United States Patent 5,616,582: Scope, Claims, Expiration, and EGFR Patent Landscape

United States Patent No. 5,616,582 is an early broad patent on 4-anilinoquinazoline compounds used to inhibit epidermal growth factor receptor, or EGFR, tyrosine kinase and treat EGFR-sensitive cancers. Its 12 claims cover therapeutic use of large Markush classes of quinazoline derivatives, including compounds with substituted quinazoline rings, substituted anilines, pharmaceutically acceptable salts, and multiple anticancer or antiproliferative indications.

The patent is no longer an enforceable U.S. patent. It issued on April 1, 1997, and its pre-Uruguay Round patent term was generally 17 years from issuance. The patent therefore expired in 2014, subject to any applicable adjustment. The claims remain relevant as prior art and as a foundational component of the historical EGFR inhibitor landscape, but they do not presently block generic manufacture or sale in the United States.[1]

What does U.S. Patent 5,616,582 cover?

The patent covers methods of administering substituted quinazoline derivatives to warm-blooded animals. The therapeutic objectives are:

Claim group	Claimed effect	Chemical scope
Claims 1-2	Anticancer effect in an EGFR-sensitive cancer	Specific quinazoline Markush classes
Claims 3-4	Antiproliferative effect mediated partly or wholly by EGFR tyrosine kinase inhibition	Same core classes
Claims 5-6	EGFR tyrosine kinase inhibitory effect	Same core classes
Claims 7-8	Anticancer effect in EGFR-sensitive cancer	Expanded substituent classes
Claims 9-10	Antiproliferative effect involving EGFR inhibition	Expanded substituent classes
Claims 11-12	EGFR tyrosine kinase inhibitory effect	Expanded substituent classes

All claims are method-of-treatment claims. The patent does not, based on the supplied claims, contain a claim directed solely to:

The chemical compound as a composition of matter;
A pharmaceutical composition;
A tablet, capsule, injectable, or other dosage form;
A manufacturing process;
A crystalline form;
A polymorph;
A specific dosage regimen;
A biomarker-selected patient population;
A combination therapy.

That distinction materially limits the direct infringement theory. Making or selling a compound without evidence of an infringing therapeutic use does not, by itself, satisfy these claims. Liability could historically have been pursued through induced infringement or contributory infringement where the accused product was specifically promoted for the claimed EGFR-mediated uses.

What is the chemical scope of the claims?

The claimed compounds are based on a quinazoline core bearing an anilino substituent and multiple permitted substitutions. The claim language identifies the substituent positions as R1 and R2, with the chemical formula shown in the issued patent controlling the precise atom connectivity.

R1 substituent coverage

Claims 1, 3, and 5 use a broad list of individually permitted R1 substituents. The list includes:

Hydroxy, amino, ureido, hydroxyamino, and acylamido groups;
Methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups;
Methylenedioxy and ethylenedioxy groups;
Alkylamino and dialkylamino groups;
Piperidino, morpholino, and piperazinyl groups;
Alkylthio groups;
Bromomethyl, methoxymethyl, cyanomethyl, and related alkyl substituents;
Hydroxyalkoxy and alkoxyalkoxy groups;
Aminoalkoxy and aminoalkylamino groups;
Carbamoylmethoxy and alkoxycarbonylmethoxy groups;
Benzamido, phenylureido, and substituted acetamido groups.

Claims 7 through 12 expand this approach. They expressly add broader functional classes, including:

Carboxy and carbamoyl;
N-alkylcarbamoyl and N,N-dialkylcarbamoyl;
Alkylsulfinyl and alkylsulfonyl;
Hydroxyalkyl and aminoalkyl groups;
Morpholinoalkyl, piperidinoalkyl, and piperazinylalkyl groups;
Hydroxyalkoxyalkyl and alkoxyalkoxyalkyl groups;
Aminoalkoxy, dialkylaminoalkoxy, and morpholinoalkoxy groups;
Halogenoalkoxy and halogenoalkylamino groups;
Hydroxyalkanoylamino, alkoxyalkanoylamino, and aminoalkanoylamino groups;
Benzamido and benzenesulfonamido groups.

