Details for Patent: 5,721,244

Summary for Patent: 5,721,244

Title:	Combination of angiotensin-converting enzyme inhibitors with calcium antagonists as well as their use in drugs
Abstract:	The invention relates to combinations of angiotensin-converting enzyme inhibitors with calcium antagonists, processes for their preparation and their use as medicaments.
Inventor(s):	Reinhard Becker, Rainer Henning, Wolfgang Ruger, Volker Teetz, Hans Jorg Urbach
Assignee:	Sanofi Aventis Deutschland GmbH
Application Number:	US08/483,961
Patent Claim Types: see list of patent claims	Use; Composition;

US Patent 5,721,244: What Is Actually Claimed, Where the Coverage Likely Sits, and How the Landscape Maps

United States Patent 5,721,244 claims a fixed therapeutic combination of (1) a specific ACE inhibitor scaffold defined by Formula I (a constrained set of R/R1/R2/R3/R4/R5 substituent possibilities that covers known ACE inhibitor candidates such as trandolapril and quinapril), plus (2) a calcium antagonist (explicitly broad as “calcium antagonist or physiologically acceptable salt”), for treatment of hypertension and related cardiovascular indications. The claims also include a use-limiting proviso tied to one exemplar calcium antagonist: if the calcium antagonist is felodipine, then the ACE inhibitor cannot be trandolapril.

The operative claim set is narrow in the sense that it is not a composition of any ACE inhibitor with any calcium antagonist. It is narrow because it is constrained by (i) the ACE inhibitor Formula I definition, (ii) the combination is for specified therapeutic effects, and (iii) the felodipine/trandolapril exclusion.

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1) What Is the Independent Claim Actually Covering (Claim 1 and its “proviso”)?

Core structure of Claim 1

Claim 1 is a pharmaceutical composition comprising:

1) (a) An ACE inhibitor of Formula I, where:

• n = 1 or 2
• R = hydrogen or substituent classes: aliphatic (C1-8), alicyclic (C3-9), aromatic (C6-12), araliphatic (C7-14), alicyclic-aliphatic (C7-14), or ORa/SRa where Ra is aliphatic (C1-4) or aromatic (C6-12)
• R1 has a similarly constrained substituent class set (hydrogen; aliphatic C1-6; alkenyl C2-6; cycloalkyl C3-9; aryl C6-12; or partially hydrogenated aryl; or side chain of a protected natural α-amino acid)
• R2 and R3 are hydrogen or aliphatic C1-6 / alkenyl C2-6
• R4 and R5 together form a heterocyclic bicyclic or tricyclic ring system selected from a list that includes:
  • tetrahydroisoquinoline, decahydroisoquinoline, octahydroindole
  • 2-azaspiro 4,5-decane
  • 2-azaspiro 4,4-nonane
  • spiro (bicyclo 2,2,1-heptane)-2,3'-pyrrolidine
  • spiro (bicyclo 2,2,2-octane)-2,3'-pyrrolidine
  • 2-azatricyclo decane (as written in claim)
  • decahydrocyclophept a b-pyrrole
  • octahydroisoindole
  • octahydrocyclocenta c-pyrrole
  • 2,2,3a,4,5,7a-hexahydroindole
  • 2-azabicyclo hexane
  • hexahydrocyclopenta b-pyrrole

and the compound can be a physiologically acceptable salt.

2) (b) A calcium antagonist or its physiologically acceptable salt.

Therapeutic limitation

Claim 1 requires that:

• the ACE inhibitor + calcium antagonist are present in amounts effective for treating hypertension.

Proviso (explicit exclusion)

Claim 1 includes:

• when the calcium antagonist is felodipine, the ACE inhibitor is not trandolapril.

This single negative proviso materially changes the coverage. Even if Formula I includes trandolapril (and it does, via Claim 3), Claim 1’s proviso removes the “felodipine + trandolapril” pair for the hypertension use class.

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2) What Additional Narrowing Appears in Dependent Claims 2–6?

Claim 2: tighter substitution class definitions

Claim 2 refines the ranges from Claim 1 into specific allowable classes for:

• n = 1 or 2
• R, R1, R2/R3, and R4/R5 selection still remain tied to Formula I, but with more constrained enumerations (for example “(C1-C6)-alkyl”, “(C3-C9)-cycloalkyl”, “(C6-C12)-aryl”, and the ring system family repeated).

Practical impact: Claim 2 narrows coverage to the subset of Formula I embodiments that fall within those specific substituent class constraints (but it does not add new partner elements; it still requires a calcium antagonist).

