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`UNITED STATES PATENT AND TRADEMARK OFFICE
`___________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
`
`
`INITIATIVE FOR MEDICINES, ACCESS & KNOWLEDGE (I-MAK), INC.
`Petitioner
`
`v.
`
`GILEAD PHARMASSET LLC
`Patent Owner
`
`___________
`
`Case No. IPR2018-00211
`U.S. Patent No. 9,393,256
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`
`
`
`
`
`PETITION FOR INTER PARTES REVIEW
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`II. MANDATORY NOTICES ............................................................................. 1
`
`A. Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1)) .................................. 1
`
`B.
`
`C.
`
`D.
`
`Related Matters (37 C.F.R. § 42.8(b)(2)) .............................................. 2
`
`Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3)) ........................... 2
`
`Service Information (37 C.F.R. § 42.8(b)(4)) ....................................... 2
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`III. REQUIREMENTS FOR REVIEW ................................................................. 2
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`A. Grounds For Standing ........................................................................... 2
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`B.
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`Identification of Challenge .................................................................... 3
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`IV. OVERVIEW OF THE ‘256 PATENT ............................................................ 4
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`V.
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`FILE HISTORY OF THE ‘256 PATENT ....................................................... 5
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`VI. PERSON OF ORDINARY SKILL IN THE ART .......................................... 6
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`VII. CLAIM CONSTRUCTION ............................................................................ 6
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`VIII. BACKGROUND KNOWLEDGE IN THE ART ........................................... 7
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`A. Nucleos(t)ide NS5B Polymerase Inhibitors PSI-7851 and PSI-7977
`(Compound 10 in ’256) for Treating HCV Were Known ..................... 7
`
`B. Nucleos(t)ide NS5B Polymerase Inhibitors Were Combined With
`Other Antiviral Agents, Including NS5A Inhibitors, To Treat HCV . 10
`
`IX. SCOPE AND CONTENT OF THE PRIOR ART ......................................... 15
`
`A.
`
`Legrand-Abravanel .............................................................................. 15
`
`B. Delaney ................................................................................................ 16
`
`i
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`
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`C.
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`Sofia ’634 ............................................................................................ 18
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`D. Guo ...................................................................................................... 18
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`X. CLAIMS 1-4 ARE UNPATENABLE ........................................................... 19
`
`A. Ground 1: Claims 1-4 Were Anticipated By And Obvious Over
`Legrand- Abravanel ............................................................................. 19
`
`B. Ground 2: Claims 1-4 Were Anticipated By Delaney ........................ 22
`
`C. Ground 3: Claims 1-4 Were Obvious Over Sofia ‘634 and Guo ....... 26
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`XI. CONCLUSION .............................................................................................. 30
`
`XII. APPENDIX – LIST OF EXHIBITS .............................................................. 31
`
`XIII. CERTIFICATE OF COMPLIANCE ............................................................ 32
`
`XIV. CERTIFICATE OF SERVICE ...................................................................... 33
`
`ii
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`
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`I.
`
`
`
`INTRODUCTION
`
`Initiative for Medicines, Access & Knowledge (I-MAK), Inc. (“Petitioner”)
`
`requests inter partes review (“IPR”) of claims 1-4 of United States Patent No.
`
`9,393,256 to Ray et al. (“the ‘256 patent”; EX1001) under the provisions of 35
`
`U.S.C. § 311, § 6 of the Leahy-Smith America Invents Act (“AIA”), and 37 C.F.R.
`
`§ 42.100 et seq. The ’256 patent issued on July 19, 2016, and is currently assigned
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`to Gilead Pharmasset LLC (“Patent Owner”). This petition demonstrates that
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`claims 1-4 are unpatentable.
`
`
`
`The ‘256 patent claims methods that were anticipated by and obvious in
`
`light of the prior art. Specifically, the ‘256 claims methods of treating hepatitis C
`
`virus (“HCV”) infection with a combination of two compounds, but both
`
`compounds were known as a result of being previously published and combining
`
`the two compounds was also known as a preferred method for treating HCV.
`
`
`
`Thus, claims 1-4 of the ‘256 patent are unpatentable and should be
`
`cancelled.
`
`II. MANDATORY NOTICES
` Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1))
`
`
`
`The real parties-in-interest for this petition are Initiative for Medicines,
`
`Access & Knowledge (I-MAK), Inc., and the Laura and John Arnold Foundation.
