Details for Patent: 8,372,828

Which drugs does patent 8,372,828 protect, and when does it expire?

Patent 8,372,828 protects PICATO and is included in one NDA.

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

Summary for Patent: 8,372,828

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 Edward Donald Crowthers, Tahir Nazir
Assignee:	AF 30 APRIL 2003 AS , Leo Laboratories Ltd
Application Number:	US13/563,720
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,372,828
Patent Claim Types: see list of patent claims	Use; Formulation;

US Patent 8,372,828: Ingenol Angelate Formulation Claims, Exclusivity and Patent Landscape

US Patent 8,372,828 protects topical pharmaceutical formulations containing highly purified ingenol-3-angelate at low concentrations in an acidic formulation with a pH below 4. The patent is formulation-focused. It does not require a particular disease, dosing schedule, container, manufacturing process, or commercial dosage form. A competing product must avoid at least one limitation of claim 1 to avoid literal infringement.

The patent is closely associated with ingenol mebutate, also called ingenol-3-angelate, the active ingredient formerly marketed by LEO Pharma as Picato. Picato was approved by the FDA in 2012 and withdrawn from the U.S. market in 2020 after regulatory concern regarding skin-cancer risk. The product’s commercial withdrawal does not, by itself, eliminate patent rights or prevent analysis of remaining formulation, manufacturing, or generic-entry barriers. [1][2]

What does US Patent 8,372,828 protect?

The independent claim protects a pharmaceutical formulation for topical use containing four cumulative elements:

Claim 1 limitation	Scope
Active ingredient	Ingenol angelate
Concentration	About 0.001% to about 0.15% w/w
Isomeric composition	At least about 99% ingenol-3-angelate, identified as isoform “b”
Acidity	pH below 4

The claim is a composition claim. It covers the formulation itself, rather than merely the act of administering ingenol angelate.

A formulation falls within the literal scope of claim 1 only if all four limitations are met. A product containing ingenol-3-angelate at 0.05% w/w and pH 3.0 would be a direct claim 1 candidate if the active ingredient is at least 99% isoform b. A product at pH 4.2, or with 0.20% active ingredient, would fall outside the express numerical limitations, subject to interpretation of “about” and possible doctrine-of-equivalents analysis.

What is the central inventive concept?

The patent’s central combination is not merely ingenol angelate. It is the combination of:

1. A defined low concentration range;
2. High isomeric purity for ingenol-3-angelate;
3. An acidic pH below 4; and
4. A topical pharmaceutical vehicle.

The purity requirement materially narrows the claim compared with a generic claim covering any ingenol angelate composition. The pH limitation also creates a technical design-around route for formulations maintained at neutral or mildly acidic pH.

How should the concentration and purity limitations be interpreted?

The concentration range is approximately 0.001% to 0.15% w/w, with “about” potentially allowing limited variation around each endpoint. The claim does not specify whether the concentration is measured:

• On a total formulation weight basis;
• At manufacture or at release;
• Before or after storage;
• On a nominal or assay-adjusted basis.

In ordinary pharmaceutical practice, “% w/w” indicates weight of active ingredient relative to total formulation weight. The specification and prosecution history would control if they define the term differently.

The purity limitation requires that at least about 99% of the ingenol angelate be ingenol-3-angelate. The claim does not necessarily require that 99% of the entire formulation be active ingredient. It instead addresses the composition of the ingenol angelate fraction.

This distinction matters because a product can have:

• 99% or greater purity within the ingenol angelate fraction; but
• Much less than 99% total active ingredient relative to the complete formulation.

A formulation using a different ingenol angelate stereoisomer or an intentionally mixed isomer profile may avoid literal infringement if the ingenol-3-angelate fraction is below the claimed threshold. The risk depends on the analytical method, impurity definition, and construction of “ingenol angelate.”

What pH range does the patent cover?

Claim 1 requires a pH below 4. The dependent claims add narrower pH embodiments:

Claim	pH limitation
1	Less than 4
2	About 3.5 or less
3	About 3.0
4	About 2.5 to less than 4.0

Claim 3 is narrower than claim 1 because it targets a pH of about 3.0. Claim 4 covers a defined acidic range beginning at approximately pH 2.5. The claims overlap. A formulation at pH 3.0 may fall within claims 1, 2, 3, and 4, assuming the other limitations are satisfied.

