US Patent 6,333,044: Intranasal Ketorolac Scope, Claims, Expiration and Patent Landscape

US Patent 6,333,044 protects intranasal liquid dosage forms and treatment methods using ketorolac, particularly ketorolac tromethamine, at concentrations of about 5% to 20% weight/volume. Its most commercially relevant subject matter is an aqueous ketorolac tromethamine spray that is rapidly absorbed through the nasal mucosa and excludes thermoresponsive viscosity-increasing polymers. The patent’s enforceable term has expired under the standard US patent-term framework, so its claims no longer create a current US exclusion right. The technical disclosure remains relevant to generic, reformulated and alternative intranasal ketorolac products. [1, 2]

What drug and dosage form does US 6,333,044 protect?

The patent covers formulations containing 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, the active moiety known as ketorolac. The claims cover:

Racemic ketorolac.
Optically active ketorolac forms.
Pharmaceutically acceptable salts.
Ketorolac tromethamine.
Aqueous solutions and suspensions.
Intranasal sprays and atomizer-delivered products.
Single-dose liquid dosage forms.
Bioadhesive formulations.
Formulations containing intranasal absorption promoters.
Treatment of pain and inflammatory conditions by nasal administration.

The commercial center of gravity is the ketorolac tromethamine aqueous spray described in claims 27-34, 42-49 and 51.

Core formulation architecture

The broad independent formulation claims require a combination of five elements:

A systemically effective amount of ketorolac or an accepted salt.
A pharmaceutically acceptable excipient or diluent.
Intranasal administration.
Rapid transmucosal absorption sufficient to produce analgesic or anti-inflammatory blood levels.
A liquid dosage form, with certain claims expressly excluding thermosetting or thermoresponsive polymers.

The claims do not require a particular commercial spray pump in every case. Claims 23 and 34 expressly add a spray container or atomizer, while the broader claims can cover a liquid dosage form intended for nasal delivery without requiring a specific device configuration.

How broad are the independent claims?

Claim 1: broad intranasal dosage-form claim

Claim 1 is directed to an analgesic or anti-inflammatory pharmaceutical liquid containing ketorolac in racemic, optically active or salt form. The dosage form must be non-thermosetting, intranasally administrable, rapidly absorbed through the nasal mucosa and capable of achieving effective systemic blood levels.

The principal limitations are functional rather than compositional. A competing product could fall within the claim even if it uses different excipients, provided the product:

Is liquid.
Is administered intranasally.
Produces effective systemic ketorolac exposure.
Is rapidly absorbed transmucosally.
Does not rely on a thermosetting dosage-form system.

The claim does not require ketorolac tromethamine specifically. It reaches the free acid, stereoisomers and pharmaceutically acceptable salts.

Claim 14: method claim corresponding to claim 1

Claim 14 covers treatment of traumatic or pathological pain and inflammatory processes using an intranasal dosage form with the same functional characteristics. It is broader than the formulation claims in one respect because infringement turns on administration and treatment, not only on sale or manufacture of the formulation.

The claim requires:

A patient with pain or inflammation.
Intranasal administration.
A systemically effective ketorolac-containing dosage form.
Rapid transmucosal absorption.
Blood levels effective for analgesic or anti-inflammatory treatment.

Claim 21: non-thermosensitive formulation claim

Claim 21 removes the express "non-thermosetting" terminology used in claim 1 but adds a negative limitation. The dosage form must be free of polymers that provide low viscosity at room temperature and increased viscosity at body temperature.

This limitation distinguishes the claimed products from thermoresponsive nasal gels. A formulation that uses a conventional viscosity modifier but does not undergo the specified temperature-dependent viscosity increase may remain within the claim. The claim is not limited to a particular viscosity, pH, osmolality or spray pattern.

Claim 51: commercially focused composition claim

Claim 51 is the narrowest and most commercially recognizable independent claim. It covers:

An aqueous intranasal solution.
A bottle suitable for delivering a spray.
About 5% to about 20% weight/volume ketorolac tromethamine.
Optional sodium EDTA below about 0.1% weight/volume.
Optional preservative.
No polymer that increases viscosity at body temperature relative to room temperature.

This claim is directed to a product configuration close to a commercial ketorolac nasal spray. The concentration range is approximately 50 to 200 mg/mL of ketorolac tromethamine, depending on how the weight/volume percentage is expressed.

What concentration ranges are covered?

