Genentech, Inc. v. Sandoz Inc.

55 F.4th 1368

GENENTECH, INC., InterMune, Inc., Plaintiffs-Appellants

v.SANDOZ INC., Lek Pharmaceuticals, D.D., Defendants-Appellees

2022-1595

United States Court of Appeals, Federal Circuit.

Decided: December 22, 2022

Daralyn Jeannine Durie, Durie Tangri LLP, San Francisco, CA, argued for plaintiffs-appellants. Also represented by Kathleen Gersh, Ryan Neil Hagglund, Warren K. MacRae, Mark Edward Waddell, Loeb & Loeb LLP, New York, NY; Dan Liu, Los Angeles, CA.

William M. Jay, Goodwin Procter LLP, Washington, DC, argued for defendants-appellees. Also represented by Edwina Clarke, Emily L. Rapalino, Daryl L. Wiesen, Boston, MA; Natasha Elise Daughtrey, Los Angeles, CA.

Before Newman, Lourie, and Prost, Circuit Judges.

Circuit Judge Newman dissents without opinion.

Lourie, Circuit Judge.

Genentech, Inc. and InterMune, Inc. (collectively, "Genentech") appeal from a decision of the United States District Court for the District of Delaware holding that: (1) the claims of its Liver Function Test ("LFT") patents¹ are unpatentable as obvious, (2) sale of Sandoz Inc.'s and Lek Pharmaceuticals, D.D.'s (collectively, "Sandoz's") generic product would not induce infringement of the LFT patents, and (3) sale of Sandoz's generic product would not directly infringe Genentech's Drug-Drug Interaction ("DDI") patents.² See Genentech, Inc. v. Sandoz, Inc. , 592 F.Supp.3d 355 (D. Del. 2022) (" Decision "). We affirm.

BACKGROUND

Pirfenidone is a drug used to treat idiopathic pulmonary fibrosis ("IPF"). IPF is a chronic, irreversible lung disease. There is no cure for IPF and patients living with the disease face an average survival of two to five years. There are currently two drugs that have been approved by the FDA for the treatment of IPF, pirfenidone and nintedanib. Approximately half of the patients on treatment for IPF are prescribed pirfenidone, and the other half are prescribed nintedanib. The major differences between the drugs center on side effects and metabolism.

Pirfenidone was first studied as an investigational new drug in 1973. Development rights to pirfenidone were sold to Shionogi for Japan, South Korea, and Taiwan, and to InterMune for the rest of the world. In 2004, the United States Food and Drug Administration ("FDA") granted pirfenidone orphan drug status for treatment of patients with IPF. In 2014, pirfenidone was approved to treat IPF in the U.S. as Esbriet^®, sold by Genentech.

Sandoz submitted two Abbreviated New Drug Applications ("ANDAs") seeking approval from the FDA to market a generic version of pirfenidone. Genentech then brought this Hatch-Waxman suit, asserting that Sandoz's generic product would induce the infringement of its LFT and DDI patents. The asserted patents do not claim pirfenidone itself, or the use of pirfenidone to treat IPF. Instead, the patents claim methods for managing certain side effects when using pirfenidone to treat IPF.

I. LFT Patents

The LFT patents are directed to methods for administering pirfenidone to a patient who has exhibited abnormal biomarkers of liver function in response to pirfenidone administration. The asserted claims in these patents recite various options, including: (1) temporarily reducing the dose of pirfenidone and then returning to the full dose, (2) maintaining the full dose of pirfenidone, (3) reducing the dose of pirfenidone, (4) discontinuing pirfenidone for a week and then returning to the full dose, and (5) discontinuing pirfenidone for a week and then returning to a reduced dose.

The claims of particular interest in this appeal are dependent claims. Therefore, for ease of understanding, we incorporate the parent claims into the claims that are asserted. The distinctions between the specific claims are not argued, so we recite the asserted claims as a group.

Asserted claim 9 of the '729 patent reads as follows:

The method of claim 1 [administering pirfenidone to treat a patient with 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 ], wherein said one or more biomarkers of liver function comprise alanine transaminase and aspartate transaminase.

