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. IPR2018-00122
`U.S. Patent No. 8,334,270
`
`___________
`
`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. IPR2018-00122
`U.S. Patent No. 8,334,270
`
`___________
`
`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 ‘270 PATENT ..........................................................4
`
`V.
`
`VI.
`
`FILE HISTORY OF THE ‘270 PATENT.....................................................5
`
`PERSON OF ORDINARY SKILL IN THE ART.........................................5
`
`VII. CLAIM CONSTRUCTION..........................................................................6
`
`VIII. BACKGROUND KNOWLEDGE IN THE ART..........................................6
`
`A.
`
`B.
`
`C.
`
`The Use of Nucleoside Analogs As Antiviral Agents And Their
`Mechanism of Action Were Known....................................................7
`
`Anti-Viral Nucleosides Must Be Converted Into Their Triphosphates
`To Be Active, Monophosphorylation Was The Rate-Limiting Step In
`Such Conversion, and 5’-Phosphate Prodrugs Enabled Nucleosides To
`Overcome This Limitation ................................................................12
`
`The Means Were Available to Determine Which Nucleosides Were
`Kinase Dependent.............................................................................17
`
`i
`
`
`
`D.
`
`E.
`
`F.
`
`Narrowing The Selection Of Options For The Phosphoramidate
`Prodrug.............................................................................................18
`
`Phosphoramidates Improved Nucleosides.........................................18
`
`The ‘270 Patent Acknowledges This Common Knowledge ..............19
`
`IX.
`
`SCOPE AND CONTENT OF THE PRIOR ART .......................................21
`
`A.
`
`B.
`
`C.
`
`Clark ‘147.........................................................................................22
`
`Clark 2005 ........................................................................................23
`
`Perrone .............................................................................................25
`
`D. McGuigan ‘327.................................................................................26
`
`X.
`
`CLAIMS 1, 2, 10-18 AND 20-25 ARE UNPATENTABLE .......................27
`
`A.
`
`Ground 1: Claims 1, 2, 10-18 and 20-25 Were Obvious Over Clark
`‘147, Clark 2005 and Perrone ...........................................................28
`
`1.
`
`2.
`
`3.
`
`Claims 1, 2, 16-18 (compound)...............................................28
`
`Claims 10-12 and 20-22 (compositions comprising compound)43
`
`Claims 13-15 and 23-25 (methods of treating viral infections)44
`
`B.
`
`Ground 2: Claims 1, 2, 10-18, 20-25 Were Obvious Over Clark ‘147,
`Clark 2005 and McGuigan ‘327........................................................45
`
`1.
`
`2.
`
`3.
`
`Claims 1, 2, 16-18 (compound)...............................................45
`
`Claims 10-12 and 20-22 (compositions comprising compound)57
`
`Claims 13-15 and 23-25 (methods of treating viral infections)57
`
`XI. CONCLUSION ..........................................................................................58
`
`XII. APPENDIX – LIST OF EXHIBITS............................................................60
`
`XIII. CERTIFICATE OF COMPLIANCE ..........................................................61
`
`ii
`
`
`
`XIV. CERTIFICATE OF SERVICE....................................................................62
`
`iii
`
`
`
`I.
`
`INTRODUCTION
`
`Initiative for Medicines, Access & Knowledge (I-MAK), Inc. (“Petitioner”)
`
`requests inter partes review (“IPR”) of claims 1, 2, 10-18 and 20-25 of United
`
`States Patent No. 8,334,270 to Sofia et al. (“the ‘270 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 ’270 patent issued on December 18,
`
`2012, and is currently assigned to Gilead Pharmasset LLC (“Patent Owner”). This
`
`petition demonstrates that claims 1, 2, 10-18 and 20-25 of the ’270 patent are
`
`unpatentable.
