LICENSE AGREEMENT FOR
CHROMOSOME ANALYSIS TECHNOLOGY
WITH CHROMOSOME-SPECIFIC PROBES
THIS LICENSE AGREEMENT is made and is effective this 15th day of August
1989 by and between THE REGENTS OF THE UNIVERSITY OF CALIFORNIA, a California
corporation having its statewide administrative offices at 000 Xxxxxxxx Xxxxx,
00xx Xxxxx, Xxxxxxx, Xxxxxxxxxx 00000-0000, hereinafter referred to as "The
Regents", and AMOCO TECHNOLOGY COMPANY, a Delaware corporation having a
principal place of business at Warrenville Road and Mill Street, P.O. Box 3011,
Xxxxxxxxxx, Xxxxxxxx 00000, hereinafter referred to as "Licensee".
RECITALS
WHEREAS, certain inventions, generally characterized as FLUORESCENCE
HYBRIDIZATION WITH CHROMOSOME-SPECIFIC PROBES, herein collectively referred to
as "the Invention", were made in the course of research at the Xxxxxxxx
Livermore National Laboratory (LLNL) by Xx. Xxx X. Xxxx, et al. and are covered
by Regents' Patent Rights as defined below;
WHEREAS, The Regents and another company have entered into an exclusive
option agreement for an exclusive license to make, use, and sell "clinical
diagnostic products" in the prenatal field of use under Regents' Patent Rights;
and as a consequence such rights are expressly
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excluded from this Agreement; make, have made, use, and sell methods,
processes, compositions of matter, and articles of manufacture as a research
reagent for prenatal test subjects under Regents' Patent Rights; and as a
consequence such rights granted to licensee hereunder are expressly subject
to and limited by such preexisting rights of such third party;
WHEREAS, Licensee is desirous of acquiring an exclusive license to any and
all of Regents' Patent Rights covering the Invention in Licensee's Field of
Interest, subject to said option granted to a third party and rights retained by
the U.S. government as hereinafter described;
WHEREAS, both parties recognize and agree that royalties due hereunder will
be paid on both pending patent applications (for a limited period of time) and
issued patents;
WHEREAS, the Invention has utility for the detection of chromosome
abnormalities, and the Licensee has an interest in obtaining rights to pursue
commercial development of the Invention in Licensee's Field of Interest subject
to the outstanding option to another party, and The Regents is willing to grant
a license for the Invention's commercialization; and WHEREAS, The Regents is
desirous that the Invention be developed and utilized to the fullest extent so
that the benefits can be enjoyed by the general public.
The parties agree as follows:
1. DEFINITIONS
As used in this Agreement, the following terms shall have the meaning set
forth below:
1.1 "Research Program" shall mean the research which is proposed in the
Research Proposal entitled "A Proposal to Develop Fluorescence Hybridization
with Chromosome-
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Specific Probes to Facilitate Cytogenetic Analysis" submitted by Xxxxxxxx
Livermore National Laboratory (LLNL) to Licensee.
1.2 "Research" shall mean the work which is carried out in performance of
the Research Program.
1.3 "Research Agreement" shall mean the agreement entitled Research
Agreement for the Development of Fluorescence Hybridization with Chromosome-
Specific Probes between The Regents and Licensee dated 15 August, 1989, for the
conduct of Research under the Research Program and any extensions or renewals
thereof, and incorporated herein by reference. In the event of any
inconsistencies between the Research Agreement and this Agreement, the terms of
this Agreement shall control.
1.4 "Background Biological Materials" shall mean biological materials
developed prior to the effective date of the present agreement by The Regents
relating to in situ hybridization with chromosome-specific probes under the
direction of Xxx X. Xxxx at LLNL under Contract W-7405-ENG-48 between The
Regents and United States Department of Energy (DOE). Background Biological
Materials includes biological materials generally described as comprising a
heterogeneous mixture of nucleic acid fragments, which fragments are derived
from known chromosome types. The fragments have selective hybridization
capacity to chromosomes of interest and are carried on plasmid constructs known
as pBS-1, pBS-2, pBS-3, pBS-4, pBS-5, pBS-6, pBS-7, pBS-8, pBS-9, pBS-10, pBS-
11, pBS-12, pBS-13, pBS-14, pBS-15, pBS-16, pBS-17, pBS-18, pBS-19, pBS-20,
pBS-21, pBS-22, pBS-X and pBS-Y (nomenclature of LLNL).
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1.5 "Background Information" shall mean all technical data, processes,
methods, inventions, Background Biological Materials, equipment, instruments,
apparatuses, devices, and articles of manufacture developed or acquired prior to
the effective date of the present Agreement (to the extent that such Background
Information may be revealed to Licensee) by The Regents relating to in situ
hybridization with chromosome-specific probes under the direction of Xxx X. Xxxx
at LLNL under Contract W-7405-ENG-48 between the United States Department of
Energy (DOE) and The Regents. Background Information does not include computer
software, information management systems, or equipment comprising a cell sorter
or component part(s) thereof. Under this Agreement, there shall be no transfer
of the physical possession of equipment, instruments, apparatuses, devices,
articles of manufacture or component part(s) thereof or intellectual property
rights to computer software, information management systems or equipment
comprising a cell sorter or component part(s) thereof that are not covered by
Regents' Patent Rights.
1.6 "Research Information" shall mean technical data, processes, methods,
inventions, compositions-of-matter, and biological materials, equipment,
instruments, apparatuses, devices, articles of manufacture or component parts(s)
thereof developed under or resulting from the performance of Research under the
Research Agreement and improvements thereof, except for improvements on new
subject matter not funded by Licensee. There shall be no creation or
development of computer software or information management systems in the
performance of Research under the Research Agreement, and there shall be no
transfer of the physical possession
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of equipment, instruments, apparatuses, devices, articles of manufacture or
component part(s) thereof comprising Research Information.
1.7 "Regents' Patent Rights" shall mean all U.S. and foreign patents and
patent applications, including any reissues, extensions, continuations,
divisions, and continuations-in-part (to the extent that such continuations-in-
part are dependent upon the parent case and subject matter of the claims funded
by Licensee under the Research Agreement) based on inventions and improvements
thereof arising out of Background Information or Research Information including:
a. Pending U.S. Patent Application Serial No. 819,314 entitled "Method
and Compositions for Chromosome-Specific Staining", filed 16 January
1986 by Xxx X. Xxxx and Xxxxxx Xxxxxx and assigned to The Regents;
b. Pending U.S. Patent Application Serial No. 6-937,793 entitled "Methods
and Compositions for Chromosome-Specific Staining" filed 4 December
1986 by Xxx X. Xxxx and Xxxxxx Xxxxxx and assigned to The Regents, a
continuation-in-part application of U.S. Serial No. 819,314;
c. Pending U.S. Patent Application Serial No. 6-934,188 entitled "Method
of Preparing and Applying Single Stranded DNA Probes to Double
Stranded Target DNAs, filed 24 November 1986 by Xxx X. Xxxx and Xxxxxx
Xxxxxx and assigned to The Regents;
d. Any U.S. Patent Application based on subject matter described in UC
Case Number 87-095-1 (renumbered UC Case Number 85-157-4) entitled
"Method for
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Determining Aneuploidy in Fetal Cells from Maternal Blood
Samples" by Xxx X. Xxxx and assigned to The Regents;
e. Any future patent rights to subject matter claimed in or covered by a
patent application(s) covering any invention arising in the
performance of work under the Research Agreement and elected by
Licensee under the provisions of Article VIII of the Research
Agreement.
1.8 "Protected Composition Products" shall mean kits, reagents and
compositions, or the performance of a process or method, or kits, reagents, or
compositions produced by processes or methods, falling within the scope of one
or more claims of Regents' Patent Rights during the term of the patent grant, in
such countries in which such claim or claims have issued, and have not expired,
been abandoned, disclaimed or found invalid or unenforceable.
1.9 "Unprotected Composition Products" shall mean kits, reagents, and
compositions or the performance of processes or methods, or kits,.reagents, or
compositions produced by processes or methods, which are not Protected
Composition Products; i) falling within the scope of one or more pending claims
of Regents' applications identified in Paragraph 1.7 a.-d. as originally filed
and set forth in Schedule A, incorporated by reference herein; or ii) one or
more pending claims which claims recite subject matter arising in the
performance of Research under the Research Agreement that does not fall within
the scope of claims originally filed as set forth in Schedule A; or iii) one or
more pending claims directed to locus specific probes, arising in the
performance of Research under the Research Agreement; during the period and in
such countries
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in which such claim or claims have not issued and are pending, and have not
expired, been abandoned, disclaimed, or found invalid or unenforceable, such
period not to exceed five years from the effective date of this Agreement, or
five years from the date in which substantially the same subject matter (set
forth in i, ii, and iii immediately above) is introduced in a patent
application in each country that such patent application is filed, whichever
is longer. For the purposes of this section only, claims attached hereto as
Schedule A, Part 4 shall be considered pending.
1.10 "Protected Instrument Products" shall mean equipment, instruments,
apparatuses, devices, articles of manufacture or component part(s) thereof or
equipment, instruments, apparatuses, devices, articles of manufacture or
component part(s) thereof produced by processes or methods, falling within the
scope of one or more claims of Regents' Patent Rights during the term of the
patent grant, in such countries in which such claim or claims have issued, and
have not expired, been abandoned, disclaimed, or found invalid or unenforceable.
1.11 "Unprotected Instrument Products" shall mean equipment, instruments,
apparatuses, devices, articles of manufacture or component part(s) thereof or
equipment, instruments, apparatuses, devices, articles of manufacture or
component part(s) thereof produced by processes or methods, which are not
Protected Instrument Products; 1) falling within the scope of one or more
pending claims of Regents' Patent Rights identified in Paragraph 1.7 a.-d. as
originally filed and set
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forth in Schedule A, incorporated by reference herein; or ii) one or more
pending claims which claims recite subject matter arising in the performance
of Research under the Research Agreement that does not fall within the scope
of claims originally filed as set forth in Schedule A; during the period and
in such countries in which such claim or claims have not issued and are
pending, and have not expired, been abandoned, disclaimed, or found invalid
or unenforceable, such period not to exceed five years from the effective
date of this Agreement, or five years from the date in which substantially
the same subject matter (set forth in i, and ii, immediately above) is
introduced in a patent application in each country that such patent
application is filed, whichever is longer. For the purposes of this Section
only claims attached hereto as Schedule A, Part 4 shall be considered pending.
1.12 "Products" shall mean Protected Composition Products Unprotected
Composition Products, Protected Instrument Products, and Unprotected Instrument
Products.
1.13 "Net Sales" shall mean Licensee's or Licensee's sublicensee's invoice
prices to purchasers or lessees, less all quantity discounts or discounts
allowed for prompt payment or cash payment, credits or allowances for returned
goods, transportation charges or allowances, sales, use, tariff, import/export
duties or other excise taxes imposed upon particular sales.
1.14 "Field of Interest" shall mean relating to analytical, research, and
diagnostic applications of technology based on chromosomal staining, marking,
and labeling. Field of Interest shall specifically exclude therapies and
treatments derived from analytical, research, and diagnostic applications.
1.15 "Affiliates" of a party means any entity, which, directly or
indirectly, controls such party, is controlled by such party or is under common
control with such party, "control" for these purposes being defined as the
actual, present capacity to elect a majority of the directors of such
affiliate. Each reference to Licensee herein shall be meant to include
its Affiliates.
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1.16 "Infringement Litigation Costs" shall mean costs incurred in an
infringement suit, provided for in Paragraphs 18.2 a. and 18.4 of this
Agreement, consisting of outside attorney's fees billed to Licensee or The
Regents, and other reasonable out-of-pocket expenss.
2. REPRESENTATIONS AND WARRANTS
2.1 Licensee represents and warrants the following:
a. Licensee intends to fund Research under the Research Agreement,
which Research shall be under the direction of Xxx X. Xxxx as
Principal Investigator.
2.2 The Regents represents and warrants the following:
a. Regents' Patent Rights were developed under Contract W-7405-ENG-48
between The Regents and the United States Department of Energy (DOE)
with additional funding and assistance from a third party(s);
b. Pursuant to the terms of Contract W-7405-ENG-48, title to Regents'
Patent Rights rests in DOE without action on the Regents' part to
acquit or retain title;
c. The Regents has petitioned the DOE for a waiver of rights which has
been granted or is pending for Regents' Patent Rights as summarized
below:
i. Pending U.S. Patent Application Serial No. 819,314 entitled
"Method and Compositions for Chromosome-Specific Staining", filed
16 January 1986 by Xxx X. Xxxx and Xxxxxx Xxxxxx and assigned to
The Regents, waiver applied for June 30, 1986, and waiver granted
November 23, 1987;
9
ii. Pending U.S. Patent Application Serial No. 6-937,793 entitled
"Methods and Compositions for Chromosome-Specific Staining" filed
4 December 1986 by Xxx X. Xxxx and Xxxxxx Xxxxxx and assigned to
The Regents, a continuation-in-part application of U.S. Serial
No. 819,314, waiver applied for June 30, 1986, and waiver granted
November 23, 1987;
iii. Pending U.S. Patent Application Serial No. 6-934,188 entitled
"Method of Preparing and Applying Single Stranded DNA Probes to
Double Stranded Target DNAs", filed 24 November 1986 by Xxx X.
Xxxx and Xxxxxx Xxxxxx and assigned to The Regents, waiver
applied for August 18, 1986, and waiver granted on October 8,
1987;
iv. Subject matter described in UC Case Number 87-095-1 (renumbered
UC Case Number 85-157-4) entitled "Method for Determining
Aneuploidy in Fetal Cells from Maternal Blood Samples: by Xxx X.
Xxxx and assigned to The Regents, waiver applied for March 22,
1988, and presently pending;
d. The list of patent and patent applications identified in subparagraphs
a.-d. of Paragraph 1.7 is a complete list of Regents' Patent Right
arising at LLNL, and that there are no other patents or patent
applications at LLNL which may constitute background patents or patent
applications;
e. The Regents own or are in the process of acquiring title to Regents'
Patent Rights, which are subject to a nontransferable, nonexclusive,
irrevocable paid-up license to practice or have practiced, such
Regent's Patent Rights for or on behalf of the
00
Xxxxxx Xxxxxx throughout the world, pursuant to 35 USC 202(c) (4)
and which are subject to an option to obtain an exclusive license
to make, use and sell methods, processes, compositions-of-matter,
articles of manufacture expressly limited to clinical diagnostic
testing in prenatal test subjects and a nonexclusive license to
make, have made, use and sell methods, processes, compositions of
matter, and articles of manufacture as a research reagent for use
in prenatal test subjects granted to one other company. No other
rights have been granted.
2.3 The Regents represents to the best of its knowledge and warrants that:
a. There are no conflicts between rights and obligations set forth in the
present Agreement and presently existing rights;
b. It is not aware of any conduct (including but not limited to
inequitable conduct of fraud) before the U.S. Patent and Trademark
Office which would invalidate or materially narrow the scope of
pending claims of Regents' Patent Rights;
c. It is not aware of anything which would be made, used, sold, or
otherwise, disposed of, performed, or played under any license granted
herein that will constitute infringement of patents of third parties
except for U.S. Patent No. 4,468,464 entitled "Process and Composition
for Biologically Functional Molecular Chimeras" by X. Xxxxx, et al.
and issued 28 August 1984, U.S. Patent no. 4,237,224 entitled "Process
and Composition for Biologically Functional Molecular Chimeras" by X.
Xxxxx, et al. and issued 26 April 1988;
11
d. The subject matter of Regents' Patent Rights was made in the course of
research by Xxx X. Xxxx and Xxxxxx Xxxxxx at the Xxxxxxxx Livermore
National Laboratory, and there are no other inventors or co-inventors
for patent applications filed at the time of the effective date of
this Agreement;
e. The license and rights granted are provided WITHOUT WARRANTY OR
MERCHANTABILITY OF FITNESS FOR A PARTICULAR PURPOSE. THE REGENTS
MAKES NO REPRESENTATION OR WARRANTY THAT THE PRODUCTS OR METHODS MADE
IN ACCORDANCE WITH REGENTS' PATENT RIGHTS WILL NOT INFRINGE ANY PATENT
OR OTHER PROPRIETARY RIGHT;
f. Nothing in this Agreement shall be construed as a warranty or
representation by The Regents as to the validity or scope of any of
Regents' Patent Rights; an obligation to bring or prosecute actions or
suits against third parties for patent infringement except as provided
in Article 18; or conferring by implication, estoppel or otherwise any
license or rights under any patents of The Regents other than Regents'
Patent Rights as defined herein, regardless of whether such patents
are dominant or subordinate to Regents' Patent Rights. Specifically,
The Regents does not grant to Licensee any rights under U.S. Patent
No. 4,468,464, U.S. Patent No. 4,237,224 and U.S. Patent No. 4,740,470
set forth in Paragraph 2.3 c. supra.
g. It is not aware of any computer software or information management
systems created or developed under the research program identified as
"IN SITU
12
Hybridization Using Chromosome-Specific Probes for Chromosomal
Analysis" under the direction of Xxx X. Xxxx at LLNL.
3. GRANT
3.1 Subject to the prior outstanding rights in Paragraph 2.2 e. supra and
to The Regents' continuing rights in Paragraph 3.4 infra, The Regents hereby
grants to Licensee exclusive, worldwide licenses under Regents' Patent Rights
within the Field of Interest to make, have made, use, sell, distribute, and
lease machines, articles of manufacture, and compositions-of-matter and to
perform processes and have others perform processes.
3.2 During the pendency of the outstanding rights described in 2.2 (e) and
during such period and to the extent such outstanding rights have vested and
have not been terminated, abandoned, disclaimed, or revoked or have not expired,
the licenses set forth in Paragraph 3.1 supra shall be limited as follows:
a. the right to make, have made, use and sell methods, processes,
compositions-of-matter for clinical diagnostic testing or hereditary
diseases in the prenatal subjects within the Field of Interest is
expressly excluded from this Agreement;
b. the right to make, have made, use and sell methods, processes and
compositions-of-matter comprising a research reagent for use in
research including prenatal subjects within the Field of Interest
shall be nonexclusive.
In the event the outstanding rights described in 2.2 (e) expire or after vesting
are terminated, abandoned, disclaimed, or revoked, such license and right shall
pass to Licensee under the grant
13
of Paragraph 3.1. In order to maintain such license and right, Licensee shall
within ninety (90) days of obtaining such rights, fund additional research at
LLNL under terms and conditions consistent with the Research Funding
Agreement in an amount not to exceed two hundred and fifty thousand dollars
($250,000) per year for a period of time not less, than two years, under a
research program and scope of the research to be negotiated.
3.3 The licenses granted in Paragraph 3.1 of this Agreement are subject to
Contract W-7405-ENG-48 between The Regents and the DOE and subject to the
limitations set forth in this Agreement.
3.4 The Regents expressly reserves the right to use Background
Information, Research Information, and Regents' Patent Rights for educational
and research purposes for so long as such educational and research purposes do
not compete with Licensee.
3.5 The licenses granted hereunder shall be subject to all the applicable
provisions of The Regents' license granted back to the United States Government.
3.6 The Regents also grants to Licensee the right to issue sublicenses to
third parties to make, have made, use, sell, distribute, lease machines,
articles of manufacture, and compositions-of-matter and to perform processes and
have others perform processes, provided that Licensee has current exclusive
rights thereto under this Agreement. To the extent applicable, such sublicenses
shall include all of the rights of and obligations due The Regents and the
United States Government that are contained in this Agreement except that
Licensee shall not be bound by the royalty rate and license issue fee contained
herein with respect to its negotiation with third parties seeking such
sublicenses, provided that no sublicense shall be
14
issued with royalty rates lower than those contained herein. However,
Licensee shall, in such third party negotiations, use its best efforts in
reaching royalty rates and license issue fees. Licensee shall be entitled to
five percent (5%) of all income generated from sublicensing as an
administration fee, and of the remaining income one half shall be paid The
Regents and one half shall be retained by Licensee. In the event Licensee
grants a sublicense under paragraph 3.7 Licensee shall be entitled to fifteen
percent (15%) of all income generated from such sublicensing as an
administration fee, and of the remaining income one half shall be paid The
Regents and one half shall be retained by Licensee.
3.7 If The Regents are approached by an applicant for a license to
Regents' Patent Rights, and if said applicant agrees to fund research at LLNL to
further develop the technology covered by Regents' Patent Rights in the Field of
Interest but outside the fields of use of cancer identification, hereditary
disease testing in postnatal subjects, hereditary disease testing in prenatal
subjects and dosimetry to test subjects for exposure to toxins during the period
when Licensee has exclusive rights herein, it will refer the request of the
applicant to the Licensee. Within ninety (90) days of such referral, Licensee
shall submit to The Regents a written report outlining Licensee's interest in
the field of use proposed by the applicant. If Licensee has no interest in
marketing Products in the field of use proposed by the applicant, then Licensee
shall enter into good-faith negotiations with the applicant for a sublicense to
Regents' Patent Rights in said field of use. If Licensee expresses an interest
in marketing such Products in the field of use proposed by applicant, then The
Regents and Licensee shall enter into good-faith negotiations to sponsor
research at least at the level of applicant and to establish reasonable
diligence provisions
15
requiring reasonable performance standards for Licensee to achieve
substantial sales of said Products within a reasonable time period in the
field of use requested by applicant.
3.8 Licensee shall identify sublicenses and the royalty rate thereof
issued hereunder, collect and guarantee payment of all royalties due The Regents
from sublicensees; and summarize and deliver all reports due The Regents from
sublicensees.
3.9 Upon termination of this Agreement for any reason, all sublicenses
shall be assigned to The Regents.
