United States Drug Patent RE46284: Claim Scope, Exclusivity, and Patent Landscape for Trifluridine/Tipiracil
U.S. Patent RE46284 protects specified oral dosing regimens for the fixed-ratio combination of trifluridine, also called α,α,α-trifluorothymidine or FTD, and tipiracil hydrochloride. The claims focus on dose, dosing frequency, treatment interval, cancer type, body-surface-area calculation, and enhanced incorporation of trifluridine into tumor DNA. The patent does not broadly claim trifluridine, tipiracil, or every use of the Lonsurf combination.
The commercially relevant product is Lonsurf, marketed in the United States by Taiho Oncology, Inc., for metastatic colorectal cancer and metastatic gastric or gastroesophageal-junction adenocarcinoma after specified prior therapies.[1] The patent’s central commercial risk is regimen overlap: an ANDA applicant or competing manufacturer could avoid literal infringement by using a materially different dose, schedule, indication, or administration instruction, subject to the doctrine of equivalents and the full Orange Book patent estate.
What drug and formulation does U.S. Patent RE46284 protect?
RE46284 covers a method of administering a composition containing:
| Element |
Claimed requirement |
| Active 1 |
α,α,α-trifluorothymidine, or trifluridine |
| Active 2 |
5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride, or tipiracil hydrochloride |
| Molar ratio |
FTD:tipiracil of 1:0.5 |
| Route |
Oral administration |
| Dose |
50 to 70 mg/m²/day in terms of FTD, with several claims fixed at 70 mg/m²/day |
| Frequency |
Two or three divided doses per day |
| Weekly schedule |
Five treatment days followed by two days off |
| Disease scope |
Digestive cancers and breast cancer |
| Narrower tumor types |
Colorectal, gastric, pancreatic, esophageal, liver, gallbladder-bile duct, and other digestive cancers |
| Additional limitation |
At least six hours between two daily administrations in specified claims |
| Cycle limitation |
Two weekly cycles followed by two weeks off treatment in specified claims |
The patent claims a treatment method rather than a tablet composition, manufacturing process, salt form, polymorph, or packaging configuration. A product containing the same active ingredients could therefore fall outside RE46284 if it is not administered under a claimed regimen. It could remain exposed to separate composition, formulation, use, or manufacturing patents.
How do the 42 claims divide by technical scope?
The claims form several overlapping groups.
Claims 1, 2, 7, 10, and 13-17: core regimen claims
Claim 1 is the broadest principal regimen claim. It requires:
- Treatment of digestive cancer or breast cancer.
- Oral administration.
- FTD and tipiracil in a 1:0.5 molar ratio.
- A daily FTD dose of 50 to 70 mg/m².
- Two or three divided doses per day.
- Five days on and two days off each week.
Claim 2 adds a cycle structure consisting of two weekly treatment cycles followed by two weeks off treatment.
Claims 7 and 10 narrow the disease category to breast cancer or specified digestive cancers. Claims 13-17 then identify colorectal, gastric, pancreatic, esophageal, liver, and related digestive cancers.
These claims are commercially significant because they track the type of dosing information commonly included in a product label. They also create multiple infringement theories around the same product if the prescribing information, clinical trial protocol, or promotional materials recommend the claimed regimen.
Claims 3-6 and 8-9, 11-12: pharmacodynamic claims
Claims 3 and 4 require a measured level of trifluridine incorporated into cancer-cell DNA. The claims specify that the amount incorporated after divided dosing must be at least:
- 1.72 times greater than after a comparable single dose after one day; or
- 1.69 times greater after three days of administration than after a single-dose regimen.
Claims 5, 6, 8, 9, 11, and 12 add divided-dose or disease limitations.
These claims are narrower and more difficult to enforce than schedule-only claims because infringement may require tumor-tissue sampling, DNA analysis, and a comparator demonstrating the specified ratio. The claim does not merely require administration of the product. It requires a biological result in the treated cancer.
Claims 18-22 and 28: colorectal-cancer regimen claims
Claims 18 and 19 are more specific than claim 1. They require:
- Colorectal cancer.
