DCT

1:23-cv-00926

Theravance Biopharma R&D IP LLC v. Eugia Pharma Specialties Ltd

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Key Events
Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:23-cv-00926, D.N.J., 02/16/2023
  • Venue Allegations: Venue is alleged to be proper in the District of New Jersey because several defendant entities have regular and established places of business in the state, have committed acts of infringement in the state, and/or have previously consented to venue in the district in prior Hatch-Waxman litigation.
  • Core Dispute: Plaintiffs allege that multiple generic drug manufacturers, by filing Abbreviated New Drug Applications (ANDAs) with the FDA, seek to market generic versions of Plaintiffs' YUPELRI® (revefenacin) inhalation solution, thereby infringing five patents related to crystalline forms of revefenacin and methods of its use for treating Chronic Obstructive Pulmonary Disease (COPD).
  • Technical Context: The dispute concerns revefenacin, a long-acting muscarinic antagonist used for maintenance treatment of COPD, a progressive lung disease, which is typically administered via inhalation.
  • Key Procedural History: This action was initiated under the Hatch-Waxman Act following Plaintiffs' receipt of Paragraph IV certification notice letters from each defendant group. In these letters, the defendants asserted that the patents-in-suit are invalid, unenforceable, or will not be infringed by their proposed generic products. The complaint was filed within the 45-day statutory window, triggering an automatic 30-month stay of FDA approval for the defendants' ANDAs.

Case Timeline

Date Event
2009-07-15 Earliest Priority Date for ’451, ’028, ’081, and ’289 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 Earliest 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
2023-01-05 Mankind, Teva, and Lupin send Paragraph IV Notice Letters
2023-01-06 Accord sends Paragraph IV Notice Letter
2023-01-09 Eugia sends Paragraph IV Notice Letter
2023-01-13 Orbicular sends Paragraph IV Notice Letter
2023-01-17 Cipla sends Paragraph IV Notice Letter
2023-02-16 Complaint Filed

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

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

The Invention Explained

  • Problem Addressed: The patent addresses the need for crystalline forms of therapeutic agents used in inhalation devices that are stable, not hygroscopic (i.e., do not readily absorb moisture from the air), and have a high melting point to allow for micronization (milling into very fine particles suitable for inhalation) without decomposition ('081 Patent, col. 1:12-24).
  • The Patented Solution: The invention provides specific crystalline forms of the biphenyl compound revefenacin. The patent describes these forms, identified as "Form III" and "Form IV," by their unique powder x-ray diffraction (PXRD) patterns, which act as a structural fingerprint for the crystal lattice ('081 Patent, col. 2:25-50). These specific forms are asserted to possess the desired physical properties for use in pharmaceutical products for treating pulmonary disorders ('081 Patent, col. 1:25-34).
  • Technical Importance: Developing a stable, manufacturable crystalline form of an active pharmaceutical ingredient is a critical step in drug development, particularly for inhaled drugs where particle size and stability directly impact safety and efficacy.

Key Claims at a Glance

  • The complaint asserts infringement of "one or more claims" of the ’451 patent (Compl. ¶293). The patent contains multiple independent claims directed to the crystalline forms and compositions containing them.
  • Representative independent claim 1 recites:
    • A crystalline freebase of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl] methylamino}ethyl)piperidin-4-yl ester
    • characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 6.6±0.1, 13.1±0.1, 18.6±0.1, 19.7±0.1, and 20.2±0.1
    • and further characterized by having five or more additional diffraction peaks at 2θ values selected from a specified list.
    • designated as Form III;
    • and having a melting point of about 125° C.

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

The Invention Explained

  • Problem Addressed: As a continuation of the application leading to the ’451 patent, the ’028 patent addresses the same technical challenge: identifying stable, non-hygroscopic, high-melting-point crystalline forms of revefenacin suitable for formulation as an inhaled therapeutic ('081 Patent, col. 1:12-24).
  • The Patented Solution: The ’028 patent claims specific crystalline forms of revefenacin, including Form III and Form IV, defining them by their characteristic PXRD patterns. The patent discloses that these forms exhibit advantageous properties, such as Form III showing reversible water uptake of less than 2% between 0 and 90% relative humidity, indicating low hygroscopicity ('081 Patent, col. 8:59-65).
  • Technical Importance: This technology provides specific, defined solid-state forms of revefenacin, which can enable consistent manufacturing and stable pharmaceutical products for treating respiratory diseases like COPD.

Key Claims at a Glance

  • The complaint asserts infringement of "one or more claims" of the ’028 patent (Compl. ¶301). The patent includes independent claims to crystalline Form III and pharmaceutical compositions containing it.
  • Representative independent claim 1 recites:
    • Crystalline freebase Form III of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl] methylamino}-ethyl)piperidin-4-yl ester
    • characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 6.6±0.1, 13.1±0.1, 18.6±0.1, 19.7±0.1, and 20.2±0.1; and
    • further characterized by having five or more additional diffraction peaks at 2θ values selected from a specified list.

