Details for Patent: 5,192,535

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Summary for Patent: 5,192,535

Title:	Ophthalmic suspensions
Abstract:	Lightly crosslinked polymers, preferably ones prepared by suspension or emulsion polymerizing at least about 90% by weight of a carboxyl-containing monoethylenically unsaturated monomer such as acrylic acid with from about 0.1% to about 5% by weight of a polyfunctional, and preferably difunctional, crosslinking agent such as divinyl glycol (3,4-dihydroxy-1,5-hexadiene), having a particle size of not more than about 50 μm in equivalent spherical diameter, when formulated with an ophthalmic medicament, e.g., fluorometholone, into suspensions in aqueous medium in which the amount of polymer ranges from about 0.1% to about 6.5% by weight, based on the total weight of the aqueous suspension, the pH is from about 3.0 to about 6.5, and the osmotic pressure (osmolality or tonicity) is from about 10 mOsM to about 400 mOsM, provide new topical ophthalmic medicament delivery systems having suitably low viscosities which permit them to be easily administered to the eye in drop form, and hence be comfortably administrable in consistent, accurate dosages. These suspension will rapidly gel in the eye after coming into contact with the eye's tear fluid to a substantially greater viscosity than that of the originally-introduced suspension and thus remain in place for prolonged periods of time to provide sustained release of the ophthalmic medicament.
Inventor(s):	Jeffrey P. Davis, Santosh K. Chandrasekaran, Yansheng Su, Roy D. Archibald, Joseph R. Robinson
Assignee:	Sun Pharmaceutical Industries Inc
Application Number:	US07/544,518
Patent Claim Types: see list of patent claims	Use; Delivery;

US Patent 5,192,535: Claim Scope, Expiration, Litigation Risk, and Ophthalmic Delivery-System Patent Landscape

US Patent 5,192,535 covers an in-situ gelling ophthalmic delivery system based on a lightly cross-linked, carboxyl-containing polymer. The claimed product is administered as a viscous aqueous drop at acidic pH and gels when exposed to higher-pH tear fluid. The patent also covers related delivery methods and preparation or packaging processes.

The patent was granted on March 9, 1993. Because it predates the modern 20-year-from-effective-filing-date regime, its ordinary US patent term was generally 17 years from grant, subject to any applicable adjustment or extension. On that basis, the patent expired no later than March 9, 2010. It does not presently create enforceable US patent exclusivity. The commercial and technical value of the patent lies in its historical role as a platform patent for ophthalmic in-situ gels, not in current US exclusionary rights.

What technology does US Patent 5,192,535 protect?

The patent protects a low-pH, viscous ophthalmic suspension that undergoes rapid viscosity increase after contact with tears. Its central mechanism has five elements:

1. An aqueous ophthalmic suspension.
2. An initial pH of approximately 3.0 to 6.5.
3. A lightly cross-linked carboxyl-containing polymer.
4. A polymer particle size of no more than approximately 50 micrometers.
5. Tear-triggered conversion from a drop-administered suspension into a substantially more viscous gel.

The claimed system is designed to address the short residence time of conventional ophthalmic drops. A conventional drop is rapidly removed through blinking, tear turnover and nasolacrimal drainage. The patented formulation is intended to remain on the ocular surface for longer and release the incorporated medicament over an extended period.

The claims focus on formulation architecture and delivery behavior. They do not require a particular disease, therapeutic indication or brand product.

Core technical limitations

Claim feature	Claimed range or requirement
Initial pH	About 3 to about 6.5
Osmotic pressure	About 10 to about 400 mOsM
Carboxyl polymer concentration	About 0.1% to about 6.5% by weight
Crosslinker level	Less than about 5% by weight of polymerized monomers
Formulation viscosity	About 1,000 to about 30,000 cP
Average polymer particle size	No more than about 50 micrometers
Administration	Drop form
Trigger	Contact with higher-pH tear fluid
Result	Rapid formation of a substantially more viscous gel
Specific polymer embodiment	Acrylic acid plus divinyl glycol
Specific osmotic agent	Sodium chloride
Specific drugs	Fluorometholone and pilocarpine

How many independent claims does US Patent 5,192,535 have?

The patent has three principal independent claim categories:

• Claim 1: a sustained-release topical ophthalmic medicament delivery system.
• Claim 19: a method of delivering an ophthalmic medicament to the eye.
• Claim 35: a method of preparing a sustained-release topical ophthalmic delivery system.

