United States Patent 4,837,223: Levetiracetam Claims, Scope, Expiration, and Patent Landscape

U.S. Patent No. 4,837,223 covered levetiracetam, the S-enantiomer of alpha-ethyl-2-oxo-1-pyrrolidineacetamide. Its two claims addressed an enantiopure pharmaceutical composition and a process-defined form of the S-enantiomer. The patent issued June 6, 1989, and expired June 6, 2006 under the pre-1995 U.S. patent-term regime. It no longer blocks generic levetiracetam manufacture, sale, or approval.

The patent was commercially important because it separated levetiracetam from the less active or differently active R-enantiomer and protected both the drug product concept and a route to producing the S-enantiomer. Its practical exclusionary value ended before the modern generic levetiracetam market developed.

What drug does U.S. Patent 4,837,223 protect?

U.S. Patent 4,837,223 protects levetiracetam, whose chemical name is:

(S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide
Common name: levetiracetam
Brand: Keppra
Therapeutic class: antiepileptic drug
Molecular formula: C8H14N2O2
Small-molecule active ingredient

The R-enantiomer is the corresponding opposite stereoisomer. The claims require the levetiracetam composition or product to be “substantially free” of that R-enantiomer.

The patent was assigned to UCB, a Belgian pharmaceutical company. Levetiracetam was later developed and commercialized by UCB as Keppra.

What are the claims of U.S. Patent 4,837,223?

The patent has two claims.

Claim	Subject matter	Principal limitation
Claim 1	Pharmaceutical composition	Therapeutically effective levetiracetam, a pharmaceutically acceptable solid or liquid diluent or carrier, and substantial absence of the R-enantiomer
Claim 2	Levetiracetam made by a specified process	Cyclization of a defined S-2-aminobutanamide precursor in an inert solvent with a base

What does claim 1 cover?

Claim 1 covers a pharmaceutical composition containing:

A therapeutically effective amount of levetiracetam;
A pharmaceutically acceptable solid or liquid diluent or carrier; and
A composition substantially free of the R-enantiomer.

The claim is broad as to dosage form. It does not specify tablets, capsules, oral solutions, injectable products, a particular excipient, a particular strength, or a particular epilepsy indication. It therefore reaches compositions such as:

Immediate-release tablets;
Capsules;
Oral solutions;
Other solid or liquid pharmaceutical dosage forms.

The claim does not cover every sample of levetiracetam as a standalone chemical. It requires a pharmaceutical composition and a carrier or diluent. A bulk active pharmaceutical ingredient would fall outside claim 1 unless it is present in a claimed pharmaceutical composition.

The central technical limitation is stereochemical purity. A racemic mixture containing both enantiomers would not satisfy the claim if the composition is not “substantially free” of the R-enantiomer. The patent does not state a numerical enantiomeric-purity threshold in the claim text supplied. That limitation would have required interpretation from the specification, prosecution history, analytical evidence, and applicable claim-construction principles.

What does claim 2 cover?

Claim 2 covers levetiracetam that is:

Substantially free of the R-enantiomer; and
Prepared by cyclizing a specified S-2-aminobutanamide precursor under defined conditions.

The process uses:

An inert solvent;
A basic substance;
A precursor containing the stereogenic S-configuration;
One of two structural pathways defined by the X and Y variables.

The claim provides two alternatives:

Route	X group	Y group	Functional pathway
First alternative	ZOOC-, where Z is C1-C4 alkyl	-CH2-	Intramolecular cyclization of an ester-containing precursor
Second alternative	HalCH2-, where Hal is a halogen	-CO-	Intramolecular cyclization of a haloacetyl-type precursor

The proviso requires the pairing of X and Y shown in the claim. It prevents arbitrary combinations of the two structural alternatives.

How broad is the patent scope?

The patent’s scope is meaningful but narrower than a composition-of-matter patent covering levetiracetam without qualification.

