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. IPR2018-00126
`U.S. Patent No. 9,284,342
`
`___________
`
`PETITION FOR INTER PARTES REVIEW
`
`
`___________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
`
`INITIATIVE FOR MEDICINES, ACCESS & KNOWLEDGE (I-MAK), INC.
`Petitioner
`
`v.
`
`GILEAD PHARMASSET LLC
`Patent Owner
`
`___________
`
`Case No. IPR2018-00126
`U.S. Patent No. 9,284,342
`
`___________
`
`PETITION FOR INTER PARTES REVIEW
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ........................................................................................1
`
`II. MANDATORY NOTICES...........................................................................1
`
`A.
`
`B.
`
`C.
`
`D.
`
`Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1)) .................................1
`
`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...............................................................3
`
`A.
`
`B.
`
`Grounds For Standing.........................................................................3
`
`Identification of Challenge..................................................................3
`
`IV. OVERVIEW OF THE ‘342 PATENT ..........................................................4
`
`V.
`
`VI.
`
`FILE HISTORY OF THE ‘342 PATENT.....................................................5
`
`PERSON OF ORDINARY SKILL IN THE ART.........................................6
`
`VII. CLAIM CONSTRUCTION..........................................................................8
`
`VIII. BACKGROUND KNOWLEDGE IN THE ART..........................................8
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`Nucleoside Analog Drugs Inhibited Viral Diseases.............................9
`
`Some Nucleoside Drugs Were Poor Substrates for Phosphorylation .13
`
`Compound 1D Was a Superior Agent Against HCV, But a Poor
`Substrate for Phosphorylation ..........................................................14
`
`ProTide Prodrugs of Nucleosides Were Well-Known to Overcome the
`Problem of Poor Phosphorylation .....................................................14
`
`ProTide Prodrugs Were Diastereomeric at Phosphorous and Such
`Diastereomers Could Possess Different Biological Activity..............16
`
`i
`
`
`
`F.
`
`G.
`
`H.
`
`ProTide Analogs of Compound 1D Were Active Against HCV........17
`
`Pharmaceutical Solids Could Exist in Multiple Forms ......................20
`
`A Solid-State and Polymorph Screen Would Always Evaluate the
`Interactions of Water with a New Drug Candidate............................21
`
`IX.
`
`SCOPE AND CONTENT OF THE PRIOR ART .......................................23
`
`A. WO 2008/121634 to Sophia (“Sophia ‘634”)....................................23
`
`B. WO 2005/003147 to Clark (“Clark”) ................................................26
`
`C.
`
`Sofia et. al., “Discovery of a b-D-2’-Deoxy-2’-a-fluoro-2’-b-C-
`methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of
`Hepatitis C Virus” J. Med. Chem., 2010, 53, 7202-7218 (“Sofia
`2010")...............................................................................................28
`
`D. Ma et. al., “Characterization of the Metabolic Activation of Hepatitis
`C Virus Nucleoside Inhibitor b-D-2’-Deoxy-2’-Fluoro-2’-C-
`methylcytidine (PSI-6130) and Identification of a Novel 5’-
`Triphosphate Species” J. Biol. Chem., 2007, 282(41), 29812-29820
`(Ma)..................................................................................................30
`
`X.
`
`CLAIMS 1-4 ARE UNPATENTABLE ......................................................32
`
`A.
`
`B.
`
`C.
`
`Ground 1: Claims 1-4 Were Obvious Over Sofia ‘634 and Sofia 201032
`
`Ground 2: Claims 1-4 Were Obvious Over Sofia ‘634 and Ma .........39
`
`Ground 3: Claims 1-4 Were Obvious Over Clark ‘147 and Ma.........45
`
`XI. CONCLUSION ..........................................................................................51
`
`XII. APPENDIX – LIST OF EXHIBITS............................................................53
`
`XIII. CERTIFICATE OF COMPLIANCE ..........................................................55
`
`XIV. CERTIFICATE OF SERVICE....................................................................56
`
`ii
`
`
`
`I.
`
`INTRODUCTION
`
`Initiative for Medicines, Access & Knowledge (I-MAK), Inc. (“Petitioner”)
`
`requests inter partes review (“IPR”) of claims 1-4 of United States Patent No.
