APOTEX ET AL. - EXHIBIT 1067
`Apotex Inc. et al. v. Novartis AG
`IPR2017-00854
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`WO 2004/078194
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`PCT/US2003/006687
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`INTERFERON DRUG THERAPY FOR THE TREATMENT OF VIRAL DISEASES AND LIVER
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`FIBROSIS
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`FIELD OF THE INVENTION
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`This invention is in the field of flaviviral infection, particularly West Nile viral
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`infection and hepatitis C viral infection, and in the field of liver fibrosis.
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`BACKGROUND OF THE INVENTION
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`The United States is currently experiencing an increase in the number of West Nile
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`viral infections. West Nile virus is a member of the alpha—like Flaviviridae, as is hepatitis C
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`virus. Most alpha—like viruses, including hepatitis C virus and poliovirus, are highly
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`sensitive to type I interferon treatment. It appears that West Nile virus will become endemic
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`in the United States because it has an avian reservoir and is transmitted by mosquitoes. West
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`Nile virus can cause a harsh, self-limiting fever, body aches, brain swelling, coma, paralysis,
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`and death. Although it is generally accepted that West Nile viral disease results in death in
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`only one out of 40,000 cases, the death rate in the US appears to be higher. In particular, 5
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`deaths were reported recently in the State of Louisiana. It is possible that the US. strain is
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`more virulent or that the US. population is genetically predisposed to more severe clinical
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`courses. In middle eastern countries, West Nile virus has been endemic for centuries, which
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`may have allowed natural selection to create populations with resistance to the virus. There
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`is no effective treatment for the disease.
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`Hepatitis C virus (HCV) infection is the most common chronic blood borne infection
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`in the United States. Although the numbers of new infections have declined, the burden of
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`chronic infection is substantial, with Centers for Disease Control estimates of 3.9 million
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`(1.8%) infected persons in the United States. Chronic liver disease is the tenth leading cause
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`of death among adults in the United States, and accounts for approximately 25,000 deaths
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`annually, or approximately 1% of all deaths. Studies indicate that 40% of chronic liver
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`disease is HCV-related, resulting in an estimated 8,000-10,000 deaths each year. HCV-
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`associated end—stage liver disease is the most frequent indication for liver transplantation
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`among adults.
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`Antiviral therapy of chronic hepatitis C has evolved rapidly over the last decade, with
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`significant improvements seen in the efficacy of treatment. Nevertheless, even with
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`combination therapy using pegylated IFN—oc plus ribavirin, 40% to 50% of patients fail
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`therapy, i.e., are nonresponders or relapsers. These patients currently have no effective
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`therapeutic alternative. In particular, patients who have advanced fibrosis or cirrhosis on
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`liver biopsy are at significant risk of developing complications of advanced liver disease,
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`including ascites, jaundice, variceal bleeding, encephalopathy, and progressive liver failure,
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`as well as a markedly increased risk of hepatocellular carcinoma.
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`The high prevalence of chronic HCV infection has important public health
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`implications for the future burden of chronic liver disease in the United States. Data derived
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`from the National Health and Nutrition Examination Survey (NHANES III) indicate that a
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`large increase in the rate of new HCV infections occurred from the late 1960s to the early
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`1980s, particularly among persons between 20 to 40 years of age. It is estimated that the
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`number of persons with long-standing HCV infection of 20 years or longer could more than
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`quadruple from 1990 to 2015, from 750,000 to over 3 million. The proportional increase in
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`persons infected for 30 or 40 years would be even greater. Since the risk of HCV—related
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`chronic liver disease is related to the duration of infection, with the risk of cirrhosis
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`progressively increasing for persons infected for longer than 20 years, this will result in a
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`substantial increase in cirrhosis-related morbidity and mortality among patients infected
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`between the years of 1965-1985.
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`Fibrosis occurs as a result of a chronic toxic insult to the liver, such as chronic
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`hepatitis C virus (HCV) infection, autoimmune injury, and chronic exposure to toxins such
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`as alcohol. Chronic toxic insult leads to repeated cycles of hepatocyte injury and repair
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`accompanied by chronic inflammation. Over a variable period of time, abnormal
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`extracellular matrix progressively accumulates as a consequence of the hostas wound repair
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`response. Left unchecked, this leads to increasing deposition of fibrous material until liver
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`architecture becomes distorted and the liver’s regenerative ability is compromised. The
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`progressive accumulation of scar tissue within the liver finally results in the histopathologic
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`picture of cirrhosis, defined as the formation of fibrous septae throughout the liver with the
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`formation of micronodules.
