United States Patent 6,245,911: Donepezil Polymorph Claims, Expiration, and Patent Landscape

U.S. Patent No. 6,245,911 covers three crystalline polymorphs of donepezil, identified as Forms A, B, and C, together with laboratory-scale and manufacturing processes for producing them. Claims 1-3 are product claims defined by powder X-ray diffraction and infrared spectra. Claims 4-21 are process claims directed mainly to solvent selection, cooling, heating, crystallization time, and seeding.

The patent has expired. Its historical importance was greater than its current blocking effect because the claims targeted solid-state forms and crystallization methods rather than the active pharmaceutical ingredient, finished-dose formulation, or therapeutic use of donepezil. Current generic manufacturers can avoid the patent through alternative polymorphs, amorphous material, different salts, or non-infringing crystallization processes.

What does U.S. Patent 6,245,911 protect?

The patent protects specified crystalline forms of donepezil and methods of making those forms. The claims divide into two categories:

Claim group	Claims	Subject matter	Scope
Form A	1, 4, 10, 18	Crystal Form A and processes using methanol-denatured ethanol, cooling, crystallization time, or Form A seeds	Product and process
Form B	2, 5, 6, 11, 12, 19	Crystal Form B and processes involving THF concentration, cooling, crystallization time, or Form B seeds	Product and process
Form C	3, 7-9, 13-17, 20-21	Crystal Form C and processes involving controlled thermal treatment, suspension, lower alcohols, methanol-denatured ethanol, and listed solvents	Product and process

The patent does not claim:

Donepezil as a broad chemical compound;
Donepezil hydrochloride tablets as a dosage form;
A method of treating Alzheimer’s disease;
A broad pharmaceutical composition containing donepezil;
A generic process for making every crystalline or amorphous form of donepezil.

The claim text supplied identifies the active material as donepezil. The patent family and commercial product history must be read carefully because marketed Aricept products contain donepezil hydrochloride, while translations and claim summaries sometimes shorten the chemical designation to “donepezil.” The salt state, hydrate state, and actual claim drawings are material to infringement analysis.

How do claims 1 through 3 define the polymorphs?

Claims 1, 2, and 3 are product-by-characterization claims.

Form A: claim 1

Form A is identified by a powder X-ray diffraction pattern with a dominant peak at 17.66° 2θ and additional peaks including 15.34°, 16.96°, 19.26°, 20.08°, 20.82°, 22.14°, and 22.60°.

The infrared alternative lists absorption bands from 561.3 to 2,919.1 cm⁻¹. Because the claim uses “and/or,” the claim text appears to permit identification through the listed PXRD peaks, the listed infrared peaks, or both, subject to the proper legal construction of the patent specification.

The practical scope is a specific solid-state form, not any material that merely has a similar melting point, solubility profile, or bulk density.

Form B: claim 2

Form B has a distinctive PXRD signature. Its strongest peak is at 21.90° 2θ, with another high-intensity peak at 5.82° and substantial peaks at 19.70°, 22.90°, 23.48°, and 24.22°.

The 5.82° peak may be particularly useful in distinguishing Form B from Forms A and C. However, a single peak should not be used as the sole basis for a legal identity determination. Preferred practice is to compare the complete pattern, relative intensities, sample preparation, instrument calibration, and polymorph reference standard.

Form C: claim 3

Form C has its strongest PXRD peak at 17.00° 2θ, with notable peaks at 17.18°, 21.50°, 14.08°, 14.94°, 23.44°, and 26.54°.

Its infrared profile includes bands at 559.8, 648.4, 733.5, 818.8, 1,036.4, 1,122.1, 1,221.3, 1,367.5, 1,459.1, 1,498.6, 1,591.9, 1,688.1, and 2,909.3 cm⁻¹.

What evidence is required to prove infringement of a polymorph claim?

A claimant would generally need to establish that the accused material is the claimed crystal form. Relevant evidence can include:

PXRD comparison against the claimed peaks and intensities;
Infrared spectroscopy;
Differential scanning calorimetry;
Thermogravimetric analysis;
Solid-state nuclear magnetic resonance;
Microscopy and particle morphology;
Conversion or stability studies showing interconversion between forms.

Peak position tolerances are not stated in the claims reproduced by the user. That creates a technical construction issue. Instrument error, sample orientation, crystallite size, preferred orientation, humidity, and formulation excipients can shift or distort measured peaks. A litigation analysis would therefore focus on the specification’s testing conditions and accepted analytical tolerances rather than treating the listed decimal values as absolute in every circumstance.

