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.
`______________________
`
`
`

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`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”) patents1 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.
`
`
`(the “’729 patent”),
`1 U.S. Patents 7,566,729
`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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`GENENTECH, INC. v. SANDOZ INC.
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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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`GENENTECH, INC. v. SANDOZ INC.
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`[administering
`The method of claim 1
`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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`GENENTECH, INC. v. SANDOZ INC.
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`5
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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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`GENENTECH, INC. v. SANDOZ INC.
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`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.
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`
`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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`GENENTECH, INC. v. SANDOZ INC.
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`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.
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`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-
`label
` The court found that the Pirespa®
`zymes.
`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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`GENENTECH, INC. v. SANDOZ INC.
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`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.
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`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:
`of
`administration
`The
`concomitant
`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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`GENENTECH, INC. v. SANDOZ INC.
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`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.
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`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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`GENENTECH, INC. v. SANDOZ INC.
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`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.
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`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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`GENENTECH, INC. v. SANDOZ INC.
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`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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`Case: 22-1595 Document: 49 Page: 17 Filed: 12/22/2022
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`GENENTECH, INC. v. SANDOZ INC.
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`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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`GENENTECH, INC. v. SANDOZ INC.
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`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 relev