Claim 1 scope

Claim 1 is a composition claim with four practical elements:

Element	Scope consequence
Therapeutically effective amount	Requires a pharmaceutical dose rather than merely trace or analytical quantities
Levetiracetam	Covers the S-enantiomer identified in the claim
Solid or liquid carrier	Reaches common oral dosage forms and other formulated products
Substantially free of R-enantiomer	Excludes formulations containing material levels of the opposite stereoisomer

The claim does not require use for epilepsy. A pharmaceutical composition satisfying the structural and formulation limitations could be within the claim even if marketed for another therapeutic purpose.

Claim 2 scope

Claim 2 is materially narrower because it includes process limitations. A competing manufacturer using a different synthetic route could argue that its levetiracetam does not satisfy the process-defined claim. The legal effect of a product-by-process claim depends on the applicable interpretation of the product and process language. In U.S. practice, product-by-process claims generally cannot be used to impose process limitations on a product that is otherwise indistinguishable, although the precise analysis depends on claim construction and infringement facts. [1]

The claim therefore provided stronger protection against the specified manufacturing routes than against every possible route to levetiracetam.

When did U.S. Patent 4,837,223 expire?

Event	Date
U.S. patent grant	June 6, 1989
Statutory term under pre-1995 regime	17 years from grant
Base expiration	June 6, 2006
Current status	Expired

The patent was granted before the Uruguay Round Agreements Act changed most U.S. utility patent terms to 20 years from the earliest effective nonprovisional filing date. Under the law applicable to this patent, the term was generally 17 years from grant. [2]

No current patent-term extension or adjustment restores exclusivity for the original patent. The patent is therefore not a present barrier to an ANDA applicant or commercial generic manufacturer.

What was the FDA regulatory status of levetiracetam?

FDA approved Keppra, containing levetiracetam, in 1999 for adjunctive treatment of partial-onset seizures in adults. Subsequent approvals expanded the product’s use, dosage forms, and patient populations.

Regulatory item	Status
Active ingredient	Levetiracetam
Reference product	Keppra
Sponsor	UCB
FDA pathway	NDA
Generic pathway	ANDA
Biologic pathway	Not applicable
FDA approval date for original Keppra NDA	1999
Original patent	U.S. 4,837,223
Original patent status	Expired

Levetiracetam is a conventional small molecule. Biosimilar risk under the Biologics Price Competition and Innovation Act does not apply. Competitive entry proceeds through the Hatch-Waxman generic framework, primarily using ANDAs rather than biosimilar applications. [3]

What was the Orange Book status of U.S. Patent 4,837,223?

The patent was associated with Keppra and was relevant to the FDA Orange Book patent-listing framework during the product’s protected period. The relevant patent category was the active-ingredient and composition protection associated with levetiracetam.

The Orange Book listing did not create exclusivity beyond the patent’s statutory term. Once the patent expired, an ANDA applicant no longer faced an unexpired patent barrier based on U.S. 4,837,223.

A current Orange Book review must distinguish:

Expired patent listings associated with immediate-release Keppra;
Later patents associated with extended-release products such as Keppra XR;
Any unexpired patents listed for specific formulations or later-approved products.

Those later patents cannot be assumed to extend the life of U.S. 4,837,223 or to cover every levetiracetam product. Orange Book listings are product- and NDA-specific. [4]

Were there Paragraph IV challenges to U.S. Patent 4,837,223?

Paragraph IV certifications became relevant when generic applicants sought approval for levetiracetam products while patents were listed for the reference product. A Paragraph IV certification asserts that a listed patent is invalid, unenforceable, or would not be infringed by the proposed generic product. [3]

For U.S. 4,837,223, the practical timeline was unusual because the patent expired in 2006 while generic levetiracetam approvals emerged after the principal patent term had ended. A later generic applicant could rely on a Paragraph III certification after expiration or, depending on the timing and listing status, challenge an unexpired listed patent with a Paragraph IV certification.

The original patent is not an active Paragraph IV risk today. Any current litigation analysis must focus on later patents covering:

Extended-release levetiracetam;
Modified-release delivery systems;
Specific dosage forms;
Later-added methods of treatment;
Manufacturing or purification technology.

