Details for Patent: 6,479,500

Summary for Patent: 6,479,500

Title:	Agents for alleviating side effects
Abstract:	The present invention provides an agent for alleviating side effects caused by use of an anti-tumor agent, which contains 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidi nedione (1) represented by formula (1):or a pharmaceutically acceptable salt thereof. The 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione or a pharmaceutically acceptable salt thereof exhibit an inflammatory-suppressing action in the digestive tract and advantageously alleviate diarrhea and loss of body weight concomitant with administration of a chemical for treating cancer without suppressing the anti-tumor effect. Thus, the compounds of the present invention are of great value as agents for alleviating side effects caused by use of an anti-tumor agent, which enable not only the chemotherapy to be continuedly carried out, but also the body exhaustion to be effectively prevented.
Inventor(s):	Masakazu Fukushima, Noriyuki Yamamoto, Norihiko Suzuki
Assignee:	Taiho Pharmaceutical Co Ltd
Application Number:	US09/701,041
Patent Claim Types: see list of patent claims	Use;

United States Patent 6,479,500: Claim Scope, Expiration, Litigation Risk, and Patent Landscape

U.S. Patent No. 6,479,500 protects a treatment method using 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione, or a pharmaceutically acceptable salt, to reduce adverse effects caused by anticancer drugs. The claims cover nausea, vomiting, diarrhea, anorexia, and weight loss, with specific coverage for trifluridine, 5-fluorouracil, irinotecan hydrochloride, and cisplatin.

The patent is an expired method-of-use patent. It does not claim the active compound as a composition, a pharmaceutical formulation, a manufacturing process, or an anticancer product. It is not a current U.S. barrier to generic or branded development.

What does U.S. Patent 6,479,500 protect?

The patent claims administration of a specific pyrimidinedione compound after an anti-tumor agent has been administered. The protected subject matter is the therapeutic use of the compound, not the compound itself.

Claim	Protected subject matter	Practical scope
1	Administration of the specified compound or pharmaceutically acceptable salt to a patient who received an anti-tumor agent, to alleviate side effects	Broadest independent method claim
2	Claim 1 limited to nausea, vomiting, diarrhea, anorexia, or weight loss	Adverse-effect limitation
3	Claim 1 or 2 limited to antimetabolites, alkylating agents, plant-derived compounds, antibiotics, or platinum agents	Drug-class limitation
4	Claim 1 or 2 limited to trifluridine, 5-fluorouracil, irinotecan hydrochloride, or cisplatin	Specific-drug limitation

The central compound is identified by its chemical name and structural formula. The claims do not extend to every uracil derivative, every pyrimidinedione, or every antiemetic or cytoprotective agent.

How should claim 1 be construed?

Claim 1 requires several elements:

1. A patient has received an anti-tumor agent.
2. The patient experiences, or is being treated for, a side effect caused by that anti-tumor agent.
3. The specified pyrimidinedione compound or a pharmaceutically acceptable salt is administered.
4. The administration is for alleviating the side effect.

The claim does not specify:

• Dose
• Route of administration
• Formulation
• Treatment duration
• Timing interval between the anticancer drug and the claimed compound
• Cancer type
• Patient age
• Disease stage
• Whether administration is prophylactic or therapeutic
• Whether the anticancer drug and the claimed compound must be administered in the same clinical setting

The phrase “to a patient to whom an anti-tumor agent has been administered” creates a sequencing requirement. The anticancer treatment must occur before, or at least be part of the patient’s treatment history before, the claimed side-effect therapy is performed.

The claim also contains a causation limitation. The relevant side effect must be caused by use of the anti-tumor agent. A treatment for unrelated nausea, diarrhea, or weight loss would not fall within the claim merely because the patient also received an anticancer drug.

What side effects are covered by claim 2?

Claim 2 identifies five adverse effects:

• Nausea
• Vomiting
• Diarrhea
• Anorexia
• Loss of body weight

The claim is written in the alternative. Proof of one listed adverse effect would satisfy the side-effect limitation, assuming the remaining limitations are met.

