U.S. Patent 4,316,839: Scope, Flumazenil Claims, Expiration, and Patent Landscape
U.S. Patent No. 4,316,839 is an early Hoffmann-La Roche patent covering imidazobenzodiazepine compounds, including flumazenil and related analogs. The patent was granted on February 23, 1982 and expired on February 23, 1999 under the 17-year U.S. patent term applicable to pre-June 8, 1995 applications. It does not create a current U.S. patent barrier to generic flumazenil or related compounds.
The strongest commercial claim is claim 17, which expressly covers ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate and its pharmaceutically acceptable acid-addition salts. That compound is flumazenil, also known as Ro 15-1788.
What compounds does U.S. Patent 4,316,839 protect?
The patent claims a broad genus of substituted imidazo- and fused diazepine compounds. Its principal structural elements are:
| Claim element |
Scope |
| Core structure |
Imidazo-fused diazepine and related fused heterocyclic systems defined by alternatives for group A |
| D substituent |
Carbonyl, >C=O, or thiocarbonyl, >C=S |
| R1 |
Cyano, lower alkanoyl, or ester, -COOR4 |
| R4 |
Methyl, ethyl, isopropyl, or 2-hydroxyethyl |
| R5 and R6 |
Hydrogen, halogen, trifluoromethyl, or lower alkyl, depending on the claim |
| R2/R3 |
Hydrogen, lower alkyl, or a fused trimethylene or propenylene bridge |
| Stereochemistry |
S or R,S configuration at the gamma carbon, with narrower claims requiring S configuration |
| Salts |
Pharmaceutically acceptable acid-addition salts where expressly recited |
The supplied claim text refers to structural groups (a) and (b) shown in chemical drawings. Those drawings are necessary to assign exact ring-system boundaries to every alternative in claim 1. The named compounds in claims 10-17, however, identify the commercially relevant scope with sufficient specificity.
Which claims cover flumazenil?
Flumazenil is covered directly by claim 17 and falls within the broader genus of claim 1.
Claim 17
Claim 17 covers:
Ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate and pharmaceutically acceptable acid-addition salts thereof.
This is the chemical identity of flumazenil. The claim covers the neutral compound and its acid-addition salts.
Claim 10
Claim 10 separately claims:
Ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate.
Claim 10 is a compound claim without the express salt language appearing in claim 17.
Claim 9
Claim 9 covers a narrower structural class requiring:
- The group (a) ring system;
- R1 as cyano or ester under the incorporated limitations;
- S configuration where the trimethylene bridge is present;
- R5 as hydrogen or fluorine;
- R6 as hydrogen, fluorine, chlorine, or methyl;
- At least one of R5 and R6 to be hydrogen.
Flumazenil, which has an 8-fluoro substituent and an unsubstituted position corresponding to the other ring position, is within this narrower class.
Claims 1, 2, 6, and 7
Flumazenil also falls within broader combinations of the following limitations:
- Claim 1: broad Markush genus;
- Claim 2: ester-substituted compounds with hydrogen or lower alkyl at the relevant side-chain positions;
- Claim 6: cyano or methyl, ethyl, or isopropyl ester;
- Claim 7: methyl substitution where R2 is hydrogen.
The exact dependence of each claim must be read with the full patent drawings and antecedent limitations. The commercial flumazenil compound is most clearly and specifically protected by claims 10 and 17.
What is the patent expiration date?
| Event |
Date |
| U.S. Patent No. 4,316,839 granted |
February 23, 1982 |
| Applicable U.S. term |
17 years from grant |
| Scheduled expiration |
February 23, 1999 |
| Current status |
Expired |
| Current blocking effect |
None |
The patent was granted before the Uruguay Round Agreements Act changed the United States from a 17-year-from-grant system to a 20-year-from-earliest-effective-filing-date system. Patent term adjustment and patent term extension provisions applicable to later patents do not revive this expired patent.
The patent therefore cannot support a present-day infringement action against a U.S. manufacturer, generic applicant, contract manufacturer, or distributor.
How broad is claim 1?
Claim 1 is a classic Markush composition-of-matter claim. It combines multiple independent variables:
- Two alternative ring systems for A;
- Carbonyl and thiocarbonyl variants;
- Cyano, alkanoyl, and ester substituents;
- Four ester alkoxy groups;
- Multiple halogen, alkyl, and trifluoromethyl combinations;
- Acyclic and ring-fused substituent arrangements;
- R and S stereochemical configurations;
- Pharmaceutically acceptable acid-addition salts.
The claim is materially broader than flumazenil. It reaches compounds with:
- Methyl, ethyl, isopropyl, and 2-hydroxyethyl esters;
- Cyano analogs;
- Thiocarbonyl analogs;
- Fluoro, chloro, trifluoromethyl, and alkyl substitutions;
- Unfused and fused pyrrolidine-like ring systems;
- Benzodiazepine and thienodiazepine-related cores identified in the dependent claims.
The practical value of claim 1 was greatest as a genus claim against follow-on compounds developed from the same Roche imidazobenzodiazepine chemistry. Its present legal value is zero because the patent has expired.
Which claims are directed to specific compounds?
