US Patent 6,592,903: Claim Scope, Expiration, Litigation Risk, and Nanoparticulate Patent Landscape

US Patent 6,592,903 covers nanoparticulate dispersions of poorly soluble active agents that contain both a polymeric surface stabilizer and dioctyl sodium sulfosuccinate, or DOSS, with an effective average particle size below 1 micron. It also covers pharmaceutical compositions containing those dispersions and a wet-milling manufacturing process.

The patent was assigned to Elan Pharma International Ltd., the developer of the NanoCrystal technology platform. Its enforceable term has expired under the standard 20-year patent-term framework. It therefore presents historical and technical relevance, but no current standalone US exclusionary risk.

What does US Patent 6,592,903 protect?

The patent protects three related categories:

A composition containing a poorly soluble active agent, polymeric surface stabilizer, DOSS, and submicron particles.
A pharmaceutical composition containing that dispersion and pharmaceutically acceptable excipients.
A manufacturing method using mechanical size reduction in the presence of grinding media.

The independent claims are claims 1, 20, and 21.

Claim	Category	Core limitation
1	Nanoparticulate dispersion	Poorly soluble active agent, polymeric surface stabilizer adsorbed to the active-agent surface, 0.1%-20% w/w DOSS, particle size below 1 micron
20	Pharmaceutical composition	Dispersion of claim 1 plus pharmaceutically acceptable excipients
21	Manufacturing method	Dispersing active-agent particles in liquid, mechanically milling with grinding media to below 1 micron, with polymeric stabilizer and DOSS added before or after milling

A product must satisfy every limitation of an asserted claim for literal infringement. The composition claims do not require a particular dosage form, route of administration, disease indication, active-agent identity, or commercial product formulation.

How broad is claim 1?

Claim 1 is technically broad but chemically constrained by four cumulative requirements:

The active agent must be poorly soluble.
A polymeric surface stabilizer must be adsorbed on the active-agent surface.
DOSS must be present at approximately 0.1%-20% w/w.
The effective average particle size must be below approximately 1 micron.

The claim is not limited to ketoprofen. Ketoprofen appears in dependent claim 15. Claims 16 and 17 separately identify MAP kinase inhibitors and angiogenesis inhibitors. Claim 14 contains a large therapeutic-category Markush group.

The most commercially important limitation is DOSS. A nanoparticulate formulation with a polymeric stabilizer and submicron particles does not fall within claim 1 if it contains no DOSS, subject to potential doctrine-of-equivalents analysis. Conversely, the presence of DOSS alone is insufficient. The formulation also must meet the polymer-adsorption and particle-size requirements.

What does "poorly soluble active agent" mean?

The patent uses the poorly soluble-drug concept functionally rather than limiting the claims to a fixed solubility threshold in the quoted claims. Claim construction would likely rely on the specification, technical evidence, and the ordinary meaning in pharmaceutical formulation practice.

This limitation creates a factual issue for products involving:

Moderately soluble active agents.
pH-dependent solubility.
Amorphous or salt forms with materially different solubility.
Lipid-based or supersaturated formulations.
Active agents whose solubility changes during milling.

A formulation sponsor would normally document aqueous solubility, solid state, particle-size distribution, and the analytical method used to establish those attributes.

What does "adsorbed" require?

The polymeric surface stabilizer must be adsorbed on the active-agent surface. Merely placing a polymer in the same liquid medium may not be sufficient if the polymer does not associate with the particle surface.

Relevant evidence could include:

Surface-chemistry testing.
Zeta potential changes.
Desorption studies.
Spectroscopic analysis.
Formulation composition and process history.
The stabilizer's known affinity for the active agent.

The claim does not require one specific polymer. Claims 18 and 19 identify nonexclusive classes and examples, including polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, dextrin, guar gum, starch, and a 3:2 vinylpyrrolidone-vinyl acetate copolymer.

What formulations are protected by US 6,592,903?