`
`-1-
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`
`
` Related Matters (37 C.F.R. § 42.8(b)(2))
`
`
`
`U.S. Patent Application No. 15/400,088 is pending and claims priority to the
`
`application that issued as the ‘256 patent. Petitioner is not aware of any other
`
`matter that would affect, or be affected by, a decision in this proceeding.
`
` Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3))
`
`
`
`Petitioner designates Daniel B. Ravicher (Reg. No. 47,015) as lead counsel.
`
`Petitioner is a not-for-profit public charity of limited resources and has been unable
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`to retain back-up counsel. Petitioner respectfully requests that the Board exercise
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`its authority under 37 C.F.R. § 42.5(b) to waive or suspend the requirement under
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`37 C.F.R. § 42.10 that Petitioner designate at least one back-up counsel.
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`
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`Service Information (37 C.F.R. § 42.8(b)(4))
`
`
`
`Papers concerning this matter should be served on the following:
`
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`Petitioner consents to service by email to dan@ravicher.com.
`
`Address: Daniel B. Ravicher
`
`
`Ravicher Law Firm PLLC
`
`
`2000 Ponce De Leon Blvd Ste 600
`
`
`Coral Gables, FL 33134
`Email:
`dan@ravicher.com
`Telephone: 786-505-1205
`
`III. REQUIREMENTS FOR REVIEW
` Grounds for Standing
`
`
`
`Petitioner certifies that the ’256 patent is available for inter partes review
`
`and that Petitioner is not barred or estopped from requesting the inter partes review
`
`-2-
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`
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`sought herein. The required fee is being paid through the Patent Trial and Appeal
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`Board End to End System. The Office is authorized to charge fee deficiencies and
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`credit overpayments to Deposit Account No. 601986.
`
`
`
`Identification of Challenge
`
`
`
`Petitioner respectfully requests cancellation of claims 1 – 4 of the ’256
`
`patent based on the following ground:
`
`# Claims
`1
`1 – 4
`2
`1 – 4
`3
`1 – 4
`
`35 U.S.C. § Prior Art
`102 and 103 Legrand- Abravanel
`102
`Delaney
`103
`Sofia ‘634 and Guo
`
`
`This Petition is supported by the declaration of Joseph M. Fortunak, Ph.D.
`
`EX1012. Dr. Fortunak is well qualified as an expert, possessing the necessary
`
`scientific, technical, and other specialized knowledge and training to assist in an
`
`understanding of the evidence presented herein, as well as possessing the expertise
`
`necessary to determine and explain the level of ordinary skill in the art as of the
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`relevant timeframe.
`
`
`
`The Petition and its supporting materials, which are listed in the Appendix,
`
`establish a reasonable likelihood that Petitioner will prevail with respect to
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`cancellation of the challenged claims. See 35 U.S.C. § 314(a).
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`
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`-3-
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`
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`IV. OVERVIEW OF THE ’256 PATENT
`
`The ’256 patent relates to compositions and therapeutic methods that are
`
`useful for treating hepatitis C virus (HCV) infection. Various compositions
`
`comprising two or more compounds are disclosed in ’256. Specifically the ’256
`
`patent claims a method of treating HCV by administering the following
`
`compounds to a human, either with or without ribavirin, but not including an
`
`interferon:
`
`Compound 10
`
`
`
`
`
`
`
`-4-
`
`
`
`
`
`Compound 6
`
`EX1001 at 79 (139:12-26) and 95.
`
`The following chart describes the ’256 patent’s 4 claims:
`
`Claim(s)
`
`Recite
`
`1, 2
`
`3, 4
`
`
`V.
`
`A method of treating an HCV infection comprising administering orally
`to a human Compound 10 and Compound 6, wherein the method does
`not include administering interferon.
`
`The method of claim 1 wherein ribavirin either is or is not
`administered.
`
`FILE HISTORY OF THE ’256 PATENT
`
`U.S. Patent Application No. 13/875,252 (“the ’252 application”), filed on
`
`May 1, 2013, issued as the ’256 patent on July 19, 2016. EX1001 at 1. The ’252
`
`application is a continuation of international application PCT/US2012/055621 filed
`
`on September 14, 2012, which claimed the benefit of two provisional applications,
`
`Provisional Application No. 61/535,885 filed on September 16, 2011, and
`
`Provisional Application No. 61/561,753 filed on November, 18, 2011. Id.
