RESEARCH AGREEMENT
between
UNIVERSITY HEALTH NETWORK
and Dr. Fei-Xxx Xxx
and
SENESCO TECHNOLOGIES, INC.
This Agreement is made as of November 6, 2003 ("Effective Date") between the
following parties: the University Health Network, located at 000 Xxxxxxxxxx
Xxxxxx, Xxxxx 0-000, Xxxxxxx, Xxxxxxx X0X 0X0 (hereinafter "UHN"), Senesco
Technologies, Inc., a New Jersey Corporation having a principal place of
business at 000 Xxxxxx Xxxxxx, Xxxxx 000, Xxx Xxxxxxxxx, XX 00000 (hereinafter
referred to as "Senesco"), and Dr. Fei-Xxx Xxx (hereinafter referred to as the
"Principal Investigator").
WHEREAS Senesco has conceived of, developed and is continuing to develop
proprietary technology relating to initiation factor eIF5A and DHS and is the
owner of proprietary rights thereto, including patent applications filed thereon
on a worldwide basis;
WHEREAS UHN maintains laboratories directed by the Principal Investigator; and
WHEREAS Senesco wishes to fund research performed by Principal Investigator
relating to the evaluation of potential efficacy of elF5A and DHS in human
nasopharyngeal carcinoma.
NOW THEREFORE, in consideration of the mutual covenants herein contained, the
parties hereby agree as follows:
DEFINITIONS.
1.1 "Budget" shall mean the budget prepared by UHN and agreed to by Senesco to
support the work to be performed under the Research Plan in Each Research Year,
attached hereto as Schedule B.
1.2 "Confidential Information" shall mean all terms of this Agreement, all
Inventions, Invention disclosure reports, Research Information and Research
Information reports as well as all information Exchanged between the parties
pursuant to the Research Plan, including all technical information, ideas, data,
compounds, molecules, cell lines, techniques, methods, processes, uses,
composites, skills, trade secrets, and business and marketing information, as
further defined in Article VII herein.
-1-
1.3 "Field" shall mean products relating to the treatment, prevention, or
detection/diagnosis of nasopharyngeal carcinoma, within the scope of the
Research Plan.
1.4 "Invention" shall mean any patented new and useful process, machine,
manufacture or composition of matter conceived of or first reduced to practice,
in whole or in part, during the term of this Agreement in the performance of
research under the Research Plan.
1.5 "Researchers" shall mean the Principal Investigator and any other
individuals conducting Research under this Agreement
1.6 "Research Information" shall mean all information, know-how, and materials
(including any chemical compound or substances, biological cell, or component
thereof, whether derived from biological material or synthesized) developed in
the course of research under the Research Plan, but which does not constitute an
Invention.
1.7 "Research Plan" shall mean the research to be performed under the direction
of the Principal Investigator relating to the evaluation of eIF5A and DHS in
human nasopharyngeal carcinoma, as detailed in Schedule A attached hereto.
1.8 "Net Sales" shall mean the total revenue received by Senesco for sales of
products in the Field excluding standard industry discounts, refunds and taxes,
all as determined from the books and records of the Senesco, or its parent and
subsidiaries, maintained in accordance with Generally Accepted Accounting
Principles consistently applied;
1.9 "Background Intellectual Property" shall mean all Inventions, Research
Information, technical information, ideas, data, compounds, molecules, cell
lines, techniques, methods, processes, uses, composites, skills, trade secrets,
and business and marketing information, that was in the possession of either
party prior to this Agreement.
II. SCOPE OF WORK.
2.1 UHN shall conduct research under the supervision of the Principal
Investigator in a laboratory at UHN in accordance with the Research Plan
attached hereto as Schedule A. The scope of research conducted pursuant to the
terms of this Agreement shall be limited to the parameters described in the
Research Plan, subject to any amendments thereto made in writing and agreed to
in writing signed by all parties. All research will be done in accordance with
the good laboratory practice established by UHN. Any inconsistent or conflicting
provisions between this Agreement and the Research Plan shall be governed by the
terms of this Agreement.
III. STAFF.
3.1 Principal Investigator. The Principal Investigator shall be Dr. Fei-Xxx
Xxx. If Xx. Xxx shall for any reason cease to conduct the research herein in
accordance with the
-2-
Research Plan in Schedule A, Senesco may, at its option, terminate this
Agreement or request that UHN appoint a new Principal Investigator acceptable to
Senesco. No new investigator shall be appointed by UHN without the prior
approval of Senesco.
3.2 UHN Staff. UHN represents that it has the professional staff, research
capabilities and facilities necessary to perform the work in accordance with
this Agreement and the Research Plan. UHN shall supply all necessary personnel
in order for it to perform the work in accordance with the Research Plan, and
shall require all such personnel to abide by the terms of Articles VI, VII, VIII
and X herein.
IV. PERIOD OF PERFORMANCE.
4.1 The period of performance of this Agreement is contemplated to be two (2)
years, at a cost as set forth in the set forth in the Budget set forth in
Schedule B, unless sooner terminated or extended as elsewhere provided herein or
by mutual agreement.
V. BUDGET AND SUPPORT FOR RESEARCH.
5.1 During the Research period, beginning on the Effective Date of this
Agreement, Senesco will pay UHN for its costs incurred in the performance of
this Research Plan. Said payment shall be made based upon the Budget prepared by
UHN and agreed to by Senesco. The proposed Budget is attached as Schedule B. Any
amendments to the Budget agreed to in writing by the parties shall be appended
hereto as an amendment to Schedule B.
Payments to UHN under this Agreement shall made payable as follows:
Date Amount
---- ------
30-Jan-04 $42,154
1-Apr-04 $42,154
1-Jul-04 $42,154
1-Oct-04 $42,154
1-Jan-05 $33,387
1-Apr-05 $33,387
1-Jul-05 $33,387
1-Oct-05 $33,387
TOTAL $302,164
Payments made to the UHN under this Agreement shall be sent to:
University Health Network
0-000 Xxxxxxxxxx Xxx.
Xxxxxxx, Xxxxxxx, Xxxxxx
X0X 0X0
Attn: Xxx XxXxxxxx, Director, Research Business Development
-3-
VI. REPORTS OF RESEARCH.
6.1 The Principal Investigator on behalf of all Researchers shall report to
UHN, who will then report to Senesco any and all Inventions or Research
Information. Such reports shall take the form of an Invention disclosure report
to Senesco.
