Case: 22-1595 Document: 30 Page: 1 Filed: 07/12/2022
`
`(cid:49)(cid:82)(cid:17)(cid:3)(cid:21)(cid:19)(cid:21)(cid:21)(cid:16)(cid:20)(cid:24)(cid:28)(cid:24)(cid:3)
`
`United States Court of Appeals
`for the Federal Circuit(cid:3)
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`(cid:3)(cid:3)
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`(cid:42)(cid:40)(cid:49)(cid:40)(cid:49)(cid:55)(cid:40)(cid:38)(cid:43)(cid:15)(cid:3)(cid:44)(cid:49)(cid:38)(cid:17)(cid:15)(cid:3)(cid:44)(cid:49)(cid:55)(cid:40)(cid:53)(cid:48)(cid:56)(cid:49)(cid:40)(cid:15)(cid:3)(cid:44)(cid:49)(cid:38)(cid:17)(cid:15)(cid:3)
`Plaintiffs-Appellants
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`(cid:54)(cid:36)(cid:49)(cid:39)(cid:50)(cid:61)(cid:3)(cid:44)(cid:49)(cid:38)(cid:17)(cid:15)(cid:3)(cid:47)(cid:40)(cid:46)(cid:3)(cid:51)(cid:43)(cid:36)(cid:53)(cid:48)(cid:36)(cid:38)(cid:40)(cid:56)(cid:55)(cid:44)(cid:38)(cid:36)(cid:47)(cid:54)(cid:15)(cid:3)(cid:39)(cid:17)(cid:39)(cid:17)(cid:15)(cid:3)
`Defendants-Appellees
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`(cid:3)
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`(cid:3)
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`(cid:42)(cid:50)(cid:50)(cid:39)(cid:58)(cid:44)(cid:49)(cid:3)(cid:51)(cid:53)(cid:50)(cid:38)(cid:55)(cid:40)(cid:53)(cid:3)(cid:47)(cid:47)(cid:51)(cid:3)
`(cid:20)(cid:28)(cid:19)(cid:19)(cid:3)(cid:49)(cid:3)(cid:54)(cid:87)(cid:85)(cid:72)(cid:72)(cid:87)(cid:15)(cid:3)(cid:49)(cid:17)(cid:58)(cid:17)(cid:3)
`(cid:58)(cid:68)(cid:86)(cid:75)(cid:76)(cid:81)(cid:74)(cid:87)(cid:82)(cid:81)(cid:15)(cid:3)(cid:39)(cid:38)(cid:3)(cid:21)(cid:19)(cid:19)(cid:22)(cid:25)(cid:3)
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`(cid:41)(cid:68)(cid:70)(cid:86)(cid:76)(cid:80)(cid:76)(cid:79)(cid:72)(cid:29)(cid:3)(cid:21)(cid:19)(cid:21)(cid:17)(cid:22)(cid:23)(cid:25)(cid:17)(cid:23)(cid:23)(cid:23)(cid:23)(cid:3)
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`(cid:42)(cid:50)(cid:50)(cid:39)(cid:58)(cid:44)(cid:49)(cid:3)(cid:51)(cid:53)(cid:50)(cid:38)(cid:55)(cid:40)(cid:53)(cid:3)(cid:47)(cid:47)(cid:38)(cid:3)
`(cid:25)(cid:19)(cid:20)(cid:3)(cid:54)(cid:82)(cid:88)(cid:87)(cid:75)(cid:3)(cid:41)(cid:76)(cid:74)(cid:88)(cid:72)(cid:85)(cid:82)(cid:68)(cid:3)(cid:54)(cid:87)(cid:85)(cid:72)(cid:72)(cid:87)(cid:3)
`(cid:23)(cid:20)(cid:86)(cid:87)(cid:3)(cid:41)(cid:79)(cid:82)(cid:82)(cid:85)(cid:3)
`(cid:47)(cid:82)(cid:86)(cid:3)(cid:36)(cid:81)(cid:74)(cid:72)(cid:79)(cid:72)(cid:86)(cid:15)(cid:3)(cid:38)(cid:36)(cid:3)(cid:28)(cid:19)(cid:19)(cid:20)(cid:26)(cid:3)
`(cid:55)(cid:72)(cid:79)(cid:72)(cid:83)(cid:75)(cid:82)(cid:81)(cid:72)(cid:29)(cid:3)(cid:21)(cid:20)(cid:22)(cid:17)(cid:23)(cid:21)(cid:25)(cid:17)(cid:21)(cid:24)(cid:19)(cid:19)(cid:3)
`(cid:41)(cid:68)(cid:70)(cid:86)(cid:76)(cid:80)(cid:76)(cid:79)(cid:72)(cid:29)(cid:3)(cid:21)(cid:20)(cid:22)(cid:17)(cid:25)(cid:21)(cid:22)(cid:17)(cid:20)(cid:25)(cid:26)(cid:22)(cid:3)
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`(cid:39)(cid:68)(cid:85)(cid:68)(cid:79)(cid:92)(cid:81)(cid:3)(cid:45)(cid:17)(cid:3)(cid:39)(cid:88)(cid:85)(cid:76)(cid:72)(cid:3)
`(cid:57)(cid:72)(cid:85)(cid:68)(cid:3)(cid:53)(cid:68)(cid:81)(cid:76)(cid:72)(cid:85)(cid:76)(cid:3)
`(cid:39)(cid:56)(cid:53)(cid:44)(cid:40)(cid:3)(cid:55)(cid:36)(cid:49)(cid:42)(cid:53)(cid:44)(cid:3)(cid:47)(cid:47)(cid:51)(cid:3)
`(cid:21)(cid:20)(cid:26)(cid:3)(cid:47)(cid:72)(cid:76)(cid:71)(cid:72)(cid:86)(cid:71)(cid:82)(cid:85)(cid:73)(cid:73)(cid:3)(cid:54)(cid:87)(cid:85)(cid:72)(cid:72)(cid:87)(cid:3)
`(cid:54)(cid:68)(cid:81)(cid:3)(cid:41)(cid:85)(cid:68)(cid:81)(cid:70)(cid:76)(cid:86)(cid:70)(cid:82)(cid:15)(cid:3)(cid:38)(cid:36)(cid:3)(cid:28)(cid:23)(cid:20)(cid:20)(cid:20)(cid:3)
`(cid:55)(cid:72)(cid:79)(cid:72)(cid:83)(cid:75)(cid:82)(cid:81)(cid:72)(cid:29)(cid:3)(cid:23)(cid:20)(cid:24)(cid:16)(cid:22)(cid:25)(cid:21)(cid:16)(cid:25)(cid:25)(cid:25)(cid:25)(cid:3)
`(cid:41)(cid:68)(cid:70)(cid:86)(cid:76)(cid:80)(cid:76)(cid:79)(cid:72)(cid:29)(cid:3)(cid:3)(cid:23)(cid:20)(cid:24)(cid:16)(cid:21)(cid:22)(cid:25)(cid:16)(cid:25)(cid:22)(cid:19)(cid:19)(cid:3)
`
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`(cid:39)(cid:56)(cid:53)(cid:44)(cid:40)(cid:3)(cid:55)(cid:36)(cid:49)(cid:42)(cid:53)(cid:44)(cid:3)(cid:47)(cid:47)(cid:51)(cid:3)
`(cid:28)(cid:24)(cid:22)(cid:3)(cid:40)(cid:68)(cid:86)(cid:87)(cid:3)(cid:22)(cid:85)(cid:71)(cid:3)(cid:54)(cid:87)(cid:85)(cid:72)(cid:72)(cid:87)(cid:3)
`(cid:47)(cid:82)(cid:86)(cid:3)(cid:36)(cid:81)(cid:74)(cid:72)(cid:79)(cid:72)(cid:86)(cid:15)(cid:3)(cid:38)(cid:36)(cid:3)(cid:28)(cid:19)(cid:19)(cid:20)(cid:22)(cid:3)
`(cid:55)(cid:72)(cid:79)(cid:72)(cid:83)(cid:75)(cid:82)(cid:81)(cid:72)(cid:29)(cid:3)(cid:21)(cid:20)(cid:22)(cid:16)(cid:28)(cid:28)(cid:21)(cid:16)(cid:23)(cid:23)(cid:28)(cid:28)(cid:3)
`(cid:41)(cid:68)(cid:70)(cid:86)(cid:76)(cid:80)(cid:76)(cid:79)(cid:72)(cid:29)(cid:3)(cid:3)(cid:23)(cid:20)(cid:24)(cid:16)(cid:21)(cid:22)(cid:25)(cid:16)(cid:25)(cid:22)(cid:19)(cid:19)(cid:3)
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`

