United States Drug Patent 4,600,708: Claim Scope, Expiration, and Propranolol Patent Landscape

US Patent 4,600,708 protects a taste-masked liquid oral composition containing propranolol hydrochloride, oil-free lecithin, and one or more basic amino acids. The patent is no longer enforceable. Its commercial importance is historical: it addressed the intense bitterness and oral-anesthetic effect of propranolol hydrochloride in liquid dosage forms. The patent did not broadly protect propranolol, propranolol tablets, sustained-release capsules, or every propranolol liquid.

What does US Patent 4,600,708 protect?

The patent covers a liquid oral therapeutic dosage form with three required elements:

Propranolol hydrochloride at a reference concentration of 10 mg/mL.
About 8% to about 14% weight by volume of oil-free lecithin for each 10 mg/mL of propranolol hydrochloride.
About 0.5% to 10% of at least one basic amino acid.

The claimed combination is directed to two sensory properties: satisfactory taste and masking of propranolol's local anesthetic or numbing effect.

Claim	Protected subject matter	Key limitation
1	Liquid oral propranolol hydrochloride composition	8% to 14% w/v oil-free lecithin and 0.5% to 10% basic amino acid per 10 mg/mL propranolol HCl
2	Claim 1 composition	Basic amino acid is L-histidine free base
3	Claim 1 composition	L-arginine free base and L-histidine hydrochloride
4	Claim 1 composition	Same amino-acid combination recited in claim 3

Claim 1 is the only independent claim. Claims 2 through 4 narrow the identity of the amino acid component but do not create separate formulation concepts outside claim 1.

The patent's principal inventive combination is therefore lecithin plus a basic amino acid in a propranolol hydrochloride liquid. A liquid containing propranolol hydrochloride but no lecithin would fall outside the literal scope of claim 1. A formulation containing lecithin outside the stated concentration range would also have a non-infringement position, subject to construction of the word "about" and possible doctrine-of-equivalents arguments.

What are the concentration requirements in Patent 4,600,708?

The lecithin limitation is concentration-dependent. The claim requires approximately 8% to 14% w/v oil-free lecithin for each 10 mg/mL of propranolol hydrochloride.

The amino-acid limitation is approximately 0.5% to 10%. The supplied claim text states "by weight" for the amino-acid range, while the lecithin limitation is expressed as weight by volume. That difference matters. The specification and prosecution history would control whether the amino-acid range was intended as w/w, w/v, or another formulation basis.

Proportional scaling

If the claim is read proportionally, the lecithin range scales with propranolol concentration:

Propranolol HCl concentration	Approximate lecithin range under claim ratio
5 mg/mL	4% to 7% w/v
10 mg/mL	8% to 14% w/v
20 mg/mL	16% to 28% w/v

The claim wording is unusual because it defines the excipient amount by reference to a propranolol concentration rather than simply stating a fixed final formulation range. The patent specification would be important in determining whether the ratio is calculated linearly or whether the claim is limited to formulations containing 10 mg/mL.

A formulation containing 4.28 mg/mL propranolol hydrochloride, for example, would require careful analysis. A literal infringement position would depend on whether the claim's "for each 10 milligrams per milliliter" language establishes a normalized ratio or a fixed concentration requirement.

What is the scope of the lecithin limitation?

The lecithin must be oil-free. This limitation excludes ordinary lecithin preparations that contain a material oil fraction, unless the product is formulated or purified so that the resulting lecithin component qualifies as oil-free.

The claim does not appear to limit the lecithin to a particular phospholipid profile, source, purity grade, phosphatidylcholine content, or manufacturing process. The important claim variables are:

Lecithin identity.
Oil-free status.
Concentration.
Use in a liquid oral propranolol hydrochloride formulation.

The claim does not require a particular flavor, sweetener, preservative, pH, viscosity, container, dosage volume, or manufacturing step. Those elements may appear in the specification or examples, but they are not express limitations of claim 1 unless imported through claim construction, which courts generally avoid absent a clear definitional or disclaimer basis.

