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`IPR2018-00126
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`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)
`Samantak Ghosh (Reg. No. L1032)
`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
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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 IPR2018-00126
`Patent 9,284,342
`____________________________________________
`PATENT OWNER’S PRELIMINARY RESPONSE
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`I. 
`II. 
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`TABLE OF CONTENTS
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`Page
`INTRODUCTION ........................................................................................... 1 
`TECHNOLOGY BACKGROUND ................................................................. 3 
`A.  Sofosbuvir ...................................................................................................... 3 
`B.  Solid Forms of Pharmaceutical Compounds ................................................. 4 
`1. 
`Crystalline Forms .................................................................................. 5 
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`2. 
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`3. 
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`Characterization of Solid Form of Compounds .................................... 6 
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`Polymorphism Is Unpredictable ............................................................ 7 
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`III.  THE CLAIMED INVENTION ....................................................................... 9 
`A.  Overview of the ’342 Patent .......................................................................... 9 
`B.  Prosecution History ..................................................................................... 10 
`IV.  PERSON OF ORDINARY SKILL IN THE ART ........................................ 11 
`V. 
`CLAIM CONSTRUCTION .......................................................................... 12 
`VI.  PETITIONER’S ASSERTED PRIOR ART REFERENCES ....................... 13 
`A.  Sofia ’634 .................................................................................................... 13 
`B.  Sofia 2010 .................................................................................................... 14 
`C.  Clark ’147 .................................................................................................... 14 
`D.  Ma ................................................................................................................ 15 
`VII.  The PETITION SHOULD BE DENIED BECAUSE NO GROUND
`HAS A REASONABLE LIKELIHOOD OF SUCCESS .............................. 16 
`A.  Ground One: Claims 1-4 Are Not Obvious Over Sofia ‘634 and
`Sofia 2010 ................................................................................................. 16 
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`2. 
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`Sofia ’634 and Sofia 2010 Do Not Teach or Suggest the
`Claimed Crystalline Form of Sofosbuvir (SP-4) ................................. 16 
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`Petitioner Has Provided No Credible Argument for Motivation
`or Reasonable Expectation of Success in Preparing Crystalline
`Sofosbuvir with the Specified XRPD Reflections .............................. 20 
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`B.  Ground Two: Claims 1-4 Are Not Obvious Over Sofia ’634 in
`Combination with Ma ............................................................................... 30 
`Sofia ’634 in Combination with Ma Does Not Teach or Suggest
`the Claimed Crystalline Form of Sofosbuvir (SP-4) ........................... 30 
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`1. 
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`2. 
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`Petitioner Has Provided No Credible Argument for Motivation
`or Reasonable Expectation of Success in Preparing Crystalline
`Sofosbuvir with the Specified XRPD Reflections .............................. 31 
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`C.  Ground Three: Claims 1-4 Are Not Obvious over Clark ’147 in
`Combination with Ma ............................................................................... 33 
`Clark ’147 in Combination with Ma Does Not Teach or Suggest
`the Claimed Crystalline Form of Sofosbuvir (SP-4) ........................... 34 
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`1. 
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`2. 
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`Petitioner Has Provided No Credible Argument for Motivation
`or Reasonable Expectation of Success in Preparing Crystalline
`Sofosbuvir with the Specified XRPD Reflections .............................. 35 
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`VIII.  THE PETITION SHOULD BE DENIED UNDER 35 U.S.C. § 325(d) ....... 37 
`IX.  PRESERVATION OF RIGHTS UNDER OIL STATES ............................. 41 
`X. 
`CONCLUSION .............................................................................................. 42 
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`TABLE OF AUTHORITIES
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` Page(s)
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`Federal Cases
`Apotex Inc. v. OSI Pharmaceuticals., Inc.,
`No. IPR2016-01284, Paper 8 (P.T.A.B. Jan. 9, 2017) ....................................... 39
`Arendi S.A.R.L. v. Apple Inc.,
`832 F.3d 1355 (Fed. Cir. 2016) .......................................................................... 22
`In re Armodafinil Patent Litigation,
`939 F. Supp. 2d 456 (D. Del. 2013) .............................................................passim
`Astrazeneca AB v. Dr. Reddy’s Laboratories Inc.,
`No. 11-2317 (JAP), 2013 WL 1847639 (D.N.J. May 1, 2013) .......................... 19
`Bicon, Inc. v. Straumann Co.,
`441 F.3d 945 (Fed. Cir. 2006) ................................................................ 12, 13, 17
`Coalition for Affordable Drugs VII LLC v. Pozen Inc.,
`No. IPR2015-01344, 2015 Pat. App. LEXIS 12669 (P.T.A.B. Dec.
