Confidential treatment has been requested with respect to certain portions of this exhibit pursuant to a request for confidential treatment under Rule 24b-2 promulgated under the Securities Exchange Act of 1934, as amended. Omitted portions have been...
Confidential
treatment has been requested with respect to certain portions of this exhibit
pursuant to a
request
for confidential treatment under Rule 24b-2 promulgated under the Securities
Exchange Act of
1934, as
amended. Omitted portions have been filed separately with the
Securities and Exchange
Commission.
COOPERATIVE RESEARCH AND
PRODUCT DEVELOPMENT AGREEMENT
This
AGREEMENT (“Agreement”), effective as of March 17, 2009, (“Effective Date”) is
between MAXIM BIOTECH, INC., a California corporation (“Maxim”), and MULTICELL
TECHNOLOGIES, INC., a Delaware Corporation (“MultiCell”).
WITNESSETH:
WHEREAS,
Maxim has certain technologies, and manufactures and sells reagents and reagent
tool kits, related to the elucidation of gene function and their encoded
proteins;
WHEREAS,
MultiCell has certain technology assets related to human hepatocyte cells and
human liver stem cells; and,
WHEREAS,
Maxim and MultiCell desire to cooperate to jointly research and develop products
related to the isolation, characterization, differentiation, and function of
human hepatocyte cells and human liver stem cells.
NOW
THEREFORE, in consideration of the mutual covenants herein contained, the
parties hereby agree as follows:
1. Conduct of
Research. Maxim and MultiCell will conduct research in
accordance with the proposal set forth in Exhibit A hereto
(“Research”). In the event of any inconsistency between this
Agreement and Exhibit A thereto, the terms of this Agreement shall
control.
2. Support for the
Research. During the term of this Agreement, an annual
Research Budget (“Budget”) shall be established. Maxim and MultiCell
shall discuss and agree to all proposed costs in advance of either party
commencing work on the Research. Maxim and MultiCell must obtain
written approval from each other before making any change in the budgetary
allocation for the Research.
3. Reports of Research;
Confidentiality.
a. Maxim
will make an Invention Disclosure Report to the MultiCell with respect to any
new and useful process, machine, manufacture or composition of matter (including
any chemical compound or substances, nucleic acid molecule, biological cell, or
component thereof, whether derived from biological material or synthesized), as
well as any and all improvements thereto, conceived of or first reduced to
practice during the term of this Agreement in the performance of Research
hereunder (“Invention”) reported to it by an employee of Maxim or a consultant
of Maxim working in collaboration with Maxim.
b. Maxim
and MultiCell will provide semi-annual written reports to their respective Board
of Directors summarizing Research activity not previously reported pursuant to
Section 3(a) hereof, which shall include a Research Information Report with
respect to information and materials (including any chemical compound or
substances, nucleic acid molecule, biological cell, or component thereof,
whether derived from biological material or synthesized) developed in the course
of Research hereunder, but which does not constitute an Invention (“Research
Information”). Maxim and MultiCell with deliver to their respective
Board of Directors a final report of the Research within thirty (30) days
following the end of the term of this Agreement.
-1-
c. Maxim
and MultiCell, their employees and consultants will treat as confidential all
Invention Disclosure Reports and Research Information Reports, as well as any
other reports, information and materials furnished hereunder designated in
writing as “Confidential”. Except to the extent required by law, for
the term of this Agreement and five (5) years thereafter, neither Maxim or
MultiCell shall not disclose or make available any information disclosed in such
Invention Disclosure Reports and Research Information Reports and other
confidential reports, information, and materials to any third party without the
other party’s written permission, and each party will use Inventions and
Research Information only for the purpose of evaluating its interest in future
research or possible commercial development of the results of Research;
provided, however, that the Maxim and MultiCell may disclose such information to
third party advisors or consultants under obligations of confidentiality and
non-use no less strict than those contained herein.
