EXHIBIT 10.8 LICENSE AGREEMENT
AGREEMENT effective on the date of the last signature hereon, by and between
YALE UNIVERSITY, a corporation organized and existing under and by virtue of a
charter granted by the general assembly of the Colony and State of Connecticut
and located in New Haven, Connecticut ("YALE"), and Oncorx, Inc. a corporation
organized and existing under the laws of the State of Delaware, and with
principal offices located in New Haven, Connecticut ("LICENSEE").
W I T N E S S E T H:
WHEREAS, in the course of research conducted under YALE auspices, Xx. Xxxx
Xxxxxxx of the Department of Dermatology, Xx. Xxxxx Xxxxxxxx of the Department
of Internal Medicine and Dr. K Xxxxxx Low of the Department of Therapeutic
Radiology, all of the Yale Medical School (the "INVENTORS"), have produced an
invention entitled "Novel Vectors for Gene Delivery and Therapy" (OCR 722) and
"Specific Vectors in Gene Delivery to HIV+ Cells" (OCR 721) and "Vectors for the
Diagnosis and Treatment of Solid Tumors Including Melanoma," US Patent
Application no. 08/486,422 (the "INVENTION"); and
WHEREAS, pursuant to an assignment by the INVENTORS to YALE of all their right,
title and interest in and to the INVENTION and any patents resulting therefrom,
YALE is the owner of the INVENTION, subject to rights reserved by the U.S.
government; and
WHEREAS, LICENSEE wishes to obtain a license to the INVENTION and any patents
resulting therefrom, and YALE is willing to grant such a license to LICENSEE
subject to the terms and conditions hereof;
NOW, THEREFORE, in consideration of the mutual covenants herein contained the
parties agree as follows:
ARTICLE I DEFINITIONS
As used in this Agreement, the following terms shall be defined as set forth
below:
1.1 The "INVENTION" shall mean the invention described in OCR (721 and 722),
copies of which are attached hereto and is incorporated herein by reference, and
in US Patent Application no. 08/486,422 entitled "Vectors for the Diagnosis and
Treatment of Solid Tumors Including Melanoma."
1.2 "LICENSED PATENTS" shall mean any United States or foreign patent
applications and patent(s) owned, in whole or in part, by YALE during the term
of this Agreement and covering or in respect to the Invention; together with any
continuations, continuations-in-part, divisional or substitute patents, any
reissues or re-examinations of any such applications or patents, and any
extension of any such patents.
1.3 "LICENSED PRODUCTS" shall mean any products which result from the
manufacture, production or use of a claim of the LICENSED PATENTS, wherever
sold.
1.4 "NET SALES" shall mean gross sales of the LICENSED PRODUCTS invoiced by
LICENSEE less delivery or shipping costs and less credits or allowances, if any,
on account of rejections or returns of LICENSED PRODUCTS previously sold.
LICENSED PRODUCTS shall be deemed to have been sold when delivered or shipped,
invoiced, or when paid for, whichever is earliest. In the event that
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LICENSEE shall transfer LICENSED PRODUCTS to a company owned or controlled by or
affiliated with LICENSEE and such company retransfers the LICENSED PRODUCTS to a
third party within one year of its receipt, then the price charged by the
affiliated company to third parties, shall be included in LICENSEE's gross
sales. If such affiliated company does not retransfer the LICENSED PRODUCTS
within one year, then the higher of i) the price charged by LICENSEE to such
affiliate company or ii) the average price charged by LICENSEE to third party
customers during such year or, in the absence of sales to third party customers,
the fair market price for the LICENSED PRODUCTS, shall be included in LICENSEE's
gross sales.
1.5 "SUBLICENSE INCOME" shall mean the gross amount received by LICENSEE,
directly or indirectly, for or on account of sublicenses of any of the rights
granted hereunder, without deduction of any kind, except deductions for taxes in
the nature of sales, use or ad valorem and similar taxes, provided however,
Sublicense Income shall not in any case include any amounts received by
LICENSEE, directly or indirectly, as payments for work which has been performed
or which is to be performed by LICENSEE at the specific direction of a
SUBLICENSEE, such payments not being creditable against future royalty payments.
1.6 "EARNED ROYALTIES" shall mean royalties paid or payable by LICENSEE to YALE
determined with respect to NET SALES and SUBLICENSE INCOME.