`
`The ‘270 patent claims pharmaceutical compounds, compositions and
`
`methods that were obvious in light of the prior art. Specifically, the ‘270 claims a
`
`specific prodrug form of a specific nucleoside compound, but
`
`the prodrug
`
`technique used by Patent Owner was entirely conventional and the nucleoside
`
`compound to which Patent Owner applied the prodrug technique had been
`
`previously disclosed (and patented) by Patent Owner years before. Taking a known
`
`prodrug approach and applying it to a known nucleoside is not an invention. It’s
`
`obvious.
`
`Thus, claims 1, 2, 10-18 and 20-25 of the ‘270 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 is filing concurrently herewith another petition for Inter Partes
`
`Review of the ‘270 patent, Case. No. IPR2018-00121, in order to comply with the
`
`word count limit for a single petition. Petitioner previously filed two petitions for
`
`Inter Partes Review of U.S. Patent No. 7,964,580, which relates to the ‘270 patent.
`
`Case Nos. IPR2018-00119 and -00120. 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
`
`-2-
`
`
`
`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.
`
`III. REQUIREMENTS FOR REVIEW
`
`A.
`
`Grounds for Standing
`
`Petitioner certifies that the ’270 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, 2, 10-18 and 20-25
`
`of the ’270 patent based on the following grounds:
`
`#
`1
`2
`
`Claims
`1, 2, 10-18, 20-25
`1, 2, 10-18, 20-25
`
`35 U.S.C. § Prior Art
`103(a)
`Clark ‘147, Clark 2005 and Perrone
`103(a)
`Clark ‘147, Clark 2005 and McGuigan
`‘327
`
`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
`
`-3-
`
`
`
`necessary to determine and explain the level of ordinary skill in the art as of the
`
`relevant timeframe.
`
`The Petition and its supporting materials, which are listed in the Appendix,
`
`establish a reasonable likelihood that Petitioner will prevail with respect
`
`to
`
`cancellation of the challenged claims. See 35 U.S.C. § 314(a).
`
`IV. OVERVIEW OF THE ‘270 PATENT
`
`The ‘270 patent relates to phosphoramidate prodrugs of nucleoside
`
`derivatives of the following general formula:
`
`EX1001 at 4:47 - 7:17. In defining the structure’s various components, the ‘270
`
`patent states that
`
`the Base is “a naturally occurring or modified purine or
`
`pyrimidine base.” EX1001 at 6:12-14. The ‘270 patent further provides a long list
`
`of substituents for each of R1, R2, R3a, R3b, R4, R5, R6, X and Y. EX1001 at 4:66 –
`
`6:11.
`
`The following chart describes claims 1, 2, 10-18 and 20-25 of the ‘270
`
`patent:
`
`-4-
`
`
`
`Claim(s)
`
`Recite
`
`1, 2, 16,
`17, 18
`
`Specific compounds (including the individual diastereomers) within
`the general formula.
`
`10 - 12,
`20 - 22
`
`13 - 15,
`23 - 25
`
`Pharmaceutical compositions having the compound of claim 1 or 16,
`including to treat hepatitis C virus infection
`
`Methods of treating a subject infected by hepatitis C virus by
`administering an effective amount of the compound of claim 1 or 16,
`including co-administering another antiviral agent.
`
`V.
`
`FILE HISTORY OF THE ‘270 PATENT
`
`U.S. Patent Application No. 13/099,671 (“the ‘671 application”), filed on
`
`May 3, 2011, issued as the ‘270 patent on December 18, 2012. The ‘270 patent
`
`claims the benefit of U.S. Patent Application No. 12/053,015 (“the ‘015
`
`application”), filed on March 21, 2008, and two provisional applications,
`
`Provisional Application No. 60/909,315 filed on March 30, 2007 (“the ‘315
`
`provisional application”), and Provisional Application No. 60/982,309 filed on
`
`October 24, 2007 (“the ‘309 provisional application”).
