United States Patent 8,377,919: Scope, Claim Construction, Expiration and Ingenol Angelate Patent Landscape

United States Patent No. 8,377,919 protects topical formulations containing highly purified ingenol-3-angelate, also known as ingenol mebutate or ingenol angelate, at acidic pH. The principal claim combination is: an ingenol angelate concentration of approximately 0.001% to 0.15% by weight, at least 95% ingenol-3-angelate isoform “b,” and a formulation pH below 4. The patent also claims formulations defined by skin-permeation performance and covers multiple dosage forms, including gels, creams, ointments, lotions and foams.

The patent is directly relevant to Picato, the former LEO Pharma product containing ingenol mebutate. Picato was approved by the FDA in 2012 and later withdrawn from the U.S. market. Patent 8,377,919 does not by itself establish current market exclusivity because regulatory status, patent listing status, patent-term calculations and any terminal disclaimer must be evaluated separately.

What does U.S. Patent 8,377,919 protect?

Patent 8,377,919 claims pharmaceutical formulations rather than ingenol angelate as a chemical compound generally. Its protection depends on the combination of active-ingredient identity, concentration or permeation, isoform purity and acidity.

Claim group	Claims	Principal limitations
Concentration and pH	1-16	Ingenol angelate at about 0.001%-0.15% w/w; at least about 95% isoform “b”; pH below 4
Dosage forms	5-15	Gel, cream, ointment, paint, lotion, foam, patch, sustained release, emulsion, oil or buccal formulation
Formulation excipients	16	Penetration enhancer, preservative, gelling agent or buffer
Skin-permeation performance	17-24	Ingenol-3-angelate at pH below 4 with a specified permeation rate
Application loading	19-20	0.01-1,000 micrograms/cm² or 0.01-100 micrograms/cm²
Specific pH limitations	2-4, 21-23	pH about 3.5 or less, about 3.0, or 2.5 to less than 4.0
Gel limitation	5, 24	Formulation is a gel

Claim 1 is the commercial center of gravity. It is a composition claim with four material limitations:

The formulation is for topical use in treatment of a subject.
It contains ingenol angelate at approximately 0.001% to 0.15% w/w.
At least approximately 95% of the ingenol angelate is ingenol-3-angelate isoform “b.”
The formulation has a pH below 4.

A competing product that omits any one of these limitations may avoid literal infringement of claim 1, although other claims or related patents could remain relevant.

How should the principal claims be construed?

What is the scope of claim 1?

Claim 1 is broad in dosage-form coverage but narrow in formulation chemistry. It does not require a gel. The claim can reach any topical formulation meeting the active-ingredient, purity, concentration and pH limitations, subject to the meaning of “pharmaceutical formulation” and the treatment-use language.

The concentration range is expansive. It includes the 0.015% and 0.05% strengths historically associated with Picato. It also includes substantially lower and higher concentrations within the claimed range.

The “at least about 95%” limitation is important. A formulation containing the correct active ingredient at acidic pH but with a materially different isoform composition may fall outside the literal scope of claim 1. The terms “about” and “at least about 95%” create potential claim-construction disputes concerning analytical tolerances, assay methodology and batch variability.

What do claims 2 through 4 add?

Claims 2 through 4 narrow the pH requirement:

Claim 2: pH of about 3.5 or less.
Claim 3: pH of about 3.0.
Claim 4: pH from about 2.5 to less than 4.0.

These claims provide fallback positions if “pH less than 4” in claim 1 is challenged or construed narrowly. Claim 3 is the narrowest pH claim but may correspond closely to commercial formulations.

What do claims 5 through 15 cover?

These claims add dosage-form limitations. The list is unusually broad for a topical pharmaceutical patent:

Gel
Cream
Ointment
Paint
Lotion
Foam
Transdermal patch
Sustained-release formulation
Emulsion
Oil
Buccal formulation

The claims are drafted as alternatives. A gel containing 0.015% ingenol-3-angelate, at least 95% isoform “b,” and pH 3.0 would potentially fall within claims 1 and 5, as well as claims 2, 3 or 4 depending on the accepted meaning of “about.”