What amino acids are covered by the patent claims?

Claim 1 uses the broader term "at least one basic amino acid." Claims 2 and 3 identify narrower species.

Claim 2: L-histidine free base

Claim 2 requires L-histidine in its free-base form. The salt form is material. L-histidine hydrochloride is not literally the same chemical form as L-histidine free base.

Claims 3 and 4: L-arginine plus L-histidine hydrochloride

Claims 3 and 4 recite L-arginine free base and L-histidine hydrochloride. The supplied text states "L-arginine, free base," which should be read as L-arginine in free-base form.

Claims 3 and 4 are identical in the text supplied. This duplication may have resulted from a drafting or transcription error. If the issued patent contains the same duplication, the claims remain separate numbered claims but provide no meaningful scope distinction. If the original issued document differs, the issued version and certificate of correction would control.

Potentially covered amino acids

Depending on the specification and prosecution history, "basic amino acid" could encompass compounds such as:

L-arginine.
L-histidine.
Lysine.
Ornithine.
Related basic amino-acid forms that provide the claimed formulation function.

A salt form may raise a separate question. Claim 3 expressly identifies L-histidine hydrochloride, showing that the patent drafter knew how to claim a salt. A defendant could argue that an unlisted salt or a different protonation state falls outside the dependent claims, although claim 1 remains broader.

Does Patent 4,600,708 cover propranolol tablets or sustained-release products?

No. The claims are limited to a liquid oral therapeutic dosage form. They do not cover:

Immediate-release tablets.
Sustained-release capsules.
Transdermal propranolol systems.
Injectable propranolol.
Propranolol base without hydrochloride.
Other beta blockers.
Liquid formulations that lack the claimed lecithin and amino-acid combination.

The patent also does not claim a method of treating hypertension, angina, migraine, arrhythmia, or infantile hemangioma. Its legal scope is formulation-based rather than therapeutic-use-based.

When did US Patent 4,600,708 lose exclusivity?

US Patent 4,600,708 issued on July 15, 1986. It was subject to the pre-Uruguay Round patent-term regime applicable to older US applications. The patent expired in 2003 under the applicable term rules, based on the 17-year period from issuance and the transition rules for older applications.[1][2]

Event	Date or status
Patent issued	July 15, 1986
Statutory patent term	Expired in 2003
Current enforceability	None
Paragraph IV risk from this patent	None
Patent-term extension relevance	None identified
Current Orange Book blocking effect	None

The patent cannot support an infringement suit against a current generic or branded liquid formulation. A formulation developer may still need to review later patents that cover different propranolol compositions, especially pediatric oral solutions and taste-masking systems.

What is the Orange Book status of Patent 4,600,708?

Patent 4,600,708 has no current Orange Book blocking effect. The Orange Book lists patents submitted by an NDA holder for an approved drug product, subject to FDA regulatory rules. An expired 1986 formulation patent cannot prevent approval or launch of a current propranolol product.[3]

The patent also predates current Orange Book practices for listing method-of-use patents and drug-product patents. Its historical relationship to the original Inderal product should not be confused with a current listing for a later propranolol product.

The relevant regulatory distinction is:

Issue	Effect of Patent 4,600,708
ANDA approval	No current bar
Paragraph IV certification	No practical relevance because the patent is expired
30-month stay	Not available
NDA patent certification	Historical only
Current pediatric propranolol product	Must be assessed against later listed patents
Propranolol active ingredient	No current exclusivity from this patent

Which later propranolol patents matter commercially?

The modern propranolol patent landscape is divided into four groups:

Legacy formulation patents, including Patent 4,600,708.
Sustained-release and modified-release products.
Pediatric liquid formulations.
Method-of-use patents, particularly for infantile hemangioma.

