DCT

2:24-cv-02689

Theravance Biopharma R&D IP LLC v. Qui Pharmaceutical Co Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 2:24-cv-02689, E.D. Pa., 06/18/2024
  • Venue Allegations: Venue is alleged to be proper in the Eastern District of Pennsylvania because Defendant Qilu Pharma Inc. is incorporated in Pennsylvania and maintains its principal place of business within the district, making it a resident for venue purposes.
  • Core Dispute: Plaintiff alleges that Defendant’s filing of an Abbreviated New Drug Application (ANDA) to market a generic version of the COPD drug YUPELRI® (revefenacin) constitutes an act of infringement of seven patents related to the drug's crystalline forms and methods of use.
  • Technical Context: The technology concerns pharmaceutical compositions of revefenacin, a long-acting muscarinic antagonist used for the maintenance treatment of chronic obstructive pulmonary disease (COPD), a progressive lung disease.
  • Key Procedural History: This lawsuit was triggered by Qilu's submission of ANDA No. 219523 to the FDA, seeking approval to market its generic revefenacin product. The complaint states that Qilu provided Plaintiffs with a Paragraph IV Certification notice on May 6, 2024, asserting that the patents-in-suit are invalid, unenforceable, or will not be infringed by Qilu's product. Such a certification provides the jurisdictional basis for this patent infringement action under the Hatch-Waxman Act.

Case Timeline

Date Event
2009-07-15 Priority Date for ’451, ’028, ’081, ’289, ’948, ’898 Patents
2013-09-24 U.S. Patent No. 8,541,451 Issues
2017-09-19 U.S. Patent No. 9,765,028 Issues
2018-08-30 Priority Date for ’531 Patent
2020-02-04 U.S. Patent No. 10,550,081 Issues
2021-05-18 U.S. Patent No. 11,008,289 Issues
2022-11-01 U.S. Patent No. 11,484,531 Issues
2023-07-04 U.S. Patent No. 11,691,948 Issues
2024-01-02 U.S. Patent No. 11,858,898 Issues
2024-05-06 Qilu sends Paragraph IV Notice Letter to Plaintiffs
2024-06-18 Complaint Filed

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

This report provides a full analysis for U.S. Patent No. 8541451, the first patent listed in the complaint, and U.S. Patent No. 11484531, which is the subject of the most detailed infringement allegations. The remaining patents are summarized in capsule form.

U.S. Patent No. 8,541,451 - "Crystalline Freebase Forms of a Biphenyl Compound," Issued September 24, 2013

The Invention Explained

  • Problem Addressed: The patent addresses the need for a stable, crystalline form of a therapeutic agent for pulmonary disorders. For use in inhalation devices like dry powder inhalers (DPIs), it is desirable to have a form of the active ingredient that is not hygroscopic (does not readily absorb moisture) and has a high melting point, which allows the material to be micronized into fine particles without significant decomposition ('081 Patent, col. 2:10-18).
  • The Patented Solution: The invention provides specific crystalline freebase forms of a biphenyl compound (revefenacin) that possess these desirable physical properties ('081 Patent, Abstract; '081 Patent, col. 2:18-24). The patent describes two distinct crystalline polymorphs, designated Form III and Form IV, which are characterized by specific powder x-ray diffraction (PXRD) patterns and melting points ('081 Patent, col. 2:35-51). These stable forms are intended to be suitable for pharmaceutical compositions delivered via inhalation ('081 Patent, col. 4:45-51).
  • Technical Importance: The development of a stable crystalline polymorph is a critical step in drug development, as the physical form of an active ingredient can significantly impact its stability, manufacturability, and bioavailability, particularly for inhaled drugs where particle size and stability are paramount ('081 Patent, col. 2:5-18).

Key Claims at a Glance

  • The complaint does not identify specific claims of the ’451 Patent asserted against Qilu, stating only that Qilu’s actions would infringe "one or more claims" (Compl. ¶82).

U.S. Patent No. 11,484,531 - "Methods for Treating Chronic Obstructive Pulmonary Disease," Issued November 1, 2022

The Invention Explained

  • Problem Addressed: The patent addresses the challenge of delivering an adequate dose of an inhaled bronchodilator to certain COPD patients. Patients with severe COPD often have a low peak inspiratory flow rate (PIFR), making them unable to generate sufficient force to effectively use dry powder inhalers, which require a strong inhalation to de-aggregate the drug powder into fine, respirable particles (Compl. ¶¶ 58-59).
  • The Patented Solution: The invention is a method of treatment that identifies a specific patient subpopulation that benefits most from a nebulized bronchodilator. The method involves first "selecting" a COPD patient based on two criteria—a PIFR of less than about 60 L/min and a lung function (percent predicted FEV₁) of less than about 50%—and then "administering" a specific dose of revefenacin using a nebulizer, which actively aerosolizes the drug, making it suitable for patients with weak inspiratory effort (’531 Patent, claim 1; Compl. ¶114).
  • Technical Importance: This method provides a targeted therapeutic approach, ensuring that a patient who are physiologically unable to benefit fully from dry powder inhalers receive an effective treatment via a nebulizer, thereby improving therapeutic outcomes in a vulnerable patient group (Compl. ¶¶ 59, 132).

