DCT

1:24-cv-01333

Astellas Pharma Inc v. Cipla Ltd

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Key Events
Amended Complaint

I. Executive Summary and Procedural Information

Case Timeline

Date Event
1999-11-02 U.S. Patent No. 6,812,238 Priority Date
2004-11-02 U.S. Patent No. 6,812,238 Issue Date
2006-09-25 U.S. Patent Nos. 10,206,879 & 10,603,280 Priority Date
2015-03-06 FDA approves New Drug Application for CRESEMBA® capsules
2019-02-19 U.S. Patent No. 10,206,879 Issue Date
2020-03-31 U.S. Patent No. 10,603,280 Issue Date
2023-12-08 FDA approves expanded indication for CRESEMBA®
2024-10-23 Hangzhou Defendants provide ANDA notice letter
2024-10-24 Cipla Defendants provide ANDA notice letter
2024-11-01 Annora provides ANDA notice letter
2024-11-02 Zenara Defendants provide ANDA notice letter
2025-03-11 Plaintiffs file Amended Complaint

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

U.S. Patent No. 6,812,238 - "N-Substituted Carbamoyloxyalkyl-Azolium Derivatives," issued November 2, 2004

The Invention Explained

  • Problem Addressed: The patent describes a need for azole antifungal compounds that are suitable for parenteral (e.g., intravenous) administration. Many existing azole compounds are highly lipophilic (not water-soluble), which makes creating injectable formulations difficult (’238 Patent, col. 1:11-15).
  • The Patented Solution: The invention is a class of water-soluble prodrugs—specifically, N-substituted carbamoyloxyalkyl-azolium derivatives. These compounds are chemically modified versions of the active antifungal agent. They are soluble in water for administration but are designed to be converted into the active antifungal drug within the body (’238 Patent, col. 1:16-24). The chemical structure provided in the complaint corresponds to isavuconazonium sulfate, an embodiment of this solution (Compl. ¶74).
  • Technical Importance: This approach allows for the administration of a potent antifungal agent both orally and parenterally, increasing its clinical utility for treating serious systemic mycoses (’238 Patent, col. 1:8-11).

Key Claims at a Glance

  • The complaint asserts at least Claim 3 against Defendant Cipla (Compl. ¶166).
  • Essential Elements of Independent Claim 3:
    • A compound having a specific chemical structure of formula (II).
    • The structure includes a moiety "Q" which is a 3-[4-(4-cyanophenyl)thiazol-2-yl)]-2-(2,5-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol moiety.
    • The structure includes a ring system "A" which is pyridin-2-yl.
    • The structure includes various other specified substituent groups (R¹, R², R⁴, R⁵, R⁶) and a pharmaceutically acceptable anion (X⁻).

U.S. Patent No. 10,206,879 - "Active Ingredient Containing Stabilised Solid Medicinal Forms and Method for the Production Thereof," issued February 19, 2019

The Invention Explained

  • Problem Addressed: The patent addresses the challenge of stabilizing solid medicinal forms (like capsules) that contain active ingredients sensitive to moisture. Water, present in both the drug and its excipients, can cause chemical degradation (hydrolysis), reducing the drug's efficacy and shelf life (’879 Patent, col. 3:41-51).
  • The Patented Solution: The invention is a specific pharmaceutical formulation designed to protect a moisture-sensitive active ingredient. It combines the active ingredient with a "pharmaceutically compatible, water soluble drying agent," specifically trimagnesium dicitrate. This agent has a high capacity to firmly bond with free water in the formulation, making the water unavailable to degrade the active ingredient (’879 Patent, col. 4:15-24). The patent claims a solid medicinal form with specific compositional ranges and resulting physical properties, such as low drying loss and low relative equilibrium moisture (’879 Patent, col. 9:48-61).
  • Technical Importance: This formulation technology provides a method for creating stable, oral solid dosage forms of drugs that would otherwise be too unstable for commercial use.

Key Claims at a Glance

  • The complaint asserts at least Claim 1 against all Defendants (Compl. ¶¶ 140, 213, 261, 309).
  • Essential Elements of Independent Claim 1:
    • A non-effervescent solid medicinal form comprising a hydroxypropylmethylcellulose (HPMC) capsule.
    • The capsule is filled with a capsule filling comprising:
      • 30 to 40% by weight of a moisture-sensitive active ingredient (which is not trimagnesium dicitrate).
      • 20 to 50% by weight of trimagnesium dicitrate acting as a drying agent.
      • 5 to 30% by weight of a microcrystalline cellulose.
    • The medicinal form exhibits a drying loss, measured at 120° C./30 min, of 0.5 to 2.5%.
    • The medicinal form exhibits a relative equilibrium moisture, measured at 25° C., of at most 15%.

