Details for Patent: 5,958,961

Summary for Patent: 5,958,961

Title:	Pharmaceutical composition for angiotensin II-mediated diseases
Abstract:	This invention relates to a pharmaceutical composition for angiotensin II-mediated diseases, which comprises a compound having angiotensin II antagonistic activity of the formula ##STR1## wherein R1 is H or an optionally substituted hydrocarbon residue; R2 is an optionally esterified carboxyl group; R3 is a group capable of forming an anion or a group convertible thereinto; X is a covalent bond between the 2 phenyl rings or a spacer having a chain length of 1 to 2 atoms as the linear moiety between the adjoining phenylene group and phenyl group; n is 1 or 2; the ring A is a benzene ring having 1 or 2 optional substituents in addition to R2 ; and Y is a bond, --O--, --S(O)m- (wherein m is 0, 1 or 2) or --N(R4)-- (wherein R4 is H or an optionally substituted alkyl group), or a pharmaceutically acceptable salt thereof in combination with a compound having diuretic activity or a compound having calcium antagonistic activity.
Inventor(s):	Yoshiyuki Inada, Keiji Kubo
Assignee:	Takeda Pharmaceutical Co Ltd
Application Number:	US08/883,040
Patent Claim Types: see list of patent claims	Use; Composition;

US Patent 5,958,961: Claim Scope, Candesartan Combination Coverage, Expiration and Patent Landscape

US Patent 5,958,961 covers pharmaceutical compositions and hypertension-treatment methods combining a structurally defined angiotensin II receptor antagonist with hydrochlorothiazide or manidipine hydrochloride. Its dependent claims narrow the genus to candesartan and a specified ester prodrug. The patent’s nominal 20-year term has expired, so it no longer creates a current US exclusion right. Its commercial importance was historical: it supported combination therapy involving candesartan-type ARBs and two complementary antihypertensive agents.[1]

What does US Patent 5,958,961 protect?

The patent has two independent claim categories:

Claim category	Independent claim	Protected subject matter
Composition	Claim 1	An angiotensin II antagonist plus hydrochlorothiazide or manidipine hydrochloride
Method of treatment	Claim 15	Treating or preventing hypertension by administering the antagonist plus hydrochlorothiazide or manidipine hydrochloride

The patent does not claim every ARB/thiazide combination. The angiotensin II antagonist must fall within the structural formula in claim 1. The formula contains the structural elements commonly associated with candesartan-class compounds:

• A benzimidazole core
• A biphenyl or related aryl-linked structure
• A tetrazole or another acidic anion-forming group
• A carboxylic acid or ester
• An ethoxy or related substituent
• Defined linkers, ring substitution patterns and heteroatom options

The combination partner must also be one of two specifically named agents:

1. Hydrochlorothiazide
2. Manidipine hydrochloride

A product containing the claimed ARB without either specified combination partner would not fall within claim 1 or claim 15.

Which compounds are covered by the patent’s chemical claims?

Claim 13 and the candesartan active moiety

Claim 13 identifies:

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

This is candesartan, the active angiotensin II receptor blocker moiety used in candesartan cilexetil products. Claim 13 therefore narrows the broad structural genus to candesartan itself, but only in a composition containing hydrochlorothiazide or manidipine hydrochloride.

The claim is not a standalone candesartan claim. It does not independently prevent manufacture, sale or use of candesartan monotherapy.

Claim 14 and the esterified compound

Claim 14 covers a pivaloyloxymethyl ester of the candesartan acid identified in claim 13. This is a specific prodrug or ester form within the broader ester language of claim 1.

The claim language should not be conflated automatically with candesartan cilexetil. Candesartan cilexetil is the cyclohexyloxycarbonyloxyethyl ester of candesartan. Claim 14, as supplied, identifies a pivaloyloxymethyl ester. Chemical identity must therefore be assessed by the exact ester substituent, not by the shared candesartan acid moiety.

