Court Opinion

ID: 9387916
Source: CourtListenerOpinion
Date Created: 2023-04-19 15:00:59.956462+00
Date Added: 2024-06-11T17:18:16.606173
License: Public Domain

Case: 22-1147   Document: 60     Page: 1     Filed: 04/19/2023

   United States Court of Appeals
       for the Federal Circuit
                 ______________________

                      AMGEN INC.,
                 Plaintiff-Cross-Appellant

                            v.

 SANDOZ INC., ZYDUS PHARMACEUTICALS (USA)
                     INC.,
              Defendants-Appellants

       MANKIND PHARMA LTD., TORRENT
      PHARMACEUTICALS LTD., GLENMARK
    PHARMACEUTICALS LIMITED, MACLEODS
 PHARMACEUTICALS LTD., MSN LABORATORIES
     PRIVATE LTD., ACTAVIS LLC, PRINSTON
        PHARMACEUTICAL INC., EMCURE
      PHARMACEUTICALS LTD., HERITAGE
 PHARMACEUTICALS INC., AUROBINDO PHARMA
 LTD., AUROBINDO PHARMA USA, INC., ANNORA
 PHARMA PRIVATE LIMITED, HETERO USA, INC.,
  CIPLA LIMITED, ALKEM LABORATORIES LTD.,
 DR. REDDY'S LABORATORIES, INC., DR. REDDY'S
         LABORATORIES, LTD., AMNEAL
   PHARMACEUTICALS LLC, PHARMASCIENCE
                      INC.,
                    Defendants
              ______________________

       2022-1147, 2022-1149, 2022-1150, 2022-1151
                ______________________

     Appeals from the United States District Court for the
 District of New Jersey in Nos. 3:18-cv-11026-MAS-DEA,
Case: 22-1147    Document: 60     Page: 2   Filed: 04/19/2023

 2                                 AMGEN INC.   v. SANDOZ INC.

 3:18-cv-11267-MAS-DEA, 3:18-cv-11269-MAS-DEA, 3:19-
 cv-18806- MAS-DEA, Judge Michael A. Shipp.
                ______________________

                  Decided: April 19, 2023
                  ______________________

    STEVEN J. HOROWITZ, Sidley Austin LLP, Chicago, IL,
 argued for plaintiff-cross-appellant. Also represented by
 PAUL J. ROGERSON, JULIA G. TABAT; JOSHUA JOHN
 FOUGERE, Washington, DC; SUE WANG, San Francisco, CA;
 ERIC MICHAEL AGOVINO, GREGORY DAVID BONIFIELD,
 CHRISTINA NICHOLE GIFFORD, DENNIS J. SMITH, STUART
 WATT, WENDY A. WHITEFORD, Amgen Inc., Thousand Oaks,
 CA; JEFFREY B. ELIKAN, MICHAEL N. KENNEDY, GEORGE
 FRANK PAPPAS, Covington & Burling LLP, Washington,
 DC; ALEXA HANSEN, San Francisco, CA.

     MAUREEN L. RURKA, Winston & Strawn LLP, Chicago,
 IL, argued for all defendants-appellants. Defendant-appel-
 lant Sandoz Inc. also represented by SAMANTHA MAXFIELD
 LERNER; EIMERIC REIG-PLESSIS, San Francisco, CA.

     MICHAEL GAERTNER, Locke Lord LLP, Chicago, IL, for
 defendant-appellant Zydus Pharmaceuticals (USA) Inc.
 Also represented by DAVID BRIAN ABRAMOWITZ, HUGH S.
 BALSAM, CAROLYN ANNE BLESSING, AUGUST MELCHER,
 EMILY SAVAS.
                 ______________________

  Before LOURIE, CUNNINGHAM, and STARK, Circuit Judges.
 LOURIE, Circuit Judge.
     Sandoz Inc. (“Sandoz”) appeals from a decision of the
 United States District Court for the District of New Jersey
 holding that claims 3 and 6 of Amgen Inc.’s (“Amgen”) U.S.
 Patent 7,427,638 (the “’638 patent”) and claims 1 and 15 of
 Amgen’s U.S. Patent 7,893,101 (the “’101 patent”) had not
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 AMGEN INC.   v. SANDOZ INC.                                3

 been shown to be invalid as obvious. Amgen cross-appeals
 from the district court’s decision holding that claims 2, 19,
 and 21 of its U.S. Patent 10,092,541 (the “’541 patent”)
 were shown to be invalid as obvious. See Amgen Inc. v.
 Sandoz Inc., No. 18-11026, 2021 WL 5366800 (D.N.J. Sept.
 20, 2021) (“Decision”). For the reasons provided below, we
 affirm.
                         BACKGROUND
     Amgen produces apremilast, which is stereomerically
 pure                (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-
 methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione,
 with the following structure:

 Amgen markets apremilast, a phosphodiesterase-4
 (“PDE4”) inhibitor, which is used for treating psoriasis and
 related conditions, under the brand name Otezla®. The
 ’638, ’101, and ’541 patents, covering Otezla, were initially
 owned by Celgene Corporation (“Celgene”) and later as-
 signed to Amgen.
     Sandoz submitted an Abbreviated New Drug Applica-
 tion (“ANDA”) seeking approval from the United States
 Food and Drug Administration (“FDA”) to market a generic
 version of apremilast. Celgene, the original plaintiff, then
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 4                                    AMGEN INC.   v. SANDOZ INC.

 brought this Hatch-Waxman suit, asserting that Sandoz’s
 generic product would infringe the ’638 and ’101 patents.
 After the ’541 patent issued, Celgene asserted infringe-
 ment of that patent as well. In February 2020, Amgen was
 substituted as plaintiff.
                      I. The ’638 Patent
     The ’638 patent is directed to pharmaceutical composi-
 tions comprising stereomerically pure apremilast, includ-
 ing oral formulations, as well as dosing forms.
     Asserted claims 3 and 6 are dependent claims. For ease
 of understanding, we incorporate the parent claims into the
 claims that are asserted.
     Asserted claim 3 of the ’638 patent reads as follows:
        3.    The pharmaceutical composition of
        claim 2 [A pharmaceutical composition
        comprising stereomerically pure (+)-2-[1-(3-
        ethoxy-4-methoxyphenyl)-2-
        methylsulfonylethyl]-4-
        acetylaminoisoindoline-1,3-dione,      or    a
        pharmaceutically acceptable salt, solvate or
        hydrate, thereof; and a pharmaceutically
        acceptable carrier, excipient or diluent,
        wherein said pharmaceutical composition is
        suitable for parenteral, transdermal, mucosal,
        nasal,     buccal,   sublingual,    or    oral
        administration to a patient], wherein said
        pharmaceutical composition is suitable for
        oral administration to a patient.
 ’638 patent at col. 31 ll. 27–39.
     Asserted claim 6 of the ’638 patent reads as follows:
        6.   The pharmaceutical composition of
        claim 5 [A pharmaceutical composition
        comprising stereomerically pure (+)-2-[1-(3-
        ethoxy-4-methoxyphenyl)-2-
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 AMGEN INC.   v. SANDOZ INC.                                  5

