[Federal Register Volume 74, Number 250 (Thursday, December 31, 2009)]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-31072]
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.
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
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
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
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
Assessment of non-invasive breath tests to study
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
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)
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;
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
firstname.lastname@example.org 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
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
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.
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
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;
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
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
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)
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
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-
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
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;
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