`
`During prosecution of the ‘671 application, the Examiner allowed the claims
`
`without making any substantive prior-art based rejections. EX1002 at ¶27.
`
`VI. PERSON OF ORDINARY SKILL IN THE ART
`
`Because the ‘270 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
`
`-5-
`
`
`
`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 ¶35.
`
`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 ‘270 patent provides definitions for certain claim terms, but these
`
`definitions are conventional. EX1002 at ¶37 Thus, there is no reason to give any of
`
`the terms of the claims of the ‘270 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
`
`-6-
`
`
`
`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 either March 30, 2007, or October 24, 2007.
`
`A.
`
`The Use of Nucleoside Analogs As Antiviral Agents And Their
`Mechanism of Action Were Known
`
`It was generally known to persons skilled in the art that viruses replicate
`
`their genetic materials in their host cell through one of two mechanisms. RNA
`
`viruses and reverse-transcribing (RT) viruses rely on their special DNA/RNA
`
`polymerase to synthesize viral DNA/RNA chains in the host cell, while DNA
`
`viruses use host-cell DNA polymerases to synthesize their viral DNA chains.
`
`EX1002 at ¶39.
`
`The basic building blocks that DNA/RNA polymerases recognize and use to
`
`synthesize viral DNA/RNA are 5’-triphosphate nucleosides (NTP, where N=A,
`
`U/T, G, C). EX1002 at ¶40. Nucleoside (N), after entering the cell, is converted
`
`into its 5’-monophosphate (NMP) by the intracellular host or viral nucleoside
`
`-7-
`
`
`
`kinase. NMP is then further converted into the 5’-triphosphate form (NTP), and
`
`finally NTP is recognized by host or viral RNA/DNA polymerases and added to
`
`the tail of the viral DNA/RNA chain being synthesized. Id. The below figure
`
`exemplifies the known mechanism for phosphorylation of nucleosides for
`
`incorporation into RNA.
`
`-8-
`
`
`
`Id.
`
`The incorporation of modified nucleosides, however, into lengthening RNA
`
`chains can result in viral inhibition, when the modified nucleoside will inhibit
`
`further incorporation of subsequent nucleoside units. EX1002 at ¶41. This
`
`inhibition is known as “chain termination.” Id. Based on this mechanism, people in
`
`the art have long used nucleoside analogs (N’) that are recognizable by viral
`
`DNA/RNA polymerases or viral nucleoside kinases to subsequently inhibit the
`
`chain extension of viral DNA/RNA. Id.
`
`Specifically, such nucleoside analogs (N’) are recognized by host or viral
`
`nucleoside kinases and converted sequentially into their 5’-triphosphate (NTP),
`
`which is then recognized by a corresponding host or viral DNA/RNA polymerase
`
`in the cell so as to compete with natural 5’-triphosphate nucleosides (NTP) and
`
`finally added to the tail of the viral DNA/RNA chain being synthesized. EX1002 at
`
`¶42. The extension of the viral DNA/RNA chain is terminated because of the
`
`difference between the analog and natural nucleosides, which results in
`
`suppression of viral replication. Id.
`
`Several references recognized this general knowledge. First, Wagner et al.
`
`“Pronucleotides: Toward the In Vivo Delivery of Antiviral and Anticancer
`
`Nucleotides” Medical Research Reviews, 2000, 20(6), 417-451 (“Wagner”;
`
`EX1010), described the use of nucleoside analogs for inhibition of various viruses.
`
`-9-
`
`
`
`EX1002 at ¶43. Second, WO 2005/003147 to Clark (“Clark ‘147”; EX1006)
`
`described research and results about use of various nucleoside analogs for
`
`treatment of Flaviviridae infections from 1994 to 2004. EX1002 at ¶43; EX1006 at
`
`12:11 – 13:4.
`
`The first commercially available antiviral nucleoside was the anti-herpes
`
`virus uridine analog Iododeoxuridine, which was synthesized in the 1950s.
