[Federal Register Volume 70, Number 170 (Friday, September 2, 2005)]
[Notices]
[Pages 52400-52403]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-17457]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Government-Owned Inventions; Availability for Licensing: Selected 
Technologies From the NIH Cancer Therapeutics Portfolio

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 contacting George G. 
Pipia, Ph.D., Technology Licensing Specialist, Office of Technology 
Transfer, National Institutes of Health, 6011 Executive Boulevard, 
Suite 325, Rockville, Maryland 20852; telephone: 301/435-5560; fax: 
301/402-0220; e-mail: [email protected]. A signed Confidential 
Disclosure Agreement will be required to receive copies of the patent 
applications.

Antitumor Macrocyclic Lactones

Michael R. Boyd (NCI).
U.S. Patent No. 6,353,019 issued 05 Mar 2002 (HHS Reference No. E-244-
1997/0-US-07) and related foreign patent applications.

Vacuolar-Type (H+)-ATPase-Inhibiting Compounds and Uses Thereof

Michael R. Boyd (NCI).
U.S. Patent Application No. 09/914,708 filed 31 Aug 2001 (HHS Reference 
No. E-244-1997/3-US-06) and related foreign patent applications.

    This technology covers a broad composition of matter which includes 
the salicylihalamides, lobatamides, and numerous other structurally 
related small molecules which have been shown to inhibit mammalian 
vacuolar ATPase at low nanomolar concentrations. The compounds are also 
potent inhibitors of cancer cell growth, with particular specificity 
for melanoma, osteosarcoma and selected lung, colon and CNS tumor cell 
lines. Experimental tumor and pharmacokinetic studies are underway

[[Page 52401]]

to select the most effective analogs for further development. The 
potential of these compounds to inhibit invasion and metastasis to bone 
sites is also under investigation.
    In addition to licensing, the technology is available for further 
development through collaborative research opportunities with the 
inventors.

Novel 2-Alkoxy Estradiols and Derivatives Thereof

Ravi Varma (NCI), et al.
U.S. Patent No. 6,136,992 issued 24 Oct 2000 (HHS Reference No. E-188-
1998/1-US-01).

    The present invention is directed to novel 2-alkoxy estradiols and 
derivatives of 2-alkoxy estradiols having anticancer activity as 
claimed in the U.S. Patent 6,136,992. The invention is also directed to 
methods of preparing these novel compounds. These compounds have 
improved activity against a wide variety of tumor cell lines, including 
lung, colon, central nervous system, melanoma, ovarian, renal, prostate 
and breast cancers, compared with 2-methoxy estradiols. It is expected 
that these compounds will be very useful in the treatment of a wide 
variety of cancers. In addition, the present compounds have a low 
affinity for the estrogen receptor and are, therefore, expected to have 
fewer side effects than estradiols.
    In addition to licensing, the technology is available for further 
development through clinical collaborative research opportunities with 
the inventors under a clinical CRADA.

A Combined Growth Factor-Deleted and Thymidine Kinase-Deleted Vaccinia 
Virus Vector for Cancer Therapy

J. Andrea McCart (NCI), David L. Bartlett (NCI), and Bernard Moss 
(NIAID).
U.S. Patent Application No. 09/991,721 filed 13 Nov 2001, claiming 
priority to 28 May 1999 (HHS Reference No. E-181-1999/0-US-05).

    Tumor-selective, replicating viruses may infect and kill cancer 
cells and efficiently express therapeutic genes in cancer cells. The 
current invention embodies mutant vaccinia virus expression vectors. 
These vectors, which are vaccinia virus growth factor-deleted and 
thymidine-kinase deleted, are substantially incapable of replicating in 
non-dividing cells, and as such have specificity for cancer cells. It 
is therefore believed that the vectors will be of value for cancer 
therapy either by directly killing cancer cells or by expressing 
therapeutic agents in cancer cells while sparing normal, non-dividing 
cells.
    This research is described, in part, in: E. Chang et al., 
``Targeting vaccinia to solid tumors with local hyperthermia,'' Hum 
Gene Ther. 2005 Apr, 16(4):435-44; J.A. McCart, ``Oncolytic vaccinia 
virus expressing the human somatostatin receptor SSTR2: molecular 
imaging after systemic delivery using 111In-pentetreotide,'' Mol Ther. 
2004 Sep, 10(3):553-61; H.J. Zeh, ``Development of a replication-
selective, oncolytic poxvirus for the treatment of human cancers,'' 
Cancer Gene Ther. 2002 Dec, 9(12):1001-12; J.A. McCart, ``Systemic 
cancer therapy with a tumor-selective vaccinia virus mutant lacking 
thymidine kinase and vaccinia growth factor genes,'' Cancer Res. 2001 
Dec 15, 61(24):8751-7.