6.2 The Principal Investigator shall furnish Senesco a bi-annual written report
summarizing research activity not previous reported pursuant to Section 6.1
hereof, which shall include a Research Information report with respect to all
Research Information, as well as any Inventions not previously disclosed under
Section 6.1 thereof. During the term and performance of this agreement, the
Principal Investigator will provide "Updates," every three (3) months,
concerning the progress of the Research Project to Dr. Xxxx Xxxxxxxx. Such
Updates may take the form of telephone call, meeting, or email. UHN will furnish
Senesco with a written report of all Inventions and Research Information
bi-annually, and a final written report within thirty (30) days following the
end of the term of this Agreement.
VII. CONFIDENTIALITY.
7.1 All terms of this Agreement, all Inventions, Invention disclosure reports,
Research Information and Research Information reports as well as all information
exchanged between the parties pursuant to the Research Plan, including all
technical information, ideas, data, compounds, molecules, cell lines,
techniques, methods, processes, uses, composites, skills, trade secrets, and
business and marketing information, shall be considered Confidential
Information.
7.2 Senesco possesses all right, title and interest to all Confidential
Information, whether disclosed by Senesco or developed under this Agreement,
with the exception of Background Intellectual Property owned by UHN.
7.3 Except as provided herein, UHN and Principal Investigator will not disclose
or make available Confidential Information to third parties without Senesco's
written consent during the term of this Agreement and for a period of five years
thereafter.
7.4 UHN 's and Principal Investigator's obligations of confidentiality under
this Section do not apply to any information which (a) is established by written
records to be in the public domain other than as a consequence of an act of UHN
or Principal Investigator; (b) was in UHN's or Principal Investigator's
possession prior to the disclosure by Senesco and is demonstrated through
written records that such information was in UHN 's or Principal Investigator's
possession prior to disclosure from Senesco, and was not the subject of any
earlier confidential relationship with Senesco; or (3) was rightfully acquired
by UHN or Principal Investigator from a third party who was lawfully in
possession of such information and was under no obligation to Senesco to
maintain its confidentiality.
7.5 UHN and Principal Investigator each agree to use Confidential Information
only
-4-
for the uses as agreed upon in this Agreement and only in connection with the
Research Plan or for other uses mutually agreeable to the parties.
7.6 Prior to the commencement of work under this Agreement, each UHN employee
to undertake work hereunder shall agree to be bound by the Confidentiality and
noncompete provisions of this Agreement by signing a copy of the form
Acknowledgement attached as Schedule C.
7.7 Senesco, recognizes that UHN, may be desirous of publishing information as
part of UHN's policy and function as a university to disseminate information for
the purpose of scholarship. UHN and Principal Investigator recognize that such
publication may jeopardize the protection of intellectual property rights
contemplated under this Agreement. Senesco agrees that UHN personnel shall be
permitted to present at symposia, national or regional professional meetings,
and to publish in journals, theses or dissertations, or otherwise of their own
choosing, methods and results of the Research Plan, PROVIDED that Senesco shall
have been provided copies of any proposed publication or presentation at least
sixty (60) days in advance of the submission of such proposed publication or
presentation to allow Senesco to file patent application(s) or seek other
protection for its proprietary subject matter contained in the proposed
presentation or publication. Senesco retains the right to postpone publication
for an additional thirty (30) days should meaningful protection not be obtained
in a timely manner, but will not unreasonably withhold the right to publish or
present. Under no circumstances will UHN or Principal Investigator be allowed to
disclose Confidential Information without providing Senesco prior written notice
as set forth under the procedure herein. The Principal Investigator will be
allowed to retain a copy of all data for the purposes of presentation and
publication only.
VIII. PATENT RIGHTS.
8.1 UHN and Principal Investigator hereby assign and agree to assign to Senesco
all right, title and interest to any Inventions and Research Information made,
conceived of or arising under this Agreement within the scope of the Research
Plan related to eIF5A and/or DHS. In consideration of the assignment granted
herein, Senesco agrees to pay UHN a royalty of 2% of Net Sales in the Field,
which include, in whole or in part, the Inventions and/or is manufactured using
the Inventions. Payments to UHN will be made quarterly (every 3 months).
8.2 Senesco has the sole discretion for the selection of the means for
intellectual property protection for the Inventions and Research Information
related to eIF5A and/or DHS, whether to maintain trade secret protection or seek
protection by patent. Senesco has the sole discretion for the selection of the
technology to protect by patent and will make all decisions regarding the scope
of protection sought.
8.3 Senesco has the sole discretion to select patent counsel or other legal
representatives to help secure patent rights to any Inventions and Research
Information related to eIF5A and/or DHS arising out of this Agreement.
-5-
8.4 If Senesco decides that a patent application is to be filed related to
eIF5A and/or DHS, Senesco, shall, at its own cost, prepare, file and prosecute
such application. Designation of inventors in a patent application is a matter
of patent law and shall be solely within the discretion of qualified patent
counsel or other legal representative for Senesco.
8.5 UHN and Principal Investigator shall, at the request and expense of
Senesco, at any time during or after the termination of this Agreement, execute
all documents and perform all such acts as Senesco may deem necessary or
advisable to confirm Senesco's sole and exclusive ownership right, title and
interest in such Inventions and Research Information related to eIF5A and/or DHS
in any country. UHN and Principal Investigator each agree to do all acts and
execute all documents at the expense and request of Senesco, that Senesco may
deem necessary to enforce its rights to the Inventions and Research Information,
including but not limited to assisting in the preparation of patent
applications, assisting in litigation, appearing for depositions and appearing
as trial witnesses.
IX. PUBLICITY.
9.1 UHN and Principal Investigator shall not disclose this Agreement with
Senesco in any publicity, advertising or news release without the prior written
approval of an authorized representative of Senesco. Senesco will not use the
name of UHN or the Principal Investigator in any publicity, advertising or news
release without the prior written approval of UHN.
9.2 Senesco may, at its own discretion, provide information relating to or
arising from this Agreement to investors, licensees, relevant government
agencies and other such parties.