        methylsulfonylethyl]-4-
        acetylaminoisoindoline-1,3-dione,      or    a
        pharmaceutically acceptable salt, solvate or
        hydrate, thereof; and a pharmaceutically
        acceptable carrier, excipient or diluent,
        wherein said pharmaceutical composition is
        suitable for parenteral, transdermal, mucosal,
        nasal,     buccal,   sublingual,    or    oral
        administration to a patient, wherein the
        amount of stereomerically pure (+)-2-[1-(3-
        ethoxy-4-methoxyphenyl)-2-
        methylsulfonylethyl]-4-
        acetylaminoisoindoline-1,3-dione is from 1 mg
        to 1000 mg, wherein the amount of
        stereomerically pure (+)-2-[1-(3-ethoxy-4-
        methoxyphenyl)-2-methylsulfonylethyl]-4-
        acetylaminoisoindoline-1,3-dione is from 5 mg
        to 500 mg], wherein the amount of
        stereomerically pure (+)-2-[1-(3-ethoxy-4-
        methoxyphenyl)-2-methylsulfonylethyl]-4-
        acetylaminoisoindoline-1,3-dione is from 10
        mg to 200 mg.
 ’638 patent at col. 31 ll. 27–36, col. 32 ll. 1–12.
      At the district court, Amgen asserted infringement of
 claims 3 and 6. In response, Sandoz alleged that those
 claims were invalid as obvious over U.S. Patent 6,020,358
 (the “’358 patent”) and PCT application WO 01/034606 (the
 “’606 application”). The ’358 patent is the first U.S. patent
 describing a racemic mixture containing apremilast, and it
 claims a genus of phosphodiesterase inhibitors, including a
 racemic mixture containing apremilast. The ’358 patent
 discloses seventeen example compounds that fall within
 the scope of the claimed genus. Example 12 of the ’358
 patent is a racemic mixture comprised of 50% of the
 (+) enantiomer      of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-
 methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione
 and 50% of the (-) enantiomer. The (+) enantiomer is
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 6                                   AMGEN INC.   v. SANDOZ INC.

 apremilast. The ’358 patent more generally discloses that
 racemates can be separated into individual enantiomers.
 The ’606 application is directed to a group of
 phosphodiesterase inhibitors and teaches that the
 individual enantiomers of racemic mixtures can be
 separated.    Sandoz asserted the ’606 application as
 reinforcing the teachings disclosed in the ’358 patent.
     The district court held that Sandoz had failed to show
 by clear and convincing evidence that claims 3 and 6 would
 have been obvious over the ’358 patent and the ’606 appli-
 cation. In particular, the court found that Sandoz failed to
 meet the burden of establishing that the ’358 patent and
 the ’606 application gave a skilled artisan reason or moti-
 vation to resolve the Example 12 racemic mixture into its
 enantiomers, further finding that there was not sufficient
 evidence to conclude that a skilled artisan would have had
 reason to believe that the desirable properties of Example
 12 derived in whole or in part from the apremilast enanti-
 omer (i.e., the (+) enantiomer). The court also concluded
 that Sandoz had not demonstrated that a skilled artisan
 would have had a reasonable expectation of success in re-
 solving Example 12 into its individual enantiomeric com-
 ponents.
     The district court also looked to objective indicia of non-
 obviousness, also known as secondary considerations. In
 particular, the court noted that apremilast unexpectedly
 provided substantial improvement over previously known
 phosphodiesterase inhibitors in terms of both efficacy and
 tolerability and that there was a nexus between the unex-
 pected potency and side-effect profile of apremilast and the
 compounds of asserted claims 3 and 6 of the ’638 patent.
 The court also looked to long-felt, unmet need, noting that
 before apremilast, there was a long-felt need for a psoriasis
 treatment that was suitable for oral administration to a pa-
 tient, without the risks and barriers to adherence that were
 common with other psoriasis treatments. The court also
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 AMGEN INC.   v. SANDOZ INC.                                 7

 found a nexus between the compounds of the asserted
 claims and this long-felt, unmet need.
      The district court further found that others in the field
 had attempted to develop other PDE4 inhibitors, but that
 several had been discontinued due to disappointing efficacy
 or failure to progress in the drug-development pipeline and
 that there had been a degree of skepticism about the safety
 of apremilast because of its structural similarity to thalid-
 omide, which was found to have teratogenic effects in fe-
 tuses leading to severe and debilitating birth defects.
 Finally, the court noted the commercial success of Otezla
 since it achieved FDA approval, noting approximately 1.7
 million prescriptions for the drug between its 2014 launch
 and April 2020. In view of these findings, the court found
 that the objective indicia of nonobviousness weighed
 strongly in favor of a finding that claims 3 and 6 of the ’638
 patent would not have been obvious over the relevant art.
     In view of its objective indicia analysis, as well as its
 finding that there was not sufficient motivation or reason-
 able expectation of success in isolating apremilast from the
 racemic mixture disclosed in Example 12 of the ’358 patent,
 the district court held that claims 3 and 6 of the ’638 patent
 were not invalid as obvious.
                       II. The ’101 Patent
     The ’101 patent is directed to solid forms (e.g., crystal-
 line polymorphic forms) of apremilast and claims priority
 from several earlier-filed applications, including U.S. Pro-
 visional Application 60/366,515 (the “’515 provisional ap-
 plication”), which was filed on March 20, 2002.
    Asserted claim 1 of the ’101 patent reads as follows:
       1.   A Form B crystal form of the compound
       of Formula (I):
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 8                                    AMGEN INC.   v. SANDOZ INC.

