Details for Patent: 4,188,390

Summary for Patent: 4,188,390

Title:	Antihypertensive 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl) piperazin-1-yl or homopiperazin-1-yl]quinazolines
Abstract:	Compounds having the formula and pharmaceutically acceptable salts thereof wherein R represents 6,7-di(lower alkoxy) or 6,7,8-tri(lower alkoxy); m is 1 or 2, X is -CHR1- or -CH2CH2-; each R1 and R0 may be the same or different and is hydrogen or lower alkyl; each of R2 and R3 is hydrogen, lower alkoxy, lower alkyl, halogen, lower alkanoyl, lower alkoxycarbonyl, -CONR4R5 or -SO2NR4R5 wherein each of R4 and R5 is hydrogen or lower alkyl; processes for their preparation; and their use as regulators of the cardiovascular system, and particularly in the treatment of hypertension.
Inventor(s):	Simon F. Campbell
Assignee:	Pfizer Corp SRL
Application Number:	US05/952,317
Patent Claim Types: see list of patent claims	Composition; Compound;

US Patent 4,188,390: Doxazosin Scope, Claim Construction, Expiration, and Patent Landscape

US Patent 4,188,390 covers a class of substituted 2-piperazinyl quinazoline compounds, including doxazosin and related analogues. The key commercial compound is 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl)piperazin-1-yl]-6,7-dimethoxyquinazoline, commonly known as doxazosin. The patent issued on February 12, 1980, and its original U.S. patent term expired on February 12, 1997. The patent no longer blocks manufacture or sale of doxazosin in the United States. [1]

What drug does US Patent 4,188,390 protect?

The patent protects quinazoline alpha-1 adrenergic receptor antagonists. Claim 5 specifically covers doxazosin, while claim 4 covers the corresponding 6,7,8-trimethoxy analogue.

Patent claim	Principal subject matter	Commercial relevance
Claim 1	Broad Markush class of substituted quinazoline compounds and acid-addition salts	Defines the genus
Claim 2	Narrower genus with specified methyl, amide, sulfonamide and related substituents	Narrows the permitted substituent set
Claim 3	6,7-dimethoxy quinazoline subclass	Contains the doxazosin structure
Claim 4	6,7,8-trimethoxy specific compound	Covers a trimethoxy analogue, not doxazosin
Claim 5	6,7-dimethoxy doxazosin compound	Direct composition-of-matter claim to doxazosin
Claim 6	Pharmaceutical composition containing a claim 1 compound or salt	Covers drug products containing the claimed compounds

Doxazosin is generally marketed as doxazosin mesylate, the methanesulfonate acid-addition salt. The free-base structure recited in claim 5 falls within the patent, and the pharmaceutically acceptable acid-addition salt language covers doxazosin mesylate.

What is the chemical scope of claim 1?

Claim 1 is a Markush claim. It does not cover one molecule only. It covers a family defined by variable substituents around a common quinazoline-piperazine-benzodioxane framework.

The core structural requirements are:

1. A 4-amino-substituted quinazoline nucleus.
2. A piperazinyl substituent at the 2-position of the quinazoline.
3. An acyl-linked 1,4-benzodioxane group attached to the piperazine nitrogen.
4. Either a 6,7-dialkoxy or 6,7,8-trialkoxy substitution pattern on the quinazoline ring.
5. Defined substituent options for R0, R1, R2 and R3.
6. The free compound or a pharmaceutically acceptable acid-addition salt.

The term “lower” ordinarily refers to short-chain organic groups, such as methyl, ethyl, propyl or related lower homologues, subject to the patent’s specification and applicable claim-construction principles. The claims expressly permit hydrogen, lower alkyl, lower alkoxy, halogen, lower alkanoyl, lower alkoxycarbonyl, carboxamide and sulfonamide substituents.

The claim does not cover every alpha-1 blocker. A competing compound must have the claimed quinazoline-piperazine-benzodioxane architecture, satisfy the alkoxy substitution requirement, and fall within the listed substituent definitions to present a literal infringement issue.

How narrow is claim 5 for doxazosin?

