Trials@uspto.gov Paper No. 7
`571.272.7822
`
` Filed: May 4, 2018
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`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`INITIATIVE FOR MEDICINES, ACCESS & KNOWLEDGE (I-MAK), INC.,
`Petitioner,
`
`v.
`
`GILEAD PHARMASSET LLC,
`Patent Owner.
`____________
`
`IPR2018-00120
`Patent 7,964,580 B2
`____________
`
`
`
`Before LORA M. GREEN, GRACE KARAFFA OBERMANN, and
`WESLEY B. DERRICK, Administrative Patent Judges.
`
`DERRICK, Administrative Patent Judge.
`
`
`DECISION
`Denying Institution of Inter Partes Review
`35 U.S.C. § 314(a)
`
`
`
`
`
`
`
`
`
`

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`IPR2018-00120
`Patent 7,964,580 B2
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`
`I. INTRODUCTION
`Initiative for Medicines, Access & Knowledge (I-MAK), Inc.
`(“Petitioner”) requests an inter partes review of claims 1–14 of U.S. Patent
`No. 7,964,580 B2 (“the ’580 patent”). Paper 2 (“Pet.”). Gilead Pharmasset
`LLC (“Patent Owner”) filed a Preliminary Response. Paper 6 (“Prelim.
`Resp.”).
`We have authority to determine whether to institute an inter partes
`review. 35 U.S.C. § 314(b); 37 C.F.R. § 42.4(a). We may not institute an
`inter partes review “unless . . . there is a reasonable likelihood that the
`petitioner would prevail with respect to at least 1 of the claims challenged in
`the petition.” 35 U.S.C. § 314(a). Applying that standard, for the reasons
`set forth below, we decline to institute an inter partes review because the
`Petitioner has not shown a reasonable likelihood that it would prevail in
`establishing the unpatentability of any challenged claim.
`
`
`
`
`II. BACKGROUND
`A. Related Proceedings
`The parties identify a concurrently-filed, second petition for inter
`partes review of the ’580 patent, IPR2018-00119. Pet. 2; Paper 4, 3. Patent
`Owner also identifies additional petitions filed by Petitioner for inter partes
`review of other patents owned by Patent Owner: IPR2018-00121 and
`IPR2018-00122 for U.S. Patent No. 8,334,270 B2; IPR2018-00103 for U.S.
`Patent No. 7,429,572 B2; IPR2018-00125 for review of U.S. Patent No.
`8,633,309 B2; and IPR2018-00126 for review of U.S. Patent No.
`9,284,342 B2. Paper 4, 3.
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`
`B. The ’580 Patent (Ex. 1001)
`The ’580 patent is directed to, inter alia, a phosphoramidate prodrug
`of a nucleoside derivative for treatment of viral infections in mammals, its
`ester, or a stereoisomer thereof. Ex. 1001, Abstract, 493:42–45. The ’580
`patent also addresses methods of treatment, uses, and processes for
`preparing such compounds. Id., Abstract.
`C. Illustrative Claims
`Independent claims 1 and 8—reproduced below—are illustrative of
`the claimed subject matter.
`
`(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-
`1.
`pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-
`2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid
`isopropyl ester or a stereoisomer thereof.
`8.
`(S)-isopropyl 2-(((S)-(2R,3R,4R, 5R)-5-(2,4-dioxo-3,4-
`dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyl-
`tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)
`amino)propanoate.
` Ex. 1001, 493:42–45, 495:27–80.
`Claim 8 is directed to the Sp stereoisomer (i.e., sofosbuvir),
`whereas claim 1 covers the Sp stereoisomer, the Rp stereoisomer, and
`mixtures of the two. Prelim. Resp. 3–4, 12; see also Pet. 28–29. The
`structure of sofosbuvir, as annotated by Patent Owner, is depicted
`below:
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`Prelim. Resp. at 4. The figure depicts the chemical structure of sofosbuvir
`with stereochemistry and identifies the compound’s phosphoroamidate
`prodrug moiety, modified sugar, and natural uracil base. Id.
`D. The Asserted Grounds of Unpatentability
`Petitioner asserts that claims 1–14 of the ’580 patent are unpatentable
`based on the following grounds. Pet. 3.