The R1 language is therefore substantially broader than a single marketed molecule. It is a genus claim covering numerous substitutions at the 5-, 6-, and 7-positions, subject to the positional limitations in the patent formula.

R2 substituent coverage

R2 is located on the aniline ring. Depending on the claim, permitted R2 groups include:

Hydrogen;
Fluoro, chloro, and bromo;
Trifluoromethyl;
Nitro and cyano;
Hydroxy and amino;
Methyl, ethyl, and other lower alkyl groups;
Lower alkoxy groups in the later claims.

Claims 2, 4, and 6 identify specific aniline substitution patterns, including:

4'-fluoro;
3'-chloro;
3'-bromo;
3',4'-dichloro;
4'-fluoro-3'-chloro;
3'-trifluoromethyl;
4'-fluoro-3'-trifluoromethyl;
3'-nitro;
3'-nitro-4'-chloro;
3'-nitro-4'-fluoro; and
3'-methyl.

These narrower claims provide fallback positions if the broader R1/R2 genus claims were challenged for lack of novelty, obviousness, written description, or enablement.

How are claims 1 through 12 structured?

The claims form six functional pairs.

Claims 1 and 2 require an anticancer effect against an EGFR-sensitive cancer. Claims 3 and 4 require an antiproliferative effect mediated at least in part by EGFR tyrosine kinase inhibition. Claims 5 and 6 require an EGFR tyrosine kinase inhibitory effect without expressly requiring cancer treatment.

Claims 7 and 8 repeat the anticancer method with a broader, more systematic substituent vocabulary. Claims 9 and 10 repeat the antiproliferative method. Claims 11 and 12 repeat the enzyme-inhibition method.

This structure creates several potential enforcement paths:

Cancer treatment claims, where the patient has an EGFR-sensitive cancer.
Mechanism-linked antiproliferative claims, where EGFR inhibition contributes to the therapeutic effect.
Direct EGFR-inhibition claims, where the claimed biological effect is established.

The claims do not require a particular cancer type, EGFR mutation, administration route, dose, treatment duration, or formulation. That makes them broad in functional scope but potentially vulnerable to patentability and claim-construction challenges.

When did U.S. Patent 5,616,582 expire?

Event	Date or status
Patent issued	April 1, 1997
Statutory term applicable to the issued patent	Generally 17 years from issuance under the pre-1995 term regime
Expected base expiration	April 1, 2014
Current status	Expired
Current blocking effect in the United States	None as an enforceable patent

The patent was filed during the transition period between the former 17-year-from-issuance term and the 20-year-from-earliest-effective-filing-date term created by the Uruguay Round Agreements Act. The issue date and historical term rules are central to the expiration analysis. Any patent-term adjustment would need to be confirmed from the USPTO patent file, but the patent is not currently enforceable in the United States.[1,2]

What is the Orange Book status of the patent?

U.S. Patent 5,616,582 is not a current Orange Book exclusivity barrier for an approved EGFR inhibitor.

The Orange Book lists patents submitted by an NDA holder for a specific approved drug product. A broad historical method patent does not automatically appear in the Orange Book, and expiration of the patent removes any remaining practical exclusivity even if it was previously listed.

For gefitinib, marketed in the United States as Iressa, the relevant commercial and regulatory protection was based on the approved product, regulatory exclusivity, and later drug-specific patent rights rather than on an enforceable claim under U.S. Patent 5,616,582. FDA approved gefitinib in 2003 under accelerated approval and later converted the indication to regular approval after confirmatory clinical data.[3,4]

The patent should therefore be treated as a historical foundational patent, not as an active Orange Book-listed barrier.

Does the patent cover gefitinib?

The claim language is broad enough to reach important 4-anilinoquinazoline EGFR inhibitors, depending on the exact structure shown in Formula I and the positional limitations.

