`___________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
`
`INITIATIVE FOR MEDICINES, ACCESS & KNOWLEDGE (I-MAK), INC.
`Petitioner
`
`v.
`
`GILEAD PHARMASSET LLC
`Patent Owner
`
`___________
`
`Case No. IPR2018-00119
`U.S. Patent No. 7,964,580
`
`___________
`
`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 ‘580 PATENT ..........................................................4
`
`V.
`
`VI.
`
`FILE HISTORY OF THE ‘580 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.............................................................................18
`
`i
`
`
`
`D.
`
`E.
`
`F.
`
`Narrowing The Selection Of Options For The Phosphoramidate
`Prodrug.............................................................................................19
`
`Phosphoramidates Improved Nucleosides.........................................19
`
`The ‘580 Patent Acknowledges This Common Knowledge ..............20
`
`IX.
`
`SCOPE AND CONTENT OF THE PRIOR ART .......................................22
`
`A.
`
`Sofia .................................................................................................23
`
`B. Ma ....................................................................................................25
`
`C.
`
`Perrone .............................................................................................26
`
`X.
`
`CLAIMS 1-14 ARE UNPATENTABLE ....................................................27
`
`A.
`
`Grounds 1: Claims 1-14 Were Anticipated By Sofia.........................28
`
`1.
`
`2.
`
`3.
`
`4.
`
`Claims 1 and 8 (compound) ....................................................28
`
`Claims 2, 3, 9 and 10 (compositions comprising compound) ..32
`
`Claims 4, 5, 11 and 12 (methods of treating viral infections) ..32
`
`Claims 6, 7, 13 and 14 (process of preparing and product)......33
`
`B.
`
`Grounds 1 and 2: Claims 1-14 Were Obvious Over Sofia and Perrone34
`
`1.
`
`2.
`
`3.
`
`4.
`
`Claims 1 and 8 (compound) ....................................................34
`
`Claims 2, 3, 9 and 10 (compositions comprising compound) ..44
`
`Claims 4, 5, 11 and 12 (methods of treating viral infections) ..45
`
`Claims 6, 7, 13 and 14 (process of preparing and product)......45
`
`C.
`
`Grounds 3: Claims 1-14 Were Obvious Over Ma and Perrone..........47
`
`1.
`
`2.
`
`Claims 1 and 8 (compound) ....................................................47
`
`Claims 2, 3, 9 and 10 (compositions comprising compound) ..56
`
`ii
`
`
`
`3.
`
`4.
`
`Claims 4, 5, 11 and 12 (methods of treating viral infections) ..57
`
`Claims 6, 7, 13 and 14 (process of preparing and product)......57
`
`XI. CONCLUSION ..........................................................................................59
`
`XII. APPENDIX – LIST OF EXHIBITS............................................................60
`
`XIII. CERTIFICATE OF COMPLIANCE ..........................................................61
`
`XIV. CERTIFICATE OF SERVICE....................................................................62
`
`iii
`
`
`
`I.
`
`INTRODUCTION
`
`Initiative for Medicines, Access & Knowledge (I-MAK), Inc. (“Petitioner”)
`
`requests inter partes review (“IPR”) of all 14 claims of United States Patent No.
`
`7,964,580 to Sofia et al. (“the ‘580 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 ’580 patent issued on June 21, 201, and is currently assigned
`
`to Gilead Pharmasset LLC (“Patent Owner”). This petition demonstrates that all 14
`
`claims of the ’580 patent are unpatentable.
`
`The ‘580 patent claims pharmaceutical compounds, compositions and
`
`methods that were already known and obvious in light of the prior art. Specifically,
`
`the ‘580 claims a specific prodrug form of a specific nucleoside compound, but
`
`that prodrug form of the nucleoside was already known as a result of being
`
`previously published at a scientific conference. In addition, the prodrug technique
`
`used was 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, the ‘580 patent’s claims 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 ‘580 patent in order to comply with the word count limit for a single
`
`petition. 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 ’580 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 1-14 of the ’580 patent
`
`based on the following grounds:
`
`# Claims
`
`35 U.S.C. § Prior Art
`
`1
`
`2
`
`3
`
`1-14
`
`1-14
`
`1-14
`
`102(a)
`
`103(a)
`
`103(a)
`
`Sofia
`
`Sofia and Perrone
`
`Ma and Perrone
`
`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
`
`-3-
`
`
`
`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 ‘580 PATENT
`
`The ‘580 patent relates to phosphoramidate prodrugs of nucleoside
`
`derivatives of the following general formula:
`
`EX1001 at 4:40 – 7:10. In defining the structure’s various components, the ‘580
`
`patent states that
`
`the Base is “a naturally occurring or modified purine or
`
`pyrimidine base.” EX1001 at 6:5-6. The ‘580 patent further provides a long list of
`
`substituents for each of R1, R2, R3a, R3b, R4, R5, R6, X and Y. EX1001 at 4:59 – 6:4.
