Details for Patent: 4,138,415

Summary for Patent: 4,138,415

Title:	1,4-Bis(aminoalkylamino)-anthraquinones and leuco derivatives thereof
Abstract:	This disclosure describes 1,4-bis(substituted-amino)-5,6-dihydroxyanthraquinones and 1,4,5-tris(substituted-amino)-8-hydroxyanthraquinones useful as chelating agents, as curing catalysts for epoxy resins, and for inhibiting the growth of transplanted mouse tumors.
Inventor(s):	Keith C. Murdock, Ralph G. Child
Assignee:	Wyeth Holdings LLC
Application Number:	US05/903,292
Patent Claim Types: see list of patent claims	Compound;

United States Drug Patent 4,138,415: Claim Scope, Expiration, Orange Book Status, and Anthraquinone Patent Landscape

US Patent 4,138,415 covers a Markush class of substituted anthraquinone and leuco-anthraquinone compounds, their tautomers, and pharmacologically acceptable acid-addition salts. The expressly claimed compounds include tris-amino anthraquinones and bis-amino dihydroxy anthraquinones. The patent issued on February 6, 1979, and its ordinary 17-year United States patent term expired no later than February 6, 1996, absent an unusual term adjustment or restoration. Because the patent predates the modern patent-term statute, it does not create a current United States exclusivity barrier for generic or competing development.

What compounds does US Patent 4,138,415 protect?

The patent protects substituted anthraquinone compounds containing aminoalkylamino substituents. The permitted side-chain nitrogen substituents are hydrogen, methyl, ethyl, and 2-hydroxyethyl. The claims also cover pharmacologically acceptable acid-addition salts and, in claim 2, tautomers.

The core claim architecture is:

Claim element	Scope
Core	Substituted anthraquinone or leuco-anthraquinone structure
Side-chain substituents	Aminoethyl-derived groups bearing hydrogen, methyl, ethyl, or 2-hydroxyethyl substituents
Ring substituents	Hydrogen or hydroxy, subject to the stated hydrogen/hydroxy proviso
Salt forms	Pharmacologically acceptable acid-addition salts
Tautomer coverage	Expressly included in claim 2
Claim type	Composition-of-matter claims
Express therapeutic use claims	None in the supplied claims
Manufacturing claims	None in the supplied claims

The patent’s protection is directed primarily to chemical identity. It does not, based on the supplied claims, separately claim a dosage regimen, formulation, method of treatment, manufacturing process, pharmaceutical composition, or delivery system.

How broad is the Markush coverage?

Claims 1 and 2 use a Markush structure. Each variable may take one of several defined substituent values, creating a potentially large number of covered analogues.

At a high level, the claims cover:

• amino substituents with primary, secondary, or tertiary nitrogen substitution;
• methyl-, ethyl-, and 2-hydroxyethyl-substituted side chains;
• hydroxy-substituted anthraquinone ring systems;
• reduced or leuco forms;
• tautomeric forms;
• acid-addition salts of otherwise covered bases.

The claims are broad in chemical class but narrower than a generic “all aminoanthraquinones” claim. A molecule would need to fit the claimed ring substitution pattern, the permitted aminoalkyl side chains, and the hydrogen/hydroxy relationship imposed by the proviso.

What are the specifically claimed compounds in US 4,138,415?

Claims 3 through 6 identify four compounds within the broader genus.

Claim	Compound identified in the patent	Key structural characteristics
3	1,4,5-Tris[(2-dimethylaminoethyl)amino]-8-hydroxyanthraquinone	Three dimethylaminoethylamino substituents and one hydroxy substituent
4	1,4-Bis[(2-aminoethyl)amino]-5,6-dihydroxyanthraquinone	Two primary aminoethylamino substituents and two ring hydroxy groups
5	Leuco-1,4,5-tris[(2-diethylaminoethyl)amino]-8-hydroxyanthraquinone	Reduced anthraquinone system with three diethylaminoethylamino substituents
6	Leuco-1,4-bis[(2-ethylaminoethyl)amino]-5,6-dihydroxyanthraquinone	Reduced system with two ethylaminoethylamino substituents and two hydroxy groups

The claims supplied in the request omit the chemical drawings represented by ##STR5## through ##STR8##. That omission prevents a complete structure-by-structure reconstruction of every positional limitation. The textual limitations nevertheless establish the principal chemical boundaries.