Pediatric propranolol oral solutions

Hemangeol, a propranolol hydrochloride oral solution approved by the FDA for proliferating infantile hemangioma, created a later patent and regulatory estate around a pediatric liquid product.[4] The product is materially different from the 1986 patent's disclosed concentration framework and commercial formulation architecture.

Later patents associated with pediatric propranolol products may claim:

Specific low-dose propranolol concentrations.
Defined excipient systems.
Flavoring and palatability.
Stability over the labeled shelf life.
Pediatric dosing regimens.
Treatment of infantile hemangioma.
Manufacturing and packaging controls.

Those patents, rather than US 4,600,708, are the relevant barriers for a developer seeking to market a competing pediatric propranolol solution.

Sustained-release propranolol products

Long-acting propranolol products historically relied on release-control technology, capsule systems, coating systems, and dose-delivery architecture. Those patents generally do not overlap claim 1 of Patent 4,600,708 because the older patent requires a liquid oral dosage form.

A liquid modified-release product could create overlap only if it also contains the claimed oil-free lecithin and basic-amino-acid system in the required amounts. The dosage-form distinction remains central.

What generic entry risks exist for a propranolol liquid?

Patent 4,600,708 creates no current generic-entry risk because it is expired. The principal risks for a current liquid propranolol product are regulatory and technical rather than infringement risks under this patent.

Risk category	Assessment under Patent 4,600,708
Composition infringement	No current risk from the expired patent
Taste-masking design-around	Commercially relevant only as prior art
Pediatric formulation patents	Potentially material under later patents
Method-of-use patents	Potentially material for hemangioma indications
FDA exclusivity	Product-specific and separate from the 1986 patent
Bioequivalence	Relevant for an ANDA or other abbreviated pathway
Stability	Relevant to approval and commercial launch
Manufacturing know-how	May remain proprietary even when patent rights expire

A generic manufacturer may use lecithin and basic amino acids without needing a license from the owner of Patent 4,600,708. It must still avoid unexpired later patents and meet FDA requirements for identity, strength, quality, stability, labeling, and bioequivalence or applicable clinical-bridging requirements.[3][5]

How strong was the patent estate for the claimed formulation?

The estate was narrow but commercially directed. Its strength came from the combination of a known active ingredient with a specific taste-masking system and a sensory-performance objective.

Strengths

It targeted a clear formulation problem: propranolol's bitter and anesthetic oral sensation.
Claim 1 captured a range of lecithin concentrations rather than one example.
The basic-amino-acid limitation was broad enough to cover more than the specific dependent-claim embodiments.
The claims did not require a particular flavor or sweetener.

Weaknesses

The claims were limited to liquid dosage forms.
The oil-free lecithin requirement narrowed the excipient universe.
The numerical ranges created design-around opportunities.
The "about" language could create boundary disputes.
The claim's concentration normalization could generate claim-construction disputes.
The patent did not cover the active ingredient, therapeutic indications, or nonliquid dosage forms.
The patent's term expired in 2003.

The patent's remaining value is therefore prior-art and historical rather than exclusionary.

Were there Paragraph IV challenges or litigation involving this patent?

No current Paragraph IV challenge can be based on Patent 4,600,708 because the patent expired long ago. Paragraph IV litigation would have been relevant only while the patent was listed and unexpired against an applicable reference product.

The patent's age also makes it unlikely to affect current approval litigation. Modern disputes involving propranolol products are more likely to concern:

Later pediatric formulation patents.
Hemangeol's indication and product patents.
Patent-listing disputes.
ANDA certifications against later patents.
Settlement agreements between branded and generic manufacturers.
Regulatory exclusivity unrelated to the 1986 formulation patent.

No current settlement agreement, active district-court case, or Federal Circuit proceeding involving Patent 4,600,708 is identified in the patent's present commercial context. Because the patent expired in 2003, any historical litigation would have no current exclusionary effect.

