DCT

1:14-cv-03168

Otsuka Pharmaceutical Co Ltd v. Zydus Pharma USA Inc

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Key Events
Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:14-cv-03168, D.N.J., 05/16/2014
  • Venue Allegations: Plaintiff alleges venue is proper in the District of New Jersey because Defendant Zydus USA was incorporated in New Jersey, maintains its principal place of business there, and conducts business in the district.
  • Core Dispute: Plaintiff alleges that Defendants' filing of Abbreviated New Drug Applications (ANDAs) with the FDA for generic versions of aripiprazole tablets and orally disintegrating tablets constitutes an act of infringement of four patents related to a specific crystalline form of the aripiprazole drug substance and its formulation.
  • Technical Context: The dispute centers on aripiprazole, the active ingredient in the widely prescribed atypical antipsychotic drug Abilify®, used for treating schizophrenia and other conditions.
  • Key Procedural History: This action arises under the Hatch-Waxman Act, triggered by Zydus USA's submission of two ANDAs (No. 90-472 and No. 90-165) seeking FDA approval to market generic aripiprazole products prior to the expiration of the asserted patents. Otsuka received letters from Zydus USA on April 3, 2014, providing notice of the ANDA filings.

Case Timeline

Date Event
2000-04-12 ’421 Patent Priority Date
2001-09-25 ’615, ’796, and ’760 Patents Priority Date
2002-11-15 FDA approves NDA No. 21-436 for aripiprazole tablets (Abilify®)
2006-06-07 FDA approves NDA No. 21-729 for orally disintegrating aripiprazole tablets (Abilify®)
2011-09-13 ’615 Patent Issued
2013-08-27 ’421 Patent Issued
2013-11-12 ’796 Patent Issued
2014-02-04 ’760 Patent Issued
2014-04-03 Otsuka receives Notice of Certification letters from Zydus USA regarding ANDA filings
2014-05-16 Complaint Filed

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

U.S. Patent No. 8,017,615 - "Low Hygroscopic Aripiprazole Drug Substance and Processes for the Preparation Thereof"

  • Issued: September 13, 2011

The Invention Explained

  • Problem Addressed: The patent’s background section describes that previously known forms of anhydrous aripiprazole crystals are "significantly hygroscopic," meaning they readily absorb moisture from the air (’615 Patent, col. 1:50-52). This hygroscopicity makes the drug substance difficult to handle during manufacturing, can lead to conversion into a less bioavailable hydrous form, and can reduce the product's shelf-life (’615 Patent, col. 1:53-col. 2:14).
  • The Patented Solution: The invention provides a novel crystalline form of anhydrous aripiprazole, termed "Anhydrous Aripiprazole Crystals B," that possesses low hygroscopicity (’615 Patent, Abstract). This specific polymorphic form is described as being more stable and easier to process into final pharmaceutical dosage forms (’615 Patent, col. 2:29-32). The patent also discloses a specific process for preparing these crystals, which involves milling a conventional hydrate form of aripiprazole to create an intermediate "Hydrate A," which is then heated to yield the desired "Crystals B" (’615 Patent, col. 8:41-63).
  • Technical Importance: Developing a stable, non-hygroscopic crystalline form of an active pharmaceutical ingredient is critical for ensuring consistent quality, bioavailability, and manufacturability of a drug product on an industrial scale (’615 Patent, col. 2:8-14).

Key Claims at a Glance

  • The complaint asserts infringement of at least one claim without specifying which one (Compl. ¶21). Independent claim 12 is a representative product claim.
  • Essential elements of Independent Claim 12:
    • Anhydrous Aripiprazole Crystals B having low hygroscopicity.
    • A moisture content of 0.40% or less after being placed for 24 hours in a desiccator at 60° C. and 100% humidity.
    • A powder x-ray diffraction spectrum with characteristic peaks at specific 2θ angles (11.0°, 16.6°, 19.3°, 20.3°, and 22.1°).
    • Having particular infrared absorption bands.
    • Exhibiting an endothermic peak near 141.5° C. in thermogravimetric/differential thermal analysis.
    • Exhibiting an endothermic peak near 140.7° C. in differential scanning calorimetry.
    • Having a mean particle size of 50 µm or less.

U.S. Patent No. 8,580,796 - "Low Hygroscopic Aripiprazole Drug Substance and Processes for the Preparation Thereof"

  • Issued: November 12, 2013

The Invention Explained

  • Problem Addressed: As with the ’615 Patent, this patent addresses the technical challenge that known forms of anhydrous aripiprazole are hygroscopic, which complicates pharmaceutical processing and can compromise the stability and bioavailability of the final drug product (’796 Patent, col. 1:49-51, col. 1:53-col. 2:12).
  • The Patented Solution: The invention is an aripiprazole drug substance characterized by its low hygroscopicity, defined by a specific quantitative limit on moisture absorption under stressed conditions (’796 Patent, Abstract; col. 5:65-col. 6:4). This property makes the drug substance more suitable for large-scale pharmaceutical manufacturing and formulation, ensuring batch-to-batch consistency and product stability (’796 Patent, col. 2:8-12).
  • Technical Importance: The invention provides a form of the aripiprazole active ingredient that overcomes practical manufacturing challenges, facilitating the reliable production of a stable, solid oral dosage form (’796 Patent, col. 2:8-12).

