Case: 22-1595 Document: 23 Page: 1 Filed: 06/14/2022
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`
`Nos. 22-1595, 22-1714
`
`UNITED STATES COURT OF APPEALS
`FOR THE FEDERAL CIRCUIT
`
`GENENTECH, INC., INTERMUNE, INC.,
`Plaintiffs-Appellants,
`
`
`
`
`
`v.
`SANDOZ INC., LEK PHARMACEUTICALS D.D.,
`
`
`
`
`
`Defendants-Appellees.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Appeal from the United States District Court for the District of Delaware
`Case No. 1:19-cv-00078, Judge Richard G. Andrews
`
`APPELLEES’ RESPONSE BRIEF
`
`
`Emily L. Rapalino
`Daryl L. Wiesen
`Edwina Clarke
`GOODWIN PROCTER LLP
`100 Northern Ave.
`Boston, MA 02210
`Tel.: 617.570.1000
`Fax.: 617.523.1231
`
`
`Counsel for Appellees Sandoz, Inc.
`and LEK Pharmaceuticals D.D.
`
`
`
`
`
`
`William M. Jay
`GOODWIN PROCTER LLP
`1900 N Street, N.W.
`Washington, DC 20036
`Tel.: 202.346.4000
`Fax.: 202.346.4444
`
`Natasha E. Daughtrey
`GOODWIN PROCTER LLP
`601 South Figueroa Street
`41st Floor
`Los Angeles, CA 90017
`Tel.: 213.426.2500
`Fax.: 213.623.1673
`
`June 14, 2022
`
`
`
`
`

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`Case: 22-1595 Document: 23 Page: 2 Filed: 06/14/2022
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`
`PATENT CLAIM AT ISSUE
`U.S. Patent No. 7,816,383, Claim 6:
`
`Claim 5:
`
`A method of administering pirfenidone therapy to a patient in need thereof
`comprising first discontinuing administration of fluvoxamine to avoid an
`adverse drug interaction with pirfenidone, and then administering to the
`patient a therapeutically effective amount of pirfenidone.
`
`Claim 6:
`
`The method of claim 5 wherein the patient has idiopathic pulmonary fibrosis
`(IPF).
`
`Appx107.
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`

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`Case: 22-1595 Document: 23 Page: 3 Filed: 06/14/2022
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`
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`CERTIFICATE OF INTEREST
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`
`
`1.
`
`2.
`
`3.
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`4.
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`5.
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`Undersigned counsel for Appellees certifies as follows:
`The full name of every entity represented by undersigned counsel is:
`Sandoz, Inc.; Lek Pharmaceuticals D.D.
`The name of the real party in interest for the entities is:
`N/A
`All parent corporations and any publicly held companies that own 10
`percent or more of the stock of the entities are:
`Sandoz, Inc.: Novartis AG
`Lek Pharmaceuticals D.D.: Novartis Pharma AG, Novartis AG
`The names of all law firms and the partners or associates that appeared
`for the entities in the trial court or agency or are expected to appear in
`this court (and who have not or will not enter an appearance) are:
`Goodwin Procter LLP: Beth Ashbridge, Cindy Chang*, Elaine H. Blais,
`Kathleen A. McGuinness, Kevin J. DeJong, Nicholas K. Mitrokostas*,
`Srikanth K. Reddy, Tara R. Melillo Thigpen, Tiffany Mahmood
`Bayard, P.A.: Ronald P. Golden III, Sarah Andrade, Stephen B. Brauerman
`The title and number of any case known to be pending in this or any other
`court or agency that will directly affect or be directly affected by this
`court’s decision in the pending appeal:
`None.
`6. Organizational victims and bankruptcy cases:
`N/A.
`
`
`s/William M. Jay
`
`
`* Denotes that attorney is no longer with Goodwin Procter LLP.
