United States Patent 4,831,031: Scope, Claims, Expiration, and Ziprasidone Patent Landscape

U.S. Patent 4,831,031 is the foundational U.S. compound patent associated with ziprasidone, the active ingredient in Geodon. It covers a broad genus of substituted benzisothiazolyl piperazine derivatives, pharmaceutical compositions containing those compounds, and their use as neuroleptic agents. The patent issued on May 16, 1989, and its ordinary 17-year patent term expired on May 16, 2006. It no longer creates an enforceable barrier to generic ziprasidone entry.[1]

The commercially important molecule ziprasidone falls within the oxindole branch of the claimed genus, principally claim 4, and within the composition and method claims that depend on that branch. Later patents covering ziprasidone solid forms, formulations, and related manufacturing subject matter provided the more relevant post-2006 protection for Geodon.

What drug does U.S. Patent 4,831,031 protect?

U.S. Patent 4,831,031 protects a class of benzisothiazolyl piperazine compounds with antipsychotic activity. Ziprasidone is the best-known commercial compound associated with the patent.

Ziprasidone is commonly identified chemically as:

5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one

The molecule contains:

A 1,2-benzisothiazol-3-yl group attached to piperazine;
A two-carbon ethyl linker;
A piperazine ring;
A 6-chloro-substituted oxindole ring.

The claim language supplied describes a formula in which the benzisothiazolyl-containing group is represented by Ar, n is 1 or 2, and X and Y define a fused bicyclic heterocycle attached to the phenyl portion of the structure.

The patent therefore uses a Markush structure rather than claiming only ziprasidone by name.

How broad is claim 1 of U.S. Patent 4,831,031?

Claim 1 is the principal genus claim. It covers compounds of the stated formula and pharmaceutically acceptable acid addition salts where:

Claim element	Scope
Ar	Benzoisothiazolyl, or its oxide or dioxide
Ar substitution	One fluoro, chloro, trifluoromethyl, methoxy, cyano, or nitro substituent
n	1 or 2
X and Y fused ring	Multiple bicyclic nitrogen-, oxygen-, or sulfur-containing systems
Salt form	Pharmaceutically acceptable acid addition salts

The fused-ring alternatives include:

Benzothiazolyl;
2-Aminobenzothiazolyl;
Benzoisothiazolyl;
Indazolyl;
2-Hydroxyindazolyl;
Indolyl;
Oxindolyl;
Benzoxazolyl;
2-Aminobenzoxazolyl;
Benzoxazolonyl;
2-Aminobenzoxazolinyl;
Benzothiazolonyl;
Benzimidazolonyl;
Benzotriazolyl.

The oxindolyl alternative is particularly important because ziprasidone contains a substituted oxindole ring.

The claim also permits limited substitution on oxindole. The listed substituents include one to three C1-C3 alkyl groups, or one chloro, fluoro, or phenyl substituent, with the phenyl group optionally bearing chloro or fluoro.

What does the Markush structure mean legally?

A Markush claim covers each individual chemical species that falls within the stated alternatives, subject to ordinary requirements of claim construction, written description, enablement, anticipation, and obviousness.

Claim 1 is broad because it combines:

Several oxidation states and substitution patterns for the benzisothiazole-related Ar group;
Two linker lengths or configurations represented by n;
A large group of fused heterocyclic ring systems;
Salt forms of the resulting bases.

The claim does not cover every antipsychotic compound. A potentially infringing compound would need to satisfy each structural limitation. A molecule with a different linker, a different piperazine attachment point, an excluded ring system, or an unlisted substitution pattern may fall outside the literal claim.

Which claims cover ziprasidone specifically?

Ziprasidone is most directly connected to claim 4 and the dependent claims that incorporate the oxindole structure.

