Details for Patent: 5,703,110

Summary for Patent: 5,703,110

Title:	Benzimidazole derivatives, their production and use
Abstract:	Benzimidazole derivatives of the formula (I): ##STR1## wherein the ring A is a benzene ring which may optionally contain substitution in addition to the R' group; R1 is hydrogen or an optionally substituted hydrocarbon residue; R2 is a group capable of forming an anion or a group convertible thereinto; X is a direct bond or a spacer having an atomic length of two or less between the phenylene group and the phenyl group; R' is carboxyl, an ester thereof, an amide thereof or a group capable of forming an anion or convertible to an anion; Y is --O--, --S(O)m -- or --N(R4)-- wherein m is an integer of 0, 1 or 2 and R4 is hydrogen or an optionally substituted alkyl group; and n is an integer of 1 or 2; and the pharmaceutically acceptable salts thereof, have potent angiotensin II antagonistic activity and antihypertensive activity, thus being useful as therapeutic agents for treating circulatory system diseases such as hypertensive diseases, heart diseases (e.g. hypercardia, heart failure, cardiac infarction, etc.), strokes, cerebral apoplexy, nephritis, etc.
Inventor(s):	Takehiko Naka, Kohei Nishikawa, Takeshi Kato
Assignee:	Takeda Pharmaceutical Co Ltd
Application Number:	US08/715,100
Patent Claim Types: see list of patent claims	Use; Composition;

US Drug Patent 5,703,110: Azilsartan Scope, Claims, Expiration, and Patent Landscape

US Patent 5,703,110 covers azilsartan, the active angiotensin II receptor blocker later developed commercially as the active moiety in Edarbi. Its principal claim is a compound claim covering azilsartan and pharmaceutically acceptable salts. The patent also claims pharmaceutical compositions and methods of antagonizing angiotensin II.

The patent’s US statutory term ended in 2015. It is therefore expired and does not currently block generic manufacture or sale of azilsartan under this patent. The patent did not, however, provide the principal long-term protection for azilsartan medoxomil, the prodrug used in Edarbi. Later patents covering the prodrug, formulations, dosage forms, and related uses formed the commercially relevant estate.

What drug does US Patent 5,703,110 cover?

US 5,703,110 covers azilsartan, chemically identified as:

2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid

Azilsartan is a nonpeptide angiotensin II type 1, or AT1, receptor antagonist. It blocks angiotensin II binding at the AT1 receptor and reduces vasoconstriction, aldosterone activity, and blood-pressure elevation.

The compound was developed by Takeda Pharmaceutical Company. Edarbi contains azilsartan medoxomil, an orally administered prodrug that is converted in vivo to azilsartan. The distinction between azilsartan and azilsartan medoxomil is central to the patent analysis.

Item	Information
Patent	US 5,703,110
Patent family	Benzimidazole angiotensin II receptor antagonists
Applicant/assignee	Takeda-related pharmaceutical interests
Key compound	Azilsartan
Commercial product	Edarbi contains azilsartan medoxomil
Therapeutic class	Angiotensin II receptor blocker
US filing date	1995
US issue date	December 30, 1997
Earliest priority	1994 Japanese priority filing
Approximate US statutory expiration	May 2015
Current status	Expired
Orange Book relevance	Historical compound protection; not current blocking protection

The patent’s claim language contains transcription errors in the supplied version, including malformed brackets and an apparent “4-)-methyl” error. The intended chemical structure is the azilsartan structure identified above. Patent scope must be determined from the issued patent and its official claim text, not from a corrupted database transcription. (U.S. Patent No. 5,703,110, 1997)

What are the claims of US Patent 5,703,110?

The patent has three claims directed to the active compound, pharmaceutical compositions, and therapeutic use.

Claim 1: Azilsartan and pharmaceutically acceptable salts

Claim 1 covers:

“2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid or a pharmaceutically acceptable salt thereof.”

This is the strongest and commercially most significant claim. It is a product claim. A valid product claim generally provides protection against making, using, selling, offering for sale, or importing the claimed compound in the United States during the patent term.

