`
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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. IPR2018-00390
`U.S. Patent No. 8,889,159
`
`
`
`
`
`
`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
`
`III. REQUIREMENTS FOR REVIEW ................................................................. 2
`
`A. Grounds For Standing ........................................................................... 2
`
`B.
`
`Identification of Challenge .................................................................... 3
`
`IV. OVERVIEW OF THE ‘159 PATENT ............................................................ 4
`
`V.
`
`FILE HISTORY OF THE ‘159 PATENT ....................................................... 6
`
`VI. PERSON OF ORDINARY SKILL IN THE ART .......................................... 7
`
`VII. CLAIM CONSTRUCTION ............................................................................ 8
`
`VIII. BACKGROUND KNOWLEDGE IN THE ART ........................................... 9
`
`A. GS-7977 Was A Known And Promising Antiviral Agent for Treating
`HCV ....................................................................................................... 9
`
`B.
`
`C.
`
`D.
`
`Crystalline Forms of GS-7977 Were Known ...................................... 10
`
`Tablet and Capsule Formulations Comprising Pharmaceutical
`Excipients Were Known ...................................................................... 14
`
`Tablet And Capsule Formulations Comprising Crystalline GS-7977
`And Pharmaceutical Excipients Were Known ................................... 15
`
`i
`
`

`

`E. GS-7977 Was Known to Be in Human Clinical Trials at a 400mg
`Daily Dose ........................................................................................... 17
`
`F. Method of Treating HCV Using A Tablet Or Capsule Comprising
`Crystalline GS-7977 And A Pharmaceutical Excipient Was Known . 19
`
`IX. SCOPE AND CONTENT OF THE PRIOR ART ......................................... 20
`
`A. Ross ’645 ............................................................................................. 20
`
`B.
`
`Ross ’257 ............................................................................................. 23
`
`X.
`
`EACH CLAIM OF THE ‘159 PATENT IS UNPATENTABLE ................. 26
`
`A. Grounds 1 and 2: Claims 1-37 Were Anticipated By And Obvious
`Over Ross ’645 .................................................................................... 26
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`Claims 1 and 2 (composition comprising compound and
`excipient) ................................................................................... 27
`
`Claims 3-12 (pharmaceutical composition comprising at least
`one pharmaceutically acceptable excipient) ............................. 31
`
`Claims 13-15 (composition comprising at least one
`pharmaceutically acceptable excipient by specific weight)...... 35
`
`Claims 16-17 (unit dosage form comprising 400mg of
`crystalline GD-7977) ................................................................ 37
`
`Claims 18-27 (unit dosage form comprising at least one
`pharmaceutical excipient) ......................................................... 38
`
`Claims 28-29 (unit dosage form comprising at least one
`pharmaceutically acceptable excipient by specific weight)...... 41
`
`Claim 30 (unit dosage form comprising a capsule or tablet) .... 42
`
`Claims 31-32 (process for preparing a tablet composition
`comprising the unit dosage form where GS-7977 is 400mg) ... 43
`
`Claims 33-37 (method of treatment comprising administering
`the composition) ........................................................................ 44
`
`ii
`
`

`

`B. Grounds 3 and 4: Claims 1-37 Were Anticipated By And Obvious
`Over Ross ’257 .................................................................................... 45
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`Claims 1 and 2 (composition comprising compound and
`excipient) ................................................................................... 45
`
`Claims 3-12 (pharmaceutical composition comprising at least
`one pharmaceutically acceptable excipient) ............................. 50
`
`Claims 13-15 (composition comprising at least one
`pharmaceutically acceptable excipient by specific weight)...... 54
`
`Claims 16-17 (unit dosage form comprising 400mg of
`crystalline GS-7977) ................................................................. 56
`
`Claims 18-27 (unit dosage form comprising at least one
`pharmaceutical excipient) ......................................................... 57
`
`Claims 28-29 (unit dosage form comprising at least one
`pharmaceutically acceptable excipient by specific weight)...... 60
`
`Claim 30 (unit dosage form comprising a capsule or tablet) .... 61
`
`Claims 31-32 (process for preparing a tablet composition
`comprising the unit dosage form where GS-7977 is 400mg) ... 62
`
`Claims 33-37 (method of treatment comprising administering
`the composition) ........................................................................ 63
`
`XI. CONCLUSION .............................................................................................. 64
`
`XII. APPENDIX-LIST OF EXHIBITS ................................................................ 65
`
`XIII. CERTIFICATE OF COMPLIANCE ............................................................ 66
`
`XIV. CERTIFICATE OF SERVICE ...................................................................... 67
`
`iii
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`