X. NOTIFICATION OF COMPETING PROJECTS
10.1 Notwithstanding any provisions of this Agreement to the contrary, the
parties agree that UHN independently works on many projects which may be similar
in some respects to the subject matter set forth in the Research Plan. The
parties agree that UHN shall not be precluded from pursuing such projects
through its own personnel; EXCEPT:
(a) Principal Investigator agrees not to conduct any research, act as a
consultant or perform any other services, either directly or indirectly, for any
entity in the world which is competitive with Senesco relating to the subject
matter of the Research Plan related to eIF5A and/or DHS during the term of this
Agreement and for a period of two (2) years after the termination of this
Agreement; and
(b) Each person working on this project agrees to first notify Senesco
prior to accepting employment or undertaking services for any entity in the
world which is
-6-
competitive with Senesco relating to the subject matter provided in the Research
Plan related to eIF5A and/or DHS. In view of the confidentiality obligations
herein, each person working on this project agrees not to personally conduct any
research, act as a consultant, or perform any other services relating to the
subject matter provided in the Research Plan related to eIF5A and/or DHS, either
directly or indirectly for any entity for a period of two (2) years after
termination of this Agreement.
10.2 The parties agree that the period of time and scope of the restrictions
specified herein are both reasonable and justifiable to prevent harm to the
legitimate business interests of Senesco, including but not limited to
preventing transfer of Confidential Information to Senesco's competitors and/or
preventing other unauthorized disclosures or use of Senesco's Inventions and
Research Information.
XI. ASSIGNMENT.
11.1 No right or obligation under this Agreement shall be assigned by UHN
without the prior written permission of Senesco. Senesco has the right to assign
its rights and obligations; however, it must also seek consent of UHN, such
consent not to be unreasonably withheld. UHN shall not subcontract any work to
be performed without Senesco's prior written consent. Any work by any
subcontractor shall be under the direct supervision of Principal Investigator.
XII. SUPPLIES AND EQUIPMENT.
12.1 UHN shall provide laboratory space, personnel and equipment already owned
by UHN for conducting the research contemplated by the Agreement. UHN shall
retain title to any equipment purchased with funds provided by Senesco under an
approved Budget under this Agreement.
XIII. TERMINATION.
13.1 Senesco has the right to terminate this Agreement upon thirty (30) days
advance written notice to UHN. In the event of such a termination, UHN shall
refund all unexpended and unobligated funds to Senesco after withholding amounts
necessary to discharge obligations that cannot be canceled. UHN agrees to
provide Senesco with copies of all work products which exist at the time of
termination.
13.2 Senesco's rights under Articles VI, VIII, IX, and X shall survive
termination of this Agreement.
13.3 In the event Senesco wishes to abandon its interest in the Inventions and
Research Information, UHN and Senesco will enter into good faith negotiations
for UHN
-7-
to acquire said Inventions and Research Information.
13.4 If Senesco fails to meet any of its obligations under this Agreement and
does not remedy these failures within 30 days after receipt of written notice of
such failures from UHN, or at any time Senesco fails to carry on business in the
normal course, UHN may terminate this agreement by giving Senesco written notice
therof.
XIV. INDEMNIFICATION.
14.1 UHN shall defend, indemnify and hold Senesco, its officers, employees and
agents harmless from and against any and all liability, loss, expense (including
reasonable attorneys' fees) or claims for injury or damages arising out of the
performance of this Agreement but only in proportion to and to the extent such
liability, loss, expense, attorneys' fees or claims for injury or damages are
caused by or result from the negligent or intentional acts or omissions of UHN,
its officers, agents or employees.
14.2 Senesco shall defend, indemnify and hold Principal Investigator and UHN,
its officers, employees and agents harmless from and against any and all
liability, loss, expense (including reasonable attorneys' fees) or claims for
injury or damages arising out of the performance of this Agreement but only in
proportion to and to the extent such liability, loss, expense, attorneys' fees
or claims for injury or damages are caused by or result from the negligent or
intentional acts or omissions of Senesco, its officers, agents or employees.
XV. GOVERNING LAW.
15.1 This Agreement shall be construed in accordance with and governed by the
laws, statutes, rules, court decisions and customs prevailing in the State of
New Jersey and the United States, except to the extent that the laws of the
Province of Ontario and the Federal Government of Canada shall govern Xxxxxxx'x
Compensation, Employment Standards Act, Ontario Human Rights Code, Environmental
Protection Act, Occupational Health and Safety Act or any other similar statutes
that would take priority.
XVI. INTEGRATION.
16.1 This Agreement states the entire contract between the parties in respect to
the subject matter of the Agreement and supersedes any previous written or oral
representations, statements, negotiations or agreements. This Agreement my be
modified only by written amendment executed by the authorized representatives of
both parties.
XVII. AGREEMENT MODIFICATION.
17.1 Any agreement to change the terms of this Agreement in any way shall be
valid only if the change is made in writing and approved by mutual agreement of
authorized representatives of the parties hereto.
-8-
XVIII. GOVERNING LANGUAGE.
18.1 In the event that a translation of this Agreement is prepared and signed by
the parties, this English language Agreement shall be the official version and
shall govern if there is a conflict between the translation and this English
language Agreement.
XIX. NOTICES.
19.1 Notices under this Agreement shall be sent by registered mail, return
receipt requested, delivered by hand, or faxed to the following address of
either party unless changed by written notice.
SENESCO: UHN:
Xxxxx Xxxxxx, President and CEO Xxx XxXxxxxx
Senesco, Technologies, Inc. Director, Research Business Development
000 Xxxxxx Xxxxxx, Xxxxx 000 University Health Network
Xxx Xxxxxxxxx, XX 00000 000 Xxxxxxxxxx Xxxxxx
Telephone: (000) 000-0000 Xxxxxxx, Xxxxxxx X0X 0X0
Facsimile: (000) 000-0000 Telephone: (000) 000-0000
Facsimile: (000) 000-0000
IN WITNESS WHEREOF, the parties hereto have caused this Agreement to be executed
by their duly authorized representatives as of the day and year first written
above.
Senesco Technologies, Inc. ("Senesco") University Health Network ("UHN")
/s/ Xxxxx Xxxxxx /s/ Xxxxxxxxxxx Xxxxx
-------------------------------------- ------------------------------------
Xxxxx Xxxxxx Xx. Xxxxxxxxxxx Xxxxx
President and CEO Vice President, of Research
Date: JAN 29, 2004 Date: JAN 27, 2004
--------------------------------- -------------------------------
I have read and understood this Agreement.
