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Patent landscape, scope, and claims: |
United States Patent 5,185,351 Claim Scope Breakdown and US Patent Estate Map for Angiotensin II Receptor Antagonist Chemotype
US Patent 5,185,351 has a broad genus claim to a tightly defined chemical scaffold (a substituted E-2-propenoic acid core) plus extensive dependent claim fallbacks and explicit embodiments, followed by formulation and method-of-use coverage (AT2/ATII receptor antagonism and multiple cardiovascular/ocular indications). The practical enforceability hinges on whether a product’s active ingredient and salt form fall inside the claim genus parameters for the core (E-alkenoic acid), the imidazole-bearing substituent, and the R1/R2/R3/R4-R6 structural variables.
What does US Patent 5,185,351 claim cover at a chemical-genus level?
Answer: A genus of substituted E-2-propenoic acid compounds, defined by a composite of (i) an aryl “R1” anchor, (ii) an alkyl/aryl “R2” phenyl-derived substituent with constrained substitution patterns, (iii) an “X” heteroatom linker, (iv) a “R3” ring/atom substituent on the scaffold, (v) “R4/R5” substitution on a heterocycle (imidazole in the examples), (vi) an esteramide-like “R6” group, and (vii) defined “A” and “W” substituent patterns, with pharmaceutically acceptable salts included in the claim set. The claims also expressly cover (E) stereochemistry in the dependent examples and multiple specific named compounds.
Claim 1 scaffold features that control infringement
The independent claim is structured as: “A compound of the formula (structure) in which …” with layered variables.
Key “hard gates” for claim coverage include:
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E-alkenoic acid motif (propenoic acid / 2-propenoic acid)
- Dependent claims and enumerated embodiments repeatedly specify (E)-3-[…]-2-(2-thienyl)methyl-2-propenoic acid, and methanesulfonates of those acids.
- This is the main “shape” constraint tying the chemistry to an E-geometry, not a mixed or Z isomer.
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Imidazole-containing substituent framework
- The examples include 1H-imidazol-5-yl as the heterocycle.
- Dependent claim language for R4/R5 includes heteroaryl options “thienyl–Y–, furyl–Y–, … imidazolyl–Y– …” which indicates the claim genus can include imidazole-bearing substituents.
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R1 aryl substitution rules are broad but enumerated
- Claim 1: R1 is adamantyl, phenyl, biphenyl, or naphthyl.
- If R1 is aryl, it is unsubstituted or substituted by 1–3 substituents chosen from a defined list (halogens, C1–C6 alkyl, nitro, carboxylic acid esters/amides/PO(OR7)2, tetrazol-5-yl, cyano, sulfonamides/sulfonates, etc.).
- This matters for product design around “typical” aromatic substitution changes: the list includes many common drug-like handles (halogens, nitro, CF3 not listed in Claim 1’s R1 list but appears in dependent Claim 3’s narrower set; PO(OR)2 and sulfonamides are listed; carboxyl and cyano are listed).
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R2 variable is limited to certain alkyl/alkenyl/alkynyl/cycloalkyl or phenyl with 1–3 substituents from a defined list
- Claim 1: R2 is C2–C10 alkyl, C3–C10 alkenyl, C3–C10 alkynyl, C3–C6 cycloalkyl, or (CH2)0-8 phenyl with substitution limits similar to R1 (halogens, alkyl/alkoxy, nitro, hydroxy, sulfonyl/sulfonamide, CO2R7, CN, CONR7R7, etc.).
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X linker options constrain the connectivity
- Claim 1: X is a single bond, S, NR7, or O.
- If a product replaces the relevant atom in the scaffold with carbon (or changes the heteroatom link in a way not mapped to the “X” positions), the compound can exit the claim.
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R4 and R5 define two substitutable positions on a heterocycle/aryl region with a “not both hydrogen/alkyl” constraint
- Claim 1: R4 and R5 are independently hydrogen, C1–C6 alkyl, or heterocyclic “–Y–” patterns including imidazolyl, triazolyl, oxazolyl, etc.
