[Federal Register Volume 74, Number 250 (Thursday, December 31, 2009)]
[Notices]
[Pages 69348-69351]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E9-31072]


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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.

Device and Method for Direct Measurement of Isotopes of Expired Gases: 
Application in Research of Metabolism and Metabolic Disorders, and in 
Medical Screening and Diagnostics

    Description of Technology: The technology offered for licensing and 
for further development concerns a novel device for intervallic 
collection of expired gas from subjects and subsequent measurement of 
the isotopic content of such expired gases. The device is specifically 
designed for medical research and clinical applications, and in 
particular in the area of metabolic disorders. The device may 
facilitate the development and testing of new therapies for such 
disorders and may be used for medical screening and diagnostics of 
metabolic diseases. The unique design of the device includes a constant 
volume respiratory chamber equipped with a series of valves and 
stopcocks to allow precise and repetitive removal of expired gases, and 
addition of air or other gas to maintain the chamber at a constant 
volume. Also included is a vacuum tube adapter linked to a port on a 
three-way stopcock to allow facile transfer of the chamber gases to 
vacuum tubes for subsequent chemical analyses. The device also includes 
gas sensors operably linked to detectors and inserted to the chamber 
through airtight ports; this allows the operator to independently and 
directly measure the carbon dioxide production rate and oxygen 
consumption of the test subject while the expired gases are removed for 
study.
    The experimental subject (e.g. mammal) is first contacted with a 
substrate (e.g. amino acid, fatty acid, organic acid) containing an 
isotope (e.g. \13\C) and placed in the chamber. The unique design 
allows easy gas removal and addition while maintaining a constant 
chamber volume. Precisely measured air samples are collected from the 
chamber by the syringe and subsequently transferred to a self-sealing 
vacuum tube which is then removed for analysis. Subsequent sampling is 
accomplished in the exact

[[Page 69349]]

