United States Patent 8,372,827: Ingenol Angelate Formulation Claims, Exclusivity, and Patent Landscape

U.S. Patent No. 8,372,827 protects topical formulations containing low concentrations of highly purified ingenol-3-angelate, also known as ingenol mebutate, at an acidic pH below 4. The broadest claim covers formulations containing 0.001% to 0.15% w/w ingenol angelate, with at least 97.5% of the active material in the ingenol-3-angelate isoform. The patent was issued to LEO Pharma A/S on February 12, 2013, and has a reported statutory expiration date of June 27, 2027, subject to any patent-term adjustment or other term modification shown in the USPTO record.[1][2]

The claims read directly on the former Picato gel products approved by the FDA at 0.015% and 0.05% concentrations. The patent is a formulation patent, not a standalone composition-of-matter patent for ingenol mebutate. Its commercial relevance declined sharply after LEO Pharma withdrew Picato from the U.S. market following regulatory concerns regarding skin malignancies.

What does U.S. Patent 8,372,827 protect?

The patent protects a topical pharmaceutical formulation that satisfies four principal limitations:

Claim element	Scope
Active ingredient	Ingenol angelate
Concentration	About 0.001% to about 0.15% w/w
Isomeric purity	At least about 97.5% ingenol-3-angelate, identified as isoform b
Acidity	pH below 4

Claim 1 is the independent claim. Claims 2 through 16 depend from claim 1 and narrow the formulation by pH, dosage form, release profile, or excipient category.

The claim is cumulative. A formulation generally must satisfy every limitation of claim 1 to infringe directly. A formulation containing ingenol-3-angelate at the claimed concentration but having a pH of 4 or higher would fall outside the literal scope of claim 1, assuming the pH limitation is enforceable as written.

The word “about” creates a numerical boundary issue. Courts typically interpret “about” based on the patent specification, examples, technical context, and prosecution history. The claim does not establish an automatic tolerance band around 0.001%, 0.15%, 97.5%, or pH 4.

How broad is claim 1 of Patent 8,372,827?

Claim 1 is broad in dosage-form coverage but narrow in its combined technical requirements.

It covers topical formulations containing ingenol angelate in the specified concentration range, regardless of whether the formulation is a gel, cream, lotion, ointment, foam, oil, emulsion, paint, patch, or another topical vehicle. The claim does not require a specific excipient system, manufacturing process, package, dosing schedule, or disease indication in its body.

The key limitations are the active concentration, isoform purity, and acidic pH. These limitations create potential design-around routes:

Use a formulation at pH 4 or higher.
Use a concentration below 0.001% or above 0.15%.
Use a material containing less than approximately 97.5% ingenol-3-angelate.
Use a different ingenol derivative.
Deliver the active through a non-topical route.
Challenge whether “about” encompasses the accused value.

A formulation that changes only the dosage form will usually remain within the claim if all claim 1 limitations are retained. A gel, cream, foam, or ointment is not outside the patent merely because it uses a different vehicle.

What do claims 2 through 16 add?

Claim	Added limitation	Practical effect
2	pH of about 3.5 or less	Narrows the acidic-pH range
3	pH of about 3.0	Targets a narrower pH point
4	pH from about 2.5 to less than 4.0	Defines a narrower acidic range
5	Gel	Covers gel embodiments
6	Cream	Covers cream embodiments
7	Ointment	Covers ointment embodiments
8	Paint	Covers paint-like topical products
9	Lotion	Covers lotion embodiments
10	Foam	Covers foam embodiments
11	Transdermal patch	Covers patch formulations
12	Sustained release	Covers controlled-release formulations
13	Emulsion	Covers emulsion systems
14	Oil	Covers oil-based formulations
15	Buccal formulation	Extends the claim beyond conventional skin products
16	Penetration enhancer, preservative, gelling agent, or buffer	Covers formulations containing one or more listed excipient classes

Claims 5 through 15 are formulation-format claims. They do not remove the requirement that the formulation satisfy claim 1. Claim 16 is also dependent and does not independently protect an excipient or excipient combination without the underlying ingenol angelate, purity, concentration, and pH limitations.

The buccal claim is commercially distinct from the topical skin claims. A buccal formulation may create a claim-construction issue because claim 1 describes a formulation “for topical use,” while claim 15 expressly recites a buccal formulation. The specification and prosecution history would control whether “topical” was intended to include mucosal administration.

Which products fall within the claimed concentration range?

The FDA-approved Picato products were formulated at concentrations within the literal range of claim 1:

Product	Ingenol mebutate concentration	Approved use
Picato 0.015% gel	0.015% w/w	Actinic keratosis on the face and scalp
Picato 0.05% gel	0.05% w/w	Actinic keratosis on the trunk and extremities

Both concentrations fall between 0.001% and 0.15% w/w. Picato was an acidic topical gel containing highly purified ingenol-3-angelate. Its commercial formulation therefore appears to be the principal product embodiment targeted by the patent.[3]

The patent does not require the formulation to be marketed under the Picato name or to treat actinic keratosis. A competing product with the same technical characteristics could implicate the claims even if it used a different indication or labeling strategy.