4. LICENSE ISSUE FEE
4.1 The Licensee agrees to pay or cause to be paid to The Regents a
License Issue Fee of One Hundred and Twenty-Five Thousand Dollars ($125,000.00)
in the following manner: Licensee shall pay The Regents fifty thousand dollars
($50,000) within ten (10) days of execution of this Agreement, and seventy-five
thousand dollars ($75,000) on or before the one-year anniversary of the date
this agreement is fully executed.
4.2 This fee is non-refundable and not an advance against royalties.
5. ROYALTIES
5.1 As consideration for this license, Licensee shall pay or cause to be
paid to The Regents an earned royalty in the following manner:
a. Licensee shall pay or cause to be paid to The Regents a royalty of
four percent (4.0%) of Net Sales on Unprotected Composition Products.
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b. Licensee shall pay or cause to be paid to the Regents a royalty of
four percent (4.0%) of Net Sales on Protected Composition Products.
c. Licensee shall pay or cause to be paid to The Regents a royalty rate
of two percent (2%) of Net Sales on Unprotected Instrument Products.
d. Licensee shall pay or cause to be paid to The Regents a royalty rate
of three and one-half percent (3.5%) of Net Sales on Protected
Instrument Products.
5.2 Beginning in the calendar year 1992, Licensee shall pay to the Regents
a minimum annual royalty as set forth below:
1992 - Five Thousand Dollars ($5,000.00)
1993 - Five Thousand Dollars ($5,000.00)
1994 - Sixty Thousand Dollars ($60,000.00)
1995 - Sixty Thousand Dollars ($60,000.00)
1996 - One Hundred Sixty Thousand Dollars ($160,000.00)
1997 - One Hundred Sixty Thousand Dollars ($160,000.00)
1998 - Four Hundred Thousand Dollars ($400,000.00)
1999 - Four Hundred Thousand Dollars ($400,000.00)
2000 - Five Hundred Thousand Dollars ($500,000.00)
In each succeeding calendar year after the year 2000, Licensee shall pay a
minimum annual royalty of Five Hundred Thousand Dollars ($500,000.00) for the
life of the Agreement. These minimum royalties shall be paid to the Regents by
February 28 of each year and shall be credited against income paid to The
Regents under Paragraph 3.6 and earned royalties quarter to quarter until
consumed for that year. In the event minimum annual royalties exceed earned
royalties, the excess may be applied to earned royalties in succeeding years
until such excess is consumed.
5.3 In addition to the minimum royalties paid under Section 5.2, beginning
in the year 1990, Licensee shall fund research within the Field of Interest at a
level of Five Hundred
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Thousand Dollars ($500,000.00) per calendar year. Licensee's obligations to
fund research under this section shall terminate on December 31, 1997, or at
such time earned royalties exceed Five Hundred Thousand Dollars ($500,000.00)
per calendar year, or at such time total research expenditures within the
Field of Interest, from the effective date forward, exceed Seven Million
Dollars ($7,000,000.00) whichever occurs first. For the purpose of this
section, Licensee's funding of Research at Xxxxxxxx Livermore National
Laboratory shall not apply to total research expenditures. Licensee shall be
entitled to credit to funding, the reasonable value of research staff,
equipment and services owned or controlled by Licensee, including Licensee's
research facilities, employees, consultants, and research performed by third
parties on behalf of Licensee.
5.4 Products shall be considered sold when invoiced and, if not invoiced,
when delivered to a third party.
5.5 Royalties accruing to The Regents shall be paid to The Regents
quarterly on or before the following dates each year:
February 28 for the preceding
calendar quarter ending December 31
May 31 for the preceding calendar
quarter ending March 31
August 31 for the preceding calendar
quarter ending June 30
November 30 for the preceding
calendar quarter ending September 30
Each such payment will be for royalties which accrued with Licensee's most
recently completed calendar quarter.
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5.6 All monies due The Regents shall be payable in United States funds
collectible at par in San Francisco, California. When Products are sold for
monies other than United States dollars, the earned royalties will first be
determined in the foreign currency of the country in which such Products were
sold and then converted into equivalent United States funds. The exchange rate
will be that established by the Bank of America in New York, New York on the
last day of the reporting period and will be quoted in the Continental terms
method of quoting exchange rates (local currency per U.S. dollar).
5.7 Royalties earned with respect to sales occurring in any country
outside the United States shall not be reduced by any value-added taxes, fees,
or other charges imposed by the government of such country on the remittance of
royalty income. The Licensee shall also be responsible for all bank transfer
charges.
5.8 If at any time legal restrictions prevent the prompt remittance of
part of all royalties by the Licensee with respect to any country where a
Product is sold, the Licensee shall have the right and option to make such
payments by depositing the amount thereof in local currency to The Regents'
account in a bank or other depository in such country.
5.9 No royalties shall be collected or paid hereunder on sales of Products
sold to the United States Government. Licensee agrees, and its sublicensees
shall be required, to reduce the amount charged for Products sold to the United
States Government by an amount equal to the royalty otherwise due The Regents.
5.10 In the event The Regents reduces Licensee's exclusive license to a
nonexclusive license under Article 6 herein and grants rights to any third party
under Regents' Patent Rights
19
(except for the U.S. government and for a license to the field-of-use
specified in Paragraph 2.2 supra) on financial terms and conditions different
than the financial terms of this Agreement, then The Regents shall notify
Licensee of such different terms and conditions. Licensee shall have the
option of adopting such terms and conditions by giving notice to The Regents
within sixty (60) days of The Regents' notification to Licensee.
6. DUE DILIGENCE
6.1 The Licensee, upon execution of this Agreement, shall diligently
proceed with the development, manufacture and sale of Products and shall
earnestly and diligently endeavor to market same within a reasonable time after
execution of this Agreement and in quantities sufficient to meet the market
demands therefore.
6.2 The Licensee shall be entitled to exercise prudent and reasonable
business judgment in meeting its due diligence obligations hereunder.
6.3 Subject to rights under the option described in Paragraph 2.2e. and
the Licensee's freedom to practice Regents' Patent Rights without infringement
of third party rights, if Licensee is unable to market a research reagent
specific for each normal human chromosome covered by Regents' Patent Rights in
the United States by 1 January 1992, then The Regents shall have the right and
option to reduce Licensee's exclusive license to a nonexclusive license. This
right, if exercised by The Regents, supersedes the rights granted in Article 3
(GRANT).
6.4 The Licensee shall endeavor to obtain necessary FDA approvals for the
manufacture, use and sale of clinical diagnostic Products.
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6.5 Subject to Licensee's rights under 6.2 and subject to the Licensee's
freedom to practice Regents' Patent Rights without infringement of third party
rights, if the Licensee is unable to perform any of the following:
a. in the event any party has demonstrated Products having a utility in
clinical diagnostic applications for cancer identification, Licensee
shall submit an application for marketing in the U.S., including, by
way of example, an IDE for a PMA, an IND for an NDA, or 510k, for
Products (but not necessarily all Products) in the field of use of
cancer identification to the appropriate United States agency,
including, by way of example, FDA on or before two (2) years from such
demonstrations;
b. market Products (but not necessarily all Products) in the field of use
of cancer identification in the United States within six (6) months of
receiving U.S. government marketing approval from the FDA, if such
approval is required for such Products;
c. market Products (but not necessarily all Products) in the field of use
of cancer identification in the United States within one (1) year from
submission of a 510k to FDA, if a 510k is required from FDA to market
such Products; or
d reasonably fill the market demand for such Products (but not
necessarily all Products) in the field of cancer identification
following commencement of marketing at any time during the exclusive
period of this Agreement;
21
then the Regents shall have the right and option to reduce the Licensee's
exclusive license to a nonexclusive license with respect to clinical diagnostic
applications for cancer identification. This right, if exercised by The
Regents, supersedes the rights granted in Article 3 (GRANT). Subject to
Licensees rights under 6.2 and subject of Licensee's freedom to practice
Regents' Patent Rights without infringement of third party rights if the
Licensee is unable to perform any of the following:
e. in the event any party demonstrates Products having clinical
diagnostic applications for hereditary disease in postnatal test
subjects, Licensee shall submit an application for marketing in the
U.S., including by way of example, an IDE for a PMA, an IND for an
NDA, or 510k Products (but not necessarily all Products) in the field
of hereditary disease testing in postnatal subjects within two (2)
years of such demonstration;
f. market Products (but not necessarily all Products) in the field of
hereditary disease testing in postnatal subjects in the United States
within six (6) months of receiving U.S. Government marketing approval,
from FDA, if such approval is required for such Products;
g. market Products (but not necessarily all Products) in the field of use
of hereditary disease testing in postnatal subjects in the United
States within one (1) year from submission of a 510k to FDA if a 510k
is required to market such Products; or;
22
h. reasonably fill the market demand for such Products in the field of
hereditary disease testing in postnatal subjects following
commencement of marketing at any time during the exclusive period of
this Agreement;
then The Regents shall have the right and option to reduce the Licensee's
exclusive license to a nonexclusive license. This right, if exercised by The
Regents, supersedes the rights granted in Article 3 (GRANT). Subject to
Licensee's rights under 6.2 and subject to the Licensee's freedom to practice
Regents' Patent Rights without infringement of third party rights, if the
Licensee is unable to perform any of the following:
i. in the event any party has demonstrated Products having a utility in
clinical diagnostic applications for toxic substance dosimetry,
Licenses shall submit an application for marketing in the U.S.
including, by way of example, an IDE for a PMA, an IND for an NDA, or
510k, for Products (but not necessarily all Products) in the field of
use of toxic substance dosimetry to the appropriate United States
agency, including, by way of example, FDA on or before two (2) years
from such demonstration;
j. market Products (but not necessarily all Products) for toxic substance
dosimetry in the United States within six (6) months of receiving U.S.
government marketing approval from the FDA, if such approval is
required for such Products;
k. market Products (but not necessarily all Products) for toxic substance
dosimetry in the United States within one (1) year from submission of
a 510k to FDA, if a 510k is required from FDA to market such Products;
or
23
1. reasonably fill the market demand for such Products (but not
necessarily all Products) for toxic substance dosimetry following
commencement of marketing at any time during the exclusive period of
this Agreement;
then the Regents shall have the right and option to reduce the Licensee's
exclusive license to a nonexclusive license with respect to clinical diagnostic
applications for toxic substance dosimetry. This right, if exercised by The
Regents, supersedes the rights granted in Article 3 (GRANT). Subject to
Licensee's rights under 6.2, subject to Licensee obtaining exclusive rights to
clinical diagnostic applications of hereditary disease testing in prenatal
subjects, and subject to Licensee's freedom to practice Regents' Patent Rights
without infringement of third party rights, if Licensee is unable to perform any
of the following:
m. in the event any party has demonstrated Products having a utility in
clinical diagnostic applications for hereditary disease testing in
prenatal subjects, Licensee shall submit an application for marketing
in the U.S. including, by way of example, an IDE for a PMA, an IND for
an NDA, or 510k, for Products (but not necessarily all Products for
hereditary disease testing in prenatal subjects to the appropriate
United States agency, including, by way of example, FDA on or before
two (2) years from such demonstration;
n. market Products (but not necessarily all Products) for hereditary
disease testing in prenatal subjects in the United States within six
(6) months of receiving U.S. government market approval from the FDA,
if such approval is required for such Products;
24
o. market Products (but not necessarily all Products) for hereditary
disease testing in prenatal subjects in the United States within one
(1) year from submission of a 510k to FDA, if a 510k is required from
FDA to market such Products; or
p. reasonably fill the market demand for such Products (but not
necessarily all Products) for hereditary disease testing in prenatal
subjects following commencement of marketing at any time during the
exclusive period of this Agreement;
then The Regents shall have the right and option to reduce the Licensee's
exclusive license to a nonexclusive license with respect to clinical diagnostic
applications for hereditary disease tests in prenatal subjects. This right, if
exercised by The Regents, supersedes the rights granted in Article 3 (GRANT).
6.6 At the request of either party, any controversy or claim arising out
of or relating to the diligence provisions of this Agreement shall be settled by
arbitration conducted in San Francisco, California in accordance with the then
current Licensing Agreement Arbitration Rules of the American Arbitration
Association. Judgment upon the award rendered by Arbitrator(s) shall be binding
on the parties and may be entered by either party in the court of forum, state
or federal, having jurisdiction.
6.7 To exercise the right to reduce Licensee's grant to one of
nonexclusivity under Paragraph 6.3 or 6.5, The Regents must give the Licensee
written notice of the deficiency. The Licensee thereafter has sixty (60) days
to cure the deficiency or to request arbitration. If The Regents has not
received a written request for arbitration or satisfactory tangible evidence
that
25
the deficiency has been cured by the end of the sixty (60) day period, then
The Regents may, at its option, reduce the Licensee's exclusive license to a
nonexclusive license by giving written notice to the Licensee.
7. PROGRESS AND ROYALTY REPORTS
7.1 Beginning 30 November 1989 and yearly thereafter, the Licensee shall
submit The Regents a progress report covering the Licensee's activities related
to the commercialization of each Product until quarterly royalty reports are
made under Paragraph 7.2 for each such Product.
7.2 After the commercial sale of the Product anywhere in the world, the
Licensee will make quarterly royalty reports to The Regents, which report shall
accompany the payments made in accordance with Paragraph 5.5. Each such royalty
report will cover the Licensee's most recently completed calendar quarter and
will show (a) the gross sales and Net Sales of Products sold by the Licensee
during the most recently completed calendar quarter; (b) a brief description of
the items sold and the quantity sold; (c) the royalties, in U.S. dollars,
payable hereunder with respect to such Net Sales; and (d) the exchange rates
used.
7.3 If no Products have been sold during any reporting period, a statement
to this effect shall be required.
8. BOOKS AND RECORDS
8.1 The Licensee shall keep books and records accurately showing all
Products manufactured, used, and/or sold under the terms of this Agreement.
Such books and records
26
shall be preserved for at least five (5) years from the date of the royalty
payment to which they pertain and shall be open to inspection, upon seven (7)
days notice during normal business hours at Licensee's normal place of
business, to a mutually agreed upon independent accountant or auditor.
Audits of Licensee's books and records shall not take place more than once in
any twelve-month period.
8.2 The fees and expenses of the accountant or auditor performing such
examination shall be borne by The Regents. However, if an error in royalties of
more than five percent (5%) of the total royalties due for any year is
discovered, then the fees and expenses of the accountant or auditor shall be
borne by the Licensee.
9. LIFE OF THE AGREEMENT
9.1 Unless otherwise terminated by operation of law or by acts of the
parties in accordance with the terms of this Agreement, this Agreement shall be
in force from the effective date recited on page one and shall remain in effect
for the life of the last-to-expire patent licensed under this Agreement.
9.2 Any Termination of this Agreement shall not affect the rights and
obligations set forth in the following Articles:
Article 8 Books and Records
Article 13 Proprietary Information
Article 16 Use of Names and Trademarks
and Nondisclosure of Agreement
Article 19 Indemnification
9.3 Termination of this Agreement shall not relieve the Licensee of any
obligation or liability accrued hereunder prior to such termination or rescind
anything done by the Licensee or
27
any payments made to The Regents hereunder prior to the time such termination
becomes effective and such termination shall not affect in any manner any
rights of The Regents arising under this Agreement prior to such termination.
10. TERMINATION BY THE REGENTS
10.1 If the Licensee should violate or fail to perform any term or covenant
of this Agreement, then The Regents may give written notice of such default
(Notice of Default) to the
Licensee. If the Licensee should fail to repair such default within sixty (60)
days of the effective date of such notice, The Regents shall have the right to
terminate this Agreement and the licenses herein by a second written notice
(Notice of Termination) to the Licensee. If a Notice of Termination is sent to
the Licensee, this Agreement shall automatically terminate on the effective date
of such notice. These notices shall be subject to Article 23 (NOTICES).
10.2 The Regents shall also have the right and option to terminate this
Agreement if the Research Agreement is prematurely terminated by Licensee and
there has been no breach of failing thereof by the Regents. Said termination of
this Agreement shall be carried out in the manner set forth in Paragraph 10.1
above.
11. TERMINATION BY THE LICENSEE
11.1 The Licensee shall have the right upon ninety (90) days written notice
to The Regents to terminate this Agreement in whole or as to any portion of
Regents' Patent Rights. Upon expiration of the ninety (90) day period,
Licensee's termination shall be effective and
28
Licensee shall stand unlicensed hereunder. Such notice of termination shall
be subject to Article 23 (NOTICES).
12. RESUPPLY OF THE BIOLOGICAL MATERIALS
12.1 The Regents agrees to initially supply Licensee with viable samples of
the Background Biological Materials and biological materials comprising Research
Information (to the extent that such biological materials are in a form
acceptable for transfer) within thirty (30) days upon request from Licensee up
until three (3) months after termination of the Research Agreement. To the
extent Licensee requires and requests additional samples from The Regents during
the term hereof, and The Regents has such additional samples in its possession,
The Regents agrees to supplY such additional samples. Licensee agrees to pay
the actual handling and shipping costs for any additional samples provided.
12.2 To the extent Licensee is able to produce biologicals, reagents,
compositions, and materials derived from Background Information or Research
Information, and subject to prudent and reasonable business judgement, Licensee
shall make reasonable efforts to provide biologicals, reagents, compositions and
materials derived from Background Information or Research Information at no
charge to The Regents for research purposes only in the Biomedical Science
Division of LLNL only. In the event Licensee provides biologicals, reagents,
compositions and materials to The Regents, such biologicals, reagents,
compositions and materials are provided WITHOUT WARRANTY OF MERCHANTABILITY OR
FITNESS FOR A PARTICULAR PURPOSE. Licensee's obligations to provide materials
shall not exceed a fair market value for such materials in excess of one hundred
fifty thousand dollars ($150,000).
29
13. PROPRIETARY INFORMATION
13.1 a. Licensee and The Regents respectively shall hold the other
party's proprietary business, patent prosecution, and technical
information in confidence for a period of five (5) years from the
date of disclosure. All proprietary information shall be labeled
or marked as appropriate by the disclosing party. All oral
information shall be reduced to writing or some other physically
tangible form, marked and labeled as above, by the disclosing
party and delivered to the receiving party within thirty (30)
days of disclosure as a record of the disclosure.
b. Nothing contained herein shall in any way restrict or impair the right
of Licensee or The Regents to use, disclose or otherwise deal with any
information or data which:
i. at the time of disclosure to a receiving party is generally
available to the public or thereafter becomes generally available
to the public by publication or otherwise through no act of the
receiving party;
ii. the receiving party can show was in its possession prior to the
time of disclosure to it hereunder and was not acquired directly
or indirectly from the disclosing party;
iii. is independently made available to the receiving party as a
matter of right by a third party; or
iv. is independently developed by agents or employees of the
receiving party without use of any disclosed information.
30
13.2 The Licensee and The Regents agree to destroy or return to the
disclosing party proprietary information received from the other in its
possession within fifteen (15) days following the effective date of
termination. However, each party may retain one copy of proprietary
information for archival purposes in nonworking files. Licensee and The
Regents are to provide each other, within thirty (30) days following
termination, with a written notice that proprietary information has been
returned or destroyed.
14. PATENT PROSECUTION AND MAINTENANCE
14.1 The Regents shall diligently prosecute and maintain the United States
and foreign patent applications and patents in Regents' Patent Rights using
counsel of its choice and after due consultation with Licensee. The Regents
shall provide Licensee with copies of all relevant documentation so that
Licensee may be currently and promptly informed and apprised of the continuing
prosecution, and Licensee agrees to keep this documentation confidential.
14.2 The Regents shall use all reasonable efforts to prepare or amend any
patent application to include claims requested by Licensee and required to
protect the Products contemplated to be sold or Patent Methods or procedures to
be practiced under this Agreement.
14.3 All past, present and future reasonable outside and LLNL in-house
counsel costs and government charges incurred by The Regents, after due
consultation with Licensee, in the filing, prosecuting and maintaining of the
United States and foreign patent applications and patents referred to in
Paragraph 14.1 above shall be borne by Licensee, subject to Paragraph 14.4,
below. In the event of the declaration of an interference by the United States
Patent and Trademark Office, The Regents may discontinue, at its sole
discretion, further prosecution. If
31
The Regents license Regents' Patent Rights to a third party in a field of
use other than that of Licensee, then such other third party shall share
equally with Licensee in all filing, prosecution and maintenance fees for
each patent and patent application licensed to such third party. Licensee
shall reimburse The Regents within thirty (30) days following receipt of a
proper invoice from The Regents to which relevant law-firm xxxxxxxx or LLNL
counsel fees (page xxxxxxxx invoiced from DOE or LLNL, and such reasonable
and customary service charges), shall be attached. The Regents shall set
forth the number of licensees and identify Licensee's share of such costs.
14.4 The Regents shall obtain, at the request of Licensee, patent
prosecution on the Invention(s) covered by Regents' Patent Rights in foreign
countries if available and if Licensee so desires. Licensee must notify the
Regents within seven (7) months of the filing of the corresponding United States
application of its decision to obtain foreign patents. This notice concerning
foreign filing shall be in writing and must identify the countries desired. The
absence of such a notice from Licensee to The Regents shall be considered an
election not to secure foreign rights. The Regents shall have the right to file
patent applications at its own expense in any country in which Licensee has not
included in the list of desired countries and such applications and resultant
patents shall not be subject to this Agreement. However, The Regents shall
notify Licensee of such foreign countries in which The Regents filed patent
applications and in which Licensee elected not to secure foreign rights.
Subject to the availability of relevant rights, Licensee shall have the right
and option to include in this Agreement those patent applications and patents
issuing thereon filed in countries not originally included in Licensee's
32
desired list at any time up to five (5) years from the filing date of such
patent applications, provided, however, that Licensee shall notify The
Regents in writing of its decision and shall share equally with other
licensees in all filing, prosecution, and maintenance fees for such
additional patents and patent applications.