`
`i
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`Case: 22-1595 Document: 23 Page: 4 Filed: 06/14/2022
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`TABLE OF CONTENTS
`
`INTRODUCTION ..................................................................................................... 1
`STATEMENT OF THE ISSUES............................................................................... 3
`STATEMENT OF THE CASE .................................................................................. 4
`I. Sandoz seeks FDA approval to market a generic form of Plaintiffs’ Esbriet®,
`and Plaintiffs bring this action under the Hatch-Waxman Act. ...................... 4
`II. The LFT patents, alleged evidence of infringement, and the prior art. ........... 5
`A. The LFT patents. ................................................................................... 5
`B. Alleged evidence of infringement: the label. ....................................... 6
`C. Evidence of obviousness: the prior art. ................................................ 8
`III. The DDI patents and the alleged evidence of infringement. .........................12
`A. The DDI patents. .................................................................................12
`B. Alleged evidence of infringement. ......................................................14
`IV.The district court finds no infringement of any claim and holds that
`the LFT claims are invalid as obvious. ..........................................................15
`V. Plaintiffs seek an injunction pending appeal, and both the district court and
`this Court deny the request. ...........................................................................21
`SUMMARY OF ARGUMENT ...............................................................................21
`ARGUMENT ...........................................................................................................25
`STANDARD OF REVIEW .....................................................................................25
`I. The district court did not clearly err in finding that Plaintiffs failed to show
`infringement of any asserted claim. ...............................................................26
`A. The district court did not clearly err in finding that Plaintiffs had
`failed to prove induced infringement of the LFT patents, because
`Sandoz’s label does not recommend any infringing use. ....................26
`1. The district court did not clearly err in finding that the label
`does not recommend infringement of the LFT patents. ............ 27
`2. The district court applied the correct legal standard to the
`
` facts............................................................................................ 30
`B. The district court did not clearly err in finding that Sandoz’s product
`would not directly infringe the DDI patents. ......................................35
`
`ii
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`Case: 22-1595 Document: 23 Page: 5 Filed: 06/14/2022
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`1. The district court committed no legal error in considering all
`the evidence in the record. ........................................................ 35
`2. The Court should reject Plaintiffs’ unsupported burden-shifting
`analysis. ..................................................................................... 39
`3. Plaintiffs have identified no clear error in the district court’s
`finding of no direct infringement. ............................................. 41
`4. This Court should not reach the other elements of induced
`infringement. ............................................................................. 45
`II. The district court did not err in holding that the LFT patents are invalid as
`obvious. ..........................................................................................................47
`A. The district court did not rely on “inherency” in finding that Azuma
`disclosed continued treatment of patients with Grade 2 liver enzyme
`elevations. ............................................................................................48
`B. The district court did not clearly err in interpreting the Pirespa® Label
`to disclose dose reduction for Grade 2 liver enzyme elevations. ........50
`C. Plaintiffs ignore other evidence on which the district court relied. ....54
`D. The district court did not err in not making specific findings for claim
`9 of the ʼ729 patent and claim 12 of the ʼ462 patent. .........................54
`E. The district court did not err in finding Plaintiffs’ secondary
`considerations of non-obviousness unpersuasive. ..............................56
`CONCLUSION ........................................................................................................59
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`iii
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`Case: 22-1595 Document: 23 Page: 6 Filed: 06/14/2022
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`
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Adapt Pharma Operations Ltd. v. Teva Pharm. USA, Inc.
