United States Patent 6,414,148: Claim Scope, Expiration, Litigation Risk and Quinazoline Patent Landscape
US Patent 6,414,148 covers a broad genus of substituted 4-anilinoquinazoline compounds, pharmaceutical compositions, manufacturing processes, and antiangiogenic or vascular-permeability-reducing methods. The patent is structurally centered on a quinazoline core bearing an anilino substituent and an oxygen-linked, highly variable side chain.
The patent does not, from the claims supplied, identify a single commercial drug by active ingredient name. Its claim set is directed to a research and development platform encompassing numerous quinazoline derivatives rather than a narrowly defined marketed product. The patent’s ordinary 20-year term appears to have expired based on its late-1990s priority history, subject to any patent-term adjustment or extension recorded by the USPTO.
What does US Patent 6,414,148 cover?
The patent covers five principal subject-matter categories:
| Claim category |
Claims |
Commercial relevance |
| Compound genus |
1-20 |
Core composition-of-matter protection |
| Specific compounds |
8-11 |
Narrower species and stereochemical protection |
| Manufacturing processes |
21 |
Process infringement and manufacturing know-how |
| Pharmaceutical compositions |
22 |
Formulated drug products |
| Therapeutic methods |
23 |
Antiangiogenic and vascular-permeability indications |
The central chemical structure is a 4-anilinoquinazoline. Claim 1 requires:
- A quinazoline ring system.
- An anilino substituent at the 4-position.
- One or two substituents on the quinazoline or associated aromatic system as defined by
m.
- An oxygen linker, because
X1 is specified as -O- in the relevant subclaims and in independent claim 17.
- A highly variable
R4 substituent attached through the oxygen linker.
- A pharmaceutically acceptable salt in embodiments that claim salts.
The claim architecture is typical of a medicinal-chemistry patent intended to cover a large analog series. It combines broad Markush language with progressively narrower claims directed to preferred substitution patterns and named examples.
How broad is independent claim 1?
Claim 1 is exceptionally broad in chemical scope. It permits:
m equal to 1 or 2;- numerous substituents on the quinazoline and aniline rings;
- halogen, alkyl, alkoxy, nitro, cyano, amino, hydroxy and trifluoromethyl substitution;
- saturated heterocyclic, acyclic, alkenyl and alkynyl side chains;
- ether, thioether, sulfoxide, sulfone, amine, amide, carbamate and sulfonamide linkages;
- substituted pyrrolidine, piperidine, morpholine, piperazine, thiomorpholine and related rings;
- salts of the claimed compounds.
The largest source of breadth is R4. The claim defines 11 alternative classes of side chain. These classes collectively cover several medicinal-chemistry strategies:
Heterocyclic alkyl ethers
Group 1 covers alkyl chains attached to saturated heterocycles. The heterocycle may contain oxygen, sulfur or nitrogen and may carry multiple substituents. This reaches compounds with morpholine, piperidine, pyrrolidine, piperazine, dioxolane, dioxane, dithiane and related groups.
Alkenyl and alkynyl side chains
Groups 2 and 3 cover alkenyl and alkynyl linkers terminating in saturated heterocycles. These claims include both carbon-linked and, in selected embodiments, nitrogen-linked heterocycles.
Polyheteroatom linkers
Group 4 covers chains containing two independently selected linking atoms or groups, including ethers, sulfides, sulfones, amides, sulfonamides and secondary amines.
Carbamate and amide side chains
Group 5 covers alkyl-linked carbamates and amides, including amino and alkoxy terminal groups.
Cycloalkyl and heterocyclic terminal groups
Group 6 covers side chains linked to cyclopentyl, cyclohexyl and saturated heterocycles, as well as selected allylic structures.
Simple alkyl and alkoxyalkyl structures
Group 7 covers C1-3 alkoxy-C2-4 alkyl and C1-4 alkyl. This class is narrowed by a proviso requiring nitro substitution on the quinazoline or aniline portion, or alkanoyloxy substitution on the aromatic ring.
Piperidine, piperazine and morpholine embodiments
Groups 8-11 cover substituted piperazine, morpholine and related ring systems. These groups are particularly important for product-specific freedom-to-operate analysis because many kinase inhibitors use solubilizing tertiary amine side chains.
What do dependent claims 2-20 add?
