DCT

1:19-cv-00219

Genentech Inc v. Invagen Pharma Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:19-cv-00219, D. Del., 02/01/2019
  • Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant InvaGen Inc. consented to jurisdiction and venue, Defendant Cipla USA is a Delaware corporation, and Defendant Cipla Limited is a foreign corporation subject to suit in any judicial district.
  • Core Dispute: Plaintiffs allege that Defendants' submission of an Abbreviated New Drug Application (ANDA) to the FDA for approval to market generic pirfenidone tablets constitutes an act of infringement of seventeen U.S. patents related to Plaintiffs' branded drug, Esbriet®.
  • Technical Context: The dispute concerns pirfenidone, the active ingredient in the drug Esbriet®, which is approved for the treatment of Idiopathic Pulmonary Fibrosis (IPF), a rare, progressive, and fatal lung disease for which there is no cure.
  • Key Procedural History: This Hatch-Waxman action was initiated after Defendant InvaGen notified Plaintiffs via a letter dated December 21, 2018, that it had filed ANDA No. 212679 seeking to market a generic version of Esbriet®. The notice included a Paragraph IV Certification asserting that the patents-in-suit are invalid, unenforceable, and/or will not be infringed by the proposed generic product.

Case Timeline

Date Event
2005-09-22 Earliest Priority Date for ’150 Patent
2006-12-18 Earliest Priority Date for ’700, ’383, ’610, ’002, ’780, ’674, ’947 Patents
2008-11-10 Earliest Priority Date for ’729, ’707, ’462, ’701 Patents
2009-07-28 Issue Date for ’729 Patent
2009-12-04 Earliest Priority Date for ’475, ’098, ’109 Patents
2009-12-22 Issue Date for ’707 Patent
2010-08-03 Issue Date for ’700 Patent
2010-10-19 Issue Date for ’383 Patent
2011-03-22 Issue Date for ’610 Patent
2011-09-06 Issue Date for ’002 Patent
2011-12-27 Issue Date for ’475 Patent
2012-11-27 Issue Date for ’780 Patent
2013-02-26 Issue Date for ’150 Patent
2013-04-16 Issue Date for ’674 Patent
2013-11-26 Issue Date for ’462 Patent
2013-12-17 Issue Date for ’701 Patent
2014-02-11 Issue Date for ’098 Patent
2014-06-17 Issue Date for ’109 Patent
2014-07-15 Issue Date for ’947 Patent
2014-10-15 FDA approval for Plaintiffs' Esbriet® NDA
2018-12-21 Date of Defendants' Notice Letter to Plaintiffs
2019-02-01 Complaint Filing Date

II. Technology and Patent(s)-in-Suit Analysis

U.S. Patent No. 7,566,729 - "Modifying Pirfenidone Treatment for Patients with Atypical Liver Function" (issued July 28, 2009) (’729 Patent)

The Invention Explained

  • Problem Addressed: The patent describes that pirfenidone therapy for conditions like Idiopathic Pulmonary Fibrosis (IPF) can be associated with adverse effects, including abnormal liver function, which may be an indicator of drug-induced liver injury (Compl. Ex. 1, '729 Patent, col. 1:59-2:2). The technical challenge is managing this potential hepatotoxicity to allow patients to continue receiving beneficial treatment.
  • The Patented Solution: The invention provides specific methods for modifying pirfenidone treatment after a patient exhibits abnormal biomarkers of liver function (Compl. Ex. 1, ’729 Patent, col. 2:7-14). The solution involves a protocol of dose reduction or temporary discontinuation until liver function biomarkers return to a safer level, followed by a re-escalation of the dose back to the full therapeutic target, thereby allowing continued therapy while managing the adverse event (Compl. Ex. 1, ’729 Patent, col. 2:14-21).
  • Technical Importance: This dose-modification regimen provides a structured, proactive approach to managing a serious side effect, potentially enabling patients to remain on a therapy for an otherwise fatal disease.

