directive or requirement of a Competent Authority
governing any Party, provided that lack of funds
shall not be interpreted as a cause beyond the
reasonable control of that Party;
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"Group" in relation to any person, being a corporate body,
that person any "subsidiary" thereof, or any
"holding company" thereof or "subsidiary" of such
"holding company" as defined in the Companies Act
Cap 50;
"Intellectual
Property" copyright and related rights, database rights,
design rights, trade marks, trade names, service
marks, domain names, Patent Rights, Know How,
Materials and other such intellectual property
rights existing now or in the future anywhere in
the world (whether registered or not) and any and
all applications or renewals for such rights;
"Joint
Research
Committee" the committee established pursuant to Clause 4;
"Know How" unpatented technical and other information related
to or useful in the Field which is not in the
public domain including, ideas, concepts,
inventions, discoveries, data, formulae,
specifications, information relating to Material,
procedures for experiments and tests and results
of experimentation and testing, results of
research and development including laboratory
records and data analyses;
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"Material" any chemical or biological substances related to
or useful in the Field including, but not limited
to any:
(a) organic or inorganic chemical element or
compound;
(b) amino acid, amino acid sequence, peptide
or protein;
(c) nucleotide or nucleotide sequence
including DNA and RNA sequences;
(d) vector or construct including plasmids,
phages or viruses; or
(e) assay or reagent;
"Parties" SGH, pSiOnco and SGHT and a "Party" shall be
construed accordingly;
"Patent
Rights" to the extent related to or useful in the Field,
patent applications, patents, author certificates,
inventor certificates, utility certificates,
improvement patents and models and certificates of
addition and all foreign counterparts of them and
includes all divisions, renewals, continuations,
continuations-in-part, extensions, reissues,
substitutions, confirmations, registrations,
revalidations and additions of or to them, as well
as any supplementary protection certificate, or
like form of protection, in respect thereof
existing now or in the future anywhere in the
world;
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"pSiOnco
Intellectual
Property" the pSiOnco Patent Rights, pSiOnco Know How and
pSiOnco Material;
"pSiOnco
KnowHow" the Know How in the Field owned by or licensed to
pSiOnco as set out in Schedule 2;
"pSiOnco
Material" the Materials in the Field owned by or licensed to
pSiOnco as set out in Schedule 3;
"pSiOnco
Patent
Rights" the Patent Rights in the Field owned by or
licensed to pSiOnco as set out in Schedule 4 and
all Patent Rights arising therefrom;
"Programme
Intellectual
Property" Any Intellectual Property arising from the
Research Programme carried out by the Research
Group during the Research Term;
"Radiotherapy
Agents" isotopes of Phosphorous and isotopes of Yitrium
and/or such other agents as agreed with pSiOnco
from time to time in accordance with the Change of
Research Programme Procedure;
"Research
Group" that part of the Department of Experimental
Surgery at SGH which is undertaking the Research
Programme and which is directed by Dr. Pierce
Chow;
"Research
Programme" the programme of research set out in Schedule 1 as
may be amended from time to time in accordance
with the Change of Research Programme Procedure;
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"Research
Term" the period during which the Research Programme
will be undertaken as set out in Clause 3.1 or
such other period as may be amended from time to
time in accordance with the Change of Research
Programme Procedure;
"SGHT
Intellectual
Property" the Intellectual Property owned by or licensed to
SGHT and SGH as set out in Schedule 5; and
"Third
Party" any entity or person other than the Parties or a
member of a Party's Group.
1.2 In this Agreement:
1.2.1 unless the context otherwise requires, all references to a
particular clause or schedule shall be a reference to that
clause or schedule in or to this Agreement as it may be
amended from time to time pursuant to this Agreement;
1.2.2 the table of contents and headings are inserted for
convenience only and shall be ignored in construing this
Agreement;
1.2.3 unless the contrary intention appears, words importing the
masculine gender shall include the feminine and vice versa
and words in the singular include the plural and vice
versa;
1.2.4 unless the contrary intention appears, words denoting
persons shall include any individual, partnership, company,
corporation, joint venture, trust association, organisation
or other entity, in each case whether or not having
separate legal personality;
1.2.5 the words "include", "included" or "including" are to be
construed without limitation to the specifics of the
subsequent words;
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1.2.6 reference to any statute or regulation includes any
modification or re-enactment of that statute or regulation;
and
1.2.7 references to each of pSiOnco, SGH and SGHT shall include
references to each of their permitted successors in title
and assigns.
2. RESEARCH LICENCES
2.1 SGHT and SGH hereby grants to pSiOnco and SGH any and all rights
and permissions required to undertake the Research Programme
whether at the premises of SGH or elsewhere including any licences
required under any and all SGHT Intellectual Property and to the
extent that the use of such SGHT Intellectual Property is
necessary to research, develop, manufacture, have manufactured,
use, market and sell the Programme Intellectual Property, SGHT
hereby grants pSiOnco a royalty-free, perpetual licence to use the
SGHT Intellectual Property for such purposes.
2.2 pSiOnco hereby grants to SGH a non-transferable, royalty free,
non-exclusive licence under the pSiOnco Intellectual Property and
any Programme Intellectual Property assigned to pSiOnco pursuant
to Clause 7.1 for the purpose of carrying out SGH's tasks in the
Research Programme within the Field.
3. RESEARCH PROGRAMME
3.1 SGH hereby undertakes to provide the services required to
undertake the Research Programme as set out in Schedule 1 (subject
to any variation thereto agreed in writing by SGH and pSiOnco in
accordance with the Change of Research Programme Procedure) with
all reasonable skill and care for a period of twenty four (24)
months from the Commencement Date (the "RESEARCH TERM");
3.2 In connection with the provision of the services under this Clause
3 SGH shall only use such employees or persons as have been
approved in advance in writing by pSiOnco for these purposes, and
SGH shall provide pSiOnco with copies of the resumes of its
employees who are to undertake any part of the Research Programme
and form part of the Research Group. For the avoidance of doubt
pSiOnco agrees to the use of the individuals identified by name as
approved in Schedule 1 who shall form the initial Research Group;
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3.3 SGH shall ensure that all employees or persons used by SGH to
perform the Research Programme (including, without limitation,
those in the Research Group) shall be bound by provisions
equivalent to those regarding confidentiality (Clause 10),
publications (Clause 11), non-compete (Clause 9.2) and ownership
of intellectual property (Clause 7) as set out in this Agreement .
