Court Opinion

ID: 9956187
Source: CourtListenerOpinion
Date Created: 2024-04-01 14:01:08.074904+00
Date Added: 2024-06-11T08:15:42.724894
License: Public Domain

Case: 22-1258   Document: 70     Page: 1   Filed: 04/01/2024

   United States Court of Appeals
       for the Federal Circuit
                 ______________________

  JANSSEN PHARMACEUTICALS, INC., JANSSEN
            PHARMACEUTICA NV,
              Plaintiffs-Appellees

                            v.

   TEVA PHARMACEUTICALS USA, INC., MYLAN
            LABORATORIES LTD.,
              Defendants-Appellants
             ______________________

                  2022-1258, 2022-1307
                 ______________________

     Appeals from the United States District Court for the
 District of New Jersey in Nos. 2:18-cv-00734-CCC-LDW,
 2:19-cv-16484-CCC-LDW, Judge Claire C. Cecchi.
                 ______________________

                 Decided: April 1, 2024
                 ______________________

     BARBARA MULLIN, Patterson Belknap Webb & Tyler
 LLP, New York, NY, argued for plaintiffs-appellees. Also
 represented by ANDREW D. COHEN, ARON RUSSELL FISCHER,
 MEGHAN LARYWON.

     JOHN C. O'QUINN, Kirkland & Ellis LLP, Washington,
 DC, argued for all defendants-appellants. Defendant-ap-
 pellant Teva Pharmaceuticals USA, Inc. also represented
 by WILLIAM H. BURGESS; CHRISTOPHER T. JAGOE, JEANNA
 WACKER, New York, NY.
Case: 22-1258      Document: 70    Page: 2    Filed: 04/01/2024

 2                          JANSSEN PHARMACEUTICALS, INC. v.
                              TEVA PHARMACEUTICALS USA, INC.

     DEEPRO MUKERJEE, Katten Muchin Rosenman LLP, for
 defendant-appellant Mylan Laboratories Ltd. Also repre-
 sented by LANCE SODERSTROM; JITENDRA MALIK, Charlotte,
 NC; JILLIAN SCHURR, Chicago, IL; ERIC THOMAS
 WERLINGER, Washington, DC.
                 ______________________

         Before DYK, PROST, and HUGHES, Circuit Judges.
 PROST, Circuit Judge.
      Janssen Pharmaceuticals, Inc. and Janssen Pharma-
 ceutica NV (collectively, “Janssen”) sued Teva Pharmaceu-
 ticals USA, Inc. (“Teva”) for patent infringement in the
 United States District Court for the District of New Jersey.
 Janssen asserted U.S. Patent No. 9,439,906 (“the ’906 pa-
 tent”). Teva stipulated to infringement but challenged va-
 lidity. Relevant here, Teva argued that all representative
 claims were invalid as obvious and that claims 19–21 were
 also invalid as indefinite. After a bench trial, the district
 court found that Teva had not proven invalidity on either
 basis. Teva appeals. 1 For the reasons below, we affirm the
 district court’s indefiniteness determination but vacate
 and remand its nonobviousness determination.
                         BACKGROUND
     Janssen markets and sells Invega Sustenna. Invega
 Sustenna is an extended-release intramuscular injectable
 of paliperidone palmitate, which is indicated for the treat-
 ment of schizophrenia in adults. J.A. 13118. After Teva

     1    Janssen also sued Mylan Laboratories Ltd.
 (“Mylan”) in a separate action. In that action, the parties
 stipulated to be bound by the final judgment in the Teva
 action with respect to infringement and validity. J.A. 49
 (final judgment). Although we refer to Teva throughout,
 Mylan is also an Appellant here.
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 filed an Abbreviated New Drug Application (“ANDA”) seek-
 ing FDA approval to sell a generic version of Invega Sus-
 tenna, Janssen sued and asserted various claims of the
 ’906 patent. The ’906 patent, which generally relates to
 dosing regimens of paliperidone palmitate, is the last re-
 maining Orange Book patent for Invega Sustenna.
                              I
     The ’906 patent is titled “dosing regimen associated
 with long acting injectable paliperidone esters.” ’906 pa-
 tent col. 1 ll. 1–3 (capitalization normalized). It was filed
 in December 2008 and claims priority to a provisional ap-
 plication filed in December 2007. Id. at col. 1 ll. 8–10. For
 purposes of this appeal, Teva does not contest that the
 ’906 patent is entitled to the December 2007 priority date.
 Appellants’ Br. 19.
     The parties agreed that claims 2, 10, 13, and 20–21
 were representative. Janssen Pharms., Inc. v. Teva
 Pharms. USA, Inc., 571 F. Supp. 3d 281, 291 n.3 (D.N.J.
 2021) (“Opinion”). All asserted claims relate to “[a] dosing
 regimen for administering paliperidone palmitate to a psy-
 chiatric patient in need of treatment for schizophrenia.”
 ’906 patent claims 1 and 8.
     Claim 2 (non-renal-impairment claim), which depends
 from claim 1, relates to a normal or non-renal-impairment
 dosing regimen. Both claims are reproduced below.
     1. A dosing regimen for administering paliperi-
     done palmitate to a psychiatric patient in need of
     treatment for schizophrenia, schizoaffective disor-
     der, or schizophreniform disorder comprising
         (1) administering intramuscularly in the
         deltoid of a patient in need of treatment a
         first loading dose of about 150 mg-eq. of
         paliperidone as paliperidone palmitate for-
         mulated in a sustained release formulation
         on the first day of treatment;
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        (2) administering intramuscularly in the
        deltoid muscle of the patient in need of
        treatment a second loading dose of about
        100 mg-eq. of paliperidone as paliperidone
        palmitate formulated in a sustained re-
        lease formulation on the 6th to about 10th
        day of treatment; and
        (3) administering intramuscularly in the
        deltoid or gluteal muscle of the patient in
        need of treatment a first maintenance dose
        of about 25 mg-eq. to about 150 mg-eq. of
        paliperidone as paliperidone palmitate in a
        sustained release formulation a month (±7
        days) after the second loading dose.
     2. The dosing regimen of claim 1 wherein after ad-
     ministration of the first maintenance dose, subse-
     quent maintenance doses of from about 25 mg-eq.
     to 150 mg-eq. are administered in the deltoid or
     gluteal muscle of the psychiatric patient in need of
     treatment at monthly (±7 days) intervals.
 ’906 patent claims 1 and 2.
     Representative claims 10 and 13 (renal-impairment
 claims) claim dosing regimens for renally impaired pa-
 tients. Claim 10 depends from claim 8. Both claims are
 reproduced below.
     8. A dosing regimen for administering paliperi-
     done palmitate to a renally impaired psychiatric
     patient in need of treatment for schizophrenia,
     schizoaffective disorder, or schizophreniform disor-
     der comprising
        (a) administering intramuscularly in the
        deltoid of a renally impaired psychiatric
        patient in need of treatment a first loading
        dose of from about 75 mg-eq. of paliperi-
        done as paliperidone palmitate formulated
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        in a sustained release formulation on the
        first day of treatment;
        (b) administering intramuscularly in the
        deltoid muscle of the patient in need of
        treatment a second loading dose of from
        about 75 mg-eq. of paliperidone as paliper-
        idone palmitate formulated in a sustained
        release formulation on the 6th to about
        10th day of treatment; and
        (c) administering intramuscularly in the
        deltoid or gluteal muscle of the patient in
        need of treatment a first maintenance dose
        of about 25 mg-eq. to about 75 mg-eq. of
        paliperidone as paliperidone palmitate in a
        sustained release formulation a month (±7
        days) after the second loading dose.
    10. The dosing regimen of claim 8 wherein the sus-
    tained release formulation is an aqueous nanopar-
    ticle suspension.
 ’906 patent claims 8 and 10.
     Claim 13 differs from claim 10 by requiring that the
 patient is in need of treatment for schizophrenia and recit-
 ing a range of 25 mg-eq. to about 50 mg-eq. for the mainte-
 nance dose.
     Claims 20 and 21 (particle-size claims) are only repre-
 sentative as they depend from claims 1 and 8. They both
 further depend from claim 19. Because for our purposes
 the particle-size limitation of claim 19 is most pertinent,
 only claim 19 is reproduced below.
    19. The dosing regimen of claims 1, 4, 8 or 11
    wherein the sustained release depot formulation is
    an aqueous nanoparticle suspension consists es-
    sentially of
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                              TEVA PHARMACEUTICALS USA, INC.

