United States Drug Patent 5,312,925: Ziprasidone Scope, Claims, Expiration, and Patent Landscape

U.S. Patent No. 5,312,925 covers ziprasidone hydrochloride monohydrate, the active pharmaceutical ingredient in Geodon. The patent contains four claim categories: the specific hydrochloride monohydrate compound, pharmaceutical compositions, therapeutic use, and a defined manufacturing process using approximately 0.7 M aqueous hydrochloric acid. The patent issued May 17, 1994, and its principal Orange Book-listed patent term expired June 4, 2012.[1][2]

The patent is important historically because it protects the marketed salt and hydrate form of ziprasidone rather than merely claiming a broad chemical genus. Its strongest commercial value was therefore concentrated in the period before generic ziprasidone entry. Today, the patent has no live exclusionary term in the United States, although its claim structure remains relevant to validity analysis, freedom-to-operate reviews, and interpretation of later formulation and process patents.

What drug does U.S. Patent 5,312,925 cover?

The compound in claim 1 is ziprasidone hydrochloride monohydrate.

Item	Information
Active ingredient	Ziprasidone
Covered form	Hydrochloride monohydrate
Brand	Geodon
Therapeutic class	Atypical antipsychotic
Primary indications	Schizophrenia and acute manic or mixed episodes associated with bipolar disorder
Patent	U.S. 5,312,925
Patent issue date	May 17, 1994
Patent holder during commercialization	Pfizer Inc.
Historical FDA approval	Geodon capsules approved February 5, 2001
Historical Orange Book expiry	June 4, 2012

Chemically, ziprasidone is a benzisothiazolylpiperazine derivative containing a chlorinated oxindole moiety. The claimed product has three defining structural and solid-state attributes:

The ziprasidone molecular structure.
The hydrochloride salt.
The monohydrate form.

Those limitations materially narrow the claim compared with a claim covering all ziprasidone salts, solvates, polymorphs, or formulations.

What does claim 1 protect?

Claim 1 protects the specific chemical entity:

5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one hydrochloride monohydrate.

In modern nomenclature, this is ziprasidone hydrochloride monohydrate.

Structural scope

The claim requires:

A 1,2-benzisothiazol-3-yl group.
A piperazine ring attached through the benzisothiazole position.
An ethyl linker from the piperazine to the oxindole nucleus.
A chlorine substituent at the specified position on the oxindole ring.
The hydrochloride salt.
One molecule of water per salt unit, subject to the interpretation of "monohydrate" and the evidence used to establish the solid form.

A product containing ziprasidone free base does not literally meet the hydrochloride limitation. A product containing a different pharmaceutically acceptable salt, such as mesylate, besylate, fumarate, or sulfate, also does not literally meet the claim. The same analysis applies to a salt-free formulation containing ziprasidone base.

Solid-state scope

The monohydrate limitation is commercially significant. Hydration state can affect:

Crystal lattice structure.
Water activity.
Stability.
Dissolution behavior.
Bulk density.
Manufacturing reproducibility.
Storage and packaging requirements.

A defendant could contest whether its material is the claimed monohydrate by relying on powder X-ray diffraction, thermogravimetric analysis, Karl Fischer water determination, differential scanning calorimetry, infrared spectroscopy, or single-crystal analysis.

A material that contains variable or nonstoichiometric water is not automatically outside the claim. The result depends on whether the product is properly characterized as the claimed monohydrate under the patent's claim construction and applicable infringement standards.

How broad is claim 2 for pharmaceutical compositions?

Claim 2 covers a pharmaceutical composition containing the compound of claim 1 in an amount effective to treat neuroleptic diseases, together with a pharmaceutically acceptable carrier.

The claim has four practical limitations:

The active ingredient must be ziprasidone hydrochloride monohydrate.
The active ingredient must be present in an effective amount.
The composition must include a pharmaceutically acceptable carrier.
The composition must have neuroleptic activity or be configured for the claimed therapeutic use.

The claim is not limited to capsules, tablets, a particular dose, excipient, release profile, or route of administration. It could therefore reach conventional oral dosage forms containing the claimed active form, subject to ordinary claim-construction and infringement requirements.