3.4 Each of SGH and pSiOnco shall keep or cause to be kept Documents
relevant to the Research Programme, such Documents shall be
maintained separately by SGH from records and notebooks of results
which are not part of the Research Programme;
3.5 Unless otherwise agreed between SGH and pSiOnco in writing,
neither SGH nor pSiOnco shall be under any obligation to provide
additional resource or facilities in connection with the Research
Programme over and above that agreed pursuant to this Clause 3 or
as set out in the Research Programme;
3.6 pSiOnco acknowledges that SGH is in receipt of funds from
charitable and governmental organisations to carry out research
and that SGH is contractually obliged to carry out that research
in accordance with the relevant terms of that funding. In the
light of this, pSiOnco agrees that those employees of SGH funded
by the said non-commercial organisations shall, at all times, be
free to pursue the research for which they have been funded and so
long as research conducted by members of the Research Group does
not conflict with or reduce or in any way diminish any proposed or
anticipated contribution by the Research Group to the Research
Programme.
3.7 If either of SGH or pSiOnco requires a licence to any Intellectual
Property owned by a person other than the Parties or any member of
a Party's Group for the purposes of the Research Programme, this
shall first be discussed by the Joint Research Committee, but no
Party shall enter into a licence for that Intellectual Property
without the prior consent of pSiOnco. To the extent that such
Intellectual Property is owned by a Party but not licensed to
either SGH or pSiOnco pursuant to this Agreement, then that Party
shall, do, or procure to be done, all further acts and execute and
deliver, procure to be executed and delivered, all such further
documents and instruments as shall be required in order for SGH or
pSiOnco to use such Intellectual Property. Neither Party shall be
in breach of this Agreement where it is unable to carry out part
of the Research Programme because to do so without such a licence
would infringe the Intellectual Property rights of a person other
than the Parties unless they were aware of the need for such
licence at the date of this Agreement.
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3.8 SGH shall not delegate to any third party the performance of the
Research Programme without the prior written consent of pSiOnco;
3.9 SGH shall have no power to enter into any agreement or accept any
commitments, liability or similar on behalf of pSiOnco.
4. JOINT RESEARCH COMMITTEE
4.1 Immediately following the execution of this Agreement SGH and
pSiOnco shall establish the Joint Research Committee in accordance
with Clause 4.3 to oversee and manage the Research Programme.
4.2 The Joint Research Committee will provide a framework for project
management and communication between pSiOnco and SGH. In
particular, the Joint Research Committee shall:
4.2.1 subject to the provisions of this Agreement and the Share
Subscription Agreement allocate the work under the Research
Programme as appropriate (taking into account the manpower,
facilities and equipment available to each of SGH and
pSiOnco);
4.2.2 monitor progress against the agreed milestones and the
timetable of the Research Programme;
4.2.3 promote and ensure the due performance of the Research
Programme;
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4.2.4 advise and assist in the resolution of any scientific or
technical difficulties which are experienced by either SGH
or pSiOnco personnel engaged on the Research Programme;
4.2.5 review the results of the Research Programme with a view to
identifying any patentable inventions and consider
opportunities for publications and patent filings, subject
to the provisions of this Agreement and the Share
Subscription Agreement;
4.2.6 prepare quarterly reports for submission to the Board, and
4.2.7 subject always to Clause 2 propose to the Board and SGH
amendments to the Research Programme from time to time as
may be necessary or desirable which shall be agreed in
accordance with the Change of Research Programme Procedure;
PROVIDED ALWAYS that the Joint Research Committee shall have no power to bind
either pSiOnco or SGH and decisions reached by it shall be treated only as
proposals or recommendations to the Board of pSiOnco and to SGH unless
specifically agreed otherwise in writing.
4.3 The Joint Research Committee shall be established and run by SGH and
pSiOnco as follows:-
4.3.1 The Joint Research Committee shall comprise six (6) members
("Members") comprising three (3) appointees from each of SGH and
pSiOnco. The initial Members of the Joint Research Committee shall
be as follows:
SGH MEMBER PSIONCO MEMBER
Pierce Chow Leigh Canham
Kai Zhang Steve Connor
Robert Tech Hin Roghieh Safie
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4.3.2 In addition to the three SGH Members SGH may invite an employee or
representative of SGH (an "INVITEE") to meetings of the Joint
Research Committee if in SGH's opinion the attendance of a SGH
employee or representative is desirable in relation to one or more
items on the agenda of the relevant meeting or for the purpose of
properly advising SGH in relation to matters under this Agreement.
Prior to any such meeting SGH shall inform pSiOnco in writing of
the SGH employee or representative who will be in attendance.
4.3.3 In addition to the three pSiOnco Members, pSiOnco may invite an
additional employee or representative of pSiOnco (an "INVITEE") to
meetings of the Joint Research Committee if in pSiOnco's opinion
the attendance of such pSiOnco employee or representative is
desirable in relation to one or more items on the agenda of the
relevant meeting or for the purpose of properly advising it in
relation to matters under this Agreement. Prior to any such
meeting pSiOnco shall inform SGH in writing of the pSiOnco
employee or representative who will be in attendance.
4.3.4 Each of SGH and pSiOnco shall be entitled to remove any Member
appointed by it and to appoint any person to fill a vacancy
arising from the removal or retirement of such Member. Each Party
shall give the others prior written notice of any proposed changes
in the identity of their Members.
4.3.5 The Parties shall use all reasonable endeavours to ensure that
their appointed Members and/or Invitees are of a level of
expertise and seniority to deal with the issues that may arise in
connection with the Research Programme.
4.3.6 The Joint Research Committee shall meet forthwith following the
Commencement Date and thereafter shall hold regular meetings at
intervals of not more than four (4) months and at any time during
normal business hours on any Business Day upon the request of
either SGH or pSiOnco.
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4.3.7 The venue for all meetings shall be in Singapore, unless otherwise
agreed, in which case (where the meeting does not take place in
Singapore at the request of pSiOnco) pSiOnco shall bear all travel
and subsistence costs incurred by SGH's Members in connection with
their attending the meeting in question. A Member or Invitee may
attend by telephone or video conference provided that all the
Members present can hear all parts of the proceedings.
4.3.8 At least fourteen (14) days' written notice of each meeting of the
Joint Research Committee shall be given to each Member by the
Party convening the meeting.
4.3.9 The quorum for meetings of the Joint Research Committee shall be
four (4) Members provided at least two (2) Members from each of
SGH and pSiOnco are present. Members may be represented at any
meeting by another Member designated in writing by the absent
Member. Members attending by telephone or by video conference
shall for the avoidance of doubt count in the quorum.
4.3.10 The chairman of the Joint Research Committee (who shall be the
research director of the Research Group or in his absence another
member of the Joint Research Committee) shall be responsible for
the preparation of the minutes of each meeting of the Joint
Research Committee. A copy of the minutes of each meeting shall be
sent to each of the Members within fourteen (14) days of the
meeting which they record. The minutes for a meeting shall be
approved by the Joint Research Committee at the next meeting.
4.3.11 The Chairman of the Joint Research Committee or his or her
designate shall prepare quarterly reports during the Research Term
summarising in reasonable detail the results of the Research
Programme during the preceding quarter. Copies of such reports
shall be sent to the Parties within 30 days of the end of the
quarter to which they relate.