`

`Case: 22-1595 Document: 30 Page: 2 Filed: 07/12/2022
`
`Counsel for Plaintiffs-Appellants
`Genentech, Inc. and InterMune, Inc.
`
`July 12, 2022
`
`
`
`Emily L. Rapalino
`Daryl L. Wiesen
`Edwina Clarke
`GOODWIN PROCTER LLP
`100 Northern Ave.
`Boston, MA 02210
`Telephone: 617.570.1000
`Facsimile: 617.523.1231
`
`Counsel for Appellees Sandoz, Inc.
`and LEK Pharmaceuticals D.D.
`
`
`
`
`
`
`
`
`
`
`

`

`Case: 22-1595 Document: 30 Page: 3 Filed: 07/12/2022
`TABLE OF CONTENTS
`
`
`Description
`Date
`03/22/2022 Trial Opinion
`
`04/01/2022
`
`Final Judgment
`
`04/01/2022 Notice of Appeal
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`U.S. Patent 7,566,729
`
`U.S. Patent 7,635,707
`
`U.S. Patent 8,592,462
`
`U.S. Patent 8,609,701
`
`U.S. Patent 7,816,383
`
`U.S. Patent 8,013,002
`
`Docket Sheet
`
`08/26/2020
`
`Joint Claim Construction Brief
`
`10/26/2021 
`
`Joint Proposed Pretrial Order
`
`10/26/2021 
`
`Joint Proposed Pretrial Order, Exhibit 1:
`Joint Statement of Uncontested Facts
`11/30/2021 Transcript of Bench Trial held on
`November 8, 2021
`11/30/2021 Transcript of Bench Trial held on
`November 9, 2021
`11/30/2021 Transcript of Bench Trial held on
`November 10, 2021
`11/30/2021 Transcript of Bench Trial held on
`November 12, 2021
`
`ECF No.
`386
`
`396
`
`397
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`156
`
`343
`
`343-1
`
`370
`
`371
`
`372
`
`373
`
`Appx No..
`Appx1 -
`Appx39
`Appx40 -
`Appx42
`Appx43 -
`Appx46
`Appx49 -
`Appx56
`Appx57 -
`Appx68
`Appx69 -
`Appx80
`Appx81 -
`Appx94
`Appx95 -
`Appx107
`Appx108 -
`Appx120
`Appx121 -
`Appx152
`Appx2023 -
`Appx2091
`Appx5990 -
`Appx6015
`Appx6016 -
`Appx6033
`Appx6936 -
`Appx7226
`Appx7227 -
`Appx7513
`Appx7514 -
`Appx7697
`Appx7698 -
`Appx7784
`
`1
`
`

`

`Case: 22-1595 Document: 30 Page: 4 Filed: 07/12/2022
`TABLE OF CONTENTS
`
`
`Date
`12/15/2021 
`
`Description
`Plaintiffs’ Post-Trial Brief on Infringement
`and Secondary Considerations
`12/15/2021  Defendants’ Post-Trial Opening Brief
`Regarding Invalidity
`01/19/2022  Defendants’ Post-Trial Answering Brief
`Regarding Noninfringement and Secondary
`Considerations
`01/19/2022  Defendants’ Proposed Findings of Fact
`Related to Noninfringement
`04/18/2022 Official Transcript of Hearing regarding
`Plaintiffs’ Emergency Motion for
`Temporary Restraining Order and For
`Injunction Pending Appeal before Judge
`Richard G. Andrews
`Defendants’ Trial Exhibit DTX0027
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`Defendants’ Trial Exhibit DTX0135
`
`Defendants’ Trial Exhibit DTX0142
`
`Defendants’ Trial Exhibit DTX0144
`
`Defendants’ Trial Exhibit DTX0179
`
`Defendants’ Trial Exhibit DTX0263
`
`Joint Trial Exhibit JTX0010
`
`Joint Trial Exhibit JTX0011
`
`Joint Trial Exhibit JTX0017
`
`Joint Trial Exhibit JTX0027
`
`ECF No.
`374
`
`376
`
`380
`
`381
`
`‐‐ 
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`Appx No..
`Appx7785 -
`Appx7809
`Appx7842 -
`Appx7878
`Appx7972 -
`Appx8000
`
`Appx8014 -
`Appx8038
`Appx8118 –
`Appx8152
`
`Appx8153 -
`Appx8161
`Appx8426 -
`Appx8455
`Appx8456 -
`Appx8477
`Appx8478 -
`Appx8503
`Appx9619 –
`Appx9804
`Appx10194 -
`Appx10214
`Appx10400 -
`Appx10675
`Appx10676 -
`Appx11028
`Appx14242 -
`Appx16514
`Appx16515 -
`Appx16535
`
`2
`
`