Key Claims at a Glance

  • The complaint asserts infringement of at least one claim without specifying which one (Compl. ¶41). Independent claim 1 is representative.
  • Essential elements of Independent Claim 1:
    • An aripiprazole drug substance of low hygroscopicity.
    • Wherein the low hygroscopicity is defined as a moisture content of 0.40% or less after the drug substance is placed for 24 hours in a desiccator maintained at a temperature of 60° C. and a humidity level of 100%.

U.S. Patent No. 8,642,760 - "Low Hygroscopic Aripiprazole Drug Substance and Processes for the Preparation Thereof"

  • Patent Identification: U.S. Patent No. 8,642,760, issued February 4, 2014.
  • Technology Synopsis: This patent, part of the same family as the ’615 and ’796 patents, is also directed to solving the problem of hygroscopicity in aripiprazole (’760 Patent, col. 1:50-52). It claims an aripiprazole drug substance defined by its low moisture absorption under specific high-temperature, high-humidity conditions, ensuring its suitability for pharmaceutical formulation (’760 Patent, Abstract; col. 6:23-30).
  • Asserted Claims: At least one claim is asserted (Compl. ¶57, ¶63). Independent claim 1 is representative.
  • Accused Features: The aripiprazole drug substance contained within Zydus's tablet generic products (ANDA 90-472) and ODT generic products (ANDA 90-165) is alleged to infringe (Compl. ¶57-58, ¶63-64).

U.S. Patent No. 8,518,421 - "Flashmelt Oral Dosage Formulation"

  • Patent Identification: U.S. Patent No. 8,518,421, issued August 27, 2013.
  • Technology Synopsis: This patent addresses the technical challenge of creating a stable, rapidly disintegrating oral dosage form ("flash-melt") without using solvents or requiring special manufacturing environments (’421 Patent, Abstract; col. 1:29-40). The solution is a specific combination of excipients including two superdisintegrants (crospovidone and croscarmellose sodium), a dispersing agent (calcium silicate), and a binder, which together allow for the creation of robust tablets that disintegrate in the mouth in under 25 seconds (’421 Patent, Abstract; claim 1).
  • Asserted Claims: At least one claim is asserted (Compl. ¶73). Independent claim 1 is representative.
  • Accused Features: The formulation of Zydus's ODT generic products (ANDA 90-165) is alleged to infringe (Compl. ¶73-74).

III. The Accused Instrumentality

  • Product Identification: The accused instrumentalities are Zydus USA's generic pharmaceutical products seeking FDA approval under ANDA No. 90-472 ("Aripiprazole Oral Tablets") and ANDA No. 90-165 ("Aripiprazole Orally Disintegrating Tablets") (Compl. ¶18, ¶20, ¶28, ¶30).
  • Functionality and Market Context: The complaint alleges that these products are generic versions of Otsuka’s Abilify® and Abilify® ODT products, containing 5, 10, 15, 20, and 30 mg of aripiprazole as the active ingredient (Compl. ¶17-18, ¶27-28). The act of infringement alleged is the filing of the ANDAs under 35 U.S.C. § 271(e)(2)(A), which seeks approval from the FDA to market these generic products in the United States before the expiration of Otsuka’s patents (Compl. ¶4, ¶22). No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not contain specific claim charts or detailed factual allegations mapping elements of the accused products to patent claims. The infringement allegations are based on Zydus's filing of its ANDAs, which by law constitutes a technical act of infringement if the product described therein would infringe the patent upon being marketed (Compl. ¶22, ¶32, ¶42, ¶48, ¶58, ¶64, ¶74). The following tables summarize the infringement theories as implied by the complaint.

