Details for Patent: 4,138,581

Summary for Patent: 4,138,581

Title:	3(Hydroxy or hydroxymethyl)-4(hydroxy)-α-(aminomethyl)benzyl alcohols
Abstract:	Mono-, di- and tri-esters of 3-(hydroxy or hydroxymethyl)-4-hydroxy-α-(aminomethyl)benzyl alcohols, obtained by methods involving reduction of the corresponding mono- and di-ester ketones, are useful for producing sympathomimetic effects, such as bronchodilation, of long duration with low cardiovascular stimulating effect, in warm-blooded mammals.
Inventor(s):	Hiroaki Minatoya, Benjamin F. Tullar, Walter D. Conway
Assignee:	Aventis Pharmaceuticals Inc
Application Number:	US05/654,700
Patent Claim Types: see list of patent claims	Compound;

United States Drug Patent 4,138,581: Claim Scope, Expiration, and Patent Landscape

US Patent 4,138,581 is an expired composition-of-matter patent covering substituted amino-alcohol esters structurally related to phenolic beta-adrenergic agonists. Its claims protect broad families of monoesters, diesters, mixed esters, and acid-addition salts, with narrower claims directed to p-toluyl, m-toluyl, benzoyl, acetyl, and related derivatives.

The patent’s 17-year United States term expired on February 6, 1996, based on its February 6, 1979 issue date. It therefore does not create a current U.S. patent barrier to generic manufacture, formulation, sale, or clinical development of compounds falling within the claimed structures. The patent also predates the modern Orange Book and Paragraph IV framework and is not, by itself, a current Orange Book-listed patent.

What does US Patent 4,138,581 cover?

The patent covers esters of substituted benzyl alcohols containing an aminoalkyl or substituted aminoalkyl side chain. The core structural elements are:

Structural element	Scope in the claims
Aromatic nucleus	3,4-dihydroxybenzyl alcohol or 3-hydroxymethyl-4-hydroxybenzyl alcohol
Basic side chain	Alpha-amino- or N-substituted aminomethyl group
Amine substituent R	Hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl
Side-chain substituent R'	Hydrogen or ethyl in claims 1-28; hydrogen or C1-C3 alkyl in claims 29-46
Ester groups	One or more acyl substituents on the phenolic or hydroxymethyl oxygen atoms
Aromatic acyl groups	Benzoyl, substituted benzoyl, toluyl, halo-benzoyl, trifluoromethylbenzoyl, and related groups
Other acyl groups	Alkanoyl, alkenoyl, cycloalkylcarbonyl, adamantanecarbonyl, phenoxyacetyl, and naphthalenecarbonyl
Salt form	Pharmaceutically acceptable acid-addition salts

The central claim strategy is to cover not only a single active compound, but also a substantial chemical space around it. The patent uses a combination of broad genus claims, narrower dependent claims, and specific compound claims.

How are the 46 claims organized?

The claims divide into two principal structural series.

Claims 1-28: 3,4-dihydroxybenzyl alcohol derivatives

Claims 1-28 cover compounds in which the aromatic nucleus is a 3,4-dihydroxybenzyl alcohol framework. The phenolic hydroxyl groups may be:

• Both esterified;
• One esterified and one unesterified;
• Substituted with different acyl groups; or
• Substituted with the same acyl group.

The key independent claims are claims 1, 5, 10, 15, 18, 24, and 28.

Claims 29-46: 3-hydroxymethyl-4-hydroxy derivatives

Claims 29-46 cover a second core in which one aromatic hydroxyl position is replaced by a hydroxymethyl substituent. This creates a more heavily functionalized benzyl alcohol structure with additional esterification options.

