`
`
`
`
`
`IPR2018-00211
`Patent Owner’s Preliminary Response
`
`
`Filed on behalf of Patent Owner Gilead Pharmasset LLC by:
`Dorothy P. Whelan (Reg. No. 33,814)
`David L. Cavanaugh (Reg. No. 36,476)
`Michael J. Kane (Reg. No. 39,722)
`Emily R. Whelan (Reg. No. 50,391)
`W. Chad Shear (Reg. No. 47,938)
`Deric Geng (Reg. No. 73,434)
`FISH & RICHARDSON P.C.
`E. Ross Cohen (Reg. No. 72,115)
`60 South Sixth Street, Suite 3200
`WILMER CUTLER PICKERING
`Minneapolis, MN 55402
`HALE AND DORR LLP
`1875 Pennsylvania Ave., NW
`Washington, DC 20006
`
`
`
`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 IPR2018-00211
`Patent 9,393,256
`____________________________________________
`PATENT OWNER’S PRELIMINARY RESPONSE
`
`

`

`
`
`
`
`
`
`IPR2018-00211
`Patent Owner’s Preliminary Response
`
`
`TABLE OF CONTENTS
`
`
`
`I.
`II.
`A. 
`
`Page
`INTRODUCTION ............................................................................................ 1
`TECHNOLOGY BACKGROUND ................................................................. 4
`Standard of Care for Hepatitis C Virus at the Time of the Priority
`Filing ............................................................................................................. 4 
`B.  Other Anti-HCV Agents and Direct Acting Antiviral Agents ...................... 5 
`III. THE CLAIMED INVENTION ........................................................................ 7
`A.  Overview of the ’256 Patent .......................................................................... 7 
`B. 
`Prosecution History ....................................................................................... 9 
`IV.  PERSON OF ORDINARY SKILL IN THE ART ......................................... 10 
`V.  CLAIM CONSTRUCTION ........................................................................... 10 
`VI.  PETITIONER’S ASSERTED REFERENCES .............................................. 11 
`A.  Legrand-Abravanel ...................................................................................... 11 
`B.  Delaney ........................................................................................................ 13 
`C. 
`Sofia ’634 .................................................................................................... 15 
`D.  Guo .............................................................................................................. 16 
`VII.  GROUND 1 – CLAIMS 1-4 ARE NOT ANTICIPATED OR RENDERED
`OBVIOUS BY LEGRAND-ABRAVANEL ................................................. 17 
`Legrand-Abravanel Cannot Anticipate the ’256 Patent Claims Because
`It Does Not Expressly or Inherently Disclose Compounds 6 and 10,
`Let Alone the Combination of These Compounds Without Interferon,
`as Claimed ................................................................................................... 18 
`Petitioner Does Not Provide Any Reasoning in Support of Its
`Obviousness Challenge ............................................................................... 24 
`VIII.  GROUND 2 – CLAIMS 1-4 ARE NOT ANTICIPATED BY DELANEY .. 32 
`
`A. 
`
`B. 
`
`i
`
`

`

`
`
`
`
`
`
`IPR2018-00211
`Patent Owner’s Preliminary Response
`
`
`A.  Delaney Does Not Disclose the Combination of Claim Limitations
`“Arranged as in the Claims” ...................................................................... 32 
`B.  Delaney Never Discloses the Limitation for Treating HCV Without
`Ribavirin (Claim 3) .................................................................................... 36 
`IX.  GROUND 3 – CLAIMS 1-4 ARE NOT OBVIOUS IN VIEW OF SOFIA
`AND GUO ..................................................................................................... 37 
`A.  Neither Sofia nor Guo Teaches or Suggests Interferon-Free
`Combination Therapy ................................................................................. 38 
`Petitioner Has Failed to Establish Any Motivation for a POSA to
`Combine Sofia ’634 with Guo to Achieve the Claimed Invention, or
`That a POSA Would Have Had a Reasonable Expectation of Success
`in Doing So ................................................................................................. 40 
`X.  THE PETITION SHOULD BE DENIED UNDER § 325(d) ........................ 44 
`XI.  PRESERVATION OF RIGHTS UNDER OIL STATES ................................ 46 
`XII.  CONCLUSION .............................................................................................. 47 
`
`B. 
`
`
`
`
`
`
`ii
`
`

