US Drug Patent 4,167,574: Claim Scope, Alfentanil Protection, Expiration, and Patent Landscape

U.S. Patent No. 4,167,574 covers a genus of N-phenyl-N-(4-piperidinyl)amide analgesics and specifically claims several tetrazolone-substituted piperidine compounds, including alfentanil. The patent issued in 1979 under the pre-URAA patent-term regime and is expired. Its claims no longer create a current U.S. patent barrier to generic alfentanil or other products that practice the claimed compounds, although separate later patents, controlled-substance requirements, manufacturing know-how, and regulatory obligations may remain relevant.[1]

What drug does U.S. Patent 4,167,574 protect?

The principal commercial compound associated with the patent is alfentanil, an ultra-short-acting synthetic opioid analgesic and anesthetic adjunct.

Claim 2 covers:

N-{1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]-4-(methoxymethyl)-4-piperidinyl}-N-phenylpropanamide

That compound is alfentanil. The corresponding pharmaceutical-composition claim is claim 9.

Patent claim	Subject matter	Commercial relevance
1	Broad genus of N-phenyl-N-(4-piperidinyl)amide compounds and acid-addition salts	Covers a large chemical class subject to the Markush limitations
2	Specific 4-ethyl tetrazolone, methoxymethyl piperidine compound	Alfentanil compound claim
3	Specific methyl piperidinecarboxylate and 4-methyl tetrazolone derivative	Individual analog
4	Specific methyl piperidinecarboxylate and N-methyl propionamide derivative	Individual analog
5	Specific propyl tetrazolone derivative	Individual analog
6	Specific 4-methyl tetrazolone and methoxymethyl piperidine derivative	Individual analog
7	Specific 1-methylethyl-linked tetrazolone derivative	Individual analog
8	Pharmaceutical composition containing the claim 1 genus	Composition counterpart to claim 1
9	Pharmaceutical composition containing the claim 2 compound	Alfentanil composition claim
10	Composition containing the claim 3 compound	Species composition claim
11	Composition containing a specified ethyl tetrazolone derivative with phenyl propionamide	Species composition claim
12	Composition containing the claim 5 compound	Species composition claim
13	Composition containing the claim 6 compound	Species composition claim
14	Composition containing the claim 7 compound	Species composition claim

The patent does not claim a named brand, a particular vial, concentration, excipient system, dosage regimen, or treatment method. Its central protection is compound-based, supported by composition claims.

How broad is claim 1 of U.S. Patent 4,167,574?

Claim 1 is a Markush genus claim. It covers compounds defined by a common N-phenyl-N-(4-piperidinyl)amide scaffold with independently variable substituents R, R1, R2, R3, R4, R5, R6, Z, and n.

The claim requires all of the following structural elements:

An N-phenyl-N-(4-piperidinyl)amide framework.
A substituted piperidine ring.
A nitrogen substituent incorporating a tetrazolone-related side chain or the corresponding disclosed structural arrangement.
Permitted substituent values at each defined position.
Z limited to oxygen or sulfur.
n limited to zero or one.
Acid-addition salts included within the claimed subject matter.
Aryl groups limited to phenyl, substituted phenyl, thienyl, or pyridinyl.

The permitted substituent classes include lower alkyl, cycloalkyl, alkenyl, alkynyl, alkoxyalkyl, aryl, arylalkyl, halo, alkoxy, trifluoromethyl, alkoxycarbonyl, alkoxymethyl, and alkylcarbonyl groups.

What limits the apparent breadth of claim 1?

The claim is broad in substituent coverage but remains limited by the exact structural formula and the defined variables. It does not cover every opioid, every piperidine, or every anilide. A product would need to fall within the claimed arrangement and satisfy the specified substituent definitions.

Important limitations include:

The amide must be part of the N-phenyl-N-(4-piperidinyl) arrangement.
The claimed piperidine substitution pattern is fixed by the formula.
Z cannot be nitrogen, carbon, or another heteroatom.
n cannot exceed one.
The aryl definition excludes many heteroaryl and fused-ring systems.
The claim covers acid-addition salts of the claimed compounds, not all possible formulations or salts of unrelated compounds.
The term “lower” must be interpreted in the context of the specification and ordinary patent construction principles applicable to the patent.

Because claim 1 is a genus claim, validity historically would have depended on written description, enablement, definiteness, anticipation, obviousness, and the relationship between the disclosed examples and the full Markush scope. Those issues are no longer commercially material for ordinary U.S. launch planning because the patent has expired.

Which claims specifically cover alfentanil?

Claims 2 and 9 are the key alfentanil claims.

Compound claim

Claim 2 covers alfentanil and its pharmaceutically acceptable acid-addition salts. A product containing alfentanil hydrochloride would fall within the salt aspect of the claim if the patent were enforceable.

