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. IPR2018-00125
`U.S. Patent No. 8,633,309
`
`___________
`
`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. IPR2018-00125
`U.S. Patent No. 8,633,309
`
`___________
`
`PETITION FOR INTER PARTES REVIEW
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ........................................................................................1
`
`II. MANDATORY NOTICES...........................................................................2
`
`A.
`
`B.
`
`C.
`
`D.
`
`Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1)) .................................2
`
`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 ‘309 PATENT ..........................................................4
`
`V.
`
`VI.
`
`FILE HISTORY OF THE ‘309 PATENT.....................................................5
`
`PERSON OF ORDINARY SKILL IN THE ART.........................................9
`
`VII. CLAIM CONSTRUCTION..........................................................................9
`
`VIII. BACKGROUND KNOWLEDGE IN THE ART........................................10
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`Nucleoside Analog Drugs Inhibited Viral Diseases...........................10
`
`Some Nucleoside Drugs Were Poor Substrates for Phosphorylation .15
`
`Compound 1D Was a Superior Agent Against HCV, But a Poor
`Substrate for Phosphorylation ...........................................................15
`
`ProTide Prodrugs of Nucleosides Were Well-Known to Overcome the
`Problem of Poor Phosphorylation .....................................................16
`
`ProTide Prodrugs Were Diastereomeric at Phosphorous and Such
`Diastereomers Could Possess Different Biological Activity..............18
`
`i
`
`
`
`F.
`
`ProTide Analogs of Compound 1D Were Active Against HCV........18
`
`IX.
`
`SCOPE AND CONTENT OF THE PRIOR ART .......................................21
`
`A. WO 2008/121634 (“Sofia ‘634”) ......................................................21
`
`B.
`
`J. Med. Chem. 2006 (“Congiatu”).....................................................24
`
`C. WO 2005/003147 (“Clark ‘147”)......................................................25
`
`X.
`
`CLAIMS 1-12 ARE UNPATENTABLE ....................................................26
`
`A.
`
`Ground 1: Claims 1-12 Were Anticipated by Sofia ‘634...................27
`
`1.
`
`2.
`
`3.
`
`Claims 1-3 (compounds).........................................................34
`
`Claims 4-6 (pharmaceutical compositions) .............................34
`
`Claims 7-12 (methods of treating hepatitis C).........................35
`
`B.
`
`Ground 2: Claims 1-12 Were Obvious Over Sofia ‘634 and Congiatu35
`
`1.
`
`2.
`
`3.
`
`Claims 1-3 (compounds).........................................................44
`
`Claims 4-6 (pharmaceutical compositions) .............................45
`
`Claims 7-12 (methods of treating hepatitis C).........................46
`
`C.
`
`Ground 3: Claims 1-12 Were Obvious Over Clark ‘147 and Congiatu46
`
`1.
`
`2.
`
`3.
`
`Claims 1-3 (compounds).........................................................46
`
`Claims 4-6 (pharmaceutical compositions) .............................51
`
`Claims 7-12 (methods of treating hepatitis C).........................52
`
`XI. CONCLUSION ..........................................................................................52
`
`XII. APPENDIX – LIST OF EXHIBITS............................................................54
`
`XIII. CERTIFICATE OF COMPLIANCE ..........................................................55
`
`ii
`
`
`
`XIV. CERTIFICATE OF SERVICE....................................................................56
`
`iii
`
`
`
`I.
`
`INTRODUCTION
`
`Initiative for Medicines, Access & Knowledge (I-MAK), Inc. (“Petitioner”)
`
`requests inter partes review (“IPR”) of claims 1-12 of United States Patent No.
`
`8,633,309 to Ross et al. (“the ‘309 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 ’309 patent issued on January 21, 2014, and is currently
`
`assigned to Gilead Pharmasset LLC (“Patent Owner”). This petition demonstrates
`
`that claims 1-12 of the ’309 patent are unpatentable.
`
`The ‘309 patent claims pharmaceutical compounds, compositions and
`
`methods that were already known and obvious in light of the prior art. Specifically,
`
`the ‘309 claims a specific diastereomeric 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 diastereomeric forms of a nucleoside
`
`compound and finding one was more active was entirely conventional and
`
`expected. Identifying a diastereomeric form that is more active than others is not
`
`inventive, but obvious.
`
`Thus, claims 1-12 of the ‘309 patent are unpatentable and should be
`
`cancelled.