         (a) 156 mg/ml of the paliperidone palmi-
         tate having an average particle size (d50) of
         from about 1600 nm to about 900 nm;
         (b) 12 mg/ml of polysorbate 20;
         (c) one or more buffering agents sufficient
         to render the composition neutral to very
         slightly basic (pH 8.5);
         (d) 30 mg/ml of a suspending agent wherein
         the suspending agent is polyethylene glycol
         4000; and
         (f) water q.s. ad 100%.
 ’906 patent claim 19 (emphasis added).
      The ’906 patent discloses that “[p]aliperidone is the
 major active metabolite of risperidone,” an antipsychotic
 that was developed in the 1990s. ’906 patent col. 1
 ll. 36–37. It further explains that due to their chemical
 properties, “paliperidone esters such as paliperidone pal-
 mitate dissolve slowly after an [intramuscular] injection
 before being hydrolyzed to paliperidone and made availa-
 ble in the systemic circulation.” Id. at col. 1 ll. 46–49. The
 specification acknowledges that persons of skill “could eas-
 ily determine the effective amount of paliperidone to ad-
 minister,” and that for purposes of the ’906 patent’s
 invention, “[t]he amount of paliperidone palmitate is pro-
 vided in sufficient amount to provide the equivalent dose of
 paliperidone after the palmitic acid moiety is removed from
 the ester (e.g.[,] 156 mg corresponds to paliperidone
 100 mg).” Id. at col. 14 ll. 13–26.
     A tablet formulation of paliperidone was already on the
 market and indicated for the treatment of schizophrenia.
 Id. at col. 1 ll. 37–41; see also U.S. Patent No. 5,158,952
 (compound patent for paliperidone, issued in 1992). How-
 ever, the specification describes the prevalence of treat-
 ment adherence problems when patients are prescribed
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 oral antipsychotic medications that need to be taken daily,
 which in turn “often result in worsening of symptoms,
 suboptimal treatment response, frequent relapses and re-
 hospitalizations, and an inability to benefit from rehabili-
 tative and psychosocial therapies.” ’906 patent col. 1
 ll. 50–57.
      The specification explains that an injectable formula-
 tion of paliperidone palmitate was previously “developed to
 provide sustained plasma concentrations of paliperidone
 when administered once monthly, which may greatly en-
 hance compliance with dosing.” Id. at col. 1 ll. 58–63. And,
 it explains that U.S. Patent Nos. 6,577,545 and 6,555,544
 (“the ’544 patent”) had already described the formulation.
 Id. The ’906 specification also describes the preferred par-
 ticle size as d(50) of preferably “1600 nm to 400 nm” and
 “most preferably 1400 nm to 900 nm.” Id. at col. 7 ll. 28–31.
 In the ’906 patent, d(50) means that “at least 50% of the
 particles have a smaller diameter” than the listed meas-
 urement. Id. at col. 7 ll. 32–38.
     The ’906 patent describes several different “dosing reg-
 imen[s] for administering paliperidone esters to a psychi-
 atric patient in need of treatment” and emphasizes the
 plasma concentration of paliperidone reached when differ-
 ent variables are changed and the time frame for reaching
 it. See generally id. at col. 2 l. 11–col. 4 l. 42 (describing
 embodiments); id. at col. 5 ll. 2–5; id. at col. 6 ll. 41–59.
      It further discloses that “deltoid injections result in a
 faster rise in initial plasma concentration” and that “to fa-
 cilitate patients’ attaining a rapid therapeutic concentra-
 tion of paliperidone it is preferred to provide the initial
 loading dose of paliperidone palmitate in the deltoids.” Id.
 at col. 5 ll. 2–8. It states that “[a]fter the first or more pref-
 erably after the second loading dose injection patients will
 be approaching a steady state concentration of paliperi-
 done in their plasma and may be injected in either the del-
 toid or the gluteal muscle thereafter. However, it is
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                               TEVA PHARMACEUTICALS USA, INC.

 preferred that the patients receive further injections in the
 gluteal muscle.” Id. at col. 5 ll. 11–16.
      Relatedly, the specification explains that there was an
 observed relationship between needle length and body
 mass index (“BMI”) and time to reach ideal initial plasma
 concentrations of paliperidone. Specifically, “[p]atients
 with high BMI had lower plasma concentration of paliper-
 idone and a lessened treatment response . . . likely due to
 unintended partial or complete injection into adipose tis-
 sue, instead of deep injection into muscle.” Id. at col. 6
 ll. 44–49. As a result, the specification explains that for
 deltoid injections 1-inch needles are sufficient for patients
 weighing less than 90kg, but 1.5-inch needles should be
 used for those who weigh more. Id. at col. 6 ll. 51–57. For
 gluteal injections, the specification simply states that “1.5-
 inch needle[s] should be used” without specifying a weight-
 based preference. Id. at col. 6 ll. 57–59.
      In terms of dosing, the specification states that “[p]ref-
 erably the first two doses will be loading dose[s] of between
 from about 100 mg-eq. to about 150 mg-eq.,” id. at col. 5
 ll. 34–36; see also id. at col. 5 ll. 8–10, and “[t]he subse-
 quent doses thereafter will drop to a therapeutic mainte-
 nance dose of from about 25 mg-eq. to 150 mg-eq. per
 month (±7 days) . . . most preferably the maintenance dose
 initially will be about 50 mg[-]eq,” id. at col. 5 ll. 38–45. It
 also explains that “[t]hose of ordinary skill in the art will
 understand that the maintenance dose may be titrated up
 or down in view of the patient[’s] condition (response to the
 medication and renal function).” Id. at col. 5 ll. 49–52.
     The ’906 patent contains three figures. Each of these
 figures shows both observed and modeled plasma paliperi-
 done concentrations. For all three figures, patients were
 given a 150 mg-eq. dose in the deltoid on day 1; day 8, 36,
 and 64 doses were either 25 mg-eq (Figure 1), 100 mg-eq.
 (Figure 2), or 150 mg-eq. (Figure 3). The day 8, 36, and 64
 doses were given in either the deltoid or the gluteus. The
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 specification indicates that the figures make apparent that
 “the plasma profiles provided by initiating paliperidone
 with 150 mg[-]eq. followed by a subsequent dose of 100 or
 150 for days 1-36 provide a rapid rise to a therapeutic dose
 level[].” Id. at col. 31 ll. 62–65 (emphasis added).
                                II
     The safety of paliperidone, its efficacy for treating
 schizophrenia, and its recommended dosing were all well
 established as of the ’906 patent’s priority date.
 J.A. 13266–79; J.A. 16209–10; J.A. 16233. Additionally,
 long acting injectables (LAIs)—administered intramuscu-
 larly—of other antipsychotics were on the market.
 J.A. 16640, 16650–52 (label for haldol decanoate, LAI of
 haloperidol); J.A. 17911, 17941 (risperdal consta, LAI of
 risperidone, of which paliperidone is the major metabolite).
     To demonstrate obviousness of the paliperidone palmi-
 tate LAI dosing regimen claims at issue here, Teva relied
 on three primary prior-art references at trial: (1) clinical
 study protocol NCT00210548 (“the ’548 protocol”); (2) the
 ’544    patent;   and    (3) International     Publication
 No. WO 2006/114384 (“WO’384”). We describe each refer-
 ence below.
                                A
      The ’548 protocol, published in 2005, is a protocol for
 an interventional Phase III clinical trial with the brief title:
 “A Study to Evaluate the Effectiveness and Safety of 3
 Doses of Paliperidone Palmitate in Treating Subjects with
 Schizophrenia.” J.A. 13244–45. The protocol explains that
 “[t]he hypothesis is that the 3 fixed doses of paliperidone
 are each more efficacious than placebo in treating subjects
 with schizophrenia.” Id. Further, the protocol’s dosing is
 outlined as follows:
     Four injections of paliperidone palmitate 50, 100,
     or 150 milligrams equivalent administered in the
     gluteal muscle (buttocks). Injections will be given
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                               TEVA PHARMACEUTICALS USA, INC.