`
`EX1002 at ¶44; Prusoff et al. “Synthesis and biological activities of
`
`iododeoxyuridine, an analog of thymidine” Biochim Biophys Acta., 1959, 32(1),
`
`295-6 (“Prusoff”; EX1011).
`
`Since then many nucleoside analogs have been discovered and used as
`
`inhibitors of viral enzymes involved in viral DNA/RNA synthesis, including those
`
`listed in the table below.
`
`Anti-viral nucleoside
`analog
`
`9-β-D-
`arabinofuranosyladeni
`ne (Vidarabine)
`
`Acycloguanosine
`(ACV, Aciclovir)
`
`Target for inhibition
`
`DNA polymerase of
`multiple viruses
`
`herpes simplex virus
`thymidine kinase;
`varicella herpes zoster
`virus thymidine kinase
`
`Analogous
`to
`
`Publication
`time
`
`adenosine
`
`1964
`
`guanosine
`
`1970s
`
`Ribavirin
`
`Hepatitis C virus (HCV)
`RNA polymerase
`
`guanosine
`/adenosine
`
`1972
`
`-10-
`
`
`
`2′,3′-dideoxy-3′-
`thiacytidine (3TC,
`Lamivudine)
`
`Hepatitis B virus (HBV)
`reverse transcriptase;
`HIV reverse transcriptase
`
`cytidine
`
`1980s
`
`Stavudine (d4T)
`
`HIV reverse transcriptase
`
`thymidine
`
`1980s
`
`Azidothymidine
`(AZT, Zidovudine)
`
`HTLV-III/LAV reverse
`transcriptase
`
`thymidine
`
`1985
`
`HIV reverse transcriptase
`
`thymidine
`
`HIV reverse transcriptase
`
`adenosine
`
`1986
`
`1988
`
`HIV reverse transcriptase
`
`cytidine
`
`1988
`
`HIV reverse transcriptase
`
`uridine
`
`1994
`
`2′,3′-dideoxyinosine
`(ddI, Didanosine)
`
`2′,3′-dideoxycytidine
`(ddC, Zalcitabine)
`
`dideoxy uridine (ddU)
`5’-phosphates
`
`Emtricitabine (FTC)
`
`HIV reverse transcriptase
`
`cytidine
`
`1996
`
`Abacavir (ABC)
`
`HIV reverse transcriptase
`
`guanosine
`
`Before 1998
`
`DHPG (Ganciclovir)
`
`Cytomegalovirus
`guanosine kinase
`
`guanosine
`
`1998
`
`Entecavir (ETV)
`
`HBV reverse transcriptase
`
`guanosine
`
`1990s
`
`(2’R)-2’-dO-2’-F-2’-
`C-methyluridine 5’-
`phosphate
`
`HCV RNA polymerase
`
`uridine
`
`2005
`
`Telbivudine
`
`HBV reverse transcriptase
`
`thymidine
`
`2005
`
`HCV RNA polymerase
`
`uridine
`
`Feb 2007
`
`4’-azido-uridine 5’-
`phosphoramidate
`
`EX1002 at ¶45.
`
`-11-
`
`
`
`Thus, as of March 2007, it was generally known that nucleoside analogs
`
`suppress viral replication by incorporation into viral DNA/RNA chains. EX1002 at
`
`¶46.
`
`B.
`
`Anti-Viral Nucleosides Must Be Converted Into Their
`Triphosphates To Be Active, Monophosphorylation Was The
`Rate-Limiting Step In Such Conversion, and 5’-Phosphate
`Prodrugs Enabled Nucleosides To Overcome This Limitation
`
`It was well known that, to interact with HCV NS5B polymerase, anti-viral
`
`nucleosides must first be converted into their triphosphate form. EX1002 at ¶47.
