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*Confidential Treatment Requested
EXHIBIT 10.16
RESEARCH AGREEMENT
THIS RESEARCH AGREEMENT ("Agreement") is made this 20th day of August, 1999,
by and between Third Wave Technologies, Inc. ("Institution"); and Xxxxxx-Xxxxxxx
Company, a Delaware corporation, with its principal place of business at 000
Xxxxx Xxxx, Xxxxxx Xxxxxx, Xxx Xxxxxx, 00000 ("Company").
RECITALS
A. Institution has developed substantial expertise in the area of assay
development for gene expression profiling and polymorphism and mutation analysis
(the "Field").
B. Company desires to obtain the services of Institution in directing certain
research in the Field relating to the development of certain assays. Such
research is hereinafter referred to as the "Development Program". Institution is
willing to direct the Development Program, all on the terms and conditions set
forth herein and in accordance with the protocol attached hereto as Exhibit A
and incorporated herein by reference (the "Protocol").
NOW, THEREFORE, in consideration of the covenants and premises herein
contained, the parties agree as follows:
1. The Development Program. Promptly following receipt of the amount set forth
in Section 2 below, Institution shall use diligent efforts to develop Invader(R)
polymorphism and mRNA transcript assays described in the Protocol, subject to
Company providing Institution the materials described in Exhibit B
(collectively, the "Company Materials"). Upon completion of the Development
Program with respect to each such particular assay, Institution agrees to
provide Company with the number of assay determinations set forth in the
Protocol for such particular assay, including enzyme, buffer and Invader probes
for such analyte (collectively, the "Institution Materials"). Accordingly,
Institution shall, after consultation with Company, direct and perform the
Development Program in a professional and diligent manner, all in accordance
with the Protocol and the terms of this Agreement.
2. Payment. In consideration for the performance of the Development Program by
Institution, Company shall pay Institution a non-refundable amount of $474,100
(the "Research Amount") within five (5) days of the date of Company's execution
of this Agreement.
3. Reporting. Company designates Xxxxxxx Xxxx or his or her successor to
function as its research and development contact (the "Contact"). Institution
shall inform the Contact of the progress of the Development Program in the
following manner:
(a) By informal verbal reports, from time to time;
(b) By response to all of Company's reasonable inquiries regarding the
status of the Development Program;
(c) By arrangements to periodically meet and discuss the progress of the
Development Program with the Contact at Institution's facilities; and
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(d) By submission of a detailed written report thirty (30) days
following the conclusion of the Development Program (the "Final Report").
4. Ownership of Data; Publication. Subject to Company's rights in the Company
Materials, all right, title and interest in and to all information disclosed by
Institution hereunder and to all Institution Materials transferred hereunder
shall remain vested in Institution. Except as otherwise provided in this Section
4 below, Company shall own all right, title and interest in and to Inventions
(collectively, "Company Inventions") and Institution hereby assigns all such
right, title and interest in the Company Inventions to Company. Furthermore,
Institution hereby agrees to only use its personnel in connection with the
Development Program. Notwithstanding the foregoing, Company hereby agrees that
Institution shall own all right, title and interest in and to Inventions
directed to subject matter comprising improvements to the Invader assay
technology, including without limitation methods of sample preparation, probe
design or production, or assay development, performance or analysis
(collectively, "Improvements") and Company hereby assigns all such right, title
and interest in the Improvements to Institution. In addition, Company hereby
grants to Institution, to the extent it has the right to do so, an exclusive,
worldwide, royalty-free, fully paid-up, irrevocable right and license, with the
right to grant and authorize sublicenses, under any and all Company Inventions,
to make, have made, use, import, offer for sale and sell products and
components, solely for diagnostic applications including for tests or assays
used to guide, prescribe or direct therapeutic regimens, treatments or drugs.
For purposes of this Agreement, "Invention" shall mean any and all discoveries,
inventions and other subject matter (whether patentable or not) made in the
course of performing the Evaluation (as defined below) or otherwise in
connection with using the Institution Materials as permitted hereunder and all
intellectual property rights therein. Nothing in this Agreement is to be
construed as granting a license to Company to utilize any information received
from Institution or Institution Materials except as expressly provided herein,
under any patent or other intellectual property rights owned by Institution,
unless a separate agreement for such rights is executed by Company and
Institution. Company and Institution further agree to perform such acts and
provide such documents as are reasonably requested by the other party to effect
the foregoing assignments.
