Genentech, Inc. v. Sandoz, Inc.
| Decision Date | 22 March 2022 |
| Docket Number | Civil Action No. 19-0078-RGA |
| Citation | 592 F.Supp.3d 355 |
| Parties | GENENTECH, INC. and InterMune, Inc., Plaintiffs, v. SANDOZ, INC. and Lek Pharmaceuticals D.D., Defendants. |
| Court | U.S. District Court — District of Delaware |
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, BAYARD, 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.
TRIAL OPINION
Plaintiffs brought this patent infringement action on January 14, 2019, alleging Defendants’ submission of Abbreviated New Drug Applications ("ANDAs") seeking approval from the FDA to market a generic version of Plaintiffs’ drug Esbriet® (pirfenidone), infringed several of its patents. (D.I. 1). Plaintiffs asserted six patents at the bench trial, which began on November 8, 2021. There were three days of testimony (D.I. 370, 371, 372, hereinafter referred to as "Tr."), closing argument (D.I. 373), and both parties submitted post-trial briefing and proposed findings of fact regarding infringement and invalidity. (D.I. 374, 375, 376, 377, 378, 379, 380, 381, 382, 383). My findings of fact and conclusions of law follow. See Fed. R. Civ. P. 52(a).
This action arises from Defendants ("Sandoz")1 filing ANDA Nos. 212600 and 212560 seeking to market 267 mg pirfenidone capsules and 267 mg and 801 mg pirfenidone tablets prior to the expiration of Plaintiffs’ patents. (D.I. 343-1 ¶¶ 1, 24-33).
Pirfenidone is a drug used to treat idiopathic pulmonary fibrosis
("IPF"). IPF is a chronic, irreversible, and devastating lung disease. (Tr. 49:9-14). The disease is characterized by scarring (fibrosis) of the network of tissue that supports the air sacs of the lungs, resulting in severe difficulty breathing and progressive impairment of a patient's ability to perform everyday activities. (Tr. 49:15-50:13). There is no cure for IPF and patients living with the disease face an average survival of two to five years. (Tr. 49:11-14, 302:16-17). There are currently two drugs that have been approved by the FDA for the treatment of IPF, pirfenidone and nintedanib. (Tr. 303:10-12). Both drugs have been proven to slow the rate of decline in lung function by about 50% over 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 CYP1A2 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") (JTX0001), (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 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." (JTX0001 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).
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-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 [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." (JTX0001 at 2; JTX0002 at 2; JTX0003 at 3; JTX0004 at 4). "Abnormal liver function may manifest as abnormalities in levels of biomarkers of liver function, including alanine transaminase ["ALT"], aspartate transaminase ["AST"], bilirubin, and/or alkaline phosphatase, and may be an indicator of drug-induced liver injury." (JTX0001 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."
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." (JTX0001 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 abnormality in one or more biomarkers of liver function after pirfenidone administration, comprising (a)...
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