`
`9,284,342 to Ross et al. (“the ‘342 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 ’342 patent issued on March 15, 2016, and is currently
`
`assigned to Gilead Pharmasset LLC (“Patent Owner”). This petition demonstrates
`
`that claims 1-4 of the ’342 patent are unpatentable.
`
`The ‘342 patent claims a pharmaceutical compound, composition and
`
`methods that were obvious in light of the prior art. Specifically, the ‘342 claims a
`
`particular crystalline form of a specific nucleoside compound that was already
`
`known, because it was the subject of a previous patent application by Patent
`
`Owner. In addition, investigating crystalline forms of a nucleoside compound to
`
`determine if one is more active was entirely conventional and expected. Identifying
`
`a specific crystalline form of a known nucleoside is not inventive, but obvious.
`
`Thus, claims 1-4 of the ‘342 patent are unpatentable and should be
`
`cancelled.
`
`II. MANDATORY NOTICES
`
`A.
`
`Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1))
`
`The real parties-in-interest for this petition are Initiative for Medicines,
`
`1
`
`
`
`Access & Knowledge (I-MAK), Inc., and the Laura and John Arnold Foundation.
`
`B.
`
`Related Matters (37 C.F.R. § 42.8(b)(2))
`
`Petitioner recently filed a petition for Inter Partes Review of U.S. Patent No.
`
`8,633,309, which relates to the ‘342 patent. Case No. IPR2018-00125. Petitioner is
`
`not aware of any other matter that would affect, or be affected by, a decision in this
`
`proceeding.
`
`C.
`
`Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3))
`
`Petitioner designates Daniel B. Ravicher (Reg. No. 47,015) as lead counsel.
`
`Petitioner is a not-for-profit public charity of limited resources and has been unable
`
`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
`dan@ravicher.com
`Email:
`Telephone: 786-505-1205
`
`Petitioner consents to service by email to dan@ravicher.com.
`
`2
`
`
`
`III. REQUIREMENTS FOR REVIEW
`
`A. Grounds for Standing
`
`Petitioner certifies that the ’342 patent is available for inter partes review
`
`and that Petitioner is not barred or estopped from requesting the inter partes review
`
`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 1-4 of the ’342 patent
`
`based on the following grounds:
`
`# Claims
`1
`1-4
`2
`1-4
`3
`1-4
`
`35 U.S.C. §
`103(a)
`103(a)
`103(a)
`
`Prior Art
`Sofia ‘634 and Sofia 2010
`Sofia ‘634 and Ma
`Clark ‘147 and Ma
`
`This Petition is supported by the declaration of Joseph M. Fortunak, Ph.D.
`
`(EX1002). 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,
`
`3
`
`
`
`establish a reasonable likelihood that Petitioner will prevail with respect
`
`to
`
`cancellation of the challenged claims. See 35 U.S.C. § 314(a).
`
`IV. OVERVIEW OF THE ‘342 PATENT
`
`The ‘342 patent claims a crystalline compound represented by the following
`
`formula:
`
`EX1001 at 89:42-58.
`
`In describing the claimed invention, the ‘342 patent states:
`
`Disclosed herein are nucleoside phosphoramidates and their use as
`agents for treating viral disease. These compounds are inhibitors of
`RNA-dependent RNA viral replication and are useful as inhibitors of
`HCV NS5B polymerase, as inhibitors of HCV replication and for
`treatment of hepatitis C infection in mammals.
`
`EX1001 at 1 (Abstract).
`
`The '342 patent discloses that form 6 of the SP-4 compound is the form with
`
`4
`
`
`
`XRPD 2Ɵ-reflections (o) at about: 6.1 and 12.7. EX1001 at 76:9-42. The '342
`
`patent also discloses that there are at least two ways that the crystalline form 6 of
`
`SP-4 can be obtained from form 1 of the same compound: 1) suspension in water
`
`(at 5-50 mg/mL) at ambient temperature for a few hours; and 2) grinding followed
`
`by slow conversion to form 6 upon standing exposed to atmospheric humidity.
