US Patent 6,455,533: Scope, Claim Construction, Expiration, and Patent-Landscape Analysis

US Patent 6,455,533 protects solid oral compositions combining a substituted benzhydrylpiperazine antihistamine, such as cetirizine, with a cyclodextrin in a non-inclusion-complex mixture. Its protection extends to composition, manufacturing, and oral-administration claims. The principal limiting elements are the solid oral dosage form, the specified active-substance family, the cyclodextrin component, and the express exclusion of inclusion complexes.

The patent has no meaningful remaining U.S. exclusivity. Its term expired no later than the statutory 20-year term measured from the earliest effective nonprovisional filing or priority date, subject to any recorded patent-term adjustment. The patent therefore presents historical relevance for formulation design and freedom-to-operate analysis, but it should not block a current U.S. product.

What invention does US Patent 6,455,533 cover?

The patent covers pharmaceutical formulations in which a substituted benzhydrylpiperazine active ingredient is physically mixed with a cyclodextrin without forming an inclusion complex.

The disclosed active ingredients include:

Cetirizine
Hydroxyzine
Efletirizine
Meclizine
Buclizine
Optically active isomers of those compounds
Pharmaceutically acceptable salts

The claimed cyclodextrins include native alpha-, beta-, and gamma-cyclodextrins and substituted derivatives, including:

Heptakis(2,6-di-O-methyl)-beta-cyclodextrin
Randomly methylated beta-cyclodextrin
Hydroxypropyl beta-cyclodextrin
Alkyl derivatives
Hydroxyalkyl derivatives

The central technical distinction is that the cyclodextrin is present as a component of the formulation but is not used to form an inclusion complex with the active ingredient.

How is the patent claim set structured?

The 18 claims divide into three independent claim groups.

Claim group	Claims	Subject matter
Composition claims	1-6	Solid oral pharmaceutical composition
Manufacturing-method claims	7-12	Mixing, optional excipient addition, and drying
Administration-method claims	13-18	Oral administration of the claimed composition

Claims 1, 7, and 13 are the independent claims. The remaining claims narrow the independent claims by dosage form, active ingredient, cyclodextrin identity, or molar ratio.

Claim 1: Broadest composition claim

Claim 1 requires:

A solid pharmaceutical composition.
Suitability for oral administration.
A substituted benzhydrylpiperazine active substance, optical isomer, or pharmaceutically active salt.
At least one cyclodextrin.
A mixture that does not contain inclusion complexes.

Claim 1 does not require a particular dosage form, a specific cetirizine salt, a defined cyclodextrin species, or a particular cyclodextrin-to-drug ratio.

The claim is therefore broad within the defined chemical and formulation genus. It can cover a chewable tablet, dry syrup, granulated product, or sublingual tablet, provided the product is solid and orally administrable.

Claims 2-6: Composition limitations

Claim 2 limits the product to a chewable tablet, dry syrup, granules, or sublingual tablet.

Claim 3 narrows the active ingredient to five named compounds and their isomers and salts.

Claim 4 covers alpha-, beta-, or gamma-cyclodextrins and alkyl or hydroxyalkyl derivatives.

Claim 5 imposes a molar ratio of cyclodextrin to active substance between 1.0 and 4.0.

Claim 6 identifies three preferred beta-cyclodextrin derivatives.

Claim 7: Manufacturing process

Claim 7 requires a process comprising:

Providing the active ingredient and cyclodextrin.
Mixing them into a non-inclusion-complex mixture.
Optionally adding a non-complexing excipient or adjuvant.
Drying the mixture to produce a solid pharmaceutical composition.

The process claim is narrower operationally than the composition claim because it requires the specified sequence of steps. A finished product could fall within claim 1 without being made by the precise process recited in claim 7.

Claim 13: Administration method

Claim 13 covers orally administering the claimed type of solid composition. It does not require a therapeutic disease indication, a specific dosage, or a named patient population.

The claim is directed to the act of administration rather than merely the product. In an infringement analysis, the relevant conduct would normally involve the administration of a composition satisfying every limitation.

What formulations are protected by the patent?

The protected formulation space is defined by the combination of active ingredient and cyclodextrin, not by a particular release profile or therapeutic indication.

Formulation variable	Scope under the claims
Dosage state	Solid
Route	Oral
Active ingredient	Substituted benzhydrylpiperazine family
Named actives	Cetirizine, hydroxyzine, efletirizine, meclizine, buclizine
Cyclodextrin	Alpha, beta, gamma, alkyl, or hydroxyalkyl forms
Complexation	Inclusion complexes expressly excluded
Ratio	1.0-4.0 only under claims 5, 11, and 17
Dosage forms	Chewable tablet, dry syrup, granules, sublingual tablet
Process	Mixing, optional excipient addition, and drying under claim 7

The non-complexation limitation is the key claim boundary. A formulation in which the active ingredient is deliberately encapsulated within the cyclodextrin cavity may avoid the literal scope of the claims, although the technical and evidentiary question would depend on how the product is characterized and tested.