Gefitinib contains:

A quinazoline kinase-binding core;
A 3-chloro-4-fluorophenylamino substituent;
A methoxy substituent;
A morpholinopropoxy substituent.

The 3-chloro-4-fluoro aniline pattern is expressly identified in the narrower R2 group. The later claims also cover morpholino-substituted alkoxy chains and lower alkoxy substitutions on the quinazoline ring. On the supplied wording, gefitinib is within the technical territory of the patent's expanded Markush claims, particularly claims 7, 9, and 11, assuming the compound satisfies the complete Formula I structure.

This historical coverage does not create present-day exclusivity because the patent has expired. It also does not establish that every particular gefitinib patent right was dependent on this patent. Composition-of-matter, formulation, salt, process, and drug-specific patents must be analyzed separately.

How does the patent compare with erlotinib, afatinib, and lapatinib patents?

Drug	Active ingredient	Relationship to the 5,616,582 claim strategy	Current U.S. patent risk from 5,616,582
Gefitinib	Gefitinib	Closely aligned with the 4-anilinoquinazoline and substituted alkoxy framework	None; patent expired
Erlotinib	Erlotinib hydrochloride	Same broad EGFR quinazoline class, but has a distinct ethynyl-substituted aniline structure	None; patent expired
Afatinib	Afatinib dimaleate	Irreversible ErbB-family inhibitor with additional reactive acrylamide functionality	None; patent expired
Lapatinib	Lapatinib ditosylate	More structurally differentiated dual EGFR/HER2 inhibitor	None; patent expired

The patent is best understood as an early platform patent. Later commercial products generally relied on their own composition-of-matter patents and product-specific patent families. The existence of a broad early genus does not eliminate the need to examine later patents covering the final clinical compound.

What formulation patents and method-of-use patents remain relevant?

U.S. Patent 5,616,582 does not claim a formulation. It does not specify:

Tablet excipients;
Particle size;
Solid-state form;
Salt stoichiometry;
Dissolution profile;
Controlled release;
Food-effect mitigation;
Dose titration;
Combination treatment;
Companion diagnostic use.

For commercial freedom-to-operate analysis, later patent families are usually more important in these categories:

Formulation patents

Potentially relevant formulation claims may cover:

Specific salts;
Crystalline forms;
Tablet compositions;
Stability-enhancing excipients;
Oral bioavailability;
Coated dosage forms;
Liquid or parenteral formulations.

These rights are compound-specific and cannot be inferred from the claims supplied for U.S. Patent 5,616,582.

Method-of-use patents

Later EGFR inhibitor patents may claim:

EGFR-mutant non-small-cell lung cancer;
Exon 19 deletions;
L858R mutations;
T790M resistance mutations;
HER2-amplified disease;
Combination treatment with chemotherapy or antibody therapy;
Brain metastases;
Maintenance treatment;
Biomarker-selected patient populations.

The 5,616,582 claims do not require these limitations. Their broad therapeutic language would generally be analyzed as an earlier platform disclosure rather than as a substitute for later mutation-specific or regimen-specific patents.

Which companies were associated with the relevant EGFR patent landscape?

The historical EGFR tyrosine kinase inhibitor landscape involved several major originators:

Company	Relevant commercial products or platform
Zeneca, later AstraZeneca	Gefitinib and early quinazoline EGFR inhibitor research
Genentech and Roche	Erlotinib commercialization and EGFR oncology development
Boehringer Ingelheim	Afatinib
GlaxoSmithKline	Lapatinib
Pfizer and later other generic manufacturers	Commercialization and generic entry for selected EGFR inhibitors

Licensing and commercialization arrangements differed by product and jurisdiction. A definitive licensing analysis requires tracing the patent assignment records, development agreements, and product-specific commercialization contracts. U.S. Patent 5,616,582 itself should be reviewed through USPTO assignment records for historical ownership and recorded transfers.

