DCT

1:19-cv-00203

Genentech Inc v. Sandoz Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:19-cv-00203, D. Del., 05/21/2019
  • Venue Allegations: Venue is based on Defendant Sandoz, Inc.'s consent to jurisdiction and venue in the District of Delaware, and on Defendant Lek Pharmaceuticals being 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 a generic version of the drug Esbriet® (pirfenidone) constitutes an act of infringement of nineteen patents covering the drug's formulation, methods of use, and treatment regimens.
  • Technical Context: The technology relates to pirfenidone, an anti-fibrotic agent for treating Idiopathic Pulmonary Fibrosis (IPF), a rare, progressive, and fatal lung disease for which few treatments exist.
  • Key Procedural History: This action arises under the Hatch-Waxman Act, triggered by Defendants' submission of ANDA No. 212600 and a corresponding Paragraph IV certification notice sent to Plaintiffs. The notice asserts that the patents-in-suit are invalid, unenforceable, or will not be infringed by the proposed generic product. Plaintiffs' drug, Esbriet®, received FDA approval in 2014 and was awarded Orphan Drug Exclusivity through October 15, 2021.

Case Timeline

Date Event
2005-09-22 Priority Date (’225, ’994, ’679 Patents)
2006-12-18 Priority Date (’236, ’700 Patents)
2008-11-10 Priority Date (’729, ’707, ’462, ’701 Patents)
2009-07-28 Issue Date (U.S. Patent No. 7,566,729)
2009-12-22 Issue Date (U.S. Patent No. 7,635,707)
2010-04-13 Issue Date (U.S. Patent No. 7,696,236)
2010-08-03 Issue Date (U.S. Patent No. 7,767,700)
2010-08-03 Issue Date (U.S. Patent No. 7,767,225)
2010-10-19 Issue Date (U.S. Patent No. 7,816,383)
2011-03-22 Issue Date (U.S. Patent No. 7,910,610)
2011-08-02 Issue Date (U.S. Patent No. 7,988,994)
2011-09-06 Issue Date (U.S. Patent No. 8,013,002)
2011-12-27 Issue Date (U.S. Patent No. 8,084,475)
2012-11-27 Issue Date (U.S. Patent No. 8,318,780)
2013-02-26 Issue Date (U.S. Patent No. 8,383,150)
2013-04-16 Issue Date (U.S. Patent No. 8,420,674)
2013-11-26 Issue Date (U.S. Patent No. 8,592,462)
2013-12-17 Issue Date (U.S. Patent No. 8,609,701)
2014-02-11 Issue Date (U.S. Patent No. 8,648,098)
2014-06-17 Issue Date (U.S. Patent No. 8,754,109)
2014-06-17 Issue Date (U.S. Patent No. 8,753,679)
2014-07-15 Issue Date (U.S. Patent No. 8,778,947)
2014-10-15 FDA approves first NDA for Esbriet®
2018-12-19 Sandoz sends Notice Letter to Plaintiffs regarding ANDA filing
2019-01-31 Plaintiffs file original Complaint
2019-05-21 Plaintiffs file First Amended Complaint

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

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

  • The Invention Explained:
    • Problem Addressed: The administration of pirfenidone for treating diseases like IPF can cause adverse effects, specifically abnormal liver function, which may manifest as elevated levels of certain biomarkers (Compl. ¶22; ’729 Patent, col. 2:62-col. 3:2). Managing this hepatotoxicity is necessary to allow patients to continue therapy safely (’729 Patent, col. 3:1-7).
    • The Patented Solution: The patent discloses a method for managing patients who exhibit specific, defined levels of liver function abnormalities (a "grade 2 abnormality") after starting pirfenidone. The method involves interrupting or reducing the pirfenidone dosage for a period of time until the liver biomarkers return to a safer level, after which the patient is re-administered the full therapeutic dose (’729 Patent, Abstract; col. 2:16-21). This protocol allows for continued long-term treatment despite the adverse event.
    • Technical Importance: This method provides a standardized safety protocol that allows clinicians to manage a significant side effect of pirfenidone, thereby enabling patients to remain on a therapy for a fatal disease that would otherwise have to be discontinued (Compl. ¶24).
  • Key Claims at a Glance:
    • The complaint asserts infringement of at least one claim (Compl. ¶80). Independent claim 1 is representative.
    • Claim 1 recites a method of administering pirfenidone to a patient with IPF who has exhibited a "grade 2 abnormality" in liver function biomarkers, comprising the steps of:
      • 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.