- It includes an explicit exception: “R4 and R5 are not both selected from hydrogen and C1–C6 alkyl.”
- That means at least one of those positions must be a substituent beyond the simple hydrogen/alkyl pattern, or one must be heterocyclic as defined.
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R6 is a “Z–COOR8 or Z–CONR7R7” functionality
- Claim 1: R6 is --Z--COOR8 or --Z--CONR7R7, with Z options including single bond, vinyl, CH2-O-CH2, substituted methylene, benzyl groups, thienylmethyl/furylmethyl, or a C(O)NHCHR9 unit with R9 enumerated.
- Dependent claims and named examples anchor R6 as COOH, COOC1-2 alkyl, or CONH2 (Claim 6).
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W is CnF2n+1 with n=1–3
- Claim 1: W is CnF2n+1 (n=1–3), meaning CF3, C2F5, C3F7 are included where W appears.
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A is a specific tether motif
- Claim 1: A is —(CH2)m—, —CH═CH—, —O(CH2)n—, or —S(CH2)n—.
- This controls internal connectivity and ring spacing.
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Salts are explicitly included
- Claim 1 ends with “or a pharmaceutically acceptable salt thereof.”
- Dependent claims explicitly include methanesulfonate for at least one embodiment (Claim 16).
Dependent claims that materially narrow the genus (but also preserve fallbacks)
Claim 2 adds a constraint: one of R4 and R5 is hydrogen or C1–C4 alkyl.
- This reduces the number of permissible substitution patterns for those positions while still keeping many alternatives.
Claim 3 narrows R1:
- R1 is phenyl or naphthyl with aryl substitution limited to:
- chloro, fluoro, trifluoromethyl, nitro, methyl, methoxy, hydroxy,
- sulfamyl, cyano, carboxy, “(CH2)1-2 carboxy,” “CH═CH-carboxy,” “OCH2-carboxy,” carb(o)C1–C6 alkoxy, carbamoyl,
- tetrazol-5-yl,
- and m is 0–2.
Claim 4–6 constrain linker and functionalization:
- Claim 4: X is single bond or S; R2 is C2–C8 alkyl.
- Claim 5: R3 is hydrogen, chloro, fluoro, or trifluoromethyl; R4 is hydrogen or C1–C4 alkyl.
- Claim 6: R6 is COOH, COOC1-2 alkyl, or CONH2.
Claim 7–8 constrain the heterocycle side-chain options and stereochemistry:
- Claim 7: R5 is specified as thienylmethyl, thienylethyl, furylmethyl, imidazolylmethyl, or pyridylmethyl, each optionally substituted by methyl or methoxy.
- Claim 8: the E isomer and “the R6 group and the imidazole are trans to each other.”
- This makes stereochemical relationship a claim limitation, not just geometry of the alkene.
Which exact compounds (examples) are enumerated in US 5,185,351?
Answer: Multiple named (E)-2-propenoic acid embodiments with explicit imidazole and thienyl/furyl substituents, plus several salt/individual substitution patterns on the aryl ring.
Named embodiments in dependent claims (high-value enforcement set)
The claims enumerate many specific analogs under Claim 9 through Claim 17 and extended compound lists under Claims 17 and 27. The most commercially and litigation-relevant are those with explicit (E)-3-[…]-2-(2-thienyl)methyl-2-propenoic acid and their methanesulfonate.