`

`Case: 22-1595 Document: 30 Page: 5 Filed: 07/12/2022
`TABLE OF CONTENTS
`
`
`Date
`--
`
`Description
`Joint Trial Exhibit JTX0028
`
`ECF No.
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`Joint Trial Exhibit JTX0029
`
`Joint Trial Exhibit JTX0030
`
`Joint Trial Exhibit JTX0031
`
`Joint Trial Exhibit JTX0033
`
`Plaintiffs’ Trial Exhibit PTX0027
`
`Plaintiffs’ Trial Exhibit PTX0032
`
`Plaintiffs’ Trial Exhibit PTX0149
`
`Plaintiffs’ Trial Exhibit PTX0180
`
`Plaintiffs’ Trial Exhibit PTX0195A
`
`Plaintiffs’ Trial Exhibit PTX0234
`
`Plaintiffs’ Trial Exhibit PTX0235
`
`Plaintiffs’ Trial Exhibit PTX0236
`
`Plaintiffs’ Trial Exhibit PTX0241
`
`Plaintiffs’ Trial Exhibit PTX0248
`
`Plaintiffs’ Trial Exhibit PTX0250
`
`Plaintiffs’ Trial Exhibit PTX0304
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`--
`
`Appx No..
`Appx16536 -
`Appx16545
`Appx16546 -
`Appx16555
`Appx16556 -
`Appx16623
`Appx16624 -
`Appx16631
`Appx16687 -
`Appx16718
`Appx16733 -
`Appx16748
`Appx16749 -
`Appx16765
`Appx17011 –
`Appx17036
`Appx18309 -
`Appx18313
`Appx18354 -
`Appx18358
`Appx18363 -
`Appz18566
`Appx18567 -
`Appx18600
`Appx18601 -
`Appx18608
`Appx18609 -
`Appx18688
`Appx18688 -
`Appx18696
`Appx18697 -
`Appx18714
`Appx18748 -
`Appx18757
`
`3
`
`

`

`Case: 22-1595 Document: 30 Page: 6 Filed: 07/12/2022
`TABLE OF CONTENTS
`
`
`Date
`--
`
`Description
`Plaintiffs’ Trial Exhibit PTX0315
`
`ECF No.
`--
`
`--
`
`--
`
`Plaintiffs’ Trial Exhibit PTX0333
`
`Plaintiffs’ Trial Exhibit PTX0363
`
`--
`
`--
`
`Appx No..
`Appx18758 -
`Appx18766
`Appx18804 -
`Appx18808
`Appx18860 -
`Appx19083
`
`
`
`CONFIDENTIAL MATERIAL OMITTED
`The information omitted from Appx18310-18311 and Appx18313 of Plaintiffs’
`Trial Exhibit PTX0180, InterMune CAPACITY DMC Data Review Meeting 1
`Open Session Minutes, was omitted because these pages discuss sensitive, non-
`public business and strategic practices and plans. In the district court, this
`information was designated as containing Genentech Confidential Information
`pursuant to the Protective Order, D.I. 73.
`The information omitted from Appx18382-18386 and Appx18549-18550 of
`Plaintiffs’ Trial Exhibit PTX0234, Type B End-of-Phase 2 Meeting Briefing
`Package (11/9/2004), was omitted because these pages discuss sensitive, non-
`public research and development as well as derivative testing information and
`information regarding new drug applications. In the district court, this information
`was designated as containing Genentech Highly Confidential Information pursuant
`to the Protective Order, D.I. 73.
`The information omitted from Appx9685 and Appx9702-9703 of Defendants’ Trial
`Exhibit DTX0179, InterMune Pirfenidone NDA 22-535 Section 2.7.4 Summary of
`Clinical Safety, was omitted because these pages discuss sensitive non-public
`clinical data, research and development, and derivative testing information. In the
`district court, this information was designated as containing Genentech Highly
`Confidential Information pursuant to the Protective Order, D.I. 73.
`
`
`4
`
`

