Case: 22-1595 Document: 21 Page: 1 Filed: 05/10/2022
`
`Nos. 2022-1595, 2022-1714
`
`United States Court of Appeals
`for the Federal Circuit
`
`
`GENENTECH, INC., INTERMUNE, INC.,
`Plaintiffs-Appellants
`
`v.
`
`SANDOZ INC., LEK PHARMACEUTICALS, D.D.,
`Defendants-Cross-Appellants
`
`
`
`
`
`
`
`
`Appeals from the United States District Court for the District of Delaware in
`C.A. No. 1:19-cv-00078-RGA, Judge Richard G. Andrews
`
`BRIEF FOR PLAINTIFFS-APPELLANTS GENENTECH, INC. AND
`INTERMUNE, INC.
`
`
`
`Kira A. Davis
`DURIE TANGRI LLP
`953 East 3rd Street
`Los Angeles, CA 90013
`Telephone: 213-992-4499
`Facsimile: 415-236-6300
`
`May 10, 2022
`
`
`
`Daralyn J. Durie
`Vera Ranieri
`DURIE TANGRI LLP
`217 Leidesdorff Street
`San Francisco, CA 94111
`Telephone: 415-362-6666
`Facsimile: 415-236-6300
`
`
`Counsel for Plaintiffs-Appellants
`Genentech, Inc. and InterMune, Inc.
`
`
`
`
`
`
`
`
`
`
`

`

`Case: 22-1595 Document: 21 Page: 2 Filed: 05/10/2022
`
`
`
`PATENT CLAIMS AT ISSUE
`
`Claim 9, U.S. Patent No. 7,566,729
`
`1. A method of administering pirfenidone to treat a
`patient with idiopathic pulmonary fibrosis (IPF), said
`patient having exhibited a grade 2 abnormality 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.
`9. The method of claim 1, wherein said one or more
`biomarkers of liver function comprise alanine
`transaminase and aspartate transaminase.
`
`Appx55.
`
`Claim 12, U.S. Patent No. 8,592,462
`
`1. A method of administering pirfenidone to treat a
`patient with idiopathic pulmonary fibrosis (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 after a first pirfenidone administration,
`comprising 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.
`3. The method of claim 1, wherein step (a) comprises
`administering to said patient pirfenidone at a dose of
`about 2400 mg/day or 2403 mg/day.
`12. The method of claim 3 further comprising, prior to
`step (a), discontinuing the first administration of
`
`i
`
`

`

`Case: 22-1595 Document: 21 Page: 3 Filed: 05/10/2022
`
`
`
`pirfenidone for about a week, or until biomarkers of liver
`function are within normal limits.
`Appx79-80.
`
`Claim 28, U.S. Patent No. 8,592,462
`
`26. A method of administering pirfenidone to treat a
`patient with idiopathic pulmonary fibrosis (IPF), said
`patient having exhibited a Grade 2 abnormality in one or
`both of alanine transaminase and aspartate transaminase
`after a first pirfenidone administration, comprising
`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.
`28. The method of claim 26 further comprising, prior to
`step (a), discontinuing the first administration of
`pirfenidone for about one week, or until biomarkers of
`liver function are within normal limits.
`
`Appx80.
`
`Claim 6, U.S. Patent No. 7,635,707
`
`1. A method of administering pirfenidone to treat a
`patient with idiopathic pulmonary fibrosis (IPF), said
`patient having exhibited a grade 2 abnormality 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.
`6. The method of claim 1, wherein said one or more
`biomarkers of liver function is selected from the group
`consisting of alanine transaminase and aspartate
`transaminase.
`
`Appx66.
`
`ii
`
`

