[Federal Register Volume 73, Number 17 (Friday, January 25, 2008)]
[Notices]
[Pages 4596-4598]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E8-1234]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Government-Owned Inventions; Availability for Licensing: 
Flavivirus Technologies

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.

Development of Antigenic Chimeric St. Louis Encephalitis Virus/Dengue 
Virus Type Four Recombinant Viruses (SLEV/DEN4) as Vaccine Candidates 
for the Prevention of Disease Caused by SLEV

    Description of Invention: St. Louis Encephalitis Virus (SLEV) is a 
mosquito-borne flavivirus that is endemic in the Americas and causes 
sporadic outbreaks of disease in humans. SLEV is a member of the 
Japanese encephalitis virus serocomplex and is closely related to West 
Nile Virus (WNV). St. Louis encephalitis is found throughout North, 
Central, and South America, and the Caribbean, but is a major public 
health problem mainly in the United States. Prior to the outbreak of 
West Nile virus in 1999, St. Louis encephalitis was the most common 
human disease caused by mosquitoes in the United States. Since 1964, 
there have been about 4,440 confirmed cases of St. Louis encephalitis, 
with an average of 130 cases per year. Up to 3,000 cases have been 
reported during epidemics in some years. Many more infections occur 
without symptoms and go undiagnosed. At present, a vaccine or FDA 
approved antiviral therapy is not available.
    The inventors have previously developed a WNV/Dengue4Delta30 
antigenic chimeric virus as a live attenuated virus vaccine candidate 
that contains the WNV premembrane and envelope (prM and E) proteins on 
a dengue virus type 4 (DEN4) genetic background with a thirty 
nucleotide deletion (Delta30) in the DEN4 3'-UTR. Using a similar 
strategy, the inventors have generated an antigenic chimeric virus, 
SLE/DEN4Delta30. Preclinical testing results indicate that 
chimerization of SLE with DEN4Delta30 decreased neuroinvasiveness in 
mice, did not affect neurovirulence in mice, and appeared to 
overattenuate the virus for non-human primates. Modifications of the 
SLE/DEN4Delta30 vaccine candidate are underway to improve its 
immunogenicity.
    This application claims live attenuated chimeric SLE/DEN4Delta30 
vaccine compositions and bivalent WNV/SLE/DEN4Delta30 vaccine 
compositions. Also claimed are methods of treating or preventing SLEV 
infection in a mammalian host, methods of producing a subunit vaccine 
composition, isolated polynucleotides comprising a nucleotide sequence 
encoding a SLEV immunogen, methods for detecting SLEV infection in a 
biological sample and infectious chimeric SLEV.
    Application: Immunization against SLEV or SLEV and WNV.

[[Page 4597]]

    Development Status: Live attenuated vaccine candidates are 
currently being developed and preclinical studies in mice and monkeys 
are in progress. Suitable vaccine candidates will then be evaluated in 
clinical studies.
    Inventors: Stephen S. Whitehead, Joseph Blaney, Alexander Pletnev, 
Brian R. Murphy (NIAID).
    Patent Status: U.S. Provisional Application No. 60/934,730 filed 14 
Jun 2007 (HHS Reference No. E-240-2007/0-US-01).
    Licensing Status: Available for exclusive or non-exclusive 
licensing.
    Collaborative Research Opportunity: The NIAID Laboratory of 
Infectious Diseases is seeking statements of capability or interest 
from parties interested in collaborative research to further develop, 
evaluate, or commercialize live attenuated virus vaccine candidates for 
St. Louis encephalitis virus. Please contact Dr. Whitehead at 301-496-
7692 for more information.