Why does pH create infringement risk?

pH can change during storage, dilution, phase separation, interaction with packaging, or contact with skin. A developer evaluating freedom to operate should identify:

• The pH specification at release;
• The permitted release range;
• The validated analytical method;
• The pH at the end of shelf life;
• Buffer composition and capacity;
• Whether pH is measured directly in the finished product or after dilution.

A formulation specified at pH 3.8 may still create risk if “about 4” is construed to include the tested value. Conversely, a formulation consistently maintained above pH 4 may have a stronger non-infringement position.

What dosage forms are covered by US 8,372,828?

Claims 5 through 15 extend claim 1 to multiple topical and mucosal dosage forms:

Claim	Dosage form
5	Gel
6	Cream
7	Ointment
8	Paint
9	Lotion
10	Foam
11	Transdermal patch
12	Sustained-release formulation
13	Emulsion
14	Oil
15	Buccal formulation

These claims do not replace the limitations of claim 1. Each depends on the same active ingredient, concentration, purity, and acidic-pH requirements.

The list is technologically broad. It reaches conventional semisolid products such as gels, creams, and ointments, as well as less conventional formats such as patches, foams, paints, oils, and buccal products. The patent therefore has potential relevance beyond the commercial Picato gel.

Does the patent cover Picato gel?

Picato was marketed as a topical gel containing ingenol mebutate, the pharmaceutical name commonly used for ingenol-3-angelate. The marketed strengths included 0.015% and 0.05%, depending on the treatment site and regimen. Those concentrations are within the numerical range of claim 1. The product’s acidic formulation and highly purified active ingredient are also consistent with the claimed formulation architecture. [2][3]

The commercial product’s exact status under the patent depends on the approved formulation, listed patents, claim interpretation, and patent-term history. The claim text alone does not establish whether every marketed Picato presentation satisfied every limitation at every point in the product’s lifecycle.

What excipients and formulation components are protected?

Claim 16 covers a formulation that further contains one or more of the following:

• A penetration enhancer;
• A preservative;
• A gelling agent; or
• A buffer.

The dependent claim is open to formulations containing any one of the listed components and does not appear to require all four. The claim also does not specify concentrations, chemical identity, or functional performance thresholds for those components.

This creates broad coverage across common topical formulation architectures. A product containing a gelling agent and buffer may fall within claim 16 if it also satisfies claim 1. A formulation without any listed component could still infringe claim 1 because claim 16 is dependent and adds an extra limitation.

The claim does not expressly require a particular vehicle, surfactant, solvent, preservative system, polymer, penetration enhancer, or buffer species. Those details may appear in the specification or examples, but they are not limitations of claim 1 unless incorporated through claim construction.

How strong is the patent estate for ingenol angelate?

The strength of US 8,372,828 depends on the commercial importance of the claimed formulation combination and the ability of competitors to design around the pH, purity, or concentration limitations.

Risk factor	Assessment
Claim type	Composition claim, generally stronger than a narrow method-of-use claim for blocking a product
Active ingredient	Limited to ingenol angelate, with emphasis on ingenol-3-angelate
Concentration	Broad low-dose range, but readily adjustable
Purity	Potentially meaningful analytical barrier
pH	Clear design-around parameter
Dosage forms	Broad dependent-claim coverage
Excipient coverage	Broad but dependent on claim 1
Disease limitation	None in claim 1
Manufacturing coverage	Not present in the provided claims
Commercial relevance	Reduced by Picato withdrawal, but technically relevant to future formulations

The strongest portion of the claim is the combination of purity and acidic pH. A competitor would need to assess whether changing one of those parameters affects stability, skin penetration, efficacy, or tolerability.

The weakest design-around points are the concentration and pH limitations. A developer can potentially test:

• A concentration outside the claimed range;
• A formulation with pH at or above 4;
• A different ingenol isomer composition;
• A non-ingenol active ingredient;
• A formulation using a prodrug, salt, derivative, or alternative chemical form.

Each route presents technical and regulatory consequences. A formulation outside the claim may not be therapeutically or commercially equivalent to the original product.

What patent-expiration and exclusivity issues apply?

