DCT

1:19-cv-02321

Taiho Pharmaceutical Co Ltd v. Accord Healthcare Inc

Log In
Key Events
Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:19-cv-02321, D. Del., 12/20/2019
  • Venue Allegations: Plaintiff alleges venue is proper in Delaware based on Defendants’ substantial and continuous business contacts with the state, intent to market and sell the accused product in Delaware, and previous consent to jurisdiction in other Delaware cases.
  • Core Dispute: Plaintiff alleges that Defendants' Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff's Lonsurf® cancer treatment infringes three patents covering methods of use and a specific crystalline form of an active ingredient.
  • Technical Context: The technology relates to oral combination chemotherapy for treating metastatic cancers, specifically using trifluridine, an antimetabolite, paired with tipiracil hydrochloride, an inhibitor that prevents trifluridine's rapid degradation in the body.
  • Key Procedural History: This Hatch-Waxman litigation was triggered by Defendants' filing of an ANDA with a Paragraph IV certification, asserting that the patents-in-suit are invalid or will not be infringed. The complaint was filed within the 45-day statutory window following receipt of the notice letter. Notably, U.S. Patent No. RE46,284 is a reissue patent, and U.S. Patent No. 9,527,833 has been subject to a reexamination proceeding, which may affect the interpretation of its claims.

Case Timeline

Date Event
2005-01-26 U.S. Patent No. RE46,284 Priority Date
2013-06-17 U.S. Patent Nos. 9,527,833 & 10,457,666 Priority Date
2015-09-22 FDA Approval of Lonsurf® (NDA No. 207981)
2016-12-27 U.S. Patent No. 9,527,833 Issue Date
2017-01-24 U.S. Patent No. RE46,284 Reissue Date
2019-09-16 Reexamination Certificate Issued for U.S. Patent No. 9,527,833
2019-09-23 Earliest Date of Accord's Alleged Awareness of Patents
2019-10-29 U.S. Patent No. 10,457,666 Issue Date
2019-11-13 Taiho Receives Accord's Paragraph IV Notice Letter
2019-12-20 Complaint Filing Date

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

U.S. Patent No. RE46,284 E - "Method of Administrating an Anticancer Drug Containing a, a, a-Trifluorothymidine and Thymidine Phosphorylase Inhibitor"

The Invention Explained

  • Problem Addressed: The patent describes that the anticancer agent trifluridine (FTD) is rapidly degraded in the human body by the enzyme thymidine phosphorylase (TP), resulting in a very short half-life that limits its effectiveness when administered orally (RE46,284 E Patent, col. 2:1-15).
  • The Patented Solution: The invention solves this problem by combining FTD with a specific thymidine phosphorylase inhibitor (TPI), which prevents FTD's degradation and maintains its concentration in the blood, enabling effective oral administration. The patent further discloses that administering this combination in divided daily doses, rather than a single daily dose, results in a significantly increased antitumor effect (RE46,284 E Patent, col. 2:16-28, 50-68).
  • Technical Importance: This approach enabled the development of an effective oral FTD-based chemotherapy, overcoming the pharmacokinetic hurdles that had previously limited the agent's clinical utility.

Key Claims at a Glance

  • The complaint asserts independent claims 1 and 18 (Compl. ¶68).
  • Independent Claim 1: A method for treating digestive or breast cancer with a composition comprising FTD and a TPI in a 1:0.5 molar ratio, with the essential elements being:
    • a dose of 50 to 70 mg/m²/day of FTD
    • administered orally in 2 divided portions per day
    • on a schedule of 5 days on, 2 days off per week
  • Independent Claim 18: A method for treating colorectal cancer with the same composition and molar ratio, with the essential elements being:
    • a dose of 70 mg/m²/day of FTD
    • administered orally in 2 divided portions per day
    • at a dosing interval of 6 hours or more
    • on a schedule of 5 days on, 2 days off per week

U.S. Patent No. 9,527,833 C1 - "Stable Crystal Form of Tipiracil Hydrochloride and Crystallization Method for the Same"