Live Attenuated Virus Vaccines for La Crosse Virus and Other 
Bunyaviridae

    Description of Invention: La Crosse virus (LACV), family 
Bunyaviridae, is a mosquito-borne pathogen endemic in the United 
States. LACV infection results in 70-130 clinical cases a year and is 
the major cause of pediatric arboviral encephalitis in North America. 
LACV was first identified as human pathogen in 1960 after its isolation 
from a 4 year-old girl from Minnesota who suffered meningoencephalitis 
and later died in La Crosse, Wisconsin. The majority of LACV infections 
are mild and never reported, however serologic studies estimate annual 
infection rates of 10-30/100,000 in endemic areas. LACV is a member of 
the California serogroup of viruses in the genus Orthobunyavirus. The 
serogroup contains members found on five continents that include human 
pathogens such as La Crosse, Snowshoe hare, and Jamestown Canyon 
viruses in North America; Guaroa virus in North and South America; 
Inkoo and Tahyna viruses in Europe; and Lumbo virus in Africa. Children 
who recover from severe La Crosse encephalitis may have significantly 
lower IQ scores than expected and a high prevalence (60% of those 
tested) of attention-deficit-hyperactivity disorder. Seizure disorders 
are also common in survivors. LACV can also cause encephalitis in 
immunosuppressed adults. Projected lifelong economic costs associated 
with neurologic sequelae range from $48,775-3,090,398 per case. At 
present, a vaccine or FDA approved antiviral therapy is not available.
    This application principally claims live attenuated LACV vaccine 
compositions, but also includes subunit vaccine compositions including 
California encephalitis virus (CEV) serogroup immunogens, attenuated 
and inactivated CEV serogroup and chimeric Bunyaviridae. Also claimed 
are methods of treating or preventing CEV serogroup infection in a 
mammalian host, methods of producing a subunit vaccine composition, 
isolated polynucleotides comprising a nucleotide sequence encoding a 
CEV serogroup immunogen, methods for detecting LACV infection in a 
biological sample and infectious chimeric Bunyaviridae.
    Application: Immunization against Bunyaviridae.
    Developmental Status: Live attenuated vaccine candidates are 
currently being developed and preclinical studies in mice and monkeys 
are in progress. Suitable vaccine candidates will then be evaluated in 
clinical studies.
    Inventors: Stephen S. Whitehead, Richard S. Bennett, Brian R. 
Murphy (NIAID).
    Publication: RS Bennett et al. Genome sequence analysis of La 
Crosse virus and in vitro and in vivo phenotypes. Virol J. 2007 May 
8;4:41.
    Patent Status: U.S. Provisional Application No. 60/920,691 filed 29 
Mar 2007 (HHS Reference No. E-158-2007/0-US-01); U.S. Provisional 
Application No. 60/928,406 filed 08 May 2007 (HHS Reference No. E-158-
2007/1-US-01); U.S. Provisional Application filed 29 Jun 2007 (HHS 
Reference No. E-158-2007/2-US-01).
    Licensing Status: Available for exclusive or non-exclusive 
licensing.
    Licensing Contact: Peter A. Soukas, J.D.; 301/435-4646; 
[email protected].
    Collaborative Research Opportunity: The NIAID Laboratory of 
Infectious Diseases is seeking statements of capability or interest 
from parties interested in collaborative research to further develop, 
evaluate, or commercialize live attenuated virus vaccine candidates for 
La Crosse virus and other Bunyaviridae. Please contact Dr. Whitehead at 
301-496-7692 for more information.

Development of Dengue Virus Type 3 Vaccine Candidates Containing Either 
(1) Nucleotide Deletions in the 3'-UTR of the Genome Consisting of More 
Than 30 Contiguous Nucleotides in One or Multiple Regions, or (2) a 3'-
UTR Derived From DEN4 and Containing the A30 Nucleotide Deletion

    Description of Technology: The disease burden associated with 
dengue virus infection has increased over the past several decades in 
the tropical and semi-tropical regions of the world, where over 2 
billion people live at risk of dengue infection. Annually, there are an 
estimated fifty (50) to one hundred (100) million cases of dengue 
fever, making development of an effective vaccine a priority. In 
addition, there is a need for a ``travelers vaccine'' to protect those 
visiting dengue virus endemic areas, similar in scope to other 
currently available ``travelers vaccines'', such as hepatitis A 
vaccine.
    The previously identified [Delta]30 attenuating mutation, created 
in each dengue virus serotype by the removal of 30 homologous 
nucleotides from the 3'-UTR, is capable of attenuating wild-type 
strains of dengue virus type 1 (DEN1), type 4 (DEN4) and to a limited 
extent type 2 (DEN2). These DEN1[Delta]30 and DEN4[Delta]30 viruses 
have been shown to be both safe and immunogenic in humans. However, the 
[Delta]30 mutation failed to have an attenuating effect on dengue virus 
type 3 (DEN3). To generate DEN3 vaccine candidates with a clearly 
attenuated phenotype, viruses were produced containing 3'-UTR deletions 
consisting of extensions of the original [Delta]30 mutation or 
additional mutations which remove stem-loop structures similar to those 
removed by [Delta]30. In addition, the entire 3'-UTR of DEN3 was 
replaced with the 3'-UTR derived from DEN4 and containing the [Delta]30 
mutation. Studies in monkeys demonstrated that these newly developed 
viruses are highly attenuated, yet sufficiently immunogenic to warrant 
their further development for use as live attenuated vaccine 
candidates. Such viruses are anticipated to become the DEN3 component 
of a tetravalent vaccine formulation designed to immunize against all 
four dengue virus serotypes.
    Application: Immunization against all four serotypes of dengue 
virus.
    Developmental Status: Vaccine candidates have been synthesized and 
preclinical studies have been performed. The vaccine candidates of this 
invention are slated to enter Phase I clinical trials in the next year.
    Inventors: Stephen S. Whitehead, Joseph E. Blaney, Brian R. Murphy 
(NIAID).
    Patent Status: PCT Application No. PCT/US2007/076004 filed 15 Aug 
2007, claiming priority to 15 Aug 2006 (HHS Reference No. E-139-2006/0-
PCT-02).
    Licensing Status: Available for exclusive or non-exclusive 
licensing.
    Licensing Contact: Peter A. Soukas, J.D.; 301/435-4646; 
[email protected].
    Collaborative Research Opportunity: The National Institute of 
Allergy and

[[Page 4598]]

Infectious Diseases, Laboratory of Infectious Diseases, is seeking 
statements of capability or interest from parties interested in 
collaborative research to further develop, evaluate, or commercialize 
these vaccines. Please contact Dr. Brian Murphy at 301-594-1616 or 
[email protected] for more information.