`

`
`
`
`
`
`
`IPR2018-00211
`Patent Owner’s Preliminary Response
`
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`
`Federal Cases
`Allergan, Inc. v. Apotex Inc., 754 F.3d 952 (Fed. Cir. 2014) ............................ 21, 27
`Amgen, Inc. v. Abbvie Biotech. Ltd., No. IPR2015-01514, 2015 Pat.
`App. LEXIS 12700 (P.T.A.B. Jan. 14, 2015) ................................................ 21
`Arendi S.A.R.L. v. Apple Inc., 832 F.3d 1355 (Fed. Cir. 2016) ............................... 26
`Bettcher Indus. v. Bunzl USA, Inc., 661 F.3d 629 (Fed. Cir. 2011) ........................ 37
`CFMT, Inc. v. YieldUp International Corp., 349 F.3d 1333 (Fed. Cir.
`2003) .............................................................................................................. 25
`Coalition for Affordable Drugs VII LLC v. Pozen Inc., No. IPR2015-
`01344, 2015 Pat. App. LEXIS 12669 (P.T.A.B. Dec. 17, 2015) ............ 26, 40
`Cuozzo Speed Technologies, LLC v. Lee, 136 S. Ct. 2131 (2016) .......................... 11
`
`Elan Pharmaceuticals, Inc. v. Mayo Foundation for Medical
`Education & Research, 346 F.3d 1051 (Fed. Cir. 2003) ............................... 23
`Hospira, Inc. v. Genentech, Inc., No. IPR2017-00739, 2017 Pat. App.
`LEXIS 10044 (P.T.A.B. July 27, 2017) ........................................................ 45
`In re Arkley, 455 F.2d 586 (C.C.P.A. 1972) ............................................................ 34
`In re Kahn, 441 F.3d 977 (Fed. Cir. 2006) .............................................................. 25
`In re Kotzab, 217 F.3d 1365 (Fed. Cir. 2000) ............................................. 27, 41, 42
`In re McLaughlin, 443 F.2d 1392 (C.C.P.A. 1971) ................................................. 29
`In re Meyer, 599 F.2d 1026 (C.C.P.A. 1979) .......................................................... 35
`In re Petering, 301 F.2d 676 (C.C.P.A. 1962) ......................................................... 34
`In re Royka, 490 F.2d 981 (C.C.P.A. 1974) ............................................................ 25
`In re Skvorecz, 580 F.3d 1262 (Fed. Cir. 2009)....................................................... 21
`In re Stepan Co., 868 F.3d 1342 (Fed. Cir. 2017) ....................................... 28, 30, 42
`
`iii
`
`

`

`
`
`
`
`
`
`IPR2018-00211
`Patent Owner’s Preliminary Response
`
`In re Translogic Technology, Inc., 504 F.3d 1249 (Fed. Cir. 2007) ....................... 11
`Innogenetics, N.V. v. Abbott Laboratories, 512 F.3d 1363 (Fed. Cir.
`2008) .............................................................................................................. 28
`Insite Vision Inc. v. Sandoz, Inc., 783 F.3d 853 (Fed. Cir. 2015) ................ 27, 28, 42
`K/S HIMPP v. Hear-Wear Technologies, LLC, 751 F.3d 1362 (Fed.
`Cir. 2014) ....................................................................................................... 26
`Kennametal, Inc. v. Ingersoll Cutting Tool Co., 780 F.3d 1376 (Fed.
`Cir. 2015) ........................................................................................... 19, 23, 33
`King Pharmaceuticals, Inc. v Eon Labs, Inc., 616 F.3d 1267 (Fed Cir.
`2010) .............................................................................................................. 18
`KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007) ................ 25, 30, 39, 41
`Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157 (Fed. Cir. 2006) ...................... 28, 29
`
`Metabolite Laboratories, Inc. v. Laboratory Corp. of America
`Holdings, 370 F.3d 1354 (Fed. Cir. 2004) .................................................... 23
`Microsoft Corp. v. Biscotti, Inc., 878 F.3d 1052 (Fed. Cir. 2017) ................ 2, 33, 35
`Mylan Pharmaceuticals Inc. v. Nissan Chemical Industries, Ltd., No.
`IPR2015-01069, 2015 WL 7303851 (P.T.A.B. Oct. 20, 2015) .................... 31
`Neil Ziegman, N.P.Z., Inc. v. Stephens, No. IPR2015-01860, 2016 Pat.
`App. LEXIS 1127 (P.T.A.B. Feb. 24, 2016) ........................................... 45, 46
`Net MoneyIN, Inc. v. VeriSign, Inc., 545 F.3d 1359 (Fed. Cir. 2008) ..................... 35
`Oil States Energy Services, LLC v. Greene’s Energy Group, LLC, No.
`16-712 (U.S. cert. granted June 12, 2017) ..................................................... 46
`PAR Pharmaceutical, Inc. v. TWI Pharmaceuticals, Inc., 773 F.3d
`1186 (Fed. Cir. 2014)............................................................................... 25, 38
`Personal Web Technologies, LLC v. Apple, Inc., 848 F.3d 987 (Fed.
`Cir. 2017) ....................................................................................................... 25
`
`iv
`
`