The patent covers formulations in which DOSS operates with a polymeric surface stabilizer in a nanoparticulate system. Claim 8 narrows DOSS to approximately 1%-10% w/w.

The claims cover several composition ranges:

Component	Claimed range
DOSS	0.1%-20% w/w
DOSS, dependent claim 8	1%-10% w/w
Active agent	99.8%-0.1% w/w
Active agent, claim 3	80%-5% w/w
Active agent, claim 4	50%-10% w/w
Polymeric stabilizer	0.01%-90% w/w
Polymeric stabilizer, claim 6	1%-75% w/w
Polymeric stabilizer, claim 7	10%-60% w/w
Particle size	Below 1 micron
Particle-size subranges	Below 800, 600, 400, or 200 nm

The nested particle-size claims create fallback positions. A product below 200 nm potentially satisfies claims 1 and 9-12, assuming the other limitations are met. A product between 600 nm and 1 micron may fall within claim 1 but not claims 9-12.

The claims use approximate language such as "about." Small deviations from a numerical boundary may still raise infringement questions depending on measurement error, formulation variability, and prosecution history.

Which active agents fall within the patent?

The claim set covers a wide range of poorly soluble active agents, including:

Ketoprofen.
MAP kinase inhibitors.
Angiogenesis inhibitors.
Oncology agents.
Anti-inflammatory drugs.
Antifungals.
Cardiovascular agents.
Antidiabetic agents.
Antiviral agents.
Antiepileptics.
Corticosteroids.
Antihistamines.
Antibiotics.
Anticoagulants.
Diagnostic and imaging agents.
Hormonal agents.
Nutraceuticals.
Proteins, peptides, and nucleotides.

The Markush language is expansive, but it does not automatically validate every theoretical species. Enforceability for a particular active agent would depend on written description, enablement, claim construction, and whether the accused formulation actually satisfies the poorly soluble and nanoparticulate limitations.

What manufacturing process is protected?

Claim 21 covers a wet-milling process with these elements:

Particles of a poorly soluble active agent are dispersed in a liquid medium.
Mechanical means are applied.
Grinding media are present.
The active agent is reduced below 1 micron.
At least one polymeric surface stabilizer and DOSS are added before or after milling.

The claim does not require DOSS or the polymeric stabilizer to be added before milling. This expressly broadens the process claim to permit addition before or after the size-reduction step.

What processes may avoid claim 21?

Potential nonliteral distinctions include:

High-pressure homogenization without grinding media.
Microfluidization without grinding media.
Precipitation, antisolvent crystallization, or controlled crystallization.
Spray drying or other particle-engineering processes.
Milling that does not produce a submicron effective average particle size.
A process using DOSS outside the claimed concentration range.
A process using a nonpolymeric stabilizer only.

These distinctions do not necessarily avoid claims 1 or 20. A non-milling process can still produce a composition that satisfies claim 1.

How many patents cover the Elan NanoCrystal platform?

US 6,592,903 is part of the broader Elan nanoparticulate drug-delivery patent landscape. Related platform patents address nanoparticulate active agents, surface stabilizers, particle-size reduction, dosage forms, and drug-specific applications.

Representative earlier Elan platform patents include:

Patent	General subject
US 5,145,684	Nanoparticulate compositions and particle-size reduction
US 5,298,262	Nanoparticulate formulations and stabilizers
US 5,302,401	Nanoparticulate compositions
US 5,356,467	Nanoparticulate active-agent systems
US 5,518,187	Nanoparticulate pharmaceutical compositions
US 5,862,999	Nanoparticulate compositions and surface stabilization
US 6,592,903	Nanoparticulate dispersions containing polymeric stabilizer and DOSS

The relevant risk analysis must separate expired foundational patents from later patents directed to specific products, dosage forms, stabilizers, manufacturing conditions, or therapeutic uses. A freedom-to-operate review based only on US 6,592,903 would be incomplete for a modern nanoparticulate product.

When did US 6,592,903 lose exclusivity?

