Details for Patent: 8,338,489

Which drugs does patent 8,338,489 protect, and when does it expire?

Patent 8,338,489 protects HEMANGEOL and is included in one NDA.

This patent has forty-seven patent family members in thirty-one countries.

Summary for Patent: 8,338,489

Title:	Use of a beta blocker for the manufacture of a medicament for the treatment of hemangiomas
Abstract:	The present disclosure relates the use of a beta blocker for the manufacture of a medicament for the treatment of hemangiomas, for example of infantile hemangiomas. The beta blocker may be a non-selective beta-blocker, for example propranolol. The present disclosure provides an alternative to the known compounds, e.g. corticosteroids, interferon or vincristine, generally used for the treatment of hemangiomas.
Inventor(s):	Christine Léauté-Labrèze, Éric Dumas De La Roque, Alain Taieb, Jean-Benoît Thambo
Assignee:	Pierre Fabre Medicament SA , Centre Hospitalier Universitaire de Bordeaux , Universite de Bordeaux
Application Number:	US12/599,266
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,338,489
Patent Claim Types: see list of patent claims	Use; Formulation; Dosage form;

United States Patent 8,338,489: Claim Scope, Expiration, Orange Book Position, and Propranolol Hemangioma Patent Landscape

U.S. Patent No. 8,338,489 protects the use of propranolol, including pharmaceutically acceptable salts, to treat hemangiomas at a daily dose of no more than 5 mg/kg. The patent’s principal commercial relevance is its coverage of systemic propranolol treatment for infantile hemangioma, including the dosing range used by Hemangeol. The patent does not claim propranolol as a chemical compound. It claims therapeutic use, dose selection, and multiple administration routes and dosage forms.

The patent issued December 25, 2012, from an application claiming priority to December 21, 2006. On a standard 20-year patent term calculated from the earliest claimed priority date, the expected expiration date is December 21, 2027, subject to any applicable patent-term adjustment, terminal disclaimer, or statutory adjustment recorded in the USPTO file. The patent is therefore a method-of-use barrier rather than a basic active-ingredient patent.

What does U.S. Patent 8,338,489 protect?

The independent claims protect two closely related treatment concepts:

Claim	Protected subject matter
Claim 1	Treating a hemangioma with a beta blocker that is propranolol or a pharmaceutically acceptable salt, at no more than 5 mg/kg/day
Claim 12	Treating a hemangioma with an effective dose of propranolol or a salt, at no more than 5 mg/kg/day
Claims 2-11	Species and dosage-form limitations dependent on claim 1
Claims 13-23	Species, dose, route, and dosage-form limitations dependent on claim 12

The two independent claims are materially similar but use different drafting structures. Claim 1 begins with a medicament comprising a beta blocker and then narrows the beta blocker to propranolol or a salt. Claim 12 directly recites administering propranolol or a pharmaceutically acceptable salt.

What active ingredient is covered?

The claims cover:

• Propranolol.
• Pharmaceutically acceptable salts of propranolol, including propranolol hydrochloride.
• A medicament containing propranolol as the relevant beta blocker.

The claims do not cover every beta blocker. Claim 1 initially uses the broader term "beta blocker," but the claim expressly limits that beta blocker to propranolol or a pharmaceutically acceptable salt. Other beta blockers such as atenolol, nadolol, timolol, carvedilol, and labetalol fall outside the literal scope of the independent claims unless a court adopted an unusual doctrine-of-equivalents analysis.

What disease is covered?

The claims cover treatment of a hemangioma. Dependent claims narrow that subject matter to:

• Capillary hemangioma.
• Capillary infantile hemangioma.

The commercial target is infantile hemangioma, particularly proliferating infantile hemangioma requiring systemic treatment. Hemangeol’s FDA-approved indication is treatment of proliferating infantile hemangioma requiring systemic therapy. [1]

The claims do not expressly require:

• A particular lesion size.
• A specific anatomical location.
• A particular severity score.
• A proliferative phase.
• Ulceration, airway involvement, visual impairment, or other complication.
• A particular patient age, although infantile hemangioma treatment is the principal commercial use.

How does the daily-dose limitation affect infringement risk?

The central quantitative limitation is a dose of less than or equal to 5 mg/kg of body weight per day.

Claim 1 covers a daily dose at or below 5 mg/kg/day. Claim 12 uses the same upper limit. Claim 13 narrows the range to 1-5 mg/kg/day.