Claim 3: explicit inclusion of two ACE inhibitors

Claim 3 states Claim 1’s ACE inhibitor is either:

• trandolapril (1-N-(1-S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl-(2S,3aR,7aS)-octahydro-1H-indole-2-S-carboxylic acid) or salt, or
• quinapril (2-N-(1-S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl-1,2,3,4-tetrahydroisoquinoline-3-S-carboxylic acid) or salt.

This is a direct anchor point to commercial molecules that reduces ambiguity about what Formula I is intended to include.

Claims 4–6: indication-specific effective-amount formulations

• Claim 4: amounts effective for “simultaneous, separate or periodic regulated use” for treating high blood pressure.
• Claim 5: amounts effective as a medicament for cardiac insufficiency.
• Claim 6: amounts effective as a medicament for “coronary head disease” (as written; it is an indication slot for coronary disease).

All keep the same structural requirements: ACE inhibitor of Formula I plus a calcium antagonist, together effective for the stated indication, and still subject to the same felodipine/trandolapril proviso as written within the claim family texts provided.

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3) What Methods Are Claimed (Claims 7–9)?

Claims 7–9 are classic method-of-treatment formulations via administration of the claimed composition:

• Claim 7: treatment of high blood pressure by administering the composition of Claim 1.
• Claim 8: treatment of cardiac insufficiency by administering the composition of Claim 1.
• Claim 9: treatment of coronary head disease by administering the composition of Claim 1.

These method claims inherit the same scope and proviso because they depend on Claim 1.

Business implication: any design-around strategy that changes either partner molecule class or the felodipine/trandolapril pairing can reduce method-claim risk for the excluded combination.

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4) What Else Is Claimed (Claims 10–12)?

Claim 10

• the composition further comprises a physiologically acceptable carrier.

This is standard formulation language and generally does not constrain the active ingredient scope.

Claim 11 and Claim 12

The text provided includes additional composition claims that appear duplicative in structure to Claim 1 but keyed to different indications:

• Claim 11: composition where ACE inhibitor + calcium antagonist are effective for cardiac insufficiency, with the same felodipine/trandolapril proviso.
• Claim 12: composition where ACE inhibitor + calcium antagonist are effective for coronary heart disease, with the same proviso.

In other words, the claim set is indication-segmented but structurally anchored to the same ACE Formula I + calcium antagonist combination logic.

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5) Scope Framing: How Broad Is the ACE Inhibitor Portion Actually?

ACE inhibitor coverage is defined by Formula I

Even without reproducing the chemical structure in text, Claim 1 specifies:

• substituent class limitations (R, R1, R2/R3, ORa/SRa),
• a defined heterocyclic ring system selection for R4/R5,
• n in {1,2},
• and salt-compatibility.

This is broader than a claim that names only one ACE inhibitor, but narrower than “any ACE inhibitor” due to the Formula I constraints.

Commercially relevant endpoints are explicitly included

Claim 3 names:

• trandolapril
• quinapril

Given the felodipine proviso references trandolapril, the claim set is clearly drafted around a practical pairing strategy among major cardiovascular drug classes.

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6) Scope Framing: How Broad Is the Calcium Antagonist Portion?

Calcium antagonist coverage is stated as:

• “a calcium antagonist or a physiologically acceptable salt thereof”
• without enumeration of the dihydropyridine, phenylalkylamine, benzothiazepine subclasses in the claim excerpt you provided.

However, the claim excerpt includes an explicit exemplar:

• felodipine is the only calcium antagonist singled out in the proviso.

Implication: absent an explicit constraint beyond “calcium antagonist,” the partner scope is wide across calcium antagonist chemistries, but the one singled-out molecule creates a targeted carve-out that only affects the ACE-inhibitor pairing with trandolapril.

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7) The Key Legal “Switch”: Felodipine + Trandolapril Is Excluded (But Not All Pairings Are).

What is excluded

Across the claim text you provided, the proviso consistently states:

• when calcium antagonist is felodipine, then ACE inhibitor is not trandolapril.

What is not excluded

From the wording provided, the claim does not exclude:

• felodipine + quinapril (if quinapril fits Formula I; it does via Claim 3)
• felodipine + other Formula I ACE inhibitors
• trandolapril + other calcium antagonists (because the proviso is conditioned on the calcium antagonist being felodipine)

This is a materially asymmetric design: it is an exclusion only for a particular pairing, not for trandolapril in general.

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8) Claim-by-Claim Landscape Positioning (What Competitors Can “Hit” and What They Can’t)

Products that match Claim 3 named ACE inhibitors

• Trandolapril: covered by Claim 3 as a Formula I instantiation.
• Quinapril: covered by Claim 3.