Representative enumerations:
- Claim 9
- (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid
- Claim 10
- (E)-3-[2-n-butyl-1-{(4-carboxy-2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid
- Claim 11
- (E)-3-[2-n-butyl-1-{(4-carboxy-3-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid
- Claim 12
- (E)-3-[2-n-propyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid
- Claim 13
- (E)-3-[2-n-hexyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid
- Claim 14
- (E)-3-[2-n-butyl-1-{(4-carboxy-2,3-dichlorophenyl)methyl}-1H-imidazol-5-yl]-2-propenoic acid
- Claim 15
- (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid
- Claim 16 (salt)
- Claim 15 compound methanesulfonate
Claim 17 contains an extended set of analogs including (E)-compounds with:
- arylmethyl imidazole substitutions such as 2-nitrophenylmethyl, 2-chlorophenylmethyl, 4-carbomethoxyphenylmethyl, 2-(4-imidazolyl)phenylmethyl,
- heteroaryl substitutions at the “2-(… )methyl” position like 2-furyl, 3-thienyl, 5-methyl-2-thienyl,
- cyano and hydroxy/carboxymethyl/hydroxyl variants on the aryl ring,
- a (2,3-dichlorophenyl)methyl analog,
- and (2-trifluoromethylphenyl)methyl.
Claim 27 repeats an extended combination list, showing the patent uses enumeration to preserve a large pocket of specific embodiments.
What this means for generic/entrant product design
Because Claim 1 is a broad genus with dense variable lists, and because dependent claims enumerate many specific analogs, a challenger must design around:
- the core E-propenoic acid + trans stereochemical relationship,
- the imidazole-containing substituent class (as reflected by R4/R5 and named imidazole),
- and the substitution patterns that remain within the listed R1/R2/R3/R6 and optional salts.
A product that changes only a single substituent on the aryl ring can still fall inside Claim 1 if the new substituent remains in the allowed list and connectivity remains mapped by the variable definitions.
What formulations are covered by US 5,185,351?
Answer: The patent claims both compound-level and formulation-level protection. It includes a generic formulation claim and explicit composition claims for specific named acids.
Composition claims
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Claim 18: A pharmaceutical composition comprising a pharmaceutical carrier and a compound of Claim 1.
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Claims 19–26: Composition embodiments for selected named compounds, including:
- the base acid forms, and
- the methanesulfonate salt form (Claim 26).
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Claims 27: A composition claim covering the extended enumerated analog set.
Litigation significance
Composition claims can support enforcement against branded product formulations even if the entrant targets the same API but varies excipients or dosage forms, as long as the entrant infringes the composition’s “compound of Claim 1” element.
What therapeutic methods of use are claimed (AT1/AT2/ATII receptor antagonist)?
Answer: The patent claims methods for antagonizing angiotensin II receptors and treating multiple conditions linked to that pathway, including hypertension, congestive heart failure, renal failure, and glaucoma.
Method-of-use claims
- Claim 28: Method of antagonizing angiotensin II receptors by administering an effective amount of a Claim 1 compound.
- Claims 29–32: Treat:
- hypertension (29)
- congestive heart failure (30)
- renal failure (31)
- glaucoma (32)
Narrowed method claims using specific acids/salts
- Claims 33–42 specify certain (E)-4-carboxyphenylmethyl-imidazole acids and their methanesulfonates in those indications.
Practical risk profile for generics
Method-of-use claims can remain relevant if a generic seeks to rely on narrow label carve-outs that avoid the patented method. If a generic’s FDA label includes the claimed method, risk increases.
Does US 5,185,351 cover salts beyond methanesulfonate?
Answer: Claim 1 includes “pharmaceutically acceptable salt thereof.” Dependent claims explicitly mention at least one salt:
- Claim 16: methanesulfonate of the Claim 15 compound.
Salt scope for enforcement is thus:
- broad at the genus claim level (acceptable salts),
- anchored by explicit salt enumeration at the dependent level.
How broad is the patent’s “chemical freedom to operate” (FTO) boundary?
Answer: Broad on paper at Claim 1, with many substitution degrees of freedom, but bounded by:
- specific heteroatom connectivity (X is bond/S/NR7/O),
- restricted stereochemistry (E and trans relationship),
- constrained R1/R2 substitution catalogs,
- fixed presence of an imidazole-linked scaffold in enumerated embodiments,
- fixed R6 functional types (Z–COOR8 or Z–CONR7R7) and optional Z chemistries.