       on Days 1, 8, 36, and 64 of the double-blind treat-
       ment period of the study.
 Id.
     Experts on both sides provided testimony about what
 the Phase III status of the protocol would indicate to them.
 Dr. Gopal, an inventor of the ’906 patent who designed clin-
 ical trials for paliperidone palmitate, testified that Phase
 III studies were expected to meet safety and efficacy end-
 points because of the requisite preexisting Phase I and II
 data. J.A. 11124:8–20; see also J.A. 11135:9–11 (“[W]e gen-
 erally don’t like to change too many things going from
 Phase II to Phase III. We want to extrapolate as much as
 possible so we try to keep them the same.”). Teva’s expert,
 Dr. Wermeling, similarly testified that a person of ordinary
 skill in the art would understand that Phase III studies
 “us[ed] doses that are thought to be safe and effective and
 are going to be confirmed in the larger patient population.”
 J.A. 10316:17–10317:2; see also J.A. 10207:5–23.
      It is undisputed that the ’548 protocol does not contain
 any results—Opinion, 571 F. Supp. 3d at 301—and Teva
 relied on how a person of ordinary skill in the art (“POSA”)
 would understand the protocol itself considering its Phase
 III status and other background knowledge in the art. And
 while the protocol is associated with Janssen’s PSY-3003
 clinical trial, the results of the PSY-3003 trial were not
 known in the prior art. As we explain in more detail
 throughout this opinion, the import of these unknown re-
 sults influenced the district court’s view about what the
 claims require, what a POSA would need to know before
 she was motivated to modify the ’548 protocol, and what
 results would be unexpected.
     Consequently, although unavailable to a POSA, some
 information about the PSY-3003 trial results provides
 helpful context for our discussion. The 50 mg-eq. study
 arm—50 mg-eq. given on days 1, 8, 36, and 64—did not
 demonstrate a statistical difference compared to placebo.
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 J.A. 10895:6–7. In contrast, the 100 mg-eq. study arm did
 demonstrate efficacy that was significantly better than pla-
 cebo. J.A. 11061:21–24; J.A. 11147:3–9; J.A. 10893:15–17;
 J.A. 10895:11–13; J.A. 13130. However, “by [its] own
 measures,” Janssen considered the day 36 onset for efficacy
 “too late.” J.A. 11062:7–11. Finally, for the 150 mg-eq.
 study arm, because of a randomization error, most patients
 who were supposed to receive the 150 mg-eq. doses mistak-
 enly received placebo instead. J.A. 11063:24–11064:8;
 J.A. 10894:6–17. As a result, the data for that study arm
 was unusable for conducting statistical analyses.
 J.A. 11064:9–12; J.A. 10895:1–6; J.A. 11169:22–25. Ulti-
 mately, Janssen considered this clinical trial a failure—it
 did not believe it had sufficient data to obtain FDA ap-
 proval. J.A. 11068:3–17; J.A. 10784:15–20.
                               B
     The ’544 patent, granted in 2003 and expired in 2018,
 is owned by Janssen. As the ’906 patent is now, the
 ’544 patent was listed in the Orange Book for Invega Sus-
 tenna before its expiration. J.A. 17768.
      The ’544 patent claims “[a] pharmaceutical composi-
 tion suitable as a depot formulation for administration by
 intramuscular or subcutaneous injection, comprising,”
 among other things, a “therapeutically effective amount” of
 paliperidone palmitate. ’544 patent claim 1. Additionally,
 it claims a method of treating schizophrenia, or other dis-
 orders, “in a warm-blooded animal in need thereof compris-
 ing administering to the animal a therapeutically effective
 amount of” the claimed composition of paliperidone palmi-
 tate. ’544 patent claim 7.
      Further, the specification emphasizes the ability to
 space out administrations by three weeks to a month. Spe-
 cifically, it states that “[t]he present invention results from
 the investigations into the development of an efficient,
 well-tolerated, sustained or delayed release (depot) formu-
 lation of a [paliperidone] alkanoic acid ester which is
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 therapeutically effective for at least three weeks or more,
 in particular about 1 month.” Id. at col. 2 ll. 38–43; see also
 id. at col. 8 ll. 17–19 (“Typically, said formulation will be
 administered approximately every three weeks or even at
 longer intervals where possible.”). It further indicates that
 “effective for at least three weeks or more” means a plasma
 level of paliperidone above 10 ng/ml and below 100 ng/ml,
 id. at col. 2 ll. 43–50, and that “[t]he dosage should range
 from about 2 to 4 mg/kg body weight,” id. at col. 8
 ll. 19–20. 2
      The ’544 patent discloses specific amounts of active and
 inactive ingredients for an LAI paliperidone palmitate for-
 mulation. Id. at col. 8 l. 60–col. 9 l. 7. Most pertinent for
 our purposes on appeal, the specification discusses the par-
 ticle size used in the formulations. Specifically, it states
 that “[t]he pharmacokinetic properties in humans of the
 aqueous suspensions of [paliperidone] alkanoic acid esters
 depend on the particle size to a much larger extent than
 previously held possible.” Id. at col. 3 ll. 52–55. And it gen-
 erally provides details related to applying “mechanical
 means” to reduce the effective average particle size. Id.
 at col. 6 ll. 1–47.
     The ’544 patent references “an effective average parti-
 cle size of less than 2,000 nm” several times, see, e.g., id.
 at col. 3 ll. 43–44, col. 5 ll. 15–26, which, as used in the
 ’544 patent, “means that at least 90% of the particles have
 a diameter of less than 2,000 nm,” id. at col. 5 ll. 16–18. In
 other words, “effective average particle size” refers to the
 d(90) value (90% of the particles have a smaller diameter)
 in the ’544 patent—this is in contrast to the ’906 patent
 which defines effective average particle size as the d(50)

      2 Dr. Wermeling testified that for a population
 weighing between 50 and 90 kg, the 2 to 4 mg/kg dosage
 range would translate to 65 mg-eq. to 230 mg-eq. paliperi-
 done palmitate. J.A. 10284:16–21.
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 value (50% of the particles have a smaller diameter). Com-
 pare id., with ’906 patent col. 7 ll. 32–36.
    The ’544 patent discloses the particle sizes of four for-
 mulations:

 See Appellants’ Br. 13 (table); ’544 patent col. 8 ll. 44–57,
 col. 9 ll. 24–33 (data).
      It further discloses that “[f]ormulations C and D were
 put on a three month stability test,” id. at col. 9 ll. 33–34,
 and that “[e]ach of the four formulations A–D were admin-
 istered to four beagle dogs intramuscularly,” id. at col. 9
 ll. 48–49.
                               C
      International Publication WO’384 was filed by Janssen
 and published in 2006. J.A. 13299–321. Although the dis-
 closure is broader, the abstract describes the invention of
 WO’384 as related to “a process for preparing aseptic crys-
 talline” paliperidone palmitate. J.A. 13299.
      As part of an example entitled “[p]reparation of fin-
 ished form,” WO’384 discloses specific amounts of active
 and inactive ingredients for an LAI paliperidone palmitate
 formulation. J.A. 13316. Janssen agrees that the compo-
 sition of this disclosed formulation matches both the com-
 position elements of claims 20 and 21 and the Invega
 Sustenna formulation. Appellees’ Br. 9. Also, as part of
 this example, WO’384 states that “[t]he suspension was
 filled aseptically into sterile syringes” in dose volumes
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                             TEVA PHARMACEUTICALS USA, INC.