5. Confidentiality. Institution and Company hereby confirm the validity of and
agree to be bound by the Mutual Confidentiality Agreement effective March 24,
1998 by and between the parties which continues in effect (the "Confidentiality
Agreement").
(a) Confidential Information. The parties may from time to time disclose
to each other Confidential Information. "Confidential Information" shall mean
any information disclosed by one party to the other party hereto which if
disclosed in tangible form is marked "confidential" or with other similar
designation to indicate its confidential or proprietary nature or if disclosed
orally is indicated orally to be confidential or proprietary by the party
disclosing such information at the time of such disclosure and is confirmed in
writing as confidential or proprietary by the disclosing party within a
reasonable period after such disclosure; provided, however, all Improvements
shall be deemed to be Confidential Information of the Institution and all
Company Inventions (except to the extent that such Company Inventions relate to
diagnostic applications) shall be deemed to be Confidential Information of the
Company. Notwithstanding the foregoing or anything herein to the contrary,
Confidential Information shall not include any information that, in each case as
demonstrated by written documentation: (i) was already known to the receiving
party or its affiliates, other than under an obligation of confidentiality, at
the time of disclosure; (ii) was generally available to the public or otherwise
part of the public domain at the time of its disclosure to the receiving party;
(iii) became generally available to the
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public or otherwise part of the public domain after its disclosure and other
than through any act or omission of the receiving party in breach of this
Agreement; or (iv) was subsequently lawfully disclosed to the receiving party or
its affiliates by a third party which is not in violation of any contractual or
legal obligation to the disclosing party with respect to such Confidential
Information.
(b) Confidentiality. Each party agrees to hold and maintain in strict
confidence all Confidential Information of the other party. Without limiting the
foregoing, neither party shall use or disclose the Confidential Information of
the other party, except as otherwise permitted by this Agreement or as may be
necessary or useful to exercise its rights or perform its obligations under this
Agreement. Nothing contained in this Section 5 shall prevent either party from
disclosing any Confidential Information of the other party (i) to accountants,
lawyers or other professional advisors to the extent reasonably necessary to
accomplish the purposes of this Agreement or to prospective lenders, investment
bankers or other financial institutions in connection with a merger, acquisition
or securities offering, subject in each case to the recipient entering into an
agreement to protect such Confidential Information from disclosure; or (ii) to
the extent is required by law or regulation to be disclosed; provided, however,
that the party subject to such disclosure requirement has provided written
notice to the other party promptly upon receiving notice of such requirement in
order to enable the other party to seek a protective order or otherwise prevent
disclosure of such Confidential Information. Upon any termination of this
Agreement, Company and Institution shall promptly return to the other party all
Confidential Information received from the other party (except one copy of which
may be retained for purposes of monitoring compliance with the provisions of
this Section 5 and for archival purposes). The foregoing provisions of this
Section 5 shall survive expiration or termination of this Agreement for a period
of seven (7) years after such expiration or termination.
6. Compliance with Applicable Laws. Institution agrees to conduct the
Development Program and maintain records and data during and after the term of
this Agreement in compliance with all applicable legal and regulatory
requirements, including without limitation any applicable requirements of the
United States Food and Drug Administration and the United States Federal Drug
Enforcement Administration.