Key Claims at a Glance

  • The complaint asserts at least one claim of the patent (Compl. ¶71). Independent claim 1 is central to the invention.
  • Claim 1 of the ’729 Patent includes the following essential elements:
    • A method of administering pirfenidone to treat a patient with IPF.
    • The patient has exhibited a grade 2 abnormality in one or more biomarkers of liver function after pirfenidone administration.
    • Administering pirfenidone at doses lower than 2400 mg/day for a time period.
    • Followed by administering pirfenidone at doses of 2400 mg/day or 2403 mg/day.
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent, but makes a general allegation against at least one claim (Compl. ¶71).

U.S. Patent No. 7,635,707 - "Pirfenidone Treatment for Patients with Atypical Liver Function" (issued December 22, 2009) (’707 Patent)

The Invention Explained

  • Problem Addressed: Similar to the ’729 Patent, this patent addresses the technical problem of managing abnormal liver function that can arise during pirfenidone therapy (Compl. Ex. 2, ’707 Patent, col. 1:12-2:2).
  • The Patented Solution: The invention provides methods for treating a patient who has exhibited a Grade 2 liver function abnormality. One patented solution is to continue administering the full target dose of pirfenidone (e.g., 2403 mg/day) without temporarily discontinuing or reducing the dose, while continuing to monitor the patient's liver function biomarkers (Compl. Ex. 2, ’707 Patent, col. 2:35-43). This provides an alternative management strategy to the dose reduction protocol of the ’729 Patent.
  • Technical Importance: This method offers clinicians an alternative protocol for managing moderate liver function abnormalities that may allow for uninterrupted delivery of the full therapeutic dose.

Key Claims at a Glance

  • The complaint asserts at least one claim of the patent (Compl. ¶82). Independent claim 1 is representative.
  • Claim 1 of the ’707 Patent includes the following essential elements:
    • A method of administering pirfenidone to treat a patient with IPF.
    • The patient has exhibited a grade 2 abnormality in one or more biomarkers of liver function after pirfenidone administration.
    • Administering to said patient pirfenidone at doses of 2400 mg/day or 2403 mg/day.
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent (Compl. ¶82).

Multi-Patent Capsule: U.S. Patent No. 7,767,700

  • Patent Identification: U.S. Patent No. 7,767,700, "Method of Providing Pirfenidone Therapy to a Patient," issued August 3, 2010 (’700 Patent).
  • Technology Synopsis: The patent addresses the need to minimize adverse events associated with pirfenidone therapy, such as gastrointestinal upset and dizziness (Compl. Ex. 3, ’700 Patent, col. 1:63-2:4). The invention provides a dose-escalation scheme over an initial period (e.g., 15 days) to allow a patient to develop tolerance before reaching the full therapeutic dosage, thereby reducing the incidence of side effects (Compl. Ex. 3, ’700 Patent, col. 2:40-52).
  • Asserted Claims: Claims 1-4, 7-10, 13-16, and 19 (Compl. ¶91, 93). Independent claims are 1, 7, 13, and 19.
  • Accused Features: The proposed generic product and its associated labeling, which will allegedly instruct users to follow the patented dose-escalation method (Compl. ¶95).

Multi-Patent Capsule: U.S. Patent No. 8,383,150

  • Patent Identification: U.S. Patent No. 8,383,150, "Granulate Formulation of Pirfenidone and Pharmaceutically Acceptable Excipients," issued February 26, 2013 (’150 Patent).
  • Technology Synopsis: This patent addresses the need for effective pharmaceutical formulations of pirfenidone that elicit desirable pharmacokinetic responses in patients (Compl. Ex. 9, ’150 Patent, col. 2:9-15). The invention is directed to a capsule formulation of pirfenidone that includes specific excipients (such as disintegrators, binders, and fillers) which are claimed to sustain desirable pharmacokinetic responses (Compl. Ex. 9, ’150 Patent, col. 2:16-30).
  • Asserted Claims: Claims 1 and 27 (Compl. ¶157).
  • Accused Features: The formulation of Defendants' proposed generic pirfenidone tablets, which are alleged to be bioequivalent to Plaintiffs' Esbriet® tablets and thus practice the claimed formulation (Compl. ¶65, 157).