The claim does not expressly require complete prevention or elimination. “Alleviating” ordinarily supports a reduction in severity, frequency, duration, or clinical impact. A treatment that reduces but does not eliminate vomiting or diarrhea could therefore fall within the claim if the other elements are satisfied.

Which anticancer drugs and drug classes are covered?

Claim 3 covers five broad categories:

Category in claim 3	Potential examples
Antimetabolites	5-fluorouracil and related agents
Alkylating agents	Cyclophosphamide and related agents
Plant-derived compounds	Taxanes, vinca alkaloids, and related agents
Antibiotics	Certain antitumor antibiotics
Platinum-containing agents	Cisplatin and related platinum drugs

Claim 4 narrows the coverage to four named agents:

• 5-Trifluoromethyl-2′-deoxyuridine, commonly known as trifluridine
• 5-Fluorouracil
• Irinotecan hydrochloride
• Cisplatin

Claim 4 is commercially significant because it ties the patent to widely used chemotherapy agents. It is also easier to analyze for infringement because the identity of the triggering anticancer drug is specific.

Does claim 1 cover anticancer drugs outside claim 3?

Yes, potentially.

Claim 1 is not limited to the five categories listed in claim 3. Claim 3 is a dependent claim that narrows claim 1. A use involving an anti-tumor agent outside those categories could still be assessed under claim 1 or claim 2 if the compound, patient sequence, side-effect purpose, and causation limitations are satisfied.

A use involving an anticancer agent listed in claim 4 would be covered by claim 4 only if the named agent and the adverse-effect requirements are met. The broader claims would remain relevant independently.

Is the patent a compound patent, formulation patent, or method-of-use patent?

It is a method-of-use patent.

IP category	Covered by U.S. 6,479,500?	Analysis
Active compound composition	No	The compound is recited as the treatment agent, not claimed as a standalone composition
Pharmaceutically acceptable salts	Yes, as part of the treatment method	Salt coverage is tied to administration for the claimed purpose
Pharmaceutical formulation	No express formulation claim	No tablet, capsule, injectable, excipient, release profile, or dosage-form limitation appears in the supplied claims
Manufacturing process	No	No synthesis or purification steps are claimed
Combination product	Limited	The claims require treatment involving an anti-tumor agent and the claimed compound, but do not claim a fixed-dose product
Method of treatment	Yes	This is the core statutory category
Method of reducing chemotherapy toxicity	Yes	The claims target specified adverse effects caused by anti-tumor therapy

A company could therefore face a different patent risk from a later patent covering a formulation, manufacturing process, salt, polymorph, combination product, or separate clinical use of the same compound. Those rights would not be established by U.S. 6,479,500.

When did U.S. Patent 6,479,500 lose exclusivity?

U.S. Patent 6,479,500 issued on November 12, 2002. Because it issued from an application filed before issuance, its ordinary patent term could not extend beyond 20 years from the relevant U.S. nonprovisional filing date, subject to any patent-term adjustment or terminal disclaimer recorded in the official patent file.

The patent is expired as of 2026. No enforceable U.S. patent exclusivity remains under the claims supplied.

Event	Date or status
U.S. patent grant	November 12, 2002
Patent type	Utility method-of-treatment patent
Ordinary term framework	20 years from the earliest effective U.S. nonprovisional filing date
Current status	Expired
Current generic blocking effect	None under this patent

The international family may have had different expiration dates, prosecution outcomes, or abandonment events. U.S. expiration does not establish the status of counterpart patents in Europe, Japan, China, or other jurisdictions.

What is the Orange Book status of U.S. Patent 6,479,500?

The patent is not an Orange Book product patent for an FDA-approved product based on the claim structure provided.

Orange Book listing generally relates to patents submitted for approved drug products, including patents covering the active ingredient, formulation, composition, or approved method of use. A patent directed to an unapproved side-effect-alleviation compound does not become Orange Book-listed merely because it mentions approved anticancer drugs.

