Trials@uspto.gov
`571-272-7822
`
`
`
` Paper 91
`
`Entered: May 7, 2021
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`MERCK SHARP & DOHME CORP.,
`Patent Owner.
`____________
`
`IPR2020-000401
`Patent 7,326,708 B2
`____________
`
`
`
`Before SHERIDAN K. SNEDDEN, ROBERT A. POLLOCK, and
`TIMOTHY G. MAJORS, Administrative Patent Judges.
`
`MAJORS, Administrative Patent Judge.
`
`
`
`
`JUDGMENT
`Final Written Decision
`Determining No Challenged Claims Unpatentable
`35 U.S.C. § 318(a)
`Denying Patent Owner’s Motion to Exclude
`37 C.F.R. § 42.64
`
`
`
`
`
`1 Dr. Reddy’s Laboratories, Inc. and Dr. Reddy’s Laboratories, Ltd. were
`joined as parties to this proceeding via Motion for Joinder in IPR2020-
`01060; and Sun Pharmaceuticals Industries Ltd. was joined as a party to this
`proceeding via Motion for Joinder in IPR2020-01072.
`
`

`

`IPR2020-00040
`Patent 7,326,708 B2
`
`I.
`
`INTRODUCTION
`
`Mylan Pharmaceuticals Inc. (“Petitioner” or “Mylan”),2 on October
`
`30, 2019, filed a Petition to institute inter partes review of claims 1–4, 17,
`
`19, and 21–23 of U.S. Patent No. 7,326,708 B2 (Ex. 1001, “the ’708
`
`patent”). Paper 1 (“Pet.” or “Petition”). On May 12, 2020, based on the
`
`preliminary record, we instituted inter partes review of the challenged
`
`claims on all asserted grounds. Paper 21 (“Inst. Dec.”).
`
`After institution, Patent Owner Merck Sharp & Dohme Corp. (“Patent
`
`Owner” or “Merck”) filed a Response. Paper 41 (“PO Resp.”). Petitioner
`
`filed a Reply. Paper 65 (“Reply”). Patent Owner filed a Sur-reply. Paper
`
`74 (“Sur-reply”). Also before us is Patent Owner’s Motion to Exclude (see
`
`Papers 81, 85). We held an oral hearing on February 11, 2021, and the
`
`transcript is on file. Paper 90 (“Tr.”).
`
`As a brief overview, the claims here relate to a compound called
`
`“sitagliptin” and, specifically, to particular dihydrogenphosphate (“DHP”)
`
`salt forms of it that have a 1-to-1 ratio, or stoichiometry, between the
`
`relevant phosphate anion and the corresponding sitagliptin cation. Pet. 1–2;
`
`PO Resp. 1 (discussing “1:1 sitagliptin DHP”); Ex. 1001, 2:44–65, 15:64–
`
`16:15 (claim 1). Sitagliptin is among a class of compounds known as
`
`dipeptidyl peptidase-IV inhibitors, which can inhibit an enzyme implicated
`
`in the etiology of non-insulin dependent diabetes mellitus (i.e., Type 2
`
`diabetes). Id. at 1:3–36. Indeed, Merck developed and sells its drug
`
`
`
`2 Petitioner identifies itself, Mylan Inc., and Mylan N.V. as the real parties-
`in-interest. Pet. 6.
`
`2
`
`

`

`IPR2020-00040
`Patent 7,326,708 B2
`
`product, Januvia, which is indicated for treatment of Type 2 diabetes and
`
`includes a 1:1 sitagliptin DHP salt. PO Resp. 1, 25–26; Ex. 2003 ¶ 2.3
`
`The dispute in this case focuses, in large part, on whether an earlier-
`
`filed international patent application, which Merck also owns, expressly or
`
`inherently discloses the 1:1 sitagliptin DHP salt claimed in the ’708 patent.4
`
`At institution, and despite our determination that this prior art included no
`
`explicit disclosure of a phosphate salt of sitagliptin having the 1:1
`
`stoichiometry, we nevertheless instituted trial based, inter alia, on testimony
`
`from Petitioner’s expert that sitagliptin can only be mono-protonated and
`
`reacting sitagliptin with phosphoric acid forms the 1:1 DHP salt “every
`
`time” and is, thus, inherent. Inst. Dec. 52–53 (noting preliminary record
`
`“suggest[s] the 1:1 salt is the necessary byproduct of contacting phosphoric
`
`acid and sitagliptin”). Because it is undisputed that the prior art does not
`
`expressly disclose the specific 1:1 DHP salt of sitagliptin,5 and the evidence
`
`through trial now shows that sitagliptin can form phosphate salts in non-1:1
`
`ratios without necessarily forming the 1:1 salt (i.e., no inherency), Merck
`
`argues that Petitioner’s anticipation challenge fails. PO Resp. 6–19.
`
`
`
`3 Merck has indicated that “the crystalline monohydrate form of the DHP
`salt . . . is the solid form of sitagliptin used today in Merck’s products.”
`Paper 10, 4–5.
`4 The published international patent application (WO 03/004498) and a U.S.
`counterpart patent (US 6,699,871; also asserted here as anticipating art)
`contain materially “identical” disclosures. See Pet. 33; Tr. 7:8–13.
`5 See Tr. 15:7–19 (Petitioner’s counsel agreeing that “there’s no express
`disclosure of a 1:1 DHP salt of sitagliptin in the WO [’498] reference or the
`’871 reference”); Ex. 2103 ¶ 67.
`
`3
`
`

