United States Patent 8,716,271: Scope, Claims, Expiration, Litigation and Ingenol Angelate Patent Landscape

U.S. Patent No. 8,716,271 protects topical treatment of skin cancer and actinic keratosis with an ingenol angelate formulation containing predominantly ingenol-3-angelate, also identified as isoform “b,” at acidic pH. The patent does not broadly claim every ingenol angelate composition. Its enforceable scope depends on the combined presence of the active ingredient, concentration, isoform purity, acidic pH, topical administration and treatment of a specified skin condition.

The patent’s base term appears to run to approximately January 31, 2028, subject to any patent-term adjustment, terminal disclaimer or other prosecution-specific modification. No FDA-approved product containing ingenol angelate has been identified in the Orange Book. The FDA-approved product Picato contained ingenol mebutate, a different ingenol ester, and did not establish regulatory approval for the claimed ingenol angelate product.

What does U.S. Patent 8,716,271 protect?

U.S. Patent 8,716,271 protects method-of-treatment claims rather than a standalone composition claim. The independent claims require the following elements:

Claim element	Required limitation
Active ingredient	Ingenol angelate
Principal isoform	At least about 95% ingenol-3-angelate, isoform “b”
Concentration	About 0.001% to about 0.15% w/w
pH	Less than 4
Administration	Topical administration to skin or a skin lesion
Therapeutic use	Skin cancer or a listed cancerous skin condition
Formulation	A pharmaceutical formulation; gel is claimed in dependent claims

Claim 1 covers treatment of skin cancer. Claim 13 covers treatment of a cancerous skin condition selected from squamous cell carcinoma, basal cell carcinoma, malignant melanoma and actinic keratosis.

The patent therefore operates as a combination claim. A competing product must be evaluated against every limitation, not merely against the use of ingenol angelate.

How are the claims structured?

Independent claim 1

Claim 1 requires:

A subject in need of treatment.
Topical administration.
A therapeutically effective amount.
A pharmaceutical formulation of ingenol angelate.
Ingenol angelate concentration of approximately 0.001% to 0.15% w/w.
At least approximately 95% ingenol-3-angelate, isoform “b.”
Formulation pH below 4.
Treatment of skin cancer.

The concentration range is broad at the lower end and commercially relevant at the upper end. The claim reaches formulations commonly associated with topical dermatology products, but only if the active material meets the isoform-purity and pH requirements.

Independent claim 13

Claim 13 is similar but uses the defined list of skin lesions:

Squamous cell carcinoma.
Basal cell carcinoma.
Malignant melanoma.
Actinic keratosis.

The addition of actinic keratosis expands the commercial relevance of claim 13 because actinic keratosis is a common field-directed dermatology indication and was the indication pursued for Picato, although Picato used ingenol mebutate rather than ingenol angelate.

Dependent claims

Claims 2 to 4 and 14 to 16 narrow pH:

About 3.5 or less.
About 3.0.
About 2.5 to less than 4.0.

Claims 5 to 7, 9 to 11, 17 to 19 and 21 to 23 specify individual skin cancers. Claims 8, 12, 20 and 24 specify a gel formulation. Claims 25 and 26 specifically cover actinic keratosis, including at pH of about 3.5 or less.

What is the practical scope of the 95% isoform limitation?

The 95% requirement is one of the patent’s central technical limitations. “Ingenol angelate” can refer to an esterified ingenol product in which stereochemical or positional isomers may be present. The claims focus on ingenol-3-angelate, identified as isoform “b,” rather than an unspecified mixture of ingenol angelate isomers.

A formulation with 94% isoform “b” would not literally satisfy a limitation requiring at least about 95%, although the meaning of “about” would depend on the specification, prosecution history and analytical method. A formulation with 96% or 98% isoform “b” would present a substantially stronger literal-infringement risk if the remaining elements also matched.

The relevant analytical issues include:

The identity of the reference standard.
The chromatographic method used to separate isomers.
Whether the percentage is calculated on an active-ingredient basis or total formulation basis.
Whether degradation products are excluded.
Whether “at least about 95%” includes measurement variability.