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

  • The Invention Explained:
    • Problem Addressed: As with the related ’729 Patent, this invention addresses the management of patients who develop abnormal liver function as a result of pirfenidone therapy (’707 Patent, col. 2:5-7).
    • The Patented Solution: This patent provides an expanded set of methods for managing patients with atypical liver function. In addition to dose reduction or temporary discontinuation, it also claims methods where pirfenidone is continued at the full target dose while biomarkers are monitored, or where a permanently reduced dose is administered (’707 Patent, Abstract; col. 2:10-26). This offers clinicians more flexible, patient-specific strategies for managing hepatotoxicity.
    • Technical Importance: The invention offers a broader range of clinical options for managing pirfenidone side effects, potentially increasing the number of patients who can safely continue treatment for IPF (Compl. ¶24).
  • Key Claims at a Glance:
    • The complaint asserts infringement of at least one claim (Compl. ¶91). Independent claim 1 is representative.
    • Claim 1 recites a method of administering pirfenidone to a patient with IPF who has exhibited a "grade 2 abnormality" in liver function biomarkers, comprising the step of:
      • 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.

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

  • Technology Synopsis: This patent addresses the need to improve patient tolerance to pirfenidone therapy by using a specific dose escalation schedule. The invention describes a method where the daily dose is gradually increased over an initial period (e.g., two weeks) to reach the full maintenance dose, which is alleged to reduce the incidence of adverse events (Compl. ¶¶102-104; ’236 Patent, col. 2:1-19, which is related to the '700 patent).
  • Asserted Claims: At least one claim (Compl. ¶102).
  • Accused Features: The proposed Sandoz ANDA product, when used as directed by its label, is alleged to be administered according to the claimed dose-escalation method (Compl. ¶104).

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

  • Technology Synopsis: This patent is directed to methods of administering pirfenidone therapy, including specific daily dosages and administration schedules (e.g., three times per day with food). The invention claims these specific administration parameters for treating IPF (Compl. ¶¶113-115; ’383 Patent, col. 1:15-18).
  • Asserted Claims: At least one claim (Compl. ¶113).
  • Accused Features: The proposed Sandoz ANDA product is alleged to have a label that instructs administration of pirfenidone at the claimed daily dosage and schedule for treating IPF (Compl. ¶115).

U.S. Patent No. 7,910,610 - "Methods of Administering Pirfenidone Therapy"

  • Technology Synopsis: This patent is directed to methods of administering pirfenidone at a specific total daily dosage of about 2400 mg/day or 2403 mg/day. The invention claims this specific dosage for treating IPF (Compl. ¶¶124-126; ’610 Patent, col. 1:15-18).
  • Asserted Claims: At least one claim (Compl. ¶124).
  • Accused Features: The proposed Sandoz ANDA product and its accompanying label are alleged to provide for a total daily dose of pirfenidone that infringes the claimed amount (Compl. ¶126).

U.S. Patent No. 8,013,002 - "Methods of Administering Pirfenidone Therapy"

  • Technology Synopsis: This patent claims methods of administering pirfenidone three times per day with food to treat IPF. This specific regimen is intended to provide therapeutic benefit while managing potential side effects (Compl. ¶¶135-137; ’002 Patent, col. 1:15-18).
  • Asserted Claims: At least one claim (Compl. ¶135).
  • Accused Features: The labeling for the Sandoz ANDA product is alleged to instruct administration three times per day with food, thereby infringing the claimed method (Compl. ¶137).

U.S. Patent No. 8,084,475 - "Pirfenidone Therapy and Inducers of Cytochrome P450"

  • Technology Synopsis: This patent addresses adverse drug interactions. It discloses methods of administering pirfenidone while avoiding inducers of CYP enzymes (like smoking), which can reduce the drug's effectiveness. The invention provides guidance for co-administration to maintain therapeutic efficacy (Compl. ¶¶146-148; ’475 Patent, col. 2:1-4).
  • Asserted Claims: At least one claim (Compl. ¶146).
  • Accused Features: The proposed Sandoz label is alleged to contain instructions regarding co-administration with CYP inducers that practice the patented method (Compl. ¶148).

