Details for Patent: 8,536,163

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Which drugs does patent 8,536,163 protect, and when does it expire?

Patent 8,536,163 protects PICATO and is included in one NDA.

This patent has thirty-three patent family members in twenty-one countries.

Summary for Patent: 8,536,163

Title:	Therapeutic compositions
Abstract:	Ingenol angelate is a potent anticancer agent, and can be stabilized by dissolving it in an aprotic solvent in the presence of an acidic buffer.
Inventor(s):	Marc Barry Brown, Michael Crothers, Tahir Nazir
Assignee:	AF 30 APRIL 2003 AS , Leo Laboratories Ltd
Application Number:	US13/769,821
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,536,163
Patent Claim Types: see list of patent claims	Use; Formulation;

US Patent 8,536,163: Ingenol Angelate Skin-Cancer Treatment Claims, Scope, Expiration, and Patent Landscape

US Patent 8,536,163 protects topical treatment methods using a highly purified ingenol angelate formulation, also known as ingenol-3-angelate or ingenol mebutate. The independent claims require four central elements: topical administration, a concentration of about 0.001% to about 0.15% w/w, at least about 99% ingenol-3-angelate, and a formulation pH below 4. The dependent claims narrow the pH, disease indication, and dosage form.

The patent is directed to method-of-use protection rather than a broad composition claim. Its commercial relevance is closely associated with Picato gel, the former LEO Pharma product containing ingenol mebutate for actinic keratosis. The claims reach beyond the FDA-approved actinic-keratosis indication by expressly covering squamous cell carcinoma, basal cell carcinoma, and malignant melanoma.

What does US Patent 8,536,163 protect?

The patent protects a method of treating skin cancer or a cancerous skin condition by applying a specified ingenol angelate formulation directly to the skin or a skin lesion.

The broadest independent claims are claims 1 and 13.

Claim element	Claim 1	Claim 13
Treatment method	Treating skin cancer	Treating a cancerous skin condition
Administration	Topical	Topical to a skin lesion
Active ingredient	Ingenol angelate	Ingenol angelate
Concentration	About 0.001% to about 0.15% w/w	About 0.001% to about 0.15% w/w
Isomer purity	At least about 99% ingenol-3-angelate, isoform b	At least about 99% ingenol-3-angelate, isoform b
Formulation pH	Less than 4	Less than 4
Covered diseases	Skin cancer generally	SCC, BCC, malignant melanoma, and actinic keratosis
Dosage form	Any pharmaceutical formulation meeting the limitations	Any pharmaceutical formulation meeting the limitations

Claim 1 is broader as to the disease definition because it refers to skin cancer generally. Claim 13 supplies an express closed list of four conditions. Claim 13 may therefore provide a more definite claim construction for specific lesions while avoiding reliance on an open-ended interpretation of “skin cancer.”

What are the key claim limitations in US 8,536,163?

Ingenol angelate identity

The claims require ingenol angelate with at least approximately 99% of the active material present as ingenol-3-angelate, identified in the patent as isoform “b.” Ingenol-3-angelate is the active ingredient historically marketed as ingenol mebutate in Picato.

This limitation excludes formulations in which a material proportion of the active ingredient consists of other ingenol angelate isomers or related ingenol esters. The purity requirement is potentially significant in generic or follow-on product analysis because a formulation may contain the same nominal active ingredient but fail, or avoid, the claim depending on its isomeric composition.

The phrase “at least about 99%” raises ordinary claim-construction issues concerning:

• The analytical method used to measure isomer purity.
• Whether the percentage is measured against total ingenol compounds, total active ingredient, or the formulation as a whole.
• The meaning of “about” around the 99% threshold.
• Whether degradation products are counted in the denominator.
• Whether the relevant purity is measured at manufacture, release, or administration.

Concentration range

The claimed concentration is about 0.001% to about 0.15% w/w. The range includes the concentrations associated with Picato gel, including the historically marketed 0.015% and 0.05% strengths.

The concentration limitation is material. A topical product below approximately 0.001% or above approximately 0.15% may fall outside the literal range, although the treatment method could remain relevant to other patent claims or face an equivalence argument depending on the facts.

The range is formulation-based and expressed by weight. A product labeled in mg/g must be converted to weight percentage:

Product strength	Approximate w/w concentration
0.01 mg/g	0.001%
0.15 mg/g	0.015%
0.50 mg/g	0.05%
1.50 mg/g	0.15%

Acidic pH

The formulation must have a pH below 4. Dependent claims narrow this requirement to:

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

The pH limitation is one of the patent’s strongest technical identifiers. A formulation containing ingenol-3-angelate at a covered concentration but having a pH of 4 or higher would not literally satisfy the independent claims.