 “between 0.25 ml and 1.50 ml depending on the dose
 needed,” J.A. 13317, which corresponds to 25 to 150 mg-eq.
 of paliperidone, J.A. 12163:15–20.
                          *   *   *
     Teva argued that all asserted claims were invalid as
 obvious and that claims 19–21 were also invalid as indefi-
 nite. After a bench trial, the district court concluded that
 Teva had not proven invalidity on either basis. Teva ap-
 peals. We have jurisdiction under 28 U.S.C. § 1295(a)(1).
                        DISCUSSION
     Teva first argues that the district court’s obviousness
 analysis, including its analysis of secondary considera-
 tions, was legally flawed in several key respects. Some of
 Teva’s arguments relate to all claims while others only re-
 late to a subset of claims. Ultimately, we vacate and re-
 mand with respect to all claims.
      We address: (1) whether the court required a showing
 of obviousness that was incongruent with the scope of the
 claims by requiring—(i) generalized or population-wide
 dosing (all claims) and (ii) mild renal impairment (claims
 10 and 13); (2) whether the court analyzed the prior art
 with a degree of rigidity foreclosed by KSR—(i) generally
 (all claims) and (ii) teaching away (particle-size claims);
 and (3) secondary considerations—(i) whether they pre-
 clude vacatur and (ii) whether individual secondary consid-
 erations were properly analyzed.
     Finally, we address Teva’s argument that the district
 court improperly determined that Teva had not demon-
 strated that claims 19–21 (particle-size claims) were inva-
 lid as indefinite. Although the claims may still be
 invalidated as obvious on remand, we nonetheless reach
 the question of indefiniteness and affirm the court’s deter-
 mination that claims 19–21 were not shown to be indefi-
 nite.
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                                I
     Obviousness is a question of law based on underlying
 factual determinations, “including (1) the scope and con-
 tent of the prior art; (2) the differences between the claims
 and the prior art; (3) the level of ordinary skill in the perti-
 nent art; and (4) any secondary considerations of non-obvi-
 ousness.” ZUP, LLC v. Nash Mfg., Inc., 896 F.3d 1365,
 1371 (Fed. Cir. 2018); see also PAR Pharm., Inc. v. TWI
 Pharms., Inc., 773 F.3d 1186, 1193–94 (Fed. Cir. 2014). We
 review the overall determination de novo and the underly-
 ing factual findings for clear error. PAR Pharm., 773 F.3d
 at 1194. Where the court applies an incorrect legal stand-
 ard in its analysis, it can be appropriate to vacate and re-
 mand for factfindings that address the correct legal
 question. See id. at 1196 (remanding where “[t]here [we]re
 simply no findings of fact addressing th[e correct legal]
 question” about inherency); Innovention Toys, LLC v. MGA
 Ent., Inc., 637 F.3d 1314, 1324 (Fed. Cir. 2011) (remanding
 on determination of nonobviousness where the district
 court applied an improperly low level of skill in the art for
 the court to “make a finding on the level of skill in the art
 and base its obviousness analysis on that level of skill” on
 remand).
      “The combination of familiar elements according to
 known methods is likely to be obvious when it does no more
 than yield predictable results.” KSR Int’l Co. v. Teleflex
 Inc., 550 U.S. 398, 416 (2007). Assessing obviousness is
 based on an “expansive and flexible approach” that “need
 not seek out precise teachings directed to the specific sub-
 ject matter of the challenged claim, for a court can take ac-
 count of the inferences and creative steps that a person of
 ordinary skill in the art would employ.” Id. at 415, 418.
                                A
     Teva makes several arguments about the district
 court’s obviousness analysis, leading with its argument
 that the district court added unclaimed limitations to the
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 claims when analyzing obviousness—specifically: (1) gen-
 eralized or population-wide dosing (all claims); and
 (2) mild renal impairment (claims 10 and 13). We address
 both arguments in turn.
                              1
     First, Teva argues that the district court’s analysis of
 obviousness required Teva to show that it would have been
 obvious to use the recited dosing regimens for the general
 population of patients—i.e., a generalized dosing regimen.
 The court found that the prior art did not demonstrate pop-
 ulation-wide safety and efficacy and thus did not teach a
 generalized dosing regimen. Teva contends that the claims
 were not directed to a generalized dosing regimen and
 therefore the district court asked for a showing of obvious-
 ness that went beyond what was claimed. We agree.
      The non-renal-impairment dosing regimen claims re-
 cite a dosing regimen for “a psychiatric patient in need of
 treatment for schizophrenia” 3: (1) a 150 mg-eq. loading
 dose on day 1 administered into the deltoid; (2) a 100 mg-
 eq. loading dose on day 6 to 10 administered into the del-
 toid; and (3) a maintenance dose of 25 to 150 mg-eq. given
 a month (±7 days) after the second loading dose adminis-
 tered into the deltoid or gluteal muscle. ’906 patent claim
 2 (emphasis added). Likewise, the renal-impairment
 claims recite a dosing regimen for “a renally impaired psy-
 chiatric patient in need of treatment for schizophrenia”:
 (1) a 75 mg-eq. loading dose on day 1 administered into the
 deltoid; (2) a 75 mg-eq. loading dose on day 6 to 10 admin-
 istered into the deltoid; and (3) a maintenance dose of 25 to
 about 75 mg-eq. (or 25 to about 50 mg-eq.) given a month
 (±7 days) after the second loading dose administered into

      3  Some claims also contemplate that the patient is in
 need of treatment for a different psychiatric disorder, but
 the parties focus on schizophrenia, so we do the same.
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 the deltoid or gluteal muscle. ’906 patent claims 10 and 13
 (emphasis added).
     Nothing in the claims requires that the regimen be
 used for—let alone be ideal for—the patient population
 generally or a certain percentage of the patient population.
 On their face, the claims only recite a dosing regimen for a
 psychiatric patient. Because “[w]hat matters is the objec-
 tive reach of the claim,” KSR, 550 U.S. at 419, the district
 court erred to the extent it effectively defined its obvious-
 ness inquiry as one concerning the “generalized” suitability
 of the dosing regimens.
     At the district court, Janssen emphasized arguments
 and evidence related to its clinical-study design and ap-
 proval process with the FDA—both of which were keyed to
 concerns about generating population-wide data. It seems
 that the court ended up conflating Janssen’s purported dif-
 ficulties in generating data to gain approval for a “univer-
 sal” or “generalized” dosing regimen with the scope of the
 claims themselves. 4 Given the scope of the claims here, it
 was important for the court to recognize the distinction and
 focus its findings on single patient administration. The
 district court did not do so.
     We are persuaded that this misunderstanding about
 the claims impacted the district court’s overall obviousness
 analysis. Certain portions of the court’s discussion provide

     4   Because we agree with Teva that it was improper
 to read this limitation into the claims, we need not assess
 what it would mean for the claimed dosing regimens to be
 “generalized” or “universal.” For example, it is unclear
 whether that requirement would indicate that physicians
 typically (or always) dose that way or that some (or all) pa-
 tients achieve a certain level of a particular unnamed re-
 sult.
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 examples of how this legal error affected the district court’s
 analysis and factfinding here.
     For example, the district court assessed whether a
 POSA would be motivated to use the deltoid (shoulder) as
 an injection site. Teva argued that the deltoid was one of
 only three finite choices for an intramuscular injection site
 (the deltoid, gluteal muscle, or thigh), J.A. 11719:9–17, and
 some patients preferred the deltoid, so using the deltoid as
 an injection site was obvious. The district court concluded
 that injecting at the deltoid was not obvious because “such
 preferences would suggest at most using deltoid admin-
 istration on an individualized basis.”               Opinion,
 571 F. Supp. 3d at 305. As a result, the district court con-
 cluded that Teva had not met its burden even by pointing
 to evidence that, when given a choice, certain populations
 of patients tend to prefer a deltoid injection over a gluteal
 one. Id.
     Likewise, while assessing whether a POSA would be
 motivated to use unequal loading doses (even where the
 loading dosage amounts were undisputedly disclosed in the
 prior art, both as a particular dose and as a point within a
 disclosed range), the district court dismissed Teva’s reli-
 ance on references related to administering unequal load-
 ing doses because they “t[aught] individualized, rather
 than generalized, dosing.” Id. at 306.
     Additionally, although the court’s analysis of reasona-
 ble expectation of success has minimal explanation, there
 too it seemed to require an expectation of success not for
 administering paliperidone palmitate to a patient accord-
 ing to the dosing regimen claimed, but rather success in
 achieving the goals a POSA would have across an (unde-
 fined) average population of patients, such that a POSA
 would expect to use the regimen as a “generalized multi-
 dose regimen.” Id. at 310. The court also appeared to con-
 flate the invention or the claims with Janssen’s approval
 process when it referred to the difficulties Janssen
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 encountered with the PSY-3003 clinical trial as an indica-
 tion of unpredictability in the “invention process.” Id.
 at 311.
     Janssen makes two arguments about why the district
 court’s framing was not erroneous. First, it argues that the
 district court simply followed Teva’s lead in referring to the
 claims as “general dosing regimens.” Second, it argues that
 the court was simply analyzing the obviousness theory that
 Teva presented, not adding limitations to the claims. Nei-
 ther argument is persuasive.
     While it is true that Teva used the phrase “general dos-
 ing regimens” to describe the non-renal-impairment
 claims, Janssen has not pointed to anything showing that
 Teva used the term “general” in the same way the district
 court used the term “generalized”—as a comparison be-
 tween individual and population-wide. Further, Teva’s use
 of the word general is far from a concession that the facts
 to be found for the obviousness inquiry should be facts
 about some (unarticulated) percentage of patients in gen-
 eral.
     Further, we are not persuaded that Teva’s motivation
 theory based on “reach[ing] therapeutic plasma levels
 faster,” J.A. 1426, or “accelerat[ing] the onset of effect,”
 J.A. 10311, justifies how the court framed its analysis.
 That theory does not imply a population-wide objective.
 And, to the extent Teva’s theory was predicated on
 knowledge of some therapeutic effect, the court required
 far more than that.
     In sum, as discussed above, the court’s framing led it to
 ask the wrong questions about important aspects of the ob-
 viousness inquiry. This error requires a remand as to all
 claims because as it currently stands, the record does not
 contain underlying obviousness factfindings that are cued
 to the “a psychiatric patient” claims at issue here. See Syn-
 tex (U.S.A.) LLC v. Apotex, Inc., 407 F.3d 1371, 1373
 (Fed. Cir. 2005) (reversing and remanding where “the
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                             TEVA PHARMACEUTICALS USA, INC.

