United States Drug Patent 5,145,684: Claim Scope, Expiration, and Nanoparticle Patent Landscape

U.S. Patent No. 5,145,684 is a foundational nanoparticle drug-delivery patent covering crystalline drug particles reduced to submicron size and stabilized with an adsorbed, non-crosslinked surface modifier. Its broad composition, dispersion, pharmaceutical-composition, treatment, and wet-grinding claims are directed to what became known commercially as drug nanocrystals or nanosuspensions.

The patent was granted September 8, 1992, and its original pre-Uruguay Round Agreement patent term expired 17 years after grant, on September 8, 2009, absent an unusual extension or enforceable continuation right. The patent therefore does not present a current U.S. blocking right. Its commercial importance remains substantial because later patents may protect specific nanoparticle products, excipients, dosage forms, manufacturing parameters, or therapeutic uses.

What does U.S. Patent 5,145,684 cover?

The patent covers four related categories:

Submicron crystalline drug particles with an adsorbed surface modifier.
Stable liquid dispersions containing those particles.
Pharmaceutical compositions containing the particles.
Methods for producing the particles by wet grinding with small, dense rigid media.

The central technical concept is a poorly water-soluble crystalline drug substance, generally having water solubility below 10 mg/mL, reduced to an effective average particle size below approximately 400 nm. A non-crosslinked surface modifier adsorbs to the particle surface and prevents or limits aggregation.

The claims do not require a particular therapeutic indication in the core particle claims. They are technology claims that can cover many active pharmaceutical ingredients, excipients, dosage forms, and routes of administration.

How broad is claim 1 of Patent 5,145,684?

Claim 1 is the broadest composition claim. It requires the following elements:

Claim element	Scope
Drug substance	Crystalline drug substance
Solubility	Less than 10 mg/mL in water
Particle size	Effective average particle size below about 400 nm
Surface modifier	Non-crosslinked modifier adsorbed on the drug surface
Modifier amount	0.1% to 90% by weight
Drug amount	99.9% to 10% by weight
Composition language	"Consisting essentially of"

The claim uses a very broad therapeutic-class definition in claim 4. The listed classes include analgesics, anti-inflammatory agents, antibiotics, corticosteroids, antineoplastics, antivirals, antihistamines, antihypertensives, steroids, sex hormones, vasodilators, and xanthines.

The practical scope is limited by the requirement that the active be both crystalline and poorly water-soluble. A formulation containing a soluble drug, an amorphous solid, a nonadsorbed stabilizer, or particles above the claimed size would not fall within the literal scope of claim 1.

What does "consisting essentially of" mean?

"Consisting essentially of" generally permits additional ingredients that do not materially affect the basic and novel characteristics of the claimed invention. The basic characteristics here are the submicron crystalline drug particles and the adsorbed non-crosslinked surface modifier.

This language is broader than "consisting of" but narrower than "comprising." A formulation containing an additional component that materially changes particle stabilization, size, crystallinity, or surface adsorption could create a claim-construction dispute.

What particle-size limitations are protected?

Claims 1 through 3 create a size hierarchy:

Claim	Particle-size limitation
Claim 1	Less than about 400 nm
Claim 2	Less than 250 nm
Claim 3	Less than 100 nm
Claim 9	Danazol below about 100 nm
Claim 10	Specified steroid below about 400 nm

The patent uses "effective average particle size," rather than a simple maximum particle diameter. That language creates several potential measurement issues:

Whether the result is based on volume, intensity, number, or another distribution;
Whether agglomerates are included;
Whether the measurement is made before or after dilution;
Whether the measured size reflects primary particles or stabilized clusters;
Whether the test method is dynamic light scattering, electron microscopy, laser diffraction, or another technique.

A product with a mean size below 400 nm but a substantial coarse-particle tail may create an infringement dispute. The patent does not appear to impose a specific particle-size distribution, polydispersity index, zeta potential, or dissolution-rate limitation in the asserted claims provided.

Which drug substances are specifically named?

Claim 6 identifies six drug substances or chemical classes:

Danazol;
5α,17α-1'-(methylsulfonyl)-1'H-pregn-20-yno-[3,2-c]-pyrazol-17-ol;
Piposulfam;
Piposulfan;
Camptothecin; and
Ethyl-3,5-diacetamido-2,4,6-triiodobenzoate.