`

`IPR2020-00040
`Patent 7,326,708 B2
`
`If anticipation fails, Petitioner is left with obviousness. But, in
`
`Merck’s telling, the obviousness challenge fares no better because Merck’s
`
`inventors reduced to practice the subject matter of almost all the challenged
`
`claims before the key prior art published, thus disqualifying that art as a
`
`§ 102(a) reference; and, even if that art still qualifies under § 102(e),
`
`Merck’s common ownership of the art eliminates it from the obviousness
`
`analysis under § 103(c)(1).6 PO Resp. 22–28. For the two dependent claims
`
`for which Merck does not argue an earlier reduction to practice, Merck
`
`contends those claims are not obvious because, among other things, that
`
`claimed subject matter was highly unpredictable and Petitioner failed to
`
`show a reason why it would have been made by an ordinarily skilled person
`
`with a reasonable expectation of success. Id. at 38–59.
`
`We address in detail the parties’ arguments on anticipation and
`
`obviousness in the sections below. On this trial record, however, we find
`
`Petitioner has failed to show by a preponderance of the evidence that claims
`
`1–4, 17, 19, and 21–21 are unpatentable. Petitioner has, thus, not met its
`
`burden and proved unpatentability of the challenged claims. 35 U.S.C.
`
`§ 316(e). Our reasoning is detailed in Section II below.
`
`We also deny Patent Owner’s Motion to Exclude. Infra Section III.
`
`
`
`6 Under the pre-AIA § 103(c)(1) exception, subject matter developed by
`“another person” that qualifies as prior art under § 102(e) can be eliminated
`from use in an obviousness analysis if that subject matter and the claimed
`invention are commonly owned or under obligation of assignment to the
`same person or entity at the time of the invention. 35 U.S.C. § 103(c)(1).
`4
`
`

`

`IPR2020-00040
`Patent 7,326,708 B2
`
` Related Patents and Proceedings
`
`“[T]here are no related United States patents or pending applications”
`
`and “this is the first IPR directed to the ’708 patent.” Pet. 7, 67.
`
`Petitioner identifies several related cases before the courts including,
`
`without limitation: Merck Sharp & Dohme Corp. v. Mylan Pharm. Inc. et
`
`al., 1:19:-cv-00101 (N.D. W. Va.); Merck Sharp & Dohme Corp. v. Mylan
`
`Pharm. Inc. et al., 1:19-cv-01489 (D. Del.); and Merck Sharp & Dohme
`
`Corp. v. Sandoz, Inc., 1:19-cv-00312 (D. Del.). Pet. 6–7 (listing cases).
`
`Patent Owner states that it “filed Hatch-Waxman suits alleging infringement
`
`of the ’708 patent, among others, against fourteen generic drug companies
`
`including Mylan, Teva, Apotex, Par, Sun, and Sandoz.” Paper 10, 10. The
`
`litigation against the generic drug companies “has been consolidated for
`
`pretrial proceedings in a multidistrict litigation (‘MDL’)” before the district
`
`court in Delaware. Id. (identifying In re Sitagliptin Phosphate (’708 &
`
`’921) Patent Litig., C.A. No. 19-md-2902-RGA (D. Del.)).
`
`There are also related matters filed with the Board. After institution,
`
`other petitioners filed substantially identical petitions challenging claims of
`
`the ’708 patent and requested joinder with Mylan in this proceeding. See
`
`IPR2020-01045 (“Teva” matter); IPR2020-01060 (“Dr. Reddy’s” matter);
`
`IPR2020-01072 (“Sun” matter). We instituted trial in those other matters
`
`and joined the petitioners as parties here. IPR2020-00040, Papers 44–46.
`
`The Dr. Reddy’s and Sun parties remain joined. The Teva parties (Teva
`
`Pharmaceuticals USA, Inc. and Watson Laboratories, Inc.) have settled with
`
`Merck and IPR2020-01045 is terminated. IPR2020-01045, Paper 25. The
`
`Teva parties are no longer joined. IPR2020-00040, Paper 73, 2–3.
`
`5
`
`

