US Patent 6,727,286: Ibuprofen-Arginine Composition, Claim Scope, Expiration, and Patent Landscape

US Patent 6,727,286 covers aqueous arginine-ibuprofen pharmaceutical compositions, manufacturing methods, and therapeutic uses where the arginine-to-ibuprofen molar ratio is no greater than 0.97:1. The patent’s commercial significance was tied to injectable ibuprofen products, particularly Caldolor. Its US patent term expired in 2021, so the patent no longer creates a current US exclusionary barrier to generic development or commercialization.

What does US Patent 6,727,286 protect?

The patent protects three principal subject-matter groups:

Pharmaceutical compositions containing aqueous arginine and ibuprofen.
Methods for preparing those solutions.
Methods of treating pain, inflammation, fever, and patent ductus arteriosus using the solutions.

The central technical limitation is the molar ratio:

Arginine:ibuprofen of less than or equal to 0.97:1.

This ratio is the principal boundary of the independent claims. A composition containing one mole or less of arginine for each mole of ibuprofen falls within the literal scope of claim 1 if the other limitations are satisfied.

Core claim architecture

Claim group	Claims	Subject matter	Main limitation
Composition	1-11, 39-40	Aqueous arginine-ibuprofen solution	Arginine:ibuprofen ≤0.97:1
Manufacturing method	12-22, 41-42	Dissolving arginine in water, then ibuprofen in the arginine solution	Arginine:ibuprofen ≤0.97:1
Treatment method	23-36, 38, 43-44	Treating pain, inflammation, fever, or patent ductus arteriosus	Administration of qualifying solution
Product-by-process composition	37	Composition prepared according to claim 12	Incorporates the claim 12 process

The dependent claims narrow the invention by specifying ratio ranges, stereochemistry, sterilization, lyophilization, route of administration, dosage, and indications.

How broad is the scope of the independent claims?

Claim 1: aqueous composition

Claim 1 requires:

A pharmaceutical composition;
An aqueous solution;
Arginine;
Ibuprofen; and
An arginine-to-ibuprofen molar ratio of no more than 0.97:1.

The claim does not, on its face, require:

Intravenous administration;
A particular concentration;
A particular pH;
A particular container;
A particular excipient;
Sterility;
A liquid dosage form at the time of sale;
Racemic or S-ibuprofen specifically; or
L-arginine specifically.

The absence of those limitations gives claim 1 materially broader coverage than the dependent claims directed to injectable, sterile, lyophilized, or stereochemically defined products.

The word “aqueous” is important. A fully dry tablet, capsule, or nonaqueous formulation would not ordinarily satisfy the express aqueous-solution limitation. A product supplied as a lyophilized powder may raise a more complex issue because claims 3 and 18 expressly address lyophilization, while the underlying claim language still refers to an aqueous solution.

Claim 12: manufacturing process

Claim 12 requires a particular sequence:

Dissolving arginine in water to form an arginine solution; and
Dissolving ibuprofen in that arginine solution.

The process also requires the ratio to be no more than 0.97:1.

The sequence can matter in an infringement analysis. A manufacturer that forms an arginine solution first and then adds ibuprofen presents a closer literal infringement case than a manufacturer that separately prepares a salt, forms a premix, or uses a different solvent system. The resulting composition may still create composition-claim exposure even if the manufacturing process differs.

Claim 23: therapeutic method

Claim 23 covers administering the qualifying aqueous solution to treat:

Pain;
Inflammation;
Fever; or
Patent ductus arteriosus.

The claim is not restricted to intravenous administration. Claims 28-30 separately identify intravenous, intramuscular, and oral administration.

The treatment claims also use the same ratio threshold. A product that falls outside the ratio limitation may avoid literal infringement of the treatment claims, subject to claim construction and doctrine-of-equivalents analysis.

What ratio ranges and formulation features are specifically protected?

