[Federal Register Volume 73, Number 206 (Thursday, October 23, 2008)]
[Notices]
[Pages 63161-63165]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E8-25210]


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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.

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.

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

[[Page 63162]]

tetravalent vaccine containing a common 30-nucleotide deletion 
(Delta30) in the 3'-untranslated region (UTR) of the genome of dengue 
virus serotypes 1, 2, 3, and 4. The previously identified Delta30 
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 Delta30 mutation yielded 
a recombinant virus attenuated in rhesus monkeys to a level similar to 
recombinant virus DEN4Delta30. This established the transportability of 
the Delta30 mutation and its attenuation phenotype to a dengue virus 
type other than DEN4. The effective transferability of the Delta30 
mutation establishes the usefulness of the Delta30 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 Delta30 mutation is being developed. 
The presence of the Delta30 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 Delta30 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.

Live Attenuated Vaccine to Prevent Disease Caused by West Nile Virus

    Description of Technology: WNV has recently emerged in the U.S. and 
is considered a significant emerging disease that has embedded itself 
over a considerable region of the U.S. WNV infections have been 
recorded in humans as well as in different animals. To date, WNV has 
killed 294 people in the U.S. and caused severe disease in more than 
4222 others. This project is part of NIAID's comprehensive emerging 
infectious disease program, which supports research on bacterial, 
viral, and other types of disease-causing microbes.
    The methods and compositions of this invention provide a means for 
prevention of WNV infection by immunization with attenuated, 
immunogenic viral vaccines against WNV. The invention involves a 
chimeric virus form consisting of parts of WNV and Dengue virus. 
Construction of the hybrids and their properties are described in 
detail in AG Pletnev et al., PNAS 2002; 99(5): 3036-3041.
    The WNV chimeric vaccine does not target the central nervous 
system, which would be the case in an infection with wild type WNV. The 
vaccine stimulates strong anti-WNV immune responses, even following a 
single dose of the vaccine. When injected into mice, the vaccine 
protected all of the immunized animals from subsequent exposure to the 
New York WNV strain. The vaccine was also effective in primates.
    The WNV vaccine may be used to protect the human population, 
particularly the elderly people, and domestic animals from WNV 
infection in the affected regions of the U.S. as well as worldwide.
    Inventors: Alexander G. Pletnev et al. (NIAID).
    Patent Status: U.S. Patent Application No. 10/871,775 filed 18 Jun 
2004 (HHS Reference No. E-357-2001/1-US-02).
    Licensing Status: Available for exclusive or non-exclusive 
licensing for developing a vaccine against WNV for humans or veterinary 
use in accordance with 35 U.S.C. 207 and 37 CFR Part 404.
    Licensing Contact: Peter A. Soukas, J.D.; 301-435-4646; 
[email protected].
    Collaborative Research Opportunity: The National Institute of 
Allergy and Infectious Diseases is seeking statements of capability or 
interest from parties interested in collaborative research to further 
develop, evaluate, and commercialize this technology. Please contact 
Percy Pan at 301-451-3523 or [email protected] 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 DEN1Delta30 and DEN4Delta30 viruses have 
been shown to be both safe and immunogenic in humans. However, the 
Delta30 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 Delta30 mutation or additional 
mutations which remove stem-loop structures similar to those removed by 
Delta30. In addition, the entire 3'-UTR of DEN3 was replaced with the 
3'-UTR derived from DEN4 and containing the Delta30 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.

[[Page 63163]]

    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 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.

Live Attenuated Virus Vaccines for La Crosse Virus and Other 
Bunyaviridae

    Description of Technology: 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: PCT Application No. PCT/US2008/056099 filed 06 Mar 
2008, claiming priority to 29 Mar 2007 (HHS Reference No. E-158-2007/3-
PCT-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 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 
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 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 Technology: 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.
    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: PCT Application No. PCT/US2008/066445 filed 10 Jun 
2008, claiming priority to 14 Jun 2007 (HHS Reference No. E-240-2007/0-
PCT-02).
    Licensing Status: Available for exclusive or non-exclusive 
licensing.
    Licensing Contact: Peter A. Soukas, J.D.; 301-435-4646; 
[email protected].

[[Page 63164]]

    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 
live attenuated virus vaccine candidates for St. Louis encephalitis 
virus. Please contact Dr. Whitehead at 301-496-7692 for more 
information.