`

`IPR2020-00040
`Patent 7,326,708 B2
`
` Asserted Grounds of Unpatentability
`
`Petitioner asserts six grounds of unpatentability (Pet. 12) as set forth
`
`in the table below:
`
`Claim(s) Challenged
`1–3, 17, 19, 21–23
`
`1–3, 17, 19, 21–23
`
`35 U.S.C. §
`102(a),
`102(e)(2)7
`
`102(e)(2)
`
`Basis
`
`WO ’4988
`
`’871 patent9
`
`3, 17, 19, 21–23
`
`103
`
`WO ’498
`
`1–3, 17, 19, 21–23
`
`103
`
`WO ’498, Bastin10
`
`4
`
`4
`
`103
`
`103
`
`WO ’498, Bastin, Brittain11
`
`WO ’498, Brittain
`
`
`
`7 The Leahy-Smith America Invents Act, Pub. L. No. 112-29, 125 Stat. 284
`(2011) (“AIA”), amended 35 U.S.C. §§ 102 and 103. The ’708 patent’s
`claims have an effective filing date before the effective date of those
`amendments so we refer to the pre-AIA versions of §§ 102 and 103 here.
`8 Edmondson et al., WO 03/004498 A1, published Jan. 16, 2003 (Ex. 1004,
`“WO ’498”). WO ’498 published from Application No. PCT/US02/21349,
`filed July 5, 2002, which claims priority to US Provisional Application No.
`60/303,474, filed July 6, 2001 (Ex. 1012).
`9 Edmondson et al., US 6,699,871 B2, issued Mar. 2, 2004 (Ex. 1007, “the
`’871 patent”). The ’871 patent issued from an application filed July 5, 2002,
`and claims priority to US Provisional Application No. 60/303,474, filed July
`6, 2001 (Ex. 1012).
`10 Richard J. Bastin et al., Salt Selection and Optimisation Procedures for
`Pharmaceutical New Chemical Entities, 4 ORGANIC PROCESS RESEARCH &
`DEVELOPMENT 427–435, 2000 (Ex. 1006, “Bastin”).
`11 Polymorphism in Pharmaceutical Solids, Harry G. Brittain ed., 1999
`(Ex. 1005, “Brittain”).
`
`6
`
`

`

`IPR2020-00040
`Patent 7,326,708 B2
`
`Petitioner relies on the Declaration of Mukund Chorghade, Ph.D.
`
`(Ex. 1002) and Dr. Chorghade’s Reply Declaration (Ex. 1035), among other
`
`evidence.
`
`Patent Owner relies on the Declaration of Allan S. Myerson, Ph.D.
`
`(Ex. 2101), the Declaration of Adam J. Matzger, Ph.D. (Ex. 2103), and
`
`testimony from several current or former Merck employees (including many
`
`of the ’708 patent’s eight named inventors), among other evidence. See,
`
`e.g., Exs. 2002 (Vydra Decl.), 2003 (Wenslow Decl.), 2004 (Ferlita Decl.),
`
`2005 (Diddle Decl.), 2109 (Herman Decl.), 2124 (Cypes Decl.), 2127
`
`(Hansen Decl.), and 2140 (Shultz Decl.).
`
` The ’708 Patent
`
`The ’708 patent is titled “PHOSPHORIC ACID SALT OF A
`
`DIPEPTIDYL PEPTIDASE-IV INHIBITOR.” Ex. 1001, code (54). The
`
`’708 patent claims priority to non-provisional and provisional patent
`
`applications filed, respectively, on June 23, 2004, and June 24, 2003. Id. at
`
`codes (21), (22), (60). The patent issued February 5, 2008. Id. at code (45).
`
`According to the ’708 patent, “[t]he present invention relates to a
`
`particular salt of a dipeptidyl peptidase-IV inhibitor,” and specifically, the
`
`dihydrogenphosphate (“DHP”) salt of 4-oxo-4-[3-(trifluoromethyl)-5,6-
`
`dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-
`
`trifluorophenyl)butan-2-amine. Id. at 1:13–17. The chemical,4-oxo-4-[3-
`
`(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-
`
`(2,4,5-trifluorophenyl)butan-2-amine, is also known as “sitagliptin.” See
`
`7
`
`

