Details for Patent: 4,072,746

Summary for Patent: 4,072,746

Title:	3-Amino-5-(pyridinyl)-2(1H)-pyridinones
Abstract:	Compounds useful as cardiotonic agents are 1-R-3-Q-5-PY-2(1H)-pyridinones (I) where R is hydrogen, lower-alkyl or lower-hydroxyalkyl, Q is amino (preferred), lower-alkylamino, di-(lower-alkyl)amino or NHAc, Ac is lower-alkanoyl or lower-carbalkoxy, and PY is 4- or 3- or 2-pyridinyl or 4- or 3- or 2-pyridinyl having one or two lower-alkyl substituents. The corresponding compounds where Q is nitro, carbamyl, cyano, halo or hydrogen are useful as intermediates and those where Q is hydrogen or cyano also are useful as cardiotonic agents. Said compounds are prepared: by reacting alpha -PY- beta -(R1R2N)acrolein (II) with malonamide to produce 1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia) and reacting Ia with a reagent capable of converting carbamyl to amino to produce 3-amino-5-PY-2(1H)-pyridinone (Ib); by reacting II or alpha -PY-malonaldehyde (II') with alpha -cyanoacetamide to produce 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) and partially hydrolyzing III to produce Ia; and, by heating 1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV) with a mixture of concentrated sulfuric acid and concentrated nitric acid to produce 3-nitro-5-PY-2(1H)-pyridinone (Ic) and then either reducing Ic to produce Ib or first reacting Ic with an alkylating agent to produce 1-R'-3-nitro-5-PY-2(1H)-pyridinone (Id) and reducing Id to produce 1-R'-3-amino-5-PY-2(1H)-pyridinone (Ib) where R' is lower-alkyl or lower-hydroxyalkyl. Other derivatives of I where Q is amino are shown.
Inventor(s):	George Y. Lesher, Chester J. Opalka, Jr.
Assignee:	Aventis Pharmaceuticals Inc
Application Number:	US05/707,235
Patent Claim Types: see list of patent claims	Use; Composition; Dosage form;

# US Patent 4,072,746: Amrinone Claims, Scope, Expiration, Litigation and Patent Landscape

US Patent 4,072,746 covers a genus of 3-substituted-5-pyridyl-2-pyridinones, including amrinone, also known as inamrinone. The strongest commercial claims are directed to 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone, its cardiotonic compositions, and methods of increasing cardiac contractility. The patent issued on February 7, 1978, and its ordinary 17-year patent term expired on February 7, 1995. It does not create a current US exclusionary barrier to amrinone or to generic development.

The patent is important historically because it claimed the amrinone chemical class before FDA approval of the drug. Its present value is primarily evidentiary and historical: it defines the original compound family, illustrates the prior-art position around pyridinone cardiotonics, and provides a reference point for later milrinone and related cardiotonic patents.

What drug does US Patent 4,072,746 protect?

US Patent 4,072,746 protects pyridinone compounds with three principal variable positions:

Variable	Claimed substituents
Core	2(1H)-pyridinone
Position 1, R	Hydrogen, lower-alkyl, or lower-hydroxyalkyl
Position 3, Q	Nitro, amino, lower-alkylamino, di-(lower-alkyl)amino, or NHAc
Position 5, PY	2-, 3-, or 4-pyridinyl, optionally carrying one or two lower-alkyl groups

The claim structure combines broad genus claims with narrower compound, composition, and treatment claims. The principal marketed compound is:

• 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone
• Common name: amrinone
• Later generic name: inamrinone
• Former US brand: Inocor
• Therapeutic category: positive inotropic cardiotonic

The patent claims both neutral compounds and pharmaceutically acceptable acid-addition salts. In practice, the marketed injectable product was amrinone lactate, a salt formulation used for short-term treatment of severe congestive heart failure.

What are the independent claims in US Patent 4,072,746?

The independent claims are claims 1, 2, 3, 14, and 16.

Claims 1 through 3: chemical genus claims

Claim 1 covers the broadest stated chemical genus. It includes compounds in which Q is:

• Nitro
• Amino
• Lower-alkylamino
• Di-(lower-alkyl)amino
• NHAc, where Ac is lower-alkanoyl or lower-carbalkoxy

Claim 2 covers a related genus but omits the unsubstituted amino option from its express Q definition. It includes nitro, lower-alkylamino, di-(lower-alkyl)amino, and NHAc substituents.