`

`Case: 22-1595 Document: 21 Page: 4 Filed: 05/10/2022
`
`
`
`Claim 14, U.S. Patent No. 7,635,707
`
`7. A method of administering pirfenidone to treat a
`patient with idiopathic pulmonary fibrosis (IPF), said
`patient having exhibited a grade 2 abnormality in one or
`more biomarkers of liver function after pirfenidone
`administration, comprising (a) administering to said
`patient pirfenidone at doses of 1600 mg/day or 1602
`mg/day.
`14. The method of claim 7, wherein said one or more
`biomarkers of liver function is selected from the group
`consisting of alanine transaminase and aspartate
`transaminase.
`
`Appx66-67.
`
`Claim 19, U.S. Patent No. 8,609,701
`
`1. A method of treating a patient in need of pirfenidone
`and suffering from a Grade 2 abnormality in a liver
`function biomarker selected from the group consisting of
`alanine transaminase (ALT) and aspartate transaminase
`(AST) and wherein the abnormality occurs after a first
`pirfenidone administration, comprising providing to said
`patient a second administration of pirfenidone,
`comprising (a) administering to said patient at doses of at
`least 1600 mg/day or 1602 mg/day.
`19. The method of claim 1, wherein the patient suffers
`from idiopathic pulmonary fibrosis.
`
`Appx92-93.
`
`Claim 6, U.S. Patent No. 7,816,383
`
`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
`
`iii
`
`

`

`Case: 22-1595 Document: 21 Page: 5 Filed: 05/10/2022
`
`
`
`pirfenidone.
`6. The method of claim 5 wherein the patient has
`idiopathic pulmonary fibrosis (IPF).
`
`Appx107.
`
`Claim 3, U.S. Patent No. 8,013,002
`
`1. A method of administering pirfenidone and
`fluvoxamine concurrently to a patient in need thereof
`comprising administering a therapeutically effective
`amount of fluvoxamine 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.
`2. The method of claim 1 wherein the pirfenidone is
`administered three times per day.
`3. The method of claim 2 wherein the patient has
`idiopathic pulmonary fibrosis (IPF).
`
`Appx120.
`
`Claim 9, U.S. Patent No. 8,013,002
`
`6. A method of providing pirfenidone therapy to a patient
`in need thereof comprising titrating the dosage of
`pirfenidone administered to the patient downward from a
`dose of about 2400 mg/day, while co-administering
`fluvoxamine, wherein the dose of pirfenidone is reduced
`by about 1600 mg/day.
`8. The method of claim 6 wherein the pirfenidone is
`administered three times per day.
`9. The method of claim 8 wherein the patient has
`idiopathic pulmonary fibrosis (IPF).
`
`
`Appx120.
`
`iv
`
`

`

`Case: 22-1595 Document: 21 Page: 6 Filed: 05/10/2022
`
`FORM 9. Certificate of Interest
`
`UNITED STATES COURT OF APPEALS
`FOR THE FEDERAL CIRCUIT
`
`CERTIFICATE OF INTEREST
`
`
`Form 9 (p. 1)
`July 2020
`
`
`Case Number
`Short Case Caption
`Filing Party/Entity
`
`
`
`
`
`Instructions: Complete each section of the form. In answering items 2 and 3, be
`specific as to which represented entities the answers apply; lack of specificity may
`result in non-compliance. Please enter only one item per box; attach
`additional pages as needed and check the relevant box. Counsel must
`immediately file an amended Certificate of Interest if information changes. Fed.
`Cir. R. 47.4(b).
`
`
`
`
`
`
`
`I certify the following information and any attached sheets are accurate and
`complete to the best of my knowledge.
`
`
`Date: _________________
`
`
`
`
`
`
`
`
`Signature:
`
`Name:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2022-1595, 2022-1714
`
`Genentech, Inc. v. Sandoz Inc.
`
`Genentech, Inc. and InterMune, Inc.
`
`Daralyn J. Durie
`
`/s/ Daralyn J. Durie
`
`05/10/2022
`
`