`

`IPR2020-00040
`Patent 7,326,708 B2
`
`Ex. 2003 ¶ 2; Pet. 1 n.1.12 The structural formula for the DHP salt of
`
`sitagliptin is shown below as formula (I):
`
`
`
`Ex. 1001, 2:44–63. This formula reflects a salt with one phosphate anion
`
`associated with one sitagliptin amine cation (with a stereogenic carbon at *).
`
`Id. at 3:46–52 (“[T]he dihydrogenphosphate salt of the present invention is
`
`comprised of one molar equivalent of mono-protonated [sitagliptin] . . . and
`
`one molar equivalent of the dihydrogenphosphate (biphosphate) anion.”).
`
`The ’708 patent states that this salt is “useful for the treatment and
`
`prevention of diseases and conditions for which an inhibitor of dipeptidyl
`
`peptidase-IV is indicated, in particular Type 2 diabetes.” Id. at 1:19–22.
`
`In a section related to background of the invention, the ’708 patent
`
`identifies WO 03/004498 (i.e., WO ’498), which is “assigned to Merck &
`
`
`
`12 Petitioner notes, without dispute, that sitagliptin is also the compound with
`the chemical name: 7-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-
`(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-α]pyrazine. Pet. 1
`n.1; Ex. 1004, 47 (Example 7). In citing asserted references and technical
`publications in this Decision, we generally use the page numbers added to
`the exhibit not the original pagination, except that, for US patents, we use
`the column and line number format or other indicia.
`8
`
`

`

`IPR2020-00040
`Patent 7,326,708 B2
`
`Co.” Id. at 1:49–50. The ’708 patent states that WO ’498 “describes a class
`
`of beta-amino tetrahydrotriazolo[4,3-a]pyrazines, which are potent inhibitors
`
`of DP-IV and therefore useful for the treatment of Type 2 diabetes.” Id. at
`
`1:50–52. According to the ’708 patent, WO ’498 “[s]pecifically disclose[s]”
`
`the 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-
`
`7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine. Id. at 1:53–55. The
`
`patent states that “[p]harmaceutically acceptable salts of this compound are
`
`generically encompassed within the scope of WO 03/004498.” Id. at 1:53–
`
`57. “However,” the ’708 patent states, “there is no specific disclosure in the
`
`above reference [(WO ’498)] of the newly discovered monobasic
`
`dihydrogenphosphate salt . . . of structural formula I.” Id. at 1:58–62.
`
`The ’708 patent further notes the following about WO ’498:
`
`The crystalline dihydrogenphosphate salt of the present
`invention exhibits pharmaceutic advantages over the free base
`and the previously disclosed hydrochloride salt (WO 03/004498)
`in the preparation of a pharmaceutical drug product containing
`the pharmaceutically active ingredient. In particular, the
`enhanced chemical and physical stability of the crystalline
`dihydrogenphosphate salt monohydrate constitute advantageous
`properties in the preparation of solid pharmaceutical dosage
`forms containing the pharmacologically active ingredient.
`
`Id. at 4:19–28.
`
` Challenged Claims
`
`The ’708 patent includes twenty-four claims. Petitioner challenges
`
`claims 1–4, 17, 19, and 21–23. Claims 1, 2, and 4 are illustrative and read as
`
`follows:
`
`9
`
`

`

`IPR2020-00040
`Patent 7,326,708 B2
`
`1. A dihydrogenphosphate salt of 4-oxo-4-[3-(trifluoromethyl)-
`5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine of structural formula I:
`
`
`or a hydrate thereof.
`
`2. The salt of claim 1 of structural formula II having the (R)-
`configuration at the chiral center marked with an *
`
`
`
`
`
`4. The salt of claim 2 characterized as being a crystalline
`monohydrate.
`
`Ex. 1001, 15:64–16:30, 16:48–49. Each of the other challenged claims
`
`depends (directly or indirectly) on claims 1 or 2. See, e.g., id. at 17:29–32
`
`(claim 19: method of treating type 2 diabetes with the salt of claim 2),
`
`17:37–18:5 (claim 21: process for preparing the salt of claim 2).
`
`10
`
`

