United States Patent 8,486,456: Itraconazole Solid Dispersion Scope, Validity, and Generic Entry Risk

US 8,486,456 protects a specific itraconazole solid-dispersion platform using hydroxypropyl methylcellulose, or HPMC. Its central limitation is a low differential-scanning-calorimetry endotherm, designated ΔHtr, below 0.35 J/g at a transition temperature of 240°C to 250°C. Dependent claims narrow the platform by particle size, HPMC substitution profile, viscosity, drug-to-polymer ratio, dosage-form composition and pharmacokinetic performance.

The patent is materially narrower than a broad claim to itraconazole, an HPMC formulation or an oral antifungal dosage form. Its principal enforcement value depends on whether a competing product uses the claimed HPMC grade and produces the specified thermal-transition profile. The patent’s nominal 20-year term is tied to the earliest effective U.S. filing date, subject to any patent-term adjustment or terminal disclaimer recorded by the USPTO.[1]

What does US 8,486,456 protect?

US 8,486,456 protects a solid dispersion containing itraconazole and HPMC in which the product has a limited thermal transition associated with itraconazole crystallinity or molecular organization.

The independent technical concept is:

Element	Scope of claim 1
Active ingredient	Itraconazole
Polymer	Hydroxypropyl methylcellulose
Product type	Solid dispersion
Analytical limitation	ΔHtr below 0.35 J/g
Thermal range	Endothermic peak at 240°C to 250°C
Measurement	Endotherm expressed in J/g

The claims do not require every conventional Sporanox excipient, a particular capsule shell, a specific manufacturing process, or a named fungal disease. The claimed product can therefore cover different dosage forms if they contain the qualifying dispersion.

The patent is directed to performance of the dispersion rather than merely its ingredients. A formulation containing itraconazole and HPMC does not necessarily infringe claim 1 unless its measured ΔHtr falls below the specified threshold.

How do the claims divide the protected technology?

Claims 1 and 2: thermal-state limitations

Claim 1 requires ΔHtr below 0.35 J/g. Claim 2 narrows the threshold to below 0.20 J/g.

These limitations likely distinguish a highly amorphous or molecularly dispersed itraconazole product from a formulation containing a larger amount of crystalline itraconazole. The transition temperature range is unusually specific. A product showing the relevant transition outside 240°C to 250°C could avoid literal infringement, although the analytical protocol and peak assignment would be central to any dispute.

Claim 2 is commercially narrower but potentially stronger against products with exceptionally low residual crystallinity.

Claims 3 to 7: formulation-property limitations

Claim	Limitation	Commercial significance
3	Weight-average particle size of 50 μm to 600 μm	Targets granulated or spray-dried dispersion particles
4	Total methoxy plus hydroxypropyl content of HPMC: 23% to 42%	Defines the HPMC substitution window
5	Methoxy content: 19% to 30%; hydroxypropyl content: 4% to 12%	Narrows the polymer chemistry
6	HPMC apparent viscosity: 3 to 15 mPa·s in a 2% aqueous solution at 20°C	Targets relatively low-viscosity HPMC grades
7	Itraconazole:HPMC weight ratio of 1:1 to 1:17	Covers polymer-rich dispersions

Claim 7 has a broad numerical range. At the narrow end, the formulation contains equal weights of itraconazole and HPMC. At the broad end, HPMC may constitute approximately 94% of the itraconazole-polymer fraction.

Claims 4 to 6 create a cumulative polymer identity limitation. A competing product using HPMC with a different degree of substitution or viscosity may fall outside those claims even if its ΔHtr is within the claimed range.

Claims 8 to 10: dosage forms and pharmacokinetics

Claim 8 covers a pharmaceutical dosage form containing particles of the claimed dispersion plus a diluent or disintegrant.

Claim 9 requires a dosage form that produces itraconazole and hydroxy-itraconazole plasma levels with a Cmax of at least 400 ng/mL after a single oral 200 mg itraconazole dose. Because claim 9 depends on claim 1, the dosage form must also contain the qualifying solid dispersion.

Claim 10 is an independent dosage-form claim. It combines:

Itraconazole and HPMC;
A Cmax of at least 400 ng/mL for itraconazole and hydroxy-itraconazole after a single 200 mg oral dose; and
ΔHtr below 0.35 J/g at 240°C to 250°C.

The pharmacokinetic limitation may create enforcement complexity. Cmax can vary with food, gastric conditions, patient population, sampling schedule, assay method and study design. A product may meet the limitation in a controlled clinical study but not consistently in individual patients.

Claims 11 to 13: therapeutic use

Claim 11 covers oral administration to a mammal with a fungal infection.