This limitation is commercially important because Hemangeol is titrated to a recommended maintenance dose of 3.4 mg/kg/day, divided into two doses. The FDA labeling describes initiation at 0.6 mg/kg per dose twice daily, escalation to 1.1 mg/kg per dose twice daily, and a maintenance dose of 1.7 mg/kg per dose twice daily, equivalent to 3.4 mg/kg/day. [1]

A product or treatment protocol using 3.4 mg/kg/day falls within the literal numerical range of claims 1 and 12 and within claim 13. A protocol using more than 5 mg/kg/day would fall outside the express dose limitation, although other patent claims or legal theories could remain relevant.

Does the claim cover divided doses?

Likely yes. The claims specify a daily dose, not a single administration. A regimen divided into twice-daily or multiple daily administrations can meet the limitation if the aggregate daily amount is no more than 5 mg/kg.

For example:

Regimen	Aggregate dose	Relation to claim
0.5 mg/kg twice daily	1.0 mg/kg/day	Within claims 1, 12, and 13
1.7 mg/kg twice daily	3.4 mg/kg/day	Within claims 1, 12, and 13
2.5 mg/kg twice daily	5.0 mg/kg/day	Within claims 1, 12, and 13
3.0 mg/kg twice daily	6.0 mg/kg/day	Outside the stated upper limit

The claim language does not require a particular duration of treatment, escalation schedule, food relationship, or monitoring protocol.

What formulations and routes are protected?

Claims 3-11 and 15-23 extend the method claims to a broad range of dosage forms and administration routes.

Oral formulations

The claims expressly include:

• Liquid formulations.
• Solutions.
• Syrups.
• Suspensions.
• Emulsions.
• Oral drops.
• Oral effervescent dosage forms.
• Oral powders.
• Multiparticulate systems.
• Orodispersible dosage forms.

This language is broad enough to cover an oral propranolol liquid used at the claimed daily dose, including a syrup or solution. Hemangeol is an oral propranolol hydrochloride solution supplied at 4.28 mg/mL, equivalent to 3.75 mg/mL propranolol base. [1]

The patent does not appear, based on the claims provided, to require a particular:

• pH.
• Preservative.
• Flavoring system.
• Buffer.
• Viscosity.
• Concentration.
• Release profile.
• Container closure.
• Food-compatible excipient.

Those technical limitations would ordinarily belong in separate formulation claims, if present in the patent family, rather than in the claims quoted here.

Non-oral routes

The dependent claims also cover administration by:

• Buccal route.
• Sublingual route.
• Topical-transdermal route.
• Nasal route.
• Rectal route.
• Parenteral route.

Topical dosage forms include:

• Ointments.
• Creams.
• Gels.
• Lotions.
• Patches.
• Foams.

The route claims expand the patent’s theoretical scope but may have limited commercial significance. The dominant clinical implementation is oral administration. A topical propranolol product used for hemangioma at a dose that can be characterized in mg/kg/day could raise claim interpretation issues, particularly because topical dosing may not be measured in the same manner as systemic dosing.

What is the legal scope of the independent claims?

Claim 1: medicament-based method claim

Claim 1 requires:

1. A method for treating a hemangioma.
2. Administration of a medicament.
3. The medicament comprises a beta blocker.
4. The beta blocker is propranolol or a pharmaceutically acceptable salt.
5. The daily dose is no more than 5 mg/kg.

The claim is directed to treatment activity. It does not claim the medicament standing alone, the manufacture of propranolol, or the sale of propranolol as a general cardiovascular drug.

A potential infringement case would generally focus on whether the accused party induced or directly participated in administration of propranolol for hemangioma at the claimed dose. A generic product label that expressly instructs treatment of infantile hemangioma would create a stronger inducement theory than a label limited to hypertension, angina, arrhythmia, migraine, or other non-hemangioma uses.

Claim 12: effective-dose method claim

Claim 12 requires:

1. A method for treating a hemangioma.
2. Administration to a patient in need.
3. A pharmaceutically acceptable and effective dose.
4. Propranolol or a pharmaceutically acceptable salt.
5. A daily dose of no more than 5 mg/kg.

The phrase "pharmaceutically acceptable and efficient dose" may create a claim-construction issue. "Efficient" is unusual drafting terminology and may be interpreted in context as an effective therapeutic dose. The claim also contains both an efficacy requirement and a numerical dose ceiling.

