Teijin Ltd v. Alkem Laboratories Ltd

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Teijin Limited, Teijin Pharma Limited (Japan); Takeda Pharmaceuticals U.S.A., Inc. (Delaware)
  • Defendant: Alkem Laboratories Limited (India); Ascend Laboratories, LLC (New Jersey)
  • Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP
• Case Identification: 1:19-cv-00768, D. Del., 04/26/2019
• Venue Allegations: Venue is alleged as proper based on Defendants’ business activities throughout the United States, including in Delaware, and their previous submission to jurisdiction in the district by filing counterclaims in prior unrelated actions.
• Core Dispute: Plaintiffs allege that Defendants’ filing of an Abbreviated New Drug Application (ANDA) to market generic febuxostat tablets constitutes an act of infringement of three patents covering a specific crystalline form of the drug and methods of its co-administration with theophylline.
• Technical Context: The case involves febuxostat (marketed as Uloric®), a xanthine oxidase inhibitor used to treat hyperuricemia (high uric acid in the blood), a condition that causes gout.
• Key Procedural History: This action was initiated under the Hatch-Waxman Act following Plaintiffs’ receipt of a notice letter, dated March 15, 2019, in which Defendants certified that the patents-in-suit are invalid or will not be infringed by their proposed generic product (a "Paragraph IV" certification). The complaint notes that Defendants’ ANDA also contains a "Paragraph III" certification for U.S. Patent No. 6,225,474, indicating an intent to launch their generic product after that patent's expiration.

Case Timeline

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

U.S. Patent No. 7,361,676 - “Solid Preparation Containing Single Crystal Form” (issued Apr. 22, 2008)

The Invention Explained

• Problem Addressed: The patent describes that the active pharmaceutical ingredient (API), febuxostat, can exist in at least six different crystalline forms (polymorphs), as well as an amorphous form. The patent notes that in formulating this API, it is difficult "to obtain preparations having no variation in the dissolution profiles of drugs" because some of these crystal forms are physically unstable and can transform over time. (’676 Patent, col. 1:50-63).
• The Patented Solution: The invention is a solid pharmaceutical preparation that uses a single, specific, stable crystalline form of febuxostat, designated "crystal A." This crystal form is defined by a characteristic X-ray powder diffraction pattern. By using only this stable polymorph, the resulting drug product is alleged to have a consistent and predictable dissolution profile, which is critical for reliable therapeutic performance. (’676 Patent, col. 2:5-9; Table 1).
• Technical Importance: Controlling the polymorphic form of an API is a critical and common challenge in pharmaceutical manufacturing, as changes in crystal structure can significantly affect a drug's stability, solubility, and bioavailability. (’676 Patent, col. 1:50-63).

Key Claims at a Glance

• The complaint alleges infringement of "one or more claims" but does not identify specific claims (Compl. ¶39). Independent claim 1 is representative:
  • A tablet comprising crystal A of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid with an X-ray powder diffraction pattern having specific peaks at a reflection angle 2θ, of 6.62°, 7.18°, 12.80°, 13.26°, 16.48°, 19.58°, 21.92°, 22.68°, 25.84°, 26.70°, 29.16° and 36.70°.
  • An excipient, and a disintegrating agent.
  • Wherein the average particle diameter of the crystal A is from 12.9 µm to 26.2 µm.

U.S. Patent No. 8,372,872 - “Methods For Concomitant Treatment of Theophylline and Febuxostat” (issued Feb. 12, 2013)

The Invention Explained

• Problem Addressed: Febuxostat is a xanthine oxidase (XO) inhibitor. Theophylline, a drug used for respiratory diseases, is metabolized in part by XO. Co-administration of theophylline with other XO inhibitors, such as allopurinol, leads to increased theophylline concentrations, creating a risk of toxicity and requiring dose adjustments. Due to this expected interaction, the original label for febuxostat (Uloric®) contraindicated its use with theophylline. (’872 Patent, col. 1:40-54; Compl. ¶¶50-51).
• The Patented Solution: The inventors conducted a clinical study and discovered, contrary to expectations, that co-administering febuxostat with theophylline did not result in a clinically significant drug-drug interaction. The patent claims a method of treating a patient with both drugs "without adjusting the amount of theophylline administered for adverse drug interactions." (’872 Patent, Claim 1).
• Technical Importance: This discovery was significant because it removed a contraindication from the Uloric® label, allowing patients who require theophylline to be treated with febuxostat without the clinical complexity and risk associated with dose adjustments. (Compl. ¶¶52-53).