Claim 9 is narrower and specifically covers crystalline danazol with polyvinylpyrrolidone adsorbed at 20% to 60% by weight, with an effective average particle size below approximately 100 nm.

Claim 10 covers the specified crystalline steroid with an ethylene oxide-propylene oxide block copolymer and a particle size below approximately 400 nm.

The narrow compound-specific claims are easier to map to a particular product but are also more vulnerable to noninfringement based on a different active ingredient, different surface modifier, or different particle-size result.

What surface modifiers are protected?

Claims 7 and 8 list extensive surface-modifier categories.

Claim 7 surface modifiers

The list includes:

Gelatin and casein;
Lecithin and gum acacia;
Cholesterol and tragacanth;
Stearic acid and calcium stearate;
Benzalkonium chloride;
Glyceryl monostearate;
Cetostearyl alcohol;
Sorbitan esters;
Polyoxyethylene compounds;
Polyethylene glycols;
Cellulose derivatives;
Sodium dodecyl sulfate;
Polyvinyl alcohol;
Polyvinylpyrrolidone;
Colloidal silicon dioxide;
Magnesium aluminum silicate; and
Triethanolamine.

Claim 8 surface modifiers

Claim 8 narrows the list to:

Polyvinylpyrrolidone;
Ethylene oxide-propylene oxide block copolymers;
Lecithin;
Alkyl aryl polyether sulfonates;
Gum acacia;
Sodium dodecyl sulfate; and
A dioctyl ester of sodium sulfosuccinic acid.

The modifier must be adsorbed on the drug-particle surface and must be non-crosslinked. A polymer chemically crosslinked before use may fall outside the express limitation. A non-crosslinked polymer that forms a physical coating or adsorbed layer generally presents a closer infringement question.

The claim language does not require covalent bonding between the modifier and active ingredient. Physical adsorption is the operative relationship.

What manufacturing methods are protected?

Claims 16 through 20 protect wet-grinding processes.

Claim 16

Claim 16 requires:

Dispersing the drug in a liquid dispersion medium;
Wet grinding the drug;
Using rigid grinding media with an average size below 3 mm;
Grinding in the presence of a surface modifier; and
Reducing the drug to below approximately 400 nm.

Claim 17

Claim 17 separates the surface-modifier step. It requires wet grinding in the presence of rigid media, followed by contacting the drug with the surface modifier by mixing it with the dispersion medium.

Claim 18

Claim 18 adds ultrasonic energy after the dispersion contains the drug and surface modifier.

Claims 19 and 20

These claims narrow the grinding media by requiring:

Average media size below 1 mm; and
Density above 3 g/cm³.

The method claims are important because they are process claims rather than product claims. They could historically have covered a manufacturer using a different final dosage form if the upstream nanoparticle process satisfied the limitations.

Potential noninfringement routes include:

Use of high-pressure homogenization rather than wet grinding;
Use of grinding media above the claimed size;
Use of media with density at or below 3 g/cm³;
Addition of the surface modifier at a materially different stage;
Dry milling;
Precipitation or antisolvent crystallization;
Production of amorphous rather than crystalline particles; or
Failure to reach the claimed effective average particle size.

When did U.S. Patent 5,145,684 lose exclusivity?

The patent's ordinary U.S. term ended September 8, 2009, based on the 17-year term applicable to patents filed before the June 8, 1995 transition to the 20-year term from the earliest effective nonprovisional filing date. The patent was granted on September 8, 1992. [1]

Event	Date
U.S. patent grant	September 8, 1992
Ordinary pre-URAA term	17 years from grant
Expected expiration	September 8, 2009
Current blocking status	Expired

Patent term extension under 35 U.S.C. § 156 is generally tied to regulatory review of a specific drug product, not to a broad platform patent covering nanoparticle technology. A platform patent of this type would not ordinarily receive product-specific regulatory patent-term extension without satisfying the statutory requirements. [2]

What is the Orange Book status of Patent 5,145,684?

Patent 5,145,684 is not itself a universal Orange Book barrier. The FDA Orange Book lists patents associated with approved drug products and their approved uses, as submitted by the relevant NDA holder. It does not create a standalone listing for an expired, general nanoparticle platform patent. [3]

The relevant Orange Book analysis for a commercial nanocrystal product would examine:

Whether the product is approved under an NDA;
Whether a product-specific formulation patent is listed;
Whether a method-of-use patent is listed;
Whether an applicable patent has expired;
Whether pediatric exclusivity or another regulatory exclusivity period remains; and
Whether an ANDA applicant must make a Paragraph IV certification.

