Taiho Pharmaceutical Co Ltd v. MSN Laboratories Private Ltd

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Taiho Pharmaceutical Co Ltd (Japan) and Taiho Pharmaceutical Co Ltd (Delaware)
  • Defendant: MSN Laboratories Private Ltd. (India) and MSN Pharmaceuticals Inc (Delaware)
  • Plaintiff’s Counsel: Ashby & Geddes
• Case Identification: 1:19-cv-02342, D. Del., 03/16/2020
• Venue Allegations: Venue is asserted based on Defendant MSN Pharmaceuticals Inc. being a Delaware corporation and both defendants allegedly having substantial and continuous business contacts with the state, intending to market the accused product in Delaware, and having previously submitted to the court's jurisdiction in other matters.
• Core Dispute: Plaintiff alleges that Defendant's Abbreviated New Drug Application (ANDA) for a generic version of the anticancer drug Lonsurf® constitutes an act of infringement of four patents related to methods of treatment, a specific crystalline form of an active ingredient, and a high-purity version of that crystalline form.
• Technical Context: The technology concerns a combination oral chemotherapy drug, Lonsurf® (trifluridine/tipiracil), used to treat certain advanced or metastatic cancers.
• Key Procedural History: This is a Hatch-Waxman action initiated after Defendant filed ANDA No. 214024 with Paragraph IV certifications, asserting that Plaintiff's patents are invalid or will not be infringed. The complaint notes that U.S. Patent No. RE46,284 is a reissue patent and that U.S. Patent Nos. 9,527,833 and 10,456,399 have undergone post-grant proceedings (reexamination or reissue), which may have implications for claim scope and validity.

Case Timeline

Date	Event
2005-01-26	Priority Date for U.S. Patent No. RE46,284 E
2013-06-17	Priority Date for U.S. Patent Nos. 9,527,833 B2 and 10,457,666 B2
2015-09-22	FDA approves NDA No. 207981 for Lonsurf® tablets
2016-02-05	Priority Date for U.S. Patent No. 10,456,399 B2
2016-12-27	U.S. Patent No. 9,527,833 issues
2017-01-24	U.S. Patent No. RE46,284 reissues
2019-09-16	Reexamination Certificate issues for U.S. Patent No. 9,527,833
2019-09-23	Alleged date of MSN's awareness of patents-in-suit
2019-10-29	U.S. Patent No. 10,456,399 issues
2019-10-29	U.S. Patent No. 10,457,666 issues
2019-11-18	Taiho receives first Paragraph IV notice letter for '284 & '833 patents
2020-02-20	Taiho receives second Paragraph IV notice letter for '399 & '666 patents
2020-03-16	First Amended Complaint filed

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

U.S. Reissue Patent No. RE46,284 E - "Method of Administrating an Anticancer Drug Containing α, α, α-Trifluorothymidine and Thymidine Phosphorylase Inhibitor," Reissued January 24, 2017

The Invention Explained

• Problem Addressed: The patent describes that the anticancer compound trifluridine (FTD) is quickly broken down in the human body by an enzyme called thymidine phosphorylase (TP). This rapid degradation results in an "extremely shortened half-life" that limits the drug's effectiveness, particularly when administered orally (’284 Patent, col. 2:1-15).
• The Patented Solution: The invention solves this problem by combining FTD with a thymidine phosphorylase inhibitor (TPI), specifically 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride. The TPI prevents the degradation of FTD, which "enables the blood concentration of FTD to be maintained" and allows for effective oral administration (’284 Patent, col. 2:16-24). The claims are directed to specific dosing schedules for this combination therapy, such as twice-daily administration for five days followed by a two-day rest period, to maximize the therapeutic effect (’284 Patent, col. 5:50-65).
• Technical Importance: This combination therapy approach transformed FTD from a compound with limited clinical utility into a viable oral anticancer drug by overcoming the key pharmacokinetic hurdle that previously hindered its use (’284 Patent, col. 2:1-24).

