Court Opinion

ID: 8210188
Source: CourtListenerOpinion
Date Created: 2022-09-29 13:00:30.647363+00
Date Added: 2024-06-11T16:41:48.232901
License: Public Domain

Case: 21-2121    Document: 49    Page: 1   Filed: 09/29/2022

   United States Court of Appeals
       for the Federal Circuit
                  ______________________

         MYLAN PHARMACEUTICALS INC.,
                  Appellant

                            v.

          MERCK SHARP & DOHME CORP.,
                     Appellee
              ______________________

                        2021-2121
                  ______________________

     Appeal from the United States Patent and Trademark
 Office, Patent Trial and Appeal Board in No. IPR2020-
 00040.
                  ______________________

                Decided: September 29, 2022
                  ______________________

     ERIC THOMAS WERLINGER, Katten Muchin Rosenman
 LLP, Washington, DC, argued for appellant. Also repre-
 sented by JITENDRA MALIK, Charlotte, NC; DEEPRO
 MUKERJEE, LANCE SODERSTROM, New York, NY.

     JEFFREY A. LAMKEN, MoloLamken LLP, Washington,
 DC, argued for appellee. Also represented by CALEB
 HAYES-DEATS, MICHAEL GREGORY PATTILLO, JR.; LAUREN F.
 DAYTON, MARK W. KELLEY, New York, NY; STANLEY E.
 FISHER, BRUCE GENDERSON, DAVID M. KRINSKY, SHAUN
 PATRICK MAHAFFY, CHARLES MCCLOUD, Williams & Con-
 nolly LLP, Washington, DC.
Case: 21-2121    Document: 49      Page: 2    Filed: 09/29/2022

 2                            MYLAN PHARMACEUTICALS INC. v.
                                MERCK SHARP & DOHME CORP.

                  ______________________

     Before LOURIE, REYNA, and STOLL, Circuit Judges.
 LOURIE, Circuit Judge.
      Mylan Pharmaceuticals Inc. (“Mylan”) appeals from
 the final written decision of the U.S. Patent and Trade-
 mark Office Patent Trial and Appeal Board (the “Board”)
 holding that it failed to show that claims 1–4, 17, 19, and
 21–23 of U.S. Patent 7,326,708 (the “’708 patent”) were an-
 ticipated or would have been obvious over the cited prior
 art at the time the alleged invention was made. See Mylan
 Pharms. Inc. v. Merck Sharp & Dohme Corp., No. IPR2020-
 00040, 2021 WL 1833325 (P.T.A.B. May 7, 2021) (“Deci-
 sion”). For the reasons provided below, we affirm.
                        BACKGROUND
      Merck Sharp & Dohme Corp. (“Merck”) owns the ’708
 patent, which describes sitagliptin dihydrogenphosphate
 (“sitagliptin DHP”). Sitagliptin DHP is a dihydrogenphos-
 phate 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-trifluoro-
 phenyl)butan-2-amine. Sitagliptin DHP belongs to the
 class of dipeptidyl peptidase-IV (“DP-IV”) inhibitors, which
 can be used for treating non-insulin-dependent (i.e., Type
 2) diabetes. Independent claim 1 recites a sitagliptin DHP
 salt with a 1:1 stoichiometry, and reads as follows:
        1. A dihydrogenphosphate salt of a 4-oxo-4-[3-
           (trifluoromethyl)-5,6-dihydro      [1,2,4]tria-
           zolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-tri-
           fluorophenyl)butan-2-amine of Formula I:
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 MYLAN PHARMACEUTICALS INC.     v.                            3
 MERCK SHARP & DOHME CORP.

