Details for Patent: 7,173,038

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Summary for Patent: 7,173,038

Title:	Quinazoline derivatives as VEGF inhibitors
Abstract:	The invention relates to quinazoline derivatives of formula (I), wherein m is an integer from 1 to 3; R1 represents halogeno or C1-3alkyl; X1 represents —O—; R2 is selected from one of the following three groups: 1) C1-5alkylR3 (wherein R3 is piperidin-4-yl which may bear one or two substituents selected from hydroxy, halogeno, C1-4hydroxyalkyl and C1-4alkoxy; 2) C2-5alkenylR3 (wherein R3 is as defined hereinbefore); 3) C2-5alkynylR3 (wherein R3 is as defined hereinbefore); and wherein any alkyl, alkenyl or alkynyl group may bear one or more substituents selected from hydroxy, halogeno and amino; and salts thereof, processes for their preparation, pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as a active ingredient. The compounds of formula (I) and the pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of number of disease states including cancer and rheumatoid arthritis.
Inventor(s):	Andrew Peter Thomas, Elaine Sophie Elizabeth Stokes, Laurent Francois Andre Hennequin
Assignee:	Genzyme Corp
Application Number:	US10/129,336
Patent Claim Types: see list of patent claims	Composition; Compound; Process;

US Patent 7,173,038: Vandetanib Claims, Scope, Expiration and Patent Landscape

US Patent 7,173,038 is a composition, compound, and manufacturing patent directed to quinazoline derivatives, including vandetanib, the active ingredient in Caprelsa. Claim 8 specifically covers vandetanib and its salts. The patent also covers related substituted piperidine quinazolines, pharmaceutical compositions, and several synthetic routes.

The patent’s US statutory term ended in March 2020 based on the Orange Book-listed expiration date. FDA orphan-drug exclusivity for Caprelsa ended in April 2018. As a result, Patent 7,173,038 no longer creates a live US patent barrier to an ANDA applicant, although separate patents, regulatory exclusivity, product-specific litigation, and manufacturing rights must be reviewed independently.

What drug does US Patent 7,173,038 protect?

The patent protects a class of 4-anilinoquinazoline compounds with a substituted piperidine-containing alkoxy group. The key commercial compound is vandetanib.

Vandetanib chemical identity

The compound recited in claim 8 is:

4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline

Vandetanib is a small-molecule tyrosine kinase inhibitor marketed by AstraZeneca as Caprelsa. The FDA-approved product is indicated for symptomatic or progressive medullary thyroid cancer that cannot be removed by surgery or has metastasized [1].

The patent claims include both the free-base compounds and pharmaceutically acceptable salts. Vandetanib is commonly used in its pharmaceutical salt form, but claim 8 is drafted to cover the named compound "or a salt thereof."

How are the claims organized?

The patent contains four principal claim categories: broad chemical genus claims, narrower species claims, process claims, and pharmaceutical-composition claims.

Claim	Category	Principal scope
1	Compound genus	Formula I quinazoline derivatives with substituted piperidin-4-yl groups
2	Dependent compound	Limits the aniline ring to five specified substitution patterns
3	Dependent compound	Limits R2 to an alkyl-linked piperidine group
4	Dependent compound	Covers piperidin-4-ylmethyl derivatives with alkyl substitution
5	Compound genus	Formula II quinazoline derivatives
6	Enumerated species	Nine expressly identified quinazoline compounds
7	Narrower species	Four N-methylpiperidine derivatives
8	Commercial species	Vandetanib and its salts
9	Salt form	Pharmaceutically acceptable salts of claims 1-8
10	Manufacturing process	Four synthetic approaches and salt formation
11	Composition	A compound of claims 1-8 with a pharmaceutical carrier or excipient

The claim structure progressively narrows from a Markush genus in claims 1 and 5 to the specific commercial molecule in claim 8.

What is the scope of claim 1?