What geographic coverage did the patent have?

US Patent 4,600,708 provided rights only in the United States. Any corresponding foreign applications or patents would have required separate analysis. US expiration did not automatically determine the status of foreign family members.

For a global launch, the relevant review would include:

European patent family members.
Canada.
Japan.
Australia.
Major emerging-market jurisdictions.
National-phase applications, if any.
Foreign term extensions or supplementary protection certificates.

No US patent can block manufacturing or sale in Europe, Canada, or other jurisdictions. Conversely, expiration of the US patent does not establish expiration of a foreign counterpart.

What manufacturing and trade-secret barriers remain?

Patent expiration does not eliminate manufacturing complexity. A commercial liquid containing propranolol hydrochloride, lecithin, and amino acids may still require control of:

Lecithin purity and oxidation.
Dispersion and emulsion behavior.
pH and salt balance.
Uniformity of propranolol concentration.
Microbial preservation.
Container compatibility.
Shelf-life stability.
Taste and mouthfeel.
Scale-up reproducibility.

These factors may be protected through know-how, confidential manufacturing procedures, supplier specifications, and regulatory data. They are not, however, rights conferred by Patent 4,600,708.

Key Takeaways

US Patent 4,600,708 covers a liquid oral propranolol hydrochloride composition with oil-free lecithin and at least one basic amino acid.
Claim 1 requires approximately 8% to 14% lecithin and 0.5% to 10% basic amino acid at the claimed propranolol concentration.
Claims 2 through 4 narrow the amino-acid component to L-histidine, or L-arginine combined with L-histidine hydrochloride.
Claims 3 and 4 are identical in the supplied text.
The patent does not cover propranolol generally, tablets, sustained-release products, or therapeutic methods.
The patent expired in 2003 and presents no current infringement, Paragraph IV, Orange Book, or launch-blocking risk.
Current propranolol liquid-product risk arises principally from later pediatric formulation and method-of-use patents, FDA requirements, and product-specific exclusivity.
The expired patent remains relevant as prior art for taste-masking and excipient selection.

FAQs About US Patent 4,600,708

Does Patent 4,600,708 cover a propranolol solution with histidine but no lecithin?

No. Claim 1 requires both oil-free lecithin and at least one basic amino acid. Histidine alone does not satisfy the full combination.

Can a generic manufacturer use the same lecithin and arginine concept today?

Yes, Patent 4,600,708 is expired. The manufacturer must still screen later unexpired patents and satisfy FDA requirements.

Is L-histidine hydrochloride equivalent to L-histidine free base?

Not automatically. Claim 2 specifies the free base, while claim 3 expressly recites L-histidine hydrochloride. Salt form can affect literal claim scope.

Does the patent cover Hemangeol?

Not as a current enforceable patent right. Hemangeol is a later pediatric propranolol oral solution subject to its own FDA regulatory and patent analysis.

Is a liquid propranolol product at 4.28 mg/mL outside claim 1?

Not necessarily. The answer depends on whether the concentration language is construed as a fixed 10 mg/mL limitation or as a normalized ratio. The patent specification, prosecution history, and any relevant claim-construction authority would control.

References

United States Patent and Trademark Office. (1986). US Patent No. 4,600,708. https://patents.google.com/patent/US4600708
United States Code. (2024). 35 U.S.C. § 154: Contents and term of patent; provisional rights. https://uscode.house.gov/view.xhtml?req=granuleid:USC-prelim-title35-section154
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/approved-drug-products-therapeutic-equivalence-evaluations-orange-book
U.S. Food and Drug Administration. (2017). Hemangeol prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022478s000lbl.pdf
U.S. Food and Drug Administration. (2024). Abbreviated new drug application process. https://www.fda.gov/drugs/types-applications/abbreviated-new-drug-application-anda-approval-process

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Canada	1269619	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,600,708

Summary for Patent: 4,600,708