Details for Patent: 8,298,568

Which drugs does patent 8,298,568 protect, and when does it expire?

Patent 8,298,568 protects VERKAZIA and is included in one NDA.

This patent has seventy-one patent family members in eighteen countries.

Summary for Patent: 8,298,568

Title:	Oil-in-water type emulsion with low concentration of cationic agent and positive zeta potential
Abstract:	A well tolerated oil-in-water emulsion useful as a delivery vehicle of hydrophobic ingredients such as pharmaceutical drugs, wherein the emulsion particles have a net positive charge and comprises 0.001 to 0.1% of a cationic agent, 0 to 1% of a non ionic surfactant and 0 to 0.5% of an anionic surfactant.
Inventor(s):	Séverine Bague, Betty Philips, Jean-Sébastien GARRIGUE, Laura Rabinovich-Guilatt, Gregory Lambert
Assignee:	Santen SAS
Application Number:	US10/991,346
Patent Claim Types: see list of patent claims	Composition;

U.S. Patent 8,298,568: Scope, Claim Construction, Patent Landscape, and Generic Entry Risk

U.S. Patent No. 8,298,568 protects a narrow cationic oil-in-water nanoemulsion platform, with specific limits on cetalkonium chloride, tyloxapol and poloxamer, phospholipid exclusion, oil concentration, particle size, and pharmaceutical use. Claim 8 narrows the protection to compositions containing sirolimus. The strongest infringement risk concerns ophthalmic sirolimus products using the claimed excipient architecture, not all sirolimus formulations or all ophthalmic emulsions.

What does U.S. Patent 8,298,568 protect?

The independent claims establish two protection categories:

1. Claim 1 protects the emulsion itself.
2. Claim 6 protects a pharmaceutical composition containing that emulsion and an active ingredient.

Claims 2 through 5 narrow the emulsion by oil concentration and particle size. Claims 7 and 8 narrow the pharmaceutical composition to ophthalmic preparations and sirolimus-containing products.

Claim	Protected subject matter	Key narrowing limitations
1	Cationic oil-in-water emulsion	Cetalkonium chloride; tyloxapol and poloxamer; no phospholipids; oil core no higher than 5% w/w; positive interfacial film
2	Emulsion of claim 1	Oil concentration about 0.5% to 3% w/w
3	Emulsion of claim 1	Average particle size about 0.1 to 1 µm
4	Emulsion of claim 3	Average particle size about 300 nm
5	Emulsion of claim 3	Average particle size about 100 to 200 nm
6	Pharmaceutical composition	Active ingredient in a pharmaceutically effective carrier consisting of the claim 1 emulsion
7	Pharmaceutical composition of claim 6	Ophthalmic preparation
8	Pharmaceutical composition of claim 6	Active ingredient is sirolimus

The patent does not claim sirolimus as a molecule, sirolimus treatment generally, or every ophthalmic emulsion. Its protection depends on the accused product meeting the compositional and structural limitations in the claims.

How should the key terms in claim 1 be construed?

"Oil-in-water emulsion"

The claim requires colloidal oil droplets dispersed in an aqueous continuous phase. A water-in-oil system, an aqueous solution without an oil phase, or a non-emulsion lipid system would fall outside the ordinary technical meaning of this limitation.

The claim also requires:

• An oily core
• An interfacial film around the core
• A positively charged overall interfacial film
• An oil core concentration no higher than 5% by weight

The structure is consistent with a cationic nanoemulsion designed for topical, particularly ophthalmic, delivery.

"Cationic agent ... being cetalkonium chloride"

This is a material-specific limitation. The claim does not broadly cover any positively charged surfactant or any quaternary ammonium compound. It identifies cetalkonium chloride as the cationic agent.

A formulation using benzalkonium chloride, stearylamine, cetrimide, or another cationic compound would not literally satisfy this limitation unless the relevant product also contains cetalkonium chloride. The doctrine of equivalents could become relevant in litigation, but substitution of the claimed cationic agent is a central design-around route.

The concentration range is 0.001% to 0.05% by weight based on total emulsion weight. A formulation below or above that range presents a literal infringement issue, subject to claim construction and the applicable treatment of numerical ranges.

"Nonionic surfactant ... consisting of tyloxapol and poloxamer"

This is one of the most restrictive elements in the claim.

The claim identifies tyloxapol and poloxamer as the nonionic surfactant system. The phrase "consisting of" generally indicates a closed limitation for the specified nonionic surfactant component. The claim therefore creates a substantial question for products using:

• Tyloxapol without poloxamer
• Poloxamer without tyloxapol
• A different nonionic surfactant
• A broader surfactant blend containing additional nonionic surfactants

The claim permits the nonionic surfactant system in an amount up to 1% by weight. It does not state a lower numerical limit beyond the amount needed to perform the claimed function and satisfy the composition as a whole.