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`There is a need in the art for improved methods for treating flaviviral infections, e. g.
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`West Nile Viral infection and hepatitis C viral infection, and for treating liver fibrosis. The
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`present invention addresses this need.
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`Literature
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`METAVIR (1994) Hepatology 20:15-20; Brunt (2000) Hepatol. 312241-246; Alpini
`
`(1997) .1 Hepatol. 27:371-380; Baroni et al. (1996) Hepatol. 23:1189-1199; Czaja et a1.
`
`(1989) Hepatol. 102795-800; Grossman et a1. (1998) J. Gastroem‘erol. Hepatol. 13:1058—
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`1060; Rockey and Chung (1994) J Invest. Med. 42:660-670; Sakaida et al. (1998) J.
`
`Hepatol. 28:471—479; Shi et al. (1997) Proc. Natl. Acad. Sci. USA 94:10663-10668; Baroni
`
`et al. (1999) Liver 19:212-219; Lortat—Jacob et a1. (1997) J. Hepatol. 26:894-903; Llorent et
`
`al. (1996) J Hepatol. 242555—563; U.S. Patent No. 5,082,659; European Patent Application
`
`EP 294,160; U.S. Patent No. 4,806,347; Balish et al. (1992) J Infect. Diseases 166:1401—
`
`1403; Katayama et al. (2001) J Viral Hepatitis 8:180-185; U.S. Patent No. 5,082,659; U.S.
`
`Patent No. 5,190,751; U.S. Patent No. 4,806,347; Wandl et al. (1992) Br. J Haematol.
`
`81 :516-5 19; European Patent Application No. 294,160; Canadian Patent No. 1,321,348;
`
`European Patent Application No. 276,120; Wandl et al. (1992) Sem. Oncol. 19:88-94; Balish
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`et al. (1992) J Infectious Diseases 166:1401-1403; Van Dijk et al. (1994) Int. J Cancer
`
`56:262—268; Sundmacher et al. (1987) Current Eye Res. 62273—276; U.S. Patent Nos.
`
`6,172,046; 6,245,740; 5,824,784; 5,372,808; 5,980,884; published international patent
`
`applications WO 96/21468; WO 96/11953; Torre et al. (2001) J Med. Virol. 642455-459;
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`Bekkering et al. (2001) J Hepatol. 34:435-440; Zeuzem et al. (2001) Gastroenterol.
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`120: 143 8—1447; Zeuzem (1999) J Hepatol. 31:61-64; Keeffe and Hollinger (1997) Hepatol.
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`26:101S-107S; Wills (1990) Clin. Pharmacokinet. 19:390-399; Heathcote et al. (2000) New
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`Engl. J Med. 343:1673-1680; Husa and Husova (2001) Bratisl. Lek. Listy 102:248-252;
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`Glue et al. (2000) Clin. Pharmacol. 68:556-567; Bailon et al. (2001) Bioconj. Chem. 12:195-
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`202; and Neumann et al. (2001) Science 282:103; Zalipsky (1995) Adv. Drug Delivery
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`Reviews S. 16, 157-182; Mann et al. (2001) Lancet 358:958-965; Zeuzem et al. (2000) New
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`Engl. J Med. 343:1666-1672; U.S. Patent Nos. 5,985,265; 5,908,121; 6,177,074; 5,985,263;
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`5,711,944; 5,382,657; and 5,908,121; Osborn et al. (2002) J Pharmacol. Exp. leerap.
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`303:540-548; Sheppard et al. (2003) Nat. Immunol. 4:63-68; Chang et al. (1999) Nat.
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`Biotechnol. 172793—797; Adolf (1995) Multiple Sclerosis 1 Suppl. 1:S44-S47.