`

`Case: 22-1595 Document: 30 Page: 7 Filed: 07/12/2022
`
`Case 1:19-cv-00078-RGA Document 386 Filed 03/22/22 Page 1 of 39 PagelD #: 15474
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`GENENTECH, INC. and
`INTERMUNE, INC.,
`
`Plaintiffs,
`
`V.
`
`SANDOZ, INC. and LEK
`PHARMACEUTICALS D.D.,
`
`Defendants.
`
`Civil Action No. 19-0078-RGA
`
`TRIAL OPINION
`
`Jack B. Blumenfeld, Karen Jacobs, Cameron P. Clark, MORRIS NICHOLS ARSHT &
`TUNNELL LLP, Wilmington, DE; Mark E. Waddell, Warren K. MacRae, Ryan Hagglund,
`Kathleen Gersh, LOEB & LOEB LLP, New York, NY; Alexandra Cavazos, Dan Liu, LOEB &
`LOEB LLP, Los Angeles, CA.
`
`Attorneys for Plaintiffs.
`
`Stephen B. Brauerman, BAY ARD, P.A., Wilmington, DE; Emily L. Rapalino, Daryl L. Wiesen,
`Nicholas K. Mitrokostas, Kathleen A. McGuinness, Tiffany Mahmood, Natasha Daughtrey,
`GOODWIN PROCTER LLP, Boston, MA.
`
`Attorneys for Defendants.
`
`March ').i, 2022
`
`1
`
`Appxl
`
`