/s/ Fei-Xxx Xxx
------------------------------------------
Dr. Fei-Xxx Xxx
-9-
SCHEDULE A
----------
EVALUATION OF POTENTIAL EFFICACY OF 5A1
IN HUMAN NASOPHARYNGEAL CARCINOMA
PRINCIPAL INVESTIGATOR: DR. FEI-XXX XXX
CO-PRINCIPAL INVESTIGATOR: DR. XXXX XXXXXXXX
XX. XXXXX XXXXXX
XX. XXXXX XXXXX
INTRODUCTION
Protein synthesis is a critical cellular event. It takes place on the
ribosomal particles in the cytoplasm, and comprises of three phases: initiation,
elongation, and termination.
The initiation phase appears to be the most highly regulated of these three
phases, through the involvement of several initiation factors (IF) (eg. IF-1,
IF-2, IF-3). Initiator tRNA binds to and forms ternary complexes with these IF's
and GTP, along with binding to 43S preinitiation complex, resulting in changing
the intra-molecular secondary structures within the mRNA, thereby allowing GPT
hydrolysis to energize the commencement of elongation. Factor 5A appears to be
involved in accelerating hydrolysis of GPT. These factors may also function as
nucleo-cytoplasmic shuttle proteins, and facilitate translation of specific
mRNA's through a translocation process.
There are two isoforms of 5A: 5A1, and 5A2. Over-expression of 5A1 induces
apoptosis; 5A2 appears to be more involved in cell cycle arrest or
differentiation. Preliminary evidence indicates that transfection of 5A1 induces
apoptosis in cancer cells, perhaps by promoting the translation of apoptotic
mRNA's. Antisense 5A1 on the other hand, prevented the induction of apoptosis.
5A1 appears to be highly toxic, since the generation of an adenoviral (adv)
vector mediating 5A1 expression driven by the non-selective CMV promoter was not
possible, presumably due to cytotoxicity of the packaging 293 cells. Hence, its
expression needs to be regulated and restricted. We hereby propose to evaluate
whether a transcriptional regulatory strategy will result in the successful
generation of an adv-mediated 5A1 vector. Specifically, we will utilize our
EBV-responsive promoter elements, denoted as oriP, and attempt to generate
adv.oriP.5A1. Subsequently, adv.oriP.5A1 will be evaluated for efficacy in the
EBV-positive nasopharyngeal carcinoma (NPC) xenograft system.
HYPOTHESIS: Introduction of 5A1 through an adv vector under oriP regulation
(adv.oriP.5A1) into NPC cancer cells will induce apoptosis, prevent tumour
formation, and cause regression of established xenograft tumours.
SPECIFIC AIMS
1. To determine whether a novel adv vector mediating 5A1 (adv.oriP.5A1) can be
constructed.
2. To determine if infection of adv.oriP.5A1 will decrease clonogenic survival
of C666-1 cells, with induction of apoptosis, activation of caspase (3, 8,
or 9) activity, and cleavage of DNA. The kinetics of 5A1 expression will be
determined using Western blotting, and its effect on cell proliferation
will be examined. The additional efficacy when combined with ionizing
radiation (RT) will be examined for either an additive or a synergistic
interaction. Potential
Evaluation of potential efficacy of 5A1 In human nasopharyngeal carcinoma 1 of 3
SCHEDULE A
----------
therapeutic gain will be evaluated by simultaneous infection of "normal"
nasopharyngeal fibroblast (KS1), and EBV-negative CNE-2Z cells.
3. To determine if adv.oriP.5A1 will prevent formation of C666-1 tumours.
C666-1 cells will be infected ex vivo with adv.oriP.5A1, then 24 hours
later implanted into the gastrocnemius muscle of SCID mice, and followed
for tumour growth.
4. To determine if adv.oriP.5A1 therapy can cause regression of established
nasopharyngeal tumours. Established C666-1 tumours will be treated with
intra-tumoural (IT) adv.oriP.5A1 +/- local tumour RT, and assessed for
tumour growth delay. Histologic sections will be removed at various time
points after treatment, for examination of expression of 5A1 (using
immunohistochemistry), apoptosis, and necrosis.
5. Safety and toxicity evaluation will be conducted by serial blood samplings
for liver, renal, bone marrow function after intravenous (IV) injection of
adv.oriP.5A1. Normal critical organs (liver, lung, kidney, spleen, brain)
will also be removed for histologic examination.
EXPERIMENTAL PROTOCOLS
1. The 5A1 cDNA will be cloned downstream of the oriP promoter elements, and
placed into the novel oriP.5A1 shuttle plasmid. This will then be ligated
with the remainder of the AEl adv genome, to generate the novel
adv.oriP.5A1. Diagnostic digests will be performed to confirm validity of
plasmid sequences. The vector will be directly sequenced to confirm
presence of the expected promoter and 5A1 sequences. Western blotting will
be conducted after infection of the EBV-positive C666-1 cells to confirm
presence of the expected protein.
2. Clonogenic survival experiments will be conducted using C666-1 cells after
infection with adv.oriP.5A1 (0-50 pfu/cell). RT (0-10 Gy) will also be
delivered in conjunction with a preselected dose of adv.5A1 which will
result in 10% cytotoxicity, to determine whether interactive effects can be
observed.
Cell lysates will be obtained at set times after infection to obtain a
Western for 5A1 expression to assess the kinetics of 5A1 protein
expression, along with determination of a dose-dependent relationship.
Cell cycling effect of adv.5A1 will be determined using flow cytometry
(dual BrDU-PI labelling of DNA), with subsequent analysis of the proportion
of cells in the various phases of the cell cycle, post-treatment.
Each experiment will be conducted at least three separate times, to obtain
a mean and standard error for each study.
3. Tumour formation experiments will be conducted by infecting C666-1 (1 x
106) cells ex vivo using a dose of adv.oriP.5A1 which will cause
99%-cytotoxicity in vitro. One day after infection, the infected cells will
be implanted into the gastrocnemius muscle of SClD mice, and tumour and leg
diameter will be monitored on a regular basis. Control arms will comprise
of PBS-treated, and same dose of an empty adv vector. For each experiment,
each arm will comprise of at least 5 mice, and each study has to be
conducted at least three times.