The patch, sustained-release and buccal limitations extend beyond conventional actinic-keratosis gel products. Their commercial importance is lower unless supported by an actual development program, because a patent claim does not establish that each claimed dosage form is clinically validated or approved.

What does claim 16 cover?

Claim 16 covers a formulation of claim 1 that further contains at least one of the following:

A penetration enhancer
A preservative
A gelling agent
A buffer

The wording is open-ended. “Further comprises” generally permits additional excipients beyond the listed ingredient. A formulation containing a buffer and gelling agent would ordinarily satisfy the claim if it also meets the limitations inherited from claim 1.

How do claims 17 through 24 differ from claims 1 through 16?

Claims 17 through 24 use a functional limitation: the rate at which ingenol-3-angelate crosses the skin.

Claim 17 requires:

Ingenol-3-angelate isoform “b”
pH below 4
A permeation rate between approximately 11 ng/cm²/hour and 2 micrograms/cm²/hour

Claim 18 narrows the upper limit to approximately 1 microgram/cm²/hour. Claims 19 and 20 add the amount applied per unit area. Claims 21 through 23 narrow pH, and claim 24 requires a gel.

Claim	Key functional limitation
17	11 ng/cm²/hour to 2 µg/cm²/hour
18	11 ng/cm²/hour to 1 µg/cm²/hour
19	Applied amount of 0.01-1,000 µg/cm²
20	Applied amount of 0.01-100 µg/cm²
21	pH about 3.5 or less
22	pH about 3.0
23	pH about 2.5 to less than 4.0
24	Gel

These claims create a different infringement analysis. A formulation could fall within claim 17 even if its active-ingredient concentration is outside claim 1, provided the product satisfies the claimed identity, pH and measured permeation rate.

The main evidentiary issue is measurement. Permeation rate depends on the skin model, donor and receptor conditions, temperature, application amount, exposure duration, sampling method and analytical assay. A party evaluating claim 17 or claim 18 would need to reproduce the patent’s test conditions or establish that the claimed result is inherent or necessarily present.

What formulations are protected by Patent 8,377,919?

The broadest practical target is an acidic topical ingenol angelate formulation containing at least 95% ingenol-3-angelate isoform “b.” A representative formulation within the principal claim set would have the following profile:

Parameter	Example within claim scope
Active ingredient	Ingenol-3-angelate, isoform “b”
Isoform purity	95% or more
Concentration	0.015% or 0.05% w/w
pH	Approximately 3.0
Dosage form	Gel
Optional excipients	Gelling agent, buffer, preservative or penetration enhancer

The patent does not require a particular polymer, solvent, preservative system, container or manufacturing process in claim 1. That gives the core claim meaningful breadth against formulation substitutions.

It also means that a design-around based solely on changing the gel vehicle may be ineffective. A cream, foam or lotion can remain within claim 1 if it retains the active-ingredient, purity, concentration and pH limitations.

When does U.S. Patent 8,377,919 lose exclusivity?

Patent 8,377,919 issued on February 19, 2013. Public patent records identify the patent as part of an ingenol angelate formulation family associated with LEO Pharma and predecessor development entities. Its ordinary 20-year term is tied to the earliest effective nonprovisional or international filing date, subject to patent-term adjustment, terminal disclaimers and any applicable patent-term extension.

The family’s effective priority is generally reported as in 2007. On that basis, the ordinary U.S. expiration is projected to occur in 2027 or 2028, rather than in 2033 based on the grant date. The exact expiration date should be taken from the USPTO Patent Center term calculation because a precise answer depends on the underlying priority chain, patent-term adjustment and any disclaimer recorded against the patent. (U.S. Patent and Trademark Office, 2013)

Patent expiration would remove the patent’s ability to block practicing the claimed formulation. It would not remove separate compound, method-of-use, manufacturing or formulation patents that expire later.

What is the Orange Book status of Patent 8,377,919?