1.7 "ROYALTY YEAR" shall mean each twelve month period commencing January 1 and
ending December 31 during the term of this Agreement, as defined in Article III,
below. For the first year of this Agreement, the ROYALTY YEAR shall be the
period of time between the signing of the Agreement and December 31.
1.8 "QUARTER YEAR" shall mean the three month periods ending March 31, June 30,
September 30 and December 31 of each Royalty Year.
1.9 "LICENSEE" shall include Oncorx and;
a) an organization of which fifty percent (50%) or more of the voting
stock is controlled or owned directly or indirectly by Oncorx;
b) an organization which directly or indirectly owns or controls fifty
percent (50%) or more of the voting stock of Oncorx;
c) an organization, the majority ownership of which is directly or
indirectly common to the majority ownership of Oncorx.
ARTICLE II GRANT OF LICENSE
2.1 YALE hereby grants to LICENSEE, under the LICENSED PATENTS and other
intellectual property rights of YALE, subject to all the terms and conditions of
this Agreement, a non-transferable worldwide exclusive license for the term
defined by ARTICLE III to make, have made, use, sell and practice the INVENTION,
subject to rights required to be granted to the U.S. Government.
2.2 LICENSEE shall have the right to sublicense the rights granted hereunder to
third parties (but not to affiliates of LICENSEE), provided that any such
sublicense shall provide for payment of SUBLICENSE INCOME by SUBLICENSEE based
on sales by SUBLICENSEE. All sublicenses hereunder granted by LICENSEE shall be
coterminable with this Agreement to the extent YALE's rights in the LICENSED
PATENTS are involved.
2.3 YALE shall retain the right to make, use and practice the Invention for its
own non-commercial purposes.
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ARTICLE III TERM OF LICENSE
The term of the LICENSE granted hereunder shall commence upon the signing hereof
and shall continue for the life of any applicable patents, and any license
granted hereunder shall expire on a country by country basis when the last to
expire patent in such country expires.
ARTICLE IV ROYALTIES
As consideration for the rights granted hereunder, LICENSEE shall make the
following royalty payments to YALE:
4.1 a. LICENSEE shall pay to YALE an initial fixed royalty of One Hundred
Thousand U.S. Dollars ($100,000) eighteen months after the execution of this
Agreement. Such payment shall be separate from and not credited against any
EARNED ROYALTIES.
b. Milestone Payments: For each disease indication (note cancer is
considered a single disease in this instance) for which product approval is
sought from the United States Food and Drug Administration (the "FDA") for a
LICENSED PRODUCT, LICENSEE shall additionally make benchmark payments to YALE as
follows:
1. Two Hundred Fifty Thousand Dollars ($250,000) upon the completion
of phase II clinical trials;
2. Two Hundred Fifty Thousand Dollars ($250,000) upon the filing of
a new drug application (`NDA") or foreign registration filing; and:
3. Five Hundred Thousand Dollars ($500,000) upon the approval by the
FDA of an NDA or foreign registration approval for such LICENSED PRODUCT.
Any payment referred to in paragraphs (1) through (3) shall not become due and
payable, even after the occurrence of the event described in such paragraph,
until at least one valid claim under the LICENSED PATENTS has issued in the
United States with respect to such LICENSED PRODUCT. All payments withheld
pending the issuance of such claim shall be paid promptly upon such issuance.
The payments referred to in (1) and (2) shall be separate from and not credited
against any EARNED ROYALTIES, however, the payment referred to in (3) shall be
credited against royalties due, pursuant to this Agreement.
4.2 In addition, LICENSEE shall pay to YALE EARNED ROYALTIES of NET SALES of
LICENSED PRODUCTS, the selling of which would, in the absence of this Agreement,
infringe a valid claim in the LICENSED PATENTS of seven percent (7%) of NET
SALES; and fifty percent (50%) of SUBLICENSE INCOME.
4.3 EARNED ROYALTIES shall be payable by LICENSEE during the period that any
LICENSED PATENT remains pending or effective in any applicable country. In the
event that a LICENSED PATENT lapses or if all of its claims are finally declared
invalid by a non-appealable decision of a court of competent jurisdiction
through no fault or cause of LICENSEE, the obligation to pay royalties for that
patent shall terminate but this Agreement shall remain in effect as to the
remaining LICENSED PATENTS or claims thereunder.
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4.4 During the term of this Agreement, LICENSEE agrees to pay YALE annual
Minimum Royalty Payments, starting at the time of first product sales, in the
amount of Fifty Thousand Dollars ($50,000) per Royalty Year.