14.5 All patents and patent applications under this Agreement shall be held
in the name of The Regents, shall be obtained using counsel of The Regents'
choice, and shall be subject to the terms and provisions hereof.
14.6 Licensee's obligation to underwrite and to pay patent prosecution and
maintenance costs shall continue for so long as this Agreement remains in
effect, provided, however, that Licensee may terminate its obligations with
respect to any patent application or patent in any or all designated countries,
upon three (3) months written notice to The Regents. The Regents will use its
best efforts to curtail the associated patent costs after such notice is
received from Licensee. The Regents may continue prosecution and/or maintenance
of such applications or patent(s) at its sole discretion and expense, provided,
however, that Licensee shall have no further right or licenses thereunder in or
with respect to those countries wherein Licensee has terminated its obligations
in accordance with the aforementioned notice.
15. MAINTENANCE OF THE BIOLOGICAL MATERIALS
15.1 The Regents agrees to instruct Xx. Xxx X. Xxxx and Xx. Xxxxxx Xxxxxx that
when circulating replicable Background Biological Materials and replicable
biological materials comprising Research Information that have not been released
in an unrestricted manner to third parties to do
33
so under the terms and conditions set forth in the Biological Material
Transmission Letter attached hereto as Appendix A. The Regents expressly
reserves the right to transfer replicable Background Biological Materials and
replicable biological materials comprising Research Information as provided
in this Paragraph 15.1 to Universities and nonprofit research organizations
to the extent that such transfer does not compete with Licensee. The Regents
shall inform Licensee of third party requests for biological materials and
shall provide Licensee with a copy of the fully executed copy of the
Biological Material Transmittal Letter. The Regents shall inform Licensee of
comments, suggestions and information provided The Regents by recipients of
biological material. Licensee shall not interfere with The Regents efforts
to bail these materials to third parties.
15.2 The Licensee agrees to maintain the proprietary value of the
replicable Background Biological Materials and replicable biological materials
comprising Research Information (to the extent that such materials are not part
of Products sold by Licensee) that are not freely available to others.
16. USE OF NAMES AND TRADEMARKS AND NONDISCLOSURE OF AGREEMENT
16.1 Nothing contained in this Agreement shall be construed as conferring
any right to use in advertising, publicity or other promotional activities any
name, trade name, trademark, or other designation of either party hereto
(including any contraction, abbreviation, or simulation of any of the
foregoing). The use of the name "The Regents of the University of California
or the name of any University of California campus is expressly prohibited
except as provided for under Article 17.
34
16.2 Each party hereto further agrees not to use or refer to this Agreement
or any license granted hereunder in any promotional activity without the express
written approval of the other party. However, The Regents shall be free to
release to the inventors of inventions covered by this Agreement the terms and
conditions of this Agreement upon request of the inventors. If such release is
made, The Regents shall request that the inventors not disclose such terms and
conditions to others. It is further understood that should a third party
inquire whether a license is available, The Regents may disclose the existence
of this Agreement and the extent of the grant in Article 3 to such third party,
but shall not disclose the name of the Licensee, except where The Regents is
required to release information under either the California Public Records Act
or other applicable law.
17. PATENT MARKING
17.1 Licensee agrees to xxxx products falling within the scope of an issued
claim within Regents' Patent Rights for anything under the terms of this
Agreement, or their containers, in accordance with the applicable patent marking
laws.
17.2 Licensee shall have the right to include in any NDA for a product, a
list of patents included within Regents' Patent Rights identifying The Regents
as patent owner.
18. PATENT INFRINGEMENT
18.1 In the event that either party learns of substantial infringement of
the exclusive rights licensed under this Agreement, the informed party shall
call such infringement to the other party's attention thereto in writing and
shall provide the other party with reasonable evidence of such infringement.
Both parties to this Agreement agree that during the period and in a
35
jurisdiction where Licensee has exclusive rights under this Agreement, neither
will notify an infringing third party of the infringement of any of Regents'
Patent Rights limited to the exclusive rights granted under this Agreement
without first obtaining consent of the other party, which consent shall not be
unreasonably denied. Both parties shall use their best efforts in cooperation
with each other to terminate such infringement without litigation.
18.2 Licensee may request that the Regents take legal action against the
infringement of Regents' Patent Rights. Such request shall be made in writing
and shall include reasonable evidence of such infringement and damages to
Licensee. If the infringing activity has not been abated within ninety (90)
days following the date of such request, The Regents shall have the right to:
a. commence suit on their own account to terminate the infringement. In
the event The Regents commences suit, Licensee shall reimburse The
Regents for fifty percent (50%) of The Regents' actual Infringement
Litigation Costs. In the event other licensees, in addition to
Licensee, request legal action, 'The Regents and Licensee shall share
equally in the contribution of such other licensee. Licensee's share
of The Regents' Infringement Litigation Costs shall be paid to The
Regents on a quarterly basis within sixty (60) days of receiving
notice from The Regents of the amount of such costs. Such
reimbursement shall continue until the suit is finally adjudicated or
settled. All recoveries shall first be applied to fully repay The
Regents and participating licensees for the cost of the suit. Any
remainder shall be shared among The Regents and licensees who joined
the suit who have
36
shared in the reimbursement, with The Regents entitled to fifty
percent (50%) of the recovery and the remainder being shared
equally among the licensees joining in the action who have shared
in the reimbursement of The Regents; or
b. refuse to participate in such suit (other than as a nominal party
plaintiff). In the event The Regents refuses to participate in such
suit, The Regents shall give notice of its election in writing to
Licensee by the end of the one-hundredth (100th) day after receiving
notice of such request from Licensee. Licensee thereafter may bring
suit for patent infringement in Licensee's own name and in the name of
The Regents as nominal party plaintiff and if the infringement
occurred during the period and in a jurisdiction where Licensee has
exclusive rights under this Agreement. In the event Licensee elects
to bring suit in accordance, with this Paragraph, The Regents may
thereafter join such suit at its own expense.
18.3 Subject to Paragraph 18.2 b. above, legal action brought jointly by
The Regents and Licensee and fully participated in by both shall be at the joint
expense of the parties and all recoveries be shared jointly by them in
proportion to the share of expense paid by each party.
18.4 In the event that The Regents refuses to participate in a suit and the
Licensee brings same, the Licensee may withhold, during pendency of the suit, up
to fifty percent (50%) of the minimum and earned royalty income otherwise due
The Regents to offset one-half of Licensee's Infringement Litigation Costs.
Licensee's Infringement Litigation Costs shall be deducted from royalty payments
on a quarterly basis, and an accounting of such deductions shall
37
be reflected in Licensee's quarterly royalty reports to The Regents provided
for in Article 7 (PROGRESS AND ROYALTY REPORTS). Said withheld royalty
income shall be applied to only those Infringement Litigation Costs that
Licensee incurred during the quarter in which such royalty income was due and
owing. Should one-half of the Infringement Litigation Costs of the suit
exceed one-half of the royalties allowed to be withheld in accordance with
this Paragraph 18.4, Licensee may apply such excess to the following quarter.
This same application of excess cost will continue until such time as the
suit is finally adjudicated. All recoveries shall first be applied to fully
repay both parties for the cost of the suit, and any remainder shall be
shared equally.
18.5 Each party agrees to cooperate with the other in litigation
proceedings instituted hereunder. Such litigation shall be controlled by the
party bringing the suit, except that The Regents may be represented by counsel
of its choice pursuant to The Regents' determination in any suit brought by
Licensee.
19. INDEMNIFICATION
19.1 Licensee and The Regents are acting as independent contractors under
this Agreement and nothing continued herein shall make either party the agent,
employee, partner, or representative of the other.
19.2 Licensee agrees to indemnify, hold harmless and defend The Regents,
its officers, employees, and agents; the sponsors of the research that lead to
the inventions covered by
38
Regents' Patent Rights; and the inventors of the patents and patent
applications comprising Regents' Patent Rights to which The Regents is owner
or co-owner of record, for any loss of or damage to the property of any
person or persons and any injury or death of any person or persons resulting
from or arising out of the exercise of this license or any sublicense granted
herein, excluding acts of negligence on the part of The Regents and claims of
infringement brought by The Regents against Licensee. Where The Regents are
held to be negligent, liability shall be apportioned according to the
percentage of negligence accorded to The Regents by an appropriate court or
forum having jurisdiction. In those states or countries where such an
allocation of the percentage of negligence is not awarded, any controversy or
claim relating to such allocation or negligence between the parties to this
Agreement shall be settled by arbitration conducted in San Francisco,
California in accordance with the then current Licensing Arbitration Rules of
the American Arbitration Association. Judgment upon the award rendered by
Arbitrator(s) shall be binding on the parties and may be entered by either
party in the court or forum, state or federal, having jurisdiction. IN NO
EVENT WILL THE REGENTS BE LIABLE FOR ANY INCIDENTAL, SPECIAL OR CONSEQUENTIAL
DAMAGES RESULTING FROM THE EXERCISE OF LICENSES OR RIGHTS GRANTED HEREIN OR
THE USE OF THE PRODUCTS OR PROCESSES MADE IN ACCORDANCE WITH REGENTS' PATENT
RIGHTS OR THE REGENTS' PROPERTY RIGHTS. In no event shall The Regents be
liable for normal commercial activities of Licensee.
19.3 The Regents shall promptly notify Licensee in writing of any claim or
suit brought against The Regents in respect of which The Regents intends to
invoke the provisions of
39
this Article 19. Licensee will keep The Regents informed on a current basis
of its defense of any claims pursuant to this Section 19.
20. WAIVER
20.1 It is agreed that no waiver by either party hereto of any breach or
default of any of the covenants or agreements herein set forth shall be deemed a
waiver as to any subsequent and/or similar breach or default.
21. ASSIGNABILITY
21.1 This agreement is binding upon and shall inure to the benefit of The
Regents, its successors and assigns, but shall be personal to Licensee and
assignable by the Licensee only with written notice to The Regents.
22. LATE PAYMENTS
22.1 In the event royalty payments or fees are not received by The Regents
when due, Licensee shall pay to The Regents interest charges at the rate of five
(5) percent plus the rate of interest which is charged by the San Francisco
Federal Reserve Bank to member banks twenty-five (25) days prior to the date the
payment was due. Such interest shall be calculated from the date payment was
due until actually received by The Regents.
23. NOTICES
23.1 Any payment, notice or other communication required or permitted to be
given to either party hereto shall be in writing and shall be deemed to have
been properly given and to be effective (a) on the date of delivery if delivered
in person or (b) on the fourth day after mailing if
40
mailed by first-class certified mail, postage paid, to the respective address
given below, or to such other address as it shall designate by written notice
given to the other party as follows:
In the case of the Licensee:
AMOCO TECHNOLOGY COMPANY
Xxxxxxxxxxx Xxxx xxx Xxxx Xxxxxx
P. O. Box 3011
Xxxxxxxxxx, Xxxxxxxx 00000
Attention: Xx. Xxxx Xxxxxx
In the case of The Regents:
THE REGENTS OF THE UNIVERSITY
OF CALIFORNIA (C/N 85-187-1)
Patent, Trademark & Copyright Xxxxxx
0000 Xxxxxx Xxx Xxxxxxx, Xxxxx 000
Xxxxxxx, Xxxxxxxxxx 00000
Attention: Director
24. GOVERNING LAWS
24.1 This Agreement shall be interpreted and construed in accordance with the
laws of the State of California.
25. FOREIGN GOVERNMENT APPROVAL OR REGISTRATION
25.1 If this Agreement or any associated transaction is required by the law
of any nation to be either approved or registered with any governmental agency,
the Licensee shall assume all legal obligations and associated costs to do so.
The Regents shall cooperate in all the Licensee's efforts.
26. EXPORT CONTROL LAWS
41
26.1 The Licensee shall observe all applicable United States and foreign
laws with respect to the transfer of Products and related technical data to
foreign countries, including, without limitation, the International Traffic in
Arms Regulations (ITAR) and the Export Administration Regulations.
27. FORCE MAJEURE
27.1 The parties to this Agreement shall be excused from any performance
required hereunder if such performance is rendered impossible or unfeasible due
to any catastrophes or other major events beyond their reasonable control,
including, without limitation, war, riot, and insurrection; laws, proclamations,
edicts, ordinances or regulations; strikes, lockouts or other serious labor
disputes; and floods, fires, explosions, or other natural disasters. When such
events have abated, the parties' respective obligations hereunder shall resume.
28. FULL DISCLOSURE
28.1 The Regents shall make its best effort to disclose Research
Information and Background Information to Licensee and shall allow Licensee
reasonable access to facilities and faculty and staff participating in Research
sponsored by Licensee. The Regents shall identify and collect relevant
materials which comprise Research Information and Background Information (to the
extent such materials do not violate the proprietary rights of others) and make
such information available in a timely manner to Licensee. To the extent The
Regents are able to do so, The Regents shall make such Background Information
and Research Information available to Licensee in a form most convenient for
transfer to and use by Licensee, including electronic media. The Regent's duty
of disclosure to Licensee for Background Information shall not extend
42
beyond the term of the Research Agreement, and the Regent's duty of
disclosure to Licensee for Research Information shall not extend beyond one
year from the date of expiration of the Research Agreement.
29. MISCELLANEOUS
29.1 The headings of the several sections are inserted for convenience of
reference only and are not intended to be a part of or to affect the meaning or
interpretation of this Agreement.
43
29.2 This Agreement will not be binding upon the parties until it has been
signed below on behalf of each party, in which event, it shall be effective as
of the date recited on page one.
29.3 No amendment or modification hereof shall be valid or binding upon the
parties unless made in writing and signed on behalf of each party.
29.4 This Agreement embodies the entire understanding of the parties and
shall supersede all previous communications, representations or understandings,
either oral or written, between the parties relating to the subject matter
hereof.
29.5 In case any of the provisions contained in this Agreement shall be
held to be invalid, illegal, or unenforceable in any respect, such invalidity,
illegality or unenforceability shall not affect any other provisions hereof, but
this Agreement shall be construed as if such invalid or illegal or unenforceable
provisions had never been contained herein.
29.6 This Agreement includes Schedule A and Appendices A, B and C which are
attached hereto.
IN WITNESS WHEREOF, both The Regents and the Licensee have executed this
Agreement, in duplicate originals, by their respective officers hereunto duly
authorized, on the day and year hereinafter written.
AMOCO TECHNOLOGY COMPANY THE REGENTS OF THE UNIVERSITY
OF CALIFORNIA
By By
------------------------- --------------------------
(Signature) (Signature)
44
Name X.X. Xxxxxxxxx Name Xxxx X. Xxxxxx
--------------------------- --------------------
(Please Print)
Title President Title Director--Patent,
--------------------------- Trademark & Copyright Office
Date 9/27/89 Date 10/4/89
--------------------------- --------------------
45
Schedule A - Part I
Methods and Compositions
for Chromosome-Specific
Staining
U.S. Serial No. 819314
UC Case No. 85-157-1
CLAIMS:
1. A chromosome-specific staining reagent comprising a heterogeneous
mixture of labeled nucleic acid fragments, the labeled nucleic acid fragments
being derived from the same chromosome type, and being substantially free of
repetitive nucleic acid sequences having hybridization capacity.
2. The chromosome-specific staining reagent according to claim 1
wherein said chromosome type is an abnormal human chromosome type.
3. The chromosome-specific staining reagent according to claim 1
wherein said chromosome type is selected from the group consisting of normal
human chromosomes 1 through 22, X, and Y.
4. The chromosome-specific staining reagent of claim 3 wherein said
heterogeneous mixture comprises labeled nucleic acid fragments derived from
substantially equal amounts of between about 10-1000 distinct cloned inserts.
5. The chromosome-specific staining reagent of claim 4 wherein said
labeled nucleic acid fragments are derived from substantially equal amounts of
between about 10-1000 distinct cloned inserts each having a length within the
range of between about 20-45 kilobases.
46
6. The chromosome-specific staining reagent of claim 5 wherein said
distinct cloned inserts form said labeled nucleic acid fragments, each fragment
having a length within the range of between about 50-500 bases.
7. The chromosome-specific staining reagent of claim 6 wherein said
labeled nucleic acid fragments are single stranded.
8. The chromosome-specific staining reagent of claim 7 wherein said
labeled nucleic acid fragments are biotinylated or modified with N-acetoxy-N-2-
acetylaminofluorene.
9. The chromosome-specific staining reagent of claim 4 wherein said
labeled nucleic acid fragments are derived from substantially equal amounts of
between about 100-400 distinct cloned unique sequence inserts.
10. The chromosome-specific staining reagent of claim 9 wherein said
distinct cloned inserts form said labeled nucleic acid fragments, each fragment
having a length within the range of between about 50-5000 bases.
11. The chromosome-specific staining reagent of claim 10 wherein said
distinct cloned inserts form said labeled nucleic acid fragments, each fragment
having a length within the range of between about 50-500 bases.
12. The chromosome-specific staining reagent of claim 11 wherein said
labeled nucleic acid fragments are single stranded.
13. The chromosome-specific staining reagent of claim 12 wherein said
labeled nucleic acid fragments Are biotinylated or modified with N-acetoxy-N-2-
acetylaminofluorene.
47
14. A chromosome-specific staining reagent produced by the process
of:
isolating chromosome-specific DNA; cloning pieces of the isolated
chromosome-specific DNA;
disabling the hybridization capacity of repeated sequences
contained in the cloned pieces of the isolated chromosome-
specific DNA to form a collection of nucleic acid fragments which
hybridize to unique chromosomal DNA sequences;
labeling the nucleic acid fragments of the collection to form a
heterogeneous mixture a of nucleic acid fragments.
15. The chromosome-specific staining reagent of claim 14, wherein
said step of disabling said hybridization capacity includes selecting cloned
pieces of said isolated chromosome-specific DNA which have substantially unique
base sequences.
16. The chromosome-specific staining reagent of claim 14 wherein said
stop of disabling said hybridization capacity includes preassocating said cloned
pieces of said isolated chromosome-specific DNA with unlabeled repetitive
sequence nucleic acid fragments.
17. A method of staining chromosomal DNA of a particular chromosome
type or portion thereof, or a particular group of chromosome types, the method
comprising the steps of:
providing a heterogeneous mixture of labeled nucleic acid
fragments, substantial portions of each labeled nucleic acid
fragment in the heterogeneous mixture having base
sequences substantially complementary to base sequences
of the Chromosomal DNA; and
48
reacting the heterogeneous mixture with the chromosomal DNA
by in situ hybridization.
49
Schedule A - Part 2
Methods and Compositions
for Chromosome-Specific
Staining
U.S. Serial No. 937793
UC Case No. 85-157-2
CLAIMS:
1. A chromosome-specific staining reagent comprising a heterogeneous
mixture of labeled nucleic acid fragments, tne libeled nucleic acid fragments
being derived from the same chromosome type and being substantially free of
repetitive nucleic acid sequences having hybridization capacity.
2. The chromosome-specific staining reagent according to claim 1
wherein said chromosome type is in abnormal human Chromosome type.
3 The Chromosome-specific staining reagent according to claim 1
wherein said chromosome type is selected from the group consisting of normal
human chromosomes I through 22, X, & Y.
4. The chromosome-specific staining reagent of claim 3 wherein said
heterogeneous mixture comprises labeled nucleic acid fragments derived from
substantially equal amounts of between about 10-1000 distinct cloned inserts.
5. The chromosome-specific staining reagent of claim 4 wherein said
labeled nucleic acid fragments are derived from substantially equal amounts of
between about 10-1000 distinct cloned inserts each having a length within the
50
range of between about 20-45 kilobases.
6 . The chromosome-specific staining reagent of claim 5 wherein said
distinct cloned inserts form said labeled nucleic acid fragments, each having a
length within the range of between about 50-500 bases.
7 . The chromosome-specific staining reagent of claim 6 wherein said
labeled nucleic acid fragments are single stranded.
8 . The chromosome-specific staining reagent of claim 7 wherein said
labeled nucleic acid fragments are biotinylated or modified with N-acetoxy-N-2-
acetylamino-fluorene.
9 . The chromosome-specific staining reagent of claim 4 wherein said
labeled nucleic acid fragments are derived from substantial equal amounts of
between about 100-400 distinct cloned unique sequence inserts.
10. The chromosome-specific staining reagent of claim 9 wherein said
distinct cloned inserts form said labeled nucleic acid fragments, each fragment
having a length within the range of between about 50-5000 bases.
11. The chromosome-specific staining reagent of claim 10 wherein said
distinct cloned inserts form said labeled nucleic acid fragments, each fragment
having a length within the range of between about 50-500 bases.
12. The chromosome-specific staining reagent of claim 1 wherein said
labeled nucleic acid fragments are single stranded.
13. The chromosome-specific staining reagent of claim 12 wherein
said labeled nucleic acid fragments are biotinylated or modified with
N-sacetoxy-N-2-acetylamino-fluorene.
51
14. A chromosome-specific staining reagent produced by the process
of:
isolating chromosome-specific DNA;
cloning pieces of the isolated chromosome-specific DNA;
disabling the hybridization capacity of repeated sequences contained
in the cloned pieces of the isolated chromosome-specific DNA to form a
collection of nucleic acid fragments which hybridize to unique chromosomal DNA
sequences;
labeling the nucleic acid fragments of the collection to form a
heterogeneous mixture of nucleic acid fragments.
15. The chromosome-specific staining reagent of claim 14, wherein
said step of disabling said hybridization capacity includes selecting cloned
pieces of said isolated chromosome-specific DNA which have substantially unique
base sequences.
16. The chromosome-specific staining reagent of claim 14 wherein said
step of disabling said hybridization capacity includes prereassociating said
cloned pieces of said isolated chromosome-specific DNA with unlabeled repetitive
sequence nucleic acid fragments.
