DCT

1:19-cv-00678

Silvergate Pharma Inc v. Amneal Pharma LLC

Log In

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:19-cv-00678, D. Del., 04/11/2019
  • Venue Allegations: Venue is alleged in the District of Delaware based on Defendant being a Delaware limited liability company, being registered to do business in Delaware, and deriving substantial revenue from product sales within the state. The complaint also alleges the district is a likely destination for the accused product.
  • Core Dispute: Plaintiff alleges that Defendant’s submission of an Abbreviated New Drug Application (ANDA) for a generic version of Plaintiff's Epaned® product infringes four patents related to stable oral liquid enalapril formulations.
  • Technical Context: The technology concerns stable, ready-to-use oral liquid formulations of enalapril, an ACE inhibitor used to treat hypertension, which are particularly significant for pediatric and geriatric patients who may have difficulty swallowing tablets.
  • Key Procedural History: This is an Abbreviated New Drug Application (ANDA) case initiated under the Hatch-Waxman Act. The lawsuit was triggered by a notice letter dated February 27, 2019, in which Defendant informed Plaintiff of its ANDA filing with the FDA. The patents-in-suit are listed in the FDA's "Approved Drug Products with Therapeutic Equivalence Evaluations" (the Orange Book) in connection with Plaintiff's Epaned® product.

Case Timeline

Date Event
2016-03-18 Priority Date for ’008, ’442, ’745, and ’987 Patents
2017-06-06 U.S. Patent 9,669,008 Issues
2017-11-07 U.S. Patent 9,808,442 Issues
2018-08-07 U.S. Patent 10,039,745 Issues
2018-12-18 U.S. Patent 10,154,987 Issues
2019-02-27 Defendant Amneal sends Notice Letter regarding ANDA submission
2019-04-11 Complaint Filed

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

U.S. Patent No. 9,669,008 - "Enalapril Formulations"

  • The Invention Explained:
    • Problem Addressed: The patent’s background section describes the difficulty certain patient populations, such as children and the elderly, have in swallowing solid oral dosage forms like tablets. It notes that pharmacist-compounded liquid formulations from crushed tablets can lead to inaccurate dosing, rapid instability of the active ingredient, and potential contamination (U.S. Patent 9,669,008, col. 5:9-41).
    • The Patented Solution: The invention provides a stable, ready-to-use oral liquid formulation of enalapril that avoids the need for on-site compounding. The solution achieves long-term stability by combining enalapril maleate with a specific buffer system (citric acid and sodium citrate), a preservative (sodium benzoate), and a sweetener, all maintained at a pH below 3.5. This specific acidic environment is described as key to minimizing the degradation of enalapril into impurities like enalaprilat and enalapril diketopiperazine over an extended shelf-life at refrigerated temperatures (’008 Patent, Abstract; col. 1:10-18; FIG. 1).
    • Technical Importance: The invention created a standardized and stable liquid dosage form of a widely-used medication, thereby improving dosing accuracy, safety, and patient compliance for vulnerable patient populations (’008 Patent, col. 5:53-63).
  • Key Claims at a Glance:
    The complaint does not specify which claims it asserts, alleging infringement of "one or more claims" of each patent (Compl. ¶¶36, 41, 46, 51). The first independent claim of the ’008 Patent, Claim 1, includes the following essential elements:
    • A stable oral liquid formulation, comprising:
    • about 1 mg/ml enalapril maleate;
    • a buffer comprising about 1.82 mg/ml citric acid and about 0.15 mg/ml sodium citrate dihydrate;
    • about 1 mg/ml of a preservative that is sodium benzoate; and
    • water;
    • wherein the pH of the formulation is less than about 3.5; and
    • wherein the formulation is stable at about 5±3° C. for at least 12 months, retaining about 95% or greater of the initial enalapril and having about 5% w/w or less total impurity.

