US Patent 5,547,994: Scope, Claim Construction, Expiration, and Levalbuterol Patent Landscape

US Patent 5,547,994 covers methods of treating an acute asthma attack with substantially pure R(-)-albuterol, now known as levalbuterol, instead of racemic albuterol. The patent claims the therapeutic use of the R enantiomer, purity thresholds above 90% and 99%, an inhaled dose of approximately 30 to 90 micrograms, and certain combination therapies.

The patent was assigned to Sepracor Inc. and issued on August 20, 1996. Its patent term expired on August 20, 2013. The patent therefore does not create current US patent exclusivity for levalbuterol products. Its historical importance was substantial because it established the core method-of-use position for Xopenex, the single-enantiomer version of albuterol.

What invention does US Patent 5,547,994 protect?

The patent protects the use of optically pure R(-)-albuterol to treat an acute asthma attack while reducing side effects associated with racemic albuterol.

R(-)-albuterol is the bronchodilating enantiomer of albuterol. The corresponding S(+)-enantiomer was claimed by the patent specification to contribute little or nothing to bronchodilation and potentially to undesirable effects. The commercial product based on R(-)-albuterol is levalbuterol.

The invention has four principal technical elements:

Treatment of an acute asthma attack.
Administration of R(-)-albuterol.
R(-)-albuterol is substantially free of S(+)-albuterol.
Treatment produces bronchodilation while reducing side effects associated with racemic albuterol.

The patent is a method-of-treatment patent. It does not, based on the supplied claims, claim the albuterol molecule itself, a particular inhaler device, a pharmaceutical composition, or a manufacturing process.

How broad is independent claim 1?

Claim 1 is broad in the therapeutic and formulation sense but narrow in the identity of the active ingredient.

Claim limitation	Scope
Patient	An individual suffering from an acute attack of asthma
Disease state	Acute asthma attack
Active ingredient	Optically pure R(-)-albuterol
Excluded material	R(-)-albuterol must be substantially free of S(+)-albuterol
Therapeutic result	Bronchodilation
Additional result	Simultaneous reduction of undesirable side effects associated with acute racemic albuterol
Route	Not expressly limited
Dose	Not expressly limited
Combination therapy	Not required

Claim 1 does not require inhalation. In principle, the claim language covers any administration route capable of delivering a sufficient quantity of R(-)-albuterol, provided the other limitations are satisfied. Claim 4 narrows the invention to inhalation and a specified dose range.

The claim also does not state a numerical purity threshold. The phrase "substantially free of its S(+) isomer" must therefore be interpreted in light of the specification, dependent claims, prosecution history, and the relevant technical meaning of optical purity. Claims 2 and 3 provide numerical examples of the purity concept, but they do not necessarily define the entire scope of claim 1.

What do claims 2 and 3 add?

Claims 2 and 3 create explicit purity-based fallback positions.

Claim	Additional requirement
Claim 2	R(-)-albuterol is greater than approximately 90% by weight
Claim 3	R(-)-albuterol is greater than 99% by weight

Claim 3 is the narrowest purity claim in the patent. It is directed to material with greater than 99% R(-)-albuterol by weight. A product containing 99% or less R(-)-albuterol would not literally satisfy the express percentage limitation of claim 3, although it could still fall within claim 1 or claim 2 depending on the evidence.

The term "approximately" in claim 2 introduces a potential claim-construction issue. The phrase allows some tolerance around 90%, but its precise scope would depend on the intrinsic evidence and the technical context. Claim 3 is less dependent on approximation because it states "greater than 99% by weight."

The purity claims are important because a generic or follow-on product could attempt to avoid a numerical claim by using a lower optical purity. That strategy would not automatically avoid claim 1, which has no numerical purity threshold but requires the material to be substantially free of the S enantiomer.

What does claim 4 protect?

Claim 4 covers:

treatment of an acute asthma attack;
administration of R(-)-albuterol substantially free of S(+)-albuterol;
administration by inhalation; and
a dose of approximately 30 to 90 micrograms per dose.

Claim 4 is narrower than claims 1 through 3 because it requires both inhalation and a dose range. It is particularly relevant to metered-dose inhalers and other inhalation products delivering a dose within or near the claimed range.

The claim does not expressly require a particular inhaler device, propellant, excipient, particle size, concentration, or dosing schedule. A product could therefore fall within claim 4 based on its delivered dose even if its device and formulation differed from the commercial Xopenex product.