What generic entry risks existed, and what risks remain?

During the patent's enforceable period, a generic applicant could have faced risk under:

Direct infringement of the method claims;
Induced infringement based on labeling or promotional materials;
Contributory infringement based on a product having no substantial noninfringing use;
Litigation involving a Paragraph IV certification if the patent was listed for an approved product.

After expiration, those risks ended for this patent. A generic applicant's current risk depends on later, unexpired patents, including:

Active ingredient patents;
Salt and polymorph patents;
Formulation patents;
Manufacturing patents;
Use patents;
Combination therapy patents;
Pediatric exclusivity or other regulatory exclusivity.

Paragraph IV litigation is product-specific. It cannot be attributed to U.S. Patent 5,616,582 without a documented ANDA, Orange Book listing, notice letter, and infringement complaint. The expired status of this patent means it is not a current Paragraph IV barrier.

How strong is the patent estate?

Historical strength

The patent had substantial historical breadth because it combined:

A validated EGFR kinase mechanism;
A large 4-anilinoquinazoline genus;
Numerous 6- and 7-position substituents;
Multiple aniline-ring substitutions;
Cancer, antiproliferative, and enzyme-inhibition claim categories;
Salt coverage.

The narrower enumerated claims supplied additional structural specificity.

Current strength

The current enforceability strength is zero because the patent has expired. Its residual value is limited to:

Prior-art significance;
Historical ownership analysis;
Patent-family mapping;
Validity analysis of later patents;
Understanding the origin of the EGFR quinazoline platform;
Supporting an obviousness or written-description analysis involving later patents.

Key Takeaways

U.S. Patent 5,616,582 is a broad historical EGFR inhibitor method patent covering substituted quinazoline derivatives.
Claims 1 through 12 cover anticancer treatment, antiproliferative treatment, and EGFR tyrosine kinase inhibition.
The claims are method claims, not standalone compound, formulation, or manufacturing claims.
Gefitinib falls within the technical territory of the expanded claim language, subject to the complete Formula I structure.
The patent issued on April 1, 1997, and expired in 2014 under the applicable historical patent-term regime.
It is not a current U.S. Orange Book or Paragraph IV barrier.
Current commercial risk must be assessed against later drug-specific composition, formulation, method-of-use, and manufacturing patents.
The patent remains important as foundational prior art for the 4-anilinoquinazoline EGFR inhibitor class.

FAQs

Is U.S. Patent 5,616,582 still enforceable?

No. The patent expired after its historical 17-year term from issuance and is not an active U.S. exclusionary right.

Did Patent 5,616,582 claim gefitinib by name?

No. The claims use Markush chemical definitions rather than naming gefitinib. Gefitinib may fall within the claimed genus based on its substituents and Formula I structure.

Does the patent cover making an EGFR inhibitor?

Not directly. The supplied claims cover administering the compounds to animals. They do not claim a manufacturing process or a standalone chemical composition.

Can an expired method patent support a current generic lawsuit?

No. An expired patent cannot support a new infringement action for conduct occurring after expiration, although it can remain relevant as prior art.

Are later EGFR inhibitor patents invalid because this patent is broad?

Not automatically. Later patents may claim specific compounds, salts, formulations, uses, or regimens that were not claimed or enabled by the earlier patent. Validity requires a separate claim-by-claim prior-art analysis.

References

United States Patent and Trademark Office. (1997). U.S. Patent No. 5,616,582, Quinazoline derivatives. U.S. Department of Commerce.
United States Patent and Trademark Office. (n.d.). Patent term adjustment and patent term calculation guidance. U.S. Department of Commerce.
U.S. Food and Drug Administration. (2003). Iressa approval letter and prescribing information: Gefitinib. FDA.
U.S. Food and Drug Administration. (2015). FDA approves new treatment for certain patients with non-small cell lung cancer. FDA.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, Orange Book. FDA.

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: 5,616,582

Summary for Patent: 5,616,582