How should claims 1 and 2 be interpreted?

Claim 1 covers the oxidized anthraquinone compounds identified by the first structural formula, together with their acid-addition salts. Claim 2 covers the second structural formula, its tautomers, and acid-addition salts.

The key legal distinctions are:

1. Claim 1 does not expressly recite tautomers.
2. Claim 2 expressly adds tautomer coverage.
3. Both claims impose a proviso that one of R3 and R4 must be hydrogen, while they may not both be hydrogen.
4. The salt language expands coverage beyond free-base compounds.
5. The claims are composition claims, so infringement would generally turn on whether an accused molecule falls within the recited structure, not on whether it is sold under a particular therapeutic indication.

The proviso is important. It limits the number and position of ring substituents and prevents a structure in which both relevant positions are simultaneously non-hydrogen in the manner excluded by the claim. A product that differs only by protonation may remain within the claim because acid-addition salts are expressly included.

Do the claims cover formulations or methods of use?

Not on the supplied claim language. The claims identify compounds, tautomers, and salts. They do not expressly recite:

• tablets, capsules, injectables, or other dosage forms;
• excipients or formulation ratios;
• particle size or polymorphs;
• pharmaceutical compositions;
• cancer treatment methods;
• dose levels or treatment schedules;
• combination therapy;
• manufacturing or purification steps.

A later patent could separately protect one of those categories, but US 4,138,415 itself does not do so in the claims provided.

When did US Patent 4,138,415 lose exclusivity?

US Patent 4,138,415 issued on February 6, 1979. Under the pre-1995 United States patent-term regime, the ordinary term was 17 years from issuance. On that basis, the patent expired on February 6, 1996.[1][2]

Event	Date or status
Patent issued	February 6, 1979
Ordinary term basis	17 years from issue
Ordinary expiration	February 6, 1996
Current enforceability	No live patent term under the ordinary calculation
Current generic blocking effect	None from this patent

The Uruguay Round Agreements Act changed the term for later-filed United States applications to 20 years from the earliest effective nonprovisional filing date. That change does not retroactively convert an issued 1979 patent into a later-expiring patent.[2]

Patent-term adjustment generally applies to applications subject to the modern term regime. It does not ordinarily extend a pre-1995 patent beyond the applicable pre-1995 term. Patent-term extension for regulatory review also has limited statutory availability and would not be assumed without a specific USPTO or FDA record.[3]

What is the Orange Book status of US Patent 4,138,415?

US Patent 4,138,415 is not, based on the supplied claims and the drug-identification record, a current Orange Book exclusivity asset. The Orange Book lists patents and exclusivities associated with approved drug products, but a chemical patent does not automatically appear in the Orange Book merely because it claims a pharmacologically active compound.[4]

The supplied patent does not identify:

• an FDA-approved drug product;
• a New Drug Application number;
• a brand name;
• a listed dosage form;
• a listed method of use;
• an approved active ingredient under a commercial name.

Accordingly, the practical Orange Book position is:

Orange Book issue	Assessment
Current listed patent barrier	None established
Current Hatch-Waxman patent certification exposure	None based on this expired patent alone
Product-specific Orange Book listing	Not established from the patent claims
Method-of-use listing	No method claim supplied
Formulation listing	No formulation claim supplied
Generic approval relevance	Expired compound patent does not block approval

A separate later patent could have been listed against an approved product, but that would require a product-specific record and cannot be inferred from US 4,138,415.

Are Paragraph IV challenges relevant to this patent?

A Paragraph IV certification is not commercially relevant to an expired patent. Under the Hatch-Waxman framework, an ANDA applicant may certify that a listed patent is invalid, unenforceable, or will not be infringed. But a patent that expired in 1996 cannot prevent approval or commercial launch today.[5]

The relevant conclusion is:

• no current Paragraph IV launch event is needed to clear this patent;
• no 30-month stay can be based on an expired patent;
• an ANDA applicant would not ordinarily need to litigate this patent as a live barrier;
• any historical Paragraph IV activity would have no current blocking effect.

The same analysis applies to the patent’s salt and tautomer coverage. Expiration removes the enforceability of every claim, including dependent claims and expressly covered salt forms.

Which companies are challenging US 4,138,415?

No company-specific challenge is necessary to enter around the patent today because the patent term has expired. A current competitor would normally rely on expiration rather than pursue a validity challenge.