U.S. Patent No. 8,318,780 - "Methods of Administering Pirfenidone Therapy"

  • Technology Synopsis: This patent claims specific methods for administering pirfenidone, focusing on a total daily dose of 2403 mg, divided into three doses of 801 mg each, for treating IPF (Compl. ¶¶157-159; ’780 Patent, col. 1:18-21).
  • Asserted Claims: At least one claim (Compl. ¶157).
  • Accused Features: The Sandoz ANDA product is alleged to be labeled for administration at a total daily dose of 2403 mg, thereby infringing the claimed method (Compl. ¶159).

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

  • Technology Synopsis: This patent is directed to a specific granulate formulation of pirfenidone with particular excipients. The formulation is designed to have desirable pharmacokinetic properties, such as controlling the drug's release profile when administered in a capsule (Compl. ¶¶168, 170; ’150 Patent, col. 2:5-14).
  • Asserted Claims: Claims 1-8, 10-14, 16-18, and 20-27 (Compl. ¶166).
  • Accused Features: The Sandoz ANDA product is alleged to be a capsule formulation containing pirfenidone and excipients that falls within the scope of the patent's claims (Compl. ¶¶166, 170).

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

  • Technology Synopsis: This patent claims a method of providing pirfenidone therapy that involves a specific dose escalation schedule over a period of about 15 days to reach the full maintenance dose. This gradual increase is intended to improve patient tolerance and reduce adverse events (Compl. ¶¶179, 181; ’674 Patent, col. 2:1-19).
  • Asserted Claims: Claims 6-12 (Compl. ¶177).
  • Accused Features: The proposed label for the Sandoz ANDA Product is alleged to instruct for the claimed dose escalation regimen (Compl. ¶181).

U.S. Patent No. 8,592,462 - "Pirfenidone Treatment for Patients with Atypical Liver Function"

  • Technology Synopsis: This patent, related to the '729 and '707 patents, claims methods of managing patients who exhibit atypical liver function during pirfenidone therapy. It includes specific protocols for dose reduction, discontinuation, and re-escalation based on liver biomarker levels (Compl. ¶¶190, 192; ’462 Patent, col. 2:10-21).
  • Asserted Claims: At least one claim (Compl. ¶190).
  • Accused Features: The label for the Sandoz product is alleged to instruct for the claimed dose modification methods in response to atypical liver function (Compl. ¶192).

U.S. Patent No. 8,609,701 - "Pirfenidone Treatment for Patients with Atypical Liver Function"

  • Technology Synopsis: This patent is also part of the family covering management of hepatotoxicity. It claims specific methods of administering pirfenidone to IPF patients who have exhibited defined liver function abnormalities, including continuing the full dose or implementing dose modifications (Compl. ¶¶201, 203; ’701 Patent, col. 2:10-26).
  • Asserted Claims: Claims 1-17 and 19 (Compl. ¶199).
  • Accused Features: The proposed Sandoz product label is alleged to instruct clinicians to follow the patented management protocols for patients with atypical liver function (Compl. ¶203).

U.S. Patent No. 8,648,098 - "Pirfenidone Therapy and Inducers of Cytochrome P450"

  • Technology Synopsis: This patent is related to the '475 patent and covers methods for administering pirfenidone while managing interactions with substances that induce cytochrome P450 enzymes. The claims focus on avoiding or discontinuing CYP inducers to ensure the therapeutic efficacy of pirfenidone is not compromised (Compl. ¶¶212, 214; ’098 Patent, Abstract).
  • Asserted Claims: At least one claim (Compl. ¶212).
  • Accused Features: The Sandoz product label is alleged to contain instructions regarding co-administration with CYP inducers that would lead to infringement (Compl. ¶214).

U.S. Patent No. 8,754,109 - "Pirfenidone Therapy and Inducers of Cytochrome P450"

  • Technology Synopsis: This patent is also in the family concerning drug interactions with CYP inducers. It claims methods for safely and effectively administering pirfenidone by advising patients to avoid or discontinue CYP inducers, such as those found in tobacco smoke (Compl. ¶¶223, 225; ’109 Patent, Abstract).
  • Asserted Claims: At least one claim (Compl. ¶223).
  • Accused Features: The instructions in the Sandoz product label regarding CYP inducers are alleged to practice the claimed method (Compl. ¶225).

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

  • Technology Synopsis: This patent is directed to methods of administering a total daily dose of 2403 mg of pirfenidone, administered as three 801 mg doses with food. This specific regimen is claimed for treating IPF (Compl. ¶¶234, 236; ’947 Patent, Abstract).
  • Asserted Claims: At least one claim (Compl. ¶234).
  • Accused Features: The Sandoz product's proposed labeling is alleged to direct administration according to this specific infringing regimen (Compl. ¶236).