`
`EX1001 at 73:10-50.
`
`The following chart describes claims 1-4 of the ‘342 patent:
`
`Claim(s)
`
`Recite
`
`1
`
`2
`
`3, 4
`
`Crystalline compound represented by the formula above having
`XRPD 2Ɵ-reflections (o) at about: 6.1 and 12.7.
`
`Pharmaceutical composition having the crystalline compound of
`claim 1 and a pharmaceutically acceptable medium.
`
`Method of treating a hepatitis C virus infection in a human by
`administering the compound of claim 1, alone or with another
`antiviral agent.
`
`V.
`
`FILE HISTORY OF THE ‘342 PATENT
`
`U.S. Patent Application No. 13/925,078 (“the ‘078 application) was filed on
`
`June 24, 2013, and issued as the ‘342 patent on March 15, 2016. The ‘078
`
`application claimed priority as a continuation of U.S. Patent Application No.
`
`13/076,552 (“the ‘552 application”) filed on Mar. 31, 2011, which claimed priority
`
`as a continuation-in-part of U.S. Patent Application No. 12/783,680 (“the ‘680
`
`application”) filed on May 20, 2010. The ‘078 application also claimed priority to
`
`5
`
`
`
`U.S. Provisional Applications Nos. 61/319,513 and 61/319,548, both of which
`
`were filed on Mar. 31, 2010, and U.S. Provisional Application 61/179,923 filed on
`
`May 20, 2009.
`
`During prosecution of the ‘078 application, the Examiner made a single
`
`substantive rejection of double patenting, which the Patent Owner overcame by
`
`submitting a terminal disclaimer. EX1004 at 175. The Examiner then issued a
`
`Notice of Allowance stating in part:
`
`The claimed invention is seen to be novel and non-obvious over
`the prior art. The prior art does not disclose a crystalline composition
`of the claimed compound having the claimed XRPD peaks.
`References to the claimed compound in the prior art (see for example
`Sofia et al. WO2008/121634, reference included with PTO-1449) do
`not disclose the specific crystal structure described in the claims, or a
`method of preparing a crystalline form of the compound that would
`have resulted in that particular crystal. Because of the unpredictability
`of crystalline polymorphs, one of ordinary skill in the art would not
`have been able to, based on the prior art disclosure, predict or make
`this particular crystal form.
`While the prior art reference US8916538 (cited in PTO-892)
`discloses a crystalline 2'-C-methyluridine-N-alanyl phosphoramidite
`having an x-ray powder diffraction pattern with peaks similar to those
`described in the claims, the compound is a thiophosphate, and
`additionally lacks the 2'-fluoro group of the claimed compound. One
`of ordinary skill in the art would have had no motivation to modify
`
`6
`
`
`
`this compound by substituting these groups to produce the claimed
`compound.
`For these reasons the claims are seen to meet the requirements
`of 35 USC 102 and 103.
`
`EX1004 at 183-184.
`
`As discussed below, the Examiner’s conclusion that the failure of the prior
`
`art to expressly disclose a crystalline composition having the claimed XRPD peaks
`
`rendered the claims not obvious was incorrect. EX1002 at ¶30. While that may be
`
`a basis to conclude the specific crystal structure claimed in the ‘342 patent was
`
`novel, it is not a basis to conclude it was also not obvious. Id.
`
`During prosecution the Examiner expressly discussed priority of the ‘078
`
`application, finding:
`
`The parent application 12/783680, and its provisional applications
`61/319513, 61/319548, and 61/179923, fail to provide support for the
`claimed invention as they do not include a written description under
`35 USC 112 of a crystalline compound having the claimed x-ray
`diffraction peaks. Therefore the effective filing date of the present
`application is the filing date of the parent application 13/076552, filed
`March 31, 2011.
`
`EX1004 at 169. Patent Owner never took issue with these findings.
`
`VI. PERSON OF ORDINARY SKILL IN THE ART
`
`Because the ‘342 patent pertains to nucleoside compounds, a POSA would
`
`have either (1) a Ph.D. in chemistry or a closely related field with some experience
`
`7
`
`
`
`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. EX1002 at ¶38
`
`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 ‘342 patent provides definitions for certain claim terms, but these
`
`definitions are conventional. EX1002 at ¶40. Thus, there is no reason to give any
`
`of the terms of the claims of the ‘342 a meaning other than their ordinary and
`
`accustomed meaning. Id.