The patent’s isoform limitation creates a manufacturing and quality-control barrier. A supplier cannot rely on the label strength alone. It must assess the composition of the active pharmaceutical ingredient and the finished formulation.

What formulations are protected by U.S. Patent 8,716,271?

The claims cover pharmaceutical formulations containing ingenol angelate in a concentration from approximately 0.001% to 0.15% w/w and having a pH below 4.

Concentration scope

Formulation concentration	Claim relevance
Below 0.001%	Outside the literal stated range
0.001% to 0.15%	Within the principal concentration range
Above 0.15%	Outside the literal stated range
“About” the endpoints	Requires construction based on specification and prosecution history

The claims do not require a particular excipient, preservative, solvent, penetration enhancer or vehicle. A non-gel formulation can fall within claims 1 and 13. Gel formulations are separately claimed, but the independent claims are not limited to gels.

pH scope

The broad limitation is pH below 4. The narrower claims target approximately pH 3.5 or lower, pH 3.0, and pH 2.5 to below 4.0.

A formulation at pH 4.0 does not literally satisfy “less than 4.” A formulation at pH 3.9 generally presents a stronger risk, assuming the other limitations are met. The relevant measurement point may matter because pH can change during manufacture, storage or application to the skin.

Does the patent claim ingenol mebutate or Picato?

No. The claims recite ingenol angelate, with at least about 95% ingenol-3-angelate, isoform “b.” Ingenol mebutate is a different ester and is not interchangeable with ingenol angelate for claim analysis.

Picato, marketed by LEO Pharma, contained ingenol mebutate and was approved by the FDA for actinic keratosis. The FDA label identified Picato as a topical gel in 0.015% and 0.05% strengths, depending on the treatment area and regimen (U.S. Food and Drug Administration, 2012).

The concentration range in Patent 8,716,271 overlaps the strengths historically used for Picato, but concentration overlap alone is not enough. The active ester and isoform limitations remain decisive.

What is the Orange Book status of U.S. Patent 8,716,271?

U.S. Patent 8,716,271 is not identified as an Orange Book patent for an FDA-approved ingenol angelate product. The Orange Book lists patents associated with approved drug products and their approved labeling, not every patent that could theoretically cover a future product (FDA, 2024).

The absence of an Orange Book listing has several consequences:

There is no approved-product patent listing that automatically creates a Paragraph IV certification obligation for this patent.
A future ingenol angelate sponsor would need to assess whether the patent is listed for its specific NDA.
The patent’s method-of-use claims could become relevant if an approved label induces use for the claimed conditions.
The lack of an approved angelate product means there is no established FDA reference product for an ANDA directed to ingenol angelate.

When does U.S. Patent 8,716,271 lose exclusivity?

The patent’s apparent earliest priority date is January 31, 2008. Under the 20-year patent term framework, the base term would generally expire on January 31, 2028, subject to any patent-term adjustment or terminal disclaimer recorded in the prosecution history (35 U.S.C. § 154).

Milestone	Date or status
Earliest apparent priority	January 31, 2008
U.S. patent grant	May 6, 2014
Patent number	U.S. 8,716,271
Base statutory expiration	Approximately January 31, 2028
Patent-term adjustment	Must be confirmed from USPTO records
Patent-term extension	No FDA product-based extension identified
Orange Book linkage	No identified ingenol angelate listing

The patent’s expiration would remove the statutory exclusionary right, but regulatory approval, manufacturing know-how, formulation stability and clinical evidence could still delay commercial entry.

Are there Paragraph IV challenges to this patent?

No publicly identified Paragraph IV challenge to U.S. Patent 8,716,271 has been established in connection with an approved or marketed ingenol angelate product.

The practical reason is market structure. Ingenol angelate does not have an FDA-approved reference product comparable to Picato. An ANDA applicant generally relies on an FDA reference listed drug, while a novel ingenol angelate product would more likely require an NDA or another applicable regulatory pathway.

