DCT

1:23-cv-00157

Theravance Biopharma R&D IP LLC v. Accord Healthcare Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:23-cv-00157, M.D.N.C., 02/17/2023
  • Venue Allegations: Plaintiff alleges venue is proper as to Defendant Accord Healthcare, Inc. because it resides and maintains a regular and established place of business in the district. Venue over the foreign defendants is alleged to be proper in any district where they are subject to personal jurisdiction.
  • Core Dispute: Plaintiffs allege that Defendants' filing of an Abbreviated New Drug Application (ANDA) to market a generic version of YUPELRI® (revefenacin) constitutes an act of infringement of five U.S. patents covering crystalline forms of the compound and methods of its use.
  • Technical Context: The technology relates to pharmaceutical compositions and methods for treating chronic obstructive pulmonary disease (COPD), a progressive lung disease, using the long-acting muscarinic antagonist revefenacin.
  • Key Procedural History: The litigation was initiated under the Hatch-Waxman Act following Defendants' submission of ANDA No. 218100 to the FDA, which included a Paragraph IV certification asserting that the patents-in-suit are invalid, unenforceable, and/or will not be infringed by the proposed generic product. Plaintiffs received a notice letter regarding the ANDA filing on January 6, 2023.

Case Timeline

Date Event
2009-07-15 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 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
2023-01-06 Accord Notice Letter Sent to Plaintiffs
2023-02-17 Complaint Filed

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

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 describes the need for therapeutic agents for pulmonary disorders that are suitable for administration by inhalation, noting that it is "highly desirable to have a crystalline form of the therapeutic agent that is neither hygroscopic nor deliquescent and which has a relatively high melting point," which allows the material to be micronized for inhalation without significant decomposition (’451 Patent, col. 2:9-17).
  • The Patented Solution: The invention provides novel crystalline forms of the biphenyl compound revefenacin, designated "Form III" and "Form IV," which are described as having different and particularly useful properties, including higher melting points, than previously known forms (’451 Patent, Abstract; col. 2:17-24). These improved physical properties are intended to make the compound more suitable for formulation into pharmaceutical compositions for inhalation devices.
  • Technical Importance: The development of stable, non-hygroscopic crystalline forms of an active pharmaceutical ingredient is a critical step in creating a reliable and manufacturable inhaled drug product with consistent dosing and a long shelf life (’451 Patent, col. 2:9-17).

Key Claims at a Glance

The complaint does not specify which claims of the ’451 patent are asserted, alleging infringement of "one or more claims" (Compl. ¶80). Independent claim 1 is representative of the patent's subject matter.

  • 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. 11,484,531 - "Methods for Treating Chronic Obstructive Pulmonary Disease"

Issued November 1, 2022.

The Invention Explained

  • Problem Addressed: The patent addresses the clinical challenge that some COPD patients with a lower-than-normal peak inspiratory flow rate (PIFR) may be unable to use dry powder inhalers effectively, suggesting that nebulizers are a better delivery method for this patient population (’531 Patent, col. 1:40-49).
  • The Patented Solution: The invention claims a targeted method of treatment. The method requires first identifying and selecting a specific sub-population of COPD patients—those who have both a low PIFR (less than about 60 L/min) and significant airflow obstruction (percent predicted FEV1 less than about 50 percent). Once this patient is selected, the method involves administering a specific dose of revefenacin (175 µg) via a nebulizer (’531 Patent, Abstract; col. 2:5-15).
  • Technical Importance: This patent claims a personalized medicine approach that tailors the drug delivery method to the physiological characteristics of the patient, aiming to improve therapeutic outcomes for a specific, difficult-to-treat patient group (’531 Patent, col. 2:1-4).

Key Claims at a Glance

The complaint asserts independent claim 1 (Compl. ¶113).

  • A method for treating chronic obstructive pulmonary disease in a patient, the method comprising:
  • (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; and
  • (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.

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

Issued September 19, 2017 (Compl. ¶35).