Claim 3 is directed specifically to the 3-amino subclass. It covers:

• 1-R-3-amino-5-PY-2(1H)-pyridinones
• R as hydrogen, lower-alkyl, or lower-hydroxyalkyl
• PY as unsubstituted or lower-alkyl-substituted 2-, 3-, or 4-pyridinyl

Claim 3 is the principal genus claim for amrinone-type compounds.

Claims 14 and 16: cardiotonic use claims

Claim 14 covers a cardiotonic composition comprising:

1. A pharmaceutically acceptable inert carrier; and
2. An effective amount of a claimed pyridinone cardiotonic.

Its Q definition includes amino, lower-alkylamino, di-(lower-alkyl)amino, and NHAc groups. Nitro compounds are excluded from the composition claim.

Claim 16 covers the method of increasing cardiac contractility by administering the claimed pyridinone orally or parenterally, in a solid or liquid dosage form.

These claims are narrower in functional scope than the composition and compound genus claims because they require a cardiotonic use and an effective administration to a patient requiring increased cardiac contractility.

Which claims specifically cover amrinone?

Amrinone falls within several claims:

Claim	Relevance to amrinone
Claim 3	Covers the 3-amino genus with permitted R and PY substituents
Claim 5	Narrows claim 3 to R = hydrogen
Claim 7	Specifically claims 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone
Claim 14	Covers cardiotonic compositions containing the relevant amino pyridinone
Claim 15	Specifically claims a composition containing amrinone
Claim 16	Covers the cardiac-contractility treatment method
Claim 17	Specifically claims treatment with amrinone

Claims 7, 15, and 17 are the most commercially direct claims for the original drug. Claims 3 and 5 provide broader compound protection around the specific molecule.

Claim 7 is a composition-of-matter claim to amrinone itself. Claim 15 is a composition claim. Claim 17 is a method-of-treatment claim. The three claims address different infringement theories and different evidentiary issues.

What is the chemical scope of the patent claims?

The chemical scope is broad but structurally bounded.

Pyridyl substitution

The PY group can be:

• 2-pyridinyl
• 3-pyridinyl
• 4-pyridinyl

The pyridyl ring can also carry one or two lower-alkyl groups. This creates positional and substitutional diversity around the pyridine ring.

Amrinone uses the 4-pyridinyl group. Claim 8 separately identifies the 3-pyridinyl analog, while claims 9 and 10 identify N-methyl and N-ethyl amrinone analogs.

N-1 substitution

The R group can be hydrogen, lower-alkyl, or lower-hydroxyalkyl. The expressly identified examples include:

• R = hydrogen: amrinone
• R = methyl: 3-amino-1-methyl-5-(4-pyridinyl)-2(1H)-pyridinone
• R = ethyl: 3-amino-1-ethyl-5-(4-pyridinyl)-2(1H)-pyridinone

This element protects N-substituted analogs that retain the pyridinone core and 3-amino pharmacophore.

Position-3 functionalization

The Q group is the main source of chemical breadth. The claims cover:

• Nitro precursors
• Primary amino compounds
• Methylamino and related secondary amines
• Dimethylamino and related tertiary amines
• Acetamido and carbamate-protected amino compounds

The patent therefore reaches both final active compounds and certain protected or precursor forms. Claims 11 and 12 specifically cover acetamide and methyl carbamate derivatives. Claim 13 covers the 3-nitro-5-(4-pyridinyl) compound.

Which individual compounds are claimed?

Claim	Compound
7	3-Amino-5-(4-pyridinyl)-2(1H)-pyridinone, amrinone
8	3-Amino-5-(3-pyridinyl)-2(1H)-pyridinone
9	3-Amino-1-methyl-5-(4-pyridinyl)-2(1H)-pyridinone
10	3-Amino-1-ethyl-5-(4-pyridinyl)-2(1H)-pyridinone
11	N-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]acetamide
12	Methyl N-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]carbamate
13	3-Nitro-5-(4-pyridinyl)-2(1H)-pyridinone
19	3-Methylamino-5-(4-pyridinyl)-2(1H)-pyridinone
21	3-Dimethylamino-5-(4-pyridinyl)-2(1H)-pyridinone

The claim set is commercially unusual because it identifies both amrinone and several analogs in dependent claims while retaining broad Markush coverage in the independent claims.

When did US Patent 4,072,746 expire?