Claim 1 is a broad chemical genus claim. It requires a quinazoline core with the following structural elements:

1. An anilino substituent at the 4-position.
2. One to three substituents on the phenyl ring.
3. An oxygen linker, represented by X1 as -O-.
4. A piperidin-4-yl group attached through an alkyl, alkenyl, or alkynyl linker.
5. Optional substitution on the piperidine ring and linker.
6. A pharmaceutically acceptable salt option.

The claim permits:

• C1-5 alkyl linkers;
• C2-5 alkenyl linkers;
• C2-5 alkynyl linkers;
• Hydroxy, halogen, and amino substitution on those linkers;
• Hydroxy, halogen, C1-4 alkyl, C1-4 hydroxyalkyl, or C1-4 alkoxy substitution on the piperidine ring.

Claim 1 therefore reaches substantially more compounds than vandetanib. It is a genus claim intended to cover structural analogues sharing the same quinazoline-piperidine architecture.

Key claim limitations

The most important limitations are:

• The linker must contain an oxygen atom.
• The piperidine substituent must be attached at the 4-position.
• The aniline substituent pattern is restricted by the claim’s formula and dependent claims.
• The R2 group must connect through an alkyl, alkenyl, or alkynyl group.
• The claim does not cover every 4-anilinoquinazoline kinase inhibitor.

A compound that replaces the piperidine with morpholine, pyrrolidine, an acyclic tertiary amine, or another ring system would generally fall outside the literal scope of claim 1 unless another claim or an equivalents theory applied.

What compounds are covered by claims 6, 7 and 8?

Claims 6 through 8 move from a finite list of compounds to vandetanib itself.

Claim 6

Claim 6 identifies nine compounds. They differ primarily in:

• The aniline-ring substitution pattern;
• Whether the piperidine nitrogen is methylated;
• The presence of 4-chloro, 4-bromo, 2-fluoro, 2,6-difluoro, or 4-methyl substituents.

The nine compounds include both:

• 1-methylpiperidin-4-ylmethoxy derivatives; and
• Unsubstituted piperidin-4-ylmethoxy derivatives.

Claim 7

Claim 7 narrows the list to four N-methylpiperidine compounds. It excludes the 2-fluoro-4-methylanilino derivative appearing in claim 6 and retains the halogenated aniline variants.

Claim 8

Claim 8 covers only:

4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline

or a salt thereof.

This is the strongest claim for the commercial product because it recites the active molecular structure with no functional or therapeutic limitation. A product containing vandetanib as the active pharmaceutical ingredient would have been directly exposed to claim 8 during the patent term.

What formulation protection does US Patent 7,173,038 provide?

Claim 11 covers a pharmaceutical composition containing a compound of claims 1-8 or a pharmaceutically acceptable salt with a pharmaceutical excipient or carrier.

The claim is broad at the formulation level. It does not require:

• A specific dosage strength;
• A particular tablet coating;
• A specified dissolution profile;
• A particular excipient;
• A controlled-release system;
• A specific manufacturing process for the finished dosage form.

A generic tablet containing vandetanib and ordinary pharmaceutical excipients would have fallen within claim 11 while the patent was in force, provided the active ingredient satisfied claims 1-8.

Claim 11 is not a detailed formulation claim. It does not independently protect a proprietary excipient combination, particle-size distribution, polymorph, coating, or release profile. Those features would normally require separate formulation or solid-state claims.

What manufacturing methods are protected by claim 10?

Claim 10 covers four routes for preparing formula I compounds or their salts:

• Displacement or substitution involving a compound of formula III and an aniline compound of formula IV;
• Alkylation or related coupling between formula V and R2-L1;
• Reaction of a quinazoline intermediate with an R2-X1-H alcohol or related nucleophile;
• Deprotection of an R2 group protected by one or more protecting groups;
• Optional conversion into a pharmaceutically acceptable salt.

Claim 10 is process-dependent. It does not cover every method of making vandetanib. A manufacturer using a materially different synthetic sequence could avoid literal infringement if the process did not practice one of the recited reaction schemes or their required intermediates.

The practical value of claim 10 was strongest where the disclosed route was commercially efficient or where alternative routes were difficult to scale. After expiration, the claim no longer blocks US commercial manufacturing.