`

`

`

`Case: 22-1595 Document: 30 Page: 9 Filed: 07/12/2022
`
`Case 1:19-cv-00078-RGA Document 386 Filed 03/22/22 Page 3 of 39 PagelD #: 15476
`
`time. (Tr. 304:1-3). Approximately half of patients "on treatment" for IPF are prescribed
`
`pirfenidone and approximately half are prescribed nintedanib. (Tr. 303:13-16). The maJor
`
`differences between the drugs "center on side effects and metabolism." (Tr. 304:4-6).
`
`Side effects associated with pirfenidone include anorexia, nausea, and photosensitive skin
`
`rash, while nintedanib has been associated with diarrhea and loose stool. (Tr. 304:6-10).
`
`Pirfenidone is primarily metabolized "through the CYPIA2 enzyme pathway" with contributions
`
`from other CYP enzymes, whereas nintedanib has a "completely different" metabolic pathway,
`
`relying primarily on ester cleavage with only "minor metabolism through the CYP3A4 pathway."
`
`(Tr. 304: 11-21 ). Pulmonologists consider a number of factors when deciding which drug to
`
`prescribe to their IPF patients, including the patient's preference/tolerance for each drug's dosing
`
`schedule and side effects and the patient's insurance coverage, as the medications each "cost about
`
`$100,000 a year." (Tr. 305: 1-7).
`
`Pirfenidone was first studied as an "investigational new drug" in 1973 by Affiliated
`
`Medical Research, Inc. (PTX0234 at 51 ). Development rights to pirfenidone were subsequently
`
`transferred to Marnac. (Id.). In 1997, Marnac sold to Shionogi rights to pirfenidone for Japan,
`
`South Korea, and Taiwan "for development in fibrotic indications," and in 2002, Marnac sold to
`
`InterMune rights to pirfenidone for the rest of the world. (Id.). On March 5, 2004, the FDA granted
`
`pirfenidone U.S. "orphan drug" status for the treatment of patients with IPF. (Id.).
`
`At trial, Plaintiffs asserted various claims of six patents directed toward treatment methods
`
`involving pirfenidone: (i) claim 9 of U.S. Patent No. 7,566,729 ("the '729 patent") (JTXOOOl), (ii)
`
`claims 6 and 14 of U.S. Patent No. 7,635,707 ("the '707 patent") (JTX0002), (iii) claims 12 and
`
`28 of U.S. Patent No. 8,592,462 ("the '462 patent") (JTX0003), (iv) claim 19 of U.S. Patent No.
`
`8,609,701 ("the '701 patent") (JTX0004), (v) claim 6 of U.S. Patent No. 7,816,383 ("the '383
`
`3
`
`Appx3
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`patent") (JTX0005), and (vi) claims 3 and 9 of U.S. Patent No. 8,013,002 ("the '002 patent")
`
`(JTX0007) (collectively, the "Asserted Patents" and "Asserted Claims").
`
`The '729, '707, '462, and '701 patents ("the Liver Function Test (LFT) patents") are
`
`directed toward methods "for administering pirfenidone to a patient that has exhibited abnormal
`
`biomarkers of liver function in response to pirfenidone administration." (JTXOOO 1 at 1; JTX0002
`
`at 1; JTX0003 at 1; JTX0004 at 1). The '383 and '002 patents ("the Drug-Drug Interaction (DDI)
`
`patents") are directed toward "methods involving avoiding adverse drug interactions with
`
`fluvoxamine and pirfenidone or other moderate to strong inhibitors of CYP enzymes." (JTX0005
`
`at 1; JTX0007 at 1 ).
`
`A. The LFT Patents
`
`Throughout InterMune's development of pirfenidone, potential hepatotoxicity issues
`
`presented by the drug were "fairly front and center" in its development plan. (Tr. 81 :7-16).
`
`InterMune knew Marnac had observed the development of "liver necrosis" in a patient taking
`
`pirfenidone and Shionogi had observed one patient who exhibited "very severe liver injury" that
`
`met the criteria for "Hy's law" 2 in its Phase II study, in which fewer than one hundred patients
`
`were dosed with pirfenidone. (Tr. 64: 13-23, 66:2-25, 150:3-18). The FDA also expressed concerns
`
`about pirfenidone and potential liver toxicity. (Tr. 65:21-66:9). Following InterMune's "End-of(cid:173)
`
`Phase-2 Meeting" with the FDA in December 2004, the FDA warned InterMune, "Because of the
`
`abnormal liver function tests noted in the Shionogi study, you should consider excluding subjects
`
`2
`"Hy's Law" describes the observation that "hepatocellular injury sufficient to impair
`bilirubin excretion [cause jaundice]" is "ominous." (PTX0149 at 7). The FDA has used Hy's Law
`to "identify drugs likely to be capable of causing severe liver injury." (Id.). The U.S. Department