        which is enantiomerically pure, and which
        has an X-ray powder diffraction pattern com-
        prising peaks at about 10.1, 13.5, 20.7, and
        26.9 degrees 2θ.
 ’101 patent at col. 59 ll. 2–24.
     Asserted claim 15 of the ’101 patent reads as follows:
        15. A solid pharmaceutical composition com-
        prising the crystal form of any one of claims 1
        and 2 to 13.
 ’101 patent at col. 60 ll. 28–29.
     At the district court, the parties disputed the priority
 date to which the ’101 patent was entitled, and therefore,
 which date should be used for purposes of an obviousness
 analysis. Amgen argued that claims 1 and 15 were entitled
 to a priority date of March 20, 2002, the filing date of the
 ’515 provisional application. Amgen asserted that Exam-
 ple 2 of the ’515 provisional application provided written
 description and enablement support for the asserted
 claims, arguing that crystalline Form B of apremilast was
 inherently disclosed in the ’515 provisional application.
     Sandoz responded, arguing that the claims of the ’101
 patent were only entitled to a priority date of March 27,
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 AMGEN INC.   v. SANDOZ INC.                                 9

 2008, the filing date of the application resulting in the ’101
 patent since, according to Sandoz, the crystalline Form B
 of apremilast was neither explicitly nor inherently dis-
 closed in the ’515 provisional application. Sandoz also ar-
 gued that Celgene represented to the European Patent
 Office that following Example 2 could result in crystalline
 Form C of apremilast as well as Form B.
     The district court held that claims 1 and 15 of the ’101
 patent were entitled to the March 2002 priority date, not-
 ing that the parties did not dispute that Example 2 of the
 ’515 provisional application disclosed a synthetic chemical
 procedure for preparing apremilast. Although the court
 noted that Example 2 did not explicitly describe the final
 resulting form of apremilast as a crystalline polymorphic
 structure, but rather as a solid, the court credited Amgen’s
 expert, who testified that Example 2 inherently produces
 crystalline Form B and that thirteen third-party experi-
 ments that replicated the procedures in Example 2 re-
 sulted in the crystalline Form B of apremilast. The court
 also noted that Amgen’s expert’s uncontradicted trial testi-
 mony stated that, although Celgene once claimed that it
 made crystalline Form C of apremilast by following the pro-
 cedures in Example 2 of the ’515 provisional application,
 Form C involves a toluene solvent, which becomes a part of
 the crystalline structure, and toluene is not mentioned in
 Example 2. Therefore, the court credited Amgen’s expert’s
 testimony that Celgene made a mistake in representing
 that Example 2 could produce crystalline Form C of apre-
 milast.
      The district court concluded that Amgen met its burden
 of showing that the ’101 patent is entitled to the ’515 pro-
 visional application’s March 20, 2002 filing date as its pri-
 ority date. The court further concluded that Sandoz failed
 to argue that art prior to March 2002 rendered the claims
 of the ’101 patent invalid for obviousness and that Sandoz’s
 arguments merely reduced to a question whether claims 1
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 10                                  AMGEN INC.   v. SANDOZ INC.

 and 15 were entitled to claim priority from March 20, 2002
 through the ’515 provisional application.
                     III. The ’541 Patent
     The ’541 patent is directed to methods for the treat-
 ment of diseases ameliorated by inhibition of phos-
 phodiesterases using dose titration of apremilast. Asserted
 claim 2 of the ’541 patent claims a dose-titration schedule
 and reads as follows:
        2.   A method for treating a patient with
        stereomerically pure (+)-2-[1-(3-ethoxy-4-
        methoxyphenyl)-2-methylsulfonylethyl]-4-
        acetylaminoisoindoline-1,3-dione,   wherein
        the patient is suffering from psoriasis, the
        method consisting of:
      (a) administering to the patient stereomerically
          pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-
          methylsulfonylethyl]-4-
          acetylaminoisoindoline-1,3-dione      in    an
          initial titration dosing schedule consisting of

          (i)     10 mg in the morning on the first day
                  of administration;

          (ii)    10 mg in the morning and 10 mg af-
                  ter noon on the second day of admin-
                  istration;

          (iii)   10 mg in the morning and 20 mg af-
                  ter noon on the third day of admin-
                  istration;

          (iv)    20 mg in the morning and 20 mg af-
                  ter noon on the fourth day of admin-
                  istration;
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 AMGEN INC.   v. SANDOZ INC.                                11

          (v)     20 mg in the morning and 30 mg af-
                  ter noon on the fifth day of admin-
                  istration; and
         (b) on the sixth and every subsequent day,
             administering to the patient 30 mg in the
             morning and 30 mg after noon of
             stereomerically pure (+)-2-[1-(3-ethoxy-4-
             methoxyphenyl)-2-methylsulfonylethyl]-
             4-acetylaminoisoindoline-1,3-dione.
 ’541 patent at col. 31 ll. 3–26.
     Asserted claim 19 of the ’541 patent reads as follows:
        19. A method as in any one of claims 1–14,
        wherein the stereomerically pure (+)-2-[1-(3-
        ethoxy-4-methoxyphenyl)-2-
        methylsulfonylethyl]-4-
        acetylaminoisoindoline-1,3-dione comprises
        greater than about 98% by weight of the (+)
        isomer of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-
        methylsulfonylethyl]-4-
        acetylaminoisoindoline-1,3-dione based on
        the total weight percent of 2-[1-(3-ethoxy-4-
        methoxyphenyl)-2-methylsulfonylethyl]-4-
        acetylaminoisoindoline-1,3-dione.
 ’541 patent at col. 36 ll. 22–29.
     Asserted claim 21 of the ’541 patent reads as follows:
        21. A method as in any one of claims 1–14,
        wherein the stereomerically pure (+)-2-[1-(3-
        ethoxy-4-methoxyphenyl)-2-
        methylsulfonylethyl]-4-
        acetylaminoisoindoline-1,3-
        dione is administered in tablet form.
 ’541 patent at col. 36 ll. 38–41.
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 12                                  AMGEN INC.   v. SANDOZ INC.