4.5 Notwithstanding anything else in this Agreement in the event that the
manufacture, sale or commercialization of a LICENSED PRODUCT requires LICENSEE'S
obtaining rights to or under any third party patents or patent applications,
then the royalty rates set forth in this Article IV shall be reduced by an
amount equal to the LICENSEEE's payments to any such third party provided that
in no event shall the royalties to be paid under this Article IV be reduced to
less than 50% of what they would have been in the absence of the section 4.5.
ARTICLE V RESEARCH AGREEMENT
5.1 Within ninety (90) days of the signing of this Agreement, LICENSEE agrees to
enter into an Agreement with YALE UNIVERSITY to extend the term of the Extension
Agreement dated July 1, 1992 between Melarx Pharmaceuticals Inc. (now known as
Oncorx Inc.) and YALE UNIVERSITY, for an additional five (5) years, under terms
and conditions substantially the same as in the Extension Agreement.
ARTICLE VI PAYMENTS AND REPORT
6.1 Within thirty (30) days after the end of each QUARTER YEAR, LICENSEE shall
furnish to YALE a written report setting forth the NET SALES and the EARNED
ROYALTIES payable thereon, accompanied by full payment of such EARNED ROYALTIES.
6.2 The reports required by this Article VI shall be certified by an officer of
LICENSEE to be correct to the best of LICENSEE's knowledge and information. Each
report shall be accompanied by LICENSEE's payment of the full amount due, less
any taxes required by a governmental agency to be withheld therefrom; provided,
however, that YALE shall have the right to contest any such taxes and LICENSEE
shall provide reasonable assistance with respect thereto. All royalties shall be
paid to YALE in U.S. dollars, and in full. In the event that conversion from
foreign currency is required in calculating a royalty payment hereunder, the
exchange rate used shall be the rate in effect at the end of the last business
day of the month just prior to the date payment is required to be made hereunder
as published in the Wall Street Journal.
6.3 If this Agreement should be terminated at any time other than at the end of
a QUARTER YEAR or ROYALTY YEAR, the last report and payment shall be made within
sixty (60) days after the effective date of such termination, and shall include
any EARNED ROYALTIES prorated to the date of termination. If the amount of
LICENSEE's or any SUBLICENSEE's existing inventory of LICENSED PRODUCTS which
had been manufactured but not sold up to the date of termination exceeds a
thirty (30) day supply, LICENSEE shall provide YALE with a report setting forth
the amount of such inventory at the date of termination, and may elect to
continue to render QUARTER YEAR reports on the sales of such existing inventory
and to make payments as though the Agreement were still in effect; provided,
however, that in any event, LICENSEE shall complete payment of EARNED ROYALTIES
thereon within one year from the effective date of termination.
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ARTICLE VII BOOKS AND RECORDS
LICENSEE and its sublicensees shall keep and maintain complete and accurate
records and books of account in sufficient detail and form so as to enable
verification of Earned Royalties payable by LICENSEE hereunder. Such records and
books of account shall be maintained for a period of no less than three (3)
years following the HALF YEAR to which they pertain. LICENSEE shall permit such
records and books of account to be examined by YALE or YALE's duly appointed
agent, to the extent necessary for Yale to verify the amount of royalties
payable. Such examination shall be at YALE's expense, during normal business
hours, and upon ten (10) days' prior written notice to LICENSEE.
ARTICLE VIII PATENT PROTECTION
8.1 It is understood as that of the date hereof no patent protection exists in
the United States or any foreign country but only the potential to realize the
same.
8.2 LICENSEE shall be responsible for all costs of prosecution and maintenance
of all U.S. patents and patent applications covering the INVENTION incurred
after the date of this Agreement, including without limitation attorney's fees,
taxes, annuities, working fees, maintenance fees, and renewal and extension
charges, and shall, at YALE's option, either punctually pay such costs directly
or punctually reimburse YALE for such costs. Any and all such U.S. patent
applications and patents resulting therefrom shall remain the property of YALE.