`

`Case: 22-1595 Document: 21 Page: 7 Filed: 05/10/2022
`
`FORM 9. Certificate of Interest
`
`1. Represented
`Entities.
`Fed. Cir. R. 47.4(a)(1).
`Provide the full names of
`all entities represented
`by undersigned counsel in
`this case.
`
`Form 9 (p. 2)
`July 2020
`
`2. Real Party in
`Interest.
`Fed. Cir. R. 47.4(a)(2).
`Provide the full names of
`all real parties in interest
`for the entities. Do not
`list the real parties if
`they are the same as the
`entities.
`
`3. Parent Corporations
`and Stockholders.
`Fed. Cir. R. 47.4(a)(3).
`Provide the full names of
`all parent corporations
`for the entities and all
`publicly held companies
`that own 10% or more
`stock in the entities.
`
`☐ None/Not Applicable ☐ None/Not Applicable
`
`Additional pages attached
`
`4
`
`Genentech, Inc.
`
`Roche Holdings Inc.
`
`Genentech, Inc.
`
`Roche Holdings Ltd.
`
`InterMune Inc.
`
`Genentech, Inc.
`
`InterMune Inc.
`
`Roche Holdings Inc.
`
`InterMune Inc.
`
`Roche Holdings Ltd.
`
`

`

`Case: 22-1595 Document: 21 Page: 8 Filed: 05/10/2022
`
`FORM 9. Certificate of Interest
`
`Form 9 (p. 3)
`July 2020
`
`4. Legal Representatives. List all law firms, partners, and associates that (a)
`appeared for the entities in the originating court or agency or (b) are expected to
`appear in this court for the entities. Do not include those who have already
`entered an appearance in this court. Fed. Cir. R. 47.4(a)(4).
`None/Not Applicable
`Additional pages attached
`
`5. Related Cases. Provide the case titles and numbers of any case known to be
`pending in this court or any other court or agency that will directly affect or be
`directly affected by this court’s decision in the pending appeal. Do not include the
`originating case number(s) for this case. Fed. Cir. R. 47.4(a)(5). See also Fed. Cir.
`R. 47.5(b).
`None/Not Applicable
`
`Additional pages attached
`
`6. Organizational Victims and Bankruptcy Cases. Provide any information
`required under Fed. R. App. P. 26.1(b) (organizational victims in criminal cases)
`and 26.1(c) (bankruptcy case debtors and trustees). Fed. Cir. R. 47.4(a)(6).
`None/Not Applicable
`Additional pages attached
`
`Jack B. Blumenfeld, Karen Jacobs, Cameron P. Clark
`Morris Nichols Arsht & Tunnell LLP
`
`Stephen J. Kraftschik
`Formerly with Morris Nichols Arsht & Tunnell LLP
`
`Mark E. Waddell, Warren K. MacRae,
`LOEB & LOEB LLP
`
`Ryan Haggland, Kathleen Gersh
`LOEB & LOEB LLP
`
`Alexandra Cavazos, Dan Liu
`LOEB & LOEB LLP
`
`4
`
`4
`
`

`

`Case: 22-1595 Document: 21 Page: 9 Filed: 05/10/2022
`
`
`
`TABLE OF CONTENTS
`
`Page
`
`STATEMENT OF RELATED CASES ..................................................................... 1
`JURISDICTIONAL STATEMENT .......................................................................... 1
`INTRODUCTION ..................................................................................................... 2
`STATEMENT OF THE ISSUES............................................................................... 4
`STATEMENT OF THE CASE .................................................................................. 5
`I.
`The Development of a Viable Treatment for IPF and the
`Asserted Patents .................................................................................... 5
`A.
`InterMune’s development of pirfenidone to treat IPF ................ 5
`B. Development of the LFT management plan ............................... 7
`C. Development of the fluvoxamine DDI plan ............................... 9
`D.
`Pirfenidone’s approved indication ............................................ 10
`The Asserted Patents and Claims ........................................................ 11
`A.
`The LFT Patents and asserted claims ....................................... 11
`B.
`The DDI Patents and asserted claims ....................................... 12
`III. Sandoz’s ANDAs ................................................................................ 13
`A.
`The Label’s recommendations for managing elevated
`liver enzymes ............................................................................ 13
`The Label’s recommendations relating to fluvoxamine ........... 16
`B.
`IV. The Prior Art to the LFT Patents ......................................................... 17
`A. Azuma ....................................................................................... 17
`B.
`The Pirespa Label ...................................................................... 19
`C.
`Prosecution history .................................................................... 21
`
`II.
`
`vi
`
`

