DCT
1:22-cv-01480
Taiho Pharmaceutical Co Ltd v. Natco Pharma Ltd
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Taiho Pharmaceutical Co., Ltd. (Japan) and Taiho Oncology, Inc. (Delaware)
- Defendant: Natco Pharma Ltd. (India) and Natco Pharma, Inc. (Delaware)
- Plaintiff’s Counsel: Foley & Lardner LLP
- Case Identification: 1:22-cv-01480, D. Del., 11/10/2022
- Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant Natco Pharma, Inc. is a Delaware corporation, and its parent, Natco Pharma Ltd., is subject to personal jurisdiction through its subsidiary, its intent to market products in Delaware, and its previous submission to jurisdiction in the district.
- Core Dispute: Plaintiff alleges that Defendant’s Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff’s cancer drug Lonsurf® constitutes an act of infringement of two patents covering methods of using the drug to treat cancer patients with severe renal impairment.
- Technical Context: The technology concerns a specific method-of-use and dosing regimen for a combination chemotherapy drug (trifluridine/tipiracil) to ensure its safety and efficacy in a specific patient sub-population that was not covered by the drug's original treatment protocols.
- Key Procedural History: This action was filed under the Hatch-Waxman Act, triggered by Defendant’s submission of an ANDA with a Paragraph IV certification, which asserts that Plaintiff's patents are invalid or will not be infringed. The complaint notes that the parties are involved in separate, related litigation concerning the same ANDA and that the '004 Patent is subject to a terminal disclaimer over the '399 Patent.
Case Timeline
| Date | Event |
|---|---|
| 2015-09-22 | FDA approves Lonsurf® New Drug Application (NDA) |
| 2016-02-05 | Priority Date for '399 and '004 Patents |
| 2019-10-29 | U.S. Patent No. 10,456,399 issues |
| 2020-03-30 | Alleged date of Natco's awareness of the '399 patent |
| 2021-03-30 | U.S. Patent No. 10,960,004 issues |
| 2021-11-23 | Alleged date of Natco's awareness of the '004 patent |
| 2022-10-04 | Taiho receives Natco's Paragraph IV notice letter |
| 2022-11-10 | Complaint for patent infringement filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 10,456,399 - "Method for treating cancer patients with severe renal impairment"
- Patent Identification: U.S. Patent No. 10,456,399, "Method for treating cancer patients with severe renal impairment," issued October 29, 2019. (Compl. ¶39; '399 Patent, cover).
The Invention Explained
- Problem Addressed: The patent addresses the challenge of safely administering a combination anticancer drug (FTD/TPI) to patients with severe renal impairment (creatinine clearance of 15-29 mL/min). Because one of the drug's components, TPI, is excreted by the kidneys, there was concern that impaired renal function could lead to increased drug exposure and heightened toxicity, making the standard dose unsafe for this population. ('399 Patent, col. 3:1-15, 49-61).
- The Patented Solution: The invention provides a specific, reduced dosing regimen for this patient population. Based on pharmacokinetic studies, the inventors determined that a reduced daily dose, administered over a specific cycle, could achieve a therapeutic effect comparable to that in patients with normal renal function while mitigating the risk of severe side effects. ('399 Patent, col. 3:31-39; Table 2).
- Technical Importance: The claimed method provides a way to extend a therapeutic option to a vulnerable patient group that was previously excluded from treatment due to safety concerns. ('399 Patent, col. 3:1-8).
Key Claims at a Glance
- The complaint asserts independent claim 1 and reserves the right to assert other claims. (Compl. ¶¶60-62).
- Claim 1, as recited in the complaint, requires:
- A method for treating gastrointestinal, large bowel, or breast cancer.
- Detecting the creatinine clearance of a patient.
- Orally administering a specific combination drug (FTD/TPI) to a patient with a creatinine clearance of less than 30 mL/min.
- The administration uses a daily dose of 30 to 40 mg/m²/day (as FTD-equivalent).
- The daily dose is divided into two to four portions for administration. (Compl. ¶62).
U.S. Patent No. 10,960,004 - "Method for Treating Cancer Patients with Severe Renal Impairment"
- Patent Identification: U.S. Patent No. 10,960,004, "Method for Treating Cancer Patients with Severe Renal Impairment," issued March 30, 2021. (Compl. ¶44; '004 Patent, cover).
The Invention Explained
- Problem Addressed: The '004 Patent, which is a continuation of the application leading to the '399 Patent, addresses the same technical problem: determining a safe and effective dosage of the FTD/TPI drug for cancer patients with severe renal impairment. ('004 Patent, col. 4:1-15).
