DCT

2:23-cv-01214

Astellas Pharma Inc v. Sandoz Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 2:23-cv-01214, D.N.J., 05/06/2024
  • Venue Allegations: Venue is alleged to be proper because Defendant Sandoz has a regular and established place of business in the District of New Jersey.
  • Core Dispute: Plaintiff alleges that Defendant’s filing of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff's XOSPATA® (gilteritinib) tablets constitutes an act of infringement of six patents related to stable pharmaceutical compositions and methods of their manufacture.
  • Technical Context: The dispute centers on pharmaceutical formulation technology designed to ensure the stability of the active ingredient gilteritinib, a treatment for acute myeloid lymphoma, by controlling its crystalline form to minimize the generation of impurities during storage.
  • Key Procedural History: This action was initiated under the Hatch-Waxman Act following Defendant's submission of ANDA No. 217683 and a corresponding Paragraph IV certification notice letter asserting that the patents-in-suit are invalid or not infringed. The filing of the original complaint on March 2, 2023, triggered a statutory stay of FDA approval for the generic product. This First Amended Complaint was filed to add five recently issued patents to the suit.

Case Timeline

Date Event
2015-07-03 Earliest Priority Date for all Patents-in-Suit
2020-09-29 U.S. Patent No. 10,786,500 Issues
2023-01-18 Defendant Sandoz sends Paragraph IV Notice Letter
2023-03-02 Original Complaint Filed
2024-03-26 U.S. Patent No. 11,938,130 Issues
2024-03-26 U.S. Patent No. 11,938,131 Issues
2024-03-26 U.S. Patent No. 11,938,132 Issues
2024-03-26 U.S. Patent No. 11,938,133 Issues
2024-04-02 U.S. Patent No. 11,944,620 Issues
2024-05-06 First Amended Complaint Filed

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

U.S. Patent No. 10,786,500 - "Stable pharmaceutical composition for oral administration"

  • Issued: September 29, 2020

The Invention Explained

  • Problem Addressed: The patent’s background section describes the problem of the active pharmaceutical ingredient, gilteritinib hemifumarate (referred to as "Compound A"), generating undesirable "related substances" or impurities during storage (ʼ500 Patent, col. 1:50-53). This instability was particularly noted when the compound was formulated using a wet granulation method with common excipients like microcrystalline cellulose, which was found to "unexpectedly" increase the level of impurities (ʼ500 Patent, col. 2:28-35).
  • The Patented Solution: The invention is a stable pharmaceutical composition wherein the generation of these impurities is inhibited. The solution is based on the discovery that the impurity generation could be suppressed by controlling the formulation process to ensure a high proportion of the active ingredient remains in its crystalline form (ʼ500 Patent, col. 2:35-41). The claims therefore require that 62% or more of the gilteritinib hemifumarate in the composition be in a crystalline state (ʼ500 Patent, col. 18:5-13).
  • Technical Importance: Minimizing impurity levels in a final drug product is critical for patient safety and is a key requirement for regulatory approval of pharmaceutical products (ʼ500 Patent, col. 1:50-65).

Key Claims at a Glance

  • The complaint asserts at least independent claim 1 (Compl. ¶90).
  • Claim 1 requires:
    • A pharmaceutical composition for oral administration comprising gilteritinib hemifumarate.
    • A proportion of crystals of the gilteritinib hemifumarate is 62% or more with respect to the total amount of the compound in the composition.
    • The composition also comprises at least one pharmaceutical additive selected from the group "consisting of" lactose, D-mannitol, anhydrous dibasic calcium phosphate, calcium stearate, and talc.
  • The complaint reserves the right to assert other claims (Compl. ¶90, n.1).