Products that match the felodipine proviso

• Felodipine is within “calcium antagonists,” and the proviso specifically targets it.

Most likely “risk matrix” behavior

• Fixed combinations or co-administration products using trandolapril + felodipine for the covered indications face direct claim obstacle due to the proviso.
• Fixed combinations using quinapril + felodipine remain within the claim family unless another constraint (not provided here) exists outside the provided excerpt.
• Fixed combinations using trandolapril + other calcium antagonists likely remain within scope if the calcium antagonist is not felodipine and if formulation/amounts satisfy “effective for treating” the specified indication.

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9) Practical Patent Landscape: How This Patent Typically Blocks Combination Space

Without file-wrapper prosecution history, expiration dates, continuation status, or CIDs, the analysis can only rely on the claim text provided. Based on those claims, the patent’s enforceable “shape” is:

1) It blocks ACE inhibitor Formula I + calcium antagonist combinations for specific indications. 2) It blocks them more strongly for pairs that fall within named ACE inhibitors (trandolapril, quinapril) because those are expressly disclosed within the claim family. 3) It introduces a pair-specific carve-out only for felodipine + trandolapril.

How to map competitor exposure

For business teams, “exposure” is driven by:

• whether the ACE inhibitor in the competitor product is one of the Formula I embodiments (with trandolapril and quinapril explicitly in-claim), and
• whether the calcium antagonist is felodipine, and
• whether the intended use matches the claim indication (hypertension, cardiac insufficiency, coronary heart disease as written).

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10) Claim Construction Levers to Expect in Litigation (Based on the Language You Provided)

Lever A: Formula I ACE inhibitor bounds

The ACE inhibitor is not defined by function alone; it is constrained by the set of allowable radicals and ring systems. This creates a clear path for both infringement and design-around analysis.

Lever B: “amounts effective” and use claims

The claims do not specify dose amounts in the excerpt you provided; they use “amounts effective for treating” a disease. That tends to be litigated by labeling, clinical evidence, and posology rather than by purely structural comparison.

Lever C: the felodipine proviso as a conditional negative limitation

The proviso is not a separate claim body; it is a built-in condition tied to the identity of the calcium antagonist. This usually forces a strict pairing analysis: one part of the combination identity changes the other part’s permissible set.

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11) Key Takeaways

1) US Patent 5,721,244 claims a fixed or functional combination of a Formula I ACE inhibitor plus a calcium antagonist for cardiovascular indications: hypertension, cardiac insufficiency, and coronary heart disease (as written). 2) The ACE inhibitor scope is defined structurally by Formula I, with explicit anchor molecules: trandolapril and quinapril. 3) The calcium antagonist scope is broad by class, but the claims include a specific exclusion: felodipine + trandolapril is excluded for the claimed compositions (by proviso). 4) Method-of-treatment claims mirror the composition scope and therefore inherit the same structural bounds and felodipine/trandolapril exclusion. 5) The patent landscape impact is concentrated in combination product development and label positioning for these ACE inhibitor/calcum antagonist pairings and these indications, with a targeted carve-out for the felodipine/trandolapril pairing.

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FAQs

1) Does the patent require the combination to be a fixed-dose product?
The claims read as a “pharmaceutical composition” and also cover “simultaneous, separate or periodic regulated use” (Claim 4), so the coverage is not limited to one specific dosing regimen format.

2) Is trandolapril included in the ACE inhibitor scope?
Yes. Claim 3 explicitly names trandolapril as a covered ACE inhibitor within the Formula I framework.

3) Is felodipine included as a calcium antagonist?
Felodipine is within the “calcium antagonist” concept and is specifically referenced in the proviso.

4) What is the key design-around lever in this patent family?
Avoid the felodipine + trandolapril pairing for the claimed uses; other calcium antagonists paired with trandolapril may remain covered depending on whether the ACE inhibitor falls within Formula I.

5) What indications are covered by the claim set you provided?
Hypertension, cardiac insufficiency, and coronary heart disease (as written).

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References

[1] US Patent 5,721,244 (claim text provided in prompt).

Drugs Protected by US Patent 5,721,244

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: 5,721,244

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Germany	36 33 496.0	Oct 02, 1986

International Family Members for US Patent 5,721,244

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0265685		SPC/GB98/047	United Kingdom
European Patent Office	0265685		99C0001	Belgium
European Patent Office	0265685		C980030	Netherlands
Argentina	243083
Austria	402894
Austria	78697