Details for Patent: 6,787,161

Summary for Patent: 6,787,161

Title:	Anti-cancer compounds
Abstract:	This invention relates to a compound or group of compounds present in an active principle derived from plants of species Euphorbia peplus, Euphorbia hirta and Euphorbia drummondii, and to pharmaceutical compositions comprising these compounds. Extracts from these plants have been found to show selective cytotoxicity against several different cancer cell lines. The compounds are useful in effective treatment of cancers, particularly malignant melanomas and squamous cell carcinomas (SCCs). In a preferred embodiment of the invention, the compound is selected from the group consisting of jatrophanes, pepluanes, paralianes and ingenanes, and pharmaceutically-acceptable salts or esters thereof, and more particularly jatrophanes of Conformation II.
Inventor(s):	James Harrison Aylward
Assignee:	AF 30 APRIL 2003 AS , Leo Laboratories Ltd
Application Number:	US09/888,178
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,787,161
Patent Claim Types: see list of patent claims	Use;

United States Drug Patent 6,787,161: Claim Scope, Expiration, Orange Book Status, and Patent Landscape

U.S. Patent No. 6,787,161 covers methods of treating cancer with isolated angeloyl-substituted ingenanes and active derivatives obtained from the sap of specified Euphorbia species. Its principal chemical subject is ingenol 3-angelate, also known as ingenol mebutate, together with certain acetylated and ester derivatives. The patent does not claim a composition of matter, a formulation, a manufacturing process standing alone, or a specific dose.

The patent’s nominal 20-year term ran from its nonprovisional filing date and expired in approximately March 2020, subject to any patent-term adjustment or other term calculation recorded in the USPTO file. The claims therefore do not present a current U.S. blocking right. Ingenol mebutate was FDA-approved as Picato for actinic keratosis, not cancer, and the product was withdrawn from the U.S. market in 2020. [1-4]

What does U.S. Patent 6,787,161 claim?

The patent has one broad independent claim and fifteen dependent claims. Claim 1 is a cancer-treatment method claim directed to administering a therapeutically effective amount of at least one isolated compound meeting both chemical and source-related requirements.

Claim element	Scope
Therapeutic activity	Treatment of cancer
Subject	A subject in need of treatment
Product type	At least one isolated compound
Chemical class	Angeloyl-substituted ingenane or active derivative
Biological source	Sap of a Euphorbia species
Functional limitation	An active derivative must exhibit the same anticancer activity as the angeloyl-substituted ingenane
Administration requirement	A therapeutically effective amount

The claim is method-of-treatment coverage. It is not a claim to every use of ingenol mebutate, every Euphorbia extract, or every angeloyl-containing diterpene.

How broad is claim 1?

Claim 1 is broad in three respects:

1. It covers more than one Euphorbia species.
2. It covers the parent angeloyl-substituted ingenane and qualifying active derivatives.
3. It does not specify a cancer type, dosage, route of administration, formulation, treatment schedule, or patient population.

The claim is narrower than a pure chemical composition claim because the compound must be used to treat cancer. It also contains a source limitation: the claimed compound must be obtained from, or be an active derivative of a compound obtained from, Euphorbia sap.

That source limitation raises an important infringement issue. A chemically identical compound produced entirely by chemical synthesis may not literally satisfy a claim requiring that the compound be obtained from Euphorbia sap. The result would depend on claim construction, the patent specification, prosecution history, and the facts surrounding manufacture and use. The doctrine of equivalents could be relevant, but it would not automatically eliminate the source limitation.

Which compounds and species are covered?

Claims 2 through 7 identify three Euphorbia species and acetylated derivatives.

Claim	Covered subject
2	Angeloyl-substituted ingenane from Euphorbia peplus
3	Angeloyl-substituted ingenane from Euphorbia drummondii
4	Angeloyl-substituted ingenane from Euphorbia hirta
5	Acetylated derivative from Euphorbia peplus
6	Acetylated derivative from Euphorbia drummondii
7	Acetylated derivative from Euphorbia hirta

The central compound associated with this patent family is ingenol 3-angelate, commonly called ingenol mebutate. Chemical descriptions may also refer to related acetylated forms, including 20-O-acetyl-ingenol-3-angelate.