Manufacturing and intellectual-property barriers

The patent does not, based on the supplied claims, claim:

• A specific crystalline form of vandetanib;
• A polymorph;
• A hydrate or solvate;
• A particle-size distribution;
• A tablet coating;
• A dissolution specification;
• A specific impurity profile;
• A biological manufacturing process.

Those subjects could be covered by separate patents or regulatory controls. Patent 7,173,038 alone should not be treated as a complete freedom-to-operate analysis for all vandetanib manufacturing routes.

When did US Patent 7,173,038 expire?

The relevant US patent timeline is:

Event	Date
Earliest family priority	March 1999
US Patent 7,173,038 issued	February 6, 2007
FDA approval of Caprelsa	April 6, 2011
FDA orphan-drug exclusivity	Through approximately April 6, 2018
Orange Book-listed patent expiration	March 12, 2020
Current status	Statutory patent term ended

The patent term is controlled by the applicable US patent-term provisions, not by the issue date. The Orange Book identifies the relevant expiration date for the listed Caprelsa patent [2]. The patent therefore did not provide an enforceable US exclusionary right after March 2020.

Did pediatric exclusivity extend the patent?

The supplied record does not establish a six-month pediatric extension for Patent 7,173,038. Pediatric exclusivity, where granted, attaches to qualifying listed patents and exclusivities and can extend enforceability beyond the ordinary expiration date. The Orange Book patent-term record should control the operative date [2, 3].

What was the FDA regulatory status of Caprelsa?

FDA approved Caprelsa tablets in 2011 for medullary thyroid cancer. The approval was associated with orphan-drug exclusivity because medullary thyroid cancer is a rare disease and the product received orphan designation.

Regulatory item	Status
Active ingredient	Vandetanib
Brand	Caprelsa
Dosage form	Oral tablets
FDA pathway	New drug application
Initial FDA approval	April 6, 2011
Approved indication	Symptomatic or progressive medullary thyroid cancer
Orphan exclusivity	Seven years from approval, ending in 2018
Patent barrier from US 7,173,038	Ended in March 2020

Orphan exclusivity is separate from patent protection. It barred FDA approval of a competing product for the same orphan indication during the exclusivity period unless an exception applied. It did not extend the patent term.

What is the Orange Book status of US Patent 7,173,038?

The patent was listed in the FDA Orange Book for Caprelsa. Its listing gave the NDA holder a mechanism to receive notice of a Paragraph IV certification from an ANDA applicant and to file an infringement action within the statutory 45-day period.

The listing did not make the patent immune from invalidity, noninfringement, or expiration challenges. Once the patent term ended, the listing no longer created a live patent-based injunction risk for future US generic entry.

The Orange Book distinction is important:

• A listed patent may be expired.
• A listed patent may be challenged by Paragraph IV certification.
• Regulatory patent listing does not itself establish validity.
• FDA approval timing and actual market launch depend on exclusivity, litigation, supply, and commercial decisions.

Which companies challenged Caprelsa exclusivity?

Publicly available records should be reviewed for each ANDA applicant and litigation docket. The supplied claims alone do not identify the identity of any generic challenger, Paragraph IV filing, or settlement agreement.

The legally relevant generic pathway would have been an ANDA containing:

• Paragraph IV certification that the listed patent was invalid, unenforceable, or would not be infringed; or
• A Paragraph III certification agreeing to wait until patent expiration.

For a drug such as vandetanib, an ANDA applicant would also need to address:

• Bioequivalence;
• Tablet strength and dissolution;
• Labeling;
• REMS or other FDA safety requirements;
• The boxed warning and risk-management obligations associated with vandetanib;
• Any remaining Orange Book patents.

What patent litigation affected vandetanib?

US Patent 7,173,038 created the principal compound and composition patent risk for vandetanib during the period before March 2020. The claims provided a straightforward infringement theory against a product containing the exact claim 8 molecule.