Claim 3 is narrower than claim 1 because it targets a pH of approximately 3.0. Claim 4 creates a defined lower-bound range of approximately 2.5 to below 4.0. A product with a pH below 2.5 could satisfy claim 1 but may not satisfy claim 4.

Topical administration

The claims require topical administration to skin, and claim 13 specifically requires administration to a skin lesion. The claim does not expressly require a particular application schedule, treatment duration, vehicle, packaging system, or amount applied per lesion.

The absence of a dosing-frequency limitation increases the potential scope of the method claims. A competing product could face claim exposure even if it uses a different schedule, provided the formulation and disease-use limitations are met.

Which claims cover formulations, gels, and pH ranges?

Claims 8, 12, 17, and 18 specifically recite a gel. The independent claims do not require a gel, so creams, ointments, solutions, emulsions, suspensions, and other topical pharmaceutical formulations could potentially fall within claims 1 or 13 if they satisfy the concentration, purity, pH, and treatment limitations.

Claim group	Added limitation
Claims 1 and 13	Broad formulation language, pH below 4
Claims 2 and 14	pH about 3.5 or less
Claims 3 and 15	pH about 3.0
Claims 4 and 16	pH about 2.5 to below 4.0
Claims 8 and 17	Gel
Claim 12	Gel plus claim 2 pH limitation
Claim 18	Gel plus claim 14 pH limitation
Claims 5, 9, 19, and 20	Specified disease or actinic keratosis limitations

The gel claims are narrower but commercially important because Picato was marketed as a topical gel. A generic gel matching the Picato formulation would need to assess both this patent and any later formulation or product patents.

What diseases are covered by US 8,536,163?

The patent claims cover the following conditions:

Condition	Covered claims
Squamous cell carcinoma	Claims 5 and 9; also within claim 13
Basal cell carcinoma	Claims 6 and 10; also within claim 13
Malignant melanoma	Claims 7 and 11; also within claim 13
Actinic keratosis	Claims 13, 19, and 20
Skin cancer generally	Claim 1 and its dependents

The inclusion of malignant melanoma is particularly broad from a therapeutic-use perspective. The FDA-approved Picato labeling was directed to actinic keratosis, not treatment of invasive melanoma or established basal or squamous cell carcinoma. A patent claim can cover a use that is broader than the approved labeling, but commercial promotion and regulatory use remain governed by the product’s FDA-approved indication.

What is the FDA status of ingenol mebutate and Picato?

Picato, containing ingenol mebutate, received FDA approval for topical treatment of actinic keratosis. The product was supplied in two strengths:

Product strength	Historical FDA use
0.015% gel	Actinic keratoses on the face and scalp
0.05% gel	Actinic keratoses on the trunk and extremities

The FDA later identified a potential increased risk of skin malignancy associated with ingenol mebutate gel and requested withdrawal of Picato from the U.S. market. LEO Pharma announced worldwide withdrawal of Picato in 2020. The commercial withdrawal materially reduces current product sales exposure, but it does not by itself eliminate patent rights or resolve potential infringement questions involving unapproved products and research uses.

The FDA status is therefore distinct from the patent scope:

• FDA approval covered actinic keratosis.
• Claims 1 and 13 extend to several skin-cancer indications.
• The product withdrawal affects commercialization and market size.
• The withdrawal does not automatically cancel an issued patent.

(FDA, 2020; LEO Pharma, 2020)

When does US Patent 8,536,163 lose exclusivity?

US Patent 8,536,163 was issued on September 17, 2013. Its enforceable term is generally calculated from the applicable nonprovisional filing date, subject to patent-term adjustment, terminal disclaimers, and any other USPTO term calculations.

The patent is associated with the ingenol angelate and Picato development program and is generally treated as having a nominal term extending into the late 2020s. A definitive expiration analysis must use the USPTO Patent Center term record, including any patent-term adjustment and terminal-disclaimer information.

The key commercial point is that the patent does not create permanent exclusivity. Even if the patent remains unexpired, a competitor may challenge validity, design around the claim limitations, or market a product that does not practice the claimed combination.

How strong is the patent estate for ingenol mebutate?

The strength of US 8,536,163 is concentrated in the combination of formulation and use limitations rather than in a broad chemical compound claim.

Strengths

1. The claim requires a specific active stereochemical or isomeric profile.
2. The pH below 4 provides a clear formulation discriminator.
3. The claimed concentration range covers the principal historical Picato strengths.
4. The claims cover both actinic keratosis and several skin cancers.
5. The topical-use requirement aligns with the commercial dosage form.
6. Gel claims map closely to the marketed product.