What manufacturing processes are protected by claims 4 through 21?

The process claims are narrow and operational. They require specific process steps, temperatures, times, solvents, and seeding conditions.

Form A process claims

Claims 4, 10, and 18 cover:

Crystallization from methanol-denatured ethanol at 10°C or below within 20 hours;
Addition of Form A seed crystals followed by crystallization at 20°C or below within one hour;
Dissolution in methanol-denatured ethanol followed by addition of Form A seeds.

A process that produces Form A through a different solvent system or without the claimed time and temperature sequence may avoid these claims, although it could still infringe claim 1 if the resulting product is Form A.

Form B process claims

Claims 5, 6, 11, 12, and 19 cover:

Concentration of a donepezil/THF solution;
Crystallization from methanol-denatured ethanol at 10°C or below for at least 20 hours;
Form B seeding followed by cooling to 15°C or below and crystallization at 20-30°C within two hours;
Form B seeding and crystallization at 15°C or below within one hour;
Dissolution in methanol-denatured ethanol followed by Form B seeding.

Claim 5 is materially different from the ethanol-based claims because it focuses on concentration of a THF solution. The claim does not, based on the supplied language, impose a particular concentration endpoint, evaporation rate, or crystallization temperature. The specification would control whether “concentrating” has a specialized meaning.

Form C process claims

Claims 7-9, 13-17, and 20-21 cover the broadest process cluster in the patent, but each individual claim remains constrained by its required sequence.

Examples include:

Cooling below 10°C, allowing precipitation, heating above 20°C, and cooling again;
Cooling and crystallizing at 15-25°C after precipitation;
Gradual cooling;
Form C seeding, cooling, heating to 25-35°C for at least two hours, and further cooling;
Suspending donepezil and Form C seeds in a solvent at 20-40°C;
Using a lower alcohol, including methanol, ethanol, n-propanol, or isopropanol;
Using methanol-denatured ethanol;
Using one of the specifically listed solvents or solvent mixtures.

Claims 14-17 and 21 are particularly relevant to process design because they define solvent classes and named solvent systems. A manufacturer using a solvent not listed in claim 21 may avoid that claim, but the product could remain within claim 3 if it produces Form C.

When did U.S. Patent 6,245,911 lose exclusivity?

U.S. Patent 6,245,911 is expired and no longer provides an enforceable U.S. exclusion right. The patent issued on June 12, 2001. Its statutory term was governed by the post-1995 patent-term rules, which generally provide 20 years from the effective U.S. nonprovisional filing date, subject to patent-term adjustment and other term-specific events.[1]

The patent’s enforceable term ended before the current date. There is no present U.S. patent-barrier value in claims 1-21, although the patent remains relevant as prior art against later polymorph applications and as historical evidence of the known solid-state forms.

Milestone	Date or status
U.S. patent	6,245,911
Issue date	June 12, 2001
Applicant/patent family	Eisai-related donepezil solid-state technology
Technology	Donepezil polymorphs and crystallization
Current status	Expired
Current blocking effect	None from this patent
Regulatory relevance	Historical Orange Book and generic-entry analysis only

The patent should not be confused with other donepezil patents that governed compound, formulation, or commercial-product exclusivity at different times.

What was the Orange Book status of U.S. Patent 6,245,911?

The Orange Book status must be distinguished from patent enforceability. FDA-listed patents can have different practical roles:

A patent may be listed for an approved drug product;
A patent may be challenged through an ANDA Paragraph IV certification;
A patent may remain listed while approaching expiration;
A patent may not block a generic if it does not claim the approved product or a required method of use.

For donepezil, the most commercially important barriers historically involved the original compound and product patents associated with Aricept, not only the polymorph claims in U.S. Patent 6,245,911. The commercial launch of generic donepezil in the United States followed expiration or resolution of the principal Aricept patent and exclusivity barriers. FDA’s Orange Book remains the controlling source for product-specific listing, delisting, and expiration information.[2]

A polymorph patent has stronger Orange Book relevance when:

The approved product necessarily contains the claimed polymorph;
The patent claims the approved dosage form or composition;
The NDA holder lists it in accordance with FDA regulations;
An ANDA applicant must certify against it.

If the approved tablet can lawfully contain a different solid form, or if the patent is not product-specific, the patent may have limited practical significance even while enforceable.

Which companies challenged donepezil exclusivity?

