DCT

1:22-cv-00464

Otsuka Pharmaceutical Co Ltd v. Mylan Laboratories Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:22-cv-00464, D. Del., 04/08/2022
  • Venue Allegations: Plaintiffs allege venue is proper in the District of Delaware because Defendant Viatris Inc. is a Delaware corporation, and allege the other Defendants are alter egos of Viatris or are alien corporations subject to suit in any district.
  • Core Dispute: Plaintiffs allege that Defendants' filing of an Abbreviated New Drug Application (ANDA) to market generic versions of Plaintiffs' ABILIFY MAINTENA® product constitutes an act of infringement of eight U.S. patents.
  • Technical Context: The technology relates to formulations and methods of using aripiprazole, an atypical antipsychotic drug, in a long-acting injectable suspension for treating schizophrenia and bipolar I disorder.
  • Key Procedural History: This Hatch-Waxman litigation was triggered by Defendants' submission of ANDA No. 216608 to the U.S. Food and Drug Administration (FDA) and their subsequent "Notice of Paragraph IV Certification" letter to Plaintiffs. The patents-in-suit are listed in the FDA's "Orange Book" for ABILIFY MAINTENA®. Several of the asserted patents are subject to terminal disclaimers, linking their expiration dates.

Case Timeline

Date Event
2001-09-25 U.S. Patent No. 8,399,469 Priority Date
2003-08-06 U.S. Patent No. 8,338,427 Priority Date
2003-10-23 U.S. Patent Nos. 7,807,680, 8,030,313, and 8,722,679 Priority Date
2010-10-05 U.S. Patent No. 7,807,680 Issued
2011-10-04 U.S. Patent No. 8,030,313 Issued
2012-12-25 U.S. Patent No. 8,338,427 Issued
2013-02-28 FDA approves NDA for ABILIFY MAINTENA®
2013-03-19 U.S. Patent No. 8,399,469 Issued
2013-09-24 U.S. Patent Nos. 10,525,057, 10,980,803, and 11,154,553 Priority Date
2014-05-13 U.S. Patent No. 8,722,679 Issued
2020-01-07 U.S. Patent No. 10,525,057 Issued
2021-04-20 U.S. Patent No. 10,980,803 Issued
2021-10-26 U.S. Patent No. 11,154,553 Issued
2022-02-23 Defendants send Paragraph IV Notice Letter to Otsuka
2022-04-08 Complaint Filed

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

U.S. Patent No. 7,807,680 - "Controlled Release Sterile Injectable Aripiprazole Formulation and Method"

The Invention Explained

  • Problem Addressed: The patent addresses the challenge of patient non-compliance with daily oral medications for chronic conditions like schizophrenia, which can lead to relapse (US7807680B2, col. 1:50-55). Aripiprazole, the active drug, has poor aqueous solubility, making it difficult to formulate as an injectable suspension (US 7,807,680 B2, col. 1:35-37).
  • The Patented Solution: The invention is a sterile, freeze-dried aripiprazole formulation that can be reconstituted with water to form an injectable suspension. The key to achieving a sustained therapeutic effect for at least one week is the control of aripiprazole's mean particle size to a range of about 1 to 30 microns (US 7,807,680 B2, col. 2:19-24). This specific particle size allows the drug to dissolve slowly after intramuscular injection, providing a controlled release of therapeutic amounts over an extended period (US 7,807,680 B2, col. 2:8-14).
  • Technical Importance: This technology enabled the creation of a long-acting injectable (LAI) version of a major antipsychotic, offering a significant therapeutic advantage by improving patient adherence and stabilizing treatment.

Key Claims at a Glance

  • The complaint asserts "one or more claims" of the ’680 patent (Compl. ¶100). Independent claim 22 is representative of the formulation claims.
  • Essential elements of Independent Claim 22:
    • A sterile freeze-dried controlled release aripiprazole formulation
    • Comprising aripiprazole having a mean particle size of about 1 to 10 microns
    • Comprising one or more suspending agents
    • The formulation is in the form of a cake obtained by freeze-drying a homogeneous aqueous suspension
    • Upon reconstitution with water, it forms a sterile injectable formulation containing from about 0.1 to about 600 mg of aripiprazole per mL
    • Upon injection, the formulation releases aripiprazole over a period of at least about two weeks.
  • The complaint does not explicitly reserve the right to assert dependent claims.