`
`VIII. BACKGROUND KNOWLEDGE IN THE ART
`
`The background discussed below reflects knowledge skilled artisans would
`
`8
`
`
`
`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 March 31, 2011.
`
`A. Nucleoside Analog Drugs Inhibited Viral Diseases
`
`Nucleosides were well-known to be found as structural components in
`
`deoxy-ribonucleic acids (DNA) or ribonucleic acids (RNA). EX1002 at ¶42.
`
`Nucleosides are glycosylamines composed of a five-carbon sugar linked to what is
`
`known as a nitrogenous base. Id. Adenine, cytosine, guanine, thymine, and uracil
`
`are naturally-occurring nitrogenous bases. Id. Naturally-occurring, five-carbon
`
`sugar rings include ribose and deoxyribose. Id. The following table shows
`
`structures for these nitrogenous bases as well as the respective products of linking
`
`these bases to ribose and deoxyribose sugar rings. Id.
`
`9
`
`
`
`Nitrogenous Base
`
`Ribose Derivative
`
`Deoxyribose Derivative
`
`Adenine
`
`Guanine
`
`Adenosine (A)
`
`Deoxyadenosine (dA)
`
`Guanosine (G)
`
`Deoxyguanosine (dG)
`
`Thymine
`
`5-Methyluridine (m5U)
`
`Thymidine (dT)
`
`Uracil
`
`Cytosine
`
`Uridine (U)
`
`Deoxyuridine (dU)
`
`Cytidine (C)
`
`Deoxycytidine (dC)
`
`It was also well known that analogs of naturally-occurring nucleosides were
`
`10
`
`
`
`attractive targets for drug discovery and that such analogs were routinely used to
`
`treat diseases including viral infections and cancers. EX1002 at ¶43. Examples of
`
`such drugs included idoxuridine (antiviral) and gemcitabine for the treatment of
`
`cancer. Id. Additional examples of nucleoside drugs for the treatment of viral
`
`diseases included azidothymidine (AZT), stavudine (d4T), and lamivudine (3TC)
`
`for the treatment of viral infections and particularly HIV. Id. Ribavirin is another
`
`nucleoside analog used for the treatment of viral diseases including hepatitis C
`
`viral infections. Id.
`
`Acyclic nucleoside analogs were also known for the treatment of viral
`
`diseases. EX1002 at ¶44. Such drugs included aciclovir, tenofovir disoproxil
`
`fumarate (TDF) and tenofovir alafenamide fumarate (TAF) for the treatment of
`
`HIV and hepatitis B viral infections. Id. Both TDF and TAF are prodrugs of the
`
`nucleotide analog tenofovir/PMPA. Id. TAF is a ProTide™ phosphonamidate
`
`prodrug of PMPA. Id. The phosphorous diastereomers of TAF were known as of
`
`2001 to possess approximately a 10-fold difference in antiviral activity against
`
`HIV. Id.; Chapman, “Practical synthesis, separation, and stereochemical
`
`assignment of the PMPA pro-drug GS-7340” Nucleosides Nucleotides and Nucleic
`
`Acids, 2001, 20(4-7), 621-628 (“Chapman”; EX1008). TDF and TAF are also used
`
`to treat hepatitis B viral infections. Id.
`
`Nucleosides, however, were also well-known to be therapeutically-useful
`
`11
`
`
`
`only after intracellular, enzymatic conversion into the corresponding 5'-
`
`phosphorylated analogs; generally, these are the triphosphates. EX1002 at ¶45.
`
`This conversion into the triphosphates was known to happen in a stepwise fashion,
`
`with the first step being conversion to the corresponding monophosphate. Id.;
`
`McGuigan et al. “Certain phosphoramidate derivatives of dideoxy uridine (ddU)
`
`are active against HIV and successfully by-pass thymidine kinase,” FEBS Letters,
`
`1994, 351, 11-14 (“McGuigan 1994”; EX1009).