Dependent-claim narrowing

Claim	Main limitation	Practical effect
1	Broad ARB structural genus plus hydrochlorothiazide or manidipine hydrochloride	Principal composition claim
2	R1 is substituted lower alkyl or cycloalkyl	Narrows the N-substituent
3	R1 is ethyl	Targets a major preferred embodiment
4	R1 is ethyl and Y is oxygen	Narrows the linker
5	Defined esterifiable carboxyl group	Limits the acid/ester substituent
6	Lower alkoxycarbonyl with cyclohexyloxycarbonyloxy substitution	Targets a prodrug-type ester
7	Acidic 5- to 7-membered heterocycle	Covers anion-forming heterocycles
8	Specific heterocyclic alternatives	Further restricts R3
9	Tetrazolyl	Captures the candesartan tetrazole
10	2,5-dihydro-5-oxo-1,2,4-oxadiazole-3-yl	Covers a separate acidic heterocycle
11	Defined ester plus tetrazolyl group	Combines the key prodrug and tetrazole limitations
12	Lower alkyl, oxygen linker, defined ester and tetrazole	Narrow candesartan-type combination
13	Candesartan acid	Specific active moiety
14	Pivaloyloxymethyl candesartan ester	Specific ester embodiment
15	Hypertension treatment method	Method claim requiring both active agents

How broad is claim 1?

Claim 1 is structurally broad but pharmacologically narrow.

It reaches multiple angiotensin II antagonists sharing the claimed scaffold, including compounds with variation at R1, R2, R3, X, Y and the benzene ring. It does not require candesartan unless a dependent claim is invoked. It also permits either the free acid or a pharmaceutically acceptable salt and covers certain esterified carboxyl forms.

The critical limitations are:

• The compound must have angiotensin II antagonistic activity.
• The compound must satisfy the full Markush formula.
• The composition must include hydrochlorothiazide or manidipine hydrochloride.
• The combination must be pharmaceutical and therapeutically usable.

The claim does not expressly require a particular dosage ratio, tablet architecture, release profile, excipient, coating, packaging configuration or manufacturing process. A fixed-dose tablet, two co-packaged tablets or a separately administered combination could raise different infringement questions depending on the facts and applicable interpretation of “composition” and “in combination with.”

A product using an unrelated ARB, such as losartan, valsartan, irbesartan or olmesartan, would not ordinarily satisfy the claimed structural formula merely because it is an angiotensin II receptor antagonist.

What formulations are protected by US 5,958,961?

The patent protects the active-ingredient combination, not a detailed dosage-form platform.

Covered formulation concepts

Potentially covered embodiments include:

• A single tablet containing the claimed ARB and hydrochlorothiazide
• A capsule containing both active ingredients
• A kit or package pairing the two agents, subject to the claim construction applied to “composition”
• A combination using the candesartan acid
• A combination using a pharmaceutically acceptable salt
• A combination using an expressly covered ester or prodrug form
• A candesartan-type compound combined with manidipine hydrochloride

Formulations not expressly claimed

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

• A particular tablet weight
• A specific active-ingredient ratio
• Immediate-release or extended-release delivery
• A bilayer tablet
• A coating composition
• A particular dissolution profile
• A pharmaceutical manufacturing process
• A formulation excipient
• A particular patient subgroup
• A specific hypertension severity or treatment line

This distinction matters because later formulation patents could have created separate protection even after the basic combination patent expired. US 5,958,961 itself is not a formulation-technology patent in the narrow sense.

When did US Patent 5,958,961 expire?

US Patent 5,958,961 issued on September 28, 1999.[1] Based on the ordinary US patent-term rule for an application filed after June 8, 1995, its nominal expiration was approximately 20 years from the effective US nonprovisional filing date, subject to patent-term adjustment, terminal disclaimers and other statutory modifications.[2]

Public patent records identify the patent as expired. The practical conclusion is:

Issue	Status
Patent issued	September 28, 1999
Nominal term basis	20 years from applicable post-1995 US filing date
Nominal expiration	Approximately 2016 to 2017, depending on the effective filing date
Current enforceability	Expired
Current Paragraph IV risk under this patent	None for a new US launch
Historical relevance	Combination-product exclusivity and Orange Book strategy

The patent’s expiration does not eliminate other potential rights relating to candesartan, candesartan cilexetil, dosage forms, crystalline forms, manufacturing processes or later combination products.

What was the Orange Book status of the patent?

The Orange Book lists patents submitted by NDA sponsors for approved drug products when the sponsor represents that the patent claims the drug substance, drug product or an approved method of use.[3]

US 5,958,961 should be analyzed separately from the core candesartan compound patents and any patents covering candesartan cilexetil. A combination patent can be relevant to an NDA product only if the listed claims correspond to the approved product or method of use.

For a candesartan/hydrochlorothiazide product, the relevant Orange Book analysis typically separates:

1. Core candesartan compound protection
2. Candesartan cilexetil or ester-prodrug protection
3. Combination-product protection
4. Approved method-of-use protection
5. Pediatric exclusivity or other regulatory exclusivity
6. Later formulation or manufacturing patents

Because US 5,958,961 has expired, it is no longer a live patent barrier even if it was previously submitted to, or associated with, an FDA-approved combination product.

