Genentech Inc v. Granules Pharma Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Genentech, Inc. (Delaware) and InterMune, Inc. (Delaware)
  • Defendant: Granules Pharmaceuticals, Inc. (Delaware), Granules India Ltd. (India), and Granules USA, Inc. (Delaware)
  • Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP
• Case Identification: 1:19-cv-00164, D. Del., 01/28/2019
• Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant entities Granules Pharmaceuticals, Inc. and Granules USA, Inc. are incorporated in Delaware.
• Core Dispute: Plaintiffs allege that Defendants' Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiffs' drug Esbriet® (pirfenidone) constitutes an act of infringement of three U.S. patents covering pharmaceutical formulations and methods of administration for pirfenidone.
• Technical Context: The technology concerns pharmaceutical compositions and therapeutic dosing regimens for pirfenidone, the active ingredient in Esbriet®, which is approved to treat Idiopathic Pulmonary Fibrosis (IPF), a rare and fatal lung disease.
• Key Procedural History: This Hatch-Waxman litigation was initiated after Defendants notified Plaintiffs via a "Notice Letter" that they had filed ANDA No. 212615 containing a Paragraph IV certification. This certification asserts that Plaintiffs' patents listed in the FDA's Orange Book for Esbriet® are invalid, unenforceable, and/or will not be infringed by the commercial manufacture and sale of Defendants' proposed generic product. The complaint also notes that Esbriet® was granted Orphan Drug Exclusivity, running until October 15, 2021.

Case Timeline

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

U.S. Patent No. 8,383,150 - “Granulate Formulation of Pirfenidone and Pharmaceutically Acceptable Excipients”

• Issued: February 26, 2013

The Invention Explained

• Problem Addressed: The patent describes a general need for effective pharmaceutical formulations of pirfenidone that can produce desirable pharmacokinetic (PK) responses in patients, which is necessary to optimize the drug's therapeutic actions (’150 Patent, col. 2:10-15).
• The Patented Solution: The invention is a capsule formulation of pirfenidone that includes specific types and amounts of pharmaceutically acceptable excipients, such as binders and disintegrators. These excipients are designed to modulate the drug's absorption and achieve a more favorable PK profile, such as an increased Area Under the Curve (AUC), which represents total drug exposure over time (’150 Patent, Abstract; col. 2:15-29).
• Technical Importance: By creating a formulation with improved and more consistent PK characteristics, the invention allows for more reliable dosing to maximize therapeutic benefit while managing potential side effects (’150 Patent, col. 2:10-15).

Key Claims at a Glance

• The complaint asserts independent claims 1 and 27 (Compl. ¶44).
• Independent Claim 1: A granulate formulation comprising:
  • 5-methyl-1-phenyl-2-(1H)-pyridone (pirfenidone).
  • Pharmaceutically acceptable excipients.
  • The excipients comprise an effective amount of a binder to increase the AUC of the pirfenidone at least 45% upon oral administration, as compared to pirfenidone without excipients.
• Independent Claim 27: A method of treating idiopathic pulmonary fibrosis by administering the formulation of claim 1.

U.S. Patent No. 8,420,674 - “Method of Providing Pirfenidone Therapy to a Patient”

• Issued: April 16, 2013

The Invention Explained

• Problem Addressed: The patent notes that adverse reactions to pirfenidone therapy (such as nausea and dizziness) are often dose-related and can be severe enough to require dose reduction or discontinuation, potentially limiting the drug's therapeutic benefit (’674 Patent, col. 2:2-19).
• The Patented Solution: The invention provides an optimized, gradual dose-escalation method where the daily dosage of pirfenidone is increased in a stepwise fashion over a period of at least two weeks. This regimen is designed to allow the patient to develop tolerance to the drug, minimizing adverse events and enabling the administration of a higher, full therapeutic dose (’674 Patent, Abstract; col. 2:41-54).
• Technical Importance: This dosing method improves the safety and tolerability profile of pirfenidone, making it possible for more patients to reach and maintain a clinically effective dose.

Key Claims at a Glance

• The complaint asserts independent claim 6 and dependent claims 7-12 (Compl. ¶55).
• Independent Claim 6: An initial dose escalation regimen method, comprising:
  • Administering a first oral daily dosage of 801 mg for days one to seven.
  • Administering a second oral daily dosage of 1602 mg for days eight to fourteen.
  • Administering a third oral daily dosage of 2403 mg for at least day fifteen.

