United States Drug Patent 8,921,374: Itraconazole Matrix Composition, Claim Scope, Expiry and Generic Risk

U.S. Patent No. 8,921,374 protects a 65 mg itraconazole oral matrix composition that is designed to provide pharmacokinetic exposure comparable to a 100 mg Sporanox-type itraconazole capsule. The claims rely on three elements: the 65 mg itraconazole dose, a polymer-containing matrix, and specified AUC, Cmax, food-effect, and therapeutic-similarity results.

The patent is commercially relevant to SUBA-itraconazole products, including Tolsura. Its principal barrier is formulation-specific rather than molecule-specific. Generic itraconazole capsules can enter after applicable formulation and method-of-use claims expire or are successfully challenged, but a product that uses the patented 65 mg polymer matrix and achieves the claimed pharmacokinetic profile could face infringement risk.

What does U.S. Patent 8,921,374 cover?

U.S. Patent 8,921,374 covers an oral pharmaceutical composition containing approximately 65 mg of itraconazole and one or more pharmaceutically acceptable polymers in a matrix system. The claims distinguish the composition from conventional itraconazole pellets or sugar-sphere capsules by requiring pharmacokinetic performance under fed and fasting conditions.

The patent does not broadly claim every itraconazole formulation. Its independent claims require:

Claim element	Required limitation
Active ingredient	About 65 mg itraconazole
Dosage form	Oral pharmaceutical composition
Excipients	One or more pharmaceutically acceptable polymers
Physical structure	Matrix system
Fed-state performance	Specified AUC exposure and therapeutic similarity to a 100 mg pellet capsule
Fasting-state performance	Specified AUC exposure and, in some claims, therapeutic similarity to the 100 mg pellet capsule
Optional polymer type	Enteric or acid-resistant polymer
Statistical performance	AUC ratio of approximately 0.70 to 1.43 within a 90% confidence interval

The reference product described in the claims contains approximately 100 mg of itraconazole, sugar spheres, hydroxypropyl methyl cellulose, and polyethylene glycol in a capsule shell. This description corresponds to the general formulation architecture of the conventional Sporanox itraconazole capsule. The claims use that formulation as the comparator for therapeutic similarity and pharmacokinetic exposure.

How do claims 1 through 10 differ?

Claims 1 and 4 are the principal composition claims. Claims 2, 3, and 5 through 10 add pharmacokinetic, food-condition, statistical, or polymer limitations.

Claim	Scope
1	65 mg itraconazole polymer matrix; fed-state AUC of 80% to 125% of approximately 650 to 1,200 h·ng/mL; fed-state therapeutic similarity to the 100 mg pellet capsule
2	Claim 1 plus fed-state Cmax of 80% to 125% of approximately 65 to 100 ng/mL
3	Claim 1 plus fasting-state therapeutic similarity to the 100 mg pellet capsule administered under fed conditions
4	65 mg itraconazole polymer matrix; fasting-state AUC of 80% to 125% of approximately 450 to 900 h·ng/mL; fed-state therapeutic similarity to the 100 mg pellet capsule
5	Claim 4 plus fasting-state therapeutic similarity to the fed 100 mg pellet capsule
6	Claim 4 plus fed-state AUC of 80% to 125% of approximately 650 to 1,200 h·ng/mL
7	Claim 1 plus an AUC ratio of approximately 0.70 to 1.43, with a 90% confidence interval
8	Claim 4 plus the same AUC-ratio limitation
9	Claim 1 plus an enteric or acid-resistant polymer
10	Claim 4 plus an enteric or acid-resistant polymer

The broadest practical protection is concentrated in claims 1 and 4. Claims 2, 7, 8, 9, and 10 may provide narrower fallback positions if a competing product avoids one or more of the broader functional limitations.

What is the practical meaning of the AUC and Cmax limitations?

The claims convert pharmacokinetic performance into a limitation of infringement. A competing product must be assessed not only by its ingredients and dosage form, but also by whether it produces the claimed exposure.

For claim 1, the stated fed-state AUC target is approximately 650 to 1,200 h·ng/mL, subject to an 80% to 125% range. If calculated mathematically across the full stated range, that creates an approximate potential span of 520 to 1,500 h·ng/mL. Claim 4 uses a fasting-state reference range of approximately 450 to 900 h·ng/mL, producing an approximate span of 360 to 1,125 h·ng/mL.

Claim 2 adds a Cmax reference range of approximately 65 to 100 ng/mL. Applying the 80% to 125% factor produces an approximate potential range of 52 to 125 ng/mL.