Key Claims at a Glance

• The complaint asserts infringement of "the sole claim of the ’872 patent" (Compl. ¶46). The patent contains only one claim.
  • A method of co-administering febuxostat and theophylline to a hyperuricemic patient suffering from gout.
  • comprising the steps of: administering to the hyperuricemic patient suffering from gout a therapeutically effective amount of febuxostat in a dose of 80 mg.
  • and administering to the patient a therapeutically effective amount of theophylline subsequent to the administration of the febuxostat.
  • without adjusting the amount of theophylline administered for adverse drug interactions.

U.S. Patent No. 9,107,912 - “Methods For Concomitant Treatment of Theophylline and Febuxostat” (issued Aug. 18, 2015)

• Technology Synopsis: As a continuation of the same family as the ’872 patent, this patent addresses the same technical problem of the expected drug-drug interaction between febuxostat and theophylline ('912 Patent, col. 1:48-59). The invention is the discovery that febuxostat can be safely co-administered with theophylline without requiring dose adjustments, which was contrary to the initial contraindication on the drug's label (Compl. ¶¶52-53).
• Asserted Claims: The complaint asserts "one or more claims," including independent claim 1 (Compl. ¶¶48, 65).
• Accused Features: The complaint alleges that Defendants' proposed product label will induce infringement by omitting the prior contraindication for theophylline and including affirmative statements that no dose adjustment is necessary, thereby encouraging doctors to practice the claimed method (Compl. ¶¶55-58, 66).

III. The Accused Instrumentality

Product Identification

The accused instrumentalities are Defendants' proposed generic febuxostat tablets in 40 mg and 80 mg strengths, for which Abbreviated New Drug Application (ANDA) No. 212924 was filed with the FDA (Compl. ¶¶15, 31).

Functionality and Market Context

The products are intended to be generic equivalents to Plaintiffs' branded drug, Uloric®, used for treating hyperuricemia (Compl. ¶29). For the method patent claims ('872 and '912), the key infringing functionality is the proposed prescribing information (the product label). The complaint alleges this label will omit the prior contraindication against use with theophylline and will include statements that "no dose adjustment is necessary," thereby instructing and encouraging medical providers to co-administer the drugs in an infringing manner (Compl. ¶¶54-58). The complaint quotes the current Uloric® label language, stating "No dose adjustment is necessary for theophylline when co-administered with ULORIC," which it alleges will be mirrored in Alkem's label (Compl. ¶56). Defendants are seeking to enter the market with a lower-cost generic alternative to the branded product prior to the expiration of the patents-in-suit (Compl. ¶31).

IV. Analysis of Infringement Allegations

The complaint does not provide sufficient detail for a claim chart analysis of the ’676 Patent. The infringement theory is based on the statutory act of filing the ANDA under 35 U.S.C. § 271(e)(2) (Compl. ¶39). The complaint alleges that the notice letter provided by Alkem contained "limited information" about the crystal form of febuxostat and that the information provided "does not demonstrate" that the proposed product will not infringe (Compl. ¶¶34-35). This suggests the central dispute for this patent will be an evidentiary one, turning on the actual polymorphic form and particle characteristics of the API in Defendants' product, to be determined through discovery.