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`SUMMARY OF THE INVENTION
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`The present invention provides methods of treating alphavirus infection; methods of
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`treating hepatitis C virus (HCV) infection; methods of treating West Nile virus infection;
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`methods of reducing liver fibrosis; methods of increasing liver fimction in an individual
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`suffering from liver fibrosis; methods of reducing the incidence of complications associated
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`with HCV and cirrhosis of the liver; and methods of reducing viral load, or reducing the time
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`to viral clearance, or reducing morbidity or mortality in the clinical outcomes, in patients
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`suffering from viral infection. The methods generally involve administering a
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`therapeutically effective amount of a Type I or Type III interferon receptor agonist and IFN-
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`7 for the treatment of viral infection or liver fibrosis.
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`FEATURES OF THE INVENTION
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`The invention features a method of treating alphaviral infection, generally involving
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`administering to an individual IFN-y and a Type I or Type III interferon receptor agonist
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`concurrently, in an amount effective to ameliorate the clinical course of the disease. The
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`invention also features a method of treating alphavirus infection by administering to an
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`individual IFN—y and a Type I or Type III interferon receptor agonist in a synergistically
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`effective amount to ameliorate the clinical course of the disease.
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`The invention features a method of treating West Nile viral infection, generally
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`involving administering to an individual a Type I or Type III interferon receptor agonist,
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`IFN—y, or IFN—y and a Type I or Type III interferon receptor agonist concurrently, in an
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`amount effective to reduce the time to Viral clearance or to reduce morbidity or mortality in
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`clinical outcomes. The invention also features a method of treating West Nile viral infection
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`by administering to an individual IFN-y and a Type I or Type III interferon receptor agonist
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`in a synergistically effective amount to reduce the time to viral clearance or to reduce
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`morbidity or mortality in clinical outcomes.
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`The invention features a method of treating hepatitis C virus (HCV) infection,
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`generally involving administering to an individual IFN—y and a Type I or Type III interferon
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`receptor agonist concurrently, in an amount effective to achieve a sustained viral response.
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`The invention also features a method of treating HCV infection by administering to an
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`individual IFN—y and a Type I or Type III interferon receptor agonist in a synergistically
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`effective amount to achieve a sustained viral response.
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`The invention features a method of reducing liver fibrosis in an individual, generally
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`involving administering a Type I or Type III interferon receptor agonist and IFN—y
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`concurrently, in an amount effective to reduce liver fibrosis. Optionally, the method of the
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`invention provides for administering to the patient the combination of a Type I or Type III
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`interferon receptor agonist and IFN-y along with an amount of pirfenidone or a pirfenidone
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`analog effective to enhance the anti-fibrotic effect or the reduction of liver fibrosis achieved
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`by the a Type I or Type III interferon receptor agonist and/or IFN-y therapy. The invention
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`also features a method of reducing liver fibrosis in an individual by administering a Type I
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`or Type III interferon receptor agonist and IFN—y in a synergistically effective amount to
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`reduce liver fibrosis, optionally including co-administering to the patient an amount of
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`pirfenidone or a pirfenidone analog effective to enhance the anti-fibrotic effect or the
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`reduction of liver fibrosis achieved by the a Type I or Type III interferon receptor agonist
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`and/or IFN-y therapy. In some embodiments, the degree of liver fibrosis is determined by
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`pre-treatment and post-treatment staging of a liver biopsy, wherein the stage of liver fibrosis,
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`as measured by a standardized scoring system, is reduced by at least one unit when
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`comparing pre—treatment with post-treatment liver biopsies.
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`The invention features a method of increasing liver function in an individual
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`suffering from liver fibrosis, generally involving administering a Type I or Type III
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`interferon receptor agonist and IFN-y concurrently, in an amount effective to increase a liver
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`function. Optionally, the method of the invention provides for administering to the patient
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`the combination of a Type I or Type III interferon receptor agonist and IFN-y along with an
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`amount of pirfenidone or a pirfenidone analog effective to enhance the anti-fibrotic effect or
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`the increase in liver function achieved by the a Type I or Type III interferon receptor agonist
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`and/or IFN—y therapy. The invention also features a method of increasing liver function in an
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`individual suffering from liver fibrosis by administering a Type I or Type III interferon
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`receptor agonist and IFN-y in a synergistically effective amount to increase a liver function,
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`optionally including (so—administering to the patient an amount of pirfenidone or a
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`pirfenidone analog effective to enhance the anti-fibrotic effect or the increase in liver
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`function achieved by the Type I or Type III interferon receptor agonist and/or IFN-y therapy.