The claim covers:

• The azilsartan free acid.
• Pharmaceutically acceptable salts of azilsartan.
• Pharmaceutical manufacture involving the claimed compound.
• Commercial products whose active pharmaceutical ingredient is the claimed compound or a covered salt.

The claim does not expressly cover every chemically related benzimidazole compound. It is limited to the specific substitution pattern recited in the claim:

• An ethoxy group on the benzimidazole ring.
• A biphenyl substituent attached through a methyl bridge.
• A 1H-tetrazol-5-yl group on the second biphenyl ring.
• A carboxylic acid at the 7-position of the benzimidazole ring.

The claim is not a broad Markush claim covering the entire class of angiotensin II receptor antagonists.

Claim 2: Pharmaceutical composition

Claim 2 covers a pharmaceutical composition containing a therapeutically effective amount of azilsartan or a pharmaceutically acceptable salt, mixed with a pharmaceutically acceptable carrier, excipient, or diluent.

This claim reaches finished pharmaceutical formulations that contain azilsartan as the active ingredient. It is narrower than the compound claim because an accused product must satisfy both the active-ingredient limitation and the composition limitations.

The claim may cover conventional oral dosage forms, including tablets, capsules, powders, and other compositions, if they contain the claimed compound and an acceptable pharmaceutical carrier. It does not expressly claim a specific dosage strength, release profile, excipient system, tablet geometry, coating, or manufacturing process.

The claim does not necessarily cover Edarbi solely because Edarbi produces azilsartan after administration. Edarbi contains azilsartan medoxomil, not azilsartan itself as the marketed active ingredient. Whether a prodrug product falls within a compound or composition claim depends on the precise claim language and the product’s composition. Claim 2, as written, is directed to a composition containing azilsartan or its salt, rather than a composition containing azilsartan medoxomil.

Claim 3: Method of antagonizing angiotensin II

Claim 3 covers administering a therapeutically effective amount of azilsartan or a pharmaceutically acceptable salt to a mammal.

This is a method-of-treatment claim. It requires:

1. A mammalian subject.
2. Administration of azilsartan or a covered salt.
3. A therapeutically effective amount.
4. Angiotensin II antagonism as the claimed therapeutic purpose.

The claim is not limited to hypertension. It is framed around antagonizing angiotensin II. Depending on claim construction and proof, the claim could reach treatment applications involving hypertension or other conditions mediated by angiotensin II activity.

Method claims generally create greater enforcement complexity than product claims because infringement requires proof that the claimed method was performed. A manufacturer may still face indirect infringement allegations if it sells a product with instructions that encourage the claimed use.

What chemical subject matter does the patent protect?

US 5,703,110 protects azilsartan as a defined molecular entity rather than a broad family of compounds.

Covered subject matter

The patent covers:

• Azilsartan free acid.
• Pharmaceutically acceptable azilsartan salts.
• Compositions containing azilsartan or a covered salt.
• Therapeutic administration of azilsartan or a covered salt to antagonize angiotensin II.

Subject matter outside the express compound claim

The patent does not expressly claim:

• Azilsartan medoxomil as a separate ester prodrug.
• A particular polymorphic form.
• A specific crystalline form.
• A specific hydrate or solvate unless covered through the salt or compound language.
• A defined sustained-release formulation.
• A specific tablet formulation.
• A manufacturing process for azilsartan.
• A specific combination with another antihypertensive.
• A particular dosage regimen, unless captured by the broader method language.

Azilsartan medoxomil is chemically distinct from azilsartan. The medoxomil group improves oral delivery and is hydrolyzed after administration. A later patent directed specifically to azilsartan medoxomil can provide protection independent of the expired azilsartan compound patent.

When did US Patent 5,703,110 expire?

The patent’s US term ended in approximately May 2015, calculated from the 1995 US nonprovisional filing date under the 20-year patent-term rule applicable to post-1995 applications. The patent issued in 1997, but issue date does not control the expiration date for this patent class.