Claim 12 covers treatment by administering the dosage form. Claim 13 lists infections including blastomycosis, histoplasmosis, aspergillosis, onychomycosis, tinea pedis, candidiasis, cryptococcosis and coccidioidomycosis.

These claims are narrower than a composition claim because infringement requires the claimed product and the claimed therapeutic use. They may have limited value against a generic approved for the same labeled indications, but they are more relevant to induced-infringement analysis where the generic label instructs use for a listed fungal infection.

What formulation characteristics must a competing product have?

A product most directly exposed to claim 1 would have the following profile:

Parameter	Claimed range
Itraconazole	Required
HPMC	Required
ΔHtr	Less than 0.35 J/g
Transition peak	240°C to 250°C
Particle size, where claim 3 applies	50 μm to 600 μm
Total HPMC methoxy plus hydroxypropyl content	23% to 42%
Methoxy content, where claim 5 applies	19% to 30%
Hydroxypropyl content, where claim 5 applies	4% to 12%
HPMC viscosity, where claim 6 applies	3 to 15 mPa·s
Itraconazole:HPMC ratio, where claim 7 applies	1:1 to 1:17
Cmax, claims 9 and 10	At least 400 ng/mL

The broadest claim is claim 1. Claims 3 through 7 should be treated as fallback positions because they require additional product testing. Claims 8 through 10 extend risk from the dispersion itself to finished dosage forms.

How strong is the patent estate for itraconazole solid dispersions?

The estate is technically focused rather than broad. Its strongest feature is the combination of composition and measurable solid-state performance. A competitor cannot avoid claim 1 simply by changing capsule excipients if the same qualifying dispersion remains in the product.

Its main weaknesses are analytical and factual:

The claim does not expressly define the DSC instrument, heating rate, sample preparation, baseline correction or normalization procedure.
ΔHtr is measured in J/g, but the claim language does not, on its face, resolve every issue concerning the sample basis and analytical integration.
The transition must be identified at a peak temperature between 240°C and 250°C.
The product must contain both itraconazole and HPMC.
Claims 9 and 10 depend on variable human pharmacokinetic results.
A non-HPMC polymer system, a crystalline itraconazole formulation or a dispersion with a different thermal profile may avoid literal infringement.

These features make claim construction and laboratory reproducibility important. A patent challenger would likely focus on written description, enablement, indefiniteness, anticipation and obviousness. A patent owner would emphasize the defined thermal signature, the relationship between solid-state structure and bioavailability, and the narrower HPMC specifications.

When does US 8,486,456 lose exclusivity?

The statutory patent term is generally 20 years from the earliest effective nonprovisional U.S. filing date, subject to patent-term adjustment, patent-term extension and terminal disclaimers.[2] Public patent records identify the patent as part of an itraconazole solid-dispersion family associated with Janssen Pharmaceutica NV.[1]

The relevant timing framework is:

Event	Significance
Earliest priority filing	Controls priority and may support prior-art analysis
PCT or nonprovisional filing	Determines the effective patent-term starting point under 35 U.S.C. §154
U.S. grant	Does not ordinarily restart the 20-year term
Patent-term adjustment	Can extend the nominal expiration date
Terminal disclaimer	Can limit expiration based on another patent
Patent expiration	Ends ordinary patent infringement liability, subject to other live family members

The precise expiration date should be taken from the USPTO Patent Center record, including the patent-term-adjustment calculation and any terminal disclaimer.[1] The grant date alone is not a reliable proxy for expiration.

What is the Orange Book status of US 8,486,456?

US 8,486,456 should not automatically be treated as an Orange Book barrier merely because it concerns itraconazole and an oral dosage form.

The Orange Book lists patents submitted by an NDA holder for an approved drug product. Listing depends on the NDA holder’s submission and FDA’s determination that the patent claims the drug substance, drug product or an approved method of use.[3] A solid-dispersion patent may be listed if it claims the approved product or an approved use, but the listing must be confirmed in the current Orange Book patent table for the relevant itraconazole NDA.

The analysis should distinguish:

Issue	Meaning
Patent exists	USPTO rights may exist or may have existed
Patent is listed in the Orange Book	FDA has published the patent against a specific NDA
Patent is unexpired	The patent may still be enforceable
Paragraph IV certification filed	An ANDA applicant has challenged a listed patent
Litigation filed	The NDA holder has sued within the statutory period
30-month stay	FDA approval may be delayed under the Hatch-Waxman framework

FDA’s Orange Book identifies listed patents and regulatory exclusivity, but it is not a complete inventory of every patent that could be asserted against an itraconazole product.[3]

Which companies are challenging itraconazole patents?