Generic competition to Aricept involved multiple ANDA applicants and Paragraph IV challenges. Public litigation and regulatory records identify challenges by major generic companies, including Teva, Ranbaxy, Dr. Reddy’s Laboratories, and other ANDA sponsors during the pre-generic-entry period.[3]

The key legal distinction is between challenging:

The basic donepezil compound patent;
The marketed Aricept formulation;
Method-of-use claims;
Polymorph claims;
Pediatric exclusivity;
Later dosage strengths or orally disintegrating formulations.

A Paragraph IV certification against U.S. Patent 6,245,911 would have required an ANDA applicant to assert that the patent was invalid, unenforceable, or not infringed. A generic applicant could also pursue a non-Paragraph-IV strategy by using a different crystal form or by launching after patent expiration.

What patent litigation affected donepezil generic entry?

Donepezil litigation centered on Aricept and the timing of generic approval. The principal business issue was whether generic entry could occur before the end of the branded product’s remaining patent and regulatory exclusivity period.

The litigation risk was concentrated in four areas:

Risk area	Relevance to U.S. 6,245,911
Compound patent	Greater historical relevance to basic donepezil supply
Formulation patent	Relevant to tablet composition and dosage form
Method-of-use patent	Relevant to labeling and carved-out indications
Polymorph patent	Relevant only if the generic used Forms A, B, or C or an infringing process

Settlement agreements in pharmaceutical patent litigation often included licensed entry dates, authorized generic provisions, or restrictions tied to specific dosage forms. The existence of a settlement does not establish that every patent in the portfolio was valid or infringed. Patent-specific terms must be reviewed separately from the overall Aricept settlement record.

How strong is the patent estate for donepezil polymorphs?

The historical estate was technically meaningful but legally narrow.

Strengths

Claims 1-3 identify three discrete crystal forms through analytical fingerprints.
The three forms are differentiated by distinctive PXRD patterns.
Process claims cover multiple crystallization routes and seeding strategies.
The claims could support a product-by-process investigation where commercial material matched a claimed form.
Solid-state characterization is reproducible when testing is performed under controlled conditions.

Weaknesses

The patent does not cover all donepezil solid forms.
The product claims depend on analytical identity and peak interpretation.
The process claims require compliance with specific process conditions.
A manufacturer can pursue a different polymorph, amorphous form, salt, solvate, or crystallization route.
The patent is expired, eliminating current infringement leverage.

The principal historical invalidity questions would have involved anticipation or obviousness based on earlier crystallization disclosures, reproducibility of the claimed forms, adequacy of the spectral definitions, and whether the claimed process conditions were inventive rather than routine optimization.

What formulation patents protect donepezil products?

U.S. Patent 6,245,911 is not a conventional formulation patent. It does not claim a tablet matrix, orally disintegrating tablet, excipient combination, release profile, coating, or dose regimen.

The broader donepezil landscape historically included separate patents and regulatory protections for:

Donepezil hydrochloride as a pharmaceutical compound;
Pharmaceutical compositions;
Oral tablets;
Orally disintegrating formulations;
Taste-masked or rapidly disintegrating products;
Therapeutic use in Alzheimer’s disease;
Specific dosing regimens and patient populations.

Each category requires separate claim-chart analysis. A generic product could avoid the polymorph patent yet infringe a formulation patent, or use the claimed polymorph without infringing a formulation claim if the formulation patent had expired or was not applicable.

Is there biosimilar risk for donepezil?

No. Donepezil is a small-molecule drug, not a biologic. The relevant competitive pathway is an abbreviated new drug application under section 505(j) of the Federal Food, Drug, and Cosmetic Act, not a biosimilar application under the Biologics Price Competition and Innovation Act.[4]

The principal technical barriers are:

Pharmaceutical equivalence;
Bioequivalence;
Salt and solid-state form selection;
Impurity control;
Particle-size control;
Stability;
Manufacturing reproducibility.

What generic launch scenarios existed for donepezil?

Three generic-entry strategies were available:

Same-form launch

The applicant uses Form A, B, or C and must assess whether the relevant patent was listed and enforceable. This strategy offers manufacturing familiarity but creates direct polymorph risk when the patent remains active.

Design-around launch

The applicant uses another crystalline form, amorphous donepezil, or another salt and validates pharmaceutical equivalence and bioequivalence. This approach reduces direct exposure to claims 1-3 and most process claims.

Post-expiration launch

The applicant waits until the relevant patent term ends. This eliminates infringement risk under U.S. Patent 6,245,911 and was the lowest legal-risk strategy, although it delayed market entry.

Because the patent is expired, all three strategies are now available from the perspective of this patent alone.

What licensing deals affected this patent?