U.S. Patent No. 11,938,130 - "Stable pharmaceutical composition for oral administration"

  • Issued: March 26, 2024

The Invention Explained

  • Problem Addressed: Similar to the ’500 patent, this patent addresses the technical problem of the active ingredient, gilteritinib, generating related substances (impurities) during storage when formulated into a pharmaceutical product (ʼ130 Patent, col. 2:47-51, Abstract).
  • The Patented Solution: The patented solution is a stable oral pharmaceutical composition that inhibits the formation of these impurities. The invention achieves this by requiring a specific proportion of the active ingredient to be in crystalline form (at least 62%) in combination with one or more additives from a specified list ('130 Patent, col. 2:52-64; col. 18:7-23). The use of these particular components is described as providing a stable formulation ('130 Patent, Abstract).
  • Technical Importance: This technology provides a method for creating a safe and stable drug product with a commercially viable shelf life, which is essential for pharmaceuticals intended for oral administration (ʼ130 Patent, col. 1:55-59).

Key Claims at a Glance

  • The complaint asserts at least independent claim 1 (Compl. ¶97).
  • Claim 1 requires:
    • A pharmaceutical composition for oral administration comprising gilteritinib hemifumarate.
    • At least one pharmaceutical additive selected from a broad group including lactose, D-mannitol, talc, magnesium stearate, microcrystalline cellulose, and others.
    • A proportion of crystals of the gilteritinib hemifumarate is 62% or more with respect to the total amount of the compound in the composition.
  • The complaint reserves the right to assert other claims (Compl. ¶97, n.2).

U.S. Patent No. 11,938,131 - "Stable pharmaceutical composition for oral administration"

  • Issued: March 26, 2024
  • Technology Synopsis: This patent claims a stable pharmaceutical composition of gilteritinib defined by multiple parameters: a specific range of crystallinity (62% to 98%), a specific ratio of pharmaceutical additive content relative to the active ingredient (1.5 to 4.5 times), and a specific stability profile, wherein the composition exhibits an increase of "no more than 0.11% of an oxidative decomposition product" after storage under specific conditions, as measured by a detailed high-performance liquid chromatography (HPLC) method also recited in the claim (Compl. ¶32).
  • Asserted Claims: At least Claim 1 is asserted (Compl. ¶104).
  • Accused Features: The complaint alleges on information and belief that Sandoz’s proposed ANDA product meets the claimed crystallinity range, additive ratio, and stability profile (Compl. ¶83-85).

U.S. Patent No. 11,938,132 - "Stable pharmaceutical composition for oral administration"

  • Issued: March 26, 2024
  • Technology Synopsis: This patent claims a method of manufacturing a stable pharmaceutical composition of gilteritinib. The method comprises combining the active ingredient with certain additives and then "granulating the mixture using fluidized bed granulation with an aqueous pharmaceutical additive solution." The resulting product is defined by the same stability profile (no more than 0.11% increase in an oxidative decomposition product) and HPLC measurement method recited in the ’131 patent (Compl. ¶39).
  • Asserted Claims: At least Claim 1 (method) and Claim 12 (product-by-process) are asserted (Compl. ¶111, ¶135).
  • Accused Features: The complaint alleges on information and belief that Sandoz's manufacturing process uses a method where gilteritinib is combined with additives, granulated with an aqueous solution, and subjected to fluidized bed granulation to produce a dried product (Compl. ¶86).

U.S. Patent No. 11,938,133 - "Stable pharmaceutical composition for oral administration"

  • Issued: March 26, 2024
  • Technology Synopsis: This patent also claims a method of manufacturing a stable gilteritinib composition. The method comprises combining the active ingredient with additives, "granulating the mixture using water," and "drying the granulated product using a fluidized bed granulation dryer." The resulting product is defined by the same stability profile and HPLC measurement method as the ’131 and ’132 patents (Compl. ¶47).
  • Asserted Claims: At least Claim 1 (method) and Claim 12 (product-by-process) are asserted (Compl. ¶118, ¶144).
  • Accused Features: The complaint alleges that Sandoz's manufacturing process involves the claimed steps of combining, granulating with an aqueous solution, and drying using fluidized bed granulation (Compl. ¶86).