`
`Statutory Basis
`§ 103
`
`References
`Clark ’147, 1 Clark 2005, 2 and
`Perrone3
`Clark ’147, Clark 2005, and
`McGuigan4
`Petitioner supports the Petition with the testimony of Joseph M.
`Fortunak, Ph.D. (Ex. 1002). Based on Dr. Fortunak’s statement of
`qualifications (id. ¶¶ 1–20) and curriculum vitae (Ex. 1003), on this record,
`
`§ 103
`
`
`1 Clark, WO 2005/003147 A2, published January 13, 2005 (Ex. 1006).
`2 Clark et al., 48 J. MED. CHEM. 5504–08 (2005) (Ex. 1007).
`3 Perrone et al., 50 J. MED. CHEM. 1840–49 (2007) (Ex. 1008).
`4 McGuigan, WO 2005/012327 A2, published February 10, 2005 (Ex. 1009).
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`we determine that he is qualified to opine from the perspective of a person of
`ordinary skill in the art.
`
`
`III. ANALYSIS
`A. Level of Ordinary Skill in the Art
`Petitioner contends that a person of ordinary skill in the art would
`have held 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.
`Pet. 5–6 (citing Ex. 1002 ¶ 35).
`Patent Owner does not expressly contest the level of ordinary skill.
`See generally Prelim. Resp.
`On this record, we adopt Petitioner’s essentially uncontested
`definition of the level of ordinary skill. We further note that the prior art
`itself demonstrates the level of skill in the art at the time of the invention.
`See Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001) (explaining
`that “specific findings on the level of skill in the art . . . [are not required]
`‘where the prior art itself reflects an appropriate level and a need for
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`testimony is not shown’” (quoting Litton Indus. Prods., Inc. v. Solid State
`Sys. Corp., 755 F.2d 158, 163 (Fed. Cir. 1985))).
`B. Claim Construction
`In an inter partes review, the Board interprets claim terms in an
`unexpired patent according to their broadest reasonable construction in light
`of the specification of the patent in which they appear. 37 C.F.R.
`§ 42.100(b); Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2142 (2016)
`(affirming applicability of broadest reasonable construction standard to inter
`partes review proceedings). Under that standard, we interpret claim terms
`using “the broadest reasonable meaning of the words in their ordinary usage
`as they would be understood by one of ordinary skill in the art, taking into
`account whatever enlightenment by way of definitions or otherwise that may
`be afforded by the written description contained in the applicant’s
`specification.” In re Morris, 127 F.3d 1048, 1054 (Fed. Cir. 1997). “Under
`a broadest reasonable interpretation, words of the claim must be given their
`plain meaning, unless such meaning is inconsistent with the specification
`and prosecution history.” Trivascular, Inc. v. Samuels, 812 F.3d 1056, 1062
`(Fed. Cir. 2016). If an inventor acts as his or her own lexicographer, the
`definition must be set forth with reasonable clarity, deliberateness, and
`precision. Renishaw PLC v. Marposs Societa′ per Azioni, 158 F.3d 1243,
`1249 (Fed. Cir. 1998). Only those terms which are in controversy need to be
`construed and only to the extent necessary to resolve the controversy. See
`Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co., 868 F.3d 1013,
`1017 (Fed. Cir. 2017).
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`Petitioner contends that “there is no reason to give any of the terms of
`the claims of the ‘580 [patent] a meaning other than their ordinary and
`accustomed meaning.” Pet. 6.
`Patent Owner does not contest that the claim terms should be given
`their ordinary and accustomed meaning. See generally Prelim. Resp. We
`determine that no claim term requires express construction for the purpose of
`determining whether to institute review.
`C. Prior Art
`
`1. Clark ’147 (Ex. 1006)
`Clark ’147 teaches (2′R)-2′-deoxy-2′-fluoro-2′-C-methyl nucleosides,
`pharmaceutically acceptable salts, and prodrugs, and their use in treating
`hepatitis C infection. Ex. 1006, 1 (Abstract). Clark ’147 teaches a general
`formula with substituents specified by reference to listings of what the
`substituents may be, some of which, if selected, would result in a phosphate
`or stabilized phosphate prodrug of (2′R)-2′-deoxy-2′-fluoro-2′-C-methyl
`uridine. Ex. 1006, 18:3–20:11, 47:16–25. Clark ’147 also discloses that
`(2′R)-2′-deoxy-2′-fluoro-2′-C-methyl cytidine has anti-viral activity,
`including against HCV (id. at 88:16–89:30) and lower toxicity than certain
`other nucleoside analogs (id. at 90:1–27).