 district court committed legal error in establishing certain
 factual predicates to its non-obviousness determination”).
                              2
     Teva argues that the court also read a “mild” limitation
 into the renal-impairment claims, whereas the claims do
 not specify a level of renal impairment. Janssen counters
 that Teva presented an obviousness theory that was pred-
 icated on dosing a patient with mild renal impairment.
     We agree that many of the district court’s statements
 suggest that it understood the claims themselves to require
 administration to a patient with mild renal impairment.
 See, e.g., Opinion, 571 F. Supp. 3d at 307 (noting “the dos-
 ing regimens address patients with mild renal impair-
 ment”). And we agree that there is no such requirement in
 the claims. Thus, we remand for the district court to ana-
 lyze obviousness without a “mild” limitation added to the
 renal-impairment claims.
                              B
     Next, Teva argues that the court’s analysis was imper-
 missibly rigid and does not comport with KSR or otherwise
 reflect this court’s obviousness jurisprudence. We first ad-
 dress this argument as it pertains to the court’s obvious-
 ness analysis more generally. Then, we address Teva’s
 specific argument about the court’s teaching-away finding
 related to particle size (claims 20 and 21).
                              1
      We agree with Teva that the district court’s analysis
 was erroneously rigid in several respects. The district
 court analyzed the prior art without giving the needed
 weight to the perspective of a POSA capable of deducing
 what references fairly suggest or employing ordinary crea-
 tivity. Instead of considering the prior art in context or in
 combination, the court’s analysis seems to tackle the ex-
 press statements of each reference one-by-one—identifying
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 each difference or dissimilarity between an individual ref-
 erence and the claims, but not fully assessing the teachings
 in toto. This seemingly siloed and inflexible approach left
 insufficient room for consideration of how background
 knowledge in the art would have impacted a POSA’s un-
 derstanding of, or motivation to modify, the primary refer-
 ences at issue, thereby inflating the significance of minor
 variations between the prior art and the claims. We vacate
 and remand on this basis too because it also seems to have
 prevented the court from carrying out its factfinding role,
 irrespective of claim scope.
     Janssen argues that the court’s rigid consideration of
 prior art references related to modifications—i.e., unequal
 loading doses, injection sites, and dose reduction for a pa-
 tient with renal impairment—is justified by the court’s de-
 termination that there was no motivation to make any
 modifications to the ’548 protocol. Appellees’ Br. 44–46.
      The district court’s obviousness analysis does begin by
 looking to the ’548 protocol and, largely without referring
 to the evidence offered specific to the modifications at issue,
 concluding that (1) there were issues with starting from
 the ’548 protocol because “it contains no information about
 the safety of the dosing regimen or its efficacy”; and
 (2) without knowledge of the results of the trial that
 Janssen considered a failure, a POSA would not be moti-
 vated to modify the protocol. Opinion, 571 F. Supp. 3d at
 301–03. To the extent the court’s analysis about a POSA’s
 motivation to start with the ’548 protocol was not entirely
 based on its misunderstanding of the claims, it too was not
 in accordance with law.
     First, the district court concluded that in the pharma-
 ceutical context, if a prior art reference does not contain
 safety and efficacy data, there is no reason to combine it
 with other prior art references. Id. at 301 (“As Dr. Sinko
 credibly testified, without such safety and efficacy infor-
 mation, a POSA would have had no reason to alter the
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                             TEVA PHARMACEUTICALS USA, INC.

 regimen disclosed in the [’548 Protocol].”); Id. at 310
 (“Therefore, to successfully arrive at a multi-dose regimen
 based on the prior art, a POSA would need safety, efficacy,
 and pharmacokinetic data in order to evaluate how a gen-
 eralized dosing regimen would perform in patients.”).
 Whatever role safety and efficacy data may play in as-
 sessing the strength of a motivation or a lack of motivation
 to combine, see Arctic Cat Inc. v. Bombardier Recreational
 Prods. Inc., 876 F.3d 1350, 1360–61 (Fed. Cir. 2017), ab-
 sence of such safety and efficacy data in the ’548 Protocol
 cannot justify simply discarding that prior art particularly
 where, as here, the claims do not have any safety and effi-
 cacy requirement.       In United Therapeutics Corp. v.
 Liquidia Techs., Inc., 74 F.4th 1360, 1369 (Fed. Cir. 2023),
 we found that “the claim language ‘treating pulmonary hy-
 pertension’ does not import any additional efficacy limita-
 tions or any safety limitations” and “[w]e decline to insert
 the FDA’s responsibilities into claims by importing require-
 ments where they do not recite such limitations.” Id. The
 district court cannot employ a different standard when an-
 alyzing prior art for obviousness than would be used to de-
 termine     infringement.         Amazon.com,      Inc.    v.
 Barnesandnoble.com, Inc., 239 F.3d 1343, 1351 (Fed. Cir.
 2001). The district court’s treatment of the prior art proto-
 col was therefore in error.
     Additionally, the court emphasized the protocol’s lack
 of results but failed to consider what the ’548 protocol
 would fairly suggest to a POSA. For example, the court did
 not discuss evidence related to the significance a POSA
 would assign to the Phase III status of the protocol,
 J.A. 11124:8–20; J.A. 11135:9–11, or that paliperidone was
 already on the market and prescribed to patients in need
 of treatment for schizophrenia, J.A. 16209. More im-
 portantly, the claims of the ’906 patent do not recite any
 particular result or outcome, nor do they recite a need for
 population-wide statistically significant data. And, alt-
 hough we recognize that obtaining specific results or
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 outcomes in a population of patients could have been one
 motivation for modifying the protocol—indeed, it seems
 that it was Janssen’s motivation—the motivation analysis
 does not look only to the data the patentee found signifi-
 cant. Cf. KSR, 550 U.S. at 420; Allergan, Inc. v. Sandoz
 Inc., 726 F.3d 1286, 1292 (Fed. Cir. 2013) (“There is no re-
 quirement in patent law that the person of ordinary skill
 be motivated to develop the claimed invention based on a
 rationale that forms the basis for FDA approval.”). While
 we do not make an initial finding about the level of back-
 ground information a POSA would require to be motivated
 to modify an existing dosing regimen for a psychiatric pa-
 tient in need of treatment, it is different from (and almost
 certainly less demanding than) the level of information de-
 sired by a POSA in deciding whether to redesign a Phase
 III clinical trial to obtain approval for a dosing regimen’s
 use across a population of patients of varying weights.
      Second, contrary to the court’s assumptions, the
 ’548 protocol did not need to hold itself out as flawed for a
 POSA to alter it. 5 Again, Janssen’s narrative that internal
 information about the PSY-3003 trial’s results caused it to
 alter the regimen used for subsequent trials did not pre-
 vent Teva from demonstrating a different motivation based
 on publicly available information. Further, although iden-
 tifying a recognized problem or need in the prior art is one
 way to demonstrate motivation, Teva was not required to
 demonstrate that there was an explicit problem with the
 ’548 protocol itself. For one thing, the motivation analysis