The dependent claims progressively narrow the broad genus.
| Claims |
Main limitation |
| 2 |
Narrows R1 to selected hydrogen, hydroxy, cyano, nitro, trifluoromethyl, alkyl and alkoxy groups |
| 3 |
Requires R2 to be hydrogen |
| 4 |
Defines the substituted phenyl ring through formula II |
| 5-6 |
Narrows the allowed R4 side chains |
| 7 |
Limits the compound to a preferred formula with hydrogen or methoxy R1, hydrogen R2, and 4-chloro-2-fluoro or 4-bromo-2-fluorophenyl |
| 8-11 |
Recite named chemical species |
| 12 |
Requires a pharmaceutically acceptable salt |
| 13 |
Requires methoxy R1 |
| 14 |
Requires two R3 substituents |
| 15 |
Requires 4-chloro-2-fluoro or 4-bromo-2-fluorophenyl |
| 16 |
Defines six preferred R4 groups |
| 17 |
Provides a separate, narrower independent compound genus |
| 18-20 |
Narrow claim 17 through methoxy R1, hydrogen R2 and formula II |
Claims 8-11 are the most commercially useful for a species-level analysis because they identify specific compounds rather than relying entirely on Markush definitions. Claim 11 is especially narrow, covering the compound identified as:
4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(methylsulphonyl)propoxy)quinazoline
and its salts.
The supplied text contains transcription errors, including malformed chemical names, inconsistent numbering and apparent OCR substitutions such as quinzoline, trifuloromethyl, piperizin-1-yl and N,N-di(C1-2alkyl)cabamoyl. The issued patent should control for claim construction, not the transcription.
What is the scope of independent claim 17?
Claim 17 is a separate independent compound claim and is narrower than claim 1 in several respects.
It requires:
X1 to be -O-;- a more restricted set of seven
R4 groups;
- fewer permitted substituent types on the terminal heterocycles;
- a more limited set of linker functionalities;
- the same general quinazoline and anilino framework;
- the same proviso for simple alkyl or alkoxyalkyl substituents.
Claim 17 appears designed to preserve protection around a commercially preferred subset after the broadest genus in claim 1. Its narrower structure may have greater resilience against validity attacks based on written description or enablement, although validity depends on the complete specification and prior-art record.
What compounds are specifically named in the patent?
Claims 8-11 identify compounds containing several recurring structural elements:
| Structural element |
Examples in claims |
| Quinazoline core |
4-anilino-6-methoxyquinazoline |
| Aniline substituent |
4-chloro-2-fluorophenyl or 4-bromo-2-fluorophenyl |
| Linker |
Methoxy, ethoxy, propoxy, butenoxy or related oxygen-linked chains |
| Terminal groups |
Morpholine, pyrrolidine, piperidine, thiomorpholine and urea derivatives |
| Polar functionality |
Methylsulfone, carbamoyl, oxoheterocycle and protected amino groups |
| Stereochemistry |
S and R piperidine-containing species; E alkenyl species |
The named species indicate that the inventors were optimizing aqueous solubility, receptor binding, pharmacokinetics and antiangiogenic activity through substitution at the 7-position of the quinazoline ring.
What do process claims 21-23 protect?
Process claim 21
Claim 21 covers several synthetic routes, including:
- displacement of a leaving group on a quinazoline precursor by an aniline;
- deprotection of phenolic protecting groups;
- ether formation between a quinazoline phenol and an
R4-containing leaving-group substrate;
- reaction of an activated quinazoline intermediate with an alcohol or amine;
- substitution with heterocyclic nucleophiles;
- alkylation of amino groups;
- reduction of nitro groups to amino groups;
- salt formation with acids or bases.
These process claims may be relevant even if a competing product falls outside the compound claims, particularly where the competitor uses the same protected-intermediate or etherification sequence.
Composition claim 22
Claim 22 covers a pharmaceutical composition containing a compound of formula I, or a salt, with a pharmaceutically acceptable excipient or carrier. It does not require a particular dosage form, release profile, excipient, strength or route of administration.
Method claim 23
Claim 23 covers administering a claimed compound to produce:
- an antiangiogenic effect; or
- a vascular-permeability-reducing effect.
The method claim is not limited to a named disease, tumor type, dose, schedule or administration route. Its enforceability against a generic or follow-on product would depend on induced-infringement evidence and the product labeling, prescribing information and actual use.
When did US Patent 6,414,148 lose exclusivity?