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5. RESEARCH FUNDING
5.1 As a contribution to SGH's costs for carrying out its allotted
tasks under the Research Programme, pSiOnco shall make payments to
SGH in accordance with the Research Plan costs outlined in
Schedule 1.
5.2 All payments shall be made by pSiOnco in Singapore dollars on a
quarterly basis upon submission of a valid invoice by SGH. Such
payments shall be made directly to SGH as directed by SGH.
5.3 SGH shall apply the payments received from pSiOnco pursuant to
Clause 5.1 exclusively for the sole purpose of carrying out the
Research Programme.
6. ACADEMIC COLLABORATIONS
6.1 The Parties acknowledge that it may be desirable to forge
collaborative links with Third Party academic groups to support
the Research Programme. In the event that SGH desires such
collaboration, the opportunity in question shall be referred to
the Board for approval of any such collaboration. pSiOnco shall
not unreasonably hinder the establishment of such links where the
Third Party in question is willing to enter into the collaboration
on reasonable terms and where the results of such Third Party
collaboration will be available to pSiOnco within the framework of
the Research Programme. SGH shall not, without the prior written
consent of pSiOnco, encumber any Programme Intellectual Property
in any such academic collaboration.
6.2 In the event that pSiOnco desires a collaboration between SGH and
a Third Party, the opportunity in question shall be referred to
the Chief Executive of SGH for written approval and SGH shall not
unreasonably hinder the establishment of such links where the
Third Party in question is willing to enter into the collaboration
on reasonable terms and where the results of such Third Party
collaboration will be available to pSiOnco within the framework of
the Research Programme. SGH shall not be under any obligation to
accept such a collaboration which by way of such a collaboration
with a Third Party significantly alters SGH's obligations to
pSiOnco as detailed in this Agreement.
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6.3 Each Party shall ensure that no Documents are published by any
Third Party collaborator unless in accordance with Clause 11.
7. OWNERSHIP AND MANAGEMENT OF INTELLECTUAL PROPERTY
7.1 SGH and SGHT hereby assign by way of present and future assignment
with full title guarantee and free from charges, liens, mortgages
or other encumbrances of any kind to hold unto pSiOnco absolutely
all their interests in and to any Programme Intellectual Property
and the full and exclusive benefits thereof and rights, privileges
and advantages associated with them including:
7.1.1 the full right to apply for and obtain patents or other
forms of protection in respect of all or any part of the
Programme Intellectual Property throughout the world;
7.1.2 the right to claim priority from the patent application
included with any programme Patents under the Paris
Convention (as amended) when making such applications;
7.1.3 the right to file divisional, continuation and
continuation-in-part applications in its own name in
respect of subject matter described in the Programme
Patents; and
7.1.4 the right to recover, and take all such proceedings as may
be necessary for the recovery of, damages or other forms of
relief in respect of all infringements of rights in
Programme Intellectual Property or any other rights
assigned under this Agreement matters taking place before
or after the Commencement Date.
7.2 SGH and SGHT hereby agree to do or procure to be done all other
acts and to execute and deliver all such further documents and
instruments as shall be required to give full effect to the
assignment under Clause 7.1 or the recording by pSiOnco of such
assignment including by signing any documents required by any
national patent office or other equivalent registry.
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7.3 The prosecution, maintenance, defence and enforcement of the
Programme Intellectual Property shall be the responsibility of
pSiOnco save that pSiOnco shall give copies of all significant
documents relating to the same to SGH and SGHT in order that SGH
and SGHT may keep records of all relevant events related to the
Programme Intellectual Property.
8 CONSIDERATION
8.1 Subject to the provisions of the Share Subscription Agreement, on
achievement of a milestone (as detailed in Clauses 8.1.1 to 8.1.3 below)
within the Research Term plus six months, SGHT together with BRV shall be
entitled to subscribe for the further number of ordinary shares in
pSiOnco set out in Clauses 8.1.1 to 8.1.3 below (in the ratio of two
thirds to SGHT and one third to BRV) [***]:
8.1.1 [***] on completion of pre-clinical studies leading to approval by
the Ethics Committee or any other appropriate committee for the
first trial in humans;
8.1.2 [***] on completion of the first clinical trial to test for safety
in a human; and
8.1.3 [***] on completion of the first clinical trial to demonstrate for
efficacy in a human.
8.2 The subscription price per share for such further tranches of shares
shall be [***].
8.3 Such shares issued in accordance with this Clause 8 will be held subject
to and in accordance with the Share Subscription Agreement and pSiOnco's
articles of association.
8.4 For the avoidance of doubt SGHT and BRV shall not be entitled to
subscribe for any shares under this Clause 8 in respect of the successful
achievement of (a) particular milestone(s) if such milestone(s) have not
been achieved before the expiry of the Research Term plus six months
unless otherwise agreed by pSiOnco.
8.5 The number of shares referred to in this Clause 8 and the par value
referred to in Clause 8.2 shall be adjusted to take account of any
sub-division or consolidation of the ordinary share capital of pSiOnco.
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9. WARRANTIES AND LIABILITY
9.1 Each Party represents and warrants to the other Parties that:
9.1.1 it has legal power, authority and right to enter into this
Agreement and to perform its respective obligations and to
grant and/or assign the rights hereunder;
9.1.2 it is not at the Commencement Date a party to any
agreement, arrangement or understanding with any Third
Party which in any material way prevents it from fulfilling
any of its material obligations hereunder;
9.1.3 this Agreement has been duly authorised, executed, and
delivered by that Party and is a valid, binding, and
legally enforceable obligation of that Party;
9.1.4 no consent, approval, authorisation, or order of any court
or governmental agency or body is required for the
consummation of the transactions contemplated by this
Agreement; and
9.1.5 all Intellectual Property generated by the Research Group
during the course of the Research Programme will vest
automatically by operation of law or pursuant to the
relevant Research Group member's contract of employment in
the Party employing the relevant Research Group member.
9.2 SGH warrants that the Research Group will not during the Research
Term collaborate in the Field with any commercial Third Party
without the prior written consent of pSiOnco.
9.3 Save as provided in Clauses 9.1 and 9.2, no Party gives any
representation or warranty to any other Party that the performance
of this Agreement will not result in the infringement of any
rights, including Intellectual Property, vested in a Third Party.
9.4 No Party shall be liable to any other Party, or members of a
Party's Group or that Party's sub-licensees in contract, tort,
negligence, breach of statutory duty or otherwise for any loss,
damage, cost or expense of an indirect or consequential nature
(including any economic loss or other loss of turnover, profits,
business or goodwill) arising out of or in connection with this
Agreement or the subject matter of this Agreement whether or not
that Party had been advised of the possibility of such loss.