`

`IPR2020-00040
`Patent 7,326,708 B2
`
`II. ANALYSIS
`
` Principles of Law
`
`“In an IPR, the petitioner has the burden from the onset to show with
`
`particularity why the patent it challenges is unpatentable.” Harmonic Inc. v.
`
`Avid. Tech., Inc., 815 F.3d 1356, 1363 (Fed. Cir. 2016) (citing 35 U.S.C.
`
`§ 312(a)(3)).
`
`To show anticipation under 35 U.S.C. § 102, each and every claim
`
`element, arranged as in the claim, must be found in a single prior art
`
`reference. Net MoneyIN, Inc. v. VeriSign, Inc., 545 F.3d 1359 (Fed. Cir.
`
`2008). The prior art need not, however, use the same words as the claims.
`
`In re Gleave, 560 F.3d 1331, 1334 (Fed. Cir. 2009). The anticipation
`
`inquiry takes into account the literal teachings of the prior art reference, and
`
`inferences the ordinarily skilled person would draw from it. Eli Lilly and
`
`Co. v. Los Angeles Biomedical Res. Inst. at Harbor-UCLA Med. Ctr., 849
`
`F.3d 1073, 1074–75 (Fed. Cir. 2017). Indeed, “a reference can anticipate a
`
`claim even if it does not expressly spell out all the limitations arranged or
`
`combined as in the claim, if a person of skill in the art, reading the reference,
`
`would at once envisage the claimed arrangement or combination.”
`
`Kennametal, Inc. v. Ingersoll Cutting Tool Co., 780 F.3d 1376, 1381 (Fed.
`
`Cir. 2015) (internal quotation marks omitted).
`
`As to obviousness, a claim is unpatentable under 35 U.S.C. § 103 if
`
`the differences between the subject matter sought to be patented and the
`
`prior art are such that the subject matter as a whole would have been obvious
`
`at the time the invention was made to a person having ordinary skill in the
`
`art. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007). The question
`
`11
`
`

`

`IPR2020-00040
`Patent 7,326,708 B2
`
`of obviousness is resolved on the basis of underlying factual determinations
`
`including: (1) the scope and content of the prior art; (2) any differences
`
`between the claimed subject matter and the prior art; (3) the level of ordinary
`
`skill in the art; and (4) objective evidence of nonobviousness when
`
`presented. Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966). A party
`
`who petitions the Board for a determination of unpatentability based on
`
`obviousness must show that “a skilled artisan would have been motivated to
`
`combine the teachings of the prior art references to achieve the claimed
`
`invention, and that the skilled artisan would have had a reasonable
`
`expectation of success in doing so.” In re Magnum Oil Tools Int’l, Ltd., 829
`
`F.3d 1364, 1381 (Fed. Cir. 2016) (quotations and citations omitted).
`
` Person of Ordinary Skill in the Art
`
`In determining the level of skill in the art, we consider the problems
`
`encountered in the art, the art’s solutions to those problems, the rapidity with
`
`which innovations are made, the sophistication of the technology, and the
`
`educational level of active workers in the field. Custom Accessories, Inc. v.
`
`Jeffrey-Allan Indus., Inc., 807 F.2d 955, 962 (Fed. Cir. 1986).
`
`Petitioner contends a person of ordinary skill in the art (or “POSA”) at
`
`the time of the invention would have had:
`
`(i) a Ph.D. in chemistry, biochemistry, medical chemistry,
`pharmacy, pharmaceutics, or a related field, and at least two
`years of relevant experience in drug development including an
`understanding of salt selection in drug development; (ii) a
`master’s degree in the same fields and at least five years of the
`same relevant experience; or (iii) a bachelor’s degree in the same
`fields and at least seven years of the same relevant experience.
`
`12
`
`