Claim	Subject matter	Relevance to ziprasidone
1	Broad compound genus and acid addition salts	Covers ziprasidone as a species within the genus
2	Benzoxazolonyl compounds	Not the primary structural branch for ziprasidone
3	Benzoxazolonyl, benzoisothiazolyl Ar, n=1	Narrow benzoxazolonyl species; not the principal ziprasidone branch
4	Oxindole compounds	Directly relevant to ziprasidone
5	Pharmaceutical composition containing claim 1 compound	Covers compositions containing a qualifying compound
6	Composition containing benzoxazolonyl compound	Not the principal ziprasidone branch
7	Narrow benzoxazolonyl composition	Not the principal ziprasidone branch
8	Composition containing oxindole compound	Directly relevant to ziprasidone formulations
9	Method of treating neuroleptic diseases	Relevant to clinical use of ziprasidone as an antipsychotic

The supplied text states "oxindole" in claim 4. In chemical terminology, the ziprasidone ring is generally described as a 1,3-dihydro-2H-indol-2-one, which is an oxindole derivative.

What is the scope of claims 2 through 4?

Claim 2: Benzoxazolonyl compounds

Claim 2 narrows claim 1 to compounds in which X and Y form a benzoxazolonyl ring system. It eliminates the other heterocyclic alternatives in claim 1.

Claim 3: A narrower benzoxazolonyl subgenus

Claim 3 further limits claim 2 by requiring:

A benzoisothiazolyl Ar group;
n = 1.

This is a comparatively narrow chemical subgenus. It does not define the oxindole branch associated with ziprasidone.

Claim 4: Oxindole compounds

Claim 4 narrows claim 1 to compounds in which X and Y form an oxindole ring system.

This is the key compound claim for ziprasidone. Because the claim is still expressed at the ring-system level, it can cover multiple oxindole substitutions rather than only the 6-chloro species.

What do the composition claims cover?

Claims 5 through 8 cover pharmaceutical compositions containing compounds within the compound claims.

Claim 5 requires:

A pharmaceutical composition;
A compound according to claim 1;
An amount effective for treating neuroleptic diseases;
A pharmaceutically acceptable carrier.

Claim 8 is the principal composition claim for an oxindole compound because it narrows claim 5 to the oxindole branch.

The composition claims are not limited to capsules. Depending on the specification and ordinary claim construction, the term "pharmaceutical composition" can encompass multiple dosage forms, including oral solid dosage forms, liquids, and other formulations containing the claimed compound and a suitable carrier.

The claims do not necessarily require a particular excipient, release profile, particle size, polymorph, or salt hydration state unless those limitations are present in the claim language. Those narrower attributes were the typical subject of later formulation and solid-state patents.

What does claim 9 cover?

Claim 9 covers a method of treating neuroleptic diseases by administering a neuroleptic amount of a claim 1 compound to a subject in need of treatment.

Its principal limitations are:

Administration to a subject in need of treatment;
Administration of a compound within claim 1;
Administration in a neuroleptic amount;
Treatment of a neuroleptic disease.

The claim is not limited to schizophrenia by its text. It uses the broader expression "neuroleptic diseases." Enforcement would depend on how that term is construed and whether the accused use, dosage, and compound satisfy all claim elements.

Because claim 9 depends structurally on claim 1, a method involving a compound outside the claim 1 genus would not infringe claim 9, even if the compound had antipsychotic activity.

When did U.S. Patent 4,831,031 expire?

Event	Date
Priority and development period	Mid-1980s
U.S. filing	1987
Patent issued	May 16, 1989
Ordinary U.S. patent term	17 years from issue for this pre-1995 patent
Expiration	May 16, 2006
Current enforceability	Expired

For a patent filed before June 8, 1995, the applicable term was generally the longer of 17 years from grant or 20 years from the earliest effective U.S. filing, subject to transitional rules. For this patent, the 17-year term from issuance produced the relevant expiration date.[1,2]

No current Paragraph IV strategy should be based solely on U.S. Patent 4,831,031. A generic applicant would not need to defeat this expired patent to obtain approval or launch.

What was the FDA regulatory status of ziprasidone?

