United States Patent 6,150,366: Ziprasidone Particle-Size, Bioavailability, Dissolution, and Manufacturing Claims

U.S. Patent No. 6,150,366 covered pharmaceutical compositions and psychosis-treatment methods using crystalline ziprasidone particles with a mean particle size of approximately 85 micrometers or less. It also covered a process for producing large crystals of ziprasidone hydrochloride monohydrate. The patent was assigned to Pfizer-related interests and had a statutory term that ended in 2018. Its claims are therefore no longer an active U.S. barrier to generic ziprasidone entry.

The patent's commercial value came from improving the oral absorption of ziprasidone, a poorly water-soluble antipsychotic marketed as Geodon. The claims focused on particle engineering rather than a new chemical entity.

What did U.S. Patent 6,150,366 protect?

The patent contained five substantive claim groups:

Claim group	Claims	Protected subject matter
Particle-size compositions	1-8	Crystalline ziprasidone free base or hydrochloride particles with mean particle size at or below approximately 85 μm
Treatment methods	9-16	Treating psychosis with the claimed particle-size compositions
Bioavailability-defined compositions	17-23	Compositions meeting particle-size and AUC/Cmax performance limits
Bioavailability-defined treatment methods	24-30	Treating psychosis with compositions meeting the same performance limitations
Manufacturing process	31-34	Producing large crystals of ziprasidone hydrochloride monohydrate using THF, water, HCl, heating and cooling

The claims did not cover every ziprasidone product. They required a specific crystalline form, particle-size limitation, formulation context, pharmacokinetic or dissolution performance in certain claims, or manufacturing sequence.

What is the scope of independent claims 1, 9, 17, 24, and 31?

Claim 1: particle-size composition

Claim 1 required all of the following:

Crystalline ziprasidone free base or crystalline ziprasidone hydrochloride.
A mean particle size of approximately 85 μm or less.
A pharmaceutically acceptable diluent or carrier.

The claim was broad within those boundaries. It did not require ziprasidone hydrochloride monohydrate, although claim 2 narrowed the composition to that hydrate. It also did not require a particular capsule, tablet, excipient, dose, dissolution profile or bioavailability result.

The particle-size limitation is the central technical limitation. A formulation containing particles with a mean size above approximately 85 μm would fall outside claim 1 unless another claim or infringement theory applied.

Claim 9: treatment method

Claim 9 covered administering an effective amount of a claim 1 composition to a patient requiring treatment for psychosis. The claim depended on the composition limitations in claim 1 and added a therapeutic-use requirement.

A product could satisfy the composition limitation but avoid claim 9 if there were no qualifying administration or treatment activity in the United States. Conversely, a generic product used for psychosis could create method-of-use exposure if the underlying composition met the particle-size limitations.

Claim 17: composition with particle size and pharmacokinetic performance

Claim 17 added two important restrictions:

Mean particle size at or below approximately 85 μm, measured by Malvern light scattering.
Mean AUC and/or Cmax at least 80% of the mean AUC exhibited by a comparator composition containing crystalline ziprasidone hydrochloride with a 20 μm mean particle size.

This claim is narrower than claim 1 because it specifies the measurement technique and pharmacokinetic relationship. The comparator language creates an infringement issue that would likely require formulation, clinical or pharmacokinetic evidence rather than particle-size testing alone.

The wording "AUC and/or Cmax" also creates alternative routes to satisfaction. Depending on claim construction, a composition could qualify by meeting the AUC threshold, the Cmax threshold, or both, subject to the exact interpretation of the claim and specification.

Claim 24: treatment method based on claim 17

Claim 24 applied the claim 17 composition limitations to a psychosis-treatment method. It was narrower than claim 9 because it incorporated the Malvern measurement and pharmacokinetic-performance requirement.

Claim 31: manufacturing process

Claim 31 covered a process for preparing large crystals of ziprasidone hydrochloride monohydrate. The process required:

Dissolving ziprasidone free base in THF and water.
Using approximately 22-35 unit volumes of THF and 1.5-8 volumes of water.
Heating the resulting solution.
Adding hydrochloric acid.
Cooling the acidified solution.

Claims 32-34 narrowed the process by specifying:

THF-to-water ratios of 24-30 to 2-6.
Maintaining the solution below reflux during HCl addition.
A temperature of 60-64°C.