     5   Although we address the flaws on both sides of the
 analysis, we also note the conundrum—the court seemed
 to conclude both that a POSA would not have looked to the
 protocol until there was data confirming that the doses
 were, on average, safe, efficacious, and fast-acting and sim-
 ultaneously that a POSA would not have modified it until
 she knew that the protocol had “failed.”
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 is not limited by the problem or need recognized by the in-
 ventors. See PAR Pharm., 773 F.3d at 1197. Further, a
 motivation “may be found in many different places and
 forms,” Allergan, 726 F.3d at 1292, and it need not be ex-
 pressly stated in the references at all, Alza Corp. v. Mylan
 Labs., Inc., 464 F.3d 1286, 1291 (Fed. Cir. 2006), let alone
 originate from the reference to be modified. A motivation
 “may be found explicitly or implicitly in market forces; de-
 sign incentives; the interrelated teachings of multiple pa-
 tents; any need or problem known in the field of endeavor
 at the time of invention and addressed by the patent; and
 the background knowledge, creativity, and common sense
 of the person of ordinary skill.” Adapt Pharma Operations
 Ltd. v. Teva Pharms. USA, Inc., 25 F.4th 1354, 1365
 (Fed. Cir. 2022) (cleaned up).
     The court’s determination that the ’548 protocol simply
 would not be modified carried through the remainder of its
 obviousness analysis.      This reasoning, contrary to
 Janssen’s suggestion, did not provide a sufficient basis to
 support the court’s entire nonobviousness determination,
 and instead evidences another reason to vacate the deci-
 sion.
     The district court also made erroneous findings regard-
 ing modifications to loading doses and injection sites.
 Without considering whether the differences in the
 ’548 protocol would be significant to a POSA, the court la-
 beled the equal loading doses and gluteal injection site ma-
 terial differences between the ’548 protocol and the claims.
 Opinion, 571 F. Supp. 3d at 301; see also id. at 303 (calling
 deltoid administration “a key component of [c]laim 2”); id.
 at 305 (naming unequal loading doses a “key feature”).
     The district court first looked to the claimed require-
 ment that the first and second doses are given in the del-
 toid—as opposed to the gluteal muscle, where the day 1 and
 8 doses of the ’548 protocol are given. The court disre-
 garded evidence related to patient preferences and
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 injection sites. A POSA can be motivated to do more than
 one thing (in other words, there was motivation both for
 the deltoid and gluteal muscle) and Teva did not need to
 show that a POSA would be singularly motivated to use the
 deltoid injection site. See Bayer Pharma AG v. Watson
 Labs., Inc., 874 F.3d 1316, 1328 (Fed. Cir. 2017) (“[O]bvi-
 ousness does not require that the motivation be the best
 option, only that it be a suitable option from which the prior
 art did not teach away.” (emphasis in original) (cleaned
 up)).
     Next, the court considered unequal loading doses. The
 ’548 protocol expressly disclosed administration of 100 mg-
 eq. loading doses on days 1 and 8 and administration of
 150 mg-eq. loading doses on days 1 and 8. J.A. 13244–45.
 However, the claims require a 150 mg-eq. dose on day 1 and
 a 100 mg-eq. dose on day 6–10. The court presumed signif-
 icance based on the unequalness itself but nonetheless dis-
 counted potential teachings related to unequal dosing
 generally because the references presented other dissimi-
 larities from the claims. For example, in addition to dis-
 counting certain references because they related to
 individualized dosing, the court also seems to have dis-
 counted them for involving the administration of a differ-
 ent antipsychotic LAI. Opinion, 571 F. Supp. 3d at 305–06.
 While it is true that the specific amounts of medication
 given in these references would not correlate to the amount
 of paliperidone palmitate claimed, that should not have led
 to disregarding the references’ teachings related to the con-
 cept of dose variation itself. On remand, the court should
 address these concerns.
     Finally, the court considered the renal-impairment
 claims, which involve two equal loading doses of 75 mg-eq.
 paliperidone followed by a maintenance dose in the range
 of 25 mg-eq. to 75 mg-eq. (or 25 mg-eq. to 50 mg-eq. in claim
 13). Teva argued that a POSA would have halved the
 150 mg-eq. paliperidone palmitate loading dose for renally
 impaired patients because the prior art taught a 50% dose
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 reduction for renal impairment. Here too, the court cut
 short the analysis required after identifying differences be-
 tween the claims and each reference, an analysis that must
 focus on what the references might fairly suggest to an or-
 dinarily creative POSA or might provide in the way of back-
 ground knowledge.
     For example, Cleton 2007 expressly disclosed that
 “[p]aliperidone plasma exposure was higher in subjects
 with renal impairment compared to healthy subjects” and
 that “[b]ased on the pharmacokinetic data, a lower dose of
 paliperidone ER should be considered for subjects with
 moderate and severe renal impairment.” J.A. 14112. The
 prior-art Invega ER label states that the maximum recom-
 mended dose for patients with mild renal impairment is
 6 mg/day and 3 mg/day for patients with moderate to se-
 vere renal impairment, whereas the maximum recom-
 mended dose for non-renally impaired patients is
 12 mg/day. J.A. 16233. The court appears to have found
 Teva’s reliance on Cleton 2007 and the Invega ER label un-
 availing, at least in part, simply because the references did
 not involve injectable paliperidone palmitate. Opinion,
 571 F. Supp. 3d at 307. The court did not explain why in-
 formation about oral paliperidone dosing for renally im-
 paired patients would not be meaningful to a POSA
 considering doses of paliperidone palmitate, which are ex-
 pressed in equivalents of paliperidone. Similarly, the
 court’s analysis placed significance on the fact that the
 ’591 application6 was titled “use of paliperidone for the
 treatment of a mental disorder in a psychiatric patient
 with reduced hepatic [liver] function” even though it was
 pointed to as evidence of a POSA’s understanding that pal-
 iperidone is cleared through the kidneys. Id. It is unclear
 how the ’591 application’s title could impair a POSA’s abil-
 ity to understand its separate teachings about renal

      6   U.S. Patent Application No. 2007/0197591 A1.
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 clearance. Ultimately, the court determined that the ref-
 erences’ failure to “expressly teach LAI paliperidone palmi-
 tate dose reductions for mild renal impairment” was
 sufficient to reject Teva’s arguments. 7 Id. at 308 (emphasis
 added).
     Overall, the court’s analysis ran afoul of KSR’s basic
 mandate in a number of ways. It failed to consider the “in-
 terrelated teachings of multiple” references, “the back-
 ground knowledge possessed by a person having ordinary
 skill in the art,” or “the inferences and creative steps that
 a person of ordinary skill in the art would employ.” See
 KSR, 550 U.S. at 418. Instead, the court sought an explicit
 indication in the ’548 protocol that an improvement was re-
 quired—at times also suggesting that it was searching for
 an indication that the claims captured the singular way the
 protocol would be modified.
                               2
     Teva also argues that the district court erroneously
 found a teaching away with respect to the “(d50) of from
 about 1600 nm to about 900 nm” particle-size limitation
 (claims 20 and 21). Appellants’ Br. 57–58. We agree that
 the district court did not apply the correct test for teaching
 away.

     7   The court also appears to have independently re-
 jected Teva’s theory because the two claimed 75 mg-eq.
 loading doses would not result “if the 150/100 mg-eq. load-
 ing doses of Claim 2 were reduced by half.” Opinion,
 571 F. Supp. 3d at 308. This was the wrong question. The
 question was whether halving the ’548 protocol’s 150 mg-
 eq. loading doses or selecting 75 mg-eq. loading doses from
 the disclosed range was obvious when administering to a
 renally impaired patient, not whether the renally impaired
 claims were obvious when starting from the non-renally
 impaired claims.
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      The prior art ’544 patent discloses the particle sizes of
 four formulations of paliperidone palmitate. ’544 patent
 col. 8 ll. 44–57, col. 9 ll. 24–33. Its formulation B has a
 d(50) particle size within the claimed range of 1600 nm to
 900 nm. Id. The court found an “express[] teach[ing]
 away” from formulation B’s d(50) value of 1380 nm (50% of
 the particles were smaller than 1380 nm) because formula-
 tion B’s d(90) value was 6830 nm (90% of the particles were
 smaller than 6830 nm), and the ’544 patent’s specification
 emphasized a d(90) value of 2000 nm.                    Opinion,
 571 F. Supp. 3d at 309 (citing ’544 patent col. 3 ll. 42–44,
 col. 5 ll. 16–21, col. 9 ll. 25–31, col. 10 ll. 27–29). A teach-
 ing that a d(90) value of 2000nm was optimal is not a crit-
 icism of all other particle sizes. See Galderma Labs., L.P.
 v. Tolmar, Inc., 737 F.3d 731, 738–39 (Fed. Cir. 2013). In
 fact, the ’544 patent stated that “[m]ost preferably, essen-
 tially all of the particles have a size of less than 2,000 nm.”
 ’544 patent col. 5 ll. 25–26 (emphasis added). That the
 ’544 patent did not disclose a preferred d(50) value does not
 amount to a teaching away either. Allergan, Inc. v. Apotex
 Inc., 754 F.3d 952, 964 (Fed. Cir. 2014) (“[S]ilence does not
 imply teaching away.”). The court should have analyzed
 whether the d(50) value was “criticize[d], discredit[ed], or
 otherwise discourage[d].” Galderma, 737 F.3d at 739. In-
 stead, it merely assessed what the ’544 patent taught about
 the optimal or standard d(90) value. 8
     We do not address Teva’s argument about optimization
 of a result-effective variable because, as Janssen’s brief
 suggests, see Appellees’ Br. 51, were the teaching away