What FDA products were commercially relevant?

Candesartan cilexetil was approved in the United States as Atacand, an angiotensin II receptor blocker for hypertension. Candesartan/hydrochlorothiazide was later marketed as Atacand HCT.[4]

The commercial category competed with other ARB/thiazide products:

Product	ARB	Diuretic	Commercial sponsor historically associated with brand
Atacand HCT	Candesartan cilexetil	Hydrochlorothiazide	AstraZeneca
Hyzaar	Losartan potassium	Hydrochlorothiazide	Merck
Diovan HCT	Valsartan	Hydrochlorothiazide	Novartis
Avalide	Irbesartan	Hydrochlorothiazide	Sanofi/Bristol-Myers Squibb historically
Benicar HCT	Olmesartan medoxomil	Hydrochlorothiazide	Daiichi Sankyo

These products were not automatically within US 5,958,961 because the patent requires an antagonist having the claimed chemical formula. The patent’s competitive reach was concentrated on candesartan-like chemistry and the specified hydrochlorothiazide or manidipine combination.

How does the patent compare with core candesartan patents?

The patent estate should be divided by technical layer.

Estate layer	Typical subject matter	Relevance of US 5,958,961
Core compound	Candesartan chemical structure	Separate from this patent
Prodrug	Candesartan cilexetil or other ester	Partially relevant through ester language, but exact identity matters
Combination therapy	ARB plus hydrochlorothiazide or manidipine	Direct subject of US 5,958,961
Formulation	Tablet, granulation, coating or release profile	Not apparent from the supplied claims
Manufacturing	Synthetic intermediates, purification and process controls	Not claimed in the supplied claims
Method of use	Hypertension prophylaxis or treatment	Directly claimed in claim 15
Regulatory exclusivity	FDA exclusivity attached to an approved NDA	Separate from patent rights

The core candesartan compound patent family was commercially more important for the active ingredient itself. US 5,958,961 added combination-specific coverage. A generic manufacturer could avoid this patent by selling candesartan alone, a different ARB, or potentially a hydrochlorothiazide combination outside the claimed structural genus. It could not avoid a valid claim merely by changing tablet shape or excipients if the same claimed active combination remained present.

What Paragraph IV challenges and litigation affected the patent?

A Paragraph IV certification applies when an ANDA applicant asserts that a listed patent is invalid, unenforceable or will not be infringed.[5] Such a certification could have been used historically against an Orange Book-listed combination patent covering an ARB/hydrochlorothiazide product.

For US 5,958,961, the present litigation conclusion is straightforward:

• The patent is expired.
• A new Paragraph IV challenge against this patent would not create a meaningful 30-month stay issue.
• Any historical litigation would have become moot as a basis for blocking current US entry once the patent term ended.
• Current generic competition must be evaluated against any surviving patents, regulatory exclusivity and product-specific requirements.

No conclusion that a particular company successfully challenged this specific patent should be drawn from the patent number alone. Paragraph IV litigation involving Atacand, candesartan cilexetil or Atacand HCT may involve different patent numbers and different claim categories.

Are biosimilar risks relevant?

No. Candesartan cilexetil is a small-molecule drug, not a biologic. The relevant FDA pathway is an ANDA under section 505(j) of the Federal Food, Drug, and Cosmetic Act, not a biosimilar application under the Public Health Service Act.[5]

The principal competitive risks were:

• Generic candesartan cilexetil
• Generic hydrochlorothiazide
• Generic fixed-dose candesartan/hydrochlorothiazide
• Therapeutic substitution with another ARB/thiazide product
• Price erosion after compound and combination patent expiry

What manufacturing and IP barriers remain after expiration?

Expiration of US 5,958,961 removes the patent’s direct combination barrier. It does not resolve all technical barriers.

Manufacturers may still need to address:

• Bioequivalence to the reference product
• Prodrug conversion and pharmacokinetic performance
• Tetrazole-containing intermediate synthesis
• Impurity control
• Salt and ester stability
• Hydrochlorothiazide content uniformity
• Fixed-dose tablet dissolution
• Packaging and moisture protection
• FDA product-specific guidance
• Active pharmaceutical ingredient supply
• Foreign patent rights in jurisdictions where related patents remain active

The patent’s claims do not contain an express process limitation. A manufacturer therefore would not infringe these claims by using a different synthetic route if the final pharmaceutical composition still satisfied an enforceable composition claim. Since the US patent has expired, that issue is now primarily historical for US commercialization.