Picato, the relevant FDA product, was approved under NDA 202833 in December 2012. The approved products were Picato 0.015% gel for facial and scalp actinic keratosis and Picato 0.05% gel for actinic keratosis on the trunk and extremities. (U.S. Food and Drug Administration, 2012)

LEO Pharma discontinued Picato in the United States in 2020 after regulatory concern regarding a possible increased risk of skin cancer. FDA drug-safety materials stated that patients should stop using Picato and discuss alternative treatments with a healthcare professional. (U.S. Food and Drug Administration, 2020)

The commercial and regulatory position is therefore distinct from the patent position:

Issue	Status
FDA approval	Previously approved
U.S. marketing	Discontinued
Reference product competition	Limited by product discontinuation
Patent 8,377,919	Remained a formulation patent during its statutory term
Current commercial value	Reduced by withdrawal and safety concerns
Generic launch economics	Weakened by the absence of an actively marketed reference product

An Orange Book listing must be checked against the historical and current NDA records. A formulation patent can be relevant to an approved product without being the only patent protecting that product. The Orange Book does not provide a complete landscape of all patents potentially relevant to a drug.

Which companies challenged Picato patents?

No material public Paragraph IV litigation specific to Patent 8,377,919 is identified in the core patent and FDA records cited here. The absence of a publicly identified challenge does not establish that no notice letter was ever sent or that no confidential patent dispute occurred.

A generic applicant seeking approval for an equivalent ingenol mebutate gel could have used an ANDA with a Paragraph IV certification if the relevant patent was listed and unexpired. Because Picato was withdrawn and had limited continuing commercial value, the incentive to fund a contested generic launch was lower than for an actively marketed high-revenue product.

What generic entry risks exist?

A generic or follow-on product would face three separate barriers:

Patent risk. An acidic gel with 0.015% or 0.05% ingenol-3-angelate and high isoform purity could read directly on claims 1 and 5, plus the narrower pH claims.
Regulatory risk. The applicant would need to address the reference product’s discontinued status, labeling, safety history and FDA requirements for an abbreviated or alternative approval pathway.
Commercial risk. A generic launch would face uncertain demand after withdrawal of Picato and the availability of alternative actinic-keratosis treatments.

Potential design-around strategies include changing the pH to 4 or higher, using a different isoform profile, selecting a concentration outside the claimed range, or developing a non-topical delivery system. Each strategy may create new pharmacokinetic, stability, tolerability or regulatory problems and may implicate other patents.

How strong is the patent estate?

Patent 8,377,919 has relatively strong literal coverage against the historical Picato-type formulation because its claim elements align with the product’s key characteristics: ingenol-3-angelate, acidic pH, low concentration and gel delivery.

Its strength is lower in three areas:

The claims cover many dosage forms that may not have been commercially developed.
The functional permeation claims may require complex and contestable testing.
The broad claim language creates potential written-description, enablement, obviousness and indefiniteness issues.

What validity issues could arise?

A validity challenge could focus on:

Prior art disclosing ingenol angelate for topical treatment.
Prior art disclosing acidic formulations of ingenol compounds.
Obviousness of selecting a pH below 4 and a known therapeutic concentration.
Enablement across gels, creams, patches, oils, buccal formulations and sustained-release systems.
Written description support for the full concentration, purity and permeation ranges.
Indefiniteness of “about,” “effective amount,” “treatment” and the specified permeation assay.
Whether isoform “b” is adequately defined by analytical method and structural terminology.

The strongest defense would likely rely on the claimed combination of purity, acidic pH, concentration and demonstrated topical permeation rather than on any individual limitation considered in isolation.

How does this patent compare with compound and method-of-use patents?

Patent type	What it protects	Relevance to a competitor
Compound patent	Ingenol angelate or related chemical entity	May block use regardless of formulation
Formulation patent	Concentration, pH, purity, vehicle and delivery characteristics	Directly relevant to product composition
Method-of-use patent	Treatment of actinic keratosis or another disease	Relevant when the product label or prescribing behavior falls within the claim
Manufacturing patent	Synthesis, purification, crystallization or isoform control	Can block supply even if the final formulation is redesigned
Regulatory exclusivity	FDA approval-related exclusivity	Separate from patent rights

Patent 8,377,919 is primarily a formulation and delivery patent. It should not be treated as a complete statement of the ingenol angelate patent estate.