The central litigation scenarios were:

1. A Paragraph IV challenge to the compound patent.
2. A patent-holder infringement action under Hatch-Waxman.
3. A 30-month FDA approval stay if the statutory requirements were satisfied.
4. Settlement permitting an agreed generic launch date.
5. Generic entry after patent expiration without a continuing patent injunction.

The supplied information does not identify a specific complaint, ANDA applicant, docket number, judgment, or settlement agreement. No particular litigation outcome can be attributed to this patent from the claim text alone.

Is there a biosimilar risk for Caprelsa?

No. Vandetanib is a chemically synthesized small molecule, not a biologic. A competing product would generally proceed through the abbreviated new drug application pathway under section 505(j) of the Federal Food, Drug, and Cosmetic Act rather than the biosimilar pathway under section 351(k) of the Public Health Service Act [3, 4].

The relevant competitive risks are:

• Generic vandetanib tablets;
• Authorized generic supply;
• Alternative kinase inhibitors;
• Competing treatments for medullary thyroid cancer;
• Off-label or guideline-driven substitution among targeted therapies.

Biosimilar approval standards, interchangeability, and biologic patent dances do not apply to this product.

How strong was the patent estate for vandetanib?

Patent 7,173,038 was strong against a product containing the exact vandetanib molecule while it remained in force because claim 8 is a direct compound claim. Compound claims generally provide broader enforcement leverage than method-of-use claims because infringement depends principally on the accused product’s chemical identity.

Strength by claim type

Claim type	Relative strength during term	Principal vulnerability
Claim 8 compound claim	High	Validity, anticipation, obviousness, claim construction
Claims 6-7 species claims	High to moderate	Prior-art disclosure of listed species
Claims 1 and 5 genus claims	Moderate	Written description, enablement, genus breadth
Claim 11 composition claim	Moderate	Scope of active ingredient and composition
Claim 10 process claim	Route-dependent	Noninfringing alternative synthesis
Method-of-use protection	Not present in supplied claims	Separate patents would be required

The absence of a therapeutic method-of-use claim in the supplied claims limits the patent’s scope to compounds, compositions, and processes. A competitor using a noninfringing compound or alternative manufacturing route would not necessarily infringe every claim.

What generic launch scenarios existed?

The principal US launch scenarios were:

Launch after ordinary patent expiration

This was the lowest-risk route. An ANDA applicant could target a launch after the March 2020 expiration date, assuming FDA approval and no other enforceable listed patent.

Paragraph IV launch

An applicant could file a Paragraph IV certification before expiration and challenge the patent. The patent holder could sue for infringement, potentially triggering a 30-month stay of final FDA approval under Hatch-Waxman [3].

Authorized generic or licensed launch

The innovator could authorize another company to market an equivalent product or license rights before patent expiration. The supplied material does not identify a license or settlement involving Patent 7,173,038.

At-risk launch

A generic company could launch after FDA approval while litigation remained unresolved. This approach could expose the company to damages and an injunction if the patent were later upheld and found infringed.

What geographic coverage did the patent provide?

US Patent 7,173,038 provided territorial rights only in the United States. The corresponding international patent family could contain counterpart applications in Europe and other jurisdictions, but each country or regional patent would have its own:

• Claim scope;
• Patent-term calculation;
• Validity record;
• Supplementary protection certificate status;
• Litigation history;
• Regulatory linkage rules.

US expiration did not automatically terminate foreign rights. A global launch review would require separate analysis of the European Patent Office and national patents, Canada, Japan, China, Australia, and other target markets.

Were there licensing deals involving the patent?

The claim text does not identify an assignment, license, co-development agreement, or settlement. AstraZeneca was the developer and marketer associated with Caprelsa. A complete licensing analysis would distinguish:

• Patent ownership;
• NDA sponsorship;
• Commercialization rights;
• Regional licenses;
• Generic settlements;
• Manufacturing and supply agreements.

No licensing right should be inferred solely from the patent’s assignee or the Caprelsa product label.

What is the commercial exposure from patent expiration?

