United States Patent 4,933,168: Flunisolide Hemihydrate Aerosol Patent Scope, Expiration, and Competitive Landscape

U.S. Patent No. 4,933,168 protects a specific crystalline form of flunisolide, inhaled aerosol methods using that form, and pressurized aerosol compositions containing flunisolide hemihydrate, surfactant, and fluorinated propellant. The patent issued June 12, 1990, and, under the pre-Uruguay Round patent term applicable to the patent, expired June 12, 2007. It no longer creates an enforceable U.S. patent barrier to generic flunisolide inhalation products.

The principal commercial subject matter was the CFC-based flunisolide inhalation aerosol marketed under the Aerobid and Aerobid-M brands. The patent did not protect all flunisolide products, all inhaled corticosteroids, or later non-CFC delivery technologies.

What compound does U.S. Patent 4,933,168 protect?

Claim 1 covers flunisolide in a defined crystalline hemihydrate form:

6α-fluoro-11β,21-dihydroxy-16α,17α-isopropylidene dioxypregna-1,4-diene-3,20-dione hemihydrate.

The active pharmaceutical ingredient is flunisolide. The claim is narrower than a claim to the flunisolide molecule generally because it identifies a particular solid-state form containing one-half mole of water per mole of flunisolide.

That distinction matters. A product containing anhydrous flunisolide, another hydrate, an amorphous form, or a different crystalline form would not literally satisfy claim 1 solely because it contains the same active steroid. Infringement could still depend on whether the accused product converts to, contains, or is manufactured using the claimed hemihydrate, but the patent’s express product claim is limited to the specified form.

Key patent information

Field	Information
Patent	U.S. Patent No. 4,933,168
Subject	Flunisolide hemihydrate aerosol compositions and inhalation use
Issue date	June 12, 1990
Patent term applicable at issue	17 years from grant
Expected expiration	June 12, 2007
Active ingredient	Flunisolide
Solid form	Crystalline hemihydrate
Dosage form	Pressurized inhalation aerosol
Principal excipients	Surfactant and fluorinated or fluorochlorinated propellant
Commercial relevance	CFC-based flunisolide metered-dose inhalers
Current enforceability	Expired

The patent record identifies the claimed invention and its priority and prosecution history. The issued claims, rather than the abstract or specification, define the enforceable scope.[1]

What do claims 1 through 5 cover?

Claims 1 through 5 establish the patent’s compound and inhalation-method framework.

Claim 1: crystalline flunisolide hemihydrate

Claim 1 is a product claim to the crystalline hemihydrate. It does not expressly require an aerosol, inhaler, surfactant, or propellant.

The claim potentially reaches the compound as a standalone pharmaceutical solid, provided the accused material has the claimed chemical identity and crystalline hemihydrate form. It does not require the particle-size limitations appearing in claims 6 and 10.

Claim 2: inhalation treatment of respiratory disease

Claim 2 covers treating a respiratory disease in a mammal by administering the claimed compound by inhalation as an aerosol.

The claim requires:

A mammal.
A respiratory disease.
Administration by inhalation.
An aerosol.
A therapeutically effective amount.
The claimed flunisolide hemihydrate.

This is a method-of-treatment claim. It does not cover oral, injectable, dermal, nasal, or ophthalmic administration unless the facts establish that the administration is also inhalation treatment of a respiratory disease.

Claim 3: aerosol with surfactant

Claim 3 narrows claim 2 by requiring an aerosol formed from:

A therapeutically effective amount of the crystalline flunisolide hemihydrate.
A pharmaceutically acceptable propellant.
An effective amount of a surfactant.

The surfactant requirement is important because it creates a formulation-specific limitation. An aerosol containing the claimed active ingredient but no surfactant would not literally satisfy claim 3, although it could remain relevant to claims 2, 6, or other claims depending on the formulation.

Claims 4 and 5: CFC propellant system

Claim 4 specifies propellants selected from:

Monofluorotrichloromethane, commonly known as CFC-11.
Dichlorodifluoromethane, commonly known as CFC-12.
Dichlorotetrafluoroethane, commonly known as CFC-114.
Mixtures of those propellants.