  • Technology Synopsis: Similar to the ’451 Patent, this patent addresses the need for stable crystalline forms of revefenacin suitable for inhaled therapies (’028 Patent, col. 2:5-17). The patent discloses and claims "Form IV," a different crystalline polymorph of the revefenacin freebase, characterized by its own unique powder X-ray diffraction pattern and thermal properties (’028 Patent, Abstract; col. 2:40-50).
  • Asserted Claims: The complaint alleges infringement of "one or more claims" without further specification (Compl. ¶88).
  • Accused Features: The accused feature is the crystalline structure of the revefenacin active pharmaceutical ingredient contained within the Accord ANDA Product (Compl. ¶66, ¶74).

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

Issued February 4, 2020 (Compl. ¶38).

  • Technology Synopsis: This patent is directed to pharmaceutical compositions containing the stable "Form III" crystalline freebase of revefenacin, as well as methods of treatment using this form (’081 Patent, Abstract; col. 2:27-54). The claims cover the formulation itself, rather than just the compound, providing a different layer of protection for the YUPELRI® product.
  • Asserted Claims: The complaint alleges infringement of "one or more claims" without further specification (Compl. ¶95).
  • Accused Features: The accused features are the pharmaceutical compositions of the Accord ANDA Product, which are alleged to contain the claimed crystalline form of revefenacin (Compl. ¶66, ¶75).

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

Issued May 18, 2021 (Compl. ¶41).

  • Technology Synopsis: This patent, like the ’451 Patent, claims the "Form III" crystalline freebase of revefenacin, characterized by its specific powder X-ray diffraction pattern (’289 Patent, col. 2:55-65). It represents a continuation of the same patent family, seeking to protect the same core invention related to a specific, stable polymorph of the drug substance.
  • Asserted Claims: The complaint alleges infringement of "one or more claims" without further specification (Compl. ¶102).
  • Accused Features: The accused feature is the crystalline structure of the revefenacin active pharmaceutical ingredient contained within the Accord ANDA Product (Compl. ¶66, ¶74).

III. The Accused Instrumentality

Product Identification

The accused instrumentality is the "Accord ANDA Product," a proposed generic revefenacin inhalation solution for which Accord Healthcare, Inc. and its affiliates filed Abbreviated New Drug Application No. 218100 with the FDA (Compl. ¶1, ¶16, ¶61).

Functionality and Market Context

The Accord ANDA Product contains revefenacin as its active ingredient and is intended for the same approved use as Plaintiffs' YUPELRI® product: the maintenance treatment of patients with COPD (Compl. ¶48, ¶66, ¶69). The product is formulated as an inhalation solution administered once daily via a nebulizer (Compl. ¶48). Accord has certified to the FDA that its product is bioequivalent to YUPELRI® (Compl. ¶67).
No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not provide sufficient detail for analysis of infringement of the ’451 Patent or the other crystalline form patents (’028, ’081, ’289). The allegations are conclusory statements that the submission of the ANDA and the future commercialization of the product will infringe one or more claims (Compl. ¶80-82, ¶88-89, ¶95-96, ¶102-103).

11,484,531 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
(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; Accord's product label will allegedly induce healthcare providers to select this specific patient population by providing information based on clinical guidelines (such as the GOLD guidelines) that identify such patients as appropriate candidates for nebulized therapy. ¶112, ¶123, ¶126, ¶131-134 col. 2:8-12
and (b) administering a pharmaceutical composition comprising about 175 µg of revefenacin...in 3 mL of an aqueous solution to the selected patient once daily using a nebulizer. Accord's ANDA Product is a revefenacin inhalation solution formulated at a strength of 175 mcg in 3 mL, and its label will instruct for once-daily administration by nebulizer. ¶111, ¶121, ¶122, ¶127 col. 2:12-15
  • Identified Points of Contention:
    • Factual Question (Crystalline Form Patents): The primary dispute for the ’451, ’028, ’081, and ’289 patents will be a factual one of physical characterization. What is the actual crystalline form of the revefenacin active pharmaceutical ingredient used in Accord's ANDA product, and does it meet the specific X-ray diffraction peak limitations recited in the asserted claims?
    • Legal Question (Method of Use Patent): The analysis of the ’531 patent will raise the legal question of specific intent to induce infringement. Does the language of Accord’s proposed product label merely state the patient population from clinical trials and describe the product's approved indication, or does it actively instruct, encourage, or promote that physicians perform the claimed two-part "selection" step, thereby demonstrating Accord's specific intent to cause infringement?