7. Materials.
(a) Company agrees that all Institution Materials obtained from
Institution pursuant to this Agreement shall be used solely for the purpose of
evaluating whether or not Company desires to enter into a licensing and other
business arrangements with Institution, all on terms and conditions as mutually
determined by Company and Institution and not for any commercial purposes (the
"Evaluation"). Institution agrees that all Company Materials obtained from
Company pursuant to this Agreement shall be used solely for the purpose of
evaluating whether or not Institution desires to enter into a licensing and
other business arrangements with Company, all on terms and conditions as
mutually determined by Company and Institution and not for any commercial
purposes other than the Development Program and commercial diagnostic
applications. Company agrees at all times to use the Institution Materials, and
Institution agrees at all times to use the Company Materials, in compliance with
all state, federal and other applicable laws, rules and regulation pertaining to
use thereof. The Institution Materials and the Company Materials shall include
the original materials transferred to Company or Institution, respectively, as
well as any derivatives or improvements developed by the receiving party
therefrom. INSTITUTION SUPPLIES THE INSTITUTION MATERIALS AND
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COMPANY SUPPLIES THE COMPANY MATERIALS WITHOUT ANY WARRANTY, REPRESENTATION OR
UNDERTAKING WHATSOEVER, EXPRESSED OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, ANY
WARRANTY RESPECTING THE EFFICIENCY, PERFORMANCE, WORKMANSHIP, CONDITION,
MERCHANTABILITY, FITNESS FOR PARTICULAR PURPOSE OR NONINFRINGEMENT.
(b) During the term of this Agreement and for five (5) years thereafter
Institution agrees to make available to Company for its own internal research
and development purposes enzyme, buffer and Invader probes developed hereunder
pursuant Institution's standard terms and conditions therefor, including
standard pricing and minimum order requirement of at least quantities to perform
one thousand (1,000) determinations for any particular polymorphism or mRNA
transcript, as applicable.
8. Institution's Representations and Warranties. Institution hereby represents,
warrants and covenants to Company the following:
(a) It has the power and authority to undertake the contractual
commitments set forth in this Agreement; and
(b) It is free to enter into this Agreement and carry out its
obligations hereunder without violating any obligation owed to a third party,
including, without limitation, any governmental or quasi-governmental agency,
group or department, or any other private or public institution, person or
company. No such third party currently has, or, except as expressly authorized
herein, will have, any option, license or other right of any kind with respect
to any Institution Materials or any data, information, inventions or discoveries
obtained or developed under this Agreement.
9. Monitoring of Development Program. During the term of this Agreement,
Institution agrees to permit representatives of Company to examine at any
reasonable time during normal business hours (i) the facilities where the
Development Program is being conducted, (ii) raw research data and (iii) any
other relevant information (and to make copies) necessary for Company to confirm
that the Development Program is being conducted in conformance with the Protocol
and in compliance with applicable laws and regulations, including those of the
United States Food and Drug Administration and the United States Federal Drug
Enforcement Administration.
10. Term. The term of this Agreement shall commence on the date that it is made
and continue for up to 180 days.
11. Termination. The Development Program may be terminated by Company at any
time in the exercise of its sole discretion upon fifteen (15) days prior written
notice to Institution. Upon receipt or giving of notice, as the case may be,
Institution agrees promptly to terminate conduct of the Development Program.
12. Publicity. Neither party shall use the name of the other party or its
divisions, affiliates, personnel or products, as applicable, for promotional
purposes without the prior written consent of the party whose name is proposed
to be used, which consent shall not be unreasonably withheld; provided, however,
that either party may (i) disclose the terms of this Agreement to prospective
lenders, investment bankers and other financial institutions of its choice
solely for the purposes of financing the business operations of such party,
either upon the written consent of the other party or if the disclosing party
obtains a signed confidentiality agreement with such
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entity or financial institution with respect to such information, and (ii) make
disclosures to the extent required to comply with applicable securities law and
in the case of (ii), if possible, the non-disclosing party shall have consented
to such disclosure, which consent shall not be unreasonably withheld. Without
limiting the foregoing, the parties shall agree, within fifteen (15) days of
executing this Agreement, upon a press release to announce the execution of this
Agreement; thereafter, each party may each disclose to third parties the
information contained in such press release without the need for further
approval by the other.
13. Independent Contractor. Institution is acting in the capacity of independent
contractor hereunder and not as employee or agent of Company.
14. Controlling Law. This Agreement shall be governed by and construed in
accordance with the law of the State of Michigan (other than provisions relating
to conflicts of laws).
15. Agreement Modifications. This Agreement may not be altered, amended or
modified except by written document signed by all parties.
16. Inconsistencies. The terms and conditions of this Agreement shall govern in
the event of conflict between it and the Protocol.