Key Claims at a Glance

• The complaint asserts independent claims 1 and 18 (Compl. ¶71).
• Independent Claim 1 elements include:
  • A method for treating at least one of a digestive cancer and a breast cancer.
  • Orally administering a composition of FTD and TPI hydrochloride in a 1:0.5 molar ratio.
  • At a dose of 50 to 70 mg/m²/day (in terms of FTD).
  • Administered in 2 divided portions per day.
  • The daily administration is for 5 days followed by 2 days off treatment in the week.
• Independent Claim 18 elements include:
  • A method for treating colorectal cancer.
  • Orally administering a composition of FTD and TPI hydrochloride in a 1:0.5 molar ratio.
  • At a dose of 70 mg/m²/day (in terms of FTD).
  • Administered in 2 divided portions per day at a dosing interval of 6 hours or more.
  • The administration is for 5 days followed by 2 days off treatment in a one-week dosing schedule.

U.S. Patent No. 9,527,833 B2 - "Stable Crystal Form of Tipiracil Hydrochloride and Crystallization Method for the Same," Issued December 27, 2016

The Invention Explained

• Problem Addressed: The patent notes that for a compound to be used as an active ingredient in a medicine, it must be physically and chemically stable to ensure quality and safe storage. Previous methods for producing tipiracil hydrochloride (TPI) could result in mixed or less stable crystalline forms, which are undesirable for pharmaceutical manufacturing (’833 Patent, col. 1:20-43).
• The Patented Solution: The invention identifies and claims a specific, stable crystalline form of TPI, named "Crystal Form I." This form is defined by a unique fingerprint of peaks observed in powder X-ray diffraction (PXRD) analysis. The patent describes this form as having superior preservation stability compared to other forms, making it suitable for use in a pharmaceutical product (’833 Patent, Abstract; col. 2:54-61).
• Technical Importance: The reliable production of a single, stable polymorph of a drug substance is critical for pharmaceutical development, as it ensures batch-to-batch consistency, predictable dissolution rates, and overall product quality and safety (’833 Patent, col. 1:20-28).

Key Claims at a Glance

• The complaint asserts independent claim 1 (Compl. ¶116). A reexamination certificate issued for the patent on September 16, 2019, amending this claim (Compl. ¶45; ’833 Patent, Reexam. Cert.).
• Independent Claim 1 (as amended) elements include:
  • A crystal of 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione hydrochloride.
  • Which is crystal Form I.
  • Exhibiting peaks at two or more angles selected from a specified group (11.6°, 17.2°, 17.8°, 23.3°, 27.1°, and 29.3°) in powder X-ray diffraction.
  • And has a crystal Form I purity of at least 90% by mass.

U.S. Patent No. 10,456,399 B2 - "Method for Treating Cancer Patients with Severe Renal Impairment," Issued October 29, 2019

• Technology Synopsis: This patent addresses the challenge of safely and effectively administering the FTD/TPI combination drug to cancer patients who also have severe renal impairment. The invention provides a method of treatment that specifies a reduced dosage range (30 to 50 mg/m²/day) for patients with a creatinine clearance below a certain threshold, aiming to provide a therapeutic benefit while mitigating the risks associated with impaired drug clearance (’399 Patent, Abstract; col. 2:1-15).
• Asserted Claims: The complaint asserts independent claim 1 (Compl. ¶151).
• Accused Features: The future product labeling for Defendant's ANDA product is accused of infringement, as it will allegedly instruct physicians to use this specific dosing method for patients with severe renal impairment (Compl. ¶154).