Claim 1 is the principal composition or system claim. Claims 2 through 18 narrow that system through polymer composition, particle size, monodispersity, osmolarity, salt and medicament limitations.

Claim 19 is a treatment or administration method claim. Claims 20 through 34 narrow the method by adding the same formulation features found in the system claims.

Claim 35 is a process claim directed to preparing and packaging the suspension for administration.

This structure gives the patent multiple infringement theories, but all three claim groups depend heavily on the same technical combination: acidic aqueous suspension, lightly cross-linked carboxyl polymer, controlled particle size, high starting viscosity and tear-induced gelation.

What is the scope of independent claim 1?

Claim 1 is broad in drug selection but narrow in formulation design.

It does not require fluorometholone or pilocarpine. Any ophthalmic medicament can satisfy the claim if the formulation meets the other limitations. Claim 3 expressly adds an ophthalmic medicament, while claim 1 describes a system in which a medicament is contained in the resulting gel.

The claim does require all of the following:

• Aqueous suspension rather than a dry product or conventional ointment.
• pH within approximately 3.0 to 6.5.
• Osmotic pressure within approximately 10 to 400 mOsM.
• Polymer concentration within approximately 0.1% to 6.5%.
• Polymer derived from carboxyl-containing monoethylenically unsaturated monomers.
• Less than approximately 5% crosslinking agent.
• Initial viscosity between approximately 1,000 and 30,000 cP.
• Average polymer particle size no greater than approximately 50 micrometers.
• Drop administration despite the high viscosity.
• Rapid, substantial viscosity increase upon contact with tear fluid.

The “rapidly gellable” and “substantially greater viscosity” language creates potential claim-construction issues. The claim does not provide a precise time limit for “rapidly” or a numerical threshold for “substantially greater.” In litigation, those terms would likely be interpreted in view of the specification, examples and technical understanding of ocular in-situ gel systems.

Which dependent claims materially narrow the patent?

Polymer composition claims

Claims 2, 10, 11, 12 and 13 narrow the polymer chemistry.

Claim 2 requires at least 50% carboxyl-containing monomers. Claim 10 permits replacement of up to 40% of those monomers with non-carboxyl-containing monoethylenic monomers. Claim 11 requires at least 90% carboxyl-containing monomers.

Claim 12 is technically important because it identifies acrylic acid and a non-polyalkenyl polyether difunctional crosslinking agent. Claim 13 narrows the crosslinker to divinyl glycol.

These claims distinguish the invention from systems using unrelated gelling mechanisms, including polysaccharides, thermoresponsive polymers, ion-sensitive polymers and non-cross-linked viscosity enhancers.

Particle-size and distribution claims

Claims 4 through 9 and 30 through 34 focus on particle engineering.

The patent claims:

• Average particle size of no more than 50 micrometers.
• In some embodiments, no more than 30 micrometers.
• A monodispersion of polymer particles.
• At least 80%, 90% or 95% of particles within a defined size band.
• Limits on the percentage of fines.
• A preferred major distribution band of approximately 1 to 5 micrometers.

These limitations appear directed to balancing two competing properties: sufficient viscosity and gelation after instillation, while retaining acceptable drop administration and ocular tolerability. A formulation could avoid the narrower particle-distribution claims while still potentially falling within claim 1 if it satisfies the broader average-particle-size limitation.

Claim 33 contains a drafting inconsistency. It refers to at least 95% of particles being within a band of no more than about 5 micrometers, while allowing no more than 20% fines. The relationship between the distribution band and the fines limitation could require prosecution-history analysis.

Osmolarity and drug claims

Claims 14 and 15 narrow osmotic control to a physiologically acceptable salt, specifically sodium chloride. Claim 16 sets the medicament concentration at approximately 0.005% to 10% by weight.

Claims 17 and 18 identify fluorometholone and pilocarpine. These claims are product-specific but do not cover every formulation of either drug. A product must also satisfy the inherited pH, viscosity, polymer, particle-size and osmotic-pressure limitations.

Does the patent cover DuraSite, carbomer and other in-situ gel systems?

The claims can read on certain carbomer-type or polyacrylic-acid systems, but the analysis depends on the precise polymer, particle size, crosslinking chemistry and formulation properties.