U.S. Patent No. 9,808,442 - "Enalapril Formulations"

  • The Invention Explained:
    • Problem Addressed: The ’442 Patent, which shares its specification with the ’008 Patent, addresses the same technical problem of providing a stable, ready-to-use liquid enalapril formulation to serve patient populations who cannot swallow tablets (U.S. Patent 9,808,442, col. 5:9-41).
    • The Patented Solution: The patent claims methods of using the specific enalapril formulation detailed in the specification. The solution is a method of treating hypertension by administering the stable oral liquid formulation containing enalapril maleate, a citrate buffer, and sodium benzoate at a pH below 3.5 (’442 Patent, col. 40:40-52).
    • Technical Importance: This patent protects the specific use of the formulated product for treating hypertension, extending protection beyond the composition itself to its therapeutic application (’442 Patent, col. 40:40-42).
  • Key Claims at a Glance:
    The first independent claim, Claim 1, is a method claim and includes the following essential elements:
    • A method of treating hypertension in a subject comprising administering a therapeutically effective amount of a stable oral liquid formulation.
    • The formulation comprises:
      • about 1 mg/ml enalapril maleate;
      • a buffer comprising about 1.82 mg/ml citric acid and about 0.15 mg/ml sodium citrate dihydrate;
      • about 1 mg/ml of a preservative that is sodium benzoate; and
      • water.
    • The formulation has a pH of less than about 3.5.
    • The formulation is stable at about 5±3° C. for at least 12 months, with stability defined by retention of ≥95% enalapril and ≤5% w/w total impurities.

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

  • Technology Synopsis: This patent, from the same family as the ’008 and ’442 patents, addresses the need for a stable, ready-to-use oral liquid enalapril formulation. The claims in this patent define the formulation’s components by their weight percentage of the total solids in the formulation, rather than by concentration in mg/ml (U.S. Patent 10,039,745, col. 42:15-32).
  • Asserted Claims: The complaint does not specify claims. Independent claim 1 is directed to a composition, and independent claim 11 recites a method of treating hypertension.
  • Accused Features: The complaint accuses the Amneal ANDA Product as a whole of infringing this patent (Compl. ¶46).

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

  • Technology Synopsis: This patent is also from the same family and addresses the same technical problem and solution as the other patents-in-suit. It claims methods of treating various conditions, including hypertension, heart failure, and left ventricular dysfunction, by administering the stable oral liquid enalapril formulation.
  • Asserted Claims: The complaint does not specify claims. Independent claims 1, 16, and 25 are directed to methods of treating hypertension, heart failure, and left ventricular dysfunction, respectively.
  • Accused Features: The complaint accuses the intended use of the Amneal ANDA Product, as will be described in its labeling, of infringing this patent’s method claims (Compl. ¶51).

III. The Accused Instrumentality

  • Product Identification: The accused instrumentality is Defendant’s proposed generic drug product that is the subject of Abbreviated New Drug Application (ANDA) No. 212894 ("the Amneal ANDA Product") (Compl. ¶31).
  • Functionality and Market Context: The complaint alleges that the Amneal ANDA Product is a generic version of Silvergate's Epaned®, which is a ready-to-use oral solution for hypertension (Compl. ¶¶1, 11). By submitting its ANDA, Amneal has represented to the FDA that its product has the same active ingredients, route of administration, dosage form, use, and strength as Epaned®, and is bioequivalent to it (Compl. ¶33). The complaint does not provide the specific formulation of the Amneal ANDA Product. The product is intended for commercial manufacture, use, and sale in the United States upon receiving FDA approval (Compl. ¶32).

IV. Analysis of Infringement Allegations

The complaint does not provide sufficient detail for a technical claim-by-claim analysis of infringement. Its infringement theory is statutory, based on 35 U.S.C. § 271(e)(2), which makes the submission of an ANDA an act of infringement if the product described therein would infringe a patent upon commercialization. The core of the allegation is that because the Amneal ANDA Product is represented to be a generic equivalent of Silvergate's Epaned® product, which is covered by the patents-in-suit, the Amneal ANDA Product will necessarily infringe (Compl. ¶¶15, 33, 36). The actual composition of the Amneal ANDA Product is confidential within its FDA filing and is not disclosed in the complaint.