17. A method of staining chromosomal DNA of a particular chromosome
type or portion thereof, or a particular group of chromosome types, the method
comprising the steps of:
providing a heterogeneous mixture of labeled nucleic acid fragments,
substantial portions of each labeled nucleic acid fragment in the heterogeneous
mixture having base sequences substantially complementary to base sequences of
the chromosomal DNA; and
reacting the heterogeneous mixture with the chromosomal DNA by in situ
hybridization.
52
Schedule A - Part 3
Method of Preparing and
Applying Single Stranded
Probes to Double Stranded
DNAs
U.S. Serial No. 934188
UC Case No. 85-157-3
WE CLAIM:
1. A method of preparing and applying single stranded DNA probes to
double stranded target DNA, the method comprising the steps of:
providing restriction fragments having staggered ends, the staggered
ends each consisting of a protruding strand and a recessed strand;
treating the restriction fragments with an exonuclease to digest a
portion of the recessed strand to form template/primers;
treating the template/primers with a DNA polymerase so that the
single strands digested by the exonuclease are resynthesized in the presence of
a labeled nucleoside triphosphate precursor to form resynthesized fragments;
breaking the resynthesized fragments into smaller pieces, so that the
labeled regions on opposite ends of each resynthesized fragment are on
separate pieces of DNA;
denaturing the broken resynthesized fragments; separating the labeled
strands of the DNA fragments from the denatured broken resynthesized
fragments to form the single stranded DNA probe;
treating the double stranded target DNA with the same restriction
endonuclease used to generate the restriction fragments;
53
after treatment with the restriction endonuclease treating the double
stranded target DNA with an exonuclease; and
after treatment with the exonuclease, applying the single stranded DNA
probe to the double. stranded target DNA.
2. The method of Claim 1 wherein said labeled nucleoside
triphosphate precursor is biotinylated uracil triphosphate and wherein said step
of separating includes passing said denatured broken synthesized fragments over
an avidin affinity column.
3. The method of Claim 2 wherein said step of breaking includes
sonicating said resynthesized fragments so that said broken resynthesized
fragments are on average about half the length of said resynthesized fragments.
4. The method of Claim 3 wherein said exonuclease is exonuclease III
and said DNA polymerase is T4 DNA polymerase.
54
Schedule A-Part 4: "Method for Determining
Aneyploid, in Fetal Cells from Maternal
Blood Samples" U.C. Case No. 87-095-1
(renumbered U.C. Case Number 85-157-4)
CLAIMS:
1. High complexity nucleic acid probes for cytogenetic analysis.
2. High complexity nucleic acid probes according to Claim 1 wherein
the complexity is greater than 100,000 bases.
3. High complexity nucleic acid probes according to Claim 2 wherein
the complexity is greater than one million bases.
4. High complexity nucleic acid probes according to Claim 3 wherein
the complexity is greater than two million bases.
5. A method of staining targeted chromosomal material with high
complexity nucleic acid probes.
6. A method according to Claim 5 wherein the probes are at a
complexity greater than 100,000 bases.
7. A method according to Claim 6 wherein the complexity is greater
than one million bases.
8. High complexity nucleic acid probes according to Claim 1 derived
from normal and/or abnormal chromosomal material.
55
9. High complexity nucleic acid probes according to Claim 8 wherein
chromosomal material is human.
10. High complexity nucleic acid probes according to Claim 9 wherein
the human chromosomal material is normal and selected from DNA of chromosomes 1
through 22, X and Y.
11. High complexity nucleic acid probes according to Claim 10 wherein
the human chromosomal material is abnormal and selected from DNA of chromosomes
1 through 22, X and Y.
12. High complexity nucleic acid probes according to Claim 1 wherein
the probe nucleic acid sequences are propagated in one or more vectors.
13. High complexity nucleic acid probes according to Claim 12
wherein said one or more vectors is or are selected from the group consisting of
hybrid cells, yeast artificial chromosomes, plasmids, bacteriophages and
cosmids.
14. High complexity nucleic acid probes according to Claim 13 wherein
the hybrid cells are selected from the group consisting of human/hamster and
human/rodent hybrid cells; wherein the plasmids are Bluescribe plasmids; wherein
the bacteriophages are lambda insertion vectors selected from the group
consisting of Charon 4A, Charon 21A, Charon 35, Charon 40 and GEM11; and wherein
the cosmids are selected from the group consisting of Lawrist 4, Lawrist 5 and
sCosl.
56
15. High complexity nucleic acid probes comprising high copy
repetitive probes and target-specific probes.
16. High complexity nucleic acid probes according to Claim 15 wherein
the repetitive probes are alpha-satellite probes and/or Alu sequence probes.
17. A method of staining targeted chromosomal material with high
complexity nucleic acid probes wherein the probe nucleic acid sequences prior to
hybridization to the targeted chromosomal material are broken into fragments of
from about 200 bases to about 2000 bases.
18. A method according to Claim 17 wherein the size of the fragments
are about 1 Kb.
19. A method according to Claim 18 wherein the size of the fragments
is from about 800 bases to about 1000 bases and, wherein the hybridization is
performed at a temperature of about 30 degrees C to about 45 degrees C, and
wherein the subsequent washing steps are performed at a temperature of from
about 40 degrees C to about 50 degrees C.
20. A method according to Claim 19 wherein the hybridization is
performed at a temperature of from about 35 degrees C to about 40 degrees C.
21. A method according to Claim 20 wherein the hybridization is
performed at a temperature of about 37 degrees C, and the subsequent washing
steps are performed at a temperature of about 45 degrees C.
22. A method according to Claim 17 wherein the labeled fragments are
detected after hybridization by flow cytometry.
23. A method according to Claim 17 wherein detection is by
microscopy.
57
24. A method according to Claim 17 wherein detection is by
fluorescent-activated cell sorting.
25. A method according to Claim 23 wherein light scattering is used.
26. High complexity probes according to Claim 1 wherein the targeted
chromosomal material of said probes is chromosomal material of fetal cells.
27. High complexity probes according to Claim 26 wherein said fetal
cells have been separated from maternal blood by non-invasive means.
28. High complexity probes according to Claim 27 wherein said non-
invasive means comprise the use of monoclonal antibodies specific for said fetal
cells.
29. High complexity probes according to Claim 28 wherein said fetal
cells are leukocytes and cytotrophoblasts.
30. High complexity probes according to Claim 26 wherein said probes
comprise chromosome-specific probes for chromosome 13, 18 and/or chromosome 21.
31. High complexity probes according to Claim 29 wherein said probes
comprise the chromosome-specific Bluescribe plasmid libraries for chromosome 13
and/or chromosome 21.
32. High complexity probes according to Claim 25 wherein the targeted
chromosomal material is in interphase and/or metaphase.
33. High complexity probes according to Claim 32 wherein the targeted
chromosomal material is in interphase.
58
34. A prenatal screening test kit comprising the high complexity
nucleic acid probes of Claim 25.
35. A method of staining targeted chromosomal material of fetal cells
with high complexity nucleic acid probes.
36. A method according to Claim 35 wherein the fetal cells have been
separated from maternal blood by non-invasive means.
59
37. A method according to Claim 36 wherein said non-invasive means
comprise the use of monoclonal antibodies specific for said fetal cells.
38. A method according to Claim 37 wherein said fetal cells are
leukocytes and cytotrophoblasts.
39. A target-specific staining reagent comprising a high complexity,
heterogeneous mixture of labeled nucleic acid fragments, wherein the labeled
nucleic acid fragments are complementary to sites on the targeted chromosomal
material and are substantially free of nucleic acid sequences having
hybridization capacity to sites on non-targeted chromosomal material.
40. The target-specific staining reagent of Claim 39 wherein said
targeted material is human chromosomal material that is either normal or
abnormal.
41. The target-specific staining reagent of Claim 40 wherein the
human chromosomal material is normal and selected from the group consisting of
DNA sequences from normal human chromosomes 1 through 22, X, and Y.
42. The target-specific staining reagent of Claim 39 wherein said
labeled nucleic acid fragments are single stranded.
43. The target-specific staining reagent of Claim 42 wherein said
nucleic acid fragments are labeled with radioactive, enzymatic, immunoreactive
and/or affinity detectable reagents.
44. The target-specific staining reagent of Claim 41 wherein said
fragments are biotinylated, modified with N-acetoxy-N-2-acetylaminofluorene,
modified with fluorescein isothiocyanate, modified with mercury/TNP ligand, or
sulfonated.
60
45. A target-specific staining reagent produced by the process of:
isolating target-specific DNA;
cloning pieces of the isolated target-specific DNA;
disabling the hybridization capacity of or removing shared repetitive sequences
contained in the cloned pieces of the isolated target-specific DNA to form a
collection of nucleic acid fragments which hybridize to the targeted chromosomal
DNA; and
labeling the nucleic acid fragments of the collection to form a
heterogeneous mixture of nucleic acid fragments.
46. The target-specific staining reagent of Claim 45 wherein said
step of disabling said hybridization capacity of or removing said shared
repetitive sequences comprises selecting cloned pieces of said isolated target-
specific DNA which pieces are substantially free of nucleic acid sequences which
are complementary to non-targeted chromosomal material.
47. A target-specific staining reagent of Claim 46 wherein said
selection of said cloned pieces comprises the use of southern hybridization.
48. A target-specific staining reagent of Claim 47 wherein said
selection of said cloned pieces comprises screening said clones for the presence
of repetitive sequences by hybridization with genomic DNA.
49. A target-specific staining reagent of Claim 48 wherein said
clones are plasmid clones.
50. A target-specific staining reagent of Claim 45 wherein said
selection of said cloned pieces comprises screening said clones for
hybridization to single-copy or repetitive
61
sequences which are known to be in the targeted chromosomal material, and
removing the clones which do not so hybridize.
51. The target-specific staining reagent of Claim 45 wherein said
step of disabling said hybridization capacity comprises hybridizing said cloned
pieces of said isolated target-specific DNA with unlabeled high copy shared
nucleic acid sequences.
52. The target-specific staining reagent of Claim 45 wherein said
step of disabling said hybridization capacity comprises the addition of
unlabeled blocking DNA during hybridization to the targeted chromosomal
material.
53. The target-specific staining reagent of Claim 52 wherein the
unlabeled blocking DNA is genomic.
54. The target-specific staining reagent of Claim 53 wherein the
genomic DNA is a high-copy fraction.
55. The target-specific staining reagent of Claim 52 wherein the
unlabeled blocking DNA is from a mixture of a few clones containing the highest
copy sequences from a genome.
56. The target-specific staining reagent of Claim 45 wherein said
step of disabling said hybridization capacity of said shared repetitive
sequences comprises self-reassociating the high complexity probe.
57. The target-specific staining reagent of Claim 45 wherein said
step of removing the shared repetitive sequences comprises the use of
hydroxyapatite chromatography.
62
58. The target-specific staining reagent of Claim 45 wherein said
step of removing the shared repetitive sequences comprises reacting the cloned
pieces of the isolated target-specific DNA with immobilized, single-stranded
nucleic acid sequences which are complementary to said shared repetitive
sequences.
59. A method of staining targeted chromosomal material with a high
complexity nucleic acid probe wherein the targeted chromosomal material is
hybridized to unlabeled high copy repetitive nucleic acid sequences prior to or
during the hybridization to the high complexity nucleic acid probe.
60. A method of staining targeted chromosomal material with high
complexity nucleic acid probes comprising the steps of:
providing a heterogeneous mixture of labeled nucleic acid
fragments, wherein substantial portions of each labeled nucleic acid fragment in
the heterogeneous mixture has base sequences substantially complementary to the
targeted chromosomal material; and
reacting the heterogeneous mixture with the targeted chromosomal DNA by in situ
hybridization.
61. High complexity nucleic acid probes which are substantially free
of shared repetitive sequences produced by a process incorporating a polymerase
chain reaction (PCR) procedure.
62. High complexity nucleic acid probes according to Claim 61 wherein
before performing said PCR procedure sequences complementary to said shared
repeats which have extended non-complementary ends or which are terminated in
nucleotides which do not permit extension by a polymerase are hybridized to said
shared repeats.
63
63. A method of staining targeted chromosomal material with high
complexity nucleic acid probes wherein the probes are not directly labeled and
detection of the probes bound to the targeted chromosomal material is by means
other than direct labeling.
64. A method of staining targeted chromosomal material according to
Claim 63 wherein the means of detecting the probes bound to the targeted
chromosomal material comprise the use of anti-RNA/DNA duplex antibodies and/or
anti-thymidine diner antibodies.
65. High complexity nucleic acid probes for cytogenetic analysis by
in situ hybridization.
66. High complexity nucleic acid probes according to Claim 65 wherein
the complexity is greater than 100,000 bases.
67. High complexity nucleic acid probes according to Claim 65 which
produce one or more bands on the targeted chromosome(s) for detection of
cytogenetic aberrations in metaphase chromosomes.
68. High complexity nucleic acid probes according to Claim 67 wherein
the bands can be spectrally distinguished.
69. High complexity nucleic acid probes according to Claim 67 wherein
the bands are placed at specific disease loci.
70. High complexity nucleic acid probes according to Claim 67 wherein
the band characteristics (location, dimension, colors) are optimized for
detection by automated means.
71. High complexity nucleic acid probes according to Claim 67 for
detection of random structural chromosome abnormalities induced by exposure to
clastogenic agents.
64
72. High complexity nucleic acid probes according to Claim 71 wherein
the probes have been optimized for rapid detection of random structural
chromosome aberrations.
73. High complexity nucleic acid probes according to Claim 71 wherein
probes have been optimized for rapid, efficient, automated detection of
aberrations.
74. High complexity nucleic acid probes according to Claim 67 for
detection of cytogenetic abnormalities in tumor cells.
75. High complexity nucleic acid probes according to Claim 74 where
detection of abnormalities is by automated means.
76. High complexity nucleic acid probes according to Claim 65 for
detection of numerical and structural chromosome abnormalities in interphase
cells.
77. High complexity nucleic acid probes according to Claim 76 wherein
the probes are optimized for detection of specific disease-linked numerical
abnormalities of entire or partial chromosomes.
78. High complexity nucleic acid probes according to Claim 76
wherein the probes have been optimized to detect specific disease-linked
structural abnormalities.
79. High complexity nucleic acid probes according to Claim 76 wherein
the probes have been optimized to detect numerical and structural abnormalities
in tumor cells.
80. High complexity nucleic acid probes according to Claim 76 wherein
the probes have been optimized to random abnormalities induced by clastogenic
agents.
81. High complexity nucleic acid probes according to Claim 76
wherein the probes have been optimized for detection of aberrations by automated
means.
65
FOR THE PURPOSE OF THIS LICENSE AGREEMENT, THE TERM "HIGH COMPLEXITY
NUCLEIC ACID PROBE(S)" MEANS PROBES CONTAINING MORE THAN 100,000 BASES OF NON-
REPEATING NUCLEIC ACID SEQUENCES THAT CAN BE USED IN AN IN SITU HYBRIDIZATION
REACTION TO STAIN REGIONS OF CHROMOSOMES OR CELL NUCLEI TO FACILITATE
CYTOGENETIC ANALYSIS.
66
AMOCO TECHNOLOGY COMPANY THE REGENTS OF THE UNIVERSITY
OF CALIFORNIA
By /s/ X.X. Xxxxxxxxx By /s/ X.X. Xxxxxx
------------------------ -----------------------------
(Signature) (Signature)
Name X.X. Xxxxxxxxx Name Xxxx X. Xxxxxx
----------------------- ---------------------------
(Please Print)
Title President Title Director--Patent,
Trademark & Copyright Office
Date 9/27/89 Date 10/4/89
------------------------ ---------------------------
67
APPENDIX A - PAGE 1A
University of California/
Xxxxxxxx Livermore National Laboratory (LLNL)
Instructions for Standard Letter Transmitting
Biological Materials to Universities and Nonprofit Institutions
The attached letter is authorized for use by University of California/LLNL
Principal Investigators and Administrators only with scientists at other
universities and nonprofit research institutions when transmitting cell lines,
plasmids and the like for non-commercial research purposes.
1. Choose the appropriate form of university or nonprofit research institution
in Paragraph 2.
2. Choose whether or not to include the phrase "our cooperative" in Paragraph
3. Insert in Paragraph 4 the amount of processing charge. If the material is
to be shipped at no charge, insert the words "no charge".
4. Send the letter IN DUPLICATE to the other scientist.
5. Do not send biological materials until you receive the duplicate copy
executed by both the scientist and the other institution.
6. Send a copy of the fully executed letter agreement to:
Xxxx X. Xxxxxxx, Director
Patent, Trademark and Copyright Office
University of California
0000 Xxxxxx Xxx Xxxxxxx, Xxxxx 000
Xxxxxxx, XX 00000
7. Any changes in the wording of this standard letter must be reviewed by the
Director of the Patent, Trademark and Copyright office before acceptance.
68
NOTE: Do not use this letter for the exchange of living plants. A separate
"Testing Agreement for Plant Varieties" is available for that purpose.
APPENDIX A - PAGE 2A
SAMPLE LETTER FOR USE PRIOR TO TRANSMISSION OF BIOLOGICAL
MATERIALS TO INVESTIGATORS AT UNIVERSITIES OR NON-PROFIT
RESEARCH INSTITUTIONS
(Date)
IN DUPLICATE
To:
This is to (acknowledge receipt of your letter) (confirm our telephone
conversation) in which you requested certain research materials developed in
this laboratory be sent to you for scientific research purposes. The materials
concerned, which belong to The Regents of the University of California/Xxxxxxxx
Livermore National Laboratory (LLNL), are: _____________________________. While
I cannot transfer ownership of these materials to you, I will be pleased to
permit your use of these materials within your (university) (Non-Profit Research
Institution) laboratory for (our cooperative) scientific research. However,
before forwarding them to you, I would like your agreement that the materials
will be received by you only for use in (our cooperative work) (scientific
research), that you will bear all risk to you or any others resulting from your
use, and that you will not pass these materials, their progeny or derivatives,
on to any other party or use them for commercial purposes without the express
written consent of The Regents of the University of California. You understand
that no other right or license to these materials, their progeny or derivatives,
is granted or implied as a result of our transmission of these materials to you.
These materials are to be used with caution and prudence in any experimental
work, since all of their characteristics are not known.
As you recognize, there is a processing cost to us involved in providing these
materials to you. We will xxxx you for our processing costs, which will amount
to $ .
If you agree to accept these materials under the above conditions, please sign
the enclosed duplicate copy of this letter, then have it signed by an authorized
representative of your
69
institution, and return it to me. Upon receipt of that confirmation I will
forward the material(s) to you.
APPENDIX A - PAGE 3A
(Note: other paragraphs discussing the relevant literature, the nature of the
work, hazards relating to materials to be sent, etc., may be appropriate. These
will vary depending on the individual circumstances and the relationship between
the two parties previously established. Be sure to retain signed copy when
received and send a photocopy of the completed agreement to the University of
California Patent Administrator, Patent Office, Systemwide Administration, 0000
Xxxxxx Xxx Xxxxxxx, Xxxxx 000, Xxxxxxx, XX 00000.)
Sincerely yours,
ACCEPTED:
RESEARCH INVESTIGATOR
-------------------------
Printed Name
-------------------------
(Signature)
-------------------------
Date
RESEARCH UNIVERSITY OR
NON-PROFIT INSTITUTION
-------------------------
Printed Name
-------------------------
(Signature)
-------------------------
Date
00
XXXXXXXX X
The INVENTORS listed below understand and agree to abide by the terms and
conditions
of Article 15 of the License Agreement between The Regents of the University of
California and Amoco Technology Corporation effective October 4, 1989 and to
instruct all relevant personnel working within their laboratory to act
accordingly. Said paragraph reads, in part, as follows:
15.1 The Regents agrees to instruct Xx. Xxx X. Xxxx and Xx. Xxxxxx Xxxxxx
that when circulating replicable Background Biological Materials and replicable
biological materials comprising Research Information that have not been released
in an unrestricted manner to third parties to do so under the terms and
conditions set forth in the Biological Material Transmission Letter attached
hereto as Appendix A. The Regents expressly reserves the right to transfer
replicable Background Biological Materials and replicable biological materials
comprising Research Information as provided in this Paragraph 15.1 to
Universities and nonprofit research organizations to the extent that such
transfer does not compete with Licensee. The Regents shall inform Licensee of
third party requests for biological materials and shall provide Licensee with a
copy of the fully executed copy of the Biological Material Transmittal Letter.
The Regents shall inform Licensee of comments, suggestions and information
provided The Regents by recipients of biological material. Licensee shall not
interfere with. The Regents efforts to bail these materials to third parties.
By /s/ Xxx X. Xxxx
-------------------
Xxx X. Xxxx
Date 10/2/89
------------------
By /s/ Xxxxxx Xxxxxx
--------------------
Xxxxxx Xxxxxx
Date 9/29/89
------------------
71
APPENDIX C
Xxxxxxxx Xxxxxxxxxx, Associate Director for Biomedical and Environmental
Research of the Xxxxxxxx Livermore National Laboratory has read and approved the
terms and conditions of the license agreement titled "License Agreement For
Chromosome Analysis Technology with Chromosome-Specific Probes".
By /s/ Xxxxxxxx Xxxxxxxxxx Date September 29, 1989
--------------------------------- ------------------------------
Xxxxxxxx Xxxxxxxxxx
Associate Director for Biomedical
and Environmental Research
72
ADDENDUM TO LICENSE AGREEMENT FOR CHROMOSOME ANALYSIS TECHNOLOGY WITH
CHROMOSOME-SPECIFIC PROBES BETWEEN AMOCO TECHNOLOGY COMPANY AND THE REGENTS OF
THE UNIVERSITY OF CALIFORNIA DATED AUGUST 15, 1989 (US CASE NO. 85-187; 072889)
PAGE 2, RECITALS, TOP OF PAGE.