d. Maxim
and MultiCell may, but are not obligated to, receive confidential information
belonging to the other party. Maxim and MultiCell will not disclose
or make available confidential information received from the other party to
third parties without the disclosing party’s prior written permission during the
term of this Agreement and five (5) years thereafter. Maxim’s and
MultiCell’s obligations under this paragraph apply only to information which the
disclosing party has designated in writing as “Confidential”.
e. The
obligations of confidentiality under this Section 3 do not apply to any
information which: (i) was in the public domain at the time of disclosure, (ii)
later became part of the public domain through no act or omission of the
recipient party, its employees agents, successors, or assigns, (iii) was
lawfully disclosed to the recipient party by a third party having the right to
disclose it, (iv) was already known by the recipient party at the time of
disclosure and recipient can so demonstrate by competent written proof or (v) is
required to be disclosed to a governmental agency pursuant to such agency’s rule
and regulations in order to secure regulatory approval or otherwise required to
be disclosed pursuant to applicable law, regulation, or court order, provided
that the recipient party shall promptly notify the disclosing party
of such disclosure requirement so that the disclosing party may seek
a protective order, should it so choose.
4. MultiCell Option and
Licenses; Indemnification; Good Laboratory Practices.
a. Subject
to any limitations imposed by law, Maxim grants MultiCell an option to obtain an
exclusive license to any Invention or Research Information. The terms
and conditions of said exclusive license will be negotiated between the parties
at the time the Invention or Research Information is conceived or is reduced to
practice.
b. Subject
to the MultiCell's license rights described in subsection (a) of this Section 4,
MultiCell shall have sole right, title, and interest to any Invention and
Research Information. Notwithstanding the foregoing, in the event
Maxim and MultiCell are unable to negotiate a mutually acceptable exclusive
license agreement, MultiCell shall have the right to negotiate an exclusive
license agreement with a third party with respect to any Invention or Research
Information on terms as good as or more favorable than those last negotiated
between the parties hereto. MultiCell shall have the right to accept
such third party license for itself under the final terms negotiated with the
third party. If MultiCell does not accept said third-party license
within five business days (5) days following the completion of final
negotiations, MultiCell shall be required to execute said third party
license.
-2-
c. Subject
to the MultiCell’s license rights described in subsection (a) or (b) of this
Section 4, the MultiCell and Maxim shall have no right to use Inventions and
Research Information for any purpose whatsoever, provided, however, MultiCell
shall have the right to publish, present, discuss or otherwise disclose the
Research Information to third parties, including , but not limited to, analysts,
investors, potential investors, partners, collaborators etc., in a manner
consistent with its status as Confidential Information pursuant to paragraph 3
herein. To the extent such Research Information encompasses an
Invention hereunder, MultiCell shall not publish, present, discuss or otherwise
disclose said Research Information until a patent application is filed, if any,
pursuant to paragraph 5 herein.
d. MultiCell
and Maxim shall indemnify, defend and hold each other harmless from and against
any and all actions, suits, claims, demands, prosecutions, liabilities, costs,
expenses, damages, deficiencies, losses or obligations (including attorneys’
fees) based on or arising out of its use of Inventions and Research Information,
except to the extent that a court of competent jurisdiction
determines that such actions, suits, claims, demands, prosecutions, liabilities,
costs, expenses, damages, deficiencies, losses or obligations (including
attorneys’ fees) are due, in whole or part, to the gross negligence,
recklessness or willful misconduct of either Maxim or MultiCell. Each
party shall reimburse the other party for the cost of enforcing this provision
unless a court of competent jurisdiction has determined that such actions,
suits, claims, demands, prosecutions, liabilities, costs, expenses, damages,
deficiencies, losses or obligations (including attorneys’ fees) were due, in
whole or part, to the gross negligence, recklessness, infringement of a third
party’s patent, or willful misconduct of the other party.
e. MultiCell
and Maxim acknowledge and agree that Maxim does not comply and the Research will
not be conducted in accordance with the requirements of 21 CFR Part 58, Good Laboratory Practice for
Nonclinical Laboratory Studies (the “GLP Regulations“). In any
submission by MultiCell to the U.S. Food and Drug Administration citing the
Research, MultiCell will state that the Research was not intended to be
performed in compliance with the GLP Regulations. MultiCell
will indemnify Maxim for all costs and expenses, including reasonable
attorneys’ fees, incurred in connection with any audit or inspection by the U.
