US Patent 5,457,105: Claim Scope, Expiration, Orange Book Status, and Quinazoline Patent Landscape

US Patent 5,457,105 is an early Zeneca quinazoline patent directed to substituted 4-anilinoquinazoline compounds, pharmaceutical compositions, anticancer methods, and receptor tyrosine kinase inhibition. Its claims cover a broad chemical genus, numerous named species, and therapeutic uses that overlap with the development history of epidermal growth factor receptor, or EGFR, inhibitors.

The patent issued on October 10, 1995. Applying the pre-URAA patent-term rule of 17 years from issuance, its ordinary US term expired on October 10, 2012, absent an unusual terminal disclaimer or term adjustment. The patent is therefore not a current US blocking right. Its commercial significance is historical: it helped establish the 4-anilinoquinazoline platform later used in EGFR-directed oncology drugs.

What compounds does US Patent 5,457,105 protect?

The independent chemical claims cover a quinazoline nucleus substituted at the 4-position with one or more anilino groups and substituted at other ring positions with a large range of chemical groups.

The claim architecture has four principal elements:

Claim element	Scope
Core scaffold	Quinazoline
4-position substituent	Anilino group, generally bearing zero, one, or two R2 substituents
Quinazoline-ring substituents	One to three R1 groups, depending on the claim
Chemical form	Free compound or pharmaceutically acceptable salt

The broadest chemical claims are claims 1 and 2. They define R1 and R2 through extensive Markush lists. The permitted R1 groups include hydroxy, amino, alkoxy, alkyl, alkylamino, morpholino, piperidino, alkylthio, alkoxyalkyl, aminoalkyl, alkoxyalkoxy, acylamino, benzamido, benzenesulfonamido, and related substituents.

R2 is principally an aniline-ring substituent. The claim permits hydrogen, hydroxy, halogen, trifluoromethyl, amino, nitro, cyano, alkyl, alkoxy, alkylamino, dialkylamino, alkylthio, alkylsulfinyl, and alkylsulfonyl groups. Claim 2 adds certain acylamino, acyl, and benzamido options.

The patent therefore protects a chemical genus rather than a single clinical candidate.

How broad are claims 1 through 9?

Claims 1 through 9 form a descending hierarchy from broad genus claims to selected species.

Claims 1 and 2: broad Markush genus

Claims 1 and 2 are the principal composition-of-matter claims. They cover:

4-anilinoquinazolines;
multiple substitution patterns on the quinazoline ring;
substituted aniline rings;
free bases and pharmaceutically acceptable salts;
one, two, or three R1 substituents, depending on the claim.

Claim 2 is similar to claim 1 but expands the R2 list to include additional acylamino, acyl, and benzamido substituents.

The exclusion proviso removes several known or specifically identified compounds, including:

4-(4'-hydroxyanilino)-6-methoxyquinazoline;
4-(4'-hydroxyanilino)-6,7-methylenedioxyquinazoline;
6-amino-4-(4'-aminoanilino)quinazoline;
4-anilino-6-methylquinazoline;
4-anilino-6,7-dimethoxyquinazoline; and
specified hydrochloride salts.

These exclusions appear designed to address prior-art compounds and preserve novelty over previously disclosed quinazoline structures.

Claims 3 and 4: narrowed substituent classes

Claims 3 and 4 narrow the R1 definition. Claim 4 is materially more restrictive because it limits m to one or two and removes many of the more complex side chains listed in claim 1.

These claims are more vulnerable to design-around strategies because a competing compound can often avoid them by changing:

the number of ring substituents;
the position of a methoxy or hydroxy group;
the linker length;
the identity of the terminal amine; or
the aniline-ring substitution pattern.

Claim 5: enumerated substituent list

Claim 5 replaces much of the generic Markush terminology with specific substituents, such as methoxy, ethoxy, propoxy, methylenedioxy, dimethylamino, morpholinomethyl, methoxyethoxymethyl, acetamido, benzamido, and methoxyacetamido.

