Court Opinion

ID: 9349593
Source: CourtListenerOpinion
Date Created: 2022-12-22 16:00:56.735636+00
Date Added: 2024-06-11T16:46:42.176992
License: Public Domain

Case: 22-1595    Document: 49     Page: 1   Filed: 12/22/2022

   United States Court of Appeals
       for the Federal Circuit
                  ______________________

       GENENTECH, INC., INTERMUNE, INC.,
              Plaintiffs-Appellants

                             v.

   SANDOZ INC., LEK PHARMACEUTICALS, D.D.,
               Defendants-Appellees
             ______________________

                        2022-1595
                  ______________________

     Appeal from the United States District Court for the
 District of Delaware in No. 1:19-cv-00078-RGA, Judge
 Richard G. Andrews.
                 ______________________

                Decided: December 22, 2022
                  ______________________

     DARALYN JEANNINE DURIE, Durie Tangri LLP, San
 Francisco, CA, argued for plaintiffs-appellants. Also rep-
 resented by KATHLEEN GERSH, RYAN NEIL HAGGLUND,
 WARREN K. MACRAE, MARK EDWARD WADDELL, Loeb &
 Loeb LLP, New York, NY; DAN LIU, Los Angeles, CA.

    WILLIAM M. JAY, Goodwin Procter LLP, Washington,
 DC, argued for defendants-appellees. Also represented by
 EDWINA CLARKE, EMILY L. RAPALINO, DARYL L. WIESEN,
 Boston, MA; NATASHA ELISE DAUGHTREY, Los Angeles, CA.
                  ______________________
Case: 22-1595      Document: 49     Page: 2    Filed: 12/22/2022

 2                             GENENTECH, INC.   v. SANDOZ INC.

     Before NEWMAN, LOURIE, and PROST, Circuit Judges.
     Opinion for the court filed by Circuit Judge LOURIE.
         Circuit Judge NEWMAN dissents without opinion.
 LOURIE, Circuit Judge.
      Genentech, Inc. and InterMune, Inc. (collectively,
 “Genentech”) appeal from a decision of the United States
 District Court for the District of Delaware holding that: (1)
 the claims of its Liver Function Test (“LFT”) patents 1 are
 unpatentable as obvious, (2) sale of Sandoz Inc.’s and Lek
 Pharmaceuticals, D.D.’s (collectively, “Sandoz’s”) generic
 product would not induce infringement of the LFT patents,
 and (3) sale of Sandoz’s generic product would not directly
 infringe Genentech’s Drug-Drug Interaction (“DDI”) pa-
 tents. 2 See Genentech, Inc. v. Sandoz, Inc., No. 19-0078,
 2022 WL 842957 (D. Del. Mar. 22, 2022) (“Decision”). We
 affirm.
                         BACKGROUND
     Pirfenidone is a drug used to treat idiopathic pulmo-
 nary fibrosis (“IPF”). IPF is a chronic, irreversible lung dis-
 ease. There is no cure for IPF and patients living with the
 disease face an average survival of two to five years. There
 are currently two drugs that have been approved by the
 FDA for the treatment of IPF, pirfenidone and nintedanib.
 Approximately half of the patients on treatment for IPF are
 prescribed pirfenidone, and the other half are prescribed
 nintedanib. The major differences between the drugs cen-
 ter on side effects and metabolism.

     1  U.S. Patents 7,566,729 (the “’729 patent”),
 7,635,707 (the “’707 patent”), 8,592,462 (the “’462 patent”),
 and 8,609,701 (the “’701 patent”).
     2  U.S. Patents 7,816,383 (the “’383 patent”) and
 8,013,002 (the “’002 patent”).
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     Pirfenidone was first studied as an investigational new
 drug in 1973. Development rights to pirfenidone were sold
 to Shionogi for Japan, South Korea, and Taiwan, and to In-
 terMune for the rest of the world. In 2004, the United
 States Food and Drug Administration (“FDA”) granted
 pirfenidone orphan drug status for treatment of patients
 with IPF. In 2014, pirfenidone was approved to treat IPF
 in the U.S. as Esbriet®, sold by Genentech.
      Sandoz submitted two Abbreviated New Drug Applica-
 tions (“ANDAs”) seeking approval from the FDA to market
 a generic version of pirfenidone. Genentech then brought
 this Hatch-Waxman suit, asserting that Sandoz’s generic
 product would induce the infringement of its LFT and DDI
 patents. The asserted patents do not claim pirfenidone it-
 self, or the use of pirfenidone to treat IPF. Instead, the
 patents claim methods for managing certain side effects
 when using pirfenidone to treat IPF.
                        I. LFT Patents
     The LFT patents are directed to methods for adminis-
 tering pirfenidone to a patient who has exhibited abnormal
 biomarkers of liver function in response to pirfenidone ad-
 ministration. The asserted claims in these patents recite
 various options, including: (1) temporarily reducing the
 dose of pirfenidone and then returning to the full dose, (2)
 maintaining the full dose of pirfenidone, (3) reducing the
 dose of pirfenidone, (4) discontinuing pirfenidone for a
 week and then returning to the full dose, and (5) discontin-
 uing pirfenidone for a week and then returning to a re-
 duced dose.
     The claims of particular interest in this appeal are de-
 pendent claims. Therefore, for ease of understanding, we
 incorporate the parent claims into the claims that are as-
 serted. The distinctions between the specific claims are not
 argued, so we recite the asserted claims as a group.
    Asserted claim 9 of the ’729 patent reads as follows:
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 4                             GENENTECH, INC.   v. SANDOZ INC.