`
`1
`
`
`
`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,
`
`Access & Knowledge (I-MAK), Inc., and the Laura and John Arnold Foundation.
`
`B.
`
`Related Matters (37 C.F.R. § 42.8(b)(2))
`
`Petitioner expects to be filing shortly hereafter a petition for Inter Partes
`
`Review of U.S. Patent No. 9,284,342, which relates to the ‘309 patent. Case No.
`
`IPR2018-00126. 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
`
`2
`
`
`
`Petitioner consents to service by email to dan@ravicher.com.
`
`III. REQUIREMENTS FOR REVIEW
`
`A.
`
`Grounds for Standing
`
`Petitioner certifies that the ’309 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 1-12 of the ’309 patent
`
`based on the following grounds:
`
`# Claims
`1
`1-12
`2
`1-12
`3
`1-12
`
`35 U.S.C. §
`102(a)
`103(a)
`103(a)
`
`Prior Art
`Sofia ‘634
`Sofia ‘634 and Congiatu
`Clark ‘147 and Congiatu
`
`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.
`
`3
`
`
`
`The Petition and its supporting materials, which are listed in the Appendix,
`
`establish a reasonable likelihood that Petitioner will prevail with respect
`
`to
`
`cancellation of the challenged claims. See 35 U.S.C. § 314(a).
`
`IV. OVERVIEW OF THE ‘309 PATENT
`
`The ‘309 patent claims a compound of the following “formula 4”:
`
`EX1001 at 76:2-15. The designation “P* represents a chiral phosphorous atom
`
`wherein the compound is at least 97% of the SP stereoisomer represented by the
`
`formula SP-4, and not more than 3% of the RP stereoisomer.” EX1001 at 76:16-48.
`
`The patent’s dependent claims further recite higher levels of chiral purity at
`
`4
`
`
`
`the phosphorous atom (98% and 99%), pharmaceutical compositions containing
`
`the SP-4 diastereomer, methods of treatment of hepatitis C viral infection using SP-
`
`4 and using SP-4 in combination with another antiviral agent. Id. at 76:49 – 77:12.
`
`The following chart describes the ‘309 patent’s 12 claims:
`
`Claim(s)
`
`Recite
`
`1-3
`
`4-6
`
`7-12
`
`The compound of formula 4 in which the compound is at least 97%,
`98% or 99% of the SP stereoisomer.
`
`compositions of claims 1 through 3 and a
`Pharmaceutical
`“pharmaceutically acceptable medium.”
`
`Methods of treating hepatitis C viral infection by administering the
`compounds of claims 1, 2 and 3 with or without another antiviral
`agent.
`
`V.
`
`FILE HISTORY OF THE ‘572 PATENT
`
`U.S. Patent Application No. 13/738,425 (“the ‘425 application”), filed on
`
`January 10, 2013, issued as the ‘309 patent on January 21, 2014. The ‘425
`
`application claimed priority as a divisional of U.S. Patent Application No.
`
`12/783,680 (“the ‘680 application”), filed on May 20, 2010. The ‘425 application
`
`also claimed the benefit of Provisional Applications Nos. 61/319,513 (“the ‘513
`
`provisional application”), filed on March 31, 2010, and 61/179,923 (“the ‘923
`
`provisional application”), filed on May 20, 2009.
`
`During prosecution of the ‘425 application, the Examiner rejected the
`
`pending claims for being obvious over a 2007 publication by Sofia and provided
`
`5
`
`
`
`the following analysis:
`
`Sofia [2nd International Workshop on HCV-Resistance and
`New Compounds, October 31, 2007] teaches a phosphoramidate
`prodrug of formula:
`
`wherein R3 is isopropyl group (page 8), which is a mixture of Sp and
`Rp stereoisomers. The disclosed phosphoramidate prodrug is a potent
`therapeutic agents for treating HCV infection (pages 1-13).
`Sofia does not expressly teach wherein the Sp stereoisomer is at
`least 97%, 98% or 99% and Rp stereoisomer is not more than 3%, 2%,
`or 1 %. Sofia does not expressly teach that the compound is in a
`pharmaceutical composition form.
`It would have been obvious to one of ordinary skill in the art at
`the time the invention was made to separate the mixture of Sp and Rp
`stereoisomers and formulate it into a pharmaceutical composition for
`treating HCV infection.