The process claims were directed to crystalline-product manufacture, not merely to the use of ziprasidone hydrochloride monohydrate in a finished dosage form.

How do the dependent claims narrow the patent?

Claims 2-8 and 10-16 narrow the basic composition and treatment claims through several technical parameters:

Limitation	Claims	Effect
Ziprasidone hydrochloride monohydrate	2, 10, 18, 25	Limits the active form to the monohydrate
Mean particle size ≤50 μm	3, 11, 19, 26	Removes compositions above 50 μm
Mean particle size 5-50 μm	4, 12, 20, 27	Adds a lower bound
Mean particle size 5-40 μm	5, 13, 21, 28	Narrows the upper range
Mean particle size 5-30 μm	6, 14, 22, 29	Creates the narrowest particle-size range
AUC/Cmax at least 80% of the 20 μm comparator	7, 15, 17	Adds pharmacokinetic performance
At least 70% dissolution within 45 minutes	8, 16, 23, 30	Adds a specified dissolution test

The 5-30 μm range is the narrowest recurring particle-size limitation. It is also the range most likely to overlap with commercial micronized or milled ziprasidone hydrochloride products.

What formulations are protected by U.S. Patent 6,150,366?

The claims potentially covered oral solid dosage forms containing:

Crystalline ziprasidone hydrochloride monohydrate.
Crystalline ziprasidone hydrochloride other than the monohydrate.
Crystalline ziprasidone free base.
A pharmaceutically acceptable carrier or diluent.
Particle sizes at or below 85 μm, with narrower protection at 50, 40 and 30 μm.

The patent did not require a particular excipient system. A capsule, tablet, powder blend or other solid formulation could satisfy the composition claims if it contained the claimed crystalline particles and carrier.

The dissolution claims are method-specific. They require testing under a defined USP-2 protocol using:

900 mL aqueous sodium dihydrogen phosphate buffer.
pH 7.5.
2% w/v sodium dodecyl sulfate.
75 rpm paddle speed.
A dose equivalent to 100 mgA or less of ziprasidone.
At least 70% dissolution within 45 minutes.

A formulation could therefore have a particle size below 85 μm but fail claim 8 if it did not meet the dissolution threshold. The converse is also possible: a formulation could meet the dissolution threshold but fall outside the particle-size limitation.

How strong were the particle-size claims?

The patent estate was technically meaningful but legally narrower than a basic compound patent.

Strengths

The composition claims were relatively broad because claim 1 covered both crystalline ziprasidone free base and crystalline ziprasidone hydrochloride. The claims also did not require a specific dosage strength or excipient combination.

The particle-size limitation had a direct pharmaceutical rationale. Ziprasidone has low aqueous solubility, and smaller particles can increase surface area and improve dissolution and oral exposure. The patent tied particle size to both dissolution and pharmacokinetic outcomes.

The manufacturing claims added a separate infringement pathway. A competitor using the claimed THF/water/HCl crystallization sequence could face process-claim exposure even if its finished-product formulation differed.

Weaknesses

Particle-size claims can be vulnerable to disputes over measurement technique, sampling, aggregation and lot-to-lot variation. Claim 17 expressly identified Malvern light scattering, but claims 1-16 and 18-30 did not consistently identify that method in the supplied language.

The AUC/Cmax limitations require comparison against a 20 μm reference formulation. That comparator may create evidentiary complexity, particularly if the accused product uses a different formulation, dose, feeding condition or pharmacokinetic study design.

The dissolution claims depend on a highly specified test. Minor differences in buffer preparation, surfactant concentration, paddle speed or sampling can affect the result.

The process claims were limited by solvent ratio, acid-addition conditions and temperature. A manufacturer could potentially design around them by changing the solvent system, water content, acid-addition temperature or crystallization sequence.

When did U.S. Patent 6,150,366 lose exclusivity?

The patent's statutory term expired in 2018, based on its earliest relevant U.S. filing date and the 20-year patent-term framework in 35 U.S.C. §154. The expiration date is generally reported as April 3, 2018 for the patent family associated with the ziprasidone particle-size and crystallization technology.

Event	Date
Earliest relevant U.S. priority or filing basis	April 3, 1997
U.S. patent application filing	April 3, 1998
Patent issued	November 21, 2000
Approximate statutory expiration	April 3, 2018
Current U.S. enforceability	Expired

The patent term should be distinguished from FDA regulatory exclusivity. FDA approval exclusivity and patent protection are separate rights. Once the patent expired, the claims no longer blocked manufacture, sale or use of otherwise approved generic ziprasidone products in the United States.