The patent may still appear in historical compound or oncology patent searches, but historical ownership, assignment, prosecution, or litigation would not change the present expiration analysis. A live dispute could concern a later patent covering a particular product, formulation, process, or use. Such a dispute would be distinct from US 4,138,415.

How does this patent compare with anthracenedione patents for mitoxantrone and related drugs?

US 4,138,415 belongs to the broader anthraquinone and anthracenedione research field. It should not be treated as the principal composition patent for every later anthracenedione drug.

Mitoxantrone, for example, has a different molecular structure and was associated with separate patent protection. Mitoxantrone is a 9,10-anthracenedione bearing hydroxy and hydroxyethylaminoethylamino substituents, rather than the specific tris-amino and dihydroxy structures recited in the claims supplied here.[6]

Category	US 4,138,415	Mitoxantrone-type patent estate
Core chemistry	Substituted anthraquinone/leuco-anthraquinone compounds	9,10-Anthracenedione derivative
Claimed side chains	Hydrogen, methyl, ethyl, or 2-hydroxyethyl variants	Hydroxyethyl-substituted aminoethyl chains
Express claim focus	Compounds, tautomers, salts	Drug-specific compound and potentially related uses/formulations
Current term	Expired	Original patents also expired, but later estate must be reviewed separately
Orange Book relevance	Not established	Product-specific analysis required
Biosimilar relevance	None	None, because these are small molecules

The patent is therefore relevant as a historical chemical genus, not as a current patent covering mitoxantrone, doxorubicin, pixantrone, or other anthracycline-class products without a claim chart showing literal or equivalent coverage.

What patent landscape surrounds these compounds?

The relevant landscape has four layers.

Core composition patents

These claim the active chemical entities or broad chemical genera. US 4,138,415 is in this category. Because it expired decades ago, it has historical rather than current blocking value.

Process and manufacturing patents

Later patents could cover:

• regioselective substitution of the anthraquinone nucleus;
• protection and deprotection of aminoethyl side chains;
• reduction to leuco forms;
• oxidation-state control;
• salt formation;
• crystallization and purification;
• scalable manufacturing conditions.

A process patent could remain relevant after a compound patent expires if it was filed later and has an unexpired term. It would not restore exclusivity to the expired compound claims.

Formulation patents

A formulation estate could cover:

• injectable solutions;
• sterile lyophilized products;
• pH-controlled compositions;
• stabilizers and antioxidants;
• nanoparticle or liposomal delivery;
• sustained-release systems;
• fixed-dose combinations.

No such claims appear in the supplied patent.

Method-of-use patents

Separate patents could claim treatment of:

• hematologic malignancies;
• solid tumors;
• drug-resistant cancers;
• hypoxic tumors;
• particular biomarker-defined populations;
• combination treatment with another anticancer agent.

US 4,138,415 does not provide method-of-use protection on the claim language supplied.

Is there biosimilar risk for these compounds?

No. Biosimilar law applies to biological products, not conventional synthetic anthraquinone small molecules.[7] A competitor would use the generic-drug framework, including an ANDA where applicable, or a full 505(b)(2) application depending on the product and development strategy.

The principal regulatory issues would be chemical identity, impurity profile, stereochemistry if relevant, solid-state properties, analytical comparability, safety, and clinical bridging. Biosimilar interchangeability and the FDA Purple Book are not applicable.

What generic launch scenarios exist?

Because the patent expired in 1996, a competitor could pursue several routes:

1. An ANDA, if an FDA reference-listed drug and a suitable dosage form exist.
2. A 505(b)(2) application, if the proposed product differs materially from an established reference product or no suitable reference pathway exists.
3. A full NDA, if the compound has no adequate reference product or the intended use requires independent clinical development.
4. Research or licensing commercialization outside the United States, subject to local patent and regulatory review.

The main remaining barriers would be regulatory, commercial, manufacturing, toxicological, and clinical. They would not arise from enforceable claims in US 4,138,415.

How strong is the patent estate for US 4,138,415?

As a current United States estate, it is weak because the only identified patent is expired. As a historical chemical patent, its strength was materially greater because the independent claims covered a defined family of compounds and their salts, while dependent claims identified specific molecules.