DELETE:
"make, have made, use, and sell methods, processes, compositions of matter, and
articles of manufacture as a research reagent for prenatal test subjects under
Regents' Patent Right; and as a consequence such rights granted to Licensee
hereunder are expressly subject to and limited by such preexisting rights of
third party;"
INSERT:
"WHEREAS, The Regents and another company have entered into a nonexclusive
option agreement for a nonexclusive license to make, have made, use and sell
methods, processes, compositions of matter, and articles of manufacture as a
research reagent for prenatal test subjects under Regents' Patent Rights; and as
a consequence such rights granted to Licensee hereunder are expressly subject to
and limited by such preexisting rights of such third party;"
73
AMOCO TECHNOLOGY COMPANY THE REGENTS OF THE
UNIVERSITY OF CALIFORNIA
By /s/ Xxxxxxx X. Xxxxxxxxx By /s/ X.X. Xxxxxx
--------------------------- ------------------------
(Signature) (Signature)
Name Xxxxxxx X. Xxxxxxxxx Name X.X. Xxxxxx
--------------------------- ------------------
Title President Title Director; PTCO
--------------------------- -----------------
Date 9/29/89 Date 10/4/89
--------------------------- ------------------
74
EXHIBIT 10.3a
[LETTERHEAD]
October 6, 1989
Xx. Xxxxxxx Xxxxxxx
University of California
Patent, Trademark and
Copyright Xxxxxx
0000 Xxxxxx Xxx Xxxxxxx
Xxxxx 000
Xxxxxxx, Xxxxxxxxxx 00000
Re: License Agreement for Chromosome Analysis Technology
with Chromosome-Specific Probes between Amoco Technology
Corporation and The Regents of the University of California
---------------------------------------------------------------
Dear Xx. Xxxxxxx:
We are indeed pleased to learn that there are no significant problems with the
License Agreement and that Amoco Technology Company will be receiving a fully
executed copy shortly. In your conversation of October 5, 1989 with Xx. Xxxxxxx
X. Xxxxxx, you noted that on page 12 of the License Agreement, Paragraph 2.3(c),
a reference to U.S. Patent 4,740,470 had been omitted.
Please accept our sincere apologies. Paragraph 2.3(c) should be modified to
read as follows:
c. It is not aware of anything which would be made, used, sold, or
otherwise disposed of, performed, or played under any license granted
herein that will constitute infringement of patents of third parties
except for U.S. Patent No. 4,468,464 entitled "Process and Composition
For Biologically Functional Molecular Chimeras" by X. Xxxxx, et al.
and issued 28 August 1984, U.S. Patent No. 4,237,224 entitled "Process
and Composition For Biologically Functional Molecular Chimeras" by X.
Xxxxx, et al. and issued 2 December 1980, and U.S. Patent No.
4,740,470 entitled "Process and Composition For Biologically
Functional Molecular Chimeras" by X. Xxxxx, et al. and issued 26
April, 1988;
We have provided duplicative originals of the present letter with signature of
Xx. X.X. Xxxxxxxxx below indicating Amoco Technology Company's agreement to the
modification. If the Regents of the University of California agree to the
modification, the present letter should be executed in duplicate by Xx. Xxxx
Xxxxxx or some other individual authorized by The Regents to effect
modifications of this type.
Xx. Xxxxxxx Xxxxxxx
October 6, 1989
Page 2
You may retain one copy of the present letter for your files. Please return one
fully executed copy to me.
Turning now to the related Research Agreement, accompanying this letter is a
check for two-hundred eighty-two dollars ($282.00). The check reflects the
difference between what we sent to The Regents, $122,000, and the contract
amount, $122,282. We also sincerely apologize for our error in drafting the
original check.
If you have any further comments or questions, please do not hesitate to contact
me.
Very truly yours,
/s/ Xxxx Xxxxxx
Xxxx Xxxxxx
Mail Code 1907
AJJ:vay
Enclosures
In witness whereof, both The Regents and The Licensee have executed this
modification of the above identified License Agreement, Paragraph 2.3(c), in
duplication originals, by their respective officers hereunto duly authorized, on
the day and year hereinafter written.
AMOCO TECHNOLOGY COMPANY THE REGENTS OF THE
UNIVERSITY OF CALIFORNIA
By /s/ X. X. Xxxxxxxxx By /s/ Xxxx X. Xxxxxxx
---------------------------- -------------------------
Name X.X. Xxxxxxxxx Name: Xxxx X. Xxxxxx
--------------------------
Title: President Title: Director-Patents, Trademark
---------------------------- and Copyright Office
Date: October 9, 1989 Date: October 13, 1989
----------------------------- --------------------------
EXHIBIT 10.3b
AMENDMENT TO LICENSE AGREEMENT FOR
CHROMOSOME ANALYSIS TECHNOLOGY
WITH CHROMOSOME-SPECIFIC PROBES
BETWEEN
THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
AND
AMOCO TECHNOLOGY COMPANY
THIS AMENDMENT is made and is effective this 1st day of July 1991 by and
between THE REGENTS OF THE UNIVERSITY OF CALIFORNIA, a California corporation
having its statewide administrative offices at 000 Xxxxxxxx Xxxxx, 00xx Xxxxx,
Xxxxxxx, Xxxxxxxxxx 00000-0000, hereinafter referred to as "The Regents", and
AMOCO TECHNOLOGY COMPANY, a Delaware corporation having its office at 000 Xxxx
Xxxxxx Xxxxxxxxx, Xxxxxxxxxx, Xxxxxxxx, 00000, hereinafter referred to as
"Licensee".
RECITALS
WHEREAS, Licensee and The Regents entered into a license agreement
effective August 15, 1989 having U.C. Agreement Control Number 89-03-0021,
hereinafter referred to as "License Agreement", covering licensure to
Licensee by The Regents of certain inventions generally characterized as
FLUORESCENCE HYBRIDIZATION WITH CHROMOSOME-SPECIFIC PROBES, hereinafter
collectively referred to as the "Invention", made in the course of research
at the Xxxxxxxx Livermore National Laboratory (LLNL) by Xxx X. Xxxx et al.;
WHEREAS, Licensee and The Regents entered into a research agreement
entitled RESEARCH AGREEMENT FOR THE DEVELOPMENT OF FLUORESCENCE HYBRIDIZATION
WITH CHROMOSOME SPECIFIC PROBES, hereinafter referred to as "Research
Agreement", effective August 15, 1989 for the purpose of developing the
Invention under a cooperative arrangement funded in part by Licensee at LLNL
under the direction of Principal Investigator, Xxx X. Xxxx;
WHEREAS, Licensee and The Regents entered into a second Research
Agreement entitled MOLECULAR CYTOGENETICS IN MEDICINE AND BIOLOGY, hereinafter
referred to as "Second Research Agreement" effective July 1, 1991 to expand the
work to be performed under the First Research Agreement to include development
of Repeat-Sequence Probes and Low-Complexity Probes as defined below and to
perform research in human cancer diagnosis and prognosis; and
WHEREAS, the purpose of this Amendment is to modify the License
Agreement to provide for rights in inventions and
Amendment to License Agreement 1
discoveries made in the performance of work under the Second Research Agreement
to be conveyed to Licensee.
Now, therefore, in consideration of the foregoing and the mutual promises
and covenants contained herein, the parties hereto agree as follows:
1. Article 1 (DEFINITIONS) of the License Agreement shall be amended to
include the following definitions:
1.1 "Research Program" shall mean the research which is
proposed in the Research Proposal entitled "A Proposal to
Develop Fluorescence Hybridization with Chromosome-Specific
Probes to Facilitate Cytogenetic Analysis" submitted by LLNL
to Licensee and "Molecular Cytogenetics in Medicine and
Biology" submitted under the Second Research Agreement by
the University of California to Licensee. For the purposes
of this License Agreement LLNL shall mean Xxxxxxxx Livermore
National Laboratory for events and activities transpiring
before July 1, 1991, and the University of California, San
Francisco shall be substituted for LLNL for events and
activities subsequent to July 1, 1991.
1.3. "Research Agreement" shall mean the agreement entitled
Research Agreement for the Development of Fluorescence
Hybridization with Chromosome Specific Probes between The
Regents and Licensee dated 15 August, 1989, and Research
Agreement for Molecular Cytogenetics in Medicine and Biology
dated July 1, 1991, for the conduct of Research under the
Research Program and any extensions or renewals thereof, and
incorporated herein by reference. In the event of any
inconsistencies between the Research Agreement and this
Agreement, the terms of this Agreement shall control.
1.17 "Repeat-Sequence Probe" shall mean a low complexity (up to
several tens of kb) collection of nucleic acid sequence.
Repeat sequence probes are targeted to sequences that are
repeated in the genome so that the target site is many times
larger than the complexity of the probe.
1.18 "High-Complexity Probe" shall mean a heterogeneous mixture
of nucleic acid fragments, with a complexity of 40 kb or
greater, that have selective hybridization capacity to the
genomic region of interest.
Amendment to License Agreement 2
1.19 "Low-Complexity Probe" shall mean a chromosome probe with
selective hybridization capacity to a single-copy (or near
single-copy) target in the genomic region of interest, and
having a complexity of less than 40 kb.
2. Subparagraph 2.2e of the License Agreement shall be replaced in its
entirety with the following:
The Regents own or are in the process of acquiring
title to Regents' Patent Rights, which are subject to a
nontransferable, nonexclusive, irrevocable paid-up license to practice
or have practiced, such Regents' Patent Rights for or on behalf of the
United States throughout the world, pursuant to 35 USC 202(c) (4) and
which are subject to an exclusive license to make, use and sell
methods, processes, and articles of manufacture covering
High-Complexity Probes and compositions-of-matter comprising
High-Complexity Probes expressly limited to clinical diagnostic
testing in prenatal test subjects and a nonexclusive license to make,
have made, use and sell methods, processes, and articles of
manufacture covering High-Complexity Probes and compositions-of-matter
comprising High-Complexity Probes as a research reagent for use in
prenatal test subjects to one other company. No other rights have
been granted.
3. Paragraph 3.2 shall be replaced in its entirety with the following:
3.2 During the pendency of the outstanding rights described in
2.2 (e) and during such period to the extent such outstanding rights have
vested and have not been terminated, abandoned, disclaimed, or revoked or
have not expired, the licenses set forth in Paragraph 3.1 supra shall be
limited as follows:
a. the right to make, have made, use and sell methods and
processes, covering High-Complexity Probes and
compositions-of-matter comprising High-Complexity Probes for
clinical diagnostic testing or hereditary disease testing in
prenatal subjects within the Field of Interest is expressly
excluded from this Agreement.
b. the right to make, have made, use and sell methods and
processes covering High-Complexity Probes and
compositions-of-matter comprising High-Complexity Probes as
a research reagent for use in research including prenatal
subjects within the Field of Interest shall be nonexclusive.
Amendment to License Agreement 3
In the event the outstanding rights described in 2.2 (e) expire or
after vesting are terminated, abandoned, disclaimed, or revoked, such
license and right shall pass to Licensee under the grant of Paragraph
3.1. In order to maintain such license and right, Licensee shall
within ninety (90) days of obtaining such rights, fund additional
research at LLNL, under terms and conditions consistent with the
Research Funding Agreement in an amount not to exceed two hundred and
fifty thousand dollars ($250,000.00) per year for a period of time not
less than two years under a research program and scope of the research
to be negotiated.
4. As consideration for this Amendment, Licensee shall pay earned
royalties to The Regents on all Products resulting from the Second Research
Agreement as future patent rights specified in Paragraph 1.7e of the License
Agreement at the royalty rate therein specified under Article 5. It is
understood that at no additional minimum royalties are due from Licensee, beyond
those presently specified in Paragraph 5.2 of the License Agreement.
5. Unless otherwise terminated by operation of law or by the acts of the
parties in accordance with the terms of the License Agreement, this Amendment
shall be in force from the effective date recited on page one and for a term
concurrent with the License Agreement.
IN WITNESS WHEREOF, both the Regents and the Licensee have executed this
Amendment, in duplicate originals, by their respective officers hereunto duly
authorized, on the day and year hereinafter written.
AMOCO TECHNOLOGY COMPANY THE REGENTS OF THE UNIVERSITY
OF CALIFORNIA
By: /s/ X.X. Xxxxxxxxx By: /s/ Xxxx X. Xxxxxxx
---------------------------- ---------------------------------
Name: X. X. Xxxxxxxxx Name: Xxxx X. Xxxxxxx
Title: President Title: Director--Patent
Amoco Technology Company Trademark and Copyright
Office
Date: July 24, 1991 Date: 7/25/91
Amendment to License Agreement 4
EXHIBIT 10.3c
SECOND AMENDMENT TO LICENSE AGREEMENT FOR
CHROMOSOME ANALYSIS TECHNOLOGY
WITH CHROMOSOME-SPECIFIC PROBES
BETWEEN
THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
AND
AMOCO TECHNOLOGY COMPANY
This Second Amendment to the License Agreement is made and is effective
this 15th day of April 1992 by and between THE REGENTS OF THE UNIVERSITY OF
CALIFORNIA, a California corporation having its statewide administrative offices
at 000 Xxxxxxxx Xxxxx, 00xx Xxxxx, Xxxxxxx, Xxxxxxxxxx 00000-0000,
hereinafter referred to as "The Regents", and AMOCO TECHNOLOGY COMPANY, a
Delaware corporation having offices at 000 Xxxx Xxxxxx Xxxxxxxxx, Xxxxxxxxxx,
Xxxxxxxx, 00000, hereinafter referred to as "Licensee".
RECITALS
WHEREAS, Licensee and The Regents entered into a license agreement
effective August 15, 1989, having U.C. Agreement Control No.: 89-03-0021,
amended on July 1, 1991 (Control No.: 89-03-0021), hereinafter referred to as
"License Agreement", covering licensure to Licensee by The Regents of
certain inventions generally characterized as FLUORESCENCE HYBRIDIZATION WITH
CHROMOSOME-SPECIFIC PROBES, hereinafter collectively referred to as the
"Invention", made in the course of research at the Xxxxxxxx Livermore
"Invention", National Laboratory (LLNL) by Xxx X. Xxxx et al.;
1
WHEREAS, Licensee and The Regents entered into a research agreement
entitled RESEARCH AGREEMENT FOR THE DEVELOPMENT OF FLUORESCENCE HYBRIDIZATION
WITH CHROMOSOME-SPECIFIC PROBES, hereinafter referred to as "First Research
Agreement", effective August 15, 1989 and terminated on June 30, 1991, for the
purpose of developing the Invention under a cooperative arrangement funded in
part by Licensee at LLNL under the direction of Principal Investigator, Xxx X.
Xxxx;
WHEREAS, Licensee and The Regents entered into a second research
agreement entitled MOLECULAR CYTOGENETICS IN MEDICINE AND BIOLOGY, hereinafter
referred to as "Second Research Agreement" effective July 1, 1991 to expand the
work to be performed under the First Research Agreement to include development
of Repeat-Sequence Probes and Low-Complexity Probes and to perform research in
human cancer diagnosis and prognosis;
WHEREAS, certain inventions were made in the course of research at
LLNL and at the University of California, San Francisco campus (UCSF) and are
specified in Subparagraphs 1.7n through 1.7s hereinafter collectively referred
to as "New Inventions", relating to the subject matter of this Second Amendment
to the License Agreement, as previously amended, and such New Inventions were
made under funding provided by the U.S. Government but were not made with
funding provided by Licensee under the Research Agreement;
WHEREAS, certain inventions were made in the course of research at
LLNL and at UCSF and are specified in Subparagraphs 1.7t through 1.7v,
hereinafter referred to as
2
"Funded Inventions" and were made under funding provided in part by Licensee and
in part by the U.S. Government;.
WHEREAS, The Regents may elect to retain title to any inventions
funded by the U.S. Government at any of its campuses; and if title is elected by
The Regents, The Regents in turn grants back to the U.S. Government a
non-transferrable, non-exclusive, irrevocable, royalty-free license to practice
or have practiced, the invention for or on behalf of the United States
throughout the world;
WHEREAS, The Regents has elected to retain title to the New Inventions
and Funded Inventions as specified in Paragraph 2.2c herein;
WHEREAS, Licensee is desirous of acquiring exclusive licenses from The
Regents to patent rights covering said New Inventions and Funded Inventions in
Licensee's Field of Interest (defined in the License Agreement) with the intent
of commercializing such New Inventions, Funded Inventions, and Products
identified directly from their use;
WHEREAS, The Regents is willing to amend the License Agreement to
grant such exclusive licenses to Licensee for the patent rights covering the New
Inventions and Funded Inventions to insure their commercialization and the
commercialization of Products identified therefrom so that the benefits can be
enjoyed by the general public; and
WHEREAS, as of the effective date recited on page one of this Second
Amendment to the License Agreement, the parties hereto have concluded, for their
convenience, that a proper value of the material that identify Protected and
Unprotected Derived Probe Products (defined below) be paid to The Regents on the
Net Sales of Protected and Unprotected Derived Probe Products at a rate set
forth herein.
3
The parties agree as follows:
1. Paragraph 1.4 (BACKGROUND BIOLOGICAL MATERIALS) shall be replaced in
its entirety with the following:
1.4 "Background Biological Materials" shall mean:
a. biological materials developed prior to the effective date
of this License Agreement by The Regents relating to in
situ hybridization with chromosome-specific probes under
the direction of Xxx X. Xxxx at LLNL under Contract
W-7405-ENG-48 between The Regents and United States
Department of Energy (DOE). Background Biological
Materials includes High-Complexity Probes and biological
materials comprising a heterogeneous mixture of nucleic
acid fragments, which fragments are derived from known
chromosome types. The fragments have selective
hybridization capacity to chromosomes of interest and are
carried on plasmid constructs known as pBS-l, pBS-2,
pBS-3, pBS -0, xXX-0, xXX-0, pBS-7, pBS-8, pBS-9, pBS-10,
pBS-ll, pBS-12, pBS-13, pBS-14,pBS-15, pBS-16, pBs-17,
pBS-18, pBS-l9, pBS-20, pBS-21, pB5-22, pBS-X and pBS-Y
(nomenclature of LLNL).
b. biological materials developed prior to the effective date
of the Second Amendment to this License Agreement by the
Regents relating to in situ hybridization with
chromosome specific probes including High Complexity
Probes, Low Complexity Probes and Repeat-Sequence Probes
and biological materials comprising a heterogeneous
mixture of nucleic acid fragments, which fragments are
derived from known chromosome types. The fragments have
selective hybridization capacity to the target of interest
and were developed:
(i) under the direction of Xxx. X. Xxxx at LLNL.
Background Biological Materials include biological
materials generally described as primers and as a
heterogeneous mixture of nucleic acid fragments
consisting of oligonucleotides, genomic DNA, and/or
cDNA clones comprising highly specific Repeat-
Sequence Probes that bind with interspersed and/or
clustered repeat-sequences to the target of interest
and include: Xxxxxxxxxxxxxxxx (XXX0, XXX0, XXX0,
XXX0, XXX0, XXX0, XXX0, WYR10, WA1, WA2,
4
WA8, WA9, WAll, WA12, W21R1, W21R2, JUN1); PCR
Products (1548 [chromosome 9], 1555 [chromosome 9],
704 [chromosome 1], 197 [chromosome 3], 864
[chromosome 6], 1004 [chromosome 9], 630 [chromosome
10], 745 [chromosome 11], 865 [chromosome 18], 554
[chromosome 12], 712 [chromosome 8], 207 [chromosome
12], 208 [chromosome 12-biot], tubes 6,7,8
containing Y-chromosome specific fragments; 248 bp
Y-chromosome-specific fragments; Bacterial clones
(W21R2-13, W21R2-17, W21R2-20, W21R2-24 [chromosome
9], 8B/7-1 [chromosome 13/21], PCR Generated SAU 3A
Libraries for Chromosomes 2,3,5 and 17 in PCR1000,
pBS609-51 [chromosome 10], 680TA-17 [chromosome 7],
pBS124Y-7 [Y chromosome]); Other DNA's and labeled
probes, such as nick translated probes etc. (FITC-,
TRITC-and AMCA-labeled nick translation products
from Imagenetics Y-specific DNA, biotinylated
pBS609-51 [chromosome 10] (nomenclature of UCSF);
(ii) under the direction of Xxxx Xxxxxxx at UCSF.
Background Biological Materials include biological
materials generally described as comprising a
heterogenous mixture of nucleic acid fragments
consisting of genomic DNA and/or cDNA clones of the
ATDC gene located at chromosome position 11q23 and
are carried on genetic constructs consisting of
cosmid clones K1, K41, 3-1 and 4-1 (nomenclature
of UCSF);
(iii) under the direction of Xxxxxxx Xxxxxx at UCSF.
Background Biological Materials include biological
materials generally described as comprising a
heterogeneous mixture of nucleic acid fragments
consisting of genomic DNA and/or cDNA clones of the
BCL-1 gene located at chromosome position 11ql3 and
are carried on genetic constructs consisting of
plasmids, phages and cosmids know as BCL-1
(nomenclature of UCSF);
2. Paragraph 1.5 (BACKGROUND INFORMATION) shall be replaced in its
entirety with the following:
1.5 "Background Information" shall mean
5
a. all technical data, processes, methods, inventions,
Background Biological Materials, equipment, instruments,
apparatuses, devices, and articles of manufacture developed
or acquired prior to August 15, 1989 (to the extent that
such Background information may be revealed to Licensee) by
The Regents relating to IN SITU hybridization with
chromosome specific probes under the direction of Xxx X.
Xxxx at LLNL under Contract W-7405-ENG-48 between the United
States Department of Energy (DOE) and The Regents.