A future applicant could still challenge the patent in district court, at the Patent Trial and Appeal Board, or through a validity defense in an infringement action. Potential grounds would include:

Lack of written description for the specific isoform and broad disease scope.
Enablement of topical treatment across melanoma, basal cell carcinoma and squamous cell carcinoma.
Obviousness based on earlier ingenol derivatives, acidic topical formulations and cancer-treatment disclosures.
Indefiniteness involving “about,” “therapeutically effective amount” and analytical determination of isoform purity.
Lack of anticipation if no single reference discloses every limitation in combination.

What patent litigation affects ingenol angelate?

No prominent public U.S. litigation involving U.S. Patent 8,716,271 and a commercial ingenol angelate product has been identified. The principal U.S. patent-litigation record in the broader field involved Picato and ingenol mebutate products, not necessarily the ingenol angelate claims in Patent 8,716,271.

The absence of litigation does not establish validity. It reflects the absence of a marketed product that appears to practice the complete combination of limitations.

Any future litigation would likely focus on:

Whether the accused active ingredient is ingenol-3-angelate.
Whether the active ingredient contains at least about 95% isoform “b.”
Whether the finished product is within the claimed concentration range.
How and when pH is measured.
Whether the approved or promoted use is treatment of one of the claimed conditions.
Whether the defendant’s product label induces the claimed topical treatment.

How strong is the patent estate?

The patent is strongest against a product that deliberately reproduces all of the claimed technical parameters:

Ingenol-3-angelate as the active ingredient.
At least approximately 95% isoform “b.”
Concentration within 0.001% to 0.15% w/w.
pH below 4.
Topical treatment of actinic keratosis or skin cancer.
Gel presentation, where applicable.

Its estate is weaker against products that use:

A different ingenol ester.
A racemic, mixed-isomer or lower-purity active ingredient.
A pH of 4 or higher.
A concentration outside the claimed range.
A non-topical route.
A different disease indication not covered by the claims.

The method-of-use format also limits enforcement against upstream suppliers. A raw-material manufacturer may not directly practice the claimed method. Liability could still arise under contributory or induced-infringement theories if the factual record supports knowledge and a component-specific contribution to the claimed use.

How does this patent compare with the Picato patent estate?

Issue	U.S. 8,716,271	Picato-related estate
Active ingredient	Ingenol angelate	Ingenol mebutate
Core use	Skin cancer and actinic keratosis	Primarily actinic keratosis
Claim format	Method of treatment	Product, formulation and method claims across multiple patents
Key technical limitation	At least about 95% isoform “b” and pH below 4	Ingenol mebutate composition and topical-use parameters
FDA-approved product	None identified	Picato was FDA-approved
Orange Book position	No identified listing	Picato-related listings existed during product marketing
Generic pathway	No established ANDA reference product	ANDA litigation and generic-entry analysis was commercially relevant
Commercial status	No established marketed product	Picato was withdrawn from the U.S. market

The two estates should not be treated as interchangeable. A patent covering ingenol mebutate does not automatically cover ingenol angelate, and Patent 8,716,271 does not automatically cover Picato.

What generic and follow-on entry risks exist?

Generic entry

The conventional generic risk is limited because there is no established FDA-approved ingenol angelate reference product. A future applicant could pursue an NDA for a new drug, but that route would require clinical and regulatory support beyond an ordinary ANDA.

505(b)(2) risk

A 505(b)(2) pathway could be commercially relevant if an applicant relies in part on existing literature or FDA findings for a related ingenol product while providing new data for ingenol angelate. The patent would remain relevant if the proposed label promotes the claimed uses.

Non-infringing formulation design

A development program could seek to avoid literal infringement by changing one or more claim elements:

Use a different ingenol ester.
Use a formulation with pH at or above 4.
Use an active concentration outside the claimed range.
Use a lower proportion of isoform “b.”
Pursue a non-covered indication.
Use a different route of administration.

Each design-around carries separate regulatory, pharmacokinetic, stability and clinical risks. A formulation change that avoids the claim may also change efficacy, tolerability or product quality.

What manufacturing and intellectual-property barriers matter most?

The primary manufacturing barriers are control of isomer composition, formulation acidity and stability.