`

`Case: 22-1595 Document: 21 Page: 10 Filed: 05/10/2022
`
`
`
`V. District Court Proceedings .................................................................. 22
`A.
`Infringement of the LFT Patents ............................................... 22
`B.
`Infringement of the DDI Patents ............................................... 23
`C. Validity of the LFT Patents ....................................................... 25
`SUMMARY OF THE ARGUMENT ...................................................................... 26
`ARGUMENT ........................................................................................................... 27
`I.
`Standard of Review ............................................................................. 27
`II.
`The District Court Erred in Entering Judgment of
`Noninfringement of the LFT Patents .................................................. 28
`A. Direct infringement is undisputed ............................................. 29
`B.
`The district court erred in finding no intent to induce that
`infringement .............................................................................. 29
`1.
`The district court did not use the correct legal test ......... 30
`2.
`Sandoz’s Label induces infringement ............................ 34
`III. The District Court Erred in Entering Judgment of
`Noninfringement of the DDI Patents .................................................. 35
`A.
`The district court erred in finding no direct infringement ........ 36
`1.
`The Label establishes direct infringement of the
`DDI Patents ..................................................................... 36
`The district court erred in requiring Plaintiffs to
`provide other evidence .................................................... 39
`Sandoz’s other noninfringement arguments should be
`rejected as legally erroneous ..................................................... 43
`1.
`Sandoz induces infringement .......................................... 44
`2.
`Divided infringement is a red herring ............................ 45
`
`B.
`
`2.
`
`vii
`
`

`

`Case: 22-1595 Document: 21 Page: 11 Filed: 05/10/2022
`
`
`
`2.
`
`3.
`
`IV. The LFT Patents’ Invalidity Judgment Should Be Reversed or
`Vacated ................................................................................................ 47
`A.
`The prior art does not disclose Grade 2 elevated liver
`enzymes and the claimed continued treatment ......................... 48
`1.
`Azuma does not disclose patients with Grade 2
`elevations in AST or ALT nor their continued
`treatment with the claimed methods ............................... 49
`The Pirespa Label does not disclose the claimed
`methods ........................................................................... 51
`There were no findings made with respect to the
`prior art and discontinuation of pirfenidone
`followed by re-administration to the full dose as
`required by claim 9 of the ’729 patent and claim 12
`of the ’462 patent ............................................................ 55
`The objective indicia of non-obviousness confirm the
`district court erred ..................................................................... 57
`CONCLUSION ........................................................................................................ 60
`ADDENDUM .......................................................................................................... 61
`CERTIFICATE OF COMPLIANCE WITH TYPE-VOLUME
`LIMITATION, TYPEFACE REQUIREMENTS, AND TYPE STYLE
`REQUIREMENTS ........................................................................................ 62
`
`B.
`
`
`
`
`
`
`viii
`
`

`

`Case: 22-1595 Document: 21 Page: 12 Filed: 05/10/2022
`
`
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`Cases
`Akamai Techs., Inc. v. Limelight Networks,
`797 F.3d 1020 (Fed. Cir. 2015) .......................................................................... 45
`Andrulis Pharm. Corp. v. Celgene Corp.,
`No. 13-644-RGA, 2015 WL 3978578 (D. Del. June 26, 2015),
`aff’d, 667 F. App’x 775 (Fed. Cir. 2016) ........................................................... 46
`Arendi S.A.R.L. v. Apple Inc.,
`832 F.3d 1355 (Fed. Cir. 2016) .......................................................................... 48
`AstraZeneca AB v. Mylan Pharm. Inc.,
`19 F.4th 1325 (Fed. Cir. 2021) ........................................................................... 27
`AstraZeneca LP v. Apotex, Inc.,
`633 F.3d 1042 (Fed. Cir. 2010) ...................................................................passim
`Commonwealth Sci. & Indus. Rsch. Org. v. Cisco Sys., Inc.,
`809 F.3d 1295 (Fed. Cir. 2015) .......................................................................... 27
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Pat.
`Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .................................................................... 57, 59
`Douglas Dynamics, LLC v. Buyers Prods. Co.,
`717 F.3d 1336 (Fed. Cir. 2013), overruled on other grounds by
`Teva Pharm. USA, Inc. v. Sandoz, Inc., 574 U.S. 318 (2015) ............................ 44
`Eli Lilly & Co. v. Teva Parenteral Meds., Inc.,
`845 F.3d 1357 (Fed. Cir. 2017) .................................................................... 34, 38
`Galderma Lab’ys, L.P. v. Teva Pharm. USA, Inc.,
`799 F. App’x 838 (Fed. Cir. 2020) ..................................................................... 28
`GlaxoSmithKline LLC v. Teva Pharms. USA, Inc.,
`7 F.4th 1320 (Fed. Cir. 2021) ........................................................... 28, 30, 31, 33
`HZNP Medicines LLC v. Actavis Lab’ys UT, Inc.,
`940 F.3d 680 (Fed. Cir. 2019) ............................................................................ 33
`
`ix
`
`