Claim group	Ketorolac concentration or dose
Claims 2 and 15	0.5-40 mg
Claims 3	2-20 mg
Claims 16	5-30 mg
Claims 5, 17, 24, 39, 44	5%-20% weight/volume
Claims 7, 18, 25, 30, 40, 45	15% weight/volume
Claims 29 and 30	5%-20% ketorolac tromethamine, with 15% specified
Claim 51	About 5%-20% ketorolac tromethamine

The claims mix dose-based and concentration-based limitations. A product can avoid a dependent claim by using a different concentration while still potentially implicating claim 1, 14, 21, 36 or 51 if all limitations of the applicable independent claim are met.

Which excipients and absorption promoters are protected?

Claims 8-10 and 13 cover formulations containing bioadhesives or mucosal absorption promoters.

Claim 10 identifies:

POE (9) lauryl alcohol.
Sodium glycocholate.
Lysophosphatidyl choline.

Claim 13 covers a mucosal absorption promoter that is not a mucosal irritant. This creates a functional limitation that may require evidence concerning irritation and absorption performance. A promoter not listed in claim 10 can still fall within claim 13 if it satisfies the non-irritant and absorption-promoting limitations.

Claims 31, 32, 46 and 47 cover aqueous ketorolac tromethamine solutions with optional excipients selected from:

Humectants.
Isotonic agents.
Antioxidants.
Buffers.
Preservatives.
Chelating agents.

Claims 32 and 47 are narrower because they focus on chelating agents and optional preservatives. Claim 51 expressly identifies sodium ethylenediaminetetraacetic acid, commonly sodium EDTA, at less than about 0.1% weight/volume.

What is the importance of the thermoresponsive-polymer exclusion?

The negative limitation appears in claims 21 and 36 and is central to claim 51. It excludes polymers that produce:

Low viscosity at room temperature; and
Increased viscosity at body temperature.

This limitation targets in situ gelling systems. Typical thermoresponsive nasal delivery technologies use polymers or polymer combinations that remain sufficiently fluid during administration and thicken after contact with nasal tissue.

A conventional aqueous spray with no temperature-triggered viscosity increase is the most direct claim target. A product using a polymer requires a formulation-specific analysis. The mere presence of a polymer does not automatically avoid the claims. The relevant question is whether the polymer provides the specified temperature-dependent viscosity profile.

How do the formulation claims compare with the method-of-use claims?

Issue	Formulation claims	Method claims
Primary subject	Product composition and delivery format	Treatment by intranasal administration
Key active	Ketorolac, salts or stereoisomers	Same
Required route	Intranasal dosage form	Intranasal administration
Required result	Effective systemic blood levels	Treatment of pain or inflammation
Concentration limitations	Present in dependent claims	Present in dependent claims
Spray-device limitation	Express in claims 23 and 34	Express in claim 38 and claim 49
Thermoresponsive-polymer exclusion	Claims 21 and 51	Claim 36 and its dependents
Commercial relevance	Product manufacture, sale and supply	Administration and treatment-use exposure

The method claims can raise different infringement questions from the composition claims. A manufacturer may face product-claim issues even where the intended use is not expressly stated. Method claims may depend on the labeled indication, prescribing information, instructions for use and actual administration.

When did US Patent 6,333,044 expire?

US Patent 6,333,044 was granted on December 25, 2001. Its term was governed by the post-1995 US patent-term statute, generally providing 20 years from the earliest effective nonprovisional filing date, subject to patent-term adjustment, patent-term extension and terminal-disclaimer issues. [1, 3]

The patent is no longer an enforceable US exclusion right. Its ordinary term expired no later than the early 2020s and appears to have expired before the current commercial period for intranasal ketorolac products. A current freedom-to-operate opinion should confirm the USPTO maintenance, term-adjustment and terminal-disclaimer records, but the patent itself should be treated as expired rather than as a live blocking patent.

The expiration of 6,333,044 does not eliminate later patents directed to:

Specific intranasal ketorolac formulations.
Spray devices.
Metered-dose delivery.
Stability improvements.
Preservative systems.
Dose regimens.
Manufacturing processes.
Commercial products approved after the patent’s filing date.

What is the Orange Book status of US 6,333,044?

US 6,333,044 is not itself the controlling Orange Book position for current intranasal ketorolac products. The Orange Book lists patents submitted by an NDA holder for an approved drug product and does not create patent rights independently of the underlying patent. [4]

The relevant FDA-approved intranasal ketorolac product is SPRIX, a prescription nasal spray containing ketorolac tromethamine. FDA approved SPRIX under NDA 022382 in 2010 for short-term treatment of moderate to moderately severe pain in adults requiring analgesia at the opioid level. [5]

For a current product assessment, the relevant Orange Book questions are:

Which patents are listed against NDA 022382?
Which listed patents cover the formulation, device or method of use?
When do the listed patents expire?
Are any patents subject to pediatric exclusivity or patent-term adjustment?
Have generic applicants submitted Paragraph IV certifications?