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9.5 Nothing in this Agreement shall be construed as a representation
made or warranty given by any Party that any patent will issue
based upon any pending patent application included in the pSiOnco
Patents or the Programme Intellectual Property, that any patent
included in the pSiOnco Patents or the Programme Intellectual
Property which issues will be valid, or that the use of any
pSiOnco Patents or the Programme Intellectual Property or pSiOnco
Know How will not infringe the patent or proprietary rights of any
other person. Furthermore, pSiOnco makes no representation or
warranty, express or implied, with respect to the pSiOnco Patents,
pSiOnco Know How or the Programme Intellectual Property, including
without limitation, any warranty of merchantability or fitness for
a particular purpose.
9.6 Except as provided in this Agreement all Materials provided by any
Party and data generated by or on behalf of that Party under this
Agreement are provided without any representation or warranty,
express or implied, including without limitation any implied
warranty of merchantability or fitness for any particular purpose
or any warranty that the use of the materials will not infringe or
violate any patent or other proprietary rights of any other
person.
9.7 Nothing in this Agreement shall be construed as a representation
made or warranty given by any Party to fund any research or
development other than as set out in the Research Programme.
10. CONFIDENTIALITY
10.1 Each Party undertakes and agrees not at any time for any reason
whatsoever to disclose or permit to be disclosed to any Third
Party or otherwise make use of or permit to be made use of (except
as expressly permitted pursuant to this Agreement), any trade
secrets or confidential information relating inter alia to another
Party's technology (including the Intellectual Property licensed
by either party pursuant to this Agreement to the extent that such
Intellectual Property has not been published) or the business
affairs or finances of another Party or a member of another
Party's Group, sub-licensee or of any suppliers, agents,
distributors or customers of another Party (the "CONFIDENTIAL
INFORMATION") which come into its possession pursuant to this
Agreement.
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10.2 The Parties shall ensure that only those of their officers,
employees, agents and consultants who are directly concerned with
the carrying out of this Agreement and who have a need to know are
given access to Confidential Information and that those who have
access to the Confidential Information of another Party are
informed of its secret and confidential nature.
10.3 Subject to the provisions of Clause 13, the obligations of
confidence referred to in this Clause 10 shall not extend to any
Confidential Information which:
10.3.1 is at the time of disclosure, or thereafter becomes,
generally available to the public otherwise than by reason
of a breach by the recipient Party of the provisions of
this Clause 10; or
10.3.2 is known to the recipient Party without obligations of
confidence prior to its receipt from another Party, as can
be shown by written record; or
10.3.3 is subsequently disclosed to the recipient Party without
obligations of confidence by another party owing no such
obligations in respect thereof; or
10.3.4 is required to be disclosed by any applicable law or any
Competent Authority to which a Party is from time to time
subject; or
10.3.5 is independently developed by a person or persons with no
access to the Confidential Information disclosed by a
Party, as demonstrated by written records.
10.4 The obligations of each Party under this Clause 10 shall survive
until the expiration of five (5) years after the expiration or
termination for whatever reason of this Agreement.
-20-
11. PUBLICATIONS
11.1 The members of the Research Group shall be entitled to publish the
results of the Research Programme provided that the provisions of
this Clause 11 have been complied with. The following provisions
shall also apply in the case of article abstracts and research
presentations.
11.2 A copy of any manuscript which a member of the Research Group
proposes to submit for publication and which contains or refers to
results from the Research Programme shall be sent to the Chairman
of the Joint Research Committee ( as defined in clause 4.3.10)
prior to its submission for publication. The Chairman of the Joint
Research Committee shall, forthwith on receipt of a draft
manuscript, send a copy to each of the other Members of the Joint
Research Committee and shall, at the same time convene a meeting
of the Joint Research Committee within forty-five (45) days of
receipt of the manuscript. If this meeting does not take place
within forty-five (45) days of the receipt of the manuscript by
the Chairman of the Joint Research Committee, the member of the
Research Group shall be entitled to submit the results for
publication. At the meeting the Joint Research Committee shall
decide whether any delay in the publication of the manuscript is
necessary or desirable for the protection of the relevant
Programme Intellectual Property. At the same meeting it shall
decide whether an application for a patent should be filed in
respect of the relevant results. If it decides that such an
application should be filed pSiOnco shall be responsible for such
a filing pursuant to Clause 7. If it decides that a delay for the
purpose of filing patent protection is necessary it may require
the delay of the submission for publication of the relevant
results for up to a period of not more than sixty (60) days from
the date of the meeting of the Joint Research Committee at which a
delay was requested or until the date on which the patent
application in question is filed, whichever is shorter. Any delay
beyond the said sixty (60) days may only be required on the prior
written agreement of both pSiOnco and SGH.
11.3 Notwithstanding the confidentiality obligations assumed by SGH
hereunder, pSiOnco acknowledges the importance of publications to
the academic standing of SGH. In the light of this, pSiOnco shall
use all reasonable efforts to facilitate early publication of the
results of the Research Programme.
-21-
12. TERM AND TERMINATION
12.1 This Agreement shall come into effect on the Commencement Date and
shall expire at the end of the Research Term or on termination or
expiry of the Patent and Know-how Licence whichever is the
earlier.
12.2 Either SGH and SGHT on the one hand or pSiOnco on the other hand
(the "TERMINATING PARTY") shall have the right to terminate this
Agreement forthwith upon giving written notice of termination to
pSiOnco on the one hand or SGH and SGHT on the other hand as the
case may be (the "DEFAULTING PARTY"), upon the occurrence of any
of the following events at any time during this Agreement:
12.2.1 the Defaulting Party commits a material breach of this
Agreement which in the case of a breach capable of remedy
shall not have been remedied within thirty (30) Business
Days of the receipt by it of a notice identifying the
breach and requiring its remedy;
12.2.2 the Defaulting Party for a period of longer than sixty (60)
Business Days suspends payment of its debts or otherwise
ceases or threatens to cease to carry on its business or
becomes bankrupt or insolvent (including without limitation
being deemed to be unable to pay its debts);
12.2.3 a proposal is made or a nominee or supervisor is appointed
for a composition in satisfaction of the debts of the
Defaulting Party or a scheme or arrangement of its affairs,
or the Defaulting Party enters into any composition or
arrangement for the benefit of its creditors, or
proceedings are commenced in relation to the Defaulting
Party under any law, regulation or procedure relating to
the re-construction or re-adjustment of debts (including
where a petition is filed or proceeding commenced seeking
any reorganisation, arrangement, composition or
re-adjustment under any applicable bankruptcy, insolvency,
moratorium, reorganisation or other similar law affecting
creditor's rights or where the Defaulting Party consents
to, or acquiesces in, the filing of such a petition); or
-22-
12.2.4 the Defaulting Party takes any action, or any legal
proceedings are started or other steps taken by a Third
Party, with a view to:
(i) the winding up or dissolution of the Defaulting
Party (other than for the reconstruction of a
solvent company for any purpose, including the
inclusion of any part of the share capital of the
Defaulting Party on a recognised public Stock
Exchange), or
(ii) the appointment of a liquidator, trustee, receiver,
administrative receiver, receiver and manager,
interim receiver custodian, sequestrator or similar
officer of the Defaulting Party against the
Defaulting Party or a substantial part of the assets
of the Defaulting Party;
or anything analogous to any of the foregoing occurs under
the laws of any country.