US 6,592,903 issued on July 15, 2003. The patent's application was filed under the modern 20-year patent-term regime. Its ordinary US patent term therefore ran approximately 20 years from the earliest effective nonprovisional filing date, subject to any patent-term adjustment, terminal disclaimer, or other adjustment recorded in the USPTO file.

Public patent records identify the patent as expired. It is not an active enforceable US patent today. The patent's expiration eliminates ordinary infringement exposure for post-expiration US activity under this patent, although it does not eliminate risk from related patents with later expiration dates.

Event	Date or status
Earliest priority framework	2000-era Elan nanoparticulate filing
US filing	2001-era nonprovisional filing
Patent issue	July 15, 2003
Patent term	Approximately 20 years from the applicable nonprovisional filing date
Current status	Expired
Current enforceability	No ordinary prospective exclusionary right under this patent

The expiration analysis should be distinguished from regulatory exclusivity. Patent expiration does not determine FDA exclusivity, and FDA exclusivity does not extend a patent term.

What is the Orange Book status of US 6,592,903?

US 6,592,903 is a platform patent, not an identified active-ingredient patent tied to a particular approved drug product. It is not generally treated as an Orange Book-listed patent that independently blocks an abbreviated new drug application.

The Orange Book lists patents submitted by NDA holders for approved drug products. A broad formulation-platform patent may be absent even if a commercial product historically used the claimed technology. Orange Book status must be evaluated at the product and NDA level, not at the platform-patent level. [2]

The patent also does not create FDA regulatory exclusivity. It has no 5-year new chemical entity exclusivity, 3-year clinical-investigation exclusivity, 7-year orphan-drug exclusivity, or 6-month pediatric extension associated with the patent itself.

Were there Paragraph IV challenges or patent litigation?

US 6,592,903 is not, by itself, a conventional Orange Book patent associated with a named reference-listed drug. As a result, a Paragraph IV challenge directed specifically to this patent would not normally be the standard pathway.

A generic applicant could still encounter:

A listed drug-specific formulation patent.
A method-of-use patent.
A later continuation or related patent.
A patent covering a particular active agent, salt, dosage form, or manufacturing process.

No current litigation risk remains under the expired patent. Historical disputes involving Elan's NanoCrystal technology or particular drug products should not be attributed to US 6,592,903 without a case-specific docket and asserted-claim record.

What generic entry risks exist?

US 6,592,903 does not currently delay generic entry. Its expiration removes the patent as a blocking right.

Historical generic-entry risk would have been highest for a product with all of the following attributes:

A poorly soluble small-molecule active agent.
Submicron particle size.
DOSS as a formulation component.
A polymeric surface stabilizer adsorbed to the particle.
A wet-milling process using grinding media.
A formulation composition within the claimed concentration ranges.

Risk would have been lower where the product used:

No DOSS.
A nonpolymeric stabilizer.
A particle size of at least 1 micron.
A non-milling process.
A different dosage form with no claimed dispersion.
A formulation outside the relevant concentration ranges.

These are historical design-around considerations. They do not replace analysis of later, unexpired patents.

Does the patent create biosimilar risk?

No meaningful biosimilar risk arises from US 6,592,903. The patent is directed to nanoparticulate dispersions and poorly soluble active agents, not to a biologic reference product, biosimilar interchangeability, protein sequence, cell line, biologic manufacturing platform, or formulation-specific biologic patent.

Claims 14 and 26 mention proteins, peptides, and nucleotides, but those references do not convert the patent into a biologic patent. A protein formulation would still need to satisfy the DOSS, polymeric surface-stabilizer, particle-size, and other claim limitations.

How strong is the patent estate?

The patent was commercially significant as a specialized formulation patent but is no longer a live asset.