- A 70 mg/m²/day FTD dose.
- Two daily administrations.
- At least six hours between doses.
- Five days on and two days off.
- For claim 19, two weekly cycles followed by two weeks off.
Claim 20 incorporates six alternative body-surface-area formulas. Claims 21 and 22 select two of those formulas. Claim 28 extends a similar two-dose, 70 mg/m² colorectal or digestive-cancer regimen to the broader digestive-cancer category.
These claims are more vulnerable to noninfringing design-around through three-dose administration, a dose below 70 mg/m²/day, a different weekly schedule, or a dosing interval shorter than six hours. Whether such a change is clinically acceptable depends on the applicable product label and medical practice.
Claims 23-27 and 29-42: disease- and dose-specific subclaims
These claims narrow the regimen by selecting:
- 70 mg/m²/day or 50 mg/m²/day;
- breast cancer or a specified digestive cancer;
- two divided doses;
- an interval of six hours or more.
Claims 39-42 combine specific digestive cancers with the six-hour interval and 70 mg/m²/day dose. The claim set is therefore repetitive, but the repetition creates fallback positions if a broader claim is invalidated.
What is the likely scope of independent claim 1?
Claim 1 requires every listed limitation. A treatment would generally need to satisfy all of the following to present a literal infringement case:
| Limitation |
Practical infringement question |
| Cancer type |
Is the treated disease breast cancer or one of the claimed digestive cancers? |
| Composition |
Does the administered product contain both FTD and tipiracil hydrochloride? |
| Ratio |
Is the FTD-to-tipiracil molar ratio 1:0.5? |
| Route |
Is the product administered orally? |
| Dose |
Is the daily FTD dose between 50 and 70 mg/m²? |
| Divided dosing |
Is the daily dose divided into two or three portions? |
| Schedule |
Are there five treatment days followed by two days off? |
| Patient |
Is the recipient a human patient in need of treatment? |
The ratio is particularly important. The claim is directed to the known fixed combination rather than arbitrary coadministration of the two compounds. A materially different molar ratio could avoid literal infringement, although prosecution history and equivalents analysis would be relevant.
The claim also uses body-surface-area dosing. A fixed milligram dose that does not correspond to 50-70 mg/m²/day would not necessarily meet the dose limitation. Conversely, a label or prescribing system that calculates the patient’s daily dose using body surface area can create a stronger factual basis for infringement.
What formulations are protected by RE46284?
RE46284 does not claim a specific tablet formulation in the supplied claims. It does not require:
- A particular excipient;
- A tablet coating;
- A specific tablet strength;
- A particular particle size;
- A polymorph;
- A dissolution profile;
- A blister package;
- A manufacturing process; or
- A particular salt form beyond the recited tipiracil hydrochloride component.
The patent can nevertheless cover administration of different oral dosage forms if they contain the claimed actives in the required ratio and are administered under the claimed regimen. A generic tablet could therefore face method-of-use exposure even if it does not copy the branded tablet’s excipients or manufacturing process.
When does RE46284 lose exclusivity?
RE46284 is a reissue patent. Its term is tied to the term of the original patent and cannot be used to extend the original patent term merely because the reissue issued later.[2] The original patent is U.S. Patent No. 8,404,703, associated with the trifluridine-tipiracil cancer-treatment technology.[3]
The projected ordinary U.S. patent-term endpoint is in November 2027, subject to the patent’s recorded term adjustments, terminal disclaimers, and any applicable statutory correction. A reissue issuance date in 2016 does not reset the expiration clock.
| Milestone |
Date or status |
| Priority basis |
Japanese priority filing preceding the U.S. application |
| Original U.S. patent |
U.S. 8,404,703 |
| Original grant |
March 26, 2013 |
| Reissue patent |
RE46284 |
| Reissue grant |
October 25, 2016 |
| Ordinary term endpoint |
November 2027, subject to official USPTO term calculation |
| Patent-term extension |
No extension is established by the supplied claim information |
Patent expiry does not automatically eliminate all Lonsurf-related exclusivity. Separate Orange Book-listed patents, pediatric exclusivity, regulatory exclusivity, or later patents could affect generic launch timing.[4]
What is the Orange Book status of RE46284?