`
`This was described, for example, in 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”; EX1005), which
`
`recognized this general knowledge, saying, “[c]onversion to the active 5’-
`
`triphosphate form by cellular kinases is an important part of the mechanism of
`
`action for nucleoside analogs.” EX1002 at ¶47; EX1005 at 2.
`
`Perrone et al. “Application of the Phosphoramidate ProTide Approach to 4’-
`
`Azidouridine Confers Sub-micromolar Potency versus Hepatitis C Virus on an
`
`Inactive Nucleoside” J. Med. Chem. 2007, 50(8), 1840-1849 (“Perrone”; EX1008)
`
`also recognized this general knowledge, saying, “[a]ll antiviral agents acting via a
`
`nucleoside analogue mode of action need to be phosphorylated, most of them to
`
`their corresponding 5'-triphosphates.” EX1002 at ¶48; EX1008 at 1.
`
`-12-
`
`
`
`It was also well known that, for incorporation of a nucleoside analog into the
`
`viral DNA/RNA chain, kinase-mediated 5’-monophosphorylation of the nucleoside
`
`analog (N’→N’MP) is generally the rate-limiting step in the course of its
`
`triphosphorylation. EX1002 at ¶49. Several references recognized this general
`
`knowledge. Id.
`
`First, Perrone recognized that, “the first phosphorylation step to produce the
`
`5’-monophosphate has often been found to be the rate-limiting step in the pathway
`
`to intracellular nucleotide triphosphate formation.” EX1002 at ¶50; EX1008 at 1
`
`(“The first phosphorylation step to produce the 5'-monophosphate has often been
`
`found to be the rate-limiting step in the pathway to intracellular nucleotide
`
`triphosphate formation”). Second, Wagner recited that ddNs’ activation is hindered
`
`at the first phosphorylation step. EX1002 at ¶50; EX1010 at 2. Third, McGuigan,
`
`et al. “Application of Phosphoramidate ProTide Technology Significantly
`
`Improves Antiviral Potency of Carbocyclic Adenosine Derivatives” J. Med.
`
`Chem., 2006, 49, 7215-7726 (“McGuigan 2006”; EX1012), recognized that, “in
`
`most cases the first phosphorylation to the 5’-monophosphate is the rate-limiting
`
`step.” EX1002 at ¶50; EX1012 at 1.
`
`Perrone (EX1008), Wagner (EX1010), and McGuigan 2006 (EX1012) also
`
`evinced the general knowledge that, although 5’-triphosphates of some nucleoside
`
`analogs (NTP) are potent viral inhibitors, these nucleoside analogs (N’) themselves
`
`-13-
`
`
`
`showed little or no activity in inhibition assays, generally because of the host cell’s
`
`lack of corresponding kinase activity which renders the 5’-monophosphorylation of
`
`these analogs extremely slow. EX1002 at ¶51.
`
`Several other references recognized this general knowledge. EX1002 at ¶52.
`
`First, 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”; EX1013), recognized that
`
`nucleoside analogs have limitations because they depend on kinase-mediated
`
`activation to generate the bioactive (tri)phosphate forms. EX1002 at ¶52; EX1013
`
`at 1. McGuigan 1994 also recognized that dideoxythymidine and 3’-O-
`
`methylthymidine are nucleoside analogs which are inactive against HIV, while
`
`their triphosphates are exceptionally potent inhibitors of HIV reverse transcriptase,
`
`and the inactivity of these nucleoside analogs is attributed to poor phosphorylation
`
`by host cells. Id.
`
`McGuigan 2006 also recognized that poor phosphorylation can be a major
`
`cause of poor activity, with several examples now known where nucleoside
`
`analogs are inactive but the corresponding triphosphates are inhibitors at their
`
`enzyme target. EX1002 at ¶53; EX1012 at 1.