The expiration of 6,333,044 does not establish that all later Orange Book-listed patents covering SPRIX have expired.

Which companies challenged or competed with the intranasal ketorolac estate?

The primary commercial competition has involved three categories.

Injectable and oral ketorolac products

Ketorolac was commercialized in oral and injectable dosage forms before intranasal products. These products compete clinically but do not necessarily practice the intranasal formulation claims of US 6,333,044.

SPRIX and its commercial owners

SPRIX is the most important branded intranasal ketorolac product. Its commercial history has involved product-rights transfers and licensing arrangements among companies active in specialty pharmaceuticals. Public commercial ownership has changed over time, including rights associated with Roxro Pharma and later specialty-pharmaceutical companies. The commercial owner at a given date must be distinguished from the original patent applicant and from the NDA holder listed by FDA.

Generic and reformulated entrants

A generic intranasal ketorolac applicant would normally use the ANDA pathway if it seeks approval as a therapeutically equivalent version of an approved product. It would need to address listed patents through a certification under 21 U.S.C. § 355(j), including a Paragraph IV certification where it contends that a listed patent is invalid, unenforceable or will not be infringed. [6]

No biosimilar pathway applies because ketorolac is a small-molecule drug, not a biologic. The relevant competitive pathway is ANDA approval, not abbreviated biologics licensing under section 351(k).

What Paragraph IV and litigation risks remain?

Patent 6,333,044

Because US 6,333,044 is expired, it should not generate a current Paragraph IV launch block. A Paragraph IV certification is directed to an unexpired listed patent. The patent can remain relevant as prior art and as evidence of technical disclosure, but it should not support a current injunction based solely on its expired claims.

Later patents

The practical litigation risk resides in later patent families covering the approved product or its delivery system. A generic applicant must evaluate:

Product-by-process limitations.
Exact ketorolac salt and concentration.
Spray-metering performance.
Bottle and actuator geometry.
Preservative and chelator content.
Label language and method-of-use claims.
Stability and storage conditions.
Any listed patent covering the FDA-approved formulation.

An ANDA certification against a live Orange Book patent can trigger a statutory 30-month stay if the NDA holder or patent owner brings a timely infringement action. [6]

Settlement agreements

Patent settlements involving intranasal ketorolac would need to be reviewed in the Federal Trade Commission’s pharmaceutical patent-settlement reporting system, SEC filings, district-court dockets and FDA product records. The existence of a settlement involving a later patent would not revive or extend the term of US 6,333,044.

How strong is the patent estate for intranasal ketorolac?

Historical strength

The patent was technically strong against products that adopted its central combination:

Ketorolac tromethamine.
Aqueous liquid.
Nasal spray.
Rapid systemic absorption.
Approximately 5%-20% weight/volume concentration.
No thermoresponsive polymer.

The broad independent claims contain functional limitations that could create factual disputes over absorption rate and effective blood levels. The narrower claims are easier to test because they specify concentration, salt, aqueous carrier, spray delivery and optional excipient categories.

Current legal strength

The current exclusionary strength of US 6,333,044 is effectively zero because the patent term has ended. Its residual business value is limited to:

Prior-art analysis.
Formulation-history research.
Claim construction for related patent families.
Identification of technical design choices.
Support for invalidity or obviousness analysis against later patents.

Vulnerability points in claim construction

Several claim elements could have limited the patent even during its term:

"Rapidly absorbable" requires a factual comparison against an appropriate standard.
"Systemically effective amount" depends on pharmacodynamic or pharmacokinetic evidence.
"Blood levels ... effective" requires evidence connecting plasma concentration with treatment.
"Non-thermosetting" and the polymer exclusion require formulation testing.
"Not a mucosal irritant" may require clinical or toxicological evidence.
"Consisting essentially of" in claims 31, 32, 46 and 47 permits only additional ingredients that do not materially alter the basic and novel characteristics.

What generic launch scenarios exist?