`

`I.
`
`
`
`INTRODUCTION
`
`Initiative for Medicines, Access & Knowledge (I-MAK), Inc. (“Petitioner”)
`
`requests inter partes review (“IPR”) of claims 1-37 of United States Patent No.
`
`8,889,159 to Cleary et al. (“the ‘159 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 ’159 patent issued on November 18, 2014, and is currently
`
`assigned to Gilead Pharmasset LLC (“Patent Owner”). This petition demonstrates
`
`that claims 1-37 are unpatentable.
`
`
`
`The ‘159 patent claims a composition and unit dosage forms for the
`
`treatment of hepatitis C virus (“HCV”) infection that were anticipated by and
`
`obvious in light of the prior art. Specifically, the ‘159 claims compositions and unit
`
`dosage forms comprising GS-7977, a known crystalline form of a known anti-
`
`HCV drug, and at least one excipient, but such compositions and unit dosage forms
`
`were known as a result of the previous disclosure of the crystalline form of the
`
`drug. Thus, claims 1-37 of the ‘159 patent are unpatentable and should be
`
`cancelled.
`
`II. MANDATORY NOTICES
`
`
`
` Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1)) A.
`
`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-
`
`

`

`
`
` Related Matters (37 C.F.R. § 42.8(b)(2)) B.
`
`U.S. Patent Application No. 15/410,438 is pending and claims priority to an
`
`application that claims priority to the ‘159 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)) C.
`
`
`
`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
`
`to retain back-up counsel. Petitioner respectfully requests that the Board exercise
`
`its authority under 37 C.F.R. § 42.5(b) to waive or suspend the requirement under
`
`37 C.F.R. § 42.10 that Petitioner designate at least one back-up counsel.
`
`D.
`
`
`Service Information (37 C.F.R. § 42.8(b)(4))
`
`
`
`Papers concerning this matter should be served on the following:
`
`
`
`
`
`
`
`
`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
`
`
`
`
`
`
`
`
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`
`
`
`
`
`Petitioner consents to service by email to dan@ravicher.com.
`
`III. REQUIREMENTS FOR REVIEW
`
`
`
` Grounds for Standing A.
`
`
`
`Petitioner certifies that the ’159 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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`

`

`sought herein. The required fee is being paid through the Patent Trial and Appeal
`
`Board End to End System. The Office is authorized to charge fee deficiencies and
`
`credit overpayments to Deposit Account No. 601986.
`
`B.
`
`
`Identification of Challenge
`
`
`
`Petitioner respectfully requests cancellation of claims 1–37 of the ’159
`
`patent on the following grounds:
`
`# Claims
`1
`1 – 37
`2
`1 – 37
`3
`1 – 37
`4
`1 – 37
`
`35 U.S.C. § Prior Art
`102
`Ross ‘645
`103
`Ross ‘645
`102
`Ross ‘237
`103
`Ross ‘237
`
`
`This Petition is supported by the declaration of Joseph M. Fortunak, Ph.D.
`
`EX1014. 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
`
`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
`
`cancellation of the challenged claims. See 35 U.S.C. § 314(a).
`
`
`
`
`
`-3-
`
`

`

`IV. OVERVIEW OF THE ‘159 PATENT
`
`The ’159 patent relates to a composition and unit dosage form for the
`
`treatment of hepatitis C virus (HCV) infection comprising GS-7977 and at least
`
`one pharmaceutically acceptable excipient. The ’159 patent also covers methods
`
`for making the composition and unit dosage form disclosed therein and a method
`
`of treatment comprising administering to (preferably) a human subject an effective
`
`amount of GS-7977 and an effective amount of ribavirin for a period of time. One
`
`aspect of the method of treatment covered in the ’159 patent is an interferon-free
`
`treatment regimen. EX1001 at 1:14-28.
`
`More specifically, the ’159 patent relates to a composition comprising a
`
`crystalline form of the compound GS-7977 (also known as PSI-7977), which has
`
`the following molecular structure:
`
`EX1001 at 46:37-52. The crystalline form covered by the ’159 patent has X-ray
`
`
`
`-4-
`
`

