DCT

1:21-cv-00900

Otsuka Pharmaceutical Co Ltd v. Lupin Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:21-cv-00900, D. Del., 03/07/2022
  • Venue Allegations: Venue is alleged to be proper as to Lupin Inc. because it is a Delaware corporation. Venue is alleged as proper for Lupin Limited because it is a foreign corporation that may be sued in any judicial district.
  • Core Dispute: Plaintiff alleges that Defendants’ Abbreviated New Drug Application (ANDA) to market generic tolvaptan tablets constitutes an act of infringement of three U.S. patents covering the drug's manufacturing process and formulation.
  • Technical Context: The technology relates to pharmaceutical manufacturing and formulation, specifically methods to produce high-purity tolvaptan and create a stable, effective oral solid dosage form for this poorly soluble compound used to treat polycystic kidney disease.
  • Key Procedural History: This Hatch-Waxman action was triggered by Lupin’s submission of ANDA No. 216063 with a Paragraph IV certification, alleging that the patents-in-suit are invalid or will not be infringed by its proposed generic product. The complaint states the action was commenced within 45 days of Otsuka’s receipt of Lupin’s notice letter, triggering a 30-month statutory stay of FDA approval for Lupin’s ANDA. The corresponding branded drug, JYNARQUE®, has orphan drug exclusivity until April 23, 2025.

Case Timeline

Date Event
2005-09-02 Earliest Priority Date for '730 and '735 Patents
2007-06-21 Earliest Priority Date for '694 Patent
2012-09-25 Issue Date for U.S. Patent No. 8,273,735
2013-08-06 Issue Date for U.S. Patent No. 8,501,730
2018-04-23 FDA Approval Date for JYNARQUE® New Drug Application
2021-02-02 Issue Date for U.S. Patent No. 10,905,694
2021-05-10 Date of Lupin's Notice of Paragraph IV Certification Letter
2022-03-07 First Amended Complaint Filing Date
2025-04-23 JYNARQUE® Orphan Drug Exclusivity Expiration Date

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

U.S. Patent No. 8,501,730 - “Process for Preparing Benzazepine Compounds or Salts Thereof”

  • Issued: August 6, 2013

The Invention Explained

  • Problem Addressed: The patent family addresses the challenge that prior art methods for synthesizing certain benzazepine compounds, like tolvaptan, are not suitable for industrial-scale production due to low yield and purity ('735 Patent, col. 2:50-58). A key issue is an "undesirable dehalogenating reaction" that can occur during a critical synthesis step ('730 Patent, col. 8:1-5).
  • The Patented Solution: The invention is a product-by-process claim for "highly pure" tolvaptan. The patent describes a specific manufacturing process wherein a ketone precursor compound is reduced to the final active pharmaceutical ingredient. This is achieved by using a specific, limited amount of a hydrogenating agent (0.25 to 1 mole per mole of the precursor), which produces the desired compound with over 99.5% purity while minimizing the formation of process-related impurities ('730 Patent, claim 1; col. 7:1-9).
  • Technical Importance: The claimed invention provides a method to manufacture a high-purity drug substance on an industrial scale, which is essential for ensuring product safety, consistency, and regulatory approval ('730 Patent, col. 11:1-11).

Key Claims at a Glance

  • The complaint asserts at least independent claim 1 (Compl. ¶45).
  • Claim 1 of the '730 patent recites:
    • A highly pure 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine... or a salt thereof;
    • having a purity of more than 99.5%;
    • which is produced by a process comprising reducing a specific benzazepine precursor (formula (1));
    • in the presence of a hydrogenating agent selected from a specific group (lithium aluminum hydride, sodium borohydride, etc.);
    • wherein the agent is used in an amount of 0.25 to 1 mole per 1 mole of the precursor compound.
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent.

U.S. Patent No. 10,905,694 - “Pharmaceutical Solid Preparation Comprising Benzazepines and Production Method Thereof”

  • Issued: February 2, 2021

The Invention Explained

  • Problem Addressed: The patent’s background section states that the benzoazepine active ingredient has poor solubility, which hinders its absorption from the gastrointestinal tract. While forming an "amorphous composite" with hydroxypropylcellulose improves solubility, directly compressing this composite into a tablet results in a product that fails to disintegrate properly, rendering the drug ineffective ('694 Patent, col. 1:31-48).
  • The Patented Solution: The invention is a pharmaceutical tablet formulation and a method of making it. The solution involves a multi-step process that first creates granules from the amorphous drug composite, and then mixes these granules with a specific disintegrant: "low substituted hydroxypropylcellulose" having a tightly controlled particle size distribution ('694 Patent, claim 1). This combination is described as providing both the necessary solubility from the amorphous state and rapid disintegration from the specific excipient, solving the competing technical problems ('694 Patent, col. 1:56-col. 2:5; Abstract).
  • Technical Importance: This formulation technology enables the creation of a commercially viable and effective oral solid dosage form for a poorly soluble, yet therapeutically important, drug compound ('694 Patent, col. 25:1-17).