`of Health and Human Services warns in its "Guidance for Industry" regarding drug-induced liver
`injury ("DILI"), "Finding one Hy's Law case in clinical trials is ominous; finding two is highly
`predictive of a potential for severe DILL" (Id. at 8).
`
`4
`
`Appx4
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`[from your pirfenidone clinical trials] with any significant liver disease." (PTX0235 at 1, 30). In
`
`response to these concerns, InterMune developed a "liver function test management plan" to find
`
`a way to safely allow patients exhibiting signs of abnormal liver function to continue pirfenidone
`
`treatment. (Tr. 81 :7-25).
`
`InterMune's "liver function test management plan" gave rise to the LFT patents, which
`
`relate to "methods for reducing abnormal liver function associated with [pirfenidone] therapy."
`
`(JTXOOOl at 2; JTX0002 at 2; JTX0003 at 3; JTX0004 at 4). "Abnormal liver function may
`
`manifest as abnormalities in levels ofbiomarkers ofliver function, including alanine transaminase
`
`["ALT"], aspartate transaminase ["AST"], bilirubin, and/or alkaline phosphatase, and may be an
`
`indicator of drug-induced liver injury." (JTXOOOl at 2). Liver function tests are graded in order of
`
`severity, with a "Grade 2" being "a severity range where the enzymes are typically two and a half
`
`to five times the upper limit of the normal range." (Tr. 85:10-15).
`
`The Asserted Claims of the LFT patents disclose methods for responding to a Grade 2
`
`abnormality in liver function biomarkers (specifically, ALT and AST) in a patient taking
`
`pirfenidone to treat IPF by doing one of the following: (1) temporarily reducing the dose of
`
`pirfenidone and then returning to the full dose (2400 mg/day or 2403 mg/day), 3 (2) maintaining
`
`the full dose of pirfenidone (2400 mg/day or 2403 mg/day), (3) reducing the dose of pirfenidone
`
`to 1600 mg/day or 1602 mg/day, (4) discontinuing pirfenidone "for about a week" and then
`
`returning to the full dose, (5) discontinuing pirfenidone "for about a week" and then returning to a
`
`dose of "at least 1600 mg/day," or (6) reducing the dose of pirfenidone to "at least 1600 mg/day
`
`or 1602 mg/day."
`
`3
`
`"The exact dose of 2,403 milligrams per day was chosen based on the capsule size, which
`was 267 milligrams, which was designed to permit thrice daily dosing with a number of capsules
`that fostered simple dose modifications, if necessary." (Tr. 284: 13-17 (Samuels)).
`
`5
`
`Appx5
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`Claim 9 of the '729 patent is a dependent claim of unasserted independent claim 1,
`
`disclosing, "The method of claim 1, wherein said one or more biomarkers of liver function
`
`comprise alanine transaminase and aspartate transaminase." (JTXOOOl at 7). Claim 1 of the '729
`
`patent discloses:
`
`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.
`
`(Id).
`
`Claim 6 of the '707 patent is a dependent claim of unasserted independent claim 1,
`
`disclosing, "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." (JTX0002
`
`at 10). Claim 1 of the '707 patent discloses:
`
`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.
`
`(Id).
`
`Claim 14 of the '707 patent is a dependent claim of unasserted independent claim 7,
`
`disclosing, "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." (Id at 11).
`
`Claim 7 of the '707 patent discloses:
`
`A method of administering pirfenidone to treat a patient with idiopathic
`pulmonary fibrosis (IPF), said patient having exhibited a grade 2
`
`6
`
`Appx6
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`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.
`
`(Id at 10).
`
`Claim 12 of the '462 patent is a dependent claim of unasserted dependent claim 3,
`
`disclosing, "The method of claim 3 further comprising, prior to step (a), discontinuing the first
`
`administration of pirfenidone for about a week, or until biomarkers of liver function are within
`
`normal limits." (JTX0003 at 12). Claim 3 of the '462 patent is a dependent claim of unasserted
`
`independent claim 1, disclosing, "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." (Id at 11). Claim 1
`
`of the '462 patent discloses:
`
`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.
`
`(Id).
`