Strength factor	Assessment
Claim breadth	Broad across active-agent classes and polymer types
Key narrowing element	DOSS combined with polymeric surface stabilization
Composition coverage	Strong for literal matches during the patent term
Process coverage	Meaningful because addition could occur before or after milling
Design-around potential	Moderate to high through excipient, process, or particle-size changes
Regulatory linkage	Low because the patent is not inherently product-specific
Current exclusionary value	None after expiration
Residual business value	Prior-art, licensing-history, and technology-landscape relevance

The claims also present potential validity pressure points that would have mattered during the term:

Whether the full breadth of the Markush active-agent categories was enabled.
Whether all claimed polymers were adequately supported.
Whether "poorly soluble" and "effective average particle size" were sufficiently definite.
Whether prior art disclosed submicron drug particles with polymeric stabilizers and surfactants.
Whether the DOSS limitation supplied a non-obvious technical distinction.
Whether the claims properly covered the claimed concentration ranges.

The issued patent's survival through examination does not establish validity against every prior-art reference or every accused product.

What licensing deals and commercial exposure are relevant?

Elan licensed or partnered its NanoCrystal technology for incorporation into commercial products, including products developed with major pharmaceutical companies. Commercial arrangements generally focused on platform access, drug-specific development, manufacturing, royalties, or milestones rather than on US 6,592,903 alone.

The patent itself cannot be assigned a current revenue value because:

It has expired.
It is not tied to one identified approved product.
Its claims cover a formulation technology across multiple therapeutic categories.
Any historical royalty stream would have depended on private agreements and related patent families.

For investment or licensing analysis, the relevant asset is the surviving NanoCrystal patent family and know-how portfolio, not this expired patent in isolation.

Key Takeaways

US 6,592,903 covers submicron dispersions of poorly soluble active agents containing DOSS and an adsorbed polymeric surface stabilizer.
Independent claims cover compositions, pharmaceutical products, and wet-milling methods.
Ketoprofen, MAP kinase inhibitors, angiogenesis inhibitors, and broad therapeutic categories are expressly included.
DOSS is the central claim limitation and the most direct composition-level design-around target.
The process claim requires mechanical size reduction in the presence of grinding media.
The patent is expired and does not create current US generic-entry or biosimilar barriers.
It is not, by itself, an Orange Book exclusivity right.
Current diligence should focus on later Elan or successor patents covering specific products, formulations, dosage forms, manufacturing processes, and uses.

FAQs

Can a DOSS-free nanoparticle formulation infringe US 6,592,903?

It would not literally satisfy claim 1 because DOSS is expressly required. Other unexpired patents could still apply.

Does a formulation below 200 nm infringe more claims?

It may satisfy the narrower particle-size claims 9 through 12 as well as claim 1, provided the DOSS, polymeric stabilizer, adsorption, and poorly soluble active-agent requirements are met.

Does high-pressure homogenization infringe the manufacturing claim?

Not literally if the process does not use grinding media. The resulting formulation could still implicate the composition claims if it contains the required ingredients and particle size.

Is US 6,592,903 relevant to a generic ketoprofen product?

Only historically under this patent. A current ketoprofen product requires review of unexpired drug-specific, formulation, method-of-use, and manufacturing patents.

Can expiration of US 6,592,903 invalidate Orange Book patents?

No. Patent expiration is assessed patent by patent. Expiration of this platform patent does not affect separate patents listed for a particular NDA product.

References

United States Patent and Trademark Office. (2003). US Patent No. 6,592,903, Nanoparticulate compositions containing a surface stabilizer and a wetting agent. U.S. Department of Commerce.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. U.S. Department of Health and Human Services.
United States Code. (2023). 35 U.S.C. § 154: Contents and term of patent; provisional rights. U.S. Government Publishing Office.
United States Patent and Trademark Office. (2024). Patent Center: Patent application and transaction history records. U.S. Department of Commerce.
Elan Pharma International Ltd. (2003). US Patent No. 6,592,903. United States Patent and Trademark Office.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	040110	⤷ Start Trial
Argentina	072134	⤷ Start Trial
Argentina	072135	⤷ Start Trial
Argentina	111501	⤷ Start Trial
Austria	293959	⤷ Start Trial
Austria	333265	⤷ Start Trial
Austria	343376	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 6,592,903

Summary for Patent: 6,592,903