Details for Patent: 6,110,918

Summary for Patent: 6,110,918

Title:	Mesylate trihydrate salt of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihy dro-2(1H)-indol-2-one (=ziprasidone), its preparation and its use as dopamine D2 antagonist
Abstract:	PCT No. PCT/IB97/00306 Sec. 371 Date Mar. 2, 1999 Sec. 102(e) Date Mar. 2, 1999 PCT Filed Mar. 26, 1997 PCT Pub. No. WO97/42190 PCT Pub. Date Nov. 13, 1997Mesylate Trihydrate Salt of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2(1H)-indol-2-one (=Ziprasidone), Its Preparation and Its Use as Dopamine D2 Antagonist The invention relates to the mesylate trihydrate salt of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2(1H)-indol-2-one ("ziprasidone mesylate trihydrate"), to pharmaceutical compositions containing ziprasidone mesylate trihydrate, and to methods of administering ziprasidone mesylate trihydrate to treat psychotic diseases.
Inventor(s):	Frank R. Busch, Carol A. Rose
Assignee:	Pfizer Inc
Application Number:	US09/180,456
Patent Claim Types: see list of patent claims	Use; Composition; Dosage form;

United States Patent 6,110,918: Scope, Claims, Expiration, and Ziprasidone Patent Landscape

U.S. Patent No. 6,110,918 covers ziprasidone mesylate trihydrate, the salt and hydrate form associated with Pfizer's antipsychotic drug Geodon. Its claims include the chemical compound, pharmaceutical compositions, and therapeutic methods involving psychotic disorders, schizophrenia, migraine pain, anxiety, parenteral administration, and intramuscular injection. The patent was directed to a defined solid-state form rather than to every form of ziprasidone.

The patent has expired. Its commercial importance was greatest before generic ziprasidone entry, when it operated with earlier ziprasidone compound patents and FDA-listed regulatory exclusivity. Current generic entry is not blocked by U.S. Patent 6,110,918.

What compound does U.S. Patent 6,110,918 protect?

Claim 1 covers:

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

This is ziprasidone mesylate trihydrate, a salt and hydrate form of ziprasidone. Ziprasidone is an atypical antipsychotic used primarily for schizophrenia and bipolar disorder. Geodon capsules contain ziprasidone hydrochloride? The marketed active form is generally described as ziprasidone mesylate, while the approved product labeling identifies the active moiety as ziprasidone and specifies the corresponding salt form for the dosage form involved (FDA, 2023).

The claim does not broadly cover:

• All ziprasidone salts;
• Ziprasidone free base;
• Every crystalline or amorphous form of ziprasidone;
• Every formulation containing ziprasidone;
• Every use of ziprasidone in psychiatry.

The claim requires the specific mesylate trihydrate form. A product using a different salt, anhydrous form, or independently characterized solid form would require separate infringement analysis.

How broad is claim 1?

Claim 1 is a narrow composition-of-matter claim with high chemical specificity. It identifies:

Claim element	Scope
Core molecule	6-chloro substituted indolinone structure
Side chain	Ethyl-linked piperazinyl group
Heterocycle	1,2-benzisothiazol-3-yl substituent
Salt	Mesylate
Solid-state state	Trihydrate
Claim type	Product or composition of matter

The claim does not use a Markush formula or functional language. It names a single chemical entity. In litigation, infringement would generally turn on whether the accused material contains the claimed ziprasidone mesylate trihydrate, including the required hydration state.

The hydrate limitation can matter commercially. A generic manufacturer could attempt to avoid the claim by using another solid form, but that strategy would not necessarily avoid other patents, regulatory requirements, or infringement under an equivalent-structure theory. Analytical testing would typically involve powder X-ray diffraction, thermogravimetric analysis, water-content testing, differential scanning calorimetry, and salt-form characterization.

What pharmaceutical compositions are protected by claim 2?

Claim 2 covers a pharmaceutical composition containing:

1. An effective amount of the compound in claim 1; and
2. A pharmaceutically acceptable carrier.

The claim is broad as to the carrier. It can cover excipients, diluents, binders, lubricants, disintegrants, solvents, stabilizers, and other conventional pharmaceutical components, provided the composition contains the claimed compound and is configured for treatment of a psychotic disorder.

Claim 2 is narrower than a generic formulation claim in one respect: the active ingredient must be the exact compound of claim 1. It is broader in another respect because it does not specify a dosage form, excipient, concentration, release profile, or administration route.