Claim 5 is substantially narrower than claim 1. It requires:

• The 6,7-dimethoxy substitution pattern;
• Hydrogen at the specified R1, R2 and R3 positions;
• The 4-amino quinazoline;
• The 2-piperazinyl linkage;
• The 1,4-benzodioxane-2-carbonyl group attached to piperazine.

This is a composition-of-matter claim directed to doxazosin itself. It is stronger against a product containing the same active ingredient than the broader genus claim because the accused molecule can be compared directly with the expressly recited structure.

The claim also covers pharmaceutically acceptable acid-addition salts. Doxazosin mesylate therefore falls within the salt coverage, assuming the compound is otherwise within the claim’s structural limitations.

What is the difference between claims 4 and 5?

Claim 4 covers the 6,7,8-trimethoxy analogue:

“4-Amino-2-[4-(1,4-benzodioxan-2-carbonyl)piperazin-1-yl]-6,7,8-trimethoxyquinazoline.”

Claim 5 covers the 6,7-dimethoxy analogue, which is doxazosin:

“4-Amino-2-[4-(1,4-benzodioxan-2-carbonyl)piperazin-1-yl]-6,7-dimethoxyquinazoline.”

The difference is one methoxy group on the quinazoline ring. Claim 4 does not cover doxazosin because doxazosin has two methoxy groups at positions 6 and 7, not three methoxy groups at positions 6, 7 and 8.

What does claim 6 protect?

Claim 6 covers a pharmaceutical composition containing:

• A compound within claim 1 or a pharmaceutically acceptable acid-addition salt; and
• A pharmaceutically acceptable diluent or carrier.

The phrase “cardiovascular regulating amount” introduces a functional dosage limitation. The claim is directed to a pharmaceutical composition rather than to the active compound alone.

For a doxazosin tablet, infringement would historically have depended on the presence of doxazosin or a covered salt in a pharmaceutical carrier and the other limitations of the incorporated compound claim. Claim 6 does not independently cover every cardiovascular composition or every alpha-1 antagonist.

When did US Patent 4,188,390 expire?

US Patent 4,188,390 issued on February 12, 1980. Because it was filed and issued under the pre-1995 U.S. patent-term regime, its term was generally 17 years from issuance. The resulting expiration date was February 12, 1997. [1]

Event	Date
U.S. patent issued	February 12, 1980
Original statutory term	17 years from issuance
Expected expiration	February 12, 1997
Current blocking status	Expired
Patent-term-extension relevance	No current blocking extension identified

The patent cannot now be asserted to block a new U.S. generic launch. Any surviving patent-right issue would have to arise from a different patent, a separately protected formulation, a later method-of-use patent, or a non-patent regulatory restriction.

What was the FDA regulatory status of doxazosin?

Pfizer commercialized doxazosin under the brand name Cardura. The FDA approved Cardura tablets for hypertension and for the signs and symptoms of benign prostatic hyperplasia. Doxazosin is an alpha-1 adrenergic receptor antagonist. [2]

Product	Active ingredient	Dosage form	Principal uses
Cardura	Doxazosin mesylate	Immediate-release tablet	Hypertension; BPH
Generic doxazosin	Doxazosin mesylate	Immediate-release tablet	Hypertension; BPH
Cardura XL	Doxazosin mesylate	Extended-release tablet	BPH

The immediate-release product was the principal commercial product protected by the compound patent. Later extended-release products depended on separate formulation and regulatory considerations rather than on the expired 1980 composition patent alone.

What is the Orange Book status of US Patent 4,188,390?

US Patent 4,188,390 is no longer an operative Orange Book barrier because it expired in 1997. Orange Book listings identify patents associated with approved drug products, but an expired patent does not prevent an ANDA applicant from receiving approval or launching a product after satisfaction of applicable regulatory requirements. [3]

The relevant distinction is:

• Historical listing: the patent could have been associated with the branded product during its enforceable term.
• Current blocking effect: none from the expired patent.
• Generic certification today: an applicant does not face a live Paragraph IV challenge to an expired patent.
• Remaining risk: later patents covering formulations, delivery systems, methods of use or manufacturing processes.