’872 Patent Infringement Allegations

Identified Points of Contention

• Scope Questions ('676 Patent): A central question will be whether the febuxostat API in Defendants' product is, in fact, "crystal A" as defined by the specific X-ray diffraction peaks in the claims. A secondary question is whether it meets the "average particle diameter" limitation of 12.9 µm to 26.2 µm.
• Technical Questions ('872 and ’912 Patents): The infringement case for the method patents hinges on a theory of inducement. A key question will be whether the content of Defendants' proposed product label, specifically the absence of a prior warning and the presence of affirmative statements regarding no dose adjustment, is sufficient to prove Defendants possessed the specific intent to encourage doctors to perform the patented method, as required for a finding of induced infringement.

V. Key Claim Terms for Construction

’676 Patent: "average particle diameter ... is from 12.9 µm to 26.2 µm" (Claim 1)

Context and Importance

This numerical range is a hard-edged limitation. Infringement will require that Defendants' product falls within this precise range. Practitioners may focus on this term because its basis in the specification (Table 7) could be scrutinized during validity challenges, and the method of measuring "average particle diameter" could become a point of dispute.

Intrinsic Evidence for Interpretation

• Evidence for a Broader Interpretation: A defendant might argue the range is not critical by pointing to specification language stating that solid preparations can be produced with particles outside this range and that "There is no limitation to the dosage form" (’676 Patent, col. 4:45-46).
• Evidence for a Narrower Interpretation: The claim language itself is explicitly narrow. The patent provides data in Figure 7 and Table 7 that correlates dissolution profiles with different particle size distributions, directly linking the claimed range (derived from "Particle 2" and "Particle 3" in Table 7) to performance. The specification also warns that particles over 50 µm lead to variable dissolution and particles under 3 µm are difficult to handle, reinforcing the technical significance of a controlled size range. (’676 Patent, col. 4:36-49).

’872 Patent: "without adjusting the amount of theophylline" (Claim 1)

Context and Importance

This negative limitation is the core of the asserted invention. Its meaning is critical for determining both infringement and validity. The dispute will center on what this phrase means in clinical practice and how it is induced by a product label.

Intrinsic Evidence for Interpretation

• Evidence for a Broader Interpretation: A defendant could argue this phrase is indefinite or that it simply means not following a specific dose-reduction protocol, while still allowing for ordinary clinical monitoring and caution, as suggested by language on the current Uloric label (Compl. ¶56).
• Evidence for a Narrower Interpretation: The patent specification repeatedly contrasts the invention with the standard of care for allopurinol, where clinicians "are required to alter the theophylline dosing." (’872 Patent, col. 1:49-51). This context suggests "without adjusting" means a complete lack of the dose modification that was previously the standard for this drug class. The patent's description of its own clinical trial results, where no adjustment was needed, provides a concrete embodiment of the term's meaning.

VI. Other Allegations

Indirect Infringement

The allegations for the ’872 and ’912 patents are entirely for induced infringement under 35 U.S.C. § 271(b). The complaint asserts that Defendants' act of filing an ANDA with a proposed product label that omits the prior contraindication and states that no dose adjustment is necessary will induce medical practitioners and patients to perform the claimed methods (Compl. ¶¶55, 58, 63, 66).

Willful Infringement

The complaint alleges pre-suit knowledge for all three patents-in-suit. It states that Defendants were "aware of the existence" of the patents and that the filing of the ANDA with a Paragraph IV certification "constituted an act of infringement" (Compl. ¶¶44, 69).

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

• A core issue will be one of factual evidence: For the ’676 patent, will discovery reveal that the API in Defendants' generic product is the specific "crystal A" polymorph and falls within the claimed particle size range? The complaint's sparse allegations suggest this is a key unknown.
• A second central issue will be one of induced infringement: For the ’872 and ’912 method patents, does the language of Defendants' proposed product label—specifically the removal of a historical contraindication—provide sufficient evidence to meet the legal standard of specific intent to induce infringement, or will Defendants successfully argue that their label is merely a statement of scientific fact that does not actively encourage infringement?
• A final question will be one of claim scope and validity: Will the specific numerical particle size range in the ’676 patent and the negative limitation "without adjusting" in the ’872 patent withstand validity challenges based on obviousness or indefiniteness, particularly in light of the disclosures within the patents' own specifications?