       The method of claim 1 [administering
       pirfenidone to treat a patient with IPF, said
       patient having exhibited a grade 2 abnormal-
       ity in one or more biomarkers of liver function
       after pirfenidone administration, comprising
       (a) administering to said patient pirfenidone
       at doses lower than 2400 mg/day for a time
       period, followed by
       (b) administering to said patient pirfenidone
       at doses of 2400 mg/day or 2403 mg/day],
       wherein said one or more biomarkers of liver
       function comprise alanine transaminase and
       aspartate transaminase.
 ’729 patent at col. 12 ll. 13–20, 48–50.
     Asserted claim 6 of the ’707 patent recites:
       The method of claim 1 [administering
       pirfenidone to treat a patient with IPF, said
       patient having exhibited a grade 2 abnormal-
       ity in one or more biomarkers of liver function
       after pirfenidone administration, comprising
       (a) administering to said patient pirfenidone
       at doses of 2400 mg/day or 2403 mg/day],
       wherein said one or more biomarkers of liver
       function is selected from the group consisting
       of alanine transaminase and aspartate trans-
       aminase.
 ’707 patent at col. 18 ll. 24–29, 42–44.
     Asserted claim 14 of the ’707 patent recites:
       The method of claim 7 [administering
       pirfenidone to treat a patient with IPF, said
       patient having exhibited a grade 2 abnormal-
       ity in one or more biomarkers of liver function
       after pirfenidone administration, comprising
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        (a) administering to said patient pirfenidone
        at doses of 1600 mg/day or 1602 mg/day],
        wherein said one or more biomarkers of liver
        function is selected from the group consisting
        of alanine transaminase and aspartate trans-
        aminase.
 Id. at col. 18 ll. 45–50, col. 20 ll. 1–3.
     Asserted claim 12 of the ’462 patent recites:
        The method of claim 3 [administering
        pirfenidone to treat a patient with IPF, said
        patient having exhibited an increase of about
        2.5-fold to about 5-fold, compared to the upper
        limit of normal, in one or both of alanine
        transaminase and aspartate transaminase af-
        ter a first pirfenidone administration, com-
        prising providing to said patient a second
        administration of pirfenidone, comprising (a)
        administering to said patient pirfenidone at a
        dose of at least 1600 mg/day, wherein step (a)
        comprises administering to said patient
        pirfenidone at a dose of about 2400 mg/day or
        2403 mg/day] further comprising, prior to
        step (a), discontinuing the first administra-
        tion of pirfenidone for about a week, or until
        biomarkers of liver function are within nor-
        mal limits.
 ’462 patent at col. 18 ll. 51–59, col. 19 ll. 33–36.
     Asserted claim 28 of the ’462 patent recites:
        The method of claim 26 [administering
        pirfenidone to treat a patient with IPF, said
        patient having exhibited a Grade 2 abnormal-
        ity in one or both of alanine transaminase and
        aspartate transaminase after a first
        pirfenidone      administration,    comprising
        providing to said patient a second
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 6                              GENENTECH, INC.   v. SANDOZ INC.

        administration of pirfenidone, comprising (a)
        administering to said patient pirfenidone at a
        dose of at least 1600 mg/day] further compris-
        ing, prior to step (a), discontinuing the first
        administration of pirfenidone for about one
        week, or until biomarkers of liver function are
        within normal limits.
 Id. at col. 20 ll. 35–42, 48–51.
     Lastly, asserted claim 19 of the ’701 patent recites:
        The method of claim 1 [treating a patient in
        need of pirfenidone and suffering from a
        Grade 2 abnormality in a liver function bi-
        omarker selected from the group consisting of
        alanine transaminase (ALT) and aspartate
        transaminase (AST) and wherein the abnor-
        mality occurs after a first pirfenidone admin-
        istration, comprising providing to said patient
        a second administration of pirfenidone, com-
        prising (a) administering to said patient at
        doses of at least 1600 mg/day or 1602
        mg/day] wherein the patient suffers from id-
        iopathic pulmonary fibrosis.
 ’701 patent at col. 18 ll. 33–41, col. 20 ll. 18–19.
    Sandoz’s proposed label includes, under the sub-head-
 ing “Dosage Modification due to Elevated Liver Enzymes,”
 the following guidance for patients exhibiting Grade 2 liver
 enzyme elevations, depending upon whether they are
 asymptomatic or symptomatic:
        Dosage modifications or interruptions may
        also be necessary when liver enzyme and bil-
        irubin elevations are exhibited. For liver en-
        zyme elevations, modify the dosage as
        follows:
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 GENENTECH, INC.   v. SANDOZ INC.                            7