An ANDA applicant would not ordinarily need to make a Paragraph IV certification against Patent 5,145,684 if the patent is expired and no enforceable patent rights remain. Paragraph IV exposure instead arises from later, unexpired listed patents. [4]

Which later patents are relevant to the nanoparticle landscape?

Patent 5,145,684 is part of a broader family of nanoparticle and nanosuspension patents associated with the early development of surface-modified drug nanoparticles. Later patents and continuation applications commonly pursued narrower subject matter, including:

Specific active ingredients;
Particular stabilizer systems;
Oral, injectable, ophthalmic, or pulmonary dosage forms;
Freeze-dried or spray-dried nanoparticle products;
Targeted delivery;
Manufacturing conditions;
High-pressure homogenization;
Milling equipment and process parameters;
Particle-size distributions;
Redispersibility;
Bioavailability improvement; and
Specific therapeutic indications.

Public patent databases identify related U.S. nanoparticle patents assigned at various times to entities including NanoSystems, Inc., Elan Corporation, and successor companies. The family and continuation structure must be reviewed separately from the legal status of Patent 5,145,684 because a continuation may have a different filing date, claims, expiration date, and terminal disclaimer. [5]

A representative landscape review should distinguish three layers:

Layer	Typical protection
Foundational platform	Crystalline drug nanoparticles with surface modifiers
Product-specific	Nanocrystal formulation for a named active ingredient
Commercial implementation	Dosage form, process, indication, and manufacturing controls

The expiration of the foundational patent does not eliminate the possibility that a commercial product remains protected by the second or third layers.

How strong was the patent estate, and what are its weaknesses?

Strengths

The patent had broad technical coverage because it combined:

A wide range of poorly soluble drugs;
A broad size threshold;
Numerous surface modifiers;
Multiple liquid dispersion media;
Pharmaceutical compositions;
Therapeutic methods;
Wet-grinding processes; and
Specific danazol and steroid embodiments.

The claims also covered both the product and important manufacturing routes. That combination historically increased the ability to challenge a competing formulation from multiple directions.

Weaknesses

The principal validity and enforcement pressure points include:

Particle-size measurement. "Effective average particle size" may require technical evidence about the measurement method and sample preparation.
Crystallinity. Products using amorphous solid dispersions, partially amorphous material, or drug-polymer complexes may avoid the crystalline-drug limitation.
Adsorption. The challenger may dispute whether the surface modifier is actually adsorbed on the drug surface or merely dissolved in the vehicle.
Non-crosslinking. A chemically crosslinked stabilizer or a different surface-coating mechanism may avoid the express limitation.
Enablement and written description. The claims span many drug classes and a large number of modifiers. For any particular unexemplified combination, an accused party could examine whether the disclosure enabled the full scope of the claim under the law applicable at the relevant time.
Prior art. Earlier milling, colloid, suspension, emulsification, and drug-particle-size references could be relevant to anticipation or obviousness. The specific combination of crystalline poorly soluble drug, adsorbed modifier, submicron size, and wet-grinding conditions was the principal inventive center.

Because the patent expired more than a decade ago, these issues have limited current commercial value unless they affect interpretation of related, unexpired family patents.

What generic launch risks exist today?

Patent 5,145,684 alone creates no current U.S. generic launch barrier. A generic or follow-on applicant can generally use the disclosed nanoparticle concept without infringing the expired patent.

Commercial launch risk may still arise from:

A later patent claiming the same active ingredient in nanoparticle form;
A listed formulation patent;
A method-of-use patent;
A patent covering a specific stabilizer ratio;
A manufacturing patent;
A patent covering a controlled-release or injectable dosage form;
Regulatory exclusivity; or
Trade-secret manufacturing know-how.

For a product that uses danazol, the expired claim 9 does not prevent commercial development. The relevant question is whether later patents protect the specific danazol dosage form, indication, excipient system, or manufacturing process.

Are biosimilar risks relevant?