SH2 Domain Binding Inhibitors

Terrence R. Burke, Jr., et al. (NCI).
U.S. Patent Application No. 10/362,231 filed 22 Aug 2001, claiming 
priority to 22 Aug 2000 (HHS Reference No. E-262-2000/0-US-03).
U.S. Patent Application No. 10/517,717 filed 17 Mar 2005, claiming 
priority to 28 Jun 2002 (HHS Reference No. E-262-2000/1-US-03).

    Signal transduction processes underlie the transfer of 
extracellular information to the interior of the cell and ultimately to 
the nucleus. A variety of signal transduction processes are critical 
for normal cellular homeostasis, with protein-tyrosine kinases (PTKs) 
playing central roles in many of these pathways. Examples of such PTKs 
include the PDGF receptor, the FGF receptor, the HGF receptor, members 
of the EGF receptor family, such as the EGF receptor, erb-B2, erb-B3 
and erb-B4, the src kinase family, Fak kinase and the Jak kinase 
family. Protein-tyrosine phosphorylation that results from the action 
of PTKs can modulate the activity of certain target enzymes as well as 
facilitate the formation of specific multi-protein signaling complexes 
through the actions of homologous protein modules termed Src homology 2 
(SH2) domains, which recognize specific phosphotyrosyl containing 
sequences. A malfunction in this system through tyrosine kinase 
overexpression and/or deregulation can be manifested by various 
oncogenic and hyperproliferative disorders, including cancers, 
inflammation, autoimmune disease, hyperproliferative skin disorders, 
psoriasis and allergy/asthma, etc. The disclosed compounds, e.g. 
peptides, preferably, macrocyclic peptides, are Grb2 SH2 domain 
signaling antagonists with enhanced binding affinity. The claims of the 
current application are directed to compositions of matter and methods 
of use which provide for the diagnosis, testing and treatment of the 
aforementioned disease states.

SH2 Domain Binding Inhibitors

Terrence R. Burke, Jr., et al. (NCI).
U.S. Provisional Application No. 60/504,241 filed 18 Sep 2003 (HHS 
Reference No. E-315-2003/0-US-01).
U.S. Patent Application No. 10/944,699 filed 17 Sep 2004 (HHS Reference 
No. E-315-2003/0-US-02).
    The present invention provides for ultra-potent Grb2 SH2 domain-
binding compounds, or a pharmaceutically acceptable salt thereof. The 
compounds of the present invention represent tetrapeptide mimetics 
whose conformation is constrained through macrocyclization. Low 
picomolar binding affinity is achieved in in vitro Grb2 SH2 domain 
binding assays. Addition of the covered agent to the extracellular 
media of erbB-2 over-expressing breast cancer cells at low nanomolar 
concentrations results in effective intracellular blockade of Grb2 
association with activated cytoplasmic erbB-2 tyrosine kinase. 
Antimitogenic effects are observed in erbB-2-dependent breast cancer 
cells in culture at sub-micromolar concentrations. The present 
invention further provides a pharmaceutical composition comprising a 
pharmaceutically or pharmacologically acceptable carrier and a compound 
of the present invention. The present invention also provides a method 
for inhibiting an SH2 domain from binding with a phosphoproteins 
comprising contacting an SH2 domain with a compound of the present 
invention. The present invention also provides a method of preventing 
or treating a disease, state, or condition by the use of the compound. 
While the invention has been described and disclosed below in 
connection with certain embodiments and procedures, it is not intended 
to limit the invention to those specific embodiments. Rather it is 
intended to cover all such alternative embodiments and modifications as 
fall within the spirit and scope of the invention.
    This research is described, in part, in: Z. Shi et al., ``A novel 
macrocyclic tetrapeptide mimetic that exhibits low-picomolar Grb2 SH2 
domain-binding affinity,'' Biochem. Biophys. Res. Commun. (2003 Oct 17) 
310(2):378-383, doi:10.1016/j.bbrc.2003.09.029; Z. Shi et al., 
``Synthesis of a 5-methylindolyl-containing macrocycle that displays 
ultrapotent Grb2 SH2 domain-binding

[[Page 52402]]

affinity,'' J. Med. Chem. (2004 Feb 12) 47(4):788-791, doi:10.1021/
jm030440b.