What was the Orange Book status of ziprasidone?

Geodon was approved by FDA as ziprasidone hydrochloride capsules and later as an intramuscular injection. The oral capsule product was the principal product relevant to the particle-size and dissolution claims.

The FDA Orange Book historically listed several patents for Geodon, including patents directed to the ziprasidone compound, formulations, crystalline forms and particle-size technology. U.S. Patent 6,150,366 was part of the patent landscape associated with the oral product, alongside other Pfizer patents such as U.S. Patent Nos. 5,312,925, 5,686,416 and 6,245,765. Orange Book listings can change over time as patents expire or are delisted, so the current listing must be read together with the FDA's current Approved Drug Products with Therapeutic Equivalence Evaluations database (FDA, n.d.-a).

The patent did not create a current regulatory exclusivity period. Its relevance is historical and may remain important for litigation, prosecution-history analysis, freedom-to-operate review and assessment of generic development strategies.

Which companies challenged ziprasidone exclusivity?

Generic manufacturers pursued ANDA approval for ziprasidone hydrochloride capsules after the core compound and formulation barriers approached expiration. Typical ANDA patent strategies for this product would include:

Paragraph IV certifications asserting invalidity or noninfringement.
Paragraph III certifications accepting delayed approval until patent expiration.
Design-around positions based on particle-size distribution, crystalline form or manufacturing process.
Arguments that a formulation does not meet the AUC, Cmax or dissolution limitations.
Challenges to Orange Book listing scope under the FDA's patent-listing rules.

Publicly reported generic competition included products from major ANDA manufacturers such as Teva, Apotex, Mylan and other suppliers. The commercial risk ultimately materialized after the relevant patents expired, and generic ziprasidone became available.

A precise list of every Paragraph IV filer and settlement term requires matching each ANDA litigation docket to the specific patent. The supplied claims alone do not establish the identity of every challenger or the terms of any private settlement.

What patent litigation affected the patent?

The likely litigation exposure centered on three questions:

Whether an ANDA product contained crystalline particles with a mean size at or below the claimed threshold.
Whether the product met the dissolution or pharmacokinetic limitations.
Whether the generic manufacturer used a process covered by claims 31-34.

For an ANDA filing, a generic applicant could avoid direct method-of-treatment exposure through a section viii statement carving out a patented indication where permitted. That strategy would not necessarily avoid composition-claim exposure if the product itself met claim 1 or claim 17.

The process claims presented a different enforcement problem. A process used solely outside the United States generally would not constitute ordinary domestic process infringement, but importing a product made by a patented process can raise issues under 35 U.S.C. §271(g). Process evidence may also be difficult to obtain without discovery.

The patent's expiration eliminated future infringement risk based solely on these claims. Historical settlement agreements, if any, may have affected launch timing before expiration but do not preserve the patent after expiration.

How did the patent compare with other ziprasidone patents?

Patent type	Typical protected subject matter	Commercial role
Basic compound patent	Ziprasidone chemical structure and salts	Primary early exclusivity
Crystalline-form patent	Ziprasidone hydrochloride monohydrate or other solid forms	Solid-state and formulation control
U.S. 6,150,366	Particle size, bioavailability, dissolution and crystallization process	Product-performance and manufacturing barrier
Formulation patents	Capsules, dosage forms, excipients or release characteristics	Product-specific protection
Method-of-use patents	Psychosis, schizophrenia or related indications	Regulatory and labeling strategy

U.S. Patent 6,150,366 was stronger than a purely process patent because its independent composition claims could reach the marketed product directly. It was weaker than a basic compound patent because a competitor could potentially design around the particle-size threshold, use a different crystalline form or alter the manufacturing process.

What generic launch risks existed before expiration?

Before April 2018, an ANDA applicant faced four principal risks:

Direct infringement of composition claims based on particle-size testing.
Infringement of bioavailability claims if the product matched the 20 μm comparator threshold.
Infringement of dissolution claims under the specified USP-2 test.
Infringement of process claims if the generic used the claimed THF/water/HCl crystallization route.

The most practical design-around would have been to control the particle-size distribution outside the claimed range, use a different crystallization process, or establish that the finished dosage form did not meet the claimed pharmacokinetic or dissolution performance. Each approach carried development and regulatory tradeoffs because particle size also affects product performance.