A key issue would be whether "per dose" refers to the nominal dose, emitted dose, or delivered dose. The patent specification and prosecution record would be relevant to that distinction. The claim language alone does not resolve it.

What do claims 5 and 6 cover?

Claim 5 covers the same core method as claim 1 but requires administration of at least one additional drug from three categories:

bronchodilators;
antihistamines; or
analgesics.

Claim 6 narrows the analgesic category to:

aspirin;
acetaminophen; or
ibuprofen.

The combination claims do not include the purity percentages of claims 2 and 3 unless those limitations are incorporated through claim dependency. Claim 5 depends directly on claim 1, so it retains claim 1's requirement that the R(-)-albuterol be substantially free of S(+)-albuterol.

The combination claims are commercially narrower than claim 1. Acute asthma treatment may involve other bronchodilators, but routine coadministration of antihistamines or analgesics would need to be established in the relevant treatment setting. Claim 6 is especially limited because it requires one of three named analgesics.

What infringement elements would have to be proven?

A method claim is infringed when a party performs the claimed method or induces another party to perform it. For US Patent 5,547,994, the principal elements would have included:

Treatment of a patient experiencing an acute asthma attack.
Administration of R(-)-albuterol.
R(-)-albuterol substantially free of S(+)-albuterol.
A quantity sufficient to produce bronchodilation.
Simultaneous reduction of undesirable side effects associated with racemic albuterol.

For claim 4, inhalation and the 30 to 90 microgram dose would also have to be shown. For claims 5 and 6, the additional drug limitation would be required.

The functional language concerning reduced side effects creates the central evidentiary issue. A patentee would need to establish that the claimed treatment has the stated therapeutic result, although the precise proof required would depend on claim construction and the litigation record. A product label instructing use of levalbuterol for acute asthma treatment could have supported induced-infringement allegations during the patent term if the label also practiced the remaining claim limitations.

When did US Patent 5,547,994 expire?

US Patent 5,547,994 expired on August 20, 2013, based on the 17-year term applicable to the relevant pre-1995 US patent application framework. The patent therefore cannot block current US manufacture, sale, or use of levalbuterol on its own.

Event	Date
Priority filing	June 22, 1993
US application filing	June 22, 1994
Patent issued	August 20, 1996
Patent term expiration	August 20, 2013

The expiration of this patent removed the principal composition-independent method-of-use barrier associated with single-enantiomer albuterol. It did not necessarily eliminate every patent that could have covered a particular levalbuterol formulation, inhaler, manufacturing process, or later-developed delivery system.

What was the FDA and Orange Book status?

Xopenex, containing levalbuterol hydrochloride, was approved by the FDA in 1999 under NDA 20-837 for treatment or prevention of bronchospasm in patients with reversible obstructive airway disease. The product was initially marketed as an inhalation solution and later as an inhalation aerosol.

US Patent 5,547,994 was historically associated with the Xopenex patent estate and was relevant to Orange Book-based generic-entry analysis. FDA Orange Book listings are product-specific and can change through delisting, expiration, patent-term adjustments, pediatric extensions, or later product approvals. Patent expiration, rather than NDA approval, determined the end of the enforceable term for this patent.

The principal regulatory milestones were:

Regulatory event	Status
Xopenex NDA approval	1999
Core method-of-use patent	US 5,547,994
Core patent expiration	August 20, 2013
3-year FDA exclusivity	Expired
Current relevance of US 5,547,994	Historical; no live patent term

FDA exclusivity and patent protection are separate. The statutory exclusivity associated with the original approval did not extend through the patent's expiration date. Generic levalbuterol entry therefore became primarily a question of additional listed patents, ANDA certification, product-specific formulation rights, and commercial readiness.

How did this patent affect Paragraph IV challenges?

Before August 2013, an ANDA applicant seeking approval for a product that relied on Xopenex could have faced a Paragraph IV certification against listed patents, including US 5,547,994 if it was listed for the relevant reference product.