        If a patient exhibits >3 but ≤5 x the upper
        limit of normal (ULN) ALT and/or AST with-
        out symptoms or hyperbilirubinemia after
        starting pirfenidone tablets therapy:
        •   Discontinue confounding medications, ex-
            clude other causes, and monitor the pa-
            tient closely.
        •   Repeat liver chemistry tests as clinically
            indicated.
        •   The full daily dosage may be maintained,
            if clinically appropriate, or reduced or in-
            terrupted (e.g., until liver chemistry tests
            are within normal limits) with subsequent
            re-titration to the full dosage as tolerated.
 J.A. 16750 (emphasis added).
     The parties agree that Sandoz’s label recommends us-
 ing pirfenidone for the treatment of IPF and includes treat-
 ment instructions for patients exhibiting Grade 2
 elevations in ALT and/or AST. The parties disagree over
 whether the third bullet point from the asymptomatic
 Grade 2 elevations sub-section induces use of any of the
 doses recited in the asserted claims.
     At the district court, Sandoz alleged that (1) the LFT
 asserted claims would have been obvious over Azuma, 3 the
 Pirespa® label, 4 and known, standard medical practices;

    3     Azuma et al., Double-blind, Placebo-controlled
 Trial of Pirfenidone in Patients with Idiopathic Pulmonary
 Fibrosis, 171 Am. J. of Respiratory & Critical Care Med.
 1040 (2005) (J.A. 16624–31).
     4    Shionogi & Co., Ltd., Pirespa® Tablets 200 mg
 (2008) (J.A. 16550–54).
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 8                             GENENTECH, INC.   v. SANDOZ INC.

 and (2) there was no specific intent for induced infringe-
 ment.
     Azuma reports on a pirfenidone clinical trial and states
 that “[f]or [patients experiencing] an adverse event of
 Grade 2 or worse,” “the dosage of [pirfenidone] was reduced
 in a stepwise manner” for as long as symptoms persisted.
 J.A. 16626. Azuma adds that “[w]hen the adverse event of
 Grade 2 or worse persisted or increased despite reducing
 the dosage . . . [pirfenidone] was discontinued.” Id. Azuma
 also lists “[e]levation of [AST]” among the “adverse events”
 observed in study patients. J.A. 16629. 5
      The Pirespa® label discloses a pirfenidone tablet for the
 treatment of IPF. Section 3(1) of the label states that “he-
 patic function disorders accompanied by increased AST
 (GOT), ALT (GPT), etc. and jaundice may occur and result
 in hepatic failure.” J.A. 16551. The label instructs that
 “[i]f any abnormalities are observed, administration should
 be discontinued . . . .” Id. Section 3(2) contains a table, and
 next to “hepatic,” the table lists, “AST (GOT), increased”
 and “ALT (GPT), increased.” Id.
     The district court began its analysis by noting that the
 parties “agree that Sandoz’s label recommends using
 pirfenidone for the treatment of IPF and includes treat-
 ment instructions for patients exhibiting Grade 2 eleva-
 tions in ALT and/or AST.” Decision at *7. The court then
 recognized that the label contained explicit dosing instruc-
 tions for patients experiencing Grade 2 elevations in AST
 or ALT describing: (1) maintaining the dose, (2) reducing
 the dose, (3) reducing the dose followed by re-titration to
 the full dose as tolerated, (4) interrupting the dose followed
 by re-titration to the full dose, and (5) discontinuing

     5   Azuma refers to “Elevation of GOT.” J.A. 16629.
 As the district court found, and the parties do not dispute,
 GOT is another name for AST. Decision at *11 n.7.
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 GENENTECH, INC.   v. SANDOZ INC.                           9

 pirfenidone. The court found that four of the five dose mod-
 ification options provided in the label were covered by the
 asserted claims. However, the court found that Sandoz did
 not infringe the LFT patents because there was no specific
 intent for induced infringement. Specifically, the portion
 of the label that referred to infringing uses did not recom-
 mend any of the infringing uses, but rather, merely de-
 scribed them.
     The district court also held that the asserted LFT
 claims are unpatentable as obvious in light of Azuma, the
 Pirespa® label, and standard medical practice disclosed in
 the prior art. The court found that a skilled artisan reading
 Azuma would have concluded that the majority of patients
 exhibiting Grade 2 AST elevations could be treated with
 the study’s dose reduction and reescalation protocol. The
 court also found that the Pirespa® label disclosed dose re-
 duction as an option for patients with elevated liver en-
 zymes.      The court found that the Pirespa® label
 distinguished between increased ALT/AST accompanied by
 jaundice, and increased ALT/AST alone. For the former,
 the court found that the label instructed discontinuation,
 whereas for the latter, the label instructed dose reduction
 or discontinuation as necessary. Lastly, the court found
 that standard medical practice established that dose reduc-
 tions, interruptions, and rechallenging were well known
 strategies for treating patients exhibiting Grade 2 eleva-
 tions of liver enzymes while taking other drugs.
                        II. DDI Patents
     The DDI patents are directed to methods for avoiding
 adverse interactions between pirfenidone and fluvoxamine.
 Fluvoxamine is a strong CYP1A2 inhibitor, which means it
 can interfere with normal drug metabolism by inhibiting
 the ability of certain CYP enzymes to metabolize the drug,
 resulting in “supratherapeutic” levels of an unmetabolized
 drug in the body. See Decision at *4. This can cause ad-
 verse events. Pirfenidone is highly susceptible to drug-
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 10                             GENENTECH, INC.   v. SANDOZ INC.