17. Force Majeure. Any party's delay or failure in performing its obligations
under this Agreement shall be excused to the extent caused by the occurrence of
events beyond that party's reasonable control, including without limitation,
war, floods, earthquakes, other acts of God, industrial disputes, civil
disobedience, strikes, fire, mobilization, changes in governmental regulation or
interpretation, requisition, embargo, restriction and shortage of transport
facilities, fuel, energy or supplies. Each party claiming the benefit of such an
excuse shall notify the other party in writing of any such delay or failure in
performance, and shall resume performance as soon as is reasonably practicable.
18. Notice. All notices given hereunder shall be in writing and shall be
delivered by hand or mailed by certified or registered mail, return receipt
requested, postage pre-paid, addressed to the parties as follows:
(a) To Company: Xxxxx-Xxxxx Pharmaceutical Research
0000 Xxxxxxxx Xxxx
Xxx Xxxxx, Xxxxxxxx 00000
Attn: Chairman
with a copy to: Xxxxx-Xxxxx Pharmaceutical Research
0000 Xxxxxxxx Xxxx
Xxx Xxxxx, Xxxxxxxx 00000
Attn: Assistant General Counsel
(b) To Institution: Third Wave Technologies, Inc.
000 Xxxxx Xxxx Xxxx
Xxxxxxx, Xxxxxxxxx 00000-0000
Attn: President
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Notice shall be deemed given when received and the parties may change the
respective addresses where notice is to be given upon prior notice hereunder.
IN WITNESS WHEREOF, the parties hereto have caused this Agreement to be
executed by their duly authorized representatives as of the date first above
written.
XXXXXX-XXXXXXX COMPANY
By: /s/ XXXXX X. XXXX
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Name: Xxxxx X. Xxxx
----------------------------
Title: President, R&D
----------------------------
THIRD WAVE TECHNOLOGIES, INC.
By: /s/ XXXXX XXXX
-------------------------------
Name: Xxxxx Xxxx
----------------------------
Title: Chief Executive Officer
----------------------------
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EXHIBIT A
PROTOCOL
The Institution will develop one hundred and eighty-one (181) discrete
Invader(TM) Assays and supply the indicated number of determinations as detailed
below; all assays will be supplied For Research Use Only and are not for use in
diagnostic procedures with humans:
NUMBER OF NUMBER OF TOTAL NUMBER
DIFFERENT DETERMINATIONS OF
ASSAYS ASSAYS PER ASSAY DETERMINATIONS
-------------- ------------ --------------- ----------------
Mouse SNPs for 100 1,000(3) 100,000
PDLMG(1)
P450 SNPs for 25 1,000(3) 25,000
REACH Study(1)
NAT(1) SNP for 1 4,000(3) 4,000
REACH Study(1)
P450 mRNA Isoforms 5 1,000 5,000
for expression
profiling(2)
mRNAs for 50 1,000 50,000
expression profiling 2
TOTALS 181 -- 184,000
(1) Each Invader(TM) Assay for Single Nucleotide Polymorphism (SNP) detection
consists of an assay or assay components which will permit the Company to detect
each allele of interest. Each Invader SNP Assay will incorporate oligonucleotide
probes for detection of the polymorphism of interest, the appropriate
Cleavase(R) enzyme and other reagents including buffers and standards needed for
the performance of such assay together with a 96 or 384-well microtiter plate.
Complete instructions will be provided for each Invader SNP Assay.
(2) Each Invader(TM) Assay for mRNA quantification consists of an assay or assay
components which will permit the Company to quantify a mRNA of interest. Each
Invader mRNA Assay will incorporate oligonucleotide probes, the appropriate
Cleavase(R) enzyme and other reagents including buffers and standards needed for
the performance of such assay together with a 96 or 384-well microtiter plate.
Each Invader mRNA assay will include control standard set to establish a
standard quantification curve. Complete instructions will be provided for each
Invader mRNA Assay.
(3) Each determination for an Invader Assays for Single Nucleotide Polymorphism
(SNP) detection include a determination for each allele, which is done in 2
separate microtiter xxxxx in the current assay configuration.