“Design-out” pathways likely to matter in practice
- Changing the alkene configuration away from (E), or eliminating the defined “trans to imidazole” relationship, targets a core limitation reflected in Claim 8.
- Replacing the heteroatom linkage corresponding to X with a carbon linker likely leaves Claim 1’s literal mapping.
- Substituting the aryl region with a group not in the enumerated allowed list reduces literal infringement risk if the new substituent falls outside Claim 1’s R1/R2/R3 substitution sets.
- Removing the R6 functionality pattern (COOH/ester/amide variants) reduces Claim 1 literal coverage, though it risks moving to a different chemotype.
What is the patent estate around 5,185,351 in the US?
Answer: This request cannot be completed from the provided information. A patent estate mapping requires:
- bibliographic details of US 5,185,351 (assignee, application number, filing date, priority), and
- retrieval of related family members and US continuations, continuations-in-part, and divisionals.
No estate map can be produced accurately solely from the claim text you supplied.
When does US 5,185,351 expire and how does exclusivity run in the US?
Answer: This request cannot be completed from the provided information. Expiration for a US utility patent requires:
- the issuance date (already implied but not confirmed),
- maintenance fee payment status, and
- whether any PTA or term adjustment applied.
No exclusivity/timeline can be stated accurately without those parameters.
What generic entry risks exist for compounds falling inside claim 1?
Answer: If an ANDA applicant or other entrant develops an API that:
- matches the Claim 1 core structure within variable definitions, and
- maintains (E)-propenoic acid geometry with the claimed trans relationship, and
- uses a pharmaceutically acceptable salt within the Claim 1 salt scope,
then the chemical and composition claims (Claims 1 and 18+) create direct infringement exposure at the API and product formulation level. If the label includes the claimed indications, the method-of-use claims can create additional exposure even if the formulation is designed to avoid composition or salt variations.
Orange Book status and FDA pathway: what does the record show?
Answer: This request cannot be completed from the provided information. Orange Book listings and FDA approvals require drug identity and retrieval.
How strong are the claims likely to be (scope vs. enforceability) under typical US claim construction?
Answer: Based on claim text structure alone:
- Claim 1 is a broad genus with extensive parameterization, increasing the chance that many close analogs remain within “literal” boundaries.
- Dependent claims add structured narrowing and include multiple stereochemical and functional constraints that can be used to build multiple infringement pathways (compound identity, composition, and method-of-use).
- The explicit enumeration of many E-(…)-2-propenoic acid embodiments and the methanesulfonate salt anchors the claim set with concrete examples for claim construction.
Key Takeaways
- US 5,185,351 Claim 1 is a broad genus covering substituted (E)-2-propenoic acid angiotensin II receptor antagonist chemotypes with a specific imidazole-containing scaffold reflected in dependent examples, plus defined variable substitution catalogs for R1/R2/R3/R4-R6 and X.
- The patent includes composition claims (carrier + Claim 1 compound) and explicit composition claims for named acids and methanesulfonate.
- It includes method-of-use claims for antagonizing angiotensin II receptors and treating hypertension, congestive heart failure, renal failure, and glaucoma, with further narrowing to specific acid/salt embodiments.
- Enforcement and generic-risk analysis will pivot on whether a product retains: (i) the E geometry and trans relationship, (ii) the functional R6 pattern, (iii) the allowed substitution lists for R1/R2/R3, and (iv) the salt scope.
FAQs
- If a competitor’s compound is the Z isomer, does it still fall within US 5,185,351?
- Do composition claims in US 5,185,351 cover different excipients and dosage forms?
- How does the “X is single bond/S/NR7/O” variable affect infringement risk for linker changes?
- Is the methanesulfonate salt specifically protected even if another acceptable salt is used?
- Can a generic mitigate method-of-use risk by label changes that avoid angiotensin II receptor antagonism indications?
References
- United States Patent No. 5,185,351. (Claims provided in prompt text).
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