US Patent 4,072,746 issued on February 7, 1978. For a pre-Uruguay Round patent, the ordinary term was 17 years from issuance. On that basis, the patent expired on February 7, 1995.

Event	Date
Patent issued	February 7, 1978
Ordinary statutory term	17 years from issuance
Calculated expiration	February 7, 1995
Current enforceability	Expired

The patent predates the US transition to the 20-year term measured from the earliest effective nonprovisional filing date. A later patent-term adjustment would not ordinarily apply to this patent under the governing pre-1995 framework. No currently enforceable claim from US 4,072,746 blocks manufacture, sale, or use of amrinone in the United States.

What is the FDA regulatory status of amrinone?

Amrinone was approved in the United States as an intravenous cardiotonic under the Inocor brand. The drug was used for short-term management of severe congestive heart failure and was administered by injection rather than as a chronic oral therapy.

The product’s regulatory profile differs from its patent status:

Regulatory issue	Status
Active ingredient	Amrinone, commonly called inamrinone
US product	Inocor injection
FDA pathway	NDA approval for a small-molecule drug
Dosage form	Intravenous injection
Therapeutic use	Short-term cardiac contractility support
Biologic status	Not a biologic
Biosimilar pathway	Not applicable
Patent blocking rights	None from US 4,072,746, which expired in 1995

FDA-approved labeling identified serious risks associated with amrinone, including thrombocytopenia, hypotension, gastrointestinal effects, and potential arrhythmias. Those safety considerations, together with the availability of other inotropes, affected the drug’s commercial position (U.S. Food and Drug Administration, n.d.).

What is the Orange Book status of amrinone?

Amrinone is an old small-molecule drug, so any Orange Book listing is materially different from the listing of a currently protected product.

The relevant Orange Book questions are:

1. Whether the Inocor reference product remains listed as an active reference listed drug.
2. Whether the product is identified as discontinued for commercial reasons rather than safety or efficacy reasons.
3. Whether any unexpired patent or regulatory exclusivity code remains associated with the product.
4. Whether an approved generic or abbreviated new drug application remains active.

US Patent 4,072,746 cannot support a current Orange Book patent certification because it expired in 1995. There is no biosimilar issue. Any present generic-entry analysis would focus on the availability of an active reference listed drug, the status of any approved ANDAs, and current manufacturing economics rather than on the expired composition-of-matter patent (FDA, 2024).

Were there Paragraph IV challenges to US Patent 4,072,746?

A current Paragraph IV challenge to US Patent 4,072,746 is legally irrelevant because the patent expired almost three decades ago.

A Paragraph IV certification applies when an ANDA applicant asserts that a listed patent is invalid, unenforceable, or will not be infringed. Once the patent has expired, an applicant would generally have no reason to make a Paragraph IV assertion against that patent. The relevant entry pathway would instead involve:

• Certification that the patent has expired;
• A Paragraph III certification if the patent were listed but unexpired at filing; or
• No effective patent challenge if the patent had been removed or was not listed.

The patent’s expiration date also predates the modern commercial period in which many generic-drug patent disputes were litigated under Hatch-Waxman procedures. No material current Paragraph IV risk remains under this patent.

What patent litigation affects amrinone?

US Patent 4,072,746 does not present a current US litigation risk. Its claims are expired and cannot support an injunction or damages claim for post-expiration activity.

The original patent may have been relevant to historical disputes involving:

• Amrinone compound manufacture
• Inamrinone lactate formulations
• Generic injectable products
• Selection of alternative cardiotonic compounds

No live US litigation based on the claims supplied affects present amrinone entry. Any analysis of historical litigation should distinguish litigation over the expired patent from later disputes over other compounds, manufacturing processes, regulatory exclusivity, or product liability.

How does the amrinone patent compare with milrinone patents?

Amrinone and milrinone are related cardiotonic agents but do not have identical structures or patent estates.

Issue	Amrinone	Milrinone
Core structure	3-amino-5-(4-pyridinyl)-2(1H)-pyridinone	Bipyridine-derived pyridone with a nitrile substituent
Original patent family	US 4,072,746	Later Sterling-related milrinone patent families
Main mechanism	Phosphodiesterase III inhibition	Phosphodiesterase III inhibition
US approval era	Early 1980s	1980s
Patent status today	Original compound patent expired	Original compound and major early patents also expired
Biosimilar risk	None	None
Current entry barrier	Manufacturing, clinical utility, and market size	Manufacturing, regulatory, and market size

Milrinone was developed as a related but distinct cardiotonic compound. Its patents cannot be assumed to cover amrinone because patent infringement depends on the claimed structure, not merely on pharmacological class or mechanism. Conversely, US 4,072,746 does not automatically cover milrinone because milrinone falls outside the specific 3-amino-5-pyridyl-2-pyridinone structure claimed for amrinone.