The claim does not necessarily cover every product that contains ziprasidone in any physical form. A formulation containing ziprasidone free base or a different salt would raise a noninfringement position based on the absence of the hydrochloride monohydrate limitation.

Formulation implications

Claim 2 is a product-composition claim, not a detailed formulation claim. It does not expressly require:

Immediate release.
Extended release.
A specific capsule shell.
A particular dissolution profile.
A specified particle-size distribution.
A particular excipient system.
A defined crystalline polymorph beyond the monohydrate identity.

Later patents could obtain separate protection for particle size, polymorphs, excipient combinations, controlled release, improved bioavailability, or manufacturing parameters without being coextensive with claim 2.

What does claim 3 protect?

Claim 3 covers administering the claimed compound to a subject in need of treatment in a neuroleptic amount.

This is a method-of-treatment claim. It is directed to use of ziprasidone hydrochloride monohydrate for treating neuroleptic diseases, rather than to the compound or dosage form alone.

The claim is broad as to:

Patient population.
Dose, unless limited by the phrase "neuroleptic amount."
Route of administration.
Treatment duration.
Specific neuroleptic disease.

The commercial significance of claim 3 was limited by the patent's 2012 expiration and by the regulatory framework governing generic drug labels. Generic applicants historically faced method-of-use issues where labeling included patented indications. A Paragraph IV applicant could challenge the patent's validity or enforceability, assert noninfringement, or use a section viii statement to omit a patented indication where permitted.

Because claim 3 is tied to the specific hydrochloride monohydrate compound, it does not independently create a broad monopoly over all antipsychotic uses of all ziprasidone forms.

What does claim 4 protect?

Claim 4 covers a process for preparing the claimed compound by reacting anhydrous ziprasidone free base with aqueous hydrochloric acid at an approximately 0.7 M concentration.

The process requires:

Anhydrous ziprasidone free base as the starting material.
Aqueous hydrochloric acid.
A hydrochloric acid concentration of about 0.7 M.
Formation of ziprasidone hydrochloride monohydrate.

The claim is narrower than a general process claim covering any conversion of ziprasidone base into a hydrochloride salt. A process using concentrated hydrochloric acid, hydrochloric acid at materially different concentration, gaseous hydrogen chloride, an organic solvent system, or another acid would present a noninfringement position unless the process falls within the claim under the interpretation of "about" or the doctrine of equivalents.

How should "about 0.7 M" be analyzed?

"About" ordinarily introduces a range rather than a single exact numerical point. The scope depends on the intrinsic evidence, prosecution history, technical context, and how a court defines the permitted deviation.

For process-risk analysis, the critical evidence would include:

The specification's examples.
The stated effect of hydrochloric acid concentration.
Any prosecution amendment or argument concerning 0.7 M.
Reproducibility of the monohydrate.
Whether concentration is measured before or during reaction.
Temperature, solvent volume, agitation, and crystallization conditions.

A process can potentially produce the same final compound while avoiding claim 4 if it does not use the claimed starting material, acid concentration, or aqueous reaction conditions. That does not avoid claim 1 if the resulting commercial product is still ziprasidone hydrochloride monohydrate.

When did U.S. Patent 5,312,925 expire?

The historical Orange Book expiration date for U.S. Patent 5,312,925 was June 4, 2012.[2] The patent predates the modern 20-year-from-earliest-effective-filing-date term rules for most applications filed after June 8, 1995. Its term was therefore governed principally by the pre-Uruguay Round Agreements Act framework, subject to applicable transitional rules and any patent-term adjustment or extension.

The patent is expired and cannot presently block U.S. generic manufacture, sale, or use on the basis of its expired claims.

Event	Date or status
Patent issued	May 17, 1994
Geodon NDA approval	February 5, 2001
Historical patent expiry	June 4, 2012
Current status	Expired
Current blocking effect	None from this patent alone

The expiration of 5,312,925 did not necessarily eliminate every possible patent issue concerning ziprasidone. Separate patents could have addressed formulation, polymorphism, manufacturing, labeling, or other aspects. Those rights must be reviewed independently.