`
`To address this widely known issue, it was contemplated in the art to use the
`
`5’-phosphate of nucleoside analogs as a prodrug to “bypass” the kinase-mediated
`
`-14-
`
`
`
`monophosphorylation so that it can be quickly converted into the active
`
`triphosphate form. EX1002 at ¶54. Since 1990 or earlier, stable 5’-phosphate-based
`
`prodrugs of nucleoside analogs have been designed and employed to improve the
`
`intracellular delivery and activation of the nucleoside analogs, and such prodrugs
`
`could readily be hydrolyzed into 5’-monophosphates of the nucleoside analogs
`
`(NMP) by enzymes inside the cell. EX1002 at ¶54; McGuigan 1994, EX 1013. The
`
`5’-monophosphate is then rapidly converted into the triphosphate form to be fully
`
`activated. Such a technique has been called “Pronucleotide” or simply “ProTide”.
`
`EX1002 at ¶54.
`
`First, Wagner, recognized that various prodrug or “pronucleotide”
`
`approaches have been devised and investigated, with the general goal of promoting
`
`passive diffusion through cell membranes and increasing the bio-availability of
`
`nucleosides or phosphorylated nucleosides. EX1002 at ¶55; EX1010 at 3 and n8.
`
`This approach of derivatization had been applied using various protecting groups
`
`for the phosphate moiety. Id.
`
`Second, Cahard et al. “Aryloxy phosphoramidate triesters as pro-tides”
`
`2004, 4(4), 371-81 (“Cahard”; EX1014) recognized that aryloxy phosphoramidate
`
`triesters are an effective pro-tide motif for the intracellular delivery of charged
`
`antiviral nucleoside monophosphates and that the phenyl alanyl phosphoramidate
`
`approach was successful on a range of nucleosides by many research groups.
`
`-15-
`
`
`
`EX1002 at ¶56; EX1014 at 1, 4.
`
`Third, Perrone recognized that unmodified nucleoside monophosphates are
`
`unstable in biological media and also show poor membrane permeation because of
`
`the associated negative charges at physiological pH. EX1002 at ¶57; EX1008 at 1.
`
`Perrone also recognized that the known aryloxy phosphoramidate ProTide
`
`approach allows bypass of the initial kinase dependence by intracellular delivery of
`
`the mono-phosphorylated nucleoside analog as a membrane-permeable ProTide
`
`form. Id. The technology greatly increased the lipophilicity of the nucleoside
`
`monophosphate analog with a consequent increase of membrane permeation and
`
`intracellular availability. Id.
`
`The “ProTide” technology was known to show great success in the
`
`intracellular delivery and activation of many nucleoside analogs. EX1002 at ¶58. A
`
`large number of thus-modified nucleosides showed a boost in the inhibition
`
`activity on virus replication by tens, hundreds, or even thousands of times, in
`
`comparison with the parent nucleoside analogs. Id.
`
`McGuigan 1994 recognized that the aryloxy phosphoramidate (3c) of a ddU
`
`increases its potency by approximately 50 times. EX1002 at ¶59; EX1013 at 3
`
`(Fig. 1).
`
`Cahard recognized that the aryloxy phosphoramidate prodrug (21) for d4A
`
`boosts the activity of the parent nucleoside analog d4A by 1000 – 4000 fold and
`
`-16-
`
`
`
`the aryloxy phosphoramidate prodrug (22) for ddA boosts the activity of the parent
`
`nucleoside analog ddA by >100 fold. EX1002 at ¶60; EX1014 at 2 (Fig. 1) and 3.
`
`McGuigan 2006 recognized that the ProTide approach was highly successful
`
`when applied to L-Cd4A with potency improvements in vitro as high as 9000-fold
`
`against HIV. EX1002 at ¶61; EX1012 at 1. McGuigan 2006 also recognized that
`
`several aryloxy phosphoramidate prodrugs achieve an anti-HIV activity at the level
`
`of about 10 nM. EX1002 at ¶61; EX1012 at 4 (Table 1).
`
`Therefore, the “Pronucleotide” or “ProTide” strategy had been a
`
`conventional technical means in the art. EX1002 at ¶62.