     At the district court, Amgen asserted infringement of
 claims 2, 19, and 21. In response, Sandoz alleged that the
 claims would have been obvious over Papp, 1 Schett, 2 and
 Pathan. 3
     Papp reports the results of a Phase IIb clinical trial in-
 vestigating the clinical efficacy and safety of different doses
 of apremilast in the treatment of patients with moderate to
 severe plaque psoriasis. The district court found that Papp
 teaches the following five-day dose titration of apremilast
 while initiating treatment to mitigate potential dose-de-
 pendent adverse events:
      •   Day 1: 10 mg first dose; 10 mg second dose
      •   Day 2: 10 mg first dose; 10 mg second dose
      •   Day 3: 20 mg first dose; 20 mg second dose
      •   Day 4: 20 mg first dose; 20 mg second dose
      •   Day 5: 30 mg first dose; 30 mg second dose.
 Decision at *31; see also J.A. 18583; Papp at 739.
      Schett reports the results of a Phase II clinical trial on
 apremilast in which patients were given a 40 mg daily dose,
 either as a single 40 mg dose or as two 20 mg doses. Alt-
 hough Schett did not evaluate treatment of plaque psoria-
 sis, it discloses a dose-escalation protocol during the first
 seven days of treatment for psoriatic arthritis with the aim

      1   Kim Papp et al., Efficacy of apremilast in the treat-
 ment of moderate to severe psoriasis: a randomised con-
 trolled trial, 380 LANCET 738 (2012).
      2   Georg Schett et al., Oral apremilast in the treat-
 ment of active psoriatic arthritis: results of a multicenter,
 randomized, double-blind, placebo-controlled study, 64
 ARTHRITIS & RHEUMATOLOGY 3156 (2012).
      3   Ejaz Pathan et al., Efficacy and safety of apre-
 milast, an oral phosphodiesterase 4 inhibitor, in ankylosing
 spondylitis, 72 ANNALS OF RHEUMATIC DISEASES 1475
 (2012).
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 AMGEN INC.   v. SANDOZ INC.                               13

 of decreasing the likelihood of adverse events related to
 treatment initiation. Schett at 3157–58. Pathan also
 teaches initiation of apremilast using a dose-escalation
 protocol, starting patients suffering from ankylosing spon-
 dylitis with 10 mg apremilast twice daily, titrating the dose
 by 20 mg every two days until a maximum dose of 30 mg
 twice daily was achieved on day 5. Pathan at 1476, 1479.
     The district court found that it would have been within
 the ability of a skilled artisan to titrate apremilast for a
 patient presenting with psoriasis and that doing so would
 have been a routine aspect of treating psoriasis with a drug
 like apremilast that was known in the art to require dose
 titration to ameliorate side effects. Thus, the court held
 that claims 2, 19, and 21 of the ’541 patent were invalid as
 obvious.
     In summary, the district court concluded that claims 3
 and 6 of the ’638 patent and claims 1 and 15 of the ’101
 patent were not invalid as obvious and that claims 2, 19,
 and 21 of the ’541 patent were invalid as obvious. Sandoz
 appealed, and Amgen cross-appealed. We have jurisdiction
 under 28 U.S.C. § 1295(a)(1).
                          DISCUSSION
     Sandoz raises two issues on appeal. First, with regard
 to the ’639 patent, Sandoz contends that the district court
 erred in failing to find a motivation to isolate apremilast
 from a known racemic mixture and also for failing to find a
 reasonable expectation of success in separating the mix-
 ture. Second, with regard to the ’101 patent, Sandoz ar-
 gues that the court erred in holding that the ’515
 provisional application inherently disclosed the crystalline
 Form B of apremilast, and thus provided the necessary
 written description support to entitle claims 1 and 15 of the
 ’101 patent to a March 2002 priority date. Amgen raises
 one issue on cross-appeal, asserting that the court erred in
 holding that the dose-titration schedule in claims 2, 19, and
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 14                                 AMGEN INC.   v. SANDOZ INC.

 21 of the ’541 patent would have been obvious. We address
 each argument in turn.
     “Obviousness is a question of law, reviewed de novo,
 based upon underlying factual questions which are re-
 viewed for clear error following a bench trial.” Aventis
 Pharma Deutschland GmbH v. Lupin, Ltd., 499 F.3d 1293,
 1300 (Fed. Cir. 2007) (quoting Alza Corp. v. Mylan Lab’ys,
 Inc., 464 F.3d 1286, 1289 (Fed. Cir. 2006)). The presence
 or absence of a motivation to arrive at the claimed inven-
 tion, and of a reasonable expectation of success in doing so,
 are questions of fact. Alza Corp., 464 F.3d at 1289.
                      I. The ’638 Patent
    We first consider Sandoz’s challenge to the district
 court’s determination that it failed to prove that claims 3
 and 6 of the ’638 patent would have been obvious over the
 ’358 patent and the ’606 application. Sandoz argues that
 the court erred in failing to find a motivation to isolate
 apremilast from a known racemic mixture. Sandoz asserts
 that, where the methods of isolation are known, as it ar-
 gues they are here, there is a motivation to separate race-
 mic mixtures.      Sandoz also asserts that its expert
 established that the ’606 application taught that com-
 pounds, including the apremilast-containing racemic mix-
 ture in Example 12, were preferably administered as
 substantially stereomerically pure and that, by the late
 1980s, there was pressure from regulatory agencies, in-
 cluding the FDA, to synthesize new drugs as single enanti-
 omers. Sandoz argues that apremilast being a thalidomide
 analogue taught toward, rather than away from, separat-
 ing the enantiomers in the racemic mixture.
    Sandoz further argues that the district court erred in
 holding that a skilled artisan would not have had a reason-
 able expectation of success in isolating apremilast from a
 known racemic mixture. Sandoz asserts that the ’358 pa-
 tent discloses a racemic mixture containing apremilast in
 Example 12 and states that apremilast can be isolated from
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 AMGEN INC.   v. SANDOZ INC.                                15

 the racemic mixture using chiral chromatography, a tech-
 nique described as well-known in the art. Sandoz also as-
 serts that the court further erred in holding that the ’358
 patent would not have enabled a skilled artisan to isolate
 apremilast without undue experimentation. Sandoz con-
 tends that a finding of obviousness does not require that
 every detail for isolation of a compound be described.
 Sandoz further argues that the court inappropriately relied
 on Amgen’s expert’s comments about difficulties he had ex-
 perienced in isolating enantiomers unrelated to apremilast
 in concluding that isolation of apremilast from the racemic
 mixture would have required undue experimentation.
 Lastly, Sandoz also argues that the district court failed to
 hold Amgen to the statement in the specification that
 methods for isolating apremilast (referred to as Compound
 A in the patent) from the racemate were known in the prior
 art. ’638 patent at col. 9 ll. 9–24.
      Sandoz also contends that the district court erred in ex-
 cluding Celgene’s alleged admission that the European
 counterpart to the ’358 patent discloses stereomerically
 pure apremilast. According to Sandoz, where a represen-
 tation to a foreign patent office is relevant and not unique
 to issues of foreign law, it must be considered. Sandoz ar-
 gues that the court misapplied Federal Rule of Evidence
 Rule 703, which allows experts to rely on otherwise inad-
 missible statements if they meet certain criteria, including
 that an expert would reasonably rely on them, in excluding
 those statements.
     Sandoz further contends that the district court erred in
 its consideration of objective indicia of nonobviousness. In
 analyzing long-felt but unmet need, failure of others, and
 skepticism, Sandoz argues that the court impermissibly
 credited evidence that lacked a nexus to the allegedly novel
 aspects of the ’638 patent claims, namely stereomerically
 pure apremilast. Sandoz concedes that the court did not
 err in considering evidence related to novel features of the
 claim in the unexpected results analysis, but that the court
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 16                                  AMGEN INC.   v. SANDOZ INC.