`

`powder diffraction (XRPD) 2θ-reflections at about 6.1 and 12.7 (°). EX1001 at
`
`46:56. The patent also discloses that the crystalline form of GS-7977 possesses a
`
`more complete set of 2θ-reflections at about: 6.1, 8.2, 10.4, 12.7, 17.2, 17.7, 18.0,
`
`18.8, 19.4, 19.8, 20.1, 20.8, 21.8, and 23.3 (°). EX1001 at 46:57-60.
`
`The pharmaceutical composition claimed by the ’159 patent contains about
`
`25%-35% by weight of crystalline GS-7977. EX1001 at 46:36-37. The
`
`pharmaceutical composition also contains at least one pharmaceutically acceptable
`
`excipient that is a diluent, disintegrant, glidant, or lubricant. EX1001 at 46:61-63.
`
`The patent further claims several choices of each type of excipient, and various
`
`amounts of each excipient contained in the pharmaceutical composition. EX1001
`
`at 46:64-48:61.
`
`The ’159 patent also discloses a unit dosage form containing about 400 mg
`
`of crystalline GS-7977. EX1001 at 47:51-52.
`
`The following chart describes the ’159 patent’s 37 claims:
`
`Claim(s)
`
`Recite
`
`1-2
`
`3-12
`
`13-15
`
`16-17
`
`A pharmaceutical composition comprising about 25%-35% by weight
`of crystalline GS-7977 and at least one excipient.
`The composition of claim 1 where at least one pharmaceutical
`excipient comprises a diluent, a disintegrant, a glidant and a lubricant,
`including various excipient options for selection.
`The composition of claim 1 wherein the at least one excipient
`comprises various weight percentages for each excipient.
`A unit dosage form containing about 400 mg of crystalline GS-7977
`
`-5-
`
`

`

`18-27
`
`28-29
`
`30
`
`31-32
`
`33-37
`
`and at least one excipient
`The composition of claim 17 where at least one pharmaceutical
`excipient comprises a diluent, a disintegrant, a glidant and a lubricant,
`including various excipient options for selection.
`The composition of claim 17 wherein the at least one excipient
`comprises a weight range for each excipient.
`The unit dosage form of claim 17 comprising a capsule or tablet.
`
`A process for preparing a tablet composition comprising the unit
`dosage form of claim 28.
`A method of treating HCV in a human by administering the
`composition of claim 1, including in combination with ribavirin as
`part of an interferon-free regimen.
`
`
`
`
`
`V.
`
`FILE HISTORY OF THE ‘159 PATENT
`
`U.S. Patent Application No. 13/686,664 (“the ’664 application”), filed on
`
`November 27, 2012, issued as the ’159 patent on November 18, 2014. The ’664
`
`application claimed priority as a continuation-in-part of application No.
`
`PCT/US2012/055621, filed on Sep. 14, 2012, and as a continuation-in-part of U.S.
`
`Patent Application No. 13/661,509 (“the ’509 application”), filed on Oct. 26, 2012.
`
`The ’664 application also claimed the benefit of Provisional Applications Nos.
`
`61/564,500 (“the ‘500 provisional application”), filed on Nov. 29, 2011, and
`
`61/707,459 (“the ‘459 provisional application”), filed on Sep. 28, 2012.
`
`During prosecution of the ’664 application, the Examiner made only one
`
`prior art based rejection of the pending claims, for being obvious over U.S. Patent
`
`Application Publication No. US 2010/0298257 to Ross (“Ross ’257”) in view of
`
`-6-
`
`

`

`US Patent Application Publication No. US 2011/0020272 to Schubert (“Schubert”)
`
`and World Health Organization, “Pharmaceutical excipients - an overview
`
`including considerations for paediatric dosing” (“WHO”). EX1002 at 85.
`
`In response to the Examiner's obviousness rejection, Patent Owner amended
`
`the claims to recite polymorphic Form 6 of GS-7977 specifically and argued, “the
`
`claims, as currently amended, render the outstanding rejection moot for at least the
`
`reason that none of the cited references teaches or suggests Form 6 of GS-7977.”
`
`EX1002 at 108.
`
`The Examiner withdrew the rejection, “because the claimed polymorph
`
`appears to be free of art.” EX1002 at 114. In the Notice of Allowability, the
`
`Examiner stated:
`
`The prior art including the applied references does not disclose or
`suggest the claimed polymorph: the crystalline GS-7977 has XRPD 2θ
`-reflections (°) at about: 6.1 and 12.7 as recited in claim 8. For
`example, while the closest prior art of Ross (US publication
`application no. 2010/0298257) does teach crystalline GS-7977 has
`XRPD 2θ -reflections (°) at about: 5.0, 7.3, 9.4 and 18.1, it requires
`different polymorph.
`EX1002 at 141.
`
`VI. PERSON OF ORDINARY SKILL IN THE ART
`
`As the ’159 patent pertains to a composition and unit dosage form of a
`
`crystalline form of the nucleos(t)ide compound GS-7977, which can be used to
`
`-7-
`
`