8.3 LICENSEE at LICENSEE's expense, shall prepare and file United States patent
applications and foreign patent applications covering the INVENTION in such
foreign countries as are determined by LICENSEE and agreed to by YALE. Any and
all such foreign patent applications and patents resulting therefrom shall
remain the property of YALE. LICENSEE shall be responsible for all costs of
prosecution and maintenance of all such foreign patents and patent applications,
including without limitation attorney's fees, taxes, annuities, working fees,
maintenance fees, and renewal and extension charges, and shall punctually pay
all such costs directly on behalf of both parties. If LICENSEE does not agree to
bear the expenses of filing patent applications or continuing prosecution in any
foreign countries in which YALE wishes to obtain or maintain patent protection,
then YALE may file and/or prosecute such application at its own expense, and
YALE may terminate LICENSEE's license to the LICENSED PATENTS in such foreign
country or countries.
8.4 All U.S. and foreign patent applications relating to the INVENTION shall be
prepared, prosecuted, filed and maintained by independent patent counsel chosen
and engaged by LICENSEE and approved by YALE. For U.S. patent applications,
LICENSEE shall retain substantive control of and responsibility for direct
prosecution, however no modifications to the original patent applications may be
made without written approval by YALE. For foreign patent applications, LICENSEE
shall have substantive control of and responsibility for direct prosecution. In
any case, YALE and LICENSEE shall instruct patent counsel to keep both YALE and
LICENSEE fully informed of the progress of all U.S. and foreign patent
applications and patents, and to give the party that is not directing
prosecution reasonable opportunity to comment on the type and scope of useful
claims and the nature of supporting disclosure. YALE will not finally abandon
any patent application for which LICENSEE is bearing expenses, nor will it
abandon the patent application referred to on the first page, above, without
LICENSEE's consent. The party directing prosecution shall have no liability to
the other party for damages, whether direct,
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indirect, incidental, consequential or otherwise, allegedly arising from its
good faith decisions, actions and omissions in connection with such prosecution.
8.5 LICENSEE shall apply, and shall require sublicensees to apply, the patent
marking notices required by the law of any country where LICENSED PRODUCTS are
made, sold or used, to the extent feasible and practical, and in accordance with
the applicable patent laws of that country.
ARTICLE IX DUE DILIGENCE IN COMMERCIALIZATION
LICENSEE shall conduct research, development, manufacturing or sublicense
programs, as appropriate, directed toward expeditious commercialization of
technology based on the Invention, and make annual reports to YALE of progress
in these programs. If in YALE's reasonable judgment taking into account the
normal course of such programs conducted with sound and reasonable business
practices, LICENSEE has failed to conduct such programs for any period of six
months after the Effective Date, YALE may request a plan from LICENSEE
indicating its schedule for reinstituting such a program. If LICENSEE fails to
provide a satisfactory plan to YALE within thirty (30) days, YALE shall have the
right to terminate this Agreement. YALE shall have the right to terminate this
Agreement after six (6) years from the Effective Date if LICENSEE has not filed
an IND for a product with the FDA, either directly or through a sublicensee.
ARTICLE X INFRINGEMENT AND LITIGATION
10.1 LICENSEE shall have the sole obligation to defend the LICENSED PATENTS
against infringement or interference by other parties in any country in which a
LICENSED PATENT is in effect hereunder, including by bringing any legal action
for infringement or defending any counterclaim of invalidity or action of a
third party for declaratory judgment of non-infringement or interference.
LICENSEE may settle any such actions solely at its own expense and through
counsel of its selection; provided, however, that YALE shall be entitled in each
instance to participate through counsel of its selection and at its own expense.
YALE shall have no obligation or responsibility with respect to any such actions
unless legally required to participate, except to provide reasonable assistance
to LICENSEE as requested, and LICENSEE shall reimburse YALE for YALE's
out-of-pocket expenses in connection with any such requested assistance LICENSEE
shall bear the expenses of such actions and shall obtain all benefits in the
recoveries, if any, whether by judgment, award, decree or settlement, the excess
of such recoveries over such expenses shall be included in LICENSEE's NET SALES.
In the event LICENSEE fails to initiate and pursue or participate in such legal
action, YALE shall have the right to initiate legal action to uphold the
LICENSED PATENTS against third parties in any country in which a LICENSED PATENT
is in effect. LICENSEE shall have no legal or contractual obligation to YALE for
its failure to initiate or participate in any such legal action, except that
YALE may terminate in such a country any then existing exclusive license granted
to LICENSEE hereunder.