The Orange Book is the controlling FDA source for patents submitted by an NDA holder for an approved drug product. The relevant inquiry is not whether a patent concerns Lonsurf generally, but whether it is listed against the applicable NDA and whether the listing covers the approved product, an approved method of use, or a drug substance or product claim.[4]
RE46284’s claim subject matter is a method of using the FTD-tipiracil combination. If listed against the Lonsurf NDA, it would be relevant to an ANDA applicant required to address method-of-use patents. A generic applicant could:
- File a Paragraph IV certification challenging validity, enforceability, or infringement;
- Use a section viii statement and carve out the patented indication or regimen where FDA rules permit;
- Await patent expiry; or
- Seek a commercial settlement with the NDA holder.
The supplied information does not establish the patent’s current Orange Book listing code or whether every claim maps to the currently approved Lonsurf labeling. FDA Orange Book records and the latest patent-listing correspondence control that analysis.[4]
How strong is the patent estate for trifluridine/ tipiracil?
RE46284 has meaningful regimen coverage but is not a complete product monopoly.
Strengths
- It maps closely to the standard oral dosing concept of trifluridine/tipiracil.
- It covers both dose range and dosing frequency.
- It includes multiple fallback cancer indications.
- It contains narrower claims directed to colorectal cancer, 70 mg/m²/day, two daily doses, and six-hour spacing.
- It includes method-of-treatment claims that may be relevant to ANDA labeling and physician instructions.
Vulnerabilities
- Several claims require a specific 1:0.5 molar ratio, limiting coverage of materially different formulations.
- The six-hour and two-dose limitations create design-around opportunities.
- Claims 3 and 4 require difficult pharmacodynamic proof.
- The claim set is vulnerable to prior-art challenges involving earlier disclosure of FTD, tipiracil, oral administration, dose selection, and treatment schedules.
- The method claims may face enablement, written-description, anticipation, obviousness, indefiniteness, or divided-infringement arguments depending on the asserted claim and evidence.
The patent is strongest against an applicant whose proposed label reproduces the claimed dose and schedule. It is weaker against a product introduced with a clean indication carve-out, a different administration schedule, or a regimen that does not instruct patients to follow the claimed five-days-on, two-days-off pattern.
What Paragraph IV challenges and litigation affect RE46284?
A complete Paragraph IV and litigation assessment requires the current FDA paragraph IV database, ANDA litigation dockets, Orange Book history, and district-court filings. The claim text alone does not establish:
- Whether an ANDA has been filed;
- Which companies submitted Paragraph IV certifications;
- Whether a 30-month stay was triggered;
- Whether a district-court action was filed;
- Whether the patent was challenged in inter partes review;
- Whether a settlement agreement exists; or
- Whether any generic has secured a licensed entry date.
Under the Hatch-Waxman framework, a Paragraph IV certification can trigger patent litigation under 35 U.S.C. §271(e)(2). The core litigation questions would be whether the proposed generic label induces administration of the claimed regimen and whether the patent claims survive validity challenges.[5]
What generic launch risks exist after patent expiry?
Generic entry risk is not uniform across all claim categories.
| Launch scenario |
RE46284 exposure |
| Generic copies the labeled Lonsurf regimen |
High method-of-use exposure before expiry |
| Generic uses a section viii carve-out for patented use |
Potentially reduced exposure, subject to FDA labeling rules |
| Generic uses different dose or schedule |
Lower literal infringement risk |
| Generic changes tablet excipients only |
Limited effect if the claimed method is otherwise practiced |
| Generic launches after RE46284 expiry but before other patents expire |
Exposure may remain under separate patents |
| Generic launches after all relevant patents and exclusivities expire |
Highest probability of unrestricted entry |
A generic applicant also must consider the separate regulatory and patent position of the active ingredients, the fixed-dose combination, approved indications, and any later-developed combination regimens.
