Genentech Inc v. Aurobindo Pharma Ltd

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Genentech, Inc. (Delaware) and InterMune, Inc. (Delaware)
  • Defendant: Aurobindo Pharma Limited (India) and Aurobindo Pharma USA, Inc. (Delaware)
  • Plaintiff’s Counsel: Morris Nichols Arsht & Tunnell LLP; Loeb & Loeb LLP
• Case Identification: 1:19-cv-00103, D. Del., 01/17/2019
• Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant Aurobindo Pharma USA, Inc. is a Delaware corporation, and Defendant Aurobindo Pharma Limited is a foreign corporation that may be sued in any judicial district.
• Core Dispute: Plaintiffs allege that Defendants' submission of an Abbreviated New Drug Application (ANDA) to the FDA for a generic version of the drug Esbriet® (pirfenidone) constitutes an act of infringement of twenty-one patents covering the drug and its methods of use.
• Technical Context: The technology concerns the drug pirfenidone, used for treating Idiopathic Pulmonary Fibrosis (IPF), a rare, progressive, and fatal lung disease for which few treatment options exist.
• Key Procedural History: This action was initiated under the Hatch-Waxman Act following Defendants' notification to Plaintiffs, via a Paragraph IV certification letter, of their ANDA filing seeking to market a generic pirfenidone product prior to the expiration of Plaintiffs' patents. The complaint notes that Esbriet® was granted Orphan Drug Exclusivity by the FDA, running until October 15, 2021.

Case Timeline

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

U.S. Patent No. 7,566,729 - "Modifying Pirfenidone Treatment for Patients with Atypical Liver Function"

• Patent Identification: U.S. Patent No. 7,566,729, titled “Modifying Pirfenidone Treatment for Patients with Atypical Liver Function,” issued July 28, 2009 (the “’729 Patent”). (Compl. ¶25).

The Invention Explained

• Problem Addressed: The administration of pirfenidone can lead to abnormal liver function, which may be an indicator of drug-induced liver injury, creating a clinical challenge for managing patients on the therapy. (’729 Patent, col. 2:63-col. 3:2).
• The Patented Solution: The patent describes a method to manage this side effect without permanently ceasing treatment. The solution involves identifying a patient with a specific level of liver function abnormality (a “grade 2 abnormality”), administering a reduced dose of pirfenidone for a period of time, and then resuming the full target dose after liver biomarkers have improved. (’729 Patent, Abstract; col. 2:37-50). This strategy aims to maximize the time a patient receives a therapeutically beneficial dose of the drug. (’729 Patent, col. 4:6-11).
• Technical Importance: This dose-modification regimen provides a structured, predictable method for clinicians to manage a known adverse event associated with pirfenidone, potentially allowing patients to remain on a therapy for a fatal disease that they might otherwise have to discontinue. (’729 Patent, col. 4:6-11).

Key Claims at a Glance

• The complaint alleges infringement of at least one claim; Independent Claim 1 is representative. (Compl. ¶75; ’729 Patent, col. 12:15-24).
• The essential elements of Independent Claim 1 include:
  • 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.
• The complaint alleges infringement of "at least one of the claims," which may include dependent claims. (Compl. ¶75).

U.S. Patent No. 7,635,707 - "Pirfenidone Treatment for Patients with Atypical Liver Function"

• Patent Identification: U.S. Patent No. 7,635,707, titled “Pirfenidone Treatment for Patients with Atypical Liver Function,” issued December 22, 2009 (the “’707 Patent”). (Compl. ¶27).

The Invention Explained

• Problem Addressed: Like its parent ’729 Patent, this patent addresses the technical problem of managing patients who develop abnormal liver function while on pirfenidone therapy. (’707 Patent, col. 2:59-col. 3:2).
• The Patented Solution: This patent claims alternative methods for managing the same clinical scenario. The claimed solutions include continuing the full target dose without reduction while monitoring biomarkers, implementing a permanent dose reduction, or temporarily discontinuing and then re-introducing the drug. (’707 Patent, Abstract; col. 2:40-44). These methods provide physicians with a broader set of patented options for tailoring treatment to an individual patient’s response.
• Technical Importance: The invention offers clinicians flexibility by patenting multiple distinct strategies for managing liver-related side effects, including an option to continue the full therapeutic dose, which may be clinically appropriate for certain patients and avoids interrupting therapy. (’707 Patent, col. 2:20-23).