`Claim 28 of the '462 patent is a dependent claim of unasserted independent claim 26,
`
`disclosing, "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." (Id at 12). Claim 26 of the '462 patent discloses:
`
`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.
`
`(Id).
`
`7
`
`Appx7
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`Claim 19 of the '701 patent is a dependent claim of unasserted independent claim 1,
`
`disclosing, "The method of claim 1, wherein the patient suffers from idiopathic pulmonary
`
`fibrosis." (JTX0004 at 13). Claim I of the '701 patent discloses:
`
`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 pirf enidone 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.
`
`(Id. at 12).
`
`B. The DDI Patents
`
`In 2008, InterMune conducted a study to examine the "effect of fluvoxamine as a strong
`
`CYPIA2 inhibitor on the [pharmacokinetics] of Pirfenidone." (Tr. 109:9-14). CYP1A2 is a
`
`member of the cytochrome P-450 system, which comprises a group of"enzymes that are involved
`
`in the metabolism of drugs and, in this case, Pirfenidone." (Tr. I 09: 15-18). "[T]he metabolism of
`
`Pirfenidone is heavily mediated through the CYP1A2 enzyme pathway ... but there are
`
`contributions from other CYP enzymes as well." (Tr. 304:13-16). Normally, when pirfenidone
`
`enters a patient's body, it is "metabolized or broken down" by enzymes, such as the CYP1A2
`
`enzyme. (Tr. 329:14-21). CYP inhibitors can interfere with normal drug metabolism by inhibiting
`
`the CYP enzymes' ability to metabolize the drug, resulting in "supratherapeutic" levels of un(cid:173)
`
`metabolized drug in the body. (Tr. 329: 14-330:6). This can cause "adverse events all throughout
`
`the body," especially when the drug is toxic in its unmetabolized form. (Id.). Fluvoxamine is well(cid:173)
`
`known as "a strong CYP1A2 inhibitor." (PTX0241 at 3).
`
`Nintedanib, which is metabolized primarily via ester cleavage, is not susceptible to drug(cid:173)
`
`drug interaction with CYP1A2 inhibitors. (Tr. 330:12-17). Pirfenidone, however, is highly
`
`susceptible to drug-drug interaction with CYP1A2 inhibitors. (Tr. 329:5-330:3). InterMune first
`
`8
`
`Appx8
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`discovered this in its 2008 study, finding "the blood concentrations of Pirfenidone on average went
`
`up six times, sixfold, in patients that were on - in subjects that were on fluvoxamine. So that's a
`
`very substantial drug-drug interaction, particularly in the context of Pirfenidone." (Tr. 110: 19-23 ).
`
`Because pirfenidone "is a drug with a lot of toxicities," InterMune understood that "to have a
`
`situation where the concentrations in the blood go up six times is almost certainly going to be a
`
`problem for patients." (Tr. 110:24-111 :2). This discovery gave rise to the DDI patents, which
`
`"relate[] to methods involving avoiding adverse drug interactions with fluvoxamine and
`
`pirfenidone or other moderate to strong inhibitors of CYP enzymes." (JTX0005 at 1; JTX0007 at
`
`1 ).
`
`Claim 6 of the '383 patent is a dependent claim of unasserted independent claim 5,
`
`disclosing, "The method of claim 5, wherein the patient has idiopathic pulmonary fibrosis (IPF)."
`
`(JTX0005 at 13). Claim 5 of the '383 patent discloses:
`
`A method of administering pirfenidone therapy to a patient in need thereof,
`comprising first discontinuing administration of fluvoxarnine to avoid an
`adverse drug interaction with pirfenidone, and then administering to the
`patient a therapeutically effective amount of pirfenidone.
`
`(Id).
`
`Claim 3 of the '002 patent is a dependent claim ofunasserted dependent claim 2, disclosing,
`
`"The method of claim 2 wherein the patient has idiopathic pulmonary fibrosis (IPF)." (JTX0007
`
`at 13). Claim 2 of the '002 patent is a dependent claim of unasserted independent claim 1,
`
`disclosing, "The method of claim 1 wherein the pirfenidone is administered three times per day."
`
`(Id). Claim 1 of the '002 patent discloses:
`
`A method of administering pirfenidone and fluvoxamine concurrently to a
`patient in need thereof comprising administering a therapeutically effective
`amount of pirfenidone to the patient, wherein the amount of the pirfenidone
`is about 801 mg/day.
`
`(Id).
`
`9
`
`Appx9
`
`