U.S. Patent No. 10,525,057 - "Method of Providing Aripiprazole to Patients Having Impaired CYP2D6 or CYP3A4 Enzyme Function"

The Invention Explained

  • Problem Addressed: The patent's background explains that aripiprazole is metabolized by liver enzymes CYP2D6 and CYP3A4. Some patients are "poor metabolizers" or take other drugs that inhibit these enzymes, which can lead to elevated, potentially toxic plasma levels of aripiprazole from a standard dose (US10525057B2, col. 3:20-40). Adjusting the dose of a long-acting injectable after administration is difficult and carries risks of extended over- or under-dosing (US 10,525,057 B2, col. 4:52-63).
  • The Patented Solution: The invention provides a method for safely administering aripiprazole to patients with impaired metabolism. The solution is to initiate treatment with a reduced starting dose of a long-acting injectable formulation. For example, for patients who are extensive metabolizers but are taking a strong CYP inhibitor, the patent teaches administering a dose that is 66% to 75% of the standard recommended initial dose to achieve therapeutic levels while avoiding excessive drug exposure (US 10,525,057 B2, col. 5:42-51, Abstract).
  • Technical Importance: This invention provides a method for personalized dosing of a long-acting injectable, improving the safety profile for specific patient populations defined by their metabolic capacity or concomitant medications.

Key Claims at a Glance

  • The complaint asserts "one or more claims" of the ’057 patent (Compl. ¶161). Independent claim 1 is a representative method claim.
  • Essential elements of Independent Claim 1:
    • A method of initiating systemic aripiprazole treatment in a patient
    • The method comprises initially intramuscularly administering 66% to 75% of a 300 or 400 mg weight equivalent dose of aripiprazole
    • The dose is in the form of a long-acting drug-containing suspension released over about one month
    • The patient is a CYP2D6 and CYP3A4 extensive metabolizer
    • The patient is concomitantly administered a strong CYP2D6 inhibitor or a strong CYP3A4 inhibitor.
  • The complaint does not explicitly reserve the right to assert dependent claims.

U.S. Patent No. 8,030,313 - "Controlled Release Sterile Injectable Aripiprazole Formulation and Method"

  • Technology Synopsis: This patent, related to the ’680 patent, claims methods of treating schizophrenia by administering a sterile injectable formulation of aripiprazole. The formulation is characterized by its components and particle size, designed to provide controlled release over at least one week (US8030313B2, col. 1:11-18, Abstract).
  • Asserted Claims: "one or more claims" (Compl. ¶111).
  • Accused Features: The administration of Defendants' proposed generic product for the treatment of schizophrenia, as will be instructed on its label (Compl. ¶113, ¶115).

U.S. Patent No. 8,722,679 - "Controlled Release Sterile Injectable Aripiprazole Formulation and Method"

  • Technology Synopsis: This patent, also related to the ’680 patent, claims specific sterile freeze-dried aripiprazole formulations. The claims focus on formulations comprising aripiprazole with a specific mean particle size (e.g., about 1 to 10 microns) and one or more suspending agents, which release the drug over at least one week (US8722679B2, col. 2:3-14, Abstract).
  • Asserted Claims: "one or more claims" (Compl. ¶125).
  • Accused Features: The composition of Defendants' proposed generic product, which is alleged to be therapeutically equivalent to the branded product and therefore contain the claimed formulation (Compl. ¶123).

U.S. Patent No. 8,399,469 - "Low Hygroscopic Aripiprazole Drug Substance and Processes for the Preparation Thereof"

  • Technology Synopsis: This patent addresses the problem that conventional anhydrous aripiprazole is hygroscopic (absorbs moisture), which complicates manufacturing and can affect stability and bioavailability (US8399469B2, col. 1:50-55). The invention claims specific, novel crystalline forms of aripiprazole (e.g., "Hydrate A" and "Anhydrous...Crystals B") that are less hygroscopic and more stable (US 8,399,469 B2, Abstract).
  • Asserted Claims: "one or more claims" (Compl. ¶136).
  • Accused Features: The active pharmaceutical ingredient in Defendants' proposed generic product, which Plaintiffs allege will be a low-hygroscopicity form of aripiprazole as claimed (Compl. ¶134).

U.S. Patent No. 8,338,427 - "Methods for Administering Aripiprazole"

  • Technology Synopsis: This patent claims methods for administering aripiprazole in an injectable composition that provides an extended release profile without the use of polymeric microspheres. The method involves injecting a suspension of aripiprazole in a vehicle, resulting in a therapeutic serum concentration for at least seven days (US8338427B2, Abstract, col. 2:27-34).
  • Asserted Claims: "one or more claims" (Compl. ¶147).
  • Accused Features: The instructions for use on the label of Defendants' proposed generic product, which allegedly will direct administration in a manner that practices the claimed method (Compl. ¶150-151).

