On Mar. 22, 2022, Delaware court found method of use patents non-infringing in Hatch-Waxman case.

 

Plaintiffs (Genentech/Intermune) sued Defendant (Sandoz/Lek pharma) as defendants filed ANDAs for tablet & capsule dosage forms to market a generic version of Plaintiffs’ drug Esbriet® (pirfenidone). The drug is used to treat idiopathic pulmonary fibrosis (“IPF”). Plaintiffs asserted various claims of 6 patents directed toward treatment methods involving pirfenidone. The 7,566,729; 7,635,707; 8,592,462; and 8,609,701 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.” The 7,816,383 and 8,013,002 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.”

 

LFT patents:

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), (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 ofpirfenidone to “at least 1600 mg/day or 1602 mg/day.”

 

Infringement:

Each method disclosed in the Asserted Claims of the LFT patents has three limitations: (1) pirfenidone administration for the treatment of IPF, (2) a patient having exhibited a Grade 2 elevation in one or more biomarkers of liver function (specifically, ALT and/or AST) following pirfenidone administration, and (3) a dose “modification.  Sandoz’s proposed label includes guidance for patients, under the sub-heading “Dosage Modification due to Elevated Liver Enzymes,” depending upon whether they are asymptomatic or symptomatic. 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. But the parties disagree over third element whether Sandoz’s label “encourages, recommends, or promotes” any of the dose modifications disclosed in the Asserted Claims. Sandoz label presents five options: (1) maintaining the dose, (2) reducing the dose, (3) reducing the dose followed by re-titration to the full dose as tolerated, (4) indefinitely/permanently interrupting/discontinuing the dose, and (5) interrupting the dose followed by re-titration to the full dose as tolerated. Four of the five dose modification options provided in the Asymptomatic Section are covered by the Asserted Claims. The only option ‘permanent discontinuation’ of pirfenidone, are not covered by any of the Asserted Claims.

 

Court agreed with Sandoz and said that while the Asymptomatic Section lists some dose modifications covered by the Asserted Claims as potential treatment options, it does not affirmatively recommend any of them. There is a clear contrast between the directive language used in the first two bullet points and the permissive language used in the third bullet point. The use of “may” shows that it merely presents options. Indeed, it describes multiple options, to wit, maintaining, reducing, interrupting, or discontinuing. “Merely describing an infringing mode is not the same as recommending, encouraging, or promoting an infringing use, or suggesting that an infringing use ‘should’ be performed.” [Takeda Pharms. US.A., Inc. v. West-Ward Pharm. (Fed. Cir. 2015)]. Second, the proposed label does affirmatively recommend some dose modifications for patients exhibiting Grade 2 ALT/AST elevations, but they are non-infringing modifications.

 

Invalidity:

Sandoz argues that each of the LFT patent claims is invalid for obviousness under 3 5 U.S. C. § 103 in view of Azuma and optionally the Pirespa Label. Court agreed with Sandoz and held that at the priority date, a POSA would have known that pirfenidone had efficacy for the treatment of IPF. Also the specific dose modifications claimed in the LFT patents would have been obvious over the disclosures of the Azuma Article and the Pirespa Label, combined with known, standard medical practices. Both the Azuma Article and the Pirespa Label expressly disclose continuing pirfenidone administration in patients exhibiting elevated liver enzymes. The evidence at trial showed it was well-known in the art that continuation of drug administration generally in patients with elevated liver enzymes was feasible, potentially following a temporary reduction or interruption in dosage. The 2008 Pirfenidone Report confirms that, although ALT increases were observed in seventeen patients during Shionogi’ s Phase III study, increased ALT and/or AST values resulted in discontinuation of the study medication in only three patients. And finally, the dose adjustment protocols for managing liver enzyme elevations disclosed in the Azuma Article and Pirespa Label were consistent with standard medical practice as of the priority date. At that time, dose reductions, interruptions, and rechallenging were well-known strategies for treating patients exhibiting Grade 2 elevations of liver enzymes with other drugs. Based on these disclosures in the prior art, a POSA would have had a reasonable expectation of success in continuing to treat patients exhibiting Grade 2 liver enzyme elevations with pirfenidone.

 

The DDI Patents:

These patents relate to methods involving avoiding adverse drug interactions with fluvoxarnine and pirfenidone by discontinuing the fluvoxarnine or reducing the dose of pirfenidone. The Asserted Claims of the DDI patents have the following limitations: (1) a patient being treated with pirfenidone for IPF, (2) the patient also being treated with fluvoxarnine during or immediately prior to pirfenidone treatment, and (3) a dose modification.

 

Infringement:

Sandoz’s proposed label warns about potential drug-drug interactions with fluvoxamine in few places and suggests discontinuation or dose  modification. Court agreed with Sandoz that Plaintiffs have failed to prove direct infringement, a prerequisite for a finding of induced infringement. Direct infringement of the DDI patents requires that a patient either take fluvoxamine and pirfenidone concurrently or stop fluvoxamine treatment in order to begin pirfenidone treatment. There was no evidence at trial of any patient receiving pirfenidone after being prescribed
fluvoxamine, or of any patient taking fluvoxamine and pirfenidone concurrently. In fact, all three medical experts testified that in the seven years pirfenidone has been available for treatment of IPF in the United States, none of them has had a single patient receive fluvoxamine before taking pirfenidone or receive both concurrently. Moreover, even if it were more likely than not that there would be a patient who is prescribed both pirfenidone and fluvoxarnine, Plaintiffs have not proven that infringement of the Asserted Claims would likely ensue.

 

Invalidity:

Sandoz argues that each of these claims is invalid for obviousness under 35 U.S.C. § 103 in view of the combination of the Pirespa Label, 2008 Pirfenidone Report, the Luvox [fluvoxamine] Label, and either the ‘ 644 Publication or the FDA DDI Guidance. Court, however, said that Sandoz has not proven, by clear and convincing evidence, that a POSA would have expected to find a significant drug-drug interaction between pirfenidone and fluvoxamine. Court said that while the Pirespa Label disclosed the five CYP enzymes (CYP1A2, 2C9, 2C19, 2D6, and 2E1) responsible for the metabolism of pirfenidone, prior to Plaintiffs’ discovery, it was not known which of these enzymes, if any, was primarily responsible for pirfenidone’ s metabolism. The 2008 Pirfenidone Report also taught that pirfenidone was not susceptible to drug-drug interactions. Therefore, the language in the Pirespa Label and the 2008 Pirfenidone Report expressly teaching pirfenidone is not susceptible to CYP inhibition by concomitant drugs. Thus, Sandoz has not proven by clear and convincing evidence that a POSA would have expected to find a drug-drug interaction between pirfenidone and fluvoxamine.