Claims 7 and 8 introduce an AUC ratio between the patented composition and the 100 mg comparator. A ratio range of 0.70 to 1.43 is materially broader than the conventional 0.80 to 1.25 bioequivalence interval. The claim language also refers to the 90% confidence interval, making study design, statistical analysis, subject population, food conditions, sampling schedule, and comparator selection central to infringement analysis.

What formulations are protected by U.S. Patent 8,921,374?

The patent protects polymer-based matrix formulations containing approximately 65 mg of itraconazole. Claims 9 and 10 specifically identify enteric polymers and acid-resistant polymers.

A formulation is more likely to fall within the claimed scope when it has the following characteristics:

Approximately 65 mg of itraconazole per oral unit.
Itraconazole dispersed, embedded, or otherwise incorporated into a polymer matrix.
A polymer that provides acid resistance, delayed release, improved dissolution, or protection in the gastric environment.
Pharmacokinetic exposure comparable to the specified 100 mg pellet capsule.
Fed-state or fasting-state performance within the claimed AUC and Cmax parameters.

The claims do not expressly require a particular capsule shell, pellet size, polymer grade, manufacturing process, dissolution apparatus, or release profile. That omission can broaden literal composition coverage, but it also increases the importance of claim construction. A competitor may argue that its formulation is a dispersion, solid solution, granule, or multiparticulate system rather than a matrix system.

The phrase "one or more pharmaceutically acceptable polymers" is broad. The dependent claims identify enteric or acid-resistant polymers, but the independent claims do not appear limited to those categories. A formulation using a non-enteric polymer could still raise risk under claims 1 or 4 if the matrix and pharmacokinetic requirements are satisfied.

How strong is the patent estate for SUBA-itraconazole?

The identified patent is strong against direct copies of the claimed 65 mg matrix formulation, but narrower against alternative itraconazole technologies.

Strengths

The patent combines structural and functional limitations. A challenger must address:

The approximate 65 mg itraconazole dose.
The polymer matrix architecture.
The relevant fed or fasting pharmacokinetic profile.
Therapeutic similarity to the specified 100 mg capsule.
The statistical AUC ratio in claims 7 and 8 where applicable.

The dose reduction from 100 mg to 65 mg, combined with improved exposure and reduced food dependence, gives the patent a product-specific profile. A generic applicant that copies the commercial product may have difficulty avoiding both composition and performance limitations.

Weaknesses

The functional limitations can create litigation vulnerability. Terms such as "therapeutically similar," "about," and "matrix system" may require expert testimony and claim construction. Bioavailability can vary across subjects and study conditions. A defendant may argue that the claimed AUC range is indefinite, not met under the tested conditions, or not sufficiently tied to a reproducible formulation characteristic.

The patent also does not claim itraconazole as a molecule. Conventional itraconazole capsules, oral solutions, and formulations outside the claimed matrix architecture are not automatically covered.

When does U.S. Patent 8,921,374 lose exclusivity?

The patent was issued on December 30, 2014. Its expected ordinary expiration is in 2031, based on the patent's priority and application timeline. The effective date must be confirmed against the USPTO patent record, including any patent-term adjustment and any patent-term extension.

Event	Date or status
Patent	U.S. 8,921,374
Issue date	December 30, 2014
Technology	65 mg itraconazole polymer matrix
Expected ordinary expiration	2031, subject to USPTO term calculation
FDA product association	SUBA-itraconazole/Tolsura product technology
Small-molecule exclusivity	No biosimilar framework applies
Generic pathway	ANDA with possible Paragraph IV certification
Patent-term adjustment or extension	Must be assessed from the official USPTO and FDA records

Patent expiration does not automatically permit every competing itraconazole product to launch. Other formulation, manufacturing, or method-of-use patents may remain enforceable. Conversely, a Paragraph IV certification can create an earlier entry opportunity if the patent is invalid, unenforceable, or not infringed and the innovator does not obtain a timely injunction.

What is the Orange Book status of itraconazole and Tolsura?

Tolsura is a small-molecule itraconazole product approved through an NDA pathway. FDA-approved drug products with relevant patents may have those patents listed in the Orange Book if they satisfy FDA listing requirements under the Hatch-Waxman framework. The Orange Book is the controlling source for current listed patents, expiration dates, and exclusivity information [1].

The relevant regulatory distinction is:

Product category	Regulatory pathway	Patent challenge
Tolsura or SUBA-itraconazole	NDA	Listed-patent and Paragraph IV framework
Conventional itraconazole generic capsule	ANDA	May certify against listed patents
Biosimilar	Not applicable	Itraconazole is a small molecule, not a biologic
505(b)(2) itraconazole product	Potentially applicable depending on formulation and reliance	May involve patent certifications and clinical bridging

FDA approval of an itraconazole generic does not establish freedom to market a 65 mg polymer matrix product. Approval and patent clearance are separate questions.