 drug interaction with CYAP1A2 inhibitors. The three as-
 serted DDI claims involve methods for administering
 pirfenidone to a patient taking fluvoxamine by either dis-
 continuing fluvoxamine or modifying the dose of
 pirfenidone and continuing fluvoxamine. Similar to the
 LFT claims, the distinctions between the specific DDI
 claims are not argued, so we treat them all as a group.
      Asserted claim 6 of the ’383 patent recites:
         The method of claim 5 [administering
         pirfenidone therapy to a patient in need
         thereof, comprising first discontinuing admin-
         istration of fluvoxamine to avoid an adverse
         drug interaction with pirfenidone, and then
         administering to the patient a therapeutically
         effective amount of pirfenidone], wherein the
         patient has [IPF].
 ’383 patent at col. 19 ll. 25–29, 30–31.
      Asserted claim 3 of the ’002 patent recites:
         The method of claim 2 [administering
         pirfenidone and fluvoxamine concurrently to a
         patient in need thereof comprising administer-
         ing a therapeutically effective amount of flu-
         voxamine to the patient and administering a
         therapeutically     effective    amount     of
         pirfenidone to the patient, wherein the amount
         of the pirfenidone is about 801 mg/day,
         wherein the pirfenidone is administered three
         times per day] wherein the patient has [IPF].
 ’002 patent at col. 19 ll. 14–19, col. 20 ll. 15–16.
      Lastly, asserted claim 9 of the ’002 patent recites:
         The method of claim 8 [providing pirfenidone
         therapy to a patient in need thereof comprising
         titrating the dosage of pirfenidone adminis-
         tered to the patient downward from a dose of
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 GENENTECH, INC.   v. SANDOZ INC.                          11

        about 2400 mg/day, while co-administering
        fluvoxamine, wherein the dose of pirfenidone
        is reduced by about 1600 mg/day, wherein the
        pirfenidone is administered three times per
        day] wherein the patient has [IPF].
 Id. at col. 20 ll. 6–10, 13–16.
      Sandoz’s proposed label warns about potential drug-
 drug interactions with fluvoxamine in three places. First,
 under the “Drug Interactions” sub-heading of the label’s
 “Highlights of Prescribing Information,” the label states
 “[d]iscontinue fluvoxamine prior to administration of
 pirfenidone or reduce [pirfenidone] to 267 mg three times a
 day,” for a total of 801 mg/day. J.A. 16749. Second, in Sec-
 tion 2.4, “Dosage Modification due to Drug Interactions,”
 under the sub-heading, “Strong CYP1A2 Inhibitors (e.g.,
 fluvoxamine, enoxacin),” the label states “Reduce
 pirfenidone tablets to 267 mg three times a day (801
 mg/day).” J.A. 16751. Finally, in Section 7.1, “CYP1A2 In-
 hibitors,” under the sub-heading, “Strong CYP1A2 Inhibi-
 tors,” the label states:
        The     concomitant      administration     of
        pirfenidone and fluvoxamine or other strong
        CYP1A2 inhibitors (e.g., enoxacin) is not rec-
        ommended because it significantly increases
        exposure to pirfenidone [see Clinical Pharma-
        cology (12.3)]. Use of fluvoxamine or other
        strong CYP1A2 inhibitors should be discon-
        tinued prior to administration of pirfenidone
        and avoided during pirfenidone treatment. In
        the event that fluvoxamine or other strong
        CYP1A2 inhibitors are the only drug of choice,
        dosage reductions are recommended. Monitor
        for adverse reactions and consider discontin-
        uation of pirfenidone as needed [see Dosage
        and Administration (2.4)].
 J.A. 16753 (emphasis in original).
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 12                             GENENTECH, INC.   v. SANDOZ INC.

