DCT

1:20-cv-00161

Silvergate Pharma Inc v. CMP Development LLC

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:20-cv-00161, D. Del., 01/31/2020
  • Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant is a limited liability company organized under the laws of Delaware.
  • Core Dispute: Plaintiff alleges that Defendant’s filing of an Abbreviated New Drug Application (ANDA) for a generic oral liquid lisinopril formulation constitutes an act of infringement of six patents covering Plaintiff's QBRELIS® product.
  • Technical Context: The technology concerns stable, oral liquid formulations of lisinopril, an angiotensin-converting enzyme (ACE) inhibitor used to treat hypertension, which are particularly significant for pediatric and geriatric patients who may have difficulty swallowing solid tablets.
  • Key Procedural History: The patents-in-suit are listed in the FDA's "Orange Book" in connection with Plaintiff's New Drug Application for its QBRELIS® product. Notably, U.S. Patent No. 9,463,183, the earliest-issued patent in the family, was the subject of a Post-Grant Review (PGR) proceeding (PGR2017-00039), which concluded with a finding that all challenged claims (1-13) were patentable. This history may inform arguments regarding the patent's validity.

Case Timeline

Date Event
2015-10-30 Earliest Patent Priority Date for all Patents-in-Suit
2016-10-11 U.S. Patent No. 9,463,183 Issues
2017-04-11 U.S. Patent No. 9,616,096 Issues
2017-11-14 U.S. Patent No. 9,814,751 Issues
2018-08-07 U.S. Patent No. 10,039,800 Issues
2019-04-23 U.S. Patent No. 10,265,370 Issues
2019-09-10 U.S. Patent No. 10,406,199 Issues
2019-12-19 Defendant sends ANDA Notice Letter to Plaintiff
2020-01-31 Complaint Filing Date

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

U.S. Patent No. 9,463,183 - “Lisinopril Formulations”

The Invention Explained

  • Problem Addressed: The patent addresses the challenges associated with administering lisinopril, a drug typically available in solid tablet form, to patient populations who have difficulty swallowing, such as children and the elderly (Compl. ¶7; ’183 Patent, col. 4:36-45). Compounding tablets into a liquid format often results in inaccurate dosing, rapid instability of the active ingredient, and potential contamination (’183 Patent, col. 5:1-7).
  • The Patented Solution: The invention is a stable, ready-to-use oral liquid formulation of lisinopril. The solution uses a specific combination of excipients—a sweetener (xylitol), a buffer (citric acid), and a preservative (sodium benzoate)—within a controlled pH range of about 4 to 5 to achieve long-term stability at room temperature (’183 Patent, col. 2:7-14, col. 5:39-54). Figure 1 illustrates the importance of the pH range, showing a marked increase in degradant formation outside of this window (’183 Patent, Fig. 1).
  • Technical Importance: The formulation provides a safe, effective, and standardized oral liquid dosage form of lisinopril, overcoming the inconsistencies and stability issues of pharmacy-compounded liquids and expanding access to an important hypertension therapy for pediatric and geriatric patients (’183 Patent, col. 4:40-45).

Key Claims at a Glance

  • The complaint does not specify which claims are asserted, but Claim 1 is the broadest independent claim.
  • Claim 1 of the ’183 Patent recites the essential elements of:
    • A stable oral liquid formulation comprising:
    • (i) lisinopril or a pharmaceutically acceptable salt or solvate thereof;
    • (ii) a sweetener that is xylitol;
    • (iii) a buffer comprising citric acid;
    • (iv) a preservative that is sodium benzoate;
    • (v) water;
    • wherein the pH of the formulation is between about 4 and about 5; and
    • wherein the formulation is stable at about 25±5° C. for at least 12 months.
  • The complaint does not explicitly reserve the right to assert dependent claims.

U.S. Patent No. 9,616,096 - “Lisinopril Formulations”

The Invention Explained

  • Problem Addressed: As a continuation of the application leading to the ’183 Patent, the ’096 Patent addresses the same technical problem: the need for a stable, ready-to-use liquid lisinopril formulation to facilitate administration to patients who cannot take solid tablets (’096 Patent, col. 4:36-45).
  • The Patented Solution: The ’096 Patent claims a method of treating hypertension by administering a specific oral liquid lisinopril formulation. The claimed formulation is defined by a group of alternative sweeteners and preservatives but contains a specific buffer system (citric acid and sodium citrate) and a stability requirement, with a proviso against combining paraben preservatives with sugar alcohol sweeteners like xylitol (’096 Patent, col. 39:4-22). This proviso addresses an incompatibility that can lead to undesirable "transesterification reaction products" (’096 Patent, col. 10:46-53).
  • Technical Importance: This patent protects the specific use of the stable liquid formulation for treating hypertension, complementing the product claims of the ’183 Patent and extending the scope of protection to the therapeutic application of the technology (’096 Patent, col. 3:31-34).