U.S. Patent No. 7,696,236 - "Method of Providing Pirfenidone Therapy to a Patient"

  • Technology Synopsis: Similar to the '700 patent, this patent covers methods of providing pirfenidone therapy that involve a dose escalation scheme to reach a final maintenance dose. The invention aims to improve patient tolerability by starting at a lower dose and titrating up over approximately two weeks (Compl. ¶¶245, 247; ’236 Patent, col. 2:1-19).
  • Asserted Claims: At least one claim (Compl. ¶245).
  • Accused Features: The Sandoz product's proposed label is alleged to instruct users to follow the patented dose escalation protocol (Compl. ¶247).

U.S. Patent No. 7,767,225 - "Capsule Formulation of Pirfenidone and Pharmaceutically Acceptable Excipients"

  • Technology Synopsis: This patent claims a capsule formulation of pirfenidone containing specific types and amounts of pharmaceutically acceptable excipients. The claimed formulation is designed to provide desirable pharmacokinetic responses, such as a prolonged absorption phase, compared to pirfenidone administered without such excipients (Compl. ¶¶256, 258; ’225 Patent, col. 4:5-14).
  • Asserted Claims: Claims 1-8 and 11-19 (Compl. ¶254).
  • Accused Features: The formulation of the Sandoz ANDA product is alleged to meet the limitations of the patent's composition claims (Compl. ¶¶256, 258).

U.S. Patent No. 7,988,994 - "Capsule Formulation of Pirfenidone and Pharmaceutically Acceptable Excipients"

  • Technology Synopsis: This patent is related to the '225 patent and is also directed to specific capsule formulations of pirfenidone. It claims formulations comprising pirfenidone and a specified range of excipients designed to achieve advantageous therapeutic and pharmacokinetic profiles (Compl. ¶¶267, 269; ’994 Patent, col. 4:5-14).
  • Asserted Claims: Claims 1-8, 10-14, 16-18, 20-24, and 26-28 (Compl. ¶265).
  • Accused Features: The composition of the Sandoz ANDA capsule product is alleged to infringe the claims of this formulation patent (Compl. ¶¶267, 269).

U.S. Patent No. 8,753,679 - "Capsule Formulation of Pirfenidone and Pharmaceutically Acceptable Excipients"

  • Technology Synopsis: This patent is also in the family of formulation patents with the '225 and '994 patents. It claims a capsule formulation of pirfenidone that includes specific excipients intended to create a stable and effective dosage form with desirable release properties (Compl. ¶¶278, 280; ’679 Patent, col. 4:5-14).
  • Asserted Claims: Claims 1-13, 15, 17-21, and 24-26 (Compl. ¶276).
  • Accused Features: The Sandoz ANDA product is alleged to be formulated in a way that infringes the patent's composition claims (Compl. ¶¶278, 280).

III. The Accused Instrumentality

  • Product Identification: The accused instrumentality is Defendants' 267 mg pirfenidone capsules (the "Sandoz ANDA Product"), for which Defendants submitted Abbreviated New Drug Application No. 212600 to the FDA for approval (Compl. ¶¶1, 9).
  • Functionality and Market Context: The Sandoz ANDA Product is a generic version of Plaintiffs' drug Esbriet®, which is used for treating Idiopathic Pulmonary Fibrosis (IPF) (Compl. ¶¶1, 22). The complaint alleges that by filing the ANDA, Defendants have represented that their product will have the same active ingredient, dosage form, dosage strength, and route of administration as Esbriet®, and will be bioequivalent (Compl. ¶73). The infringement action is based on the act of filing the ANDA, which seeks approval to market the generic product before the expiration of the patents-in-suit (Compl. ¶80). The central infringement theory for the method patents is that the proposed labeling for the Sandoz ANDA Product will instruct physicians and patients to use the generic drug in a manner that practices the steps claimed in the patents-in-suit (Compl. ¶85).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

The complaint does not provide a claim chart or sufficient narrative detail to construct a representative claim chart for any of the asserted patents. The infringement allegations are pleaded generally on "information and belief," stating that the submission of the Sandoz ANDA infringed at least one claim of each asserted patent under 35 U.S.C. § 271(e)(2)(A), and that the future commercial manufacture, use, or sale of the Sandoz ANDA Product would infringe under 35 U.S.C. §§ 271(a), (b), and/or (c) (Compl. ¶¶80-81, 91-92). The core of the infringement theory for the method-of-use patents is that the proposed product label for the Sandoz ANDA Product will inevitably adopt the same FDA-approved instructions as the Esbriet® label, which Plaintiffs allege embodies their patented methods (Compl. ¶85). For the formulation patents, the theory is that the Sandoz ANDA Product's composition will be the same as or equivalent to the claimed formulations (Compl. ¶170).