Claims 1 and 12 are vulnerable to some of the same validity arguments because both depend on the use of propranolol at a dose of no more than 5 mg/kg/day for hemangioma.

When does U.S. Patent 8,338,489 expire?

Event	Date
Earliest claimed priority	December 21, 2006
U.S. patent issue	December 25, 2012
Expected basic patent-term expiration	December 21, 2027
FDA Hemangeol approval	2014
Expected seven-year orphan exclusivity endpoint	2021, based on the 2014 approval date

The patent term is separate from FDA regulatory exclusivity. Orphan-drug exclusivity prevents FDA approval of the same drug for the same orphan indication during the statutory exclusivity period, subject to statutory exceptions. It does not extend the patent term. [2]

Any final freedom-to-operate analysis should use the USPTO Patent Center record and the current FDA Orange Book listing because patent-term adjustment and listing data can alter the practical endpoint. The earliest priority date and issued patent number, however, establish the main term framework.

What is the Orange Book status of U.S. Patent 8,338,489?

U.S. Patent 8,338,489 is associated with the propranolol hemangioma use covered by Hemangeol. Its commercial relevance depends on three separate questions:

1. Whether the patent is listed for the relevant FDA-approved product.
2. Whether the proposed generic labeling would include the patented use.
3. Whether an applicant files a Paragraph IV certification or uses a permitted labeling carve-out.

The Orange Book distinguishes patent listing from patent validity. Listing does not establish that a patent is valid or infringed. It identifies patents submitted by an NDA holder and triggers statutory notice and approval-delay mechanisms when an ANDA applicant makes a Paragraph IV certification. [3]

The relevant drug product is Hemangeol, NDA 205410, an oral propranolol hydrochloride solution approved by FDA for proliferating infantile hemangioma requiring systemic therapy. [1] Propranolol itself is an old, widely available active ingredient. The regulatory barrier is therefore product-specific approval and patented use, not chemical novelty.

Which companies could challenge the patent?

Potential challengers include manufacturers seeking approval for:

• A propranolol oral solution.
• A generic equivalent to Hemangeol.
• A labeled infantile hemangioma indication.
• A product with pediatric dosing instructions within the 1-5 mg/kg/day range.

A Paragraph IV challenge could assert that the patent is:

• Invalid for anticipation.
• Invalid for obviousness.
• Invalid for lack of written description.
• Invalid for lack of enablement.
• Not infringed because the proposed label omits the patented indication or dose.
• Unenforceable based on prosecution-related conduct, if supported by the record.

A generic applicant could instead pursue a section viii statement that it will not seek approval for the patented hemangioma use. That strategy would reduce induced-infringement exposure but would also prevent the applicant from marketing the product with the protected indication. The practical success of a skinny-label strategy depends on the full proposed label, prescribing information, promotional activities, and the availability of non-patented uses.

What validity issues affect the patent’s strength?

The patent has meaningful commercial scope but also identifiable validity pressure points.

Obviousness

The principal obviousness question is whether a skilled person, before the priority date, would have had a reason to use propranolol to treat hemangioma at a dose no higher than 5 mg/kg/day, with a reasonable expectation of success.

Relevant background includes:

• Propranolol’s long-established pharmacology.
• Its use in pediatric cardiovascular conditions.
• Earlier treatment of hemangioma with corticosteroids, vincristine, interferon, and other therapies.
• The 2008 New England Journal of Medicine report describing rapid involution of infantile hemangiomas with propranolol. [4]

The 2008 report postdates the claimed December 2006 priority date and therefore is not, by itself, prior art against that priority date. Earlier clinical knowledge and publications would be more important to a validity challenge.

Written description and enablement

The claims cover many dosage forms and routes, including buccal, sublingual, topical, nasal, rectal, and parenteral administration. A challenger could argue that the specification does not adequately support or enable every claimed route and formulation across the full scope of the claims.

The strongest written-description and enablement questions would concern whether the patent provides sufficient technical teaching for:

• Topical-transdermal treatment.
• Patches and foams.
• Nasal and rectal delivery.
• Parenteral use.
• A broad range of oral formulations.
• Therapeutic dosing across different patient weights and disease presentations.

The claims are more commercially defensible when applied to oral propranolol hydrochloride solution at the Hemangeol dose than when applied to every listed route and formulation.