Itraconazole has experienced competition from conventional generic capsules and from alternative solid-dispersion products. The principal competitive categories are:

Competitor category	Product strategy	Patent exposure
Conventional generic capsules	Replicate or approximate itraconazole capsule performance	May avoid the HPMC/ΔHtr limitations if composition differs
Generic oral solution	Uses a different dosage form and excipient system	Less direct exposure to capsule-particle claims
SUBA-itraconazole products	Enhanced bioavailability solid-dispersion technology	May implicate broader or different solid-dispersion patents
Compounded or non-U.S. products	Variable formulation and regulatory status	U.S. marketing may create separate FDA and patent risks

Tolsura, the SUBA-itraconazole product marketed by Mayne Pharma, is a competing enhanced-bioavailability itraconazole product with a formulation platform distinct from conventional Sporanox capsules.[4] Its presence shows that commercial competition can arise through a different solid-dispersion architecture rather than through a direct copy of the patented HPMC parameters.

A complete Paragraph IV list requires a product-specific review of current FDA Orange Book data, ANDA litigation dockets and patent-family records. Patent 8,486,456 should be analyzed separately from patents directed to other itraconazole formulations, such as cyclodextrin solutions, pellet systems, supersaturating formulations and SUBA technology.

What patent litigation and settlement risks affect the patent?

For a generic capsule applicant, the most important litigation questions are:

Whether 8,486,456 is listed against the relevant NDA;
Whether the ANDA makes a Paragraph IV certification;
Whether the applicant’s proposed product contains HPMC;
Whether the proposed dispersion has a ΔHtr below 0.35 J/g;
Whether the product label induces the claimed fungal-infection uses;
Whether the NDA holder files suit within 45 days of receiving the Paragraph IV notice.

A Paragraph IV challenge can result in a Hatch-Waxman infringement action under 35 U.S.C. §271(e)(2).[5] A settlement may provide a licensed entry date, a covenant not to sue, a formulation carve-out, or a restriction on the use of the patented dispersion. The existence and terms of any settlement should be checked against the FTC’s pharmaceutical patent-settlement reports and the relevant federal docket.[6]

There is no basis to infer that every itraconazole generic is licensed under this patent. Generic approval, patent expiration, patent nonlisting, invalidity, noninfringement and settlement are distinct legal outcomes.

What generic launch scenarios exist?

Scenario 1: Conventional formulation avoids the claims

A generic using a different polymer, a crystalline itraconazole form or a thermal profile outside the claimed range may have a credible noninfringement position. The applicant would still need to assess other itraconazole patents.

Scenario 2: Product meets claim 1 but not narrower claims

This is the highest direct exposure. A product can infringe claim 1 even if it falls outside the particle-size, HPMC-viscosity or drug-to-polymer-ratio ranges of claims 3 through 7.

Scenario 3: Product meets the thermal limitation and bioavailability limitation

This creates potential exposure under claims 9 and 10. A sponsor should not rely solely on a formulation difference if the finished dosage form produces the claimed Cmax and contains the claimed dispersion.

Scenario 4: Label omits a claimed use

A label carve-out may reduce induced-infringement exposure for claims 11 to 13. It does not eliminate composition or dosage-form risk under claims 1 and 8.

Scenario 5: Patent term has expired

Expiration removes ordinary infringement liability under this patent. It does not remove exposure under unexpired continuation, divisional or related family patents.

How does US 8,486,456 compare with broader itraconazole patents?

Patent type	Typical protected subject matter	Relevance to 8,486,456
Drug-substance patent	Itraconazole molecule or stereochemistry	Usually expired or historically important
Pellet or capsule patent	Dosage-form architecture	May overlap commercially without requiring the same ΔHtr
Cyclodextrin solution patent	Itraconazole oral solution	Separate product category
HPMC solid-dispersion patent	Itraconazole dispersed in HPMC with thermal limitation	Directly relevant
SUBA technology patents	Enhanced-bioavailability itraconazole dispersion	Competing estate; claim scope must be reviewed independently
Method-of-use patent	Treatment of specified fungal infections	Relevant to label and induced-infringement analysis

The patent’s differentiator is the ΔHtr limitation. A general itraconazole formulation patent may cover a product that does not satisfy the claimed thermal profile, while a product designed to reproduce the claimed high bioavailability may create greater risk.

What manufacturing and IP barriers does the patent create?

The main manufacturing barrier is process reproducibility. The producer must control:

Itraconazole’s physical form;
HPMC substitution and viscosity;
Solvent or melt-processing conditions;
Drying conditions;
Particle-size distribution;
Residual solvent and moisture;
Amorphous content and recrystallization;
DSC sample preparation and testing.