The Orange Book must be reviewed by product and NDA, not only by active ingredient. A later formulation patent may be listed against Cardura XL or another product even though the original compound patent has expired.

Were there Paragraph IV challenges to this patent?

A Paragraph IV certification is used when an ANDA applicant asserts that a listed patent is invalid, unenforceable or will not be infringed. It is most relevant before patent expiration.

Because US Patent 4,188,390 expired in 1997, a current ANDA applicant would not need to defeat it through Paragraph IV litigation. Generic companies could rely on the patent’s expiration, subject to other listed patents and regulatory exclusivities.

Public generic entry for immediate-release doxazosin occurred after the compound patent term ended. The resulting market entry was therefore primarily an expiration-driven launch rather than a continuing patent litigation contest over claim 5.

What formulation patents protect doxazosin products?

The original patent protects the active chemical entity and compositions containing covered compounds. It does not, on the face of the supplied claims, claim:

• A specific extended-release matrix;
• An osmotic delivery system;
• A defined dissolution profile;
• A particular tablet coating;
• A multiparticulate dosage form;
• A specific manufacturing process for doxazosin mesylate;
• A particular combination with another active ingredient.

Those features would require separate claims in later patents. Cardura XL and other modified-release products therefore require a separate patent-family review. The expired compound patent does not, by itself, establish freedom to operate for a controlled-release formulation.

For generic applicants, the principal technical workstreams are:

1. Active pharmaceutical ingredient synthesis.
2. Salt formation and crystallization.
3. Polymorph and solid-state control.
4. Immediate-release tablet formulation.
5. Modified-release delivery, if applicable.
6. Bioequivalence testing.
7. Labeling and method-of-use carve-outs.

The composition patent creates no current manufacturing barrier. Process patents or solid-state patents, if valid and unexpired, could still affect commercial manufacture.

Does doxazosin have biosimilar risk?

No. Doxazosin is a synthetic small-molecule drug, not a biologic. The relevant competitive pathway is the ANDA process for generic drugs, not the abbreviated pathway for biosimilars under the Public Health Service Act.

The commercial risk is therefore generic substitution by manufacturers of doxazosin mesylate tablets. Biosimilar concepts such as reference-product exclusivity, interchangeability and biosimilar naming do not apply.

Which companies compete with branded Cardura?

The competitive field includes:

• Pfizer as the original Cardura sponsor;
• Generic manufacturers marketing doxazosin mesylate tablets;
• Manufacturers of other alpha-1 blockers, including terazosin, prazosin, tamsulosin and alfuzosin;
• Combination-product and modified-release developers where applicable.

Doxazosin competes primarily in two markets:

Market	Doxazosin position	Main competitive pressure
Hypertension	Broad therapeutic alternatives and low-cost generics	Generic erosion and newer antihypertensives
BPH	Alpha-1 blocker class	Tamsulosin, alfuzosin, terazosin and 5-alpha-reductase inhibitors

Doxazosin’s patent-based differentiation ended in 1997. After that date, competition shifted from patent exclusivity to manufacturing cost, formulary position, supply reliability and clinical prescribing patterns.

How strong is the patent estate for doxazosin?

The original estate was strong during the compound patent term because claim 5 directly covered the commercial active ingredient. Its principal characteristics were:

Factor	Assessment
Core composition claim	Strong during term
Breadth	Broad genus in claim 1; narrower species in claim 5
Salt coverage	Expressly included
Product-form coverage	Claim 6 covers pharmaceutical compositions
Remaining term	None
Biosimilar exposure	Not applicable
Generic exposure	High after 1997
Formulation protection	Requires separate later patents
Manufacturing protection	Requires separate process claims
Current U.S. blocking strength	None from US 4,188,390

The patent’s historical strength came from the composition-of-matter claim. Its current commercial value is limited because the patent has expired and the active ingredient is available through generic suppliers.

What generic launch scenarios exist?

For immediate-release doxazosin mesylate, the principal launch scenario is an established generic market with no remaining barrier from US 4,188,390.