V. Key Claim Terms for Construction

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

(from claim 1 of the ’451 Patent and similar claims in the other crystalline form patents)

  • Context and Importance: This term is the central limitation defining the patented invention for the crystalline form patents. Infringement will depend entirely on whether scientific analysis of Accord's product shows a PXRD pattern that falls within the scope of this language. Practitioners may focus on this term because the precision of the peak values (e.g., 6.6±0.1) and the meaning of "comprising" will be critical to the infringement analysis.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The use of "comprising" suggests that the presence of the listed peaks is required, but the presence of additional, unlisted peaks would not defeat a finding of infringement (’451 Patent, col. 8:14-19). The specification’s use of ranges (e.g., ±0.1) for the peak positions also supports a construction that does not require absolute mathematical identity with the patent's examples.
    • Evidence for a Narrower Interpretation: Defendants may argue that "characterized by" requires that the listed peaks be the distinguishing features of the crystalline form. The patent provides a specific graphical representation of the PXRD pattern for Form III (e.g., ’451 Patent, FIG. 1), which could be used to argue that substantial identity to the overall pattern is required, not just the presence of a subset of peaks.

The Term: "selecting a patient... based on"

(from claim 1 of the ’531 Patent)

  • Context and Importance: This active step is the preamble to the method claim and is essential for infringement. The dispute will likely center on what actions by a healthcare provider constitute "selecting...based on" the two specified criteria (low PIFR and low FEV1). An inducement claim requires showing that the accused infringer's instructions inevitably lead to this step being performed.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The claim language does not specify how the selection must be made. A plaintiff might argue that a physician's mental recognition that a patient meets the two criteria, followed by a prescription for the nebulized drug, is sufficient to meet this limitation.
    • Evidence for a Narrower Interpretation: A defendant could argue that "selecting...based on" implies an affirmative diagnostic or filtering step performed for the specific purpose of making the treatment decision, as opposed to simply prescribing a drug to a patient who happens to have those characteristics. The complaint itself points to external guidelines and clinical knowledge, which may support an argument that the physician's selection is based on their own medical judgment rather than being dictated by the product's label (Compl. ¶126, ¶129, ¶131).

VI. Other Allegations

  • Indirect Infringement: The complaint's theory for the ’531 method-of-use patent is entirely one of indirect infringement. It alleges that upon FDA approval, Accord will actively induce infringement under 35 U.S.C. § 271(b) by marketing its product with an FDA-approved package insert that will "direct healthcare providers and patients" to perform the claimed method (Compl. ¶110-112). The complaint alleges Accord knows and "specifically intends" that healthcare providers will select the claimed patient population for treatment with its product (Compl. ¶132, ¶134).
  • Willful Infringement: The complaint alleges that Accord had knowledge of all five patents-in-suit when it submitted its ANDA and that its infringement "has been, and continues to be, deliberate" (Compl. ¶70, ¶84, ¶91, ¶98, ¶105). This allegation is based on the statutory scheme of the Hatch-Waxman Act, which requires an ANDA filer with a Paragraph IV certification to notify the patent holder.

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

  1. A central factual question will be one of physical characterization: Does the revefenacin active pharmaceutical ingredient in Accord's ANDA Product exhibit the specific crystalline structure, as defined by the powder X-ray diffraction peaks recited in the asserted claims of the ’451, ’028, ’081, and ’289 patents, or does it utilize a non-infringing amorphous or alternative polymorphic form?
  2. A core legal issue for the method-of-use patent will be one of specific intent for inducement: Does the language of Accord's proposed product label constitute specific instruction or encouragement for physicians to perform the claimed method—including the affirmative step of "selecting" a patient based on the dual criteria of low PIFR and low FEV1—or does the label merely provide clinical trial data without actively promoting the patented selection method?