`2. Clark 2005 (Ex. 1007)
`Clark 2005 reports the synthesis of the (2′R)-2′-deoxy-2′-fluoro-2′-C-
`methyl analogs of both cytidine and uridine, these analogs’ level of anti-
`HCV activity, and their level of cytotoxicity. Ex. 1007, 1, 3. Clark 2005
`reports that the cytidine analog, i.e., compound 1, has anti-HCV activity and
`low cellular toxicity. Id. Clark 2005 reports that the uridine analog, i.e.,
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`compound 9, “demonstrated no activity or cytotoxicity in any assay.” Id.
`at 3.
`
`
`3. Perrone (Ex. 1008)
`Perrone reports that “4′-[a]zidouridine did not inhibit HCV, although
`4′-azidocytidine was a potent inhibitor of HCV replication under similar
`assay conditions” and that “4′-azidouridine triphosphate was a potent
`inhibitor of RNA synthesis by HCV polymerase.” Ex. 1008, 1. Perrone
`reports the synthesis of a number of different phosphoramidate derivatives
`of 4′-azidouridine, their level of anti-HCV activity, and their level of
`cytotoxicity. Id. at 2–4. The derivatives include phenyl phosphoramidate
`and 1-naphthyl nucleotide derivatives, 5 including one derivative,
`compound 15, with a phenyl L-alanine isopropyl ester phosphoramidate
`moiety. Id. at 4. Perrone further teaches that the reported results
`“demonstrate[] the ability . . . to successfully bypass the rate limiting initial
`phosphorylation of a ribonucleoside analogue and thus confer significant
`antiviral activity on an inactive parent nucleoside.” Id. at 5.
`
`4. McGuigan (Ex. 1009)
`McGuigan teaches nucleotide derivatives according to a general
`formula I, reproduced below, with substituents Ar, Q, R, R′, R′′, X, Y, Z,
`and Z.
`
`
`
`
`5 Perrone states that “the phenyl substituent on the phosphate [of the phenyl
`phosphoramidates was replaced] with . . . 1-naphthyl” in the 1-naphthyl
`analogs. Ex. 1008, 4; see also id. (Scheme 3, Tables 1 & 3), id. at 4 (Fig. 2).
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`Ex. 1009, 5:11–14. Formula I depicts common structure and points of
`substitution with substituents. Id. McGuigan sets forth different
`possibilities for these substituents. Id. at 5:16–6:8, 7:22–13:22.
`D. Alleged Unpatentability of the Challenged Claims
`1. Obviousness over Clark ’147, Clark 2005, and Perrone
`Petitioner contends that claims 1–14 are unpatentable as obvious over
`the combination of Clark ’147, Clark 2005, and Perrone. Pet. 28–45.
`Petitioner relies generally on Clark ’147 and Clark 2005 for the 2′-
`deoxy-2′-fluoro-2′-C-methyluridine nucleoside and on Perrone for the
`phosphoramidate moiety. Petitioner contends that one of ordinary skill in
`the art, informed by the teachings of Clark ’147 and Clark 2005, would have
`been led to 2′-deoxy-2′-fluoro-2′-C-methyluridine, a known nucleoside
`compound, and motivated “to use the well-known strategy to select a
`suitable stable 5’-phosphate group for (2’R)-2’-deoxy-2’-fluoro-2-C-
`methyluridine . . . in order to increase its activity.” Id. at 28–37. As to the
`“suitable stable 5’-phosphate group” (id. at 37), Petitioner contends that
`“[o]ne would have been specifically motivated to refer to Perrone, which
`taught a phosphoramidate ‘ProTide’ approach to confer potency against
`hepatitis C virus by activating otherwise inactive nucleosides” (id.).