Claims 8-11, 13-16, and 24-27 specify the following ratio ranges or points:

Ratio	Claim coverage
0.10:1 to 0.97:1	Claims 8, 13, 24
0.92:1	Claims 9, 14, 25
0.60:1	Claims 10, 15, 26
0.97:1	Claims 11, 16, 27
0.60:1 to 0.97:1	Claims 39, 41, 43
0.92:1 to 0.97:1	Claims 40, 42, 44

The later-issued claims 39-44 concentrate protection around the 0.60:1 to 0.97:1 and 0.92:1 to 0.97:1 ranges. Those claims may have been added or amended during prosecution or post-grant proceedings, but they remain dependent on the original composition, manufacturing, or treatment framework.

Other limitations include:

Terminal sterilization: claims 2 and 17;
Lyophilization: claims 3 and 18;
Racemic ibuprofen: claims 4 and 19;
S-ibuprofen: claims 5 and 20;
L-arginine: claims 6 and 21;
D-arginine: claims 7 and 22;
Ibuprofen doses of approximately 100 mg to 800 mg: claim 31;
Approximately 400 mg: claim 32;
Approximately 7.5 mg/kg: claim 33;
Intravenous, intramuscular, or oral delivery: claims 28-30.

The claims therefore cover both racemic and S-ibuprofen and both L- and D-arginine. The patent does not limit the broadest composition claim to L-arginine or to a particular ibuprofen enantiomer.

When did US Patent 6,727,286 expire?

US Patent 6,727,286 expired in approximately March 2021 based on the patent’s US filing and priority record and the 20-year patent-term rule applicable to the application. The patent issued on February 10, 2004, but the issue date did not determine the expiration date under the post-1995 patent-term regime.

Event	Date
Earliest reported priority	March 30, 2000
US patent application filing	2001
Patent issued	February 10, 2004
Patent number	US 6,727,286
Approximate US expiration	March 30, 2021

The relevant legal point is that patent protection generally runs from the earliest effective nonprovisional filing date, not from issuance, for applications filed under the modern US patent-term system. The patent’s expiration removed the ordinary enforceable exclusionary right in the United States, although historical infringement claims arising before expiration can remain legally relevant.

What was the Orange Book status of the patent?

Caldolor, an injectable ibuprofen product marketed by Cumberland Pharmaceuticals, was approved by the FDA in 2009 under NDA 022959. US Patent 6,727,286 was associated with the product’s formulation and was listed in FDA patent-listing materials for the product.

The Orange Book listing did not mean that every possible ibuprofen product was covered. Orange Book relevance depended on whether the listed patent claimed the approved drug, an approved method of use, or an approved formulation under FDA listing rules.

Regulatory milestones

Regulatory event	Information
Product	Caldolor
Active ingredient	Ibuprofen
Dosage form	Injection
NDA	022959
Sponsor	Cumberland Pharmaceuticals, Inc.
FDA approval	2009
Listed patent	US 6,727,286
Patent status	Expired in 2021

The patent was principally relevant to injectable ibuprofen because the claimed aqueous solution and sterilization concepts corresponded to the technical requirements of a parenteral product. Its claims were not limited to the Caldolor trade name or to one specific commercial concentration.

What generic-entry risks existed before patent expiration?

Before 2021, a generic applicant seeking approval for a product that matched the claimed arginine-ibuprofen formulation could have faced a Paragraph IV challenge to US Patent 6,727,286.

A Paragraph IV certification would typically assert that the patent was:

Invalid;
Unenforceable; or
Not infringed.

The most credible technical positions would have included:

Ratio design-around. Use an arginine-to-ibuprofen ratio above 0.97:1, if the resulting formulation remained commercially and clinically acceptable.
Alternative solubilization system. Use another counterion, buffer, cosolvent, or solubilizing agent instead of the claimed arginine solution.
Different manufacturing sequence. Avoid dissolving arginine in water before dissolving ibuprofen in that solution.
Nonaqueous or solid formulation. Develop a dosage form outside the aqueous-solution limitation.
Validity challenge. Attack the claims for anticipation, obviousness, written description, enablement, or claim-construction defects.

The ratio design-around would not necessarily eliminate all risk. A product with a ratio above 0.97:1 could still face arguments based on claim construction or equivalents, although the numerical limitation would provide a comparatively clear literal-infringement boundary.

Which technical features created the strongest patent barrier?