U.S. Patent No. 10,457,666 B2 - "Stable Crystal Form of Tipiracil Hydrochloride and Crystallization Method for the Same," Issued October 29, 2019

• Technology Synopsis: This patent, related to the ’833 patent, also concerns the stable "Crystal Form I" of the TPI active ingredient. It claims the specific crystal form, identified by its characteristic powder X-ray diffraction peaks, and explicitly adds a purity limitation requiring that the crystal form comprise at least 90% of the material by mass. This ensures the production of a high-purity, stable drug substance for pharmaceutical formulation (’666 Patent, Abstract; col. 3:11-20).
• Asserted Claims: The complaint asserts independent claim 1 (Compl. ¶189).
• Accused Features: The TPI hydrochloride active pharmaceutical ingredient within Defendant's ANDA product is accused of being the claimed high-purity Crystal Form I (Compl. ¶¶190, 193).

III. The Accused Instrumentality

Product Identification

Defendant MSN's Abbreviated New Drug Application (ANDA) No. 214024 for generic trifluridine and tipiracil oral tablets, and the product that will be commercially manufactured and sold upon FDA approval (Compl. ¶¶8, 13).

Functionality and Market Context

The accused product is a generic version of Plaintiff's Lonsurf® drug, an oral anticancer therapy indicated for treating patients with metastatic colorectal cancer or metastatic gastric/gastroesophageal junction adenocarcinoma who have undergone prior treatments (Compl. ¶38). The product is a combination of two active ingredients: trifluridine (FTD), which has an antitumor effect, and tipiracil hydrochloride (TPI), which inhibits the degradation of FTD (Compl. ¶35; ’284 Patent, col. 2:16-24). The complaint alleges that MSN's ANDA product has the same use as Lonsurf®, and that its proposed product labeling will be substantially the same as the approved labeling for Lonsurf® (Compl. ¶¶72-73).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

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...	The product labeling for MSN's ANDA Product will allegedly instruct medical personnel and patients to treat digestive cancer.	¶78	col. 5:50-52
...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...	MSN's ANDA Product contains FTD and TPI in this composition and molar ratio, and the proposed labeling will instruct its oral administration. The ANDA relies on Taiho's NDA for Lonsurf®, which has this formulation.	¶¶72, 78	col. 2:22-26
...at a dose of 50 to 70 mg/m²/day in terms of FTD in 2 divided portions per day...	The proposed labeling for the ANDA product will instruct administration at the claimed dosage range and frequency.	¶78	col. 2:67 - col. 3:2
...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 labeling will instruct users to follow this specific dosing regimen.	¶78	col. 6:46-51

• Identified Points of Contention:
  • Scope Questions: The core of the dispute will likely be whether the final, FDA-approved label for MSN's generic product instructs the performance of every element of the claimed method. A central question is whether MSN can or will "carve out" the patented method of use from its label to avoid inducement. The complaint's allegation that the proposed label is "substantially the same" as the Lonsurf® label is the central battleground for the inducement claim (Compl. ¶73).
  • Technical Questions: As this is an inducement claim based on a product label, the primary questions are legal and factual regarding the content of the label's instructions, rather than technical mismatches in operation.

9,527,833 B2 Infringement Allegations

Claim Element (from Independent Claim 1, as amended)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
A crystal of 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione hydrochloride, which is crystal Form I...	MSN's ANDA Product contains tipiracil HCl, and the complaint alleges discovery will show it is the claimed Crystal Form I.	¶¶120-121	col. 3:23-26
...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.	The complaint alleges that discovery will demonstrate that MSN's product exhibits the characteristic PXRD peaks that define Crystal Form I.	¶121	col. 3:13-18
...and has a crystal Form I purity of at least 90% by mass.	The complaint alleges infringement of the claim, which, post-reexamination, includes this limitation. It is alleged that the ANDA product is covered by the claim.	¶¶117, 120	Reexam. Cert., col. 2:1-10

• Identified Points of Contention:
  • Scope Questions: A potential dispute may arise over the meaning of "exhibiting peaks." Does this require the accused product's PXRD pattern to be substantially identical to the reference pattern for Crystal Form I, or merely that it contains at least two of the listed peaks, regardless of other peaks or relative intensities?
  • Technical Questions: The primary question is factual: does the tipiracil HCl in MSN's ANDA product actually possess the crystalline structure of "Crystal Form I" as defined by the claim's PXRD peaks and the 90% purity requirement? This will be determined by expert analysis of the physical and chemical properties of MSN's active pharmaceutical ingredient.