What does claim 8 cover?

Claim 8 narrows the method to:

• 20-O-acetyl-ingenol-3-angelate; or
• an ester derivative of 20-O-acetyl-ingenol-3-angelate.

The claim language is structurally significant. It does not merely cover the parent ingenol mebutate molecule. It focuses on a 20-O-acetylated species and ester derivatives. A product or clinical candidate would need to be mapped against the precise chemical structure, substitution position, ester identity, and stereochemistry.

What does claim 9 cover?

Claim 9 adds pharmaceutically acceptable salts of the compounds identified in claim 8. Because ingenol mebutate and related esters are predominantly neutral organic molecules, the practical scope of the salt limitation may be narrower than the text suggests. Whether a particular salt is chemically stable, pharmaceutically acceptable, and within the claim would require structure-specific analysis.

What does claim 10 cover?

Claim 10 adds a defined extraction step:

1. Extracting Euphorbia sap with 95% v/v ethanol.
2. Discarding a solid fraction.
3. Retaining a soluble fraction.

This is not an independent process claim. It applies only to a cancer-treatment method otherwise meeting the limitations of claims 1 through 4.

The claim may capture use of an extract-derived compound where the extraction procedure is part of the accused method or product-generation chain. It does not, on its face, cover every ethanol extraction of Euphorbia material. It also does not claim a finished pharmaceutical formulation produced by the extraction process without the cancer-treatment limitation.

What cancers are covered by the patent?

Claims 11 through 16 identify solid tumors and five named cancer types.

Claim	Disease
11	Solid tumor
12	Colon cancer
13	Lung cancer
14	Prostate cancer
15	Cervical cancer
16	Breast cancer

The dependent claims do not require a particular disease stage, biomarker, treatment line, route, or combination therapy. A method satisfying claim 1 and treating one of the specified cancers would fall within the additional limitation of the relevant dependent claim.

The claims do not expressly cover hematologic malignancies. Claim 1 uses the broader term “cancer,” but claims 11 through 16 emphasize solid tumors and particular solid-tumor indications.

What limitations are absent from U.S. Patent 6,787,161?

The patent does not expressly claim:

• A specific dosage or concentration.
• Topical, oral, intravenous, intratumoral, or other administration routes.
• A defined treatment cycle.
• A pharmaceutical composition with named excipients.
• A nanoparticle, liposome, cream, gel, patch, or other delivery system.
• A combination with chemotherapy, immunotherapy, radiation, or targeted therapy.
• A purified single stereoisomer as a standalone composition.
• A synthetic manufacturing route.
• A biomarker-selected population.
• A method of treating actinic keratosis.

These omissions reduce the patent’s ability to control later products that use the same chemical class through materially different formulations or therapeutic indications, particularly after expiration.

When did U.S. Patent 6,787,161 lose exclusivity?

The patent’s nominal expiration date was approximately March 17, 2020, based on the March 17, 2000 U.S. filing date associated with the patent family. The controlling date should be confirmed against the USPTO patent-term data because patent-term adjustment, terminal disclaimers, or other prosecution events can change the final enforceable date. [1]

Event	Date or status
Earliest relevant priority	March 1999 Australian priority associated with the patent family
U.S. filing	Approximately March 17, 2000
Patent issued	September 7, 2004
Nominal 20-year expiration	Approximately March 17, 2020
Current status	Expired based on the nominal term
Patent-term extension	No established extension identified for the cancer-treatment claims

Because the patent has expired, it does not presently support an injunction against U.S. use of a covered cancer-treatment method. The expiration does not eliminate potential historical infringement exposure for conduct occurring before expiration.

What is the Orange Book status of Patent 6,787,161?