            or a hydrate thereof.
 ’708 patent col. 15 l. 64–col. 16 l. 15.
     Sitagliptin contains a single asymmetric carbon, indi-
 cated by the asterisk in the above chemical structure. The
 (R)-configuration and (S)-configuration of sitagliptin DHP
 are recited in dependent claims 2 and 3, respectively. A
 crystalline monohydrate form of the (R)-configuration is re-
 cited in dependent claim 4.
      Mylan petitioned for inter partes review (“IPR”) of
 claims 1–4, 17, 19, and 21–23 of the ’708 patent. J.A. 177.
 Mylan argued that claims 1–3, 17, 19, and 21–23 were an-
 ticipated    by      International   Patent    Publication
 WO 2003/004498 (the “’498 publication”), a Merck-owned
 publication, and the equivalent U.S. Patent 6,699,871 (the
 “’871 patent”) (collectively, “Edmondson”). 1
      Edmondson “is directed to compounds which are inhib-
 itors of the dipeptidyl peptidase-IV enzyme (‘DP-IV inhibi-
 tors’) and which are useful in the treatment or prevention
 of diseases in which the dipeptidyl peptidase-IV enzyme is
 involved, such as diabetes and particularly type 2 diabe-
 tes.” Decision, 2021 WL 1833325, at *6. Specifically, Ed-
 mondson discloses a genus of DP-IV inhibitors and
 33 species, one of which is sitagliptin. ’498 publication
 col. 54 l. 16–col. 60 l. 5. Edmondson further discloses that
 pharmaceutically acceptable salts can be formed using one
 of eight “[p]articularly preferred” acids. Id. at col. 10
 ll. 14–15. Phosphoric acid is in the list of “particularly pre-
 ferred” acids. Edmondson also discloses that the salts may

     1    The parties agree that the ’498 publication and the
 ’871 patent are identical in relevant part. Appellant’s
 Br. 1; Appellee’s Br. 5, n.1. The Board also treated them as
 identical in relevant part. Decision, 2021 WL 1833325, at
 *1, n.4.
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 4                            MYLAN PHARMACEUTICALS INC. v.
                                MERCK SHARP & DOHME CORP.

 exist in crystalline forms, including as hydrates. Id. at col.
 9 ll. 32–34.
     Mylan also argued that claims 1–4, 17, 19, and 21–23
 would have been obvious over Edmondson and two addi-
 tional publications titled “Structural Aspects of Hydrates
 and Solvates” (“Brittain”) 2 and “Salt Selection and Optimi-
 sation Procedures for Pharmaceutical New Chemical Enti-
 ties” (“Bastin”). 3
     Brittain describes the pharmaceutical importance and
 prevalence of crystalline hydrates of pharmaceutical com-
 pounds. J.A. 438–94. Specifically, Brittain teaches that
 approximately one third of studied pharmaceutical active
 ingredients could form crystalline hydrates, and half of
 those one-third were monohydrates. J.A. 441. In other
 words, Brittain illustrates that approximately one sixth of
 the analyzed pharmaceutical compounds formed crystal-
 line monohydrates. Brittain also cites various challenges
 that arise during the manufacturing and development of
 hydrates, including lower solubility, chemical instability,
 and discoloration. J.A. 440.
     Bastin teaches salt selection and optimization proce-
 dures during the development of pharmaceutical com-
 pounds. J.A. 495–97. Specifically, Bastin teaches that a
 range of possible salts should be prepared for each new sub-
 stance to compare adequately the properties of each salt
 during the development process. J.A. 495. Bastin also