S. Food and Drug Administration concerning Maxim’s compliance or non-compliance
with the GLP regulations in the conduct of the Research resulting from any
submission by MultiCell to the U. S. Food and Drug Administration citing the
Research.
5. Patent
Prosecution.
a. Within
ninety (90) days of receiving an Invention Disclosure Report under Section 3(a),
the MultiCell will advise Maxim in writing whether it wishes a patent
application to be made with respect to such Invention. However, in no
event shall such a patent application constitute, nor be deemed to constitute,
any grant of right to MultiCell to exploit or otherwise use such Invention in
the absence of the execution of a license to such Invention pursuant to Section
4(a) of this Agreement.
b. If
the MultiCell determines that it desires a patent application to be made,
MultiCell, by qualified counsel selected after reasonable consultation with the
Maxim and to whom the Maxim has no reasonable objection, shall prepare, file and
prosecute such application in MultiCell’s name and in countries designated by
MultiCell. MultiCell shall promptly provide copies to Maxim of any
proposed patent application filing and any communications from any patent office
relating to any patent application made with respect to such
Invention. MultiCell shall pay reasonable expenses incurred in filing
and prosecuting such patent applications, including attorneys' fees, taxes,
annuities, issue fees, working fees, maintenance fees and renewal charges
provided, however, that the exclusive license option granted to MultiCell
pursuant to Section 4(a) of this Agreement or any license obtained pursuant to
Section 4(b) of this Agreement is still in force.
-3-
c. Both
parties agree to cooperate with the other party to execute all lawful papers and
instruments, to make all rightful oaths and declarations and to provide
consultation and assistance as may be necessary in the preparation, prosecution,
maintenance, and reinforcement of all such patent applications and
patents.
d. If
the MultiCell does not wish to have a patent application filed or prosecution
continued with respect to an Invention in a particular country or countries,
Maxim may file such application or continue prosecution at its own expense, and
Maxim will be free to enter into a licensing agreement for or otherwise dispose
of its patent rights in such Invention for the countries for which Maxim has
filed such applications or continued such prosecution at its own expense with
any other person or persons on any terms.
6. Financial Records and
Reports. MultiCell and Maxim will maintain records of its
expenditures of funds received under this Agreement in accordance with its
customary accounting policies and procedures and, within 120 days following the
end of any calendar quarter, each party shall provide the other party with a
summary of all costs incurred and expenditures made under this
Agreement. During the term of this Agreement, and for two years after
the term of this Agreement, on reasonable notice and during normal business
hours, either party may examine the other party’s accounting records with
respect to cost incurred and expenditures made under this
Agreement.
7. Governance of the Research;
Title to Property; Independent Contractor. Maxim and MultiCell
shall be jointly responsible for the governance of the Research conducted under
this Agreement. Professional and other staff working on the Research
will be employees or consultants of Maxim or MultiCell appointed in accordance
with and subject to Maxim's and MultiCell’s respective employment policies and
procedures. Title to all equipment acquired by Maxim or MultiCell
used to perform the Research and all equipment, materials, and other tangible
results of the Research will vest with the acquiring party upon acquisition,
subject to all applicable terms of this Agreement. Maxim and
MultiCell are independent contractors and neither party is an agent or affiliate
of the other party.
8. Project Disclosure and
Publication. All individuals conducting Research under this
Agreement (“Researchers”) shall be required to comply with the project
disclosure and publication conditions described in this
Agreement. Maxim and MultiCell shall promptly deliver to each
other copies of any proposed scientific articles, papers or abstracts it
receives from Researchers. Maxim and MultiCell shall have sixty (60)
days from the date drafts of such proposed scientific articles, papers or
abstracts which disclose Inventions are sent to jointly decide whether to submit
such proposed scientific articles, papers or abstracts for
publication. Maxim and MultiCell shall review the proposed scientific
articles, papers or abstracts as they are made available, and will conduct their
review of such portions in a manner comparable to its review of complete
proposed publications. MultiCell may request the filing of a patent
application at MultiCell’s expense relating to said proposed scientific article,
paper or abstract prior to their publication by either party.