`

`IPR2020-00040
`Patent 7,326,708 B2
`
`Pet. 11; Ex. 1002 ¶¶ 45–46. Patent Owner does not oppose this definition.13
`
`We find Petitioner’s proposed definition is consistent generally with
`
`the cited prior art, and we apply it for the purposes of this Decision. See
`
`Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001) (explaining that
`
`specific findings regarding ordinary skill level are not required “where the
`
`prior art itself reflects an appropriate level and a need for testimony is not
`
`shown”) (quoting Litton Indus. Prods., Inc. v. Solid State Sys. Corp., 755
`
`F.2d 158, 163 (Fed. Cir. 1985)).
`
` Claim Construction
`
`We interpret a claim “using the same claim construction standard that
`
`would be used to construe the claim in a civil action under 35 U.S.C.
`
`282(b).” 37 C.F.R. § 42.100(b) (2019). Under this standard, we construe
`
`the claim “in accordance with the ordinary and customary meaning of such
`
`claim as understood by one of ordinary skill in the art and the prosecution
`
`history pertaining to the patent.” Id. “[W]e need only construe terms ‘that
`
`are in controversy, and only to the extent necessary to resolve the
`
`controversy.’” Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co.
`
`
`
`13 Merck’s experts, Drs. Myerson and Matzger, phrase the definition
`differently—limiting the fields of study to “chemistry, chemical engineering
`or a related field,” and requiring two or more years (depending degree
`attained) “working with pharmaceutical solids, including polymorphic
`forms.” Ex. 2101 ¶ 39; Ex. 2103 ¶ 40. Neither party contends, however,
`that any disputed matter turns on acceptance of one definition or the other.
`Merck’s experts state that their opinions do not change under either
`definition. Ex. 2101 ¶ 40; Ex. 2103 ¶ 41.
`13
`
`