US Patent 6,414,148 issued on July 2, 2002. Its patent term is governed by the 20-year term rules applicable to the relevant application history, not by the issue date.[1] The patent’s underlying priority history is from the late 1990s, placing the ordinary expiration period in the late 2010s.
| Event |
Timing |
| Priority and underlying application history |
Late 1990s |
| US patent issue |
July 2, 2002 |
| Nominal 20-year term |
Approximately late 2010s |
| Current status for ordinary patent term purposes |
Expired, absent an unusual extension |
| Post-expiration effect |
Patent claims generally cannot block new US manufacture, sale or use under the expired claims |
The authoritative expiration date should be taken from the USPTO patent record, including any recorded patent-term adjustment, terminal disclaimer or patent-term extension. A patent-term extension under 35 U.S.C. § 156 would require an eligible approved product and regulatory filing history. Nothing in the claim text establishes such an extension.[2]
What is the FDA and Orange Book status?
The patent claims themselves do not establish FDA approval, Orange Book listing or regulatory exclusivity. An Orange Book listing requires an approved drug application and an applicable patent submitted by the applicant.[3]
Based on the supplied claims, the patent should be treated as follows:
| Regulatory issue |
Assessment |
| FDA-approved active ingredient identified in claims |
No |
| Drug product named in claims |
No |
| Orange Book status established by patent text |
No |
| Small-molecule patent type |
Composition, process, composition and method |
| Biologic or biosimilar relevance |
None apparent |
| Regulatory exclusivity |
Not established |
| Patent-based generic delay |
Not established |
The patent is not a biologic patent and does not create biosimilar risk. Any FDA relevance would arise only if a claimed compound became the active ingredient of an approved small-molecule drug.
Are there Paragraph IV challenges or generic litigation risks?
A Paragraph IV certification applies to a patent listed for an approved drug in the Orange Book. The patent text alone does not show that US 6,414,148 was listed for an approved product or challenged in an abbreviated new drug application.
The practical risk profile is therefore:
| Risk type |
Assessment |
| Live composition-of-matter blocking risk |
Low if the patent is expired |
| Paragraph IV litigation risk |
Not established from the patent record supplied |
| Method-of-use risk |
Low after expiration; historical relevance only |
| Process infringement risk |
Low after expiration |
| Patent-term-extension risk |
Must be confirmed in USPTO records |
| Regulatory exclusivity risk |
Not shown |
| Trade-secret manufacturing risk |
Potentially separate from patent rights |
If a product was developed using a claimed compound before expiration, historical infringement exposure could still depend on sales dates, the applicable claim scope and any litigation or settlement agreement. New commercial activity after expiration generally is not blocked by the expired patent.
How strong is the patent estate?
The patent had strong theoretical breadth while in force, but its present commercial strength is principally historical.
Strengths
- Broad Markush genus in claim 1.
- Separate narrower independent genus in claim 17.
- Numerous preferred heterocyclic side chains.
- Specific species claims in claims 8-11.
- Process coverage for multiple synthetic routes.
- Composition and therapeutic-method claims.
- Coverage of salts and stereochemical embodiments.
Weaknesses
- Extensive breadth increases written-description and enablement exposure.
- The claims cover a large number of structures with different polarity, size and pharmacology.
- Several alternatives may have limited support unless exemplified or demonstrated in the specification.
- Method claim 23 is broad and may depend on proving the claimed biological effect.
- Patent expiration eliminates ordinary prospective enforcement value.
The strongest historical positions were likely the specifically exemplified compounds and the narrower 4-chloro-2-fluoroanilino or 4-bromo-2-fluoroanilino subgenera. The broadest generic language would have presented greater validity and claim-construction risk.
What geographic coverage does the patent provide?
US 6,414,148 provides rights only in the United States. International protection would depend on corresponding applications in the Patent Cooperation Treaty national phase and other jurisdictions.
Potentially relevant foreign-family jurisdictions would include:
- United Kingdom;
- European Patent Office states;
- Japan;
- Canada;
- Australia;
- other countries designated in the underlying international application.
Foreign counterparts require separate review because claim scope, prosecution amendments, opposition outcomes and expiration dates can differ. A US patent does not itself prevent manufacture, sale or use in Europe, Japan, China or other markets.