9. Prohibition Against Use of
Name. MultiCell and Maxim shall not use the other
party’s name, insignia, symbols, or trademarks, or any variation or combination
thereof, or the name of an employee or a Board of Directors member or a
Scientific Advisory Board member for any purpose whatsoever without the other
party's prior written consent, provided, however, that MultiCell may note in
various corporate communications and filings with the SEC that it is conducting
research in cooperation with Maxim.
-4-
10. Term of
Agreement.
a. Subject
to federal, state, local or internal compliance requirements, this Agreement
shall be effective as of the date first set forth above and shall continue in
full force and effect, unless earlier terminated as herein provided, for five
(5) years (the Research Period) after the Effective
Date. Neither MultiCell or Maxim warrant any particular result
from the Research or that the Research shall be completed by the end of the
Research Period. MultiCell reserves the right to continue
the Research Period indefinitely to allow for continuing work on the
Research.
b. If
either party commits a material breach of this Agreement, the non-breaching
party shall have the right to terminate this Agreement upon ninety (90) days
prior advance written notice to the breaching party unless the breaching party
shall have cured the breach complained of within the ninety day notice period,
in which case the Agreement shall continue in full force and
effect.
c. This
Agreement shall automatically terminate if either party commits any act of
bankruptcy, becomes insolvent, files a petition under any bankruptcy or
insolvency act or has any such petition filed against it.
d. All
rights and obligations accruing to the parties shall survive termination of this
Agreement. Except for termination because of the MultiCell's default,
MultiCell's rights under Section 4 of this Agreement shall survive the
termination of this Agreement.
e. On
termination of this Agreement due to a default by one party and failure to cure
such default within the time period set forth in Section 10(b) hereof, the
defaulting party shall have no further rights hereunder other than any rights
intended to survive the termination of this Agreement.
f.
Under no circumstances whatsoever, shall the liability
of Maxim or MultiCell exceed the payments made to by one party to the other
under this Agreement.
11. Notices. Any
notice required or permitted to be given under this Agreement shall be
sufficient if sent by certified mail (return receipt requested), postage
prepaid,
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if
to Maxim:
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Xxx
Maa, Ph.D.
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President
& CEO
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Maxim
Biotech, Inc.
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0000
X. Xxxx Xxxxx
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Xxxxxxxxx,
XX 00000
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if
to MultiCell:
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W.
Xxxxxx Xxxxxx
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Chairman
& Acting CEO
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00
Xxxxxxxxxx Xxxxxx, Xxxxx 000
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Xxxxxxxxxx,
XX 00000
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copy
to:
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Xxxxxx
Xxxxxxxxx
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EVP
& Managing Director
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The
Emmes Group, Inc.
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00
Xxxxxx Xxxxxx, Xxxxx 000
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Xxx
Xxxxxxxxx, XX
00000
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or to such other address as a party may specify by notice hereunder.
-5-
12. Assignment. This Agreement and all rights and obligations hereunder may not be assigned by either party without the written consent of the non-assigning party, and any attempt to assign without such consent shall be void; provided, however, that either party may assign this Agreement in connection with (i) the sale or transfer of all or substantially all the business to which this Agreement pertains; or (ii) the merger or consolidation of either party with another company. This Agreement shall be binding upon and inure to the benefit of Maxim, MultiCell and their respective permitted assigns and successors in interest.
13. Entire Agreement;
Amendment. This Agreement sets forth the entire agreement
between the parties and supersedes all previous agreements, written or
oral. This Agreement may be amended only by an instrument in writing
duly executed on behalf of the parties.