`
`In summary, it was generally known that, for antiviral 5’-phosphate
`
`prodrugs, the antiviral activity lies in the nucleoside itself. EX1002 at ¶63. It was
`
`also generally known that the intracellular delivery (cell membrane permeation)
`
`relies on the lipophilicity rendered by the modified phosphate group and that their
`
`intracellular hydrolysis into the monophosphate form is mainly attributed to the
`
`structural nature of the modified phosphate group and the corresponding enzymes
`
`in the host cell. Id.
`
`C.
`
`The Means Were Available to Determine Which Nucleosides
`Were Kinase Dependent
`
`The general knowledge that many nucleosides were kinase-dependent in
`
`activation to their triphosphates was reflected in an early reference in the field by
`
`McGuigan 1994. EX1002 at ¶64; EX 1013 at 1-3. The means existed to assess the
`
`-17-
`
`
`
`cellular uptake and subsequent phosphorylation of nucleosides. EX1002 at ¶64;
`
`EX1005 (Ma) at 4-8. Thus, it was generally known that the identification of
`
`nucleoside analogs whose activity was kinase-dependent was readily available.
`
`EX1002 at ¶64.
`
`D.
`
`Narrowing The Selection Of Options For The Phosphoramidate
`Prodrug
`
`Phosphoramidate prodrugs have optional substation to be selected at the: 1)
`
`amino acid moiety; 2) ester group on the amino acid; 3) ester group on
`
`phosphorous; and 4) optional substitution on nitrogen of the amino acid. EX1002
`
`at ¶65. Of these possibilities, the range of realistic options is reasonably limited. Id.
`
`Perrone demonstrates how the amino acid moiety is most often glycine, alanine or
`
`valine, and how the ester group on the amino acid is most often methyl, isopropyl,
`
`or benzyl. EX1002 at ¶65; EX1008. The useful ester groups on phosphorous are
`
`aryl (typically phenyl). EX1002 at ¶65.
`
`It would be readily known to a POSA that designing an appropriate ProTide
`
`involves a selection process that is limited in scope and adaptable to a nucleoside
`
`that is the promising drug candidate. EX1002 at ¶66. As such, the selection of a
`
`phosphoramidate prodrug moiety would require labor, but with a limited selection
`
`of options and a high degree of probable success. Id.
`
`E.
`
`Phosphoramidates Improved Nucleosides
`
`It was well-known in the art, e.g. McGuigan 1994, that the biological
`
`-18-
`
`
`
`activity of nucleosides could be hampered due to poor phosphorylation by one or
`
`more of the kinases needed for conversion to the active triphosphate form. EX1002
`
`at ¶67. This limitation was known to be overcome by the incorporation of
`
`phosphoramidate ProTide technology. EX1002 at ¶67; EX1012 (McGuigan 2006)
`
`Such phosphoramidates were known to be precursors of active triphosphates and to
`
`inhibit viral replication in infected whole cells. EX1002 at ¶67.
`
`Phosphoramidates were also known to improve physicochemical properties
`
`of nucleosides, resulting in dramatic increases in intracellular concentrations of
`
`nucleoside analogs. EX1002 at ¶68; EX1013 (McGuigan 1994). Enzyme-mediated
`
`hydrolysis of the phosphoramidates resulted in the nucleoside monophosphate
`
`being released, thus bypassing the need for the slow, first-step
`
`monophosphorylation. EX1002 at ¶68.
`
`F.
`
`The ‘270 Patent Acknowledges This Common Knowledge
`
`The ‘270 patent acknowledged that the antiviral principle of nucleoside
`
`analogs and the use of 5’-phosphate-based prodrugs of nucleoside analogs to
`
`bypass the rate-limiting mono-phosphorylation and promote intracellular delivery
`
`was generally known. EX1002 at ¶69. In particular, the ‘270 patent uses the term
`
`“pronucleotides” to refer to exactly the conventional knowledge described above
`
`that had been repeatedly published for more than a decade. EX1001 at 4:30;
`
`EX1002 at ¶69.