 did err in basing its analysis on a difference of degree (i.e.,
 that apremilast was 20-fold more potent than the racemic
 mixture), rather than a difference in kind, which would
 have, Sandoz asserts, resulted in a finding of obviousness.
     Amgen responds that the district court did not err in
 finding a lack of a motivation to resolve the racemate to
 achieve the claimed composition of apremilast. Amgen as-
 serts that the prior art taught away from thalidomide ana-
 logues due to safety concerns, and that no known desirable
 property of apremilast would have motivated a skilled ar-
 tisan to defy that teaching to select any of the multitude of
 compounds disclosed in the ’358 patent as a starting point,
 much less the known racemic mixture of Example 12.
 Amgen asserts that, without any biological data, a skilled
 artisan would not have been motivated to pursue a com-
 pound that was likely to be suitable for patient administra-
 tion, and that a skilled artisan would not have been able to
 predict properties of the individual enantiomers in the ra-
 cemic mixture.
     Amgen further contends that the district court did not
 err in finding the absence of a reasonable expectation of
 success in resolving the racemic mixture in Example 12.
 Amgen contends that resolving a racemic mixture is a time-
 consuming, trial-and-error process filled with unpredicta-
 bility, and that the ’358 patent does not provide any specific
 procedure beyond general techniques like chiral chroma-
 tography. Even assuming a reasonable expectation of suc-
 cess in isolating apremilast, Amgen contends that Sandoz
 would have needed to prove a reasonable expectation of
 success in obtaining a compound as claimed, here, apre-
 milast for use in a pharmaceutical composition that is suit-
 able for oral administration to a patient. Amgen asserts
 that there was no reason to believe which enantiomer of
 the Example 12 racemic mixture would have therapeutic
 utility or be useful in a pharmaceutical composition.
 Amgen also contends that Sandoz is incorrect to suggest
 that the court required the ’358 patent to be fully enabled,
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 AMGEN INC.   v. SANDOZ INC.                              17

 and instead asserts that Sandoz’s contentions amount to a
 disagreement with the court’s finding that there would
 have been no reasonable expectation of success in isolating
 apremilast.
    Amgen further asserts that the court’s exclusion under
 Federal Rule of Evidence Rule 703 of statements made dur-
 ing European prosecution was not an abuse of discretion.
 Amgen asserts that chemists would not routinely rely on
 the statements of patent lawyers, and so Rule 703 subse-
 quently would not apply. 4
    Amgen also asserts that the court did not err in finding
 strong objective indicia of nonobviousness. In particular,
 Amgen notes that apremilast was unexpectedly potent,
 showing a 20-fold increase in potency relative to the race-
 mic mixture, and that apremilast was met with widespread
 skepticism among industry participants because of its
 structural similarity to thalidomide. Amgen also asserts
 that apremilast met a long-felt need for better psoriasis
 treatments, and it succeeded where many other psoriasis
 drugs have failed.
     We agree with Amgen that the district court did not err
 in finding that claims 3 and 6 of the ’638 patent were not
 shown to have been obvious by a standard of clear and con-
 vincing evidence over the ’358 patent and the ’606 applica-
 tion. We find no clear error in the court’s holding that
 Sandoz did not meet its burden of establishing that the
 prior art gave a skilled artisan reason or motivation to re-
 solve the Example 12 racemic mixture into its enantio-
 mers, to conclude that a skilled artisan would have had
 reason to believe that the desirable properties of the

     4   Given our conclusions, particularly as to the
 strength of the objective evidence of nonobviousness, any
 error in this evidentiary determination—even assuming
 there was error—was harmless.
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 18                                 AMGEN INC.   v. SANDOZ INC.

 Example 12 racemic mixture derived in whole or in part
 from the apremilast isomer, or that a skilled artisan would
 have had a reasonable expectation of success in resolving
 the mixture of Example 12. In making these findings, the
 court appropriately credited the statements of both
 Amgen’s and Sandoz’s experts, finding the statements of
 Amgen’s expert more persuasive. Included in that testi-
 mony was information establishing that resolving a race-
 mic mixture is a difficult process based on trial-and-error
 experimentation and that using chiral chromatography to
 resolve the Example 12 racemic mixture into its enantio-
 mers would require a skilled artisan to find an appropriate
 solvent system for the chiral column, of which there were
 many possible options at the time the invention was made.
 Decision at *14–15.
     The district court did not err in not holding Amgen to
 the statements set forth in the specification regarding iso-
 lating apremilast. See Appellant’s Br. 30–32 (citing Phar-
 maStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342,
 1362 (Fed. Cir. 2007)). In PharmaStem, we held that it was
 not unfair to hold the inventors to the consequences of their
 admissions because their characterization of the prior art
 references was not unreasonable, and the prior art refer-
 ences themselves strongly supported the interpretation.
 491 F.3d at 1362. In contrast, here, the district court found
 that Sandoz’s own expert conceded that the formation of
 chiral salts was not a viable method for separating the Ex-
 ample 12 enantiomers contrary to the statement in the
 specification. Decision at *14 (“[B]oth Amgen’s and De-
 fendants’ experts appear to agree that the formation of chi-
 ral salts was not a viable method for separating the
 enantiomers of Example 12, notwithstanding the ’358 Pa-
 tent’s representation to the contrary.”). Considering the
 unpredictable nature of resolving racemic mixtures and the
 district court’s acceptance of Amgen’s expert testimony as
 credible, PharmaStem is distinguishable from this case.
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 AMGEN INC.   v. SANDOZ INC.                                19