- The Patented Solution: The invention, grounded in the same pharmacokinetic analysis, provides a specific method of treatment for patients whose creatinine clearance falls within the precise range of 15 mL/min to 29 mL/min. The method recites a specific daily dose and administration frequency. ('004 Patent, col. 4:45-53; Table 2).
- Technical Importance: Similar to the '399 patent, this invention enables the treatment of a specific, high-risk cancer patient population. ('004 Patent, col. 4:5-15).
Key Claims at a Glance
- The complaint asserts independent claim 1 and reserves the right to assert other claims. (Compl. ¶¶101-103).
- Claim 1 requires:
- A method for treating gastrointestinal, large bowel, or breast cancer in a patient with a creatinine clearance of 15 mL/min-29 mL/min.
- Orally administering a specific combination drug (FTD/TPI).
- The administration uses a daily dose of 30 to 40 mg/m²/day (as FTD-equivalent).
- The daily dose is administered in two to four doses per day to a patient with a creatinine clearance of 15 mL/min-29 mL/min. (Compl. ¶103).
III. The Accused Instrumentality
Product Identification
The accused instrumentality is Natco’s generic tipiracil HCl/trifluridine oral tablets, for which it seeks FDA approval via Abbreviated New Drug Application (ANDA) No. 214008. (Compl. ¶7).
Functionality and Market Context
The product is a generic equivalent of Taiho's Lonsurf®, a combination drug used for treating certain types of cancer, including metastatic colorectal cancer. (Compl. ¶¶13, 38). The infringement allegations are not based on the composition of the drug itself, but on the method of its use that will allegedly be instructed by the proposed product labeling accompanying Natco's ANDA Product. (Compl. ¶¶58, 63). The complaint alleges this proposed label will be "substantially the same" as the approved label for Lonsurf® and will instruct physicians and patients to use the drug in a manner that infringes the patents-in-suit. (Compl. ¶¶58, 63, 104).
IV. Analysis of Infringement Allegations
No probative visual evidence provided in complaint.
10,456,399 Infringement Allegations
| Claim Element (from Independent Claim 1, per Compl. ¶62) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method for cancer which is one of gastrointestinal cancer, large bowel cancer and breast cancer, comprising: detecting a creatinine clearance of a patient; | The proposed product labeling for Natco's ANDA Product will allegedly instruct medical personnel to treat large bowel cancer in patients with severe renal impairment, which requires detecting a patient's creatinine clearance to identify them as part of the correct treatment population. (Compl. ¶63). | ¶63 | col. 5:30-41 |
| orally administering to the patient with a creatinine clearance of less than 30 mL/min a combination drug comprising a,a,a-trifluorothymidine (FTD) and 5-chloro-6-[(2-iminopyrrolidine-1-yl)methyl]pyrimidine-2,4(1H,3H)-dione hydrochloride in a molar ratio of 1:0.5, | The labeling will allegedly instruct oral administration of Natco's product (which is the claimed FTD/TPI combination) to patients identified as having severe renal impairment (i.e., CLcr of less than 30 mL/min). (Compl. ¶63). | ¶63 | col. 3:20-30 |
| a dose of 30 to 40 mg/m²/day as FTD-equivalent, divided into two to four portions for administration. | The labeling will allegedly instruct administration of the drug at a daily dose of 30 to 40 mg/m²/day, divided into multiple portions. (Compl. ¶63). | ¶63 | col. 7:59-col. 8:1 |
10,960,004 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method for treating gastrointestinal cancer, large bowel cancer or breast cancer in a patient with a creatinine clearance of 15 mL/min-29 mL/min, comprising: orally administering a drug comprising a,a,a-trifluorothymidine (FTD) and 5-chloro-6-[(2-iminopyrrolidine-1-yl)methyl]pyrimidine-2,4(1H,3H)-dione hydrochloride in a molar ratio of 1:0.5, | The proposed product labeling will allegedly instruct medical personnel to treat patients with gastrointestinal and/or large bowel cancer who are specifically identified as having a creatinine clearance of 15-29 mL/min, by orally administering Natco's FTD/TPI combination drug. (Compl. ¶104). | ¶104 | col. 4:24-31 |
| at a daily dose of 30 to 40 mg/m2/day as FTD-equivalent, in two to four doses a day to the patient with a creatinine clearance of 15 mL/min-29 mL/min. | The labeling will allegedly instruct administering the drug at the specified daily dose (30 to 40 mg/m²/day), divided into two to four doses, specifically to patients within the claimed creatinine clearance range. (Compl. ¶104). | ¶104 | col. 4:50-53 |
- Identified Points of Contention:
- Pleading Discrepancy: The complaint quotes Claim 1 of the '399 patent as requiring a dose of "30 to 40 mg/m²/day" (Compl. ¶62), whereas the issued '399 patent's Claim 1 recites a range of "30 to 50 mg/m²/day" ('399 Patent, col. 7:10-12). This discrepancy between the pleading and the patent document raises a question of how the plaintiff will proceed with its infringement theory for this patent.