  • Identified Points of Contention:
    • Factual Question (Label Content): A primary issue will be the actual content of the Sandoz ANDA's proposed label. Discovery will be required to determine if the label's instructions for dosing, dose escalation, and management of adverse events (such as liver function abnormalities) correspond to the steps recited in the asserted method claims.
    • Technical Question (Formulation): For the formulation patents, a key dispute will concern whether the specific combination and percentages of pirfenidone and excipients in the Sandoz ANDA Product meet the limitations of the asserted composition claims, either literally or under the doctrine of equivalents.
    • Legal Question (Claim Scope & Validity): A central legal dispute will likely revolve around the validity of the method patents. Defendants may argue that the claimed methods of dose adjustment and management of side effects reflect standard medical practices and are therefore obvious over the prior art. The construction of claim terms will be critical in determining both infringement and validity.

V. Key Claim Terms for Construction

  • The Term: "grade 2 abnormality" (from claims of the ’729, ’707, ’462, and ’701 patents)

    • Context and Importance: This term defines the clinical trigger for the patented methods of dose modification. The infringement analysis for this family of patents will depend on whether the criteria for dose adjustment in the Sandoz label meet this definition. Practitioners may focus on this term because its definition is crucial for establishing direct infringement by the end-user as instructed by the label.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The term itself is not facially limited to specific biomarkers, which could suggest a broader application to general liver dysfunction.
      • Evidence for a Narrower Interpretation: The specifications of the patents provide a precise definition in table format, correlating "Grade 2" with specific fold-increases over the upper limit of normal (ULN) for biomarkers such as ALT, AST, and bilirubin (’729 Patent, Table 1, col. 7). This explicit definition strongly suggests a narrow construction that will likely be adopted by a court.

  • The Term: "about 2403 mg" (from claims of the ’729, ’707, ’947, and other patents)

    • Context and Importance: The term "about" qualifies the specific numerical dosage claimed in many of the patents. The scope of infringement will hinge on how much deviation from "2403 mg" is permitted by "about." This is critical because the Sandoz product is a generic equivalent and is expected to be dosed identically.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The use of "about" indicates the inventors did not intend to be limited to the exact number, allowing for routine manufacturing and clinical variances. The specification may describe ranges around this value, supporting a broader scope (’707 Patent, col. 2:30-34).
      • Evidence for a Narrower Interpretation: The specification repeatedly uses the precise "2403 mg" figure, derived from a specific regimen of three 267 mg capsules taken three times a day (’236 Patent, col. 14:1-4). A defendant may argue this context limits "about" to a very narrow range, if any.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges both induced and contributory infringement for all asserted patents. The primary basis for induced infringement is that Defendants' proposed product labeling, promotional materials, and package inserts will actively encourage and instruct physicians and patients to perform the patented methods of treatment (Compl. ¶¶85-86). The basis for contributory infringement is that the Sandoz ANDA product is not a staple article of commerce suitable for substantial non-infringing use and is especially made or adapted for use in an infringing manner (Compl. ¶¶83-84).
  • Willful Infringement: The complaint includes a general allegation that Defendants' activities were undertaken with knowledge of the Asserted Patents and without a good faith belief that they were not infringing, based on the Paragraph IV certification (Compl. ¶286).

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

  • A central evidentiary question will be one of direct correspondence: Will the specific instructions in Sandoz's yet-to-be-disclosed product label for dosage, dose escalation, and management of liver abnormalities mirror the steps recited in the asserted method claims? Similarly, will the precise chemical composition of the Sandoz capsule fall within the scope of the asserted formulation claims?
  • A core legal issue will be one of patentable subject matter and obviousness: Can the methods for dose modification and management of adverse events, as claimed in multiple patents, withstand a validity challenge based on arguments that they represent standard, obvious clinical practices for managing drug-induced toxicity rather than a patentable invention?
  • A key question of claim construction will be one of definitional precision: Will the term "grade 2 abnormality," which is explicitly defined by specific biomarker thresholds in the patents' specifications, be interpreted narrowly, and if so, will the Sandoz product label use an identical or equivalent definition to trigger a dose modification?