`
`-5-
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`
`
`During prosecution of the ’252 application, the Examiner allowed the
`
`currently granted claims without making any substantive prior-art based rejections.
`
`EX1012 ¶27.
`
`VI. PERSON OF ORDINARY SKILL IN THE ART
`
`Because the ’256 patent pertains to compounds (namely a nucleos(t)ide
`
`NS5B polymerase inhibitor and an NS5A inhibitor) useful for treating viral
`
`infections such as HCV, a POSA would have either (1) a Ph.D. in chemistry or a
`
`closely related field with some experience in an academic or industrial laboratory
`
`focusing on drug discovery or development, and would also have some familiarity
`
`with antiviral drugs and their design and mechanism of action, or (2) a Bachelor’s
`
`or Master’s degree in chemistry or a closely related field with significant
`
`experience in an academic or industrial laboratory focusing on drug discovery
`
`and/or development for the treatment of viral diseases. EX1012 ¶34.
`
`VII. CLAIM CONSTRUCTION
`
`In an inter partes review, a claim in an unexpired patent is given its broadest
`
`reasonable construction in light of the specification. 37 C.F.R. § 42.100(b). Claim
`
`terms are also “generally given their ordinary and customary meaning,” which is
`
`the meaning that the term would have to a person of ordinary skill in the art at the
`
`time of the invention in view of the specification. In re Translogic Tech., Inc., 504
`
`F.3d 1249, 1257 (Fed. Cir. 2007). Under either standard, there is a reasonable
`
`-6-
`
`
`
`likelihood that Petitioner will prevail with respect to the challenged claims.
`
`The ’256 patent provides definitions for certain claim terms, but these
`
`definitions are conventional. EX1012 ¶36. Thus, there is no reason to give any of
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`the terms of the claims of the ’256 a meaning other than their ordinary and
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`accustomed meaning. EX1012 ¶36.
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`VIII. BACKGROUND KNOWLEDGE IN THE ART
`
`
`
`The background discussed below reflects knowledge skilled artisans would
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`bring to bear in reading the prior art at the time of the invention and thereby assists
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`in understanding how one would have inherently understood the references and
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`why one would have been motivated to combine the references as asserted in this
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`Petition. Ariosa Diagnostics v. Verinata Health, Inc., No. 15-1215, slip op. 1, 11-
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`12 (Fed. Cir. 2015). This knowledge of a skilled artisan is part of the store of
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`public knowledge that must be consulted when considering whether a claimed
`
`invention would have been obvious. KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398,
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`406 (2007); Randall Mfg. v. Rea, 733 F.3d 1355, 1362-63 (Fed. Cir. 2013).
`
`Below is a description of some of the relevant aspects of what was generally
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`known in the art as of September 16, 2011.
`
` Nucleos(t)ide NS5B Polymerase Inhibitors PSI-7851 and PSI-7977
`(Compound 10 in ’256) for Treating HCV Were Known
`
`WO 2005/003147 to Clark (“Clark”; EX1002) taught modified fluorinated
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`nucleoside analogs. EX1012 ¶38. More specifically, Clark taught (2’R)-2’-deoxy-
`
`-7-
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`
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`2’-fluoro-2’-C-methyl nucleosides, their pharmaceutically acceptable salt forms
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`and prodrugs. Id.; EX1002 at 18:3-17. Clark taught that these compounds could be
`
`used to treat Flaviviridae viruses, including HCV infections. Id.; EX1002 at 1
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`(Abstract).
`
`It was well known that, to interact with HCV NS5B polymerase, anti-viral
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`nucleosides must generally first be converted into their triphosphate form. EX1012
`
`¶39. This was described, for example, in Ma et al. “Characterization of the
`
`Metabolic Activation of Hepatitis C Virus Nucleoside Inhibitor β-D-2'-Deoxy-2-
`
`Fluro-2'-C -Methylcytidine (PSI-6130) and Identification of a Novel Active 5'-
`
`Triphosphate Species,” J. Biol. Chem., 2007, 282(41), 29812-29820 (“Ma”;
`
`EX1003), which recognized this general knowledge, saying, “[c]onversion to the
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`active 5’-triphosphate form by cellular kinases is an important part of the
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`mechanism of action for nucleoside analogs.” Id.; EX1003 at 2.