`25 F.4th 1354 (Fed. Cir. 2022) ........................................................................... 50
`Anderson v. Bessemer City,
`470 U.S. 564 (1985) ............................................................................................ 50
`AstraZeneca LP v. Apotex, Inc.,
`633 F.3d 1042 (Fed. Cir. 2010) .................................................................... 33, 34
`Bristol-Myers Squibb Co. v. Royce Labs., Inc.,
`69 F.3d 1130 (Fed. Cir. 1995) ............................................................................ 36
`Douglas Dynamics, LLC v. Buyers Products Co.,
`717 F.3d 1336 (Fed. Cir. 2013) .................................................................... 46, 47
`Eli Lilly & Co. v. Teva Parenteral Meds., Inc.,
`845 F.3d 1357 (Fed. Cir. 2017) ........................................................ 23, 34, 37, 40
`Ferring v. Watson Laby’s,
`764 F.3d 1401 (Fed. Cir. 2014) .................................................................... 36, 39
`Glaxo, Inc. v. Novopharm, Ltd.,
`110 F.3d 1562 (Fed. Cir. 1997) .............................................................. 36, 40, 41
`GlaxoSmithKline LLC v. Teva Pharmaceuticals USA, Inc.,
`7 F.4th 1320 (Fed. Cir. 2021) ....................................................................... 30, 31
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) ................................................................................................ 51
`Grunenthal GMBH v. Alkem Lab’ys Ltd.,
`919 F.3d 1333 (Fed. Cir. 2019) .................................................................... 25, 31
`Hospira, Inc. v. Fresenius Kabi USA, LLC,
`946 F.3d 1322 (Fed. Cir. 2019) .......................................................................... 26
`HZNP Medicines LLC v. Actavis Laboratories UT, Inc.,
`940 F.3d 680 (Fed. Cir. 2019) ................................................................ 17, 31, 32
`
`iv
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`

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`Case: 22-1595 Document: 23 Page: 7 Filed: 06/14/2022
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`
`
`Mobility Workx, LLC v. Unified Patents, LLC,
`15 F.4th 1146 (Fed. Cir. 2021) ........................................................................... 44
`Par Pharm., Inc. v. TWi Pharm., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .................................................................... 49, 51
`Sciele Pharma Inc. v. Lupin Ltd.,
`684 F.3d 1253 (Fed. Cir. 2012) .......................................................................... 52
`Syntex (U.S.A.) LLC v. Apotex, Inc.,
`407 F.3d 1371 (Fed. Cir. 2005) .......................................................................... 48
`Takeda Pharm. U.S.A., Inc. v. West-Ward Pharm. Corp.,
`785 F.3d 625 (Fed. Cir. 2015) .......................................................... 23, 27, 37, 38
`Teva Pharmaceuticals USA, Inc. v. Sandoz, Inc.,
`574 U.S. 318 (2015) ............................................................................................ 51
`Vanda Pharm. Inc. v. Roxane Lab’ys, Inc.,
`203 F. Supp. 3d 412 (D. Del. 2016).............................................................. 38, 39
`Vanda Pharmaceuticals Inc. v. West-Ward Pharmaceuticals Int’l Ltd.,
`887 F.3d 1117 (Fed. Cir. 2018) ...................................................................passim
`Vitronics Corp. v. Conceptronic, Inc.,
`90 F.3d 1576 (Fed. Cir. 1996) ............................................................................ 45
`W. Union Co. v. MoneyGram Payment Sys., Inc.,
`626 F.3d 1361 (Fed. Cir. 2010) .......................................................................... 57
`Warner-Lambert Co. v. Apotex Corp.,
`316 F.3d 1348 (Fed. Cir. 2003) .................................................................... 34, 41
`Statutes
`35 U.S.C. § 271(e)(2) ............................................................................................... 41
`35 U.S.C. § 271(e)(4)(A) ........................................................................................... 1
`
`v
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`Case: 22-1595 Document: 23 Page: 8 Filed: 06/14/2022
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`Other Authorities
`FDA, Memorandum Explaining Basis for Declining Request for
`Emergency Use Authorization of Fluoxamine Maleate, available at
`https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/EUA
`110 Fluvoxamine Decisional Memo_Redacted.pdf ........................................... 43
`Fed. R. Civ. P. 52(a)(6) ............................................................................................ 50
`Fed. R. Evid. 201(b)(2) ............................................................................................ 44
`Fed. R. Evid. 301 ..................................................................................................... 40
`
`
`
`vi
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`

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`Case: 22-1595 Document: 23 Page: 9 Filed: 06/14/2022
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`’729 patent
`
`’707 patent
`
`’462 patent
`
`’701 patent
`
`’383 patent
`
`’002 patent
`
`ALT
`
`AST
`
`Azuma
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`
`
`GLOSSARY
`U.S. Patent No. 7,566,729 (Appx49-56)
`
`U.S. Patent No. 7,635,707 (Appx57-68)
`
`U.S. Patent No. 8,592,462 (Appx69-80)
`
`U.S. Patent No. 8,609,701 (Appx81-94)
`
`U.S. Patent No. 7,816,383 (Appx95-107)
`
`U.S. Patent No. 8,013,002 (Appx108-120)
`
`alanine transaminase
`
`aspartate transaminase
`
`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), JTX-31 (Appx16624-16631)
`
`DDI
`
`Drug-drug interaction
`
`DDI patents
`
`U.S. Patent Nos. 7,816,383 and 8,013,002
`
`DILI
`
`IPF
`
`LFT
`
`LFT patents
`
`Plaintiffs
`
`POSA
`
`Sandoz
`
`Drug-induced liver injury
`
`Idiopathic pulmonary fibrosis
`
`Liver function test
`
`U.S. Patent Nos. 7,566,729, 7,635,707, 8,592,462, and
`8,609,701
`
`Plaintiffs-Appellants Genentech, Inc. and Intermune,
`Inc.