A formulation using a lightly cross-linked polyacrylic-acid polymer may present a technical overlap if it:

• Is administered as an acidic suspension;
• Has the claimed polymer concentration and viscosity;
• Uses particles no larger than the claimed size;
• Gels through neutralization or pH change caused by tears; and
• Falls within the claimed crosslinker and monomer parameters.

The patent does not automatically cover every ophthalmic in-situ gel. Important non-overlapping technologies include:

• Gellan-gum systems activated by tear ions;
• Thermosensitive poloxamer systems;
• Alginate or pectin systems;
• Mucoadhesive systems that do not rapidly gel through tear-fluid pH;
• Liposomal, nanoparticle and implant delivery systems;
• Conventional suspensions that remain suspensions after instillation.

DuraSite-based products may raise historical technology-overlap questions, but a DuraSite formulation cannot be assessed from its brand name alone. The relevant comparison is the actual polymer identity, crosslinking level, particle size, pH, viscosity and in-eye gelation behavior.

What patent landscape surrounds US Patent 5,192,535?

The surrounding landscape divides into four technology groups.

1. Cross-linked carboxyl polymer systems

This is the closest technical field. Patents in this group generally address polyacrylic-acid or carbomer particles, crosslink density, particle size, neutralization, viscosity and ocular residence time.

US Patent 5,192,535 is strongest where a later product uses substantially the same combination of low-pH administration and tear-triggered gelation. Its claims are weaker against systems using different polymer families or a different gelation trigger.

2. Ion-activated ophthalmic gels

Products based on gellan gum, xanthan gum or related polysaccharides gel in response to cations in tear fluid. Their mechanism differs from the pH-triggered carboxyl-polymer mechanism claimed in US 5,192,535.

A technically distinct ion-activated product would generally present a lower literal infringement risk, although formulation-specific claim overlap would require review of the complete patent set.

3. Mucoadhesive and bioadhesive delivery systems

Other patents claim polymers that increase ocular residence by adhesion rather than rapid pH-induced viscosity change. These systems may include cellulose derivatives, chitosan, hyaluronic acid or thiolated polymers.

The distinction is material. Long ocular residence alone is not enough to satisfy the claims. The accused product must meet the specific polymer and gelation limitations.

4. Drug-specific sustained-release products

Later patent estates often claim a particular active ingredient, concentration, dosing schedule, preservative system, delivery vehicle or indication. These patents may remain relevant even though US Patent 5,192,535 has expired.

Examples of relevant product categories include:

• Azithromycin ophthalmic suspensions;
• Besifloxacin ophthalmic suspensions;
• Glaucoma products using gel-forming vehicles;
• Steroid ophthalmic suspensions;
• Pilocarpine and fluorometholone delivery systems.

A freedom-to-operate review must therefore separate expired platform patents from live drug-specific, formulation and manufacturing patents.

When did US Patent 5,192,535 lose exclusivity?

The patent’s ordinary US term ended in 2010 based on its March 9, 1993 grant date and the pre-1995 17-year patent-term rule. The patent is therefore expired and cannot support a new US patent infringement action.

The expiration does not eliminate:

• Patent rights in other jurisdictions;
• Later patents claiming improvements;
• Regulatory exclusivity;
• Trade-secret protection for manufacturing processes;
• Contractual restrictions;
• Patent rights covering a specific commercial product.

No biosimilar issue arises directly from this patent. It covers a formulation platform, not a biologic active ingredient. Generic-drug companies could have encountered Paragraph IV risk during the patent’s active term, but the patent is no longer a live US Paragraph IV barrier.

What is the Orange Book status of US Patent 5,192,535?

US Patent 5,192,535 is not itself an Orange Book regulatory exclusivity period. Orange Book listing depends on submission by an NDA holder and linkage to an approved drug product, indication or method of use under FDA regulations.

The patent claims do not identify a single approved product, NDA, dosage strength or labeled indication. On the supplied claim text alone, no reliable conclusion can be made that the patent was listed in the Orange Book against fluorometholone, pilocarpine or another product.

The patent’s platform character also limits its Orange Book utility. A broad formulation patent can be listed only if it meets applicable FDA patent-listing requirements and is tied to an approved product.

What Paragraph IV and litigation risks were associated with the patent?