Scenario	Patent impact of US 6,333,044	Commercial implication
Aqueous ketorolac tromethamine spray at 15%	Expired patent does not block launch	Later listed patents and FDA exclusivity control timing
Spray using a thermoresponsive polymer	Patent 6,333,044 may not cover the product because of the exclusion	Other formulation patents may apply
Non-aqueous ketorolac nasal formulation	May avoid aqueous claims and some dependent claims	Requires separate safety, stability and device analysis
Lower-concentration spray	May avoid concentration dependents	Broad independent claims and later patents remain relevant
Different ketorolac salt	May remain within broad Markush claims, but patent is expired	Salt-specific patents and regulatory requirements may matter
Alternative nasal device	Claims 23 and 34 may not apply if no claimed container or atomizer is used	Device patents may create separate exposure
Oral, topical or injectable ketorolac	Outside the intranasal route limitations	Separate product and method estates apply

What manufacturing and intellectual-property barriers remain?

Manufacturing barriers are more likely to arise from later product-specific rights and FDA requirements than from US 6,333,044. A competing intranasal product must control:

Ketorolac concentration and salt form.
Solution clarity and precipitation.
pH and osmolality.
Microbial quality.
Preservative compatibility.
Pump dose uniformity.
Droplet-size distribution.
Container-closure integrity.
Nasal tolerability.
Stability after repeated actuation.

The patent’s claim 51 architecture suggests a relatively simple aqueous formulation, but commercial equivalence also depends on the delivery device and dose delivered per spray. FDA approval requires product quality and clinical or bioequivalence support appropriate to the regulatory pathway, not merely a formulation that falls outside an expired claim. [5, 7]

Key Takeaways

US 6,333,044 is directed to intranasal ketorolac liquid dosage forms and treatment methods.
The most relevant commercial embodiments are aqueous ketorolac tromethamine sprays at approximately 5%-20% weight/volume.
Claim 51 specifically targets a spray bottle containing about 5%-20% ketorolac tromethamine, optional low-level sodium EDTA and optional preservative.
Claims 21, 36 and 51 exclude thermoresponsive polymers that increase viscosity at body temperature.
Claims 8-10 and 13 cover bioadhesives and selected mucosal absorption promoters.
The patent’s US term has expired, so it should not be treated as a current launch-blocking patent.
Current risk must be assessed against later Orange Book-listed patents for SPRIX or other approved intranasal ketorolac products.
Ketorolac is a small molecule, so generic competition proceeds through the ANDA pathway rather than the biosimilar pathway.
A Paragraph IV challenge would focus on unexpired later-listed patents, not on the expired 6,333,044 patent.
The remaining technical barriers are device performance, dose uniformity, stability, nasal tolerability and FDA approval requirements.

FAQs on US Patent 6,333,044 and Intranasal Ketorolac

Does US 6,333,044 cover SPRIX?

The patent covers the technical concept embodied by an aqueous intranasal ketorolac tromethamine spray, including concentration ranges and non-thermoresponsive formulations. It is not, by itself, the complete current patent position for SPRIX.

Can a company launch an intranasal ketorolac product after expiration of US 6,333,044?

Expiration removes the patent’s exclusion right, but a launch still requires FDA approval and a review of later patents, Orange Book listings, device rights, trademarks and regulatory exclusivities.

Does using ketorolac tromethamine avoid the broad claims?

No. Ketorolac tromethamine is expressly covered by dependent claims 26-34 and 41-49 and falls within the broader salt language in the independent claims.

Does a formulation with a conventional polymer necessarily avoid the patent?

No. The relevant issue is whether the polymer provides low viscosity at room temperature and increased viscosity at body temperature. A conventional non-thermoresponsive polymer may not satisfy that exclusion.

Is a biosimilar application required for intranasal ketorolac?

No. Ketorolac is a small-molecule active ingredient. A competing product would generally use the ANDA route or, depending on the product and regulatory strategy, an NDA pathway.

References

United States Patent and Trademark Office. (2001). US Patent No. 6,333,044, intranasal ketorolac dosage forms and methods.
35 U.S.C. § 154. Patent term.
35 U.S.C. § 156. Patent-term extension and restoration.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
U.S. Food and Drug Administration. (2010). SPRIX (ketorolac tromethamine) nasal spray prescribing information.
21 U.S.C. § 355(j). Abbreviated new drug applications and patent certifications.
U.S. Food and Drug Administration. (2013). Guidance for industry: Bioequivalence recommendations for ketorolac tromethamine nasal spray.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Italy	MI91A2024	Jul 22, 1991

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	130758	⤷ Start Trial
Germany	69206345	⤷ Start Trial
Denmark	0524587	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 6,333,044