10.2 Each party shall promptly notify the other in writing in the event that a
third party shall bring a claim of infringement against YALE or LICENSEE, either
in the United States or in any foreign country in which there is a LICENSED
PATENT. If the alleged infringement is so substantial as to threaten the
competitive position of LICENSEE and/or LICENSEE is temporarily enjoined from
exercise of its license hereunder, and if YALE elects not to defend against such
claim and not to obtain a license to permit LICENSEE to exercise its license
free of such claim, then LICENSEE may in its own name and
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at its sole expense defend such claim and may compromise, settle or otherwise
pursue such defense in such a manner and on such terms as LICENSEE shall see
fit. YALE, at its own expense and through counsel of its selection may become a
party to such defense and/or settlement and compromise. In any event, YALE shall
have the right to defend, at its own expense, any such third party claim or
action and to settle or compromise the same in such manner as its shall see fit.
LICENSEE may participate in such litigation or claim on its behalf at its own
expense.
10.3 In the event LICENSEE is permanently enjoined from exercising its license
rights granted hereunder pursuant to an infringement action brought by a third
party, or if both LICENSEE and YALE elect not to undertake the defense or
settlement of such a claim of alleged infringement for a period of six months
from notice of such claim or suit, then LICENSEE shall have the right to
terminate this Agreement with respect to the infringing patent claims following
thirty (30) days' written notice to YALE and in accordance with the terms of
Article XII hereof.
ARTICLE XI USE OF YALE'S NAME
LICENSEE shall not use the name "Yale" or "Yale University" for any purpose
without prior written consent obtained from YALE in each instance.
ARTICLE XII TERMINATION
12.1 YALE may terminate this Agreement following thirty (30) days written notice
to LICENSEE in the event LICENSEE:
(i) fails to make, within the sixty (60) day period set by the notice, any
payment which is due and payable pursuant to this Agreement and the Research
Agreement (Article V), and has been in arrears for more than one (1) month; or
(ii) commits a material breach of any other obligation of this Agreement
which is not cured (if capable of being cured) within the thirty (30) day period
set by the notice; or
(iii) becomes insolvent or a petition in bankruptcy is filed against
LICENSEE and is consented to, acquiesced in or remains undismissed for ninety
(90) days; or makes a general assignment for the benefit of creditors, or a
receiver is appointed for LICENSEE, and LICENSEE does not return to solvency
before the expiration of said thirty (30) day period set by the notice; or
(iv) fails to exercise due diligence in bringing the LICENSED PRODUCTS to
market in accordance with Article IX; or
(v) fails to enter into a Research Agreement as specified in Article V.
12.2 LICENSEE shall be entitled to terminate this Agreement upon thirty (30)
days advance written notice to YALE, in the event of YALE's material breach of
any of the provisions of this Agreement, which breach is not cured (if capable
of being cured) within the thirty (30) day period set by the notice, or if the
conditions of Section 10.3 apply.
12.3 Upon termination of this Agreement and except as otherwise expressly
provided herein, all licenses granted to LICENSEE under the terms of this
Agreement and, at YALE's option, any sublicenses granted by LICENSEE, shall
terminate and LICENSEE must return to YALE all materials containing the
INVENTION; provided, however, that LICENSEE and its SUBLICENSEES shall have the
right for one year thereafter to dispose of all LICENSED PRODUCTS then in its
inventory, and shall
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pay EARNED ROYALTIES thereon, in accordance with the provisions of Article IV,
as though this Agreement had not terminated.
12.4 Termination of this Agreement shall not affect any rights or obligations
accrued prior to the effective date of such termination and specifically
LICENSEE's obligation to pay all EARNED ROYALTIES specified by Article IV.
12.5 The rights provided in this Article XII shall be in addition and without
prejudice to any other rights which the parties may have with respect to any
breach or violations of the provisions of this Agreement.
12.6 Waiver by either party of a single default or breach or of a succession of
defaults or breaches shall not deprive such party of any right to terminate this
Agreement pursuant to the terms hereof upon the occasion of any subsequent
default or breach.
ARTICLE XIII NO WARRANTIES; INDEMNIFICATION; INSURANCE
13.1 Yale makes no representations or warranties that any LICENSED PATENT is
valid, or that the manufacture, use, sale or other disposal of the LICENSED
PRODUCTS does not infringe upon any patent or other rights not vested in YALE.
13.2 YALE DISCLAIMS ALL WARRANTIES WHATSOEVER, WITH RESPECT TO THE LICENSED
PATENTS, THE INVENTION, AND THE LICENSED PRODUCTS, EITHER EXPRESS OR IMPLIED,
INCLUDING WARRANTIES AS TO THE MERCHANTABILITY OR FITNESS OF THE LICENSED
PRODUCTS FOR A PARTICULAR PURPOSE and LICENSEE shall make no statements,
representations or warranties whatsoever to any third parties which are
inconsistent with such disclaimer by YALE.