How does this patent compare with a modern generic quinazoline patent estate?
| Issue |
US 6,414,148 |
Typical later-stage quinazoline estate |
| Core protection |
Broad chemical genus |
Often narrower clinical candidate |
| Side-chain coverage |
Extensive Markush alternatives |
Focused composition-of-matter claims |
| Formulation protection |
Minimal in listed claims |
Often separate solid-form and formulation patents |
| Method-of-use protection |
Broad antiangiogenic language |
Disease-specific and dosing-specific claims |
| Process protection |
Multiple synthetic alternatives |
Frequently route-specific |
| Regulatory linkage |
Not established |
Often Orange Book-linked |
| Current commercial value |
Mainly historical |
Depends on remaining term and product sales |
The patent does not, from the claims supplied, contain modern solid-form, polymorph, crystal, particle-size, sustained-release or combination-therapy claims. Those areas would normally be reviewed in later continuation, divisional, improvement or formulation families.
What licensing, settlement and litigation information is established?
No licensing agreement, Paragraph IV settlement, post-grant review, inter partes review or infringement judgment is established by the claim text. Patent ownership and litigation history should be distinguished from the scientific disclosure.
The patent’s commercial significance could have been affected by:
- assignments from the original applicant;
- exclusive licenses;
- continuation patents;
- terminal disclaimers;
- FDA listing activity;
- ANDA certifications;
- infringement settlements;
- covenants not to sue;
- patent-term adjustment or extension.
Those events are not inferable from the claims alone. The US patent file, assignment database, FDA Orange Book and federal court docket are the controlling sources for those issues.[1-4]
What generic launch scenarios exist now?
If the patent has expired without an operative extension, the principal launch scenarios are:
- A generic or new drug applicant develops a non-infringing quinazoline compound.
- A manufacturer launches a product containing a specifically claimed compound after patent expiration.
- A competitor relies on an alternative synthetic route, although process protection would no longer ordinarily block activity after expiration.
- A follow-on product avoids any separately surviving continuation, formulation or salt patent.
- A product launches outside the United States subject to separate foreign patent analysis.
The key residual risk is not US 6,414,148 itself but an unreviewed family member or later patent covering the same active ingredient, formulation, salt, polymorph, method of use or manufacturing route.
Key Takeaways
- US 6,414,148 covers a broad 4-anilinoquinazoline platform with oxygen-linked heterocyclic side chains.
- Claim 1 is a wide Markush composition-of-matter claim with 11 major
R4 classes.
- Claim 17 is a narrower independent genus focused on oxygen-linked side chains.
- Claims 8-11 identify specific compounds, including chloro-fluoroanilino and bromo-fluoroanilino quinazolines.
- Claim 21 covers multiple synthesis routes; claim 22 covers pharmaceutical compositions; claim 23 covers antiangiogenic and vascular-permeability-reducing methods.
- The patent’s ordinary term appears to have ended in the late 2010s, subject to the recorded USPTO term calculation.
- The patent text does not establish FDA approval, Orange Book listing, Paragraph IV litigation, biosimilar exposure or a live US exclusivity period.
- Current freedom-to-operate analysis must prioritize continuations, foreign counterparts, assignments, later formulation patents and any patent-term adjustment or extension.
FAQs
Does US Patent 6,414,148 cover gefitinib or erlotinib?
The supplied claims do not identify gefitinib or erlotinib by name. Structural overlap must be determined by mapping each marketed molecule against every limitation of the asserted claim.
Does the patent cover salts of the claimed quinazoline compounds?
Yes. Multiple claims expressly include salts, and claim 12 separately requires a pharmaceutically acceptable salt.
Does claim 23 cover cancer treatment?
Claim 23 recites an antiangiogenic effect and a vascular-permeability-reducing effect, but it does not expressly limit treatment to a specific cancer type.
Can an expired process claim still block generic manufacturing?
An expired US process claim generally cannot block new manufacturing activity. Separate unexpired patents, trade secrets or regulatory restrictions may create independent barriers.
Is this patent relevant to biosimilar competition?
No direct biosimilar issue is apparent. The patent covers small-molecule quinazoline derivatives, not biologic molecules subject to the biosimilar pathway.
References
- United States Patent and Trademark Office. (2002). US Patent No. 6,414,148, Quinazoline derivatives.
- United States Code. (2023). 35 U.S.C. §§ 154 and 156: Patent term and patent term extension.
- U.S. Food and Drug Administration. (2023). Approved drug products with therapeutic equivalence evaluations: Orange Book.
- United States Patent and Trademark Office. (2023). Patent Center and Patent Assignment Search.