`
`Person of ordinary skill in the art
`
`Defendants-Appellees Sandoz, Inc. and Lek
`Pharmaceuticals D.D.
`
`vii
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`Case: 22-1595 Document: 23 Page: 10 Filed: 06/14/2022
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`STATEMENT OF RELATED CASES
`The following cases are related to these consolidated appeals, as defined by
`
`Fed. Cir. R. 47.4(a)(5):
`
`None.
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`viii
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`INTRODUCTION
`This case concerns pirfenidone, a pharmaceutical composition indicated to
`
`treat idiopathic pulmonary fibrosis (“IPF”), a devastating lung disease. There are no
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`remaining patents on either the composition or its use to treat IPF. Because of the
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`district court decision here, the defendants (together “Sandoz”) secured FDA
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`approval and brought the first generic pirfenidone product to market.
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`Plaintiffs seek to restore their monopoly for their brand-name pirfenidone
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`product, Esbriet®, using two sets of very narrow method patents that claim particular
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`dosing regimens for particular groups of patients—groups ranging from extremely
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`narrow to nonexistent. The first set of methods is for treating the small number of
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`patients who show “Grade 2” elevated liver enzymes on a liver function test (the
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`“LFT patents”). The other set is for managing a single drug-drug interaction (the
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`“DDI patents”), between pirfenidone and fluvoxamine. Plaintiffs sought to leverage
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`these narrow method claims to obtain an order under 35 U.SC. § 271(e)(4)(A),
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`blocking Sandoz’s generic from the market entirely.
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`After a bench trial, the district court found no claim infringed. It also held
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`that the LFT patents were invalid as obvious. This Court should reject Plaintiffs’
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`multi-pronged attack on the judgment. The district court did not clearly err in finding
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`that Sandoz does not infringe any claim in either set of patents, and it correctly held
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`that the asserted claims of the LFT patents are invalid as well.
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`1
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`

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`LFT infringement: Aided by medical testimony from both sides, the district
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`court found that the language in Sandoz’s proposed label did not “recommend,
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`encourage, or promote” use of the patented methods by doctors, as required to show
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`induced infringement. In the label section dealing with elevated liver enzymes, the
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`only recommended dose modification (discontinue pirfenidone) is non-infringing;
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`its mention of other possible regimens defers to doctors’ clinical judgment and
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`contains no recommendation. Plaintiffs barely engage with the district court’s
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`findings. Instead, over-reading cases in which this Court has affirmed infringement
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`findings on deferential review, Plaintiffs claim that this Court has created a legal rule
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`that required the district court to find infringement. That is incorrect. This Court
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`takes each case on its own facts. Where, as here, the factfinder concludes that the
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`label merely “describes” an infringing mode without recommending it, this Court
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`has not hesitated to affirm noninfringement findings. It should do the same here.