Background information does not include computer software,
information management systems, or equipment comprising a
cell sorter or component part(s) thereof. Under this
Agreement, there shall be no transfer of the physical
possession of equipment, instruments, apparatuses,
devices, articles of manufacture or component part(s)
thereof or intellectual property rights to computer
software, information management systems or equipment
comprising a cell sorter or component part(s) thereof that
are not covered by Regents' Patent Rights.
b. all technical data, processes, methods, inventions,
Background Biological Materials, equipment, instruments,
apparatuses, devices, and articles of manufacture developed
or acquired prior to the effective date of the Second
Amendment to this License Agreement (to the extent that such
Background Information may be revealed to the Licensee)
by The Regents relating to the New Inventions set forth
under Subparagraphs 1.7n through 1.7q under the direction of
Xxx X. Xxxx at LLNL. Background Information does not
include computer software, information management systems,
or equipment comprising a cell sorter or component part(s)
thereof. Under this Agreement, there shall be no transfer
of physical possession of equipment, instruments,
apparatuses, devices, articles of manufacture or component
part(s) thereof or intellectual property rights to computer
software, information management systems or equipment
comprising a cell sorter or component part(s) thereof that
are not covered by Regents' Patent Rights.
c. all technical data, processes, methods, inventions,
Background Biological Materials, equipment, instruments,
apparatuses, devices, and articles of manufacture developed
or acquired prior to the Second Amendment to this License
Agreement (to the extent that such Background Information
may be revealed to the Licensee) by The Regents relating to
the New Inventions set forth under Subparagraph 1.7r under
the direction of Xxxx
6
Xxxxxxx at UCSF. Background Information does not include
computer software, information management systems, or
equipment comprising a cell sorter or component part(s)
thereof. Under this Agreement, there shall be no transfer of
physical possession of equipment, instruments, apparatuses,
devices, articles of manufacture or component part(s)
thereof or intellectual property rights to computer
software, information management systems or equipment
comprising a cell sorter or component part(s) thereof that
are not covered by Regents' Patent Rights.
d. all technical data, processes, methods, inventions,
Background Biological Materials, equipment, instruments,
apparatuses, devices, and articles of manufacture developed
or acquired prior to the Second Amendment to this License
Agreement (to the extent that such Background Information
may be revealed to the Licensee by The Regents relating to
the New Inventions set forth under Subparagraph 1.7s under
the direction of Xxxxxxx Xxxxxx at UCSF. Background
Information does not include computer software, information
management systems, or equipment composing a cell sorter or
component part(s) thereof. Under this Agreement, there
shall be no transfer of physical possession of equipment,
instruments, apparatuses, devices, articles of manufacture
or component part(s) thereof or intellectual property
rights to computer software, information management systems
or equipment comprising a cell sorter or component part(s)
thereof that are not covered by Regents' Patent Rights.
3. Paragraph 1.6 (RESEARCH INFORMATION) shall be replaced in its entirety
with the following:
1.6 "Research Information" shall mean technical data, processes,
methods, inventions, compositions-of-matter, and biological materials
(including but not limited to High-Complexity Probes, Low-Complexity
Probes and/or Repeat-Sequence Probes), equipment, instruments,
apparatuses, devices, articles of manufacture or component part(s)
thereof developed under or resulting from the performance of Research
under the Research Agreement and improvements
7
thereof, except for improvements on new subject matter not funded by
Licensee. There shall be no creation or development of computer
software or information management systems in the performance of
Research under the First Research Agreement and there shall be no
transfer of the physical possession of equipment, instruments,
apparatuses, devices, articles of manufacture or component part(s)
thereof comprising Research Information.
4. Paragraph 1.7 (REGENTS' PATENT RIGHTS) shall be replaced in its
entirety by the following:
1.7 "Regents' Patent Rights" shall mean all U.S. and foreign
patents and patent applications, including any reissues,
extensions, continuations, divisions, and continuations-in-part
(to the extent that such continuations-in-part are dependent upon
the parent case and subject matter arising out of the Research
Agreement) based on inventions and improvements thereof arising
out of Background Information or Research Information including:
a. Pending U.S. Patent Application Serial No.: 819,314
(UC Case No.: 85-157-1) entitled "Method and
Compositions for Chromosome Specific Staining", by
Xxx X. Xxxx and Xxxxxx Xxxxxx filed 16 January 1986
and assigned to The Regents, abandoned in favor
of U.S. Patent Application Serial No.: 382,094 (UC
Case No.: 85-157-5);
b. U.S. Patent Application Serial No.: 937,793 (UC Case
No.: 85-157-2) entitled "Methods and Compositions
for Chromosome Specific Staining" by Xxx X. Xxxx and
Xxxxxx Xxxxxx filed 4 December 1986 and assigned to
The Regents, a continuation-in-part application of
U.S. Serial No.: 819,314 (UC Case No.: 85-157-1),
abandoned in favor of US Application Serial No.:
627,707 (UC Case No.: 85-157-9);
8
c. U.S. Patent Application Serial No.: 934,188 (UC
Case No.: 85-157-3) entitled "Method of Preparing
and Applying Single Stranded DNA Probes to Double
Stranded Target DNAs, by Xxx X. Xxxx and Xxxxxx
Xxxxxx filed 24 November 1986 and assigned to The
Regents, abandoned in favor of U.S Patent No.:
5,028,525 (UC Case No.: 85-157-8);
d. U.S. Patent Application Serial No.: 444,669 (UC Case
No.: 85-157-4) entitled "Method for Determining
Aneuploidy in Fetal Cells from Maternal Blood
Samples" by Xxx X. Xxxx and Xxxxxx Xxxxxx filed 1
December, 1989 and assigned to The Regents, a
continuation-in-part application of U.S. Patent
Application Serial No.: 937,793 (UC Case No.:
85-157-2),
e. U.S. Patent Application Serial No.: 382,094 (UC Case
No.: 85-157-5) entitled "Methods and Compositions for
Chromosome-Specific Staining", by Xxx X. Xxxx and
Xxxxxx Xxxxxx filed 19 July, 1989 and assigned to
The Regents, a file-wrapper-continuation of U.S.
Patent Application Serial No.: 819,314(UC Case No.:
85-157-1).
f. U.S. Patent Application Serial No.: 497,098 (UC Case
No.: 85-157-6) entitled "Chromosome-Specific Staining
to Detect Genetic Rearrangements" by Xxx X. Xxxx,
Xxxxxx Xxxxxx and Xxxxxxx Xxxxxxx, filed 20 March
1990 and assigned to The Regents, a
continuation-in-part application of U.S. Patent
Application Serial No.: 446,669 (UC Case No.:
85-157-4);
g. U.S. Patent Application Serial No.: 537,305 (UC Case
No.: 85-157-7) entitled "Chromosome Specific Staining
to Detect Genetic Rearrangements" by Xxx X. Xxxx,
Xxxxxx Xxxxxx and Xxxxxxx Xxxxxxx filed 12 June 1990
and assigned to The Regents, a
continuation-in-part-application of U.S. Patent
Application Serial No.: 497,098 (UC Case No.:
85-176-6).
h. U.S Patent No.: 5,028,525 (UC Case No.: 85-157-8)
entitled "Method of Preparing and Applying Single
Stranded DNA Probes to Double Stranded Target DNAs
In Situ", by Xxx Xxxx and Xxxxxx Xxxxxx filed 26
June 1990 and assigned to The Regents, issuing from
a continuation application of Patent Application
Serial No.: 934,188 (UC Case No.: 85-157-3);
i. U.S. Patent Application Serial No.: 627,707 (UC Case
No.: 85-157-9) entitled "Methods and Compositions for
Chromosome-
9
Specific Staining) by Xxx X. Xxxx and Xxxxxx Xxxxxx
filed 14 December 1990 and assigned to The Regents,
a continuation application of U.S. Patent
Application Serial No.: 937-793 (UC Case No.:
85-157-2);
j. U.S. Patent Application Serial No.: 659,974 (UC Case
No.: 85-157-A entitled "Chromosome-Specific Staining
to Detect Genetic Rearrangements" by Xxx X. Xxxx,
Xxxxxx Xxxxxx, Xxxx Xxxxxxxxxxx, Masara Sakamoto,
and Olli-Pekka Kallioniemi filed 22 February 1991
and assigned to The Regents, a continuation-in-part
application of U.S. Patent Application Serial No.:
537-305 (UC Case No.: 85-157-7),
k. U.S. Patent Application Serial No.: 670,242 (UC Case
No.: 85-157-B) entitled "Chromosome-Specific Staining
to Detect Genetic Rearrangements" by Xxx X. Xxxx,
Xxxxxx Xxxxxx, Xxxx Xxxxxxxxxxx, Masara Sakamoto,
and Olli-Pekka Kallioniemi filed 14 March 1991 and
assigned to The Regents, a continuation-in-part
application of U.S. Patent Application Serial No.:
659,974 (UC Case No.: 85-157-A);
1. U.S. Patent Application Serial No.: 721,236 (UC
Case No.: 91-155-2) entitled "Linker
Chromosome-Specific Painting Probes" by Xxx X. Xxxx,
Xxxxxx Xxxxxx, Xxxxxxx Xxxxxxx and Xxx Xxxxxxx filed
27 June, 1991 and assigned to The Regents and
separately to the University of Miami, a
continuation-in-part application of Patent
Application Serial No.: 659,974 (UC Case No.:
85-157-A)
m. U.S. Patent Application Serial No.: 743,524 (UC Case
No.: 91-155-3) entitled "Linker Chromosome-Specific
Painting Probes and Painting Therewith" by Xxx X.
Xxxx, Xxxxxx Xxxxxx, Xxxxxxx Xxxxxxx and Xxx
Xxxxxxx filed 9 August, 1991 and assigned to The
Regents and separately to the University of Miami, a
continuation-in-part application of Patent
Application Serial No.: 721,236 (UC Case No.:
91-155-2);
n. U.S. Patent Application Serial No.: 594,922 (UC Case
No.: 89-269-1) entitled "Y Specific Nucleic Acid
Probe and Diagnostic Method for Determining Fetal
Gender from Maternal Blood Samples" by Xxxxx-Xxxxxx
X. Xxxxx et al., filed 10 October, 1990 and
assigned to The Regents;
10
o. U.S. Patent Application Serial No.: 683,441 (UC Case
No.: 89-263-1) entitled "Repeat Sequence Chromosome
Specific Nucleic Acid Probes" by Xxxxx-Xxxxxx X.
Xxxxx et al., filed 9 April, 1991 and assigned to
The Regents;
p. U.S. Patent Application Serial No.: 594,921 (UC Case
No.: 90-249-1) entitled "Y Chromosome Specific
Nucleic Acid Probe and Method for Identifying the Y
Chromosome In Situ" by Dr. Xxx Xxxx et al., filed 10
October, 1990 and assigned to The Regents;
q. Any future patent application describing any
invention disclosed under UC Case No.: 91-196
entitled "Specific Oglionucleotide to Stain the
Centromeric Region of Human Chromosomes" by
Xxxxx-Xxxxxx X. Xxxxx et al;
r. Any patent application describing any invention
disclosed under UC Case No.: 91-077 entitled "Probe
for AT Genes" by Xxxx Xxxxxxx et al;
s. Any patent application describing any invention
disclosed under UC Case No.: 91-210 entitled "Human
Oncogene Probes" by Xxxxxxx Xxxxxx et al;
t. Any patent application describing any invention
disclosed under UC Case No.: 92-005 entitled "Gene
Probes" by Xxxxxx Xxxxxx et al;
u. Any patent application describing any invention
disclosed under UC Case No.: 92-006 entitled "B/B
-xxx-B2" by Xxxxxx Xxxxxx et al;
v. U.S. Patent Application Serial No.: 776,550 (UC Case
No.: 91-053) entitled "Simultaneous In-Situ
Hybridization and Cell Proliferation Analyses" by
Xxx X. Xxxx, Xxxxxx Xxxxxx and Xxxxxxxxx Xxxxxxx
filed 1 October, 1991 and assigned to The Regents;
w. Any future patent rights to subject matter claimed
in or covered by a patent application(s) covering
any invention arising in the performance of work
under the Research Agreement and elected by Licensee
under the provisions of Article VIII of the Research
Agreement.
11
x. U.S. Patent Application Serial No.: ____________ (UC
Case No.: 85-157-C) entitled "Method for Determining
Aneuploidy in Fetal Cells from Maternal Blood
Samples" by Xxx X. Xxxx and Xxxxxx Xxxxxx filed, 2
April, 1992 and assigned to The Regents, a
continuation of U.S. Patent Application Serial No.:
444,669 (UC Case No.: 85-157-4)
5. Paragraph 1.8 (PROTECTED COMPOSITION PRODUCTS) shall be replaced
in its entirety with the following:
1.8 "Protected Composition Products" shall mean kits, reagents and
compositions (including, but not limited to, High-Complexity Probes,
Low-Complexity Probes, and/or Repeat-Sequence Probes), or the
performance of a process or method, or such kits, reagents, or
compositions produced by processes or methods, falling within the
scope of one or more claims of Regents' Patent Rights during the
term of the patent grant, in such countries in which such claim or
claims have issued, and have not expired, been abandoned, disclaimed
or found invalid or unenforceable.
6. Paragraph 1.9 (UNPROTECTED COMPOSITION PRODUCTS) shall be replaced in
its entirety with the following:
1.9 "Unprotected Composition Products" shall mean kits, reagents, and
compositions (including but not limited to, High-Complexity Probes,
Low-Complexity Probes and/or Repeat Sequence Probes) or the
performance of processes or methods, or kits, reagents, or
compositions produced by processes or methods, which are not Protected
Compositions Products; i)
12
falling within the scope of one or more pending claims of Regents'
applications identified in Subparagraph 1.7a through Subparagraph 1.7d
as originally filed and set forth in Schedule A, incorporated by
reference herein; or ii) falling within the scope of one or more
pending claims of Regents' applications identified in Subparagraph
1.7e through Subparagraph 1.7x; during the period and in such
countries in which such claim or claims have not issued and are
pending, and have not expired, been abandoned, disclaimed, or found
invalid or unenforceable, such period not to exceed five years from
the effective date of this Agreement, or five years from the date in
which substantially the same subject matter (set forth in i and ii
immediately above) is first introduced in a patent application in each
country that such patent application is filed, whichever is longer.
7. Paragraph 1.11 (UNPROTECTED INSTRUMENT PRODUCTS) shall be replaced in
its entirety with the following:
1. 11 "Unprotected Instrument Products" shall mean equipment,
instruments, apparatuses, devices, articles of manufacture or
component part(s) thereof or equipment, instruments, apparatuses,
devices, articles of manufacture or component part(s) thereof produced
by processes or methods, which are not Protected Instrument Products;
i) falling within the scope of one or more pending claims of Regents'
Patent Rights identified in Subparagraph 1.7a.-d. as originally filed
and set forth in Schedule A, incorporated by reference herein; or ii)
falling within the scope of one or more pending claims of
13
Regents' applications identified in Subparagraph 1.7e through
Subparagraph 1.7x; during the period and in such countries in which
such claim or claims have not issued and are pending, and have not
expired, been abandoned, disclaimed, or found invalid or
unenforceable, such period not to exceed five years from the effective
date of this Agreement, or five years from the date in which
substantially the same subject matter (set forth in i and ii
immediately above) is first introduced in a patent application in each
country that such patent application is filed, whichever is longer.
8. Paragraph 1.17 (REPEAT-SEQUENCE PROBES) shall be replaced in its
entirety with the following:
1.17 "Repeat-Sequence Probes" shall mean a heterogeneous mixture of
nucleic acid fragments comprising highly specific chromosome
Repeat-Sequence Probes that bind with interspersed and/or clustered
sequences that are repeated in the genome so that the target site is
many times larger than the complexity of the probe.
9. Paragraph 1.18 (HIGH-COMPLEXITY PROBES) shall be replaced in its
entirety with the following:
1.18 "High Complexity Probe" shall mean a heterogeneous mixture that
contains labeled nucleic acid fragments that are substantially
complementary to targeted unique sequence regions of complexity of at
least 35 kilobases (kb) on one or more specific chromosomes, one or
more specific subsets of chromosomes, or one or more specific
sub-regions of specific chromosomes
14
which mixture either is substantially free of repetitive nucleic acid
sequences or contains sufficient unlabeled repetitive nucleic acid
sequences to inhibit substantial binding of the labeled repetitive
nucleic acid sequences to repetitive nucleic acid sequences in said
chromosomes, said subsets of chromosomes or said sub-regions of
chromosomes such that the targeted sequences bind sufficiently more
labeled probe during in situ hybridization than non-targeted sequences
so that they can be detected and distinguished from non-targeted
sequences whether the targeted sequences are present at copy numbers
that are normal for haploid or diploid cells or are present at higher
copy numbers.
10. Paragraph 1.19 (LOW-COMPLEXITY PROBES) shall be replaced in its
entirety with the following:
1.19 "Low-Complexity Probe" shall mean a heterogeneous mixture of
nucleic acid fragments that have selective hybridization capacity to a
single-copy (or near single-copy) target in the genomic region of
interest, and having a complexity of less than 35 kb.
12. Article 1 (DEFINITIONS) shall be further amended to include the
following definitions:
1.20 "Protected Derived Probe Products" shall mean kits, reagents, or
compositions both a) comprising a chromosome probe, DNA sequence, or
fragment thereof, or any other material produced through any method,
including but not limited to chemical synthesis, whereby said kits,
reagents or compositions were identified using any material or
maternal fragment, or any
15
material or material fragment produced by any process or method and b)
falling within the scope of one or more claims under Regents' Patent
Rights during the term of the patent grant, in such countries in which
such claim or claims have issued, and have not expired, been
abandoned, disclaimed, or found invalid or unenforceable.
1.21 "Unprotected Derived Probe Products" shall mean kits, reagents
and compositions both a) comprising a chromosome probe, DNA sequence
or fragment thereof, or any other material produced through any
method, including but not limited to chemical synthesis, whereby
said kits, reagents and compositions were identified using any
material or material fragment, or any material or material fragment
produced by any process or method and b) falling within the scope of
one or more pending claims of Regents' Patent Rights during the
period and in such countries in which such claim or claims have not
issued and are pending, and have not expired, been abandoned,
disclaimed, or found invalid or unenforceable, such period not to
exceed five (5) years from the effective date of the Second
Amendment to this License Agreement, or for five (5) years from the
date in which a first patent application covering the material used,
or any material produced by processes or methods used, to identify
such Unprotected Derived Probe Product, is introduced in each
country that such patent application is filed, whichever is longer.
12. Paragraph 1.12 (PRODUCTS) shall be replaced in its entirety as
follows:
16
1.12 Products shall mean Protected Composition Products, Unprotected
Composition Products, Protected Instrument Products, Unprotected
Instrument Products, Protected Derived Probe Products, and Unprotected
Derived Probe Products.
13. Paragraph 2.2 (REPRESENTATIONS AND WARRANTS) shall be replaced in its
entirety with the following:
2.2 The Regents represents and warrants the following:
a. Regents' Patent Rights were developed under
Contract W-7405-ENG-48 between The Regents and the United
States Department of Energy (DOE) and from grants provided
by other U.S. Government agencies and with additional
funding and assistance from a third party(s) as well as by
Licensee;
b. Pursuant to the terms of Contract W-7405-ENG-48 and
PL96-517, as amended, title to Regents' Patent Rights rests
in the U.S. Government without action on the Regents' part
to acquire or retain title;
c. The Regents has petitioned the DOE for a waiver of rights
which has been granted or has elected to retain title to an
invention covered by Regents' Patent Rights as summarized
below:
i. Pending U.S. Patent Application Serial No.: 819,314
(UC Case No.: 85-157-1) entitled "Method and
Compositions for Chromosome Specific Staining" by
Xxx X. Xxxx and Xxxxxx Xxxxxx, filed 16 January 1986
and assigned to The Regents, waiver applied for 30
June 1986 and waiver granted November 23, 1987;
ii. U.S. Patent Application Serial No.: 937,793 (UC Case
No.: 85-157-2) entitled "Methods and Compositions
for Chromosome Specific Staining" by Xxx X. Xxxx and
Xxxxxx Xxxxxx, filed 4 December 1986 and assigned to
The Regents, waiver applied for June 30, 1986 and
waiver granted November 23, 1987
17
iii. U.S. Patent Application Serial No.: 934,188 (UC Case
No.: 85-157-3) entitled "Method of Preparing and
Applying Single Stranded DNA Probes to Double
Stranded Target DNAs" by Xxx X. Xxxx and Xxxxxx
Xxxxxx, filed 24 November 1986 and assigned to The
Regents, waiver applied for August 18, 1986 and
waiver granted October 8, 1987;
iv. U.S. Patent Application Serial No.: 444,669 (UC
Case No.: 85-157-4) entitled "Method for Determining
Aneuploidy in Fetal Cells from Maternal Blood
Samples" by Xxx X. Xxxx and Xxxxxx Xxxxxx, filed 1
December, 1989 and assigned to The Regents, waiver
granted November 23, 1987;
v. U.S. Patent Application Serial No.: 382,094 (UC Case
No.: 85-157-5) entitled "Methods and Compositions
for Chromosome-Specific Staining" by Xxx X. Xxxx and
Xxxxxx Xxxxxx, filed 19 July, 1989 and assigned to
The Regents, waiver applied for June 30, 1986 and
waiver granted November 23, 1987;
vi. U.S. Patent Application Serial No.: 497,098 (UC Case
No.: 85-157-6) entitled "Chromosome-Specific
Staining to Detect Genetic Rearrangements" by Xxx X.