Did U.S. Patent 6,150,366 create biosimilar risk?

No. Ziprasidone is a small-molecule drug, not a biologic. The relevant competitive pathway was the ANDA route under the Hatch-Waxman framework, not a biosimilar application under the Public Health Service Act.

The competitive risks were generic substitution, ANDA litigation, Paragraph IV challenges, manufacturing design-arounds and price erosion. FDA approval of a therapeutically equivalent generic could support pharmacy-level substitution depending on the approved dosage form and state law.

What is the geographic coverage of the patent estate?

U.S. Patent 6,150,366 applied only to the United States. Related foreign applications could have produced corresponding rights in Europe, Canada, Japan and other jurisdictions, but each right depended on national prosecution, maintenance fees, claim amendments and local expiration rules.

The U.S. expiration did not automatically determine foreign status. A global freedom-to-operate review would need to identify the patent family, continuations, divisionals and national-stage filings, then check each jurisdiction's legal status.

Key Takeaways

U.S. Patent 6,150,366 targeted crystalline ziprasidone particle size, oral performance and manufacture.
The broadest composition claim required crystalline ziprasidone particles with a mean size of approximately 85 μm or less plus a pharmaceutically acceptable carrier.
Narrower claims covered 5-30 μm particles, a defined dissolution threshold and at least 80% relative AUC or Cmax.
Claims 31-34 covered a THF/water/HCl process for producing large crystals of ziprasidone hydrochloride monohydrate.
The patent was materially narrower than a basic ziprasidone compound patent but could reach finished products directly.
Its U.S. patent term expired approximately April 3, 2018.
It is no longer an active U.S. patent barrier to generic ziprasidone.
The relevant competitive pathway was generic ANDA approval, not biosimilar approval.
Historical Paragraph IV activity and settlements may have affected pre-expiration launch timing, but they do not restore exclusivity after expiration.

Frequently Asked Questions

Could a generic ziprasidone capsule infringe claim 1 without using Pfizer's manufacturing process?

Yes. Claim 1 is a composition claim. It could be infringed by a qualifying finished dosage form regardless of whether the manufacturer used the patented crystallization process.

Does a particle size below 5 μm avoid all claims?

No. Claims 4-6 and related treatment claims specify ranges beginning at 5 μm, but claim 1 and other claims use an upper-bound limitation without the same lower bound. A particle size below 5 μm could still fall within a broader claim if all other limitations are satisfied.

Is ziprasidone hydrochloride monohydrate itself patented by U.S. Patent 6,150,366?

The patent claims compositions and a process involving the monohydrate. The supplied claims do not claim every isolated quantity of ziprasidone hydrochloride monohydrate independent of particle size, formulation or process conditions.

Can a company avoid the dissolution claims by changing the tablet excipients?

Possibly, but changing excipients would not necessarily avoid the composition claims. The product would still require separate analysis under the particle-size and crystalline-form limitations.

Does expiration of U.S. Patent 6,150,366 eliminate all ziprasidone patent risk worldwide?

No. It eliminates this U.S. patent as a current U.S. exclusion right. Separate U.S. patents, foreign counterparts, regulatory requirements and manufacturing-process rights must be assessed independently.

References

U.S. Patent No. 6,150,366. (2000). Ziprasidone compositions and processes for preparation thereof. United States Patent and Trademark Office. https://patents.google.com/patent/US6150366
U.S. Food and Drug Administration. (n.d.-a). Approved drug products with therapeutic equivalence evaluations. https://www.fda.gov/drugs/drug-approvals-and-databases/orange-book-data-files
U.S. Food and Drug Administration. (n.d.-b). Geodon label. https://www.accessdata.fda.gov/drugsatfda_docs/label/
United States Code, 35 U.S.C. §154. (2024). Contents and term of patent; provisional rights. https://uscode.house.gov/
United States Code, 35 U.S.C. §§271, 355. (2024). Patent infringement and abbreviated new drug applications. https://uscode.house.gov/

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
African Regional IP Organization (ARIPO)	1216	⤷ Start Trial
Argentina	015553	⤷ Start Trial
Austria	240732	⤷ Start Trial
Australia	3398399	⤷ Start Trial
Australia	753820	⤷ Start Trial
Bulgaria	103489	⤷ Start Trial
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Details for Patent: 6,150,366

Summary for Patent: 6,150,366