`17, 2015) ............................................................................................................. 18
`Cuozzo Speed Technologies, LLC v. Lee,
`136 S. Ct. 2131 (2016) ........................................................................................ 12
`In re Depomed Patent Litigation,
`No. CV 13-4507, 2016 WL 7163647 (D.N.J. Sept. 30, 2016) ................. 2, 23, 24
`Eisai Co. v. Dr. Reddy’s Laboratories, Ltd.,
`533 F.3d 1353 (Fed. Cir. 2008) .......................................................................... 24
`Fedex Corp. v. Intellectual Ventures II LLC,
`No. IPR2017-00750, 2017 WL 4349383 (P.T.A.B. Sept. 5, 2017) ................... 22
`Hospira, Inc. v. Genentech, Inc.,
`No. IPR2017-00739, 2017 Pat. App. LEXIS 10044 (P.T.A.B. July
`27, 2017) ............................................................................................................. 41
`Intelligent Bio-Systems, Inc. v. Illumina Cambridge Ltd.,
`821 F.3d 1359 (Fed. Cir. 2016) .......................................................................... 37
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`KSR International Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 24, 26
`Lupin Ltd. v. Janssen Sciences Ireland UC,
`No. IPR2015-01030, 2015 Pat. App. LEXIS 12746 (P.T.A.B. Oct.
`16, 2015) ......................................................................................................... 2, 29
`Medichem, S.A. v. Rolabo, S.L.,
`437 F.3d 1157 (Fed. Cir. 2006) .......................................................................... 28
`Merck & Cie v. Watson Laboratories, Inc.
`125 F. Supp. 3d 503 (D. Del. 2015), rev’d on other grounds, 822
`F.3d 1347 (Fed. Cir. 2016) ................................................................................. 22
`In re Miller,
`441 F.2d 689 (C.C.P.A. 1971) ............................................................................ 17
`Neil Ziegman, N.P.Z., Inc. v. Stephens,
`No. IPR2015-01860, 2016 Pat. App. LEXIS 1127 (P.T.A.B. Feb.
`24, 2016) ............................................................................................................. 40
`Oil States Energy Services, LLC v. Greene’s Energy Group, LLC,
`No. 16-712 (U.S. cert. granted June 12, 2017) ................................................... 41
`PAR Pharmaceutical, Inc. v. TWI Pharmaceuticals, Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .......................................................................... 20
`Pitney Bowes, Inc. v. Hewlett-Packard Co.,
`182 F.3d 1298 (Fed. Cir. 1999) .......................................................................... 13
`Prism Pharma Co. v. Choongwae Pharma Corp.,
`No. IPR2014-00315, 2014 Pat. App. LEXIS 4429 (P.T.A.B. July
`8, 2014) ............................................................................................................... 39
`SmithKline Beecham Corp. v. Apotex Corp.,
`403 F.3d 1331 (Fed. Cir. 2005) .......................................................................... 24
`Takeda Pharmaceutical Co. v. Handa Pharmaceuticals, LLC,
`No. C-11-00840 JCS, 2013 WL 9853725 (N.D. Cal. Oct. 17, 2013) ................ 25
`In re Translogic Technology, Inc.,
`504 F.3d 1249 (Fed. Cir. 2007) .......................................................................... 12
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`Unified Patents Inc. v. Berman,
`No. IPR2016-01571, 2016 Pat. App. LEXIS 13480 (P.T.A.B. Dec.