`

`
`
`
`
`
`
`IPR2018-00211
`Patent Owner’s Preliminary Response
`
`
`Procter & Gamble Co. v. Teva Pharmaceuticals USA, Inc., 566 F.3d
`989 (Fed. Cir. 2009)........................................................................... 28, 30, 43
`Structural Rubber Products Co. v. Park Rubber Co., 749 F.2d 707
`(Fed. Cir. 1984) .............................................................................................. 21
`Trintec Industries, Inc. v. Top-U.S.A. Corp., 295 F.3d 1292 (Fed. Cir.
`2002) .............................................................................................................. 19
`Unified Patents Inc. v. Berman, No. IPR2016-01571, 2016 Pat. App.
`LEXIS 13480 (P.T.A.B. Dec. 14, 2016) ....................................................... 46
`Federal Statutes
`35 U.S.C. § 325(d) ......................................................................................... 3, 44, 47
`Regulations
`37 C.F.R. § 42.65(a) ........................................................................................... 26, 39
`37 C.F.R. § 42.100(b) .............................................................................................. 11
`37 C.F.R. § 42.104(b)(4) ........................................................................ 18, 20, 25, 38
`
`
`
`
`v
`
`

`

`
`
`I.
`
`
`
`
`
`IPR2018-00211
`Patent Owner’s Preliminary Response
`
`
`INTRODUCTION
`The Board should deny this fundamentally flawed Petition filed by Initiative
`
`for Medicines, Access & Knowledge (“Petitioner”) for at least the following
`
`reasons: it fails to address key claim limitations missing from the alleged prior art;
`
`it fails to meet the strict standard for anticipation; it and relies on nothing more
`
`than conclusory statements or hindsight for the obviousness grounds set forth to
`
`challenge the claims of U.S. Patent No. 9,393,256 (“the ’256 patent”). Because the
`
`Petitioner has fallen well short of demonstrating a reasonable likelihood of success
`
`on any of the grounds, the Board should deny the Petition.1
`
`The ’256 patent claims a method of treating hepatitis C virus (“HCV”)
`
`comprising administering to a human a combination of two specific chemical
`
`compounds, “compound 6” and “compound 10,” without interferon. Compound 6
`
`
`1 In fact, this Petition is one of the many IPR petitions filed by Petitioner
`
`challenging Patent Owner’s patents, all of which suffer from similar fundamental
`
`defects. See IPR2018-00103 (filed Oct. 25, 2017); IPR2018-00119 (filed Oct. 25,
`
`2017); IPR2018-00120 (filed Oct. 25, 2017); IPR2018-00121 (filed Oct. 26, 2017);
`
`IPR2018-00122 (filed Oct. 26, 2017); IPR2018-00123 (filed Nov. 9, 2017);
`
`IPR2018-00125 (filed Oct. 30, 2017); IPR2018-00126 (filed Nov. 2, 2017);
`
`IPR2018-00211 (filed Dec. 6, 2017); IPR2018-00390 (filed Dec. 26, 2017).
`
`1
`
`