     We also agree with Amgen that the district court did
 not err in its finding of strong objective indicia of nonobvi-
 ousness. A court’s evaluation of the objective indicia of
 nonobviousness “is not just a cumulative or confirmatory
 part of the obviousness calculus but [rather] constitutes in-
 dependent evidence of nonobviousness.” Ortho-McNeil
 Pharm., Inc. v. Mylan Lab’ys, Inc., 520 F.3d 1358, 1365
 (Fed. Cir. 2008). The obviousness inquiry is one that is “ex-
 pansive and flexible.” KSR Int’l Co. v. Teleflex Inc., 550
 U.S. 398, 415 (2007). Thus, there are a variety of objective
 indicia of nonobviousness that may inform the circum-
 stances surrounding the origin of the subject matter sought
 to be patented including, but not limited to, “commercial
 success, long-felt but unresolved need, failure of others,
 copying, and unexpected results.” Ruiz v. A.B. Chance Co.,
 234 F.3d 654, 660 (Fed. Cir. 2000).
     “[A] court need not find that all factors are present to
 determine that the objective considerations support a find-
 ing of nonobviousness.” Mitsubishi Tanabe Pharma Corp.
 v. Sandoz, Inc., 533 F. Supp. 3d 170, 204 (D.N.J. 2021) (cit-
 ing Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966)).
 We focus our analysis of the objective indicia of nonobvi-
 ousness on the alleged unexpected potency of apremilast
 discovered relative to the apremilast-containing racemic
 mixture during testing and experimentation. The district
 court found that the trial record established the presence
 of unexpected results, crediting testimony from Dr. Peter
 H. Schafer, a Celgene researcher listed as an inventor on
 the ’638 patent. The court credited the testimony as estab-
 lishing that apremilast was much more effective than the
 apremilast-containing racemic mixture at reducing pro-
 duction of tumor necrosis factor alpha (“TNFα”), a pro-
 moter of the inflammatory response linked to clinical
 problems associated with psoriasis, in murine models. De-
 cision at *17. Dr. Schafer noted a 20-fold difference in po-
 tency between apremilast alone and the apremilast-
 containing racemic mixture and stated that the inventors
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 20                                  AMGEN INC.   v. SANDOZ INC.

 “didn’t expect a 20-fold difference in potency . . . . Nor-
 mally, if a racemate is a 50/50 mixture of two enantiomers,
 you might expect a two-fold difference in potency, all things
 being equal.” Id. Dr. Schafer’s credited testimony, in ad-
 dition to a 20-fold difference in potency between apremilast
 and the racemic mixture, is sufficient to establish the pres-
 ence of unexpected results, and thus to support a finding of
 nonobviousness. The district court did not err in so finding.
     There is no specific fold-difference that defines what
 may, or may not, support a finding of nonobviousness. Nor
 do we draw a line between a difference in degree insuffi-
 cient to rebut a showing of obviousness and a difference in
 kind that may be sufficient to do so; each inquiry need be
 fact-specific. Bristol-Myers Squibb Co. v. Teva Pharms.
 USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014) (“‘[D]iffer-
 ences in degree’ of a known and expected property are not
 as persuasive in rebutting obviousness as differences in
 ‘kind’—i.e., a new property dissimilar to the known prop-
 erty.”). Instead, we hold that the 20-fold difference, when
 an otherwise two-fold difference would have been expected
 by the skilled artisan, as shown in this case, suffices to sup-
 port a finding of an unexpected result and thus to affirm
 the district court’s finding that claims 3 and 6 of the ’638
 patent would not have been obvious.
     We further agree with Amgen, and subsequently affirm
 the district court’s finding, that there is no clear error in
 the district court’s finding of a nexus between the unex-
 pected potency of apremilast and claims 3 and 6 of the ’638
 patent. “To accord substantial weight to . . . evidence [of
 objective indicia of nonobviousness], it ‘must have a
 “nexus” to the claims, i.e., there must be “a legally and fac-
 tually sufficient connection” between the evidence and the
 patented invention.’” Quanergy Sys., Inc. v. Velodyne Lidar
 USA, Inc., 24 F.4th 1406, 1417 (Fed. Cir. 2022) (quoting
 Teva Pharms. Int’l GmbH v. Eli Lilly & Co., 8 F.4th 1349,
 1360 (Fed. Cir. 2021)). The court credited evidence estab-
 lishing that apremilast’s potency over the Example 12
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 AMGEN INC.   v. SANDOZ INC.                                 21

 racemic mixture derives from the separation of apremilast
 from the other enantiomer. Further, the unexpected prop-
 erties of a compound necessarily have a nexus to that com-
 pound. Thus, we find no clear error in the court’s holding.
     Although we do not find error in the district court’s find-
 ing of unexpected potency of apremilast relative to the ra-
 cemic mixture, and we also find it to be dispositive, we also
 affirm the district court’s findings pertaining to the other
 objective indicia of nonobviousness.
     First, the district court did not err in determining that,
 before apremilast, there was a long-felt need for a psoriasis
 treatment that was suitable for oral administration to a pa-
 tient without the risks and barriers to adherence that were
 common with other psoriasis treatments. In making this
 finding, the court credited expert testimony establishing
 that topical treatments, including creams and ointments,
 had several drawbacks for patients suffering from moder-
 ate to severe psoriasis, including messiness, difficulty of
 application to large areas of affected skin, inability to treat
 associated psoriatic arthritis, and the tendency for topicals
 to lose efficacy over time. The credited expert testimony
 also established that older oral systemic treatments had
 their own compliance barriers, including treatments that
 required lab monitoring before, during, and sometimes af-
 ter treatment, and for being contraindicated in immuno-
 suppressed patients. Decision at *18.
     We also find no clear error with respect to the district
 court’s findings that others in the field had tried and failed
 to develop other PDE4 inhibitors, including expert testi-
 mony establishing that many PDE4 inhibitors failed to pro-
 gress in experimentation and trials or were not sufficiently
 effective at tolerable doses. We also find no clear error in
 the court’s finding that there was industry and regulatory
 skepticism about the safety of apremilast because of its
 structural similarity to thalidomide, evidenced by credited
 expert testimony, id. at *20–21, or that Otezla has achieved
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 22                                 AMGEN INC.   v. SANDOZ INC.