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`Petitioner maintains Clark ’147 suggests or teaches the nucleoside
`analog. Petitioner relies on Example 5 of Clark ’147, which discloses that
`(2′R)-2′-deoxy-2′-fluoro-2′-C-methyl-cytidine has anti-viral activity,
`including against HCV (Ex. 1006, 88:16–89:30), and lower toxicity than
`certain other nucleoside analogs (id. at 90:1–27). Petitioner further relies on
`the common knowledge that uracil is one of the four bases in RNA, and
`contends that “a [person of ordinary skill in the art] would have been
`motivated to replace the cytidine in the active (2’R)-2’-deoxy-2’-fluoro-2’-
`C-methyl cytidine 5’-triphosphate with a uridine,” and also that they would
`have “had an expectation that this would produce a likewise active and
`potent HCV inhibitor.” Pet. 33–34 (citing Ex. 1002 ¶ 174).
`Petitioner maintains Clark ’147 also suggests or teaches
`phosphorylated, or prodrug forms, of the nucleoside analog. Petitioner
`contends that “a [person of ordinary skill in the art] would have been fully
`motivated to specifically choose, from the various compounds encompassed
`by Claim 40 [of Clark ’147], the 5’-phosphate (including monophosphate,
`diphosphate, triphosphate, or a stabilized phosphate prodrug) of (2’R)-2’-
`deoxy-2’-fluoro-2’-C-methyl uridine as a practicable HCV inhibitor.” Pet.
`34 (citing Ex. 1002 ¶ 175). Petitioner further relies on a portion of Clark
`’147 that reads:
`A number of nucleotide prodrug ligands are known. In general,
`alkylation, acylation or other liphophilic modification of the
`mono-, di- or triphosphate of the nucleoside reduces polarity
`and allows passage into cells. . . . Any of these can be used in
`combination with the disclosed nucleosides to achieve a desired
`effect.
`Pet. 35–36 (quoting Ex. 1006, 58:15–24, with added emphasis); Ex. 1002
`¶ 177. Petitioner contends Clark ’147 “explicitly [teaches] that alkylation,
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`acylation, arylation, or other lipophilic modification can be made to the
`phosphate group in the 5’-phosphate of (2’R)-2’-deoxy-2’-C-methyluridine
`to increase its activity, bioavailability and stability, and that the modified
`prodrug will convert into the 5’-monophosphate form (U’MP) after its entry
`into the cell.” Pet. 36 (citing Ex. 1002 ¶ 179).
`Clark 2005 discloses the nucleoside analog. Petitioner relies on
`Clark 2005’s report that the (2′R)-2′-deoxy-2′-fluoro-2′-C-methyl analog of
`cytidine—compound 1—has anti-HCV activity and low cytotoxicity and
`that the uridine analog—compound 9—has “no activity or cytotoxicity in
`any assay.” Id. at 37; Ex. 1007, 1, 3. Petitioner also relies on Clark 2005,
`without elaboration, as teaching “that the cytidine form of the Clark ‘147
`nucleoside could metabolically convert in vivo to the uridine form.” Pet. 36
`(citing Ex. 1007, 3).
`Petitioner contends that “[t]he Clark 2005 results would have
`motivated a [person of ordinary skill in the art] to understand the lack of
`activity of the uridine form and to pursue methods to activate the uridine if
`the lack of activity were due to inefficient phosphorylation.” Id. at 37 (citing
`Ex. 1002 ¶ 184).
`Petitioner also contends that “[a person of ordinary skill in the art]
`would investigate the 2'-deoxy-2'-fluoro-2'-C-methyluridine nucleoside in
`Clark 2005 as a lead compound.” Pet. 41 (citing Ex. 1002 ¶ 195). In
`contending this, without explanation, Petitioner fails to specifically address
`its earlier contention, as to Clark ’147, that “a [person of ordinary skill in the
`art] would have been fully motivated to specifically choose, from . . . the 5’-
`phosphate (including monophosphate, diphosphate, triphosphate, or a
`stabilized phosphate prodrug) of (2’R)-2’-deoxy-2’-fluoro-2’-C-methyl
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`uridine as a practicable HCV inhibitor.” Pet. 34 (citing Ex. 1002 ¶ 175).