During its active term, an ANDA applicant could have used a Paragraph IV certification to challenge the patent. The principal attack routes would have included:

• Lack of written description for broad polymer classes;
• Enablement across the full pH, viscosity and particle-size ranges;
• Obviousness over prior ophthalmic suspensions and carbomer gels;
• Indefiniteness of “rapidly gellable” and “substantially greater viscosity”;
• Lack of infringement based on different gelation mechanisms;
• Failure to meet the claimed osmotic-pressure or particle-size limits.

The method claims could also have raised divided-infringement questions, particularly where a manufacturer supplies a product but does not itself administer it. The system claims would have been more practical against a manufacturer or marketer of a formulation meeting every limitation.

No current generic-launch risk arises from this patent alone because it expired in 2010. A current launch analysis must focus on later patents, Orange Book listings, regulatory exclusivity and product-specific formulation rights.

How strong is the patent estate for this technology today?

The patent was technically significant as a platform claim set but is legally weak today because it is expired.

Risk category	Current assessment
US infringement risk from US 5,192,535	None from an expired patent
Historical platform coverage	Broad but technically constrained
Drug-specific coverage	Limited to named dependent-claim embodiments
Biosimilar relevance	Minimal
Orange Book relevance	Product- and listing-dependent
Manufacturing barrier	Potentially relevant only through later or separate patents
Foreign enforcement	Requires jurisdiction-by-jurisdiction review
Generic launch barrier	None from this patent alone
Freedom-to-operate value	Mainly prior-art and landscape significance

What are the main design-around strategies?

A product developer could reduce historical overlap by using:

• A polymer other than a carboxyl-containing cross-linked acrylic polymer;
• An ion-triggered rather than pH-triggered gel;
• A thermoresponsive vehicle;
• Polymer particles larger than the claimed thresholds, if performance permits;
• A starting viscosity outside the claimed range;
• A pH outside the claimed range;
• A formulation that does not rapidly become substantially more viscous in tear fluid;
• A non-suspension delivery format;
• A different crosslinking chemistry.

These strategies do not eliminate risk from later patents. They address only the claim architecture of US Patent 5,192,535.

Key Takeaways

• US Patent 5,192,535 claims an acidic, viscous ophthalmic suspension that rapidly gels at the higher pH of tear fluid.
• Claim 1 is the principal platform claim; claim 19 covers administration, and claim 35 covers preparation and packaging.
• The most important limitations are polymer chemistry, crosslink density, particle size, viscosity, pH, osmotic pressure and tear-triggered gelation.
• Claims 12 through 18 narrow the invention toward acrylic acid, divinyl glycol, sodium chloride, fluorometholone and pilocarpine.
• The patent’s ordinary US term expired in 2010.
• It creates no current US patent barrier to generic launch or formulation development.
• Later patents covering DuraSite, gellan gum, drug-specific formulations, preservatives, dosing regimens or manufacturing processes may remain relevant.
• A formulation’s use of an in-situ gel does not by itself establish infringement. The claimed technical elements must be present.

FAQs

Is US Patent 5,192,535 still enforceable?

No. The patent’s ordinary US term expired in 2010 based on its 1993 grant date and the pre-1995 patent-term rules.

Does the patent cover all carbomer eye drops?

No. Coverage depends on the complete claim combination, including pH, viscosity, polymer concentration, particle size, crosslinking and tear-triggered gelation.

Does fluorometholone automatically infringe claim 17?

No. Fluorometholone is only one limitation. The formulation must also satisfy all limitations inherited from claims 3, 16 and 1.

Can a gellan-gum ophthalmic gel infringe this patent?

A gellan-gum product using ion-triggered gelation would generally be technically distinct from the claimed carboxyl-polymer, pH-triggered system. The complete formulation and claim language would control.

Does expiration of this patent clear all IP risk for an ophthalmic in-situ gel?

No. Expiration clears this patent only. Later patents may cover the active ingredient, formulation, manufacturing process, preservative system, dosage regimen or approved indication.

References

1. U.S. Patent No. 5,192,535. (1993). Ophthalmic medicament delivery system. United States Patent and Trademark Office.

2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA.

3. U.S. Food and Drug Administration. (2024). Approved drug product and patent listing requirements. FDA.

4. United States Code, 35 U.S.C. § 154. Patent term.

5. United States Code, 21 U.S.C. § 355. New drug applications and patent certifications.

Drugs Protected by US Patent 5,192,535

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

International Family Members for US Patent 5,192,535

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	243728
Austria	112157
Austria	113841
Austria	152907