Conversely, merely labeling a product as a physical mixture would not necessarily avoid the claims if analytical evidence showed that an inclusion complex formed during manufacture or storage. The claim language makes the absence of inclusion complexes material.

How strong is the patent estate for cetirizine formulations?

The patent is technically focused but commercially narrow.

Its strength came from claiming a formulation approach rather than a new active molecule. The claims could reach multiple dosage forms and several antihistamines, but they depend on several cumulative limitations:

The product must be solid.
The product must be intended for oral administration.
The active must fall within the substituted benzhydrylpiperazine family.
A cyclodextrin must be present.
The mixture must not contain inclusion complexes.

The estate is weaker against products using:

Liquid formulations
Non-cyclodextrin taste-masking systems
Conventional tablets without cyclodextrin
Inclusion-complex formulations
Different active ingredients outside the named genus
Cyclodextrin levels outside the dependent-claim ratio
Nonoral dosage forms

The 1.0-to-4.0 molar-ratio limitation appears only in dependent claims. A product outside that range could still be evaluated against claim 1 if it satisfies the other limitations.

Does the patent cover Zyrtec or cetirizine generally?

No. The patent does not claim cetirizine as a molecule, cetirizine generally, or every cetirizine dosage form.

It claims a particular formulation combination involving cetirizine or another covered active and a cyclodextrin in a solid oral mixture without inclusion complexes. Ordinary cetirizine tablets, capsules, oral solutions, or products using other excipients are not automatically within the claims.

The patent also does not claim a specific therapeutic use, such as treatment of allergic rhinitis or chronic urticaria. Its method-of-use claims are limited to orally administering the defined formulation.

When did US Patent 6,455,533 lose exclusivity?

The patent’s enforceable term has expired. U.S. utility patents generally have a term of 20 years from the earliest effective nonprovisional filing date, subject to patent-term adjustment and limited restoration provisions under 35 U.S.C. §§ 154 and 156.

Event	Legal significance
Patent grant	Created enforceable U.S. rights, subject to validity and term
20-year statutory term	Established the ordinary expiration framework
Current status	Expired
Current blocking risk	No ordinary infringement liability based solely on the expired patent

Expiration eliminates the right to exclude future practice of the claimed invention. It does not erase historical infringement exposure that accrued before expiration, and it does not eliminate the value of the patent as prior art.

A definitive term calculation should rely on the USPTO Patent Center record, including any patent-term adjustment, terminal disclaimer, or patent-term extension entry. No patent-term extension would ordinarily be expected for a formulation patent that was not the subject of qualifying regulatory-delay restoration.

What is the Orange Book status of US Patent 6,455,533?

US Patent 6,455,533 should not be treated as an Orange Book drug-substance or drug-product patent solely because it concerns a cetirizine formulation.

Orange Book listing is tied to an approved new drug application and the patent-listing requirements administered by FDA. A formulation patent may be listed if it claims an approved drug product or an approved method of use, but the existence of a patent does not itself establish listing.

The supplied claim set does not identify:

An NDA number
A listed reference product
An Orange Book patent-use code
A current FDA patent-listing entry
A Paragraph IV notice
An FDA-recognized pediatric-exclusivity period

The patent is expired in any event, so it does not present a current Orange Book exclusivity barrier.

Were Paragraph IV challenges or generic litigation relevant?

A Paragraph IV certification would have been relevant only while the patent was listed against an approved reference drug and remained unexpired.

The claim set alone does not establish that a Paragraph IV certification was filed or that litigation occurred. A generic applicant could have designed around the patent by using a non-cyclodextrin formulation, a liquid product, an inclusion complex, or a composition outside the relevant active-ingredient scope.

Because the patent has expired, a current generic applicant does not need to make a Paragraph IV challenge to launch a product solely because of this patent. A generic sponsor may still need to address other patents, regulatory exclusivities, trademarks, labeling restrictions, or unrelated formulation rights.

What manufacturing and intellectual-property barriers does the patent create?

During its term, the main manufacturing risk was the combination of mixing and drying steps in claim 7.

Potentially relevant process questions included:

Whether the cyclodextrin and active were mixed before drying.
Whether the process produced a solid composition.
Whether the excipients were non-complexing.
Whether inclusion complexes formed despite the intended process.
Whether the finished product had the claimed active-cyclodextrin ratio.
Whether the product fell within one of the specified dosage forms.

The process claim does not require a particular drying technology. Spray drying, tray drying, fluid-bed drying, or another drying method could potentially satisfy the claim if the other limitations were met. The claim does not appear limited to a proprietary equipment configuration.