The complaint lists thirteen additional patents-in-suit. These patents are generally directed to further methods of administering pirfenidone therapy, including methods for managing interactions with other drugs (e.g., cytochrome P450 inducers) and additional protocols for managing atypical liver function. For each, the complaint alleges infringement based on the Defendants' ANDA submission and the future manufacture, use, and sale of the generic product in accordance with its proposed labeling (Compl. ¶¶101-155, 165-230).

III. The Accused Instrumentality

Product Identification

The accused instrumentality is the "InvaGen ANDA Product," which consists of proposed generic pirfenidone tablets in 267 mg and 801 mg dosage strengths (Compl. ¶1, 9). The act of infringement is Defendants' submission of ANDA No. 212679 to the FDA seeking approval to market this product (Compl. ¶1).

Functionality and Market Context

The complaint alleges that by filing the ANDA, Defendants have represented that their proposed generic product will have the same active ingredient (pirfenidone), route of administration, dosage form, and dosage strengths as Plaintiffs' FDA-approved Esbriet® tablets (Compl. ¶65). It is further alleged that the proposed product will be bioequivalent to Esbriet® and that its proposed labeling will instruct users to administer it for the same approved uses, namely the treatment of IPF (Compl. ¶1, 65). The commercial context is the introduction of a generic competitor to a branded drug that treats a rare and fatal disease (Compl. ¶22-24).

No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not contain detailed claim charts. The analysis below summarizes the infringement theory for the lead patents as inferred from the complaint's allegations, which are based on the premise that the Defendants' proposed product label will instruct physicians and patients to use the generic drug in a manner that infringes the asserted method claims.

’729 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of administering pirfenidone to treat a patient with idiopathic pulmonary fibrosis (IPF)... Defendants' ANDA seeks approval to market generic pirfenidone for treating IPF, and the product label will allegedly instruct this use. ¶73 col. 11:16-17
...said patient having exhibited a grade 2 abnormality in one or more biomarkers of liver function after pirfenidone administration... The proposed label will allegedly instruct physicians to monitor for liver function abnormalities and to identify when a patient meets the criteria for a "grade 2 abnormality." ¶73 col. 11:15-18
...comprising (a) administering to said patient pirfenidone at doses lower than 2400 mg/day for a time period... The proposed label will allegedly direct physicians to reduce the pirfenidone dose to a level below the full target dose upon detection of a grade 2 abnormality. ¶73 col. 11:19-22
...followed by (b) administering to said patient pirfenidone at doses of 2400 mg/day or 2403 mg/day. Following the period of dose reduction, the proposed label will allegedly direct physicians to re-escalate the dose back to the full therapeutic dose. ¶73 col. 11:23-25

Identified Points of Contention

  • Scope Questions: A central question will be whether the specific instructions for dose modification in Defendants' proposed product label meet every limitation of the asserted claims. For instance, does the label direct the specific dose reduction and subsequent re-escalation protocol as claimed, or does it provide for different or more discretionary steps?
  • Technical Questions: The dispute may turn on whether the clinical criteria for a "grade 2 abnormality" described or implied in the generic label are the same as those defined by the patent.