What was the FDA and Orange Book status of the patent?

Geodon was approved by the FDA as an oral capsule product containing ziprasidone hydrochloride.[3] The FDA Orange Book historically listed U.S. 5,312,925 for the product. The listing connected the approved drug product with the patent used to support the innovator's market exclusivity under the Hatch-Waxman framework.[2][4]

Ziprasidone is a small-molecule drug. It is not a biologic and does not present a biosimilar pathway issue. Generic applicants filed abbreviated new drug applications rather than biosimilar applications.

The principal regulatory exclusivity periods were separate from patent protection:

New chemical entity exclusivity protected the product from certain ANDA submissions for five years after approval.
Patent listing created a separate pathway for Paragraph IV challenges and potential 30-month stays.
Any pediatric exclusivity would have operated as a six-month extension if granted and applicable to the relevant listed protection.

Patent expiration, FDA exclusivity, and approval timing should not be treated as identical dates. Generic approval can occur after statutory exclusivity ends but before patent expiry only in circumstances permitted by the patent and Hatch-Waxman framework.

Which companies challenged or entered against Geodon?

The relevant competitive group included generic manufacturers such as Teva, Mylan, Dr. Reddy's, and Zydus, among others. Generic competition developed after the expiration of the principal Geodon patent protection in 2012.

The commercial challenge generally involved:

ANDA filings for ziprasidone hydrochloride capsules.
Paragraph IV certifications against listed patents where applicable.
Patent litigation in federal district court.
Potential settlements or launch arrangements.
FDA approval after resolution or expiration of the relevant barriers.

The absence of a currently enforceable term under 5,312,925 means that a later generic entrant cannot be sued successfully for infringement of this patent based solely on commercial manufacture or sale occurring after expiry.

How strong was the patent estate for ziprasidone?

Strengths

The patent had substantial pre-expiry value because claim 1 targeted the marketed hydrochloride monohydrate form. That alignment reduced the practical value of switching to another salt or hydrate if the innovator's approved product required the claimed form.

Claim 4 also gave the patent holder a process-based enforcement theory against manufacturers using the specified aqueous hydrochloric acid conversion step.

Claim 2 extended protection into finished pharmaceutical compositions, while claim 3 addressed therapeutic use.

Limitations

The estate had several limitations:

Claim 1 did not cover every ziprasidone salt or solvate.
Claim 2 depended on the claimed compound and did not provide a detailed formulation monopoly.
Claim 3 was limited to treatment using the claimed compound.
Claim 4 was tied to a specific starting material and acid concentration.
The patent expired in 2012.
Manufacturing evidence would be needed to prove infringement of the process claim.
Solid-state characterization would be needed to prove monohydrate infringement.

The patent was strongest against a manufacturer selling the same hydrochloride monohydrate active ingredient. It was weaker against alternative salts, alternative hydrates, or processes that produced a different solid form.

What generic entry risks existed before expiration?

Before June 4, 2012, a generic manufacturer faced several risk paths:

Risk area	Principal issue
Compound infringement	Product contained ziprasidone hydrochloride monohydrate
Composition infringement	Finished dosage form contained the claimed active form
Method infringement	Label directed treatment of claimed neuroleptic conditions
Process infringement	Manufacturing used approximately 0.7 M aqueous hydrochloric acid
Regulatory stay	Paragraph IV litigation could trigger a 30-month stay
Validity challenge	Anticipation, obviousness, written description, enablement, or indefiniteness
Solid-state dispute	Whether the product was actually the claimed monohydrate

The principal design-around strategy would have been to use a different salt or solid form. That approach could create new regulatory, stability, bioequivalence, and manufacturing problems, and it would not necessarily be commercially equivalent to the approved product.

How does this patent compare with later formulation and process rights?