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`Liver function may be indicated by measuring a parameter selected from the group
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`consisting of serum transaminase level, prothrombin time, serum bilirubin level, blood
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`platelet count, serum albumin level, improvement in portal wedge pressure, reduction in
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`degree of ascites, reduction in a level of encephalopathy, and reduction in a degree of
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`internal varices.
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`The invention features a method of reducing the incidence of a complication of
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`cirrhosis of the liver. The methods generally involve administering a Type I or Type III
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`interferon receptor agonist and IFN-y concurrently, in an amount effective to reduce the
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`incidence of a complication of cirrhosis of the liver. Optionally, the method of the invention
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`provides for administering to the patient the combination of a Type I or Type III interferon
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`receptor agonist and IFN-y along with an amount of pirfenidone or a pirfenidone analog
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`effective to enhance the anti-fibrotic effect or the reduction of the incidence of a
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`complication of cirrhosis of the liver achieved by the Type I or Type III interferon receptor
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`agonist and/or IFN-y therapy. The invention also features a method of reducing the
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`incidence of a complication of cirrhosis of the liver by administering a Type I or Type III
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`interferon receptor agonist and IFN—y in a synergistically effective amount to reduce the
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`incidence of a complication of cirrhosis of the liver, optionally including co-administering to
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`the patient an amount of pirfenidone or a pirfenidone analog effective to enhance the anti-
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`fibrotic effect or the reduction of the incidence of a complication of cirrhosis of the liver
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`achieved by the a Type I or Type III interferon receptor agonist and/or IFN—y therapy.
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`Examples of complications of cirrhosis of the liver are portal hypertension, progressive liver
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`insufficiency, and hepatocellular carcinoma.
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`In carrying out the methods of combination therapy for alphaviral infection, hepatitis
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`C viral infection, West Nile Viral infection and/or liver fibrosis in an individual as described
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`above, a Type I or Type III interferon receptor agonist and IFN-y are administered to the
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`individual. In some embodiments, the Type I or Type III interferon receptor agonist and
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`IFN—y are administered in the same formulation. In other embodiments, the Type I or Type
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`III interferon receptor agonist and IFN-y are administered in separate formulations. When
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`administered in separate formulations, a Type I or Type III interferon receptor agonist and
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`IFN—y can be administered substantially simultaneously, or can be administered within about
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`24 hours of one another. In many embodiments, a Type I or Type III interferon receptor
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`agonist and IFN—y are administered subcutaneously in multiple doses. Optionally, the Type I
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`or Type III interferon receptor agonist and/or IFN—y is administered to the individual by a
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`controlled drug delivery device. Optionally, the Type I or Type III interferon receptor
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`agonist and/or IFN-y is administered to the individual substantially continuously or
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`continuously by a controlled drug delivery device. Optionally, the controlled drug delivery
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`device is an implantable infusion pump and the infilsion pump delivers the a Type I or Type
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`III interferon receptor agonist and/or IFN—y to the individual by subcutaneous infusion.
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`In some embodiments utilizing combination therapy, IFN-y is administered during
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`the entire course of a Type I or Type III interferon receptor agonist treatment. In other
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`embodiments, IFN-y is administered for a period of time that is overlapping with that of the
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`Type I or Type III interferon receptor agonist treatment, e. g., the IFN-y treatment can begin
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`before the Type I or Type III interferon receptor agonist treatment begins and end before the
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`Type I or Type III interferon receptor agonist treatment ends; the IFN-y treatment can begin
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`after the Type I or Type III interferon receptor agonist treatment begins and end after the
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`IFN-y treatment ends; the IFN-y treatment can begin after the Type I or Type III interferon
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`receptor agonist treatment begins and end before the Type I or Type III interferon receptor
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`agonist treatment ends; or the IFN—y treatment can begin before the IFN—or treatment begins
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`and end after the Type I or Type III interferon receptor agonist treatment ends. In
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`embodiments utilizing co-administration of pirfenidone or a pirfenidone analog, the duration
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`of therapy with pirfenidone or a pirfenidone analog can be coincident with the duration of
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`therapy with a Type I or Type III interferon receptor agonist and/or IFN—y. In other
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`embodiments, the course of therapy with pirfenidone or a pirfenidone analog can overlap
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`with the course of therapy with a Type I or Type III interferon receptor agonist and/or IFN—y,
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`e.g., the pirfenidone or pirfenidone analog treatment can begin before the treatment with a
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`Type I or Type III interferon receptor agonist and/or IFN—y begins and end before treatment
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`with a Type I or Type III interferon receptor agonist and/or IFN—y ends; the pirfenidone
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`treatment can being after the treatment with IFN-(x and/or IFN-y begins and end before the
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`treatment with a Type I or Type III interferon receptor agonist and/or IFN-y ends; or the
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`pirfenidone treatment can begin before the treatment with a Type I or Type III interferon
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`receptor agonist and/or IFN—y begins and end after treatment with a Type I or Type III
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`interferon receptor agonist and/or IFN—y ends.
