United States Patent 5,198,226: Scope, Claims, Expiration, and Nicardipine Patent Landscape

U.S. Patent No. 5,198,226 covers sustained-release nicardipine hydrochloride multiparticulates with tightly controlled particle geometry and size. The core claim requires non-amorphous nicardipine hydrochloride in essentially spherical, non-coated, non-rugose particles containing a pH-dependent binder. The patent issued on March 30, 1993, and its ordinary 17-year patent term would have expired on March 30, 2010, absent a patent-term extension or other legally effective adjustment. No current U.S. exclusivity based on this patent should remain.

The strongest technical limitation is the combination of particle morphology, particle size, nicardipine loading, and pH-dependent polymer content. A product using a different release mechanism, coated pellets, a different particle geometry, or a substantially different particle-size distribution would have substantial non-infringement positions. The patent is now primarily relevant to historical formulation analysis, invalidity studies, freedom-to-operate review of legacy products, and prosecution strategy.

What does U.S. Patent 5,198,226 cover?

The patent covers oral sustained-release compositions containing non-amorphous nicardipine hydrochloride. The claimed product is not merely nicardipine in a controlled-release dosage form. It must have a defined multiparticulate structure.

Claim element	Required limitation
Active ingredient	Non-amorphous nicardipine hydrochloride
Particle form	Essentially spherical particles
Surface	Non-coated and non-rugose
Particle diameter	Approximately 0.5 to 1.2 mm in claim 1
Drug loading	Approximately 10% to 25% by weight
Binder	Approximately 5% to 25% by weight
Binder function	Less soluble at lower pH and more soluble at higher pH
Intended performance	Long-acting release; claim 4 specifies twice-daily plasma concentrations
Dosage form	May include an inert carrier, including a hard gelatin capsule
Therapeutic use	Treatment of cardiovascular disease

The patent therefore claims a formulation architecture rather than a new chemical entity. It does not broadly monopolize nicardipine hydrochloride, all sustained-release nicardipine products, or every twice-daily nicardipine dosage form.

How should the independent claims be interpreted?

Claims 1, 6, and 10 are the principal claim groups.

Claim 1: broad composition claim

Claim 1 requires all of the following:

A long-acting sustained-release pharmaceutical composition.
A therapeutically effective amount of non-amorphous nicardipine hydrochloride.
Essentially spherical particles.
Non-coated and non-rugose particles.
Particle diameters of approximately 0.5 to 1.2 mm.
Nicardipine hydrochloride at approximately 10% to 25% by weight.
A pH-dependent binder at approximately 5% to 25% by weight.
A binder that is less soluble at low pH and more soluble at high pH.

The phrase “comprises essentially” creates an open-ended formulation structure with a meaningful exclusion. It allows additional ingredients, but additional components cannot materially defeat the claimed sustained-release characteristics or alter the basic composition defined by the claim.

The claim does not require a specific polymer. The functional binder definition is central. A formulation can potentially fall within claim 1 even if it does not use one of the specific polymer classes later listed in claim 5, provided the binder satisfies the pH-dependent solubility limitation.

Claim 2: circularity and particle shape

Claim 2 narrows claim 1 by requiring an area-radius-to-circumference-radius ratio of 0.85 to 1.0.

This limitation is directed to particle roundness. A perfect circle would approach a ratio of 1.0. Lower values indicate increasing deviation from circular geometry. The claim creates a quantitative morphology requirement that would likely require image analysis, microscopy, or a validated particle-shape measurement method.

A product with irregular, elongated, angular, or highly rugose particles would have a stronger non-infringement position if its measured ratio falls outside the claimed range.

Claim 3: particle-size uniformity

Claim 3 requires that at least 70% by weight of the spherical particles have diameters within upper and lower limits that differ by no more than the square root of two.