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`WO 2008/121634 to Sofia et al. (“Sofia ‘634”; EX1004) disclosed specific
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`phosphoramidate prodrugs of nucleoside derivatives claimed in Clark, which are
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`useful for the treatment of viral infections, including HCV. EX1012 ¶40. The
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`phosphoramidate prodrugs disclosed
`
`in Sofia
`
`‘634 also
`
`included
`
`their
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`stereoisomers, salts (acid or basic addition salts), hydrates, solvates or crystalline
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`forms as represented by the following structure:
`
`-8-
`
`
`
`
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`Id.; EX1004 at 10.
`
`While Sofia ‘634 disclosed and claimed many compounds within the
`
`formula, it specifically disclosed Compound 10 as claimed in the ’256 patent.
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`EX1012 ¶41. In particular, Sofia ’634 disclosed and claimed the molecule shown
`
`in Table IX-25 as compound IX-25-2. Id.; EX1004 at 255. This molecule was
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`further disclosed as having been prepared and characterized, as example compound
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`25. EX1012 ¶41; EX1004 at 684. Compound 25 is further disclosed as one of 19
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`compounds for which antiviral testing results are revealed. EX1012 ¶41; EX1004
`
`at 696. This compound is further disclosed in claim 2. EX1012 ¶41; EX1004 at
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`703:48-50. This compound is also known as PSI-7851 and “(S)-2-
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`{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-
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`hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-
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`propionic acid isopropyl ester”, also known as PSI-7977 or GS-7977. EX1012 ¶41.
`
`Indeed, this is confirmed in the ’256 patent where U.S Patent No.7,964,580 (which
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`-9-
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`
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`corresponds to Sofia ’634) is incorporated by reference. EX1001 at 13 (8:42);
`
`EX1012 ¶41.
`
` Nucleos(t)ide NS5B Polymerase Inhibitors Were Combined With
`Other Antiviral Agents, Including NS5A Inhibitors, To Treat
`HCV
`
`It was widely known that monotherapy with a direct acting antiviral
`
`polymerase inhibitors such as a nucleos(t)ide NS5B polymerase inhibitor was
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`limited because of resistance mutations of HCV to nucleos(t)ide analogs. EX1012
`
`¶42; Legrand-Abravanel et al. “New NS5B Polymerase Inhibitors for Hepatitis C,
`
`Expert Opinion on Investigational Drugs,” 2010, 19(8): 963-75 (“Legrand-
`
`Abravanel”; EX1005) at 7. Therefore, it was recognized in the field that
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`combination therapy with small molecule inhibitors such as NS5A inhibitors
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`without interferon was the optimal standard of care. EX1012 ¶42; EX1005 at 9.
`
`Clark taught that its nucleoside NS5B polymerase inhibitors could be
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`administered as a nucleotide prodrug in combination or in alternation with one or
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`more other effective therapeutic agents i.e. another antiviral agent. EX1012 ¶43.
`
`For example, Clark taught:
`
`In another embodiment for the treatment, inhibition, prevention
`
`and/or prophylaxis of any viral infection described herein, the active
`compound, derivative or salt can be administered in combination or
`alternation with another anitiviral agent. In general, in combination
`therapy, effective dosages of two or more agents are administered
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`-10-
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`
`
`together, whereas during alternation therapy, an effective dosage of
`each agent is administered serially. The dosage will depend on
`absorption, inactivation and excretion rates of the drug as well as
`other factors known to those of skill in the art. It is to be noted that
`dosage values will also vary with the severity of the condition to be
`alleviated. It is to be further understood that for any particular subject,
`specific dosage regimens and schedules should be adjusted over time
`according to the individual need and the professional judgment of the
`person administering or supervising the administration of the
`compositions.
`
`It has been recognized that drug-resistant variants of
`flaviviruses, pestiviruses or HCV can emerge after prolonged
`treatment with an antiviral agent. Drug resistance most typically
`occurs by mutation of a gene that encodes for an enzyme used in viral
`replication. The efficacy of a drug against the viral infection can be
`prolonged, augmented or restored by administering the compound in
`combination or alternation with a second, and perhaps a third,
`antiviral compound that induces a different mutation from that caused
`by the principle drug. Alternatively, the pharmacokinetics,
`biodistribution or other parameter of the drug can be altered by such
`combination or alternation therapy. In general, combination therapy is
`typically preferred over alternation therapy because it induces
`multiple simultaneous stresses on the virus.