`

`treat a subject infected with HCV, a POSA with respect to the ’159 patent would
`
`(1) have a Ph.D. in chemistry or a closely related field with some experience in an
`
`academic or industrial laboratory focusing on drug discovery and/or development,
`
`including formulations, 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, including
`
`formulations, for the treatment of viral diseases. EX1014 at ¶39.
`
`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
`
`likelihood that Petitioner will prevail with respect to the challenged claims.
`
`The ’159 patent provides definitions for certain claim terms, but these
`
`definitions are conventional. EX1014 at ¶41. Thus, there is no reason to give any
`
`of the terms of the claims of the ’159 a meaning other than their ordinary and
`
`accustomed meaning. EX1014 at ¶41.
`
`-8-
`
`

`

`VIII. BACKGROUND KNOWLEDGE IN THE ART
`
`The background discussed below reflects knowledge skilled artisans would
`
`bring to bear in reading the prior art at the time of the invention and thereby assists
`
`in understanding how one would have inherently understood the references and
`
`why one would have been motivated to combine the references as asserted in this
`
`Petition. Ariosa Diagnostics v. Verinata Health, Inc., No. 15-1215, slip op. 1, 11-
`
`12 (Fed. Cir. 2015). This knowledge of a skilled artisan is part of the store of
`
`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,
`
`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
`
`known in the art as of November 29, 2011.
`
`A. GS-7977 Was A Known and Promising Antiviral Agent for
`Treating HCV
`
`WO 2008/121634 to Sofia et al. (“Sofia ’634”; EX1003) disclosed specific
`
`phosphoramidate prodrugs of nucleoside derivatives, which are useful for the
`
`treatment of viral
`
`infections,
`
`including HCV. EX1014 at ¶43. The
`
`phosphoramidate prodrugs disclosed
`
`in Sofia
`
`’634 also
`
`included
`
`their
`
`stereoisomers, salts (acid or basic addition salts), hydrates, solvates or crystalline
`
`forms as represented by the following structure:
`
`-9-
`
`

`

`
`
`EX1003 at 699.
`
`While Sofia ‘634 disclosed and claimed many compounds within the
`
`formula, it specifically covered the compound (S)-2-{[(2R,3R,4R,5R)-5-(2,4-
`
`Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-
`
`furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid isopropyl ester,
`
`also known as GS-7977 (or PSI-7977). EX1003 at 703:48-50. Indeed, the ’159
`
`confirms this. EX1001 at 8:3 (citing U.S Patent No.7,964,580, which corresponds
`
`to Sofia ’634).
`
`B. Crystalline Forms of GS-7977 Were Known
`Multiple crystalline forms of GS-7977 were already known in the art.
`
`EX1014 at ¶45. Sofia et al. “Discovery of β-D-2’ Deoxy-2’-α-fluoro-2’-β-C-
`
`methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis
`
`Virus”, September 16, 2010, 53, 7202-7218 (“Sofia 2010”; EX1004) disclosed a
`
`dichloromethane solvate crystalline form of GS-7977. EX1004 at 8.
`
`-10-
`
`

`

`U.S Publication No. 2010/0298257 to Ross et al. (“Ross ’257”; EX1005),
`
`which is identified as prior art by the ’159 patent, EX1001 at 8:3-47, disclosed the
`
`following compounds Rp-4 and Sp-4, also known as GS-7977:
`
`
`
`
`
`
`
`EX1005 at ¶¶0080-0109.
`
`Ross ’257 also taught solvates, hydrates, or mixed solvate-hydrate forms of
`
`Sp-4. Sp-4 was also disclosed to possibly exist as a mixed solvate-hydrate form with
`
`additional adsorbed water. EX1005 at ¶0081. The compound represented by Sp-4
`
`-11-
`
`