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`DDI infringement: The district court found that Plaintiffs had failed even to
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`prove direct infringement, so it did not need to reach inducement. There was no
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`evidence that any IPF patient would be prescribed fluvoxamine and an infringing
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`regimen of pirfenidone. The three medical experts, including Plaintiffs’, testified
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`that in their decades of experience, they had never treated a patient taking both
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`pirfenidone and fluvoxamine. And Plaintiffs presented no evidence at trial that this
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`would change in the future. The district court found that, even if an IPF patient
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`2
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`

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`Case: 22-1595 Document: 23 Page: 13 Filed: 06/14/2022
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`taking fluvoxamine existed, a doctor would most likely prescribe a different,
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`noninfringing drug for IPF. Plaintiffs argue that the courts are required to infer from
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`the DDI warning in the label that direct infringement would occur. That is incorrect.
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`Nothing in this Court’s cases requires a factfinder to assume the existence of real-
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`world infringement in the face of contrary evidence. Rather, in a Hatch-Waxman
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`case, the court asks what would happen if the allegedly infringing product entered
`
`the market. Here Plaintiffs failed to show that Sandoz’s product would infringe.
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`LFT invalidity: Plaintiffs argue that, as a factual matter, the district court
`
`misinterpreted two key prior-art references, including the label for the Japanese
`
`pirfenidone product used to treat IPF at the priority date. The district court did not
`
`clearly err in interpreting those references to disclose the claimed methods of
`
`continuing to treat patients with pirfenidone despite elevated liver enzymes. And
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`the district court bolstered its findings with extensive evidence of standard medical
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`practice at the time, which Plaintiffs ignore.
`
`STATEMENT OF THE ISSUES
`1. Whether the district court clearly erred in finding that Sandoz’s generic
`
`pirfenidone product would not induce infringement of the LFT patents.
`
`2. Whether the district court clearly erred in finding that Sandoz’s generic
`
`pirfenidone product would not directly infringe the DDI patents.
`
`3. Whether the district court erred in holding that the asserted claims of
`
`3
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`

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`Case: 22-1595 Document: 23 Page: 14 Filed: 06/14/2022
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`the LFT patents are invalid as obvious.
`
`STATEMENT OF THE CASE
`Sandoz seeks FDA approval to market a generic form of Plaintiffs’
`Esbriet®, and Plaintiffs bring this action under the Hatch-Waxman Act.
`Pirfenidone is indicated to treat IPF, a chronic, irreversible, and devastating
`
`I.
`
`
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`pulmonary disease characterized by scarring of the tissue that supports the air sacs
`
`of the lungs, resulting in severe difficulty breathing and progressive impairment of
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`a patient’s ability to perform everyday activities. Appx2. There is no cure for IPF,
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`and people with the disease survive an average of two to five years. Appx2. There
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`are only two drugs approved by FDA to treat IPF. Appx2. Approximately half of
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`IPF patients are prescribed pirfenidone and half are prescribed the other drug,
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`nintedanib, which is marketed as Ofev®. Appx3.
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`Sandoz submitted two Abbreviated New Drug Applications (“ANDAs”)
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`seeking approval from FDA to market a generic version of Plaintiffs’ product
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`Esbriet®. Appx2.1 Plaintiffs brought this Hatch-Waxman suit, asserting that
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`Sandoz’s generic pirfenidone product would induce the infringement of six of
`
`Plaintiffs’ patents.2 None of the asserted patents claims pirfenidone itself, or the use
`
`
`1 One ANDA sought approval for 267 mg pirfenidone capsules, and the other sought
`approval for 267 mg and 801 mg pirfenidone tablets. Appx2.
`2 Plaintiffs asserted other patents at the beginning of the case, but chose not to pursue
`them at trial, and the judge ultimately dismissed those claims with prejudice.
`Appx40-42.