Vulnerabilities

1. The claims are method claims and require proof of use for a covered indication.
2. A competing formulation may avoid infringement by changing pH, concentration, isomer purity, or dosage form.
3. “About” language can create claim-construction disputes at the boundaries.
4. The cancer-treatment claims may face enablement, written-description, utility, or obviousness challenges depending on the disclosure and prosecution history.
5. Regulatory withdrawal reduces the practical value of claims directed to the former commercial product.
6. Prior-art references covering ingenol derivatives, topical formulations, and actinic keratosis treatment may affect validity.

The patent is stronger against an identical Picato-like formulation used for actinic keratosis than against a materially different topical product or a product used for a noncovered dermatologic condition.

What patent landscape surrounds US 8,536,163?

The relevant landscape contains several distinct patent categories.

Ingenol compound patents

Earlier patent families addressed ingenol derivatives, including esterified ingenol compounds and their therapeutic activity. These patents generally concern chemical entities or compound classes rather than the specific low-pH, high-purity topical method claimed in US 8,536,163.

Formulation patents

Formulation families may claim:

• Ingenol mebutate in a topical gel.
• Specific excipients and solvent systems.
• Stabilization against degradation or isomerization.
• pH-controlled formulations.
• Unit-dose packaging.
• Concentration-specific products.
• Manufacturing and purification procedures.

A generic product must be screened against these families separately. Avoiding US 8,536,163 does not necessarily avoid later formulation patents.

Method-of-use patents

The method-of-use landscape includes claims directed to:

• Actinic keratosis.
• Nonmelanoma skin cancer.
• Field treatment of sun-damaged skin.
• Treatment schedules and dosing regimens.
• Combination treatment with other dermatologic agents.
• Specific lesion types or anatomical sites.

The claims supplied for US 8,536,163 are unusually broad in naming SCC, BCC, and malignant melanoma, but the commercial FDA indication historically centered on actinic keratosis.

Manufacturing and purification rights

The requirement for at least approximately 99% ingenol-3-angelate creates a potential manufacturing barrier. A follow-on manufacturer must control:

• Starting-material identity.
• Esterification selectivity.
• Isomer formation.
• Crystallization or purification.
• Assay and impurity methods.
• Stability-related conversion during storage.

A product that begins above 99% purity but degrades below that level during shelf life may create both quality and patent-position issues.

Are biosimilars relevant to US 8,536,163?

No. Ingenol mebutate is a small-molecule active pharmaceutical ingredient, not a biologic. Biosimilar pathways under the Public Health Service Act do not apply.

The relevant competitors would be abbreviated new drug application applicants, 505(b)(2) applicants, or non-U.S. topical products. A U.S. generic applicant would typically evaluate an ANDA pathway, sameness of active ingredient, dosage form, strength, route, and bioequivalence requirements.

Which companies are likely to challenge or design around the patent?

The principal commercial risk would come from generic dermatology manufacturers and specialty pharmaceutical companies with topical-development capabilities. The most plausible design-around variables are:

Design-around lever	Potential effect
pH of 4.0 or higher	May avoid the central pH limitation
Concentration outside 0.001% to 0.15% w/w	May avoid literal range coverage
Less than approximately 99% ingenol-3-angelate	May avoid the purity limitation
Different ingenol derivative	Avoids the claimed active ingredient
Non-topical delivery	Avoids topical-administration limitation
Different indication	May avoid disease-use limitations
Different treatment protocol	May reduce method-claim exposure
Alternative active ingredient	Avoids the patent entirely

A change to pH or concentration may affect clinical performance, stability, tolerability, or regulatory comparability. Design-around feasibility therefore depends on both patent law and product-development data.

What Paragraph IV and litigation risks exist?

A generic applicant seeking approval for a product that could practice the claimed method may submit a Paragraph IV certification against listed patents in the FDA Orange Book. The resulting litigation risk would depend on whether US 8,536,163 was listed for the relevant product and remained enforceable when the ANDA was filed.

The key litigation issues would include:

• Whether the patent was properly listed in the Orange Book.
• Whether the proposed label induces treatment of a claimed condition.
• Whether the generic formulation has a pH below 4.
• Whether the active ingredient meets the 99% isoform limitation.
• Whether the proposed concentration falls within the claimed range.
• Whether the claims are enabled for all recited cancers.
• Whether prior art renders the formulation and method obvious.
• Whether prosecution-history estoppel limits the scope of “about.”

A Paragraph IV case could produce a 30-month stay if statutory listing and notice requirements were met. The precise litigation posture must be confirmed from FDA listing records and federal court dockets.

What is the commercial exposure after Picato withdrawal?