`

`Case: 22-1595 Document: 21 Page: 13 Filed: 05/10/2022
`
`
`
`Impax Lab’ys, Inc. v. Aventis Pharm., Inc.,
`545 F.3d 1312 (Fed. Cir. 2008) .......................................................................... 54
`Institut Pasteur & Universite Pierre et Marie Curie v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) .......................................................................... 57
`K/S Himpp v. Hear-Wear Techs., LLC,
`751 F.3d 1362 (Fed. Cir. 2014) .......................................................................... 48
`Neptune Generics, LLC v. Eli Lilly & Co.,
`921 F.3d 1372 (Fed. Cir. 2019) .......................................................................... 58
`In re Oelrich,
`666 F.2d 578 (C.C.P.A. 1981) ...................................................................... 49, 50
`Orexigen Therapeutics, Inc. v. Actavis Lab’ys FL, Inc.,
`282 F. Supp. 3d 793 (D. Del. 2017), aff’d in part, rev’d in part,
`934 F.3d 1344 (Fed. Cir. 2019) .......................................................................... 46
`Ortho-McNeil Pharm., Inc. v. Mylan Lab’ys, Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) .......................................................................... 57
`Par Pharm., Inc. v. TWi Pharm., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) ........................................................ 28, 49, 50, 51
`In re Rijckaert,
`9 F.3d 1531 (Fed. Cir. 1993) .............................................................................. 49
`Takeda Pharm. U.S.A., Inc. v. West-Ward Pharm. Corp.,
`785 F.3d 625 (Fed. Cir. 2015) ................................................................ 28, 38, 39
`Teva Pharm. USA, Inc. v. Sandoz, Inc.,
`574 U.S. 318 (2015) ...................................................................................... 44, 51
`Univ. of Strathclyde v. Clear-Vu Lighting LLC,
`17 F.4th 155 (Fed. Cir. 2021) ............................................................................. 50
`Vanda Pharm. Inc. v. Roxane Lab’ys, Inc.,
`203 F. Supp. 3d 412 (D. Del. 2016) .............................................................. 28, 37
`Vanda Pharms. Inc. v. West-Ward Pharms. Int’l Ltd.,
`887 F.3d 1117 (Fed. Cir. 2018), cert. denied, 140 S. Ct. 911 (2020) .........passim
`
`x
`
`

`

`Case: 22-1595 Document: 21 Page: 14 Filed: 05/10/2022
`
`
`
`W.L. Gore & Assocs., Inc. v. Garlock, Inc.,
`721 F.2d 1540 (Fed. Cir. 1983) .......................................................................... 28
`Warner-Lambert Co. v. Apotex Corp.,
`316 F.3d 1348 (Fed. Cir. 2003) .......................................................................... 35
`Statutes
`28 U.S.C. § 1295 ........................................................................................................ 1
`28 U.S.C. § 1331 ........................................................................................................ 1
`28 U.S.C. § 1338 ........................................................................................................ 1
`28 U.S.C. § 2201 ........................................................................................................ 1
`28 U.S.C. § 2202 ........................................................................................................ 1
`35 U.S.C. § 103 ........................................................................................................ 17
`35 U.S.C. § 271 .................................................................................................... 1, 32
`35 U.S.C. § 282 ........................................................................................................ 56
`
`
`
`xi
`
`