Potentially covered products could include:

• Immediate-release oral capsules;
• Sterile injectable compositions;
• Lyophilized parenteral products;
• Reconstituted injection solutions;
• Other dosage forms containing ziprasidone mesylate trihydrate.

The claim does not expressly require a particular capsule strength or injection concentration.

What treatment methods are protected by claims 3 through 7?

Claims 3 through 7 create a descending method-of-use hierarchy.

Claim	Subject matter	Relative scope
3	Treating a psychotic disorder in a mammal using an effective amount of claim 1	Broadest method claim
4	Claim 3 where the disorder is schizophrenia, migraine pain, or anxiety	Disease-specific limitation
5	Claim 3 where the disorder is schizophrenia	Narrower than claim 3
6	Claim 3 where administration is parenteral	Route-specific limitation
7	Claim 6 where administration is intramuscular injection	Narrowest route-specific claim

Claim 3 requires administration to a mammal. It does not expressly limit the route, dose, frequency, treatment duration, or particular formulation beyond the requirement that the administered compound be the claim 1 compound.

Claim 5 is commercially important because schizophrenia is the core indication associated with Geodon. Claim 7 is directed to intramuscular use, which corresponds to the acute-treatment setting for ziprasidone injection.

The supplied text for claim 4 identifies "migraine pain" and "anxiety" as types of psychotic disorder. That language is internally unusual because migraine pain and anxiety are not ordinarily classified as psychotic disorders. The claim must be read from the issued patent and its prosecution history, including any claim amendments or formal corrections. The literal wording remains relevant, but the practical commercial value of claim 4 is lower than that of the schizophrenia claim.

What patents protect ziprasidone besides U.S. Patent 6,110,918?

The central U.S. ziprasidone patent estate included earlier compound patents, later salt or solid-state patents, and regulatory listings associated with Geodon.

Patent or right	General subject matter	Commercial relevance
U.S. Patent 5,312,925	Ziprasidone compound and related therapeutic subject matter	Earlier foundational compound protection
U.S. Patent 6,110,918	Ziprasidone mesylate trihydrate, compositions, and treatment methods	Salt/hydrate and use protection
FDA-listed product patents	Product-specific patents listed for Geodon	Relevant to ANDA certification and launch timing
FDA regulatory exclusivity	New-drug, pediatric, or other statutory exclusivity	Separate from patent protection

U.S. Patent 5,312,925 was the principal earlier ziprasidone composition patent. It was litigated in Pfizer Inc. v. Apotex, Inc., a Federal Circuit case involving generic challenges to the ziprasidone patent estate (Pfizer Inc. v. Apotex, Inc., 2007).

The two patents had different technical roles. The earlier patent focused on the ziprasidone compound and related pharmaceutical use. U.S. Patent 6,110,918 focused on the mesylate trihydrate form and associated applications. A generic applicant therefore had to assess both the active moiety and the specific salt or hydrate used in its proposed product.

When did U.S. Patent 6,110,918 expire?

The patent term ended in the United States in 2017 or 2018 depending on the applicable patent-term calculation and the specific Orange Book record used for the product. FDA Orange Book records historically associated the patent with Geodon and identified an expiration date in the late 2017 period. The patent is now expired and does not provide a current U.S. barrier to generic launch (FDA, Orange Book, 2024).

The relevant exclusivity categories were separate:

Protection	Typical legal basis	Status
U.S. Patent 6,110,918	Salt, hydrate, composition, and method claims	Expired
Earlier ziprasidone patent	Foundational compound protection	Expired
FDA regulatory exclusivity	NDA approval and statutory exclusivity periods	Expired
Pediatric exclusivity, if awarded	Six-month extension under applicable FDA law	Expired

Patent expiration did not automatically end all market protection on the same date. Generic entry depended on the full set of listed patents, ANDA certifications, litigation, settlements, FDA approval timing, and any applicable exclusivity.

What was the Orange Book status of U.S. Patent 6,110,918?

U.S. Patent 6,110,918 was listed in connection with Geodon products in the FDA Orange Book. Orange Book listing matters because a generic applicant referencing the relevant NDA must address listed patents through a Paragraph I, II, III, or IV certification, as applicable.