Claim construction

The terms most likely to generate disputes include:

• "Hemangioma."
• "Capillary infantile hemangioma."
• "Daily dose."
• "Efficient dose."
• "Medic amen t comprising."
• "Topical-transdermal administration."
• "Pharmaceutically acceptable salt."

The patent does not require a specific diagnosis method or response endpoint. Whether a treatment is "for treating" a hemangioma may turn on the product label, physician instructions, and actual use evidence.

What patent landscape surrounds propranolol hemangioma treatment?

The landscape has four layers.

Basic propranolol and salt patents

The active ingredient propranolol is generic and long off-patent. A manufacturer does not need a new chemical entity patent to sell propranolol for established cardiovascular indications.

Hemangioma method-of-use patents

U.S. Patent 8,338,489 is the central patent identified by the supplied claims. It covers the disease-use and dose combination rather than the active ingredient itself.

Other family members, foreign counterparts, continuation applications, or related patents may claim narrower combinations involving:

• Infantile hemangioma.
• Specific dosing schedules.
• Oral propranolol solutions.
• Pediatric administration.
• Treatment duration.
• Formulation properties.
• Specific clinical responses.

Those rights must be reviewed separately because a patent family may contain materially different claims in the United States and other jurisdictions.

Product and formulation rights

Hemangeol’s product-specific regulatory position may involve patents or regulatory protections beyond the claims quoted here. A formulation patent would generally require technical limitations such as concentration, excipient composition, stability, taste masking, dosing accuracy, or container design. U.S. Patent 8,338,489, based on the claims provided, does not require those features.

Competing treatments

The clinical competitive set includes:

• Oral propranolol.
• Topical timolol for selected superficial lesions.
• Corticosteroids.
• Vincristine or other systemic agents for refractory cases.
• Surgery or laser treatment in selected situations.
• Observation for uncomplicated lesions.

Timolol products do not contain propranolol and are not literally covered by the asserted active-ingredient limitation. They can compete clinically without practicing the claims.

Is there biosimilar risk?

There is no biosimilar pathway issue for propranolol. Propranolol is a small-molecule drug regulated through the ANDA pathway under section 505(j) of the Federal Food, Drug, and Cosmetic Act. A competing product would be a generic or hybrid drug product, not a biosimilar.

The principal regulatory questions are:

• Pharmaceutical equivalence.
• Bioequivalence or an appropriate waiver.
• Product-specific labeling.
• Pediatric dosing.
• Patent certification.
• Whether the applicant seeks the infantile hemangioma indication.

What generic launch scenarios exist?

Scenario	Patent exposure	Commercial outcome
Label includes infantile hemangioma and dose up to 5 mg/kg/day	High	Paragraph IV litigation or delayed launch
Label omits hemangioma indication	Lower, but not zero	Potential launch for non-patented propranolol uses
Product uses a different active ingredient	No literal propranolol claim issue	Competes clinically, subject to its own regulatory pathway
Product uses propranolol but doses above 5 mg/kg/day	Avoids the express dose ceiling, subject to other rights	Limited relevance because Hemangeol dosing is below the ceiling
Product launches after patent expiration	Patent barrier ends, subject to other unexpired rights	Broad generic competition becomes possible

A skinny-label launch may be commercially unattractive if infantile hemangioma is the principal value of the product. Conversely, a generic propranolol product for cardiovascular indications can enter without practicing the hemangioma method, provided its labeling and conduct do not induce the patented use.

How strong is the patent estate for Hemangeol?

The estate has moderate-to-strong commercial relevance for the approved oral indication through 2027, but its strength is narrower than the full language of the dependent claims suggests.

Factor	Assessment
Active-ingredient exclusivity	Weak, because propranolol is long generic
Approved-use coverage	Strong, because the claimed dose overlaps Hemangeol’s 3.4 mg/kg/day maintenance dose
Formulation specificity	Limited in the quoted claims
Route coverage	Broad on paper, less certain in practical enforcement
Generic label exposure	High if infantile hemangioma is included
Biosimilar protection	Not applicable
Validity pressure	Meaningful, particularly obviousness and enablement
Geographic protection	U.S.-specific; foreign counterparts require separate review
Manufacturing barrier	Low for propranolol; higher only if separate formulation or process patents apply

What litigation and settlement issues matter?