     At the district court, Sandoz argued that there was in-
 sufficient evidence of direct infringement. The court
 agreed and added that the language in Sandoz’s label that
 encourages, recommends, or promotes an infringing use
 without any additional evidence showing such an infring-
 ing use will in fact occur, is insufficient for a finding of di-
 rect infringement. The court elaborated and stated that
 Genentech had not shown that any patient would be pre-
 scribed both pirfenidone and fluvoxamine such that the
 methods of the DDI patents would even be relevant. The
 court added that even if an IPF patient were prescribed flu-
 voxamine, a physician would likely choose a non-infringing
 treatment adjustment over any of the claimed methods.
     Genentech appealed the district court’s holdings that
 the asserted claims in the LFT patents would have been
 unpatentable as obvious, that sale of Sandoz’s product
 would not induce infringement of the LFT patents, and
 that Sandoz’s product would not directly infringe the DDI
 patents. We have jurisdiction under 28 U.S.C. § 1295(a)(1).
                          DISCUSSION
     After a bench trial, we review the district court’s judg-
 ment for legal error or clearly erroneous findings of fact.
 Grunenthal GMBH v. Alkem Lab’ys Ltd., 919 F.3d 1333,
 1339 (Fed. Cir. 2019). Infringement, including induced in-
 fringement, is a question of fact that we review for clear
 error. Id.
     Whether a claim is invalid as obvious is a question of
 law, based on underlying factual determinations. E.g.,
 Hospira, Inc. v. Fresenius Kabi USA, LLC, 946 F.3d 1322,
 1329 (Fed. Cir. 2019). The ultimate legal question is re-
 viewed de novo, and the underlying factual determinations
 are reviewed for clear error. Id. at 1328. “Where there are
 two permissible views of the evidence, the fact-finder’s
 choice between them cannot be clearly erroneous”; rather,
 a finding is clearly erroneous only when the reviewing
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 GENENTECH, INC.   v. SANDOZ INC.                          13

 court is “left with a definite and firm conviction that the
 district court was in error.” Id. (citations omitted).
      To succeed on a theory of induced infringement in a
 Hatch-Waxman case, in which infringement is defined by
 filing an ANDA before the infringing product is marketed,
 the plaintiff is required to prove by a preponderance of the
 evidence (1) direct infringement, i.e., if defendant’s drug
 was “put on the market, it would infringe the relevant pa-
 tent”; and (2) “that [defendant] possessed the specific in-
 tent to encourage another’s infringement.” Vanda Pharms.
 Inc. v. W.-Ward Pharms. Int’l Ltd., 887 F.3d 1117, 1129–30
 (Fed. Cir. 2018). Specific intent may be shown if the de-
 fendant’s proposed label recommends, encourages, or pro-
 motes an infringing act. See Takeda Pharms. U.S.A., Inc.
 v. W.-Ward Pharms. Corp., 785 F.3d 625, 631 (Fed. Cir.
 2015).
                        I. LFT Patents
     With respect to obviousness, Genentech argues that
 the district court improperly supplied missing claim limi-
 tations, read the prior art in ways that cannot be supported
 based on plain meaning, and failed to make any legal or
 factual findings with respect to claim 9 of the ’729 patent
 and claim 12 of the ’462 patent. Genentech asserts that
 neither Azuma nor the Pirespa® label literally discloses
 Grade 2 elevated liver enzymes or the claimed continued
 treatment of patients with pirfenidone. It adds that these
 elements are not within the knowledge of those skilled in
 the art. Genentech also argues that the court’s analysis of
 the Pirespa® label is not entitled to deference, and should
 be reviewed de novo, because it involved no fact finding.
 Lastly, Genentech asserts that objective indicia of nonobvi-
 ousness weighed in its favor because it showed skepticism
 regarding pirfenidone’s efficacy and safety, as well as evi-
 dence of a long-felt and unmet need of treating patients fol-
 lowing Grade 2 AST/ALT elevations.
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 14                            GENENTECH, INC.   v. SANDOZ INC.

     Sandoz responds that the district court properly found
 that Azuma expressly disclosed reescalation of dosage after
 temporary dose reduction for patients with Grade 2 liver
 enzyme elevations. It adds that a skilled artisan could in-
 fer that patients with Grade 2 AST/ALT elevations were
 treated in accordance with the reduction and reescalation
 protocol for Grade 2 adverse events. Regarding the
 Pirespa® label, Sandoz argues that the court did not clearly
 err in interpreting the label to recommend discontinuing
 pirfenidone only for patients with elevated liver enzymes
 accompanied by jaundice and not for patients with elevated
 liver enzymes without jaundice.
     With respect to the objective indicia of nonobviousness,
 Sandoz asserts that Genentech’s evidence of skepticism did
 not relate to using the LFT methods to treat Grade 2 liver
 enzyme elevations. It further asserts that Genentech did
 not establish a long-felt and unmet need for continuing to
 treat patients with pirfenidone following a Grade 2 eleva-
 tion.
     Before reviewing the details of the district court’s thor-
 ough analysis, it is worth noting our initial perception that,
 as the district court noted, varying doses in response to the
 occurrence of side effects would seem to be a well-estab-
 lished, hence obvious, practice. Thus, claiming it as an in-
 vention would appear to be at best a long shot. The district
 court gave it careful scrutiny, however, as do we.
      We agree with Sandoz that the district court did not err
 in its conclusion of obviousness. It properly held that the
 specific dose modifications claimed in the LFT patents
 would have been obvious over the disclosures in Azuma
 and the Pirespa® label, combined with well-known stand-
 ard medical practices. Specifically, the court found that
 Azuma disclosed reescalation of dosage after temporary
 dose reduction for patients with Grade 2 or worse adverse
 events, and that liver enzyme elevations were included in
 the list of observed adverse events. The court added that
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 GENENTECH, INC.   v. SANDOZ INC.                           15