14. Governing Law;
Miscellaneous. This Agreement shall be governed by
Delaware law applicable to agreements made and to be performed in
Delaware, without regards to conflict of law principles in any
jurisdiction. Nothing in this Agreement will be construed as a
promise by either party to achieve any specific research result. In
the event of a conflict between this Agreement and any attachment hereto, the
terms of this Agreement will govern.
IN
WITNESS WHEREOF, the parties hereto have caused this Agreement to be executed by
their duly authorized representatives as of the day and year first written
above.
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By:
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||
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W.
Xxxxxx Xxxxxx
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Chairman
and Acting Chief Executive Officer
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FOR
MAXIM BIOTECH, INC.:
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By:
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Xxx
Maa, Ph.D.
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||
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President
and Chief Executive Officer
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-6-
EXHIBIT
A
Cooperative
Research and Product Development Agreement
Project
Scope and Specific Aims
Background
Multicell
Technologies owns unique cell-based technology for use in drug discovery
applications, and sells human hepatocyte cell lines used by the pharmaceutical
industry to screen new drugs and therapeutics for toxicity. While
growing in culture, Multicell’s human hepatocytes (BioFactories™) continue to
secrete a spectrum of therapeutic proteins including Factor VIII, Factor XI, and
alpha-1-antitrypsin that are virtually indistinguishable from the native
proteins. MultiCell's immortalized human hepatocyte cell lines,
designated Ea1C-35 and Fa2N-4, are protected by several issued and pending
patents.
Multicell
also has significant assets related to the isolation and differentiation of
liver stem cells, and has been issued two U.S. patents (6,872,389 and 6,129,911)
relating to the isolation of primary liver cell clusters (primary hepatocyte
cell together with an undifferentiated liver stem cell), and methods for
obtaining liver stem cells from primary liver cell clusters. These
liver stem cells are isolated from adult tissue, and can be further studied as a
potential means to treat degenerative liver diseases or inherited deficiencies
of liver function.
Maxim
Biotech owns technologies which improve the manner in which life science and
medical researchers perform nucleic acid amplification assays and other
molecular biology-related techniques. Maxim’s core competency in
developing multiplex amplification assay systems affords researchers the
opportunity to significantly increase their assay through-put while reducing the
time consuming and laborious nature that is typical of many of today’s
amplification assay systems. Maxim sells over 1,000 different
molecular biology reagents and reagent tool kits.
Multicell
and Maxim propose to work together to develop, manufacture, and market a family
of reagents and reagent tool kits sold under Multicell’s brand name which target
life science research (LSR) applications with a particular focus on products
used for liver stem-related LSR applications.
Phase 1 – Initial
Products
Multicell
currently has two human hepatocyte cell lines, the Fa2N-4 and Ea1C-35 cell
lines. Multicell also has procedures (SOPs) which it uses internally
to isolate and immortalize primary human hepatocyte cells, and to isolate and
differentiate human liver stem cells. The Fa2N-4 immortalized human
hepatocyte cell line is presently sold by Multicell and Corning/Xenotech for
drug toxicity testing applications. The SOPs will be “productized” by
Multicell and Maxim to produce the following LSR reagents and reagent tool
kits:
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1.
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Isolation
of primary human hepatocytes.
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2.
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Isolation
of human liver stem cells via liver cell
clusters.
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3.
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Immortalization
of human hepatocytes.
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4.
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Cell
growth media for the maintenance and expansion of human
hepatocytes.
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5.
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Protein
expression using human hepatocytes.
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Maxim
Biotech has identified several products within their existing product portfolio
which can be private labeled by Multicell including:
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1.
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BDtract
Genomic DNA Isolation kit.
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2.
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GStract
Total RNA Isolation kit.
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-7-
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3.
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RDtract
DNA/RNA Isolation kit.
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4.
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PCR-ready
cDNA (human).
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5.
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Single-Step
RT-PCR kit.
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6.
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Tissue
Blocks.
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7.
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PCR/MPCR
optimization reagents and buffers, and other general molecular biology
reagents.
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8.
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Enzyme
Immunoassay reagents, including blocking buffer, conjugate diluent,
substrate diluent and stabilization buffer,
etc.
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9.