What formulation patents protect levetiracetam products?

The original patent protects a broad pharmaceutical composition concept but does not claim a specific controlled-release matrix, dissolution profile, particle-size distribution, coating system, or excipient combination.

Later levetiracetam patent activity has generally been more relevant to product differentiation than U.S. 4,837,223. The most commercially important distinction is between:

Product type	Relevance of U.S. 4,837,223
Immediate-release tablets	Historical composition protection; expired
Oral solution	Historical composition protection; expired
Generic immediate-release products	No current blocking effect from 4,837,223
Extended-release tablets	May implicate separate formulation patents
Keppra XR-type products	Requires separate Orange Book and patent review
Alternative delivery systems	Potentially governed by later formulation or device patents

A formulation patent may remain enforceable even when the underlying active-ingredient patent has expired. This is the principal distinction between an expired foundational patent and a later product-line patent.

What manufacturing and IP barriers did the patent create?

The patent created three historical barriers.

Stereochemical control

Manufacturers had to produce levetiracetam with sufficient control over the S-configuration and limit the R-enantiomer. Enantiomeric purity affects both regulatory specifications and infringement analysis.

Route selection

The second claim identified specific cyclization routes. A manufacturer using one of those routes could have faced process-claim exposure during the patent term. A different route would have required analysis against the claim’s process limitations and any other process patents.

Pharmaceutical formulation

A product containing a therapeutically effective amount of substantially enantiopure levetiracetam with a pharmaceutical carrier was within the conceptual scope of claim 1 during the patent term. This made formulation design alone an ineffective way to avoid the claim if the composition still met its limitations.

How strong was the patent estate for levetiracetam?

The patent estate was strong during the early commercial period because U.S. 4,837,223 combined:

A stereochemically defined active ingredient;
A pharmaceutical composition claim;
A manufacturing process claim;
Broad coverage of solid and liquid carriers;
No limitation to a single dosage strength or epilepsy indication.

Its weaknesses were structural:

The patent had only two claims;
Claim 1 depended on the potentially litigated phrase “substantially free”;
Claim 2 was process-defined;
The patent expired in 2006;
Later products could be protected only by separate patents.

The estate is now historically important rather than commercially blocking. Current patent strength for levetiracetam depends on later formulation, delivery, or manufacturing patents, not on U.S. 4,837,223.

Which companies challenged or competed with Keppra?

Generic competition came from multiple ANDA applicants after the foundational patent expired. Companies active in generic levetiracetam have included major generic manufacturers such as Teva, Mylan, Sandoz, and other FDA-approved suppliers, depending on dosage form, market period, and product authorization.

The competitive landscape includes:

Segment	Principal competitors
Immediate-release tablets	Multiple ANDA-approved generic manufacturers
Oral solution	Multiple generic suppliers
Extended-release products	Generic manufacturers subject to product-specific patents and regulatory requirements
Branded products	UCB’s Keppra and Keppra XR products
Biosimilars	None; levetiracetam is not a biologic

Generic entry risk for immediate-release levetiracetam is therefore high and established. The principal residual risks concern product-specific patents, regulatory exclusivity, formulation differences, and supply-chain execution.

What litigation and settlement issues affect the patent?

U.S. 4,837,223 is expired and does not present an active infringement threat. Any historical Hatch-Waxman litigation involving levetiracetam should be separated into two categories:

Litigation concerning the foundational compound and composition patent; and
Litigation concerning later patents for extended-release or other specialized products.

Settlement agreements, if any, must be evaluated by product, NDA, patent number, and entry date. A settlement involving a later Keppra XR patent does not revive or extend the term of U.S. 4,837,223.

The patent record itself establishes the claim scope and expiration. Settlement terms are typically found in court dockets, FTC submissions, or public company disclosures rather than in the patent document. [5]

What is the commercial impact of patent expiration?

Levetiracetam became exposed to generic substitution after expiration of the foundational patent. The commercial consequences included:

Loss of compound-level exclusivity;
Price erosion in immediate-release products;
Increased formulary substitution;
Multiple-source generic competition;
Reduced value of the original patent estate;
Continued differentiation for extended-release products and branded formulations.