US 8,372,828 was issued on February 12, 2013. Its enforceable term is governed by the earliest effective nonprovisional filing date, with any applicable patent-term adjustment or patent-term extension. Public patent records associate the patent family with the ingenol angelate development program and LEO Pharma’s commercial product portfolio. [4]

Patent expiration must be distinguished from FDA regulatory exclusivity:

Protection	Relevance
Patent term	Blocks conduct covered by valid, enforceable claims
New-drug exclusivity	Restricts certain FDA approvals for a defined period
Orphan exclusivity	Applies only if an orphan designation and approval qualify
Pediatric exclusivity	Can add six months to eligible regulatory protections
Orange Book listing	Gives notice of patents submitted for an approved drug
Product withdrawal	Does not automatically cancel issued patent rights

Picato received FDA approval in 2012. Its commercial withdrawal in 2020 materially reduced the practical value of product-specific market exclusivity, but patent rights are separate from marketing status. [1][2]

The patent’s remaining commercial value is therefore more likely to arise from a new formulation, a reformulated topical product, or a licensing transaction than from continued sales of Picato itself.

What is the Orange Book status of Picato and related patents?

Picato was approved under NDA 202833. The FDA later recorded the product as discontinued after LEO Pharma removed it from the U.S. market. The FDA’s public materials identify the skin-cancer concern associated with ingenol mebutate and the resulting withdrawal of the product from commercial distribution. [1][2]

Orange Book treatment should be analyzed separately from FDA approval status:

1. The product may be listed as discontinued.
2. Patents previously submitted for the product may remain visible in historical or current patent listings depending on FDA record treatment.
3. A discontinued reference product can create complications for ANDA strategy.
4. The basis for discontinuation matters when determining whether an ANDA may rely on the product.
5. A patent listing does not establish patent validity or infringement.

The claim set supplied for US 8,372,828 is broader than a conventional label-based method-of-use claim because it does not limit the formulation to actinic keratosis, a particular body site, or a defined treatment schedule.

Are Paragraph IV challenges or generic launches known?

The principal generic-entry issue is practical rather than purely patent-based. A generic applicant would need a legally usable reference-product pathway after Picato’s withdrawal, while also addressing the formulation claims.

A Paragraph IV strategy could challenge listed patents by asserting:

• Noninfringement because the product has a pH of 4 or higher;
• Noninfringement because concentration falls outside the claimed range;
• Noninfringement because the active ingredient contains less than the required amount of isoform b;
• Invalidity for anticipation or obviousness;
• Indefiniteness or lack of written description for “about,” the purity requirement, or the pH limitation;
• Lack of enablement across the full range of dosage forms.

No biosimilar pathway applies. Ingenol-3-angelate is a small-molecule active ingredient, not a biologic. Any abbreviated application would generally be considered under the ANDA framework or another small-molecule pathway, not under section 351(k) of the Public Health Service Act.

No commercially established U.S. generic replacement for Picato has emerged as a significant market competitor following the withdrawal. That limits the immediate value of a Paragraph IV challenge, although a future sponsor could pursue a new drug application for a related formulation or indication.

Which companies and institutions are associated with the patent landscape?

The commercial program surrounding ingenol mebutate was developed through Peplin and later commercialized by LEO Pharma. LEO Pharma acquired Peplin in 2009, obtaining rights connected with ingenol mebutate and its development program. [5]

The relevant competitive landscape includes:

Entity type	Strategic relevance
LEO Pharma	Original commercial sponsor of Picato
Peplin	Originator associated with development of ingenol mebutate
Academic and natural-products licensors	Potential source of ingenol and related diterpene technology
Generic manufacturers	Potential ANDA applicants, subject to reference-product and patent issues
Dermatology companies	Potential licensees for reformulated or replacement products
Specialty pharmaceutical developers	Potential developers of new topical delivery systems

A licensee developing a new topical product would need to review not only US 8,372,828 but also composition, process, impurity, crystalline-form, stability, packaging, and method-of-use patents in the broader ingenol family.

What litigation and settlement risks affect the patent?

The supplied claims do not establish litigation history, validity rulings, or settlement terms. Those issues must be evaluated through the patent’s prosecution record, PACER litigation records, FDA patent listings, and any ANDA notice letters.