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Custom
Services – including GMP plasmid construction and preparation, specific
PCR target amplification, and immunoassay
development.
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Phase 2 – Human
Hepatocellular Carcinoma and Liver Stem Cells
Certain
LSR applications that need accurate replication often require large amounts of
high-quality DNA for analysis and archiving. Areas where high
fidelity, low mutation whole genome amplification (WGA) is necessary include
molecular cloning, single cell analysis, and genome-wide analysis of single
nucleotide polymorphisms (SNP).
The
development of WGA methods (reviewed in [1,2]) has recently made it possible to
analyze multiple genomic loci from single cells. Early methods were
based on PCR and included degenerate oligonucleotide-primed (DOP) PCR [3],
primer extension pre-amplification (PEP) [4], and ligation-mediated PCR
[5]. PCR-based WGA techniques were used to amplify genomes of single
cells such as blastomeres in pre-implantation genetic diagnosis (reviewed in
[6,7]), lymphocytes [8], hepatocytes [9], sperm [10], oocytes [11], bone marrow
cells [12,13], and even single chromosomes [14].
Tumor
tissues are composed of heterogeneous cell populations. A minority of
tumor cells are “cancer stem cells” that may be important for resistance to
therapy and metastasis [15]. The tumor microenvironment contains
various non-malignant cells such as lymphocytes and fibroblasts that interact
with the malignant cells [16]. Importantly, while significant
progress was made in developing cancer therapies that result in cytoreduction
and thus tumor regression, the control of cancer over a longer interval and
especially of metastatic disease, remains a key goal. Cancer stem
cells, believed to be responsible for cancer relapse by being less sensitive to
conventional therapies, may thus offer a unique opportunity to identify and
develop a new generation of more effective anticancer agents (both small
molecules and biotherapies) [17]. The ability to analyze, at the
single cell level, the genomes of various malignant and non-malignant cells is
expected to increase our understanding of cancer.
In an
effort to review the evidence that liver cancer stem cells exist, two
fundamental questions must be addressed. First, do hepatocellular
carcinomas (HCC) arise from liver stem cells? Second, do HCCs contain
cells that possess properties of cancer stem cells?
For many
years the finding of preneoplastic nodules in the liver during experimental
induction of HCCs by chemicals was interpreted to support the hypothesis that
HCC arose by dedifferentiation of mature liver cells. More recently,
recognition of the role of small liver oval cells in the carcinogenic process
led to a new hypothesis that HCC arises by maturation arrest of liver stem
cells. Analysis of the cells in HCC supports the presence of cells
with stem-cell properties (i.e., immortality, transplantability, and resistance
to therapy). However, definitive markers for these putative cancer
stem cells have not yet been found, and a liver cancer stem cell has not been
isolated [18].
-8-
The objective of Phase 2 of the cooperative research program being conducted between Multicell and Maxim is to develop:
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1.
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LSR
reagent tool kits used to identify and isolate human cancer stem cells
(liver and other types);
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2.
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A
family of human hepatocyte and human liver stem cell whole genome
amplification LSR reagents and reagent tool kits, and other related
reagents and reagent tool kits used for the study of the development of
liver cancer in humans.
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3.
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A
family of cancer stem cell whole genome, transcriptome amplification LSR
reagents, proteomics reagents and reagent tool kits, and other related
reagents and reagent tool kits used for the study of the development of
human cancers in general, and identification of therapeutic targets, and
diagnostic and prognostic markers.
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In
addition, Multicell and Maxim will explore the possibility of acquiring new
reagents and know-how to isolate and characterize cancer stem cells, to amplify
Multicell’s LSR reagent and reagent tool kit product lines to support
identification of new therapies for cancer and organ insufficiency.
[***]
Multicell
intends to leverage the human hepatocellular carcinoma and liver stem cell
research effort not only by selling reagents and reagent tool kits to LSR
investigators, but hopes to additionally obtain novel clinical diagnostic and
therapeutic product opportunities for the identification and treatment of liver
cancer in humans.