The patent does not appear to establish:

• An approved new drug application for the claimed pyrimidinedione
• A listed reference drug product
• A current FDA exclusivity period
• A current approved indication for the claimed side-effect treatment

The Orange Book therefore does not create a current abbreviated new drug application barrier based on this patent. FDA approval status must be evaluated separately from patent status. Patent issuance is not evidence of FDA approval.[2]

Are Paragraph IV challenges relevant?

A Paragraph IV certification is relevant only when a generic applicant seeks approval for a drug product that references an Orange Book-listed drug and challenges an unexpired listed patent.

U.S. Patent 6,479,500 does not present a current Paragraph IV obstacle because:

1. The patent is expired.
2. The claimed compound is not established by the supplied record as an FDA-approved reference drug.
3. The claims are directed to a treatment method rather than an approved commercial product identified in the Orange Book.

A generic applicant developing a separate approved product would not need to file a Paragraph IV certification against an expired, non-listed patent. Depending on the regulatory pathway and the target product, the applicant could instead address the patent through a patent certification that reflects expiration or non-applicability.

What generic launch risks exist?

There is no current launch risk from U.S. Patent 6,479,500 itself.

The practical risk analysis is:

Development activity	Risk from U.S. 6,479,500
Generic 5-fluorouracil	None from this expired patent
Generic irinotecan hydrochloride	None from this expired patent
Generic cisplatin	None from this expired patent
Development of the claimed side-effect compound	No current U.S. patent injunction risk from this patent
Development of a different antiemetic or cytoprotective compound	None
Development of a formulation using the same active compound	No risk from this patent alone; later formulation rights must be searched
Foreign commercialization	Requires separate country-by-country analysis

The principal remaining risks would arise from later patents, regulatory exclusivities, data exclusivity, trade secrets, manufacturing know-how, or patents covering a different salt, polymorph, formulation, or indication.

How strong is the patent estate?

The patent estate represented by the supplied U.S. patent is narrow in asset count but broad within its specific method category.

Strengths

• Claim 1 covers the compound across anti-tumor agents without limiting the claim to one cancer type.
• Claim 2 expressly identifies clinically recognizable chemotherapy side effects.
• Claim 3 reaches multiple anticancer drug classes.
• Claim 4 identifies important chemotherapy products, including 5-fluorouracil, irinotecan, and cisplatin.
• The claims do not impose dose, route, or formulation limitations.

Weaknesses

• The patent does not claim the compound itself.
• The claims depend on a treatment purpose and a causal relationship between the anticancer drug and the adverse effect.
• A competitor could avoid the claims by using a different side-effect treatment compound.
• A competitor could develop a different treatment objective, such as treating an unrelated gastrointestinal disorder, if the facts do not support chemotherapy-induced toxicity.
• Broad claims covering several anticancer categories could face written-description, enablement, or prior-art challenges depending on the specification and prosecution record.
• The patent has expired, eliminating present enforcement value.

The strongest historical claim was likely claim 4 because the triggering drugs are specifically identified. The broadest historical claim was claim 1, but its scope depended on proving the compound, the anti-tumor treatment, the causal side effect, and the alleviation purpose.

What patent litigation affects this patent?

The supplied record does not establish an active U.S. infringement action, Paragraph IV case, or settlement agreement involving U.S. Patent 6,479,500. Because the patent is expired, a new U.S. infringement action based solely on these claims would not provide prospective exclusivity.

Any historical litigation would have to be confirmed through PACER, district-court dockets, appellate decisions, or the USPTO assignment and maintenance records. Patent expiration would not necessarily eliminate claims for damages based on pre-expiration conduct, but it would prevent prospective enforcement after expiration.

Are biosimilar risks relevant?

No. Biosimilar legislation applies to biological products licensed under the Public Health Service Act. The claimed compound is a chemically synthesized small molecule, not a biologic.

The relevant competitive pathways are:

• Abbreviated new drug applications for small-molecule products
• 505(b)(2) applications for products relying partly on published or third-party data
• Full new drug applications for a new therapeutic use or new active ingredient

A biosimilar applicant would not be the expected competitor for this patent.

What manufacturing and IP barriers remain?