13.3 With the exception of infringement claims or actions covered by ARTICLE X,
LICENSEE shall defend, indemnify and hold harmless YALE, its fellows, officers,
employees, and agents, from and against any and all claims, demands, damages,
losses and expenses of any nature (including attorney's fees), including, but
not limited to death, personal injury, illness, property damage or products
liability arising from or in connection with any of the following:
(i) the use by LICENSEE of any method or process related to the LICENSED
PATENTS; or
(ii) any use, sale or other disposition on any of the LICENSED PRODUCTS by
LICENSEE and/or other transferees or any statement, representation or warranty
of LICENSEE or other transferees with respect thereto; or
(iii) the use of the LICENSED PRODUCTS by any person.
YALE shall reasonably cooperate with LICENSEE in defending any such claim. YALE
shall be entitled to receive information regarding the status of any such matter
and shall be entitled to retain counsel on its own behalf and at its sole
expense, in addition to counsel retained by LICENSEE to defend YALE, if YALE is
named party and if YALE is not satisfied with the defense provided by LICENSEE
for any reason.
13.4 LICENSEE shall purchase and maintain in effect or shall require its
sublicensees to purchase and maintain in effect a policy of products liability
insurance covering all claims with respect to any
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LICENSED PRODUCTS manufactured or sold within the term of any license granted
hereunder, which policy shall i) be in such form and amount of coverage and
written by such company as YALE shall approve, ii) provide that such policy is
primary and not excess or contributory with regard to other insurance YALE may
have, iii) provide at least 30 days notice to YALE of cancellation, and iv)
include YALE and YALE's directors, officers and employees, as additional named
insureds. LICENSEE shall furnish a certificate of such insurance to YALE on or
before the date of first sale or use of any LICENSED PRODUCTS.
ARTICLE XIV NOTICES
Any notice required by this Agreement shall be sent by Registered or Certified
U.S. Mail, or by telex or cable and shall be deemed delivered if sent to the
following addresses of the respective parties or such other address as is
furnished by proper notice to the other party:
FOR YALE: FOR LICENSEE:
Yale University Oncorx Inc.
Xx. Xxxxxx X. Xxxxxxxxx, Director Xxxx Xxxxxx, President and CEO
Office of Cooperative Research Oncorx Inc.
000 Xxxxxx Xx., Xxx 000 Four Science Park Xxx
Xxxxx, XX 00000 Xxx Xxxxx, XX 00000
ARTICLE XV LAWS AND REGULATIONS
LICENSEE shall comply with all foreign and United States federal, state, and
local laws, regulations, rules and orders applicable to the testing, production,
transportation, packaging, labeling, export, sale and use of the LICENSED
PRODUCTS. In particular, LICENSEE shall be responsible for assuring compliance
with all U.S. export laws and regulations applicable to this license and
LICENSEE's activities hereunder.
ARTICLE XVI MISCELLANEOUS
16.1 Any delays in or failure by either party in performance of any obligations
hereunder shall be excused if and to the extent caused by such occurrences
beyond such party's reasonable control, including but not limited to such
occurrences as acts of God, strikes or other labor disturbances, war, and other
causes which cannot reasonably be controlled by the party who failed to perform.
16.2 This Agreement may not be amended except by written agreement signed by
both of the parties, and shall not be assigned by LICENSEE except upon the
advance written consent of YALE. This Agreement constitutes the entire agreement
of the parties relating to the subject matter hereof, and all prior
representations and understandings are merged into and superseded hereby.
16.3 This Agreement shall be governed by and in accordance with the laws of the
state of Connecticut except where the federal laws of the United States are
applicable and have precedence.
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16.4 The provisions of this Agreement shall be deemed separable. If any part of
this Agreement is rendered void, invalid, or unenforceable, such shall not
affect the validity or enforceability of the remainder of this Agreement unless
the part or parts which are void, invalid or unenforceable shall substantially
impair the value of the entire Agreement as to either party.
IN WITNESS WHEREOF, the parties hereto have caused this Agreement to be executed
in duplicate originals by their duly authorized representatives.
YALE UNIVERSITY ONCORX INC.