`
`4
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`of pirfenidone to treat IPF. Rather, the patents all claim methods for managing
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`certain side effects of using pirfenidone to treat IPF for small or nonexistent groups
`
`of patients. Plaintiffs argued that the instructions on the proposed labeling showed
`
`that Sandoz’s product would be used in ways that would infringe the claimed
`
`methods and that Sandoz intended to promote those infringing uses. Sandoz
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`disputed infringement and asserted that the claims were invalid as obvious.
`
`II. The LFT patents, alleged evidence of infringement, and the prior art.
`A.
`The LFT patents.
`The “Liver Function Test” or “LFT” patents3 are directed to methods “for
`
`administering pirfenidone to a patient that has exhibited abnormal biomarkers of
`
`liver function in response to pirfenidone administration.” Appx4.
`
`In particular, the six asserted claims disclose methods for responding to a
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`“Grade 2”4 abnormality in one or more biomarkers of liver function—specifically,
`
`alanine transaminase (“ALT”) or aspartate transaminase (“AST”)—in a patient
`
`taking pirfenidone to treat IPF. The methods entail various dosing regimes:
`
`• for claim 6 of the ʼ707 patent, administration of the full dose of “2400
`mg/day or 2403 mg/day” (Appx66);
`
`• for claim 14 of the ʼ707 patent, dose reduction to a dose of “1600 mg/day
`or 1602 mg/day” (Appx66-67);
`
`3 U.S. Patent Nos. 7,566,729, 7,635,707, 8,592,462, and 8,609,701.
`4 Liver-function test results are graded in order of severity, with a “Grade 2”
`abnormality being “a severity range where the enzymes are typically two and a half
`to five times the upper limit of the normal range.” Appx5.
`
`5
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`

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`Case: 22-1595 Document: 23 Page: 16 Filed: 06/14/2022
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`• for claim 19 of the ʼ701 patent, dose reduction to “at least 1600 mg/day or
`1602 mg/day” (Appx92-93);
`
`• for claim 9 of the ʼ729 patent, dose reduction to “doses lower than 2400
`mg/day for a time period” followed by a return to the full dose of “2400
`mg/day or 2403 mg/day” (Appx55);
`
`• for claim 12 of the ʼ462 patent, dose interruption “for about a week, or
`until biomarkers of liver function are within normal limits,” followed by
`returning to a full dose of “2400 mg/day or 2403 mg/day” (Appx79-80);
`and
`
`
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`
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`• for claim 28 of the ʼ462 patent, dose interruption “for about a week, or
`until biomarkers of liver function are within normal limits” followed by
`returning to a dose of “at least 1600 mg/day” (Appx79-80).
`
`
`None of the asserted claims encompasses responding to a Grade 2 abnormality by
`
`discontinuing pirfenidone permanently.
`
`B. Alleged evidence of infringement: the label.
`Plaintiffs attempted to prove inducement to infringe by pointing to Sandoz’s
`
`
`
`proposed product label. Under the sub-heading “Dosage Modification due to
`
`Elevated Liver Enzymes,” that label includes the following guidance for patients
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`exhibiting Grade 2 elevations:
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`6
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`Appx16750.5 The first set of bullet points applies to an asymptomatic Grade 2
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`elevation, and instructs, “Discontinue confounding medications, exclude other
`
`causes, and monitor the patient closely,” and “Repeat liver chemistry tests as
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`clinically indicated.” Appx16750. It also states, “The full dosage may be
`
`maintained, if clinically appropriate, or reduced or interrupted (e.g., until liver
`
`chemistry tests are within normal limits) with subsequent re-titration to the full
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`dosage as tolerated.” Appx16750. The second set of bullet points applies to a
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`symptomatic Grade 2 elevation, and instructs, “Permanently discontinue pirfenidone
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`tablets” and “Do not rechallenge patient with pirfenidone tablets.” Appx16750.6
`
`
`5 As the text makes readily apparent, Plaintiffs are wrong that the language of
`Sandoz’s label “precisely matched the patents at issue in this case.” Br. 2-3.