No probative visual evidence provided in complaint.

  • Identified Points of Contention:
    • Technical Questions: Since the ANDA product's formulation is not public, a primary technical question for the litigation will be whether the specific excipients, their concentrations (e.g., of citric acid, sodium citrate, and sodium benzoate), and the final pH of the Amneal ANDA Product fall within the scope of the asserted claims. A further question will be whether the Amneal ANDA Product meets the claims' specific stability requirements.
    • Scope Questions: The dispute may raise questions about the proper construction of claim terms. For example, a key question may be how to interpret the term "about" as it applies to the specific concentrations and pH values recited in the claims. The outcome of this construction could determine whether Amneal's formulation, if it varies slightly from the recited values, literally infringes.

V. Key Claim Terms for Construction

  • The Term: "stable"

  • Context and Importance: This term is a central limitation in the independent claims of the ’008 and ’442 patents. The determination of whether the Amneal ANDA Product meets this functional requirement is fundamental to the infringement analysis.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: A party might argue for the plain and ordinary meaning of "stable" as generally understood in the pharmaceutical arts.
    • Evidence for a Narrower Interpretation: The claims themselves provide an explicit definition: "wherein the stable oral liquid formulation has about 95% 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" (’008 Patent, col. 42:43-48). This provides very strong intrinsic evidence that the patentee acted as its own lexicographer, which may support a narrow and specific construction of the term.

  • The Term: "about" (as applied to concentrations and pH)

  • Context and Importance: This term modifies all numerical limitations for the formulation's components and pH. The scope afforded by "about" will be critical for determining literal infringement, as pharmaceutical formulations can have minor batch-to-batch variations or may be intentionally formulated near the boundaries of a claimed range.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: A party could argue that "about" should be given its ordinary meaning of "approximately" to account for normal manufacturing and measurement tolerances.
    • Evidence for a Narrower Interpretation: A party could argue that in the context of a detailed pharmaceutical patent with precise values (e.g., "1.82 mg/ml"), "about" should be construed narrowly. The specification’s detailed examples and figures, which show the effects of small changes in pH on stability, may be cited to argue that the inventors viewed these parameters as requiring a high degree of precision (’008 Patent, FIG. 1; Table A-1).

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that if Amneal's ANDA is approved, its commercial activities will constitute infringement under 35 U.S.C. § 271(a)-(c), which includes indirect infringement (Compl. ¶37). For the asserted method claims (e.g., in the ’442 and ’987 patents), an allegation of induced infringement would be premised on Amneal's proposed product labeling instructing physicians and patients to use the generic product to treat hypertension, thereby encouraging the performance of the claimed methods.
  • Willful Infringement: The complaint alleges that Amneal had "actual and constructive knowledge" of the patents-in-suit prior to submitting its ANDA and was aware that the submission constituted an act of infringement (e.g., Compl. ¶38, 43, 48, 53). This allegation of pre-suit knowledge forms the basis for the willfulness claim.

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

  • A core factual question will be one of compositional identity: does the precise formulation of the Amneal ANDA Product—including its specific excipients, their concentrations, and its final pH as detailed in the confidential ANDA filing—meet every limitation of the asserted composition claims?
  • A central legal issue will be one of claim scope: how broadly will the court construe the term "about" as applied to the specific concentrations and pH values recited in the claims, and will the explicit definition of "stable" in the claims be adopted without modification?
  • For the asserted method claims, a key question will be whether Amneal's proposed product label will direct users to administer the product for treating hypertension in a manner that directly corresponds to the steps of the claimed methods, which would be central to a finding of induced infringement.