Chemistry: molecular biology and microbiology – Virus or bacteriophage – except for viral vector or...
Reexamination Certificate
1995-06-06
2002-09-17
Wortman, Donna (Department: 1648)
Chemistry: molecular biology and microbiology
Virus or bacteriophage, except for viral vector or...
C436S820000, C435S005000
Reexamination Certificate
active
06451578
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates generally to a group of infectious viral agents causing hepatitis in man, and more particularly, relates to materials such as polynucleotides derived from this group of viruses, polypeptides encoded therein, antibodies which specifically bind to these polypeptides, and diagnostics and vaccines that employ these materials.
Hepatitis is one of the most important diseases transmitted from a donor to a recipient by transfusion of blood products, organ transplantation and hemodialysis; it also can be transmitted via ingestion of contaminated food stuffs and water, and by person to person contact. Viral hepatitis is known to include a group of viral agents with distinctive viral genes and modes of replication, causing hepatitis with differing degrees of severity of hepatic damage through different routes of transmission. In some cases, acute viral hepatitis is clinically diagnosed by well-defined patient symptoms including jaundice, hepatic tenderness and an elevated level of liver transaminases such as aspartate transaminase (AST), alanine transaminase (ALT) and isocitrate dehydrogenase (ISD). In other cases, acute viral hepatitis may be clinically inapparent. The viral agents of hepatitis include hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis delta virus (HDV), hepatitis E virus (HEV), Epstein-Barr virus (EBV) and cytomegalovirus (CMV).
Although specific serologic assays available by the late 1960's to screen blood donations for the presence of HBV surface antigen (HBsAg) were successful in reducing the incidence of post-transfusion hepatitis (PTH) in blood recipients, PTH continued to occur at a significant rate. H. J. Alter et al.,
Ann. Int. Med
. 77:691-699 (1972); H. J. Alter et al.,
Lancet
ii:838-841 (1975). Investigators began to search for a new agent, termed “non-A, non-B hepatitis” (NANBH), that caused viral hepatitis not associated with exposure to viruses previously known to cause hepatitis in man (HAV, HBV, CMV and EBV). See, for example, S. M. Feinstone et al.,
New Engl. J. Med
. 292:767-770 (1975); Anonymous editorial,
Lancet
ii:64-65 (1975); F. B. Hollinger in B. N. Fields and D. M. Knipe et al.,
Virology
, Raven Press, New York, pp. 2239-2273 (1990).
Several lines of epidemiological and laboratory evidence have suggested the existence of more than one parenterally transmitted NANB agent, including multiple attacks of acute NANBH in intravenous drug users; distinct incubation periods of patients acquiring NANBH post-transfusion; the outcome of cross-challenge chimpanzee experiments; the ultrastructural liver pathology of infected chimpanzees; and the differential resistance of the putative agents to chloroform. J. L. Dienstag,
Gastroenterology
85:439-462 (1983); J. L. Dienstag,
Gastroenterology
85:743-768 (1983); F. B. Hollinger et al., J. Infect. Dis. 142:400-407 (1980); D. W. Bradley in F. Chisari, ed.,
Advances in Hepatitis Research
, Masson, N.Y., pp. 268-280 (1984); and D. W. Bradley et al.,
J. Infect. Dis
. 148:254-265 (1983).
A serum sample obtained from a surgeon who had developed acute hepatitis was shown to induce hepatitis when inoculated into tamarins (Saguinus species). Four of four tamarins developed elevated liver enzymes within a few weeks following their inoculation, suggesting that an agent in the surgeon's serum could produce hepatitis in tamarins. Serial passage in various non-human primates demonstrated that this hepatitis was caused by a transmissible agent; filtration studies suggested the agent to be viral in nature. The transmissible agent responsible for these cases of hepatitis in the surgeon and tamarins was termed the “GB agent.” F. Dienhardt et al.,
J. Exper. Med
. 125:673-688 (1967). F. Dienhardt et al.,
J. Exper. Med
., supra; E. Tabor et al.,
J. Med. Virol
. 5:103-108 (1980); R. O. Whittington et al.,
Viral and Immunological Diseases in Nonhuman Primates
, Alan R. Liss, Inc., New York, pp. 221-224 (1983)
Although it was suggested that the GB agent may be an agent causing NANBH in humans and that the GB agent was not related to the known NANBH agents studied in various laboratories, no definitive or conclusive studies on the GB agent are known, and no viral agent has been discovered or molecularly characterized. F. Dienhardt et al.,
Am. J. Med. Sci
. 270:73-80 (1975); and J. L. Dienstag et al.,
Nature
264:260-261 (1976). See also E. Tabor et al.,
J. Med. Virol
., supra; E. Tabor et al.,
J. Infect. Dis
. 140:794-797 (1979); R. O. Whittington et al., supra; and P. Karayiannis et al.,
Hepatology
9:186-192 (1989).