`14, 2016) ............................................................................................................. 39
`In re Wilson,
`424 F.2d 1382 (C.C.P.A. 1970) .................................................................... 12, 17
`Federal Statutes
`35 U.S.C. § 325(d) ................................................................................................... 37
`Regulations
`37 C.F.R. § 42.65(a) ................................................................................................. 18
`37 C.F.R. § 42.100(b) .............................................................................................. 12
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`INTRODUCTION
`The Board should deny this fundamentally flawed Petition at least for the
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`following reasons: it fails to address key claim limitations; it flouts well-
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`established law regarding non-obviousness of new crystalline forms; and it merely
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`repeats arguments overcome during prosecution without providing any new
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`evidence that can support reconsideration.
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`The ’342 patent relates to sofosbuvir (SP-4), a potent antiviral compound
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`included in Gilead’s hepatitis C treatments Sovaldi®, Harvoni®, Epclusa®, and
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`Vosevi®. The challenged claims are directed to a new crystalline form of
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`sofosbuvir (Form 6) characterized by specific XRPD 2θ-reflections. Petitioner
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`admits that the prior art does not disclose limitations of the challenged claims,
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`particularly the XRPD reflections characterizing Form 6. However, Petitioner
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`inexplicably asks the Board to ignore the recited XRPD reflections by arguing that
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`they are “of no scientific or technical significance.” Paper 2 at 36. The Board
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`should decline that invitation. It is black letter law that every limitation in a claim
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`should be accorded significance, as claim limitations define the metes and bounds
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`of the patented invention and the scope of the patent owner’s rights. In this case,
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`the XRPD reflections, which were unknown until the inventions of the ’342 patent,
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`are critical because they are the very limitations that represent the atomic
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`arrangement of the particular crystalline form claimed, which impacts the
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`physicochemical properties of the compound and differentiates the claimed
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`invention from the prior art.
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`Unable to present any credible evidence that the prior art teaches or suggests
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`the claimed crystalline polymorph of sofosbuvir, Petitioner argues that there was a
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`“general motivation” in the art to screen potential drug compounds for
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`polymorphism. See Paper 2 at 36-38. The same “obvious to try” arguments made
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`by Petitioner have been considered by courts and the Board and rightly rejected. In
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`finding claims directed to new crystalline forms non-obvious, courts and the Patent
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`Office have acknowledged that polymorphism is a “decidedly unpredictable field.”
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`In re Depomed Patent Litig., No. CV 13-4507 (CCC-MF), 2016 WL 7163647, at
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`*51, 54 (D.N.J. Sept. 30, 2016); see also Lupin Ltd. v. Janssen Scis. Ireland UC,
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`No. IPR2015-01030, 2015 Pat. App. LEXIS 12746, at *29 (P.T.A.B. Oct. 16,
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`2015) (acknowledging “the demonstrated unpredictability in the field of hydrate
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`formation”). Courts have concluded that a general motivation to identify new
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`polymorphs is not enough to establish obviousness of a specific crystalline form.
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`See, e.g., In re Armodafinil Patent Litig., 939 F. Supp. 2d 456, 500 (D. Del. 2013)
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`(finding the claimed crystalline form non-obvious “because there was no more than
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`a general motivation to find new crystal forms of [the drug] with nothing directed
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`to the unknown [polymorph] itself”). Petitioner provides no reason to deviate from
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`this settled case law.
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`Finally, because each of Petitioner’s asserted grounds for unpatentability
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`relies on the same or substantially similar art and arguments that were overcome
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`during the prosecution of the ’342 patent, the Board should exercise its discretion
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`to deny the Petition under 35 U.S.C. § 325(d). All of the prior art references
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`asserted by Petitioner were disclosed during prosecution, and listed among the
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`cited references for the ’342 patent. Sofia ’634 (Grounds One and Two) was
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`expressly considered and remarked upon by the Examiner in allowing the claims.
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`See Ex. 1001 at 4:55-59; Ex. 1004 at 183-84. The other prior art references are
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`substantially similar, and therefore cumulative. The Petition presents the same or
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`even weaker arguments than those considered and overcome during prosecution,
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`without identifying any new teaching that was not already before the Examiner. In
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`such circumstances, it is appropriate for the Board to reject the Petition pursuant to
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`35 U.S.C. § 325(d).
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`II. TECHNOLOGY BACKGROUND
`A.