     2   Kenneth R. Morris, Structural Aspects of Hydrates
 and Solvates, in Polymorphism in Pharmaceutical Solids
 125–181 (Harry G. Brittain ed., 1999).
     3   Richard J. Bastin, Michael J. Bowker, & Brian J.
 Slater, Salt Selection and Optimisation Procedures for
 Pharmaceutical New Chemical Entities, 4 Organic Process
 Rsch. & Dev. 427 (2000).
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 discloses disadvantages of certain salts used in drug for-
 mulations, including hydrochloric acid (“HCl”). J.A. 496.
     First, the Board determined that there was no express
 disclosure of all of the limitations of the 1:1 sitagliptin DHP
 salt in Edmondson, and that Mylan could not fill in the
 gaps by arguing that a skilled artisan would “at once en-
 visage” what is missing. Decision, 2021 WL 1833325, at
 *10, *12. The Board also concluded that Mylan had not
 proven an inherent disclosure of the 1:1 sitagliptin DHP
 salt in Edmondson, and that evidence, both experimental
 and from the technical literature, undeniably showed that
 1:1 sitagliptin DHP does not form every time sitagliptin
 and DHP were reacted. Id. at *15–16. The Board con-
 cluded that claims 1–3, 17, 19, and 21–23 were neither ex-
 pressly nor inherently anticipated by Edmondson. Id. at
 *16.
     Next, the Board determined that claims 1–4, 17, 19,
 and 21–23 would not have been obvious in view of Edmond-
 son, Bastin, or Brittain. First, the Board considered the
 threshold issue whether Merck could antedate Edmondson
 with evidence that it had reduced to practice the subject
 matter of claims 1, 2, 17, 19, and 21–23 before Edmondson
 had been published on January 16, 2003. Id. at *16–20.
 The Board concluded that Merck had reduced to practice at
 least as much, and in fact more, of the claimed subject mat-
 ter than was shown in Edmondson. Id. at *20. Thus,
 Merck could successfully antedate the subject matter of
 claims 1, 2, 17, 19, and 21–23, and thus Edmondson was
 not a 35 U.S.C. § 102(a) reference, but merely a 35 U.S.C.
 § 102(e) (pre-AIA) reference. Id. Because it was undis-
 puted that the inventions claimed in the ’708 patent and
 the subject matter of Edmondson were commonly owned by
 Merck, or under obligation of assignment to Merck, at the
 time of the invention, the Board determined that the
 35 U.S.C. § 103(c)(1) (pre-AIA) exception applied to claims
 1, 2, 17, 19, and 21–23. Id. Merck did not assert a prior-
 reduction-to-practice argument for claims 3 and 4. Id.
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 6                           MYLAN PHARMACEUTICALS INC. v.
                               MERCK SHARP & DOHME CORP.

     The Board considered whether claim 3, which recites
 the (S)-configuration of sitagliptin DHP, and claim 4, which
 recites the crystalline monohydrate form of (R)-sitagliptin,
 would have been obvious in view of Edmondson, Bastin,
 and Brittain. The Board found that neither Edmondson
 nor Bastin disclosed anything related to (S)-sitagliptin or
 even a racemic mixture of any sitagliptin salt. Id. at *21.
 The Board thus concluded that Mylan did not show that
 claim 3 would have been obvious to a skilled artisan at the
 time the invention was made. Id. at *22. The Board also
 found that Mylan provided no rationale to explain why a
 person of ordinary skill would have been motivated to
 make the claimed crystalline monohydrate form of 1:1
 sitagliptin DHP of claim 4 and failed to show that a skilled
 artisan would have had a reasonable expectation of success
 in making the crystalline monohydrate form of the 1:1
 sitagliptin DHP salt. Id. at *24, *26. The Board thus con-
 cluded that Mylan failed to show that claim 4 would have
 been obvious to a person of ordinary skill at the time the
 invention was made. Id. at *26.
      In summary, the Board concluded that Mylan had not
 demonstrated that claims 1–4, 17, 19, and 21–23 were an-
 ticipated or would have been obvious at the time the inven-
 tion was made. Mylan appealed. We have jurisdiction
 under 28 U.S.C. § 1295(a)(4).
                        DISCUSSION
     Mylan raises three challenges on appeal. First, Mylan
 contends that the Board erred in determining that a 1:1
 stoichiometry of sitagliptin DHP was not anticipated, ei-
 ther expressly or inherently, by Edmondson. Second,
 Mylan contends that the Board erred in determining that
 the ’708 patent antedates Edmondson. 4 Third, Mylan