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`In other embodiments, ribavirin is co-administered with a Type I or Type III
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`interferon receptor agonist and IFN-y. In still other embodiments, ribavirin is co-
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`administered with a Type I or Type III interferon receptor agonist, IFN-y and pirfenidone (or
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`a specific pirfenidone analog).
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`In many embodiments, any of the above-described methods involve administering
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`IFN-a and IFN—y. In some of these embodiments, the methods involve co-administering
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`ribavirin, IFN-OL, and IFN—y. In other embodiments, the methods involve co—administering
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`IFN—d, IFN-y, and pirfenidone or a pirfenidone analog.
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`BRIEF DESCRIPTION OF THE DRAWING
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`Figure l is a graph depicting HCV replicon assay results after treatment of infected
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`cells with various doses of Actimmune, Infergen, a combination of 2.5 ng/mL Actimmune
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`and 0.2 ng/mL Infergen, or a combination of 25 ng/mL Actimmune and 0.2 ng/mL Infergen.
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`DEFINITIONS
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`As used herein, the term “hepatic fibrosis,” used interchangeably herein with “liver
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`fibrosis,” refers to the growth of scar tissue in the liver that can occur in the context of a
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`chronic hepatitis infection.
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`The terms “individual,” “host,” “subject,” and “patient” are used interchangeably
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`herein, and refer to a mammal, including, but not limited to, primates, including simians and
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`humans.
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`As used herein, the term “alphavirus,” and its grammatical variants, refers to a group
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`of viruses characterized by (i) an RNA genome (ii) viral replication in the cytoplasm of host
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`cells and (iii) no DNA phase occurs in the viral‘replication cycle.
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`As used herein, the term “liver function” refers to a normal function of the liver,
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`including, but not limited to, a synthetic function, including, but not limited to, synthesis of
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`proteins such as serum proteins (e. g., albumin, clotting factors, alkaline phosphatase,
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`aminotransferases (e. g., alanine transaminase, aspartate transarninase), 5’-nucleosidase, y—
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`glutarninyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis
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`of bile acids; a liver metabolic function, including, but not limited to, carbohydrate
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`metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid
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`metabolism; detoxification of exogenous drugs; a hemodynamic function, including
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`splanchnic and portal hemodynarnics; and the like.
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`The term “sustained viral response” (SVR; also referred to as a “sustained response”
`or a “durable response”), as used herein, refers to the response of an individual to a treaiment
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`regimen for HCV infection, in terms of serum HCV titer. Generally, a “sustained viral
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`response” refers to no detectable HCV RNA (e.g., less than about 500, less than about 200,
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`or less than about 100 genome copies per milliliter serum) found in the patient’s serum for a
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`period of at least about one month, at least about two months, at least about three months, at
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`.least about four months, at least about five months, or at least about six months following
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`cessation of treatment.
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`"Treatment failure patients" as used herein generally refers to HCV-infected patients
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`who failed to respond to previous therapy for HCV (referred to as ”non—responders") or who
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`initially responded to previous therapy, but in whom the therapeutic response was not
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`maintained (referred to as "relapsers"). The previous therapy generally can include
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`treatment with IFN—oc monotherapy or IFN-oc combination therapy, where the combination
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`therapy may include administration of IFN—oc and an antiviral agent such as ribavirin.