`
`The mono-, di-, and triphosphate forms of the C2’-deoxy-C2’-methyl(up)-
`
`C2’-fluoro(down) uridine nucleoside are shown below. EX1002 at ¶46.
`
`Compounds 1A, 1B and 1C are phosphorylated analogs of an SP-4 compound (the
`
`compound of '342 claim 1), while compound 1D is un-phosphorylated. Id.
`
`12
`
`
`
`It was well-known that compound 1C was a preferred compound for the
`
`treatment of human hepatitis C viral infections. EX1002 at ¶47; Ma et al.
`
`“Characterization of the Metabolic Activation of Hepatitis C Virus Nucleoside
`
`Inhibitor -D-2'-Deoxy-2-Fluro-2'-C-Methylcytidine (PSI-6130) and Identification
`
`of a Novel Active 5'-Triphosphate Species” J. Biol. Chem., 2007, 282(41), 29812-
`
`29820 (“Ma”; EX1010). For instance, it was known that the triphosphate
`
`compound 1C had a much longer intracellular half-life than its cytidine analog (38
`
`hours vs. 4.7 hours) resulting in a much longer duration of action. EX1002 at ¶47;
`
`EX1010 at 1 and 8.
`
`B. Some Nucleoside Drugs Were Poor Substrates for
`Phosphorylation
`
`A problem presented itself, however, in the identification of compound 1C
`
`as a promising antiviral drug. EX1002 at ¶48. Many nucleoside drugs – in
`
`particular, thymidines and uridines – were also known to be poor substrates for
`
`conversion into their monophosphate forms. Id.; EX1009 (McGuigan 1994) at 1-2;
`
`Perrone P., "Application of the Phosphoramidate ProTide Approach to 4'-
`
`Azidouridine Sub-micromolar Potency versus Hepatitis C Virus on an Inactive
`
`Nucleoside," Journal of Medicinal Chemistry, 2007, 50(8), 1840-1843 (“Perrone”;
`
`EX1012) at 1.
`
`This was also known to be more common for virally-infected cells, which
`
`are often kinase-deficient. EX1002 at ¶49. Such knowledge was very important
`
`13
`
`
`
`because drugs that would otherwise be very potent for disease treatment would be
`
`inactive if they did not undergo this phosphorylation process inside an infected
`
`cell. Id.
`
`C. Compound 1D Was a Superior Agent Against HCV, But a Poor
`Substrate for Phosphorylation
`
`Compound 1D had been disclosed in WO 2005/003147 to Clark (“Clark
`
`‘147”; EX1007) and in Clark, J., "Design, Synthesis, and Antiviral Activity of 2′-
`
`Deoxy-2′-fluoro-2′-C-methylcytidine, a Potent Inhibitor of Hepatitis C Virus
`
`Replication," Journal of Medicinal Chemistry, 2005, 48(17), 5504-5508 (“Clark
`
`2005”; EX1011). EX1002 at ¶50. Clark 2005 indicated that compound 1D – the
`
`unmodified nucleoside - had no activity in the HCV Replicon assay. EX1011 at 3.
`
`Ma showed, however, that the triphosphate form of 1D (compound 1C) was
`
`a superior agent against hepatitis C virus, with excellent potency and a long
`
`intracellular half-life. EX1002 at ¶51; EX1010 at 1 and 8.
`
`These publications established that - although compound 1C was an
`
`excellent antiviral agent - compound 1D was inactive because it could not be
`
`efficiently phosphorylated inside virally-infected cells to be converted to 1C.
`
`EX1002 at ¶52.
`
`D. ProTide Prodrugs of Nucleosides Were Well-Known to Overcome
`the Problem of Poor Phosphorylation
`
`ProTide prodrugs of nucleosides were first described in the early 1990s.
