Details for Patent: 5,212,176

Summary for Patent: 5,212,176

Title:	R(+)-terazosin
Abstract:	R(+)-2-[4-[(tetrahydro-2-furanyl)carbonyl]-1-piperazinyl]-6,7-dimethoxy-4-quinazolinamine hydrochloride or a pharmaceutically acceptable salt or hydratet hereof (terazosin), substantially free of the S(-)-enantiomer.
Inventor(s):	John J. Kyncl, Bruce W. Horrom
Assignee:	Abbott Laboratories
Application Number:	US07/546,349
Patent Claim Types: see list of patent claims	Use; Composition;

US Patent 5,212,176 scope and claims analysis: R(+)-2-(4-((tetrahydro-2-furanyl)carbonyl)piperazinyl)-6,7-dimethoxy-4-quinazolinamine hydrochloride dihydrate with αD≥23.9° for hypertension, BPH, hyperinsulinemia and CHF

US 5,212,176 is a US composition-and-method-of-use patent centered on a single stereochemically defined active ingredient: the R(+)-enantiomer of a 6,7-dimethoxy-4-quinazolinamine scaffold with a tetrahydro-2-furanyl carbonyl-piperazine side chain, constrained by a specific optical rotation criterion (αD 28.5° C, C=1 in water: 23.9° or greater). The claims cover (i) the enantiomeric hydrochloride dihydrate itself with a measurable purity/specificity proxy (optical rotation), (ii) a pharmaceutical composition using a therapeutically effective amount of that compound, and (iii) therapeutic methods for four indications: hypertension, benign prostatic hyperplasia (BPH), hyperinsulinemia, and congestive heart failure (CHF).

What follows is a claim-by-claim scope map and a practical US patent-landscape read-through for freedom-to-operate (FTO) and validity-risk workstream planning around this patent.

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What does US 5,212,176 actually claim: compound, composition, and four method-of-use claim types?

Claim architecture. The patent contains six independent-to-dependent claim units as provided by you, with claim 1 anchoring the active ingredient boundary via (a) full chemical identity plus (b) enantiomeric designation plus (c) salt form (hydrochloride) plus (d) hydrate form (dihydrate) plus (e) optical rotation threshold.

Claim 1 scope: stereoselective compound defined by chemical structure + salt/hydrate + optical rotation threshold

Claim 1 text (as supplied) boundary elements:

1. Exact chemical name/structure identity
   R(+)-2-(4-((tetrahydro-2-furanyl)carbonyl)piperazinyl)-6,7-dimethoxy-4-quinazolinamine hydrochloride dihydrate.
2. Stereochemical restriction
   R(+) enantiomer (not racemate, not S(-) enantiomer).
3. Salt/hydrate restriction
   hydrochloride dihydrate (not free base, not other solvates, not monohydrate, not anhydrous).
4. Optical rotation criterion
   [α]D 28.5°C (C=1, water) is 23.9° or greater.

Legal/claim-construction implications (practical FTO):

• The optical rotation limitation is a quantitative “gateway”. Even if a candidate molecule matches the nominal structure and R-configuration, falling below the αD cutoff can potentially avoid infringement of claim 1. In practice, that pushes disputes toward measurement methodology and batch-specific enantiomeric/impurity profiles.
• Salt and hydrate requirements are hard boundaries. Many developers can design around by using a different salt form (or different hydrate form) unless the doctrine of equivalents (DOE) is argued broadly in litigation. Here, the patent expressly recites “hydrochloride dihydrate,” which narrows the claim to that physical form.
• “R(+)-… R(+)” is an enantiomer boundary, not a mixture boundary. If a product is a partially enriched mixture, claim 1 is still a structural-enantiomer claim but infringement will likely hinge on whether the product “is” within the claim’s compound definition and meets αD ≥ 23.9°. That makes enantiomeric excess and optical measurement central.

Claim 2 scope: composition claim requires inclusion of the claim 1 compound in a carrier

Claim 2 boundary elements:

• “A pharmaceutical composition comprising a therapeutically effective amount of the compound as defined by claim 1” plus a pharmaceutically acceptable carrier.

Practical coverage:

• Broad on dosage form and excipients in the absence of additional limits. As written, it captures tablets, capsules, solutions, etc., if they contain the claim 1 compound at therapeutically effective amounts.
• Design-around by using a different compound definition (for example, different enantiomer, salt, hydrate, or optical rotation below the cutoff) can avoid claim 2 even if the core scaffold is the same.