The strongest commercial protection was likely concentrated in the combination of:

Aqueous ibuprofen;
Arginine as the solubilizing or formulation component;
A controlled substoichiometric arginine ratio;
Sterile injectable presentation; and
A process that dissolves arginine before ibuprofen.

A generic developer could avoid one claim category and still encounter another. For example:

A different manufacturing process could avoid claim 12 but not claim 1.
A different ratio could avoid claim 1 but potentially affect formulation performance.
A nonaqueous formulation could avoid the composition claims but may not be substitutable for an approved injectable product.
A sterile product with a qualifying ratio could implicate claims 1, 2, and potentially treatment claims.

The patent’s value therefore came from overlapping composition, process, and method-of-treatment claims rather than from a single claim alone.

How does this patent compare with ordinary ibuprofen patents?

US Patent 6,727,286 did not protect ibuprofen as a molecule. Ibuprofen was an established active pharmaceutical ingredient before the patent’s filing. The patent protected a delivery and formulation approach based on aqueous solubilization with arginine.

Patent category	Coverage	Relevance after 2021
Ibuprofen compound patents	The active molecule	Generally expired long before US 6,727,286
Arginine-ibuprofen formulation patents	Aqueous composition and ratio	US 6,727,286 expired
Injectable product patents	Sterility, concentration, container, stability, administration	Must be reviewed separately
Method-of-use patents	Treatment indications and dosing	Must be reviewed separately
Manufacturing patents	Mixing, sterilization, lyophilization, filling	May remain relevant if separately patented
Regulatory exclusivity	FDA approval protection independent of patent rights	Product-specific and time-limited

The expiration of US 6,727,286 did not automatically invalidate other patents covering a particular injectable ibuprofen product, device, manufacturing process, or later-developed formulation.

What patent landscape surrounds arginine-ibuprofen products?

The surrounding landscape has four practical layers.

Formulation patents

These may claim:

Ibuprofen concentration;
Arginine concentration;
pH;
Osmolality;
Buffer systems;
Preservative-free compositions;
Stability during terminal sterilization;
Container closure systems; or
Lyophilized cakes and reconstitution conditions.

US 6,727,286 is significant because it uses the ratio rather than a single concentration as its main formulation boundary.

Method-of-use patents

Method claims may cover:

Intravenous treatment of pain;
Fever reduction;
Postoperative analgesia;
Treatment of inflammation;
Patent ductus arteriosus in premature infants; or
Weight-based dosing.

A generic applicant may need to address use-code patents separately even after the composition patent expires.

Manufacturing and process patents

Process protection may address:

The order of addition;
Temperature control;
Dissolution conditions;
Sterilization cycles;
Lyophilization;
Reconstitution; and
Aseptic filling.

Claims 12 and 17-18 illustrate how manufacturing details can be used to supplement composition protection.

Geographic coverage

US 6,727,286 created rights only in the United States. Foreign family members, if granted, had separate terms, prosecution histories, claim scopes, and legal outcomes. A US expiration date cannot be applied automatically to European, Canadian, Australian, or other family patents.

What litigation and settlement issues affect the patent?

The expiration of US 6,727,286 means that current US commercial exposure under this patent is generally limited to historical conduct before expiration. A complete litigation assessment would require review of PACER, PTAB records, ANDA litigation filings, and settlement terms.

No current enforceable US exclusionary period arises from the patent merely because it was once listed in the Orange Book. A prior listing could still matter when analyzing:

Historical Paragraph IV litigation;
Accrued damages;
Launch dates;
Settlement agreements;
At-risk launches; and
Regulatory approval timing.

Patent expiration also does not establish that every historical infringement claim was waived or resolved. The legal effect of any settlement would depend on its terms.

What is the commercial impact for Caldolor and generic ibuprofen injection?

The commercial impact is now primarily competitive rather than exclusionary. Caldolor’s differentiation rests on:

Injectable delivery;
Hospital use;
Avoidance of oral administration;
Dosing flexibility;
Established clinical and regulatory history; and
Institutional purchasing and formulary position.