Key Claims at a Glance

  • The complaint does not specify which claims are asserted, but Claims 1, 11, and 16 are the independent method claims.
  • Claim 1 of the ’096 Patent recites the essential elements of:
    • A method of treating hypertension in a subject by administering a stable oral liquid formulation comprising:
    • (i) about 1 mg/ml lisinopril;
    • (ii) a sweetener selected from a specified group (e.g., xylitol, sucralose);
    • (iii) a buffer comprising citric acid and sodium citrate;
    • (iv) a preservative selected from a specified group (e.g., sodium benzoate, parabens);
    • (v) water;
    • with a proviso that if a paraben is used, the sweetener is not xylitol or mannitol; and
    • a requirement that the formulation is stable for at least 6 months.
  • The complaint does not explicitly reserve the right to assert dependent claims.

U.S. Patent No. 9,814,751 - “Lisinopril Formulations”

  • Technology Synopsis: This patent is directed to stable oral liquid lisinopril formulations, similar to the ’183 Patent. It claims specific formulations defined by a list of alternative excipients and stability requirements, further detailing the chemical environment needed to prevent degradation of the active ingredient.
  • Asserted Claims: The complaint does not specify claims, but Claim 1 is the broadest independent claim.
  • Accused Features: The entirety of Defendant's proposed generic lisinopril oral liquid formulation as described in its ANDA is accused of infringement (Compl. ¶¶ 52-53).

U.S. Patent No. 10,039,800 - “Lisinopril Formulations”

  • Technology Synopsis: This patent claims methods of using the stable oral liquid lisinopril formulations to treat specific cardiovascular conditions, including hypertension, heart failure, and acute myocardial infarction. It expands upon the method-of-use claims of the ’096 Patent.
  • Asserted Claims: The complaint does not specify claims, but Claims 1, 11, and 16 are the independent claims.
  • Accused Features: The use of Defendant's proposed generic product for its labeled indications is accused of infringing the patent's method claims (Compl. ¶¶ 57-58).

U.S. Patent No. 10,265,370 - “Lisinopril Formulations”

  • Technology Synopsis: This patent covers stable oral liquid lisinopril formulations with claims that specify concentrations of components and define stability over various time periods. It appears to claim specific embodiments of the general formulation concept.
  • Asserted Claims: The complaint does not specify claims, but Claims 1, 19, and 20 are the independent claims.
  • Accused Features: The entirety of Defendant's proposed generic lisinopril oral liquid formulation as described in its ANDA is accused of infringement (Compl. ¶¶ 62-63).

U.S. Patent No. 10,406,199 - “Lisinopril Formulations”

  • Technology Synopsis: This patent claims methods of treating hypertension, heart failure, and myocardial infarction by administering the stable oral liquid lisinopril formulation. It is similar to the ’800 Patent but may cover different claim scopes or patient populations.
  • Asserted Claims: The complaint does not specify claims, but Claims 1, 11, and 16 are the independent claims.
  • Accused Features: The use of Defendant's proposed generic product for its labeled indications is accused of infringing the patent's method claims (Compl. ¶¶ 67-68).

III. The Accused Instrumentality

  • Product Identification: The accused instrumentality is Defendant CMP's proposed generic version of Silvergate's QBRELIS® product, which is the subject of Abbreviated New Drug Application No. 213935 (the "ANDA Product") (Compl. ¶¶ 1, 39).
  • Functionality and Market Context: The complaint alleges that by filing its ANDA, CMP has represented to the FDA that its ANDA Product has the same active ingredient (lisinopril), route of administration (oral liquid), dosage form, strength, and use as QBRELIS® (Compl. ¶40). The product is intended for the treatment of hypertension (Compl. ¶7). The filing indicates CMP's intent to engage in the commercial manufacture, use, and sale of the ANDA Product upon receiving FDA approval (Compl. ¶39).