U.S. Patent No. 8,778,947 - “Methods of Administering Pirfenidone Therapy”

• Issued: July 15, 2014
• Technology Synopsis: This patent addresses a drug-drug interaction between pirfenidone and ciprofloxacin, a common antibiotic. Ciprofloxacin inhibits CYP1A2, a key enzyme responsible for metabolizing pirfenidone, leading to significantly increased and potentially unsafe levels of pirfenidone in the body (’947 Patent, col. 2:16-41). The invention provides a method for safely managing this interaction by reducing the daily dose of pirfenidone when it is co-administered with ciprofloxacin (’947 Patent, Abstract; col. 3:20-41).
• Asserted Claims: The complaint alleges infringement of "at least one of the claims of the '947 patent" without identifying specific claims (Compl. ¶66).
• Accused Features: The accused act is the filing of the ANDA, which seeks approval for a product whose label will foreseeably instruct co-administration with CYP1A2 inhibitors like ciprofloxacin, thereby inducing infringement of the patented method (Compl. ¶¶ 66, 71).

III. The Accused Instrumentality

Product Identification

• Defendants' 267 mg and 801 mg pirfenidone tablets, for which Defendants seek FDA approval via Abbreviated New Drug Application No. 212615 (the "Granules ANDA Product") (Compl. ¶¶ 1, 8).

Functionality and Market Context

• The accused product is a generic version of Plaintiffs' FDA-approved drug, Esbriet®, used to treat Idiopathic Pulmonary Fibrosis (Compl. ¶¶ 1, 21). As part of the ANDA process, Defendants have represented to the FDA that their product contains the same active ingredient (pirfenidone), has the same dosage form and strength, and is bioequivalent to Esbriet® (Compl. ¶40). The complaint alleges that Defendants are relying on Plaintiffs' proprietary clinical trial data to secure approval and enter the market prior to the expiration of Plaintiffs' patents (Compl. ¶26).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

’150 Patent Infringement Allegations

’674 Patent Infringement Allegations

Identified Points of Contention

• Scope Questions: A primary issue for the ’150 Patent will be whether the specific formulation in the Granules ANDA, once produced in discovery, meets the functional limitation requiring an AUC increase of "at least 45%" compared to a formulation without excipients. The definition and measurement of this "increase" may be a central point of dispute.
• Technical Questions: For the ’674 and ’947 patents, infringement will turn on the specific instructions included in the proposed label for the Granules ANDA Product. A key question for the court will be whether those instructions direct users to perform all steps of the claimed methods, which is a prerequisite for a finding of induced infringement.

V. Key Claim Terms for Construction

• The Term: "effective amount of binder to increase the AUC ... at least 45%" (’150 Patent, Claim 1)
• Context and Importance: This functional limitation is the central inventive concept of the ’150 Patent's composition claim. The infringement analysis will depend entirely on whether the accused product's formulation is proven to achieve this specific pharmacokinetic result. Practitioners may focus on this term because its construction will determine the scope of evidence required to prove or disprove infringement.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: The claim language itself presents a clear numerical threshold ("at least 45%"), which may support an interpretation that any formulation meeting this objective criterion via standard bioequivalence testing infringes, regardless of the specific binder used.
  • Evidence for a Narrower Interpretation: The specification discloses specific embodiments and PK data derived from them (’150 Patent, FIG. 5; col. 7:21-48). A party may argue that the term should be limited by the context of these examples, potentially tying the "effective amount" to the types of binders (e.g., povidone, microcrystalline cellulose) and testing conditions described in the patent.

VI. Other Allegations

• Indirect Infringement: The complaint alleges that Defendants will induce and contribute to infringement of all asserted patents. This is based on the allegation that Defendants know of the patents and intend for their product to be used in an infringing manner, as will be directed by the product's package insert and other promotional materials (Compl. ¶¶ 47-50, 58-61, 69-72).
• Willful Infringement: The complaint alleges that Defendants' activities were undertaken with knowledge of the Asserted Patents (as evidenced by the Paragraph IV certification) and "without a good faith belief that they are not infringing," characterizing the case as "exceptional" (Compl. ¶74). This forms the basis for a potential claim for enhanced damages and attorneys' fees.

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

• A central issue for the composition claims will be one of functional performance: once the formulation of the Granules ANDA Product is disclosed, does it, in fact, produce a pharmacokinetic profile that meets the "at least 45% AUC increase" required by the '150 patent, or is there a material difference in its formulation and performance?
• A key evidentiary question for the method claims will be one of inducement via labeling: will the final, FDA-approved label for the Granules product contain instructions that direct users to follow the specific dose-escalation schedule of the '674 patent and the dose-reduction steps of the '947 patent, thereby satisfying the requirements for induced infringement?
• Underlying the entire case is the question of patent validity: given that Defendants filed a Paragraph IV certification, they will argue that the asserted claims are invalid (e.g., as obvious over prior art). The resolution of the case will therefore depend not only on infringement but on whether Plaintiffs' patents are found to be valid and enforceable.