`
`-19-
`
`
`
`The ‘270 patent acknowledges that its purported invention is merely
`
`selecting a specific nucleoside analog and modified 5’-phosphate groups based on
`
`the well-known “ProTide” approach. EX1002 at ¶70.
`
`For example, the ‘270 patent states in its Background that:
`
`Nucleoside inhibitors of NS5B polymerase can act either as a
`non-natural substrate that
`results in chain termination or as a
`competitive inhibitor which competes with nucleotide binding to the
`polymerase. To function as a chain terminator the nucleoside analog
`must be taken up by the cell and converted in vivo to a triphosphate to
`compete for the polymerase nucleotide binding site. This conversion
`to the triphosphate is commonly mediated by cellular kinases which
`imparts additional structural requirements on a potential nucleoside
`polymerase inhibitor. Unfortunately, this limits the direct evaluation
`of nucleosides as inhibitors of HCV replication to cell-based assays
`capable of in situ phosphorylation.
`In some cases,
`the biological activity of a nucleoside is
`hampered by its poor substrate characteristics for one or more of the
`kinases needed to convert
`it
`to the active triphosphate form.
`Formation of the monophosphate by a nucleoside kinase is generally
`viewed as the rate limiting step of the three phosphorylation events.
`To circumvent the need for the initial phosphorylation step in the
`metabolism of a nucleoside to the active triphosphate analog, the
`preparation of
`stable phosphate prodrugs has been reported.
`Nucleoside phosphoramidate prodrugs have been shown to be
`precursors of the active nucleoside triphosphate and to inhibit viral
`
`-20-
`
`
`
`cells
`infected whole
`replication when administered to viral
`(McGuigan, C, et al., J. Med. Chem., 1996, 39, 1748- 1753; Valette,
`G., et al., J. Med. Chem., 1996, 39, 1981-1990; Balzarini, J., et al.,
`Proc. National Acad Sci USA, 1996, 93, 7295-7299; Siddiqui, A. Q.,
`et al., J. Med. Chem., 1999, 42, 4122-4128; Eisenberg, E. J., et al.,
`Nucleosides, Nucleotides and Nucleic Acids, 2001, 20, 1091-1098;
`Lee, W.A., et al., Antimicrobial Agents and Chemotherapy, 2005, 49,
`1898); US 2006/0241064; and WO 2007/095269.
`Also limiting the utility of nucleosides as viable therapeutic
`agents is their sometimes poor physicochemical and pharmacokinetic
`properties. These poor properties can limit the intestinal absorption of
`an agent and limit uptake into the target tissue or cell. To improve on
`their properties prodrugs of nucleosides have been employed. It has
`been demonstrated that preparation of nucleoside phosphoramidates
`improves the systemic absorption of a nucleoside and furthermore, the
`phosphoramidate moiety of these "pronucleotides" is masked with
`neutral lipophilic groups to obtain a suitable partition coefficient to
`optimize uptake and transport into the cell dramatically enhancing the
`intracellular concentration of the nucleoside monophosphate analog
`relative to administering the parent nucleoside alone. Enzyme-
`mediated hydrolysis of
`the phosphate ester moiety produces a
`nucleoside monophosphate wherein
`the
`rate
`limiting
`initial
`phosphorylation is unnecessary.
`EX1001 at 3:64 – 4:46 (emphasis added).
`
`IX.
`
`SCOPE AND CONTENT OF THE PRIOR ART
`
`The ‘315 provisional application does not include a description of the
`
`-21-
`
`
`
`specific compounds claimed by the ‘270 patent. EX1002 at ¶72. While the ‘315
`
`provisional discusses broad genera of compounds, it does not discuss the specific
`
`comp
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