`

`was also disclosed as having solid state properties of being crystalline, crystal-like,
`
`or amorphous. EX1005 at ¶0092.
`
`Furthermore, Ross ’257 taught multiple crystalline forms of Sp-4. EX1014 at
`
`¶48. Specifically, Ross ’257 disclosed XRPD patterns and 2θ-reflection angles for
`
`six distinct crystalline forms of Sp-4. EX1005 at ¶¶0098-0106. Ross ’257 also
`
`taught a substantially pure crystalline Sp-4. EX1014 at ¶48. This disclosure of the
`
`subtantially pure crystalline Sp-4 therefore teaches that a genus of crystalline forms
`
`of Sp-4 existed including any additional crystalline forms. EX1005 at ¶¶0107-0108;
`
`EX1014 at ¶48.
`
`Indeed, selecting a single crystalline form of a compound possessing the
`
`preferred combination of optimal properties including (e.g., stability, dissolution,
`
`and bioavailability) is a necessary and routine step in ensuring optimal drug
`
`performance. EX1014 at ¶49.
`
`The ICH Q6A Guideline “Specifications: Test Procedures and Acceptance
`
`Criteria For New Drug Substances and New Drug Products: Chemical
`
`Substances” (“ICH”; EX1006) provides in Section 3.3.1 New Drug Substances:
`
`c) Polymorphic forms: Some new drug substances exist in different
`crystalline
`forms, which differ
`in
`their physical properties.
`Polymorphism may also include solvation or hydration products (also
`known as pseudopolymorphs) and amorphous forms. Differences in
`these forms could, in some cases, affect the quality or performance of
`
`-12-
`
`

`

`the new drug products. In cases where differences exist which have
`been shown to affect drug product performance, bioavailability or
`stability, then the appropriate solid state should be specified.
`EX1006 at 12. ICH taught a set of three Decision Trees for guidance about the
`
`need to set acceptance criteria for polymorphism in drug substances and drug
`
`products: “Decision trees #4(1) through 4(3) provide additional guidance on when,
`
`and how, polymorphic forms should be monitored and controlled.” EX1006 at 13,
`
`28.
`
`It was also known that the selection of a single most-preferred solid-state
`
`form was a matter of concern for drug regulatory agencies. EX1014 at ¶51.
`
`Routine approaches (including decision trees) to guide the evaluation and selection
`
`of an optimal crystalline form of a new drug substance for development are
`
`available in many relevant publications, including Byrn et al., “Pharmaceutical
`
`Solids: A Strategic Approach to Regulatory Considerations,” Pharmaceutical
`
`Research, 12(7), 1995, 945-954 (“Byrn”; EX1007).
`
`WO2011/123645 to Ross (“Ross ’645”; EX1008) also taught both GS-7977
`
`compounds Rp-4 and Sp-4. EX1008 at 8:1-5. Ross ’645 specifically disclosed
`
`multiple crystalline forms of Sp-4. EX1014 at ¶52. In particular, Ross ’645
`
`disclosed the specific crystalline form of compound Sp-4 as claimed in the
`
`pharmaceutical composition of the ’159 patent. EX1008 at 20:16-18. Indeed, the
`
`‘159 patent concedes this. EX1001 at 8:3 (citing US 2011/0251152, which relates
`
`-13-
`
`