Milestone	Date
Earliest Japanese priority	May 1994
US application filing	May 1995
US patent issue	December 30, 1997
Approximate 20-year US term end	May 2015
Current enforceability	Expired

The expiration of US 5,703,110 eliminates the patent’s ability to block a current generic product based solely on azilsartan or an azilsartan salt. It does not eliminate later patent rights covering azilsartan medoxomil, formulation technology, dosage forms, or other product-specific features.

Patent-term adjustment or terminal-disclaimer data should be confirmed in the official USPTO patent record when calculating a historical infringement date. The ordinary term calculation places the patent’s expiration in 2015. (U.S. Patent and Trademark Office, n.d.)

What was the Orange Book status of azilsartan and Edarbi?

The FDA approved Edarbi in 2011 for hypertension. Edarbi contains azilsartan medoxomil, not azilsartan free acid as the marketed active ingredient. The regulatory product and its patent position therefore depend primarily on patents directed to azilsartan medoxomil and its formulations.

Regulatory issue	Assessment
FDA product	Edarbi
Active ingredient in marketed product	Azilsartan medoxomil
Active metabolite	Azilsartan
Approval pathway	New drug application
Approval year	2011
Primary indication	Treatment of hypertension
US 5,703,110 status	Expired
Current blocking value of US 5,703,110	None by itself
Relevant later protection	Prodrug, formulation, dosage, and use patents

The Orange Book may list patents associated with Edarbi, but an Orange Book listing does not establish that every listed patent covers every generic formulation. It identifies patents and exclusivity information relevant to abbreviated new drug application certification and litigation under the Hatch-Waxman Act. (U.S. Food and Drug Administration, n.d.-a)

What patents protected azilsartan medoxomil and Edarbi?

The commercial patent estate developed beyond US 5,703,110. It generally consisted of four layers:

1. Compound protection for azilsartan.
2. Prodrug protection for azilsartan medoxomil.
3. Formulation and dosage-form protection.
4. Method-of-use and regulatory exclusivity protection.

The first layer expired in 2015. The second and third layers were more important to generic-entry timing for Edarbi.

Compound patents

US 5,703,110 is the foundational compound patent for azilsartan. It protected the active metabolite and certain salts but did not by itself provide a complete patent barrier against products containing a distinct prodrug.

Prodrug patents

Azilsartan medoxomil patents protect the esterified prodrug and may include:

• The prodrug compound itself.
• Pharmaceutical compositions containing the prodrug.
• Conversion of the prodrug to azilsartan in vivo.
• Use of the prodrug for hypertension.
• Specific salt, crystalline, or solid-state forms.

These patents can remain relevant after expiration of the parent active-metabolite patent because the prodrug is a separate chemical entity.

Formulation patents

Later formulation patents may cover:

• Tablet compositions.
• Stabilized formulations.
• Specific excipient combinations.
• Dissolution characteristics.
• Solid-state forms.
• Manufacturing conditions.
• Dosage strengths or administration schedules.

A generic applicant can avoid some formulation claims by using a non-infringing formulation. Product claims covering the prodrug itself are harder to design around.

Method-of-use patents

Method patents may cover treatment of hypertension or specific administration regimens. Their practical value depends on:

• The label proposed by the generic applicant.
• Whether the indication is protected.
• Whether the generic applicant uses a section viii statement to omit a patented indication.
• Whether induced-infringement allegations can be established from labeling and marketing conduct.

Which companies challenged Edarbi patent protection?

Generic competition against Edarbi would typically proceed through an ANDA filed under section 505(j) of the Federal Food, Drug, and Cosmetic Act. The applicant could certify that listed patents were expired, would expire on a specified date, were not infringed, or were invalid under Paragraph IV.

A Paragraph IV certification is a legal assertion by the ANDA applicant. It does not itself invalidate a patent. The patent holder may sue within 45 days, triggering an automatic 30-month stay of FDA approval for the affected application, subject to statutory exceptions. (21 U.S.C. § 355(j); U.S. Food and Drug Administration, n.d.-b)

Publicly available patent litigation records should be reviewed separately for:

• The specific defendant.
• The asserted patent numbers.
• The filing date.
• The court’s jurisdiction.
• Whether the case settled.
• Whether the litigation concerned azilsartan medoxomil or only a formulation patent.
• The authorized-generic or launch date.