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`As used herein, the terms “treatment,” “treating,” and the like, refer to obtaining a
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`desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of
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`completely or partially preventing a disease or symptom thereof and/or may be therapeutic in
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`terms of a partial or complete cure for a disease and/or adverse affect attributable to the
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`disease. “Treatment,” as used herein, covers any treatment of a disease in a mammal,
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`particularly in a human, and includes: (a) preventing the disease from occurring in a subject
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`Which may be predisposed to the disease but has not yet been diagnosed as having it; (b)
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`inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e.,
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`causing regression of the disease.
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`The terms “individual,” “host,” “subject,” and “patient” are used interchangeably
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`herein, and refer to a mammal, including, but not limited to, murines, simians, humans,
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`mammalian farm animals, mammalian sport animals, and mammalian pets.
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`A f‘specific pirfenidone analog,” and all grammatical variants thereof, refers to, and
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`is limited to, each and every pirfenidone analog shown in Table 1.
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`As used herein, the term “a Type I interferon receptor agonist” refers to any naturally
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`occurring or non—naturally occurring ligand of human Type I interferon receptor, which
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`binds to and causes signal transduction via the receptor. Type I interferon receptor agonists
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`include interferons, including naturally-occurring interferons, modified interferons, synthetic
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`interferons, pegylated interferons, fusion proteins comprising an interferon and a
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`heterologous protein, shuffled interferons; antibody specific for an interferon receptor; non—
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`peptide chemical agonists; and the like.
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`As used herein, the term “a Type III interferon receptor agonist” refers to any
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`naturally occurring or non-naturally occurring ligand of humanIL-ZS receptor or (“IL—28R”),
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`the amino acid sequence of which is described by Sheppard, et al., infra, that binds to and
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`causes signal transduction via the receptor.
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`The term "dosing event" as used herein refers to administration of an antiviral agent
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`to a patient in need thereof, which event may encompass one or more releases of an antiviral
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`agent from a drug dispensing device. Thus, the term “dosing event,” as used herein,
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`includes, but is not limited to, installation of a continuous delivery device (e.g., a pump or
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`other controlled release inj ectible system); and a single subcutaneous injection followed by
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`installation of a continuous delivery system.
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`"Continuous delivery" as used herein (e. g., in the context of "continuous delivery of a
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`substance to a tissue”) is meant to refer to movement of drug to a delivery site, e. g. , into a
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`tissue in a fashion that provides for delivery of a desired amount of substance into the tissue
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`over a selected period of time, where about the same quantity of drug is received by the
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`patient each minute during the selected period of time.
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`"Controlled release" as used herein (e.g., in the context of "controlled drug release")
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`is meant to encompass release of substance (e. g., a Type I or Type III interferon receptor
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`agonist, e. g., IFN-u) at a selected or otherwise controllable rate, interval, and/or amount,
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`which is not substantially influenced by the environment of use. "Controlled release" thus
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`encompasses, but is not necessarily limited to, substantially continuous delivery, and
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`patterned delivery (e. g. , intermittent delivery over a period of time that is interrupted by
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`regular or irregular time intervals).
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`"Patterned" or "temporal" as used in the context of drug delivery is meant delivery of
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`drug in a pattern, generally a substantially regular pattern, over a pre-selected period of time
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`(6. g. , other than a period associated with, for example a bolus injection). "Patterned" or
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`"temporal" drug delivery is meant to encompass delivery of drug at an increasing,
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`decreasing, substantially constant, or pulsatile, rate or range of rates (e. g. , amount of drug
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`per unit time, or volume of drug formulation for a unit time), and further encompasses
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`delivery that is continuous or substantially continuous, or chronic.
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`The term ”controlled drug delivery device" is meant to encompass any device
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`wherein the release (e.g., rate, timing of release) of a drug or other desired substance
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`contained therein is controlled by or determined by the device itself and not substantially
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`influenced by the environment of use, or releasing at a rate that is reproducible within the
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`environment of use.
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`By "substantially continuous" as used in, for example, the context of "substantially
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`continuous infusion" or "substantially continuous delivery" is meant to refer to delivery of
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`drug in a manner that is substantially uninterrupted for a pre-selected period of drug
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`delivery, where the quantity of drug received by the patient during any 8 hour interval in the
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`pre-selected period never falls to zero. Furthermore, ”substantially continuous" drug
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`delivery can also encompass delivery of drug at a substantially constant, pre-selected rate or
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`range of rates (a. g. , amount of drug per unit time, or volume of drug formulation for a unit
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`time) that is substantially uninterrupted for a pre-selected period of drug delivery.