The FDA approved Geodon capsules, containing ziprasidone hydrochloride, under NDA 020825 on February 5, 2001.[3] The product was approved for schizophrenia and later for acute manic or mixed episodes associated with bipolar disorder.

Ziprasidone is a small-molecule drug. FDA competitors proceed through the abbreviated new drug application pathway, not the biosimilar pathway.

Regulatory issue	Status
Active ingredient	Ziprasidone
Original brand	Geodon
Original sponsor	Pfizer
FDA pathway	NDA
Generic pathway	ANDA
Biologic status	Not a biologic
Biosimilar exposure	None
Current competition	Multiple generic manufacturers

The original five-year new chemical entity exclusivity associated with a 2001 approval would have ended in 2006, subject to any applicable pediatric extension. It did not preserve a durable post-2006 market barrier because the core compound patent also expired in 2006.[2,3]

What was the Orange Book status of U.S. Patent 4,831,031?

U.S. Patent 4,831,031 was historically listed in FDA Orange Book records for Geodon-related protection. The listing covered the foundational compound and associated product protection during the period when the patent remained unexpired.[4]

Its present commercial significance is historical:

It is an expired patent;
It cannot support a current injunction against generic entry;
It cannot create a current 30-month stay under the Hatch-Waxman framework;
It cannot support a new Paragraph IV litigation campaign;
It remains relevant to the historical scope of Pfizer's original exclusivity.

Orange Book analysis must distinguish the expired core patent from later patents that may have covered a particular formulation, solid form, or method of use. An Orange Book listing for a later patent would not revive the expired claims of U.S. Patent 4,831,031.

What later patents protected Geodon after the core patent expired?

The post-expiration landscape centered on patents covering subject matter narrower than the original compound genus. Publicly identified Geodon-related protection included later patents directed to ziprasidone formulations, solid forms, and related pharmaceutical technology.

The commercial relevance of these patents generally followed this hierarchy:

Protection category	Typical subject matter	Strategic value
Core compound patent	Ziprasidone chemical structure	Highest historical value; expired in 2006
Salt patent	Specific pharmaceutically acceptable salt	May delay or limit particular generic products
Solid-state patent	Crystalline form, hydrate, or polymorph	Can create formulation-specific litigation risk
Formulation patent	Capsule composition or dosage technology	May affect a particular ANDA product
Method-of-use patent	Treatment of a specified condition	May support a label or carve-out dispute
Process patent	Manufacturing route or purification	More relevant to supply-chain strategy than ordinary ANDA entry

Later U.S. patents associated with ziprasidone included patents commonly cited in commercial and litigation materials as covering formulations or solid-state forms, including U.S. Patent 5,807,855 and related patent-family members. The legal effect of each patent depended on its exact claims, Orange Book listing, expiration date, terminal disclaimers, and any litigation settlement.[4,5]

The later estate did not restore broad exclusivity over all ziprasidone. A generic company could potentially avoid a later formulation or solid-form claim by using a different form, excipient system, manufacturing process, or label.

Which companies challenged Geodon exclusivity?

Generic competition developed through ANDA filings by multiple manufacturers, including Teva, Apotex, Lupin, Mylan, Sandoz, and Zydus-related entities. The precise litigation posture varied by applicant and by the patent challenged.

The principal generic strategies were:

Certification that listed patents were invalid or not infringed;
Paragraph IV challenges to unexpired later patents;
Use of non-infringing solid forms or manufacturing processes;
Paragraph III certification where an applicant accepted a delayed approval date;
Labeling strategies designed to avoid patented uses.

The core compound patent was no longer a viable Paragraph IV obstacle once it expired in May 2006. Later litigation focused on surviving formulation and solid-state rights rather than on the broad chemical genus of U.S. Patent 4,831,031.[4,5]

What patent litigation affected ziprasidone generic entry?

Ziprasidone litigation followed the standard Hatch-Waxman pattern. Brand protection depended on later patents that could be asserted after generic applicants submitted ANDAs with Paragraph IV certifications.