Evaluation of potential efficacy of 5A1 In human nasopharyngeal carcinoma 2 of 3
SCHEDULE A
----------
4. Therapeutic experiments will be performed by treating established C666-1
tumours in SCID mice. At a set point (eg tumour + leg diameter of 9 mm),
these tumours will be treated using a series of IT injections of
adv.oriP.5A1 (1 x 108 pfu/injection). One possible regimen could be daily
injections x 6 consecutive days. Tumour RT (2 or 4 Gy each) will be
delivered twice during this 6-day schedule. There will be 5 arms for each
tumour model: PBS only, empty adv.oriP IT (same dose), adv.oriP.5A1 alone,
RT alone, and adv.oriP.5A1 + RT.
Each mouse will be monitored for tumour growth, weight, and general
appearance. Each arm will comprise of at least 5 mice, and each study needs
to be performed at least 3 times.
Additional tumour-bearing and treated mice will also have their tumour and
normal organs removed for histologic evaluation of 5A1 expression, (by
either Western or IHC), and H & E for apoptosis or necrosis.
5. Safety and toxicity profile can be grossly determined based on appearance
and weight of treated (IT injection) mice. Blood analyses will be conducted
after IV injection (tail vein or IP) of adv.oriP.5A1, and then mice will be
sacrificed for LFT's (alk phos, SGOT, SGPT, bilirubin, amylase), marrow
(CBC), kidney (creat, BUN) at 48 hrs, and 14 days post-treatment. Normal
organs will also be removed for histologic examination using hematoxylin &
eosin.
CONCLUSION
Upon the completion of this series of studies, we will be able to determine
if the novel adv.oriP.5A1 can be generated. Subsequently, we will be able to
assess if 5A1 has any efficacy against C666-1 cells in vitro, and effect in
vivo, of either prevention of tumour formation, or cause regression of
established tumours. We also be able to assess the type of interaction of
adv.oriP.5A1 with RT (either additive, synergistic, or even sub-additive).
Finally, the safety profile of adv.oriP.5A1 will also be determined, when
administered IT or IV.
Dec 1st, 2002
Evaluation of potential efficacy of 5A1 In human nasopharyngeal carcinoma 3 of 3
SCHEDULE B1
-----------
EVALUATION OF POTENTIAL EFFICACY OF 5A1
IN HUMAN NASOPHARYNGEAL CARCINOMA
BUDGET JUSTIFICATION; PI: LIU
-----------------------------
(I) GENERATION OF NOVEL ADV.ORIP.5A1:
--------------------------------------
l. Xx. Xxxx-Xxx Xx (Level 2 Research Technician) will be devoting 3 months
(January-March 2003) full-time, in attempting to generate the adv.oriP.5A1
vector. His current salary is $52,231, with 21% benefit this would equal
$62,300. Three months' salary would hence translate to $15,800.
2. Supply costs will include media, sera, extensive tissue culture expenses.
In addition, we will need specialised reagents and restriction enzymes for
sub-cloning strategy the novel adenovirus. Primers will be required to
confirm the sequencing, along with additional methods (Westerns) to verify
the generation of the appropriate protein of interest. Hence, the cost of
generating the novel vector will be approximately $22.8K.
PERMANENT EQUIPMENT
-------------------
Due to the extensive demands on our incubator space (required for adenoviral
propagation in 293 cells), we will require the addition of a new incubator
($11,939 (quotation attached)). No additional permanent equipment costs would be
required.
Therefore, to generate the novel adenoviral vector, the total cost would be
$34,739.
(II) SUPPLIES AND EXPENSES FOR NASOPHARYNGEAL EXPERIMENTS:
----------------------------------------------------------
a) Media, sera, plastic culture plates are needed to propagate several cell
lines: 293, C666-1, CNE-2Z, KS1, HeLa and other cells as needed.
b) Specialized reagents, kits and disposables will be needed for Western
blotting, preparation of large-scale plasmid and recombinant adenoviral
stocks, adenoviral plaque assays, cell viability (e.g. MTT) assays. Kodak
films and transfer membranes will be needed for Western blotting.
c) Antibodies and kits for caspase activities, other apoptosis markers e.g.
AO-EB; in addition to propidium iodide staining for cell cycle analyses,
will be required.
d) Our flow cytometry facility charges $30/hr, and we would estimate 30 hrs
per year.
e) SCID mice are provided at a cost of $45 per animal and will be utilized as
host animals for our xenograft experiments. The tumour formation
experiments will have 3 arms (PBS, adv.oriP, adv.oriP.5A1); each arm will
have 9 mice, total # will be 27, and each experiment needs to be conducted
three times, translating into 81 mice. The therapeutic experiments will
have 6 arms (PBS, adv.oriP, adv.oriP.5A1, RT, RT + adv.oriP, and RT +
adv.oriP.5A1); each arm will have 9 mice; total will be 162 mice (6x9x3).
We will have an additional 50 mice for inadvertent death or no tumour
formation, plus additional mice for histology and safety/toxicity
evaluations. Hence, total # of required mice will be 293 (81 + 162 + 50).
The grand total # of mice required will therefore be 293 @$45/mouse =
$13,185. There is also housing cost of
1
SCHEDULE B1
-----------
$0.60 cents per cage per day charged by the OCI/PMH animal colony (5
animals per cage); we will follow each animal to a minimum of 100 days,
hence this will total $3516. Therefore, the total animal cost will be
$16,701 ($13,185+ $3516). This will take place over 2 years, translating
into $8,351 per year.
f) Toxicity profiling for liver, kidney and bone marrow functions is out
sourced (VitaTech), and this would cost approximately $3K.
Immunohistochemical analyses will be required to determine apoptosis in
vivo, along with expression of 5A1. Our histology department charges
approximately $10/slide.
g) Our Division of Experimental Therapeutics at OCI/PMH has common equipment
with the access to centrifuges, balances, spectrophotometers,
phosphoimagers, etc.; the use of which is contained within a yearly fee of
approximately $1000. Furthermore, central glass washing and research
computing services at OCI/PMH amounts to $3000 per year. Cell storage in
liquid nitrogen costs $1000 per year. Total of these thereby equals
$5000/yr.
h) Our biostatistical dept charges approximately $100/hr; there may be
approximately 10 hrs of statistical analyses/year required.
i) We plan to produce 1 paper at the end of the 2nd year; coloured
photomicrographs are very expensive, so that 1 paper would cost $2K.
(II) SALARIES
1. Xx. Xxxx-Xxx Xx (Level 2 Research Technician) will be working 50% full-time
on this project for the in vitro component. His current salary is $52,231,
with 21% benefit equals $62,300, which translates into $31,600/annum.