U.S. 5,312,925 is a foundational compound patent with secondary composition, method, and process claims. Later ziprasidone patents, where applicable, would generally fall into narrower categories:

Specific crystal forms.
Particle-size control.
Improved dissolution or bioavailability.
Capsule or tablet formulations.
Combination products.
Manufacturing crystallization conditions.
Dosage regimens.
Alternative salts or solvates.

The strategic distinction is important. Patent 5,312,925 protected the identity of the active pharmaceutical ingredient in its marketed salt-hydrate form. A later patent might protect how that ingredient is processed or delivered. Expiration of the foundational patent therefore permits generic entry unless a separate, unexpired patent independently covers the generic product, process, or labeling.

What is the current commercial significance?

The direct revenue exposure associated with 5,312,925 ended when the patent expired. Geodon generated more than $1 billion annually for Pfizer near its peak commercial period, but sales declined as generic ziprasidone entered the market.[5]

The patent's current value is analytical rather than exclusionary:

It identifies the protected form of ziprasidone.
It helps distinguish the innovator product from alternative salts.
It provides historical context for ANDA litigation.
It informs interpretation of later formulation patents.
It remains relevant to prior-art and obviousness analysis.
It can support due diligence on historical licensing and litigation records.

No biosimilar risk applies because ziprasidone is a chemically synthesized small molecule. The competitive risk is generic substitution through the ANDA pathway.

Key Takeaways

U.S. Patent 5,312,925 covers ziprasidone hydrochloride monohydrate, the active form used in Geodon.
Claim 1 is the core product claim and requires the hydrochloride monohydrate form.
Claim 2 covers pharmaceutical compositions containing that compound.
Claim 3 covers therapeutic administration for neuroleptic diseases.
Claim 4 covers a manufacturing route using anhydrous ziprasidone, aqueous hydrochloric acid, and approximately 0.7 M acid concentration.
The historical Orange Book expiry date was June 4, 2012.
The patent is expired and does not presently block U.S. generic entry.
Alternative ziprasidone salts or hydrates may avoid literal infringement of claim 1, but regulatory and formulation consequences remain separate issues.
No biosimilar pathway applies.
Any current freedom-to-operate analysis must review later formulation, solid-state, process, labeling, and jurisdiction-specific patents separately.

FAQs About U.S. Patent 5,312,925 and Ziprasidone

Does U.S. Patent 5,312,925 cover ziprasidone free base?

No. Claim 1 requires the hydrochloride monohydrate form. Ziprasidone free base does not literally satisfy that limitation.

Does the patent cover ziprasidone mesylate or another ziprasidone salt?

No, not literally under claim 1. A different salt would require separate analysis of any later patent and any doctrine-of-equivalents theory.

Can a generic manufacturer use a different manufacturing process?

Yes, after patent expiry. Before expiry, a different process could avoid claim 4, but the resulting ziprasidone hydrochloride monohydrate could still infringe claim 1 or claim 2.

Is Geodon protected by a biologic patent or biosimilar exclusivity?

No. Geodon contains ziprasidone, a small-molecule active ingredient regulated through the NDA and ANDA framework.

Did patent expiry automatically eliminate all ziprasidone patent risk?

No. Expiry of 5,312,925 eliminated the blocking effect of that patent only. Separate patents covering formulations, crystal forms, manufacturing methods, dosing, or labeling would require independent review.

References

United States Patent and Trademark Office. (1994). U.S. Patent No. 5,312,925: Benzisothiazolyl piperazine derivative. U.S. Department of Commerce.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: The Orange Book. FDA.
U.S. Food and Drug Administration. (2001). Geodon (ziprasidone hydrochloride) capsules prescribing information. FDA.
Food and Drug Administration. (2023). Abbreviated new drug application regulations and patent certifications. 21 C.F.R. §§ 314.94, 314.107.
Pfizer Inc. (2012). Annual report. Pfizer Inc.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	206422	⤷ Start Trial
Austria	273976	⤷ Start Trial
Australia	4600493	⤷ Start Trial
Australia	642836	⤷ Start Trial
Australia	657231	⤷ Start Trial
Brazil	9302065	⤷ Start Trial
Brazil	9303014	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,312,925

Summary for Patent: 5,312,925