A New Approach Toward Macrocyclization of Peptides

Terrence R. Burke, Jr., et al. (NCI).
U.S. Provisional Application No. 60/614,800 filed 30 Sep 2004 (HHS 
Reference No. E-327-2004/0-US-01).

    The invention relates to cyclic peptides for use as inhibitors of 
oncogenic signal transduction for cancer therapy. The current invention 
discloses novel cyclic peptides resulting from ring closure between the 
alpha and beta positions of C-terminal and N-terminal residues, 
respectively. This allows retention of key functionality needed for 
binding to target proteins, which results in increased affinity.
    Cyclic peptides that retain key chemical functionality may be of 
particular importance in inhibiting oncogenic signaling cascades for 
therapeutic benefit. In many oncogenic signal transduction cascades, 
tyrosine protein kinases phosphorylated target proteins. Propagation of 
the signal is achieved when these phosphorylated tyrosyl residues are 
bound by proteins bearing SH2 domains. Cyclic peptides that disrupt the 
interaction between proteins with SH2 domains and proteins with 
phosphorylated tyrosyl residues could block oncogenic signals and serve 
as powerful cancer therapeutic agents. As several moieties are required 
for optimal recognition by SH2 domains, the cyclic peptides of the 
current invention could be more effective inhibitors of SH2 domain 
proteins, or of other proteins where increased specificity is desired. 
The inventors have determined that the peptides of the current 
invention bind to the Grb2-SH2 domain with high affinity, supporting 
their potential use as therapeutic agents. The current invention is 
related to U.S. Provisional Application No. 60/504,241 (HHS Reference 
No. E-315-2003/0-US-01).

Conjugates of Ligand, Linker, and Cytotoxic Agent and Related 
Compositions and Methods of Use

Nadya Tarasova, Christopher J. Michejda, Marcin Dyba, Carolyn Cohran 
(NCI).
U.S. Patent Application No. 10/505,239 filed 19 Aug 2004, claiming 
priority to 27 Feb 2002 (HHS Reference No. E-057-2002/2-US-02).

    Systemic toxicity of drugs is one of the most serious problems in 
cancer chemotherapy and frequently is dose limiting. Specific delivery 
of cytotoxic drugs to cancer cells remains among the most intractable 
problems of cancer therapy. Targeted delivery of anti-proliferation 
drugs through the cell surface receptors that are over expressed on 
cancer cells can reduce systemic toxicity and increase effectiveness of 
a treatment.
    The present invention describes cytotoxic compounds with an 
intracellular target that can selectively enter tumor cells through 
specific receptors on the cell surface. The invention also describes a 
conjugate comprising a cytotoxic agent, a linker arm and a ligand 
capable of delivering a cytotoxic agent in a cell specific manner. Such 
conjugates of a cytotoxic agent and a ligand (delivery moiety) have 
increased selectivity for tumor cells. The toxic moiety and the ligand 
are joined by a linker arm that is stable in circulation, but is easily 
cleaved in lysosomes upon internalization of the conjugate. A panel of 
compounds comprised of a variety of cytotoxic warheads, against various 
intracellular targets linked to an assortment of ligands, has been 
developed and tested in a model system. Ligand moieties of these 
conjugates are capable of specific delivery of cytotoxic agents to 
receptors that are frequently over expressed in gastric, colon, lung, 
breast, ovarian and pancreatic tumors. These compounds have the 
potential to be highly effective anti-tumor agents with considerably 
little negative effect. This disclosed technology could provide new and 
exciting methodologies to treat cancer.
    In addition to licensing, the technology is available for further 
development through collaborative research opportunities with the 
inventors.

DNA-Binding Polyamide Drug Conjugates

Zoltan Szekely, Humcha K. Hariprakasha, Marek W. Cholody, Christopher 
J. Michejda (NCI).
U.S. Patent Application No. 10/506,085 filed 01 Oct 2004, claiming 
priority to 27 Feb 2002 (HHS Reference No. E-060-2002/2-US-02).

