[Federal Register Volume 71, Number 54 (Tuesday, March 21, 2006)]
[Notices]
[Pages 14222-14223]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E6-4077]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Government-Owned Inventions; Availability for Licensing

AGENCY: National Institutes of Health, Public Health Service, HHS.

ACTION: Notice.

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SUMMARY: The inventions listed below are owned by an agency of the U.S. 
Government and are available for licensing in the U.S. in accordance 
with 35 U.S.C. 207 to achieve expeditious commercialization of results 
of federally-funded research and development. Foreign patent 
applications are filed on selected inventions to extend market coverage 
for companies and may also be available for licensing.

ADDRESSES: Licensing information and copies of the U.S. patent 
applications listed below may be obtained by writing to the indicated 
licensing contact at the Office of Technology Transfer, National 
Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, 
Maryland 20852-3804; telephone: (301) 496-7057; fax: (301) 402-0220. A 
signed Confidential Disclosure Agreement will be required to receive 
copies of the patent applications.

Rapid Methods for Human Artificial Chromosome (HAC) Formation

Vladimir Larionov (NCI), Hiroshi Masumoto (NCI), Megumi Nakano (NCI), 
Vladimir Noskov (NCI), Natalay Kouprina (NCI), J. Carl Barrett (NCI), 
et al.
U.S. Provisional Application No. 60/669,589 filed April 8, 2005 (HHS 
Reference No. E-128-2005/0-US-01)
Licensing Contact: Susan Carson, D. Phil.; 301/435-5020; 
[email protected].

    Human artificial chromosomes (HACs) provide a unique opportunity to 
develop a new generation of vectors for therapeutic use as gene 
expression and delivery systems. The advantages of a high-capacity, 
non-integrating chromosome-based vector capable of autonomous 
replication and long-term gene expression are evident for potential use 
in gene therapy and this area is one of active research. In particular, 
the generation of a functional centromere (a complex structure needed 
for segregation at cell division) has been recognized as key in the 
production of synthetic chromosomes. However, a typical human 
centromere extends over many millions of base pairs containing mainly 
alphoid satellite DNA (171 bp repeating units) organized into higher 
order repeats (HORs), which have been difficult to fully characterize 
or modify readily. There remains a need to elucidate the structural 
requirements of alphoid DNA arrays for efficient de novo assembly of 
centromere structure in order to construct HAC vectors able to carry 
intact mammalian genes capable of fully regulated gene expression and 
which can be stably maintained in the host nucleus for use in gene 
therapy.
    The group of Dr. Larionov at the NCI and colleagues have recently 
developed a novel strategy to rapidly construct large synthetic alphoid 
DNA arrays with a predetermined structure by in vivo recombination in 
yeast (Nucleic Acids Res., Sep 2005; 33: e130). The invention is a two 
step method involving (1) rolling-circle amplification (RCA) of a short 
alphoid DNA multimer (e.g. a dimer) and (2) subsequent assembly of the 
amplified fragments by in vivo homologous recombination during 
transformation with a Transformation-Associated Recombination targeting 
vector (TAR-NV) into yeast cells. This method or Recombinational 
Amplification of Repeats (RAR) has been used to construct sets of 
different synthetic alphoid DNA arrays varying in size from 30 to 120 
kb which were shown to be competent in HAC formation. Thus, these long 
arrays are engineered centromere-like regions that permit construction 
of mammalian artificial chromosomes with a predefined centromeric 
region structure. As any nucleotide can be easily changed into an 
alphoid dimer before its amplification, this new system is optimal for 
identifying the critical regions of the alphoid repeat for de novo 
centromere seeding.
    The Mammalian Artificial Chromosome Portfolio [HHS Ref. No. E-128-
2005/0-US-01 and HHS Ref. No. E-253-2000/0-US-03], including methods of 
generating engineered centromeric sequences, mammalian artificial 
chromosomes and methods of their use is available for licensing and 
will be of direct use to those interested in vectors providing long-
term regulated expression of genes used in therapy for human disease.
    Related technologies available for licensing also include: the TAR 
cloning Portfolio [HHS Ref. No. E-121-1996/0-US-06 (USPN 6,391,642 and 
global IP coverage); HHS Ref. No. E-158-2001/0-US-02, U.S. Publication 
No. US2004/0248289 filed October 4, 2002].
    In addition to licensing, the technology is available for further 
development through collaborative research opportunities with the 
inventors.

Transformation-Associated Recombination (TAR) Cloning

Vladimir Larionov (NCI), Natalay Kouprina (NCI), Michael A. Resnick 
(NIEHS), et al.
U.S. Patent No. 6,391,642 issued May 21, 2002 (HHS Reference No. E-121-
1996/0-US-06) and global IP coverage
Licensing Contact: Susan Carson, D. Phil., 301/435-5020; 
[email protected].