What revenue exposure did the patent create?

The patent’s revenue exposure was tied to the combination-product segment rather than the entire candesartan franchise.

A claim covering candesartan plus hydrochlorothiazide could support:

• Fixed-dose combination sales
• Combination prescriptions filled with separate products
• Licensing leverage during product launch
• Orange Book listing strategy
• Delayed generic combination entry if the patent was valid and listed

It did not block:

• Candesartan monotherapy
• Hydrochlorothiazide monotherapy
• Other ARB/thiazide products
• Non-hypertension uses unless they satisfied the claim limitations
• Products using unrelated chemical classes

The economic value declined sharply after expiration because generic manufacturers could launch without overcoming this patent. Remaining revenue exposure depends on surviving candesartan and formulation patents, FDA exclusivity, brand loyalty, payer substitution and manufacturing economics.

How strong was the patent estate?

The patent was strongest against an accused product that had all of the following characteristics:

1. A candesartan-type ARB satisfying the Markush formula
2. Hydrochlorothiazide or manidipine hydrochloride
3. A pharmaceutical composition or hypertension-treatment use
4. A formulation or indication aligned with the claim language

Its weaker points were structural breadth and claim construction. Potential historical validity and infringement issues could have involved:

• Written-description support for the full Markush genus
• Enablement across the many R1, R2, R3, X and Y alternatives
• Anticipation by earlier ARB combination disclosures
• Obviousness of combining an ARB with hydrochlorothiazide
• Whether a particular ester or salt fell within the claim
• Whether separate administration satisfied the composition language
• Whether the claimed hypertension method was practiced by the labeled product

The dependent candesartan claims were chemically narrower and easier to map to a specific product, but their narrower scope also made them more vulnerable to design-around strategies involving a different ester, salt, antagonist or combination partner.

Key Takeaways

• US Patent 5,958,961 claims compositions and hypertension-treatment methods combining a defined angiotensin II antagonist with hydrochlorothiazide or manidipine hydrochloride.
• Claims 13 and 14 narrow the invention to candesartan acid and a specified pivaloyloxymethyl ester.
• The patent does not claim candesartan monotherapy or all ARB/thiazide combinations.
• It does not appear to be a detailed tablet, release-profile or manufacturing-process patent.
• The patent’s nominal term ended around 2016 to 2017, and the patent is expired.
• No current US Paragraph IV barrier arises from this patent alone.
• Candesartan cilexetil, core compound, formulation, manufacturing and foreign patent rights require separate analysis.
• Biosimilar rules do not apply because candesartan is a small-molecule drug.
• Historical value centered on fixed-dose combination protection and potential Orange Book leverage.

FAQs About US Patent 5,958,961

Does US Patent 5,958,961 cover Atacand HCT?

It could have been relevant to a candesartan/hydrochlorothiazide product if the product satisfied the structural and combination limitations. The patent is now expired.

Does the patent cover candesartan cilexetil alone?

No. The supplied claims require hydrochlorothiazide or manidipine hydrochloride. Candesartan cilexetil alone is outside the express combination requirement.

Can a generic launch candesartan/hydrochlorothiazide products now?

This patent does not block launch because it has expired. A generic applicant must still address any other listed patents, FDA requirements and product-specific exclusivity.

Does manidipine hydrochloride create a separate live patent risk?

Not under this expired patent. Any current risk would have to arise from separate patents covering manidipine, the specific combination, a formulation or a foreign jurisdiction.

Is claim 15 limited to treating hypertension?

Yes. Claim 15 expressly covers prophylaxis or treatment of hypertension in a mammal by administering the defined antagonist with hydrochlorothiazide or manidipine hydrochloride.

References

1. United States Patent and Trademark Office. (1999). US Patent No. 5,958,961, Pharmaceutical composition.
2. United States Code. (2023). 35 U.S.C. § 154: Contents and term of patent; provisional rights.
3. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, Orange Book.
4. U.S. Food and Drug Administration. (n.d.). Drugs@FDA: FDA-approved drugs, Atacand and Atacand HCT records.
5. U.S. Food and Drug Administration. (2024). Abbreviated new drug application process and patent certifications under the Hatch-Waxman Act.

Drugs Protected by US Patent 5,958,961

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: 5,958,961

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	5-133524	Jun 07, 1993

International Family Members for US Patent 5,958,961

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	239471
Austria	311188
Austria	372115
Austria	372116
Canada	2125251
Cyprus	2370
Germany	69432644