`One having ordinary skill in the art at the time the invention
`was made would have been motivated to separate the mixture of Sp
`and Rp stereoisomers and formulate it into a pharmaceutical
`composition for treating HCV infection because the disclosed
`
`6
`
`
`
`phosphoramidate prodrug containing a mixture of Sp and Rp isomers
`is known to have potential therapeutic effect and usefulness in treating
`HCV infection, and separation the two isomers of a known therapeutic
`drug and identifying the therapeutic potency of each isomer are well
`known in the art. One of ordinary skill in the art would have
`reasonably expected the success because separating the isomers of the
`known therapeutic agents and identifying the potency of each isomer
`and formulate into a pharmaceutical composition is well within the
`ordinary and routine level of one skilled in the art.
`Thus, the claimed invention as a whole is prima facie obvious
`over Sofia.
`EX1004 at 12-13.
`
`Patent Owner responded by arguing that the Office failed to establish a
`
`prima facie case of obviousness because (i) the Sofia article taught away from
`
`selecting an isopropyl group for R3, (ii) neither the Sofia article nor any other cited
`
`reference supported the assertion that one skilled in the art would have been
`
`motivated to separate the RP and SP stereoisomers and obtain compounds of at least
`
`97%, 98% and 99% of the SP stereoisomer, and (iii) one skilled in the art could not
`
`have predicted the anti-hepatitis C virus activity of either the SP or RP stereoisomer.
`
`EX1004 at 21-34.
`
`Patent Owner also argued that non-obviousness of the claimed invention was
`
`supported by unexpected results, namely that the SP stereoisomer was more potent
`
`than the mixture of the two phosphorous-based stereoisomers and >20 times more
`
`7
`
`
`
`potent than the corresponding RP stereoisomer. EX1004 at 24.
`
`The Examiner responded to Patent Owner’s arguments by withdrawing the
`
`rejection because of the argument relating to unexpected results, not the arguments
`
`relating to the prima facie case of obviousness. EX1004 at 39.
`
`Specifically, the Examiner said:
`
`Id.
`
`Applicant's arguments, submitted May 21, 2013, with respect to the
`rejection of instant claims 82-93 under 35 USC 103(a) for being
`obvious over Sofia et al., have been fully considered and found to be
`persuasive to remove the rejection as Applicant has demonstrated that
`the enantiomer Sp-4 is unexpectedly more potent in inhibiting HCV
`replication than the Rp-4 enantiomer, thereby overcoming the prima
`facie case of obviousness.
`
`Similarly, in his Reasons for Allowance, the Examiner said:
`
`While it is known in the art to make phosphoramidate compounds
`such as the instantly claimed ones, for example as described in US
`patent 7964580 (of record in previous action) and furthermore to
`resolve chiral compounds into individual enantiomers, Applicant has
`discovered that the Sp enantiomer of the claimed compound is
`unexpectedly more potent in inhibiting HCV replication as disclosed
`on p. 97 of the specification as originally filed. Therefore any prima
`facie case of obviousness is overcome by this finding of unexpected
`results. For these reasons the claims meet the requirements of 35 USC
`102 and 103.
`
`8
`
`
`
`Id. at 56.
`
`Again, the Examiner noted that it was the issue of purported unexpected
`
`results that overcame the pending rejections, not Patent Owner’s arguments with
`
`respect to the prima facie case of obviousness.
`
`VI. PERSON OF ORDINARY SKILL IN THE ART
`
`Because the ‘309 patent pertains to nucleoside compounds, a person of
`
`ordinary skill in the art (“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. EX1002 at ¶41.
`
`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
`
`9
`
`
`
`likelihood that Petitioner will prevail with respect to the challenged claims.
`
`The ’309 patent provides definitions for certain claim terms, but these
`
`definitions are conventional. EX1002 at ¶42.Thus, there is no reason to give any of
`
`the terms of the claims of the ‘309 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
`
`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 May 20, 2009.
`
`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 ¶44.
`
`10
`
`
`
`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.
`
`Nitrogenous Base
`
`Ribose Derivative
`
`Deoxyribose Derivative
`
`Adenine
`
`Guanine
`
`Adenosine (A)
`
`Deoxyadenosine (dA)
`
`Guanosine (G)
`
`Deoxyguanosine (dG)
`
`Thymine
`
`5-Methyluridine (m5U)
`
`Thymidine (dT)
`
`11
`
`
`
`Uracil
`
`Cytosine
`
`Id.