Xxxx, Xxxxxx Xxxxxx and Xxxxxxx Xxxxxxx, filed 20
March 1990 and assigned to The Regents, elected
April 30, 1990;
vii. U.S. Patent Application Serial No.: 537,305 (UC Case
No.: 85-157-7) entitled "Chromosome Specific
Staining to Detect Genetic Rearrangements" by Xxx X.
Xxxx, Xxxxxx Xxxxxx and Xxxxxxx Xxxxxxx, filed 12
June 1990 and assigned to The Regents, elected
November 27, 1990;
viii. U.S Issued Patent No.: 5,028,525 (UC Case No.:
85157-8) entitled "Method of Preparing and Applying
Single Stranded DNA Probes to Double Stranded Target
DNA's in Situ" by Xxx Xxxx and Xxxxxx Xxxxxx, filed
26 June 1990 and assigned to The Regents, elected
November 27, 1990;
18
ix. U.S. Patent Application Serial No.: 627,707 (UC Case
No.: 85-157-9) entitled "Methods and Compositions
for Chromosome-Specific Staining" by Xxx X. Xxxx and
Xxxxxx Xxxxxx, filed 14 December 1990 and assigned
to The Regents, waiver applied for August 18, 1986
and waiver granted October 8, 1987;
x. U.S. Patent Application Serial No.: 659,974 (UC Case
No.: 85-157-A) entitled "Chromosome-Specific
Staining to Detect Genetic Rearrangements" by Xxx X.
Xxxx, Xxxxxx Xxxxxx, Xxxx Xxxxxxxxxxx, Masara
Sakamoto, and Olli-Pekka Kallioniemi, filed 22
February 1991 and assigned to The Regents, elected
March 27, 1991;
xi. U.S. Patent Application Serial No.: 670,242 (UC Case
No.: 85-157-B) entitled "Chromosome-Specific
Staining to Detect Genetic Rearrangements" by Xxx X.
Xxxx, Xxxxxx Xxxxxx, Xxxx Xxxxxxxxxxx, Masara
Sakamoto, and Olli-Pekka Kallioniemi, filed 14 March
1991 and assigned to The Regents, elected February
25, 1992;
xii. U.S. Patent Application Serial No.: 721,236 (UC
Case No.: 91-155-2) entitled "Linker
Chromosome-Specific Painting Probes" by Xxx X. Xxxx,
Xxxxxx Xxxxxx, Xxxxxxx Xxxxxxx and Xxx Xxxxxxx, filed
27 June, 1991 and assigned to The Regents and
separately to the University of Miami, elected March
16, 1992.
xiii. U.S. Patent Application Serial No.: 743,524 (UC
Case No.: 91-155-3) entitled "Linker
Chromosome-Specific Painting Probes and Painting
Therewith" by Xxx X. Xxxx, Xxxxxx Xxxxxx, Xxxxxxx
Xxxxxxx and Xxx Xxxxxxx, filed 9 August, 1991 and
assigned to The Regents and separately to the
University of Miami, elected March 16, 1992;
xiv. U.S. Patent Application Serial No.: 594,922 (UC Case
No.: 89-269) entitled "Y Specific Nucleic Acid Probe
and Diagnostic Method for Determining Fetal Gender
from Maternal Blood Samples" by Xxxxx-Xxxxxx X.
Xxxxx et al., filed 10 October, 1990 and assigned to
The Regents, elected September 26, 1989;
19
xv. U.S. Patent Application Serial No.: 683,441 (UC Case
No.: 89-263) entitled "Repeat Sequence Chromosome
Specific Nucleic Acid Probes" by Xxxxx-Xxxxxx X.
Xxxxx et al., filed 9 April, 1991 and assigned to
The Regents elected November 19, 1990;
xvi. U.S. Patent Application Serial No.: 594,921 (UC Case
No.: 90-249) entitled "Y Chromosome Specific Nucleic
Acid Probe and Method for Identifying the Y
Chromosome in Situ" by Dr. Xxx Xxxx et al., filed 10
October, 1990 and assigned to The Regents, waiver
applied for September 26, 1989, not yet granted;
xvii. Any patent application describing any invention
disclosed under UC Case No.: 91-196 entitled
"Specific Oglionucleotide to Stain the Centromeric
Region of Human Chromosomes" by Xxxxx-Xxxxxx X.
Xxxxx et al., and assigned to The Regents; elected
March 18, 1992;
xviii. Any patent application describing any invention
disclosed under UC Case No.: 91-077 entitled " Probe
for AT Genes" by Xxxx Xxxxxxx et al., and assigned
to The Regents, elected October 1, 1991;
xix. U.S. Patent Application Serial No.: 776,550 (UC
Case No.: 91-053) entitled "Simultaneous In-Situ
Hybridization and Cell Proliferation Analyses" by
Xxx X. Xxxx, Xxxxxx Xxxxxx and Xxxxxxxxx Xxxxxxx,
filed 1 October, 1991 and assigned to The Regents,
elected March 28, 1991;
xx. Any patent application describing any invention
disclosed under UC Case No.: 91-210 entitled "Human
Oncogene Probes" by Xxxxxxx Xxxxxx, and assigned to
The Regents, to be elected by The Regents;
xxi. Any patent application describing any invention
disclosed under UC Case No.: 92-005 entitled "Gene
Probes" by Xxxxxx Xxxxxx et al., and assigned to The
Regents, elected 2/24/92;
xxii. Any patent application describing any invention
disclosed under UC Case No.: 92-006 entitled
"C-xxx-B2" by
20
Xxxxxx Xxxxxx et al., and assigned to
The Regents, to be elected by The Regents;
xxiii. U.S. Patent Application Serial No.:________________
(UC Case No.: 85-157- C) entitled "Method for
Determining Aneuploidy in Fetal Cells from
Maternal Blood Samples" by Xxx X. Xxxx and Xxxxxx
Xxxxxx, filed 2 April, 1992 and assigned to The
Regents.
d. The list of patent and patent applications identified in
subparagraph 1.7a. through subparagraph 1.7x is a complete
list of Regents' Patent Right arising at LLNL and UCSF, and
that there are no other patents or patent applications at
LLNL covering inventions made under the direction of Xxx
Xxxx which may comprise Background Biological Materials and
Background Information;
e. The Regents own or are in the process of acquiring title to
Regents' Patent Rights, which are subject to a
nontransferable, nonexclusive, irrevocable paid-up license
to practice or have practiced, such Regent's Patent Rights
for or on behalf of the United States throughout the world,
pursuant to 35 USC 202(c) (4) and which are subject to an
exclusive license to make, use and sell methods, processes,
articles of manufacture covering High-Complexity Probes and
compositions-of-matter comprising High-Complexity Probes
expressly limited to clinical diagnostic testing in prenatal
test subjects and a nonexclusive license to make, have made,
use and sell methods, processes and articles of manufacture
covering High-Complexity Probes and compositions of matter
comprising High-Complexity Probes as a research reagent for
use in prenatal test subjects granted to one other company.
No other rights have been granted.
14. Paragraph 3.2 (GRANT) shall be replaced in its entirety with the
following:
3.2 During the pendency of the outstanding rights described in 2.2 (e)
to one other company and during such period to the extent such
outstanding rights have vested and have not been terminated,
abandoned, disclaimed, or revoked or have not expired, the licenses
set forth in Paragraph 3.1 above shall be limited as follows:
21
a. the right to make, have made, use and sell methods and
processes, covering High-Complexity Probes and
compositions-of-matter comprising High-Complexity Probes
for clinical diagnostic testing or hereditary disease
testing in prenatal subjects within the Field of Interest
is expressly excluded from this Agreement.
b. the right to make, have made, use and sell methods and
processes covering High-Complexity Probes and
compositions-of-matter comprising High-Complexity Probes
as a research reagent for use in research including
prenatal subjects within the Field of Interest shall be
nonexclusive.
In the event the outstanding rights described in 2.2(e) to said one
other company expire or after vesting are terminated, abandoned,
disclaimed, or revoked, Licensee shall be permitted to acquire, at its
option, such license and right under the same terms and conditions as
such license and right were granted to said one other company.
Licensee shall have ninety (90) days following its receipt of said
terms and conditions in writing to exercise its option. In addition,,
in order to maintain such license and right, Licensee shall within
ninety (90) days of obtaining such rights, fund additional research at
LLNL, under terms and conditions consistent with the Research
Agreement in the amount of Two Hundred and Fifty Thousand Dollars
($250,000) per year for a period of time not less than two years under
a research program to be negotiated.
15. Paragraph 3.3 (GRANT) shall be replaced in its entirety with the
following:
3.3. The licenses granted in Paragraph 3.1 of this Agreement are
subject to Contract W-7405-ENG-48 between The Regents and the DOE, PL
96-517 as amended, and subject to the limitations set forth in this
Agreement.
22
16. The Regents and Licensee agree that U. S. Patent Application Serial No.
721,236 (UC Case No. 91-155-2)) filed June 27, 1991 (Subparagraph 1.71) and
U.S. Patent Application Serial; No. 743,524 (UC Case No. 91-155-3) filed August
9, 1991 (Subparagraph 1.7m) and any corresponding foreign patent applications
and any patents issuing therefrom within Regents' Patent Rights are exempt from
the provisions of Article 6 (Due Diligence). In addition, Licensee will pay The
Regents the costs reasonably incurred by The Regents in resolving issues as to
inventorship and title to said patent applications and patents, and in obtaining
the assignment from the University of Miami of its full right, title and
interest in said patent applications and patents issuing therefrom.
17. Paragraph 15.1 (MAINTENANCE OF BIOLOGICAL MATERIALS) shall be
replaced in its entirety. as follows:
15.1 The Regents agrees to instruct Xx. Xxx X. Xxxx, Xx. Xxxxxx
Xxxxxx, Xx. Xxxxx-Xxxxxx Xxxxx, Xx. Xxxx Xxxxxxx and Xx. Xxxxxxx
Xxxxxx that when circulating replicable Background Biological
Materials and replicable biological materials comprising Research
Information that has not been released in an unrestricted manner to
third parties to do so under the terms and conditions set forth in the
Biological Material Transmission Letter attached hereto as Appendix A.
The Regents expressly reserves the right to transfer replicable
Background Biological Materials and replicable biological materials
comprising Research Information as provided in this Paragraph 15.1 to
Universities and nonprofit research organizations to the extent that
such transfer does not compete with Licensee. The Regents shall inform
Licensee of
23
third party requests for biological materials and shall provide
Licensee with a copy of the fully executed copy of the Biological
Material Transmittal Letter. The Regents shall inform Licensee of
comments, suggestions and information provided The Regents by
recipients of biological material. Licensee shall not interfere with
The Regents efforts to bail these materials to third parties.
18. As partial consideration for this Second Amendment to the License
Agreement, Paragraph 5.1 shalt be replaced in its entirety with the following:
5.1 As consideration for this license, Licensee shall pay or cause to
be paid to The Regents an earned royalty in the following manner:
a Licensee shall pay or cause to be paid to The Regents a
royalty of four percent (4.0%) of Net Sales on Unprotected
Composition Products.
b Licensee shall pay or cause to be paid to The Regents a
royalty of four percent (4.0%) of Net Sales on Protected
Composition Products.
c Licensee shall pay or cause to be paid to The Regents a
royalty rate of two percent (2%) of Net Sales on Unprotected
Instrument Products.
d Licensee shall pay or cause to be paid to The Regents a
royalty rate of three and one-half percent (3.5%) of Net
Sales on Protected Instrument Products.
e Licensee shall pay or cause to be paid to The Regents a
royalty of four percent (4%) of Net Sales on Protected
Derived Probe Products.
f Licensee shall pay or cause to be paid to The Regents a
royalty of four percent (4%) of Net Sales on Unprotected
Derived Probe Products.
24
The Regents and Licensee agree that in no case shall Licensee be
obligated to pay to The Regents a royalty rate greater than four
percent (4%) of Net Sales for Protected Derived Probe Products or
Unprotected Derived Probe Products.
19. As further consideration for this Second Amendment to the License
Agreement, Licensee agrees to pay The Regents a license issue fee of Ninety-Five
Thousand Dollars ($95,000) as follows:
a Licensee agrees to pay The Regents Fifty Thousand Dollars
($50,000) within ten working days of the day this Second
Amendment to the License Agreement is fully executed; and
b Forty-Five Thousand Dollars ($45,000) on or before January 15,
1993.
25
20. Unless otherwise terminated by operation of law or by the acts of the
parties in accordance with the terms of the License Agreement, this Second
Amendment to the License Agreement shall be in force from the effective date
recited on page one and for a term concurrent with the License Agreement.
IN WITNESS WHEREOF, both The Regents and the Licensee have executed this
Second Amendment to the License Agreement, in duplicate originals, by their
respective officers hereunto duly authorized, on the day and year hereinafter
written.
AMOCO TECHNOLOGY COMPANY THE REGENTS OF THE UNIVERSITY
OF CALIFORNIA
By: /s/ X.X. Xxxxxxxxx By: /s/ [ILLEGIBLE]
------------------------------- --------------------------------
(signature) (signature)
Name: X. X. Xxxxxxxxx Name: Xxxx X. Xxxxxxx
Title: President Title: Assoc. Director
Amoco Technology Company Office of Technology
Date: June 25, 1992 Date: 6/29/92
----------------------------- ------------------------------
[STAMP]
26
EXHIBIT 10.3d
SUBSTITUTION OF LICENSEE
This substitution of licensee agreement ("Agreement") is effective this 1st
day of June, 1994 among THE REGENTS OF THE UNIVERSITY OF CALIFORNIA ("The
Regents"), a California corporation having statewide administrative headquarters
at 000 Xxxxxxxx Xxxxx, 00xx Xxxxx, Xxxxxxx, Xxxxxxxxxx 00000-0000; AMOCO
TECHNOLOGY COMPANY ("ATC"), a Delaware Corporation having a principal place of
business at Warrenville Road and Mill Street, P.O. Box 3011, Xxxxxxxxxx,
Xxxxxxxx 00000; and IMAGENETICS INCORPORATED ("Imagenetics"), an Illinois
corporation having a principal place of business at 000 Xxxx Xxxxxxxxxxx Xxxx,
X.X. Xxx 0000, Xxxxxxxxxx, Xxxxxxxx 00000-0000.
RECITALS
Whereas, The Regents and ATC entered into a license agreement effective
August 15, 1989 (UC Control No. 89-03-0021) entitled CHROMOSOME ANALYSIS
TECHNOLOGY WITH CHROMOSOME-SPECIFIC PROBES ("License Agreement") and under this
License Agreement The Regents granted a license under Regents' Patent Rights (as
defined in the License Agreement);
Whereas, ATC desires that Imagenetics be substituted as Licensee (defined
in the License Agreement) in place of ATC and The Regents is agreeable to such
substitution; and
Whereas, Imagenetics has read the License Agreement and agrees to abide by
its terms and conditions:
The parties agree as follows:
1. Imagenetics assumes all liability under the License Agreement and is
bound by all the terms in all respects as if it were the original Licensee in
place of ATC.
2. The Regents allows the substitution of the Licensee and acknowledges
that Imagenetics assumes all liability and obligations under the License
Agreement as if
Imagenetics were originally named as the Licensee as of the effective date of
the License Agreement.
3. The Regents releases ATC from all liability and obligations under the
License Agreement arising before or after the effective date of this Agreement.
The parties have executed this Agreement in triplicate originals by their
respective authorized officers on the following day and year.
AMOCO TECHNOLOGY COMPANY: THE REGENTS OF THE UNIVERSITY
OF CALIFORNIA:
By /s/ X.X. Xxxx By /s/ Xxxxxxx X. Xxxxxxx
------------------------------ ----------------------------------
(Signature) (Signature)
Name X. X. Xxxx Name: Xxxxxxx X. Xxxxxxx
---------------------------- ---------------------------------
Title President Title: Manager, Licensing
---------------------------- Office of Technology Transfer
Date June 1, 1994 Date 6/20/94
---------------------------- ---------------------------------
IMAGENETICS INCORPORATED
By /s/ X.X. Xxxxxx
------------------------------
Name: X. X. Xxxxxx
----------------------------
Title: President
---------------------------
Date: June 1, 1994
----------------------------
2
EXHIBIT 10.3e
[LETTERHEAD]
June 6, 1994
The Regents of the University of California
Office of Technology Transfer
0000 Xxxxx Xxx Xxxxxxx, Xxxxx 000
Xxxxxxx, XX 00000
Attention: Director
Letter Agreement re Third Party Licensing under
License Agreement Control No. 89-03-0021
----------------------------------------
Gentlemen:
This is to confirm Imagenetics Incorporated's and The Regents of the
University of California's agreement concerning certain third party licensing
by Imagenetics under License Agreement Control No. 89-03-0021 (the "1st
License") between Imagenetics' parent company Amoco Technology Company
("ATC") and The Regents of the University of California ("The Regents").
Whereas, Imagenetics and The Regents simultaneously herewith are entering into a
new Research Agreement covering Molecular Cytogenetics Research beginning July
1, 1994 at the University of California - San Francisco, which excludes
instrumentation research, and
Whereas, Dr. Xxx Xxxx, a Principal Investigator under the Research Agreement for
The Regents from time to time may explore third party instrument research which
may require licenses from Imagenetics to commercialize.
Imagenetics and The Regents in consideration of the above and the promises
below, agree as follows:
(1) Imagenetics agrees that upon the request of Dr. Xxx Xxxx it will hold
discussions with a limited number of third parties interested in performing
instrument research jointly with Xx. Xxxx concerning a license under the rights
granted to ATC to permit commercialization by the third party of instruments
developed jointly with Xx. Xxxx.
(2) The Regents agrees that Imagenetics is not obligated hereunder to grant any
license under the rights granted to ATC, and that any license granted will be
on terms and conditions satisfactory to Imagenetics.
(3) This Letter Agreement shall terminate upon the date of termination of the
Research Agreement.
(4) This Letter Agreement is the entire agreement between the parties
concerning Imagenetics' discussions with research collaborators of Xx. Xxxx.
If The Regents finds the above acceptable, please show your agreement by signing
below.
Accepted and agreed to:
IMAGENETICS INCORPORATED
/s/ X. X. Xxxxxx
------------------------------------------------
X. X. Xxxxxx
President
THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
/s/ X. X. Xxxxxxx
------------------------------------------------
By: Xxxx X. Xxxxxxx
--------------------------------------------
Title: Director, Office of Technology Transfer
------------------------------------------
EXHIBIT 10.3f
UNIVERSITY OF CALIFORNIA
[LETTERHEAD]
June 28, 1994
IMAGENETICS INCORPORATED
00 Xxxxxx Xxxx.
Xxxxx 000
Xxxxxxxxxx, XX 00000-0000
Attention: Mr. Xxxxx Xxx
Reference: Letter Agreement re Third Party Licensing under License
Agreement Control No. 89-03-0021, UC Case No. 85-157
----------------------------------------------------
Gentlemen:
This letter is to confirm Imagenetics Incorporated's and The Regents of the
University of California's understanding concerning licensing rights owed to
Imagenetics Incorporated that arise under a third-party collaboration between an
employee of the Division of Molecular Cytometry at UCSF receiving funding under
the new Research Agreement covering Molecular Cytogenetics (July 1, 1994) and a
third-party collaborator either at the University of California outside of the
Division of Molecular Cytometry or outside of the University of California.
The new Research Agreement covering Molecular Cytogenetics beginning July 1,
1994, grants to Imagenetics exclusive licenses only to patent applications
claiming inventions made within the field of Research by the Principal
Investigators or employees under their direction in the Division of Molecular
Cytometry at UCSF. If said Principal Investigator(s) or his/her employee(s)
collaborates with scientists employed outside the Division of Molecular
Cytometry at UCSF or at another campus of the University of California and a
joint invention is made, then Imagenetics would be granted an exclusive license
to such inventions subject to outstanding rights to the third party. If a third
party has rights to the other scientist's inventions, then Imagenetics would be
granted a limited nonexclusive license where the total number of licenses
granted would be limited to Imagenetics and the third party.
Secondly, it was agreed that the Principal Investigators and their employees are
not restricted from collaborating with scientists outside the University. If a
joint invention is made with a scientist that is not an employee of the
University, subject to the terms of the new Research Agreement,
IMAGENETICS INCORPORATED
June 28, 1994
Page 2
Imagenetics is entitled to an exclusive license to the University's undivided
interest in any patent applications claiming inventions made jointly by the
Principal Investigator or his/her employee in the Division of Molecular
Cytometry at UCSF and the outside scientist.
If you are in agreement with the above understanding, please show your agreement
by signing below.
Very truly yours,
/s/Xxxxx Xxxx for
Xxxxxxx X. Xxxxxxx
Manager, Licensing
AGREED:
IMAGENETICS INCORPORATED
------------------------------------
By: /s/ Xxxxx Xxx
---------------------------------
Title: Vice President
------------------------------
Date: 7 July 1994
-------------------------------
EXHIBIT 10.3g
THIRD AMENDMENT TO LICENSE AGREEMENT
CHROMOSOME ANALYSIS TECHNOLOGY
WITH CHROMOSOME-SPECIFIC PROBES
BETWEEN
THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
AND
IMAGENETICS INCORPORATED
THIRD AMENDMENT TO LICENSE AGREEMENT
CHROMOSOME ANALYSIS TECHNOLOGY
WITH CHROMOSOME-SPECIFIC PROBES
BETWEEN
THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
AND
IMAGENETICS INCORPORATED
This Third Amendment to the License Agreement is made and is effective this
1st day of July 1994 by and between THE REGENTS OF THE UNIVERSITY OF CALIFORNIA,
a California corporation having its statewide administrative offices at 000
Xxxxxxxx Xxxxx, 00xx Xxxxx, Xxxxxxx, Xxxxxxxxxx 00000-0000 ("The Regents"), and
IMAGENETICS INCORPORATED, a Delaware corporation having offices at 000 Xxxx
Xxxxxxxxxxx Xxxx, X.X. Xxx 0000, Xxxxxxxxxx, Xxxxxxxx 00000-0000 ("Licensee").