No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not provide sufficient detail for analysis of infringement on a claim-element-by-element basis. The infringement allegations are premised on 35 U.S.C. § 271(e)(2)(A), which defines the submission of an ANDA seeking approval to market a generic drug before the expiration of a patent claiming that drug as a technical act of infringement (Compl. ¶¶ 42, 47). The complaint alleges that CMP’s ANDA Product, if approved and marketed, will infringe one or more claims of the patents-in-suit (Compl. ¶¶ 43, 48).

  • Identified Points of Contention:
    • Scope Questions: Since the infringement analysis will depend entirely on the contents of the confidential ANDA filing, a central question will be whether the specific formulation in CMP's ANDA Product—including its precise combination of excipients, their concentrations, and its final pH—falls within the scope of the asserted product claims. Likewise, it raises the question of whether the proposed label for the ANDA product will instruct users to perform the steps recited in the asserted method claims.
    • Technical Questions: A key technical question for the court will be whether CMP's ANDA Product achieves the same stability profile ("stable at about 25±5° C. for at least 12 months") as required by claims like Claim 1 of the ’183 Patent. The evidence for this will be contained in the stability data submitted by CMP to the FDA as part of its ANDA.

V. Key Claim Terms for Construction

  • The Term: "stable"

    • Context and Importance: This term is central to the invention, as the primary technical problem solved was the instability of prior art liquid lisinopril formulations. The definition of "stable" will directly impact whether Defendant's formulation infringes. Practitioners may focus on this term because the claims explicitly define it with time and temperature parameters, but disputes could arise over the methodology used to measure stability and the threshold for what constitutes an unstable amount of degradants.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The specification states that "'Stable' as used herein refer to lisinopril oral liquid formulations having about 95% or greater of the initial lisinopril amount and about 5% w/w or less total impurities or related substances at the end of a given storage period," which provides a clear functional definition (’183 Patent, col. 15:23-28).
      • Evidence for a Narrower Interpretation: The claims themselves provide specific temporal and temperature limits (e.g., "stable at about 25±5° C. for at least 12 months") (’183 Patent, col. 8:13-14). A defendant might argue that this specific language limits the term more narrowly than the general specification definition, and that any deviation from these exact testing conditions falls outside the claim.

  • The Term: "a buffer comprising citric acid and sodium citrate" (’096 Patent, Claim 1)

    • Context and Importance: The buffer system is critical for maintaining the pH range that ensures stability. The precise composition of the buffer in the accused product will determine infringement of patents like the ’096 Patent.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The term itself does not specify concentrations, suggesting that any buffer formed by the combination of citric acid and sodium citrate that performs the buffering function could be covered.
      • Evidence for a Narrower Interpretation: The specification provides detailed examples with specific concentrations of anhydrous citric acid and anhydrous sodium citrate (e.g., about 0.86 mg/ml and 1.44 mg/ml, respectively) (’096 Patent, col. 8:62-64). A party could argue that these examples define the operative scope of the term for achieving the invention's purpose.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that CMP had "actual and constructive knowledge" of each patent prior to filing its ANDA and had "specific intent to infringe" (Compl. ¶¶ 44, 49, 54, 59, 64, 69). For the method patents, infringement could be induced by the product's labeling, which would instruct physicians and patients on the infringing use. The complaint further alleges there are "no substantial non-infringing uses" for the ANDA Product, a key element for contributory infringement (Compl. ¶¶ 44, 49, 54, 59, 64, 69).
  • Willful Infringement: While the term "willful" is not used, the complaint alleges pre-suit knowledge of the patents for each count of infringement (e.g., "CMP had actual and constructive knowledge of the '183 patent prior to filing ANDA No. 213935") (Compl. ¶44). These allegations could form the basis for a later claim of willful infringement.

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

  • A core issue will be one of factual correspondence: does the confidential formulation disclosed in CMP's ANDA literally meet every limitation of the asserted claims? This will involve a technical comparison of the respective products' excipients, concentrations, pH levels, and stability data.
  • A key legal question will be one of obviousness: despite the ’183 Patent surviving a Post-Grant Review, it raises the question of whether a person of ordinary skill in the art, aware of the stability problems of liquid lisinopril, would have been motivated to combine this specific set of known excipients at the claimed pH range with a reasonable expectation of success.
  • A central evidentiary question will be one of claim scope: can the term "stable," which is explicitly defined by time and temperature in the claims, be interpreted to cover formulations whose stability is demonstrated under different, albeit arguably equivalent, testing protocols?