2. Xx. Xxxxx Xxx is another Level 2 Research Technician, and her current
salary is $43,000, plus 21% benefit, would equal $52,030. She will devote
50% full-time to the in vivo, safety experiments, along with
immunohistochemical analyses of xenograft studies. This would translate
into $26,015/annum. Both individual's salary levels will increase by
10%/annum.
Jan 8th, 2004
Schedule B2
PROPOSED 5A1 RESEARCH BUDGET
Yr1 Yr2
SUPPLIES
PERMANENT EQUIPMENT
Incubator $11,939
SUB-TOTAL $11,939
(I) ADV GENERATION
media, sera, tissue culture expenses $3,000
specialized reagents + films $2,000
primers, enzymes, antibodies $2,000
salary cost (25% of Xx. Xx'x salary) $15,800
SUB-TOTAL $22,800
(II) REMAINDER OF PROJECT SUPLIES
media, sera $7,000 $7,000
specialized reagents + films $5,000 $5,000
caspase antibodies, apoptosis markers $4,000 $4,000
flow cytometry $1,000 $1,000
animal costs $8,351 $8,351
safety testing, immuno $6,000 $6,000
common equipment charges $5,000 $5,000
statistical cost $1,000 $1,000
publication $2,000
SUB-TOTAL $37,351 $39,351
SALARIES
Xx. Xx 50% FTE $31,600 $34,760
post-doc (Xx. Xxx) 50% FTE $26,015 $28,617
SUB-TOTAL $57,615 $63,377
TOTAL $129,705 $102,728
--------------------------------------------------------------------------------
30% OVERHEAD $168,617 $133,546
================================================================================
SCHEDULE C
ACKNOWLEDGEMENT OF EMPLOYEES AND RESEARCHERS
In consideration of the substantial benefits that I have or will continue to
receive as a condition to being able to participate in the project described in
the Research Agreement executed between Senesco Technologies, Inc. ("Senesco")
and UHN, and Dr. Fei-Xxx Xxx effective as of January 30, 2004, I hereby agree to
be bound to the confidentiality and non-disclosure provisions set forth below:
CONFIDENTIALITY
7.1 All terms of this Agreement, all Inventions, Invention disclosure
reports, Research Information and Research Information reports as well as
all information exchanged between the parties pursuant to the Research
Plan, including all technical information, ideas, data, compounds,
molecules, cell lines, techniques, methods, processes, uses, composites,
skills, trade secrets, and business and marketing information, shall be
considered Confidential Information.
7.2 Senesco possesses all right, title and interest to all Confidential
Information, whether disclosed by Senesco or developed under this
Agreement.
7.3 Except as provided herein, UHN and Principal Investigator will not
disclose or make available Confidential Information to third parties
without Senesco's written consent during the term of this Agreement and for
a period of five years thereafter.
7.4 UHN's and Principal Investigator's obligations of confidentiality
under this Section do not apply to any information which (a) is established
by written records to be in the public domain other than as a consequence
of an act of UHN or Principal Investigator; (b) was in UHN's or Principal
Investigator's possession prior to the disclosure by Senesco and is
demonstrated through written records that such information was in UHN's or
Principal Investigator's possession prior to disclosure from Senesco, and
was not the subject of any earlier confidential relationship with Senesco;
or (3) was rightfully acquired by UHN or Principal Investigator from a
third party who was lawfully in possession of such information and was
under no obligation to Senesco to maintain its confidentiality.
7.5 UHN and Principal Investigator each agree to use Confidential
Information only for the uses as agreed upon in this Agreement and only in
connection with the Research Plan or for other uses mutually agreeable to
the parties.
7.6 Prior to the commencement of work under this Agreement, each UHN
employee to undertake work hereunder shall agree to be bound by the
Confidentiality and non-compete provisions of this Agreement by signing a
copy of the form Acknowledgement attached as Schedule C.
7.7 Senesco, recognizes that UHN, may be desirous of publishing
information as part of UHN's policy and function as a university to
disseminate information for the purpose of scholarship. UHN and Principal
Investigator recognize that such publication may jeopardize the protection
of intellectual property rights contemplated under this Agreement. Senesco
agrees that UHN personnel shall be permitted to present at symposia,
national or regional professional meetings, and to publish in journals,
theses or dissertations, or otherwise of their own choosing, methods and
results of the Research Plan, PROVIDED that Senesco shall have been
provided copies of any proposed publication or presentation at least sixty
(60) days in advance of the submission of such proposed publication or
presentation to allow Senesco to file patent application(s) or seek other
protection for its proprietary subject matter contained in the proposed
presentation or publication. Senesco retains the right to postpone
publication for an additional thirty (30) days should meaningful protection
not be obtained in a timely manner, but will not unreasonably withhold the
right to publish or present. Under no circumstances will UHN or Principal
Investigator be allowed to disclose Confidential Information without
providing Senesco prior written notice. The Principal Investigator will be
allowed to retain a copy of all data for the purposes of presentation and
publication only.
X. NOTIFICATION OF COMPETING PROJECTS
10.1 Notwithstanding any provisions of this Agreement to the contrary,
the parties agree that UHN independently works on many projects which may
be similar in some respects to the subject matter set forth in the Research
Plan. The parties agree that UHN shall not be precluded from pursuing such
projects through its own personnel; however, each person working on this
project agrees to first notify Senesco prior to accepting employment or
undertaking services for any entity in the world which is competitive with
Senesco relating to the subject matter provided in the Research Plan
related to eIF5A and/or DHS.
I Acknowledge and agree that any inventions or rights which may be
protectable under intellectual property law developed, created, or
conceived of by me (either in whole or in part) relating to eIF5A and/or
DHS, shall be owned solely by Senesco, and I hereby agree to take any
actions requested by Senesco in order to more fully vest title in the same
in Senesco as required by such Agreement.