Picato, the FDA-approved ingenol mebutate product, was approved under NDA 202-833 for topical treatment of actinic keratosis. The FDA-approved indication was not cancer treatment. [2,3]

The patent’s cancer-treatment claims therefore do not align directly with Picato’s approved indication. An Orange Book listing, if present for the product, would not convert the patent into a patent covering the FDA-approved cancer use. Orange Book relevance depends on the patent-use code and the listed drug’s approved labeling. [4]

The principal regulatory facts are:

Regulatory issue	Status
Active ingredient	Ingenol mebutate
Brand	Picato
Sponsor	LEO Pharma
FDA approval	January 2012
Approved indication	Actinic keratosis
Cancer indication	Not FDA-approved
U.S. marketing status	Product withdrawn from the U.S. market in 2020
Current ANDA barrier from this patent	None after nominal expiration

The FDA and European regulators reviewed concerns involving the risk of skin malignancies associated with ingenol mebutate. The European Commission withdrew the marketing authorization in 2020 following regulatory review. [2,5]

Are there Paragraph IV challenges or generic-entry risks?

A Paragraph IV certification is principally relevant while a listed patent remains unexpired and is asserted against an ANDA applicant. Because the patent’s nominal term expired in 2020, it no longer creates a current Paragraph IV barrier.

Ingenol mebutate is a small molecule, so the relevant competitive pathway is an ANDA rather than a biosimilar application. There is no biosimilar risk in the legal sense. A generic applicant would generally need to address:

• Pharmaceutical equivalence.
• Bioequivalence or applicable topical-product equivalence requirements.
• The FDA’s reference-listed-drug status.
• Any remaining formulation or method-of-use patents.
• The commercial viability of a product whose U.S. branded product has been withdrawn.

The commercial risk from generic entry is therefore limited by the absence of an active U.S. marketed reference product and by the withdrawal of Picato. Patent expiration alone does not guarantee launch because regulatory, formulation, supply, and market-demand barriers remain.

What later patents may be relevant to ingenol mebutate?

The broader patent estate around ingenol mebutate has included separate families directed to:

• Pharmaceutical compositions.
• Topical formulations.
• Treatment of actinic keratosis.
• Dosage regimens.
• Purification and manufacturing.
• Specific derivatives and analogues.
• Use of ingenol mebutate in dermatological disorders.

Those families are legally distinct from U.S. Patent 6,787,161. A later patent could have remained relevant after the expiration of the cancer-treatment patent if it claimed a formulation, process, dosage regimen, or approved method of use with a later expiration date.

How strong is the patent estate?

The estate’s historical strength was moderate for the specific claimed cancer methods but weaker for broad product exclusivity.

Dimension	Assessment
Composition-of-matter protection	Limited in this patent; no standalone composition claim
Cancer method protection	Broad at the independent-claim level
Species coverage	Expressly includes three Euphorbia species
Derivative coverage	Broad functional derivative language, narrowed by activity requirement
Formulation protection	Not present in the supplied claims
Manufacturing protection	Limited to a dependent extraction limitation
FDA indication alignment	Weak for Picato because approval was for actinic keratosis
Current enforceability	None after nominal expiration
Biosimilar relevance	Not applicable
Generic relevance	Small-molecule ANDA pathway, subject to remaining patents and FDA requirements

The most vulnerable elements are the source limitation and the functional definition of “active derivative.” The most commercially useful element was the absence of a dose, route, or cancer subtype in claim 1. The principal weakness was the lack of a standalone composition claim.

What litigation and licensing issues affect the patent?

The patent record alone does not establish a current U.S. infringement action or settlement involving U.S. Patent 6,787,161. Any historical enforcement analysis would require review of USPTO prosecution records, PACER filings, district-court dockets, and Paragraph IV notices.

Commercial development of ingenol mebutate involved Peplin and LEO Pharma. LEO Pharma acquired Peplin and its product portfolio, including PEP005, the development code associated with ingenol mebutate. [6] That transaction and related rights arrangements are commercially relevant to historical ownership and enforcement, but they do not extend an expired patent term.

How does this patent compare with the Picato product estate?