    Many current anti-cancer drugs have the DNA of cancer cells as 
their principal target. However, in most instances, the drugs are not 
selective and are plagued by toxicities, which are frequently dose 
limiting. The present invention seeks to enhance anti-tumor selectivity 
and decrease unspecific toxicity. It has been known that various 
polyamides can target the minor groove of DNA, and rules have been 
devised to ascertain the sequence-reading properties of the component 
residues of the polyamide chain. The present invention utilizes 
sequence-selective polyamide technology together with groups that 
modify DNA, either by sequence-selective alkylation or strand cleavage. 
The DNA-modifying moieties that are used for this purpose are novel 
derivatives based on the cyclopropylbenzindole (CBI) core structure. 
These compounds alkylate the DNA only when bound into the minor groove, 
and they provide some DNA-sequence recognizing capability of their own. 
The DNA-modifying agents are either embedded in the polyamide chain as 
components of the chain or are located at the termini. These compounds 
are highly toxic to cancer cells that over-express a targeted DNA 
sequence (e.g. the c-Myc oncogene promoter sequence) and are much less 
toxic to non-cancerous tissue. The compounds of the present invention 
represent a novel method for targeting DNA of cancer cells.
    In addition to licensing, the technology is available for further 
development through collaborative research opportunities with the 
inventors.

New Building Blocks for DNA Binding Agents

Zoltan Szekely et al. (NCI).
U.S. Provisional Application No. 60/508,543 filed 03 Oct 2003 (HHS 
Reference No. E-291-2003/0-US-01).
PCT Application No. PCT/US04/32617 filed 01 Oct 2004, which published 
as WO 2005/032594 on 14 Apr 2005 (HHS Reference No. E-291-2003/0-PCT-
02).

    There remains a need for therapeutic conjugates that have improved 
antitumor selectivity and nucleic acid sequence-binding specificity. 
Ideally such conjugates will have fewer side effects and lower 
cytotoxicity to healthy cells and tissues. The knowledge of the 
geometry of conjugates allows for a rational design of therapeutic 
conjugates, ones that have increased specificity of binding to a minor 
groove of the DNA, while maintaining maximum activity of the alkylating 
subgroup of the conjugates. The present invention provides such 
conjugates. The conjugates of the present invention bind to the minor 
grove of DNA in a sequence-specific manner and deliver an alkylating 
moiety to a specific site on the DNA. The present invention provides a 
pharmaceutical composition comprising a pharmaceutically or 
pharmacologically acceptable carrier and compounds of the present 
invention. The present invention also provides a method of preventing 
or treating a disease or condition by the use of the compound. The NIH 
inventors currently are testing the conjugates in in-vitro assay and 
are

[[Page 52403]]

starting pre-clinical studies of the conjugates using animal cancer 
models.
    In addition to licensing, the technology is available for further 
development through collaborative research opportunities with the 
inventors.

Maleiimide Anti-Tumor Phosphatase Inhibitors

Christopher J. Michejda et al. (NCI).
U.S. Provisional Application No. 60/546,841 filed 22 Feb 2004 (HHS 
Reference No. E-110-2004/0-US-01).
PCT Application No. PCT/US05/05742 filed 22 Feb 2005 (HHS Reference No. 
E-110-2004/0-PCT-02).

    The present invention describes novel phosphatase inhibitors that 
appear to target the CDC25 family of phosphatases. The new compounds 
have potent activity against human liver cancer cells in vitro and in 
vivo against an orthotopic liver cancer in rats. In tumor cells, these 
new inhibitors appear to target the phosphorylation status of several 
cell cycle proteins that are important for cell survival and thus could 
represent a novel class of chemotherapeutic agents targeting cancer 
cells.

2-Amino-O4-Substituted Pteridines and Their Use as Inactivators of O6-
Alkylguanine-DNA Alkyltransferase

Robert C. Moschel et al. (NCI).
U.S. Provisional Application No. 60/534,519 filed 06 Jan 2004 (HHS 
Reference No. E-274-2003/0-US-01).
PCT Application No. PCT/US04/41577 filed 10 Dec 2004 (HHS Reference No. 
E-274-2003/0-PCT-02).