`
`For example, one skilled in the art will recognize that any
`antiviral drug or therapy can be used in combination or alternation
`with any nucleoside of the present invention. Any of the viral
`treatments described in the Background of the Invention can be used
`
`-11-
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`
`
`in combination or alternation with the compounds described in this
`specification. Nonlimiting examples of the types of antiviral agents or
`their prodrugs that can be used in combination with the compounds
`disclosed herein include: interferon, including interferon alpha 2a,
`interferon alpha 2b, a pegylated interferon, interferon beta, interferon
`gamma, interferon tau, and interferon omega, an interleukin, including
`interleukin 10 and interleukin 12, ribavirin; interferon alpha, or
`pegylated interferon alpha in combination with ribavirin or levovirin;
`levovirin; a protease inhibitor, including an NS3 inhibitor, a NS3-4A
`inhibitor; a helicase inhibitor; polymerase inhibitor including HCV
`RNA polymerase and NS5B polymerase inhibitor, gliotoxin; an IRES
`inhibitor; and antisense oligonucleotide, a thiazolidone derivative; a
`benzanilide, a ribozyme; another nucleoside, nucleoside prodrug or
`nucleoside derivative; a 1-amino-alkylcyclohexane; an antioxidant
`including vitamin E; squalene; amantadine; a bile acid; N-
`(phosphonoacetyl)-L-aspartic acid; a benzenedicarboxamide; a
`polyadenylic acid; a benzimidazoles; thymosin; a beta tubulin
`inhibitor; a prophylactic vaccine; an immune modulator, an IMPDH
`inhibitor, silybin-phosphatidylcholine phytosome; and
`mycophenolate.
`
`EX1002 at 62:7 – 63:26 (emphasis added); EX1012 ¶43.
`
`Ma taught β-D-2’-deoxy-2’-fluoro-2’-C-methyluridine (RO2433, PSI-6026),
`
`a deaminated derivative of β-D-2’-deoxy-2’-fluoro-2’-C-methylcytidine (PSI-
`
`6130) and how antiviral agents targeting essential processes of HCV replication as
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`part of optimized combination regimens could achieve increased clinical efficacy
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`-12-
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`
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`and potentially improved adverse event profiles as well as shortened treatment
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`duration as compared to the current standard of care. EX1003 at 1; EX1012 ¶44.
`
`Sofia et al, “β-D-2′-Deoxy-2′-C-methyluridine Phosphoramidates: Potent
`
`and Selective Inhibitors of HCV RNA Replication”, Poster #P-259, presented at the
`
`14th International Symposium on Hepatitis C Virus and Related Viruses, Glasgow,
`
`Scotland, UK, Sep. 9-13, 2007. (“Sofia 2007”; EX1006) taught a prodrug of β-D-
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`2’-deoxy-2’-fluoro-2’-C-methylcytidine (PSI-6130) for the treatment of chronic
`
`HCV and the need for direct acting antivirals for use in combination with the
`
`standard of care. EX1012 ¶45.
`
`Sofia ’634 taught that the nucleotide NS5B polymerase inhibitors disclosed
`
`and claimed therein, including PSI-7851 and PSI-7977 (Compound 10 in the ‘256
`
`patent) could be directed to a method of treatment in combination with another
`
`antiviral agent, wherein the administration is concurrent or alternative. EX1012
`
`¶46. Sofia ’634 further suggested examples of “another antiviral agent” to include
`
`NS5A inhibitors. Id. Sofia ’634 also provided:
`
`It is contemplated that another antiviral agent includes, but is not limited to
`interferon-α, interferon-β, pegylated interferon-α, ribavirin, levovirin,
`viramidine, another nucleoside HCV polymerase inhibitor, a HCV non-
`nucleoside polymerase inhibitor, a HCV protease inhibitor, a HCV helicase
`inhibitor or a HCV fusion inhibitor. When the active compound or its
`derivative or salt are administered in combination with another antiviral
`agent the activity may be increased over the parent compound. When the
`
`-13-
`
`
`
`treatment is combination therapy, such administration may be concurrent or
`sequential with respect to the nucleoside derivatives. “Concurrent
`administration” as used herein thus includes administration of the agents at
`the same time or different times. Administration of two or more agents at the
`same time can be achieved by a single formulation containing two or more
`active ingredients or by substantially simultaneous administration of two or
`more dosage forms with a single active agent.