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

Technology Synopsis

The ’081 Patent, part of the same family as the ’451 and ’028 patents, claims pharmaceutical compositions containing specific crystalline forms of revefenacin. The invention is directed to formulations suitable for treating pulmonary disorders by delivering these stable crystalline forms ('081 Patent, Abstract).

Asserted Claims

"one or more claims" (Compl. ¶308).

Accused Features

The proposed generic revefenacin inhalation solution, which allegedly is or contains a claimed crystalline form of revefenacin (Compl. ¶172).

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

Technology Synopsis

This patent continues the same line of invention, claiming methods of treating COPD by administering an aqueous pharmaceutical composition of revefenacin via a nebulizer. The claims are directed to the administration of a solution prepared by dissolving one of the specific crystalline forms of revefenacin ('289 Patent, claim 1).

Asserted Claims

"one or more claims" (Compl. ¶315).

Accused Features

The defendants' proposed use of their generic revefenacin products, which are aqueous solutions for nebulization intended to treat COPD (Compl. ¶175).

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

Technology Synopsis

The ’531 Patent claims a method for treating a specific subgroup of COPD patients. The method involves first selecting a patient who has both a low peak inspiratory flow rate (PIFR < ~60 L/min) and severe airflow obstruction (FEV1 < ~50% predicted), and then administering a specific dose of revefenacin using a nebulizer ('531 Patent, Abstract; claim 1).

Asserted Claims

Independent Claim 1 (Compl. ¶325).

Accused Features

The defendants' proposed product labeling, which Plaintiffs allege will instruct and encourage healthcare providers to select this specific patient subgroup and administer the generic drug, thereby inducing infringement (Compl. ¶323-324).

III. The Accused Instrumentality

Product Identification

The accused instrumentalities are the proposed generic "revefenacin inhalation solution" products for which each defendant group has filed an ANDA with the FDA (e.g., the "Eugia ANDA Product," "Mankind ANDA Product," etc.) (Compl. ¶168, 185, 203, 221, 239, 256, 274).

Functionality and Market Context

The defendants' products are described as generic versions of YUPELRI®, intended for the same indication: the maintenance treatment of patients with COPD (Compl. ¶175, 193). The ANDA submissions assert that the proposed generic products are bioequivalent to YUPELRI® (Compl. ¶173, 191). Functionally, they are sterile aqueous solutions of revefenacin provided in unit-dose vials for oral inhalation via a nebulizer (Compl. ¶155, 334). The filing of the ANDAs represents a commercial effort by the defendants to enter the market for revefenacin inhalation solutions prior to 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 alleges that the submission of an ANDA for a product containing a crystalline form of revefenacin constitutes infringement of one or more claims of the ’451 patent (Compl. ¶292). The complaint does not specify asserted claims or provide a detailed mapping. The following table summarizes the infringement theory for a representative claim.

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A crystalline freebase of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl] methylamino}ethyl)piperidin-4-yl ester... The active ingredient of the Defendants' ANDA products is revefenacin, the same active ingredient described in the claim. ¶172, ¶190 col. 6:52-58
...characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 6.6±0.1, 13.1±0.1, 18.6±0.1, 19.7±0.1, and 20.2±0.1...designated as Form III... The complaint alleges that the Defendants' ANDA products contain or are made from compositions claimed in the patents-in-suit. This implies the products contain the crystalline form defined by these characteristic peaks. ¶172, ¶180 col. 8:1-24
...and having a melting point of about 125° C. The complaint alleges infringement of claims covering crystalline forms that possess specific physical properties, such as a distinct melting point. ¶172, ¶180 col. 8:40-43
  • Identified Points of Contention:
    • Factual Question: A central issue will be whether the specific crystalline form of revefenacin in each defendant's proposed generic product is, in fact, the "Form III" (or other form) claimed in the patent. This will likely be determined through expert analysis of technical data from the defendants' ANDAs, such as PXRD and DSC results.
    • Scope Question: Does the manufacturing process used by each defendant result in a product that meets the specific set of diffraction peaks recited in the asserted claims? Minor variations in PXRD patterns could become a focus of dispute.

'028 Patent Infringement Allegations

The infringement allegations for the ’028 patent are substantively identical to those for the ’451 patent, as it claims related crystalline forms of the same compound (Compl. ¶300-301).