 while Azuma “does not specify how many of these AST ele-
 vations were Grade 2 elevations,” a skilled artisan could
 infer from the disclosure that patients with Grade 2 AST
 elevations were treated in accordance with the reduction
 and reescalation protocol for Grade 2 adverse events. See
 Decision at *11. These findings are not clearly erroneous.
     With respect to the Pirespa® label, it is well established
 that what the prior art teaches is a factual question we re-
 view for clear error. See Adapt Pharma Operations Ltd. v.
 Teva Pharms. USA, Inc., 25 F.4th 1354, 1364 (Fed. Cir.
 2022). The standard of review does not change when the
 district court is assessing documentary evidence rather
 than testimony. See Fed. R. Civ. P. 52(a)(6) & advisory
 committee’s note (1985) (explaining that bench trial find-
 ings are reviewed for clear error whether interpreting doc-
 umentary or oral evidence). The scope and content of the
 prior art are characterized as factual findings.
      Moving to the merits, Genentech fails to identify any
 clear error in the district court’s interpretation of the
 Pirespa® label. Genentech argues that the Pirespa® label
 instructs prescribers to look to Section 3(1) for any patients
 with increased AST/ALT, and not only for patients suffer-
 ing from jaundice. It adds that Section 3(1)’s language that
 “[i]f any abnormalities are observed, administration should
 be discontinued” encompasses an increase in AST or ALT
 without jaundice. See J.A. 16551. Genentech’s interpreta-
 tion is not persuasive.
      Section 2(3), on which Genentech relies, states that
 “[h]epatic function disorders accompanying increased AST
 (GOT), ALT (GPT), etc. and jaundice may occur,” and refers
 clinicians to Section 3(1) which employs the same language
 and recommends discontinuation. Furthermore, as the dis-
 trict court found, Section 3(1)’s instruction for “any abnor-
 malities” applies to only the particular abnormalities
 mentioned previously in that instruction—i.e., elevated
 AST/ALT with jaundice. See Decision at *12. Genentech’s
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 16                            GENENTECH, INC.   v. SANDOZ INC.

 interpretation would also create a conflict, whereby Section
 3(1) would instruct a clinician to discontinue treatment
 upon observing elevated AST/ALT, while Section 3(2)
 would allow dose reduction or discontinuation for the same
 event.
     Contrary to Genentech’s assertion, the district court’s
 interpretation of Azuma and the Pirespa® label also relied
 on extensive record evidence. That evidence illustrated
 that standard medical practice at the time was not to dis-
 continue medical treatment with pirfenidone or other
 drugs for patients experiencing Grade 2 liver enzyme ele-
 vations. This evidence included expert testimony as well
 as FDA guidance. See J.A. 7387–89; 8488–89.
      Lastly, the district court did not err by not making spe-
 cific findings for claim 9 of the ’729 patent and claim 12 of
 the ’462 patent. These claims relate to dose reescalation
 after dose reduction (claim 9 of the ’729 patent) and dose
 interruption (claim 12 of the ’462 patent). The court ex-
 pressly found that Azuma disclosed that “‘[i]f the adverse
 event had resolved or decreased with [a] reduction in dose,’
 the patient’s dose was increased back to the original
 amount.” Decision at *11 (citing J.A. 16626). Azuma also
 states that for individuals with a “Grade 2 or worse” event,
 the dose was “reduced in a stepwise manner: from 9 tablets
 per day to 6 tablets per day.” J.A. 16626. It adds that if
 the adverse event persisted, then “the study medication
 was discontinued and patients observed.” Id. The Pirespa®
 label states that “[w]hen gastrointestinal disorder, etc. oc-
 curs, dose reduction or drug withdrawal is considered as
 necessary” and that “[w]hen the symptom is relieved, it is
 desirable that the dose is gradually increased to [the origi-
 nal amount].” J.A. 16550. These two references discuss
 the same reescalation and dose reduction techniques en-
 compassed by claim 9 of the ’729 patent and claim 12 of the
 ’462 patent. Therefore, these two references would have
 rendered those claims obvious, and the court did not err in
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 GENENTECH, INC.   v. SANDOZ INC.                          17