/s/ Xxxxx Xxx
------------------------------
Xx. Xxxxx Xxx
January 17, 2004
------------------------------
Date
SCHEDULE C
ACKNOWLEDGEMENT OF EMPLOYEES AND RESEARCHERS
In consideration of the substantial benefits that I have or will continue to
receive as a condition to being able to participate in the project described in
the Research Agreement executed between Senesco Technologies, Inc. ("Senesco")
and UHN, and Dr. Fei-Xxx Xxx effective as of January 30, 2004, I hereby agree to
be bound to the confidentiality and non-disclosure provisions set forth below:
CONFIDENTIALITY
7.1 All terms of this Agreement, all Inventions, Invention disclosure
reports, Research Information and Research Information reports as well as
all information exchanged between the parties pursuant to the Research
Plan, including all technical information, ideas, data, compounds,
molecules, cell lines, techniques, methods, processes, uses, composites,
skills, trade secrets, and business and marketing information, shall be
considered Confidential Information.
7.2 Senesco possesses all right, title and interest to all Confidential
Information, whether disclosed by Senesco or developed under this
Agreement:
7.3 Except as provided herein, UHN and Principal Investigator will not
disclose or make available Confidential Information to third parties
without Senesco's written consent during the term of this Agreement and for
a period of five years thereafter.
7.4 UHN's and Principal Investigator's obligations of confidentiality
under this Section do not apply to any information which (a) is established
by written records to be in the public domain other than as a consequence
of an act of UHN or Principal Investigator; (b) was in UHN's or Principal
Investigator's possession prior to the disclosure by Senesco and is
demonstrated through written records that such information was in UHN's or
Principal Investigator's possession prior to disclosure from Senesco, and
was not the subject of any earlier confidential relationship with Senesco;
or (3) was rightfully acquired by UHN or Principal Investigator from a
third party who was lawfully in possession of such information and was
under no obligation to Senesco to maintain its confidentiality.
7.5 UHN and Principal Investigator each agree to use Confidential
Information only for the uses as agreed upon in this Agreement and only in
connection with the Research Plan or for other uses mutually agreeable to
the parties.
7.6 Prior to the commencement of work under this Agreement, each UHN
employee to undertake work hereunder shall agree to be bound by the
Confidentiality and non-compete provisions of this Agreement by signing a
copy of the form Acknowledgement attached as Schedule C.
7.7 Senesco, recognizes that UHN, may be desirous of publishing
information as part of UHN's policy and function as a university to
disseminate information for the purpose of scholarship. UHN and Principal
Investigator recognize that such publication may jeopardize the protection
of intellectual property rights contemplated under this Agreement. Senesco
agrees that UHN personnel shall be permitted to present at symposia,
national or regional professional meetings, and to publish in journals,
theses or dissertations, or otherwise of their own choosing, methods and
results of the Research Plan, PROVIDED that Senesco shall have been
provided copies of any proposed publication or presentation at least sixty
(60) days in advance of the submission of such proposed publication or
presentation to allow Senesco to file patent application(s) or seek other
protection for its proprietary subject matter contained in the proposed
presentation or publication. Senesco retains the right to postpone
publication for an additional thirty (30) days should meaningful protection
not be obtained in a timely manner, but will not unreasonably withhold the
right to publish or present. Under no circumstances will UHN or Principal
Investigator be allowed to disclose Confidential Information without
providing Senesco prior written notice. The Principal Investigator will be
allowed to retain a copy of all data for the purposes of presentation and
publication only.
X. NOTIFICATION OF COMPETING PROJECTS
10.1 Notwithstanding any provisions of this Agreement to the contrary,
the parties agree that UHN independently works on many projects which may
be similar in some respects to the subject matter set forth in the Research
Plan. The parties agree that UHN shall not be precluded from pursuing such
projects through its own personnel; however, each person working on this
project agrees to first notify Senesco prior to accepting employment or
undertaking services for any entity in the world which is competitive with
Senesco relating to the subject matter provided in the Research Plan
related to eIF5A and/or DHS.
I Acknowledge and agree that any inventions or rights which may be
protectable under intellectual property law developed, created, or
conceived of by me (either in whole or in part) relating to eIF5A and/or
DHS, shall be owned solely by Senesco, and I hereby agree to take any
actions requested by Senesco in order to more fully vest title in the same
in Senesco as required by such Agreement.
/s/ Xxxx-Xxx Xx
----------------------------------
Xx. Xxxx-Xxx Xx
January 16, 2004
----------------------------------
Date
SCHEDULE C
ACKNOWLEDGEMENT OF EMPLOYEES AND RESEARCHERS
In consideration of the substantial benefits that I have or will continue to
receive as a condition to being able to participate in the project described in
the Research Agreement executed between Senesco Technologies, Inc. ("Senesco")
and UHN, and Dr. Fei-Xxx Xxx effective as of January 30, 2004, I hereby agree to
be bound to the confidentiality and non-disclosure provisions set forth below:
CONFIDENTIALITY
7.1 All terms of this Agreement, all Inventions, Invention disclosure
reports, Research Information and Research Information reports as well as
all information exchanged between the parties pursuant to the Research
Plan, including all technical information, ideas, data, compounds,
molecules, cell lines, techniques, methods, processes, uses, composites,
skills, trade secrets, and business and marketing information, shall be
considered Confidential Information.
7.2 Senesco possesses all right, title and interest to all Confidential
Information, whether disclosed by Senesco or developed under this
Agreement.
7.3 Except as provided herein, UHN and Principal Investigator will not
disclose or make available Confidential Information to third parties
without Senesco's written consent during the term of this Agreement and for
a period of five years thereafter.
7.4 UHN 's and Principal Investigator's obligations of confidentiality
under this Section do not apply to any information which (a) is established
by written records to be in the public domain other than as a consequence
of an act of UHN or Principal Investigator; (b) was in UHN's or Principal
Investigator's possession prior to the disclosure by Senesco and is
demonstrated through written records that such information was in UHN 's or
Principal Investigator's possession prior to disclosure from Senesco, and
was not the subject of any earlier confidential relationship with Senesco;
or (3) was rightfully acquired by UHN or Principal Investigator from a
third party who was lawfully in possession of such information and was
under no obligation to Senesco to maintain its confidentiality.
7.5 UHN and Principal Investigator each agree to use Confidential
Information only for the uses as agreed upon in this Agreement and only in
connection with the Research Plan or for other uses mutually agreeable to
the parties.
7.6 Prior to the commencement of work under this Agreement, each UHN
employee to undertake work hereunder shall agree to be bound by the
Confidentiality and non-compete provisions of this Agreement by signing a
copy of the form Acknowledgement attached as Schedule C.