Composition claim

Claim 9 covers a pharmaceutical composition comprising an inert carrier and an effective analgesic amount of alfentanil or its pharmaceutically acceptable acid-addition salts.

The composition claim does not specify:

Injection concentration.
Container or vial configuration.
Preservative system.
pH.
Route of administration.
Infusion rate.
Particular excipient.
Manufacturing process.
Clinical indication.

The phrase “effective analgesic amount” is functional language that connects the composition to analgesic activity. It does not establish a modern dosage-form patent covering every alfentanil product independently of the compound claim.

What formulations are protected by the patent?

The patent protects compositions containing the claimed active compounds with an inert carrier. It does not disclose, in the claims provided, a narrow formulation platform comparable to a modern formulation patent.

Formulation issue	Coverage under the listed claims
Alfentanil active ingredient	Yes, through claims 2 and 9
Alfentanil hydrochloride	Yes, as a pharmaceutically acceptable acid-addition salt
Injectable solution	Potentially within claim 9 if it contains the claimed compound and carrier
Specific concentration	Not expressly claimed
Specific excipient	Not expressly claimed
Liposomal or depot formulation	Not expressly claimed
Transdermal delivery system	Not expressly claimed
Sustained-release formulation	Not expressly claimed
Tablet or capsule	Potentially within the broad composition language, depending on claim construction
Manufacturing process	Not claimed in claims 1-14
Method of treating pain	Not claimed in claims 1-14

The claims therefore provide active-ingredient and general composition protection, rather than detailed product-by-process or delivery-system coverage.

When did U.S. Patent 4,167,574 expire?

U.S. Patent 4,167,574 was issued under the former U.S. patent-term system, under which utility patents generally ran for 17 years from issuance. The patent issued on September 11, 1979, producing a nominal expiration date of September 11, 1996, absent an adjustment or extension affecting the term.[1][2]

Event	Date
Earliest priority period	1976, according to the patent record
U.S. filing	1977
Patent issued	September 11, 1979
Nominal 17-year term end	September 11, 1996
Current status	Expired
Current blocking effect	None from this patent

The patent predates the 20-year-from-earliest-effective-filing-date regime introduced by the Uruguay Round Agreements Act. Patent-term restoration under 35 U.S.C. § 156 is generally relevant only to qualifying regulatory review periods and does not convert an expired 1979 chemical patent into a currently enforceable right without a recorded extension. Current FDA Orange Book patent listings, if any, should be reviewed separately for later patents and regulatory exclusivities.[2][3]

What is the Orange Book status of alfentanil?

Alfentanil is an FDA-approved opioid analgesic and anesthetic adjunct. FDA labeling identifies alfentanil hydrochloride injection as a parenteral product used in anesthesia and administered under controlled clinical conditions.[4]

The original compound patent is too old to provide an active Orange Book patent barrier today. A generic applicant’s relevant regulatory issues would instead include:

The applicable reference listed drug.
ANDA product sameness and bioequivalence.
Injectable-product quality requirements.
Controlled-substance registration and distribution controls.
Any currently listed formulation, labeling, or method-of-use patents.
FDA withdrawal or discontinuation status of particular listed products.

Orange Book patent listings are product-specific and can change over time. The existence of an approved alfentanil product does not, by itself, indicate that U.S. Patent 4,167,574 remains listed or enforceable.[3]

Are there Paragraph IV challenges to U.S. Patent 4,167,574?

No current Paragraph IV challenge can meaningfully target U.S. Patent 4,167,574 because the patent expired decades ago.

A Paragraph IV certification is relevant only when a listed patent remains unexpired and an ANDA applicant asserts that the patent is invalid, unenforceable, or will not be infringed. An expired patent ordinarily does not support a current patent-based launch delay, 30-month stay, or patent litigation strategy.

For alfentanil, any modern ANDA dispute would more likely concern:

Later patents listed for a specific reference product.
Formulation or container patents.
Use patents.
Pharmaceutical composition patents filed after the original compound patent.
Regulatory exclusivity rather than patent term.

What method-of-use patents cover alfentanil?

The listed claims contain no method-of-treatment claims. Claims 8 through 14 are composition claims, not treatment-method claims.

The patent therefore does not expressly claim:

Induction of anesthesia.
Maintenance of anesthesia.
Analgesia during surgery.
Sedation.
Reduction of opioid withdrawal.
A particular dosing regimen.
Use in a defined patient population.
Combination therapy with another anesthetic or opioid.

A later patent could theoretically claim a specific clinical use, dosing schedule, or patient population, but such rights would have to be analyzed independently from U.S. Patent 4,167,574.

How does the patent compare with later fentanyl-family patents?