`Sofosbuvir
`Sofosbuvir is a potent antiviral agent discovered by Pharmasset, developed
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`by Gilead, and approved by the U.S. Food and Drug Administration (FDA) for
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`treatment of HCV in Gilead’s products Sovaldi®, Harvoni®, Epclusa®, and
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`Vosevi®. Sofosbuvir’s approval in December 2013 was hailed throughout the
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`scientific and popular press, including the front pages of the New York Times and
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`Wall Street Journal, and was recognized as a “game changer” for the treatment of
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`HCV. See Ex. 2001; Ex. 2002; Ex. 2003. The molecular structure of sofosbuvir is
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`shown below. It has a prodrug portion comprising a phosphoramidate moiety,
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`which is attached to a nucleoside analog. See Ex. 1001 at 37:20-23.
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`The ’342 patent claims a novel and advantageously stable, non-hygroscopic
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`crystalline form of sofosbuvir, Form 6. See Ex. 1001 at 76:10-43, 89:42-59; see
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`also id. Ex. 2004 at 8:50-56. This crystalline form is the form of sofosbuvir used
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`in commercial products, such as Sovaldi®. The ’342 patent discloses a total of six
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`crystalline forms of sofosbuvir, identified as Forms 1-6. Subsequently, two other
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`crystalline forms, identified as Forms 7 and 8 were discovered. See Ex. 2005.
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`B.
`Solid Forms of Pharmaceutical Compounds
`A given chemical compound, including an active pharmaceutical ingredient,
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`may exist in multiple solid-state forms, depending on how the molecules of the
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`compound are arranged in three-dimensional space. Solid state forms may include
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`crystalline and amorphous forms.
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`1.
`Crystalline Forms
`A crystalline solid has a regularly repeating three-dimensional structure, also
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`referred to as “three-dimensional long-range order.”1 See Ex. 2006 at 1. The
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`smallest repeating unit in a crystal structure is the “unit cell,” which is the
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`fundamental building block of that crystalline material. A compound may be
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`capable of crystallizing in more than one crystal structure—a phenomenon known
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`as polymorphism. See id. Some compounds also may crystallize in different
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`solvated forms, wherein one or more molecules of a solvent become incorporated
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`into the crystal structure. See id. The different crystalline forms that a compound
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`can take are known as “polymorphs.”
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`Because of the intimate relationship between a compound’s three-
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`dimensional structure and its properties, different solid forms of a compound can,
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`and often do, exhibit different properties. See id.
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`1 In contrast, amorphous solids lack such three-dimensional long-range order. See
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`Ex. 2006 at 1.
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`2.
`Characterization of Solid Form of Compounds
`Numerous analytical methods are available to characterize and differentiate
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`solid forms of compounds. See generally Ex. 2007 at 21-81. These methods
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`include microscopy, crystallography, spectroscopy, and thermal analysis. See id.
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`X-ray powder diffraction (“XRPD”), a crystallographic method, is one of the most
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`commonly used methods for identifying and distinguishing polymorphs. See id. at
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`38-39.
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`The challenged claims recite XRPD “2θ-reflections” that uniquely
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`differentiate the specific crystalline form of sofosbuvir known as “Form 6” from
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`other known crystalline forms of this compound. XRPD involves directing X-rays
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`at a powdered sample of the material and observing the diffraction pattern of the
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`X-rays. The resulting X-ray diffraction pattern (or “diffractogram”) is prepared by
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`plotting the intensity of the diffraction reflections against their 2θ diffraction
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`angles. See id. at 38-56. These plots appear in the form of intensity peaks
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`corresponding to the 2θ diffraction angles (see figure below), and are commonly
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`referred to as XRPD “peaks.” See id.
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`XRPD Diffractogram
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`The XRPD diffractogram is often referred to as a “fingerprint” of a
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`crystalline structure that uniquely identifies that structure. Id. at 39. A subset of
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`XRPD reflections also may be used for characterizing a particular crystalline form.
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`Id. at 48-50.
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`3.