U.S. Patent No. 10,980,803 - "Method of Providing Aripiprazole to Patients Having Impaired CYP2D6 or CYP3A4 Enzyme Function"

  • Technology Synopsis: This patent, related to the ’057 patent, claims methods of treating schizophrenia in specific patient populations, such as a CYP2D6 poor metabolizer. The method involves administering an adjusted dose (e.g., about 300 mg) of a long-acting aripiprazole formulation to account for the patient's impaired metabolism (US10980803B2, Abstract).
  • Asserted Claims: "one or more claims" (Compl. ¶175).
  • Accused Features: The instructions on the label of Defendants' proposed generic product, which allegedly will instruct physicians to administer adjusted doses to patients with impaired metabolism (Compl. ¶178-179).

U.S. Patent No. 11,154,553 - "Method of Providing Aripiprazole to Patients Having Impaired CYP2D6 or CYP3A4 Enzyme Function"

  • Technology Synopsis: This patent, also in the family of the ’057 patent, claims methods of treating schizophrenia or bipolar I disorder in patients with impaired metabolism. It specifically claims methods involving co-administration of an oral antipsychotic after the initial adjusted dose of the long-acting injectable (US11154553B1, Abstract).
  • Asserted Claims: "one or more claims" (Compl. ¶189).
  • Accused Features: The instructions on the label of Defendants' proposed generic product, which allegedly will instruct physicians on dosing regimens for specific patient populations, including the co-administration of an oral antipsychotic (Compl. ¶192-193).

III. The Accused Instrumentality

Product Identification

  • Defendants' aripiprazole for extended-release injectable suspension, 300 mg/vial and 400 mg/vial, for which Defendants seek FDA approval under ANDA No. 216608 (Compl. ¶1, 91).

Functionality and Market Context

  • The accused products are generic versions of Otsuka's ABILIFY MAINTENA® and are intended for the treatment of schizophrenia and bipolar I disorder (Compl. ¶1, 58).
  • The complaint alleges that Defendants have represented to the FDA that their generic products are pharmaceutically and therapeutically equivalent to ABILIFY MAINTENA® (Compl. ¶98). This implies the generic products are designed to have the same active ingredient, dosage form, strength, route of administration, and bioequivalence as the branded product.
  • The complaint alleges that Defendants' filing of the ANDA predicts their intent to market and sell the generic products in the United States upon approval (Compl. ¶50).
  • No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not provide specific claim charts. The following summaries are based on the infringement theory articulated in the complaint, which relies on the alleged therapeutic equivalence between the accused generic products and the branded ABILIFY MAINTENA® product.

U.S. Patent No. 7,807,680 Infringement Allegations

Claim Element (from Independent Claim 22) Alleged Infringing Functionality Complaint Citation Patent Citation
A sterile freeze-dried controlled release aripiprazole formulation which comprises: (a) aripiprazole having a mean particle size of about 1 to 10 microns, The complaint's allegation of therapeutic equivalence suggests the accused products are freeze-dried formulations containing aripiprazole with a particle size within the claimed range to achieve the required controlled-release profile. ¶98 col. 2:19-24
and (b) one or more suspending agents, The allegation of pharmaceutical equivalence suggests the accused products' formulation includes suspending agents necessary to form a stable injectable suspension upon reconstitution. ¶98 col. 4:32-35
wherein said sterile freeze-dried controlled release aripiprazole formulation is in the form of a cake obtained by freeze-drying a homogeneous aqueous suspension... The allegation of pharmaceutical equivalence suggests the accused product is manufactured via a freeze-drying process that results in a cake form, consistent with the claimed formulation. ¶98 col. 3:5-7
and wherein upon injection into a subject, said sterile injectable formulation releases aripiprazole over a period of at least about two weeks from the date of administration. The allegation of therapeutic equivalence suggests the accused products are designed to provide a similar extended-release profile, releasing aripiprazole over at least two weeks post-injection. ¶98 col. 2:8-14
  • Identified Points of Contention:
    • Scope Questions: A central dispute may involve the term "about 1 to 10 microns." The analysis will question whether the actual mean particle size of the aripiprazole in Defendants' ANDA product falls within a reasonable construction of this claimed range.
    • Technical Questions: What evidence does the complaint provide, beyond the general allegation of equivalence, that the accused product is a "freeze-dried" formulation as opposed to another form of sterile powder for suspension? The infringement analysis will depend on the specific formulation details disclosed in the ANDA.