Generation of Wild-Type Dengue Viruses for Use in Rhesus Monkey 
Infection Studies

    Description of Technology: Dengue virus is a positive-sense RNA 
virus belonging to the Flavivirus genus of the family Flaviviridae. 
Dengue virus is widely distributed throughout the tropical and 
semitropical regions of the world and is transmitted to humans by 
mosquito vectors. Dengue virus is a leading cause of hospitalization 
and death in children in at least eight tropical Asian countries. There 
are four serotypes of dengue virus (DEN-1, DEN-2, DEN-3, and DEN-4) 
that annually cause an estimated 50-100 million cases of dengue fever 
and 500,000 cases of the more severe form of dengue virus infection 
known as dengue hemorrhagic fever/dengue shock syndrome (DHFIDSS). This 
latter disease is seen predominately in children and adults 
experiencing a second dengue virus infection with a serotype different 
than that of their first dengue virus infection and in primary 
infection of infants who still have circulating dengue-specific 
maternal antibody. A vaccine is needed to lessen the disease burden 
caused by dengue virus, but none is licensed.
    Because of the association of more severe disease with secondary 
dengue virus infection, a successful vaccine must induce immunity to 
all four serotypes. Immunity is primarily mediated by neutralizing 
antibody directed against the envelope (E) glycoprotein, a virion 
structural protein. Infection with one serotype induces long-lived 
homotypic immunity and a short-lived heterotypic immunity. Therefore, 
the goal of immunization is to induce a long-lived neutralizing 
antibody response against DEN-1, DEN-2, DEN-3, and DEN-4, which can 
best be achieved economically using live attenuated virus vaccines. 
This is a reasonable goal since a live attenuated vaccine has already 
been developed for the related yellow fever virus, another mosquito-
borne flavivirus present in tropical and semitropical regions of the 
world.
    The evaluation of live attenuated dengue vaccine candidates in 
rhesus monkeys requires wild type control viruses for each of the four 
dengue serotypes. These control viruses are used for comparison to the 
attenuated strains and post-vaccination challenge to assess vaccine 
efficacy. As such, these viruses need to be well characterized and 
sufficiently pure to ensure that they will replicate to consistent 
levels in rhesus monkeys. Characterization generally includes sequence 
analysis, titration, and evaluation in monkeys. The following viruses 
have been characterized: (1) DEN1 WP (2) DEN1 Puerto Rico/94 (3) DEN2 
NGC prototype (4) DEN2 Tonga/74 (5) DEN3 Sleman/78 and (6) DEN4 
Dominica/81.
    Application: Dengue/flavivirus vaccine studies, dengue/flavivirus 
diagnostics, dengue/flavivirus research tools.
    Development Status: Materials are available for transfer.
    Inventors: Stephen S. Whitehead and Joseph E. Blaney, Jr. (NIAID).
    Publications:
    1. AP Durbin, RA Karron, W Sun, DW Vaughn, MJ Reynolds, JR 
Perreault, B Thumar, R Men, C-J Lai, WR Elkins, RM Chanock, BR Murphy, 
SS Whitehead. A live attenuated dengue virus type 4 vaccine candidate 
with a 30 nucleotide deletion in the 3' untranslated region is highly 
attenuated and immunogenic in humans. Am J Trop Med Hyg. 2001 Nov; 
65(5): 405-413.
    2. SS Whitehead, B Falgout, KA Hanley, JE Blaney Jr., L Markoff, BR 
Murphy. A live, attenuated dengue virus type 1 vaccine candidate with a 
30-nucleotide deletion in the 3' untranslated region is highly 
attenuated and immunogenic in monkeys. J Virol. 2003 Jan; 77(2): 1653-
1657.
    3. SS Whitehead, KA Hanley, JE Blaney Jr., LE Gilmore, WR Elkins, 
BR Murphy. Substitution of the structural genes of dengue virus type 4 
with those of type 2 results in chimeric vaccine candidates which are 
attenuated for mosquitoes, mice, and rhesus monkeys. Vaccine 2003 Oct 
1; 21(27-30): 4307-4316.
    4. JE Blaney Jr., CT Hanson, KA Hanley, BR Murphy, SS Whitehead. 
Vaccine candidates derived from a novel infectious cDNA clone of an 
American genotype dengue virus type 2. BMC Infect Dis. 2004 Oct 4;4:39.
    5. JE Blaney Jr., CT Hanson, CY Firestone, KA Hanley, BR Murphy, SS 
Whitehead. Genetically modified, live attenuated dengue virus type 3 
vaccine candidates. Am J Trop Med Hyg. 2004 Dec; 71(6): 811-821.
    6. JE Blaney Jr., JM Matro, BR Murphy, SS Whitehead. Recombinant, 
live-attenuated tetravalent dengue virus vaccine formulations induce a 
balanced, broad, and protective neutralizing antibody response against 
each of the four serotypes in rhesus monkeys. J Virol. 2005 May; 79(9): 
5516-5528.
    7. JE Blaney Jr., NS Sathe, CT Hanson, CY Firestone, BR Murphy, SS 
Whitehead. Vaccine candidates for dengue virus type 1 (DEN1) generated 
by replacement of the structural genes of rDEN4 and rDEN4Delta30 with 
those of DEN1. Virol J. 2007 Feb 28; 4:23.
    Patent Status: HHS Reference No. E-042-2008/0--Research Tool. 
Patent protection is not being pursued for this technology.
    Licensing Status: Available for nonexclusive biological materials 
licensing only.
    Licensing Contact: Peter A. Soukas, J.D.; 301-435-4646; 
[email protected].