`Polymorphism Is Unpredictable
`While many pharmaceutical compounds have been found to exist in a
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`number of different solid forms, each compound presents a unique situation
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`regarding polymorphs. For example, it is impossible to predict with any degree of
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`confidence if a substance will be polymorphic at all, let alone which particular
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`crystalline form(s) might exist; which might be stable under various conditions
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`(such as those relevant to the manufacture, shipment, and storage of a
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`medicament); and how they might be obtained on either a research or commercial
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`scale. See, e.g., Ex. 2007 at 11 (“The predicted existence of any particular
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`polymorphic structure for a single compound, the conditions and methods required
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`to obtain it, and the properties it will exhibit are still problems that will challenge
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`researchers for many years to come.”). Similarly, even knowing that one or more
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`crystalline forms of a compound exist, it is not possible to predict each form’s
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`properties—such as relative stability, solubility, or tendency to convert to other
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`forms—or the likelihood that any additional forms may exist. See id.
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`It is generally understood that numerous factors impact whether a crystalline
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`form would be generated and what specific form would be produced, including
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`“solvent system (pH level, temperature, type of solvent, polarity, evaporation or
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`solvent removal conditions); mixing/stirring conditions (time, speed, type of
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`equipment, temperature); and ways in which the solvent is removed or permitted to
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`evaporate, including drying conditions (temperature, pressure, time).” See Ex.
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`2009 at 21 (citing various articles from scientific journals). Moreover, “[t]here is
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`no standard strategy or foolproof recipe for the search of crystal forms.” See id. at
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`23 (citation omitted); see also Ex. 2007 at 79 (“[M]ost polymorphs have been
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`discovered by serendipity, rather than as the result of a systematic search.”). As
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`such, it is well understood that “polymorphism is inherently unpredictable.” In re
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`Armodafinil, 939 F. Supp. 2d at 491.
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`III. THE CLAIMED INVENTION
`A. Overview of the ’342 Patent
`The ’342 patent, titled “Nucleoside Phosphoramidates,” is directed generally
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`to the treatment of HCV infection. The ’342 patent specification discloses a
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`compound represented by formula 4 and its respective phosphorus-based
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`diastereomers represented by formulas SP-4 and RP-4. Ex. 1001 at 4:65-5:34. The
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`chemical structures are shown below:
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`The compound of formula SP-4 is sofosbuvir.
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`The ’342 patent discloses six crystalline forms of SP-4, identified as Forms
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`1-6. The challenged claims recite XRPD 2θ-reflections that are uniquely attributed
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`to Form 6. The specification characterizes Form 6, including by X-ray powder
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`diffraction, and describes specific methods for preparing Form 6. See Ex. 1001 at
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`73:10-50, 76:10-43, 82:1-11, 82:41-42.
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`Claim 1, the sole independent claim, reads as follows:
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`A crystalline compound represented by the formula (SP-
`4):
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`having XRPD 2θ-reflections (°) at about: 6.1 and 12.7.
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`Ex. 1001 at 89:42-59. These XRPD reflections are associated with Form 6 of
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`sofosbuvir. See Ex. 1001 at 76:10-43 (Ex. 21-5); see also id. Fig. 21. The
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`challenged dependent claims are directed to a pharmaceutical composition (claim
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`2) and methods of treating HCV (claims 3 and 4) using the crystalline compound
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`of claim 1.
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`B.
`Prosecution History
`The ’342 patent originated from U.S. Application No. 13/925,078 (“the ’078
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`application”), which was filed on June 24, 2013. During prosecution of the ’078
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`application, the Examiner issued no art-based §§ 102/103 rejections, even after
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`considering dozens of cited references, including WO 2008/121634 (“Sofia ’634”),
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`which was cited in the specification. See generally Ex. 1004 at 178-185; see also
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`Ex. 1001 at 4:55-59. The Examiner issued a Notice of Allowance concluding that
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`“[t]he claimed invention is seen to be novel and non-obvious,” as “[t]he prior art
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`claimed XRPD peaks.” Ex. 1004 at 183. The Examiner specifically considered
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`and distinguished the teaching of Sofia ’634. See id. at 183-84. While Sofia ’634
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`discloses a compound having the same chemical formula as the SP-4 compound,
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`the Examiner correctly stated: “References to the claimed compound in the prior
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`art (see for example Sofia [’634], . . . ) [do] not disclose the specific crystal
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`structure described in the claims, or a method of preparing a crystalline form of the
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`compound that would have resulted in that particular crystal.” Id. Moreover, the
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`Examiner stated that, “[b]ecause of the unpredictability of crystalline polymorphs,
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`one of ordinary skill in the art would not have been able to, based on the prior art
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`disclosure, predict or make this particular crystal form.” Id. at 184.