`

`
`
`
`
`
`
`IPR2018-00211
`Patent Owner’s Preliminary Response
`
`
`and compound 10 correspond, respectively, to Gilead’s anti-HCV drugs ledipasvir
`
`and sofosbuvir, which in combination make up Gilead’s revolutionary HCV
`
`therapy Harvoni®, the first once-a-day pill approved for the treatment of HCV.
`
`Petitioner’s Ground 1 challenge argues that the claims are anticipated, or “at
`
`a minimum” rendered obvious, by the prior art reference Legrand-Abravanel (Ex.
`
`1005). Yet Legrand-Abravanel discloses neither compound 6 nor compound 10,
`
`let alone their combination without interferon, thus dooming Petitioner’s
`
`anticipation theory. Moreover, Petitioner wholly fails to state a prima facie case of
`
`obviousness based on Legrand-Abravanel.
`
`Petitioner’s Ground 2 anticipation challenge based on Delaney (Ex. 1010)
`
`fails to identify where the reference discloses the particular combination of
`
`compound 6 and compound 10 as claimed, out of at least thousands of different
`
`possible combinations of compounds disclosed by Delaney, let alone their
`
`combination without interferon. Without any guidance in the prior art to combine
`
`or join the limitations together as they are arranged in the claims, a person of
`
`ordinary skill in the art (“POSA”) could not “at once envisage” the claimed
`
`invention, and, thus, there can be no anticipation. See Microsoft Corp. v. Biscotti,
`
`Inc., 878 F.3d 1052, 1068-70 (Fed. Cir. 2017).
`
`Petitioner’s Ground 3 obviousness challenge similarly fails to meet the
`
`obviousness standard established by case law. Despite separately identifying
`
`2
`
`

`

`
`
`
`
`
`
`IPR2018-00211
`Patent Owner’s Preliminary Response
`
`
`disclosures of compound 6 in Guo (Ex. 1011) and compound 10 in Sofia ’634 (Ex.
`
`1004), Petitioner fails to advance any reason, other than hindsight, why a POSA
`
`would have selected the specific combination of compound 6 and compound 10, or
`
`explain why a POSA would have had any reasonable expectation of success in
`
`doing so to arrive at a HCV treatment as claimed. Additionally, Petitioner fails to
`
`identify any teaching or suggestion of interferon-free methods of treatment, as
`
`required by the claims. Petitioner provides nothing more than conclusory,
`
`boilerplate statements that a POSA would have been motivated to combine prior
`
`art references to achieve the claimed invention, or would have had a reasonable
`
`expectation of success in doing so. Such statements are insufficient to make a
`
`prima facie showing of obviousness, and the Petition is completely silent as to any
`
`objective considerations. Thus, Petitioner’s obviousness challenge must fail.
`
`Finally, the Board should reject the Petition pursuant to 35 U.S.C. § 325(d).
`
`For each of its asserted grounds, Petitioner relies on “the same or substantially the
`
`same” prior art references and arguments that were before the Examiner during
`
`the ’256 patent’s prosecution. Delaney, Sofia, and Guo are all cited on the face of
`
`the ’256 patent and were considered by the Examiner, who nonetheless found the
`
`claims novel and non-obvious. See Ex. 2001 at 16, 29, 32. Legrand-Abravanel, a
`
`review article summarizing the then-current progress in HCV treatment
`
`3
`
`

`

`
`
`
`
`
`
`IPR2018-00211
`Patent Owner’s Preliminary Response
`
`
`development, is, at best, cumulative and provides no new evidence or reason to
`
`revisit the Examiner’s analysis.
`
`The Board should deny the Petition.
`
`II. TECHNOLOGY BACKGROUND
`A.
`Standard of Care for Hepatitis C Virus at the Time of the Priority
`Filing
`Approximately 1.8% percent of the U.S. population possesses some
`
`evidence of HCV infection, with most of the cases being associated with “chronic
`
`active infection.” Ex. 1001 at 1:25-28. As of September 2011, when the priority
`
`application for the ’256 patent was filed, the “standard-of-care” treatment for HCV
`
`was pegylated interferon-α combined with ribavirin. Ex. 1001 at 2:39-46.
`
`Interferon does not directly fight the virus but, rather, acts as an indirect antiviral
`
`compound by boosting the host’s immune system response. Ex. 2002 at 69, 76. At
`
`the time, it was “administered weekly by subcutaneous injection for 24 to 48
`
`weeks, dependent upon the HCV viral genotype being treated.” Ex. 1001 at 2:1-5.
`
`Ribavirin was administered in combination with interferon and moderately
`
`improved overall treatment outcomes. Id. at 2:37-42.
`
`Although many patients initially saw some suppression of the virus under
`
`this standard of care, “a significant proportion of these patients [had] viral relapse.”
`
`Id. at 2:5-9, 2:42-44. Moreover, the interferon resulted in severe side effects,
`
`4
`
`