      8  The court can reassess its reliance on expert testi-
 mony on remand. However, as it stands, we are not per-
 suaded that the court looked to expert testimony for more
 than an indication that a different d(90) value was pre-
 ferred by the ’544 patent itself. See, e.g., J.A. 11785:2–13,
 J.A. 11529:24–11530:8.
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 analysis sound, the court may have deemed it unnecessary
 to address optimization, and we do not discern an analysis
 of this issue in the court’s opinion. On remand, the court
 will reassess the obviousness of these claims in light of our
 opinion. The court can address optimization as part of that
 renewed analysis.
                                 C
     We agree with Teva that the district court’s determina-
 tions related to secondary considerations do not disturb our
 conclusion that vacatur is required here.
     On remand, the district court will need to reassess the
 significance of the secondary considerations as part of its
 renewed obviousness analysis. Even if the district court’s
 consideration of individual secondary considerations had
 been error free—and it was not, for at least the reasons dis-
 cussed below—those same conclusions, left undisturbed,
 might well be inadequate to support a conclusion of nonob-
 viousness when considered in conjunction with a proper as-
 sessment of the other Graham factors. See, e.g., Tokai
 Corp. v. Easton Enters., Inc., 632 F.3d 1358, 1371 (Fed. Cir.
 2011) (“A strong case of prima facie obviousness . . . cannot
 be overcome by a far weaker showing of objective indicia of
 nonobviousness.”); Bristol-Myers Squibb Co. v. Teva
 Pharms. USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014)
 (“While secondary considerations must be taken into ac-
 count, they do not necessarily control the obviousness de-
 termination.”); ZUP, 896 F.3d at 1373 (“[M]inimal evidence
 of secondary considerations does not create a genuine dis-
 pute of fact sufficient to withstand summary judgment on
 the question of obviousness.”). Moreover, as Teva correctly
 notes, the district court here did not explain in the first in-
 stance what significance it assigned to secondary consider-
 ations within its overall assessment of obviousness.
     Additionally, with respect to individual secondary con-
 siderations, the district court will necessarily need to
 reevaluate nexus because, as discussed above, the court’s
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 misunderstanding of claim scope carried throughout its ob-
 viousness analysis. And a proper nexus analysis must
 “consider the correspondence between the objective evi-
 dence and the claim scope.” Henny Penny Corp. v. Frymas-
 ter LLC, 938 F.3d 1324, 1332 (Fed. Cir. 2019); see also
 Merck & Cie v. Gnosis S.P.A., 808 F.3d 829, 837 (Fed. Cir.
 2015) (“Where objective indicia result from something
 other than what is both claimed and novel in the claim,
 there is no nexus to the merits of the claimed invention.”
 (cleaned up) (first emphasis added)).
     Teva also presents specific arguments related to the
 district court’s analysis of certain subcategories of second-
 ary considerations. For at least the sake of judicial effi-
 ciency, we address some of those specific arguments as
 well. 9

      9   Because the court only afforded evidence of copying
 “some limited weight,” Opinion, 571 F. Supp. 3d at 319, we
 do not envision the factor playing a large role on remand.
 As a result, we find it unnecessary to address the parties’
 dispute about this consideration in detail. However, we do
 note that the court relied on a case that involved copying a
 claimed manufacturing process for preparation of a drug.
 Id. (citing Merck Sharp & Dohme Corp. v. Hospira, Inc.,
 874 F.3d 724, 728, 731 (Fed. Cir. 2017)). The claims here
 do not recite the process of manufacturing a drug. Further,
 it was undisputed that particle size, which the court fo-
 cused on for copying, impacted the pharmacokinetic prop-
 erties of the paliperidone palmitate LAI.          See, e.g.,
 ’544 patent col. 3 ll. 52–55; J.A. 11777:18–21 (Janssen’s ex-
 pert agreeing that the ’544 patent’s statements teach that
 particle size impacts pharmacokinetics, “and that’s con-
 sistent with scientific principles”). In previous ANDA
 cases, this court has emphasized that “a showing of bioe-
 quivalence is required for FDA approval” when discussing
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                              1
     We first address the district court’s treatment of unex-
 pected results. “In considering unexpected results, courts
 ask whether the claimed invention exhibits some superior
 property or advantage that a person of ordinary skill in the
 relevant art would have found surprising or unexpected”
 compared to the prior art as of the priority date. Forest
 Labs., LLC v. Sigmapharm Labs., LLC, 918 F.3d 928, 937
 (Fed. Cir. 2019) (cleaned up). The starting reference point
 for evaluating unexpectedness is the closest prior art. See
 Bristol-Myers, 752 F.3d at 977; Kao Corp. v. Unilever U.S.,
 Inc., 441 F.3d 963, 970 (Fed. Cir. 2006).
      The district court found that “the [r]epresentative
 [c]laims led to unexpected results” and that the “unex-
 pected results indicator weigh[ed] in favor of nonobvious-
 ness.” Opinion, 571 F. Supp. 3d at 315–16. Teva argues
 that the district court erred because, among other things,
 it did not make the correct comparisons. We agree.
     First, the district court compared the claims to “the
 conventional wisdom,” related to antipsychotics generally,
 that dosing should “start low and go slow.” Id. at 315 (cit-
 ing expert testimony related to the dosing of risperidone,
 haloperidol decanoate, and risperdal consta). The court
 then cited a prior-art reference that provided an overview
 of drug delivery by injection, infusion, or implantation for
 the proposition that LAIs are “indicated for maintenance
 treatment rather than initiation of therapy.” Id. (citing
 J.A. 14134). The court concluded that “[t]he claimed dos-
 ing regimens run contrary to these prior art teachings

 why evidence of copying was not probative.          Bayer
 Healthcare Pharms., Inc. v. Watson Pharms., Inc., 713 F.3d
 1369, 1377 (Fed. Cir. 2013); see also Adapt Pharma,
 25 F.4th at 1374–75.
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 because they use depot injections of high, rather than low,
 loading doses to initiate treatment.” Id.
     To the extent this analysis related to results (unex-
 pected or otherwise), it clearly does not involve a compari-
 son of the closest prior art. 10 All the testimony cited for the
 “start low and go slow” proposition relates to medications
 with active ingredients other than paliperidone. Risperi-
 done was used as a reference, and it does not have the ac-
 tive ingredient of paliperidone, and is not an injectable
 medication. J.A. 16244. Similarly, the reference discuss-
 ing LAIs generally is not about paliperidone palmitate. In
 contrast, the prior art ’548 protocol discloses administering
 a paliperidone palmitate injection of 150 mg-eq. on days 1
 and 8. J.A. 13244. Evaluating unexpectedness via a com-
 parison of the “start low and go slow” paradigm for other
 medications was improper. There is simply nothing unex-
 pected about starting with a dose of the paliperidone pal-
 mitate LAI that was already disclosed simply because
 other medications were dosed differently.
     Next, the district court concluded that the results were
 unexpected in view of the ’548 protocol too. Although the
 ’548 protocol is the closest prior art, the court did not use
 the required reference point for evaluating unexpected-
 ness. The question was whether, as of the priority date,
 using the claimed dosing regimens yielded unexpected re-
 sults when compared with a POSA’s expectations based on
 the state of the prior art. The court instead based its find-
 ing of unexpectedness on two different comparisons: (1) a
 comparison between Janssen’s expectations of the ’548 pro-
 tocol results and its disappointment in the results of the
 PSY-3003 clinical trial (including the lack of data gener-
 ated by one study arm); and (2) a comparison between the

      10  Janssen itself acknowledges that the ’548 protocol
 is the closest prior art. Appellees’ Br. 62.
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 unknown results of the PSY-3003 clinical trial and the re-
 sults of Invega Sustenna.
      As to the first comparison, the court found that the “in-
 ventors expected the Phase III clinical trials to be a suc-
 cess, especially because they built on the promising results
 of the SCH-201 study, which showed rapid efficacy.” Opin-
 ion, 571 F. Supp. 3d at 315. Then, instead of comparing
 this expectation to the results achieved with the claimed
 regimens, the court looked to the unexpectedness of “the
 inventors encounter[ing] several clinical failures during
 Phase III.” Id. It is unclear how, if at all, the unexpected-
 ness of these failures relates to the claims. In addition, the
 court did not address the extent to which these failures re-
 lated to the dosing regimen used in the trial as opposed to
 the fact that certain patients were not dosed in accordance
 with the protocol or study design.
     As to the second comparison, the court found unexpect-
 edness based on “Invega Sustenna improv[ing] patient
 treatment adherence through its use of high initial loading
 doses that rapidly achieved therapeutic concentrations of
 paliperidone palmitate and monthly loading doses which
 maintained these concentrations,” compared with the data
 generated from the PSY-3003 clinical trial. Id. (emphasis
 added). Regardless of whether the clinical trial was later
 considered unsuccessful—and whether this was tied to the
 dosing regimens used instead of how the trial was con-
 ducted—the results of the clinical trial were not known or
 in the prior art. A POSA could not have been surprised by
 results of the claimed regimens compared with the
 ’548 protocol results because a POSA would not have been
 aware of those results. See Forest Labs., 918 F.3d at 937
 (“At the time of the claimed invention, a person of ordinary
 skill could not have been surprised that the sublingual
 route of administration did not result in cardiotoxic effects
 because the person of ordinary skill would not have been
 aware that other routes of administration do result in car-
 diotoxic effects.”).
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      Even if the correct comparison had been made between
 expectations based on information available to a POSA and
 the claimed regimens’ results, it is still not entirely clear
 what result the district court was evaluating. For example,
 it is unclear whether the district court intended to analyze
 the unexpectedness of the level of treatment adherence
 achieved by the claimed regimen, the time required to
 reach therapeutic concentrations of paliperidone palmi-
 tate, or some combination of both. Likewise, the court la-
 belled the ’548 protocol a “failure” and the claimed
 regimens a “success” without explaining what metrics it
 was considering in its assessment of success and failure.
                              2
     Next, Teva challenges the court’s industry praise find-
 ings, arguing that the court relied on industry praise with
 no nexus to the claims. We do not address whether it would
 have been appropriate to find a nexus between the praise
 and the claims because we do not discern any analysis of
 nexus in this part of the court’s opinion. See Opinion,
 571 F. Supp. 3d at 317–18. Although the court generally
 stated that the secondary considerations evidence “is
 linked to the high loading dose deltoid injections and sub-
 sequent maintenance injections” before it addressed the
 specific secondary considerations, id. at 314, its industry
 praise analysis did not address this supposed link. 11 On