- Evidentiary Question (Label Content): The infringement allegations for both patents depend entirely on the content of Natco's proposed product label. A central factual dispute will be whether discovery confirms that the label instructs the specific, infringing method of use, or whether Natco has attempted to "carve out" the patented use from its label.
- Divided Infringement ('399 Patent): Claim 1 of the '399 Patent requires both a "detecting" step, likely performed by a physician, and an "administering" step, which may be performed by the patient. This raises a potential defense of divided infringement, where the court will have to determine if all steps of the claim are attributable to a single actor. The omission of the "detecting" step in Claim 1 of the '004 Patent may have been intended to avoid this issue.
V. Key Claim Terms for Construction
The Term: "detecting a creatinine clearance of a patient" ('399 Patent, Claim 1)
- Context and Importance: This is the first active step of the method claimed in the '399 Patent. Its definition is critical for determining what action constitutes infringement and is central to any divided infringement analysis. Practitioners may focus on this term because its interpretation will determine whether a physician merely reviewing a lab report satisfies the claim step, or if a more direct diagnostic action is required.
- Evidence for a Broader Interpretation: The specification describes classifying patients based on CLcr values calculated from standard equations, which could support an interpretation that any act of determining or reviewing a patient's CLcr value to make a treatment decision satisfies the "detecting" step. (Compl. ¶41; '399 Patent, col. 3:61-65).
- Evidence for a Narrower Interpretation: The patent's description arises from a clinical trial context where patient evaluation and classification were affirmative, protocol-driven steps. This could support an argument that "detecting" requires a more formal or direct diagnostic act than simply noting a pre-existing value in a patient's chart. ('399 Patent, col. 7:64-col. 8:4).
The Term: "a patient with a creatinine clearance of 15 mL/min-29 mL/min" ('004 Patent, Claim 1)
- Context and Importance: This phrase defines the specific patient population to which the claimed method applies in the '004 Patent. The precision of this numerical range is key to defining the scope of infringement.
- Evidence for a Broader Interpretation: The patent equates this numerical range with the clinical classification of "severe renal impairment." ('004 Patent, col. 5:35-38). This may support an interpretation where any patient clinically classified as having severe renal impairment is covered, allowing for minor or transient fluctuations around the claimed numerical boundaries.
- Evidence for a Narrower Interpretation: The patent's own pharmacokinetic analysis and the resulting Table 2 are based on binning patients into discrete numerical ranges. ('004 Patent, col. 8, Table 2). This could support a narrow construction requiring strict proof that a patient’s CLcr was within the exact 15-29 mL/min range at the time of administration for infringement to occur.
VI. Other Allegations
- Indirect Infringement: The complaint alleges both induced and contributory infringement. The inducement theory is based on allegations that Natco’s proposed product labeling will actively instruct and encourage medical personnel and patients to perform the patented methods of treatment. (Compl. ¶¶66, 107). The contributory infringement theory alleges that Natco's product is a material part of the invention, is specially made or adapted for an infringing use, and has no substantial non-infringing use. (Compl. ¶¶69-71, 110-112).
- Willful Infringement: The complaint alleges willful infringement based on Natco’s alleged pre-suit knowledge of both patents. It claims Natco was aware of the '399 patent as early as March 30, 2020, and the '004 patent as early as November 23, 2021, and nonetheless proceeded to file its ANDA without a reasonable good-faith belief of non-infringement or invalidity. (Compl. ¶¶74, 91-92, 115, 132-133).
VII. Analyst’s Conclusion: Key Questions for the Case
- A central issue will be one of evidentiary proof: will discovery confirm that the final, FDA-approved label for Natco’s generic product contains language that explicitly instructs or implicitly encourages physicians to treat patients with severe renal impairment using the specific dosage and administration schedule required by the asserted claims?
- For the '399 patent, a key legal question will be one of divided infringement: can Taiho establish that a single actor, such as the prescribing physician, directs or controls all claimed steps, including both the "detecting" of creatinine clearance and the subsequent "administering" of the drug by the patient, to satisfy the legal standard for direct infringement?
- A threshold procedural question for the '399 patent is one of pleading accuracy: how will the parties and the Court resolve the material discrepancy between the dosage range recited in the complaint's infringement count ("30 to 40 mg/m²/day") and the broader range present in the actual asserted claim of the '399 patent ("30 to 50 mg/m²/day")?