Project Plan and
Budget
A more
detailed project plan and budget will be jointly prepared by Multicell and Maxim
prior to the commencement of any work.
References
|
|
1.
|
Xxxxxx,
XX; Egholm, M. Whole genome amplification: abundant supplies of DNA from
precious samples or clinical specimens. Trends Biotechnol.
2003;21:531–535. doi:
10.1016/j.tibtech.2003.09.010.
|
|
|
2.
|
Xxxxxxx,
S; Xxxxxxx, G; Espen, L; Xxxxxxx, G; Xxxxxxxxxx, V. Towards the analysis
of the genomes of single cells: further characterisation of the multiple
displacement amplification. Gene. 2006;372:1–7. doi:
10.1016/j.gene.2006.01.032.
|
|
|
3.
|
Telenius,
H; Xxxxxx, XX; Xxxx, XX; Nordenskjold, M; Xxxxxx, XX; Tunnacliffe, A.
Degenerate oligonucleotide-primed PCR: general amplification of target DNA
by a single degenerate primer. Genomics. 1992;13:718–725. doi:
10.1016/0888-7543(92)90147-K.
|
|
|
4.
|
Xxxxx,
X; Cui, X; Xxxxxxx, K; Xxxxxx, R; Xxxxxx, W; Arnheim, N. Whole genome
amplification from a single cell: implications for genetic analysis. Proc Natl Acad Sci U S A.
1992;89:5847–5851. doi:
10.1073/pnas.89.13.5847.
|
|
|
5.
|
Xxxxxxxx,
XX; Xxxxxx, XX; Ashburner, M; Siden-Kiamos, I; Louis, C; Monastirioti, M;
Savakis, C; Kafatos, F. PCR amplification of DNA microdissected from a
single polytene chromosome band: a comparison with conventional
microcloning. Nucleic
Acids Res. 1989;17:9027–9037. doi:
10.1093/nar/17.22.9027.
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-9-
|
|
6.
|
Coskun,
S; Alsmadi, O. Whole genome amplification from a single cell: a new era
for preimplantation genetic diagnosis. Prenat Diagn.
2007;27:297–302. doi:
10.1002/pd.1667.
|
|
|
7.
|
Peng,
W; Takabayashi, H; Ikawa, K. Whole genome amplification from single cells
in preimplantation genetic diagnosis and prenatal diagnosis. Eur J Obstet Gynecol Reprod
Biol. 2007;131:13–20. doi:
10.1016/j.ejogrb.2006.07.027.
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|
|
8.
|
Hu,
DG; Xxxx, G; Xxxxxx, N. Aneuploidy detection in single cells using DNA
array-based comparative genomic hybridization. Mol Hum Reprod.
2004;10:283–289. doi:
10.1093/humrep/gah038.
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|
|
9.
|
Xxxxxxxxx,
XX; Xxxxxxx, MS. Phylogenetic fate mapping. Proc Natl Acad Sci U S A.
2006;103:5448–5453. doi:
10.1073/pnas.0601265103.
|
|
10.
|
Xxxxxxx-Xxxxxx,
XX; Benet, J; Xxxxxxxxx-Xxxxx, C; Xxxx Seculi, J; Monros, E; Xxxxxxx, J.
Multiple mutation analysis of the cystic fibrosis gene in single cells.
Mol Hum Reprod.
2005;11:463–468. doi:
10.1093/molehr/gah176.
|
|
11.
|
Xxxxx,
CA; Xxxxxxx-Xxxxxxx, O; Xxxxxxx, XX; Xxxxxx, K; Xxxxxxxx, MR; Riethmuller,
G. Comparative genomic hybridization, loss of heterozygosity, and DNA
sequence analysis of single cells. Proc Natl Acad Sci U S A.
1999;96:4494–4499. doi:
10.1073/pnas.96.8.4494.
|
|
12.
|
Gangnus,
R; Xxxxxx, S; Xxxxx, E; Xxxxxx, K; Xxxxxxxx, MR. Genomic profiling of
viable and proliferative micrometastatic cells from early-stage breast
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