Claim 5 permits at least one additional pharmaceutically acceptable propellant in combination with the propellants identified in claim 4.

These claims are directed to the CFC aerosol technology used before regulatory and environmental restrictions phased out chlorofluorocarbon inhalers. They do not expressly cover every modern hydrofluoroalkane, dry-powder, nebulized, or soft-mist formulation.

What formulations are protected by claims 6 through 11?

Claims 6 through 11 cover composition-specific formulations. They provide more concrete concentration and particle-size limitations than the method claims.

Claim	Principal limitations
6	0.01% to about 20% flunisolide hemihydrate; 0.1% to about 20% surfactant; remainder pharmaceutically acceptable liquid aerosol propellant; active particle size below 100 microns
7	Claim 6 composition using a fluorinated or fluorochlorinated lower-alkane propellant
8	Lower-alkane propellant selected from CFC-11, CFC-12, CFC-114, or mixtures
9	Composition maintained under pressure as an aerosol bomb
10	0.04% to 1.0% active; 97.5% to 99.21% propellant; 0.25% to 1.5% sorbitan trioleate; active particle size below 25 microns
11	Claim 10 composition using 50% CFC-12, 25% CFC-11, and 25% CFC-114 by weight

Claim 6: broad composition range

Claim 6 is the broadest formulation claim. It requires all of the following:

Crystalline flunisolide hemihydrate.
Particle size below 100 microns.
Active concentration of 0.01% to about 20% by weight.
Surfactant concentration of about 0.1% to about 20% by weight.
Liquid aerosol propellant as the remainder.

The claim is broader than claim 10 in both active concentration and particle size. A formulation with 50-micron flunisolide particles could fall within claim 6 but outside claim 10.

Claims 7 and 8: propellant limitations

Claim 7 limits the propellant to a fluorinated or fluorochlorinated lower alkane. Claim 8 identifies the specific CFCs.

The issued text supplied for claim 8 refers to “the composition of claim 3,” even though claim 3 is a method claim and does not introduce a lower-alkane composition. That dependency appears internally inconsistent. A court would construe the issued claim based on the official patent text, prosecution history, and applicable claim-construction principles. The apparent drafting error could affect the enforceability or practical usefulness of claim 8.

Claim 9: pressurized aerosol container

Claim 9 requires that the composition be kept under pressure as an aerosol bomb. This limitation ties the claim to a pressurized metered-dose inhaler or comparable pressure vessel.

It does not naturally reach dry-powder inhalers, nebulizer solutions, or unpressurized devices.

Claims 10 and 11: narrow commercial formulation

Claim 10 narrows the formulation to:

0.04% to about 1.0% flunisolide hemihydrate.
Particle size below 25 microns.
97.5% to 99.21% propellant.
0.25% to 1.5% sorbitan trioleate.

Claim 11 adds the specific CFC blend:

50% dichlorodifluoromethane, or CFC-12.
25% monofluorotrichloromethane, or CFC-11.
25% dichlorotetrafluoroethane, or CFC-114.

Claims 10 and 11 are technically narrow but commercially significant because they correspond closely to the type of suspension aerosol used in legacy flunisolide metered-dose inhalers.

When did U.S. Patent 4,933,168 lose exclusivity?

The patent expired on June 12, 2007, based on its June 12, 1990 issue date and the 17-year term applicable to pre-1995 U.S. patents.[1] The patent therefore cannot support a current U.S. infringement action against a generic flunisolide product.

Milestone	Date or status
U.S. patent issued	June 12, 1990
Statutory term	17 years from issue
Patent expiration	June 12, 2007
Current status	Expired
Remaining patent-based generic blocker	None under this patent

The 2007 expiration date is materially different from the 20-year-from-earliest-effective-filing-date regime used for most later U.S. patents. The patent’s age places it within the earlier grant-based term system.

What was the FDA and Orange Book status of flunisolide aerosol?