`

`to Ross’645).
`
`C. Tablet And Capsule Formulation Comprising Pharmaceutical
`Excipients Were Known
`
`Tablet formulations were well known and routine for use in the
`
`pharmaceutical industry for drug delivery. EX1014 at ¶53. Several textbooks and
`
`guides existed setting out general principles of tablet design, excipient selection,
`
`and tablet manufacture, all of which are commonly practiced in the field. EX1014
`
`at ¶53. Examples of such principles are explained in, Lieberman, Lachman and
`
`Schwartz, “Pharmaceutical Dosage Forms: Tablets”, Volume 1, Chapter 3, 1989
`
`by Marcel Dekker (“Lieberman”; EX1009), U.S Pharmacopeia 24 (NF19),
`
`“Pharmaceutical Dosage Forms”, General Information 1151-1161, 2117-2118,
`
`2000 (“USP”; EX1010), and Remington, “The Science and Practice of
`
`Pharmacy”, 19th Edition, 1995 (“Remington”; EX1011).
`
`Both Ross ’257 and Ross ’645 incorporate Remington by reference in
`
`relation to describing suitable formulations and pharmaceutical carriers, diluents
`
`and excipients. EX1005 at ¶0119; EX1008 at 23:13-16.
`
`The ’159 patent itself states that its embodiments may be modified using the
`
`materials and methods taught by Remington. EX1001 at 17:54-58.
`
`Rowe et al., “Handbook of Pharmaceutical Excipients”, Fourth Edition,
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`2003 (“Rowe”; EX1012) provided a more thorough review of the excipients
`
`approved for use by the U.S Food and Drug Administration. Rowe taught a
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`compendium of monographs for excipients used in pharmaceutical compositions.
`
`EX1014 at ¶56. The monographs for each excipient provide information on the
`
`functional category, application in formulations, description, specifications, typical
`
`properties, incompatibilities, method of manufacture, and regulatory status of each
`
`excipient listed, as well as published references to such excipients. See, e.g.,
`
`EX1012 at 12, 28, and 33. The monographs also provide information on typical
`
`quantities of excipients used in various types of formulations. EX1014 at ¶56.
`
`The’159 patent cites an earlier version of Rowe from 1994 as teaching ‘Tablet
`
`Preparation’. EX1001 at 15:21-17:67
`
`D. Tablet And Capsule Formulations Comprising Crystalline GS-
`7977 And Pharmaceutical Excipients Were Known
`
`Sofia ’634 taught that the compounds disclosed therein, including GS-7977,
`
`could be directed to a composition comprising a pharmaceutically acceptable
`
`medium selected from among an excipient, carrier, diluent, and equivalent medium
`
`and a compound, that is intended to include its salts (acid or basic addition salts),
`
`hydrates, solvates and crystalline forms. EX1003 at 661:1-12.
`
`Sofia ’634 also taught that compounds of the invention therein, including
`
`GS-7977, could be formulated in a wide variety of oral administration dosage
`
`forms and carriers, including tablets. EX1003 at 661:13-16. Compound or
`
`compounds of the invention taught in Sofia’634 could be placed into the form of
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`pharmaceutical compositions and unit dosages with one or more conventional
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`excipients, carriers or diluents. EX1003 at 661:22-25.
`
`Sofia’634 further taught that the pharmaceutical compositions and unit
`
`dosage forms may be comprised of conventional ingredients in conventional
`
`proportions, with or without additional active compounds and the unit dosage form
`
`may contain any suitable effective amount of the active ingredient commensurate
`
`with the intended daily dosage range to be employed. EX1003 at 661:25-29. In
`
`particular, Sofia’634 taught that a typical preparation will contain from about 5%
`
`to about 95% active compound or compounds (w/w). EX1003 at 662:2-3.
`
`Furthermore, Sofia ’634 disclosed that the compounds therein will generally be
`
`administered in admixture with one or more suitable pharmaceutical excipients,
`
`diluents or carriers selected with regard to the intended route of administration and
`
`standard pharmaceutical practice. EX1003 at 661:11-15.
`
`Sofia ’634 also provided a non-exhaustive list of suitable carriers for tablets,
`
`including starch, sugar, talc, methylcellulose, sodium carboxymethylcellulose,
`
`magnesium stearate and lactose. EX1003 at 663:7-20.
`
`Ross ’257 taught dosage, administration and use, providing:
`
`An aspect of this embodiment is directed to a composition for
`
`the treatment of any of the viral agents disclosed herein said
`composition comprising a pharmaceutically acceptable medium
`selected from among an excipient, carrier, diluent and equivalent
`medium and any of the compounds 4, Rp-4, or Sp-4, that is intended
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`to include its hudrates, solvates, and any crystalline forms of any of
