DCT

1:23-cv-00833

Azurity Pharma Inc v. Zydus Pharma USA Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:23-cv-00833, D. Del., 08/02/2023
  • Venue Allegations: Plaintiffs allege venue is proper because Defendants Zydus Worldwide and Zydus Lifesciences are foreign corporations that may be sued in any U.S. judicial district. Venue over Zydus USA is alleged to be proper based on its subjection to personal jurisdiction in the district and prior consent to venue in other Delaware patent cases.
  • Core Dispute: Plaintiffs allege that Defendants’ submission of Abbreviated New Drug Applications (ANDAs) to the U.S. Food and Drug Administration for generic versions of the hypertension drugs EDARBI® and EDARBYCLOR® constitutes an act of infringement of three patents related to pharmaceutical compositions and methods of use.
  • Technical Context: The technology concerns solid oral dosage forms for azilsartan medoxomil, an angiotensin II receptor blocker used to treat hypertension, focusing on formulations that improve the drug's stability and dissolution properties.
  • Key Procedural History: The action was initiated under the Hatch-Waxman Act following Plaintiffs' receipt of notice letters from Zydus concerning its ANDA submissions. These letters included Paragraph IV certifications asserting that the patents-in-suit are invalid, unenforceable, or would not be infringed by the proposed generic products. The complaint was filed within the 45-day statutory period, triggering a potential 30-month stay of FDA approval for the generic products.

Case Timeline

Date Event
2007-03-28 Earliest Priority Date for ’936 Patent
2008-07-31 Earliest Priority Date for ’238 Patent
2008-12-23 Earliest Priority Date for ’249 Patent
2015-06-30 ’936 Patent Issued
2015-10-27 ’238 Patent Issued
2016-07-12 ’249 Patent Issued
2023-06-19 Plaintiffs Received Notice Letter for ANDA No. 218451
2023-07-19 Plaintiffs Received Notice Letter for ANDA No. 218658
2023-08-02 Complaint Filed

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

U.S. Patent No. 9,066,936 - “Solid pharmaceutical composition comprising a benzimidazole-7-carboxylate derivative and a pH control agent” (Issued June 30, 2015)

The Invention Explained

  • Problem Addressed: The patent addresses a formulation challenge where the active pharmaceutical ingredient, a benzimidazole-7-carboxylate derivative (azilsartan medoxomil), is unstable in the neutral pH range typically used for pharmaceutical preparations but has low solubility in the acidic pH range where it is stable (’936 Patent, col. 2:6-12). This makes it difficult to create a dosage form that is both stable during storage and dissolves effectively for absorption in the body.
  • The Patented Solution: The invention is a solid pharmaceutical composition that combines the active ingredient with a "pH control agent." This agent is designed to adjust the internal pH of the preparation to an acidic range (pH 3 to 5), which stabilizes the active ingredient. Unexpectedly, this acidic microenvironment, which lowers the compound's intrinsic solubility, was found to improve the overall dissolution property of the drug from the final dosage form (’936 Patent, col. 2:26-34; Abstract).
  • Technical Importance: This approach provided a method to formulate a chemically sensitive drug into a stable and effective oral tablet, overcoming a common obstacle in pharmaceutical development where stability and bioavailability are competing properties.

Key Claims at a Glance

  • The complaint does not specify asserted claims, but Claim 1 is the sole independent claim.
  • Claim 1 requires:
    • A solid pharmaceutical composition comprising the compound (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate potassium salt (azilsartan medoxomil potassium).
    • A solid pH control agent that provides a pH of 3 to 5 when measured in a 1% w/v aqueous solution or suspension at 25°C.
  • The complaint reserves the right to assert additional claims.