`
`14
`
`
`
`EX1002 at ¶53; EX1009 (McGuigan 1994) at 2-3. These analogs were well-known
`
`to provide advantages over unmodified nucleoside drugs in terms of
`
`physicochemical properties, cellular absorption, improved half-life, and very
`
`importantly, in terms of overcoming the problem of lack of biological activity due
`
`to poor intracellular phosphorylation. EX1002 at ¶53. The ProTide approach had
`
`been applied to activate nucleosides through kinase bypass for hepatitis C antiviral
`
`compounds as in Perrone. EX1002 at ¶53; EX1012 at 1. Thus, the ProTide
`
`approach was an obvious potential solution for overcoming the problem of poor
`
`intracellular phosphorylation of compound 1D. EX1002 at ¶53.
`
`Prior publications had disclosed that nucleoside compounds that were
`
`inefficiently phosphorylated inside a virally-infected cell could be converted into
`
`very active prodrugs for the treatment of viral diseases and cancer. EX1002 at ¶54;
`
`EX1009 (McGuigan 1994) at 2-4; EX1012 (Perrone) at 2.
`
`Perrone, in particular, had shown that conversion into a ProTide nucleoside
`
`analog completely overcame the lack of antiviral activity in the HCV Replicon
`
`Assay for the compound AZU (1), resulting in a very potent compound (2) against
`
`the hepatitis C virus. EX1002 at ¶55; EX1012. Thus, it was known that an
`
`important component of nucleoside drug discovery was the assessment of whether
`
`a nucleoside drug could be efficiently phosphorylated inside a virally-infected cell.
`
`EX1002 at ¶55. It was also known that the limitation of poor phosphorylation
`
`15
`
`
`
`could be overcome in many cases by the application of ProTide prodrug
`
`technology. Id.
`
`As an example, Perrone taught the following:
`
`EX1012 (Perrone) at 2.
`
`E. ProTide Prodrugs Were Diastereomeric at Phosphorous and Such
`Diastereomers Could Possess Different Biological Activity
`
`ProTide prodrugs have incorporated a phosphorous atom that is chiral.
`
`EX1002 at ¶57. This was illustrated for both the phosphonic acid ProTide prodrugs
`
`of tenofovir, EX1008 (Chapman) at 1, and for phosphoramidate prodrugs of
`
`nucleosides. EX1002 at ¶57; Congiatu et al., “Novel potential anticancer naphthyl
`
`phosphoramidates of BVdU: separation of diastereoisomers and assignment of the
`
`absolute configuration of the phosphorus center,” Journal of Medicinal Chemistry,
`
`2006, 49, 452-455 (“Congiatu”; EX1006) at 1.
`
`Such isomeric compounds differ in the configuration of this single chiral
`
`16
`
`
`
`center. EX1002 at ¶58. This difference in chirality at a single chiral center (with
`
`multiple chiral centers present) means that these compounds are diastereomeric;
`
`i.e., they can exist as a mixture of two diastereomers. Id.
`
`F. ProTide Analogs of Compound 1D Were Active Against HCV
`
`As discussed above, compound 1D was known, but reported to have no
`
`activity in the HCV Replicon assay. EX1011 (Clark 2005) at 3. Ma showed that
`
`the tri-phosphorylated analog of 1D (i.e., compound 1C) was a superior agent
`
`against hepatitis C virus, with a long intracellular half-life and excellent antiviral
`
`activity. EX1010 at 1 and 8.
`
`As an example, the triphosphate of 1D possessed an intracellular half-life of
`
`38 hours. EX1002 at ¶60; EX1010. This compared to the intracellular half-life of
`
`only 4.7 hours for the analogous cytidine, which was previously shown to be very
`
`promising for the treatment of hepatitis C viral infection. Id.
`
`Indeed, WO 2008/121634 to Sofia (“Sofia ‘634”; EX1005) disclosed that
`
`such ProTide prodrug moieties were effective for activating compound 1D,
`
`transforming 1D from a compound with no antiviral activity into a series of very
`
`potent compounds for the treatment of hepatitis C viral infections. EX1002 at ¶61;
`
`EX1005 at 695:15-698:3. Thus, a compound that lacked antiviral activity was
`
`readily transformed into a substantial number of ProTide analogs that possessed
`
`excellent activity against hepatitis C viral infection. EX1002 at ¶61.