`

`Case: 22-1595 Document: 21 Page: 15 Filed: 05/10/2022
`
`
`
`STATEMENT OF RELATED CASES
`
`This is an appeal following a bench trial in Genentech, Inc. v. Sandoz Inc.,
`
`C.A. No. 1:19-cv-00078-RGA (D. Del.). Counsel is aware of no pending case in
`
`this or any other court that would affect or be affected by the outcome of this
`
`appeal.
`
`JURISDICTIONAL STATEMENT
`
`This is an appeal from a final judgment in a Hatch-Waxman patent
`
`infringement action brought under 35 U.S.C. §§ 271(e)(2) and (e)(4). The district
`
`court had jurisdiction under 28 U.S.C. §§ 1331, 1338(a), 2201 and 2202. The
`
`district court granted final judgement on April 1, 2022. Appx40-42. Appellants
`
`Genentech, Inc. and InterMune, Inc. filed their notice of appeal that same day.
`
`Appx43-46. This Court has jurisdiction under 28 U.S.C. § 1295(a)(1).
`
`
`
`
`
`1
`
`

`

`Case: 22-1595 Document: 21 Page: 16 Filed: 05/10/2022
`
`
`
`INTRODUCTION
`
`Forty years after it was first studied, pirfenidone was approved in the United
`
`States to treat idiopathic pulmonary fibrosis (“IPF”), a devastating disease that had
`
`no other viable treatment option. When InterMune acquired the rights to
`
`pirfenidone, it was viewed as having questionable efficacy and was known to cause
`
`potentially fatal liver damage. Twelve years later, InterMune succeeded not just in
`
`proving that pirfenidone could safely treat IPF but also in devising a strategy to
`
`maximize the number of patients who could benefit from it. InterMune did so
`
`using a novel liver function test management plan that allowed patients with
`
`“Grade 2” abnormalities to continue to receive the benefits of treatment—an
`
`approach that was unexpectedly safe, endorsed by FDA, and included in
`
`Genentech’s Esbriet® label. InterMune also devised ways to minimize dangers
`
`arising from the co-administering of pirfenidone and fluvoxamine (a selective
`
`serotonin reuptake inhibitor, or SSRI). This approach was likewise deemed
`
`critically important by FDA, which insisted that InterMune include these methods
`
`in the Esbriet® label as well.
`
`When Sandoz applied to sell a generic version of pirfenidone, it copied the
`
`Esbriet® label in full, including its liver function test management methods
`
`(covered by the “LFT Patents”) and fluvoxamine co-administration instructions
`
`(covered by the “DDI Patents”). There is no dispute that the language of Sandoz’s
`
`2
`
`

`

`Case: 22-1595 Document: 21 Page: 17 Filed: 05/10/2022
`
`
`
`two labels (the “Label”) precisely matched the patents at issue in this case. The
`
`district court agreed that four dosage “modification options” listed in Sandoz’s
`
`Label “are covered by” the LFT Patents, and that the Label instructs the reader to
`
`perform the methods claimed in the DDI Patents.
`
`The district court nevertheless found that Sandoz does not infringe. It did so
`
`by faulting Plaintiffs for not meeting legal tests that are contrary to this Court’s
`
`jurisprudence. The correct legal test should result in reversal. At the least, the
`
`judgment should be vacated, and the case remanded for further proceedings.
`
`The district court also erred in finding the LFT Patents invalid over art that
`
`had already been considered and overcome during prosecution. Sandoz asserted
`
`two prior art references (“Azuma” and the “Pirespa Label”). Both were discussed
`
`extensively during prosecution, and the examiner correctly concluded that neither
`
`teaches the claimed methods, which require administration of pirfenidone to
`
`patients even after they experience a Grade 2 abnormality in certain liver enzymes.
`
`Rather, the Pirespa Label affirmatively instructs the opposite—that if “any” liver
`
`abnormality is observed in a patient taking pirfenidone, the drug should be
`
`discontinued. Sandoz’s arguments to the contrary, and the district court’s
`
`acceptance of them, are based on a misapplication of the law, a plain misreading of
`
`the prior art, and a failure to consider each of the asserted claims individually. The
`
`district court’s judgment should be reversed or vacated.
`
`3
`
`