RECITALS
WHEREAS, Licensee and The Regents entered into a license agreement
effective August 15, 1989, having U.C. Agreement Control No.: 89-03-0021,
amended on July 1, 1991 (Control No.: 89-03-0021), and on April 15, 1992
(Control No. 89-03-0021M), covering licensure to Licensee by The Regents of
certain inventions generally characterized as FLUORESCENCE HYBRIDIZATION WITH
CHROMOSOME-SPECIFIC PROBES, ("Invention"), made in the course of research at the
Xxxxxxxx Livermore National Laboratory ("LLNL") and The University of
California, San Francisco Campus ("UCSF") by Xxx X.Xxxx, et al.;
WHEREAS, Licensee and The Regents entered into a research agreement
1
entitled RESEARCH AGREEMENT FOR THE DEVELOPMENT OF FLUORESCENCE HYBRIDIZATION
WITH CHROMOSOME-SPECIFIC PROBES, ("First Research Agreement"), effective August
15, 1989 and terminated on June 30, 1991, for the purpose of developing the
Invention under a cooperative arrangement funded in part by Licensee at LLNL
under the direction of Principal Investigator, Xxx X. Xxxx;
WHEREAS, Licensee and The Regents entered into a second research agreement
entitled MOLECULAR CYTOGENETICS IN MEDICINE AND BIOLOGY ("Second Research
Agreement"), effective July 1, 1991, to expand the work to be performed under
the First Research Agreement to include development of chromosome Probes and to
perform research in human cancer diagnosis and prognosis;
WHEREAS, under the terms of the First Research Agreement and the Second
Research Agreement, The Regents granted the right to Licensee to elect to
include any and all inventions made in the conduct of research performed under
the First Research Agreement and the Second Research Agreement in the Licensee
Agreement;
WHEREAS, Licensee and The Regents want to continue the collaborative
relationship developed under the First Research Agreement and the Second
Research Agreement and, consequently, have entered into a third research
agreement entitled "Research Agreement for the Development of Molecular
Cytogenetics" effective July 1, 1994 ("Third Research Agreement");
WHEREAS, this third amendment to the License Agreement grants to Licensee
the right to elect to include inventions that employ the technique of In Situ
2
Hybridization and that are made in the performance of research under the Third
Research Agreement in this Agreement;
WHEREAS, Xxx X. Xxxx and Xxxxxx Xxxxxx hold joint appointments at UCSF and
at the Xxxxxxxx Berkeley Laboratory ("LBL");
WHEREAS, this third amendment to the License Agreement grants to Licensee
the right to elect to include in the License Agreement any inventions employing
the technique of In Situ Hybridization and made in the performance of work at
LBL under the direction of Xxx X. Xxxx or Xxxxxx Xxxxxx;
WHEREAS, difficulties with provisions contained in the License Agreement
have arisen due to circumstances unforeseen by the parties at the time of the
Invention's licensure; and
WHEREAS, this third amendment to the License Agreement solves these
difficulties.
The parties agree as follows:
1. Subparagraph 1.7.5 of the License Agreement is replaced in its
entirety with the following:
1.7.5 Any future patent rights to subject matter claimed in or
covered by a patent application(s) covering any Inventions
used in or requiring the performance of the technique In
Situ Hybridization and elected (1) by Licensee under the
provisions of Article VIII of the Third Research Agreement
or (2) by Licensee and made in the performance of research
at LBL under the direction of Xxx X. Xxxx or Xxxxxx Xxxxxx.
3
2. "In Situ Hybridization" shall mean a nucleic acid hybridization
technique where the target nucleic acid remains in its natural biological
setting, e.g. DNA in chromosomes or cell nucleic, albeit fixed or altered by
preparative techniques.
3. Paragraph 1.8 (Protected Composition Products) is replaced in its
entirety with the following:
1.6 "Protected Composition Products" shall mean (a) any kit,
composition of matter, material, or product; (b) any kit,
composition of matter, material, or product to be used in a
manner requiring the performance of the Patent Method, or
any kit, composition of matter, material, or product
produced by the Patent Method, or (c) the practice of the
Patent Method itself to the extent the manufacture, use, or
sale of (a), (b), or (c) immediately above falls within the
scope of one or more claims of Regents' Patent Rights during
the term of the patent grant, in countries in which such
claim or claims have issued and have not expired, been
abandoned, disclaimed, or found invalid or unenforceable.
4. Paragraph 1.9 ("Unprotected Composition Products") is replaced in its
entirety with the following:
1.9 "Unprotected Composition Products" shall mean (a) any kit,
composition, of matter, material or product; (b) any kit,
composition of matter, material, or product to be used in a
manner requiring the performance of the Unprotected Method,
or any kit, composition of matter, material, or product
produced by the Unprotected Method, or (c) the practice of
the Unprotected Method itself to the extent the manufacture,
use, or sale of (a), (b), or (c) immediately above falls
within the scope of one or more pending claims within
Regents' Patent Rights during the period and in such
countries in which such claim or claims have not issued, and
have not expired, been abandoned, disclaimed, or found
invalid or unenforceable, such period not to exceed five
years from the effective date of the License Agreement, or
five years from the date in which substantially the same
subject matter is first introduced in a patent application
in each country that such patent application is filed,
whichever is longer.
4
5. Paragraph 1.10 (Protected Instrument Products) is replaced in its
entirety with the following:
1.10 "Protected Instrument Products" shall mean (a) equipment,
instruments, apparatuses, devices , articles of manufacture,
or component parts thereof, or (b) equipment, instruments,
apparatuses, devices, articles of manufacture, or component
parts thereof produced by the Patent Method to the extent
the manufacture, use, or sale of (a) or (b) immediately
above falls within the scope of one or more claims of
Regents's Patent Rights during the term of the patent grant,
in countries in which such claim or claims have issued and
have not expired, been abandoned, disclaimed, or found
invalid or unenforceable. When a Protected Instrument
Product carries out a Patent Method, then The Regents and
Licensee shall promptly enter into good-faith negotiations
to determine a reasonable royalty based on the Net Sales of
the Protected Instrument Product.
6. Paragraph 1.11 (Unprotected Instrument Products) is replaced in its
entirety with the following:
1.11 "Unprotected Instrument Products" shall mean (a) equipment,
instruments, apparatuses, devices, articles of manufacture
or component parts thereof, equipment, or (b) equipment,
instruments, apparatuses, devices, articles of manufacture
or component parts thereof produced by the Unprotected
Method to the extent the manufacture, use, or sale of (a) or
(b) immediately above falls within the scope of one or more
pending claims within Regents' Patent Rights during the
period and in such countries in which such claim or claims
have not issued, and have not expired, been abandoned,
disclaimed, or found invalid or unenforceable, such period
not to exceed five years from the effective date of the
License Agreement, or five years from the date in which
substantially the same subject matter is first introduced
in a patent application in each country that such patent
application is filed, whichever is longer. When an
Unprotected Instrument Product carries out an Unprotected
Method, then The Regents and Licensee shall promptly enter
into good-faith negotiations to determine a reasonable
royalty based on the Net Sales of the Unprotected Instrument
Product.
7. The definitions of "Patent Method" and "Unprotected Method" shall be
5
included in the License Agreement as follows:
a) "Patent Method" means any process or method the use or
practice of which would constitute in a particular country,
but for the license granted to the Licensee pursuant to this
Agreement, an infringement of an unexpired claim of a patent
within Regents' Patent Rights in that country in which the
Patent Method is used or practiced.
b) "Unprotected Method" means any process or method the use or
practice of which would constitute in a particular country,
but for the license granted to the Licensee pursuant to this
Agreement an infringement of any unabandoned, pending claim
of a patent application within Regents' Patent Rights if
such patent application in that country in which the
Unprotected Method is used or practiced had issued.
8. "Prenatal Test Subjects" shall mean any test of fetal nucleic acid or
any nucleic acid resulting from fertilization of an egg cell suitable as a
target for In Situ Hybridization regardless of how such fetal nucleic acid or
nucleic acid resulting from fertilization is obtained.
9. Paragraph 1.16 (Infringement Litigation Costs) is replaced in its
entirety with the following:
1.16 "Infringement Litigation Costs" means costs incurred in the
infringement suit, provided for in Article 18 (PATENT
INFRINGEMENT) of this Agreement, consisting of outside
attorney's fees billed to Licensee and The Regents,
royalties (due The Regents) that were used to offset the
infringement suit costs in accordance with Paragraph 18.4,
Licensee's outside attorney fees that were used to offset
the infringement suit costs in accordance with Paragraph
18.2a, and other out-of-pocket expenses of both parties.
10. Paragraph 2.2e is replaced in its entirety with the following:
e. The Regents own or are in the process if acquiring title to
Regents' Patent Rights, which are subject to a
nontransferable, nonexclusive, irrevocable paid-up license
to practice or have
6
practiced, such Regents' Patent Rights for or on behalf of
the United States throughout the world, pursuant to 35 USC
202(c) (4) and which are subject to an exclusive license to
make, use and sell methods, processes, articles of
manufacture, and compositions of matter expressly limited to
clinical diagnostic testing in Prenatal Test Subjects and a
nonexclusive license to make, have made, use and sell
methods, processes, articles of manufacture and compositions
of matter as a research reagent for use in Prenatal Test
Subjects granted to one other company. No other rights have
been granted.
11. Paragraphs 3.2.1 and 3.2.2 are replaced in their entirety with the
following:
3.2.1 the right to make, have made, use and sell methods,
processes compositions-of-matter for clinical diagnostic
products to detect hereditary diseases in Prenatal Test
Subjects within the Field of Interest is expressly excluded
from this Agreement;
3.2.2 the right to make, have made, use and sell methods,
processes and compositions-of-matter comprising a research
reagent for use in research including Prenatal Test Subjects
within the Field of Interest shall be nonexclusive.
12. Paragraph 3.7 is replaced in its entirety with the following:
3.7 If the Regents is approached by an applicant for a license
to Regents' Patent Rights, and if said applicant agrees to
fund research at the University of California under the
direction of Xxx Xxxx or Xxxxxx Xxxxxx to further develop
the technology covered by Regents' Patent Rights in the
Field of Interest but outside the fields of use of cancer
identification, hereditary disease testing in postnatal
subjects, hereditary disease testing in Prenatal Test
Subjects and dosimetry to test subjects for exposure to
toxins during the period when Licensee has exclusive rights
herein, it will refer the request of the applicant to the
Licensee. Within ninety (90) days of such referral,
Licensee shall submit to The Regents a written report
outlining Licensee's interest in the Field of Use proposed
by the applicant. If Licensee has no interest in marketing
Products in the Field of Use proposed by the applicant, then
Licensee shall enter into good-faith negotiations with the
applicant for a sublicense to Regents' Patent Rights in said
Field
7
of Use. If Licensee expresses an interest in marketing such
Products in the Field of Use proposed by applicant, then The
Regents and Licensee shall enter into good-faith
negotiations to sponsor research at least at the level of
applicant and to establish reasonable diligence provisions
requiring reasonable performance standards for Licensee to
achieve substantial sales of said Products within a
reasonable time period in the Field of Use requested by
applicant.
13. Paragraph 1.17 (Repeat-Sequence Probe), Paragraph 1.18
(High-Complexity Probe), and Paragraph 1.19 (Low-Complexity Probe) as defined in
the second amendment to the License Agreement effective April 15, 1992 (UC
Agreement Control No. 89-03-0021M) are removed in their entirety from the
License Agreement.
14. Paragraph 6.5 shall be replaced in its entirety with the following:
6.5 Subject to Licensee's rights under 6.2 and subject to the
Licensee's freedom to practice Regents' Patent Rights
without infringement of third party rights, if the Licensee
is unable to perform any of the following:
6.5.1 If a chromosome abnormality is independently correlated with
a disease by at least two independent studies (each study
having at least 100 patients and having a correlation p
value of .01), and if Licensee has rights to a Clinically
Useful Product that identifies the chromosome abnormality,
and if the chromosome abnormality correlates to a disease
that has a potential market of 100,000 tests per year in the
United States, then Licensee shall enter into preclinical
trials for each such Product within one (1) year of the
above conditions being satisfied;
6.5.2 Licensee shall submit an application for marketing in the
United States, including, by way of example, an IDE for a
PMA, an IND for an NDA, or 510k, for products to the
appropriate United States agency, including, by way of
example, FDA, on or before one year from entering
preclinical trials for each Product, provided that Licensee
shall not be obligated to submit applications for marketing
in the United States for more than two Products at any one
time.
8
6.5.3 Market Products in the United States within six (6) months
of receiving U.S. government marketing approval from the
FDA, if such approval is required for such Products; or
6.5.4 Reasonably fill the clinical market demand for such Products
following commencement of marketing at any time during the
exclusive period of this Agreement;
then The Regents shall have the right and option to reduce the Licensee's
exclusive license to a nonexclusive license. This right, if exercised by The
Regents, supersedes the rights granted in Article 3 (GRANT).
15. "Clinically Useful" shall mean (a) that there is an available
treatment for the disease, condition, or symptoms caused by a chromosomal
abnormality, (b) that there is a recommended lifestyle change to improve the
quality of life for patients or progeny of patients having the chromosomal
abnormality, or (c) that there is useful information available due to the
diagnosis of the chromosomal abnormality that will enable patients to make
informed choices about current or future reproductive activities.
16. Paragraph 7.1 is replaced in its entirety with the following:
7.1 Beginning November 30, 1994, and annually thereafter, the
Licensee shall submit to The Regents a progress report
covering the Licensee's activities related to the
development and testing of each Product and the obtaining of
the governmental approvals necessary for marketing. These
progress reports shall be provided to The Regents to cover
the progress of the research and development of the Product
until its first commercial sale in the United States These
progress reports shall include, but not be limited to, the
following topics so that The Regents may be able to
determine the progress of the development of each Product
and may also be able to determine whether or not Licensee
has met its diligence obligations set forth in Article 6
(DUE DILIGENCE) above:
- summary of work completed
9
- key scientific discoveries
- summary of work in progress
- current schedule of anticipated events or
milestones specified in Paragraph 6.5
- market plans for introduction of each Product
- activities of sublicensees, if any.
The Licensee also agrees to report to The Regents in its immediately subsequent
progress and royalty report the date of first commercial sale of a Product in
each country.
17. Paragraph 15.2 of the License Agreement will be replaced in its
entirety with the following:
15.2 Licensee may distribute biological materials comprising
Background Biological Materials and Research Information to
the research community. Biological materials that Licensee
will distribute to the research community will be limited to
only those biological materials that Licensee accepts for
retransfer or sale. If Licensee sells such biological
materials to the research community, it will offer them at a
price reasonable for a typical research product. In the
alternative, Licensee may elect to make the biological
materials available through other means, including, without
limitation, by ATCC deposit. If Licensee declines to accept
the biological materials for distribution to the research
community, then The Regents shall be free to distribute the
materials by any means without further obligation to
Licensee.
18. Unless otherwise terminated by operation of law or by the acts of the
parties in accordance with the terms of the License Agreement, this Second
Amendment to the License Agreement shall be in force from the effective date
recited on Page One and for a term concurrent with the License Agreement.
10
IN WITNESS WHEREOF, both The Regents and the Licensee have executed this
Third Amendment to the License Agreement, in duplicate originals, by their
respective officers hereunto duly authorized, on the day and year hereinafter
written.
IMAGENETICS INCORPORATED THE REGENTS OF THE UNIVERSITY
OF CALIFORNIA
By: /s/ Xxxx X. Xxxxxx By: /s/ Xxxx X. Xxxxxxx
----------------------------- --------------------------------------
(Signature) (Signature)
Name: Xxxx X. Xxxxxx Name: Xxxx X. Xxxxxxx
--------------------------- ------------------------------------
(Please Print) (Please Print)
Title: President Title: Director
-------------------------- -----------------------------------
Office of Technology Transfer
Date: June 7, 1994 Date: June 11, 1994
-------------------------- -----------------------------------
[STAMP]
11
EXHIBIT 10.3h
FOURTH AMENDMENT TO THE LICENSE AGREEMENT FOR
CHROMOSOME ANALYSIS TECHNOLOGY
WITH CHROMOSOME-SPECIFIC PROBES
BETWEEN
THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
AND
VYSIS, INC.
FOURTH AMENDMENT TO THE LICENSE AGREEMENT FOR
CHROMOSOME ANALYSIS TECHNOLOGY
WITH CHROMOSOME-SPECIFIC PROBES
BETWEEN
THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
AND
VYSIS, INC.
This fourth amendment ("Fourth Amendment") to the License Agreement is made
and is effective this 1st day of September 1994, by and between The Regents of
the University of California ("The Regents"), a California corporation having
its statewide administrative offices at 000 Xxxxxxxx Xxxxx, 00xx Xxxxx, Xxxxxxx,
Xxxxxxxxxx 00000-0000, and Vysis, Inc. ("Licensee"), an Illinios corporation
having offices at 000 Xxxx Xxxxxxxxxxx Xxxx, P. O. Xxx 0000, Xxxxxxxxxx,
Xxxxxxxx 00000-0000.
RECITALS
Whereas, Licensee and The Regents entered into a license agreement
effective August 15, 1989 ("License Agreement"), having UC Agreement Control No.
89-03-0021, which was amended on July 1, 1991 (Control No. 89-03-0021I), on
April 15, 1992 (Control No. 89-03-0021M), and on July 1, 1994 (Control No.
89-03-0021R-33), covering licensure to Licensee by The Regents of certain
inventions generally characterized as Fluorescence Hybridization with
Chromosome-Specific Probes ("Invention"), made in the course of research at the
Xxxxxxxx Livermore National Laboratory ("LLNL") and The University of
California, San Francisco Campus ("UCSF") by Xxx X. Xxxx et al.;
1
Whereas, Licensee and The Regents entered into a research agreement
entitled "Research Agreement for the Development of Molecular Cytogenetics"
("Research Agreement"), effective July 1, 1994, granting to Licensee the right
to elect to include in the Licensee Agreement inventions that employ the
technique of In Situ Hybridization and that are made in the performance of
research under the Research Agreement under the direction of Xxx X. Xxxx or
Xxxxxx Xxxxxx;
Whereas, The Regents originally licensed to another company the exclusive
rights to make, use, and sell methods, processes, compositions-of-matter, and
articles of manufacture expressly limited to clinical diagnostic testing in
prenatal test subjects;
Whereas, The Regents has terminated the agreement with the other company,
and, consequently, the rights to clinical diagnostic testing in prenatal test
subjects are available;
Whereas, the License Agreement provides that if such rights become
available, then Licensee would be granted such rights in exchange for Licensee's
funding additional research by The Regents;
Whereas, Licensee and The Regents entered into a letter agreement dated
June 6, 1994, having UC Agreement Control No. 89-03-0021R-34, which provides
that if The Regents obtained the right to grant prenatal test rights, then The
Regents would waive certain research funding rights under the License Agreement
that would be owed by Licensee to The Regents in return for Licensee's agreeing
to delay its right to terminate the Research Agreement, thus guaranteeing
funding of $1.5 million under the Research Agreement;
Whereas, Licensee and The Regents entered into a first amendment to the
Research Agreement, effective September 1, 1994, providing that Licensee will
waive its rights to
2
terminate the agreement without cause until after August 1, 1996, thus
guaranteeing funding of $1.5 million under the Research Agreement;
Whereas, the execution of the first amendment to the Research Agreement, to
be executed concurrently with this Fourth Amendment, is the consideration for
this Fourth Amendment;
Whereas, Licensee agrees to undertake negotiations in good faith for a
grant of a sublicense under such rights to at least one clinical testing
laboratory under terms acceptable to Licensee;
Whereas, The Regents is desirous that the prenatal rights be developed and
utilized to the fullest extent so that the benefits can be enjoyed by the
general public.
The parties agree as follows:
1. Subparagraph 3.2 of Article 3 (Grant) of the License Agreement is
deleted entirely.
2. Subparagraph 3.10 of Article 3 (Grant) of the License Agreement is
added as follows:
3.10 Licensee will undertake negotiations in good faith for a
grant of a sublicense under the prenatal test rights to at least one
clinical testing laboratory under terms acceptable to Licensee.
3. Subparagraph 4.3 of Article 4 (License Issue Fee) of the License
Agreement is added as follows:
3
4.3 As consideration for this Fourth Amendment to the License
Agreement, Licensee will guarantee $1.5 million in research funding
under the research agreement entitled "Research Agreement for the
Development of Molecular Cytogenetics," effective July 1, 1994, by
entering into the first amendment to the Research Agreement for the
Development of Molecular Cytogenetics, effective September 1, 1994,
that waives its right to terminate the Research Agreement until after
August 1, 1996.
Unless otherwise terminated by operation of law or by the acts of the
parties in accordance with the terms of the License Agreement, this Fourth
Amendment to the License Agreement will be in force from the effective date
recited on page one and for a term concurrent with the License Agreement.
In witness whereof, both The Regents and the Licensee have executed this
Fourth Amendment to the License Agreement, in duplicate originals, by their
respective officers hereunto duly authorized, on the day and year hereinafter
written.
VYSIS, INC. The Regents of the University
of California
By: /s/ X. X. Xxxxxx By: /s/ Xxxxxxx X. Xxxxxxx
--------------------------- ---------------------------
(Signature) (Signature)
Name: X. X. Xxxxxx Name: Xxxxxxx X. Xxxxxxx
------------------------- -------------------------
(Please Print) (Please Print)
Title: President Title: Manager, Licensing
------------------------ -------------------------
(Please Print) (Please Print)
Date: November 18, 1994 Date: December 16, 1994
------------------------- -------------------------
[STAMP]
4