12.3 pSiOnco shall be entitled to terminate this Agreement immediately
by notice in writing to SGH or SGHT if either SGH or SGHT
challenges the validity of the pSiOnco Patents or any of them.
13. CONSEQUENCES OF TERMINATION
13.1 Upon expiry or termination of this Agreement:
13.1.1 the licence right granted by pSiOnco pursuant to Clause 2.2
shall terminate;
13.1.2 pSiOnco shall pay to SGH within sixty (60) Business Days
all sums due to SGH hereunder which have accrued prior to
the date of termination unless such termination is the
result of a material breach of this Agreement by SGH or
SGHT;
13.2 If pSiOnco terminates this Agreement for any reason other than for
the default of SGH or SGHT it shall pay to SGH within 30 days of
such termination all sums which would have been paid to SGH as set
out in Schedule 1 and which relate to costs that SGH can
demonstrate are legally committed that cannot otherwise be
utilised by SGH elsewhere by SGH for the remainder of the Research
Term. For the avoidance of doubt, SGH shall have an obligation to
mitigate to the extent possible the level of any such committed
costs. Where committed costs cannot otherwise by re-utilised by
SGH, the Parties will negotiate in good faith to find ways in
which the Parties can constructively use any such committed costs
to the benefit of all the Parties.
-23-
13.3 Termination or expiry of this Agreement for whatever reason shall
not affect the accrued rights of the Parties arising in any way
out of this Agreement as at the date of termination or expiry and
in particular but without limitation the right to recover damages
and interest, and the provisions of Clauses 2.1, 7, 8, 9, 10, 11,
15, 16, 17, 20, 21 23, 24 and 25 shall remain in full force and
effect.
14. CHANGE OF RESEARCH PROGRAMME
14.1 Either SGH or pSiOnco may propose any reasonable modification to
any element of the Research Programme in accordance with the
Change of Research Programme Procedure (the "PROPOSER") by written
notice to the other (the "PROPOSEES") specifying in as much detail
as is reasonably practicable the nature of the Change and the
additional work or materials required.
14.2 As soon as reasonably practicable thereafter and in any case
within 30 days of sending or receipt of a request for a change,
the Proposer will provide a brief written proposal including but
not limited to:
14.2.1 details of the proposed Change;
14.2.2 any difference in the costs set out in Schedule 2
necessitated as a result of the proposed Change;
14.2.3 a timetable for the implementation, together with any
proposals for acceptance, of the proposed Change; and
14.2.4 details of the likely impact, if any, of the proposed
Change on any existing services being performed in
accordance with the Research Programme.
-24-
14.3 The Proposee will, unless otherwise agreed, review the proposal
within 15 Business Days after its receipt and will either:
14.3.1 accept the proposed Change and vary this Agreement
accordingly and SGH will implement the Change in accordance
with agreed timetable; or
14.3.2 reject the proposed Change; or
14.3.3 refer the proposed Change to an alternative appropriate
forum for discussion.
14.4 If the Proposee rejects the proposed Change, it shall provide in
writing to the Proposer the reasons for rejecting the proposed
Change and the Proposer shall have the opportunity, should it so
wish, to provide an amended Change proposal for the other Party to
review in accordance with Clause 14.3. Neither SGH nor pSiOnco
shall unreasonably withhold its agreement to any proposed Change.
14.5 SGH will not commence work in connection with any Change or
addition to the scope of the services provided under the Research
Programme until the relevant Change is agreed by the parties in
writing in accordance with this Clause 14.
15. WAIVER
No Party shall be deemed to have waived any of its rights or remedies
conferred by this Agreement unless the waiver is made in writing and
signed by a duly authorised representative of that Party. In particular,
no delay or failure of any Party in exercising or enforcing any of its
rights or remedies conferred by this Agreement shall operate as a waiver
of those rights or remedies or so as to preclude or impair the exercise
or enforcement of those rights or remedies nor shall any partial exercise
or enforcement of any right or remedy by any Party preclude or impair any
other exercise or enforcement of that right or remedy by that Party.
16. ENTIRE AGREEMENT/VARIATIONS
16.1 This Agreement and the Share Subscription Agreement constitutes
the entire agreement and understanding between the Parties in
relation to the subject matter of this Agreement and supersedes
all prior oral or written understandings, arrangements,
representations or agreements between them relating to the subject
matter of this Agreement. No director, employee or agent of any
Party is authorised to make any representation or warranty to
another Party not contained in this Agreement, and each Party
acknowledges that it has not relied on any such oral or written
representations or warranties.
-25-
16.2 No variation, amendments, modification or supplement to this
Agreement shall be valid unless made in writing in the English
language and signed by a duly authorised representative of each
Party.
17. NOTICES
17.1 Any notice to be given pursuant to this Agreement shall be in
writing in the English language and shall be delivered by hand,
sent by registered or recorded delivery airmail post or sent by
facsimile confirmed by registered or recorded delivery post to the
address or facsimile number of the recipient set out below or such
other address or facsimile number as a Party may from time to time
designate by written notice to the other Parties.
ADDRESS OF SGH
for the attention of: Chief Executive Officer
Executive Office
Block 7, Level 1
Outram Road
Singapore
169608
fax number: (65) 6222 1720
ADDRESS OF PSIONCO
for the attention of: Dr. Roger Aston/Mr. Sunny Wong
c/o Wong Tan & Molly Lim
80 Robinson Road 17-02
Singapore 068898
fax number: (65) 6222 8001
-26-
ADDRESS OF SGHT
for the attention of: c/o Singapore General Hospital Pte. Ltd.
Chief Executive Officer
Executive Office
Block 7, Level 1
Outram Road
Singapore
169608
fax number: (65) 6222 1720
17.2 Any notice given pursuant to this Clause 17 shall be deemed to
have been received:
17.2.1 in the case of delivery by hand, when delivered; or
17.2.2 in the case of sending by post:
(i) where posted in the country of the addressee, on the
third Business Day following the day of posting; and
(ii) where posted in any other country, on the seventh
Business Day following the day of posting; or
17.2.3 in the case of facsimile, on acknowledgement by the
recipient facsimile receiving equipment on a Business Day
if the acknowledgement occurs before 1700 hours local time
of the recipient and in any other case on the following
Business Day.
18. ASSIGNMENT
18.1 Save as otherwise provided in this Agreement, no Party shall
without the prior written consent of the other Parties, assign the
benefit and/or burden of this Agreement nor sub-contract any of
its obligations hereunder unless otherwise permitted by the
written agreement of all Parties.