U.S. Patent 6,479,500 does not claim manufacturing. It therefore does not block synthesis of the compound after expiration.

Commercial development could still encounter practical barriers involving:

• Synthetic route patents filed after the 6,479,500 priority date
• Process improvements
• Impurity controls
• Solid-state forms
• Salt selection
• Stability and degradation products
• Pharmaceutical formulation patents
• Clinical data requirements
• Unpublished manufacturing know-how
• Foreign patents with later expiration dates

These issues are separate from the expired treatment-method claims and require a full family, assignment, prosecution, and non-U.S. search.

How does this patent compare with a typical modern oncology patent estate?

Attribute	U.S. 6,479,500	Typical modern oncology estate
Primary protection	Method of treatment	Composition, formulation, method, biomarker, process, and combination claims
Active ingredient claim	No	Often yes
Biomarker limitation	No	Common for targeted therapies
Formulation claim	No	Common for oral and injectable products
Manufacturing claim	No	Frequently present
Orange Book relevance	Limited or absent	Often central
Biosimilar relevance	None	Relevant for biologics
Current enforceability	Expired	Often extends through multiple later-filed patents
Design-around options	Relatively broad because the compound is fixed but the use is narrow	More difficult where multiple patent layers exist

Key Takeaways

• U.S. Patent 6,479,500 is a method-of-treatment patent for reducing adverse effects of anticancer therapy.
• The required treatment agent is 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione or a pharmaceutically acceptable salt.
• The claims cover nausea, vomiting, diarrhea, anorexia, and weight loss.
• Claim 4 specifically identifies trifluridine, 5-fluorouracil, irinotecan hydrochloride, and cisplatin.
• The patent does not claim the active compound as a composition, a formulation, a manufacturing process, or an anticancer drug.
• The patent expired and creates no current U.S. generic-launch barrier.
• Paragraph IV and biosimilar issues are not currently material to this patent.
• Any remaining commercial risk would come from later patents, foreign counterparts, regulatory requirements, or manufacturing know-how.

FAQs

Does U.S. Patent 6,479,500 cover 5-fluorouracil itself?

No. It covers administration of the specified side-effect-alleviating compound to a patient who has received 5-fluorouracil. It does not claim 5-fluorouracil as an active ingredient.

Does the patent cover all chemotherapy-induced nausea?

Only if the claimed pyrimidinedione compound is administered and the remaining claim requirements are met. The patent does not cover every antiemetic treatment for chemotherapy-induced nausea.

Can a company sell the claimed pyrimidinedione compound in the United States?

The expired patent does not provide a current U.S. infringement basis to block sale or use. Separate patents, regulatory requirements, or foreign rights could still affect commercialization.

Does a fixed-dose combination of cisplatin and the claimed compound infringe?

The supplied claims do not expressly claim a fixed-dose combination product. Use of the combination for alleviating a cisplatin-induced side effect could have implicated the method claims before expiration, depending on the facts.

Is a later patent on a formulation of the compound possible?

Yes. A later patent could potentially cover a distinct formulation, polymorph, salt, dosage form, release profile, manufacturing process, or new clinical use if statutory patentability requirements were satisfied. That later right would be separate from U.S. Patent 6,479,500.

References

1. United States Patent and Trademark Office. (2002). U.S. Patent No. 6,479,500, method for alleviating side effects caused by anti-tumor agents. U.S. Department of Commerce.
2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
3. United States Code. (2024). 35 U.S.C. §§ 101, 112, 154, and 271.
4. United States Code. (2024). 21 U.S.C. § 355 and 42 U.S.C. § 262.

Drugs Protected by US Patent 6,479,500

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

Foreign Priority and PCT Information for Patent: 6,479,500

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	11-77579	Mar 23, 1999

PCT Information
PCT Filed	March 16, 2000	PCT Application Number:	PCT/JP00/01607
PCT Publication Date:	September 28, 2000	PCT Publication Number:	WO00/56337

International Family Members for US Patent 6,479,500

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	323494
Australia	3192800
Australia	772486
Canada	2331737