`

`Case: 22-1595 Document: 21 Page: 18 Filed: 05/10/2022
`
`
`
`STATEMENT OF THE ISSUES
`
`1. Whether the district court erred in concluding that Plaintiffs did not
`
`prove infringement of the asserted claims of the LFT Patents where the district
`
`court reached that conclusion not by assessing whether the Label encouraged,
`
`recommended, or promoted infringement, but instead by examining whether
`
`Sandoz’s Label “require[d]” infringement and used “directive” language rather
`
`than “passive-voice verb[s].”
`
`2. Whether the district court erroneously failed to apply this Court’s law
`
`as described in Vanda Pharmaceuticals Inc. v. West-Ward Pharmaceuticals
`
`International Ltd., 887 F.3d 1117 (Fed. Cir. 2018), cert. denied, 140 S. Ct. 911
`
`(2020), when it determined that Plaintiffs did not show direct infringement of the
`
`DDI Patents even though Sandoz’s Label directs that pirfenidone be used in a
`
`manner that infringes the asserted claims.
`
`3. Whether the invalidity judgment of the LFT Patents should be
`
`reversed or remanded because the district court supplied missing claim limitations
`
`based on probabilities, misconstrued language in a prior art label, and ignored
`
`certain claim limitations in finding that the elements of the patented methods were
`
`taught in the prior art.
`
`
`
`
`
`4
`
`

`

`
`
`I.
`
`Case: 22-1595 Document: 21 Page: 19 Filed: 05/10/2022
`
`STATEMENT OF THE CASE
`
`The Development of a Viable Treatment for IPF and the Asserted
`Patents
`A.
`InterMune’s development of pirfenidone to treat IPF
`
`Idiopathic pulmonary fibrosis, or “IPF,” is a chronic, irreversible, and fatal
`
`lung disease. Appx6984 (49:9-14). There are about 150,000 patients with IPF in
`
`the United States. Appx7147 (212:1-2). The disease is characterized by scarring
`
`or fibrosis of the lattice-like network of tissue that supports the air sacs of the
`
`lungs. Appx50 (1:30-37); Appx6984-6985 (49:15-50:2). The cause of IPF is not
`
`known. Appx6984 (49:9-11); Appx16524 (§12.1). Patients suffering from IPF
`
`“can’t breathe, essentially.” Appx6985 (50:3-4). As a result of an overwhelming
`
`shortness of breath, patients will lose the ability to perform tasks as simple as
`
`sitting down for dinner or getting out of bed. Appx6985 (50:3-13). There was no
`
`approved treatment for IPF in the U.S. until 2014, when Esbriet® (pirfenidone)
`
`was approved based on years of diligent work by InterMune. Appx16515. It is
`
`sold today by Genentech. Appx6019.
`
`When InterMune began to work with pirfenidone as a potential treatment for
`
`IPF, it was an old molecule with no approved use. Appx18413; Appx16515.
`
`Development rights for pirfenidone in Japan were owned by Shionogi & Co. Ltd.,
`
`Appx18413, and the trial data that Shionogi had developed was viewed with
`
`skepticism in the U.S. Early on, InterMune put together a summary for FDA of the
`
`5
`
`