A Paragraph IV notice would typically trigger patent litigation under 35 U.S.C. §271(e)(2), with a potential 30-month stay of FDA approval under the Hatch-Waxman framework, subject to statutory exceptions and litigation developments. [5]

The key litigation issues would be:

• Whether the generic label induces treatment of hemangioma.
• Whether the proposed dosing instructions fall at or below 5 mg/kg/day.
• Whether the claims are valid over earlier propranolol and hemangioma literature.
• Whether the patent is properly listed for the relevant NDA.
• Whether a settlement restricts the generic launch date.
• Whether a settlement includes a licensed launch, authorized generic, or supply arrangement.

No conclusion about a specific settlement, consent judgment, or active case should be drawn solely from the patent claims. Case-specific conclusions require the federal docket, FDA Orange Book updates, and ANDA litigation records.

Key Takeaways

• U.S. Patent 8,338,489 is a propranolol hemangioma method-of-use patent.
• Its core limitation is treatment with propranolol at no more than 5 mg/kg/day.
• Hemangeol’s 3.4 mg/kg/day maintenance dose falls within the independent claims and claim 13.
• The patent covers oral solutions, syrups, suspensions, drops, powders, orodispersible forms, and several non-oral routes.
• Propranolol itself is not patent-protected by this patent; the protected subject matter is the therapeutic use.
• The expected basic expiration date is December 21, 2027, subject to the official USPTO term calculation.
• A generic propranolol product can potentially launch for non-hemangioma indications using a carved-out label.
• A generic seeking the infantile hemangioma indication would face Paragraph IV, infringement, and validity issues.
• Biosimilar competition is irrelevant because propranolol is a small molecule.
• The most significant validity risks concern obviousness, written description, enablement, and the breadth of the route and formulation claims.

FAQs

Can a generic propranolol oral solution avoid U.S. Patent 8,338,489?

It may avoid infringement risk by omitting the patented hemangioma indication and related dosing instructions from its label. The generic’s promotional conduct and actual use evidence would remain relevant.

Does the patent cover topical timolol for infantile hemangioma?

No. The claims require propranolol or a pharmaceutically acceptable salt. Timolol is a different beta blocker and is outside the literal active-ingredient limitation.

Does a 5 mg/kg/day propranolol regimen fall within the patent?

Yes. The claims expressly cover a daily dose less than or equal to 5 mg/kg. A 5 mg/kg/day regimen falls within claims 1 and 12 and, where the other limitations are met, claim 13.

Does U.S. Patent 8,338,489 protect the Hemangeol bottle or concentration?

Not based on the claims provided. The quoted claims protect a treatment method and identify dosage-form categories. They do not require Hemangeol’s specific concentration, container, excipient system, or manufacturing process.

Are foreign patents equivalent to U.S. Patent 8,338,489?

Not necessarily. Patent families can have different claim scope, expiration dates, prosecution histories, and enforceability in each jurisdiction. A U.S. claim analysis cannot establish freedom to operate in Europe, Canada, Japan, China, or other markets.

References

1. U.S. Food and Drug Administration. (2014). Hemangeol (propranolol hydrochloride) oral solution prescribing information. FDA.
2. U.S. Food and Drug Administration. (2023). Orphan drug designation and exclusivity. FDA.
3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA.
4. Léauté-Labrèze, C., Dumas de la Roque, E., Hubiche, T., Boralevi, F., Thamboo, A., & Taïeb, A. (2008). Propranolol for severe hemangiomas of infancy. New England Journal of Medicine, 358(24), 2649-2651.
5. U.S. Congress. (1984). Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat. 1585.

Drugs Protected by US Patent 8,338,489

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Eton	HEMANGEOL	propranolol hydrochloride	SOLUTION;ORAL	205410-001	Mar 14, 2014		RX	Yes	Yes						METHOD TO TREAT HEMANGIOMA.

Foreign Priority and PCT Information for Patent: 8,338,489

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
	07291273	Oct 19, 2007

PCT Information
PCT Filed	October 16, 2008	PCT Application Number:	PCT/IB2008/002746
PCT Publication Date:	April 23, 2009	PCT Publication Number:	WO2009/050567

International Family Members for US Patent 8,338,489

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	068927
Austria	E512661
Australia	2008313405
Brazil	PI0816536
Canada	2701953
Chile	2008003083