U.S. Patent No. 9,169,238 - “Solid pharmaceutical composition” (Issued October 27, 2015)

The Invention Explained

  • Problem Addressed: This patent addresses the difficulty of formulating a combination drug product containing both azilsartan medoxomil and a diuretic. The stability and dissolution challenges of azilsartan medoxomil, as described in the ’936 patent, are compounded by the need to ensure the stability and proper release of the second active ingredient (’238 Patent, col. 2:8-17).
  • The Patented Solution: The invention is a solid preparation structured with two distinct parts. The first part contains azilsartan medoxomil and a pH control agent to create the stabilizing acidic microenvironment. The second part contains the diuretic (chlorthalidone) and is "obtained by granulating separately from the first part" (’238 Patent, Claim 1). This physical separation is intended to prevent undesirable chemical interactions between the active ingredients and excipients, thereby improving the stability and dissolution of both drugs from a single tablet.
  • Technical Importance: This patent describes a formulation strategy for combination therapies that allows chemically distinct or incompatible active ingredients to be delivered in a single, stable, and effective oral dosage unit.

Key Claims at a Glance

  • The complaint does not specify asserted claims, but Claim 1 is an independent claim.
  • Claim 1 requires:
    • A solid preparation comprising a first part and a second part.
    • The first part comprises azilsartan medoxomil potassium and a pH control agent that provides a pH of 2 to 5.
    • The second part comprises chlorthalidone.
    • The second part is "obtained by granulating separately from the first part."
  • The complaint reserves the right to assert additional claims.

U.S. Patent No. 9,387,249 - “Methods of treating hypertension with at least one angiotensin II receptor blocker and chlorthalidone” (Issued July 12, 2016)

Technology Synopsis

This patent claims methods of treating hypertension. The invention is not a composition but a method of use, comprising the administration of an angiotensin II receptor blocker (such as azilsartan medoxomil) in combination with the diuretic chlorthalidone to a patient (’249 Patent, Abstract). The patent also discloses that this combination can treat hypertension while potentially reducing side effects like hypokalemia (’249 Patent, col. 13:62-65).

Asserted Claims

The complaint does not specify asserted claims, but Claim 1 is an independent method claim.

Accused Features

The complaint alleges that the use of "Zydus's Azilsartan Medoxomil and Chlorthalidone ANDA Product" in accordance with its proposed labeling would induce infringement of this method patent (Compl. ¶¶46, 74).

III. The Accused Instrumentality

Product Identification

The accused instrumentalities are two proposed generic drug products for which Zydus has filed applications with the FDA:

  1. "Zydus's Azilsartan Medoxomil ANDA Product" (ANDA No. 218658), a proposed generic equivalent to Plaintiffs' EDARBI® product, containing 40 mg or 80 mg of azilsartan medoxomil (Compl. ¶36).
  2. "Zydus's Azilsartan Medoxomil and Chlorthalidone ANDA Product" (ANDA No. 218451), a proposed generic equivalent to Plaintiffs' EDARBYCLOR® product, containing azilsartan medoxomil and chlorthalidone (Compl. ¶46).

Functionality and Market Context

The complaint alleges that these products contain the same active ingredients as Plaintiffs’ corresponding brand-name drugs and are intended to be sold as lower-cost generic alternatives for the treatment of hypertension upon receiving FDA approval (Compl. ¶¶37, 47). The filing of the ANDAs is an artificial act of infringement under 35 U.S.C. § 271(e)(2) that enables Plaintiffs to litigate their patent rights before the generic products enter the market.

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

The complaint does not provide sufficient detail for a formal claim chart analysis, as Plaintiffs state they have not been provided with technical details of the accused ANDA products beyond notice letters (Compl. ¶¶41-42, 51-52). The infringement theory is based on the statutory act of filing the ANDAs with Paragraph IV certifications, which allows for a lawsuit before the products are marketed (Compl. ¶¶55, 61, 67, 73).

Plaintiffs allege that upon information and belief, Zydus’s proposed products will, if approved and sold, meet all the limitations of the asserted claims. For the composition claims of the ’936 and ’238 Patents, this implies that the generic formulations will contain the specified active ingredients and excipients that function as the claimed "pH control agent" and, for the ’238 Patent, will be formulated using separate granulation. For the method claims of the ’249 Patent, the complaint alleges the product's proposed labeling will instruct users to administer the drug in a manner that infringes (Compl. ¶74).