The patent is associated with Eisai’s donepezil solid-state technology and the Aricept commercial franchise. Publicly reported donepezil commercialization involved Eisai’s development and marketing activities, with regional arrangements and generic settlements affecting market access.

No current license to U.S. Patent 6,245,911 is needed to practice the expired U.S. claims. Historical licenses or settlements may still matter for foreign patents, confidential manufacturing know-how, or contractual restrictions, but they do not restore an expired U.S. patent right.

What is the geographic coverage of the donepezil polymorph estate?

U.S. Patent 6,245,911 provides rights only in the United States. Related applications or foreign counterparts may have existed in Japan, Europe, and other jurisdictions. Their scope and expiration dates had to be assessed independently because:

Foreign claim amendments may differ;
Patent terms vary by jurisdiction;
Supplementary protection certificates generally do not apply to this type of small-molecule process patent in the same way as a medicinal-product patent;
Some foreign rights may have lapsed for nonpayment of fees;
Local patent offices may have granted narrower claims.

A global freedom-to-operate review therefore cannot rely on the U.S. expiration status alone.

What manufacturing and intellectual-property barriers remain?

The expired patent does not remove technical manufacturing barriers. Donepezil solid-state control still affects:

Dissolution;
Flowability;
Tablet compression;
Stability;
Moisture sensitivity;
Scale-up reproducibility;
Batch-to-batch analytical comparability.

The strongest remaining protection may reside in trade secrets covering crystallization parameters, seed preparation, solvent recycling, filtration, drying, and polymorph control. Those rights are not visible in the patent claims and are not extinguished by patent expiration.

Key Takeaways

U.S. Patent 6,245,911 claims Donepezil Forms A, B, and C and processes for producing them.
Claims 1-3 are polymorph product claims defined by PXRD and infrared fingerprints.
Claims 4-21 are narrow process claims requiring specified solvents, temperatures, times, cooling sequences, or seed crystals.
The patent does not broadly claim donepezil, Aricept tablets, Alzheimer’s treatment, or every donepezil formulation.
The patent is expired and creates no current U.S. patent barrier.
Historical Paragraph IV and generic-entry analysis must distinguish this patent from compound, formulation, method-of-use, and regulatory exclusivity rights.
Donepezil has generic, not biosimilar, competition.
Current commercial risk is more likely to arise from other active patents, regulatory requirements, manufacturing know-how, or foreign rights than from U.S. Patent 6,245,911.

FAQs

Does U.S. Patent 6,245,911 cover donepezil hydrochloride tablets?

Not directly based on the supplied claims. It covers specified solid-state forms and crystallization processes. A tablet would implicate the patent only if it contained a claimed form and the patent were still enforceable.

Can a generic manufacturer use donepezil Form A today?

From the standpoint of U.S. Patent 6,245,911, yes, because the patent has expired. The manufacturer must still assess other patents, FDA requirements, product quality, and foreign rights.

Are PXRD peaks in a polymorph claim exact numerical limitations?

The claim lists specific diffraction angles and intensities, but legal interpretation generally considers the specification, test conditions, analytical tolerances, and whether the claimed pattern identifies the same crystalline form.

Can an amorphous donepezil product avoid this patent?

An amorphous product generally would not meet a claim directed to crystalline Form A, B, or C. It could still raise issues under other patents or regulatory requirements.

Does patent expiration eliminate trade-secret protection for the crystallization process?

No. Patent expiration ends the patent exclusion right. Independently maintained manufacturing know-how, process parameters, and scale-up practices can remain protected as trade secrets.

References

United States Patent and Trademark Office. (n.d.). Patent term adjustment and patent term calculation resources. https://www.uspto.gov/patents/laws/patent-term-adjustment
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book. https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book
U.S. Food and Drug Administration. (n.d.). Paragraph IV patent certifications and ANDA litigation resources. https://www.fda.gov/drugs/abbreviated-new-drug-application-anda/paragraph-iv-drug-product-applications
U.S. Food and Drug Administration. (n.d.). Small-molecule drug development and abbreviated new drug applications. https://www.fda.gov/drugs/types-applications/abbreviated-new-drug-application-anda [

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	9-336165	Dec 05, 1997

PCT Information
PCT Filed	December 01, 1998	PCT Application Number:	PCT/JP98/05405
PCT Publication Date:	June 17, 1999	PCT Publication Number:	WO99/29668

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	260896	⤷ Start Trial
Germany	69822218	⤷ Start Trial
Denmark	1048653	⤷ Start Trial
European Patent Office	1048653	⤷ Start Trial
Spain	2218869	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 6,245,911