The language is technically awkward because it refers to limits differing by a factor of approximately 1.414. The practical objective is narrow particle-size distribution. A formulation with a broad distribution, substantial fines, or significant oversized particles could avoid this limitation while still requiring analysis under claim 1.

The relevant evidence would include sieve analysis, laser diffraction, microscopy, or another validated particle-size method. The measurement technique can affect infringement analysis, particularly for irregular particles or agglomerates.

Claim 4: twice-daily performance

Claim 4 adds a pharmacokinetic limitation requiring therapeutic plasma concentrations suitable for twice-daily administration.

This is a product-performance limitation rather than a purely compositional limitation. In an infringement dispute, the patentee would likely need to establish that the accused dosage form produces the claimed therapeutic concentration profile. The limitation may be assessed through pharmacokinetic data, dissolution testing, dosing intervals, or product labeling.

A formulation could meet the structural limitations of claim 1 but avoid claim 4 if it does not provide the specified twice-daily exposure profile. Conversely, a twice-daily label alone would not establish infringement of the structural limitations in claim 1.

What formulations are protected by claims 5, 8, and 10?

Claim 5: specified pH-dependent binder classes

Claim 5 identifies eligible binder classes, including:

Phthalic acid derivatives of vinyl polymers and copolymers.
Hydroxyalkylcelluloses.
Alkylcelluloses.
Cellulose acetates.
Hydroxyalkylcellulose acetates.
Cellulose ethers.
Alkylcellulose acetates.
Partial esters of those materials.
Polymers and copolymers of lower alkyl acrylic acids and lower alkyl acrylates.
Partial esters of those acrylic materials.

The claim text contains apparent drafting errors, including “hydroxylakylcelluloses” and an incomplete dependency reference. Those errors do not automatically invalidate the claim. Claim construction would depend on the specification, prosecution history, and whether a person skilled in the art could understand the intended limitation.

Claim 5 does not necessarily require every listed material. It permits a single material or a mixture selected from the listed groups.

Claim 8: methacrylic-acid copolymer

Claim 8 narrows the dosage form by specifying a copolymer of methacrylic acid and methacrylic or acrylic acid ethyl ester. This language appears directed to enteric or pH-responsive methacrylate polymers, including materials commonly associated with Eudragit-type technology.

The claim is narrower than claim 1 because it requires a particular polymer chemistry. A formulation using a neutral, non-pH-dependent polymer, a lipid matrix, an osmotic system, or a different pH-sensitive material would have a potential design-around position.

Claim 10: most technically specific composition claim

Claim 10 requires:

Sustained-release nicardipine hydrochloride.
Essentially spherical, non-coated, non-rugose particles.
An area-radius-to-circumference-radius ratio of 0.85 to 1.0.
Particle diameters of approximately 0.7 to 1.0 mm.
Approximately 10% to 25% nicardipine hydrochloride.
Approximately 5% to 25% polymethacrylate.
A polymethacrylate substantially insoluble below pH 4.5.
At least 70% by weight of particles within the specified size-distribution limits.
Suitability for twice-daily administration.

Claim 10 is narrower than claim 1 in particle size, shape, binder identity, polymer solubility, distribution, and intended dosing frequency. It is likely the most commercially descriptive claim for a product using the patent’s preferred formulation.

What is the patent expiration date for U.S. Patent 5,198,226?

U.S. Patent 5,198,226 issued on March 30, 1993. For a pre-Uruguay Round patent subject to the former 17-year term measured from issuance, the ordinary expiration date was March 30, 2010.[1]

Event	Date
Patent issued	March 30, 1993
Ordinary 17-year term	March 30, 2010
Current enforceability	Expired under ordinary term analysis
Current Orange Book patent exclusivity	None based on this expired patent

Patent-term restoration under 35 U.S.C. § 156 would require a qualifying regulatory review period and a timely extension application. Nicardipine hydrochloride is an old small-molecule active ingredient, and no current enforceable exclusivity should be attributed to this patent without a specific extension record.[2]

What is the Orange Book status of the nicardipine formulation?