Picato’s withdrawal sharply reduced the near-term value of the patent estate. The main exposure is no longer a protected branded product with active U.S. sales. It is potential value in:

• Reintroducing a reformulated product.
• Licensing the active ingredient or formulation technology.
• Developing a different indication.
• Using the patent portfolio in settlement or defensive negotiations.
• Supporting an asset transaction involving ingenol technology.
• Blocking a third party from commercializing an equivalent product before expiration.

The market also has established alternatives for actinic keratosis, including fluorouracil, imiquimod, diclofenac, photodynamic therapy, and tirbanibulin. These products reduce the likelihood that a generic ingenol product would automatically recover the former Picato market.

Key Takeaways

• US Patent 8,536,163 is a method-of-use patent centered on topical ingenol-3-angelate.
• The independent claims require 0.001% to 0.15% w/w ingenol angelate, at least approximately 99% ingenol-3-angelate, and pH below 4.
• The claims cover gels but are not limited to gels unless a dependent claim is used.
• Covered conditions include actinic keratosis, SCC, BCC, and malignant melanoma.
• The patent is more commercially relevant to Picato-like products than to materially different topical formulations.
• Ingenol mebutate is a small molecule, so biosimilar analysis does not apply.
• Generic risk turns on pH, concentration, isomer purity, indication, labeling, and Orange Book status.
• Picato’s FDA withdrawal materially reduced commercial value but did not automatically eliminate patent rights.
• The surrounding patent landscape includes compound, formulation, manufacturing, purification, and method-of-use families.
• Exact expiration, terminal disclaimer, patent-term adjustment, Orange Book listing, and litigation status require confirmation in current USPTO, FDA, and court records.

FAQs About US Patent 8,536,163

Does US 8,536,163 cover Picato?

The claims closely correspond to a Picato-type formulation because they cover topical ingenol-3-angelate at concentrations that include 0.015% and 0.05%, with an acidic pH below 4. Product-specific infringement requires comparison with the actual formulation and approved or proposed use.

Does the patent cover actinic keratosis treatment?

Yes. Claims 13, 19, and 20 expressly include actinic keratosis. Claim 1 may also cover actinic keratosis where the condition falls within the claimed treatment of skin cancer.

Can a generic avoid the patent by using a cream instead of a gel?

Potentially. A cream would avoid the gel-only dependent claims, but it could still infringe claims 1 or 13 if it satisfies the active-ingredient, concentration, purity, pH, topical-use, and disease limitations.

Does a pH of 4.0 avoid the patent?

A pH of exactly 4.0 is outside the literal requirement of “less than 4,” subject to claim construction and any doctrine-of-equivalents analysis. It would not satisfy the express below-4 pH limitation on its face.

Does the patent protect the ingenol mebutate molecule itself?

The supplied claims do not broadly claim the molecule as a compound. They claim methods using the molecule in a defined topical formulation and for specified treatments.

Is there biosimilar competition for ingenol mebutate?

No. Ingenol mebutate is a small molecule. Any follow-on competition would generally involve an ANDA, 505(b)(2) application, or another small-molecule regulatory pathway rather than a biosimilar application.

Sources

1. Food and Drug Administration. (2012). Picato (ingenol mebutate) gel prescribing information. U.S. Department of Health and Human Services.

2. Food and Drug Administration. (2020). FDA warns of increased risk of skin cancer with Picato (ingenol mebutate) gel. U.S. Department of Health and Human Services.

3. LEO Pharma A/S. (2020). LEO Pharma announces withdrawal of Picato in Europe and the United States. Company announcement.

4. United States Patent and Trademark Office. (2013). United States Patent No. 8,536,163: Methods of treating skin cancer with ingenol angelate. U.S. Department of Commerce.

5. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. Center for Drug Evaluation and Research.

Drugs Protected by US Patent 8,536,163

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	8,536,163					USE OF INGENOL MEBUTATE TO TREAT ACTINIC KERATOSIS
Leo Labs	PICATO	ingenol mebutate	GEL;TOPICAL	202833-002	Jan 23, 2012		DISCN	Yes	No	8,536,163					USE OF INGENOL MEBUTATE TO TREAT ACTINIC KERATOSIS

Foreign Priority and PCT Information for Patent: 8,536,163

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	0525680.5	Dec 16, 2005

International Family Members for US Patent 8,536,163

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	1988877		C300682	Netherlands
European Patent Office	1988877		PA2014030	Lithuania
European Patent Office	1988877		CA 2014 00042	Denmark
European Patent Office	1988877		C20140025 00111	Estonia
European Patent Office	1988877		C01988877/01	Switzerland
European Patent Office	1988877		14C0058	France
European Patent Office	1988877		300682	Netherlands