This claim is narrower in literal scope but may be stronger against products that fall squarely within its expressly listed examples.

Claims 6 and 8: defined combination classes

Claims 6 and 8 identify specific combinations of R1 and R2 groups. Examples include:

6,7-dimethoxy;
6,7-diethoxy;
6-hydroxy-7-methoxy;
7-hydroxy-6-methoxy;
6-amino-7-methoxy;
6-methoxy-7-isopropoxy;
6,7-methylenedioxy;
6-(2-methoxyethoxy);
6-acetamido;
6-(2-methoxyethylamino);
3'-chloro-4'-fluoro;
3',4'-dichloro;
3'-trifluoromethyl;
3'-nitro; and
3'-methyl aniline substitution.

These claims are important for identifying the patent's preferred chemical space. The patent does not merely claim arbitrary quinazolines. It concentrates on substituent combinations associated with kinase inhibition and anticancer activity.

Claims 7 and 9: selected species

Claim 7 covers ten expressly named quinazoline compounds. Claim 9 covers three additional compounds, including:

6,7-di-(2-methoxyethoxy)-4-(3'-methylanilino)quinazoline;
6-dimethylamino-4-(3'-methylanilino)quinazoline; and
6-benzamido-4-(3'-methylanilino)quinazoline.

Species claims generally provide clearer infringement analysis than broad genus claims because the structural comparison is direct. They may also provide fallback positions if a genus claim is challenged for lack of novelty or inadequate written description.

What therapeutic uses are covered?

Claims 10 through 12 cover pharmaceutical compositions and general anticancer treatment.

Claims 10 and 11 recite compositions containing a compound within the quinazoline genus. Claim 11 expands the R2 definition to include acylamino, acyl, and benzamido substituents.

Claim 12 covers administering a claimed compound to produce an anticancer effect in a warm-blooded animal. The claim is not limited to a particular tumor type, biomarker, dosing regimen, or route of administration.

Claims 13 and 14 identify additional species and a specific compound:

6-amino-4-(3'-methylanilino)quinazoline.

Claims 15 through 22 move into receptor tyrosine kinase-related methods. They cover:

anticancer treatment of receptor tyrosine kinase-sensitive cancers;
treatment of leukemia, breast, lung, colon, rectal, stomach, prostate, bladder, pancreatic, and ovarian cancers;
antiproliferative treatment;
inhibition of receptor tyrosine kinase;
treatment of malignant-cell proliferation; and
treatment of diseases mediated in whole or in part by receptor tyrosine kinase.

Claims 23 through 29 cover individual species in anticancer methods, including acetamido, methoxyethylamino, methoxyethoxy, chloroacetamido, methylamino, and chloro-fluoro anilino derivatives.

What is the relationship between the composition and method claims?

The composition claims are potentially broader from a product perspective because they attach to the compound itself. A composition-of-matter claim can cover manufacture, sale, importation, and use of the claimed compound, subject to claim construction and validity.

The method claims are narrower in a different way. They require performance of the claimed therapeutic method. A compound may fall within a method claim only when used according to the claimed treatment purpose. Claims 15 through 22 also require a receptor tyrosine kinase-related disease, mechanism, or therapeutic effect.

The patent includes substantial overlap among the method claims. Claims 15 through 22 repeat similar therapeutic concepts with different disease or mechanism language. Such redundancy is common in older pharmaceutical patents and provides multiple infringement theories, but it does not extend the patent term.

Which compounds are most commercially relevant?

The patent's commercially relevant chemistry is the 4-anilinoquinazoline class, particularly compounds bearing:

6,7-dimethoxy substitution;
6,7-diethoxy substitution;
methoxyethoxy side chains;
amino or acetamido groups;
3'-methyl aniline substitution; and
3'-chloro-4'-fluoro aniline substitution.

The patent should not be treated as a definitive patent for every later EGFR inhibitor. Later products may have been protected by separate composition, formulation, polymorph, dosing, manufacturing, or method-of-use patents.