`6 Symptomatic Grade 2 elevations are Grade 2 elevations that are accompanied by
`elevated bilirubin and/or jaundice. Elevated ALT/AST alone was known to occur
`with mild liver injury that resulted in leakage of ALT/AST from otherwise intact
`liver cells into the blood. When elevated ALT/AST was accompanied by
`hyperbilirubinema and jaundice, this was a sign of more serious liver dysfunction,
`reflecting the inability of the liver to perform one of its basic functions—clearing
`bilirubin from the blood. Appx7240-7243(305:8-308:10).
`
`7
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`Evidence of obviousness: the prior art.
`C.
`As relevant to this appeal, the parties disputed whether the prior art disclosed
`
`
`
`
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`the element, present in all the claims, of continuing to treat patients with pirfenidone
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`despite Grade 2 liver-enzyme elevations, as opposed to discontinuing pirfenidone
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`treatment entirely.7 Two prior-art references were particularly significant, and were
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`consistent with significant evidence of standard medical practice at the time.
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`
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`The Azuma Article: Azuma reports on a double-blind, placebo-controlled trial
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`of pirfenidone in patients with IPF. Appx16624. Azuma states, in describing the
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`trial’s protocol, that “[f]or [patients experiencing] an adverse event of Grade 2 or
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`worse,” “the dosage [of pirfenidone] was reduced in a stepwise manner” as long as
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`symptoms persisted. Appx16626. Patients were then monitored for 14-day periods
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`between each stepwise reduction. Appx16626. “When the adverse event of Grade
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`2 or worse persisted or increased despite reducing the dosage …, the study
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`medication was discontinued.” Appx16626. “If the adverse event had resolved or
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`decreased with reduction in the dose, the investigator was allowed to increase the
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`dose up to [the original amount].” Appx16626; see also Appx7421(486:9-20);
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`Appx7462-7463(527:4-528:1). Azuma also lists “Elevation of [AST]” among the
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`7 There were other invalidity disputes, but this is the only issue Plaintiffs press on
`appeal.
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`8
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`Case: 22-1595 Document: 23 Page: 19 Filed: 06/14/2022
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`“adverse events” observed in study patients, and states that 10 patients with elevated
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`AST were observed, and only one was discontinued from the study. Appx16629.
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`Sandoz’s expert Dr. Duncan testified at trial that Azuma disclosed that “for
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`grade 2 abnormalities,” doctors could “continue the dose, reduce the dose in
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`increments, or discontinue the dose,” and that discontinuation “could be temporary
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`or permanent.” Appx7406-7407(471:12-472:12). He testified that “in most cases,
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`most physicians would titrate the dose back up again,” because “[t]his is standard
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`operating procedure at this time and before.” Appx7407(472:13-21).
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`The Pirespa® Label: Pirespa® is a pirfenidone tablet for the treatment of IPF
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`that has been produced by Shionogi & Co. for the Japanese market since before the
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`priority date. Appx16550. Section 3 of Pirespa®’s label is titled “Adverse
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`Reactions,” and is divided into two sub-sections, “Clinically significant adverse
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`reactions” (Section 3(1)) and “Other adverse reactions” (Section 3(2)). Appx16551.
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`Section 3(1) states that “hepatic function disorders accompanied by increased
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`AST(GOT), ALT(GPT), etc. and jaundice may occur and result in hepatic failure.”
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`Appx16551. It indicates that this occurs in less than 1% of patients. Appx16551.
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`The label instructs in this section that “[i]f any abnormalities are observed,
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`administration should be discontinued and appropriate therapeutic measures should
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`be taken.” Appx16551. Dr. Duncan testified that a POSA would understand this
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`9
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`Case: 22-1595 Document: 23 Page: 20 Filed: 06/14/2022
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`section to give instructions for situations in which elevated AST or ALT are
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`accompanied hyperbilirubinemia or jaundice. Appx7401-7402(466:22-467:19).
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`Section 3(2) states that “If the following adverse reactions occur, appropriate
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`therapeutic measures such as dose reduction or discontinuation of administration
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`should be performed as necessary.” Appx16551. A table follows; next to “hepatic,”
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`the table lists, “AST (GOT), increased” and “ALT (GPT), increased.” Appx16551.