same manner, after an equivalent volume of ambient air, or other gas 
such as pure oxygen, is reinjected in the chamber to maintain pressure 
and volume. Air samples from the chamber are collected periodically and 
the content of the isotope (\13\C) accumulated in the chamber gas due 
to metabolism and the formation of \13\CO2 is measured (e.g. 
via Isotope Ratio Mass Spectroscopy (IRMS)) from the collected samples. 
The rate of the metabolite's development (i.e. \13\CO2) can 
thus be determined and can thus provide information on the metabolic 
status of the subject, such as the rate and extent of oxidation of the 
administered isotope. Furthermore, results of such analysis can provide 
fundamental information on the ability of the subject to metabolize a 
compound, quantitate the effectiveness of an experimental therapy (i.e. 
enzyme replacement, gene therapy, hormone administration, etc.) and 
thus facilitate progress in the development of interventional 
therapies.
    Applications:
     Research in the area of metabolic disorders.
     Development of therapies (including enzyme replacement and 
gene therapy) for metabolic disorders.
     Potential applications in screening and diagnostics of 
metabolic disorders.
     Assessment of non-invasive breath tests to study 
metabolism.
    Advantages:
     The device of this invention is uniquely designed for 
precise periodic collection of expired gas samples from a test subject 
and their transfer for analytical processing while the carbon dioxide 
production rate and oxygen consumption rate are independently and 
simultaneously measured.
     The unique configuration of the device and the manner in 
which the valves and stopcocks are attached to the main chamber 
facilitates the performance of repetitive measurements in a seamless, 
precise and reliable fashion.
     The technique and device uses stable isotopes, so treated 
animals can be returned to the cage after study with no concerns of 
radioactive contamination. This also allows animals that are difficult 
and expensive to create, such as genetically engineered rodents, to be 
repeatedly studied, pre- and post-intervention(s) and with various 
compounds at different times.
     The device can be readily fabricated in a relatively 
inexpensive manner and operated with simple instructions.
    Development Status: The invention is fully developed. A prototype 
functioning device was fabricated.
    Market: Metabolic disorders affect millions of people worldwide. 
Thousands of metabolic diseases, including inborn errors of metabolism 
and endocrinopathies, have been identified in humans. Apart for 
affecting the life quality of people afflicted with these diseases, 
some of them are responsible for large numbers of morbidity and 
mortality. The World Health Organization (WHO) estimates that type 2 
diabetes affects 135 million people worldwide and that 300 million 
people meet the criteria for obesity. Dyslipidemia is another major 
metabolic disorder, affecting approximately 300 million people in the 
United States, Japan, and Western Europe. These three disorders alone--
type 2 diabetes, obesity, and dyslipidemia (high blood cholesterol and 
triglycerides is lipid disorder)--are highly prevalent and lead to 
significant morbidity and mortality. Many other known metabolic 
disorders such as polycystic ovarian syndrome (PCOS), and non-alcoholic 
steatohepatitis (NASH) are common in the population, and although they 
may be less severe, still account for significant morbidity and 
mortality, especially in the pediatric population. A large group of 
metabolic diseases have received extensive attention due to the 
implementation of population newborn screening are caused by the body's 
inability to break down certain proteins and fats and the undesirable 
buildup of amino and organic acids in the blood. Examples include amino 
acid disorders such as phenylketonuria (PKU) and maple syrup urine 
disease (MSUD); fatty acid oxidation defects such as medium- and long-
chain acyl-CoA dehydrogenase deficiencies (VLCADD and MCADD), and 
organic acidemias including methylmalonic, propionic and isovaleric 
acidemia. Most states in the USA are now testing every baby for these, 
and other conditions as part of routine newborn screening. These 
diseases are caused by genetic defects and are inherited; for example 
MMA (Methylmalonic Acidemia) is estimated to occur in 1 in 25,000-
48,000 babies. Similarly, Propionic Acidemia, caused by a deficiency of 
the enzyme propionyl-CoA carboxylase, affects 1 in 100,000 new born 
babies in the U.S. and even more than that in other countries. While 
the disorders are individually infrequent, collectively, they occur at 
an incidence of approximately 1 in 6000 births. The device of this 
invention is particularly suitable for research in this area of 
diseases and an example related to its application in MMA is provided 
in the patent application and a recent publication (RJ Chandler and CP 
Venditti. Long-term rescue of a lethal murine model of methylmalonic 
acidemia using adeno-associated viral gene therapy. Mol Ther 2009 Oct 
27. Epub ahead of print, PMID: 19861951).
    Huge efforts have been made by many pharmaceutical companies to 
develop and market drugs for the treatment of metabolic diseases, and 
many commercial opportunities exist in this area. The magnitude of the 
potential market can be further exemplified by the following data 
published in commercial market research analyses:
     The global market for prescription endocrine and metabolic 
disease drugs was $66.2 billion in 2005 and $72.3 billion in 2006. At a 
compounded annual growth rate (CAGR) of 5.2%, the market will reach 
$96.4 billion by 2011.
     Drugs for hypercholesterolemia dominated the highest share 
of the market, worth almost $37.1 billion in 2006, a 51.3% share. By 
2011 its share will drop slightly to 47.2% ($45.5 billion of the total 
market), though it will remain the largest sector of the market.
     Obesity drugs and treatment have the highest growth 
potential throughout the forecast period. A relatively small market, 
its growth however is booming at a CAGR of 23.8%. By 2011 the sector 
will be worth more than $4.0 billion.
     2007 sales of the recombinant enzyme replacement therapies 
(ERT) reached a record level of US$ 2.3 billion shared predominantly by 
three companies (Genzyme, Shire and Biomarin Pharmaceuticals) for a 
total of seven different products. Companies are working to extending 
the market by developing novel ERTs for further human genetic diseases 
as well as by profiling small molecule therapies for enhancement of 
enzymatic activities. Porcine-derived extracts containing pancrelipase 
(a mixture of lipase, amylase and protease among others) recently were 
forced by the FDA to undergo regulatory review of an NDA. Now these 
products are exposed to upcoming competition with enzymes produced by 
recombinant DNA technology which intent to capture a part or maintain 
existing sales of exocrine enzyme replacement therapies (2007 sales > 
US$ 300 million).
    The huge market for drugs and diagnostics for metabolic diseases 
and the need to develop newer treatments increase the demand for new 
tools to facilitate and accelerate research in this area. The present 
invention therefore presents a favorable commercial opportunity.
    Inventors: Randy Chandler and Charles P. Venditti (NHGRI)
    Related Publications:


[[Page 69350]]


    1. CP Venditti, E Manoli, RJ Chandler. A Method To Determine The In 
Vivo Oxidative Capacity For 13C Isotopomers In Mice: Use To Study 
Intermediary Metabolism And To Monitor Transgene Activity. Presented at 
the American Society of Gene Therapy 12th Annual Meeting, May 2009.
    2. RJ Chandler and CP Venditti. Long-term rescue of a lethal murine 
model of methylmalonic acidemia using adeno-associated viral gene 
therapy. Mol Ther. 2009 Oct 27; Epub ahead of print.