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
Crystalline freebase Form III of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl] methylamino}-ethyl)piperidin-4-yl ester... The active ingredient of the Defendants' ANDA products is revefenacin. ¶172, ¶190 col. 6:52-58
...characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 6.6±0.1, 13.1±0.1, 18.6±0.1, 19.7±0.1, and 20.2±0.1... The complaint alleges that the proposed generic products contain the claimed crystalline Form III of revefenacin, which is defined by this set of structural fingerprints. ¶172, ¶180 col. 8:1-17
  • Identified Points of Contention:
    • Evidentiary Question: The key dispute will be a factual one, turning on scientific evidence. What do the defendants' confidential ANDA filings show regarding the precise crystalline structure of the revefenacin active ingredient they intend to market?
    • Claim Scope: As with the ’451 patent, the interpretation of the term "characterized by" and the precision required to match the listed 2θ values will be important. The analysis will question whether defendants' products fall within the literal scope of the claims or if an argument under the doctrine of equivalents is necessary.

V. Key Claim Terms for Construction

For the compound patents (’451, ’028, ’081, ’289), a central issue will be the definition of the crystalline forms themselves. For the ’531 method patent, the key terms define the targeted patient population.

Term: "crystalline freebase... characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of..."

(from claims of ’451 and ’028 patents)

  • Context and Importance: This language defines the patented invention. Infringement will depend entirely on whether the defendants' products possess a crystal structure that generates the claimed PXRD "fingerprint." Practitioners may focus on this language because the case will turn on a comparison of analytical data, and any ambiguity in how to interpret "comprising" or the ±0.1 margin of error could be dispositive.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The use of the open-ended term "comprising" suggests that a product could infringe even if its PXRD pattern includes additional, unlisted peaks, as long as it contains the required ones ('081 Patent, col. 2:39-50).
    • Evidence for a Narrower Interpretation: The claims recite specific 2θ values with a defined margin (±0.1). A defendant may argue that its product's peaks, even if similar, fall outside this precise range, or that the overall pattern, when viewed holistically, represents a different, non-infringing crystalline form ('081 Patent, col. 10:9-24).

Term: "selecting a patient... 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"

(from claim 1 of the ’531 patent)

  • Context and Importance: This phrase defines the specific sub-population of COPD patients for whom the patented method is intended. The inducement allegation against the defendants hinges on whether their product labels will lead doctors to identify and treat this exact group. Practitioners may focus on this term because its construction will determine the scope of infringing conduct that Plaintiffs must prove is induced.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The use of "about" for both the PIFR and FEV1 values suggests the claim is not limited to exact numerical cutoffs and may cover patients with values close to 60 L/min or 50 percent ('531 Patent, col. 2:11-16).
    • Evidence for a Narrower Interpretation: The patent specification provides specific clinical context for these values, linking them to patients for whom nebulizers are recommended over dry powder inhalers. A defendant might argue that the term should be limited to this specific clinical scenario, where a physician makes a conscious choice of a nebulizer for a patient with demonstrably poor inspiratory capability ('531 Patent, col. 2:1-5).

VI. Other Allegations

Indirect Infringement

The complaint makes detailed allegations of induced infringement, particularly concerning the ’531 method patent. It alleges that upon FDA approval, the defendants will market their ANDA products with a package insert that will "direct healthcare providers and patients in the use" of the product (Compl. ¶323). This direction, which allegedly mirrors the YUPELRI® label, is claimed to encourage and instruct medical professionals to perform the patented method of selecting specific patient types and administering the drug, thereby actively and intentionally inducing infringement (Compl. ¶324, ¶335, ¶346).

Willful Infringement

Willfulness is alleged based on the defendants' knowledge of the patents-in-suit at the time they filed their ANDAs, as evidenced by their Paragraph IV certifications (Compl. ¶176, 194, 212, 230, 247, 265, 282). The complaint asserts that each defendant's infringement "has been, and continues to be, deliberate" (Compl. ¶296, 303, 310, 317, 354).

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

This Hatch-Waxman litigation will likely center on three fundamental questions for the court:

  • A core issue will be one of structural identity: Do the crystalline forms of revefenacin in the defendants' proposed generic products, as detailed in their confidential ANDA filings, fall within the scope of the specific PXRD patterns and physical properties claimed in the ’451, ’028, ’081, and ’289 patents?
  • A key legal and factual question will be one of induced infringement: Will the defendants' final, FDA-approved product labels contain instructions that actively encourage or instruct physicians to perform the patented method of Claim 1 of the ’531 patent—specifically, to select the defined sub-population of COPD patients (low PIFR and low FEV1) for treatment with the nebulized product?
  • Finally, the case will involve a significant question of patent validity: Although not detailed in the complaint, the defendants' Paragraph IV certifications assert that the patents are invalid. A central battleground will therefore be whether the defendants can prove, by clear and convincing evidence, that the asserted claims are invalid as obvious, not enabled, or otherwise failing to meet statutory requirements.