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`IV. PERSON OF ORDINARY SKILL IN THE ART
`A person of ordinary skill in the art (“POSA”) would have at least a
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`bachelor’s degree in chemistry, pharmaceutical sciences or a related discipline,
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`along with experience working in pharmaceutical solid product development
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`and/or solid-state chemistry. Additionally, a POSA would have knowledge and
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`experience, and/or access to others with knowledge and experience, in developing
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`antiviral drugs.
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`Petitioner’s definition of a POSA is flawed because it does not require any
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`experience in solid-state chemistry, which is the focus of the ’342 patent claims
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`and its claims reciting XRPD 2θ-reflections. The differences in the parties’
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`definitions of a POSA, however, do not affect any of the arguments discussed
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`below, and the claims are patentable even under Petitioner’s proposed definition.
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`V. CLAIM CONSTRUCTION
`In an IPR proceeding, the terms of the challenged claims are to be given
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`their broadest reasonable interpretation in light of the specification as commonly
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`understood by those of ordinary skill in the art. See 37 C.F.R. § 42.100(b); Cuozzo
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`Speed Techs., LLC v. Lee, 136 S. Ct. 2131 (2016). Petitioner does not propose a
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`definition for any term. See Paper 2 at 8 (“[T]here is no reason to give any of the
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`terms of the claims of the ’342 [patent] a meaning other than their ordinary and
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`accustomed meaning.”). For the purposes of this Preliminary Response, Patent
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`Owner does not propose any claim construction. Hence, the terms of the
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`challenged claims should be given their ordinary and customary meaning. See In
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`re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007).
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`As discussed below, however, many of Petitioner’s arguments seek to ignore
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`or render meaningless certain claim limitations. Although not specifically labeled
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`“claim construction” arguments, these assertions contravene the well-established
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`canon that “claims are interpreted with an eye toward giving effect to all terms in
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`the claim.” See Bicon, Inc. v. Straumann Co., 441 F.3d 945, 950 (Fed. Cir. 2006);
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`see also In re Wilson, 424 F.2d 1382, 1385 (C.C.P.A. 1970) (“All words in a claim
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`must be considered in judging the patentability of that claim against the prior art.”).
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`According to these established principles, all limitations in the challenged claims
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`must be given weight and meaning. See Bicon, 441 F.3d at 950; cf. Pitney Bowes,
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`Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305 (Fed. Cir. 1999) (explaining that
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`a claim preamble constitutes a claim limitation—and must be given patentable
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`weight—when it helps define the “complete invention” or “is ‘necessary to give
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`life, meaning, and vitality’ to the claim” (quoting Kropa v. Robie, 187 F.2d 150,
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`152 (C.C.P.A. 1951))). Petitioner should not be permitted to simply ignore claim
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`terms it finds inconvenient.
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`VI. PETITIONER’S ASSERTED PRIOR ART REFERENCES
`A.
`Sofia ’634
`Sofia ’634 is a PCT application published on October 9, 2008. Ex. 1005.
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`Sofia ’634 expressly discloses sofosbuvir. Id. at 696 (compound 25). But it does
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`not provide any teaching or suggestion about whether sofosbuvir exists in
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`crystalline or amorphous forms, how many crystalline forms exist, or how to make
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`any crystalline forms, let alone the particular crystalline form claimed in the ‘342
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`patent. Sofia ’634 was specifically cited in the specification of the ‘342 patent, and
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`the Examiner expressly distinguished its teachings in the Notice of Allowance,
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`concluding that “[t]he claimed invention is seen to be novel and non-obvious,” as
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`“[t]he prior art does not disclose a crystalline composition of the claimed
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`compound having the claimed XRPD peaks.” Ex. 1004 at 183; see also Ex. 1001
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`at 4:55-59; Section III.B supra.
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`B.