     4  The ’498 publication was published on January 16,
 2003, and the ’871 patent was published on May 29, 2003.
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 contends that the Board erred in determining that it failed
 to prove that claims 3 and 4 of the ’708 patent would have
 been obvious over Edmondson, Brittain, and Bastin. We
 address each argument in turn.
      We review the Board’s legal determinations de novo, In
 re Elsner, 381 F.3d 1125, 1127 (Fed. Cir. 2004), but we re-
 view the Board’s factual findings underlying those deter-
 minations for substantial evidence.         In re Gartside,
 203 F.3d 1305, 1316 (Fed. Cir. 2000). A finding is sup-
 ported by substantial evidence if a reasonable mind might
 accept the evidence as adequate to support the finding.
 Consol. Edison Co. v. NLRB, 305 U.S. 197, 229 (1938). And
 “[i]f two ‘inconsistent conclusions may reasonably be drawn
 from the evidence in the record, [the PTAB]’s decision to
 favor one conclusion over the other is the epitome of a de-
 cision that must be sustained upon review for substantial
 evidence.’” Elbit Sys. of Am., LLC v. Thales Visionix, Inc.,
 881 F.3d 1354, 1356 (Fed. Cir. 2018) (alteration in original)
 (quoting In re Cree, Inc., 818 F.3d 694, 701 (Fed. Cir.
 2016)).
     Anticipation is a question of fact. Genentech, Inc. v.
 Hospira, Inc., 946 F.3d 1333, 1337 (Fed. Cir. 2020). The
 prior art may be deemed to disclose each member of a ge-
 nus when, reading the reference, a person of ordinary skill
 can “at once envisage each member of this limited class.”
 In re Petering, 301 F.2d 676, 681 (C.C.P.A. 1962).
     Obviousness is a “mixed question of law and fact,” and
 we review “the Board’s ultimate obviousness determina-
 tion de novo and underlying fact-findings for substantial
 evidence.” Hologic, Inc. v. Smith & Nephew, Inc., 884 F.3d
 1357, 1361 (Fed. Cir. 2018).

 Since the ’498 publication was published earlier, we con-
 sider Edmondson, for purposes of antedation, to have been
 published on January 16, 2003.
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 8                             MYLAN PHARMACEUTICALS INC. v.
                                 MERCK SHARP & DOHME CORP.

                               I
     We first consider Mylan’s challenge to the Board’s de-
 termination that it failed to prove that Edmondson antici-
 pates claims 1–3, 17, 19, and 21–23. Mylan argues that
 Edmondson anticipates the claims because it discloses
 sitagliptin in a list of 33 compounds. Mylan further asserts
 that Edmondson discloses acids forming “pharmaceutically
 acceptable salts,” including phosphoric acid in a list of eight
 “particularly preferred” acids. Mylan, therefore, asserts
 that sitagliptin DHP is effectively disclosed in Edmondson,
 and Edmondson thus anticipates the challenged claims.
     Mylan further asserts that a skilled artisan would “at
 once envisage” a 1:1 stoichiometry of the sitagliptin DHP
 salt for two reasons. First, Example 7 of Edmondson dis-
 closes a sitagliptin hydrochloride salt (“sitagliptin HCl”)
 having a 1:1 stoichiometry. Second, experimental data pre-
 sented by Mylan’s expert Dr. Chorghade illustrate that
 only a 1:1 sitagliptin DHP stoichiometry forms under con-
 ditions allegedly similar to those disclosed in Edmondson.
 Mylan contends that the Board thus erred in holding that
 a 1:1 stoichiometry was not anticipated by Edmondson.
     Merck responds that the Board’s holding that the
 claims are not anticipated by Edmondson was supported by
 substantial evidence. Merck asserts that a skilled artisan
 would not “at once envisage” all members of the entire ge-
 nus of DP-IV-inhibitor salts disclosed in Edmondson.
 Merck further contends that the combined list of 33 com-
 pounds and eight preferred salts, taking into account vari-
 ous stoichiometric possibilities, would result in 957 salts,
 some of which may not even form under experimental con-
 ditions. That, Merck asserts, does not meet the standard
 set by the “at once envisage” theory. Merck argues that
 Mylan seeks to expand the theory inappropriately, improp-
 erly focusing on whether skilled artisans could have envis-
 aged 1:1 sitagliptin DHP among the members of the class
 instead of envisaging each member of the disclosed class.
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 MYLAN PHARMACEUTICALS INC.    v.                           9
 MERCK SHARP & DOHME CORP.