The Invention Explained

  • Problem Addressed: The patent identifies the need for a physically and chemically stable crystalline form of tipiracil hydrochloride (TPI), the inhibitor component of Lonsurf®, which is suitable for use as an active pharmaceutical ingredient. Prior art methods for producing TPI resulted in less stable or mixed crystal forms ('833 Patent, col. 1:21-42).
  • The Patented Solution: The invention is a specific, stable polymorph of tipiracil hydrochloride, designated "Crystal Form I." This form is defined by a unique set of characteristic peaks in a powder X-ray diffraction (PXRD) analysis, which distinguishes it from other, less stable forms ('833 Patent, Abstract; col. 5:23-41).
  • Technical Importance: Discovering a stable, highly pure, and reproducible crystalline form of a drug substance is critical for ensuring consistent quality, safety, and efficacy in pharmaceutical manufacturing.

Key Claims at a Glance

  • The complaint asserts independent claim 1 (Compl. ¶110).
  • Independent Claim 1 (as amended by reexamination): A crystal of tipiracil hydrochloride with the essential elements being:
    • It is "crystal Form I"
    • It exhibits peaks at "two or more" specific angles in a PXRD analysis (11.6°, 17.2°, 17.8°, 23.3°, 27.1°, and 29.3° at 2θ±0.1°)
    • It has a "crystal Form I purity of at least 90% by mass"

U.S. Patent No. 10,457,666 B2 - "Stable Crystal Form of Tipiracil Hydrochloride and Crystallization Method for the Same"

Technology Synopsis

  • This patent, part of the same family as the '833 patent, is also directed to the stable "Crystal Form I" of tipiracil hydrochloride. The invention addresses the pharmaceutical need for a pure and stable form of the active ingredient by defining the crystal by its characteristic powder X-ray diffraction pattern and a minimum purity level ('666 Patent, col. 1:21-42, 55-65).

Asserted Claims

  • The complaint asserts independent claim 1 (Compl. ¶141).

Accused Features

  • The complaint alleges that Defendants' ANDA Product contains tipiracil hydrochloride and that discovery will show it is the claimed Crystal Form I, exhibiting the required PXRD peaks and purity of at least 90% by mass (Compl. ¶144).

III. The Accused Instrumentality

Product Identification

  • The accused instrumentality is "Accord's ANDA Product," a generic version of Taiho's Lonsurf® (trifluridine and tipiracil) oral tablets, identified as ANDA No. 214036 (Compl. ¶¶ 7, 53).

Functionality and Market Context

  • The product is a proposed generic oral anticancer drug intended for the same therapeutic uses as Lonsurf®, which include the treatment of metastatic colorectal cancer and metastatic gastric cancer (Compl. ¶¶ 38, 65). The complaint alleges that Defendants' ANDA Product has the same use as Lonsurf® and that its proposed product labeling will be substantially the same as the FDA-approved labeling for Lonsurf® (Compl. ¶¶ 65-66). The filing of the ANDA itself is the statutorily defined act of infringement that gives rise to this lawsuit under the Hatch-Waxman Act (Compl. ¶56).

IV. Analysis of Infringement Allegations

RE46,284 E Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method for treating at least one of a digestive cancer and a breast cancer, comprising orally administering a composition comprising α,α,α-trifluorothymidine (FTD) and 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride in a molar ratio of 1:0.5... The proposed product labeling for Accord's ANDA Product will allegedly instruct medical personnel and patients to treat digestive cancer using the specified composition. ¶71 col. 5:61-68
...at a dose of 50 to 70 mg/m²/day in terms of FTD in 2 divided portions per day to a human patient... The proposed product labeling for Accord's ANDA Product will allegedly instruct administration of the drug at the claimed dose and in two divided portions per day. ¶71 col. 6:50-55
...wherein the administration of a daily dose of said composition is in 2 portions per day for 5 days followed by 2 days off treatment in the week on a one-week dosing schedule... The proposed product labeling for Accord's ANDA Product will allegedly instruct administration according to the claimed dosing schedule. ¶71 col. 6:40-51