Which companies are challenging U.S. Patent 8,921,374?

The patent claims alone do not establish a Paragraph IV challenger, an ANDA filing, a district-court action, or a settlement agreement. A reliable challenger analysis requires the current FDA Orange Book, FDA Paragraph IV notice records where available, PACER litigation records, and subsequent patent assignments.

No specific challenger, litigation date, or settlement should be attributed to this patent solely from the claim text. Any current challenge assessment must distinguish:

A conventional 100 mg itraconazole generic.
A 65 mg matrix formulation.
A 505(b)(2) product.
A product that uses a different polymer or delivery system.
A product that relies on a Paragraph IV certification against an Orange Book-listed patent.

The absence of an identified challenge in the supplied material does not establish that no challenge exists. The relevant legal record is the FDA and court docket history, not the issued claims alone.

What patent litigation affects the itraconazole formulation market?

The principal litigation risks are likely to arise from claim construction and product testing rather than from the basic itraconazole compound.

Literal infringement

A product may present literal infringement risk if it contains approximately 65 mg itraconazole in a polymer matrix and meets the claimed AUC or Cmax requirements under the specified conditions.

Doctrine of equivalents

A formulation that uses a functionally similar polymer system, a slightly different dose, or a nonidentical matrix architecture could still raise doctrine-of-equivalents issues. Prosecution-history estoppel may limit that theory if the patent applicant narrowed the claims to obtain allowance.

Invalidity

Potential invalidity theories include:

Anticipation by prior itraconazole polymer formulations.
Obviousness based on Sporanox, solid-dispersion technology, enteric polymers, and dose-reduction studies.
Indefiniteness involving "about," "therapeutically similar," or "matrix system."
Written-description or enablement challenges to the breadth of the polymer and pharmacokinetic limitations.
Double-patenting issues if related continuation claims overlap.

The AUC and Cmax limitations may help distinguish the claims from prior art, but their value depends on whether the specification provides sufficient formulation and clinical support for the claimed ranges.

What generic entry risks exist for a 65 mg itraconazole matrix product?

Generic entry risk is product-dependent.

Generic strategy	Risk under Patent 8,921,374	Commercial assessment
Conventional 100 mg itraconazole pellet capsule	Lower direct risk from this patent	Could compete with conventional itraconazole products but may not substitute for Tolsura
Copy of 65 mg polymer matrix	High	Most exposed to composition and PK claims
65 mg formulation using a different nonmatrix system	Moderate to lower	Depends on claim construction and equivalents
65 mg matrix with materially different exposure	Moderate	May avoid functional limitations but could face equivalents arguments
Itraconazole oral solution	Lower under these claims	Different dosage-form architecture
New enteric delivery system	Moderate to high	Enteric polymers are expressly identified in dependent claims
505(b)(2) reformulation	Moderate	Patent certifications and clinical bridging may be required

The most defensible design-around path would generally involve changing at least one core claim feature: dose, matrix architecture, polymer function, or pharmacokinetic profile. Changing only capsule appearance or excipient grade would provide weak protection if the product still satisfies the claimed formulation and performance requirements.

How does Patent 8,921,374 compare with conventional Sporanox protection?

The patent does not protect the conventional 100 mg pellet capsule as such. Instead, it uses that capsule as a comparator.

Issue	Conventional Sporanox capsule	Patent 8,921,374 composition
Itraconazole amount	Approximately 100 mg	Approximately 65 mg
Physical platform	Sugar spheres or pellets in capsule	Polymer matrix
Food dependence	Food administration is important for exposure	Designed for improved fed and fasting performance
Claim focus	Conventional product and related uses	Composition plus PK profile
Substitution objective	Original itraconazole delivery	Comparable exposure at lower dose
Patent risk	Depends on separate product and use patents	Directly relevant to the 65 mg matrix product

The claimed comparison is commercially important because it supports substitution of a lower-dose matrix product for the conventional 100 mg capsule. It does not, by itself, create patent rights in the comparator formulation.

What manufacturing and intellectual-property barriers exist?

The manufacturing barrier is likely higher than the API barrier. Itraconazole is an established active ingredient with generic supply. The protected value lies in achieving consistent drug loading, matrix uniformity, dissolution behavior, acid resistance, and exposure across fed and fasting conditions.