 not discussing its factual findings with respect to those
 claims specifically.
     With respect to the objective indicia of nonobviousness,
 the district court properly found Genentech’s evidence un-
 persuasive. “[W]eak secondary considerations generally do
 not overcome a strong prima facie case of obviousness.” W.
 Union Co. v. MoneyGram Payment Sys., Inc., 626 F.3d
 1361, 1371 (Fed. Cir. 2010). Here, Genentech’s evidence of
 objective indicia does not outweigh Sandoz’s affirmative
 case of obviousness.
      First, Genentech did not provide evidence showing
 skepticism regarding rechallenging patients with Grade 2
 liver enzyme elevations compared to patients with more se-
 rious Grade 3 or higher elevations. Thus, Genentech’s evi-
 dence does not establish skepticism for the claimed
 methods. Second, in its argument of long-felt but unmet
 need, Genentech cites evidence that one expert at trial
 “ha[s] seen many patients with [G]rade 2 elevations” and
 that the Esbriet® label states that “dose modification or
 treatment discontinuation” can reverse liver damage in
 some patients with elevated liver enzymes. J.A. 7293,
 16517–18; see also Appellant’s Br. at 59. These two pieces
 of evidence, however, do not establish any long-felt, unmet
 need for the claimed methods. Furthermore, FDA guid-
 ance recommended not dropping patients with Grade 2 el-
 evations from clinical trials. J.A. 7383. Thus, Genentech
 has not demonstrated that the court clearly erred with re-
 spect to its factual findings regarding skepticism and long-
 felt, unmet need.
      For these reasons, we affirm the court’s holding that
 the asserted claims in the LFT patents would have been
 obvious over Azuma and the Pirespa® label, combined with
 well-known, standard medical practices. The asserted
 claims in the LFT patents do not represent the invention of
 a new drug, nor do they recite a novel application of an ex-
 isting drug. Instead, these claims recite adjusting doses in
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 18                            GENENTECH, INC.   v. SANDOZ INC.

 the presence of side effects, which clinicians routinely do,
 and which would have been obvious in view of the prior art.
     In light of our invalidity holding, we need not review
 the court’s infringement findings.
                       II. DDI Patents
      Turning to the DDI patents, Genentech argues that the
 district court erred in finding that the asserted claims were
 not infringed. Specifically, Genentech asserts that the
 court erred in concluding that Sandoz’s proposed label,
 which encourages, recommends, and promotes infringe-
 ment, is not dispositive. It adds that, even if other evidence
 could overcome the label’s instruction to infringe, here,
 there was no evidence to negate the label’s language. In-
 stead, Genentech asserts, the court treated the label as
 having no evidentiary force and faulted Genentech for fail-
 ing to adduce more evidence of infringement. Lastly,
 Genentech argues that if we reverse on the issue of direct
 infringement, we should also find that Sandoz had the spe-
 cific intent to induce infringement.
      Sandoz responds that the district court did not clearly
 err in weighing the relevant evidence, including the label’s
 instruction and physician practice. It adds that while
 Genentech was not required to show an actual incident of
 direct infringement by a physician, past conduct was rele-
 vant to what would happen in the future. Lastly, Sandoz
 argues that if we find direct infringement, we should allow
 the lower court to decide whether there was specific intent
 to induce infringement in the first instance.
     We agree with Sandoz. It is true that although the
 Hatch-Waxman Act provides that the filing of an ANDA
 before a patent covering a compound or a use expires meets
 the technical jurisdictional requirement of infringement,
 that is not the same as the direct infringement that serves
 as a predicate for finding induced infringement. See 35
 U.S.C. § 271(e)(2)(A) (filing an ANDA before a patent
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 expires is “an act of infringement”); Glaxo, Inc. v. Novo-
 pharm, Ltd., 110 F.3d 1562, 1568–69 (Fed. Cir. 1997) (“The
 plain language of [§ 271(e)(2)(A)] does not alter a patentee’s
 burden of proving infringement . . . .”). Infringement still
 requires a finding that accused subject matter would meet
 the terms of a claim.
     Here, Genentech fails to identify any legal error or
 clear factual error in the district court’s direct infringement
 analysis. In order to prove direct infringement, Genentech
 must show that “if a particular drug were put on the mar-
 ket, it would infringe the relevant patent.” Vanda, 887
 F.3d at 1129–30. Determining what will, or would, happen
 when a product enters the market requires “consideration
 of all the relevant evidence,” including the proposed label’s
 instructions and physician practice. Ferring v. Watson
 Lab’ys, 764 F.3d 1401, 1408 (Fed. Cir. 2014); see also Glaxo,
 110 F.3d at 1570 (stating that “[t]he relevant inquiry [for
 direct infringement] is whether the patentee has proven by
 a preponderance of the evidence that the alleged infringer
 will likely market an infringing product,” and further con-
 cluding that “the district court properly considered the
 ANDA itself, the materials submitted by Novopharm to
 FDA, and the other pertinent evidence provided by the par-
 ties”). The court recognized that “a patentee does not need
 to prove an actual past instance of direct infringement by
 a physician to establish infringement in an ANDA case.”
 Vanda, 887 F.3d at 1129–30. While this is correct, as
 Sandoz notes, past conduct is relevant to what will happen
 in the future.
      We regularly consider evidence outside a proposed la-
 bel in evaluating whether a product will be used in a way
 that directly infringes method claims. In Eli Lilly, for ex-
 ample, we relied on “[t]he product labeling, combined with
 [] testimony [discussing physicians’ general practices]” to
 conclude that there was sufficient evidence “that physi-
 cians condition . . . treatment on” the patients’ perfor-
 mance of the patented method, thereby satisfying the
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 20                            GENENTECH, INC.   v. SANDOZ INC.