7.7 Senesco, recognizes that UHN, may be desirous of publishing
information as part of UHN's policy and function as a university to
disseminate information for the purpose of scholarship. UHN and Principal
Investigator recognize that such publication may jeopardize the protection
of intellectual property rights contemplated under this Agreement. Senesco
agrees that UHN personnel shall be permitted to present at symposia,
national or regional professional meetings, and to publish in journals,
theses or dissertations, or otherwise of their own choosing, methods and
results of the Research Plan, PROVIDED that Senesco shall have been
provided copies of any proposed publication or presentation at least sixty
(60) days in advance of the submission of such proposed publication or
presentation to allow Senesco to file patent application(s) or seek other
protection for its proprietary subject matter contained in the proposed
presentation or publication. Senesco retains the right to postpone
publication for an additional thirty (30) days should meaningful protection
not be obtained in a timely manner, but will not unreasonably withhold the
right to publish or present. Under no circumstances will UHN or Principal
Investigator be allowed to disclose Confidential Information without
providing Senesco prior written notice. The Principal Investigator will be
allowed to retain a copy of all data for the purposes of presentation and
publication only.
X. NOTIFICATION OF COMPETING PROJECTS
10.1 Notwithstanding any provisions of this Agreement to the contrary,
the parties agree that UHN independently works on many projects which may
be similar in some respects to the subject matter set forth in the Research
Plan. The parties agree that UHN shall not be precluded from pursuing such
projects through its own personnel; however, each person working on this
project agrees to first notify Senesco prior to accepting employment or
undertaking services for any entity in the world which is competitive with
Senesco relating to the subject matter provided in the Research Plan
related to eIF5A and/or DHS.
I Acknowledge and agree that any inventions or rights which may be
protectable under intellectual property law developed, created, or
conceived of by me (either in whole or in part) relating to eIF5A and/or
DHS, shall be owned solely by Senesco, and I hereby agree to take any
actions requested by Senesco in order to more fully vest title in the same
in Senesco as required by such Agreement.
/s/ Xxxxx Xxxxxx
------------------------------
Xx. Xxxxx Xxxxxx
January 15, 2004
------------------------------
Date
SCHEDULE C
ACKNOWLEDGEMENT OF EMPLOYEES AND RESEARCHERS
In consideration of the substantial benefits that I have or will continue to
receive as a condition to being able to participate in the project described in
the Research Agreement executed between Senesco Technologies, Inc. ("Senesco")
and UHN, and Dr. Fei-Xxx Xxx effective as of January 30, 2004, I hereby agree to
be bound to the confidentiality and non-disclosure provisions set forth below:
CONFIDENTIALITY
7.1 All terms of this Agreement, all Inventions, Invention disclosure
reports, Research Information and Research Information reports as well as
all information exchanged between the parties pursuant to the Research
Plan, including all technical information, ideas, data, compounds,
molecules, cell lines, techniques, methods, processes, uses, composites,
skills, trade secrets, and business and marketing information, shall be
considered Confidential Information.
7.2 Senesco possesses all right, title and interest to all Confidential
Information, whether disclosed by Senesco or developed under this
Agreement.
7.3 Except as provided herein, UHN and Principal Investigator will not
disclose or make available Confidential Information to third parties
without Senesco's written consent during the term of this Agreement and for
a period of five years thereafter.
7.4 UHN's and Principal Investigator's obligations of confidentiality
under this Section do not apply to any information which (a) is established
by written records to be in the public domain other than as a consequence
of an act of UHN or Principal Investigator; (b) was in UHN's or Principal
Investigator's possession prior to the disclosure by Senesco and is
demonstrated through written records that such information was in UHN's or
Principal Investigator's possession prior to disclosure from Senesco, and
was not the subject of any earlier confidential relationship with Senesco;
or (3) was rightfully acquired by UHN or Principal Investigator from a
third party who was lawfully in possession of such information and was
under no obligation to Senesco to maintain its confidentiality.
7.5 UHN and Principal Investigator each agree to use Confidential
Information only for the uses as agreed upon in this Agreement and only in
connection with the Research Plan or for other uses mutually agreeable to
the parties.
7.6 Prior to the commencement of work under this Agreement, each UHN
employee to undertake work hereunder shall agree to be bound by the
Confidentiality and non-compete provisions of this Agreement by signing a
copy of the form Acknowledgement attached as Schedule C.
7.7 Senesco, recognizes that UHN, may be desirous of publishing
information as part of UHN's policy and function as a university to
disseminate information for the purpose of scholarship. UHN and Principal
Investigator recognize that such publication may jeopardize the protection
of intellectual property rights contemplated under this Agreement. Senesco
agrees that UHN personnel shall be permitted to present at symposia,
national or regional professional meetings, and to publish in journals,
theses or dissertations, or otherwise of their own choosing, methods and
results of the Research Plan, PROVIDED that Senesco shall have been
provided copies of any proposed publication or presentation at least sixty
(60) days in advance of the submission of such proposed publication or
presentation to allow Senesco to file patent application(s) or seek other
protection for its proprietary subject matter contained in the proposed
presentation or publication. Senesco retains the right to postpone
publication for an additional thirty (30) days should meaningful protection
not be obtained in a timely manner, but will not unreasonably withhold the
right to publish or present. Under no circumstances will UHN or Principal
Investigator be allowed to disclose Confidential Information without
providing Senesco prior written notice. The Principal Investigator will be
allowed to retain a copy of all data for the purposes of presentation and
publication only.
X. NOTIFICATION OF COMPETING PROJECTS
10.1 Notwithstanding any provisions of this Agreement to the contrary,
the parties agree that UHN independently works on many projects which may
be similar in some respects to the subject matter set forth in the Research
Plan. The parties agree that UHN shall not be precluded from pursuing such
projects through its own personnel; however, each person working on this
project agrees to first notify Senesco prior to accepting employment or
undertaking services for any entity in the world which is competitive with
Senesco relating to the subject matter provided in the Research Plan
related to eIF5A and/or DHS.
I Acknowledge and agree that any inventions or rights which may be
protectable under intellectual property law developed, created, or
conceived of by me (either in whole or in part) relating to eIF5A and/or
DHS, shall be owned solely by Senesco, and I hereby agree to take any
actions requested by Senesco in order to more fully vest title in the same
in Senesco as required by such Agreement.
/s/ Xxxxx Xxxxx
-------------------------------
Xx. Xxxxx Xxxxx
January 16, 2004
-------------------------------
Date