`
`The following chart describes the ‘580 patent’s 14 claims:
`
`Claim(s)
`
`Recite
`
`1, 8
`
`Specific compounds within the general formula and its stereoisomers.
`
`-4-
`
`
`
`2, 9
`
`3, 10
`
`4, 11
`
`5, 12
`
`6, 13
`
`7, 14
`
`Compositions having the compound of claim 1 or 8.
`
`Compositions for treating hepatitis C virus having an effective amount
`of the compound of claim 1 or 8.
`
`Methods of treating a subject infected by one of several viruses by
`administering an effective amount of the compound of claim 1 or 8.
`
`Methods of treating a subject infected by hepatitis C virus by
`administering an effective amount of the compound of claim 1 or 8.
`
`Processes for preparing the compound of claim 1 or 8.
`
`Products having the compound of claim 1 or 8 made by the process of
`claim 6 or 13.
`
`V.
`
`FILE HISTORY OF THE ‘580 PATENT
`
`U.S. Patent Application No. 12/053,015 (“the ‘015 application”), filed on
`
`March 21, 2008, issued as the ‘580 patent on June 21, 2011. The ‘580 patent
`
`claims the benefit of 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 ‘015 application, the Examiner allowed the claims
`
`without making any substantive prior-art based rejections.
`
`VI. PERSON OF ORDINARY SKILL IN THE ART
`
`Because the ‘580 patent pertains to nucleoside compounds, a POSA would
`
`have either (1) a Ph.D. in chemistry or a closely related field with some experience
`
`-5-
`
`
`
`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 ¶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 ‘580 patent provides definitions for certain claim terms, but these
`
`definitions are conventional. Thus, there is no reason to give any of the terms of
`
`the claims of the ‘580 a meaning other than their ordinary and accustomed
`
`meaning.
`
`VIII. BACKGROUND KNOWLEDGE IN THE ART
`
`The background discussed below reflect knowledge skilled artisans would
`
`-6-
`
`
`
`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 30, 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. EX1002
`
`at ¶39. 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.
`
`Id.
`
`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
`
`-7-
`
`
`
`into its 5’-monophosphate (NMP) by the intracellular host or viral nucleoside
`
`kinase. Id. 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. Id.
`
`[continued on next page]
`
`-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
`
`-9-
`
`
`
`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. EX1002 at ¶43. 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. Id. 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. Id.; EX1006 at 12:11 –
`
`13:4.
`
`The first commercially available antiviral nucleoside was the anti-herpes
`
`-10-
`
`
`
`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. EX1002 at ¶45.
`
`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
`
`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
`
`1986
`
`-11-
`
`
`
`2′,3′-dideoxyinosine
`(ddI, Didanosine)
`
`2′,3′-dideoxycytidine
`(ddC, Zalcitabine)
`
`dideoxy uridine (ddU)
`5’-phosphates
`
`HIV reverse transcriptase
`
`adenosine
`
`1988
`
`HIV reverse transcriptase
`
`cytidine
`
`1988
`
`HIV reverse transcriptase
`
`uridine
`
`1994
`
`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
`
`4’-azido-uridine 5’-
`phosphoramidate
`
`HCV RNA polymerase
`
`uridine
`
`Feb 2007
`
`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
`
`-12-
`
`
`
`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.” Id.; 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.
`
`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
`
`-13-
`
`
`
`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
`
`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
`
`-14-
`
`
`
`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
`
`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; EX1013 (McGuigan 1994).
`
`-15-
`
`
`
`The 5’-monophosphate is then rapidly converted into the triphosphate form to be
`
`fully activated. EX1002 at ¶54. Such a technique has been called “Pronucleotide”
`
`or simply “ProTide”. Id.
`
`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.
`
`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
`
`-16-
`
`
`
`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
`
`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
`
`-17-
`
`
`
`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
`
`cellular uptake and subsequent phosphorylation of nucleosides. EX1002 at ¶64; Ma
`
`EX1005 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.
`
`-18-
`
`
`
`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. Id.; 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
`
`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; EX1013. This limitation was known to be overcome by the incorporation of
`
`phosphoramidate ProTide technology. EX1002 at ¶67; EX1012 (McGuigan 2006).
`
`-19-
`
`
`
`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 ‘580 Patent Acknowledges This Common Knowledge
`
`The ‘580 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 ‘580 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.
`
`The ‘580 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 ‘580 patent states in its Background that:
`
`Nucleoside inhibitors of NS5B polymerase can act either as a
`
`-20-
`
`
`
`results in chain termination or as a
`non-natural substrate that
`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
`replication when administered to viral
`infected whole
`cells
`(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,
`
`-21-
`
`
`
`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 3:56 – 4:39 (emphasis added).
`
`IX.
`
`SCOPE AND CONTENT OF THE PRIOR ART
`
`The following references, alone or in combination with each other, taught or
`
`suggeste