`
`17
`
`
`
`The compounds of Sofia ‘634 were also known to exist as different
`
`diastereomers at phosphorous. EX1002 at ¶62; EX1005 at 693-694. Sofia ‘634
`
`Example 81 taught:
`
`Certain exemplified compounds were obtained as mixture of
`diastereomers because of chirality at phosphorous. The diastereomers
`were separated on a ChiralPak-AS-H (2 X 25 cm) column under
`Supercritical Fluid Chromatography (SFC) conditions using 20%
`methanol in carbon dioxide as solvent. The absolute stereochemistry
`of the P-chiral center of the diastereomers were not determined.
`However chromatographic resolution of these two diastereomers
`provides for isomers that are characterized as fast eluting and slow
`eluting isomers. Some examples are shown below.
`
`18
`
`
`
`EX1005 at 693-694.
`
`Compounds whose diastereomers at phosphorous were separated and tested
`
`separately for hepatitis C antiviral activity were identified in Sofia ‘634 as
`
`compounds 15, 39, and 49. EX1005 at 693-694. Thus, Sofia ‘634 also illustrated
`
`separation of the phosphorous diastereomers of ProTide analogs of 1D. EX1002 at
`
`¶63. Upon separation and subsequent testing in the HCV Replicon Assay, a
`
`substantial difference was seen in biological activity between the respective
`
`diastereomers of examples 15, 39, and 49 of Sofia ‘634, as shown in the table
`
`above. EX1002 at ¶63; EX1005 at 694.
`
`Thus, a POSA would readily know that the chiral phosphorous atom of
`
`phosphoramidate nucleoside prodrugs would exist in separate diastereomeric forms
`
`and that these different diastereomers would likely have different antiviral activity.
`
`EX1002 at ¶64. Specifically, Sofia ‘634’s example isomers showed a difference of
`
`activity on the order of 5-fold, 39-fold and 190-fold. EX1005 at 693-694. Thus, a
`
`POSA would expect that isomers of Sofia ‘634’s compounds could have difference
`
`in activity of several orders of magnitude. EX1002 at ¶64.
`
`In light of Sofia ‘634’s examples, it would have been entirely expected that
`
`isomers of its compounds could have much more than 20 times difference in
`
`activity. EX1002 at ¶65.
`
`19
`
`
`
`G. Pharmaceutical Solids Were Well-Known to Exist in Multiple
`Solid-State and Crystalline Forms
`
`A POSA was readily aware that SP-4 could potentially exist in multiple
`
`solid-state forms. EX1002 at ¶66; Byrn S., “Pharmaceutical Solids: A Strategic
`
`Approach to Regulatory Considerations,” Pharmaceutical Research, 1995, 12(7),
`
`945-954 (“Byrn”; EX1013); Hilfiker R., POLYMORPHISM IN THE PHARMACEUTICAL
`
`INDUSTRY, Wiley-VCH (2006), “Relevance of Solid State Properties for
`
`Pharmaceutical Products,” Chapter 1, 1-19 (“Hilfiker Chapter 1”; EX1015). These
`
`forms might variously be amorphous, crystalline, hydrates, or solvates. Id. A
`
`POSA would also recognize that any crystalline form might exist in multiple
`
`molecular packing arrangements. Id. These different crystalline packing
`
`arrangements of a solid form are known as polymorphs. Id.
`
`A POSA also knew that this difference in crystalline packing was a potential
`
`source of variability in properties, such as melting point, stability, aqueous
`
`solubility, formulation characteristics, bioavailability, bioequivalence, that are
`
`critical for understanding and controlling drug performance. EX1002 at ¶67.
`
`It was routine and obligatory practice in the pharmaceutical industry to
`
`conduct solid-state and polymorph screening for new drug candidates. EX1002 at ¶
`
`68. “[I]n fact the whole existence of a drug is affected by the properties of the solid
`
`form, and the final goal of solid form development is to find and select the solid
`
`with the optimal characteristics for its intended use.” EX1015 at 3.
`
`20
`
`
`
`Most active pharmaceutical ingredients (APIs) are produced by
`
`crystallization. EX1002 at ¶69. This is done to (among other things) assure the
`
`purity and consistency of APIs. Id.; EX1013 at 1-2. The ability of an API to exist
`
`in multiple crystalline forms (polymorphs) was therefore well-known to be
`
`important. EX1002 at ¶69.