Dengue Tetravalent Vaccine Containing a Common 30-Nucleotide Deletion 
in the 3'-UTR of Dengue Types 1, 2, 3, and 4

    Description of Technology: The invention relates to a dengue virus 
tetravalent vaccine containing a common 30-nucleotide deletion 
([Delta]30) in the 3'-untranslated region (UTR) of the genome of dengue 
virus serotypes 1, 2, 3, and 4. The previously identified [Delta]30 
attenuating mutation, created in dengue virus type 4 (DEN4) by the 
removal of 30 nucleotides from the 3'-UTR, is also capable of 
attenuating a wild-type strain of dengue virus type 1 (DEN1). Removal 
of 30 nucleotides from the DEN1 3'-UTR in a highly conserved region 
homologous to the DEN4 region encompassing the [Delta]30 mutation 
yielded a recombinant virus attenuated in rhesus monkeys to a level 
similar to recombinant virus DEN4[Delta]30. This established the 
transportability of the [Delta]30 mutation and its attenuation 
phenotype to a dengue virus type other than DEN4. The effective 
transferability of the [Delta]30 mutation establishes the usefulness of 
the [Delta]30 mutation to attenuate and improve the safety of 
commercializable dengue virus vaccines of any serotype.
    A tetravalent dengue virus vaccine containing dengue virus types 1, 
2, 3, and 4 each attenuated by the [Delta]30 mutation is being 
developed. The presence of the [Delta]30 attenuating mutation in each 
virus component precludes the reversion to a wild-type virus by 
intertypic recombination. In addition, because of the inherent genetic 
stability of deletion mutations, the [Delta]30 mutation represents an 
excellent alternative for use as a common mutation shared among each 
component of a tetravalent vaccine.
    Inventors: Stephen S. Whitehead (NIAID), Brian R. Murphy (NIAID), 
Lewis Markoff (FDA), Barry Falgout (FDA), Kathryn A. Hanley (NIAID), 
Joseph E. Blaney (NIAID).
    Patent Status: U.S. Patent Application No. 10/970,640 filed 21 Oct 
2004, claiming priority to 03 May 2002 (HHS Reference No. E-089-2002/1-
US-02).
    Licensing Contact: Peter A. Soukas, J.D.; 301/435-4646; 
[email protected].
    Collaborative Research Opportunity: The National Institute of 
Allergy and Infectious Diseases, Laboratory of Infectious Diseases, is 
seeking statements of capability or interest from parties interested in 
collaborative research to further develop, evaluate, or commercialize 
these vaccines. Please contact Dr. Brian Murphy at 301-594-1616 or 
[email protected] for more information.

Development of Mutations Useful for Attenuating Dengue Viruses and 
Chimeric Dengue Viruses

    Description of Technology: Although flaviviruses cause a great deal 
of human suffering and economic loss, there is a shortage of effective 
vaccines. This invention relates to dengue virus mutations that may 
contribute to the development of improved dengue vaccines. Site 
directed and random mutagenesis techniques were used to introduce 
mutations into the dengue virus genome and to assemble a collection of 
useful mutations for incorporation in recombinant live attenuated 
dengue virus vaccines. The resulting mutant viruses were screened for 
several valuable phenotypes, including temperature sensitivity in Vero 
cells or human liver cells, host cell restriction in mosquito cells or 
human liver cells, host cell adaptation for improved replication in 
Vero cells, and attenuation in mice or in mosquitoes. The genetic basis 
for each observed phenotype was determined by direct sequence analysis 
of the genome of the mutant virus. Mutations identified through these 
sequencing efforts have been further evaluated by re-introduction of 
the identified mutations, singly, or in combination, into recombinant 
dengue virus and characterization of the resulting recombinant virus 
for phenotypes. In this manner, a menu of attenuating and growth 
promoting mutations was developed that is useful in fine-tuning the 
attenuation and growth characteristics of dengue virus vaccine 
candidates. The mutations promoting growth in Vero cells have 
usefulness for the production of live or inactivated dengue virus 
vaccines.
    Inventors: Stephen S. Whitehead, Brian R. Murphy, Kathryn A. 
Hanley, Joseph E. Blaney (NIAID).
    Patent Status: U.S. Patent No. 7,226,602 issued 05 Jun 2007 (HHS 
Reference No. E-120-2001/0-US-04); U.S. Patent Application No. 11/
446,050 filed 02 Jun 2006 (HHS Reference No. E-120-2001/0-US-10).
    Licensing Contact: Peter A. Soukas, J.D.; 301/435-4646; 
[email protected].
    Collaborative Research Opportunity: The National Institute of 
Allergy and Infectious Diseases, Laboratory of Infectious Diseases, is 
seeking statements of capability or interest from parties interested in 
collaborative research to further develop, evaluate, or commercialize 
these vaccines. Please contact Dr. Brian Murphy at 301-594-1616 or 
[email protected] for more information.

    Date: January 10, 2008.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. E8-1234 Filed 1-24-08; 8:45 am]
BILLING CODE 4140-01-P