'729 patent at col. 12 ll. 13–20, 48–50.

Asserted claim 6 of the '707 patent recites:

The method of claim 1 [administering pirfenidone to treat a patient with IPF, said patient having exhibited a grade 2 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 ], wherein said one or more biomarkers of liver function is selected from the group consisting of alanine transaminase and aspartate transaminase.

'707 patent at col. 18 ll. 24–29, 42–44.

Asserted claim 14 of the '707 patent recites:

The method of claim 7 [administering pirfenidone to treat a patient with IPF, said patient having exhibited a grade 2 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 ], wherein said one or more biomarkers of liver function is selected from the group consisting of alanine transaminase and aspartate transaminase.

Id. at col. 18 ll. 45–50, col. 20 ll. 1–3.

Asserted claim 12 of the '462 patent recites:

The method of claim 3 [administering pirfenidone to treat a patient with IPF, said patient having exhibited an increase of about 2.5-fold to about 5-fold, compared to the upper limit of normal, in one or both of alanine transaminase and aspartate transaminase 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, wherein step (a) comprises administering to said patient pirfenidone at a dose of about 2400 mg/day or 2403 mg/day ] further comprising, prior to step (a), discontinuing the first administration of pirfenidone for about a week, or until biomarkers of liver function are within normal limits.

'462 patent at col. 18 ll. 51–59, col. 19 ll. 33–36.

Asserted claim 28 of the '462 patent recites:

The method of claim 26 [administering pirfenidone to treat a patient with IPF, said patient having exhibited a Grade 2 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 ] 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 col. 20 ll. 35–42, 48–51.

Lastly, asserted claim 19 of the '701 patent recites:

The method of claim 1 [treating a patient in need of pirfenidone and suffering from a Grade 2 abnormality in a liver function 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 ] wherein the patient suffers from idiopathic pulmonary fibrosis.

'701 patent at col. 18 ll. 33–41, col. 20 ll. 18–19.

Sandoz's proposed label includes, under the sub-heading "Dosage Modification due to Elevated Liver Enzymes," the following guidance for patients exhibiting Grade 2 liver enzyme elevations, depending upon whether they are asymptomatic or symptomatic:

Dosage modifications or interruptions may also be necessary when liver enzyme and bilirubin elevations are exhibited. For liver enzyme elevations, modify the dosage as follows:

If a patient exhibits >3 but =5 x the upper limit of normal (ULN) ALT and/or AST without symptoms or hyperbilirubinemia after starting pirfenidone tablets therapy:

• Discontinue confounding medications, exclude other causes, and monitor the patient closely.

• Repeat liver chemistry tests as clinically indicated.

• The full daily 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 dosage as tolerated.

J.A. 16750 (emphasis added).

The parties agree that Sandoz's label recommends using pirfenidone for the treatment of IPF and includes treatment instructions for patients exhibiting Grade 2 elevations in ALT and/or AST. The parties disagree over whether the third bullet point from the asymptomatic Grade 2 elevations sub-section induces use of any of the doses recited in the asserted claims.

At the district court, Sandoz alleged that (1) the LFT asserted claims would have been obvious over Azuma,³ the Pirespa^® label,⁴ and known, standard medical practices; and (2) there was no specific intent for induced infringement.

Azuma reports on a pirfenidone clinical trial and states that "[f]or [patients experiencing] an adverse event of Grade 2 or worse," "the dosage of [pirfenidone] was reduced in a stepwise manner" for as long as symptoms persisted. J.A. 16626. Azuma adds that "[w]hen the adverse event of Grade 2 or worse persisted or increased despite reducing the dosage ... [pirfenidone] was discontinued." Id. Azuma also lists "[e]levation of [AST]" among the "adverse events" observed in study patients. J.A. 16629.⁵

The Pirespa^® label discloses a pirfenidone tablet for the treatment of IPF. Section 3(1) of the label states that "hepatic function disorders accompanied by increased AST (GOT), ALT (GPT), etc. and jaundice may occur and result in hepatic failure." J.A. 16551. The label...