The patent should not be treated as a current Orange Book barrier solely because it historically covered a sustained-release nicardipine formulation.

The FDA Orange Book identifies patents and regulatory exclusivities associated with approved drug products. An expired formulation patent cannot block an ANDA through a current patent listing. Historical listing status, delisting, product discontinuation, and approval status must be evaluated at the product level rather than inferred from the patent number alone.[3]

Nicardipine has been marketed in multiple dosage forms, including oral capsules and intravenous products. A patent directed to oral sustained-release multiparticulates does not necessarily cover injectable nicardipine, immediate-release capsules, or later formulations using different release technologies.

When did nicardipine lose exclusivity?

Nicardipine lost practical new-drug exclusivity long before the expiration of Patent 5,198,226. The active ingredient was approved decades ago, and the patent’s 2010 expiration date is relevant only to the specific formulation and claim scope.

The principal categories are:

Exclusivity category	Relevance to Patent 5,198,226
Active-ingredient exclusivity	Expired long before the patent term ended
Original product patent protection	Not established by the supplied claims
Sustained-release formulation patent	Expired March 30, 2010 under ordinary term analysis
Method-of-use protection	Claim 9 is expired and limited to the claimed composition
Biologic exclusivity	Not applicable
Current small-molecule patent barrier	None attributable to Patent 5,198,226

Were there Paragraph IV challenges or patent litigation?

A Paragraph IV certification against this patent would have had practical relevance only before its expiration. After March 30, 2010, the patent could not provide a continuing patent-based obstacle to an ANDA.

The supplied information does not establish a specific Paragraph IV notice letter, ANDA litigation action, settlement agreement, or court judgment involving Patent 5,198,226. The patent number alone is not evidence of litigation. Any litigation assessment must distinguish:

Patent infringement actions under 35 U.S.C. § 271(e)(2).
Declaratory-judgment cases.
ANDA approval litigation.
Product-liability or commercial disputes unrelated to patent validity.
Patent cases involving other nicardipine patents.

Because the patent has expired, any historical case would now have limited prospective commercial effect unless it involved damages, validity, claim construction, or a settlement record.

How strong is the patent estate for sustained-release nicardipine?

The patent estate is no longer commercially blocking, but the claim strategy was technically focused.

Strengths

Quantitative particle-size limitations.
Quantitative roundness limitation.
Defined drug-loading range.
Defined binder-loading range.
Functional pH-dependent solubility requirement.
Separate claims for polymer classes and methacrylate polymers.
Twice-daily pharmacokinetic objective.
Capsule and loading-dose embodiments.

Vulnerabilities

The claims are limited to non-coated particles.
The claims require essentially spherical particles.
The claims depend on narrow size ranges and distribution measurements.
Claim 10 requires a specific polymethacrylate behavior below pH 4.5.
The specification and prosecution history would be important for interpreting “non-rugose,” “essentially spherical,” “therapeutically effective,” and “suitable for twice-daily administration.”
The claim language contains apparent typographical and dependency errors.
The patent is expired.

The strongest historical design-around routes would have included coated pellets, matrix tablets, osmotic delivery, lipid-based systems, nanoparticles, substantially different particle sizes, non-spherical particles, or polymers that release through mechanisms other than the claimed pH-dependent solubility profile.

How does this patent compare with competing nicardipine technologies?

Technology	Likely relationship to Patent 5,198,226
Immediate-release nicardipine capsule	Generally outside the sustained-release particle claims
Intravenous nicardipine formulation	Generally outside the oral multiparticulate claims
Coated sustained-release pellets	Potentially outside the express non-coated limitation
Matrix tablet	Potentially outside the spherical-particle limitations
Osmotic dosage form	Potentially outside the claimed binder and particle architecture
Multiparticulates using non-pH-dependent polymers	Potentially outside the binder limitation
Other calcium-channel blockers	Outside the nicardipine-specific claims
Generic nicardipine product with matching pellets	Historically higher technical risk, but no current risk from this expired patent

What generic entry risks exist today?