U.S. Patent No. 10,603,280 - "Active Ingredient Containing Stabilised Solid Medicinal Forms and Methods for the Production Thereof," issued March 31, 2020

  • Technology Synopsis: Similar to the ’879 Patent, this patent is directed to stabilizing solid medicinal forms containing a moisture-sensitive active ingredient. It claims a specific formulation using trimagnesium dicitrate as a drying agent to prevent hydrolysis, but with different compositional weight percentages for the active ingredient compared to the ’879 Patent (Compl. ¶152).
  • Asserted Claims: The complaint asserts at least Claim 1 (Compl. ¶152).
  • Accused Features: The accused features are the specific formulations of Defendants' proposed generic capsules, which are alleged to contain a moisture-sensitive active ingredient (isavuconazonium sulfate), trimagnesium dicitrate, and microcrystalline cellulose in amounts and with physical properties that fall within the scope of the claims (Compl. ¶155).

III. The Accused Instrumentality

Product Identification

  • The accused instrumentalities are the generic isavuconazonium sulfate capsules, in 74.5 mg and 186 mg dosages, that are the subject of ANDA Nos. 219268 (Cipla), 219867 (Hangzhou), 219439 (Annora), and 219402 (Zenara) (Compl. ¶31).

Functionality and Market Context

  • The proposed generic products are intended to be generic versions of Plaintiffs' CRESEMBA® capsules (Compl. ¶31). They are intended for oral use for the treatment of invasive aspergillosis and invasive mucormycosis (Compl. ¶¶ 89, 105, 117, 128). As generic drugs submitted via the ANDA pathway, they are required to be bioequivalent to the branded CRESEMBA® product. The complaint alleges that the formulation of CRESEMBA® itself is covered by the asserted formulation patents (Compl. ¶¶ 141, 153).

IV. Analysis of Infringement Allegations

U.S. Patent No. 6,812,238 Infringement Allegations

Claim Element (from Independent Claim 3) Alleged Infringing Functionality Complaint Citation Patent Citation
The Compound having formula (II), wherein... The complaint alleges Defendants' generic products will contain the compound isavuconazonium sulfate, which has the chemical structure claimed by the patent. A visual representation of the accused compound's structure is provided in the complaint (Compl. ¶74), and the patent's claimed formula is also depicted (Compl. ¶166). ¶164, ¶167 col. 52:1-53:11
A...is pyridin-2-yl; The pyridin-2-yl group is present in the isavuconazonium sulfate structure. ¶74, ¶166 col. 52:45-47
Q is a 3-[4-(4-cyanophenyl)thiazol-2-yl)]-2-(2,5-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol moiety... This moiety, the core active part of the drug, is alleged to be the same as that in isavuconazonium sulfate. ¶74, ¶166 col. 52:50-56
X⁻ is a pharmaceutically acceptable anion; Isavuconazonium sulfate includes a sulfate anion, which is a pharmaceutically acceptable anion. ¶74 col. 53:1-2

Identified Points of Contention

  • Scope Questions: A potential question for the court could be whether the specific salt form (sulfate) and stereochemistry of the API in Defendants' ANDAs falls within the scope of the asserted claims. The complaint presents the infringement as a direct structural match.
  • Technical Questions: The infringement analysis for the ’238 Patent appears to be a direct comparison of chemical structures. A primary technical question will be whether discovery reveals any structural differences between the claimed compound and the defendants' proposed API that could support a non-infringement argument.

U.S. Patent No. 10,206,879 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A non-effervescent solid medicinal form comprising a hydroxypropylmethylcellulose (HPMC) capsule... Defendants’ proposed generic products are alleged to be non-effervescent solid medicinal forms in HPMC capsules, mirroring the CRESEMBA® product. ¶143 col. 6:49-54
...filled with a capsule filling comprising: a. 30 to 40% by weight of a moisture-sensitive active ingredient... The filling of the generic capsules is alleged to contain isavuconazonium sulfate, a moisture-sensitive active ingredient, within this weight range. ¶143 col. 4:5-13
b. 20 to 50% by weight of trimagnesium dicitrate acting as a drying agent that stabilizes the moisture sensitive agent... The generic formulation is alleged to contain trimagnesium dicitrate as a stabilizer within this weight range. ¶143 col. 4:15-20
c. 5 to 30% by weight of a microcrystalline cellulose... The generic formulation is alleged to contain microcrystalline cellulose within this weight range. ¶143 col. 7:10-17
...wherein said medicinal form exhibits a drying loss, measured at 120° C./30 min, of 0.5 to 2.5%... The generic product is alleged to exhibit this specific physical property related to its water content. ¶143 col. 4:32-44
...and a relative equilibrium moisture, measured at 25° C., of at most 15%. The generic product is alleged to exhibit this specific physical property related to its water activity and stability. ¶143 col. 5:8-17