After expiration, these process limitations remain relevant for prior-art analysis and historical litigation, but they do not create an ongoing U.S. manufacturing barrier.

How does this patent compare with conventional cetirizine formulation patents?

Issue	US 6,455,533	Conventional cetirizine patent
Primary focus	Cyclodextrin-containing solid mixture	Active ingredient, salt, dosage form, or release profile
Complexation	Inclusion complexes excluded	May claim complexes or other delivery systems
Dosage forms	Chewable, dry syrup, granules, sublingual tablet	Often tablet, capsule, solution, or extended-release form
Active scope	Multiple substituted benzhydrylpiperazines	Often limited to cetirizine or a specific salt
Method claims	Mixing and drying	May claim therapeutic use or manufacturing chemistry
Current status	Expired	Must be assessed patent by patent
Generic risk today	No direct blocking effect	Depends on each unexpired patent

The patent’s commercial value was strongest for orally disintegrating, chewable, dry-syrup, or taste-masked products in which cyclodextrin improved palatability or handling without intentional complex formation.

What is the competitive and commercial significance?

The patent did not control the cetirizine market as a whole. It covered one formulation strategy within the broader antihistamine field.

Its potential commercial relevance was greatest for:

Pediatric solid oral products
Chewable antihistamine tablets
Dry syrups requiring reconstitution
Sublingual or rapidly dissolving formulations
Formulations seeking taste improvement or altered dissolution
Products using substituted beta-cyclodextrins

The patent did not create a continuing biosimilar issue. Cetirizine, hydroxyzine, meclizine, and buclizine are small molecules, not biologics. The relevant competitive pathway is generic drug approval under an abbreviated new drug application, not biosimilar approval under the Biologics Price Competition and Innovation Act.

No reliable revenue attribution can be assigned to this patent from the claim set alone. Any revenue exposure would have depended on whether a marketed product practiced the claims, whether the patent was listed against that product, and the commercial share of the relevant dosage form.

What geographic coverage does the patent provide?

The patent provides U.S. rights only. Comparable protection would require separate national or regional patents in other jurisdictions.

A U.S. patent cannot block:

Manufacture entirely outside the United States with no qualifying import or U.S. commercial activity.
Sale of a noninfringing product in another country.
Practice of the invention in a jurisdiction where the corresponding patent was never granted or has expired.

Foreign family members must be assessed independently for filing dates, grant status, claim scope, opposition history, and expiration.

Key Takeaways

US Patent 6,455,533 claims solid oral compositions containing a substituted benzhydrylpiperazine active and a cyclodextrin.
The claims expressly exclude inclusion complexes.
Cetirizine is one covered active, but the patent does not claim cetirizine generally.
Independent claims cover compositions, manufacturing processes, and oral administration.
Dependent claims narrow the invention by dosage form, active ingredient, cyclodextrin type, and a 1.0-to-4.0 molar ratio.
The patent does not create current U.S. launch risk because its statutory term has expired.
The patent is not a biosimilar barrier and does not itself establish current Orange Book protection.
Historical design-around options included liquid products, non-cyclodextrin formulations, inclusion complexes, and formulations outside the claimed active or ratio limitations.
Current generic risk must be assessed against other unexpired patents, FDA exclusivities, labeling restrictions, and product-specific intellectual property.

FAQs

Can a current manufacturer sell a cetirizine chewable tablet without this patent’s permission?

Yes, because the patent has expired. Other unexpired patents, trademarks, regulatory requirements, or product-specific rights may still apply.

Does using hydroxypropyl beta-cyclodextrin automatically infringe the patent?

No. The product must satisfy all applicable claim limitations, including the covered active ingredient, solid oral form, and absence of inclusion complexes. The patent’s expiration also removes current infringement risk from the patent itself.

Does the 1.0-to-4.0 cyclodextrin ratio apply to every claim?

No. The ratio appears in claims 5, 11, and 17. It does not appear in independent claims 1, 7, or 13.

Could an inclusion-complex formulation avoid the patent?

Potentially, because the claims require that the mixture not contain inclusion complexes. The product’s actual physical state, however, would control rather than its formulation label.

Is US Patent 6,455,533 relevant to a cetirizine oral solution?

Generally no, because the independent composition claim requires a solid pharmaceutical composition. A liquid product would also need to be evaluated against any other relevant patents.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Belgium	9700572	Jul 03, 1997

PCT Information
PCT Filed	July 02, 1998	PCT Application Number:	PCT/BE98/00100
PCT Publication Date:	January 14, 1999	PCT Publication Number:	WO99/01133

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	224717	⤷ Start Trial
Australia	727140	⤷ Start Trial
Australia	8201598	⤷ Start Trial
Belgium	1011251	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 6,455,533

Summary for Patent: 6,455,533