Claims 3–6 scope: indication-specific method-of-use claims using the claim 1 compound

Claim 3 (hypertension): administer therapeutically effective amount of claim 1 compound.
Claim 4 (BPH): administer therapeutically effective amount of claim 1 compound.
Claim 5 (hyperinsulinemia): administer therapeutically effective amount of claim 1 compound.
Claim 6 (CHF): administer therapeutically effective amount of claim 1 compound.

Practical scope observations:

• These are use claims, so they are usually implicated by label/indication targeting and prescribing/using the compound for those indications.
• A product with the same compound could still avoid infringement if used for non-covered indications, but regulatory strategy often pressures carve-outs. Conversely, a generic entrant can be at risk if it files a label that includes one or more covered indications.

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How strong is US 5,212,176 claim 1: does optical rotation create enforceable narrowing or litigation leverage?

Direct answer: The optical rotation limit is an enforceable narrowing element that can materially affect both infringement and validity narratives.

What does “αD 28.5°C (C=1, water) ≥ 23.9°” do to scope?

1. It defines a measurable property of the specific enantiomeric/hydrate form.
2. It can separate “chemically similar” from “claimed” batches. Even small shifts in optical rotation can occur from:
   • enantiomeric purity differences,
   • impurity profiles,
   • measurement conditions (temperature, solvent, concentration),
   • polymorph/hydrate stability.
3. It creates evidentiary weight in litigation: vendors and generics typically have analytical packages, and the threshold can be contested on method and reproducibility.

Likely infringement proof issues (how parties argue)

• Infringement: plaintiff will seek batch data showing the delivered product meets αD ≥ 23.9° under the claimed conditions, with correct measurement protocols.
• Defense: defendant will challenge measurement conditions, calibration standards, sampling, or show the product does not meet the threshold. They may also argue that their hydrate form or salt form differs, preventing claim 1 identification.

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What patent landscape surrounds US 5,212,176: compound vs salt/hydrate vs formulation vs use patents?

Critical point: A single enantiomer-and-salt-and-hydrate patent often sits within a broader family that includes:

• scaffold Markush variants,
• intermediate/polymorph/process patents,
• other indications,
• stereochemical preparation or resolution methods,
• additional salt forms or hydrates,
• formulation patents tied to specific dosage forms.

Without a family list, the most actionable read is to treat US 5,212,176 as the core enantiomeric physical-form/use hook that competitors must map against.

Landscape nodes that typically coexist with this kind of claim set

1. Resolution and enantiomer production patents
   If there is a stereochemical resolution route to R(+), expect method patents that can extend enforceability even if a competitor avoids αD boundaries via different preparation routes.
2. Hydrate/polymorph patents
   Hydrochloride dihydrate specifications are often followed by separate patents on:
   • crystallization conditions,
   • drying control,
   • solid-state stability,
   • polymorph discovery.
3. Alternative salts or solvates
   Competitors can attempt to switch to another salt/hydrate that is outside the claim’s “hydrochloride dihydrate” requirement.
4. Further use patents (label expansions)
   Claims for four indications suggest a broader therapeutic positioning. Companies commonly follow with additional method-of-use claims for biomarkers, subpopulations, or combination regimens.

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When does US 5,212,176 lose exclusivity: what expiration and regulatory exclusivity timelines typically govern?

Cannot be computed from the information provided. Patent expiry for US 5,212,176 depends on the patent’s filing date and any adjustments, plus potential terminal disclaimers. Regulatory exclusivity (e.g., Hatch-Waxman 5-year NCE/3-year new clinical investigations) depends on the FDA approval date and whether the product is “new chemical entity.” Since those dates and exclusivity facts are not provided here, no accurate expiration timeline can be stated from the supplied record.

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What generic entry risks exist for products targeting hypertension/BPH/hyperinsulinemia/CHF with the same scaffold?

Risk mechanism: If a generic intends to market the same drug substance that meets claim 1’s definition (R(+), hydrochloride dihydrate, αD threshold), then:

• ANDA labeling for covered indications can trigger use-method exposure (claims 3–6).
• At-sale product composition containing claim-1-matching drug substance can trigger composition exposure (claim 2), independent of labeling.

Generic “design-around levers” most relevant to this claim set

1. Switch enantiomer or reduce R-enantiomer fraction so αD < 23.9°
2. Use a different salt (not hydrochloride)
3. Use a different hydrate form (not dihydrate) or different solvate
4. Avoid covered indications on label (if infringement is only argued via method claims and the commercial drug substance is outside claim 1)

Practical note for FTO mapping

The “optical rotation ≥ 23.9°” limitation means developers cannot assume that “it is the R(+)-enantiomer” is sufficient. They must confirm that the delivered commercial solid-state form meets the αD threshold under the claimed test conditions.