V. Key Claim Terms for Construction

For the RE46,284 Patent:

• The Term: "a method for treating"
• Context and Importance: In the context of an inducement claim based on a product label, the construction of this phrase is critical. The dispute will center on whether the instructions on the accused label direct users to perform the patented method. Practitioners may focus on this term because the infringement allegation depends entirely on the content of the label and how it is interpreted by the target audience (physicians and patients).
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: The patent claims the method broadly for "digestive cancer and a breast cancer" (Claim 1) and "colorectal cancer" (Claim 18), without limiting it to specific stages or patient histories. This may support an argument that any label instructing use for these general conditions according to the claimed regimen infringes.
  • Evidence for a Narrower Interpretation: A defendant may argue that the method should be construed in light of the clinical trials discussed in the patent's prosecution history or the specific FDA-approved indications for Lonsurf®, potentially limiting the claim's scope to later-line treatment of metastatic cancers.

For the 9,527,833 Patent:

• The Term: "crystal Form I"
• Context and Importance: This term is not explicitly defined by a plain language definition but by a set of technical characteristics (PXRD peaks). Its construction will determine the scope of the patent's protection over different physical forms of the TPI molecule. Practitioners may focus on this term because polymorphism is a common area of dispute in pharmaceutical patents, and the case will turn on whether the accused product falls within the technical boundaries of this definition.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: The claim requires only "two or more" peaks from a list of six, suggesting that a perfect match is not required and that the presence of the key identifying peaks is sufficient, even if other, non-claimed peaks are present (’833 Patent, col. 4:3-8).
  • Evidence for a Narrower Interpretation: The specification provides a full PXRD pattern in Figure 1 for Crystal Form I. A defendant may argue that "crystal Form I" should be construed to mean a polymorph that substantially conforms to the entire pattern shown in Figure 1, not just a subset of its peaks, to distinguish it from other potential polymorphs (’833 Patent, Fig. 1).

VI. Other Allegations

• Indirect Infringement: The complaint heavily relies on theories of indirect infringement. For the method patents ('284 and '399), it alleges induced infringement, stating that MSN's proposed product labeling will instruct medical personnel and patients to perform the claimed dosing methods (Compl. ¶¶83-85, 105-107, 157-159). For the composition and crystal form patents ('833 and '666), it alleges contributory infringement and inducement, based on knowledge that the product is specifically adapted for and will be used in an infringing manner (Compl. ¶¶86-87, 123-125, 196-198). Knowledge and intent are predicated on MSN's Paragraph IV notice letters (Compl. ¶¶60-61).
• Willful Infringement: The complaint alleges willful infringement for all four patents. It asserts that MSN was aware of the patents "at least as early as September 23, 2019," prior to filing its ANDA certifications, and acted "without a reasonable basis for a good faith belief that it would not be liable" for infringement (Compl. ¶¶91, 129, 165, 184).

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

The resolution of this case will likely depend on the answers to two central questions:

• A core issue will be one of technical identity: Will expert evidence demonstrate that the tipiracil hydrochloride active ingredient in MSN's proposed generic product is, in fact, the specific "Crystal Form I" as defined by the structural and purity requirements of the '833 and '666 patents?
• A key legal question will be one of induced infringement: Will MSN's final, FDA-approved product label contain instructions that unambiguously direct medical professionals to administer the drug according to the specific dosage regimens for both the general population and renally-impaired patients, as claimed in the '284 and '399 patents, or will the label successfully "carve out" these patented uses?