`

`
`
`
`
`
`
`IPR2018-00211
`Patent Owner’s Preliminary Response
`
`
`including “flu-like symptoms, thrombocytopenia, anemia, and serious psychiatric
`
`side effects.” Id. at 2:15-16. Thus, the standard of care as of 2011 was
`
`“suboptimal” due to its severe side effects, lack of efficacy against a range of HCV
`
`genotypes, and complicated dosing schedules. Id. at 2:17-21, 2:55-59.
`
`B. Other Anti-HCV Agents and Direct Acting Antiviral Agents
`To address the shortcomings in the standard of care, in the mid-2000s, a
`
`wide variety of compounds were investigated as potential anti-HCV agents,
`
`including several in clinical or pre-clinical trials. Ex. 2002 at 69, 74 tbl. 1, 77.
`
`These agents included various modified interferons, vaccines, antibodies,
`
`immunomodulators, direct antiviral small molecules, and antifibrotics. Id. at 74
`
`tbl. 1, 81. However, as of 2011, despite extensive research by academic
`
`institutions and pharmaceutical companies, it was far from clear which approach
`
`ultimately would lead to a successful HCV treatment.
`
`Direct acting antiviral (“DAA”) agents in anti-HCV therapy, as the name
`
`implies, directly interfere with the viral processing and replication mechanisms.
`
`Ex. 2002 at 69, 79. However, there were numerous different viral processes and
`
`proteins which presented potential targets for DAA-based therapy. By the mid-
`
`2000s, researchers had identified various classes of compounds, which were
`
`developed and studied for anti-HCV activity, including NS5A inhibitors,
`
`metalloprotease inhibitors, serine protease inhibitors, protease active-site mimics,
`
`5
`
`

`

`
`
`
`
`
`
`IPR2018-00211
`Patent Owner’s Preliminary Response
`
`
`polymerase inhibitors, helicase inhibitors, NS4B protein inhibitors, HCV entry
`
`inhibitors, HCV assembly inhibitors, HCV egress inhibitors, nucleoside analogs,
`
`non-nucleoside NS5B inhibitors, and IMPDH. See, e.g., Ex. 2003 at 3006; Ex.
`
`2004 at 45. While some researchers had reported that combinations of inhibitors
`
`with different viral targets may produce greater HCV viral load decreases, see e.g.,
`
`Ex. 2003 at 3006-07, there was no consensus in the published literature regarding
`
`which specific combination of compounds would effectively treat HCV. As of
`
`September 2011, there was no approved combination therapy having two or more
`
`DAA agents.
`
`Furthermore, as of 2011, there was no DAA-based therapy that eliminated
`
`the need for interferon or interferon-ribavirin combination. In fact, it was believed
`
`that DAA agents, even if approved, would need to be used in combination with the
`
`interferon-based standard of care for treating HCV. Ex. 1001 at 2:46-49; see also
`
`Ex. 2002 at 79, 85 (“We are convinced that direct antiviral compounds make an
`
`important addition to the existing therapies. Nevertheless, direct antiviral agents
`
`bear the risk of leading to the development of treatment-resistant viruses . . . . [W]e
`
`anticipate that direct antiviral drugs, such as NS5B inhibitors, will reach market
`
`approval and will be added to the [pegylated interferon-α]/ribavirin combination
`
`therapy.”).
`
`6
`
`