Potential manufacturing controls include:

Polymer selection and grade.
Itraconazole particle-size distribution.
Solid-state form and dispersion characteristics.
Mixing and granulation conditions.
Matrix compression or encapsulation parameters.
Acid-stage dissolution performance.
Release-stage dissolution performance.
Content uniformity at the 65 mg dose.
Stability under humidity and temperature stress.

A competitor may avoid literal infringement through a different manufacturing process, but process differences do not eliminate risk if the resulting product still falls within the composition and pharmacokinetic claims. Conversely, a different manufacturing process can support a noninfringement position when it produces a distinct dosage-form structure or materially different exposure profile.

What is the revenue exposure associated with this patent?

Revenue exposure is concentrated in branded or authorized 65 mg SUBA-itraconazole sales, not in the entire itraconazole market. Conventional generic itraconazole products may compete in overlapping indications without practicing the patented matrix claims.

Commercial exposure depends on:

The share of Tolsura prescriptions that can be substituted by conventional itraconazole.
The number of ANDA or 505(b)(2) entrants.
Whether a challenger copies the 65 mg matrix platform.
Payer preference for the 65 mg product.
The expiration or invalidation of related patents.
Any authorized-generic or settlement arrangement.
The ability of competitors to match food-independent or reduced-food-effect performance.

A 65 mg product with equivalent exposure may command differentiated pricing if it reduces dosing burden or food-related variability. That commercial advantage also makes the product a more attractive target for formulation-focused generic entry.

Key Takeaways

U.S. Patent 8,921,374 is a formulation patent, not a basic itraconazole compound patent.
Its core subject is an oral composition containing approximately 65 mg itraconazole in a polymer matrix.
Claims 1 and 4 are the principal independent composition claims.
The patent uses AUC, Cmax, food conditions, and therapeutic similarity to define the protected product profile.
Claims 9 and 10 expressly identify enteric and acid-resistant polymers.
The patent is most exposed to an invalidity challenge based on obviousness, indefiniteness, or inadequate support for broad pharmacokinetic limitations.
A direct copy of a 65 mg SUBA-itraconazole matrix product presents the highest infringement risk.
Conventional 100 mg itraconazole pellet capsules are not automatically covered.
Itraconazole is a small molecule, so biosimilar analysis does not apply.
The patent issued on December 30, 2014, with expected ordinary expiration in 2031, subject to the official USPTO term calculation.
Current Orange Book listing, Paragraph IV activity, litigation, and settlement status must be determined from the FDA and court records rather than from the claim text.

Frequently Asked Questions

Does Patent 8,921,374 cover all 65 mg itraconazole products?

No. The claims require a polymer matrix and specified pharmacokinetic or therapeutic-similarity characteristics. A 65 mg product using a different dosage-form architecture may avoid the literal scope.

Does the patent cover Sporanox 100 mg capsules?

No. The 100 mg pellet capsule is used primarily as the comparator in the claims. The patented composition is the approximately 65 mg polymer matrix product.

Can a generic applicant file an ANDA before the patent expires?

Yes. An ANDA applicant may submit a Paragraph IV certification against a listed patent. Commercial launch may be delayed by litigation, a court injunction, a settlement, or other applicable exclusivity.

Is the 0.70 to 1.43 AUC ratio a conventional bioequivalence standard?

No. The range is broader than the commonly used 0.80 to 1.25 interval. Claims 7 and 8 apply that range with a 90% confidence-interval limitation to the comparison against the 100 mg capsule.

Does a different polymer automatically avoid infringement?

No. The independent claims require one or more pharmaceutically acceptable polymers but do not appear limited to a single named polymer. A different polymer may still fall within the claims if the product has the required matrix structure and pharmacokinetic profile.

References

U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. https://www.accessdata.fda.gov/scripts/cder/ob/
U.S. Patent and Trademark Office. (2014). U.S. Patent No. 8,921,374: Itraconazole compositions. Google Patents. https://patents.google.com/
U.S. Food and Drug Administration. (2018). Tolsura (itraconazole) capsules prescribing information. FDA.
U.S. Food and Drug Administration. (2024). Abbreviated new drug application and patent certification requirements. FDA.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, patent and exclusivity information. FDA.

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Mayne Pharma	TOLSURA	itraconazole	CAPSULE;ORAL	208901-001	Dec 11, 2018		RX	Yes	Yes	8,921,374	⤷ Start Trial	Y				⤷ 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

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Australia	2012902624	Jun 21, 2012

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2013278001	⤷ Start Trial
Australia	2018201298	⤷ Start Trial
Australia	2020217438	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 8,921,374

Which drugs does patent 8,921,374 protect, and when does it expire?

Summary for Patent: 8,921,374