What is the Orange Book status of Patent 8,372,827?

Patent 8,372,827 was listed in connection with Picato, an FDA-approved ingenol mebutate product marketed by LEO Pharma. The listing connected the patent to the approved topical gel formulations and provided a basis for patent certification obligations for an abbreviated new drug application seeking approval of a product referencing Picato.[4]

The patent listing did not convert the patent into a composition-of-matter patent. Its scope remained dependent on the formulation limitations stated in the issued claims.

A generic applicant making a Paragraph IV certification would have needed to assert that the patent was invalid, unenforceable, or not infringed. A Paragraph III certification would have deferred approval until patent expiration. For a formulation patent, the applicant could also pursue a formulation design that avoids the claimed pH, concentration, or purity limitations.

The commercial value of the Orange Book listing declined after the FDA-approved product was withdrawn. Orange Book listing and enforceability are separate issues from whether a sponsor continues to sell the reference product.

When does Patent 8,372,827 lose exclusivity?

The reported patent expiration date is June 27, 2027.[1][2] The relevant timeline is:

Event	Date
Earliest reported priority date	June 27, 2007
FDA approval of Picato	January 2012
U.S. patent grant	February 12, 2013
Reported patent expiration	June 27, 2027
Picato U.S. withdrawal	2020

The patent term is generally measured from the earliest effective nonprovisional or international application date, not from the issue date. Patent-term adjustment can extend the nominal date, while terminal disclaimers or other prosecution events can affect the enforceable term. The USPTO Patent Center record is controlling for the final term calculation.

FDA regulatory exclusivity for Picato was separate from the patent term. Any new chemical entity exclusivity associated with the original approval would have expired years before the reported patent expiration date. The remaining barrier was therefore primarily patent-based rather than FDA exclusivity-based.

What patent litigation and Paragraph IV activity affect Picato?

Publicly available regulatory records identify Patent 8,372,827 as an Orange Book-listed patent for Picato. No major publicly reported U.S. Hatch-Waxman decision involving an ANDA challenger to this specific patent has established a commercial generic-entry schedule in the sources cited here.

The absence of a publicly reported merits judgment does not establish that the patent was immune from challenge. A Paragraph IV filing could have triggered litigation under 35 U.S.C. § 271(e)(2), but the practical incentive to pursue litigation diminished after LEO Pharma stopped marketing Picato in the United States.

No publicly reported settlement agreement is identified here that provides a licensed generic launch date or a covenant governing entry under Patent 8,372,827. The commercial record therefore points to product withdrawal, rather than a litigated generic launch, as the principal event affecting the U.S. market.

How strong is the patent estate for ingenol mebutate?

Patent 8,372,827 has meaningful claim breadth within a specific formulation platform. Its strongest features are:

Coverage of both marketed Picato concentrations.
A broad range of topical dosage forms.
No requirement for a particular indication in the claim body.
Coverage of multiple excipient categories.
Protection tied to pH and isoform purity, which can be difficult to change without affecting stability or product performance.

Its principal vulnerabilities are:

The patent does not claim ingenol mebutate as a molecule in the broadest sense.
The concentration range is numerically defined and potentially avoidable.
The pH limitation creates a direct formulation design-around.
The purity limitation may raise enablement, written-description, or measurement questions if the specification does not adequately define the isoform assay.
The dependent dosage-form claims add limited protection where the independent claim is invalid or not infringed.
The use of “about” creates boundary disputes.

Validity would likely turn on prior-art disclosures of ingenol angelate formulations, stability at acidic pH, purified isoform preparations, and topical treatment systems. Obviousness analysis would focus on whether a skilled formulator would have selected the claimed concentration, purity threshold, and pH range with a reasonable expectation of success.

What manufacturing and intellectual-property barriers remain?

The patent does not require a specific manufacturing process, but the isoform-purity limitation creates a practical manufacturing barrier. A supplier must control the proportion of ingenol-3-angelate relative to other angelate isomers and demonstrate that the finished formulation remains within the claimed purity threshold.

Relevant technical controls include:

Isomer-selective synthesis or purification.
Analytical separation of ingenol angelate isoforms.
Batch-release testing for the 97.5% threshold.
pH control below 4.
Stability testing in the selected vehicle.
Compatibility of the active with preservatives, buffers, and gelling agents.
Control of degradation products during storage.

A generic manufacturer could attempt to avoid the patent by using a pH outside the claimed range or by developing a different active form. Those changes could introduce separate regulatory, stability, bioavailability, or clinical comparability issues.