Key Claims at a Glance

  • The complaint asserts independent claim 1 (Compl. ¶114).
  • The essential elements of claim 1 are:
    • A method for treating COPD in a patient, comprising:
    • (a) selecting a patient having COPD for treatment based on the patient having a peak inspiratory flow rate less than about 60 L/min and a percent predicted force expiratory volume in one second less than about 50 percent; and
    • (b) administering a pharmaceutical composition comprising about 175 µg of revefenacin, or a salt thereof, in 3 mL of an aqueous solution to the selected patient once daily using a nebulizer.
  • The complaint notes that dependent claims may also be asserted (Compl. ¶115).

U.S. Patent No. 9,765,028 - "Crystalline Freebase Forms of a Biphenyl Compound," Issued September 19, 2017

  • Technology Synopsis: This patent, part of the same family as the '451 patent, also claims specific stable crystalline forms of revefenacin suitable for use in pharmaceutical compositions, particularly for inhaled therapies for pulmonary disorders (Compl. ¶30).
  • Asserted Claims: The complaint does not identify specific asserted claims (Compl. Count II).
  • Accused Features: The complaint alleges that Qilu's ANDA Product, containing revefenacin, will infringe the patent (Compl. ¶90).

U.S. Patent No. 10,550,081 - "Crystalline Freebase Forms of a Biphenyl Compound," Issued February 4, 2020

  • Technology Synopsis: This patent continues the same family of inventions, claiming specific crystalline polymorphs of revefenacin with advantageous physical properties for pharmaceutical formulation (Compl. ¶33).
  • Asserted Claims: The complaint does not identify specific asserted claims (Compl. Count III).
  • Accused Features: The complaint alleges that the Qilu ANDA Product will infringe the patent (Compl. ¶97).

U.S. Patent No. 11,008,289 - "Crystalline Freebase Forms of a Biphenyl Compound," Issued May 18, 2021

  • Technology Synopsis: This patent also claims specific crystalline forms of revefenacin, focusing on polymorphs with stability and manufacturing characteristics suitable for inhaled drugs (Compl. ¶36).
  • Asserted Claims: The complaint does not identify specific asserted claims (Compl. Count IV).
  • Accused Features: The complaint alleges infringement by the Qilu ANDA Product (Compl. ¶¶ 103-104).

U.S. Patent No. 11,691,948 - "Crystalline Freebase Forms of a Biphenyl Compound," Issued July 4, 2023

  • Technology Synopsis: This patent is another member of the family directed to stable crystalline polymorphs of revefenacin for use in treating pulmonary disorders (Compl. ¶42).
  • Asserted Claims: The complaint does not identify specific asserted claims (Compl. Count VI).
  • Accused Features: The complaint alleges infringement by the Qilu ANDA Product (Compl. ¶¶ 140-141).

U.S. Patent No. 11,858,898 - "Crystalline Freebase Forms of a Biphenyl Compound," Issued January 2, 2024

  • Technology Synopsis: The most recent patent in the family, it also claims specific crystalline forms of revefenacin with properties advantageous for pharmaceutical development and delivery (Compl. ¶45).
  • Asserted Claims: The complaint does not identify specific asserted claims (Compl. Count VII).
  • Accused Features: The complaint alleges infringement by the Qilu ANDA Product (Compl. ¶148).

III. The Accused Instrumentality

Product Identification

  • The accused instrumentality is Qilu's proposed generic revefenacin inhalation solution, submitted to the FDA for approval under ANDA No. 219523 (the "Qilu ANDA Product") (Compl. ¶¶ 1, 62).

Functionality and Market Context

  • The Qilu ANDA Product contains revefenacin, which is the same active ingredient as in Plaintiffs' YUPELRI® product (Compl. ¶67). It is formulated as an inhalation solution for oral administration via a nebulizer for the maintenance treatment of patients with COPD (Compl. ¶¶ 1, 70).
  • Qilu seeks approval for the same indication as YUPELRI® and asserts that its product is bioequivalent to YUPELRI® (Compl. ¶¶ 68-69). The commercialization of the Qilu ANDA Product is contingent on FDA approval, which Plaintiffs seek to prevent until after the expiration of the patents-in-suit (Compl. ¶1).
  • No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

’451 Patent Infringement Allegations

The complaint does not provide sufficient detail for analysis of specific infringement allegations for the ’451 Patent. Count I contains general allegations that the commercial manufacture, use, or sale of the Qilu ANDA Product would infringe one or more claims of the patent, but it does not identify which claims are asserted or map any claim limitations to features of the accused product (Compl. ¶¶ 81-83).