`

`Case: 22-1595 Document: 21 Page: 20 Filed: 05/10/2022
`
`
`
`prior studies done with pirfenidone, including a very small Phase II study.
`
`Appx18419; Appx6990 (55:12-16). InterMune told FDA that “due to limitations
`
`in design and conduct, these [studies] cannot be considered as ‘adequate and well-
`
`controlled’ clinical trials . . . .” Appx18419; Appx6991-6992 (56:22-57:15). FDA
`
`agreed: “The completed Phase 2 studies have many limitations and therefore, do
`
`little to support the efficacy of pirfenidone for the treatment of IPF.” Appx18588;
`
`Appx6996 (61:2-19); Appx18602-18603.
`
`The lack of convincing efficacy data was not pirfenidone’s only problem.
`
`There was also a serious safety issue. One patient in the Shionogi study had a
`
`severe liver injury that met the criteria for “Hy’s Law.” Appx18549-18550;
`
`Appx18693-18694; Appx9685; Appx9702-9703. “Hy’s Law” is the informal
`
`name given to an observation that a particular type of liver injury has important
`
`predictive value for identifying drugs likely to cause severe liver injury.
`
`Appx17017. InterMune’s Dr. Williamson Bradford explained that although
`
`Shionogi had “only dosed less than a hundred patients[,] [t]hey had a case of Hy’s
`
`Law . . . .” Appx6999 (64:9-23); see also Appx18709. The occurrence of a Hy’s
`
`Law case was “a really big issue to” InterMune. Appx7001 (66:6-67:11); see also
`
`Appx7085-7086 (150:20-151:7). “Experience has indicated that the occurrence of
`
`even one or two well-documented cases of [Hy’s Law] is ominous, indicating a
`
`likelihood that the drug will cause severe liver injury.” Appx17026. And another
`
`6
`
`

`

`Case: 22-1595 Document: 21 Page: 21 Filed: 05/10/2022
`
`
`
`company that had tried (and failed) to develop pirfenidone (MARNAC) also saw a
`
`patient develop liver necrosis. Appx7001 (66:6-67:11); Appx7526 (591:5-9);
`
`Appx7560 (625:7-14).
`
`B. Development of the LFT management plan
`
`Despite these red flags, InterMune decided to cautiously move forward with
`
`two Phase III clinical trials. Appx7004 (69:11-22); Appx18382-18386;
`
`Appx18860. Inventors Dr. Bradford and Dr. Javier Szwarcberg devised a
`
`treatment plan to keep patients safely on pirfenidone.
`
`Two liver enzymes are particularly relevant to this case: alanine
`
`transaminase (“ALT”) and aspartate transaminase (“AST”). These enzymes
`
`normally exist within the liver and, if a liver cell is damaged, are released into the
`
`bloodstream. Elevations in AST or ALT thus indicate active liver inflammation.
`
`Appx7164-7165 (229:22-230:19); Appx52-53 (6:56-7:4). Numeric grades are used
`
`to describe the results of liver function tests, with higher grades indicating
`
`increasing severity:
`
`Grade Level of elevation in ALT and/or AST (x) as a
`factor of the upper limit of normal (“ULN”)
`0
`0 < x <= ULN
`1
`ULN < x <= 2.5ULN
`2
`2.5ULN < x <= 5ULN
`3+
`5ULN < x
`
`Appx53 (7:39-8:16); Appx7020 (85:10-15).
`
`7
`
`

`

`Case: 22-1595 Document: 21 Page: 22 Filed: 05/10/2022
`
`
`
`The treatment plan developed by the inventors focused on continuing to treat
`
`patients with Grade 2 elevations by temporarily interrupting or temporarily
`
`reducing pirfenidone dosing followed by re-introduction or re-escalation of
`
`pirfenidone (i.e., “rechallenging”), permanently reducing the pirfenidone dose, or
`
`maintaining pirfenidone after the Grade 2 elevation was observed, rather than
`
`stopping treatment. See Appx5.
`
`This approach was met with skepticism. One prominent pulmonologist, Dr.
`
`Robert Wise of an independent data monitoring committee, “was not in favor of
`
`rechallenging these patients and taking them back to full dose. He was concerned
`
`about what had happened in the Shionogi trial and MARNAC experience, and here
`
`we are seeing these [serious adverse events] early on.” Appx7026 (91:2-9).
`
`Ultimately the com