Key Claims at a Glance

  • The complaint asserts at least independent claim 1 (Compl. ¶53).
  • Claim 1 of the '694 patent recites a pharmaceutical solid preparation obtained by a method comprising:
    • Step 1: producing amorphous composites of the drug and hydroxypropylcellulose.
    • Step A: processing the amorphous composites with crystalline cellulose and corn starch/lactose into granules.
    • Step 2: mixing the granules with "low substituted hydroxypropylcellulose" that has an average particle diameter of 45 to 65 µm and a 90% cumulative particle diameter of 150 to 200 µm.
    • Step 3: processing the resulting mixture into a solid preparation.
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent.

Multi-Patent Capsule

  • Patent Identification: U.S. Patent No. 8,273,735, “Process for Preparing Benzazepine Compounds or Salts Thereof,” issued September 25, 2012.
  • Technology Synopsis: This patent claims a specific process for manufacturing tolvaptan. It addresses the same industrial-scale production challenges as the '730 patent, focusing on a reduction step that converts a ketone precursor into the final hydroxylated drug. The claimed process uses a specific, limited quantity of a hydrogenating agent to achieve high yield and purity by minimizing side reactions ('735 Patent, Abstract; col. 4:28-40).
  • Asserted Claims: Claims 6-8 and 10 are asserted (Compl. ¶62). Independent claim 6 is a process claim.
  • Accused Features: The complaint alleges that Lupin’s ANDA products will be imported into the U.S. and are made by a process that infringes the '735 patent, giving rise to infringement under 35 U.S.C. § 271(g) (Compl. ¶¶60, 62, 64).

III. The Accused Instrumentality

Product Identification

  • The accused instrumentalities are Lupin’s proposed generic tolvaptan tablets in 15, 30, 45, 60, and 90 mg dosage strengths, as described in ANDA No. 216063 (Compl. ¶2).

Functionality and Market Context

  • The accused products are generic versions of Otsuka’s JYNARQUE® tablets (Compl. ¶34). The complaint alleges that Lupin has represented to the FDA that its products are "pharmaceutically and therapeutically equivalent" to JYNARQUE® (Compl. ¶¶41, 51). JYNARQUE® is a prescription medication used to slow the decline of kidney function in adult patients with rapidly progressing autosomal dominant polycystic kidney disease (ADPKD) (Compl. ¶21). The infringement alleged is statutory, arising from the act of submitting the ANDA to the FDA seeking approval to market these generic products prior to the expiration of the patents-in-suit (Compl. ¶¶43, 53).

IV. Analysis of Infringement Allegations

The complaint alleges infringement under 35 U.S.C. § 271(e)(2) for the '730 and '694 patents, based on the submission of the ANDA. For the '735 patent, it alleges future infringement under 35 U.S.C. § 271(g) based on the importation of a product made by a patented process. The complaint does not provide claim charts or detailed factual support for how Lupin's proposed product meets each claim limitation, instead relying on the statutory act of infringement and the representation of therapeutic equivalence.

No probative visual evidence provided in complaint.

'730 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A highly pure 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine... or a salt thereof Lupin’s ANDA products are tolvaptan tablets, which contain the specified chemical compound (Compl. ¶2). The product is alleged to be "pharmaceutically and therapeutically equivalent" to JYNARQUE® (Compl. ¶41), which embodies the claimed invention. ¶2, ¶41 col. 16:29-31
having a purity of more than 99.5% The complaint alleges that Lupin's submission of ANDA No. 216063 for a product equivalent to JYNARQUE® constitutes infringement of the claim (Compl. ¶43, ¶45). The specific purity of Lupin's proposed product is not detailed in the complaint. ¶43, ¶45 col. 16:31-32
which is produced by the process which comprises reducing a benzazepine compound of the formula (1)... in the presence of a hydrogenating agent selected from the group consisting of lithium aluminum hydride, sodium borohydride, zinc borohydride, and diborane in an amount of 0.25 to 1 mole per 1 mole of the compound (1). As a product-by-process claim, infringement may turn on the characteristics of the final product. The complaint does not specify the process Lupin intends to use but alleges infringement based on the submission of the ANDA itself, which seeks approval to market a product that Otsuka alleges is covered by the claim (Compl. ¶43, ¶45). ¶43, ¶45 col. 16:32-41

'694 Patent Infringement Allegations

The complaint does not provide sufficient detail for a full claim chart analysis. The infringement theory is based on the statutory act of filing an ANDA for a product that is therapeutically equivalent to Otsuka's JYNARQUE®, which is presumably manufactured according to the patented method (Compl. ¶¶51, 53). The complaint does not contain specific factual allegations regarding the excipients or manufacturing steps described in Lupin's confidential ANDA. The core allegation is that by filing the ANDA, Lupin has committed an act of infringement of at least claim 1 of the '694 patent (Compl. ¶53).