US 5,703,110 itself is no longer a viable Paragraph IV litigation target because it expired in 2015. Any current or historical Edarbi challenge would principally concern later patents listed against azilsartan medoxomil products.

What generic entry risks exist for azilsartan?

The risk profile differs between azilsartan and Edarbi.

Azilsartan API or azilsartan-salt product

Generic entry risk against US 5,703,110 is complete because the patent expired. A manufacturer can pursue an azilsartan product without infringing this expired patent, subject to other active patents, regulatory requirements, and non-patent barriers.

Azilsartan medoxomil product

The risk is more complex. A generic Edarbi applicant may need to address:

• The prodrug compound patent.
• Orange Book-listed formulation patents.
• Dosage-form patents.
• Method-of-use patents.
• FDA exclusivity.
• Labeling restrictions.
• Patent settlements or licenses.

A generic product could avoid some use claims through a section viii carve-out, but a compound patent covering azilsartan medoxomil would remain a direct product barrier.

Launch scenarios

Scenario	Commercial effect
All relevant patents expired	Full generic entry becomes possible
Paragraph IV litigation filed	FDA approval may be delayed by the 30-month stay
Successful invalidity or non-infringement challenge	Early launch may occur, subject to other rights
Settlement with delayed entry	Entry date depends on settlement terms
Formulation patent remains valid	Alternative formulation may support design-around
Method patent only	Carved-out label may reduce exposure
Authorized generic launch	Price erosion may precede independent generic entry

Does biosimilar risk apply to azilsartan?

No. Azilsartan and azilsartan medoxomil are small-molecule drugs, not biologics. The relevant competitive pathway is the ANDA pathway for generic drugs, not the biosimilar pathway under the Public Health Service Act.

The FDA Purple Book is therefore not the relevant patent or interchangeability database. The Orange Book and FDA-approved drug-label records are the relevant regulatory sources. (U.S. Food and Drug Administration, n.d.-c)

How strong is the patent estate for azilsartan?

US 5,703,110 was strong during its term because it contained a defined chemical compound claim. A compound claim generally provides broader enforcement coverage than a method or formulation claim because it can reach the product itself.

Its current strength is zero as an enforceable US right because the patent has expired.

The broader azilsartan commercial estate was stronger than US 5,703,110 alone because it combined multiple patent categories. Its practical durability depended on whether later patents claimed the prodrug itself or only narrower formulations and uses.

Patent category	Historical strength	Current strategic value
Azilsartan compound	High during term	None after expiration
Azilsartan salts	High during term	None under this patent
Azilsartan medoxomil compound	Potentially high	Depends on later patent expiry
Formulation	Moderate to high	Product- and claim-specific
Method of use	Moderate	Depends on label and enforcement
Manufacturing process	Variable	Relevant if process is difficult to design around
Regulatory exclusivity	Time-limited	Separate from patent rights

What manufacturing and IP barriers remain?

The expired compound patent does not remove all barriers to generic development. A manufacturer still must address:

• Synthesis of the benzimidazole core.
• Introduction of the biphenyl tetrazole group.
• Control of regioisomers and impurities.
• Tetrazole chemistry and purification.
• Salt selection.
• Solid-state characterization.
• Conversion between azilsartan and azilsartan medoxomil.
• Bioequivalence.
• Stability and dissolution.
• Patent claims covering the prodrug or formulation.

The manufacturing process may be commercially important even when it is not independently patent-blocking. A process that produces acceptable purity and solid-state properties at scale can reduce development cost and regulatory risk.

What licensing deals affect the patent landscape?

Takeda was the originating developer and commercial sponsor of Edarbi in the United States. The record for US 5,703,110 does not establish a separate third-party license that changes ownership or extends the patent term.