`EX1004 at 668:24 – 669:8 (emphasis added); EX1012 ¶46.
`
`U.S. Pub. No. 2006/0276511 to Serrano-Wu et al. (“Serrano-Wu”; EX1007)
`
`taught some of the early NS5A inhibitor compounds designed to inhibit the
`
`function of HCV NS5A protein. EX1012 ¶47. Serrano-Wu suggested how the
`
`NS5A compounds disclosed therein could be used in combination therapy with
`
`other antiviral agents, including compounds that inhibit NS5B protein such as
`
`Compound 10 in ’256. EX1007 at 3 (¶0026); EX1012 ¶47.
`
`WO2006/100310 to Simmen et al. (“Simmen”; EX1008) taught the NS5A
`
`inhibitors disclosed therein could be co-administered in combination with small
`
`molecule antagonists such as NS5B polymerase antagonists to treat HCV
`
`infections. EX1008 at 28:1-28; EX1012 ¶48.
`
`Pockros “New Direct-Acting Antivirals in the Development for Hepatitis C
`
`Virus Infection”, Therapeutic Advances in Gastroenterology, May 2010, 3(3) 191-
`
`202 (“Pockros”; EX1009), taught that the compound BMS-790052 (daclatasvir), a
`
`first-in-class potent HCV NS5A inhibitor, was additive/synergistic with protease
`
`-14-
`
`
`
`and polymerase inhibitors (i.e. nucleos(t)ide NS5B polymerase inhibitors) in the
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`replicon model and which may eventually be used in combination with protease
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`and/or polymerase inhibitors. EX1009 at 8; EX1012 ¶49.
`
`IX. SCOPE AND CONTENT OF THE PRIOR ART
`
`The following prior art references, alone or in combination with each other,
`
`teach or suggest the methods recited in claims 1-4 of the ’256 patent. EX1012 ¶50.
`
` Legrand-Abravanel et al. New NS5B Polymerase Inhibitors for
`Hepatitis C, Expert Opinion on Investigational Drugs, 2010, 19(8):
`963-75 (“Legrand-Abravanel”; EX1005)
`
`Legrand-Abravanel was published online on July 15, 2010. See
`
`http://www.tandfonline.com/doi/full/10.1517/13543784.2010.500285. Therefore, it
`
`is prior art to the ‘256 patent under 35 U.S.C. § 102(b) because it was published
`
`more than one year before the filing of the earliest application to which the ‘256
`
`patent claims priority.
`
`Legrand-Abravanel taught that NS5B polymerase inhibitors will form an
`
`integral part of more effective anti-HCV therapy, in combination with interferon or
`
`with other directly acting antiviral agents. EX1005 at 1; EX1012 ¶52.
`
`Legrand-Abravanel also highlighted that nucleos(t)ide inhibitors PS-7851
`
`and PSI-7977 (Compound 10 in the ‘256 patent) had been selected for further
`
`clinical development. EX1005 at 4-5; EX1012 ¶53.
`
`However, due to the resistant mutations of HCV to nucleos(tide) analogues,
`
`-15-
`
`
`
`Legrand-Abravanel taught that combination therapy with small molecule inhibitors
`
`and without IFN (interferon) was the ultimate goal and should be studied early
`
`with innovative drug development approaches. EX1012 ¶54. Legrand-Abravanel
`
`further suggested that several new antiviral compounds were in development and
`
`could be associated with polymerase inhibitors, including NS5A inhibitors.
`
`EX1005 at 9; EX1012 ¶54.
`
` US Pub No. 2011/0306541 to Delaney (“Delaney”; EX1010)
`
`Delaney is a U.S. Patent Application Publication of an application that was
`
`filed on June 10, 2011, and that claims priority to a provisional application filed on
`
`June 10, 2010. EX1010 at 1. Therefore, it is prior art to the ‘256 patent under 35
`
`U.S.C. § 102(e) because it is a published patent application that was filed before
`
`the earliest application to which the ‘256 patent claims priority.
`
`Delaney taught a dosing regimen for the treatment of HCV comprising the
`
`administering of one or more anti-HCV compounds or a pharmaceutically
`
`acceptable salts thereof and ribavirin, but not one or more interferon. EX1010 at 3
`
`(¶0012); EX1012 ¶56.
`
`Delaney also taught pharmaceutical formulations and routes of
`
`administration for the described dosing regimens, including oral administration.