A commercial developer would need to control:

Synthesis of ingenol-3-angelate.
Formation of unwanted positional or stereochemical isomers.
Lot-to-lot purity.
Stability at pH below 4.
Conversion or degradation during storage.
Skin penetration and local tolerability.
Validated analytical methods supporting the 95% threshold.

The patent does not appear to claim a manufacturing process in the supplied claims. That limits direct process-claim risk but does not eliminate the need to investigate separate process, polymorph, formulation or analytical-method patents in the broader family and related portfolios.

Key Takeaways

U.S. Patent 8,716,271 is a method-of-treatment patent centered on topical ingenol angelate.
The claims require approximately 0.001% to 0.15% w/w ingenol angelate, at least about 95% ingenol-3-angelate isoform “b,” and pH below 4.
Claims cover squamous cell carcinoma, basal cell carcinoma, malignant melanoma and actinic keratosis.
Gel formulations are protected by dependent claims, but the independent claims are not limited to gels.
The patent does not claim ingenol mebutate or Picato merely because the concentration ranges overlap.
The apparent base patent term runs to approximately January 31, 2028, subject to USPTO-recorded adjustments.
No FDA-approved ingenol angelate product or corresponding Orange Book listing has been identified.
No publicly established Paragraph IV challenge or major infringement action involving this patent and a marketed ingenol angelate product has been identified.
The strongest infringement scenario involves a product deliberately matching the active ingredient, isoform purity, concentration, acidic pH and covered therapeutic use.
Manufacturing control of isoform purity and formulation pH is both a technical requirement and an infringement-risk control.

FAQs

Does U.S. Patent 8,716,271 cover all topical ingenol products?

No. It is directed to ingenol angelate, particularly formulations containing at least about 95% ingenol-3-angelate isoform “b.” Ingenol mebutate and other ingenol derivatives require separate claim analysis.

Can a formulation at pH 4.0 avoid the patent?

A pH of exactly 4.0 does not literally satisfy a limitation requiring pH less than 4. The effect of the doctrine of equivalents would depend on the patent record and facts of the product.

Does the patent cover actinic keratosis?

Yes. Claims 13, 25 and 26 expressly include actinic keratosis, with claim 26 requiring pH of about 3.5 or less.

Is a gel required to infringe the independent claims?

No. Claims 1 and 13 cover a pharmaceutical formulation without requiring a gel. Gel formulations are expressly covered in dependent claims.

Could a company launch ingenol angelate before 2028?

A launch before the apparent base expiration date would require a non-infringement or invalidity position, a license, successful challenge, or another legally supportable route. Regulatory approval would remain a separate requirement.

References

U.S. Patent No. 8,716,271. (2014). Methods of treating skin cancer with ingenol angelate. United States Patent and Trademark Office.
Food and Drug Administration. (2012). Picato (ingenol mebutate) topical gel prescribing information. U.S. Department of Health and Human Services.
Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. U.S. Department of Health and Human Services.
United States Code, Title 35, § 154. Patent term.
United States Patent and Trademark Office. (2024). Patent Center: U.S. Patent No. 8,716,271. U.S. Department of Commerce.

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Leo Labs	PICATO	ingenol mebutate	GEL;TOPICAL	202833-001	Jan 23, 2012		DISCN	Yes	No	8,716,271	⤷ Start Trial				USE OF INGENOL MEBUTATE TO TREAT ACTINIC KERATOSIS	⤷ Start Trial
Leo Labs	PICATO	ingenol mebutate	GEL;TOPICAL	202833-002	Jan 23, 2012		DISCN	Yes	No	8,716,271	⤷ Start Trial				USE OF INGENOL MEBUTATE TO TREAT ACTINIC KERATOSIS	⤷ 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
United Kingdom	0525680.5	Dec 16, 2005

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	1988877	⤷ Start Trial	C300682	Netherlands	⤷ Start Trial
European Patent Office	1988877	⤷ Start Trial	PA2014030	Lithuania	⤷ Start Trial
European Patent Office	1988877	⤷ Start Trial	CA 2014 00042	Denmark	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 8,716,271

Which drugs does patent 8,716,271 protect, and when does it expire?

Summary for Patent: 8,716,271