U.S. 4,837,223 had its highest value before and during the early Keppra launch period. It has no present revenue-protection value by itself. Current revenue exposure for a levetiracetam portfolio depends on brand retention, extended-release products, supply reliability, and any remaining product-specific patents.

How does U.S. Patent 4,837,223 compare with later levetiracetam patents?

Issue	U.S. 4,837,223	Later levetiracetam patents
Core subject	Enantiopure levetiracetam and process	Formulations, delivery systems, uses, or manufacturing
Claim breadth	Broad composition concept plus narrow process claim	Usually narrower, technology-specific claims
Dosage-form limitation	Solid or liquid carrier, without detailed formulation limits	Often detailed release, coating, excipient, or dissolution limitations
Expiration	June 6, 2006	Patent-specific
Current blocking effect	None	Must be assessed individually
Generic relevance	Historical foundational barrier	Potential current barrier for defined products
Biosimilar relevance	None	None for small-molecule levetiracetam

Key Takeaways

U.S. Patent 4,837,223 is the foundational U.S. patent for levetiracetam.
Claim 1 covers pharmaceutical compositions containing therapeutically effective levetiracetam substantially free of the R-enantiomer.
Claim 2 covers levetiracetam made through specified S-precursor cyclization routes.
The patent issued June 6, 1989, and expired June 6, 2006.
The patent is no longer a barrier to generic immediate-release levetiracetam.
Later formulation and extended-release patents must be analyzed separately.
Levetiracetam is a small molecule, so biosimilar pathways do not apply.
Current generic-entry risk is high for immediate-release products and depends on later patents for specialized dosage forms.
The patent’s historical strength came from its combination of stereochemical, composition, and process coverage.
The original patent does not protect a specific extended-release technology or modern delivery system.

FAQs

Does U.S. Patent 4,837,223 cover racemic etiracetam?

No. The claims require the S-enantiomer and substantial freedom from the R-enantiomer. A racemic mixture would not ordinarily satisfy that stereochemical limitation.

Can a generic manufacturer avoid claim 1 by using different excipients?

Not necessarily. Claim 1 is not limited to particular excipients. A product using different excipients could still have satisfied the claim during its term if it contained therapeutically effective levetiracetam, a pharmaceutically acceptable carrier, and was substantially free of the R-enantiomer.

Does the patent cover levetiracetam for every medical indication?

Claim 1 does not specify epilepsy or another indication. Its composition language is not limited to the original FDA-approved use, although infringement analysis would still depend on the product’s actual composition and applicable legal doctrines.

Is an enantiomeric-purity specification still relevant after patent expiration?

Yes. Enantiomeric purity remains relevant to FDA quality requirements, product specifications, bioequivalence, and manufacturing control even though the expired patent no longer creates an exclusionary right.

Does expiration of U.S. 4,837,223 eliminate all patent risk for Keppra-type products?

No. It eliminates the risk from that patent. Later patents may still cover extended-release formulations, delivery technologies, manufacturing processes, or specific product configurations.

References

U.S. Patent No. 4,837,223, Levetiracetam, a process for its preparation and pharmaceutical compositions containing it (1989). U.S. Patent and Trademark Office.
35 U.S.C. § 154. Patent term and patent rights.
Drug Price Competition and Patent Term Restoration Act, 21 U.S.C. § 355(j). Abbreviated new drug applications and patent certifications.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA, Center for Drug Evaluation and Research.
Federal Trade Commission. (2023). Authorized generic drugs and pharmaceutical competition resources. Federal Trade Commission.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	84/12357	May 15, 1984

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0162036	⤷ Start Trial	SPC/GB00/030	United Kingdom	⤷ Start Trial
European Patent Office	0162036	⤷ Start Trial	2000C/032	Belgium	⤷ Start Trial
European Patent Office	0162036	⤷ Start Trial	C300028	Netherlands	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,837,223

Summary for Patent: 4,837,223