-27-
19. FORCE MAJEURE
19.1 If a Party (the "Non-Performing Party") is unable to carry out any
of its obligations under this Agreement due to Force Majeure this
Agreement shall remain in effect but the Non-Performing Party's
relevant obligations under this Agreement and the relevant
obligations of the other Parties ("the Innocent Parties") under
this Agreement shall be suspended for a period equal to the
duration of the circumstance of Force Majeure provided that:
19.1.1 the suspension of performance is of no greater scope than
is required by the Force Majeure;
19.1.2 the Non-Performing Party gives the Innocent Parties prompt
notice describing the circumstance of Force Majeure,
including the nature of the occurrence and its expected
duration, and continues to furnish regular reports during
the period of Force Majeure;
19.1.3 the Non-Performing Party uses all reasonable efforts to
remedy its inability to perform and to mitigate the effects
of the circumstance of Force Majeure; and
19.1.4 as soon as practicable after the event which constitutes
Force Majeure the Parties shall discuss how best to
continue their operations as far as possible in accordance
with this Agreement.
19.2 If Force Majeure is continuing at the expiry of 3 months either of
the Innocent Parties may give thirty (30) Business Days written
notice to terminate this Agreement to the Non-Performing Party and
termination shall occur if the Force Majeure is continuing at the
end of that thirty (30) Business Day notice period.
19.3 SGHT and SGH shall not be entitled to claim that Force Majeure
applies as a result of the actions, decrees or otherwise of any
Singaporean Government body if the primary purpose of such
actions, decrees or otherwise was to enable SGHT and/or SGH to
claim Force Majeure.
20. ARBITRATION
20.1 Any question, difference or dispute which may arise concerning the
construction meaning or effect of this Agreement or concerning the
rights and liabilities of the Parties hereunder or any other
matter arising out of or in connection with this Agreement shall
first be submitted to the Chairman of the Board of Directors of
pSiOnco, and the CEO of SGH for resolution, who may call on others
to advise them as they see fit.
-28-
20.2 If the discussions under Clause 20.1 should fail to resolve the
question, difference or dispute within ninety (90) Business Days
of commencement of the discussions under Clause 20.1 then any of
the Parties to the dispute may refer the matter for determination
by arbitration at the Singapore International Arbitration Centre
("SIAC") and such submission shall be a submission to arbitration
in accordance with the Rules of the SIAC as presently in force by
which the Parties in dispute agree to be so bound. The place of
arbitration shall be Singapore and the arbitration shall be
conducted wholly in the English language.
21. SEVERANCE OF TERMS
21.1 If the whole or any part of this Agreement is or becomes or is
declared illegal, invalid or unenforceable in any jurisdiction for
any reason (including both by reason of the provisions of any
legislation and also by reason of any court or Competent Authority
which either has jurisdiction over this Agreement or has
jurisdiction over any of the Parties):
21.1.1 in the case of the illegality, invalidity or
un-enforceability of the whole of this Agreement it shall
terminate only in relation to the jurisdiction in question;
or
21.1.2 in the case of the illegality, invalidity or
un-enforceability of part of this Agreement that part shall
be severed from this Agreement in the jurisdiction in
question and that illegality, invalidity or
un-enforceability shall not in any way whatsoever prejudice
or affect the remaining parts of this Agreement which shall
continue in full force and effect.
21.2 If in the reasonable opinion of any Party any severance under this
Clause 21 materially affects the commercial basis of this
Agreement, the Parties shall discuss, in good faith, ways to
eliminate the material effect.
-29-
22. THIS AGREEMENT NOT TO CONSTITUTE A PARTNERSHIP
22.1 None of the provisions of this Agreement shall be deemed to
constitute a partnership between the Parties and none of the
Parties shall have any authority to bind the others in any way
except as provided in this Agreement.
23. PUBLIC STATEMENTS
23.1 Except as provided in Clause 23.2, no Party will, without the
prior written consent of each other Party:
23.1.1 use in advertising, publicly or otherwise, any trade-name,
personal name, trademark, trade device, service mark,
symbol, or any abbreviation, contraction or simulation
thereof, owned by another Party; or
23.1.2 represent, either directly or indirectly, that any product
or service of another Party is a product or service of the
representing Party or that it is made in accordance with or
utilises the information or documents of the another Party.
23.2 The restrictions in Clause 22.1 shall not apply to the following:
23.2.1 a press release, in a form agreed to in writing by all the
Parties, publicly announcing this Agreement; or
23.2.2 use as required by any applicable law or governmental
regulation.
24. COSTS
24.1 Each Party shall bear its own legal costs, legal fees and other
expenses incurred in the preparation and execution of this
Agreement.
25. GOVERNING LAW AND JURISDICTION
25.1 The validity, construction and performance of this Agreement shall
be governed by the laws of Singapore and subject to the exclusive
jurisdiction of the courts of the Republic of Singapore.
-30-
SCHEDULE 1
OUTLINE RESEARCH PLAN
Part 1
COLLABORATIVE ONCOLOGY RESEARCH
Between:
PSIONCOLOGY PTE. LTD AND SINGAPORE GENERAL HOSPITAL, DEPT OF EXPERIMENTAL
SURGERY
Dr. Pierce Chow
Director, Dept of Experimental Surgery
Singapore General Hospital
Outram Road
Singapore 169608
SUMMARY OF RESEARCH AIMS AND METHODOLOGY
pSiOnco and SGH wish to carry out proof-of-principle research to verify the
above hypotheses.
Established commercial tumour cell lines will be implanted into either nude or
skid mice and allowed to develop to a suitable size. Barbs made from BioSilicon
(TM) and suitably impregnated with chemotherapeutic agents or a radiation source
as appropriate are then introduced into the tumour using a novel device (to be
developed by pSiMedica). The tumours are monitored and compared with those in
control groups.
RESEARCH SITE AND FACILITIES
The above animal research will be carried out in the animal laboratory of the
Dept of Experimental Surgery, Singapore General Hospital. Researchers from the
Dept. together with other technical staff will procure the necessary animals,
which will be housed in the laminar flow facility in the laboratory designed for
nude/skid animals. The same researchers will be responsible for introducing the
tumour lines into the animals and subsequently introducing the BioSilicon (TM)
barbs into the tumours and monitoring the progress of the tumours. Tumour
regression will be documented both macroscopically and by histology. HPLC
facilities in the laboratory will be used for monitoring of serum levels of
drugs.
pSiOnco will be responsible for preparing impregnated BioSilicon (TM) barbs and
developing a novel device for introducing the barbs into biological tissues. The
barbs and device will be shipped to the Dept of Experimental Surgery for the
purpose of the research.
-31-
CELL LINES AND CHEMOTHERAPEUTIC AGENTS
The following cell lines will be used. These are lines that staff of the Dept of
Experimental Surgery are familiar with and have direct experience of.