Identified Points of Contention

  • Scope Questions: The '730 and '694 patents contain product-by-process claims. A threshold legal question will be whether the process limitations impart patentably significant structural or functional differences to the final product. If they do not, the claims may be construed to cover the product regardless of the manufacturing process, simplifying Otsuka's burden. If they do, Otsuka may need to prove that Lupin's product possesses those specific characteristics.
  • Technical Questions: The dispute will likely focus on facts contained within Lupin's confidential ANDA. Does Lupin's manufacturing process for its drug substance fall within the process parameters of the '735 patent? Does Lupin's final drug product meet the ">99.5% purity" limitation of the '730 patent? Does Lupin's tablet formulation use a "low substituted hydroxypropylcellulose" with the specific particle size distribution required by claim 1 of the '694 patent?

V. Key Claim Terms for Construction

  • The Term: "highly pure... having a purity of more than 99.5%" ('730 patent, claim 1)
  • Context and Importance: The entirety of claim 1 depends on this limitation. The dispute will center on what this purity level means and how it is measured. Practitioners may focus on this term because infringement depends on a specific, quantifiable parameter that may be defined by the impurities the patented process was designed to avoid.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The claim language itself simply states a numerical percentage, which could support an argument that any standard method of purity analysis (e.g., HPLC area percentage) showing a value over 99.5% is sufficient.
    • Evidence for a Narrower Interpretation: The specification discusses the formation of specific impurities (Compounds A, B, C, and D) that the inventive process avoids ('730 patent, col. 14:35-42). A party could argue that "purity" should be construed in this context, meaning "substantially free of" these specific process-related impurities, rather than a general purity level.
  • The Term: "low substituted hydroxypropylcellulose, ... has an average particle diameter of 45 to 65 µm, and has a 90% cumulative particle diameter of 150 to 200 µm" ('694 patent, claim 1)
  • Context and Importance: This limitation defines the specific disintegrant required by the invention. Infringement of the '694 patent hinges on whether the excipient used in Lupin's proposed product meets these precise physical parameters.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: A party may argue that the numerical ranges should be given their plain and ordinary meaning, and that any scientifically accepted particle size analysis method can be used to determine if an excipient falls within the claimed ranges.
    • Evidence for a Narrower Interpretation: The specification identifies a specific commercial product, "LH-11," as a suitable example ('694 patent, col. 16:5-8). Further, it describes measuring particle size using a "laser diffraction type particle size distribution analyzer" ('694 patent, col. 7:13-18). A party may argue that the claim terms should be construed in light of these specific examples and measurement techniques.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that upon approval, Lupin will actively induce and contribute to infringement of the '730 and '694 patents (Compl. ¶¶45, 55). The factual basis for these allegations is not detailed but is typical in ANDA cases, where the act of seeking approval for a drug with a specific label is alleged to induce infringement by prescribing physicians and patients.
  • Willful Infringement: The complaint does not contain a formal count for willful infringement. However, it explicitly alleges that Lupin has "actual knowledge" of the '730, '694, and '735 patents (Compl. ¶¶42, 52, 63). These allegations may serve as a basis for a later claim of willful infringement, particularly for any infringing acts that occur after the filing of the complaint.

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

This case appears to be a technically complex ANDA dispute where the outcome will depend on the specific details within Lupin's confidential regulatory filing. The central questions for the court will likely be:

  • A core issue will be one of process versus product: For the product-by-process claims ('730 and '694 patents), does Otsuka need to prove that Lupin uses the claimed manufacturing process, or is it sufficient to show that Lupin’s final drug product is substantively identical to one made by that process?
  • A key evidentiary question will be one of factual correspondence: Does the evidence from Lupin’s confidential ANDA establish that its proposed product will meet the specific claim limitations regarding purity (>99.5% for the '730 patent) and excipient particle size (for the '694 patent), and that its manufacturing method falls within the process claims of the '735 patent?
  • The resolution may also depend on a question of definitional scope: How will the court construe the term "purity" in the '730 patent—as a general measure or as freedom from specific, process-related impurities—and will this construction be dispositive of infringement?