Gefitinib, erlotinib, lapatinib, vandetanib, and afatinib all belong to the broader kinase-inhibitor landscape, but their commercial patent positions must be assessed against their own structures and patent families. A claim to a broad quinazoline genus does not automatically establish infringement by every later quinazoline drug.

What are the principal claim-construction issues?

Several issues materially affect the scope analysis.

The formula is essential

The supplied text omits the actual structural drawing represented by "formula I." The written substituent lists alone do not establish:

the exact attachment point for every R1 group;
the location of the anilino nitrogen;
the permitted ring numbering;
whether substituents are attached directly or through a linker; or
the valence and substitution limits of the quinazoline core.

The formula must be read with the claims. Chemical claim scope cannot be determined from the Markush lists in isolation.

R1 nomenclature includes positional limitations

Terms such as "6-(1-4C)alkoxy," "7-(1-4C)alkoxy," and "6-hydroxy-7-methoxy" are positional limitations. A compound with the same substituents in a different arrangement may fall outside a narrower claim even if it remains within a broader genus.

Salt coverage is expressly included

Most claims cover pharmaceutically acceptable salts. Claims 6 through 9 refer specifically to pharmaceutically acceptable acid-addition salts. A salt form may therefore be within the literal scope even when the free base is the commercially active form.

The exclusions limit the genus

The excluded compounds cannot be used to infer that every closely related compound is excluded. The exclusions are specific. A structurally adjacent compound may remain within the claim if it satisfies all other limitations.

When did US Patent 5,457,105 lose exclusivity?

US Patent 5,457,105 issued on October 10, 1995. Under the pre-URAA rule applicable to an application filed before June 8, 1995, the ordinary term was 17 years from issuance, producing an expected expiration date of October 10, 2012.[1][2]

Event	Date
US patent filing period	Before June 8, 1995
Patent issued	October 10, 1995
Ordinary statutory term	17 years from issuance
Expected expiration	October 10, 2012
Current status	Expired by term

Patent expiration eliminates enforceability of the patent in the United States. It does not eliminate historical relevance, nor does it invalidate separate later patents covering the same commercial product.

What is the Orange Book status?

US Patent 5,457,105 is not a current enforceable Orange Book barrier solely by virtue of its historical listing. Orange Book relevance depends on the specific drug, NDA, patent listing, and current FDA status.[3]

For an approved EGFR inhibitor, the relevant analysis must distinguish:

whether the patent was ever listed for the product;
whether the listing covered the active ingredient, formulation, or method of use;
whether the listed patent has expired;
whether later patents remained listed; and
whether an ANDA applicant faced a Paragraph IV certification.

An expired compound patent cannot support a current injunction against generic entry. A later formulation or method-of-use patent may still create a regulatory or litigation issue if it remains unexpired and is properly listed.

Were there Paragraph IV challenges or settlements?

The claim text does not establish whether an ANDA applicant filed a Paragraph IV certification, whether litigation occurred, or whether a settlement agreement was executed. Those events arise from FDA ANDA records, district-court dockets, and settlement disclosures rather than from the patent claims.

For an expired 1995 patent, any historical Paragraph IV challenge would no longer affect current enforceability. The relevant commercial question is whether separate later patents, rather than US 5,457,105, controlled generic entry.

Does this patent create biosimilar risk?

No. US Patent 5,457,105 covers small-molecule quinazoline compounds and their uses. It does not cover a biologic or biosimilar product. The applicable competitive pathway is an abbreviated new drug application under section 505(j), not a biosimilar application under section 351(k) of the Public Health Service Act.[4]

How strong is the patent estate?

The patent was strong historically as a platform patent because it combined:

a recognizable kinase-inhibitor scaffold;
broad genus claims;
extensive substituent coverage;
selected species claims;
pharmaceutical composition claims; and
multiple anticancer and receptor tyrosine kinase method claims.