’531 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method for treating chronic obstructive pulmonary disease in a patient, the method comprising: Qilu is seeking approval to market its ANDA Product for the maintenance treatment of patients with COPD. ¶70 col. 4:40-44
(a) selecting a patient having chronic obstructive pulmonary disease for treatment based on the patient having a peak inspiratory flow rate less than about 60 L/min and a percent predicted force expiratory volume in one second less than about 50 percent; The complaint alleges that healthcare providers, guided by the product’s package insert and clinical guidelines, will select patients with these specific characteristics because such patients are known to be poor candidates for dry powder inhalers and are preferentially treated with nebulized drugs. ¶124, ¶132-135 col. 3:40-44
(b) administering a pharmaceutical composition comprising about 175 µg of revefenacin, or a pharmaceutically acceptable salt thereof, in 3 mL of an aqueous solution to the selected patient once daily using a nebulizer. The Qilu ANDA Product is a 175 mcg/3 mL revefenacin solution, and its package insert, expected to be substantially similar to the YUPELRI® insert, will instruct for once-daily administration via a nebulizer. ¶118, ¶122, ¶123, ¶128 col. 4:6-10
  • Identified Points of Contention:
    • Scope Questions ('451 and other form patents): The primary question will be factual: does the revefenacin active ingredient in the Qilu ANDA Product, as manufactured by Qilu, possess the specific crystalline structure defined by the claims of these patents? This will turn on physical evidence obtained through discovery, such as PXRD and other analytical data.
    • Technical Questions ('531 patent): The infringement theory for the '531 patent is one of inducement. The central question will be whether Qilu’s proposed package insert instructs, encourages, or promotes the specific "selecting" step of claim 1. Does the label merely describe the patient population from clinical trials (e.g., those with "moderate to very severe COPD"), or does it actively guide prescribers to select patients based on the specific PIFR and FEV₁ thresholds recited in the claim? The distinction between merely providing information and actively inducing a specific method of use will be critical.

V. Key Claim Terms for Construction

Analysis of key claim terms for the crystalline form patents ('451, '028, etc.) is not possible as the complaint does not identify any asserted claims. For the '531 patent, one term is central.

  • The Term: "selecting a patient ... based on" the specified PIFR and FEV₁ criteria (’531 Patent, claim 1).
  • Context and Importance: This "selecting" limitation constitutes a mental step performed by a healthcare provider. The viability of Plaintiffs' inducement claim against Qilu, a drug manufacturer, depends on whether Qilu's product label can be shown to cause a provider to perform this specific selection. Practitioners may focus on this term because its construction will determine what level of information on a drug label crosses the line from describing a drug's use to inducing infringement of a patented method.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: A party could argue that "based on" does not require the PIFR and FEV₁ criteria to be the sole or even primary reason for selection, but merely influential factors. The patent's specification may describe the general clinical problem of treating patients with low inspiratory flow, suggesting that any label guiding use in this population meets the "based on" requirement.
    • Evidence for a Narrower Interpretation: A party could argue that "selecting... based on" requires a deliberate application of the two specific numerical criteria recited in the claim. The claim's recitation of specific thresholds ("< about 60 L/min" and "< about 50 percent") may support an interpretation that a prescriber must consciously apply these cutoffs for the selection step to be performed as claimed.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that Qilu will actively induce infringement of the '531 patent upon approval of its ANDA (Compl. ¶111). The basis for this allegation is that Qilu will market its product with an FDA-approved package insert that will "direct healthcare providers and patients in the use of Qilu's ANDA Product," thereby causing them to perform the steps of the patented method (Compl. ¶¶ 112-113).
  • Willful Infringement: The complaint alleges that Qilu had knowledge of the patents-in-suit when it submitted its ANDA and that its infringement "has been, and continues to be, deliberate" (Compl. ¶¶ 85, 92, 99, 106, 135, 143, 150). This allegation of pre-suit knowledge and deliberate conduct forms the basis for a potential claim of willful infringement.

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

The resolution of this case will likely depend on the answers to two central questions, one factual and one a mixed question of fact and law:

  1. A core issue will be one of physical form: Does the revefenacin active pharmaceutical ingredient within Qilu's proposed generic product, as it will be commercially manufactured, exhibit the specific crystalline polymorph structures defined by the claims of the six composition-of-matter patents?
  2. A key question will be one of inducement: Does the language in Qilu’s proposed drug label rise to the level of actively instructing or encouraging physicians to perform the specific two-part "selecting" step of claim 1 of the '531 patent, or does it merely provide clinical information that leaves the selection criteria to the independent medical judgment of the prescriber?