DCT

1:19-cv-02100

Azurity Pharma Inc v. Alkem Laboratories Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:19-cv-02100, D. Del., 04/13/2021
  • Venue Allegations: Plaintiff alleges venue is proper based on Defendant’s persistent and continuous business contacts with Delaware, substantial revenue derived from the state, and a history of engaging in patent litigation in the district.
  • Core Dispute: Plaintiff alleges that Defendant’s submission of an Abbreviated New Drug Application (ANDA) to the FDA for a generic version of Plaintiff’s Epaned® oral solution constitutes an act of infringement of seven U.S. patents related to stable liquid enalapril formulations.
  • Technical Context: The technology concerns pharmaceutical formulations of enalapril, an ACE inhibitor for treating hypertension, specifically as a stable, ready-to-use oral liquid solution suitable for pediatric and other patients unable to swallow tablets.
  • Key Procedural History: This is a Hatch-Waxman action initiated after Defendant Alkem sent Notice Letters to Plaintiff Silvergate on September 23, 2019, and February 2, 2021, advising of its ANDA filing seeking approval to market a generic version of Silvergate's Epaned® product prior to the expiration of the patents-in-suit. All asserted patents are listed in the FDA's "Orange Book" in connection with Silvergate's New Drug Application for Epaned®.

Case Timeline

Date Event
2016-03-18 Earliest Patent Priority Date for all Patents-in-Suit
2017-06-06 U.S. Patent No. 9,669,008 Issued
2017-11-07 U.S. Patent No. 9,808,442 Issued
2018-08-07 U.S. Patent No. 10,039,745 Issued
2018-12-18 U.S. Patent No. 10,154,987 Issued
2019-09-23 Alkem Notice Letter regarding ’008, ’442, ’745, ’987 patents
2020-09-15 U.S. Patent No. 10,772,868 Issued
2020-09-29 U.S. Patent No. 10,786,482 Issued
2021-02-02 Alkem Notice Letter regarding ’868 and ’482 patents
2021-02-16 U.S. Patent No. 10,918,621 Issued
2021-04-13 First Amended Complaint Filed

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

Seven patents are asserted in the complaint. A full analysis is provided for U.S. Patent Nos. 10,039,745 and 10,154,987, the first two asserted patents for which documents were provided. Capsule summaries are provided for the other asserted patents.

U.S. Patent No. 10,039,745 - Enalapril Formulations

  • Patent Identification: U.S. Patent No. 10,039,745, "Enalapril Formulations," issued August 7, 2018.

The Invention Explained

  • Problem Addressed: The patent addresses the difficulty certain patient populations, such as children and the elderly, have in swallowing solid oral dosage forms like enalapril tablets. It also notes that creating liquid versions by crushing tablets in a pharmacy setting leads to inaccurate dosing, instability, and potential contamination. (’745 Patent, col. 5:9-41).
  • The Patented Solution: The invention is a stable, ready-to-use oral liquid formulation of enalapril. Stability is achieved through a specific combination of excipients: a sucralose sweetener, a citric acid buffer, and a sodium benzoate preservative, all maintained at a pH of less than about 3.5. This combination is described as stable for at least 12 months at refrigerated temperatures. (’745 Patent, Abstract; col. 2:9-17). The patent further notes that these formulations do not require mannitol or silicon dioxide, which were described as necessary for stability in prior powder-based compositions. (’745 Patent, col. 5:48-55).
  • Technical Importance: This formulation provides a safe, effective, and stable oral liquid form of enalapril that allows for accurate dosing and improved patient compliance, particularly for pediatric patients. (’745 Patent, col. 5:55-63).

Key Claims at a Glance

  • The complaint asserts "one or more claims" of the ’745 Patent (Compl. ¶60). Independent claims 1 and 11 are composition claims.
  • Essential elements of Independent Claim 1 include:
    • A stable oral liquid formulation comprising about 0.6 to about 1.2 mg/ml enalapril.
    • A buffer comprising about 0.8 to about 3.5 mg/ml citric acid and about 0.1 to about 0.8 mg/ml sodium citrate.
    • About 0.7 to about 1.2 mg/ml sodium benzoate.
    • Water.
    • Wherein the formulation is stable at about 5±3° C. for at least 12 months and has about 95% w/w or greater of the initial enalapril amount and about 5% w/w or less total impurity at the end of the storage period.

U.S. Patent No. 10,154,987 - Enalapril Formulations

  • Patent Identification: U.S. Patent No. 10,154,987, "Enalapril Formulations," issued December 18, 2018.