What formulation patents protect amrinone lactate?

US 4,072,746 contains formulation and administration claims, but they are functional composition and method claims rather than detailed platform claims directed to a specific injectable excipient system.

Claim 14 covers a cardiotonic composition with:

• The claimed active pyridinone;
• A pharmaceutically acceptable inert carrier; and
• An effective amount of active ingredient.

Claim 16 covers oral or parenteral administration in solid or liquid dosage form. These limitations are broad and include injectable products, but they do not identify a particular concentration, buffer, pH range, container, stabilizer, preservative, or manufacturing process.

For present-day entry analysis, the expired patent does not block:

• Amrinone lactate injection;
• Alternative salt forms;
• New concentrations;
• New containers or infusion systems;
• New sterile manufacturing processes;
• New labeling that does not infringe a live method claim.

A later formulation patent could create a separate barrier, but it would need to be identified independently from US 4,072,746. The supplied claims do not establish a surviving formulation patent.

How strong is the patent estate for amrinone?

The historical patent estate was strong at issuance but is now legally exhausted.

Strength factor	Assessment
Composition-of-matter protection	Strong historically
Genus coverage	Broad across pyridyl and 3-amino analogs
Species coverage	Direct claim to amrinone
Formulation protection	Broad but relatively nonspecific
Method-of-treatment protection	Direct cardiotonic use claims
Remaining patent term	None
Current freedom-to-operate value	No exclusionary value from this patent
Manufacturing barrier	Potentially relevant, but not created by the expired claims
Biosimilar barrier	None
Litigation leverage	None for current activity

The strongest historical feature was the combination of genus and species protection. Claim 7 directly covered amrinone, while claims 3 and 5 covered a broader chemical neighborhood. Claims 15 and 17 extended protection into compositions and cardiac-contractility treatment.

The weakest feature from a modern commercial perspective is the lack of surviving rights. Patent strength is assessed against current enforceability, not only claim breadth. On that measure, the patent estate represented by US 4,072,746 has no remaining blocking strength.

Which companies challenged or competed with the amrinone product?

Sterling Drug and its successors were associated with the original amrinone development and Inocor commercialization. Later competition came from:

• Milrinone developers and manufacturers
• Generic injectable-drug companies
• Hospitals using alternative intravenous inotropes
• Manufacturers of dobutamine and related cardiac-support products

The competitive threat was pharmacological and commercial rather than based solely on patent invalidity. Amrinone competed against agents with different safety, dosing, monitoring, and hospital-use profiles. Generic manufacturers also faced limited demand because amrinone is a hospital-administered product with a relatively narrow clinical role.

No biosimilar manufacturer can challenge amrinone because amrinone is a chemically synthesized small molecule. The appropriate regulatory competitors are ANDA applicants and, where relevant, 505(b)(2) applicants.

What generic launch scenarios exist for amrinone?

Because the original patent expired in 1995, a generic launch would not require waiting for US 4,072,746. The practical scenarios are:

ANDA launch for an equivalent injectable

A manufacturer could pursue an ANDA if an appropriate reference listed drug and equivalence pathway are available. The key requirements would include:

• Pharmaceutical equivalence;
• Bioequivalence or appropriate parenteral-product showing;
• Sterility and particulate control;
• Container-closure compatibility;
• Manufacturing-process validation;
• Labeling consistent with the reference product.

505(b)(2) development

A 505(b)(2) application could be relevant if the proposed product differs in formulation, concentration, delivery system, or clinical use from the reference product. This route could be more practical where the reference product is discontinued or where the applicant proposes a materially different injectable presentation.

No-launch scenario

A technically available generic may still have no commercial launch because of:

• Small or declining hospital demand;
• Sterile injectable manufacturing costs;
• Low expected price;
• Limited distributor interest;
• Competition from established inotropes;
• Clinical preference for other therapies.

The principal current risk is therefore commercial feasibility, not patent infringement.

