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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GENENTECH, INC. v. SANDOZ INC. 3
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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GENENTECH, INC. v. SANDOZ INC. 5
(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).
Case: 22-1595 Document: 49 Page: 8 Filed: 12/22/2022
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-
Case: 22-1595 Document: 49 Page: 10 Filed: 12/22/2022
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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GENENTECH, INC. v. SANDOZ INC. 19
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