U.S. Patent No. 11,944,620 - "Stable pharmaceutical composition for oral administration"

  • Issued: April 2, 2024
  • Technology Synopsis: This patent claims a stable pharmaceutical composition of gilteritinib defined by a minimum crystallinity (at least 62%) and the same specific stability profile (no more than 0.11% increase in an oxidative decomposition product) and HPLC measurement method recited in the ’131, ’132, and ’133 patents (Compl. ¶55).
  • Asserted Claims: At least Claim 1 is asserted (Compl. ¶125).
  • Accused Features: The complaint alleges that Sandoz’s proposed ANDA product meets the claimed crystallinity and stability profile (Compl. ¶83-85).

III. The Accused Instrumentality

Product Identification

  • The accused instrumentality is "Sandoz’s Proposed ANDA Product," identified as 40 mg gilteritinib fumarate film-coated oral tablets, for which Sandoz is seeking FDA approval under ANDA No. 217683 (Compl. ¶65, ¶70).

Functionality and Market Context

  • The product is a generic version of Astellas’s XOSPATA® tablets, intended for the treatment of acute myeloid lymphoma (AML) (Compl. ¶57, ¶65). The complaint provides the structural formula for the active ingredient, gilteritinib hemifumarate (Compl. ¶60). Based on a review of Sandoz's ANDA, the complaint alleges the proposed product contains gilteritinib hemifumarate with a crystalline proportion of 62% or more, and at least one of a specified list of pharmaceutical additives (Compl. ¶83). Further allegations state the product has an additive content 1.5 to 4.5 times that of the active ingredient and exhibits an increase of no more than 0.11% of a specific oxidative decomposition product after storage, aligning with limitations in several of the asserted patents (Compl. ¶84-85). The complaint alleges Sandoz's manufacturing process involves combining the active ingredient with an additive, followed by granulation and drying (Compl. ¶86).

IV. Analysis of Infringement Allegations

U.S. Patent No. 10,786,500 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A pharmaceutical composition for oral administration comprising: 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate... Sandoz's Proposed ANDA Product is an oral tablet containing gilteritinib fumarate. ¶83 col. 1:15-21
...wherein a proportion of crystals of [gilteritinib hemifumarate] is 62% or more with respect to a total amount of [gilteritinib hemifumarate] in the pharmaceutical composition... The complaint alleges, on information and belief, that the Sandoz product comprises crystalline gilteritinib hemifumarate that is 62% or more of the total amount. ¶83 col. 2:48-56
...and at least one pharmaceutical additive selected from the group consisting of lactose, D-mannitol, anhydrous dibasic calcium phosphate, calcium stearate, and talc. The complaint alleges, on information and belief, that the Sandoz product contains at least one pharmaceutical additive from a broader list that includes these specific additives. ¶83 col. 18:41-44
  • Identified Points of Contention:
    • Scope Questions: Claim 1 of the ’500 Patent recites a closed Markush group of five specific additives ("consisting of"). A potential point of contention is whether the complaint provides sufficient factual basis that the Sandoz product contains one of these five specific additives, as the complaint alleges the presence of an additive from a much broader list that encompasses additives from other patents-in-suit (Compl. ¶83).
    • Technical Questions: The central technical limitation is the "proportion of crystals... is 62% or more." A key question will be what evidence the plaintiff can adduce to prove the accused product meets this numerical threshold and whether the defendant's measurement methodology yields a different result.

U.S. Patent No. 11,938,130 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A pharmaceutical composition for oral administration comprising: [gilteritinib hemifumarate] and at least one pharmaceutical additive selected from the group consisting of lactose, D-mannitol, anhydrous dibasic calcium phosphate, talc, calcium stearate, magnesium stearate, microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, corn starch, low-substituted hydroxypropyl cellulose, and croscarmellose sodium... Sandoz’s Proposed ANDA Product is alleged to be an oral tablet containing gilteritinib fumarate and at least one of these specified pharmaceutical additives. ¶83 col. 18:7-16
...wherein a proportion of crystals of [gilteritinib hemifumarate] is 62% or more with respect to a total amount of [gilteritinib hemifumarate] in the pharmaceutical composition. The complaint alleges, on information and belief, that the Sandoz product comprises crystalline gilteritinib hemifumarate that is 62% or more of the total amount. ¶83 col. 18:17-23
  • Identified Points of Contention:
    • Technical Questions: As with the ’500 patent, the infringement analysis will raise the question of what evidence demonstrates that the accused product meets the "62% or more" crystallinity limitation. The case may focus on disputes over the proper methods for measuring crystallinity in a finished drug product, such as the near-infrared spectroscopy method detailed in the patent specification (ʼ130 Patent, col. 14:10-40).