Once US 6,727,286 expired, a competing injectable ibuprofen product no longer needed to design around that patent. The remaining barriers are more likely to involve:

FDA approval requirements;
Sterile manufacturing capacity;
Product stability;
Hospital contracting;
Supply reliability;
Labeling and substitution rules;
Other unexpired patents; and
Commercial scale.

Biosimilar risk is not relevant. Ibuprofen is a small-molecule drug, and competing products proceed through the ANDA or other applicable drug-approval pathways, not the biosimilar pathway under the Public Health Service Act.

How strong was the patent estate?

The patent estate was technically focused but commercially useful. Its strengths were:

A broad independent composition claim;
Parallel process and treatment claims;
Coverage of racemic and S-ibuprofen;
Coverage of L- and D-arginine;
Multiple ratio subranges;
Sterilization and lyophilization claims; and
Relevance to injectable ibuprofen development.

Its limitations were:

Dependence on an aqueous solution;
Dependence on the numerical ratio;
Exposure to prior-art attacks involving ibuprofen salts and amino-acid solubilization;
Potential design-around through alternative formulation chemistry; and
Eventual expiration in 2021.

The patent was stronger as a commercial product barrier during its term than as a long-term monopoly over injectable ibuprofen generally.

Key Takeaways

US Patent 6,727,286 covers aqueous arginine-ibuprofen compositions with an arginine-to-ibuprofen molar ratio of no more than 0.97:1.
The patent also covers specified manufacturing sequences and therapeutic administration methods.
Claims include broad coverage of racemic and S-ibuprofen and both L- and D-arginine.
Sterilization, lyophilization, dose, route, and ratio limitations create narrower dependent-claim positions.
The patent was associated with Caldolor, an FDA-approved injectable ibuprofen product under NDA 022959.
The US patent term expired in approximately March 2021.
The patent no longer presents a current US blocking right for generic development.
Other formulation, manufacturing, method-of-use, regulatory, or foreign rights must be analyzed separately.
Biosimilar analysis is inapplicable because ibuprofen is a small-molecule drug.
The main historical design-around strategy was to use a different ratio, solubilization system, manufacturing sequence, or dosage form.

FAQs

Does US Patent 6,727,286 cover oral ibuprofen tablets?

No. The broad claims require an aqueous solution of arginine and ibuprofen or a method involving that solution. Conventional solid oral ibuprofen tablets generally fall outside those limitations unless they are made or supplied in a qualifying aqueous form.

Does the patent cover ibuprofen lysine?

Not necessarily. Ibuprofen lysine is a different salt or formulation system from an aqueous arginine-ibuprofen solution. Coverage would depend on the actual composition and whether the product satisfies the issued claim limitations.

Could a generic injectable ibuprofen product launch after the patent expired?

Yes, the expiration removed this patent as a US patent barrier. The applicant would still need FDA approval and would need to evaluate any other unexpired patents or applicable regulatory exclusivities.

Is patent ductus arteriosus coverage still commercially important?

The claim expressly includes patent ductus arteriosus, but the commercial value depends on the approved labeling, pediatric clinical use, competing therapies, and any separate patents or regulatory protections applicable to that indication.

Does patent expiration eliminate all Caldolor exclusivity?

No. Patent expiration eliminates the rights provided by US Patent 6,727,286. It does not necessarily eliminate other patents, regulatory exclusivity, trademarks, contracts, manufacturing protections, or market-based advantages.

References

U.S. Patent and Trademark Office. (2004). U.S. Patent No. 6,727,286, Pharmaceutical compositions comprising ibuprofen and arginine.
U.S. Food and Drug Administration. (2009). Caldolor prescribing information, NDA 022959. Cumberland Pharmaceuticals, Inc.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. Center for Drug Evaluation and Research.
U.S. Food and Drug Administration. (2024). Orange Book: Approved drug products with therapeutic equivalence evaluations.
United States Code. (2024). 35 U.S.C. § 154: Contents and term of patent; provisional rights.
United States Code. (2024). 21 U.S.C. § 355: New drugs.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
World Intellectual Property Organization (WIPO)	2005065674	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 6,727,286

Summary for Patent: 6,727,286