    This invention is directed to 2-amino-O4-benzylpteridine 
derivatives targeted for use in cancer treatment in combination with 
chemotherapeutic agents such as 1,3-bis(2-chloroethyl)-1-nitrosurea 
(BCNU) or temozolomide. The derivatives of the present invention 
inactivate the O6-alkylguanine-DNA-alkyltransferase repair protein and 
thus enhance activity of such chemotherapeutic agents. Examples of 
these derivatives have advantages over the earlier O6-benzylguanine 
compounds from this research group. Some compounds of the current 
invention are more water soluble compared to O6-benzylguanine and they 
exhibit greater specificity for inactivating O6-alkylguanine-DNA-
alkyltransferase in certain tumor cells, compared to normal cells.
    In addition to licensing, the technology is available for further 
development through collaborative research opportunities with the 
inventors.

Beta-Glucuronidase Cleavable Prodrugs of O6-Alkylguanine-DNA 
Alkyltransferase Inactivators

Robert C. Moschel et al. (NCI).
U.S. Provisional Application No. 60/608,045 filed 08 Sep 2004 (HHS 
Reference No. E-307-2004/0-US-01).

    The present invention relates to prodrugs of inactivators of O6-
alkylguanine-DNA alkyltransferase. The prodrugs are cleaved by the 
beta-glucuronidase enzyme found in tumor cells or co-administered to 
the patient, and the drugs are targeted for use in cancer treatment in 
combination with antineoplastic alkylating agent such as 1,3-bis(2-
cloroethyl)-1-nitrosouria or temozolomide.

Identification of a Tricyclic Amino Amide (NSC-644221) Inhibitor of the 
Hypoxic Signaling Pathway

Giovanni Melillo (NCI).
U.S. Provisional Application No. 60/618,279 filed 12 Oct 2004 (HHS 
Reference No. E-185-2004/0-US-01).
U.S. Provisional Application No. 60/570,615 filed 12 May 2004 (HHS 
Reference No. E-185-2004/1-US-01).
PCT Application filed 11 May 2005 (HHS Reference No. E-185-2004/2-PCT-
01).

    This invention describes the identification of a tricyclic (1,4-
dioxane) amino amide with confirmed potent activity in inhibiting HIF-1 
transcriptional activity.
    HIF-1 is a transcription factor and plays an important role in 
adaptation of cancer cells to an hypoxic environment. HIF-1 
significantly increases the ability of cancer cells to survive under 
strenuous conditions. It contributes to the ability of cancer cells to 
migrate and invade surrounding tissue, and is important for the 
formation of new blood vessels that are essential for growth and 
metastasis of cancer cells. Thus HIF-1 mediates survival and spreading 
of cancer cells. Previous studies have shown that HIF-1 is also 
important in human cancers, and therefore, inhibition of HIF-1 activity 
is contemplated in the field as a therapy for cancer patients.
    The inventors, using a cell-based high throughput screen, 
identified a new compound, NSC-644221, with potent inhibitory activity 
of the HIF-1 pathway. The compound inhibits expression of HIF-1 and 
reduces its accumulation in the cell. This compound also inhibits 
expression of endogenous genes that are under control of HIF-1, such as 
Vascular Endothelial Growth Factor (VEGF) that is essential for the 
formation of new blood vessels. Preliminary experiments in xenograft 
models have indicated that NSC-644221 reaches the tumor tissue when 
administered intraperitoneally and inhibits HIF-1-dependent luciferase 
expression in U251-HRE cells.
    In addition to licensing, the technology is available for further 
development through collaborative research opportunities with the 
inventors.

Inhibitors of the Protein Kinase Chk2 to Abrogate Apoptosis and 
Sensitize Cancer Cells to DNA Targeted Therapies

Yves Pommier et al. (NCI).
U.S. Provisional Application filed 29 Jul 2005 (HHS Reference No. E-
211-2005/0-US-01).

    Chk2 is a protein kinase activated in response to DNA double strand 
breaks. In normal tissues, Chk2 phosphorylates and thereby activates 
substrates that induce programmed cell death, or apoptosis, via 
interactions with p53, E2F1, PML proteins. In cancer tissues, where 
apoptosis is suppressed, Chk2 phosphorylates and inactivates cell cycle 
checkpoints (via interactions with Cdc25, phosphatases and Brca1 
proteins), which allows cancer cells to repair and tolerate DNA damage. 
Hence, Chk2 inhibitors would be expected to protect normal tissues by 
reducing apoptosis, and to sensitize cancer cells to DNA-targeted 
agents.
    In addition to licensing, the technology is available for further 
development through collaborative research opportunities with the 
inventors.

    Dated: August 25, 2005.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. 05-17457 Filed 9-1-05; 8:45 am]
BILLING CODE 4140-01-P