U.S. Patent 4,167,574 sits within the broader synthetic opioid and 4-anilidopiperidine patent field. Its claim architecture differs from later patents directed to individual marketed products, improved formulations, delivery systems, or specific clinical uses.

Patent category	U.S. Patent 4,167,574	Later patent families
Core active ingredient	Yes	Often yes, for later analogs or salts
Markush genus	Yes	Sometimes
Alfentanil species	Yes	May claim alternative forms or uses
Injectable formulation	Broadly, through composition claims	Often more specifically
Transdermal system	No	Relevant to fentanyl products, not necessarily alfentanil
Method of treatment	No	Possible in later filings
Manufacturing process	No	Possible in later filings
Device or delivery system	No	Possible in later filings
Current enforceability	No	Depends on individual patent

Alfentanil should not be analyzed as though all fentanyl-family patents apply to it. Fentanyl, sufentanil, remifentanil, carfentanil, and alfentanil have materially different structures and patent estates. A patent directed to fentanyl transdermal delivery, for example, does not automatically cover alfentanil injection.

How strong is the current patent estate for alfentanil?

The current estate created by U.S. Patent 4,167,574 is legally weak for market-exclusion purposes because the patent is expired. Its historical scope was substantial because claims 1 and 8 reached a broad genus, while claims 2 and 9 targeted alfentanil specifically.

Historical strength

The patent had several features favorable to the originator:

A broad chemical genus claim.
Multiple expressly claimed species.
Parallel compound and composition claims.
Coverage of pharmaceutically acceptable acid-addition salts.
Direct coverage of the commercial alfentanil structure.

Current strength

Its current exclusionary value is zero. The remaining commercial barriers are operational and regulatory rather than patent-based:

Controlled-substance compliance.
Sterile injectable manufacturing.
Supply of qualified active pharmaceutical ingredient.
FDA quality and bioequivalence requirements.
Hospital procurement and shortage management.
Product discontinuation or limited commercial demand.

What generic entry risks exist for alfentanil?

Generic entry is not blocked by the original alfentanil compound patent. The commercial risk profile is more nuanced than the patent position.

Risk category	Assessment
Expired compound patent	No current barrier
Expired composition patent	No current barrier
Paragraph IV litigation on patent 4,167,574	Not a current risk
Active formulation patent	Must be checked against the current listed product
Sterile injectable approval	Material regulatory barrier
Controlled-substance compliance	Material operational barrier
API supply	Potentially material
Small market size	Commercial deterrent
Hospital procurement	Important launch factor
Biosimilar pathway	Not applicable

Alfentanil is a small molecule, not a biologic. Biosimilar litigation, reference-product exclusivity under the Public Health Service Act, and interchangeable-biologic requirements do not apply. The relevant pathway is generally the ANDA pathway for a small-molecule generic, subject to product-specific FDA requirements.[3][5]

Which companies are challenging or competing with the alfentanil originator?

The patent record alone does not establish a current litigation challenge to U.S. Patent 4,167,574. Because the patent expired in 1996, present competition is better evaluated through FDA-approved product listings, manufacturer status, and supply records rather than Paragraph IV activity.

Historically, Janssen Pharmaceuticals and related entities were associated with alfentanil development and commercialization. Later U.S. alfentanil products have been associated with generic injectable manufacturers and specialty pharmaceutical suppliers. Manufacturer participation can change because alfentanil has a relatively narrow anesthesiology market and is a Schedule II controlled substance.

The competitive set includes:

Generic alfentanil hydrochloride injection suppliers.
Fentanyl injection manufacturers.
Remifentanil manufacturers.
Sufentanil manufacturers.
Other short-acting anesthetic adjunct suppliers.

These products compete clinically but are not interchangeable solely because they share a fentanyl-related pharmacologic class. Differences in onset, duration, dosing, metabolism, formulation, and controlled-substance handling affect hospital purchasing decisions.

What manufacturing and intellectual-property barriers remain?

The patent does not claim a manufacturing route. A generic manufacturer can therefore develop an independent process without infringing the listed claims, provided the resulting product does not practice a separately enforceable patent.

The main non-patent barriers are:

Sterile injectable production

Alfentanil injection requires aseptic processing, validated sterilization controls, container-closure integrity, particulate control, and stability data. These requirements can be more difficult than producing a conventional oral solid.

Controlled-substance controls

Alfentanil is a Schedule II opioid in the United States. Manufacturing, storage, ordering, distribution, recordkeeping, quotas, and diversion controls create operational requirements beyond ordinary generic-drug production.[4]

API and analytical capability

A supplier must demonstrate identity, assay, impurities, degradation products, sterility, and stability. The tetrazolone-containing structure creates a need for validated impurity methods and reliable control of potentially process-dependent impurities.