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A. The Development Program for each Invader Assay for Single Nucleotide
Polymorphism detection assay will encompass the following when the starting
sample material is a PCR product or genomic DNA:
1. At the initiation of the Development Program, the Company shall
provide the Institution with the appropriate PCR product and/or
genomic DNA containing the target sequence of interest as set forth
on Exhibit B.
2. Primary Invader Reaction:
- The Institution will design three (3) target-specific
oligonucleotide probes for use in the Primary Invader
Reaction: (i) an "Invader" probe (a probe designed
hybridize to the 3' portion of the target sequence, and
form a region that overlaps the duplex formed by the
appropriate Signal probe and target by at least a single
nucleotide base); (ii) a "Signal" probe for the major
allele ("wild-type") sequence and (iii) a "Signal" probe
for the mutant or minor allele ("mutant") sequence. Each
Signal probe will comprise a probe designed to hybridize
to the 5' portion of the appropriate target sequence and
overlap with the Invader probe. The Institution's
proprietary Cleavase enzymes will recognize the
structure created by this overlapping region and cleave
the 5' end of the wild-type and mutant probes for use in
the Secondary Invader Reaction (described below).
- The melting temperature (T(m)) of both the wild-type and
mutant Signal probes will be estimated. In order to
optimize signal generation, a temperature near the T(m)
of these probes will be utilized for the both the
Primary and Secondary Invader Reactions such that the
reaction cycle (hybridization of a Signal probe,
cleavage of its 5' end, and release of the remaining 3'
portion) will occur rapidly under isothermal conditions.
The rapid isothemal cycling of the Signal probes allows each
copy of PCR product or genomic DNA target to serve as the
substrate for multiple Signal probe cleavage events during
reaction incubation. The accumulation of 5' fragments of the
wild-type Signal probe is directly proportional to the number of
wild-type target molecules present in the test sample. Likewise,
the accumulation of 5' fragments of the mutant Signal probe is
directly proportional to the number of mutant target molecules
present in the test sample. Since the Primary and Secondary
Invader Reactions will take place simultaneously, the Primary
and Secondary Reaction temperature optima will be designed to be
compatible.
3. Secondary Invader Reaction:
- The Institution will design an oligonucleotide that will
function as both a Secondary target and a "Secondary
Signal" probe in the Secondary Invader Reaction. After
cleavage in the Primary Invader Reaction the 5' end of
the wild-type and mutant Signal probes from the Primary
Invader Reaction will be designed to act as "Secondary
Invader" probes in the Secondary Invader Reaction (i.e.,
the Secondary Signal probe will be designed such that
the 3'
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end of the Secondary Invader probe (5' of the Signal
probe from the Primary Invader Reaction) will overlap
the 5' most region of hybridization of the Secondary
Signal probe/Secondary target complex). The
Institution's proprietary Cleavase enzymes will
recognize the structure created by this overlapping
region and cleave the 5' end of the Signal probe for
subsequent detection. The Secondary Signal probe will be
designed to include a quencher dye and a
fluorescein-phosoramadite label. Due to the proximity of
these dyes in the uncleaved Secondary Signal probe, the
fluorescein label is quenched by the quencher dye via a
Fluorescence Resonance Energy Transfer (FRET) mechanism.
Cleavage of the 5' end of the Secondary Signal probe
between the labels enables spacial separation of the
quencher dye and fluorescein, thus enabling fluorescence
detection using FRET technology.
- The melting temperature (T(m)) of the Secondary Invader
probe will be estimated and sequence optimized in order
to optimize signal generation, a temperature near the
T(m) of the Secondary Invader probe will be utilized for
the Invader reaction such that the reaction cycle
(hybridization of Secondary Invader probe, cleavage of
the 5' end of the Signal probe, release of the Secondary
Invader probe) will occur rapidly under isothermal
conditions.
As a result of the Secondary Signal/Secondary target complex
being present in excess and the rapid isothemal cycling of the
Secondary Invader probe allowing each copy of Secondary Invader
probe to cause multiple signal generation cleavage events during
reaction incubation, the accumulation of 5' fragments of the
Secondary Signal probe is directly proportional to the number of
Secondary Invader probe molecules generated in the Primary
Invader Reaction.