`the compounds 4, Rp-4, or Sp-4 or its hydrates and solvates thereof.
`EX1005 at ¶0111.
`
`Ross ’257 also taught that compounds 4, Rp-4, or Sp-4 (GS-7977), could be
`
`used for oral addministration in the form of tablets. EX1005 at ¶0112. Ross ’257
`
`further taught the use of compounds 4, Rp-4, or Sp-4 (GS-7977) with one or more
`
`pharmaceutical excipients where the typical preparation would contain from about
`
`5% to about 95% active compound or compounds (w/w). EX1005 at ¶0113.
`
`Suitable carriers for tablets were also taught in Ross ’257 to have activity as
`
`diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders,
`
`preservatives, tablet disintegrating agents, or an encapsulating material. EX1005 at
`
`¶0113. Suitable carriers for tablets were also taught in Ross ‘257 as including but
`
`not limited to magnesium stearate starch, sugar, talc, methylcellulose, sodium
`
`carboxymethylcellulose and lactose. EX1005 at ¶00115.
`
`Ross ’645 also taught dosage, administration and use as described in Ross
`
`’257, albeit in relation to additional crystalline forms including the specific
`
`crystalline form of compound Sp-4 as claimed in the pharmaceutical composition
`
`of the ’159 patent. EX1008 at 21-23.
`
`E. GS-7977 Was Known To Be In Clinical Trials at a 400mg Daily
`Dose
`
`Sofia 2010 disclosed that PSI-7977 (GS-7977) was in phase II clinical
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`development for the treatment of HCV infection. EX1004 at 9.
`
`Lawitz et al.,“High Rapid Virologic Response (RVR) with PSI-7977 Daily
`
`Dosing Plus PEG-IFN/RBV in a 28-day Phase 2a Trial” 61th Annual Meeting of
`
`the American Association for the Study of Liver Diseases, October 30- November
`
`3, 2010 (“Lawitz”; EX1013) disclosed that the 200 mg and 400 mg daily doses of
`
`PSI-7977 (GS-7977) with PEG-IFN (pegylated interferon) and RBV (ribavirin)
`
`provided a more durable virological response than the 100 mg daily dose of PSI-
`
`7977. EX1013 at 1. Thus, a POSA would know that a 400 mg QD dose was one of
`
`two preferred doses for sustained virologic response when dosed with PEG-IFN
`
`and RBV. EX1014 at ¶65.
`
`Ross ‘257 taught a therapeutically effective amount of the compounds 4, Rp-
`
`4, or Sp-4 (GS-7977) for oral administration for a daily dosage to be between
`
`0.001 and about 10g, including all values in between, such as 0.001-9.5g per day.
`
`In particular, Ross ’257 taught a daily dosage to be between 0.01 and 1g per day,
`
`including all incremental values of 0.01g (i.e., 10mg) in between. EX1005 at
`
`¶0126.
`
`Ross ’645 also taught the same therapeutically effective amount for
`
`compounds 4, Rp-4, or Sp-4 (GS-7977) for oral administration for a daily dosage.
`
`EX1008 at 24:26-25:14.
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`F. Method of Treating HCV Using A Tablet or Capsule Comprising
`Crystalline GS-7977 And A Pharmaceutical Excipient Was
`Known
`
`Sofia ’634 taught that the nucleotide NS5B polymerase inhibitors disclosed
`
`and claimed therein, including GS-7977, could be directed to a method of
`
`treatment alone or in combination with another antiviral agent, wherein the
`
`administration is concurrent or alternative. EX1003 at 8-12. Sofia ’634 further
`
`suggested examples of “another antiviral agent” to include ribavirin. EX1003 at
`
`668:26-27. Furthermore, Sofia’634 disclosed that administration of two or more
`
`agents at the same time could 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. EX1003 at 669:5-8
`
`Ross ’257 taught that compounds 4, Rp-4, or Sp-4 (GS-7977) could be
`
`administered in a therapeutically effective amount to the subject. EX1005 at
`
`¶00123. Ross ’257 also taught that the said compounds could be alongside another
`
`antiviral agent, including ribavirin. EX1005 at ¶¶0128-0129. As taught in ’Sofia
`
`‘634, Ross’257 disclosed that administration of two or more agents at the same
`
`time could 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. EX1005 at ¶0128-¶0129.
`
`As disclosed in Ross ’257, Ross ’645 also taught that compounds 4, Rp-4, or
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`Sp-4 (GS-7977) could be administered in a therapeutically effective amount to the
`
`subject. EX1008 at 25:24-31. Further, Ross ’645 disclosed that the said compounds
`
`could be alongside another antiviral agent, including ribavirin. EX1008 at 26:20.
`
`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 the claims of the ’159 patent. EX1014 at
`
`¶50.
`
`A. WO 2011/123645 to Ross (“Ross ’645”; EX1008)
`Ross ‘645 was published on October 6, 2011, before the filing of the earliest
`
`application to which the ‘159 patent claims priority. Therefore, Ross ‘645 is prior
`
`art to the ‘159 patent under 35 U.S.C. § 102(a).
`
`Ross ’645 taug