Patent 5,198,226 does not create a current generic-entry block. A generic manufacturer’s remaining risks would arise from other sources:

FDA approval requirements, including bioequivalence.
Current patents not identified in the supplied claim set.
Product-specific Orange Book listings.
Manufacturing reproducibility.
Dissolution-profile matching.
Particle-size and content-uniformity controls.
Regulatory requirements for modified-release dosage forms.
Trade-secret or know-how barriers involving pellet manufacture.
Commercial discontinuation or limited market size.

For an ANDA applicant, the historical formulation claims still have technical value as prior-art benchmarks. They may affect freedom-to-operate only if a related, unexpired continuation, reissue, foreign counterpart, or later patent claims substantially the same formulation. The supplied patent claims alone do not establish such a surviving right.

What manufacturing and intellectual-property barriers remain?

The patent describes a manufacturing concept based on controlled spherical particles rather than a simple blend. Relevant process capabilities include:

Formation of particles within approximately 0.5 to 1.2 mm.
Control of particle roundness.
Uniform distribution of nicardipine hydrochloride.
Control of polymer concentration.
Prevention of surface rugosity.
Control of particle-size distribution.
Consistent dissolution across gastrointestinal pH conditions.
Capsule filling without segregation or fracture.

Those capabilities may remain commercially useful even though the patent has expired. The likely surviving barriers are process know-how, scale-up data, analytical methods, supplier qualification, and bioequivalence performance rather than enforceable rights under Patent 5,198,226.

Key Takeaways

U.S. Patent 5,198,226 covers non-amorphous nicardipine hydrochloride in spherical, non-coated, non-rugose sustained-release particles.
The principal quantitative limitations are particle size, roundness, drug loading, binder loading, and size distribution.
Claim 10 is the narrowest and most technically specific formulation claim.
Claim 9 is a method-of-treatment claim limited by its dependency on the claimed formulation.
The patent issued on March 30, 1993, and ordinarily expired on March 30, 2010.
It does not create a current U.S. patent barrier to generic nicardipine entry.
Coated systems, matrix tablets, osmotic systems, non-spherical particles, and non-pH-dependent release systems are the principal historical design-around categories.
A complete current freedom-to-operate conclusion requires review of related patents, continuations, reissues, Orange Book records, and current FDA approvals.

FAQs

Does U.S. Patent 5,198,226 cover all sustained-release nicardipine products?

No. It is limited to a defined particle-based formulation using non-amorphous nicardipine hydrochloride, essentially spherical non-coated particles, and a pH-dependent binder.

Could a coated nicardipine pellet avoid the patent claims?

Historically, coating could provide a meaningful non-infringement position because the claims expressly require non-coated particles. The expired status eliminates current infringement risk from this patent.

Does claim 9 cover treatment with any nicardipine product?

No. Claim 9 depends on the claimed composition. It does not independently cover every method of treating cardiovascular disease with nicardipine.

Is a polymethacrylate formulation automatically within claim 10?

No. The formulation must also satisfy the particle geometry, particle size, drug and polymer percentages, pH-solubility behavior, size-distribution, and twice-daily requirements.

Does expiration of this patent eliminate all nicardipine patent risk?

No. It eliminates risk based on this patent. Other patents, regulatory requirements, manufacturing rights, or product-specific Orange Book records must be evaluated separately.

References

U.S. Patent No. 5,198,226, “Long acting sustained release pharmaceutical compositions containing nicardipine hydrochloride,” issued March 30, 1993.
35 U.S.C. §§ 154, 155, 156, 271(e), and 282.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. FDA.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	81973	⤷ Start Trial
Australia	604672	⤷ Start Trial
Australia	6810287	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,198,226

Summary for Patent: 5,198,226