By: /s/ Xxxxx Xxxxxxxx By: /s/ Xxxx Xxxxxx
------------------------ ---------------------------------
Its: Associate V.P. for Finance Its: President
Date: 12/15/1995 Date: 11/28/1995
---------------------- -------------------------------
00
XXXX XXXXXXXXXX XXX XX. 000
Xxxxxx of Cooperative Research
000 Xxxxxx Xx., Xxxxx 000
432-7240 FAX 432-7245
INVENTION DISCLOSURE
1) Title of Invention.
Specific Vectors in Gene Delivery to HIV+ Cells.
2) Name(s) and Title(s) of Inventor(s).
Xxxxx Xxxxxxxx, Ph.X. X. Xxxxxx Low, Ph.D. Xxxx X. Xxxxxxx, Ph.D.
Associate Research Scientist Professor (Adjunct) Research Senior Research Scientist
Internal Medicine Therapeutic Radiology Dermatology
3) Sponsorship. During the time the invention was made, identify all sources of
funds for all inventors including salaries, materials and equipment. (Check all
appropriate boxes.)
Government Industry Foundation University
|_| |X| |_| |_|
a) Name of Sponsor: OncoRx, Inc.
b) Contract or Grant Number(s): None
c) Project Title: Vectors for the Diagnosis and Treatment of Human Melanoma
and Other Cancers.
d) Principal Investigator: Xxxx X. Xxxxxxx
4) Description of the Invention:
This invention focuses on the design of vectors for specific delivery of genes
to human immunodeficiency virus (HIV)-infected cells. We have recently
demonstrated that certain bacterial and protozoan organisms, e.g. Salmonella
typhymurium, Leishmania amazonensis, and Mycobacterium avium exhibit invasion
preference for human melanoma or colon carcinoma cells over normal human
melanocytes and colon epithelium in culture. Further, mutants of Salmonella
typhymurium were isolated showing enhanced specificity for melanoma and colon
carcinoma cells over that already shown by the wild type parental strain. One
such superinfective, tumor-specific mutant was further transfected with a Herpes
simplex thymidine kinase gene that was able to convert the non-toxic prodrug,
ganciclovir, to its toxic phosphorylated form when the Salmonella was infected
into melanoma tumors, thus reducing the size of the tumors. The current
invention uses similar technology to isolate mutants of Salmonella typhimurium
or other suitable vectors that show specific invasion preference for HIV+ cells.
Once isolated, such mutants are subjected to further genetic modifications to
express and secrete suicide gene products into the cytoplasm of the HIV+ cells.
Targets for the suicide gene products include both the HIV-infected cells and/or
the AIDS virus itself.
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5) Discussion of Novelty of Invention. Discuss the novel or unusual features of
the invention telling how it differs from present technology; what advantages
does it have over existing technology?
To our knowledge, no such therapy for HIV infection is available.
6) Uses of Invention. Describe as many applications/uses of the invention as you
can envision.
Anti-AIDS therapy.
7) Future Research Needed to Develop the Invention. Discuss any disadvantage or
limitations of the invention that might be eliminated by future research work.
Invention needs to be tested in AIDS models--culture and animal.
8) Publications.
a. Public Disclosure. Give the date, Place and circumstances of the first
public disclosure, if any has been made. if a talk, poster session or
publication of an abstract or paper is planned, give proposed date/place.
None
b. Attach any available descriptions, manuscripts, preprints, reprints,
etc., relating to invention to this disclosure form.
See Patent Application on file at OCR entitled VECTORS FOR THE DIAGNOSIS
AND TREATMENT OF SOLID TUMORS INCLUDING MELANOMA by Xxxxxxxx, Low, Xxxxxxx.
Submitted to US Patent Office June 7, 1995.
c. Laboratory records. Give reference number(s) and physical location.
None
d. Was the invention disclosed in a Government grant application which was
later approved? If "Yes," please give approval date.
No
e. Note any related patents or publications and attach copies (if
available) to this disclosure.
Already on file at OCR--see b.
12
None
9) Additional Information. Add information that might be helpful.
10) Interested Companies. List any companies and, if possible, specific persons
in that company, that might be interested in the invention.
Do not know at this point. OncoRx has the right of first refusal.
Signature(s) Date
/s/ Xxxx Xxxxxxx 8/17/1995
---------------------------------------
/s/ Xxxxx Xxxxxxxx 8/17/1995
---------------------------------------
/s/ X. Xxxxxx Low 8/17/1995
---------------------------------------
00
XXXX XXXXXXXXXX XXX XX. 000
Office of Cooperative Research
000 Xxxxxx Xx., Xxxxx 000
432-7240 FAX 432-7245
INVENTION DISCLOSURE
1) Title of Invention.