`
`Uridine (U)
`
`Deoxyuridine (dU)
`
`Cytidine (C)
`
`Deoxycytidine (dC)
`
`It was also well known that analogs of naturally-occurring nucleosides were
`
`attractive targets for drug discovery and that such analogs were routinely used to
`
`treat diseases including viral infections and cancers. EX1002 at ¶46. 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 ¶46. Such drugs included aciclovir, tenofovir disoproxil
`
`fumarate (TDF) and tenofovir alafenamide fumarate (TAF) for the treatment of
`
`12
`
`
`
`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. TDF and TAF are also used to treat hepatitis B viral infections. 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).
`
`Nucleosides, however, were also well-known to be therapeutically-useful
`
`only after intracellular, enzymatic conversion into the corresponding triphosphate
`
`analogs. EX1002 at ¶47. 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.
`
`13
`
`
`
`EX1002 at ¶48. Compounds 1A, 1B and 1C are phosphorylated analogs of a SP-4
`
`compound, while compound 1D is un-phosphorylated. Id.
`
`It was well-known that compound 1C was a preferred compound for the
`
`treatment of human hepatitis C viral infections. EX1002 at ¶49; 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 that its cytidine analog (38
`
`hours vs. 4.7 hours) resulting in a much longer duration of action. EX1002 at ¶49;
`
`14
`
`
`
`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 ¶50. Many nucleoside drugs – in
`
`particular, uridines – were also known to be poor substrates for conversion into
`
`their monophosphate forms. EX1002 at ¶50; EX1009 (McGuigan 1994) at 1-2.
`
`This was also known to be more common for virally-infected cells, which are often
`
`kinase-deficient. EX1002 at ¶50. Such knowledge was very important 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 ¶51. Clark 2005 indicated that compound 1D – the
`
`unmodified nucleoside - had no activity in the HCV Replicon assay. EX1002 at
`
`¶51; EX1011 at 3.
`
`Ma showed, however, that the triphosphate form of 1D (compound 1C) was
`
`15
`
`
`
`a superior agent against hepatitis C virus, with excellent potency and a long
`
`intracellular half-life. EX1002 at ¶52; 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 ¶53.
`
`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.
`
`EX1002 at ¶54; EX1009 (McGuigan 1994) at 2-3. These analogs were well-known
`
`to provide advantages over base 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 ¶54. The ProTide approach had been applied to
`
`activate nucleosides through kinase bypass for hepatitis C antiviral compounds as
`
`in 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). EX1002 at ¶54. Thus, the ProTide approach was an obvious
`
`potential solution for overcoming the problem of poor intracellular
`
`phosphorylation of compound 1D. Id.
`
`16
`
`
`
`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 ¶55;
`
`EX1012 (Perrone) at 2; EX1009 (McGuigan 1994) at 2-4.
`
`Perrone, in particular, showed 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 ¶56. 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.
`
`Id. It was also known that the limitation of poor phosphorylation could be
`
`overcome in many cases by the application of ProTide prodrug technology.
`
`EX1012 (Perrone) at 2.
`
`17
`
`
`
`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 2001) at 1, and for phosphoramidate prodrugs of
`
`nucleosides. Congiatu et al., “Novel potential anticancer naphthyl
`
`phosphoramidates of BVdU: separation of diastereoisomers and assignment of the
`
`absolute configuration of the phosphorus center,” J Med Chem 2006, 49, 452-455
`
`(“Congiatu”; EX1006) at 1. EX1002 at ¶57.
`
`Such isomeric compounds differ in the configuration of this single chiral
`
`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. EX1002 at ¶59; 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. EX1002 at ¶59; EX1010 at 1 and 8.
`
`As an example, the triphosphate of 1D possesses an intracellular half-life of
`
`38 hours. EX1002 at ¶60; EX1010 at 1 and 8. This compares to the intracellular
`
`18
`
`
`
`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.
`
`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.
`EX1005 at 693-694.
`
`19
`
`
`
`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 separate 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
`
`below.
`
`Id.; EX1005 at 694.
`
`Thus, a POSA would readily know that the chiral phosphorous atom of
`
`20
`
`
`
`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. Id. 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.
`
`IX.
`
`SCOPE AND CONTENT OF THE PRIOR ART
`
`The following references taught or suggested the compounds, compositions
`
`and methods recited in claims 1-12 of the ’309 patent. EX1002 at ¶66.