`

`
`
`
`
`
`
`IPR2018-00211
`Patent Owner’s Preliminary Response
`
`
`III. THE CLAIMED INVENTION
`A. Overview of the ’256 Patent
`The ’256 patent, titled “Methods of Treating HCV,” is directed to
`
`combinations of therapeutic compounds for the treatment of HCV. The ’256
`
`patent specification discloses the chemical structures of sixteen different
`
`compounds (identified as Compound 1, Compound 2, Compound 3, . . . Compound
`
`16); combinations including two or more of these compounds; methods of
`
`synthesizing these compounds; and methods of treating HCV infection using
`
`combinations of these compounds. Ex. 1001 at 5:19–110:41. Additionally, the
`
`specification discloses in vitro and in vivo biological data for these compounds,
`
`individually as well in combination with each other. Id. at 113:47–138:29.
`
`The ’256 patent claims focus on compound 6 and compound 10, shown
`
`below:
`
`Compound 10
`Compound 6
`The specification teaches that compound 6 is an NS5A inhibitor, and compound 10
`
`
`
`
`
`is an NS5B nucleoside prodrug. Id. at 134:55-65. Biological Example 7 in the
`
`7
`
`

`

`
`
`
`
`
`
`IPR2018-00211
`Patent Owner’s Preliminary Response
`
`
`specification describes a study examining the cross-resistance profiles of
`
`Compounds 6 and 10, with the results “indicat[ing] that resistance mutations for
`
`Compound 10 and Compound 6 do not demonstrate cross-resistance and
`
`support[ing] the use of these compounds in future combination therapy for the
`
`treatment of HCV.” Id. at 131:9-12. Biological Example 8 in the specification
`
`describes a study examining the antiviral effect of the combination of Compounds
`
`6 and 10. Id. at 131:15–135:5. The combination demonstrated “no significant
`
`cytotoxicity,” id. at 133:51-53, and antiviral activity for the combination was found
`
`to be “additive,” id. at 134:25-67. As further taught by the specification, the
`
`combination of compound 6 and compound 10 provides improved treatment for a
`
`“wide range of HCV genotypes” and “a Sustained Virologic Response (SVR) that
`
`is significantly higher than that achieved by current therapies,” without the
`
`negative side effects of interferon-based therapies. Id. at 4:55-67.
`
`Claim 1, the sole independent claim of the ’256 patent, recites:
`
`A method of treating an HCV infection in a human,
`comprising administering to the human: 1) compound 10
`[] or a pharmaceutically acceptable salt thereof and 2)
`compound 6 [] or a pharmaceutically acceptable salt
`thereof, wherein
`the method does not
`include
`administering interferon.
`
`8
`
`

`

`
`
`
`
`
`
`IPR2018-00211
`Patent Owner’s Preliminary Response
`
`
`Id. at 139:8–140:21 (chemical structures omitted). Dependent claim 2 recites that
`
`compound 10 and compound 6 are administered orally. Id. at 140:22-23.
`
`Dependent claim 3 recites that ribavirin is not also administered. Id. at 140:24-25;
`
`see also id. at p.95 (Certificate of Correction addressing typographical error in
`
`claim 3). Dependent claim 4 recites that ribavirin is also administered. Id. at
`
`140:26-27.
`
`Compound 6 is the compound ledipasvir. Compound 10 is the compound
`
`sofosbuvir. In 2014, the FDA approved the combination of ledipasvir and
`
`sofosbuvir as the drug Harvoni®. Harvoni® was the first once-a-day pill approved
`
`for the treatment of HCV and the first treatment to eliminate the need for
`
`interferon and ribavirin in genotype 1 HCV patients. See Ex. 2005.
`
`B.
`Prosecution History
`The ’256 patent originated from U.S. Application No. 13/875,252 (“the ’252
`
`application”), which was filed on May 1, 2013. The ’252 application claimed
`
`priority to U.S. Provisional Application Nos. 61/535,885 (filed September 16,
`
`2011), and 61/561,753 (filed November 18, 2011).
`
`During prosecution, the Examiner considered Delaney, Sofia ’634, and Guo
`
`and yet issued no prior art-based §§ 102/103 rejection. See Ex. 2001 at 16, 29, 32.
`
`Applicant overcame the Examiner’s obviousness-type double patenting rejections
`
`9
`
`