A Paragraph IV certification asserts that a listed patent is invalid, unenforceable, or will not be infringed by the proposed generic product. If the NDA holder receives timely notice, the filing of an infringement action can trigger a statutory 30-month stay of ANDA approval, subject to exceptions and court action.

The listing did not mean every ziprasidone generic necessarily infringed every claim. The legal question depended on the generic's selected salt, hydrate, formulation, labeling, and method of use.

Which companies challenged the Geodon patent estate?

Generic applicants challenged Pfizer's Geodon protection during the ANDA approval period. Publicly reported litigation included Pfizer's disputes with Apotex and other generic manufacturers concerning ziprasidone patents, particularly the foundational U.S. Patent 5,312,925.

The principal challenge mechanisms were:

• Paragraph IV invalidity and noninfringement certifications;
• Obviousness challenges to the ziprasidone compound;
• Challenges involving claim scope and pharmaceutical use;
• Settlement negotiations concerning the date of generic entry;
• Product-specific arguments based on the proposed generic salt or formulation.

The Federal Circuit's decision in Pfizer v. Apotex addressed the earlier ziprasidone patent and remains relevant to the historical strength of the broader estate. It did not convert U.S. Patent 6,110,918 into a perpetual barrier, and it did not eliminate the need to analyze the later patent's distinct mesylate trihydrate limitation.

What litigation and settlements affected generic ziprasidone entry?

Generic entry occurred after litigation and commercial settlement activity involving Pfizer's ziprasidone patents. The key issue was whether generic companies could launch before the expiration of the relevant listed patents.

The litigation risk had several components:

1. The foundational compound patent created the earliest and broadest technical barrier.
2. The mesylate trihydrate patent created a salt and hydrate-specific barrier.
3. Method claims created additional risk if the generic labeling encouraged a patented indication.
4. Injectable products faced separate formulation, manufacturing, and route-of-administration analysis.
5. Settlement terms could permit entry before the final listed patent expiration.

Publicly available records support the conclusion that generic ziprasidone entered the U.S. market before or around the end of the late-stage patent term. Once U.S. Patent 6,110,918 expired, its claims no longer supported an infringement action against continuing commercial sales.

How strong was the patent estate?

The estate was strong during its active term but had different strengths by claim category.

Claim category	Historical strength	Main vulnerability
Exact chemical compound	High if valid and properly identified	Prior-art obviousness and enablement challenges
Mesylate trihydrate	High for products using that exact form	Alternative salt or hydrate forms
Broad pharmaceutical composition	Moderate to high	Noninfringing formulation or different active form
General psychotic-disorder method	Moderate	Labeling, divided-infringement, and claim-construction issues
Intramuscular method	Stronger for injectable products	Alternative route, formulation, or indication
Schizophrenia treatment	Commercially significant	Expired patent term and generic labeling strategies

Claim 1 was the most technically valuable claim because it covered the defined active form. Claims 2 through 7 supplied additional enforcement theories but were more dependent on proof of use, product composition, labeling, and treatment conduct.

The estate's remaining value has shifted from exclusionary rights to historical relevance, freedom-to-operate analysis, validity precedent, and technical knowledge concerning ziprasidone salt and hydrate forms.

What manufacturing and intellectual-property barriers remain?

No current U.S. patent barrier from U.S. Patent 6,110,918 prevents manufacture of ziprasidone mesylate trihydrate. Commercial barriers can still include:

• Control of particle size and polymorphic form;
• Reproducible hydration state;
• Stability during storage;
• Sterile manufacturing for intramuscular injection;
• Bioequivalence for oral products;
• Manufacturing validation;
• Drug-master-file confidentiality;
• Supply-chain control for active pharmaceutical ingredient;
• Other unexpired patents in jurisdictions outside the United States.

The expired patent may still be technically relevant because a manufacturer seeking to reproduce the historical product form must control water content and solid-state properties. That is a manufacturing challenge, not an enforceable patent restriction.

How does Geodon compare with competing antipsychotics?

Ziprasidone competed with risperidone, olanzapine, quetiapine, aripiprazole, and later generic versions of those products. Each product had a separate patent and regulatory history.

Drug	Brand	Principal historical patent issue
Ziprasidone	Geodon	Compound, mesylate trihydrate, formulation, and method patents
Risperidone	Risperdal	Compound and formulation protection
Olanzapine	Zyprexa	Compound and formulation protection
Quetiapine	Seroquel	Compound, formulation, and extended-release protection
Aripiprazole	Abilify	Compound, formulation, and long-acting injectable protection

Ziprasidone's injectable product gave Pfizer a differentiated acute-treatment product, while the oral product competed in the atypical antipsychotic market. After patent expiry, generic competition reduced the branded product's pricing power and revenue exposure.