V. Key Claim Terms for Construction

  • The Term: "proportion of crystals ... is 62% or more" (and its variants across the patents, e.g., "at least 62%," "62% to 98%")

    • Context and Importance: This quantitative limitation is the core of the asserted patents' solution to the impurity problem and is central to the infringement allegations. The definition and, critically, the accepted methodology for measuring this proportion will be determinative of infringement. Practitioners may focus on this term because the entire dispute may devolve into a battle of experts over analytical chemistry techniques and results.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The specification discloses multiple methods for calculating the proportion of crystals, including "a differential scanning calorimeter analysis (DSC analysis) method, a powder X-ray diffraction method, a solid-state NMR method, a near-infrared spectroscopy (NIR) method, or the like" (ʼ500 Patent, col. 5:67-col. 6:3). This language may support an argument that the claim is not limited to any single measurement technique.
      • Evidence for a Narrower Interpretation: The specification provides a detailed description of using near-infrared (NIR) spectroscopy, including specific instrument parameters, to calculate the crystal proportion in the working examples (ʼ500 Patent, col. 13:66-col. 14:19). This detailed example could be cited to argue that the claim term should be understood and measured by the specific NIR method disclosed and exemplified by the inventors.

  • The Term: "oxidative decomposition product having a relative retention time of 1.06" (as recited in the ’131, ’132, ’133, and ’620 patents)

    • Context and Importance: This term defines the specific impurity that the invention seeks to minimize. The claims in the later patents require that the composition exhibit an increase of "no more than 0.11%" of this specific product under defined conditions. Infringement of these patents requires identifying and quantifying this exact substance in the accused product.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The term is defined functionally by its retention time in a specific HPLC method. A party could argue that any product that elutes at that time under the claimed HPLC conditions is the claimed "oxidative decomposition product," regardless of its precise chemical structure.
      • Evidence for a Narrower Interpretation: The patents state that the related substance having a retention time of "about 1.06" is "presumed to be an oxidative decomposition product of Compound A" (ʼ131 Patent, col. 5:5-10). This language suggests a specific chemical entity, and a party could argue that infringement requires proving not only the retention time but also that the substance is, in fact, an oxidative decomposition product of gilteritinib.

VI. Other Allegations

  • Willful Infringement: While the complaint does not include a separate count for willful infringement, it requests treble damages and attorneys' fees, remedies associated with such a finding (Compl. ¶F, G). The basis for willfulness appears to be knowledge of the patents. The complaint alleges that Sandoz had pre-suit knowledge of the ’500 patent via the Paragraph IV notice letter dated January 18, 2023 (Compl. ¶66). For the five patents issued in March and April 2024, the complaint alleges Sandoz had knowledge "no later than when it issued" (Compl. ¶133, ¶142), suggesting a basis for post-suit willfulness for infringement of those patents.

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

  • A core issue will be one of evidentiary proof: What analytical evidence will Astellas present from its testing of Sandoz's ANDA product to demonstrate that it meets the quantitative "62% or more" crystallinity threshold and the "no more than 0.11%" impurity limit recited in the various claims, and how will Sandoz challenge those measurements and methodologies?
  • A key question for the method patents (’132 and ’133) will be one of process equivalence: Can Astellas, through discovery of Sandoz's confidential ANDA, prove that the commercial manufacturing process Sandoz intends to use practices the specific granulation and drying steps recited in the method claims?
  • A dispositive question for the ’500 patent will be one of claim scope and factual infringement: Does Sandoz's product contain one of the five specific additives listed in the "consisting of" Markush group of claim 1, or does its formulation fall outside the scope of this older, more narrowly drafted claim?