Its current strength is low because the patent term has expired. The remaining commercial risk, if any, would come from separate patent families covering:

a specific marketed molecule;
polymorphs or crystalline forms;
salts;
formulations;
dosing schedules;
combination therapy;
biomarkers or patient selection;
manufacturing intermediates; or
improved synthetic processes.

The manufacturing claims in US 5,457,105, as reflected in the supplied claims, are limited. The patent does not appear to provide a dedicated process monopoly comparable to a later manufacturing patent. A generic manufacturer that can make the active ingredient without practicing an unexpired process claim would face no current barrier from this patent.

What generic launch scenarios follow from expiration?

The principal scenarios are:

Scenario	Effect of US 5,457,105
Generic uses an exact claimed compound	No current restriction from this expired patent
Generic uses a salt of a claimed compound	No current restriction from this expired patent
Generic uses a different formulation	Review later formulation patents
Generic uses a different indication	Review method-of-use patents
Generic uses a different synthetic route	Review process patents and trade secrets
Generic launches an EGFR quinazoline analog	Analyze structure against live patent families
Generic files an ANDA for a branded product	Evaluate all currently listed Orange Book patents, not only US 5,457,105

What are the main design-around options?

A later developer could potentially design around narrower claims by changing:

the aniline substitution pattern;
the number or position of quinazoline-ring substituents;
the linker between the ring and a terminal amine;
the nature of the salt;
the heterocyclic substituent;
the therapeutic indication; or
the dosage regimen.

Design-around analysis must begin with the complete formula and the issued claim construction. A change that avoids claim 7 may still fall within claim 1, while a change that avoids the composition claims may implicate an unexpired method or formulation patent elsewhere in the family.

Key Takeaways

US Patent 5,457,105 is a broad early patent covering substituted 4-anilinoquinazoline compounds.
Claims 1 and 2 are the principal Markush composition claims.
Claims 5 through 9 narrow the field to defined substituent classes and named species.
Claims 10 and 11 cover pharmaceutical compositions.
Claims 12 through 29 cover anticancer, antiproliferative, and receptor tyrosine kinase-related methods.
The patent issued on October 10, 1995, and its ordinary 17-year term expired on October 10, 2012.
The patent is not a current US exclusivity barrier.
It is a small-molecule patent and has no biosimilar relevance.
Current generic-entry risk must be assessed against later compound, formulation, method-of-use, polymorph, and manufacturing patents.
The missing structural drawing for formula I prevents a complete compound-by-compound infringement determination from the text alone.

FAQs About US Patent 5,457,105

Does US Patent 5,457,105 still block generic quinazoline products?

No. The patent's ordinary US term expired in 2012. Later patents may still affect a particular product.

Does the patent cover gefitinib?

The supplied claims cover a broad quinazoline genus, but coverage of gefitinib requires comparison of the complete gefitinib structure with formula I and each relevant issued claim. The patent number alone does not establish infringement.

Does an expired composition patent prevent an ANDA launch?

No. An expired patent cannot independently prevent launch. An applicant must still address any other unexpired patents listed for the reference drug.

Are the receptor tyrosine kinase method claims still enforceable?

No, not under US Patent 5,457,105 after expiration. Similar methods may be covered by later patents.

Can a company license US Patent 5,457,105 for current US exclusivity?

A license cannot restore an expired patent right. The patent may retain historical, technical, or foreign-family value, but it cannot provide current US patent exclusivity.

References

United States Patent and Trademark Office. (1995). US Patent No. 5,457,105, Quinazoline derivatives. U.S. Department of Commerce.
35 U.S.C. § 154. Patent term and adjustment.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
U.S. Food and Drug Administration. (2024). Abbreviated new drug application approvals and patent certifications.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	9201095	Jan 20, 1992
United Kingdom	9213572	Jun 26, 1992
United Kingdom	9223735	Nov 12, 1992

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	130000	⤷ Start Trial
Australia	3101093	⤷ Start Trial
Australia	661533	⤷ Start Trial
Canada	2086968	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,457,105

Summary for Patent: 5,457,105