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`The table states that this increase occurs in 5% or more of patients. Appx16551. Dr.
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`Duncan testified that a POSA would understand this section to apply to “other
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`nonserious adverse reactions,” including “a grade 2 elevation in ALT or AST alone,”
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`without hyperbilirubinemia or jaundice. Appx7402-7404(467:20-469:20). He
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`testified that, based on this label, a POSA would be motivated to “consider a dose
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`reduction or drug discontinuation as necessary” or “just continue the drug” if “a
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`patient exhibited a grade 2 elevation in ALT or AST alone,” without
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`hyperbilirubinemia or jaundice. Appx7404(469:14-23).8
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`Standard medical practice: Sandoz also introduced evidence that it was
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`standard medical practice at the time of the invention for doctors treating patients
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`who experienced Grade 2 elevations to reduce or interrupt drug treatment and then
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`8 As explained above, at note 6, a Grade 2 elevation in ALT/AST without
`hyperbilirubinemia or jaundice is referred to on Sandoz’s label as a Grade 2 elevation
`“without symptoms,” and a Grade 2 elevation with hyperbilirubinemia or jaundice
`is referred to as a Grade 2 elevation “accompanied by symptoms.”
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`10
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`Case: 22-1595 Document: 23 Page: 21 Filed: 06/14/2022
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`rechallenge. Dr. Duncan gave three examples of drugs other than pirfenidone whose
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`labels included “specific instructions or information about how to manage LFT
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`abnormalities,” including dose modifications followed by rechallenging. See
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`Appx7387-7389(452:19-454:22); see also Appx8153, Appx8156, Appx8160-8161
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`(Actimmune); Appx8476-8477 (Gleevec); Appx10194, 10206-10207 (Tarceva).
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`There was other evidence that automatic discontinuation of treatment after
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`observing a Grade 2 elevation was not a favored approach at the time of the
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`invention. The “Guidance for Industry Drug-Induced Liver Injury” released by the
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`U.S. Department of Health and Human Services in October 2007 (“the FDA DILI
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`Guidance”), Appx8478-8503, counseled that “Because transient rises and falls of
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`ALT or AST are common, and progression to severe [Drug Induced Liver Injury] or
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`acute liver failure is uncommon, automatic discontinuation of study drug upon
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`finding a greater than 3xULN [upper limit of normal] elevation of ALT or AST”—
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`a level that includes Grade 2 elevations—may be unnecessary,” and “For most
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`people, the liver appears capable of adapting to injury by foreign chemical
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`substances.” Appx8478-8489.
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`Consistent with the FDA DILI Guidance, Dr. Duncan testified that “[l]ivers
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`develop tolerance” to treatments and that at the time of the invention a POSA facing
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`elevated liver function tests would “follow standard operating procedure, standard
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`medical practice” of not ceasing administration of a drug generally (including
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`11
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`Case: 22-1595 Document: 23 Page: 22 Filed: 06/14/2022
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`pirfenidone) based solely upon a moderate elevation of ALT/AST. Appx7412-
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`7412(476:19-477:22), accord Appx7418-7419(483:16-484:7) (“standard operating
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`or standard clinical practice at the time” was not “automatically discontinu[ing] a
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`medication for any minor elevation in LFTs [including a Grade 2 elevation],
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`particularly in cases where we thought the medicine was important, as it would be
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`in IPF, to treat with an antifibrotic agent”). He explained that stopping treatment
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`would “unnecessarily deny patients a potentially important therapy.” Appx7386-
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`7387(451:17-452:18).
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`III. The DDI patents and the alleged evidence of infringement.
`A.
`The DDI patents.
`The “Drug-Drug Interaction” or “DDI” patents9 are directed to methods for
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`avoiding adverse interactions between pirfenidone and a different drug called
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`fluvoxamine. Appx4. Fluvoxamine is a strong “CYP1A2 inhibitor,” which means
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`it can interfere with normal drug metabolism by