What licensing and geographic issues matter?

LEO Pharma acquired rights to ingenol mebutate through its relationship with Peplin and related development arrangements. The commercial rights, patent ownership and licensing history should be separated from the identity of the product sponsor and the FDA applicant.

The patent is a U.S. right. Corresponding international family members may exist in Europe, Canada, Australia and other jurisdictions, but claim scope, prosecution history, term and litigation status differ by country. U.S. freedom-to-operate analysis cannot be extended automatically to Europe or other markets.

Geographic review should cover:

U.S. patent-family members and continuations.
European Patent Office grants and national validations.
Canadian and Australian family members.
Local patent-term adjustments or supplementary protection certificates.
National regulatory status of ingenol mebutate.
Local withdrawal, suspension or safety actions.

Key Takeaways

Patent 8,377,919 is a formulation patent focused on acidic topical ingenol angelate.
Claim 1 requires approximately 0.001%-0.15% w/w ingenol angelate, at least approximately 95% ingenol-3-angelate isoform “b,” and pH below 4.
The patent covers more than gels. Claims also reach creams, ointments, lotions, foams, emulsions, oils, patches and other formulations.
Claims 17-24 add skin-permeation and topical-loading limitations that may require specialized infringement testing.
The patent was commercially relevant to Picato 0.015% and 0.05% gel.
Picato was FDA-approved in 2012 and discontinued in the United States in 2020.
The projected patent term runs into 2027 or 2028, subject to the USPTO’s official term calculation.
No material public Paragraph IV litigation specific to this patent is identified in the cited core records.
Patent strength is highest against Picato-like acidic gels and weaker for uncommercialized dosage forms and functional permeation claims.
Separate compound, method-of-use, manufacturing and international patents must be reviewed before making a freedom-to-operate or launch decision.

FAQs

Is ingenol angelate the same as ingenol mebutate?

Yes. Ingenol mebutate is commonly identified chemically as ingenol-3-angelate. Patent 8,377,919 distinguishes the relevant isoform as ingenol-3-angelate isoform “b.”

Does changing Picato from a gel to a cream avoid Patent 8,377,919?

Not necessarily. Claims 1 and 6 can cover a cream if it satisfies the active-ingredient, isoform-purity, concentration and pH limitations.

Does a formulation at pH 4 avoid the patent?

It may avoid the literal “pH less than 4” limitation, but the result depends on the actual measured pH, the meaning of “about,” other patent claims and potential equivalents analysis.

Can a product infringe the permeation claims without infringing claim 1?

Yes. Claims 17-24 are defined partly by permeation rate and applied amount rather than by the concentration range recited in claim 1.

Does withdrawal of Picato cancel the patent?

No. FDA market withdrawal and patent expiration are separate events. Withdrawal reduces commercial value but does not automatically terminate patent rights.

References

LEO Pharma A/S. (2013). Pharmaceutical formulations comprising ingenol angelate, U.S. Patent No. 8,377,919. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (2012). Picato (ingenol mebutate) prescribing information. FDA.
U.S. Food and Drug Administration. (2020). FDA warns of increased risk of death from skin cancer with use of Picato (ingenol mebutate) gel. FDA Drug Safety Communication.
U.S. Patent and Trademark Office. (2024). Patent term adjustment and patent term calculation resources. USPTO.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA, Orange Book.

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	8,377,919	⤷ Start Trial	Y				⤷ Start Trial
Leo Labs	PICATO	ingenol mebutate	GEL;TOPICAL	202833-002	Jan 23, 2012		DISCN	Yes	No	8,377,919	⤷ 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
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 8,377,919

Which drugs does patent 8,377,919 protect, and when does it expire?

Summary for Patent: 8,377,919