The most likely litigation issues would be:

• Construction of “about 0.001%” and “about 0.15%”;
• Meaning of “at least about 99%”;
• Analytical testing methods for isomeric purity;
• pH measurement conditions;
• Whether a formulation is a gel, cream, foam, paint, or emulsion;
• Whether the doctrine of equivalents can extend the pH or concentration boundaries;
• Enablement across the full list of dosage forms.

Settlement agreements could restrict generic launch dates, but no launch date or settlement term follows from the claim language alone.

What generic launch scenarios exist?

Three scenarios are commercially plausible.

Scenario 1: No near-term generic development

The withdrawal of Picato and the safety concerns surrounding ingenol mebutate may make a conventional generic launch unattractive. In that scenario, the patent has limited blocking value despite broad formulation language.

Scenario 2: Design-around topical product

A developer could pursue a formulation with:

• pH at or above 4;
• A different active concentration;
• An alternative isomer ratio;
• A different chemical derivative;
• A distinct delivery system.

The sponsor would need to establish that the design-around remains clinically effective and acceptable to FDA.

Scenario 3: New clinical program or licensed reformulation

A company could license the technology and develop a new indication, delivery system, or dosing regimen. The patent may provide formulation protection during development, but any commercial program would require a full freedom-to-operate review of later-filed patents and regulatory exclusivities.

Key Takeaways

• US 8,372,828 is a formulation patent centered on ingenol-3-angelate, low concentration, high isomeric purity, and pH below 4.
• Claim 1 is broad across topical pharmaceutical vehicles but narrow in its cumulative technical limitations.
• Claims 5 through 15 extend coverage to gels, creams, ointments, paints, lotions, foams, patches, sustained-release systems, emulsions, oils, and buccal formulations.
• Claim 16 covers formulations containing a penetration enhancer, preservative, gelling agent, or buffer.
• The patent does not require a specific disease, dose, treatment schedule, container, or manufacturing process.
• The most practical design-around routes are pH, concentration, and isomeric composition.
• Picato was FDA-approved in 2012 and withdrawn from the U.S. market in 2020 after skin-cancer concerns.
• No biosimilar pathway applies because ingenol-3-angelate is a small molecule.
• The patent’s commercial significance is reduced by product withdrawal but remains relevant to reformulation, licensing, and future topical development.
• Patent expiration, Orange Book status, and any Paragraph IV exposure must be confirmed against the current USPTO and FDA records rather than inferred solely from the claim text.

FAQs

Can a formulation at pH 4.0 avoid US 8,372,828?

Potentially, but the answer depends on how “less than 4” and “about” are construed and how pH is measured. A consistently documented pH of 4.0 or higher presents a stronger noninfringement position than a product specified at pH 3.9.

Does the patent cover ingenol mebutate at any concentration?

No. The claims require a concentration from about 0.001% to about 0.15% w/w. A formulation outside that range may avoid literal infringement, although the endpoint terms include “about.”

Does claim 16 require all listed excipients?

No. The language covers a formulation comprising a penetration enhancer, preservative, gelling agent, or buffer. One listed component can satisfy the added limitation if the base claim is also met.

Can a company develop a neutral-pH ingenol formulation?

A neutral-pH formulation may avoid the express pH limitation, but it would require independent evaluation of stability, skin penetration, efficacy, safety, regulatory approval, and other patents.

Is US 8,372,828 a method-of-treatment patent?

No. The supplied claims are directed to pharmaceutical formulations. The reference to topical use and treatment appears in the claim preamble, while the operative limitations define the composition.

References

1. U.S. Food and Drug Administration. (2020). FDA warns of increased risk of death from skin cancer with use of Picato (ingenol mebutate) gel.
2. U.S. Food and Drug Administration. (2012). Picato prescribing information.
3. LEO Pharma A/S. (2012). Picato product information and formulation materials.
4. United States Patent and Trademark Office. (2013). U.S. Patent No. 8,372,828, pharmaceutical formulation comprising ingenol angelate.
5. LEO Pharma A/S. (2009). LEO Pharma acquires Peplin and ingenol mebutate development program.

Drugs Protected by US Patent 8,372,828

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	8,372,828		Y
Leo Labs	PICATO	ingenol mebutate	GEL;TOPICAL	202833-002	Jan 23, 2012		DISCN	Yes	No	8,372,828		Y

Foreign Priority and PCT Information for Patent: 8,372,828

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 8,372,828

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