 commercial success since receiving FDA approval, based on
 credited expert testimony from Amgen’s economic expert,
 id. at *21–22.
     In summary, the district court did not err in finding
 that the objective indicia of nonobviousness strongly weigh
 in favor of a finding that claims 3 and 6 of the ’638 patent
 would not have been obvious over the ’358 patent or the
 ’606 application. Accordingly, we affirm the court’s holding
 that Sandoz did not meet its burden to show by clear and
 convincing evidence that claims 3 and 6 of the ’638 patent
 would have been obvious over the ’358 patent and the ’606
 application.
                     II. The ’101 Patent
    We next consider Sandoz’s challenge to the district
 court’s determination that it failed to prove that claims 1
 and 15 of the ’101 patent would have been obvious. In es-
 sence, Sandoz challenges the priority date to which claims
 1 and 15 of the ’101 patent are entitled.
     Sandoz argues that the district court erred in finding
 that the ’515 provisional application inherently disclosed
 crystalline Form B of apremilast, and thus provided the
 necessary support for claims 1 and 15 of the ’101 patent to
 be entitled to a March 2002 priority date. Sandoz asserts
 that Amgen was required to show that the ’515 provisional
 application met the written description requirements of 35
 U.S.C. § 112 and that it failed to do so. Sandoz contends
 that the ’515 provisional application does not explicitly dis-
 close crystalline Form B of apremilast, and that Amgen is
 barred from relying on inherency because crystalline Form
 B and the claimed X-ray powder diffraction peaks of claims
 1 and 15 were material to the patentability of the claims,
 but an allegedly inherent limitation cannot be material to
 the patentability of the invention. As proof of the materi-
 ality to the patentability of the invention, Sandoz notes
 that Celgene relied on crystalline Form B of apremilast and
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 AMGEN INC.   v. SANDOZ INC.                               23

 the peaks recited in the asserted claims to overcome prior
 art rejections during prosecution. J.A. 11383–84.
      Sandoz further notes that, even assuming that crystal-
 line Form B of apremilast and the associated X-ray powder
 diffraction peaks were immaterial to patentability, the dis-
 trict court erred in determining that the ’515 provisional
 application inherently disclosed crystalline Form B of apre-
 milast. Sandoz contends that Amgen was required to es-
 tablish that Example 2 of the ’515 provisional application
 necessarily disclosed crystalline Form B of apremilast, but
 at most, it presented thirteen third-party experiments that
 varied parameters of Example 2, and each experiment pro-
 duced crystalline Form B. That, Sandoz contends, is not
 sufficient to establish inherency.
     Sandoz also argues that the district court erred in dis-
 regarding Celgene’s affirmative admissions made during
 prosecution that Example 2 of the ’515 provisional applica-
 tion could produce crystalline Form C of apremilast, not
 only Form B, using procedures that fall within the confines
 of Example 2 of the ’515 provisional application.
      Amgen responds that the ’515 provisional application
 provides written description support for the ’101 patent
 claims. Amgen asserts that it presented thirteen experi-
 ments replicating Example 2 of the ’515 provisional appli-
 cation under a variety of conditions and that Sandoz did
 not produce any studies or findings showing that Example
 2 of the ’515 provisional application failed to produce crys-
 talline Form B of apremilast.
     Amgen further contends that the prosecution state-
 ments were made in error because Form C requires tolu-
 ene, which is not within the scope of Example 2. Amgen
 thus asserts that the procedure in Example 2 of the ’515
 provisional application necessarily discloses the claimed
 invention and inherently discloses crystalline Form B of
 apremilast. Thus, Amgen’s argument concludes that
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 24                                  AMGEN INC.   v. SANDOZ INC.

 claims 1 and 15 are entitled to the priority date of the ’515
 provisional application.
     We agree with Amgen that the district court did not
 clearly err in finding that claims 1 and 15 of the ’101 patent
 were entitled to the March 2002 priority date (i.e., the filing
 date of the ’515 provisional application). As a starting
 point, the parties did not dispute that the ’515 provisional
 application, filed on March 20, 2002, discloses a synthetic
 procedure for preparing apremilast in Example 2. Amgen
 provided the results of over a dozen experiments following
 the procedure in Example 2 of the ’515 provisional applica-
 tion, all of which resulted in crystalline Form B of apre-
 milast. In response, Sandoz did not produce the results of
 any experiments showing that Example 2 of the ’515 provi-
 sional application did not produce crystalline Form B of
 apremilast. Thus, although Sandoz alleges that Example
 2 may have been capable of producing a crystalline Form
 other than Form B, it provided no evidence to establish
 that contention.
     We also note that the district court based its holding on
 the finding that the ’515 provisional application inherently
 disclosed crystalline Form B of apremilast. In doing so, the
 district court relied on Yeda Research & Development Co.
 v. Abbott GmbH & Co. KG, 837 F.3d 1341 (Fed. Cir. 2016),
 a case cited to us by both Sandoz and Amgen on appeal.
 Appellant’s Br. 55; Cross-Appellant’s Br. 74–75. Demon-
 strating inherent disclosure requires meeting a stringent
 standard. See, e.g., Bettcher Indus., Inc. v. Bunzl USA, Inc.,
 661 F.3d 629, 639 (Fed. Cir. 2011) (“Inherency can be es-
 tablished when ‘prior art necessarily functions in accord-
 ance with, or includes, the claimed limitations,’” but “‘may
 not be established by probabilities or possibilities.’” (first
 quoting In re Cruciferous Sprout Litig., 301 F.3d 1343,
 1349 (Fed. Cir. 2002); and then quoting In re Oelrich, 666
 F.2d 578, 581 (CCPA 1981))). But in Yeda, 837 F.3d at
 1345–46, we held that an earlier-filed application con-
 tained adequate written description of a claimed protein
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 AMGEN INC.   v. SANDOZ INC.                               25