Cell lines: HepG2, AGS, HTB-88, 224-CCL
The following chemotherapeutic agents are suitable for the above cell lines and
will be used. Drugs: Adriamycin, chlorambucil, gemcitabine, actinomycin D,
cisplatin The above are by no means exhaustive and if some of the suggested
drugs are not suitable for BioSilicon (TM) for technical reasons, others can be
substituted.
RADIATION SOURCES
It is proposed that 32P, a beta emitter with a maximum energy of 1.71MeV (range
800 microns in photographic emulsion) and a half life of 14.3 days be used as a
radiation source. This radionuclide can be created throughout the Si skeleton
itself via the well-developed Si industry process of "neutron transmutation
doping"
OUTLINE OF RESEARCH PROTOCOL AND TIME-FRAME
Each of the 4 cell-lines is introduced into equal groups of skid and nude mice
giving a final tally of:
- ------------------- -------- --------------------- --------------------
CELL-LINE BRACHYTHERAPY CHEMOTHERAPY
- ------------------- -------- --------------------- --------------------
HepG2 Nude 20 20
- ------------------- -------- --------------------- --------------------
Skid 20 20
- ------------------- -------- --------------------- --------------------
AGS Nude 20 20
- ------------------- -------- --------------------- --------------------
Skid 20 20
- ------------------- -------- --------------------- --------------------
HTB-88 Nude 20 20
- ------------------- -------- --------------------- --------------------
Skid 20 20
- ------------------- -------- --------------------- --------------------
224-CCL Nude 20 20
- ------------------- -------- --------------------- --------------------
Skid 20 20
- ------------------- -------- --------------------- --------------------
Control Nude 20 20
- ------------------- -------- --------------------- --------------------
Skid 20 20
- ------------------- -------- --------------------- --------------------
Total
- ------------------- -------- --------------------- --------------------
1. The cell lines are introduced subcutaneously into the flanks of the
animals under anesthesia and the growth monitored every 3 days.
2. At between 3 - 5 weeks (depending on the cell lines) once the
tumours have developed to a size when the greatest diameter is
between 2-3 cm, appropriate barbs are introduced into the tumours
under anesthesia after surgical reflection of the skin.
3. Further progress of the tumour is monitored. Animals will be
sacrificed if the tumours continue to progress and has grown by 50%
of diameter size or more.
4. 1 ml of blood will be collected from the femoral vein of the animal
treated with chemotherapy when the barbs are introduced and at
sacrifice or when the tumour has regressed to 20% of the original
diameter. Baseline and subsequent levels of the chemotherapeutic
agents will be determined by HPLC.
-32-
Endpoints
Primary end-point Tumour regression
Secondary end-point Survival of animals, drugs levels
References
1. Int J Oncol 1999 May;14(5):861-7. GSH, GSH-related enzymes and GS-X
pump in relation to sensitivity of human tumor cell lines to
chlorambucil and adriamycin. Zhang K, Yang EB, Wong KP, Mack P.
2. Cancer Lett 2000 Feb 28;149(1-2):213-20. Glutathione-related factors
are not correlated with sensitivity of human tumour cells to
actinomycin D. Zhang K, Yang EB, Zhao YN, Wong KP, Mack P.
3. Int J Oncol 2000 Mar;16(3):599-610. Transforming growth factor-beta
and response to anticancer therapies in human liver and gastric
tumors in vitro and in vivo. Liu P, Menon K, Alvarez E, Lu K,
Teicher BA.
4. J Hepatol 1998 Mar;28(3):504-9. Antitumor effect of the nucleoside
analogs 2-chlorodeoxyadenosine and 2',2'-difluorodeoxycytidine on
human hepatoma HepG2 cells. Graziadei I, Kelly T, Schirmer M, Geisen
FH, Vogel W, Konwalinka G.
5. Int J Mol Med 1999 Aug;4(2):203-12. Modulation of biological
phenotypes for tumor growth and metastasis by target-specific
biological inhibitors in gastric cancer. Rha SY, Noh SH, Kim TS, Yoo
NC, Roh JK, Min JS, Kim BS.
6. Invest New Drugs 1991 Feb;9(1):29-36. Relationship between
glutathione levels and drug or radiation sensitivities in human
gastric cancer cell lines in vitro. Barranco SC, Weintraub B,
MacLean KK, Beasley EG, Jenkins VK, Townsend CM Jr.
7. Invest New Drugs 1990;8 Suppl 1:S9-18. Schedule dependent
potentiation of antitumor drug effects by
alpha-difluoromethylornithine in human gastric carcinoma cells in
vitro. Barranco SC, Townsend CM Jr, Ho BY, Reumont KJ, Koester SK,
Ford PJ.
8. Mol Pharmacol 2001 Apr;59(4):837-43Modulation of cisplatin
cytotoxicity and cisplatin-induced DNA cross-links in HepG2 cells by
regulation of glutathione-related mechanisms. Zhang K, Chew M, Yang
EB, Wong KP, Mack P.
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SCHEDULE 1
PART 2
RESEARCH PLAN COSTINGS
COSTINGS FOR COLLABORATIVE RESEARCH:
COSTING AND WORK SCHEDULE
FOR COLLABORATIVE RESEARCH
BETWEEN
PSI ONCOLOGY PTE LTD
AND
DEPT OF EXPERIMENTAL SURGERY
SINGAPORE GENERAL HOSPITAL
The rates and work schedule below refer to the collaborative research
("research") previously discussed between PsiOnco and Dept of Experimental
Surgery (document "Outline Research Plan" 3rd Jan 2002, d) and are not
reflective of the general rates or cost of research carried out at the facility.
Quotes are in Singapore dollars and valid for 6 months.
1. ASSAY DEVELOPMENT AND QUANTIFICATION OF DRUGS IN TISSUE:
The Department of Experimental Surgery will undertake work to develop suitable
method(s) for quantification of drug levels in tissues (both tumour tissue and
surrounding non-tumour tissue). The methods developed may be novel and specific
for the purpose of the research.
COST OF DEVELOPMENT OF ASSAY
Cost of work done (inclusive of material) [***]
COST OF QUANTIFICATION OF DRUG LEVEL
*Cost per point quantification of drug level [***]
*It would be more equitable to the JV to cost on the basis of number of assays
rather than upfront because:
1. work using radioactive therapeutic source does not require
quantification of drug level
2. there will be animal attrition
3. each good animal will require 10 tissue and 2 blood samples
-34-
We estimate at least 26 good animals per research "unit" of 40 animals (see
below) and hence projected cost will be 26 X [***]
2. COST OF A SINGLE RESEARCH UNIT
The cost below refers to a single research "unit" of 40 animals for a period of
[***].