    Patent Status: U.S. Patent Application No. 12/418,795 filed 09 Apr 
2009 (HHS Reference No. E-099-2009/0-US-01).
    Licensing Status: Available for licensing.
    Licensing Contacts: Uri Reichman, PhD, MBA; 301-435-4616; 
UR7a@nih.gov; Michael Shmilovich, Esq.; 301-435-5019; 
shmilovm@mail.nih.gov.
    Collaborative Research Opportunity: The Organic Acid Research 
Section, Genetic and Molecular Biology Branch, National Human Genome 
Research Institute (NHGRI) is seeking statements of capability or 
interest from parties interested in collaborative research to further 
develop, evaluate, or commercialize this technology or related 
laboratory interests. Please contact Claire T. Driscoll at 
cdriscol@mail.nih.gov for more information.

Vaccines Against Malarial Diseases

    Description of Technology: The invention offered for licensing is 
in the field of use of vaccines for malaria. The invention provides 
gene sequences encoding an erythrocyte binding protein of a malaria 
pathogen for the expression of the erythrocyte binding protein. The 
codon composition of the synthetic gene sequences approximates the 
mammalian codon composition. The synthetic gene sequences are useful 
for incorporation into DNA vaccine vectors, for the incorporation into 
various expression vectors for production of malaria proteins, or both. 
The synthetic genes may be modified to avoid post-translational 
modification of the encoded protein in other hosts. Administration of 
the synthetic gene sequences, or the encoded protein, as an 
immunization agent is useful for induction of immunity against malaria, 
treatment of malaria, or both. The approach presented in this 
invention, i.e. vaccine that may block the binding of the malaria 
parasite and subsequent erythrocyte invasion, may work independently or 
in combination with other vaccines which are based on different 
mechanisms.
    Applications: Vaccines compositions against Malaria in the form of 
DNA vaccines or as protein immunogens.
    Advantage: Due to the complex nature of the malaria parasite, 
multiple approaches have been attempted to develop malaria vaccines. In 
particular, due to the diversity attributed to the different life cycle 
stages of the parasite, there are several sites that can be used as 
vaccine targets. The approach offered in the present invention, i.e. 
blockage of the binding to blood erythrocyte, may work independently or 
in combination with other vaccines based on different mechanisms to 
create an effective vaccine against malaria.
    Development Status: Proof of concept demonstrated.
    Market: Malaria is a major public health problem in more than 90 
countries, inhabited by more than 2.4 billion people--40% of the 
world's population. The disease is estimated to kill approximately one 
(1.0) million people a year, and to cause up to 600 million new 
infections worldwide annually. Although the disease is mostly prevalent 
in developing countries and in particular in Sub-Saharan Africa, it 
also presents a significant health problem for the developed countries 
due to the extensive travelling between continents at this age of 
global economy.
    Despite of the urgent need to find an effective cure against 
malaria, such cure has not been developed yet. Although several small 
molecule drugs have been used to alleviate the symptoms of the disease, 
a vaccine that can prevent the disease, or eradicate it altogether has 
not been developed yet, in spite of the many efforts to develop such a 
vaccine. The challenge in developing a malaria vaccine is due to the 
nature of the parasites that cause the disease, primarily the 
Plasmodium falciparum parasite. The parasite, which is transmitted to 
the human body via mosquito's bite, is quite complex and is 
characterized by structural diversity associated with the different 
stages of its life cycle.
    The urgent public health need in a vaccine against malaria may 
present a substantial commercial opportunity to any vaccine or 
pharmaceutical company. The approach described and claimed in the 
present invention, i.e. blocking of the binding of the parasite to the 
blood erythrocytes, may therefore be an opportunity for vaccine 
developers. Furthermore, a vaccine of this invention may work 
effectively in combination with other malaria vaccines based on 
different mechanisms (i.e. RTS,S vaccine currently developed by GSK 
Biologicals and others).
    Inventors: David Narum (NIAID) et al.
    Related Publications:

    1. H Liang and BK Sim. Conservation of structure and function of 
the erythrocyte-binding domain of Plasmodium falciparum EBA-175. Mol 
Biochem Parasitol. 1997 Feb;84(2):241-245.
    2. DL Narum et al. Codon optimization of gene fragments encoding 
Plasmodium falciparum merzoite proteins enhances DNA vaccine protein 
expression and immunogenicity in mice. Infect Immun. 2001 
Dec;69(12):7250-7253.
    3. DL Narum et al. A novel Plasmodium falciparum erythrocyte 
binding protein-2 (EBP2/BAEBL) involved in erythrocyte receptor 
binding. Mol Biochem Parasitol. 2002 Feb;119(2):159-168.