 In essence, Merck asserts that Mylan uses hindsight to sin-
 gle out one compound from the large class. Merck further
 argues that Mylan’s own expert conceded that Edmondson
 does not direct a skilled artisan to sitagliptin from among
 the 33 DP-IVs, nor does it disclose a phosphate salt of any
 DP-IV inhibitor.
     We agree with Merck that the Board’s decision was
 supported by substantial evidence. The Board did not err
 in determining that Edmondson does not expressly disclose
 a 1:1 sitagliptin DHP salt. The Board grounded its finding
 in the testimony from Mylan’s own expert, Dr. Chorghade,
 stating that nothing in Edmondson directs a skilled artisan
 to sitagliptin from among the 33 listed DP-IV inhibitors.
 J.A. 2342, 2373–74; Chorghade Dep. 61:7–62:9, 188:6–
 189:8. Further, nothing in Edmondson singles out phos-
 phoric acid or any phosphate salt of any DP-IV inhibitor,
 and the list of “pharmaceutically preferred” salts comes 44
 pages earlier in the specification. The Board reasonably
 concluded that Edmondson does not expressly disclose the
 1:1 sitagliptin DHP salt.
     We also agree with Merck that the Board did not err in
 determining that Edmondson does not inherently disclose
 a 1:1 sitagliptin DHP salt. In re Petering stands for the
 proposition that a skilled artisan may “at once envisage
 each member of [a] limited class, even though the skilled
 person might not at once define in his mind the formal
 boundaries of the class.” 301 F.2d at 681 (emphasis added).
 The key term here is “limited.” As Merck asserted, and as
 the Board considered, the list of 33 compounds, with no di-
 rection to select sitagliptin from among them, plus the
 eight “pharmaceutically preferred” acids and various stoi-
 chiometric possibilities, results in 957 salts, some of which
 may not exist. That is a far cry from the 20 compounds
 “envisaged” by the narrow genus in Petering. Id. Mylan’s
 own expert, Dr. Chorghade, even stated that salt formation
 is an unpredictable art that requires a “trial and error
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 10                           MYLAN PHARMACEUTICALS INC. v.
                                MERCK SHARP & DOHME CORP.

 process.” Decision, 2021 WL 1833325, at *8; J.A. 2355–56;
 Chorghade Dep. 116:22–117:3.
     We cannot provide a specific number defining a “lim-
 ited class.” In re Petering, 301 F.2d at 681. It depends on
 the “class.” But we agree with Merck and hold that the
 Board did not err in finding that a class of 957 predicted
 salts that may result from the 33 disclosed compounds and
 eight preferred acids, some of which may not even form un-
 der experimental conditions, is insufficient to meet the “at
 once envisage” standard set forth in Petering.
                              II
     We next consider Mylan’s challenge to the Board’s de-
 termination that Mylan failed to prove that claims 1–4, 17,
 19, and 21–23 would have been obvious to a person of ordi-
 nary skill in the art at the time the invention was made.
                              A
      We must first consider the threshold issue of Mylan’s
 antedation challenge and application of the 35 U.S.C.
 § 103(c)(1) exception. Under 35 U.S.C. § 102(a) (pre-AIA),
 “[a] person shall be entitled to a patent unless the inven-
 tion was known or used by others in this country, or pa-
 tented or described in a printed publication in this or a
 foreign country, before the invention thereof by the appli-
 cant for a patent.” But a party can overcome the § 102(a)
 barrier if it can antedate a reference “by showing that the
 invention was conceived before the effective date of the ref-
 erence, with diligence to actual or constructive reduction to
 practice.” In re Steed, 802 F.3d 1311, 1320 (Fed. Cir. 2015).
 To prove antedation, the patent owner must show that it
 reduced to practice at least as much as “the reference
 shows of the claimed invention” before the reference’s pub-
 lication date. In re Clarke, 356 F.2d 987, 991 (C.C.P.A.
 1966).
     Mylan does not dispute that Merck reduced 1:1 (R)-
 sitagliptin DHP salt to practice before Edmondson was
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 MERCK SHARP & DOHME CORP.