Regulatory documentation

An ANDA sponsor must establish pharmaceutical equivalence and bioequivalence or satisfy the FDA’s applicable requirements for the injectable product. Labeling must conform to the reference product, subject to permitted ANDA differences.[5]

What patent litigation affects alfentanil?

No ongoing litigation can be attributed to U.S. Patent 4,167,574 based on the claims and patent status. The patent’s expiration eliminates a viable infringement claim based solely on practicing the claimed alfentanil compound or composition in the United States.

Any later litigation would require a separate enforceable right, such as:

A later alfentanil formulation patent.
A process patent.
A device patent.
A product-by-process claim.
A method-of-use patent.
Trade-secret or contract claims involving manufacturing information.

The expired patent itself cannot support a current injunction against generic alfentanil manufacture, sale, or use.

Were there settlement agreements involving this patent?

No settlement agreement is material to the current U.S. status of the patent. Any historical settlement would not revive the expired patent or extend its statutory exclusionary term.

A settlement involving a later patent, a brand product, or a different fentanyl-family compound should not be attributed to U.S. Patent 4,167,574 without a specific court docket or agreement identifying this patent.

How does alfentanil compare with remifentanil and fentanyl patent risk?

Product	Chemical type	Original compound-patent status	Typical current patent issue
Alfentanil	Synthetic 4-anilidopiperidine opioid	U.S. Patent 4,167,574 expired	Later formulation, supply, and regulatory issues
Fentanyl	Synthetic opioid	Original patents expired	Delivery systems, formulations, devices, and uses
Remifentanil	Ultra-short-acting opioid	Separate patent estate	Formulation, synthesis, and product-specific rights
Sufentanil	Potent fentanyl analog	Separate patent estate	Formulation, delivery, and product-specific rights

The expiration of the alfentanil patent does not establish freedom to operate for fentanyl-family products generally. Each active ingredient requires a separate patent and regulatory review.

Key Takeaways

U.S. Patent 4,167,574 covers a broad N-phenyl-N-(4-piperidinyl)amide genus and several specifically named tetrazolone derivatives.
Claim 2 is the principal alfentanil compound claim.
Claim 9 is the corresponding alfentanil pharmaceutical-composition claim.
Claims 1 and 8 are broad genus claims; claims 2-7 and 9-14 are species-level compound and composition claims.
The patent has no manufacturing, device, dosage-regimen, or method-of-use claims in the claim set provided.
The patent issued on September 11, 1979, and its nominal 17-year term expired on September 11, 1996.
The patent cannot create a current Paragraph IV, 30-month stay, or infringement barrier.
Alfentanil is a small molecule, so biosimilar provisions do not apply.
Current generic-entry risks arise primarily from sterile injectable manufacturing, controlled-substance compliance, API supply, FDA requirements, and any later product-specific patents.
The patent’s historical scope was meaningful; its current exclusionary value is none.

FAQs About U.S. Patent 4,167,574 and Alfentanil

Does U.S. Patent 4,167,574 cover alfentanil hydrochloride?

Yes. Claim 2 covers alfentanil and its pharmaceutically acceptable acid-addition salts. Alfentanil hydrochloride is the principal marketed salt form.

Can a company manufacture generic alfentanil without a license under this patent?

Yes, with respect to U.S. Patent 4,167,574, because the patent expired in 1996. The manufacturer must still satisfy FDA, controlled-substance, quality, and other applicable legal requirements.

Is claim 1 invalid because it covers many compounds?

Breadth alone does not determine validity. A Markush claim is assessed under written description, enablement, definiteness, novelty, and obviousness standards. Those validity questions are commercially superseded here by patent expiration.

Does the patent cover remifentanil or fentanyl?

No automatic coverage follows from pharmacologic similarity. Remifentanil and fentanyl have different chemical structures and require separate claim-by-claim infringement analysis.

Is alfentanil eligible for a biosimilar application?

No. Alfentanil is a chemically synthesized small molecule. A generic alfentanil product would ordinarily proceed through the small-molecule drug approval framework, generally including the ANDA pathway where applicable.

References

United States Patent and Trademark Office. (1979). U.S. Patent No. 4,167,574, N-(4-piperidinyl)-N-phenylamides.
United States Code, 35 U.S.C. §§ 154, 156.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, commonly known as the Orange Book.
U.S. Food and Drug Administration. (n.d.). Alfentanil hydrochloride injection prescribing information.
U.S. Food and Drug Administration. (n.d.). ANDA submissions: Content and format.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	368994	⤷ Start Trial
Austria	A322078	⤷ Start Trial
Australia	3552278	⤷ Start Trial
Australia	514360	⤷ Start Trial
Belgium	866710	⤷ Start Trial
Canada	1105464	⤷ Start Trial
Switzerland	635585	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,167,574

Summary for Patent: 4,167,574