Early studies indicated that the GB agent was unrelated to any known human hepatitis virus. S. M. Feinstone et al.,
Science
182:1026-1028 (1973); P. J. Provost et al.,
Proc. Soc. Exp. Biol. Med
. 148:532-539 (1975); J. L. Melnick,
Intervirology
18:105-106 (1982); A. W. Holmes et al.,
Nature
243:419-420 (1973); and F. Dienhardt et al.,
Am. J. Med. Sci
., supra. However, questions were raised regarding whether the GB agent was a virus which induced hepatitis infection in humans, or a latent tamarin virus activated by the GB serum and once activated, easily passaged to other tamarins, inducing hepatitis in them. Also, a small percentage of marmosets inoculated with GB-positive serum did not develop clinical hepatitis (4 of 52, or 7.6%), suggesting that these animals may have been naturally immune and thus, that the GB agent may be a marmoset virus. W. P. Parks et al.,
J. Infect. Dis
. 120:539-547 (1969); W. P. Parks et al.,
J. Infect. Dis
. 120:548-559 (1969). Morphological studies have been equivocal, with immune electron microscopy studies in one report indicating that the GB agent formed immune complexes with a size distribution of 20-22 nm and resembling the spherical structure of a parvovirus, while another study reported that immune electron microscopy data obtained from liver homogenates of GB-positive tamarins indicated that aggregates of 34-36 nm with icosahedral symmetry were detected, suggesting that the GB agent was a calici-like virus. See, for example, J. D. Almeida et al.,
Nature
261:608-609 (1976); J. L. Dienstag et al.,
Nature
, supra.
Two hepatitis-causing viruses recently have been discovered and reported: HCV, which occurs primarily through parenteral transmission, and HEV, which is transmitted enterically. See, for example, Q. L. Choo et al.,
Science
244:359-362 (1989), G. Kuo et al.,
Science
244:362-364 (1989), E. P. Publication No. 0 318 216 (published May 31, 1989), G. R. Reyes et al.,
Science
247:1335-1339 (1990). HCV is responsible for a majority of PTH ascribed to the NANBH agent(s) and many cases of acute NANBH not acquired by transfusion. Anonymous editorial,
Lancet
335:1431-1432 (1990); J. L. Dienstag,
Gastroenterology
99:1177-1180 (1990); and M. J. Alter et al.,
JAMA
264:2231-2235 (1990).
While the detection of HCV antibody in donor samples eliminates 70 to 80% of NANBH infected blood in the blood supply system, the discovery and detection of HCV has not totally prevented the transmission of hepatitis. H. Alter et al.,
New Eng. J. Med
. 321:1494-1500 (1989). Recent publications have questioned whether additional hepatitis agents may be responsible for PTH and for community acquired acute and/or chronic hepatitis that is not associated with PTH. For example, of 181 patients monitored in a prospective clinical survey conducted in France from 1988 to 1990, investigators noted a total of 18 cases of PTH. Thirteen of these 18 patients tested negative for anti-HCV antibodies, HBsAg, HBV and HCV nucleic acids. The authors speculated as to the potential importance of a non-A, non-B, non-C agent causing PTH. V. Thiers et al.,
J. Hepatology
18:34-39 (1993). Also, of 1,476 patients monitored in another study conducted in Germany from 1985 to 1988, 22 cases of documented cases of PTH were not related to infection with HBV or HCV. T. Peters et al.,
J. Med. Virol
. 39:139-145 (1993).
It would be advantageous to identify and provide materials derived from a group of
Buijk Sheri L.
Dawson George J.
Desai Suresh M.
Erker James Carl
Leary Thomas P.
Abbott Laboratories
Becker Cheryl L.
Casuto Dianne
Wortman Donna
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