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`
`Claim 9 of the '002 patent is a dependent claim of unasserted dependent claim 8, disclosing,
`
`"The method of claim 8 wherein the patient has idiopathic pulmonary fibrosis (IPF)." (Jd. ). Claim
`
`8 of the '002 patent is a dependent claim of unasserted independent claim 6, disclosing, "The
`
`method of claim 6 wherein the pirfenidone is administered three times per day." (Id). Claim 6 of
`
`the '002 patent discloses:
`
`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 with
`fluvoxamine, wherein the dose of pirfenidone is reduced by about 1600
`mg/day.
`
`(Id).
`
`II.
`
`LEGAL ST AND ARD
`
`A. Infringement
`
`A patent is directly infringed when a person "without authority makes, uses, offers to sell,
`
`or sells any patented invention, within the United States . . . during the term of the patent .... "
`
`35 U.S.C. § 271(a). A two-step analysis is employed in making an infringement determination.
`
`See Markman v. Westview Instruments, Inc., 52 F.3d 967, 976 (Fed. Cir. 1995) (en bane), aff'd,
`
`517 U.S. 370 (1996). First, the court must construe the asserted claims to ascertain their meaning
`
`and scope. See id. The trier of fact must then compare the properly construed claims with the
`
`accused infringing product. See id. at 976. This second step is a question of fact. See Bai v. L &
`
`L Wings, Inc., 160 F.3d 1350, 1353 (Fed. Cir. 1998).
`
`"Under § 271 (b ), whoever actively induces infringement of a patent shall be liable as an
`
`infringer." Warner-Lambert Co. v. Apotex Corp., 316 F.3d 1348, 1363 (Fed. Cir. 2003). To prevail
`
`on a theory of induced infringement, a plaintiff must prove (1) direct infringement and (2) "that
`
`the defendant possessed specific intent to encourage another's infringement and not merely that
`
`the defendant had knowledge of the acts alleged to constitute infringement." Vanda Pharm. Inc. v.
`
`10
`
`AppxlO
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`
`West-Ward Pharm. Int'! Ltd., 887 F.3d 1117, 1129 (Fed. Cir. 2019) (quoting DSU Med. Corp. v.
`
`JMA Co., 471 F.3d 1293, 1306 (Fed. Cir. 2006)).
`
`In a Hatch-Waxman case, a plaintiff "can satisfy its burden to prove the predicate direct
`
`infringement by showing that if the proposed ANDA product were marketed, it would infringe the
`
`[asserted patent]." Vanda, 887 F.3d at 1130. For method-of-treatment patents, if an ANDA
`
`applicant's "proposed label instructs users to perform the patented method ... , the proposed label
`
`may provide evidence of [the ANDA applicant's] affirmative intent to induce infringement."
`
`AstraZeneca LP v. Apotex, Inc., 633 F.3d 1042, 1060 (Fed. Cir. 2010). "When proof of specific
`
`intent depends on the label accompanying the marketing of a drug inducing infringement by
`
`physicians, the label must encourage, recommend, or promote infringement." V