`Rather, Petitioner simply settles, in effect, on the 2'-deoxy-2'-fluoro-2'-C-
`methyluridine nucleoside as its lead compound without adequate
`explanation, which suggests Petitioner relies on an improper hindsight
`reconstruction. Pet. 37, 41; see Prelim. Resp. 2 (persuasively arguing that
`Petitioner “provides no evidence to establish that the genus resulting from its
`proposed Clark ’147/Clark 2005 combination is an appropriate starting point
`or that it is sufficiently narrow to define a lead compound”).
`As to the prodrug moiety, despite the teaching in Clark ’147,
`identified above, that “[a] number of nucleotide prodrug ligands are known”
`and that “[a]ny of these can be used” (Pet. 35–36 (quoting Ex. 1006, 58:17,
`23–24); Ex. 1002 ¶ 177), Petitioner contends that “[o]ne would have been
`specifically motivated to refer to Perrone [Ex. 1008], which taught a
`phosphoramidate ‘ProTide’ approach to confer potency against hepatitis C
`virus by activating otherwise inactive nucleosides” (Pet. 37). Petitioner’s
`declarant identifies increased activity and reduced toxicity as improvements
`desired in modifying a lead compound. Ex. 1002 ¶ 32. Petitioner also
`contends, in respect to compositions, that “Perrone also taught that applying
`its phosphoramidate ProTide approach to nucleosides could activate them as
`HCV inhibitors for use in treating people.” Pet. 43 (citing Ex. 1008, 1); Ex.
`1002 ¶ 203.
`Petitioner further contends that a person of ordinary skill in the art
`would have “had a reasonable expectation of success . . . because of the
`general knowledge that nucleosides needed to be phosphorylated to [be]
`active in HCV replication and the fact that Perrone provided several
`examples of comparable nucleosides being triphosphorylated by its ProTide
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`approach.” Pet. 38; Ex. 1002 ¶ 188. Petitioner maintains that “[i]n
`considering the similarity of Clark ‘147, Clark 2005 and Perrone, a [person
`of ordinary skill in the art] would not focus on the structural differences
`between the parent nucleosides, 2′-deoxy-2′-fluoro-2′-C-methyluridine and
`4′-aziduridne [sic, 4′-azidouridine].” Pet. 41; Ex. 1002 ¶ 195.
`Petitioner refers to additional references, including Wagner
`(Ex. 1010), McGuigan 2006 (Ex. 1012), McGuigan 1994 (Ex. 1013), and
`Cahard (Ex. 1014), in discussing the background knowledge in the art
`(Pet. 16–22), and contends that “it was generally known that, for antiviral 5’-
`phosphate prodrugs, the antiviral activity lies in the nucleoside itself” (id. at
`18 (citing Ex. 1002 ¶ 63)). Cahard is cited, in particular, for teaching “that
`the phenyl alanyl phosphoramidate approach was successful on a range of
`nucleosides by many research groups.” Id. at 16 (citing Ex. 1002 ¶ 56; Ex.
`1014, 1, 4).
`Petitioner also contends that “the range of realistic options is
`reasonably limited” for substitutions to (or the identity of) the amino acid
`moiety, the ester on the amino group, the ester group on the phosphorus, and
`optional substitution on nitrogen of the amino acid. Pet. 19; Ex. 1002 ¶¶ 65–
`66. Petitioner cites to Perrone, without further analysis, as demonstrating
`“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,” and contends, without cited support, that “[t]he useful ester groups
`on phosphorous are aryl (typically phenyl).” Pet. 19; Ex. 1002 ¶¶ 65–66;
`Ex. 1008.
`Although Petitioner cites to Wagner (Ex. 1010), McGuigan 2006
`(Ex. 1012), McGuigan 1994 (Ex. 1013), and Cahard (Ex. 1014), including in
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`referring to specific compounds, Petitioner provides little, if any, analysis as
`to the effects of the various disclosed substitutions (or identities) of various
`elements of the phosphoramidate moiety (see, e.g., Pet. 17–18, 42 (citing
`Ex. 1012, 1, 4), 14–15, 17 (citing Ex. 1013, 3), 17 (citing Ex. 1014, 2–3)).