`
`A POSA knew that all new drug candidates that were solids would undergo
`
`a polymorph screen to assess the potential for multiple crystalline forms to exist,
`
`and their relative stability. EX1002 at ¶70; EX1013.
`
`A POSA also knew that, while screening for polymorphs required significant
`
`labor, it was a conventional and routine exercise – and indeed, a required exercise
`
`for the pharmaceutical industry - with many publications describing the general
`
`approach for identification and characterization of polymorphs, hydrates, and
`
`solvates. EX1002 at ¶71; EX1013; Alvarez "Polymorph Screening: Comparing an
`
`Automated Approach with a High Throughput Method", Crystal Growth and
`
`Design, 2009, 9(9), 4181-4188 (“Alvarez”; EX1016).
`
`H. A Solid-State and Polymorph Screen for New Drug Candidates
`Would Always Evaluate the Impact of Water
`
`The interactions of water with a pharmaceutical solid are critically important
`
`to evaluate for every new drug candidate. EX1002 at ¶72; Hilfiker R.,
`
`POLYMORPHISM IN THE PHARMACEUTICAL INDUSTRY, Wiley-VCH (2006),
`
`“Physical Characterization of Hygroscopicity in Pharmaceutical Solids,” Chapter
`
`21
`
`
`
`9, 235-256 (“Hilfiker Chapter 9”; EX1017). A POSA thus knew that the
`
`interactions of a compound with water either by vapor sorption/desorption or by
`
`suspension/dissolution in aqueous solution were thoroughly investigated as part of
`
`routine evaluation for any new drug candidate in the pharmaceutical industry.
`
`EX1002 at ¶72.
`
`Moisture can affect the stability of an API and its formulations. EX1002 at
`
`¶73. The adsorption or absorption of water molecules into a drug or its
`
`formulation(s) can often induce hydrolytic instability. Id.; Yoshioka et al.,
`
`“Rational Storage Conditions for Accelerated Testing of Stability of Solid
`
`Pharmaceuticals,” 79:10, 943-944 (1990) (“Yoshioka”; EX1018).
`
`Other important properties such as crystal structure, powder flow,
`
`dissolution rate, lubricity, and compaction can be critically affected by moisture
`
`adsorption. EX1002 at ¶74; Ahlneck et al., “The molecular basis of moisture
`
`effects on the physical and chemical stability of drugs in the solid state,” Intl. J.
`
`Phar., 62:2-3, 87-95 (1990) (“Ahlneck”; EX1019).
`
`A POSA also knew that the most common case of solvation for
`
`pharmaceutical solids is by incorporation of water molecules. EX1002 at ¶75;
`
`Gibson, “Pharmaceutical Preformulation and Formulation, A Practical Guide
`
`from Candidate Drug Selection to Commercial Dosage Form,” IHS Health Group,
`
`Chapter 3, 43- 44 (2004) (“Gibson”; EX1020). A POSA knew, therefore, that
`
`22
`
`
`
`evaluating the impact of water on a pharmaceutical solid would include
`
`characterization of the crystalline form obtained (i.e., polymorphic form and
`
`stability). EX1002 at ¶75.
`
`Thus, the methods described for the preparation of SP-4, form 6 in the ‘342
`
`patent, EX1001 at 73:10-50, were well within the routine and customary tests
`
`performed on all new drug candidates to evaluate the stability of crystalline forms.
`
`EX1002 at ¶76. Indeed, such tests were an obligatory part of early drug
`
`development and are routinely reported to regulatory agencies. Id.; EX1013; Ex
`
`1015; EX1017.
`
`IX.
`
`SCOPE AND CONTENT OF THE PRIOR ART
`
`The following references taught or suggested the compounds, compositions
`
`and methods recited in claims 1-4 of the ’342 patent. EX1002 at ¶77.
`
`A. WO 2008/121634 to Sofia (“Sofia ‘634”; EX1005)
`
`Sofia ‘634 is prior art under 35 U.S.C. § 102(b) to the ‘342 patent because it
`
`was
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