The Invention Explained

  • Problem Addressed: The patent addresses the same technical problems as the ’745 Patent: the unsuitability of solid tablets for certain patients and the instability and inconsistency of pharmacist-compounded liquid versions of enalapril. (’987 Patent, col. 1:21-36; col. 5:16-48).
  • The Patented Solution: The invention is a method of treating hypertension by administering a stable oral liquid enalapril formulation. The formulation's stability is based on the same specific combination of a sucralose sweetener, a citric acid/sodium citrate buffer, and a sodium benzoate preservative at a controlled pH. (’987 Patent, Abstract; col. 2:20-41). The specification also highlights that, unlike prior art powder formulations, the invention does not require mannitol or silicon dioxide for stability. (’987 Patent, col. 6:55-61).
  • Technical Importance: The invention provides a method for using a stable, ready-to-use liquid enalapril formulation, which facilitates accurate dosing and administration for treating hypertension in patients who cannot take solid dosage forms. (’987 Patent, col. 5:62-65).

Key Claims at a Glance

  • The complaint asserts "one or more claims" of the ’987 Patent (Compl. ¶65). Independent claims 1 and 13 are method of treatment claims.
  • Essential elements of Independent Claim 1 include:
    • A method of treating hypertension in a subject by administering a stable oral liquid formulation.
    • The formulation comprises about 0.6 to about 1.2 mg/ml enalapril.
    • It includes a buffer comprising about 0.8 to about 3.5 mg/ml citric acid and about 0.1 to about 0.8 mg/ml sodium citrate.
    • It includes about 0.7 to about 1.2 mg/ml sodium benzoate.
    • The formulation must be stable at about 5±3° C. for at least 12 months with specified limits on degradation.

Multi-Patent Capsule: U.S. Patent No. 10,772,868

  • Patent Identification: U.S. Patent No. 10,772,868, "Enalapril Formulations," issued September 15, 2020 (Compl. ¶33).
  • Technology Synopsis: Based on its title and relationship to the analyzed patents, this patent covers stable liquid oral formulations of enalapril designed to overcome the limitations of solid tablets and pharmacist-compounded liquids, using a specific combination of excipients to ensure long-term stability. (’868 Patent, Abstract; col. 1:12-30).
  • Asserted Claims: The complaint asserts "one or more claims" of the ’868 patent (Compl. ¶70). The patent includes independent claims directed to compositions (Claim 14) and methods of treatment (Claims 1, 13).
  • Accused Features: The accused feature is Defendant's "Alkem ANDA Product," a proposed generic version of Silvergate’s Epaned® oral solution, which is alleged to have the same formulation characteristics as the patented invention (Compl. ¶¶48, 70).

Additional patents asserted in the complaint include U.S. Patent Nos. 9,669,008, 9,808,442, 10,786,482, and 10,918,621. Based on their identical titles and inventorship, they appear to relate to the same technology of stable enalapril formulations. However, as the patent documents were not provided, a detailed technical analysis is not possible.

III. The Accused Instrumentality

Product Identification

The accused instrumentality is Defendant Alkem's proposed generic version of Silvergate's Epaned® Product, identified as the "Alkem ANDA Product" (Compl. ¶43). The act of infringement alleged is Alkem's submission of Abbreviated New Drug Application No. 213714 to the FDA seeking approval for its commercial manufacture, use, and sale (Compl. ¶1, 43, 50).

Functionality and Market Context

The complaint alleges that by filing its ANDA, Alkem has represented to the FDA that its product has the same active ingredients, route of administration, dosage form, and strength as Silvergate's Epaned® Product, and that it is bioequivalent (Compl. ¶48). Silvergate's Epaned® is described as the only FDA-approved ready-to-use oral solution of an ACE inhibitor for treating hypertension in children (Compl. ¶13). Alkem allegedly intends to engage in commercial manufacture and sale of its product promptly upon receiving FDA approval (Compl. ¶46).

No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not provide sufficient detail for a claim-chart analysis. The infringement theory is based on the Hatch-Waxman Act, under which submitting an ANDA seeking approval to market a generic drug before patent expiration is a statutory act of infringement (Compl. ¶50). The complaint alleges that because Alkem's ANDA Product is represented to be a generic copy of Epaned®—having the same active ingredient, dosage form, strength, and route of administration—it will necessarily meet the limitations of the asserted claims, which are listed in the Orange Book as covering the Epaned® product (Compl. ¶¶17-18, 48, 50).