`Petitioner also does not provide particular analysis or evidence to support its
`implicit contention that the effect of any particular phosphoramidate, or
`other prodrug, moiety of a nucleoside analog prodrug is independent of the
`structure of the parent nucleoside analog. See generally Pet.
`As to Perrone’s disclosure, Petitioner emphasizes that “Perrone . . .
`prepared about 20 stable phosphate-based prodrugs of [4′-azidouridine]” (id.
`at 38), including compound 15 which has a phenyl L-alanine isopropyl ester
`phosphoramidate moiety (id. at 39). Petitioner maintains that “only 6 highly
`active phosphoramidate groups [are] particularly identified in Perrone (i.e.
`No.14, 15, 17, and 33–35)” and contends that “[a person of ordinary skill in
`the art] would have been motivated to try to attach each [] to the 5’-position
`of . . . (2’R)-2’-deoxy-2’-2’-fluoro-2’-C-methyluridine resulting[, when the
`phosphoramidate of compound is used,] in the compounds of claims 1 and
`8.” Id. at 40 (citing Ex. 1002 ¶ 192; Ex. 1008, 4). Petitioner further
`contends that a person of ordinary skill in the art “would in particular
`prepare the derivatives . . . that correspond to compounds 14, 15 and 17 in
`Perrone because they are described as having ‘exceptional’ antiviral
`activity.” Id. at 41; Ex. 1002 ¶ 194; Ex. 1008, 3–4.
`Petitioner has, in effect, set forth two different, intertwined, theories
`of obviousness; a lead compound theory grounded on selection of 2′-deoxy-
`2′-fluoro-2′-C-methyluridine as a lead compound, followed by its
`modification, and a theory grounded on combining 2′-deoxy-2′-fluoro-2′-C-
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`methyluridine, or the corresponding portion of a 5′-phosphate or stabilized
`prodrug, with the phosphoramidate moiety of a phosphoramidate 4′-
`azidouridine analog to arrive at the claimed subject matter.
`The lead compound analysis follows a two-part inquiry. In the first
`part, we “determine[] whether a chemist of ordinary skill would have
`selected the asserted prior art compounds as lead compounds, or starting
`points, for further development efforts.” Otsuka Pharm. Co. v. Sandoz, Inc.,
`678 F.3d 1280, 1291 (Fed. Cir. 2012). The question of whether a person of
`ordinary skill in the art would have selected a compound as a lead compound
`is “guided by evidence of the compound’s pertinent properties.” Id. at 1292.
`In the second part, we determine whether the artisan would have had reason
`to modify the lead compound to make the claimed compound, and whether
`they “would have had a reasonable expectation of success in doing so.” Id.
`As to the non-lead compound analysis, we simply determine whether
`“a skilled artisan would have had reason to combine the teaching of the prior
`art references to achieve the claimed invention, and that the skilled artisan
`would have had a reasonable expectation of success from doing so.” In re
`Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig.,
`676 F.3d 1063, 1069 (Fed. Cir. 2012) (internal quotation marks and citation
`omitted). “Where a skilled artisan merely pursues ‘known options’ from ‘a
`finite number of identified, predictable solutions,’ the resulting invention is
`obvious under section 103.” Id. at 1070 (quoting KSR Int’l Co. v. Teleflex
`Inc., 550 U.S. 398, 421 (2007)).
`Evidence of obviousness, especially when that evidence is
`proffered in support of an “obvious-to-try” theory, is
`insufficient unless it indicates that the possible options skilled
`artisans would have encountered were “finite,” “small,” or
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`“easily traversed,” and that skilled artisans would have had a
`reason to select the route that produced the claimed invention.
`Id. at 1072 (citing Ortho–McNeil Pharm., Inc. v. Mylan Labs., Inc., 520 F.3d
`1358, 1364 (Fed. Cir. 2008)).
`Although Patent Owner presents its arguments generally as addressing
`deficiencies as to a lead compound theory of obviousness (Prelim. Resp. 13–
`17), some arguments are applicable to both theories (id. at 17–32).