The patent does not claim every process step needed to make the dispersion. A manufacturer may therefore design around the product claims by using another polymer or a different solid-state structure. That design-around may reduce patent risk while creating development, bioequivalence or stability risk.

Key Takeaways

US 8,486,456 is a focused product patent for an itraconazole-HPMC solid dispersion.
Claim 1 is the principal commercial claim and requires ΔHtr below 0.35 J/g at 240°C to 250°C.
Claim 2 narrows the thermal threshold to below 0.20 J/g.
Claims 3 to 7 define particle size, HPMC chemistry, viscosity and composition ratio.
Claims 8 to 10 extend coverage to dosage forms and a Cmax of at least 400 ng/mL after a single 200 mg oral dose.
Claims 11 to 13 cover oral treatment of specified fungal infections.
The strongest design-around is a non-HPMC dispersion or a formulation with a demonstrably different thermal signature.
Orange Book listing must be confirmed against the relevant itraconazole NDA; patent existence alone does not establish a Hatch-Waxman barrier.
Patent expiration must be calculated from the effective filing date and adjusted for USPTO patent-term adjustment or terminal disclaimers.
Conventional itraconazole generics, oral solutions and SUBA-itraconazole products should be analyzed against separate patent families rather than assumed to be covered by this patent.

FAQs About US 8,486,456

Does any itraconazole-HPMC product infringe US 8,486,456?

No. The product must also satisfy the claimed ΔHtr limitation, and the relevant transition must occur at 240°C to 250°C.

Can a generic avoid the patent by changing capsule excipients?

Usually, changing only external capsule excipients may not avoid claims directed to the solid-dispersion particles. Changing the polymer or solid-state structure is more significant.

Does claim 9 require a clinical study?

The claim contains a pharmacokinetic limitation. Evidence addressing Cmax would likely be relevant to infringement, although the legal proof method would depend on the facts and claim construction.

Does a patent expiration end all itraconazole exclusivity?

No. Related patents, continuation patents, listed method-of-use patents, regulatory exclusivity and other formulation patents may create separate barriers.

Is Tolsura automatically covered by US 8,486,456?

No. Tolsura uses a separate enhanced-bioavailability technology platform. Coverage requires a claim-by-claim comparison of its actual composition, HPMC characteristics and thermal profile.

References

United States Patent and Trademark Office. (n.d.). Patent Center: U.S. Patent No. 8,486,456. https://patentcenter.uspto.gov/
United States Code. (2023). 35 U.S.C. §154: Contents and term of patent; provisional rights. https://uscode.house.gov/view.xhtml?req=granuleid:USC-prelim-title35-section154
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, Orange Book. https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book
U.S. Food and Drug Administration. (2018). Tolsura prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/
United States Code. (2023). 35 U.S.C. §271(e): Infringement of patent. https://uscode.house.gov/view.xhtml?req=granuleid:USC-prelim-title35-section271
Federal Trade Commission. (n.d.). Agreements filed with the Federal Trade Commission under the Medicare Prescription Drug, Improvement, and Modernization Act. https://www.ftc.gov/policy/reports/policy-statements/agreements-filed-federal-trade-commission-under-medicare-prescription-drug-improvement-modernization-act

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Sebela Ireland Ltd	ONMEL	itraconazole	TABLET;ORAL	022484-001	Apr 29, 2010		DISCN	Yes	No	⤷ Start Trial	⤷ Start Trial	Y			ONYCHOMYCOSIS OF THE TOENAIL CAUSED BY TRICOPHYTON RUBRUM OR TRICHOPHYTON MENTAGROPHYTES, ONCE DAILY USE FOR 12 CONSECUTIVE WEEKS	⤷ Start Trial
>Applicant	>Tradename	>Generic Name	>Dosage	>NDA	>Approval Date	>TE	>Type	>RLD	>RS	>Patent No.	>Patent Expiration	>Product	>Substance	>Delist Req.	>Patented / Exclusive Use	>Submissiondate

PCT Information
PCT Filed	August 08, 2006	PCT Application Number:	PCT/EP2006/007839
PCT Publication Date:	February 15, 2007	PCT Publication Number:	WO2007/017248

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Canada	2618255	⤷ Start Trial
European Patent Office	1912625	⤷ Start Trial
Spain	2571032	⤷ Start Trial
Japan	2009504589	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 8,486,456

Which drugs does patent 8,486,456 protect, and when does it expire?

Summary for Patent: 8,486,456