Key Claims at a Glance

• The complaint alleges infringement of at least one claim; Independent Claim 1 is representative of a different treatment strategy than claimed in the ’729 Patent. (Compl. ¶86; ’707 Patent, col. 11:50-56).
• The essential elements of Independent Claim 1 include:
  • 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.
• The complaint alleges infringement of "at least one of the claims," which may include dependent claims. (Compl. ¶86).

U.S. Patent No. 7,767,700 - "Method of Providing Pirfenidone Therapy to a Patient"

• Patent Identification: U.S. Patent No. 7,767,700, titled “Method of Providing Pirfenidone Therapy to a Patient,” issued August 3, 2010. (Compl. ¶29).
• Technology Synopsis: This patent addresses the problem of adverse events associated with pirfenidone therapy. It provides an optimized dose escalation schedule over an initial period (e.g., 14 days) to allow the patient to develop tolerance, thereby reducing the incidence of side effects when the full maintenance dose is administered. (’700 Patent, col. 2:42-55).
• Asserted Claims: The complaint asserts at least one claim. (Compl. ¶97).
• Accused Features: The proposed use of the Aurobindo ANDA Product according to its label, which is expected to include a dose escalation schedule for initiating therapy. (Compl. ¶¶ 69, 99).

U.S. Patent No. 7,816,383 - "Methods of Administering Pirfenidone Therapy"

• Patent Identification: U.S. Patent No. 7,816,383, titled “Methods of Administering Pirfenidone Therapy,” issued October 19, 2010. (Compl. ¶31).
• Technology Synopsis: This patent addresses adverse drug interactions between pirfenidone and drugs that inhibit cytochrome P450 enzymes, particularly CYP1A2. The invention provides methods for administering pirfenidone therapy that involve avoiding or discontinuing fluvoxamine, a strong CYP1A2 inhibitor, to prevent a significant increase in pirfenidone exposure and associated toxicity. (’383 Patent, col. 2:5-11, 26-30).
• Asserted Claims: The complaint asserts at least one claim. (Compl. ¶108).
• Accused Features: The proposed use of the Aurobindo ANDA Product, which will be governed by a label that is expected to contain instructions regarding drug-drug interactions. (Compl. ¶¶ 69, 110, 113).

For the remaining 17 patents-in-suit, the complaint alleges infringement but does not provide sufficient detail for individual analysis beyond identifying the patent and the general allegation that the Aurobindo ANDA product will infringe one or more of its claims (Compl. ¶¶ 116-280). These patents cover additional methods of administration, specific formulations, and methods for managing other specific adverse events.

III. The Accused Instrumentality

• Product Identification: The accused instrumentality is Defendants' generic pirfenidone 267 mg capsules, for which Aurobindo has filed Abbreviated New Drug Application No. 212597 with the FDA (the "Aurobindo ANDA Product"). (Compl. ¶1, 8).
• Functionality and Market Context: The Aurobindo ANDA Product is a generic version of Plaintiffs’ drug Esbriet®, intended for the treatment of Idiopathic Pulmonary Fibrosis (IPF). (Compl. ¶1, 18). By filing an ANDA, Defendants represent to the FDA that their product contains the same active ingredient, has the same dosage form and strength, and is bioequivalent to the branded Esbriet® capsules. (Compl. ¶69). The act of filing the ANDA to obtain approval for commercial manufacture, use, and sale of this generic product prior to the expiration of the Asserted Patents is the basis for the infringement action under 35 U.S.C. § 271(e)(2)(A). (Compl. ¶1, 75).

IV. Analysis of Infringement Allegations

The complaint does not provide a claim chart or detailed, patent-specific infringement allegations. The infringement theory is based on the premise that the Aurobindo ANDA Product, as a generic equivalent, will be prescribed and used in the same manner as the branded Esbriet® product, and that this use will infringe the asserted method claims.

For the method of treatment patents, such as the ’729 and ’707 Patents, the infringement allegation rests on the future actions of physicians and patients who will use the Aurobindo ANDA Product. The complaint alleges that the FDA-approved label for the branded product is covered by the Asserted Patents. (Compl. ¶65). It further alleges that Defendants' product, when used as directed by its own label, will be used in a manner that directly infringes the patents. (Compl. ¶¶ 77, 88). Defendants' submission of the ANDA is alleged to constitute infringement under the Hatch-Waxman Act, and their future promotional activities and package inserts are alleged to actively induce infringement by others. (Compl. ¶¶ 75, 81, 86, 92).