A Paragraph IV certification asserts that a listed patent is invalid, unenforceable, or will not be infringed. Under the Hatch-Waxman framework, the filing of a Paragraph IV notice can trigger patent litigation and a 30-month FDA approval stay if the patent holder files suit within the statutory period.[3]

For this patent, the key challenge theories would have included:

Challenge theory	Potential issue
Invalidity for obviousness	Whether use of the R enantiomer for bronchodilation would have been predictable
Lack of written description	Whether the specification adequately supported the claimed purity and side-effect reduction
Lack of enablement	Whether the full scope of "substantially free" material was enabled
Indefiniteness	Meaning of "optically pure," "substantially free," and "undesirable side effects"
Noninfringement	Product not used for acute asthma attacks, insufficient purity, or no claimed therapeutic result
Prior public use or publication	Earlier disclosure of enantiomeric albuterol or stereoselective bronchodilation

Because the patent expired in 2013, it no longer presents a current Paragraph IV barrier. Any present generic-entry dispute would have to arise from later patents or regulatory exclusivities.

Which patent categories were relevant to the levalbuterol estate?

The commercial patent landscape for Xopenex extended beyond US Patent 5,547,994. The relevant categories included the following.

Core single-enantiomer method patents

These patents covered treating asthma or bronchospasm with R(-)-albuterol instead of racemic albuterol. US Patent 5,547,994 is the principal example in the supplied claim set.

Formulation patents

Later patents could cover:

levalbuterol inhalation solutions;
concentration and pH ranges;
preservative-free formulations;
stability-enhancing excipients;
unit-dose ampoules;
aerosol formulations;
hydrofluoroalkane propellant systems; and
particle or droplet characteristics.

A formulation patent would require separate claim analysis. A generic could avoid a formulation claim by using different excipients, concentrations, containers, or delivery technologies while still practicing the expired method claims.

Device and delivery patents

Inhaler patents could cover:

metered-dose valve structures;
actuator designs;
dose counters;
nebulizer components;
aerosolization methods; and
delivery profiles.

US Patent 5,547,994 does not require a particular device. Device patents therefore would have created a separate infringement question.

Manufacturing and process patents

Process protection could cover:

resolution of racemic albuterol;
asymmetric synthesis;
purification of the R enantiomer;
salt formation;
crystallization;
control of residual S enantiomer; and
manufacture of stable inhalation products.

These rights could create manufacturing barriers even after expiration of the core therapeutic-use patent. They would not, however, restore exclusivity over the broad use of levalbuterol once the method patent expired.

How strong was the patent estate?

US Patent 5,547,994 was commercially strong during its term because it targeted the central clinical distinction between racemic albuterol and levalbuterol. The claim set reached the active-enantiomer treatment concept rather than a narrow excipient or device configuration.

Its strongest features were:

coverage of acute asthma treatment;
coverage of R(-)-albuterol substantially free of S(+)-albuterol;
explicit fallback claims above 90% and 99% purity;
a clinically relevant inhaled-dose claim; and
coverage of certain combination regimens.

Its principal weaknesses were claim-construction and proof issues:

"optically pure" is not a fixed numerical term in claim 1;
"substantially free" lacks an express percentage in the independent claims;
"reducing undesirable side effects" is functional language;
the claims are directed to a method, not a composition or device;
the additional combination claims are commercially narrow; and
the patent's term has ended.

The patent was strongest as a blocking right against a labeled generic product expressly directed to acute asthma treatment with high-purity levalbuterol during the patent term. It would have been less certain against an unlabeled or differently labeled product, a lower-purity formulation, or a product that avoided the claimed acute-attack indication.

How does US Patent 5,547,994 compare with racemic albuterol patents?

Issue	US 5,547,994	Racemic albuterol patent estate
Active ingredient	R(-)-albuterol, levalbuterol	Racemic albuterol
Core protection	Method of treating acute asthma	Compound, formulation, method, or device rights
S-enantiomer	Must be substantially excluded	Present by definition
Purity limitation	Express claims above 90% and 99%	Generally not applicable
Dose limitation	Inhaled 30 to 90 micrograms in claim 4	Product-specific
Current patent status	Expired in 2013	Depends on the individual patent
Primary commercial product	Xopenex	Ventolin and other albuterol products

Levalbuterol competed commercially with racemic albuterol on the theory that removing the S enantiomer could provide bronchodilation with fewer adverse effects. The patent's claims reflect that product-positioning strategy directly.

What generic-entry risks existed?

During the patent term, the principal risk was a generic product that:

contained highly purified levalbuterol;
was labeled for acute asthma or bronchospasm;
was administered by inhalation;
used a dose within the 30 to 90 microgram range; or
included one of the claimed additional drugs.