`
`A. WO 2008/121634 to Sofia (“Sofia ‘634”, EX1005)
`
`Sofia ‘634 is prior art under 35 U.S.C. § 102(a) to the ‘309 patent because it
`
`was published on October 9, 2008, before the May 29, 2009, filing date of the
`
`earliest application to which the ‘309 patent claims priority.
`
`Sofia ‘634 taught nucleoside phosphoramidate prodrugs of the following
`
`Formula I:
`
`21
`
`
`
`EX1005 at 1. While Sofia ‘634 taught many compounds within the formula, it
`
`highlighted some specific compounds, including “(S)-2-{[(2R,3R,4R,5R)-5-(2,4-
`
`Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-
`
`furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid isopropyl ester.”
`
`EX1005 at 702:48-50 (claim 2).
`
`Sofia ‘634 also taught a composition for treatment of viral diseases using
`
`any of the viral agents disclosed. Id. at 707:23-709:26 (claim 3). Such
`
`compositions are also taught to comprise a pharmaceutically acceptable medium
`
`Id. at 710:1-6 (claim 4). Further, Sofia ‘634 taught a method of treatment which
`
`comprises administering a therapeutically effective amount of a compound of
`
`formula I to a subject. Id. at 723:43-727:36 (claim 7).
`
`Sofia ‘634 contained a substantial series of tables of “contemplated species”
`
`within the structure of formula I. Id. at 101-660. Notably, Example 25, is identical
`
`to formula 4 claimed by the ‘309 patent, even though it does not indicate the
`
`22
`
`
`
`diastereomeric composition at phosphorous to be SP-4, RP-4, or a mixture of both.
`
`EX1005 at 684.
`
`Sofia ‘634 further taught the separation of such mixtures of diastereomers
`
`into their respective individual diastereomers. Id. at 693-694, Example 81.
`
`Notably, Example 81 of Sofia ‘634 taught the separation of isomers at phosphorous
`
`into their individual diastereomers. Sofia ‘634 further taught that these
`
`diastereomers displayed differences in antiviral activity in three respective
`
`examples of: 1) 5-fold; 2) 39-fold; and 3) 190-fold. Thus Sofia ‘634 taught that the
`
`different diastereomers of its compounds, including compound 25, could be
`
`separated, and that these diastereomers would be expected to have substantially
`
`different antiviral activity. Id.; EX1002 at ¶70.
`
`This teaching of the wide variability in activity of Sofia ‘634’s phosphorous
`
`diastereomers would have motivated a POSA to investigate them. EX1002 at ¶71.
`
`Sofia ‘634’s teaching would have given a POSA a reasonable expectation of
`
`success in isolating and testing the stereoisomers of its compounds. Id.
`
`Sofia ‘634 further taught the use of such compounds and pharmaceutical
`
`compositions in combination with other antiviral agents for the treatment of
`
`hepatitis C viral infections. Id. at 665:19-23, and 667:8-668:13.
`
`23
`
`
`
`B.
`
`Congiatu et al., “Novel potential anticancer naphthyl
`phosphoramidates of BVdU: separation of diastereoisomers and
`assignment of the absolute configuration of the phosphorus
`center,” J Med Chem vol. 49, pp. 452-455 (2006) (“Congiatu”;
`EX1006)
`
`Congiatu is prior art under 35 U.S.C. § 102(b) to the ‘309 patent because it
`
`was published on December 17, 2005, more than a year before the May 29, 2009,
`
`filing date of the earliest application to which the ‘309 patent claims priority.
`
`Congiatu taught that nucleosides are useful for the treatment of cancer and
`
`viral infections. EX1006 at 1. Congiatu also taught that the “phosphoramidate
`
`approach” (ProTide prodrugs of nucleoside mono-phosphates) was introduced by
`
`McGuigan et al. in 1992 to improve cellular penetration of nucleosides and to
`
`bypass the first step of kinase-mediated activation of nucleosides. Id. Congiatu
`
`taught that this was one of the most successful approaches for the delivery of
`
`nucleoside monophosphates inside cells. Id.
`
`Congiatu further taught separation of diastereomers of nucleoside
`
`phosphoramidates. Id. at 2-3. Congiatu further taught that diastereomers of the
`
`publication had an approximately 15-fold difference in activity (0.5 micromolar vs.
`
`7.4 micromolar). Id. Congiatu thus taug
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