 published, nor does it dispute that Merck commonly owned
 Edmondson and the ’708 patent. Mylan, instead, argues
 that the Board erred in finding that Merck’s reduction to
 practice of the 1:1 (R)-sitagliptin DHP salt antedates Ed-
 mondson, because Edmondson discloses sitagliptin hy-
 drates, and Merck had not made hydrates of 1:1 sitagliptin
 DHP until March 2003, about two months after the Janu-
 ary 16, 2003 Edmondson publication date. Mylan also ar-
 gues that the Board erred in finding that Edmondson does
 not disclose hydrates of sitagliptin phosphate.
      Merck responds that the Board did not err in finding
 that Merck’s work on the subject matter in claims 1, 2, 17,
 19, and 21–23 of the ’708 patent antedated Edmondson.
 Merck argues that it had reduced to practice the subject
 matter of these claims before Edmondson had been pub-
 lished on January 16, 2003. As a result, Merck asserts,
 Edmondson could not serve as 35 U.S.C. § 102(a) prior art
 and would merely be a 35 U.S.C. § 102(e) reference. Be-
 cause it is undisputed that the invention claimed in the
 ’708 patent and the subject matter of Edmondson were
 commonly owned by Merck at the time of the invention, the
 exception in § 103(c)(1) applies. Section 103(c)(1) (pre-AIA)
 provides that “[s]ubject matter developed by another per-
 son, which qualifies as prior art only under one or more
 subsections (e), (f), and (g) of section 102, shall not preclude
 patentability under this section where the subject matter
 and the claimed invention were, at the time the claimed
 invention was made, owned by the same person or subject
 to an obligation of assignment to the same person.” Merck
 therefore argues that Edmondson cannot serve as an obvi-
 ousness reference for claims 1, 2, 17, 19, and 21–23. With-
 out Edmondson, the obviousness challenge to these claims
 fails. Decision, 2021 WL 1833325, at *20.
     We agree with Merck that the Board’s antedation de-
 termination was supported by substantial evidence. As
 Merck asserts, and as the Board considered, Merck showed
 that it developed a 1:1 sitagliptin DHP salt in December
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                                MERCK SHARP & DOHME CORP.

 2001 with experimental confirmation in early 2002. As
 Merck highlights, Mylan did not argue that claim 4, di-
 rected to a crystalline monohydrate, was anticipated by Ed-
 mondson, which it could have done had it believed that
 Edmondson disclosed a crystalline monohydrate. The
 Board’s finding that Edmondson does not disclose 1:1
 sitagliptin DHP was supported by substantial evidence;
 thus, the Board’s finding that it does not disclose a hydrate
 of that salt was likewise supported by substantial evidence.
 We therefore agree with the Board that Merck reduced to
 practice “more . . . than what is shown in [Edmondson] for
 the claimed subject matter.” Decision, 2021 WL 1833325,
 at *18.
                              B
     We next turn to whether the Board erred in holding
 that Mylan failed to prove that claims 3 and 4 of the ’708
 patent would have been obvious to a skilled artisan at the
 time the invention was made.
      Mylan argues that the Board erred in holding that it
 failed to prove that claim 3, which recites the (S)-configu-
 ration of 1:1 sitagliptin DHP, would have been obvious.
 Mylan argues that Edmondson, in combination with Bas-
 tin, would have allowed a skilled artisan to envisage and
 create 1:1 (S)-sitagliptin DHP. According to Mylan, Bastin,
 which cites disadvantages of hydrochloric acid in pharma-
 ceutical formulations, would encourage a skilled artisan to
 replace the hydrochloric acid in Example 7 of Edmondson.
 Furthermore, Mylan states that sitagliptin has one asym-
 metric carbon, and a skilled artisan would thus have a rea-
 sonable expectation of success in creating both (R)-
 sitagliptin and (S)-sitagliptin.
      Mylan further argues that the Board erred in holding
 that it failed to prove that claim 4, which recites the crys-
 talline monohydrate form of (R)-sitagliptin, would have
 been obvious. Mylan asserts that a skilled artisan would
 have had a reasonable expectation of success in creating a
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 crystalline monohydrate in view of Edmondson in combi-
 nation with Brittain. First, Mylan argues that Edmondson
 states that the described salts exist in more than one crys-
 tal structure and in the form of a hydrate. Second, Mylan
 argues that Brittain’s discussion of hydrates would have
 provided motivation for a skilled artisan to explore hy-
 drates in the development process.
     Merck argues that the Board did not err in holding that
 claim 3 would not have been obvious, and that the Board’s
 underlying factual findings were supported by substantial
 evidence. As the Board considered, Bastin does not provide
 a specific motivation, including any screening or optimiza-
 tion protocol that, combined with Edmondson, would lead
 to 1:1 sitagliptin DHP, the (S)-configuration, or even a ra-
 cemic mixture.
      Merck also argues that the Board did not err in holding
 that claim 4 would not have been obvious, and that the
 Board’s underlying factual findings were supported by sub-
 stantial evidence. Merck argues that the Board was correct
 in finding that Mylan did not provide a persuasive motiva-
 tion for making the crystalline monohydrate form of
 sitagliptin. Merck asserts evidence that skilled artisans
 would avoid making hydrates due to solubility and stability
 challenges during the drug-production process. Merck also
 contends that the monohydrate has unexpectedly favorable
 properties, and that these properties are objective indicia
 of nonobviousness.
     We agree with Merck that the Board’s decision that
 Mylan failed to show that claims 3 and 4 of the ’708 patent
 would have been obvious to a skilled artisan at the time the
 invention was made was supported by substantial evi-
 dence.
     With respect to claim 3, the Board found that there was
 no motivation to combine Edmondson and Bastin to make
 sitagliptin DHP, that the two cited references did not pro-
 vide motivation to make (S)-sitagliptin, and that there was
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                                MERCK SHARP & DOHME CORP.