The second series includes broad genus claims and specific compounds, including:

• 3,4-bis(p-toluyloxy)-alpha-[(isopropylamino)methyl]benzyl alcohol methanesulfonate;
• 3-benzoyloxy-4-p-toluyloxy-alpha-[(tert-butylamino)methyl]benzyl alcohol methanesulfonate;
• 3,4-bis(benzoyloxy)-alpha-[(tert-butylamino)methyl]benzyl alcohol hydrochloride;
• 3,4-bis(p-toluyloxy)-alpha-[(tert-butylamino)methyl]benzyl alcohol methanesulfonate;
• 3,4-bis(m-toluyloxy)-alpha-[(tert-butylamino)methyl]benzyl alcohol methanesulfonate;
• 3-acetoxy-4-p-toluyloxy-alpha-[(tert-butylamino)methyl]benzyl alcohol methanesulfonate; and
• 3-hydroxy-4-m-toluyloxy-alpha-[(tert-butylamino)methyl]benzyl alcohol methanesulfonate.

What compounds are most directly protected?

The most commercially relevant claim targets are the compounds with tert-butylamino or isopropylamino substitution and aromatic ester groups.

Tert-butylamino compounds

Claims 7, 9, 10-12, 15-20, 24, 27, and 34-46 repeatedly narrow toward tert-butylamino derivatives. The patent particularly emphasizes:

• Bisbenzoyl compounds;
• Bis-p-toluyl compounds;
• Bis-m-toluyl compounds;
• Mixed benzoyl/toluyl compounds;
• Acetyl/toluyl compounds; and
• Monoester compounds retaining a free phenolic hydroxyl group.

These structures are consistent with a prodrug-oriented strategy. Esterifying phenolic hydroxyl groups can alter lipophilicity, absorption, duration of action, and metabolic conversion to the underlying phenolic beta-agonist.

Isopropylamino compounds

The claims also cover isopropylamino derivatives, including the specific compound identified in claim 28:

3,4-bis(p-toluyloxy)-alpha-[1-(isopropylamino)ethyl]benzyl alcohol hydrochloride.

This compound has an ethyl-substituted side chain at the alpha carbon and an isopropyl-substituted amine. It falls within the patent’s defined R and R' variables.

What is the broadest independent claim?

Claim 1 is the principal broad genus claim for the first structural series. It covers an ester of a 3,4-dihydroxy-alpha-(amino- or N-substituted aminomethyl)benzyl alcohol where:

1. R may be hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl;
2. R' may be hydrogen or ethyl;
3. Y may be a broad set of acyl groups;
4. Y1 and Y2 may be hydrogen or acyl groups;
5. At least one of Y and Y1 must be a phenyl-derived acyl group of the defined type; and
6. The compound may be present as a pharmaceutically acceptable acid-addition salt.

The requirement that at least one of Y and Y1 be a Z-CnH2n-CO group is a material limitation. A compound having only aliphatic acyl groups would fall outside claim 1, even if all other structural elements matched.

Claim 29 is the corresponding broad genus claim for the 3-hydroxymethyl-4-hydroxy series.

What are the key narrowing limitations?

The dependent claims narrow the scope through several recurring variables.

Acyl-group limitations

Claims 2-5 and 10-12 focus on compounds where both ester groups are aromatic acyl groups. Claim 11 narrows to alkylbenzoyl, and claim 12 identifies toluyl as the preferred alkylbenzoyl group.

Claims 13-20 cover mixed esters, with one aromatic acyl group and one alkanoyl group. Claim 20 narrows the aromatic group to toluyl.

Claims 21-27 cover monoesters in which one of Y or Y1 is an aromatic acyl group and the other is hydrogen.

Linker limitations

The broad claims allow n to equal zero, one, or two in the Z-CnH2n-CO group. The narrower claims frequently require n to equal zero. That limitation converts a phenylacetyl or phenylpropionyl-type structure into a directly attached benzoyl-type structure.

Amine limitations

The claims cover unsubstituted amino groups as well as N-substituted amino groups. The specific compounds concentrate on:

• Isopropylamino;
• tert-Butylamino; and
• Related C1-C4 alkylamino substituents.

A compound with a larger N-substituent would generally fall outside the express R definition unless another claim construction or doctrine applied.

Do the claims cover formulations or methods of use?

No. The claims provided are composition claims. They do not expressly claim:

• Tablets;
• Capsules;
• Inhalation formulations;
• Nebulizer solutions;
• Transdermal systems;
• Injectable formulations;
• Controlled-release dosage forms;
• Treatment of asthma or chronic obstructive pulmonary disease;
• Treatment of bronchospasm;
• Dosage regimens;
• Combination therapy; or
• Manufacturing processes.