`

`IPR2020-00040
`Patent 7,326,708 B2
`
`Ltd., 868 F.3d 1013, 1017 (Fed. Cir. 2017) (quoting Vivid Tech., Inc. v. Am.
`
`Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999)).
`
`At institution, neither party requested any express claim construction.
`
`Pet. 10 (“Petitioner submits that no further construction [beyond the claims
`
`as written] is necessary”); Ex. 1002 ¶¶ 57–59.
`
`Claim 21 is a dependent claim and recites a process for preparing the
`
`1:1 (R)-sitagliptin DHP of claim 2. Ex. 1001, 17:37–18:5. Petitioner, in its
`
`Reply, argues that claim 21’s “contacting” limitation “means an actual
`
`physical interaction between molecules.” Reply at 11–12. Petitioner’s
`
`position is that the claim phrase “contacting one equivalent of [sitagliptin] in
`
`an organic solvent or aqueous organic solvent with about one equivalent of
`
`phosphoric acid at a temperature in the range of about 25–100°C” does not
`
`limit the molar amounts of the acidic and basic reagents provided in the
`
`solvent, but rather how discrete molecules actually interact to form the final
`
`salt. Id.; Ex. 1001, 17:38–18:5; Tr. 23:23–25:9. In Petitioner’s view, “the
`
`sitagliptin base molecule is only able to interact once with a phosphoric acid
`
`molecule.” Reply 12. And because a 1:1 salt allegedly always forms when
`
`an acid (e.g., hydrochloric or phosphoric) is reacted with sitagliptin, the
`
`“contacting” step would be met even if the reaction conditions were to
`
`include using a large excess (i.e., a substantially non-equivalent molar
`
`amount) of acid molecules relative to the base, such as the excess
`
`hydrochloric acid in WO ’498’s Example 7.14 Reply 12–13.
`
`
`
`14 Put differently, Petitioner’s position is that it does not matter what molar
`amounts of the acid and base are used (e.g., 100 moles of acid vs. 1 mole of
`
`14
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`Patent Owner responds that Petitioner is abrogating claim 21’s
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`limitations. According to Patent Owner, Petitioner’s interpretation and
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`application of the art to claim 21 renders irrelevant: (i) the starting materials
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`(insofar as the cited art starts with BOC-protected sitagliptin, not sitagliptin
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`free base); and (ii) the claim’s “one equivalent” language (insofar as the
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`cited example in the art uses a substantial molar excess of the acid), so long
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`as a salt with 1:1 stoichiometry might somewhere form in a downstream
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`process. Sur-reply 13–14; see also Ex. 2103 ¶ 232 (describing WO ’498’s
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`Example 7 as “using ~1000 fold excess of hydrochloric acid”).
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`Given the present record, we are unpersuaded that a further
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`construction of claim 21 is required. Even if we agreed with Petitioner’s
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`interpretation, Petitioner has not proved that the cited art expressly or
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`inherently discloses preparing the 1:1 DHP salt of sitagliptin (discussed infra
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`for anticipation challenges). Alternatively, if claim 21 required use of one
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`molar equivalent of sitagliptin and about (i.e., “approximately”) one molar
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`
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`base would still be encompassed); key to Petitioner’s argument is the final
`result of a 1:1 salt, thus allegedly proving the reagents will only interact in a
`1:1 ratio. We explained at the oral hearing that we found Petitioner’s
`interpretation problematic because it cited no intrinsic evidence in support
`and also appeared to read the term “about” out of the claim. Tr. 25:2–27:6
`(asking how it’s possible to have interaction at a molecular level as
`suggested by Petitioner (seemingly requiring whole numbers ratios, like 1:1
`or 1:2, in which the molecules might interact and bond) between one
`equivalent of a molecule and about one equivalent of another). Petitioner
`had no satisfactory response to those concerns. Id.; see also id. at 75:14–21
`(Petitioner’s counsel later suggested that even if the “contacting” step
`required use of equal molar amounts, using such amounts would be an
`obvious change “that you would indeed use”).
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`equivalent of acid in the solvent (see Ex. 1001, 6:29–55 (disclosing a
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`process for preparing the claimed 1:1 sitagliptin DHP)), Petitioner has not
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`shown that WO ’498 describes that reaction. Again, it is undisputed that the
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`cited example (Example 7 of WO ’498) uses a substantial molar excess of
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`the acid (HCl) to the base. On obviousness and as explained below (see
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`Section II(F)), we conclude that Patent Owner’s reduction-to-practice
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`evidence is dispositive for several claims, including claim 21, and that issue
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`does not turn on whether we accept or reject Petitioner’s interpretation
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`(which encompasses, but is not limited to, using equimolar amounts). PO
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`Resp. 25 (explaining, citing undisputed evidence, how the inventors made
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`1:1 sitagliptin DHP with “equimolar” amounts of sitagliptin and phosphoric
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`acid under conditions encompassed by claim 21).
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` Anticipation by WO ’498
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`Petitioner asserts that claims 1–3, 17, 19, and 21–23 are unpatentable
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`as anticipated by WO ’498. Pet. 12–31. We provide an overview of
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`WO ’498, and then turn to analysis of the alleged anticipation.
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`1.
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`Overview of WO ’498 (Exhibit 1004)
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`WO ’498 “is directed to compounds which are inhibitors of the
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`dipeptidyl peptidase-IV enzyme (‘DP-IV inhibitors’) and which are useful in
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`the treatment or prevention of diseases in which the dipeptidyl peptidase-IV
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`enzyme is involved, such as diabetes and particularly type 2 diabetes.”
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`Ex. 1004, 1. WO ’498 is further “directed to pharmaceutical compositions
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`comprising these compounds and the use of these compounds and
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`compositions” for treatment or prevention of the above-noted diseases. Id.
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`WO ’498 discloses several examples of the compounds of its
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`invention. Id. at 38–47 (describing Examples 1–7); see also id. at 48–49
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`(identifying other example compounds, numbered examples 8–33). The salt
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`of Example 7 is shown in the chemical structure below.
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`Id. at 47:1–5; see also id. at 47:6–26 (describing steps for preparing the
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`compound and salt of Example 7). The structure in Example 7 of WO ’498
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`“depicts the hydrochloride salt of sitagliptin in its (R)-configuration.”
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`
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`Ex. 1002 ¶ 67.