`
`EX1010 at 6 – 8 (¶¶ 0044 – 0073); EX1012 ¶57.
`
`Delaney further taught non-limited examples of suitable combinations
`
`-16-
`
`
`
`included combinations of one or more compounds with one or more additional
`
`therapeutic [sic] for HCV treatment including nucleos(t)ide inhibitors of HCV
`
`NS5B polymerase and NS5A inhibitors. EX1012 ¶58. Delaney specifically taught
`
`that one or more of its compounds may be combined with one or more compounds
`
`selected from a group including the nucleos(t)ide inhibitors of HCV NS5B
`
`polymerase, PSI-7851 and PSI-7977 (Compound 10 in the ’256 patent). EX1010 at
`
`8 – 9 (¶¶ 0074-75); EX1012 ¶58.
`
`Notably one of the compounds taught in Delaney that could be combined
`
`with PSI-7851 or PSI-7977 is GS-5885 (now known as ledispasvir), Example 16,
`
`Compound 16 as shown below.
`
`EX1010 at 47 – 49 (¶218) and 55 (Table 1); EX1012 ¶59. Indeed, Compound 16 in
`
`Delaney is the same compound as Compound 6 claimed in claim 1 of the ’256
`
`
`
`patent. EX1012 ¶59.
`
`-17-
`
`
`
` WO 2008/121634 to Sofia (“Sofia ’634”; EX1004)
`
`Sofia ‘634 was published on October 9, 2008. Therefore, it is prior art to the
`
`‘256 patent under 35 U.S.C. 102(b) because it was published more than year before
`
`the filing of the earliest application to which the ‘256 patent claims priority.
`
`Sofia ’634 taught that the nucleotide NS5B polymerase inhibitors disclosed
`
`and claimed therein, including PSI-7851 and PSI-7977 (Compound 10 in the ’256
`
`patent) could be directed to a method of treatment in combination with another
`
`antiviral agent, wherein the administration is concurrent or alternative. EX1012
`
`¶61. Sofia ’634 further suggested examples of “another antiviral agents” to include
`
`NS5A inhibitors. EX1004 at 667:8 – 669:8; EX1012 ¶61.
`
`Sofia ’634 further taught that when the active compound or its derivative or
`
`salt are administered in combination with another antiviral agent the activity may
`
`be increased over the parent compound. EX1012 ¶62. Sofia ’634 also taught that
`
`when the treatment is combination therapy, it included administration of the agents
`
`at the same time and which could be achieved by a single formulation containing
`
`two or more ingredients. EX1004 at 667:8-669:8; EX1012 ¶62.
`
` WO 2010/132601 to Guo (“Guo”; EX1011)
`
`Guo was published on November 18, 2010. Therefore, it is prior art to the
`
`‘256 patent because it was published before the filing of the earliest application to
`
`which the ‘256 patent claims priority.
`
`-18-
`
`
`
`Guo taught NS5A inhibitor compounds, including GS-5885 (now called
`
`ledipasvir), which is Compound 6 as claimed in the ’256 patent. EX1011 at 673
`
`and 984; EX1012 ¶64.
`
`Guo also taught that compounds of the invention, including GS-5885
`
`(ledipasvir) could be combined with nucleos(t)ide inhibitors of HCV NS5B
`
`polymerase such as PSI-6130, a compound taught in Clark, as well as interferons
`
`and ribavirin. EX1011 at 31; EX1012 ¶65.
`
`X. CLAIMS 1-4 ARE UNPATENTABLE
`
`Each and every feature of claims 1-4 of the ’256 patent can be found in the
`
`prior art references identified below. EX1012 ¶66. In addition, a POSA would have
`
`been motivated to modify the references as discussed below and had a reasonable
`
`expectation of success of arriving at the claims of the ’256 patent. Id.
`
`Each of claims 1-4 is presented below, followed by an analysis of the claims.
`
`The analysis below identifies exemplary disclosure of the cited references
`
`respective to the corresponding claim elements, and is not meant to be exhaustive.
`
` Ground 1: Claims 1-4 Were Anticipated By And Obvious Over
`Legrand-Abravanel
`
`All of the claims of the ’256 patent were anticipated by Legrand-Abravanel.
`
`EX1012 ¶68. Claims 1-4 were also obvious over Legrand-Abravanel because a
`
`POSA would have been motivated to take the teachings in Legrand-Abravanel and
`
`arrive at the combination of anti-viral agents for treating HCV claimed in the ’256
`
`-19-
`
`
`
`patent. Id.