`Patent Owner argues that Petitioner has failed to establish the requisite
`motivation to combine the 2′-deoxy-2′-fluoro-2′-C-methyluridine nucleoside
`with any of Perrone’s phosphoramidate moieties, and particularly the
`(phenyl)(isopropyl-L-alaninyl)phosphate. Prelim. Resp. 27–32. Patent
`Owner further argues that Petitioner ignores structural differences between
`2′-deoxy-2′-fluoro-2′-C-methyluridine and Perrone’s 4′-azidocytidine
`nucleoside and that such differences “can have a huge impact on the
`properties of the final molecule, including whether the molecule is effective
`against HCV and whether it has toxic side effects.” Id. at 28–29. Patent
`Owner further argues that Petitioner “offers no evidence . . . that a person of
`ordinary skill would disregard these structural differences.” Id. at 29 (citing
`Pet. 38–41; Ex. 1002 ¶¶ 18, [sic] 195).
`Patent Owner contends that “for a different nucleoside compound one
`would need to conduct research to determine which phosphoramidate
`prodrugs may or may not work.” Id. at 29–30. Patent Owner cites to
`Perrone itself as teaching that “the disclosed phosphoramidate prodrugs
`would be expected to behave differently if used with different parent
`compounds” in having “noted that ‘quite distinct [structure-activity
`relationships]’ were found for the particular nucleoside studied compared to
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`nucleosides previously studied.” Prelim. Resp. 29 (citing Ex. 1008, 4).
`Perrone also reports, in discussing certain phosphoramidate variants:
`These results [with 4′-azidouridine] were striking when
`compared to the 60–70 fold reduction in anti-HIV potency for
`d4T ProTides with an L-alanine to glycine replacement and a
`20–40 fold reduction for the corresponding abacavir ProTides.
`This reinforces our earlier conclusion that a separate ProTide
`motif optimization process is needed for each nucleoside
`analogue versus a given target.
`Ex. 1008, 4 (emphasis added) (endnotes omitted).
`Patent Owner similarly contends that “[a] person of ordinary skill . . .
`would not have had a reasonable expectation that combining Perrone’s
`phosphoramidates with 2’-deoxy-2’-fluoro-2’-C-methyluridine would yield
`an anti-HCV drug that was both effective and non-toxic.” Prelim. Resp. 30.
`Patent Owner relies on the fact that “Perrone teaches that the most active
`compound prepared [compound 33], which was also nontoxic, was a
`1-napthyl [sic] substituted compound . . . [while] applying a 1-napthyl [sic]
`substitution to a 2’-deoxy-2’-fluoro-2’-C-methyluridine nucleoside resulted
`in a toxic compound.”6 Id. at 30–31 (citing Ex. 1008, 5; Ex. 2015 (Sofia
`2010)). Patent Owner cites to the “report[] that ‘[a]lthough the 1-naphthol
`ester substitution produced the most potent HCV inhibitor, this substitution
`also led to substantial cytotoxicity and was therefore not considered a viable
`substituent.” Id. (quoting Ex. 2015, 4, with added emphasis). Sofia 2010
`
`
`6 Patent Owner inadvertently refers to 4′-azidocytidine in stating that
`“applying a 1-napthyl [sic] substitution to 4’-azidocytidine resulted in a non-
`toxic compound” (Prelim. Resp. 30) rather than 4′-azidouridine which was
`the parent nucleoside in each of compounds 11–35 (see, e.g., Ex. 1008, 5
`(“Interestingly, application of similar ProTide methods to the active 4′-
`azidocytidine gave little or no boost in anti-HCV activity (data not shown)).”
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`reports, in particular, that compound 29, the compound with a 1-naphthol
`ester substitution, significantly inhibits cellular rRNA replication (95.4%
`inhibition) under conditions in which the corresponding phenyl ester,
`compound 12, does not inhibit cellular rRNA replication (0% inhibition).
`Compare Ex. 2015, 4, Table 2, with Table 1.
`Patent Owner also argues that Petitioner “ignores that the most active
`phosphoramidate disclosed in Perrone is . . . naphthyl-substituted” and that
`“even if motivated to modify the 2’-deoxy-2’-fluoro-2’-C-methyluridine . . .