After expiration, the core risk shifted from US Patent 5,547,994 to:

later formulation patents;
inhaler or nebulizer patents;
manufacturing patents;
regulatory exclusivity;
product-specific labeling;
supply-chain control of high-purity R-albuterol; and
commercial substitution and reimbursement barriers.

Biosimilar risk does not apply in the conventional statutory sense. Levalbuterol is a small-molecule drug, not a biologic. Competitors enter through the ANDA pathway as generic drugs rather than through the biosimilar pathway under the Biologics Price Competition and Innovation Act.

What licensing and litigation issues were associated with the patent?

Sepracor developed and commercialized the single-enantiomer albuterol program and marketed Xopenex. The relevant commercial structure was based primarily on Sepracor's own product development and later corporate transactions, including the acquisition of Sepracor by Dainippon Sumitomo Pharma in 2010. The patent was therefore part of a broader corporate asset transfer involving Xopenex, rather than a stand-alone molecule license that remained commercially decisive after expiration.[4]

The principal litigation risk during the term would have involved ANDA applicants challenging the patent under Paragraph IV. After August 20, 2013, the patent could no longer support an injunction against future generic manufacture or sale. Any settlement that delayed entry beyond expiration would have had to be evaluated against the antitrust standards applicable to patent settlements and the remaining scope of any unexpired patents.

Key Takeaways

US Patent 5,547,994 covers treating acute asthma with substantially pure R(-)-albuterol, now called levalbuterol.
Claim 1 is a broad method-of-treatment claim with no express numerical purity threshold.
Claims 2 and 3 provide explicit purity positions above approximately 90% and above 99%.
Claim 4 covers inhaled doses of approximately 30 to 90 micrograms.
Claims 5 and 6 cover specified combination therapies.
The patent does not claim the albuterol molecule, a specific inhaler, a particular formulation, or a manufacturing process.
The patent expired on August 20, 2013.
It no longer creates current US patent exclusivity or a current Paragraph IV barrier.
Levalbuterol is a small molecule, so biosimilar analysis is not applicable.
Current competitive risk depends on later formulation, device, manufacturing, regulatory, and commercial rights rather than this expired patent.

FAQs About US Patent 5,547,994 and Levalbuterol

Does US Patent 5,547,994 cover Xopenex itself?

No. The supplied claims cover methods of using R(-)-albuterol. They do not, by themselves, claim every composition or device containing levalbuterol.

Can a generic avoid claim 3 by using 98% R(-)-albuterol?

A product containing 98% R(-)-albuterol would not literally satisfy the "greater than 99% by weight" limitation of claim 3. It could still raise issues under claim 1 or claim 2, subject to the meaning of "substantially free" and "greater than approximately 90%."

Does the patent cover treatment of chronic asthma?

The supplied claims are directed to an "acute attack of asthma." Chronic maintenance treatment is outside the express wording unless the facts establish that the claimed acute-attack limitation is satisfied.

Does claim 1 require an inhaler?

No. Claim 1 does not specify inhalation. Claim 4 expressly adds inhalation and the 30 to 90 microgram dose range.

Is levalbuterol subject to biosimilar competition?

No. Levalbuterol is a small-molecule drug. The relevant pathway is generic approval through an ANDA, not biosimilar approval.

References

United States Patent and Trademark Office. (1996). US Patent No. 5,547,994, Method of treating asthma using R-albuterol. U.S. Department of Commerce.
U.S. Food and Drug Administration. (1999). Xopenex (levalbuterol hydrochloride) inhalation solution, NDA 20-837: Approval information and prescribing information. U.S. Department of Health and Human Services.
U.S. Food and Drug Administration. (2023). Approved drug products with therapeutic equivalence evaluations: Orange Book. U.S. Department of Health and Human Services.
Dainippon Sumitomo Pharma Co., Ltd. (2010). Acquisition of Sepracor Inc. and related product and intellectual-property information. Corporate transaction materials.
21 U.S.C. §§ 355 and 371. (2023). Federal Food, Drug, and Cosmetic Act provisions governing abbreviated applications, patent certifications, and regulatory exclusivity.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	135908	⤷ Start Trial
Australia	7174191	⤷ Start Trial
Canada	2073181	⤷ Start Trial
Germany	69118359	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,547,994

Summary for Patent: 5,547,994