`

`
`
`
`
`
`
`IPR2018-00211
`Patent Owner’s Preliminary Response
`
`
`by filing a terminal disclaimer. The Examiner issued the Notice of Allowance on
`
`March 29, 2016.
`
`IV. PERSON OF ORDINARY SKILL IN THE ART
`Petitioner proposes that 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.” Paper 2 at 6.
`
`Patent Owner states that a POSA also would include, or would have access to, an
`
`individual with an M.D. who has experience developing or researching antiviral
`
`treatment methods, such as treatment for HCV, or experience treating viral
`
`infections such as HCV. Because the arguments herein apply equally and the
`
`claims are patentable regardless of which definition applies, for purposes of this
`
`Preliminary Response, Patent Owner takes no position on Petitioner’s proposed
`
`definition of a POSA.
`
`V. CLAIM CONSTRUCTION
`In an IPR proceeding, the terms of the challenged claims are to be given
`
`their broadest reasonable interpretation in light of the specification as commonly
`
`10
`
`

`

`
`
`IPR2018-00211
`Patent Owner’s Preliminary Response
`
`understood by those of ordinary skill in the art. See 37 C.F.R. § 42.100(b); Cuozzo
`
`
`
`
`
`Speed Techs., LLC v. Lee, 136 S. Ct. 2131 (2016). Petitioner does not propose a
`
`definition for any term. See Paper 2 at 7 (“[T]here is no reason to give any of the
`
`terms of the claims of the ’256 [patent] a meaning other than their ordinary and
`
`accustomed meaning.”). For purposes of this Preliminary Response, Patent Owner
`
`does not propose any claim construction. Therefore, the terms of the challenged
`
`claims should be given their ordinary and customary meaning. See In re
`
`Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007).
`
`VI. PETITIONER’S ASSERTED REFERENCES
`A. Legrand-Abravanel
`Legrand-Abravanel is a review article discussing anti-HCV compounds in
`
`preclinical or clinical development. Ex. 1005. Legrand-Abravanel generally
`
`describes NS5B polymerase inhibitors as including six different classes of
`
`compounds: (1) HCV nucleoside analogue polymerase inhibitors; (2) HCV
`
`nucleotide analogue polymerase inhibitors; (3) non-nucleoside inhibitors (“NNIs”)
`
`for site 1; (4) NNIs for site 2; (5) NNIs for site 3; and 6) NNIs for site 4. Id. at 2-
`
`6. As shown by Legrand-Abravanel, even when focusing only on compounds in
`
`preclinical or clinical trials for HCV treatment, there were a multitude of different
`
`anti-HCV agents in development. Id. at 1, 3 tbl. 1. Among the numerous
`
`compounds described, the nucleotide inhibitor PSI-7851 and its diastereomers PSI-
`
`11
`
`

`

`
`
`
`
`
`
`IPR2018-00211
`Patent Owner’s Preliminary Response
`
`
`7976 and PSI-7977 are mentioned. Id. at 4-5. However, Legrand-Abravanel does
`
`not disclose the chemical structures of these or any other compound discussed.
`
`Legrand-Abravanel states that, although “[c]ombination therapy with small-
`
`molecule inhibitors and without [interferon] is the ultimate goal,” “it is likely that
`
`pegylated [interferon] and ribavirin will remain the backbone of treatment for
`
`chronic HCV to prevent HCV resistance.” Id. at 8, 9 (emphasis added). Regarding
`
`combination therapy, Legrand-Abravanel does not recommend specific
`
`combinations of compounds or discuss whether certain types of combinations
`
`would be especially attractive for further study. Instead, Legrand-Abravanel only
`
`vaguely suggests that the NS5B polymerase inhibitors (including the more than
`
`twenty different agents shown in Table 1) and undisclosed numbers of “NS3
`
`protease inhibitors, NS3 helicase inhibitors, p7 inhibitors, NS5A inhibitors,
`
`cyclophilin inhibitors, and immunomodulators” “could be associated” in therapy,
`
`which results in at least thousands of different theoretical combinations. Id. at 9
`
`(end notes omitted). Indeed, Legrand-Abravanel itself concedes that these possible
`
`combinations “represent[] a huge field for investigation.” Id. (emphasis added).
`
`Furthermore, Legrand-Abravanel nowhere discloses compound 6 by chemical
`
`name, compound code, trade name, or chemical structure.
`
`12
`
`