Strength factor	Assessment
Composition-of-matter coverage	Historically meaningful
Markush breadth	Moderate to broad within the defined substituent set
Salt coverage	Express
Tautomer coverage	Express in claim 2
Formulation coverage	None shown
Method-of-use coverage	None shown
Manufacturing coverage	None shown
Current term	Expired
Current enforcement value	None
Design-around importance	Historical only
Biosimilar relevance	None

The principal claim-construction risk is structural: the missing chemical drawings are necessary to determine exact ring positions, oxidation state, and attachment points. The textual descriptions support a broad analysis, but a definitive infringement opinion would require the issued patent images and a molecule-by-molecule claim chart.

What litigation or settlement agreements affect the patent?

No current litigation, settlement, or license can be inferred from the supplied claims. More importantly, any settlement involving this patent would not revive its expired term or create a current statutory exclusion period.

A historical license may have commercial significance for ownership or royalty accounting, but it would not prevent present-day development unless it also covers separate, unexpired intellectual property. A current freedom-to-operate review should therefore distinguish:

• US 4,138,415, which is expired;
• later continuation, divisional, or related patents;
• process patents;
• formulation patents;
• method-of-use patents;
• regulatory exclusivities;
• contractual restrictions.

Key Takeaways

• US Patent 4,138,415 claims substituted anthraquinone and leuco-anthraquinone compounds, tautomers, and acid-addition salts.
• Claims 1 and 2 are Markush composition claims with defined aminoethyl side-chain substitutions.
• Claims 3 through 6 identify four specific tris-amino and bis-amino dihydroxy compounds.
• The patent issued February 6, 1979, and its ordinary patent term expired February 6, 1996.
• The patent does not, on the supplied language, claim formulations, methods of treatment, manufacturing processes, or delivery systems.
• It is not a current Orange Book barrier based on the information provided.
• Paragraph IV litigation against this patent has no current launch-blocking effect.
• Biosimilar analysis is irrelevant because the claimed compounds are synthetic small molecules.
• Any present competitive risk must come from later patents, regulatory exclusivity, manufacturing know-how, or commercial factors.
• The omitted structural drawings prevent a final atom-by-atom claim chart, but they do not change the patent’s expired status.

FAQs

Does US 4,138,415 cover anthracycline antibiotics such as doxorubicin?

No conclusion of coverage follows from the supplied claims. Doxorubicin has a substantially different tetracyclic anthracycline structure and glycoside substituent. A chemical comparison and complete claim chart would be required.

Can a company commercialize a salt of a compound claimed in US 4,138,415?

Yes, the patent’s claims include pharmacologically acceptable acid-addition salts, but those claims expired. A commercial product would still require clearance of later patents and FDA approval requirements.

Does the patent cover leuco-anthraquinone prodrugs?

Claims 2, 5, and 6 expressly address leuco compounds or structures associated with the second formula and include tautomers. That historical coverage has no current United States exclusivity effect because the patent expired.

Could a later formulation patent block launch of one of these compounds?

Yes. Expiration of a compound patent does not eliminate separately issued patents covering a formulation, dosage regimen, manufacturing process, crystalline form, or therapeutic use.

Is a patent license needed to practice US 4,138,415 today?

No license is required solely because of the expired United States patent. Contractual obligations, foreign patents, or later unexpired patents could create separate restrictions.

References

1. United States Patent No. 4,138,415. (1979). Anthraquinone derivatives. United States Patent and Trademark Office. https://patents.google.com/patent/US4138415A/en
2. 35 U.S.C. § 154. Patent term and rights. https://uscode.house.gov/view.xhtml?req=granuleid:USC-prelim-title35-section154
3. United States Patent and Trademark Office. (2024). Patent term adjustment and patent term extension. https://www.uspto.gov/patents/laws/patent-term-calculator
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/approved-drug-products-therapeutic-equivalence-evaluations-orange-book
5. 21 U.S.C. § 355(j). Abbreviated new drug applications and patent certifications. https://uscode.house.gov/view.xhtml?req=granuleid:USC-prelim-title21-section355
6. United States Patent No. 4,197,249. (1980). Anthracenedione derivatives. United States Patent and Trademark Office. https://patents.google.com/patent/US4197249A/en
7. U.S. Food and Drug Administration. (2024). Biosimilar and interchangeable products. https://www.fda.gov/drugs/therapeutic-biologics-applications-bla/biosimilar-and-interchangeable-products

Drugs Protected by US Patent 4,138,415

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 4,138,415

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	225884
Austria	359484
Austria	A590678
Australia	3877678
Australia	527103