Novel Vectors for Gene Delivery and Therapy
2) Name(s) and Title(s) of Inventor(s).
Xxxxx Xxxxxxxx, Ph.X. X. Xxxxxx Low, Ph.D. Xxxx X. Xxxxxxx, Ph.D.
Associate Research Scientist Professor (Adjunct) Research Senior Research Scientist
Internal Medicine Therapeutic Radiology Dermatology
3) Sponsorship. During the time the invention was made, identify all sources of
funds for all inventors including salaries, materials and equipment. (Check all
appropriate boxes.)
Government Industry Foundation University
|_| |X| |_| |_|
a. Name of Sponsor OncoRx, Inc.
b. Contract or Grant Number(s) None
c. Project Title Vectors for the Diagnosis and
Treatment of Human Melanoma and
Other Cancers.
d. Principal Investigator Xxxx X. Xxxxxxx
4) Describe the Invention.
This invention focuses on the design of vectors for specific delivery of genes
to cells with impairments in gene expression, the goal being to correct such
impairments with a functional gene delivered by the vector and integrated into
the host chromosome. We have recently demonstrated that certain bacterial and
protozoan organisms, e.g. Salmonella typhymurium, Leishmania amazonensis, and
Mycobacterium avium exhibit invasion preference for human melanoma or colon
carcinoma cells over normal human melanocytes and colon epithelium in culture.
More important, mutants of Salmonella typhymurium were isolated showing enhanced
specificity for melanoma and colon carcinoma cells over that already shown by
the wild type parental strain. One such superinfective, tumor-specific mutant
was further transfected with a Herpes simplex thymidine kinase gene that was
able to convert the non-toxic prodrug, ganciclovir, to its toxic phosphorylated
form when the Salmonella was infected into melanoma tumors, thus reducing the
size of the tumors. The current invention uses similar technology to isolate
mutants of Salmonella typhimurium or other suitable vectors that show specific
invasion preference for cells of specific tissues or organs, for example
pancreatic islet cells. Once obtained, such mutants are subjected to further
genetic modifications to facilitate the transfer and expression of genes, e.g.
for insulin synthesis, to target cells of the pancreas. In this example,
transfer of genes for insulin synthesis to pancreatic islet cells deficient in
this process could ultimately correct the diabetic symptoms resulting from
insulin insufficiency. Other genetic disorders would be approached similarly.
14
5) Discussion of Novelty of Invention. Discuss the novel or unusual features of
the invention telling how it differs from present technology; what advantages
does it have over existing technology?
No such approach for gene therapy has been reported.
6) Uses of Invention. Describe as many applications/uses of the invention as you
can envision.
There are numerous uses for this invention, as there are numerous genetic
disorders in humans.
7) Future Research Needed to Develop the Invention. Discuss any disadvantage or
limitations of the invention that might be eliminated by future research work.
The invention needs to be tested in culture and animal models.
8) Publications.
a. Public Disclosure. Give the date, place and circumstances of the first
public disclosure, if any has been made. If a talk, poster session or
publication of an abstract or paper is planned, give proposed date/place.
None
b. Attach any available descriptions, manuscripts, preprints, reprints,
etc., relating to invention to this disclosure form.
See Patent Application on file at OCR entitled VECTORS FOR THE DIAGNOSIS
AND TREATMENT OF SOLID TUMORS INCLUDING MELANOMA by Xxxxxxxx, Low, Xxxxxxx.
Submitted to US Patent Office June 7, 1995.
c. Laboratory records. Give reference number(s) and physical location.
None
d. Was the invention disclosed in a Government grant application which was
later approved? If "Yes," please give approval date.
No
e. Note any related patents or publications and attach copies (if
available) to this disclosure.
Already on file at OCR--see b.
15
9) Additional Information. Add information that might be helpful.
None
10) Interested Companies. List any companies and, if possible, specific persons
in that company, that might be interested in the invention.
Do not know at this point. OncoRx has the right of first refusal.
Signature(s) Date
/s/ Xxxx Xxxxxxx 8/17/1995
---------------------------------------
/s/ Xxxxx Xxxxxxxx 8/17/1995
---------------------------------------
/s/ X. Xxxxxx Low 8/17/1995
---------------------------------------
16