4. The Institution will determine appropriate assay cut-off values for
assessment of genotype (wild-type homozygous, mutant homozygous,
wild-type/mutant heterozygous) based on fluorescence signal.
5. The Institution estimates that a minimum of 20pg of PCR product or
100ng of genomic DNA will be required in each test sample for
detection in the assay.
B. The development program for each Invader mRNA quantification assay will
encompass the following:
1. At the initiation of the Development Program, the Company will
provide the Institution with the appropriate genetic sequence
specifying the mRNA target of interest as set forth on Exhibit B.
Additionally, the Company will provide the Institution with total
cellular RNA material known to contain the mRNA target of interest
at a minimal expression level, and secondarily, at a maximal
expression level. The Institution estimates that >/=10 micrometer
(g) of total cellular RNA material will be required.
2. Primary Invader Reaction:
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- The Institution will design two (2) target-specific
oligonucleotide probes (an "Invader" probe and a
"Primary" probe) for use in the Primary Invader
Reaction. The Invader probe will be designed to
hybridize to the 3' portion of the target sequence, and
form a region that overlaps the duplex formed by the
Primary probe and target by at least a single nucleotide
base. The Institution's proprietary Cleavase enzymes
will recognize the structure created by this overlapping
region and cleave the 5' end of the Primary probe for
use in the Secondary Invader Reaction.
- The melting temperature (T(m)) of the target-specific
Primary probe will be estimated. In order to optimize
signal generation, a temperature near the T(m) of the
Primary probe will be utilized for the Primary Invader
Reaction such that the reaction cycle (hybridization of
Primary probe, cleavage of the 5' end of the Primary
probe, release of the remaining 3' portion of the
Primary probe) will occur rapidly under such conditions.
The rapid cycling of the Primary probes allows each copy of mRNA target
to serve as the substrate for multiple Primary probe cleavage events
during reaction incubation. The accumulation of 5' fragments of the
Primary probe is directly proportional to the number of mRNA target
present in the test sample.
3. Secondary Invader Reaction:
- The Institution will design oligonucleotides that will
function as a Secondary target and a "Signal" probe in
the Secondary Invader Reaction. The cleaved 5' end of
the Primary probe from the Primary Invader Reaction is
designed to act as a "Secondary Invader" probe in the
Secondary Invader Reaction (i.e., the Signal probe will
be designed such that the 3' end of the Secondary
Invader probe (5' of the Primary probe from the Primary
Invader Reaction) will overlap the 5' most region of
hybridization of the Signal probe/Secondary target
complex). The Institution's proprietary Cleavase enzymes
will recognize the structure created by this overlapping
region and cleave the 5' end of the Signal probe for
subsequent detection. The Signal probe will include a
quencher dye and a fluorescein-phosoramadite label. Due
to the proximity of these dyes in the uncleaved Signal
probe, the fluorescein label is quenched by the quencher
dye via a Fluorescence Resonance Energy Transfer (FRET)
mechanism. Cleavage of the 5' end of the Signal probe
between the labels enables spacial separation of the
quencher dye and fluorescein, thus enabling fluorescence
detection using FRET technology.
- The melting temperature (T(m)) of the Signal probe will
be estimated. In order to optimize signal generation, a
temperature near the T(m) of the Signal probe will be
utilized for the Secondary Invader Reaction such that
the reaction cycle (hybridization of Signal probe,
cleavage of the 5' end of the Signal probe, release of
the remaining 3' portion of the Signal probe) will occur
rapidly under such conditions.
This rapid cycling allows multiple Signal probes to be cleaved during
reaction
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incubation. The accumulation of signal (5' fragments of the Signal
probe) is directly proportional to the number of Secondary Invader
probes (from the Primary Invader reaction) generated in the Primary
Invader Reaction.
4. The Institution will develop appropriate standards (in vitro RNA
transcripts) for use in the assay and will demonstrate assay
proof-of-principle using this material. From time to time during the assay
Development Program, the Company will provide the Institution with
appropriate cellular material known to have the mRNA target of interest
expressed at various levels. The Institution will use this material for
further assay refinement and optimization.
5. The Institution estimates that a minimum of 1 attomole of the mRNA target
will be required in each test sample for detection in the assay.
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