"0% by weight of phospholipids"

This is an express exclusion. A product containing phospholipids as an intentional formulation component would face a strong non-infringement position for claim 1, although analytical questions may arise over trace impurities, raw-material contamination, or excipient identity.

The exclusion is commercially significant because many lipid emulsions and ocular delivery systems use phospholipids to stabilize the oil-water interface. A phospholipid-containing product may avoid the literal scope of the claim even if it otherwise uses a cationic emulsion.

"Overall positive charge"

The claim focuses on the charge of the interfacial film rather than merely the presence of a cationic ingredient. An accused product would likely be evaluated through formulation composition, zeta-potential data, pH, ionic strength, and analytical testing.

Cetalkonium chloride supports positive surface charge, but the presence of the compound alone may not resolve whether the interfacial film has an overall positive charge under the relevant testing conditions.

What formulations are protected by claims 2 through 5?

Claims 2 through 5 create narrower fallback positions around concentration and particle size.

Oil concentration

Claim 2 covers an oil-core concentration of approximately 0.5% to 3% w/w. This is narrower than claim 1's upper limit of 5% w/w.

The concentration limitation can affect infringement analysis in two ways:

• A product above 3% but at or below 5% may remain within claim 1 while avoiding claim 2.
• A product below 0.5% may avoid claim 2 but still fall within claim 1.

The term "about" introduces ordinary claim-construction flexibility. It does not automatically convert the range into an unlimited concentration band.

Particle size

Claim 3 covers average particle sizes of about 0.1 to 1 µm. Claims 4 and 5 add narrower particle-size ranges:

• About 300 nm
• About 100 to 200 nm

A product with a mean particle size of 150 nm may fall within claims 3 and 5 if the other limitations are met. A product with a mean size of 300 nm may fall within claims 3 and 4. The relevant measurement method, sampling conditions, distribution metric, and treatment of polydispersity can materially affect the result.

The patent does not require every droplet to fall within the stated range. The claims refer to average particle size.

How broad is claim 6 for pharmaceutical compositions?

Claim 6 extends the emulsion protection to a pharmaceutical composition containing:

• A pharmaceutically effective amount of an active ingredient
• A well-tolerated carrier
• The carrier being the claim 1 oil-in-water emulsion

Claim 6 does not limit the active ingredient to sirolimus. It may cover other actives if the complete claim 1 emulsion is present and the composition satisfies the pharmaceutical and tolerability limitations.

The claim language is less precise than claim 1 because "well tolerated" and "pharmaceutically effective amount" are functional or context-dependent concepts. Those terms may be supported by the specification, clinical data, formulation history, and the intended route of administration.

A pharmaceutical composition that uses the same emulsion vehicle with a different active ingredient could potentially implicate claim 6 while avoiding claim 8.

What ophthalmic and sirolimus products are covered?

Claim 7 narrows claim 6 to an ophthalmic preparation. Claim 8 narrows the active ingredient to sirolimus.

An ophthalmic sirolimus product would need to satisfy the following claim 8 combination:

1. Oil-in-water emulsion
2. Oily core with a positively charged interfacial film
3. Cetalkonium chloride at 0.001% to 0.05% w/w
4. Tyloxapol and poloxamer as the claimed nonionic surfactant system
5. No phospholipids
6. Oil core no higher than 5% w/w
7. Sirolimus as the active ingredient

A sirolimus ophthalmic solution without an oil phase would not satisfy the emulsion limitation. A sirolimus suspension, liposome, micelle, phospholipid emulsion, or neutral nanoemulsion may also avoid literal infringement depending on its composition.

When does U.S. Patent 8,298,568 lose exclusivity?

The issue date for U.S. Patent 8,298,568 is October 30, 2012. Its enforceable expiration date cannot be established from the claims alone because U.S. patent term depends on the earliest effective nonprovisional priority date, continuity data, patent-term adjustment, terminal disclaimers, and any applicable patent-term extension.

The patent should be analyzed against the full USPTO continuity and term records before a launch date, licensing valuation, or freedom-to-operate conclusion is adopted. The issued claims themselves do not state the expiration date.

The patent term is separate from FDA regulatory exclusivity. Patent expiration does not determine whether a product can be approved, and FDA exclusivity does not extend the patent term.

What is the Orange Book status of U.S. Patent 8,298,568?

A patent appears in the FDA Orange Book only if it has been submitted for an approved drug product and accepted for listing under FDA requirements. Patent 8,298,568 is a formulation patent directed to an emulsion platform and sirolimus pharmaceutical composition. Its presence or absence in the Orange Book cannot be inferred from the issued claims.

If the patent is listed for an approved product, an ANDA applicant could face a Paragraph IV certification. If it is not listed, the patent may still be enforceable against commercial manufacture or sale, but it would not automatically create an Orange Book-based ANDA stay.