  • Identified Points of Contention:
    • ’936 Patent – Technical Questions: The central infringement question will be factual: do the excipients in Zydus’s Azilsartan Medoxomil ANDA product constitute a “solid pH control agent” that provides a pH of 3 to 5 as required by Claim 1? Resolution of this issue will depend on discovery into the composition of the ANDA product.
    • ’238 Patent – Structural and Process Questions: The dispute is likely to focus on the structure of Zydus’s combination product. Does its manufacturing process result in a final dosage form where the chlorthalidone-containing part is "obtained by granulating separately from the first part" containing azilsartan medoxomil? This raises questions about both the physical structure of the tablet and the specific manufacturing steps used to produce it.

V. Key Claim Terms for Construction

“solid pH control agent which provides a pH of 3 to 5 when dissolved or suspended in water at a concentration of 1% w/v at 25° C.” (’936 Patent, Claim 1)

  • Context and Importance: This term is the central inventive concept of the ’936 Patent and a key element of the ’238 Patent. The infringement analysis will depend entirely on whether any component or combination of components in Zydus’s formulations meets this functional definition. Practitioners may focus on this term because its construction will determine whether a wide range of acidic excipients fall within the claim scope.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification provides a broad list of potential acidic substances that can function as the pH control agent, including tartaric acid, citric acid, fumaric acid, and malic acid, as well as combinations of acidic and basic substances adjusted to the claimed pH range (’936 Patent, col. 5:4-24). This may support an interpretation where any solid excipient that achieves the claimed pH function infringes.
    • Evidence for a Narrower Interpretation: The specification also mentions that preferable examples are those whose solutions have a “buffering ability,” such as monosodium fumarate (’936 Patent, col. 6:36-39). A defendant may argue that the term should be limited to agents that provide a buffering capacity, not merely any substance that results in an acidic pH, pointing to specific embodiments and examples in the patent.

“obtained by granulating separately from the first part” (’238 Patent, Claim 1)

  • Context and Importance: This phrase defines the required structural and manufacturing relationship between the two active ingredients in the combination product. Infringement of the ’238 Patent hinges on whether Zydus’s generic product is made using a process that results in this claimed separation.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The plain language of the claim suggests that any manufacturing process that involves creating granules for the diuretic component in a step separate from the creation of granules for the azilsartan medoxomil component would satisfy this limitation. The patent itself describes different preparation methods, including single-layer and multi-layer tablets, that could embody this concept (’238 Patent, col. 7:46-54).
    • Evidence for a Narrower Interpretation: A defendant might argue that its specific manufacturing process (e.g., direct compression blending, use of a non-granulated powder, or a specific type of coating) does not constitute "granulating separately" as that term would be understood by a person of ordinary skill in the art, potentially distinguishing its process from the specific granulation methods detailed in the patent's examples (’238 Patent, e.g., Example 9).

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that upon approval, Defendants will induce and contribute to infringement by marketing and selling their products with proposed labeling that instructs physicians and patients to use them in an infringing manner (Compl. ¶¶56, 62, 68, 74).
  • Willful Infringement: The complaint alleges that Zydus was aware of the patents-in-suit, at the latest, upon sending the Paragraph IV notice letters. This alleged knowledge forms the basis for potential claims of willful infringement should infringement be found after the ANDAs are approved and the products are launched (Compl. ¶¶59, 65, 71, 77).

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

  • A primary issue will be one of factual determination: what is the precise composition and manufacturing process of the accused generic products as detailed in Zydus’s confidential ANDA submissions? Lacking this information, the complaint relies on statutory infringement allegations, and the case will turn on whether discovery reveals that Zydus’s formulations contain a "pH control agent" and utilize "separate granulation" as claimed.
  • A key legal question will be one of claim scope: how broadly will the court construe the functional term “solid pH control agent”? The outcome may depend on whether the term is interpreted to cover any excipient that achieves the claimed pH result, or if it is narrowed to the types of buffering agents and specific embodiments disclosed in the patent specifications.
  • A central question for the ’238 Patent will be one of process and structure: does the accused combination product’s manufacturing method and final form fall within the scope of a tablet "obtained by granulating separately" the two active components? This highlights a potential dispute over the intersection of process limitations and the resulting product structure.