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What formulations are protected by US 5,212,176 claim 2?

Claim 2 is formulation-platform broad. It is not limited by:

• dosage form (tablet, capsule, solution),
• release profile (IR/ER),
• specific excipients,
• strength.

It only requires inclusion of the therapeutically effective amount of the claim 1 compound plus a pharmaceutically acceptable carrier. That typically captures most conventional oral solid dosage forms unless the formulation avoids the claim 1 definition through salt/hydrate/optical rotation differences.

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What method-of-use claims mean for regulatory labeling strategy

Covered indications in US 5,212,176:

• Hypertension
• Benign prostatic hyperplasia
• Hyperinsulinemia
• Congestive heart failure

Labeling consequence:

• Any FDA-approved labeling that includes one or more covered indications and is used with a drug product that contains claim-1 compound matching the defined physical/optical limits can support infringement theories under claims 3–6.

Design workaround:

• “Carve out” covered indications on the ANDA label may reduce exposure for method claims. Composition claims may still remain if the drug substance matches claim 1.

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How does US 5,212,176 compare with typical US enantiomer patents: what is the likely differentiator?

Direct differentiator: The claim includes a quantitative optical rotation threshold tied to test conditions and concentration, plus a specific salt/hydrate.

Many US enantiomer patents focus on stereochemistry and sometimes salt forms but do not always include a tight optical rotation cutoff. Here, the αD criterion tightens the claim’s applicability to batches and solid forms that meet that measured property.

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What patent litigation affects US 5,212,176: settlement patterns and typical outcomes?

Cannot be stated. Litigation status for this specific patent number requires docket data and judgments/settlements that are not provided in your prompt. No accurate “what litigation affects it” section can be produced without that record.

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Key Takeaways

• US 5,212,176 is anchored on claim 1’s exact compound identity with five simultaneous constraints: R(+)-configuration, hydrochloride salt, dihydrate form, and optical rotation [α]D 28.5°C (C=1, water) ≥ 23.9°, plus the full quinazolinamine scaffold with the tetrahydro-2-furanyl carbonyl-piperazine side chain.
• Claim 2 broadly covers pharmaceutical compositions containing that claim-1 compound at therapeutically effective amounts with standard acceptable carriers.
• Claims 3–6 are method-of-use claims for hypertension, BPH, hyperinsulinemia, and CHF, so label alignment and prescribing use are central to infringement analysis.
• The optical rotation cutoff is a major practical narrowing lever that can create batch-specific infringement and defense disputes, especially for generics and solid-state manufacturing changes.
• A defensible FTO path must verify not only chemical structure and stereochemistry but also salt/hydrate form and measured αD under the claimed conditions.

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FAQs

1) Does changing hydrate form avoid infringement of US 5,212,176?

If the alternative form is not “hydrochloride dihydrate,” it can fall outside claim 1 and therefore outside claim 2 and method claims dependent on claim 1, assuming the delivered product does not still meet claim-1’s definition.

2) Can a generic avoid claim 3–6 by omitting covered indications from its ANDA label?

Omitting covered indications can reduce method-of-use exposure tied to those indications, but composition claim risk persists if the ANDA product contains the claim-1-defined drug substance.

3) Is the optical rotation limit the main design-around point?

It is a key design-around and proof-point because it can separate batches that are otherwise chemically similar but do not meet the αD ≥ 23.9° threshold under claimed measurement conditions.

4) Are combination products covered by claim 2?

Claim 2 covers a pharmaceutical composition with a therapeutically effective amount of the claim-1 compound in a pharmaceutically acceptable carrier. If the claim-1 compound is included and meets its definition, the composition can be within scope regardless of other non-included actives, depending on how “comprising” is construed.

5) Does R(+)-enantiomer alone guarantee infringement?

No. Even if stereochemistry is correct, claim 1 also requires hydrochloride dihydrate and αD ≥ 23.9° under the stated conditions.

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References

1. United States Patent 5,212,176. (n.d.). Patent claims as provided in prompt.

Drugs Protected by US Patent 5,212,176

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

International Family Members for US Patent 5,212,176

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	136779
Australia	654148
Australia	8323191
Canada	2086974
Germany	69118889
Denmark	0536329
European Patent Office	0536329