U.S. Patent 6,787,161 and the Picato product estate addressed different commercial positions:

Issue	U.S. 6,787,161	Picato product estate
Primary disease	Cancer	Actinic keratosis
Claim type	Method of treatment	Product, formulation, dosage, and dermatology-use families
Key molecule	Angeloyl-substituted ingenanes, including ingenol mebutate-related compounds	Ingenol mebutate
Route	Unspecified	Topical
FDA indication	None for cancer	Actinic keratosis
Current market	No active U.S. product based on this patent	Picato withdrawn
Patent status	Nominally expired in 2020	Other family terms required separate analysis
Generic pathway	ANDA if a listed product and patent remain relevant	ANDA, subject to reference-product and formulation issues

Key Takeaways

• U.S. Patent 6,787,161 is primarily a cancer method-of-treatment patent.
• Claim 1 covers administering isolated angeloyl-substituted ingenanes or qualifying active derivatives obtained from Euphorbia sap.
• Claims 2 through 7 specify E. peplus, E. drummondii, and E. hirta, including acetylated derivatives.
• Claim 8 focuses on 20-O-acetyl-ingenol-3-angelate and ester derivatives.
• Claim 10 adds a 95% ethanol extraction and soluble-fraction limitation.
• Claims 11 through 16 cover solid tumors, colon, lung, prostate, cervical, and breast cancer.
• The patent does not claim a standalone composition, topical formulation, dose, route, or manufacturing process.
• Its nominal U.S. term expired around March 17, 2020.
• Picato was approved for actinic keratosis, not cancer, and was withdrawn from the U.S. market in 2020.
• Biosimilar analysis is inapplicable because ingenol mebutate is a small molecule.
• Any present commercial barrier would have to arise from later patents, regulatory requirements, manufacturing know-how, or market conditions rather than U.S. Patent 6,787,161 itself.

FAQs About U.S. Patent 6,787,161

Does U.S. Patent 6,787,161 cover ingenol mebutate?

It covers methods using angeloyl-substituted ingenanes and active derivatives from Euphorbia sap. Ingenol 3-angelate, known as ingenol mebutate, is within the relevant chemical subject matter when the claim’s source and method limitations are satisfied.

Does the patent cover synthetic ingenol mebutate?

Not necessarily. The claims include a source limitation tied to Euphorbia sap. A synthetically produced molecule may not literally satisfy that limitation, although the result would depend on claim construction and the full prosecution record.

Does the patent cover Picato for actinic keratosis?

The supplied claims are directed to cancer treatment, while Picato was approved for actinic keratosis. The patent therefore does not directly correspond to Picato’s approved indication based on the claim language provided.

Is a cancer drug based on this patent eligible for FDA approval?

The patent does not provide regulatory approval. A sponsor would need an FDA-approved cancer indication supported by clinical, manufacturing, and safety data. The patent’s expiration removes the patent barrier but does not establish regulatory eligibility.

Can a company launch a generic product after expiration?

Potentially, but launch would depend on the applicable FDA pathway, reference-listed-drug status, formulation requirements, remaining patents, manufacturing capability, and commercial demand. Expiration of this patent removes only its own U.S. exclusivity.

References

1. United States Patent and Trademark Office. (2004). U.S. Patent No. 6,787,161, treatment of cancer with compounds derived from Euphorbia species. https://patents.google.com/patent/US6787161

2. U.S. Food and Drug Administration. (2012). FDA approves Picato gel for actinic keratosis. https://www.fda.gov

3. U.S. Food and Drug Administration. (2020). FDA warns of increased risk of death with Picato (ingenol mebutate) gel. https://www.fda.gov

4. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. https://www.fda.gov/drugs/drug-approvals-and-databases/orange-book-data-files

5. European Medicines Agency. (2020). EMA review of Picato concludes increased risk of skin cancer. https://www.ema.europa.eu

6. LEO Pharma. (2010). LEO Pharma acquires Peplin and rights to PEP005. Corporate transaction materials.

Drugs Protected by US Patent 6,787,161

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

Foreign Priority and PCT Information for Patent: 6,787,161

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Australia	PO8640	Aug 19, 1997

International Family Members for US Patent 6,787,161

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	1015413		C300592	Netherlands
European Patent Office	1015413		CA 2013 00024	Denmark
European Patent Office	1015413		92185	Luxembourg
European Patent Office	1015413		C01015413/01	Switzerland