The major legal questions in such litigation included:

Whether the generic product used the patented crystalline or hydrated form;
Whether the formulation satisfied each claim limitation;
Whether the later patent was valid over earlier ziprasidone disclosures;
Whether the asserted claims were obvious;
Whether an ANDA filing created an act of infringement under 35 U.S.C. §271(e)(2);
Whether a generic label induced infringement of a patented method of treatment.

Any 30-month stay associated with an Orange Book-listed patent would have applied only to the patent and NDA identified in the statutory notice. It would not have extended the term of U.S. Patent 4,831,031.

Reported generic launches occurred after the core patent expiration and after resolution or expiration of relevant later patent barriers. FDA approval records show multiple ANDA approvals for ziprasidone hydrochloride capsules, confirming that the market was no longer controlled by the original compound patent.[3]

Were there settlement agreements affecting generic launch?

Generic settlements in the Geodon field were commercially significant because they could establish launch dates before the expiration of every later-listed patent. Hatch-Waxman settlements can include:

Authorized-generic arrangements;
Delayed entry dates;
Covenants not to sue;
License grants;
Restrictions tied to a particular formulation or manufacturing process.

The existence and terms of any specific agreement must be assessed from the applicable district-court docket, FTC materials, FDA patent certifications, and settlement documents. A settlement involving a later ziprasidone patent would not change the May 16, 2006 expiration of U.S. Patent 4,831,031.

What is the patent strength of U.S. Patent 4,831,031?

Historical strength

The patent had high historical value because claim 1 reached a broad chemical genus and claim 4 captured the oxindole subgroup containing ziprasidone. The composition and method claims supplied additional infringement theories against finished products and therapeutic use.

The strongest historical claims were:

Claim 1, because it covered the broad compound genus and salts;
Claim 4, because it focused on oxindole derivatives;
Claim 8, because it addressed pharmaceutical compositions containing oxindole compounds.

Current strength

The patent has no remaining exclusionary strength in the United States because it expired in 2006. Its remaining value is limited to:

Prior-art analysis;
Patent-family research;
Historical freedom-to-operate analysis;
Assessment of later patent validity;
Identification of the original chemical disclosure;
Review of generic launch timing.

Expiration eliminates infringement liability for post-expiration manufacture, sale, importation, and use, although the patent remains relevant as prior art against later applications.

Are biosimilar risks relevant to ziprasidone?

No. Ziprasidone is a synthetic small molecule, not a biologic. Competitive risk arises from generic ANDA products rather than biosimilars.

The relevant commercial issues are:

ANDA approval;
Paragraph IV certification;
Formulation or solid-form design-around;
Product-specific patent listing;
State substitution and pharmacy-channel penetration;
Generic pricing and reimbursement.

How does U.S. Patent 4,831,031 compare with later ziprasidone patents?

Issue	U.S. Patent 4,831,031	Later ziprasidone patents
Primary target	Chemical compounds	Salts, forms, formulations, processes, or uses
Claim breadth	Broad genus and species coverage	Generally narrower
Ziprasidone coverage	Direct chemical coverage	Product-specific or technology-specific
Expiration	May 16, 2006	Varied by patent and patent-family term
Current enforceability	None	Depends on the individual patent
Generic design-around	Difficult before expiration	Often more feasible
Orange Book importance	Historical core listing	Potentially relevant to later ANDA disputes
Biosimilar relevance	None	None

The central distinction is that the original patent protected the molecule itself. Later patents, if valid and unexpired, could protect only defined aspects of the marketed product or its use.

What manufacturing and intellectual-property barriers remain?

No manufacturing barrier remains from U.S. Patent 4,831,031. A company can manufacture ziprasidone after the patent's expiration without obtaining a license from the original patent owner.

Potential barriers may still arise from:

Unexpired process patents;
Specific crystalline or hydrated forms;
Formulation patents;
Regulatory exclusivity linked to a newly approved indication;
Trade secrets involving scale-up, impurity control, or particle engineering;
Controlled supply of qualified starting materials;
Quality requirements for the active pharmaceutical ingredient.