No probative visual evidence provided in complaint.

• Identified Points of Contention:
  • Scope Questions: A central question for the method claims will be whether the instructions, warnings, and clinical information on Aurobindo's proposed product label will actively induce physicians and patients to perform all steps of the claimed methods. The dispute may focus on whether the label language directs, encourages, or merely informs about the patented treatment regimens.
  • Technical Questions: As this is an ANDA case concerning a bioequivalent product, the primary technical questions will likely relate to the formulation patents. For the method patents, the key question is not a mismatch in how the drug works, but whether the clinical scenarios described in the patents (e.g., a "grade 2 abnormality") and the responsive actions (e.g., dose reduction) are both present on, and encouraged by, the proposed generic label.

V. Key Claim Terms for Construction

• The Term: "a grade 2 abnormality in one or more biomarkers of liver function" (’729 Patent, Claim 1; ’707 Patent, Claim 1)

  • Context and Importance: This term defines the clinical event that triggers the application of the patented methods. The scope of this term is critical because it determines the circumstances under which infringement can occur. Practitioners may focus on this term because its definition—whether tied to a specific numerical table in the patent or a broader clinical standard—will dictate how closely a generic drug's label must match the patent's disclosure to be found infringing.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The claim language "one or more biomarkers" is open-ended. Dependent claims in the patent family specify particular biomarkers (e.g., alanine transaminase, aspartate transaminase), suggesting that the independent claim is not limited to only those examples. (’729 Patent, col. 12:46-51).
    • Evidence for a Narrower Interpretation: The specification provides a detailed table titled "Modified Common Toxicity Criteria" that gives specific numerical ranges for what constitutes a "Grade 2" abnormality (e.g., ">2.5-5 x ULN" for ALT/AST). (’729 Patent, col. 7, Table 1). A party could argue that the patentee defined the term by this explicit disclosure.

• The Term: "administering...at doses lower than 2400 mg/day for a time period" (’729 Patent, Claim 1)

  • Context and Importance: This phrase defines the dose-reduction step. The construction of "for a time period" will determine the required duration and conditions of the dose reduction for an act to be infringing.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification lists numerous possible durations, such as "one week, two weeks, three weeks, four weeks, one month, six weeks, or two months," suggesting "time period" is not narrowly limited. (’729 Patent, col. 2:37-39).
    • Evidence for a Narrower Interpretation: Specific embodiments link the duration of the reduced dose to a clinical outcome, stating it is administered "for about one week, or until the liver function biomarkers return to grade 0 or grade 1." (’729 Patent, col. 2:41-44). This language could support an argument that the "time period" is not of an arbitrary length but is defined by the patient's clinical response.

VI. Other Allegations

• Indirect Infringement: The complaint pleads both induced and contributory infringement for all asserted patents. Inducement is primarily based on the allegation that Defendants' promotional activities and the package insert for the Aurobindo ANDA Product will instruct and encourage physicians and patients to use the generic drug in a manner that directly infringes the claims. (Compl. ¶¶ 80-81, 91-92).
• Willful Infringement: The complaint does not use the word "willful" but alleges that Defendants' activities "were undertaken with knowledge of the Asserted Patents and without a good faith belief that they are not infringing," which provides a basis for a later claim of willfulness. (Compl. ¶281). This knowledge is predicated on the Paragraph IV notice provided to Plaintiffs before the suit was filed.

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

• A core issue will be one of induced infringement: will the final, FDA-approved label for Aurobindo's generic product contain language that instructs or encourages physicians to practice the specific dose-modification and administration steps recited in the asserted method claims, or will it merely provide information that leaves the decision entirely to clinical judgment?
• A key legal and factual question will be one of claim scope: can the term "grade 2 abnormality," as used in the claims, be defined by the specific numerical criteria provided in the patents' detailed description, and if so, will Aurobindo's proposed label recommend actions based on those same criteria?
• Ultimately, the dispute will likely turn on a comparison of the court's construction of the patent claims against the specific text of the proposed label for the Aurobindo ANDA Product, which was not available at the time of the complaint's filing.