Flunisolide inhalation aerosol was approved in the United States before the patent issued. The Aerobid product was a prescription inhalation aerosol for maintenance treatment of asthma. FDA labeling identified flunisolide as the active corticosteroid and described administration through a metered-dose aerosol inhaler.[2]

The historical product used CFC propellants. FDA and environmental restrictions on ozone-depleting CFCs led to withdrawal or discontinuation of many CFC-based inhalers, including legacy flunisolide aerosol products. The regulatory issue was separate from patent expiration.

Orange Book implications

Patent 4,933,168 is no longer an operative Orange Book patent barrier because it expired in 2007. A generic applicant filing an ANDA today would not face a viable Paragraph IV challenge to this patent. The patent’s expiration makes a Paragraph III certification or a Paragraph IV certification unnecessary as to this expired patent, depending on the relevant FDA listing and application context.

Orange Book analysis must distinguish among:

The approved reference product.
Any listed active ingredient or formulation patents.
Unexpired patents.
Regulatory exclusivity.
Discontinued or withdrawn dosage forms.

The patent itself did not confer perpetual market exclusivity on flunisolide. FDA approval, historical labeling, and patent protection were separate legal mechanisms.[3]

Did the patent create formulation or manufacturing barriers?

The principal technical barrier was formulation development rather than synthesis of flunisolide. The claims require a suspension aerosol with:

A defined crystalline hemihydrate.
Controlled particle size.
Surfactant.
Liquid fluorinated or fluorochlorinated propellant.
In narrower claims, a specified CFC blend.

The specification and claims indicate that physical properties such as particle size, suspension stability, dispersibility, and aerosol performance were central to the invention.[1] A manufacturer would have needed to control:

Crystal form and hydration state.
Milling or micronization.
Particle-size distribution.
Surfactant concentration.
Propellant composition.
Valve and container compatibility.
Dose uniformity during canister use.

Those development barriers were not equivalent to a permanent patent barrier. Once the patent expired, a competitor could develop a formulation around the limitations, use a different delivery platform, or reproduce a claimed formulation without facing infringement liability under this patent.

Which companies challenged or competed with the patent?

The patent’s expiration removes the current litigation incentive. Historical generic competition involved flunisolide inhalation aerosol products and ANDA applicants, but the supplied claim set does not establish a specific Paragraph IV litigant, settlement, or court judgment.

No biosimilar pathway applies. Flunisolide is a chemically synthesized small molecule, not a biologic. Competitive entry would proceed through the ANDA or another small-molecule regulatory pathway, not a biosimilar application under the Public Health Service Act.

The principal competitive products included:

Product category	Relationship to Patent 4,933,168
Aerobid flunisolide aerosol	Historical commercial product associated with the claimed inhaled formulation technology
Aerobid-M	Historical formulation/product variant
Generic flunisolide aerosol	Potentially relevant to expired formulation claims, subject to product-specific regulatory status
Fluticasone propionate inhalers	Competing inhaled corticosteroid; chemically and patent-wise distinct
Beclomethasone inhalers	Competing inhaled corticosteroid; separate active ingredient and patent estate
Budesonide inhalers	Competing inhaled corticosteroid; separate active ingredient and formulation technology
Dry-powder inhalers	Generally outside the pressurized CFC aerosol limitations
HFA inhalers	Potentially outside claims limited to specified CFC propellants, depending on exact formulation and claim construction

How strong was the patent estate for flunisolide aerosol?

The patent estate was commercially useful during the CFC metered-dose inhaler period but narrow in several respects.

Strengths

Claim 1 covered a defined crystalline hemihydrate.
Method claims linked the compound to inhaled aerosol treatment.
Composition claims covered active concentration, surfactant, particle size, and propellant.
Claims 10 and 11 addressed a commercially recognizable CFC suspension formulation.
The claims combined chemical identity with physical-form and device-delivery limitations.

Limitations

The patent did not claim flunisolide generally.
It did not expressly cover all dosage forms or inhalation devices.
Several claims depend on narrow CFC propellant systems.
Claim 8 contains an apparent dependency inconsistency.
CFC regulation reduced the commercial life of the claimed technology.
The patent expired in 2007.
No current patent enforceability remains.