These are distinct from the expired compound patent. A manufacturing freedom-to-operate review must map the selected synthetic route and final drug product against each unexpired patent family in the target jurisdiction.

What is the commercial exposure from loss of exclusivity?

Geodon experienced the standard small-molecule loss-of-exclusivity pattern. Once the core patent and regulatory exclusivity barriers ended, generic entry placed pressure on:

Brand prescription volume;
Average selling price;
Medicaid and commercial reimbursement;
Hospital purchasing;
Pharmacy substitution;
Brand gross margin.

The largest exposure was tied to the capsule product because the compound patent covered the active ingredient rather than a narrow presentation. Later formulation or solid-state patents could delay particular generic products, but they could not preserve broad control of ziprasidone indefinitely.

What geographic coverage did the patent have?

U.S. Patent 4,831,031 provided protection only in the United States. Corresponding foreign rights would have depended on separate national applications, patent grants, term calculations, and local maintenance.

A global freedom-to-operate review should separate:

United States;
European national rights or European Patent Convention family members;
Canada;
Japan;
Australia;
Other markets where ziprasidone was approved.

Expiration dates would not necessarily align across countries because of different filing dates, patent-term rules, supplementary protection certificates, pediatric extensions, and maintenance status.

Key Takeaways

U.S. Patent 4,831,031 is the foundational ziprasidone compound patent.
Claim 1 covers a broad Markush genus of substituted benzisothiazolyl piperazine derivatives and acid addition salts.
Claim 4 is the principal structural claim for ziprasidone because it covers the oxindole branch.
Claims 5 and 8 extend protection to pharmaceutical compositions.
Claim 9 covers treatment of neuroleptic diseases using a claim 1 compound.
The patent issued May 16, 1989, and expired May 16, 2006.
The patent cannot support current generic litigation or a present-day market exclusion.
Ziprasidone is a small molecule and faces generic, not biosimilar, competition.
Later Geodon patents focused on formulations, solid forms, salts, methods, and manufacturing technology.
Current risk analysis must examine later, unexpired patent families rather than U.S. Patent 4,831,031.

FAQs

Does U.S. Patent 4,831,031 claim ziprasidone by name?

No. It claims a chemical genus and narrower structural subgroups. Ziprasidone falls within the claimed oxindole subgroup based on its substituted indolinone structure.

Can a company obtain a license to the expired ziprasidone compound patent?

A license is not required for activities covered only by an expired U.S. patent. A commercial agreement could still be relevant to trademarks, know-how, trade secrets, or other unexpired intellectual property.

Did the patent cover ziprasidone hydrochloride?

The claims cover pharmaceutically acceptable acid addition salts of compounds within the claimed genus. Ziprasidone hydrochloride is therefore within the salt coverage if its structure satisfies the remaining limitations.

Could a different ziprasidone polymorph avoid U.S. Patent 4,831,031?

No, not if the polymorph is the same claimed ziprasidone compound or salt. A polymorph may matter under a later solid-state patent, but it does not remove the molecule from an expired compound claim.

What is the main current patent risk for a new ziprasidone manufacturer?

The principal risks are later patents covering a selected salt, crystalline form, formulation, manufacturing process, or patented method of use. The original compound patent itself presents no current U.S. infringement risk.

References

United States Patent and Trademark Office. (1989). U.S. Patent No. 4,831,031, Benzisothiazole derivatives. U.S. Department of Commerce.
United States Code, 35 U.S.C. §§ 154, 156, and 271(e)(2).
U.S. Food and Drug Administration. (2001). Geodon (ziprasidone hydrochloride) prescribing information and approval history. FDA.
U.S. Food and Drug Administration. (Various years). Approved drug products with therapeutic equivalence evaluations, Orange Book. FDA.
U.S. Patent and Trademark Office. (Various years). Patent Center and Patent Examination Data System records for ziprasidone-related U.S. patent families. U.S. Department of Commerce.

Details for Patent: 4,831,031

Summary for Patent: 4,831,031