`one of ordinary skill would be directed towards” a naphthyl rather than
`phenyl ester at the phosphate and a benzyl rather than isopropyl ester of the
`amino acid moiety. Prelim. Resp. 32.
`We have considered Petitioner’s arguments and evidence along with
`the Preliminary Response, and, on this record, for reasons that follow, we
`agree with Patent Owner that Petitioner has not met the threshold for
`instituting an inter partes review of the ’580 patent.
`We turn first to the lead compound analysis. As set forth above,
`Petitioner contends that Clark ’147 “explicitly taught that alkylation,
`acylation, arylation, or other lipophilic modification can be made to the
`phosphate group in the 5’-phosphate of (2’R)-2’-deoxy-2’-fluoro-2’-C-
`methyluridine” for improved properties and that “the 5’-phosphate
`(including monophosphate, diphosphate, triphosphate, or a stabilized
`phosphate prodrug) . . . [are] practicable HCV inhibitor[s]” providing
`increased activity, bioavailability, and stability. Pet. 34, 36; Ex. 1002
`¶¶ 175, 179.
`In selecting the 2'-deoxy-2'-fluoro-2'-C-methyluridine nucleoside as
`the lead compound, Petitioner fails to adequately explain why this particular
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`compound was chosen over other compounds, particularly the
`monophosphate, or any of a number of stabilized monophosphate prodrugs.
`See generally Pet.
`Also, as set forth above, Petitioner and its declarant contend that one
`of ordinary skill in the art—with the known nucleoside 2′-deoxy-2′-fluoro-
`2′-C-methyluridine in hand—would turn first to Perrone for its teaching of
`phosphoramidate prodrug moieties, and then to those moieties that provide
`greater activity, without significant toxicity, in phosphoramidate
`4′-azidouridines. The difficulty, however, is that Petitioner fails to set forth
`a sufficient showing that a person of ordinary skill in the art would have had
`a reasonable expectation of the same benefit with 2′-deoxy-2′-fluoro-2′-C-
`methyluridine.
`Petitioner relies variously on asserted similarity in structure of the
`parent nucleosides without directly addressing the structural differences
`(Pet. 41; Ex. 1002 ¶ 195) and on the notion that the antiviral activity lies on
`the nucleoside itself (Pet. 18). This reliance is insufficient, however, in light
`of potentially significant differential effects on activity (and toxicity) when a
`particular phosphoramidate moiety is used to modify different nucleoside
`analogs, as highlighted by Patent Owner. See, e.g., Prelim. Resp. 29–31.
`Petitioner’s citation to other references that disclose phosphoramidate
`nucleoside analog prodrugs, likewise, as discussed above, is inadequate to
`support trial institution because there is insufficient analysis by Petitioner,
`particularly as to the likelihood of obtaining useful activity without
`significant toxicity. See, e.g., Pet. 10–18, 20–22, and 42. That is to say, in
`the face of evidence that the effect of a particular phosphoramidate moiety
`of a nucleoside analog prodrug is not independent of the structure of the
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`parent nucleoside analog, more is required of Petitioner than general
`assertions that the nucleoside analogs are similar, and that similar
`approaches with other nucleoside analogs provided success.
`Under a non-lead compound analysis, Petitioner has likewise failed to
`set forth a sufficient basis for obviousness, within the meaning of 35 U.S.C.
`§ 103, to meet its threshold burden. “[O]bviousness concerns whether a
`skilled artisan not only could have made but would have been motivated to
`make the combinations or modifications of prior art to arrive at the claimed
`invention.” Belden Inc. v. Berk-Tek LLC, 805 F.3d 1064, 1073 (Fed. Cir.
`2015). The deficiency as to a reasonable expectation of success in obtaining
`an active and nontoxic agent, discussed above, is also relevant here because
`it goes to whether there are “identified, predictable solutions” that the skilled
`artisan would have been motivated to pursue at the time of the invention.
`Cf. Cyclobenzaprine Hydrochloride, 676 F.3d at 1070.
`Further, Petitioner provides no sound basis for “the possible options
`skilled artisans would have encountered [being] ‘finite,’ ‘small,’ or ‘easily
`traversed.’”