The patent was strongest against a CFC-based pressurized aerosol using the claimed hemihydrate, surfactant, particle-size range, and propellant blend. It was weaker against non-CFC formulations, alternative solid forms, dry powders, nebulizer products, and unrelated flunisolide dosage forms.

What generic launch risks remain?

Patent-based launch risk under U.S. Patent 4,933,168 is effectively zero because the patent expired. Remaining launch risks would arise from other sources:

FDA approval requirements and product-specific bioequivalence.
Reference-product availability and discontinuation issues.
Device compatibility and dose-uniformity requirements.
CMC reproducibility for the flunisolide solid form.
Other unexpired patents not identified in this patent.
Labeling, exclusivity, or regulatory-market restrictions.
Commercial viability of a CFC-based product after environmental restrictions.

A generic applicant would not need to design around this patent for a current U.S. launch. It would still need to determine whether any later patents cover a different formulation, device, propellant, manufacturing process, or indication.

What licensing deals and settlements affected the patent?

Patent 4,933,168 does not disclose a licensing agreement, royalty arrangement, or generic settlement in its issued claims. A patent document cannot establish the full commercial licensing history of its owner or products.

The patent also does not establish a current settlement obligation because it expired in 2007. Any historical license or settlement would require separate transaction, litigation, or court records. No active restriction can be inferred from the expired patent alone.

Key Takeaways

U.S. Patent 4,933,168 covers crystalline flunisolide hemihydrate and aerosol formulations using that form.
The broad formulation claim requires sub-100-micron particles, surfactant, and liquid aerosol propellant.
The narrow claims target a CFC suspension aerosol with defined particle size, concentrations, and propellant blend.
Claim 8 contains an apparent dependency error because it refers to claim 3 while imposing composition limitations.
The patent issued June 12, 1990, and expired June 12, 2007.
It is not a current U.S. patent barrier to generic flunisolide inhalation products.
No biosimilar pathway applies because flunisolide is a small-molecule corticosteroid.
CFC restrictions and product discontinuation reduced the commercial relevance of the claimed technology independently of patent expiration.
Current launch analysis must focus on later patents, FDA requirements, device performance, formulation reproducibility, and market availability.

FAQs About U.S. Patent 4,933,168 and Flunisolide

Does Patent 4,933,168 claim flunisolide itself?

No. Claim 1 claims a specified crystalline hemihydrate form of flunisolide. The patent does not claim every physical form of the flunisolide molecule.

Can a generic use HFA propellant without infringing the patent?

The claims expressly identify CFC propellants in the narrower claims. An HFA product may avoid those limitations, but infringement would depend on the complete formulation and whether another claim applies.

Is flunisolide subject to biosimilar competition?

No. Flunisolide is a chemically synthesized small molecule. Generic competition uses the ANDA framework rather than the biosimilar pathway.

Did the patent protect Aerobid’s inhaler device?

The claims primarily protect the active crystalline form, aerosol composition, and method of inhalation treatment. They do not broadly claim every mechanical inhaler component or device architecture.

Can the expired patent still block a flunisolide launch?

No. An expired patent cannot support an infringement injunction or damages claim for post-expiration conduct. A launch could still face separate regulatory, manufacturing, labeling, or later-patent issues.

References

United States Patent No. 4,933,168. (1990). Flunisolide hemihydrate aerosol compositions. U.S. Patent and Trademark Office.
U.S. Food and Drug Administration. (n.d.). Aerobid and Aerobid-M flunisolide inhalation aerosol prescribing information. FDA.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA, Center for Drug Evaluation and Research.
U.S. Environmental Protection Agency. (n.d.). Protection of stratospheric ozone: Class I ozone-depleting substances and CFC restrictions. EPA.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	357702	⤷ Start Trial
Austria	A388376	⤷ Start Trial
Australia	1430176	⤷ Start Trial
Australia	506080	⤷ Start Trial
Belgium	842192	⤷ Start Trial
Canada	1075228	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,933,168

Summary for Patent: 4,933,168