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`By “substantially steady state” as used in the context of a biological parameter that
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`may vary as a function of time, it is meant that the biological parameter exhibits a
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`substantially constant value over a time course, such that the area under the curve defined by
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`the value of the biological parameter as a function of time for any 8 hour period during the
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`time course (AUCghr) is no more than about 20% above or about 20% below, and preferably
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`no more than about 15% above or about 15 % below, and more preferably no more than
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`about 10% above or about 10% below, the average area under the curve of the biological
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`parameter over an 8 hour period during the time course (AUCmlr averaga). The AUCghr average is
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`defined as the quotient (q) of the area under the curve of the biological parameter over the
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`entirety of the time course (AUCtotal) divided by the number of 8 hour intervals in the time
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`course (ttotau/gdays), i.e., q = (AUCtotaly (mom/Mays). For example, in the context of a serum
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`concentration of a drug, the serum concentration of the drug is maintained at a substantially
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`steady state during a time course when the area under the curve of serum concentration of
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`the drug over time for any 8 hour period during the time course (AUCghr) is no more than
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`about 20% above or about 20% below the average area under the curve of serum
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`concentration of the drug over an 8 hour period in the time course (AUCghr avmy), i.e., the
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`AUC311r is no more than 20% above or 20% below the AUCg;1r average for the serum
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`concentration of the drug over the time course.
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`Before the present invention is further described, it is to be understood that this
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`invention is not limited to particular embodiments described, as such may, of course, vary.
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`It is also to be understood that the terminology used herein is for the purpose of describing
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`particular embodiments only, and is not intended to be limiting, since the scope of the
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`present invention will be limited only by the appended claims.
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`Where a range of values is provided, it is understood that each intervening value, to
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`the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between
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`the upper and lower limit of that range and any other stated or intervening value in that
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`stated range is encompassed within the invention. The upper and lower limits of these
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`smaller ranges may independently be included in the smaller ranges is also encompassed
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`within the invention, subject to any specifically excluded limit in the stated range. Where
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`the stated range includes one or both of the limits, ranges excluding either both of those
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`included limits are also included in the invention.
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`Unless defined otherwise, all technical and scientific terms used herein have the same
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`meaning as commonly understood by one of ordinary skill in the art to which this invention
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`belongs. Although any methods and materials similar or equivalent to those described
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`herein can also be used in the practice or testing of the present invention, the preferred
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`methods and materials are now described. All publications mentioned herein are
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`incorporated herein by reference to disclose and describe the methods and/or materials in
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`connection with which the publications are cited.
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`It must be noted that as used herein and in the appended claims, the singular forms
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`“a,” “and,” and “the” include plural referents unless the context clearly dictates otherwise.
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`Thus, for example, reference to “a method” includes a plurality of such methods and
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`reference to “a dose” includes reference to one or more doses and equivalents thereof known
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`to those skilled in the art, and so forth.
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`The publications discussed herein are provided solely for their disclosure prior to the
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`filing date of the present application. Nothing herein is to be construed as an admission that
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`the present invention is not entitled to antedate such publication by virtue of prior invention.
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`Further, the dates of publication provided may be different from the actual publication dates
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`which may need to be independently confirmed.
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`DETAILED DESCRIPTION OF THE INVENTION
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`The present invention provides methods of treating alphaviral infections, including
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`methods of treating West Nile viral infection and methods of treating HCV infection, and
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`methods of treating liver fibrosis, including reducing clinical liver fibrosis, reducing the
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`likelihood that liver fibrosis will occur, and reducing a parameter associated with liver
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`fibrosis. The methods generally involve administering an effective amount of a Type I or
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`Type III interferon receptor agonist and IFN—y, to an individual in need thereof. Of
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`particular interest in many embodiments is treatment of humans.
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`Liver fibrosis is a precursor to the complications associated with liver cirrhosis, such
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`as portal hypeltension, progressive liver insufficiency, and hepatocellular carcinoma. A
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`reduction in liver fibrosis thus reduces the incidence of such future complications.
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`Accordingly, the present invention further provides methods of reducing the l