Monoclonal Antibodies Against Dengue and Other Viruses With Deletion in 
Fc Region

    Description of Technology: The four dengue virus (DENV) serotypes 
(DENV-1 to DENV-4) are the most important arthropod-borne flaviviruses 
in terms of morbidity and geographic distribution. Up to 100 million 
DENV infections occur every year, mostly in tropical and subtropical 
areas where vector mosquitoes are abundant. Infection with any of the 
DENV serotypes may be asymptomatic or may lead to classic dengue fever 
or more severe dengue hemorrhagic fever (DHF) and dengue shock syndrome 
(DSS), which are increasingly common in the dengue endemic areas. 
Immunity to the same virus serotype (homotypic immunity) is life-long, 
whereas immunity to different serotypes (heterotypic immunity) lasts 2-
3 months so that infection with a different serotype virus is possible. 
DHF/DSS often occurs in patients with second, heterotypic DENV 
infections or in infants with maternally transferred dengue immunity. 
Severe dengue is a major cause of hospitalization, and fatality rates 
vary from <1% to 5% in children.
    Antibody-dependent enhancement (ADE) has been proposed as an 
underlying pathogenic mechanism of DHF/DSS. ADE occurs because 
preexisting subneutralizing antibodies and the infecting DENV form 
complexes that bind to Fc receptor-bearing cells, leading to increased 
virus uptake and replication. ADE has been repeatedly demonstrated in 
vitro using dengue immune sera or monoclonal antibodies and cells of 
monocytic and recently, B

[[Page 63165]]

lymphocytic lineages bearing Fc receptors. ADE of DENV-2 infection has 
also been demonstrated in monkeys infused with a human dengue immune 
serum.
    We have identified chimpanzee-human chimeric IgG1 mAbs capable of 
neutralizing or binding to one or more DENV serotypes. Cross-reactive 
IgG 1A5 neutralizes DENV-1 and DENV-2 more efficiently than DENV-3 and 
DENV-4, and type-specific IgG 5H2 neutralizes DENV-4 at a high titer. 
Analysis of antigenic variants has localized the IgG 1A5 binding site 
to the conserved fusion peptide in E. Thus, IgG 1A5 shares many 
characteristics with the cross-reactive antibodies detected in 
flavivirus infections.
    This application claims a variant of an antibody comprising a 
polypeptide in the Fc region, which binds an Fc gamma receptor 
(FcgammaR) with lower affinity than the parent antibody. The variant 
polypeptide comprises a deletion of nine amino acids at the N-terminus 
of the CH2 domain in the Fc region. Introduction of the Fc 
variant abrogates the antibody-mediated dengue virus replication 
enhancing activity. This invention has important implications for the 
antibody-mediated prevention of dengue virus infection.
    Application: Immunization against Dengue and/or flaviviruses.
    Developmental Status: Antibody candidates have been synthesized and 
preclinical studies have been performed.
    Inventors: Ana Goncalvez, Robert Purcell, C.J. Lai (NIAID).
    Publication: AP Goncalvez et. al. Monoclonal antibody-mediated 
enhancement of dengue virus infection in vitro and in vivo and 
strategies for prevention. Proc Natl Acad Sci USA. 2007 May 29; 
104(22): 9422-9427.
    Patent Status: PCT Application No. PCT/US2008/059313 filed 03 Apr 
2008, claiming priority to 04 Apr 2007 (HHS Reference No. E-159-2007/3-
PCT-01).
    Licensing Status: Available for exclusive or non-exclusive 
licensing.
    Licensing Contact: Peter A. Soukas, J.D.; 301-435-4646; 
[email protected].