      11 To the extent the court’s nexus analysis consists of
 the mere observation that Invega Sustenna is a product
 that embodies the claims and the praise related to Invega
 Sustenna, that was insufficient. For example, Janssen
 clearly asserts that the ’906 patent covers an invention dif-
 ferent from the ’544 patent; however, both read on the In-
 vega Sustenna product. Cf. Fox Factory, Inc. v. SRAM,
 LLC, 944 F.3d 1366, 1377 (Fed. Cir. 2019) (“Where a prod-
 uct embodies claims from two patents, a presumption of
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 remand, the court should assess whether the praise “re-
 sult[ed] from something . . . [that] is both claimed and
 novel.” See Merck & Cie, 808 F.3d at 837 (cleaned up) (em-
 phasis in original).
                               3
     Finally, Teva argues that the district court improperly
 disregarded the impact of blocking patents when assessing
 long-felt need and commercial success. This court has ex-
 plained that “if all other variables are held constant, a
 blocking patent diminishes possible rewards from a non-
 owner’s or non-licensee’s investment activity aimed at an
 invention whose commercial exploitation would be infring-
 ing, therefore reducing incentives for innovations in the
 blocked space by non-owners and non-licensees of the
 blocking patent.” Acorda Therapeutics, Inc. v. Roxane
 Labs., Inc., 903 F.3d 1310, 1339 (Fed. Cir. 2018). In turn,
 this decrease in incentives “can discount the significance of
 evidence” of commercial success and long-felt need (among
 other secondary considerations not addressed in this ap-
 peal) because the failure for others to achieve the claim
 may be more indicative of deterrence than inventiveness.
 Id. However, the degree of disincentive and its resultant
 deterrence (or lack of deterrence) is a fact-specific inquiry.
 Id.
     We do not address the court’s factual evaluation of the
 level of disincentive or corresponding deterrence present
 based on the blocking patents in this case. See id. (listing
 at least six variables that are generally relevant to the de-
 terrence inquiry). And we do not address Teva’s arguments
 about the court’s assessment of the foundation for Teva’s
 expert testimony. However, we do agree with Teva that
 the blocking-patent analysis rested on two faulty premises.

 nexus can be appropriate only if the claims of both patents
 generally cover the same invention.”).
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     First, the consideration of the impact of the blocking
 patents should have focused on the blocked space that re-
 lated to Invega Sustenna because that is what Janssen con-
 tended was commercially successful and filling an unmet
 need. The observation that there was testimony that “it
 was     possible     to   practice    [c]laim   2    of   the
 ’906 [p]atent . . . without infringing the claims of the ’544
 and ’843 [p]atents,” presumably by dosing a different for-
 mulation of paliperidone palmitate (i.e., not Invega Sus-
 tenna), Opinion, 571 F. Supp. 3d at 324, was therefore not
 pertinent.
      Second, to the extent the determination of no deter-
 rence rested on the existence of the safe harbor provision
 alone, that was error. See id. at 324–35. “[A] potential in-
 novator might or might not be willing to research in the
 blocked space without a license to a blocking patent—even
 if the research itself is within the safe harbor provided by
 35 U.S.C. § 271(e)(1).” Acorda, 903 F.3d at 1338. The ex-
 istence of the safe harbor provision is a single aspect—one
 that is always present in the ANDA context—of the com-
 mercial realities that might impact whether blocking pa-
 tents deter. If it were true that the existence of the safe
 harbor provision mitigates any deterrence from blocking
 patents, the fact-specific inquiry previously described
 would be unnecessary in every case implicating § 271. The
 ability to avoid infringement liability for conduct related to
 preparing FDA submissions does not end the inquiry into
 the potential deterrence associated with the risk of market
 entry preclusion once those submissions are complete.
     We therefore remand for the district court to conduct
 its analysis of secondary considerations consistent with
 this opinion.
                               II
     We now address Teva’s indefiniteness arguments. In-
 definiteness, like claim construction, is a question of law
 that can involve underlying factfindings based on extrinsic
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 evidence. We review the overall determination de novo and
 any underlying factual determinations for clear error. Eli
 Lilly & Co. v. Teva Parenteral Meds., Inc., 845 F.3d 1357,
 1370 (Fed. Cir. 2017). Because the district court’s indefi-
 niteness determination here rests on factual findings that
 Teva has not shown to be clearly erroneous, we affirm.
     To satisfy the definiteness requirement, “a patent’s
 claims, viewed in light of the specification and prosecution
 history, [must] inform those skilled in the art about the
 scope of the invention with reasonable certainty.” Nauti-
 lus, Inc. v. Biosig Instruments, Inc., 572 U.S. 898, 910
 (2014). This court has held that claim scope is not reason-
 ably certain where a claimed characteristic can be meas-
 ured in multiple ways, those different measurements
 “would typically yield a different result” when applied to
 the same sample, and the intrinsic record fails to provide
 reasonable certainty about which measurement was in-
 tended by the claims. Teva Pharms. USA, Inc. v. Sandoz,
 Inc., 789 F.3d 1335, 1341, 1345 (Fed. Cir. 2015).
     Claim 19 contains a particle-size limitation for the pal-
 iperidone palmitate used in the formulations administered:
 “paliperidone palmitate having an average particle size
 (d50) of from about 1600 nm to about 900 nm.” ’906 patent
 claim 19. In turn, representative claims 20 and 21—which
 are representative only as they depend from claims 1 and
 8—both depend from claim 19.
      The claims do not specify what measurement technique
 should be used to determine whether the average particle
 size d(50) is from 1600 nm to 900 nm. Similarly, the spec-
 ification states that particle size can be “measured by art-
 known conventional techniques, such as sedimentation
 field flow fractionation, photon correlation spectroscopy or
 disk centrifugation.” Id. at col. 7 ll. 36–38. Example 1 pro-
 vides particle-size distributions “measured by laser diffrac-
 tion.” Id. at col. 14 l. 52–col. 15 l. 14.
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      Teva argued that the different particle-size measure-
 ment techniques, which were all allowed by the claims,
 would yield meaningfully different results, creating a situ-
 ation where the same physical samples of paliperidone pal-
 mitate would simultaneously fall inside and outside the
 claim depending only on how its particle-size measurement
 is taken. And it did point to evidence that, for particles in
 general, different particle-size measurement techniques
 can yield different results. J.A. 16306 (explaining how the
 particle size of imperfect spheres are defined “using the
 concept of equivalent spheres” and that “different measure-
 ment techniques use different equivalent sphere models
 and therefore will not necessarily give exactly the same re-
 sult for the particle diameter”); J.A. 16434 (“[E]quivalent
 particle diameter is defined not only by the physical parti-
 cle attribute measured, geometric or behavioral, but also
 by the measurement technique.”). However, the district
 court found that the actual discrepancy in particle-size
 measurement of paliperidone palmitate that Teva relied on
 was “an outlier measurement taken with a defective de-
 vice,” i.e., was not based on a discrepancy typical of the
 measurement technique used. Opinion, 571 F. Supp. 3d
 at 335 n.52.
     Teva has not shown that the court’s outlier finding was
 clearly erroneous. As a result, the district court correctly
 determined that, on this record, Teva did not meet its bur-
 den to show that claims 20 and 21 are invalid as indefinite.
 Specifically, if the measurement discrepancy is an outlier,
 Teva did not present evidence that different measurement
 techniques would typically yield different particle-size
 measurements of paliperidone palmitate. See Takeda
 Pharm. Co. v. Zydus Pharms. USA, 743 F.3d 1359, 1366–67
 (Fed. Cir. 2014) (explaining that the “mere possibility of
 different results” is insufficient for indefiniteness). As a
 result, we need not reach the parties’ arguments about
 whether, were it typical, this measurement discrepancy—
 which caused the particle-size measurement to fall both
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 inside and outside the claimed range—would be significant
 or meaningful.
                       CONCLUSION
     We vacate and remand the district court’s determina-
 tion of nonobviousness for proceedings consistent with this
 opinion. We affirm the court’s determination on indefinite-
 ness.
      AFFIRMED-IN-PART AND VACATED AND
             REMANDED-IN-PART
                           COSTS
 No costs.