U.S. Patent No. 10,525,057 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of initiating systemic aripiprazole treatment in a patient... The complaint alleges induced infringement based on the proposed product label, which would instruct physicians on how to treat patients. ¶165 col. 4:36-42
...comprising initially intramuscularly administering to the patient 66% to 75% of a 300 or 400 mg weight equivalent dose... The complaint alleges the proposed package insert will instruct physicians to use a reduced dose for certain patient populations, suggesting that this recommended dose reduction falls within the claimed 66% to 75% range. ¶164, ¶165 col. 6:1-5
...wherein the patient is a CYP2D6 and CYP3A4 extensive metabolizer and is concomitantly administered a strong CYP2D6 inhibitor or a strong CYP3A4 inhibitor. The complaint alleges the proposed package insert will recommend or suggest use in this specific patient population, thereby inducing infringement. ¶165 col. 4:6-15
  • Identified Points of Contention:
    • Scope Questions: Does the language of the Defendants' proposed package insert recommend a dose reduction that strictly falls within the "66% to 75%" range, or does it provide a different range or more general guidance that might not literally meet this limitation?
    • Technical Questions: A key evidentiary question is whether the instructions in the proposed package insert will specifically identify the patient as an "extensive metabolizer" taking a "strong...inhibitor," or if it will use more general language that may not map directly onto the claim's definition of the patient population.

V. Key Claim Terms for Construction

  • The Term: "mean particle size of about 1 to 10 microns" (’680 Patent, Claim 22)

  • Context and Importance: This term is the central technical limitation defining the formulation's controlled-release property. Its construction, particularly the scope of "about," will likely be determinative of literal infringement for the formulation patents. Practitioners may focus on this term because a generic manufacturer could design a product with a particle size just outside the 1-10 micron range to argue non-infringement, making the interpretation of "about" critical.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The specification states that a "mean particle size...within the range from about 1 to about 30 microns is essential" (US 7,807,680 B2, col. 2:19-21), suggesting that the inventors contemplated a wider range as functional. This could support a reading where "about 10" extends somewhat beyond 10.
    • Evidence for a Narrower Interpretation: The patent distinguishes between different release profiles based on particle size, stating that for a release of "about three to four weeks," the mean particle size is preferably "from about 2 to about 4 microns, and most preferably about 2.5 microns" (US 7,807,680 B2, col. 4:15-20). This specific teaching for a desired release duration could be used to argue against an overly broad interpretation of "about."

  • The Term: "66% to 75% of a 300 or 400 mg weight equivalent dose" (’057 Patent, Claim 1)

  • Context and Importance: This numerical range defines the specific dose adjustment that constitutes the patented method. Infringement of this method claim hinges on whether the accused product's label instructs administration within this precise percentage range. Practitioners may focus on this term because even a small deviation in the recommended dosage reduction on the generic label could be a basis for a non-infringement defense.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The patent summary describes the dose adjustment more generally as "no more than about 75%" (US 10,525,057 B2, col. 2:43-44), which could suggest some flexibility. The patent also provides several different percentage reductions for different patient scenarios (e.g., "about 75%" for poor metabolizers, "about 50%" for poor metabolizers also taking an inhibitor) (US 10,525,057 B2, col. 5:15-22, col. 5:22-34), indicating the inventors claimed specific ranges for specific scenarios.
    • Evidence for a Narrower Interpretation: The claim uses the specific range "66% to 75%." The specification provides explicit calculations resulting in these percentages (e.g., 200 mg is 66% of 300 mg; 300 mg is 75% of 400 mg) (US 10,525,057 B2, col. 6:61-67). This precise numerical disclosure may support a narrow construction limited to the recited range.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges induced infringement for all asserted method patents (’313, ’427, ’057, ’803, ’553). The basis for these allegations is that Defendants' proposed package insert for their generic products "will recommend, suggest, encourage and/or instruct" healthcare professionals and patients to use the products in a manner that directly infringes the claimed methods (Compl. ¶115, ¶151, ¶165, ¶179, ¶193).
  • Willful Infringement: The complaint does not allege willful infringement. However, it does allege that Defendants have "actual knowledge" of the patents-in-suit, evidenced by their Paragraph IV Notice Letter (Compl. ¶99, ¶110, ¶124, ¶135, ¶146, ¶160, ¶174, ¶188). This allegation of pre-suit knowledge could potentially form the basis for a later willfulness claim.

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

  • A core issue will be one of factual correspondence: For the formulation patents, will the specific physical and chemical properties of the Defendants' proposed generic product—such as aripiprazole particle size distribution and crystalline form—as detailed in its ANDA, fall within the scope of the asserted claims? This will likely require expert testimony and detailed product testing.
  • A second key issue will be one of induced infringement via labeling: For the method-of-use patents, does the instructional language in the Defendants' proposed product label direct medical professionals to administer the drug using the exact dosing percentages and for the specific patient subpopulations (e.g., poor metabolizers) recited in the claims, or does the label provide different or more general guidance?
  • A foundational question will be the validity of the asserted claims: While the complaint is predicated on infringement, Defendants' Paragraph IV certification asserts that the patents are invalid and/or unenforceable (Compl. ¶92), raising the question of whether the claims can withstand challenges based on prior art or other invalidity grounds such as lack of enablement or written description.