Identified Points of Contention

  • Scope Questions: The dispute may turn on the interpretation of functional language, such as what it means for trimagnesium dicitrate to be "acting as a drying agent that stabilizes."
  • Technical Questions: A central question will be whether Defendants' final commercial formulation for their generic products will actually meet the specific weight percentage ranges and the physical property limitations (drying loss and relative equilibrium moisture) as measured by the methods specified or understood in the art. The complaint notes that Defendants' notice letters do not dispute that their products will meet these limitations, a point Plaintiffs may leverage to argue there is no factual dispute (Compl. ¶142).

V. Key Claim Terms for Construction

For the '238 Patent

  • The Term: "The Compound having formula (II)"
  • Context and Importance: This term defines the entire scope of the chemical entity protected by Claim 3. Infringement hinges on whether the defendants' isavuconazonium sulfate API is encompassed by this structural definition. Practitioners may focus on this term to determine if any subtle structural variations in the accused product could place it outside the literal scope of the claim.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The claim uses Markush group language for various substituents (e.g., R¹, R²), which is designed to cover a class of related compounds, not just a single embodiment (’238 Patent, col. 52:48-49).
    • Evidence for a Narrower Interpretation: The patent provides specific examples of synthesized compounds, which a defendant might argue implicitly limit the scope of the broader generic formulas to the types of compounds actually made and tested (’238 Patent, col. 9-50).

For the '879 Patent

  • The Term: "relative equilibrium moisture, measured at 25° C., of at most 15%"
  • Context and Importance: This term defines a critical physical property of the final claimed product, linked directly to its stability. Infringement requires the accused product to meet this specific, numerically-limited parameter. The parties may dispute the precise methodology for this measurement and whether the accused product satisfies the "at most 15%" limitation.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patent describes the measurement generally, suggesting that any standard, art-recognized method for determining equilibrium relative humidity at the specified temperature would suffice (’879 Patent, col. 5:8-34).
    • Evidence for a Narrower Interpretation: The specification discloses a specific device (a HygroLab with an AWVC measuring cell from Rotronic) used for the measurement. A defendant may argue that this term should be construed as being limited to measurements made using this specific apparatus or an equivalent one, potentially creating non-infringement if their product meets the limit under a different testing protocol (’879 Patent, col. 5:29-32).

VI. Other Allegations

Indirect Infringement

  • While the primary counts are for the statutory act of infringement via an ANDA filing under § 271(e)(2), Plaintiffs also bring declaratory judgment counts for infringement under § 271(a) that will occur upon commercial launch (Compl. Counts IV-VI, IX-X, XIII-XIV, XVII-XVIII). The basis for indirect infringement would be the defendants' sale of the generic drug with a label instructing physicians and patients on its FDA-approved (and allegedly infringing) use.

Willful Infringement

  • The complaint alleges that defendants had pre-suit knowledge of the patents via their Orange Book listings and their own Paragraph IV notice letters (Compl. ¶¶ 145, 157, 168). It further alleges that defendants "copied the claimed invention" and that their assertions of non-infringement and invalidity are devoid of an objective good faith basis, thereby making the case "exceptional" and warranting enhanced damages and attorneys' fees (Compl. ¶¶ 146, 148, 158, 160, 169, 171).

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

  • A central issue for the composition of matter patent ('238 Patent) will be one of structural identity: Does the active pharmaceutical ingredient in the Defendants’ proposed generic products fall squarely within the chemical structure defined by the asserted claims, or are there any differences in stereochemistry, salt form, or purity that could support a non-infringement defense?
  • For the formulation patents ('879 and '’280 Patents), a key question will be one of evidentiary proof and measurement: Can Plaintiffs demonstrate that the Defendants' proposed final generic formulations will, in fact, meet the precise compositional percentages and physical property limitations (e.g., "relative equilibrium moisture," "drying loss") recited in the claims, and will the parties' respective testing methodologies for these properties become a point of contention?
  • A significant procedural question will be the effect of Defendants’ alleged omissions in their notice letters. The court will need to consider Plaintiffs' argument that by not disputing certain claim limitations in their notice letters, Defendants have effectively conceded that their products meet those limitations, potentially narrowing the scope of the infringement dispute.