    Patent Status: U.S. Patent No. 7,078,507 issued 18 Jul 2006, 
entitled ``Synthetic genes for malarial proteins and methods of use'' 
(HHS Reference No. E-052-2004/0-US-02)
    Licensing Status: Available for licensing.
    Licensing Contacts: Uri Reichman, PhD, MBA; 301-435-4616; 
UR7a@nih.gov.
    Collaborative Research Opportunity: The NIAID Office of Technology 
Development is seeking statements of capability or interest from 
parties interested in collaborative research to further develop, 
evaluate, or commercialize the erythrocyte binding protein as a malaria 
vaccine. Please contact Dana Hsu at 301-496-2644 for more information.

Novel Acylthiol Compositions and Methods of Making and Using Them 
Against HIV

    Description of Technology: This invention provides a novel family 
of acylthiols and uses thereof. More specifically, this invention 
provides effective inhibitors of HIV that selectively target its highly 
conserved nucleocapsid protein (NCp7) by interacting with metal 
chelating structures of a zinc finger-containing protein. Because of 
the mutationally intolerant nature of NCp7, drug resistance is much 
less likely to occur with compounds attacking this target. In addition, 
these drugs should inactivate all types and strains of HIV and could 
also inactivate other retroviruses, since most retroviruses share one 
or two highly conserved zinc fingers that have the CCHC motif of the 
HIV Ncp7. Finally, this invention could be very useful for the large-
scale practical synthesis of HIV inhibitors, because these compounds 
can be prepared by

[[Page 69351]]

using inexpensive starting materials and facile reactions. Thus, it 
opens the possibility that an effective drug treatment for HIV could be 
made available to much larger populations. These thioesters may also be 
used as an active component in topical applications that serve as a 
barrier to HIV infection.
    Inventors: John K. Inman (NIAID), Atul Goel (NCI), Ettore Appella 
(NCI), James A. Turpin (NIAID), Marco Schito (NCI)
    Publications:

    1. ML Schito, A Goel, Y Song, JK Inman, RJ Fattah, WG Rice, JA 
Turpin, A Sher, E Appella. In vitro antiviral activity of novel human 
immunodeficiency virus type 1 nucleocapsid p7 zinc finger inhibitors in 
a transgenic murine model. AIDS Res Hum Retroviruses. 2003 
Feb;19(2):91-101.
    2. P Srivastava, M Schito, RJ Fattah, T Hara, T Hartman, RW 
Buckheit Jr, JA Turpin, JK Inman, E Appella. Optimization of unique, 
uncharged thioesters as inhibitors of HIV replication. Bioorg Med Chem. 
2004 Dec 15;12(24):6437-6450.
    3. LM Jenkins, JC Byrd, T Hara, P Srivastava, SJ Mazu, SJ Stahl, JK 
Inman, E Appella, JG Omichinski, P Legault. Studies on the mechanism of 
inactivation of the HIV-1 nucleocapsid protein NCp7 with 2-
mercaptobenzamide thioesters. J Med Chem. 2005 Apr 21;48(8):2847-2858.
    4. V Basrur, Y Song, SJ Mazur, Y Higashimoto, JA Turpin, WG Rice, 
JK Inman, E Appella. Inactivation of HIV-1 nucleocapsid protein P7 by 
pyridinioalkanoyl thioesters. Characterization of reaction products and 
proposed mechanism of action. J Biol Chem. 2000 May 19;275(20):14890-
14897.
    5. JA Turpin, Y Song, JK Inman, M Huang, A Wallqvist, A Maynard, DG 
Covell, WG Rice, E Appella. Synthesis and biological properties of 
novel pyridinioalkanoyl thiolesters (PATE) as anti-HIV-1 agents that 
target the viral nucleocapsid protein zinc fingers. J Med Chem. 1999 
Jan 14;42(1):67-86.

    Patent Status:
     U.S. Patent No. 7,528,274 issued 05 May 2009 (HHS 
Reference No. E-329-2000/0-US-06)
     U.S. Patent Application No. 12/414,321 filed 30 Mar 2009 
(HHS Reference No. E-329-2000/0-US-07)
    Licensing Status: Available for licensing.
    Licensing Contact: Sally H. Hu, PhD, MBA; 301-435-5605; 
hus@mail.nih.gov.

    Dated: December 23, 2009.
Richard U. Rodriguez,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. E9-31072 Filed 12-30-09; 8:45 am]
BILLING CODE 4140-01-P