The relevant regulatory questions are:

• Whether an approved NDA identifies the patented formulation
• Whether the patent was submitted within the applicable FDA listing framework
• Whether the approved product's labeling corresponds to claims 7 or 8
• Whether the patent is listed against the active ingredient, dosage form, formulation, or method of use

Does this patent create a Paragraph IV risk?

A Paragraph IV challenge would be strongest against an approved ophthalmic sirolimus product whose formulation appears to match claim 8.

Potential Paragraph IV positions include:

Non-infringement

An ANDA applicant could design around one or more limitations by using:

• No cetalkonium chloride
• A different cationic agent
• No tyloxapol
• No poloxamer
• A different nonionic surfactant
• Phospholipids
• More than 5% oil
• A neutral or negatively charged interface
• A non-emulsion delivery system

Invalidity

The principal invalidity theories would likely involve:

• Anticipation by an earlier cationic ophthalmic emulsion
• Obviousness based on combining known cationic agents with known nonionic surfactants
• Written-description or enablement challenges concerning the full numerical ranges
• Indefiniteness arguments directed to "about," "overall positive charge," "well tolerated," or "pharmaceutically effective amount"

The closed formulation limitations may make anticipation more difficult if no single reference discloses all elements, but they can also support an obviousness theory if the combination was predictable from prior emulsion technology.

How strong is the patent estate?

The strength of Patent 8,298,568 depends on whether it is viewed as a stand-alone patent or as one member of a broader cationic-emulsion family.

Strengths

• Claim 1 contains multiple compositional limitations that can distinguish over broad oil-in-water emulsion prior art.
• Cetalkonium chloride is specifically identified.
• The phospholipid exclusion may distinguish the claimed system from conventional phospholipid-stabilized emulsions.
• Claims 2 through 5 provide narrower concentration and particle-size positions.
• Claim 8 directly targets a sirolimus pharmaceutical composition.

Weaknesses

• The independent formulation claim is highly specific and may be easier to design around.
• The requirement for both tyloxapol and poloxamer narrows the commercial reach.
• The 0% phospholipid requirement excludes a large class of lipid delivery systems but also limits the patent's coverage.
• Particle-size claims may depend on test methodology and batch variability.
• The patent does not broadly cover all ophthalmic uses of sirolimus.

The estate is strongest where a product reproduces the complete excipient combination. It is weaker against products that use a different cationic agent, a different surfactant package, a phospholipid interface, or a non-emulsion dosage form.

Which companies and products are most relevant?

The commercial comparison should separate platform technology from marketed products.

Product or platform	General formulation category	Relevance to Patent 8,298,568
Cationic ophthalmic emulsion platforms	Positively charged oil-in-water systems	Potentially relevant if cetalkonium chloride, tyloxapol, poloxamer and no phospholipids are present
Restasis, cyclosporine ophthalmic emulsion	Ophthalmic emulsion	Product-level similarity does not establish infringement; the excipient and charge profile must be compared
Cequa, cyclosporine ophthalmic solution	Nanomicellar solution	Likely outside an oil-in-water emulsion claim if the dosage form lacks an oily core
Xiidra, lifitegrast ophthalmic solution	Aqueous ophthalmic solution	Not directed to the claimed oil-in-water emulsion architecture
Vevye, cyclosporine ophthalmic solution	Ophthalmic solution	Requires product-specific analysis; a solution does not automatically meet the emulsion limitations
Sirolimus ophthalmic candidates	Various suspension, solution, or emulsion approaches	Claim 8 risk depends on the complete excipient and particle structure

Restasis and other ophthalmic emulsion products are useful comparator technologies, but a branded product's emulsion status alone does not establish coverage by this patent. The decisive facts are cetalkonium chloride concentration, surfactant identity, phospholipid content, oil percentage, surface charge, and particle-size distribution.

What manufacturing and formulation barriers does the patent create?

The patent creates practical process barriers in addition to legal claim limitations.

A developer seeking to avoid infringement must control:

• Selection and concentration of the cationic agent
• Interfacial adsorption of cetalkonium chloride
• Choice of nonionic surfactants
• Exclusion of phospholipids
• Oil-phase loading
• Homogenization and particle-size control
• Zeta potential and charge stability
• Sirolimus solubilization or dispersion
• Sterility and preservative strategy
• Long-term physical stability

Changing one excipient may create new problems involving ocular tolerability, droplet stability, drug loading, viscosity, osmolality, or shelf life. The patent therefore has more commercial value than its claim count suggests if its formulation is difficult to reproduce without the claimed excipient architecture.