For a new product, the risk profile depends on the product type:

Product scenario	Primary intellectual-property issue
Immediate-release doxazosin tablet	Expired composition patent; remaining Orange Book listings must be checked
New dosage strength	ANDA requirements and possible exclusivity issues
Extended-release doxazosin	Later formulation and delivery patents
New combination product	Combination or method-of-use patents
New indication	Later method-of-use patents
New manufacturing route	Process patents and trade secrets
Foreign launch	Country-specific patent terms and SPCs

A generic applicant should not treat expiration of US 4,188,390 as conclusive freedom to operate for every doxazosin product. It is conclusive only as to the rights created by that patent.

What is the geographic patent coverage?

US 4,188,390 has U.S. territorial effect. Foreign protection would depend on corresponding national patents or regional patent grants in the relevant jurisdictions. U.S. expiration does not establish that all foreign family members have expired.

For international commercialization, the relevant review should include:

• European national or European Patent Office family members;
• Canada;
• Japan;
• Australia;
• Brazil;
• China;
• India;
• Any supplementary protection certificates or patent-term extensions;
• Local Orange Book equivalents and regulatory exclusivity rules.

The U.S. patent’s 1997 expiration date cannot be transferred mechanically to foreign jurisdictions because filing dates, patent terms, prosecution adjustments and supplementary protection mechanisms differ.

What patent litigation affects doxazosin today?

US Patent 4,188,390 does not create an active U.S. patent-litigation risk because its term expired in 1997. Current litigation exposure, if any, would need to arise from later patents involving:

• Controlled-release doxazosin;
• Tablet composition;
• Solid-state forms;
• Manufacturing processes;
• Combination therapies;
• New indications;
• Device or delivery technology.

The supplied patent claims do not contain a continuing enforceable right against a present-day immediate-release generic manufacturer.

Key Takeaways

• US Patent 4,188,390 is the foundational U.S. patent for doxazosin and related quinazoline compounds.
• Claim 5 specifically covers doxazosin, including its pharmaceutically acceptable acid-addition salts.
• Claim 1 covers a broader Markush genus with defined alkoxy, alkyl, halogen, amide and sulfonamide substituents.
• Claim 6 covers pharmaceutical compositions containing covered compounds.
• The patent issued on February 12, 1980, and expired on February 12, 1997.
• The patent no longer blocks generic doxazosin manufacture or sale in the United States.
• Doxazosin is a small molecule, so biosimilar law is irrelevant.
• Remaining commercial IP risk must be assessed through later formulation, method-of-use, process and delivery patents.
• Cardura’s historical market exclusivity rested primarily on the expired composition-of-matter patent.
• Generic competition, not the original patent, determines current pricing and market access.

FAQs

Is doxazosin covered by US Patent 4,188,390?

Yes. Claim 5 specifically recites the 6,7-dimethoxy doxazosin structure, and the patent also covers pharmaceutically acceptable acid-addition salts such as doxazosin mesylate.

Can a company launch generic doxazosin after the patent expired?

Yes, subject to FDA approval and any other unexpired patents or regulatory exclusivities applicable to the specific product.

Does US Patent 4,188,390 cover tamsulosin?

No. Tamsulosin has a different chemical structure and is not within the quinazoline-piperazine-benzodioxane genus recited by this patent.

Does the patent cover Cardura XL?

The patent covers the doxazosin active ingredient, but the supplied claims do not specifically claim an extended-release delivery system. Cardura XL requires separate analysis of later formulation and delivery patents.

Are doxazosin products subject to biosimilar competition?

No. Doxazosin is a small-molecule drug. Competition occurs through generic-drug approvals under the ANDA pathway.

References

1. U.S. Patent and Trademark Office. (1980). Quinazoline derivatives, U.S. Patent No. 4,188,390.
2. U.S. Food and Drug Administration. (n.d.). Cardura: Doxazosin mesylate prescribing information. Drugs@FDA.
3. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations. Orange Book.

Drugs Protected by US Patent 4,188,390

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: 4,188,390

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	46128/77	Nov 05, 1977
Denmark	4286/78	Sep 27, 1978

International Family Members for US Patent 4,188,390

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	219562
Argentina	223015
Austria	365186
Austria	366684