1. nude/skid mice 40 Nos. X [***]
2. cell line preparation (inclusive of media,
flask, serum, tubes etc.) 40 Nos. X [***]
3. Histology (excluding pathologist service) 40 Nos. X [***]
4. Animal care [***] 30 X [***]
5. Facility [***] Special collaborator's rate [***] 30 X [***]
Total: [***]
3. WORK SCHEDULE
1. Time from confirmation to start of research [***]
1. the assay will be developed in this period
2. animals will be ordered, quarantined, housed
3. it is assumed the pSiOnco has decided on the choice of agent(s) and
cell-line(s) at the time of confirmation
2. Time from start of research to end of animal experiment [***]
3. Time from end of animal experiments to final analysis and reports [***]
Notes: 1. (1) and (3) may take less than [***]
2. as previously discussed, work on the different research units may
start at different time-points - i.e. may be staggered
Robert Ng
Manager, Experimental Surgery
Pierce Chow
Director, Experimental Surgery
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SCHEDULE 1
PART 3
PROPOSED RESEARCH WORK SCHEDULE WITH ESTIMATES COSTS FOR 2002/2003:
Research project structure is based upon `the Outline Research Plan' dated
January 2002 and shown in Schedule 1, Part 2.
Research project costs at The Department of Experimental Surgery at Singapore
General Hospital are based upon `the costings and work schedule' dated 5th April
2002 and shown in Schedule 1, Part 3.
A summary of projected pre-clinical R&D is shown in Gant format in this Schedule
1, Part 4.
The projected costs for R&D are based upon the following assumptions:
Each `Research Unit' comprises approx 80 mice
The programme comprises the following `research grade materials' to enter
pre-clinical studies:
1. 32P silicon
2. Research grade cytotoxic drug A) loaded onto porous silicon
3. 90Y porous silicon
4. Research grade cytotoxic drug B) loaded onto porous silicon
- -------------------------------------------------------------- --------------------- --------------------
2002 2003
- -------------------------------------------------------------- --------------------- --------------------
32P Radiopharmaceutical powder [***] [***]
- -------------------------------------------------------------- --------------------- --------------------
Drug loaded powders, research grade Drug A [***] [***]
- -------------------------------------------------------------- --------------------- --------------------
2nd Line: 90Y / Drug B) research grade powders [***]
- -------------------------------------------------------------- --------------------- --------------------
Technical staff (recruitment Q4 2002) [***]
- -------------------------------------------------------------- --------------------- --------------------
- -------------------------------------------------------------- --------------------- --------------------
Total: [***] [***]
- -------------------------------------------------------------- --------------------- --------------------
- -------------------------------------------------------------- --------------------- --------------------
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[***]
-37-
SCHEDULE 2
PSIONCO KNOW-HOW
For the avoidance of doubt the following pSiMedica Know-how has been licensed by
pSiMedica to pSiOnco within the Field under a Patent and Know-how Licence of
even date of which this Agreement is subject.
To the extent that pSiOnco is reasonably able, pSiOnco will supply SGH with such
Know-How as is required by, SGH to use the pSiOnco Materials and pSiOnco Patent
Rights.
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SCHEDULE 3
PSIONCO MATERIAL
For the avoidance of doubt the following pSiMedica Material have been licensed
by pSiMedica to pSiOnco within the Field under a Patent and Know-how Licence of
even date of which this Agreement is subject.
Biocompatible Silicon (BioSilicon (TM)) and any other articles which pSiOnco may
furnish to SGH from time to time which may fall under the scope of the pSiOnco
Patent Rights.
-39-
SCHEDULE 4
PSIONCO PATENT RIGHTS
For the avoidance of doubt the following pSiMedica Patents have been licensed by
pSiMedica to pSiOnco within the Field under a Patent and Know-how Licence of
even date of which this Agreement is subject.
PSIMEDICA PATENTS
PATENTS 1-3 PUBLISHED ; INFO IN PUBLIC DOMAIN
1. BIOMATERIAL: GB 9801317.0, WO 97/06101, FILED 3RD AUGUST 1995.
TOPIC AREAS: in-vitro tests of porous and poly Si
demonstrating bioactivity and biodegradability in
simulated human plasma & effects of electrical bias
CLAIMS: bioactive silicon, resorbable silicon, biocompatible
silicon in/on the body
STATUS: PCT phase with publication date 20th February 1997
2. IMPLANTS FOR ADMINISTERING SUBSTANCES AND METHODS OF PRODUCING
IMPLANTS: GB 9808052.6, WO 99/53898, FILED 17TH APRIL 1998.
TOPIC AREAS: 6 month in-vivo test of porous Si in the
subcutaneous site; controlled and slow delivery of
drugs (eg: hormones or microminerals) from implanted
capsules, either via micromachined reservoirs and pSi
barriers or via pore-entrapment.
CLAIMS: erodable silicon implants containing beneficial
substances
STATUS: PCT phase with publication date 28th October 1999
3. DERIVATIZED POROUS SILICON: GB 9909996.2, WO 00/66190, FILED 1ST MAY 1999.
TOPIC AREAS: the use of derivitisation to improve the
stability and haemocompatibility of pSi for
therapeutic uses; stability tests were conducted
in-vitro in simulated human plasma. Implantable
devices proposed include biofilters, batteries,
microelectrodes, wound repair structures,
radiotherapy microparticles and mirrors.
CLAIMS: use of derivitised porous silicon in/on the body
STATUS: PCT phase with publication date 9th November 2000
PATENT 4; UNPUBLISHED BUT COMPLETE
4. CANCER TREATMENT: GB 0104383.5, FILED 22ND FEBRUARY 2001.
TOPIC AREAS: pSi microparticles of tunable density, loaded
with either a radionuclide or cytotoxic drug for the
treatment of liver cancer.
CLAIMS: cytotoxic and biodegradable porous silicon
microparticles (tbf)
STATUS: 2nd filing due on 22nd February 2002.
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SCHEDULE 5
SGHT INTELLECTUAL PROPERTY
Any and all Know-How related directly to the Field and owned by SGHT or SGH
-41-
IN WITNESS whereof this Agreement has been executed by duly authorised officers
of the Parties on the date first above written.
Signed by: /s/Pierce Chow
------------------------------------------
Name: Pierce Chow
Title: Director
For and on behalf of
PSIONCOLOGY PTE. LTD.
Witnessed By: /s/Tan Swee Gek
------------------------------------------
Name: Tan Swee Gek
Advocate & Solicitor, Singapore
Signed by: /s/ Ong Yong Yau
------------------------------------------
Name: Professor Ong Yong Yau
Title: Chief Executive Officer
For and on behalf of
SINGAPORE GENERAL HOSPITAL PTE LTD
Witnessed By: /s/Tan Swee Gek
------------------------------------------
Name: Tan Swee Gek
Advocate & Solicitor, Singapore
Signed by: /s/Wong Chiang Yin
------------------------------------------
Name: Dr. Wong Chiang Yin
Title: Director
For and on behalf of
SGH TECHNOLOGY VENTURES PTE LTD
Witnessed By: /s/Tan Swee Gek
------------------------------------------
Name: Tan Swee Gek
Advocate & Solicitor, Singapore