How does RE46284 compare with composition and formulation patents?
RE46284 is a use patent. Its protection depends on how the product is administered.
| Patent category |
Main protected subject matter |
Relevance to generic entry |
| Composition patent |
FTD, tipiracil, salts, combinations, or chemical structure |
Can block product manufacture or sale |
| Formulation patent |
Tablet composition, coating, release profile, stability, or dosage form |
Can block copying of the branded dosage form |
| Manufacturing patent |
Synthetic process, purification, crystallization, or scale-up |
Can restrict production routes |
| Method-of-use patent |
Cancer indication, dose, schedule, or patient population |
Can affect labeling and induced infringement |
| RE46284 |
Oral FTD-tipiracil regimen with specified dose and schedule |
Primarily a regimen and labeling risk |
The commercial strength of the overall estate depends on the interaction of these categories, not on RE46284 alone.
What licensing and commercial rights are relevant?
Lonsurf was developed by Taiho Pharmaceutical Co., Ltd. Taiho Oncology commercializes the product in the United States, within the broader Otsuka group structure. FDA approval records identify the NDA holder and approved indications; commercial distribution and licensing arrangements may differ from patent ownership.[1]
The supplied claim information does not establish a license, settlement, covenant not to sue, or authorized generic agreement relating specifically to RE46284. Those rights must be determined from executed agreements, SEC disclosures, court filings, or FDA patent records.
Key Takeaways
- RE46284 is a regimen patent covering oral trifluridine-tipiracil treatment.
- The principal limitations are the 1:0.5 molar ratio, 50-70 mg/m²/day FTD dose, two or three divided doses, and five-days-on, two-days-off schedule.
- Narrow claims add 70 mg/m²/day, colorectal cancer, two daily doses, six-hour spacing, cycle structure, and body-surface-area formulas.
- Pharmacodynamic claims require enhanced trifluridine incorporation into tumor DNA and would require more complex infringement proof.
- The patent is a reissue of U.S. 8,404,703 and does not receive a new patent term merely because the reissue issued in 2016.
- The ordinary term endpoint is in November 2027, subject to the official USPTO term calculation and any applicable adjustments.
- RE46284 does not independently protect every Lonsurf composition, formulation, manufacturing process, or later combination therapy.
- Generic risk is highest where an ANDA label reproduces the patented regimen and lower where the applicant lawfully carves out the relevant use or adopts a noninfringing schedule.
- Current Paragraph IV challengers, Orange Book listing status, settlements, and litigation cannot be established from the claim text alone.
FAQs About U.S. Patent RE46284 and Lonsurf
Does RE46284 cover the Lonsurf tablets themselves?
No. The supplied claims are method claims. They cover administration of the FTD-tipiracil combination under specified conditions, not every tablet containing the active ingredients.
Does a 70 mg/m²/day regimen automatically infringe RE46284?
No. The other limitations must also be satisfied, including the 1:0.5 molar ratio, oral route, divided dosing, cancer type, and five-days-on, two-days-off schedule.
Can a generic avoid RE46284 by using three doses instead of two?
Potentially. Three-dose administration is expressly included in several claims, so switching from two to three doses does not necessarily avoid infringement. The full claim language and product labeling must be analyzed.
Are the DNA-incorporation claims likely to be asserted independently?
They can be asserted independently, but proof may require tumor-tissue testing and comparison against the claimed single-dose control. That makes them more technically demanding than schedule-only claims.
Does expiration of RE46284 guarantee immediate generic launch?
No. Other patents, regulatory exclusivities, litigation outcomes, settlement terms, or formulation and manufacturing patents may delay or condition generic entry.
References
- U.S. Food and Drug Administration. (2023). Lonsurf (trifluridine and tipiracil) prescribing information.
- 35 U.S.C. § 251.
- U.S. Patent and Trademark Office. (2016). U.S. Patent No. RE46,284, reissue of U.S. Patent No. 8,404,703.
- U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
- 35 U.S.C. § 271(e)(2).