`

`
`
`
`
`
`
`IPR2018-00211
`Patent Owner’s Preliminary Response
`
`
`B. Delaney
`Delaney is a U.S. patent application filed on June 10, 2011, and published on
`
`December 15, 2011.2 Ex. 1010. The application, titled “Methods for Treating
`
`HCV,” generally describes methods of treating HCV with one or more chemical
`
`compounds and ribavirin. Delaney broadly states that its anti-HCV compounds
`
`can be “an NS3 protease inhibitor, NS4B inhibitor nucleoside, NS5B polymerase
`
`inhibitor, nonnucleoside NS5B polymerase inhibitor, NS5A inhibitor, an HCV
`
`entry inhibitor, an HCV assembly inhibitor or an HCV infectivity inhibitor.” Ex.
`
`1010 at 3, ¶[0023]. Delaney discloses at least 17 examples of its anti-HCV
`
`compounds, including compound 16:
`
`Id. at 10-53.
`
`
`
`
`2 Patent Owner does not concede that Delaney is prior art. Nevertheless, for
`
`purposes of deciding whether to grant the Petition, it is not necessary to reach this
`
`issue because Petitioner’s arguments are deficient regardless of whether Delaney is
`
`or is not prior art.
`
`13
`
`

`

`
`
`IPR2018-00211
`Patent Owner’s Preliminary Response
`
`Delaney does not disclose any specific combinations including compound 16
`
`
`
`
`
`for treating HCV. Instead, Delaney merely states that “one or more compounds of
`
`the present invention may be combined with one or more compounds selected
`
`from the group consisting of” 11 different classes of compounds exemplified by at
`
`least 120 specific compounds. Id. at 8-9, ¶[0074] (emphasis added). Among the
`
`list of 11 different classes and 120 specific compounds, “PSI-7851” and “PSI-
`
`7977” are mentioned. Id. Thus, even assuming that a POSA would have chosen
`
`one of the 17 exemplified compounds for combination, Delaney teaches at least
`
`thousands of different possible combinations, a very small number of which may
`
`involve PSI-7977 or compound 16.3 Finally, each of the embodiments described in
`
`Delaney references the treatment of HCV necessarily with ribavirin. See, e.g., id.
`
`
`3 For instance, if a POSA were to select one compound from compounds 1-17
`
`disclosed in Delaney, and one compound from the 120 other identified compounds,
`
`there would have been 2,040 different possible combinations (17 x 120 = 2,040).
`
`If a POSA were to select one compound from compounds 1-17 disclosed in
`
`Delaney and two compounds from the 120 other identified compounds, there
`
`would have been 121,380 different possible combinations (17 x 120 x 119/2 =
`
`121,380).
`
`14
`
`

`

`
`
`
`
`
`
`IPR2018-00211
`Patent Owner’s Preliminary Response
`
`
`at 3, ¶¶[0012]-[0022]. Delaney does not teach or suggest the treatment of HCV in
`
`the absence of ribavirin.
`
`Delaney was cited during prosecution, considered by the Examiner, and is
`
`listed on the face of the patent. See Ex. 1001 at p.3 (citing application no.
`
`2011/0306541 A1, Delaney, IV et al.); Ex. 2001 at 32.
`
`C.
`Sofia ’634
`Sofia ’634 is a PCT application published on October 9, 2008. Ex. 1004.
`
`Sofia ’634 disclosed a genus of phosphoramidate nucleoside compounds having
`
`general formula I:
`
`
`
`wherein R1, R2, R3a, R3b, R4, R5, R6, and the base could vary among a list of
`
`possible chemical entities. Id. at 10-14. Sofia ’634 discloses the claimed
`
`compound 10. See id. at 696 (compound 25).
`
`Sofia ’634 states that its compounds of formula I can be co-administered
`
`with “another antiviral agent” including “interferon-, interferon-, pegylated
`
`interferon-.” Id. at 668. Sofia ‘634 thus contemplates the use of the disclosed
`
`compounds, including its compound 25 (corresponding to compound 10 in
`
`the ’256 patent), with interferon, consistent with the standard of care at the time.
`
`15
`
`

`

`
`
`
`
`
`
`IPR2018-00211
`Patent Owner’s Preliminary Response
`
`
`Sofia ’634 was cited during prosecution, considered by the Examiner, and
`
`listed on the face of the patent. See Ex. 1001 at p.4; Ex. 2001 at 16. Sofia ’634
`
`shares the same disclosure as U.S. Patent