 no reasonable expectation of success in combining the ref-
 erences. The Board adequately credited Dr. Chorghade’s
 testimony, which stated that the (S)-enantiomer was not
 disclosed in Edmondson. Decision, 2021 WL 1833325, at
 *21. The Board further highlighted that Mylan advanced
 no expected or theoretical benefit to making the (S)-enan-
 tiomer of 1:1 sitagliptin DHP, and that the general disclo-
 sure on diastereomers in Edmondson encompasses millions
 of potential compounds and salts with no motivation to
 make the (S)-enantiomer with a reasonable expectation of
 success, particularly in an unpredictable activity like salt
 formation. Id. at *22. We thus agree with Merck that the
 Board’s decision was supported by substantial evidence.
     With respect to claim 4, the Board found that there was
 no motivation to combine Edmondson, Bastin, and Brit-
 tain, and that a person of ordinary skill would have had no
 reasonable expectation of success in doing so. The Board
 credited Dr. Chorghade’s testimony, which stated that a
 skilled artisan “couldn’t predict with any degree of cer-
 tainty” hydrate formation. Id. at *21; Chorghade Dep.
 238:8–18. The Board also addressed the numerous down-
 sides of hydrates reported in the literature, including those
 stating that a skilled artisan would have several reasons
 for avoiding hydrates. Decision, 2021 WL 1833325, at *23.
 The Board also credited Merck’s expert, Dr. Myerson, who
 stated that a skilled artisan would have sought to avoid
 hydrates, Decision, 2021 WL 1833325, at *22; Myerson
 Decl., ¶¶ 127–38, and that forming crystalline salts, includ-
 ing hydrates, is highly unpredictable. Decision, 2021 WL
 1833325, at *24; Myerson Decl., ¶¶ 146–49. We thus agree
 with Merck that the Board’s decision was supported by
 substantial evidence.
     Finally, the Board did not err in its evaluation of pur-
 ported objective indicia of nonobviousness. Although the
 Board did not consider in detail the alleged unexpected
 properties of the claimed crystalline monohydrate of
 claim 4, the Board stated that such unexpected results
Case: 21-2121    Document: 49      Page: 15   Filed: 09/29/2022

 MYLAN PHARMACEUTICALS INC.   v.                          15
 MERCK SHARP & DOHME CORP.

 served as further evidence undermining Mylan’s challenge
 to claim 4. See Hamilton Beach Brands, Inc. v. f’real Foods,
 LLC, 908 F.3d 1328, 1343 (Fed. Cir. 2018) (holding that
 there is no need to reach objective indicia of nonobvious-
 ness where the petitioner has not made a showing neces-
 sary to prevail on threshold obviousness issues).
                        CONCLUSION
     We have considered Mylan’s remaining arguments, but
 we find them unpersuasive. The Board’s decision was sup-
 ported by substantial evidence and not erroneous as a mat-
 ter of law. For the foregoing reasons, the decision of the
 Board is affirmed.
                        AFFIRMED