The claims protect the chemical compounds and their acid-addition salts. A formulation containing a claimed compound could have been commercially relevant during the patent term, but the patent does not independently claim the formulation architecture.

What is the patent’s expiration date?

The patent issued on February 6, 1979. For a U.S. patent subject to the pre-Uruguay Round patent term rules, the term generally ran for 17 years from issue. On that basis, US 4,138,581 expired on February 6, 1996.[1]

Event	Date
U.S. patent issue	February 6, 1979
Statutory term under 17-year issue-based rule	17 years
Estimated expiration	February 6, 1996
Current enforceability	Expired
Current Paragraph IV significance	None as an enforceable patent
Current Orange Book barrier	None attributable to this expired patent

The patent cannot support a current U.S. infringement action. It may still have historical value in prior-art analysis, freedom-to-operate reviews, prosecution history research, and assessment of obviousness or written-description issues involving related compounds.

What is the Orange Book status of US 4,138,581?

US 4,138,581 is not a current Orange Book patent barrier. The FDA Orange Book lists patents submitted for approved drug products, including applicable substance, formulation, and method-of-use patents.[2] The patent’s age and expired status make it commercially irrelevant as an exclusivity listing.

The patent also does not create a present-day Paragraph IV challenge opportunity. Paragraph IV certifications apply when an ANDA applicant asserts that a listed patent is invalid, unenforceable, or not infringed. An expired patent does not block approval on that basis.[3]

Were biosimilar or generic challenges relevant?

Biosimilar risk is not relevant. The claims cover small-molecule chemical compounds, not biological products. The applicable competitive pathway would have been an ANDA or, depending on the product and regulatory history, an NDA or 505(b)(2) application.

Current generic risk is also not constrained by this patent. A modern applicant would instead need to evaluate:

• Later patents covering a marketed active ingredient;
• Formulation patents;
• Salt, polymorph, or solid-state patents;
• Process patents;
• Regulatory exclusivity;
• Trade-secret manufacturing controls;
• Patent rights in the target country; and
• Any patent estate associated with a specific commercial product.

Those rights cannot be inferred from US 4,138,581 alone.

What is the patent’s geographic coverage?

The patent has U.S. territorial scope only. It does not establish protection in:

• Europe;
• Canada;
• Japan;
• Australia;
• China;
• India; or
• Other jurisdictions.

Related foreign applications may have been filed, but foreign rights require separate family-level review. The U.S. patent number cannot establish the existence, status, or expiration of corresponding foreign patents.

For current product development, geographic risk would depend on the relevant national patent families, supplementary protection certificates, national-phase applications, and any surviving improvement patents.

How strong was the patent estate?

Strengths

The patent had several features associated with a potentially meaningful composition-of-matter estate:

• Broad coverage of the amino-alcohol scaffold;
• Multiple permissible N-substituents;
• Broad acyl-group definitions;
• Coverage of both diesters and monoesters;
• Coverage of mixed ester combinations;
• Express salt coverage;
• Specific claims to commercially recognizable toluyl derivatives; and
• A second structural series covering hydroxymethyl-substituted analogues.

The broad genus claims could have presented substantial freedom-to-operate risk for compounds closely matching the disclosed scaffold during the patent term.

Weaknesses

The estate also had limiting features:

• The claims require a defined phenyl-derived acyl group;
• The R and R' variables are confined to relatively narrow substituent classes;
• The claims are composition-focused and do not cover use or formulation inventions;
• The patent is now expired;
• The specific compounds would have been vulnerable to validity scrutiny based on enablement, written description, obviousness, and claim-construction issues; and
• The broad genus language may not automatically reach structurally remote compounds without a close match to every limitation.

Patent strength must be assessed claim by claim. A compound is outside the claims if it lacks any required element, such as the specified amino-alcohol core, the permitted R group, or the required aromatic acyl substitution.

Which claim-design strategies would avoid the expired patent?