 even though the application did not explicitly disclose the
 complete N-terminus sequence of that protein. Here we
 need not reach the issue of inherent disclosure because the
 trial evidence credited by the district court, including the
 experiment-related evidence introduced by Amgen (and the
 lack of contrary evidence from Sandoz) as well as testimony
 of Amgen’s expert, see Decision at *36, establishes that
 crystalline Form B of apremilast is actually disclosed in the
 ’515 provisional application. A finding of inherency is not
 required, and therefore, the district court did not clearly
 err in holding that claims 1 and 15 of the ’101 patent were
 entitled to the March 2002 priority date.
      The district court adequately considered Amgen’s un-
 contradicted trial testimony that crystalline Form C of
 apremilast requires the use of a toluene solvent, which be-
 comes a part of the crystal structure that comprises crys-
 talline Form C of apremilast. As the court noted, and as
 Amgen’s expert stated, toluene is not mentioned in Exam-
 ple 2 of the ’515 provisional application, and thus the court
 did not clearly err in finding that Celgene had made a mis-
 take in asserting to the European Patent Office that Exam-
 ple 2 of the ’515 provisional application could produce
 forms of apremilast other than crystalline Form B.
     We further note, as the district court found, that
 Sandoz fails to argue that any prior art from before March
 2002 renders the ’101 patent claims invalid for obvious-
 ness, and thus its arguments reduce to a question whether
 claims 1 and 15 of the ’101 patent are entitled to the March
 2002 priority date. We therefore affirm the court’s holding
 that Sandoz failed to prove that claims 1 and 15 of the ’101
 patent were not entitled to the March 2002 priority date or
 that they are otherwise not invalid as obvious.
                      III. The ’541 Patent
     We finally consider Amgen’s cross-appeal challenge to
 the district court’s determination that claims 2, 19, and 21
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 26                                AMGEN INC.   v. SANDOZ INC.

 of the ’541 patent would have been obvious over Papp,
 Schett, and Pathan.
     Amgen argues that the district court relied on general-
 ized characterizations of a dose-titration schedule and in-
 appropriately analyzed the “gist” of the invention rather
 than the invention as claimed. Amgen argues that this er-
 ror resulted in a failure to make express findings that a
 skilled artisan would have been motivated to achieve the
 claimed dosage schedule. Amgen also asserts that the
 court’s motivation-to-combine findings did not address why
 a skilled artisan would have had good reason to pursue cer-
 tain features of the claimed schedule, including a dosing
 schedule with asymmetric dosing versus symmetric dosing,
 a dosing schedule that mixes once-a-day and twice-a-day
 dosing, or using a six-day dosing schedule, all of which
 were absent in the prior art. Amgen further asserts that
 the court’s obvious-to-try statements do not remedy the al-
 leged errors in the court’s motivation-to-combine analysis.
 Amgen contends that evidence proffered in support of an
 obvious-to-try theory must show that the possible options
 skilled artisans would have encountered were finite, small,
 or easily traversed. Cross-Appellant’s Br. 86 (citing In re
 Cyclobenzaprine Hydrochloride Extended-Release Capsule
 Pat. Litig., 676 F.3d 1063, 1072 (Fed. Cir. 2012)). Amgen
 notes that its expert alleged that there were over 70,000
 possible six-day dose-titration schedules. To determine
 whether any were efficacious and tolerable, Amgen con-
 tends, a skilled artisan would have had to administer each
 schedule to patients in a controlled setting.
     Sandoz responds that the district court did not err in
 determining that claims 2, 19, and 21 of the ’541 patent
 would have been obvious over the prior art or in crediting
 expert testimony stating that dose-titration modification
 would have been routine to a skilled artisan. Sandoz as-
 serts that a skilled artisan would have been motivated to
 modify the dosing schedule in Papp, which begins with two
 days of two 10 mg doses of apremilast, followed by two days
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 AMGEN INC.   v. SANDOZ INC.                                27

 of two 20 mg doses of apremilast, and followed by a fifth
 day of two doses of 30 mg of apremilast, Decision at *31; see
 also J.A. 18583; Papp at 739, to further reduce known side
 effects and would have had a reasonable expectation of suc-
 cess in doing so. Sandoz further contends that the court
 did not reduce the claims to a “gist” in its motivation-to-
 combine analysis, and even if it did, the process of the
 claims would have been obvious to try. Amgen further as-
 serts that there was evidence that a skilled artisan would
 have been motivated to ease the dose-escalation burden on
 patients to reduce the risk of known side effects by moving
 to a one-step-at-a-time regimen starting at 10 mg apre-
 milast per day and increasing by 10 mg per day. Sandoz
 asserts that that logic naturally leads to the claimed dose-
 titration regimen.
      Sandoz further argues that the court appropriately re-
 jected as inflated the estimate that there were over 70,000
 possible dose-titration schedules. Sandoz asserts that the
 faulty estimate was based on two incorrect assumptions:
 (1) that there were six available dose strengths of apre-
 milast instead of three and (2) that a skilled artisan would
 not have preferred an evenly titrated dose, each of which is
 incorrect. Sandoz concludes that correction of these as-
 sumptions reduces the possible estimate to eighteen possi-
 ble dose-titration schedules.
     We agree with Sandoz that the district court did not err
 in holding that claims 2, 19, and 21 of the ’541 patent would
 have been obvious over the prior art, principally Papp and
 Schett. The court credited expert testimony establishing
 that it was well within a skilled artisan’s ability to titrate
 an apremilast dose for a patient presenting with psoriasis
 and that doing so would have been a routine aspect of treat-
 ing psoriasis. Decision at *31. The court did not err in
 finding that the twice-daily fixed apremilast dosing sched-
 ule, initiating treatment at 10 mg and increasing toward a
 30 mg twice-daily target dose in 10 mg increments, was
 rendered obvious by the prior art. Further, the court
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 28                                 AMGEN INC.   v. SANDOZ INC.

 appropriately noted that, when prescribing apremilast or
 other drugs with known dose-dependent adverse events in
 the early weeks of treatment, a skilled artisan would have
 been motivated to use the Papp schedule as a starting point
 and extend it to titrate the dosing up in smaller amounts.
      We have previously held that varying a dose in re-
 sponse to the occurrence of side effects is a well-known,
 standard medical practice that may well lead to a finding
 of obviousness. Genentech, Inc. v. Sandoz Inc., 55 F.4th
 1368, 1376–77 (Fed. Cir. 2022) (“[I]t is worth noting our in-
 itial perception that, as the district court noted, varying
 doses in response to the occurrence of side effects would
 seem to be a well-established, hence obvious, practice.
 Thus, claiming it as an invention would appear to be at best
 a long shot.”). We note here, as in Genentech, that varying
 a dose in response to the occurrence of side effects is well-
 known and obvious to the skilled artisan. Accordingly, we
 find no error in the district court’s findings that claims 2,
 19, and 21 would have been obvious over Papp, Schett, and
 Pathan.
                        CONCLUSION
     We have considered the parties’ remaining arguments
 but find them unpersuasive. For the foregoing reasons,
 we affirm the district court’s decision.
                          AFFIRMED
                            COSTS
 No costs.