U.S. Patent No. 8,017,615 Infringement Allegations

Claim Element (from Independent Claim 12) Alleged Infringing Functionality Complaint Citation Patent Citation
Anhydrous Aripiprazole Crystals B having low hygroscopicity The aripiprazole active pharmaceutical ingredient (API) in Zydus's ANDA products is alleged to be the claimed "Anhydrous Aripiprazole Crystals B." ¶21-22 col. 45:61-62
wherein said low hygroscopicity is a moisture content of 0.40% or less after placing said Crystals for 24 hours in a dessicator maintained at a temperature of 60° C. and a humidity level of 100% The aripiprazole API in Zydus's ANDA products is alleged to exhibit a moisture content of 0.40% or less under the specified test conditions. ¶21-22 col. 45:63-67
have a powder x-ray diffraction spectrum having characteristic peaks at 2θ=11.0°, 16.6°, 19.3°, 20.3°, and 22.1° The aripiprazole API in Zydus's ANDA products is alleged to have the claimed powder x-ray diffraction spectrum. ¶21-22 col. 46:1-3
have a mean particle size of 50 µm or less The aripiprazole API in Zydus's ANDA products is alleged to have a mean particle size of 50 µm or less. ¶21-22 col. 46:17-18

U.S. Patent No. 8,580,796 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
An aripiprazole drug substance of low hygroscopicity The aripiprazole API in Zydus's ANDA products is alleged to have the claimed property of low hygroscopicity. ¶41-42 col. 46:39-40
wherein said low hygroscopicity is a moisture content of 0.40% or less after placing said drug substance for 24 hours in a dessicator maintained at a temperature of 60° C. and a humidity level of 100% The aripiprazole API in Zydus's ANDA products is alleged to meet the specific quantitative definition of low hygroscopicity recited in the claim. ¶41-42 col. 46:41-46
  • Identified Points of Contention:
    • Scope Questions: For the ’615, ’796, and ’760 patents, a central question will be one of polymorphic identity: does the aripiprazole substance in Zydus's proposed generic products meet the specific structural and performance characteristics (e.g., specific XRD peaks, low hygroscopicity) of the claimed crystalline forms, or has Zydus developed a different, non-infringing polymorph?
    • Technical Questions: For the ’421 patent, a key question will be one of compositional identity: does the formulation of Zydus's orally disintegrating tablet contain the specific combination of excipients—particularly a "superdisintegrant," a "dispersing agent," and a "distributing agent"—as those terms are defined and used within the patent?

V. Key Claim Terms for Construction

The complaint does not provide sufficient detail for analysis of specific claim terms. However, based on the technology, certain terms may become central to the dispute.

  • The Term: "low hygroscopicity" (from the ’615, ’796, and ’760 patents)

  • Context and Importance: The patentability of the drug substance claims hinges on this property, which distinguishes the invention from prior art aripiprazole. Infringement will depend on whether Zydus's product exhibits this characteristic as defined by the claims. Practitioners may focus on this term because it is a term of degree that the patent attempts to define with a specific quantitative test.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The background describes prior art aripiprazole as "significantly hygroscopic," suggesting "low hygroscopicity" could be interpreted as any form that is demonstrably and materially less hygroscopic than what was previously known (’615 Patent, col. 1:51-52).
    • Evidence for a Narrower Interpretation: The claims themselves provide a precise, quantitative definition: "a moisture content of 0.40% or less" after testing under specific conditions (60° C. / 100% RH for 24 hours) (’615 Patent, claim 12). The specification provides experimental data showing the inventive crystals meeting this limit while prior art forms do not, reinforcing that this specific test is the standard for what the patent means by the term (’615 Patent, Table 1).

  • The Term: "dispersing agent" (from the ’421 patent)

  • Context and Importance: This term is a required element in the claimed flash-melt formulation. Whether Zydus's ODT product infringes may depend on whether one of its excipients functions as a "dispersing agent" within the meaning of the patent.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The term itself suggests a functional definition—an agent that helps disperse the other ingredients upon contact with saliva. A party might argue that any excipient performing this function, regardless of its chemical name, meets the limitation.
    • Evidence for a Narrower Interpretation: The specification explicitly lists examples of dispersing agents, stating they "include calcium silicate... magnesium trisilicate or silicic acid," with calcium silicate identified as "preferred" (’421 Patent, col. 7:24-29). This list could be used to argue that the term is limited to this specific class of compounds.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that Defendant Cadila Healthcare Limited, the parent company of Zydus USA, acted in concert with and provided "cooperation, participation and assistance" for the filing of the ANDAs (Compl. ¶9, ¶23, ¶33). These allegations may form the basis for claims of induced or contributory infringement against the parent entity.
  • Willful Infringement: The complaint does not contain an explicit allegation of willful infringement.

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

  • A core issue will be one of polymorphic equivalence: Does the aripiprazole active pharmaceutical ingredient in Zydus’s generic products possess the specific, low-hygroscopicity crystalline structure defined by the asserted patents, or has Zydus formulated its products with a distinct, non-infringing polymorph? The case will likely involve extensive expert analysis of competing analytical data (e.g., XRD, DSC, IR spectroscopy) for the respective drug substances.
  • A second key issue will be one of compositional scope: For the orally disintegrating tablet, does the term "dispersing agent" as used in the ’421 patent read on the specific excipients used in Zydus's formulation, or did Zydus successfully design around the patent by using alternative ingredients that fall outside the claimed combination?