`
`Claim 1 of the ‘256 patent recites “[a] method of treating an HCV infection
`
`in a human, comprising administering to the human: 1) compound 10 having the
`
`structure:
`
`or a pharmaceutically acceptable salt thereof and 2) compound 6 having the
`
`
`
`structure:
`
`or a pharmaceutically acceptable salt thereof, wherein the method does not include
`
`administering interferon.” EX1001 at 79 and 95.
`
`Claims 2, 3 and 4 cover the method of claim 1, “wherein compound 10 and
`
`
`
`-20-
`
`
`
`compound 6 are administered orally” (claim 2); “wherein ribavirin is not
`
`administered to the human” (claim 3); and “further comprising administering
`
`ribavirin to the human” (claim 4). EX1001 at 79 and 95.
`
`As set out in the background knowledge above, Compound 10, a nucleotide
`
`inhibitor of NS5B polymerase was already known. EX1012 ¶71. Indeed, the ’256
`
`patent states U.S Patent No.7,964,580 (which corresponds to Sofia ’634) is
`
`incorporated by reference. EX1001 at 13 (8:42-46). Legrand-Abravanel also
`
`discloses Compound 10 when referring to the compound names PSI-7851 and PSI-
`
`7977. EX1005 at 3-5; EX1012 ¶71. Ribavirin and interferon were also known and
`
`formed part of the combination therapy for treating HCV at the time the parent
`
`applications to the ’256 patent was filed. EX1012 ¶71. Furthermore, NS5A
`
`inhibitors (the class of compound which Compound 6 falls within) were also
`
`known to be useful for treating HCV in combination with other antiviral agents
`
`such as nucleotide inhibitors of NS5B polymerase. See Serrano-Wu (EX1007),
`
`Simmen (EX1008) and Pockros (EX1009); EX1012 ¶71.
`
`Legrand-Abravanel taught that NS5B polymerase inhibitors will form an
`
`integral part of more effective anti-HCV therapy, in combination with interferon or
`
`with other directly acting antiviral agents. EX1005 at 1; EX1012 ¶72.
`
`Legrand-Abravanel also highlighted that nucleos(t)ide inhibitors PS-7851
`
`and PSI-7977 (Compound 10 in the ‘256 patent) had been selected for further
`
`-21-
`
`
`
`clinical development. EX1005 at 4-5; EX1012 ¶73.
`
`However, due to the resistant mutations of HCV to nucleos(tide) analogues,
`
`Legrand-Abravanel taught that combination therapy with small molecule inhibitors
`
`and without IFN (interferon) was the ultimate goal and should be studied early
`
`with innovative drug development approaches. EX1012 ¶74. Legrand-Abravanel
`
`further suggested that several new antiviral compounds were in development and
`
`could be associated with polymerase inhibitors, including NS5A inhibitors.
`
`EX1005 at 9; EX1012 ¶74.
`
`Taking into account the background knowledge in the art and the teachings
`
`of Legrand-Abravanel, claims 1-4 of ’256 were anticipated and obvious. EX1012
`
`¶75. In particular, Legrand-Abravanel taught, or at least suggested, combination
`
`therapies to treat HCV without administering interferon, and which may or may
`
`not include ribavirin. Id. Moreover, Legrand-Abravanel inherently taught the
`
`combination of NS5A inhibitors, such as Compound 6, with polymerase inhibitors
`
`such as Compound 10. Id. Legrand-Abravanel, therefore, anticipated claims 1-4 of
`
`the ’256 patent, or at minimum rendered them obvious. Id.
`
` Ground 2: Claims 1-4 Were Anticipated By Delaney
`
`All of the claims of the ’256 patent were anticipated by Delaney. EX1012
`
`¶76.
`
`Claim 1 of the ‘256 patent recites “[a] method of treating an HCV infection
`
`-22-
`
`
`
`in a human, comprising administering to the human: 1) compound 10 having the
`
`structure:
`
`or a pharmaceutically acceptable salt thereof and 2) compound 6 having the
`
`
`
`structure:
`
`
`
`or a pharmaceutically acceptable salt thereof, wherein the method does not include
`
`administering interferon.” EX1001 at 79 and 95.
`
`Claims 2, 3 and 4 cover the method of claim 1, “wherein compound 10 and
`
`c
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