Because the patent has expired, design-around analysis is historical rather than an active U.S. enforcement issue. Structurally, compounds could have avoided the literal scope by changing one or more required limitations, including:

1. Replacing the 3,4-dihydroxybenzyl alcohol core with a different substitution pattern;
2. Removing the required phenyl-derived acyl group;
3. Using an N-substituent outside hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl;
4. Using an alpha substituent outside hydrogen or ethyl where applicable;
5. Employing a non-permitted acyl group;
6. Altering the hydroxymethyl-substituted second series; or
7. Developing a non-ester prodrug or a different chemical class.

These changes would have required a separate analysis of other patents, prior art, pharmacology, toxicity, and regulatory suitability.

What patent litigation or settlement agreements affect US 4,138,581?

No current litigation or settlement agreement can be inferred from the claims alone. Since the patent expired in 1996, any historical litigation would no longer create an active U.S. exclusivity barrier. A litigation review would need to distinguish:

• Infringement suits filed during the patent term;
• Declaratory-judgment actions;
• Patent interference or opposition proceedings;
• ANDA litigation;
• Assignments and licenses;
• Terminal disclaimers; and
• Post-expiration royalty or settlement obligations.

The claim text does not identify a licensee, patent assignment, commercial product, or settlement partner.

What commercial products were protected?

The supplied claims do not identify a brand name, active pharmaceutical ingredient designation, FDA approval number, sponsor, or marketed product. The compounds appear to be substituted beta-adrenergic amino-alcohol ester candidates, but a commercial product cannot be reliably assigned solely from the claim language.

The patent’s commercial value would have depended on whether one of the claimed compounds was selected for development and whether subsequent patents covered the selected molecule, dosage form, manufacturing method, or clinical use.

Key Takeaways

• US 4,138,581 is a composition-of-matter patent covering substituted amino-alcohol esters and acid-addition salts.
• Claims 1-28 cover 3,4-dihydroxybenzyl alcohol derivatives.
• Claims 29-46 cover a related 3-hydroxymethyl-4-hydroxy series.
• The principal protected structures include bisbenzoyl, bis-toluyl, mixed benzoyl/toluyl, acetyl/toluyl, and monoester compounds.
• The patent covers tert-butylamino and isopropylamino derivatives, among other permitted amine substituents.
• The patent issued February 6, 1979, and its 17-year U.S. term expired February 6, 1996.[1]
• It is not a current U.S. patent barrier and has no present Paragraph IV or biosimilar significance.
• The claims do not cover formulations, methods of treatment, dosage regimens, or manufacturing processes.
• Any current commercial risk would arise from later patents, not from US 4,138,581 itself.
• Foreign patent rights cannot be established from the U.S. patent number alone.

FAQs

Does US Patent 4,138,581 still block generic entry?

No. The patent’s U.S. term expired in 1996. It cannot currently block an ANDA applicant or support a U.S. infringement claim.

Does the patent claim terbutaline itself?

No. The claims cover esterified amino-alcohol derivatives and salts. They do not, on their face, claim the unmodified terbutaline molecule.

Are p-toluyl derivatives specifically claimed?

Yes. Claims 12, 20, 28, and 40-45 expressly identify or narrow toward p-toluyl derivatives. The claims also cover m-toluyl and broader substituted benzoyl structures.

Can a patent-expired compound still face regulatory exclusivity?

Yes, in principle, but regulatory exclusivity would arise from a later FDA approval and statutory exclusivity period, not from US 4,138,581. The expired patent itself provides no current exclusivity.

Does the patent cover a pharmaceutical salt?

Yes. The claims expressly include pharmaceutically acceptable acid-addition salts, including hydrochloride and methanesulfonate forms identified in the specific compound claims.

References

1. United States Patent and Trademark Office. (1979). U.S. Patent No. 4,138,581. Washington, DC: U.S. Department of Commerce.

2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. Silver Spring, MD: U.S. Department of Health and Human Services.

3. U.S. Food and Drug Administration. (2024). Abbreviated new drug application submissions: Patent certifications and exclusivity. Silver Spring, MD: U.S. Department of Health and Human Services.

Drugs Protected by US Patent 4,138,581

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

International Family Members for US Patent 4,138,581

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	300762
Belgium	748178
Canada	923132
Switzerland	522589