Patent expiration removed the principal US compound barrier to generic vandetanib. Commercial exposure depends on:

• The size of the medullary thyroid cancer market;
• The number of approved ANDAs;
• Generic pricing;
• Treatment persistence;
• Physician familiarity with vandetanib;
• Competing kinase inhibitors;
• Safety monitoring and risk-management requirements.

The patent expiration did not guarantee immediate generic substitution. Vandetanib’s restricted indication, safety profile, and relatively specialized prescribing base can limit the number of commercially viable entrants. Standalone Caprelsa revenue should be assessed from AstraZeneca financial disclosures and IQVIA or equivalent market data rather than inferred from patent status.

Key Takeaways

• US Patent 7,173,038 covers quinazoline derivatives containing substituted piperidinyl alkoxy groups.
• Claim 8 specifically covers vandetanib and its salts.
• Claim 11 covers pharmaceutical compositions containing the claimed compounds.
• Claim 10 covers selected synthetic routes and salt-conversion steps.
• The patent is a compound and manufacturing patent, not a method-of-use patent based on the supplied claims.
• Caprelsa received FDA approval on April 6, 2011.
• FDA orphan-drug exclusivity ended approximately April 6, 2018.
• The Orange Book-listed patent expiration was March 12, 2020.
• Vandetanib is a small molecule, so generic competition proceeds through the ANDA pathway, not biosimilar approval.
• The patent’s US exclusionary term has ended, but separate formulation, process, method-of-use, regulatory, and foreign rights require independent review.
• The supplied record does not establish a specific Paragraph IV challenger, litigation outcome, settlement, or license.

FAQs

Does US Patent 7,173,038 cover vandetanib hydrochloride?

Yes. Claim 8 covers vandetanib "or a salt thereof," which encompasses pharmaceutically acceptable salt forms, subject to the precise identity and scope of the salt.

Does the patent cover every quinazoline kinase inhibitor?

No. The claims require specific anilinoquinazoline and piperidine-containing structures. Other quinazoline kinase inhibitors may fall outside the literal claim scope.

Is claim 11 a patent on Caprelsa tablets?

Claim 11 covers a pharmaceutical composition containing a claimed quinazoline compound and a pharmaceutically acceptable carrier or excipient. It is broad and does not recite every commercial tablet characteristic.

Can a generic company manufacture vandetanib using a different process?

After expiration of the patent, the US patent no longer blocks manufacturing. Before expiration, a different process could avoid claim 10 only if it did not practice the claimed route or an applicable equivalent. Compound claims could still have blocked the resulting product.

Does patent expiration eliminate all US market-entry risk for vandetanib?

No. It eliminates the barrier created by Patent 7,173,038, but remaining risks could include other listed patents, regulatory requirements, exclusivity, product liability, supply constraints, and separate patents covering formulations, uses, polymorphs, or manufacturing processes.

References

1. U.S. Food and Drug Administration. (2011). Caprelsa (vandetanib) prescribing information.
2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
3. U.S. Food and Drug Administration. (2023). Abbreviated new drug application submissions: Refuse-to-receive standards.
4. U.S. Congress. (2010). Biologics Price Competition and Innovation Act of 2009, Public Law 111-148, §7002.
5. United States Patent and Trademark Office. (2007). U.S. Patent No. 7,173,038, Quinazoline derivatives.

Drugs Protected by US Patent 7,173,038

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

Foreign Priority and PCT Information for Patent: 7,173,038

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
	99402759	Nov 05, 1999
	99402877	Nov 19, 1999

PCT Information
PCT Filed	November 01, 2000	PCT Application Number:	PCT/GB00/04181
PCT Publication Date:	May 10, 2001	PCT Publication Number:	WO01/32651

International Family Members for US Patent 7,173,038

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	1244647		C300543	Netherlands
European Patent Office	1244647		PA2012015	Lithuania
European Patent Office	1244647		CA 2012 00032	Denmark
European Patent Office	1244647		92057	Luxembourg
European Patent Office	1244647		2012/029	Ireland
European Patent Office	1244647		1290028-8	Sweden