What revenue exposure did expiration create?

Geodon generated material revenue for Pfizer during its protected period, but the relevant exposure declined sharply after generic entry. The financial effect depended on:

• The share of U.S. sales subject to generic substitution;
• The timing of generic approvals;
• The number of approved ANDA holders;
• Price erosion after launch;
• Continued sales of injectable ziprasidone;
• International patent expiry dates;
• Payer substitution and formulary placement.

The expiration of U.S. Patent 6,110,918 removed one layer of protection from the product's U.S. estate. It did not by itself determine global loss of exclusivity because patent terms and regulatory regimes differed by country.

What generic launch risks existed?

Before expiration, a generic manufacturer faced five primary risks:

1. Infringement of the exact mesylate trihydrate claim.
2. Infringement of composition claims through use of the claimed active form.
3. Infringement of method claims through a label directed to schizophrenia or another claimed use.
4. ANDA delay from Paragraph IV litigation and a 30-month stay.
5. Separate patent or regulatory issues involving injectable ziprasidone.

After expiration, the principal risks became regulatory and commercial rather than patent-based. These included bioequivalence failure, manufacturing deviations, supply interruptions, product liability, and competition among multiple generic suppliers.

Key Takeaways

• U.S. Patent 6,110,918 specifically covers ziprasidone mesylate trihydrate.
• Claim 1 is a narrow product claim requiring the defined chemical salt and trihydrate form.
• Claims 2 through 7 cover pharmaceutical compositions and treatment methods, including schizophrenia treatment and intramuscular administration.
• The patent was part of the Geodon patent estate, which also included earlier foundational ziprasidone protection.
• The patent and related U.S. exclusivity periods have expired.
• Historical generic challenges involved Paragraph IV certifications, infringement litigation, and settlement activity.
• The patent remains relevant for historical freedom-to-operate analysis and solid-state manufacturing knowledge, but it is not a current U.S. exclusionary right.

FAQs

Does U.S. Patent 6,110,918 cover ziprasidone free base?

No. The claim requires ziprasidone mesylate trihydrate. Ziprasidone free base is chemically distinct from the claimed salt and hydrate.

Does the patent cover all ziprasidone capsules?

No. Coverage depends on whether the capsule contains the claimed mesylate trihydrate form and satisfies the other claim limitations. A different salt or solid form would require separate analysis.

Did the patent cover Geodon intramuscular injection?

Claim 7 expressly covers intramuscular administration of the compound of claim 1 for the claimed treatment method. Product-level infringement would depend on the injectable composition and actual use.

Can a company launch generic ziprasidone after this patent expired?

Yes, subject to FDA approval, ANDA requirements, bioequivalence, manufacturing compliance, and any other applicable patents or regulatory exclusivities.

Is U.S. Patent 6,110,918 still enforceable outside the United States?

U.S. expiration has no automatic effect on foreign rights. Foreign counterparts must be evaluated separately by country, patent family, and local expiration date.

References

1. Food and Drug Administration. (2023). Geodon (ziprasidone mesylate) prescribing information. U.S. Department of Health and Human Services.

2. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. U.S. Department of Health and Human Services.

3. Pfizer Inc. v. Apotex, Inc., 480 F.3d 1348 (Fed. Cir. 2007).

4. U.S. Patent No. 5,312,925. (1994). Benzisothiazolyl piperazine derivatives. U.S. Patent and Trademark Office.

5. U.S. Patent No. 6,110,918. (2000). Ziprasidone mesylate trihydrate. U.S. Patent and Trademark Office.

Drugs Protected by US Patent 6,110,918

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

Foreign Priority and PCT Information for Patent: 6,110,918

PCT Information
PCT Filed	March 26, 1997	PCT Application Number:	PCT/IB97/00306
PCT Publication Date:	November 13, 1997	PCT Publication Number:	WO97/42190

International Family Members for US Patent 6,110,918

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0904273		PA2003004	Lithuania
European Patent Office	0904273		PA2003004,C0904273	Lithuania
African Regional IP Organization (ARIPO)	838
African Regional IP Organization (ARIPO)	9700978
Argentina	007003