What manufacturing and intellectual-property barriers remain?

US 4,072,746 does not create a surviving manufacturing barrier. A current manufacturer would instead assess:

• Chemical synthesis and impurity control;
• Salt formation, particularly amrinone lactate;
• Sterile filtration or aseptic processing;
• Injectable stability;
• Container compatibility;
• Supply of qualified active pharmaceutical ingredient;
• FDA inspection and current good manufacturing practice compliance;
• Any later process or formulation patents.

The patent’s broad claims could once have implicated the active ingredient, analogs, and certain intermediates. They cannot now be used to prevent manufacturing or sale in the United States after expiration.

Geographic coverage is also exhausted in the United States. Foreign counterparts, if any, would have had separate terms and enforceability. Expiration of the US patent does not establish the status of counterpart patents in Europe, Japan, Canada, or other jurisdictions.

What is the commercial exposure associated with US Patent 4,072,746?

The patent no longer protects current revenue. The original commercial exposure was tied to Inocor and to any generic or branded amrinone product sold before February 7, 1995.

Current exposure is limited to:

• Legacy product liability;
• Historical royalty or license obligations, if any survived contractually;
• Regulatory maintenance costs;
• Potential value in a discontinued-product portfolio;
• Manufacturing know-how not disclosed or exhausted by the patent.

No current royalty stream should be attributed to US 4,072,746 solely because it once covered amrinone. Patent expiration terminates the patent owner’s exclusionary rights, but it does not automatically terminate private contractual obligations. Those obligations cannot be inferred from the claims alone.

Key Takeaways

• US Patent 4,072,746 covers amrinone and a broad family of 3-substituted-5-pyridyl-2-pyridinones.
• Claim 7 directly covers 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone, or amrinone.
• Claims 15 and 17 separately cover cardiotonic compositions and cardiac-contractility treatment with amrinone.
• The patent issued on February 7, 1978, and expired on February 7, 1995, under the applicable 17-year term.
• No current Paragraph IV challenge or patent litigation risk remains under this patent.
• Amrinone is a small molecule, so biosimilar regulation does not apply.
• Current generic-entry barriers are regulatory, manufacturing, clinical, and commercial rather than patent-based.
• Later milrinone patents cover a distinct compound and cannot be treated as automatic amrinone patents.
• Any surviving barrier would have to arise from a later patent, regulatory exclusivity, contract, or manufacturing right not contained in US 4,072,746.

FAQs About US Patent 4,072,746 and Amrinone

Is amrinone still protected by a US composition-of-matter patent?

No. The direct amrinone claim in US Patent 4,072,746 expired on February 7, 1995.

Can a company launch generic amrinone without a Paragraph IV certification?

Yes, the expired patent does not require a Paragraph IV challenge. The applicable FDA certification depends on the current Orange Book listing and the status of any other listed patents.

Does US Patent 4,072,746 cover milrinone?

No. Milrinone has a different chemical structure and was protected by separate patent families.

Is amrinone lactate covered by the patent?

The patent covers pharmaceutically acceptable acid-addition salts of the claimed pyridinones and broadly covers cardiotonic compositions. It does not create a current barrier because the patent expired.

What is the main commercial obstacle to a new amrinone injection?

The main obstacles are limited demand, sterile injectable manufacturing costs, reference-product and ANDA strategy, and competition from other hospital inotropes.

References

1. United States Patent and Trademark Office. (1978). US Patent No. 4,072,746, Pyridinone cardiotonics. U.S. Department of Commerce. https://patents.google.com/patent/US4072746A

2. U.S. Food and Drug Administration. (n.d.). Inocor (amrinone lactate injection) prescribing information. U.S. Department of Health and Human Services.

3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, 44th edition. U.S. Department of Health and Human Services. https://www.fda.gov/drugs/drug-approvals-and-databases/orange-book-data-files

4. U.S. Code, 35 U.S.C. § 154. (2024). Contents and term of patent; provisional rights. Cornell Law School Legal Information Institute. https://www.law.cornell.edu/uscode/text/35/154

5. U.S. Food and Drug Administration. (n.d.). Orange Book: Approved drug products with therapeutic equivalence evaluations. U.S. Department of Health and Human Services. https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm

Drugs Protected by US Patent 4,072,746

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 4,072,746

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	220512
Argentina	223137
Argentina	231541
Austria	357534
Austria	359494
Austria	362375
Austria	A4380