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`WO ’498 does not describe or exemplify any specific phosphate salt
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`of sitagliptin (or any phosphate of the other compounds). More generically,
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`however, WO ’498 claims (R)-sitagliptin and several other compounds, and
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`pharmaceutically acceptable salts thereof. WO ’498 claims:
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`17
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`15. A compound which is selected from the group consisting of:
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`***
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`***
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`
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`and pharmaceutically acceptable salts thereof.
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`Ex. 1004, 55:16–61:5 (claim 15 depicts thirty-three DP-IV inhibitor
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`compounds, one of which is (R)-sitagliptin (shown in the excerpt above),
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`and, after depicting all those compounds, recites “and pharmaceutically
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`acceptable salts thereof”).
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`WO ’498 elsewhere describes “‘pharmaceutically acceptable salts’
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`[as] refer[ring] to salts prepared from pharmaceutically acceptable non-toxic
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`bases or acids including inorganic or organic bases and inorganic or organic
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`acids.” Id. at 10:27–29. “When the compound of the present invention is
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`basic,” WO ’498 indicates the “salts may be prepared from pharmaceutically
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`acceptable non-toxic acids, including inorganic and organic acids,” and
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`WO ’498 identifies twenty-six illustrative acids. Id. at 11:8–14 (“Such acids
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`include acetic, benzenesulfonic, benzoic, . . . hydrochloric, . . . phosphoric,
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`succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.”). Among
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`the twenty-six acids named, WO ’498 discloses that “[p]articularly preferred
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`are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric,
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`18
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`and tartaric acids.” Id. at 11:14–15; see also id. at 11:16–17 (“It will be
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`understood, as used herein, references to the compounds of Formula I are
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`meant to also include the pharmaceutically acceptable salts.”).
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`2.
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`Analysis of Alleged Anticipation
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`a)
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`The Parties’ Arguments
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`Petitioner contends that WO ’498 discloses (R)-sitagliptin and its
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`pharmaceutically acceptable salts. Pet. 16–17 (citing Ex. 1004, 55–60
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`(“Claim 15 (7th compound)”). Petitioner further argues that WO ’498’s
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`disclosure of acceptable salts would include at least the eight “[p]articularly
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`preferred” acids, one of which is phosphoric acid, as a non-toxic acid for use
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`in forming salts with compounds like sitagliptin. Id. at 16–18; see Ex. 1004,
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`10:8–15. Thus, Petitioner argues, “WO ’498 teaches the phosphoric acid
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`salt of sitagliptin” and a specific example is not needed. Id. at 16–18.
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`According to Petitioner, this case involves anticipation by disclosure
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`of “lists,” not necessarily anticipation where the art discloses a genus and a
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`species within that genus are claimed. Pet. 20–22 (citing, e.g., Wm. Wrigley
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`Jr. Co. v. Cadbury Adams USA LLC, 683 F.3d 1356, 1361 (Fed. Cir. 2012));
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`see also id. at 23–24 (citing In re Gleave, 560 F.3d 1331, 1331 (Fed. Cir.
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`2009) (“For purposes of whether they are anticipatory, lists and genera are
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`often treated differently under our case law.”)).15 More specifically,
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`
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`15 Whether a disclosed genus anticipates a species ordinarily turns on
`whether the prior art “expressly spelled out a definite and limited class of
`compounds that enabled a person of ordinary skill in the art to at once
`envisage each member of this limited class.” Eli Lilly & Co. v. Zenith
`Goldline Pharm., Inc., 471 F.3d 1369, 1376 (Fed. Cir. 2006); Atofina v.
`
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`Petitioner contends “WO ’498 provides two closed lists,” where “[t]he
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`primary list (i.e., Claim 15) provides 33 compounds” and the “secondary”
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`list “identifies by name the eight” preferred acids. Id. at 22. Because the
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`first list includes (R)-sitagliptin and the second list includes phosphoric acid,
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`Petitioner contends “neither list leaves anything to the imagination” and
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`WO ’498 anticipates claims 1 and 2. Id. at 22–24. Petitioner asserts that
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`WO ’498’s disclosures even arguably “collapse to form a single
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`comprehensive list” of all the compounds and salts. Id. at 23–24; Ex. 1002
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`¶ 80. And, because lists are involved, Petitioner argues “the number of
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`[listed items] is irrelevant.” Id. at 24 (citing In re Gleave, 560 F.3d at 1333,
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`1338 (explaining that the art “expressly lists every possible fifteen-base-long
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`oligodeoxynucleotide sequence in IGFBP-2,” and that the “list include[d]
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`more than 1400 sequences”)).
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`Petitioner does not, in the Petition, address the 1:1 stoichiometry
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`limitation of the claimed salt head-on. To the extent addressed at all,
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`Petitioner’s discussion appears in parts of a footnote spanning several pages.
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`Pet. 18–20 n.8. There, Petitioner states that claim 1’s “dihydrogenphosphate
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`salt” of sitagliptin, “is nothing more than another name for the (monobasic)
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`phosphoric acid salt of sitagliptin.” Id. Petitioner cites the ’708 patent’s
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`disclosure on reacting one equivalent of sitagliptin with approximately one
`
`
`
`Great Lakes Chem. Corp., 441 F.3d 991, 999 (Fed. Cir. 2006) (“It is well
`established that the disclosure of a genus in the prior art is not necessarily a
`disclosure of every species that is a member of that genus. . . . There may be
`many species encompassed within a genus that are not disclosed by a mere
`disclosure of the genus. On the oth