Biosimilar risk is generally not relevant to Patent 5,145,684 because the patent covers small-molecule drug particles, not a biologic active. The applicable competitive pathway is usually an ANDA, a 505(b)(2) application, or, in limited cases, a full NDA rather than a biosimilar application under the Biologics Price Competition and Innovation Act. [6]

A 505(b)(2) applicant using the nanoparticle platform could face listed patents covering the reference product, formulation, dosage form, or method of use. The expired platform patent itself would not provide a basis for an injunction.

What licensing deals affected the technology?

The nanoparticle technology associated with the patent was commercialized through NanoSystems and later Elan Corporation. Elan developed the NanoCrystal technology and entered product and development arrangements involving poorly soluble drugs and nanoparticle formulations.

The commercial license analysis is separate from patent ownership. An agreement may cover:

Know-how;
Manufacturing technology;
Regulatory data;
Trade secrets;
Improvements;
Field-of-use rights; or
Product-specific patents.

Expiration of Patent 5,145,684 does not automatically terminate contractual obligations relating to confidential know-how or royalty-bearing improvements. Publicly available patent rights and private licensing rights should therefore be analyzed separately.

What geographic coverage does the patent provide?

Patent 5,145,684 provides U.S. rights only. Comparable protection would require separate foreign patents or national-phase rights. The international landscape may include patents in Europe, Japan, Canada, Australia, and other jurisdictions, each with independent expiration and validity rules.

The U.S. patent's expiration does not establish the status of foreign counterparts. A product may be free to practice in the United States while remaining subject to an unexpired foreign patent.

Key Takeaways

U.S. Patent 5,145,684 is a foundational drug-nanoparticle patent.
Its core claims cover crystalline, poorly water-soluble drug particles below approximately 400 nm with an adsorbed non-crosslinked surface modifier.
Claims 2, 3, and 9 narrow the particle size to below 250 nm, 100 nm, and 100 nm, respectively.
Claim 9 specifically covers danazol with polyvinylpyrrolidone.
Claims 16 through 20 cover wet-grinding processes using rigid media below specified size and density thresholds.
The patent expired on September 8, 2009, based on the ordinary 17-year term for the applicable pre-URAA patent.
It is not, by itself, a current Orange Book or Paragraph IV barrier.
Current risk depends on later product, formulation, method-of-use, manufacturing, and dosage-form patents.
Biosimilar analysis is generally inapplicable because the invention concerns small-molecule drug particles.
Foreign counterpart status must be assessed independently from the expired U.S. patent.

FAQs About U.S. Patent 5,145,684

Can a company manufacture drug nanocrystals in the United States without licensing Patent 5,145,684?

Yes. The patent's U.S. term expired in 2009. A company must still clear later patents and confidential know-how rights.

Does claim 9 prevent generic danazol products?

No. Claim 9 is expired. Later patents may still cover a particular danazol formulation, dosage form, indication, or process.

Does the patent cover nanoparticles made by high-pressure homogenization?

The issued claims provided focus on wet grinding with rigid grinding media. A high-pressure homogenization process would require separate analysis and may avoid the literal process limitations, although the resulting product could historically have raised product-claim issues.

Are particles below 400 nm automatically covered by the patent?

No. The particles must also contain a crystalline drug with water solubility below 10 mg/mL and a non-crosslinked surface modifier adsorbed on the drug surface in the claimed amount.

Can expired Patent 5,145,684 be used as prior art against a later nanoparticle patent?

Yes. An expired patent remains publicly available technical disclosure and can be cited in novelty or obviousness analyses against later patent claims, subject to the applicable priority dates and legal standards.

References

U.S. Patent No. 5,145,684. (1992). Surface modified drug nanoparticles. U.S. Patent and Trademark Office.
35 U.S.C. §§ 154, 156. (2024). Patent term and patent term extension. United States Code.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA, Center for Drug Evaluation and Research.
U.S. Food and Drug Administration. (2024). ANDA submissions: Patent certifications and statements. FDA, Center for Drug Evaluation and Research.
Google Patents. (2024). U.S. Patent No. 5,145,684 and related patent-family records. Google.
U.S. Food and Drug Administration. (2024). Biosimilar and interchangeable products. FDA.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	150297	⤷ Start Trial
Austria	184202	⤷ Start Trial
Austria	190835	⤷ Start Trial
Austria	195416	⤷ Start Trial
Australia	1014592	⤷ Start Trial
Australia	1014792	⤷ Start Trial
Australia	4156093	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,145,684

Summary for Patent: 5,145,684