The practical design-around routes are clearest when the product can tolerate:

• A different cationic compound
• A neutral formulation
• A phospholipid-stabilized system
• A non-emulsion delivery system
• A different nonionic surfactant combination

What litigation and settlement issues should be monitored?

The supplied claim set does not identify litigation, settlements, licenses, or covenant-not-to-sue agreements. Those matters cannot be determined from the claims.

For diligence, the legally relevant records are:

• USPTO assignment and continuity records
• Federal court complaints and docket entries
• Patent Trial and Appeal Board proceedings
• FDA Orange Book listings
• NDA and ANDA litigation records
• SEC filings describing licenses or settlements
• European and other foreign family prosecutions

A settlement involving one product would not necessarily resolve risk for another product because the claims are formulation-specific and the agreement's scope may be limited by product, territory, affiliate, or field of use.

How does Patent 8,298,568 compare with broad platform patents?

Patent 8,298,568 is narrower than a patent claiming any cationic oil-in-water emulsion. It requires a particular combination of:

• Cetalkonium chloride
• Tyloxapol and poloxamer
• No phospholipids
• Low oil content
• Positive interfacial charge

It is potentially stronger against an exact formulation match than a broad platform patent, but it covers fewer alternative products.

Patent type	Breadth	Design-around difficulty	Main commercial value
Broad cationic-emulsion platform patent	Higher	Higher	Covers multiple excipient choices
Patent 8,298,568 formulation claim	Moderate to narrow	Moderate	Protects a defined formulation architecture
Particle-size dependent claim	Narrow	High if process can shift size	Protects optimized physical characteristics
Sirolimus composition claim	Narrowest	Depends on drug and vehicle	Targets a specific ophthalmic product configuration

Key Takeaways

• U.S. Patent 8,298,568 is a formulation patent, not a broad sirolimus patent.
• Claim 1 requires cetalkonium chloride, tyloxapol and poloxamer, no phospholipids, a positively charged interfacial film, and oil content no higher than 5% w/w.
• Claims 2 through 5 narrow the invention by oil concentration and average particle size.
• Claim 8 is the most commercially relevant claim for ophthalmic sirolimus products.
• A product using another cationic agent, another surfactant system, phospholipids, a neutral interface, or a non-emulsion dosage form may avoid literal infringement.
• Orange Book listing and Paragraph IV exposure cannot be determined from the issued claims alone.
• The expiration date requires the patent's priority, continuity, term-adjustment, and terminal-disclaimer records.
• The strongest infringement case would involve an ophthalmic sirolimus nanoemulsion reproducing the complete claimed excipient and physical-property profile.

FAQs

Is Patent 8,298,568 a sirolimus patent?

No. It is primarily a cationic oil-in-water emulsion patent. Sirolimus is covered only by dependent claim 8 when formulated in the emulsion required by claim 6.

Can a formulation with phospholipids infringe this patent?

Literal infringement of claim 1 is unlikely because the claim expressly requires 0% by weight of phospholipids. The complete product and claim construction would control any doctrine-of-equivalents analysis.

Does using benzalkonium chloride instead of cetalkonium chloride avoid the patent?

It may avoid literal infringement of claim 1 because the claim specifically identifies cetalkonium chloride. The remaining claims and any equivalents analysis would require separate review.

Can a sirolimus ophthalmic solution infringe claim 8?

A conventional aqueous solution would generally not satisfy the required oil-in-water emulsion and oily-core limitations. A product described as a solution could still require technical analysis if it contains colloidal oil structures.

Are claims 4 and 5 alternative particle-size protections?

Yes. Claim 4 targets an average particle size of about 300 nm, while claim 5 targets about 100 to 200 nm. Both depend on claim 3 and therefore retain all limitations of the broader emulsion claims.

References

1. United States Patent and Trademark Office. (2012). U.S. Patent No. 8,298,568. Washington, DC: U.S. Department of Commerce.

2. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations. Silver Spring, MD: U.S. Department of Health and Human Services.

3. U.S. Food and Drug Administration. (n.d.). Orange Book: Approved drug products with therapeutic equivalence evaluations, patent and exclusivity information. Silver Spring, MD: U.S. Department of Health and Human Services.

Drugs Protected by US Patent 8,298,568

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Harrow Eye	VERKAZIA	cyclosporine	EMULSION;OPHTHALMIC	214965-001	Jun 23, 2021		RX	Yes	Yes			Y

Foreign Priority and PCT Information for Patent: 8,298,568

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
	04292645	Nov 9, 2004

International Family Members for US Patent 8,298,568

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	1809237		C300741	Netherlands
European Patent Office	1809237		CA 2015 00030	Denmark
European Patent Office	1809237		122015000043	Germany
European Patent Office	1809237		300741	Netherlands
European Patent Office	1809237		CR 2015 00030	Denmark
European Patent Office	1809237		C01809237/01	Switzerland