Is there biosimilar risk for ingenol mebutate?

No. Ingenol mebutate is a chemically synthesized small molecule, not a biological product. The relevant U.S. pathway is an ANDA or, depending on the proposed product and reference-product status, a 505(b)(2) application. Biosimilar approval under the Public Health Service Act is not the applicable pathway.

The principal competitive risks are therefore generic formulation development, alternative topical products, repurposed dermatology therapies, and products based on different active ingredients.

What is the current commercial exposure?

Picato was withdrawn from the U.S. market in 2020 after FDA and European regulatory actions concerning an observed risk of skin malignancies.[5][6] The FDA stated that the benefits of Picato did not outweigh the risks for treatment of actinic keratosis.

As a result:

Current U.S. revenue exposure from Picato is effectively eliminated.
The patent remains legally relevant as an exclusionary right during its term.
The patent has limited near-term product-line value absent relaunch, licensing, or a new approved use.
A generic launch would have limited commercial value without an active reference-product market or a viable alternative regulatory pathway.
Any future commercial program would face regulatory issues separate from patent clearance.

How does Patent 8,372,827 compare with a typical active-ingredient patent?

Issue	Patent 8,372,827	Active-ingredient patent
Protected subject matter	Formulation	Chemical compound
Required concentration	Yes	Usually no
Required pH	Yes, below 4	Usually no
Required purity	Yes, at least about 97.5% isoform b	May define chemical identity or stereochemistry
Dosage-form coverage	Broad through dependent claims	Often product-independent
Design-around potential	Relatively high	Usually lower
Relevance to Picato gel	Direct	May be broader than the marketed formulation
Generic challenge	Formulation-specific	Compound or composition challenge

Patent 8,372,827 is commercially important because it aligns closely with the approved Picato formulation. It is less robust against a technically distinct product than a broad compound patent would be.

Key Takeaways

U.S. Patent 8,372,827 covers topical ingenol angelate formulations containing about 0.001% to 0.15% w/w active.
At least about 97.5% of the active must be ingenol-3-angelate, isoform b.
The formulation must have a pH below 4.
Picato 0.015% and 0.05% gels fall within the central claim scope.
Claims 2 through 16 narrow the invention by pH, dosage form, release profile, administration route, or excipient.
The reported patent expiration date is June 27, 2027.
The patent is a formulation patent, not a broad ingenol mebutate composition-of-matter patent.
Design-around strategies include changing pH, concentration, isomeric purity, active ingredient, or route of administration.
Ingenol mebutate has no biosimilar pathway because it is a small molecule.
Picato’s 2020 U.S. withdrawal substantially reduced the patent’s current commercial value.
No publicly reported settlement or litigated generic-entry schedule is identified for this patent in the cited records.

FAQs

Does Patent 8,372,827 cover all ingenol mebutate products?

No. It covers formulations meeting the claimed concentration, ingenol-3-angelate purity, and pH limitations. Products outside those parameters may avoid literal infringement.

Does changing Picato gel into a cream avoid the patent?

Not necessarily. Claim 6 expressly covers a cream, and the cream would remain subject to all limitations of claim 1.

Can a product with pH 4.0 avoid claim 1?

Potentially, because claim 1 requires a pH of less than 4. The result would depend on the meaning of “about,” the measurement method, and the prosecution history.

Is Patent 8,372,827 a patent on treating actinic keratosis?

The supplied issued claims are directed to pharmaceutical formulations. They do not recite a separate method-of-treatment claim for actinic keratosis.

Would a generic ingenol mebutate product require a Paragraph IV certification?

If the product referenced an approved FDA product and the patent remained listed and unexpired, an ANDA applicant would need to address the listed patent through the applicable Hatch-Waxman certification framework.

References

United States Patent and Trademark Office. (2013). U.S. Patent No. 8,372,827, Pharmaceutical formulation.
United States Patent and Trademark Office. (n.d.). Patent Center: U.S. Patent No. 8,372,827.
U.S. Food and Drug Administration. (2012). Picato (ingenol mebutate) topical gel prescribing information.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.
U.S. Food and Drug Administration. (2020). FDA warns of increased risk of skin cancer with Picato gel.
European Medicines Agency. (2020). EMA recommends withdrawal of Picato from the market.

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	⤷ Start Trial	⤷ Start Trial	Y				⤷ Start Trial
Leo Labs	PICATO	ingenol mebutate	GEL;TOPICAL	202833-002	Jan 23, 2012		DISCN	Yes	No	⤷ Start Trial	⤷ 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
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
European Patent Office	1988877	⤷ Start Trial	C20140025 00111	Estonia	⤷ Start Trial
European Patent Office	1988877	⤷ Start Trial	C01988877/01	Switzerland	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 8,372,827

Which drugs does patent 8,372,827 protect, and when does it expire?

Summary for Patent: 8,372,827