’707 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of administering pirfenidone to treat a patient with idiopathic pulmonary fibrosis (IPF)... Defendants' ANDA seeks approval to market generic pirfenidone for treating IPF, and the product label will allegedly instruct this use. ¶84 col. 10:1-2
...said patient having exhibited a grade 2 abnormality in one or more biomarkers of liver function after pirfenidone administration... The proposed label will allegedly instruct physicians to monitor for and identify a "grade 2 abnormality" in liver function biomarkers. ¶84 col. 10:3-5
...comprising (a) administering to said patient pirfenidone at doses of 2400 mg/day or 2403 mg/day. The proposed label will allegedly instruct physicians to continue administering the full therapeutic dose of pirfenidone even after a patient exhibits a grade 2 abnormality. ¶84 col. 10:6-7

Identified Points of Contention

  • Scope Questions: Infringement of this patent raises the question of whether the Defendants' label will instruct physicians to continue the full dose as one of the potential management strategies for a grade 2 liver abnormality, thereby directly reading on the claim. If the label only instructs dose reduction or discontinuation, infringement of this patent may be contested.

V. Key Claim Terms for Construction

  • The Term: "grade 2 abnormality"
  • Context and Importance: This term is the trigger for the claimed methods of managing pirfenidone therapy in both the ’729 and ’707 Patents. Its definition is critical to determining whether a physician or patient would perform the claimed steps. Practitioners may focus on this term because its construction will define the specific clinical conditions under which the patented methods apply, and any mismatch between the patent's definition and the generic label's instructions could be a basis for a non-infringement argument.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The term "abnormality" itself could be argued to encompass a range of clinical judgments regarding liver function tests. The specification refers generally to "abnormal biomarkers of liver function" and "abnormal liver function" (Compl. Ex. 1, ’729 Patent, Abstract; col. 2:9-10).
    • Evidence for a Narrower Interpretation: The patent specifications provide a highly specific definition. Table 1, titled "Modified Common Toxicity Criteria," explicitly defines "Grade 2" abnormalities for specific biomarkers: an elevation in ALT, AST, ALP, or GGT of ">2.5-5 x ULN (upper limit of normal)" or an elevation in Bilirubin of ">1.5-3 x ULN" (Compl. Ex. 1, ’729 Patent, col. 7, Table 1). This table provides strong intrinsic evidence for a narrow and precise construction of the term.

VI. Other Allegations

  • Indirect Infringement: The complaint's core theory is indirect infringement. It alleges that Defendants will actively induce infringement by providing a product with package inserts and promotional materials that will instruct and encourage medical professionals and patients to use the generic product in a manner that directly infringes the asserted method claims (Compl. ¶¶ 76-77, 87-88). Contributory infringement is also alleged, based on the assertion that the generic product is especially made or adapted for use in an infringing manner and is not a staple article of commerce suitable for substantial noninfringing use (Compl. ¶¶ 74-75, 85-86).
  • Willful Infringement: The complaint does not contain a separate count for willful infringement but alleges that "Defendants' activities, as alleged herein, were undertaken with knowledge of the Asserted Patents and without a good faith belief that they are not infringing those patents," and characterizes the case as "exceptional" (Compl. ¶231). This forms the basis for a potential willfulness claim and a request for enhanced damages and attorneys' fees.

VII. Analyst’s Conclusion: Key Questions for the Case

  • A core issue will be one of induced infringement: Will the instructions for use, warnings, and dosing recommendations in the Defendants' proposed generic product label direct, encourage, or instruct physicians to perform each and every step of the asserted method claims, including the specific dose escalation and dose modification protocols for managing liver toxicity?
  • A second key issue will be one of claim validity: As indicated by the Defendants' Paragraph IV certification, the validity of the patents will be challenged. A central question for the court will be whether the claimed methods for managing a known side effect of pirfenidone through specific dose-adjustment protocols would have been obvious to a person of ordinary skill in the art at the time of the inventions.
  • A third evidentiary question will relate to claim construction: The dispute will likely involve construing the scope of key terms, such as "grade 2 abnormality." The outcome will depend on whether the court adopts the narrow, specific biomarker thresholds defined in the patents' specifications or a broader interpretation, and how that construction maps onto the language of the accused product's label.