    Transformation-Associated Recombination (TAR) cloning in yeast is a 
unique method for selective isolation of large chromosomal fragments or 
entire genes from complex genomes without the time-consuming step of 
library construction (PNAS (1996) 93, 491-496). The technique involves 
homologous recombination during yeast spheroplast transformation 
between genomic DNA and a TAR vector that has short (approximately 
60bp) 5' and 3' gene targeting sequences (hooks). Further, because up 
to 15% sequence divergence does not prevent recombination in yeast, TAR 
cloning is highly efficient for isolation of gene homologs and 
synthenic regions. Using this technology, chromosomal regions up to 
250kb can be rescued in yeast as circular YACs within 3-5 working days 
(NAR (2003) 31, e29; Current Protocols in Human Genetics (1999) 
5.17.1).
    NIH researchers Drs. Larionov, Kouprina and Resnick have championed 
the use of this technology and TAR cloning has been used to efficiently 
isolate haplotypes, gene families (Genome Research (2005) 15, 1477) as 
well as genomic regions which are not present in existing BAC 
libraries. Known mutations and new modifications, including point 
mutations, deletions and insertions, can easily be introduced into DNA 
fragments hundreds of kilobases in size without introducing any 
unwanted alterations. The modified DNAs can then be tested functionally 
in mammalian cells and transgenic mice. TAR has also been used for 
structural

[[Page 14223]]

biology studies, long-range haplotyping, evolutionary studies, 
centromere analysis and analysis of other regions which cannot be 
cloned by a routine technique based on in vitro ligation (Kouprina and 
Larionov (2005) Recent Developments in Nucleic Acids Research, in 
press). In particular, construction of human artificial chromosome 
vectors and the combining of a HAC vector with a gene of interest can 
be effectively performed using the TAR methodology. Human genes 
isolated by TAR for expression in HACs include HPRT (60kb), BRCA1 
(84kb), BRCA2 (90kb), PTEN (120kb), hTERT (60kb), KA11 (200kb), ASPM 
(70kb), SPANX-C (83kb) among others. TAR is a flexible and efficient 
means for employing in vivo recombination in yeast in order to clone 
entire genomic loci which can then be used for structural and 
functional analysis and for expression in HAC vectors for a variety of 
uses including for potential use in gene therapy.
    The TAR cloning Portfolio [HHS Ref. No. E-121-1996/0-US-06 and HHS 
Ref. No. E-158-2001/0-US-02, U.S. Patent Application Publication No. 
US2004/0248289 filed 04 Oct 2002], including methods of use and 
vectors, is available for licensing and will be of direct use to those 
using a functional genomics approach in their work.
    Related technologies available for licensing also include: the 
Mammalian Artificial Chromosome Portfolio [HHS Ref. No. E-128-2005/0-
US-01, U.S. Provisional Patent Application No. 60/669,589 filed 08 Apr 
2005 and HHS Ref. No. E-253-2000/0-US-03, U.S. Patent Application 
Publication No. U.S. 2004/0245317 filed April 8, 2002].
    In addition to licensing, the technology is available for further 
development through collaborative research opportunities with the 
inventors.

Monoclonal Antibodies Which Specifically Bind to the Ligand Hepatocyte 
Growth Factor (HGF) and are Useful in the Treatment of Cancer

Boliang Cao and George Vande Woude (both of NCI)
U.S. Patent Application No. 10/129,596 filed September 30, 2002 (HHS 
Reference No. E-262-1999/1-US-02), which is a 371 application of PCT/
US00/31036 filed November 9, 2000 and which claims priority to U.S. 
Provisional Application No. 60/164,173 filed November 9, 1999
Licensing Contact: Susan S. Rucker; 301/435-4478; 
[email protected].

    The invention described and claimed in this patent application 
provides for compositions and methods for the treatment of cancers 
associated with hepatocyte growth factor (HGF). In particular, the 
patent application describes compositions and methods which employ a 
combination of monoclonal antibodies which bind to HGF and prevent it 
from binding to its receptor met in a manner that HGF/met signaling is 
neutralized. The combination of monoclonal antibodies has been shown to 
be neutralizing in tumor-bearing nude mice.
    HGF/met signaling has been most widely studied in settings related 
to cancer. It has been demonstrated to have a role in metastasis and 
angiogenesis. In addition to cancer, HGF activity has also been linked, 
through its role in apoptosis, to Alzheimer's disease and 
cardiovascular disease.
    The application has been published as WO 01/34650 (May 17, 2001). 
The work has also been published at Cao B, et al PNAS USA 98(13):7443-8 
(June 19, 2001) [http://www.pnas.org/cgi/content/full/98/13/7443]. The 
hybridomas which can be used to produce the various monoclonal 
antibodies have been deposited with the ATCC and are available to 
licensees. Only U.S. Patent protection has been sought for this 
technology. There are no foreign counterpart patent applications. This 
application is available for license only. Licenses for the development 
of therapeutics may be exclusive or non-exclusive. The principal 
investigators are no longer at the NIH and are not available for NIH 
collaborative projects under the CRADA mechanism.

    Dated: March 14, 2006.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. E6-4077 Filed 3-20-06; 8:45 am]
BILLING CODE 4140-01-P