 requirements for proving direct infringement. Eli Lilly &
 Co. v. Teva Parenteral Meds., Inc., 845 F.3d 1357, 1364–68
 (Fed. Cir. 2017). Similarly, in Takeda, we looked at evi-
 dence outside the label to determine whether the plaintiffs
 had proven direct infringement of certain drug-drug inter-
 action patents. We considered the dosage form and size of
 the defendant’s product in determining that plaintiffs had
 failed to prove that a patient would take a dose equal to
 half that size, as required by the drug-drug interaction
 claims at issue. See Takeda, 785 F.3d at 634–35. And we
 also considered, with respect to different method patents
 requiring concomitant administration of two drugs, the fact
 that “physician experts declared that they try to and can
 easily avoid concomitant administration of the drugs.” Id.
 at 635. Although the label in Takeda did not recite the spe-
 cific claimed doses at issue in that case, our analysis did
 not hinge on that.
     Lastly, Vanda involved conducting a genotyping assay
 to determine (1) whether a patient is a poor metabolizer of
 iloperidone; and (2) if so, administering a lower dose. The
 district court found that the generic label directed the in-
 fringing method, including the genotyping test. See Vanda
 Pharms. Inc. v. Roxane Lab’ys, Inc., 203 F. Supp. 3d 412,
 432–33 (D. Del. 2016). The defendant argued that the label
 was not determinative because physicians did not actually
 administer a genotyping test before making a dosing deter-
 mination. Id. at 433. However, because plaintiffs had in-
 troduced evidence that physicians did genotype their
 patients, the court rejected defendant’s argument. Id. On
 appeal, we affirmed and cited Ferring for the proposition
 that “[t]he infringement determination is . . . based on con-
 sideration of all the relevant evidence.” Vanda, 887 F.3d
 at 1130 (citing Ferring, 764 F.3d 1408).
     Here, as in Eli Lilly and Takeda, the district court did
 not clearly err by considering all the relevant evidence, in-
 cluding Sandoz’s proposed label and physician practice.
 Sandoz presented evidence of how pirfenidone would be
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 GENENTECH, INC.   v. SANDOZ INC.                          21

 prescribed in practice, including testimony from physicians
 that, in their decades of treating IPF patients, they had
 never prescribed pirfenidone to an IPF patient taking flu-
 voxamine; and were they to find themselves in that posi-
 tion, they would choose a noninfringing response—i.e.,
 prescribing nintedanib instead. See Decision at *16; see
 also J.A. 7196, 7269, 7270–71. The court did not clearly err
 by considering physician evidence, weighing it against the
 language in Sandoz’s proposed label, and finding that
 Genentech failed to prove direct infringement. Genen-
 tech’s arguments to the contrary are unavailing.
      Genentech argues that the DDI instructions must be
 important because the FDA insisted on including them in
 the label. However, Genentech cites no evidence to support
 its speculation. Even if the FDA had been concerned about
 the possibility that a patient may be treated with both
 pirfenidone and fluvoxamine, that does not establish by a
 preponderance of the evidence that if Sandoz’s drug “were
 put on the market, it would infringe” the asserted DDI
 claims. See Vanda, 887 F.3d 1129–30 (citation omitted).
 Second, Genentech’s argument that fluvoxamine could be
 used to treat COVID-19, and that at least one patient living
 with IPF could be prescribed both fluvoxamine and
 pirfenidone was properly rejected by the district court as
 speculative. Third, Genentech argues that the district
 court improperly credited Sandoz’s physician evidence.
 Specifically, it argues that if an IPF patient needed fluvox-
 amine, instead of a doctor prescribing nintedanib to treat
 their IPF, the doctor could prescribe pirfenidone and an al-
 ternative to fluvoxamine. However, as Sandoz’s expert
 stated, a pulmonologist prescribing pirfenidone would not
 be able to alter another physician’s prescription of fluvox-
 amine or take over that aspect of the patient’s treatment.
 Therefore, the pulmonologist would prescribe nintedanib to
 be taken in conjunction with the patient’s preexisting pre-
 scription of fluvoxamine.
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 22                           GENENTECH, INC.   v. SANDOZ INC.

     Weighing all the evidence, the district court did not
 clearly err in finding that Genentech had not met its bur-
 den to show that if Sandoz’s drug were put on the market,
 it would directly infringe the asserted claims of the DDI
 patents which require use of both pirfenidone and fluvox-
 amine. In light of our finding of no direct infringement, we
 need not reach the issue of whether Sandoz possessed the
 specific intent to induce infringement of the asserted
 claims in the DDI patents.
                        CONCLUSION
     We have considered Genentech’s remaining arguments
 but find them unpersuasive. For the foregoing reasons, we
 conclude that the district court properly held that the as-
 serted claims in the LFT patents would have been obvious
 over the prior art and standard medical practice, and it did
 not clearly err in finding that Sandoz’s generic product
 would not directly infringe the asserted claims in the DDI
 patents.
                        AFFIRMED