Monoclonal Antibodies That Bind or Neutralize Dengue Virus

    Description of Technology: Among the arthropod-borne flaviviruses, 
the four dengue virus serotypes, dengue type 1 virus (DENV-1), dengue 
type 2 virus (DENV-2), dengue type 3 virus (DENV-3), and dengue type 4 
virus (DENV-4 are most important in terms of human morbidity and 
geographic distribution. Dengue viruses cause dengue outbreaks and 
major epidemics in most tropical and subtropical areas where Aedes 
albopictus and Aedes aegypti mosquitoes are abundant. Dengue infection 
produces fever, rash, and joint pain in humans. A more severe and life-
threatening form of dengue, characterized by hemorrhagic fever and 
hemorrhagic shock, has occurred with increasing frequency in Southeast 
Asia and Central and South America, where all four dengue virus 
serotypes circulate. A safe and effective vaccine against dengue is 
currently not available. Passive immunization with monoclonal 
antibodies from non-human primates or humans represents a possible 
alternative to vaccines for prevention of illness caused by dengue 
virus.
    The application claims monoclonal antibodies that bind or 
neutralize dengue type 1, 2, 3, and/or 4 viruses. The application also 
claims fragments of such antibodies retaining dengue virus-binding 
ability, fully human or humanized antibodies retaining dengue virus-
binding ability, and pharmaceutical compositions including such 
antibodies. The application also claims isolated nucleic acids encoding 
the antibodies of the invention. Additionally, application claims 
prophylactic, therapeutic, and diagnostic methods employing the 
antibodies and nucleic acids of the invention.
    Application: Prophylaxis against dengue serotypes 1, 2, 3 and 4.
    Development Status: Antibodies have been synthesized and 
preclinical studies have been performed.
    Inventors: Ching-Juh Lai and Robert Purcell (NIAID).
    Publications: The antibodies are further described in:
    1. R Men et al. Identification of chimpanzee Fab fragments by 
repertoire cloning and production of a full-length humanized 
immunoglobulin G1 antibody that is highly efficient for neutralization 
of dengue type 4 virus. J Virol. 2004 May; 78(9): 4665-4674.
    2. AP Goncalvez et al. Chimpanzee Fab fragments and a derived 
humanized immunoglobulin G1 antibody that efficiently cross-neutralize 
dengue type 1 and type 2 viruses. J Virol. 2004 Dec; 78(23): 12910-
12918.
    3. AP Goncalvez et al. Epitope determinants of a chimpanzee Fab 
antibody that efficiently cross-neutralizes dengue type 1 and type 2 
viruses map to inside and in close proximity to fusion loop of the 
dengue type 2 virus envelope glycoprotein. J Virol. 2004 Dec; 78(23): 
12919-12928.
    4. AP Goncalvez et al. Monoclonal antibody-mediated enhancement of 
dengue virus infection in vitro and in vivo and strategies for 
prevention. Proc Natl Acad Sci U.S.A. 2007 May 29; 104(22): 9422-9427.
    Patent Status: U.S. Patent Application No. 10/582,006 filed 07 Jun 
2006 (HHS Reference No. E-066-2003/5-US-02); Canadian Patent 
Application No. 2548808 filed 03 Dec 2004 (HHS Reference No. E-066-
2003/5-CA-03).
    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 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 
this technology. Please contact Ching-Juh Lai at 301-594-2422 for more 
information.

     Dated: October 14, 2008.
Richard U. Rodriguez,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. E8-25210 Filed 10-22-08; 8:45 am]
BILLING CODE 4140-01-P