9,527,833 C1 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A crystal of 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione hydrochloride... Accord's ANDA Product allegedly contains tipiracil HCl as one of its active ingredients. ¶113 col. 1:47-54
...which is crystal Form I, exhibiting peaks at two or more angles selected from the group consisting of 11.6°, 17.2°, 17.8°, 23.3°, 27.1°, and 29.3° as a diffraction angle (20±0.1°) in powder X-ray diffraction. Discovery will allegedly show that the tipiracil HCl in Accord's ANDA Product is Crystal Form I and exhibits the characteristic PXRD peaks recited in the claim. ¶113 col. 5:23-41
...and has crystal Form I purity of at least 90% by mass. The complaint does not provide sufficient detail for analysis of this specific element, but implies that discovery will show the accused product meets the purity limitation. --- '833 C1 Patent, col. 2:1-10

Identified Points of Contention

  • Scope Questions: For the '284 patent, a central question will be whether the specific instructions in Accord's proposed product labeling will be found to meet all the limitations of the asserted method claims, thereby inducing infringement by doctors and patients. The defense may argue that its label allows for, but does not require, administration in a way that maps onto every claim element.
  • Technical Questions: For the '833 and '666 patents, the dispute will be primarily factual and evidentiary. A key question is whether Accord's ANDA product actually contains the specific "Crystal Form I" of tipiracil hydrochloride. This will turn on expert analysis of the accused product to determine if its PXRD pattern falls within the claimed peak locations and precision (e.g., ±0.1° or ±0.2°) and meets the claimed purity level.

No probative visual evidence provided in complaint.

V. Key Claim Terms for Construction

The Term

  • "exhibiting peaks at two or more angles selected from the group consisting of..." (from claim 1 of the '833 patent)

Context and Importance

  • The infringement analysis for the '833 and '666 patents hinges on whether the crystalline form in Accord's product meets this precise analytical definition. Practitioners may focus on this term because the outcome of the case could depend on how strictly the PXRD peak requirements are interpreted and applied to the physical evidence from Accord's product.

Intrinsic Evidence for Interpretation

  • Evidence for a Broader Interpretation: The claim language requires only "two or more" of the listed peaks, not all of them, which could support a finding of infringement even if the accused product's PXRD pattern is not a perfect match to the reference pattern for Crystal Form I. The specification also acknowledges that peak values may have a margin of error ('833 Patent, col. 7:65-col. 8:2).
  • Evidence for a Narrower Interpretation: The patent explicitly identifies the invention as "Crystal Form I" and provides a definitive list of peaks and a representative diffraction chart (Fig. 1). A party could argue that to "be" Crystal Form I, a crystal must exhibit a pattern that substantially conforms to the full reference pattern, not just an arbitrary subset of two peaks. The explicit precision of the diffraction angle (2θ±0.1°) could also be argued as a strict, limiting boundary.

VI. Other Allegations

Indirect Infringement

  • The complaint alleges induced infringement of the '284 patent, stating that Accord's proposed product labeling will instruct and encourage medical personnel and patients to perform the patented methods of administration (Compl. ¶¶ 76-78). It also alleges contributory infringement, asserting that Accord's product is specifically adapted for the infringing use and has no substantial non-infringing use (Compl. ¶¶ 79-81).

Willful Infringement

  • The complaint alleges that Accord was aware of the patents-in-suit prior to filing its ANDA and acted "without a reasonable basis for a good faith belief that it would not be liable for infringing" (Compl. ¶¶ 84, 122, 163). The alleged pre-suit knowledge is based on the patents' Orange Book listings and is asserted to support a claim for enhanced damages.

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

  • A core issue will be one of induced infringement: For the '284 method-of-use patent, will the language of Accord's proposed product label be found to affirmatively instruct or encourage clinicians and patients to follow the specific dosing and scheduling regimen required by the claims, or does it provide sufficient latitude for a substantial non-infringing use?
  • A key evidentiary question will be one of physical characterization: For the '833 and '666 composition patents, does the tipiracil hydrochloride in Accord's actual ANDA product, upon forensic analysis, possess the specific crystalline structure (Crystal Form I) defined by the claimed powder X-ray diffraction peaks and purity levels?