Any later agreement involving Edarbi or azilsartan medoxomil must be analyzed by its specific terms. A patent settlement may permit a generic launch before the listed patent’s expiration without granting a general license to all azilsartan-related patents. Commercial agreements can also address authorized-generic supply, launch dates, royalties, or geographic rights.

Patent ownership, FDA listing, and commercial licensing are separate questions. An assignee shown in the USPTO record does not by itself establish the terms of a later commercialization agreement.

Key Takeaways

• US Patent 5,703,110 covers azilsartan, the active metabolite associated with Edarbi.
• Claim 1 is the core product claim and covers azilsartan and pharmaceutically acceptable salts.
• Claim 2 covers pharmaceutical compositions containing azilsartan or a covered salt.
• Claim 3 covers administration of azilsartan to antagonize angiotensin II in a mammal.
• The patent does not expressly claim every azilsartan prodrug, formulation, polymorph, or manufacturing process.
• The US patent term ended in approximately May 2015.
• US 5,703,110 no longer blocks generic azilsartan.
• Edarbi’s later patent position depended mainly on azilsartan medoxomil, formulation, dosage, and method-of-use patents.
• Azilsartan is a small molecule, so generic competition proceeds through the ANDA pathway rather than biosimilar regulation.
• Any current generic-entry analysis must focus on active Orange Book-listed patents other than US 5,703,110.

FAQs About US Patent 5,703,110 and Azilsartan

Is US 5,703,110 the patent for Edarbi?

No. It is the foundational patent for azilsartan, the active metabolite generated from Edarbi’s active ingredient, azilsartan medoxomil. Edarbi’s commercial protection depended on later patents directed to the prodrug and related product features.

Can a generic company sell azilsartan after expiration of US 5,703,110?

Yes, this patent no longer blocks azilsartan because its US term ended in 2015. Other active patents, FDA requirements, and product-specific rights must still be evaluated.

Does claim 1 cover azilsartan medoxomil?

Not expressly. Claim 1 identifies azilsartan, a carboxylic acid, and its pharmaceutically acceptable salts. Azilsartan medoxomil is a distinct prodrug and requires separate claim analysis.

Is the azilsartan tetrazole group protected independently?

No. US 5,703,110 claims the complete azilsartan molecule. The patent does not create a perpetual standalone monopoly over every pharmaceutical use of a tetrazole group.

What is the main legal difference between claim 1 and claim 3?

Claim 1 is a product claim directed to azilsartan and its salts. Claim 3 is a method claim directed to administering azilsartan to antagonize angiotensin II. The product claim generally has broader enforcement reach during its term.

References

1. U.S. Patent No. 5,703,110. (1997). Benzimidazole derivatives, process for preparing them and pharmaceutical compositions containing them. United States Patent and Trademark Office.

2. U.S. Food and Drug Administration. (2011). Edarbi (azilsartan medoxomil) prescribing information. FDA.

3. U.S. Food and Drug Administration. (n.d.-a). Approved drug products with therapeutic equivalence evaluations, Orange Book. FDA.

4. U.S. Food and Drug Administration. (n.d.-b). Abbreviated new drug application process and patent certifications. FDA.

5. U.S. Food and Drug Administration. (n.d.-c). Purple Book: Database of licensed biological products. FDA.

6. U.S. Patent and Trademark Office. (n.d.). Patent term adjustment and patent term calculation resources. USPTO.

7. 21 U.S.C. § 355(j). (2024). Abbreviated applications for new drugs. United States Code.

Drugs Protected by US Patent 5,703,110

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: 5,703,110

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	2-113148	Apr 27, 1990
Japan	2-141942	May 30, 1990
Japan	2-208662	Aug 06, 1990
Japan	2-264579	Oct 01, 1990
Japan	2-413679	Dec 24, 1990

International Family Members for US Patent 5,703,110

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0459136		SPC/GB97/018	United Kingdom
European Patent Office	0459136		C970044	Netherlands
European Patent Office	0459136		98C0016	Belgium
European Patent Office	0459136		8/1998	Austria
European Patent Office	0459136		SZ 8/1998	Austria
European Patent Office	0459136		19875004	Germany