`Sofia 2010
`Sofia 2010 is directed to the development of phosphoramidate prodrugs of
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`β-D-2’-Deoxy-2’-α-fluoro-2’-β-C-methyluridine. Ex. 1014. It also discloses
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`sofosbuvir, and the methylene chloride solvate of sofosbuvir. Id. at 8-9 (compound
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`51). Sofia 2010 explains that “[t]his [was] the first demonstrated crystallization
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`and X-ray structure determination of a phosphoramidate nucleotide prodrug.” Id.
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`at 8. Sofia 2010 does not disclose Form 6; in fact, it does not disclose any
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`crystalline form of sofosbuvir other than the methylene chloride solvate. Sofia
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`2010 was identified by the Applicant during prosecution and is listed among the
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`cited references on the ’342 patent. See Ex. 1001 at 8.
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`C. Clark ’147
`Clark ’147 is directed to the study of β-D-2’-Deoxy-2’-α-fluoro-2’-β-C-
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`methyl nucleosides in the treatment of HCV. See Ex. 1007. Clark ’147 discloses
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`the following genus for a nucleoside analog:
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`Ex. 1007 at 102. Clark ’147 states generally that this genus of nucleoside analogs
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`encompassed pharmaceutically acceptable salts or prodrugs thereof, id., but does
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`not teach sofosbuvir, let alone any crystalline forms of sofosbuvir. Clark ’147 was
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`identified by the Applicant during the prosecution and is listed among the cited
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`references on the ’342 patent. See Ex. 1001 at 2.
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`D. Ma
`Ma is directed to the study of the metabolism and mechanism of action of
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`PSI-6130, shown below, a cytidine analog of β-D-2’-Deoxy-2’-α-fluoro-2’-β-C-
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`methyluridine (RO2433). See Ex. 1010.
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`PSI-6130
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`Like Clark ‘147, Ma does not disclose sofosbuvir, let alone any crystalline form of
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`this compound. Moreover, Ma was identified by the Applicant during the
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`prosecution, and is listed among the cited references on the ‘342 patent. See Ex.
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`1001 at 8.
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`VII. THE PETITION SHOULD BE DENIED BECAUSE NO GROUND
`HAS A REASONABLE LIKELIHOOD OF SUCCESS
`The claims of the ’342 patent recite different crystalline forms of sofosbuvir
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`(SP-4), as characterized by particular XRPD 2θ-reflections. Yet Petitioner does not
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`even attempt to argue that any reference included in its asserted grounds of
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`unpatentability teaches crystalline sofosbuvir as claimed, or suggests the specific
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`claimed XRPD reflections. Instead, Petitioner improperly urges the Board simply
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`to ignore these claim limitations, and to find the claims unpatentable solely on the
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`basis that crystalline forms generally would have been obvious. Petitioner also
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`repeats unpersuasive arguments about a “general motivation” to discover new
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`crystalline forms of a drug—arguments that courts and the Board have consistently
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`and categorically rejected. Compounding these fatal flaws, Petitioner fails to
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`provide any credible argument for a reasonable expectation of success in preparing
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`crystalline sofosbuvir having the claimed XRPD 2θ-reflections. As such, the
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`Petition should be denied because each of the grounds is fundamentally deficient.
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`A. Ground One: Claims 1-4 Are Not Obvious Over Sofia ‘634 and
`Sofia 2010
`1.
`Sofia ’634 and Sofia 2010 Do Not Teach or Suggest the
`Claimed Crystalline Form of Sofosbuvir (SP-4)
`Petitioner acknowledges that Sofia ’634 does not teach the claimed
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`crystalline form of sofosbuvir. Paper 2 at 36. Petitioner also does not contend that
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`Sofia 2010 teaches or suggests crystalline sofosbuvir having the recited XRPD
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`reflections. Nor could it: neither of these references teaches or suggests Form 6 of
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`sofosbuvir, or a crystalline form of sofosbuvir characterized by the recited XRPD
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`reflections. In fact, Petitioner admits that “a POSA would not have been able to
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`predict this exact recitation of [] XRPD 2θ-reflections.” Id. Thus, Petitioner
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`concedes that the prior art neither teaches nor suggests the claimed XRPD 2θ-
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`reflections. The Petition should be denied on this basis alone.
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`Neverthe