10,039,745 Patent Infringement Allegations

  • Identified Points of Contention: The central questions for infringement will depend on the precise formulation disclosed in Alkem's ANDA, which is not detailed in the complaint.
    • Scope Questions: A potential dispute may arise over the claim term "stable," which is defined in the claim by specific numerical criteria for remaining enalapril and total impurities. The infringement analysis will depend on whether Alkem's stability data for its ANDA product falls within these claimed parameters.
    • Technical Questions: Does Alkem's formulation contain every component required by the claims? For example, does it utilize a "buffer comprising... citric acid and... sodium citrate" and "sodium benzoate" as the preservative, or has it "designed around" the patent by using different, non-infringing excipients to achieve a stable liquid formulation?

10,154,987 Patent Infringement Allegations

  • Identified Points of Contention: The infringement analysis for this method-of-use patent will also turn on the specifics of Alkem's ANDA.
    • Scope Questions: The primary question for a method claim in an ANDA case is whether the proposed label for the generic product instructs or encourages physicians and patients to perform the claimed method. A dispute could arise if Alkem's proposed label seeks an indication other than "treating hypertension" as claimed.
    • Technical Questions: As with the ’745 Patent, the technical question is whether the formulation Alkem intends to sell for the claimed method meets all the compositional limitations recited in the claim.

V. Key Claim Terms for Construction

"stable ... for at least 12 months" (’745 Patent, Claim 1; ’987 Patent, Claim 1)

  • Context and Importance: This limitation defines a required performance characteristic of the claimed formulation. The definition of "stable" and the methodology for measuring it over the specified period will be critical to determining both infringement and validity, as Alkem's product must meet this requirement for infringement to be found.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The claims themselves provide a specific, quantitative definition: "about 95% w/w or greater of the initial enalapril amount and about 5% w/w or less total impurity or related substances at the end of the given storage period" (’745 Patent, col. 41:43-48). A party may argue that any formulation meeting these numerical thresholds satisfies the claim, regardless of the specific degradation profile.
    • Evidence for a Narrower Interpretation: The specification provides detailed stability data for specific exemplary formulations (e.g., ’745 Patent, Tables C-2, D-2, E-2). A party may argue that the term should be construed in light of these examples, potentially limiting its scope to formulations exhibiting similar stability characteristics under similar testing conditions.

"a buffer comprising ... citric acid and ... sodium citrate" (’745 Patent, Claim 1; ’987 Patent, Claim 1)

  • Context and Importance: The construction of "comprising" will determine whether the presence of additional buffering agents in Alkem's product would avoid infringement. Practitioners may focus on this term because formulation chemistry often involves complex mixtures, and the presence of other excipients with buffering capacity could be a central point of non-infringement arguments.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: "Comprising" is a transitional phrase that is presumptively open-ended in patent law, meaning it does not exclude additional, unrecited elements. A party could argue that as long as citric acid and sodium citrate are present in the claimed amounts, the presence of other buffers is irrelevant to infringement. (’745 Patent, col. 41:37-39).
    • Evidence for a Narrower Interpretation: The specification consistently describes the invention in the context of a citric acid/sodium citrate buffer system without mentioning other buffering agents. (’745 Patent, col. 9:46-52). A party could argue that the patent teaches away from or is silent on other buffers, potentially supporting a construction that limits the claim to a buffer consisting essentially of the recited components.

VI. Other Allegations

Indirect Infringement

The complaint alleges that Alkem had "actual and constructive knowledge" of the patents and that its commercial manufacture, use, or sale of the ANDA product after FDA approval will induce infringement by others (e.g., Compl. ¶¶51-52, 89). The basis for this allegation is Alkem's filing of the ANDA itself with the intent to market the product for the patented use.

Willful Infringement

The complaint does not contain an explicit allegation of willful infringement or a request for enhanced damages under 35 U.S.C. § 284. It does, however, request a finding that the case is "exceptional" under 35 U.S.C. § 285 for the purpose of awarding attorneys' fees (Compl. ¶g, p. 16).

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

  • A core issue will be one of chemical composition: does the specific formulation disclosed in Alkem's confidential ANDA submission contain every element recited in the patents' composition claims—specifically, the sucralose sweetener, the citric acid/sodium citrate buffer, and the sodium benzoate preservative—or has Alkem formulated a stable liquid using a different, non-infringing combination of excipients?
  • A key question of claim construction will be the scope of the term "stable." The resolution of the case will likely depend on whether the court construes this performance limitation based solely on the quantitative impurity thresholds in the claims or narrows it in light of the specific examples and stability profiles detailed in the patent specifications.
  • An ultimate evidentiary question will be one of bioequivalence versus infringement: while Alkem's product may be bioequivalent to Epaned® for FDA purposes, the legal inquiry will focus on whether it achieves this result by practicing the specific chemical formulation claimed in the patents-in-suit.