Claims 10-17 provide the clearest compound-by-compound coverage.
| Claim |
Compound category |
Commercial relevance |
| 10 |
Ethyl 8-fluoro, 5-methyl imidazobenzodiazepine carboxylate |
Flumazenil |
| 11 |
Ethyl 7-fluoro analog |
Flumazenil regioisomer |
| 12 |
Ethyl 7-chloro analog |
Chlorinated analog |
| 13 |
Ethyl (S)-8-chloro pyrrolobenzodiazepine analog |
Chiral fused analog |
| 14 |
Ethyl R,S unsubstituted pyrrolobenzodiazepine analog |
Racemic or mixed stereochemical analog |
| 15 |
Ethyl 8-fluoro pyrrolobenzodiazepine analog |
Fluorinated fused analog |
| 16 |
List of ester, cyano, thiocarbonyl, benzodiazepine, pyrrolobenzodiazepine, and thienodiazepine compounds |
Species collection |
| 17 |
Flumazenil and acid-addition salts |
Core commercial compound claim |
Claim 16 is a closed list. It does not claim every compound falling within claim 1. It claims only the enumerated compounds, including methyl, ethyl, and isopropyl ester variants, selected fluoro and chloro analogs, cyano compounds, thiocarbonyl compounds, and thienodiazepine derivatives.
What formulations are protected by the patent?
U.S. Patent 4,316,839 is primarily a compound patent. The reproduced claims do not claim:
- Injectable formulations;
- Infusion compositions;
- Specific concentrations;
- Preservative systems;
- Containers or delivery devices;
- Tablets, capsules, or oral dosage forms;
- Methods for treating benzodiazepine overdose;
- Methods for reversing sedation;
- Manufacturing processes.
The claims cover the active chemical entity and, in selected claims, acid-addition salts. A formulation containing flumazenil would have been exposed to the compound claims during the patent term because it incorporated the claimed active ingredient. The patent does not, based on the supplied claims, independently protect a formulation after expiration of the compound claims.
Are there method-of-use claims?
No method-of-use claim appears in the supplied claims. The patent claims compounds and salts. It does not claim use of flumazenil for:
- Reversal of benzodiazepine sedation;
- Treatment of benzodiazepine overdose;
- Reversal of anesthesia;
- Diagnosis or management of benzodiazepine-induced respiratory depression.
Any use protection would have had to come from a separate patent. Such use claims would also have expired no later than their applicable statutory term unless a later patent family had been granted.
What is the FDA and Orange Book status of flumazenil?
Flumazenil was approved by the FDA as Romazicon, an injectable benzodiazepine antagonist. The product is administered intravenously and is used to reverse the central sedative effects of benzodiazepines in appropriate clinical settings.[2]
The relevant regulatory facts are:
| Regulatory issue |
Status |
| Active ingredient |
Flumazenil |
| Original reference product |
Romazicon |
| Dosage form |
Injection |
| Route |
Intravenous |
| Therapeutic role |
Benzodiazepine antagonist |
| FDA pathway |
NDA approval followed by abbreviated generic approvals |
| Composition patent 4,316,839 |
Expired |
| Current generic barrier from this patent |
None |
The Orange Book is relevant to listed patents and regulatory exclusivity, but an expired 1982 composition patent cannot block an ANDA applicant. A generic applicant would typically address any listed patent through certification under section 505(j) of the Federal Food, Drug, and Cosmetic Act, including Paragraph III or Paragraph IV depending on the listing status and expiration date.[3]
Because U.S. Patent 4,316,839 expired in 1999, it cannot support a current Paragraph IV litigation strategy. Any present Orange Book issue would have to arise from a separate later patent, not from this patent.
When did generic entry become possible?
Generic entry became legally possible after the patent expired on February 23, 1999, subject to FDA approval and any separate regulatory or patent barriers.
The principal entry scenarios were:
| Entry scenario |
Legal position |
| ANDA filed before expiration |
Potential Paragraph IV litigation or Paragraph III delay |
| ANDA filed after February 23, 1999 |
No delay from Patent 4,316,839 |
| 505(b)(2) application |
Could rely partly on FDA findings for the reference product |
| New formulation |
Could face separate formulation patents, if any |
| Same flumazenil active ingredient |
Not blocked by Patent 4,316,839 |
Generic flumazenil does not face biosimilar regulation. Flumazenil is a chemically synthesized small molecule, not a biologic. The applicable route is an ANDA or, for a materially different product or indication, a 505(b)(2) application. The Public Health Service Act biosimilar pathway is not relevant.[4]
Which companies challenged or licensed this patent?
The supplied claims do not identify a license, settlement, Paragraph IV notice, or litigation proceeding. The patent was assigned to the Roche group, and the commercial reference product was developed and marketed as Romazicon.
No current licensing value remains in the patent because the patent expired more than two decades ago. Any historical license or settlement would have had commercial significance only before February 23, 1999 and would not restrict current manufacture absent an independent surviving contractual obligation.
A patent-number search alone does not establish a Paragraph IV challenge. Paragraph IV notices are associated with specific ANDA applicants and listed patents, while older compound patents can also be absent from current Orange Book listings after expiration.
How strong was the patent estate?
Composition-of-matter strength
The composition claims were strong during their term because they included:
- A broad Markush genus;
- Explicit flumazenil species claims;
- Ester and cyano variants;
- Halogenated analogs;
- Chiral and racemic fused-ring compounds;
- Acid-addition salts.
Claims 10 and 17 would have been comparatively easy to map against a product containing the named flumazenil molecule. A manufacturer could not avoid those claims through a different salt, dosage form, or route of administration if the underlying active compound remained within the claim.
Weaknesses and design-around opportunities
During the patent term, potential design-around strategies included:
- Changing the fused ring system;
- Replacing the ester with a nonclaimed substituent;
- Modifying the 8-fluoro or corresponding ring position;
- Using a nonclaimed stereochemical form;
- Replacing the carbonyl with a different functionality;
- Developing a compound outside the listed A-group alternatives.
Those strategies would have required a compound outside both the broad genus and the asserted dependent claims. After expiration, the design-around question became commercially irrelevant for flumazenil because the patented compound could be copied directly.
Current strength
| Factor |
Current assessment |
| Legal enforceability |
None; expired |
| Claim specificity for flumazenil |
High |
| Historical blocking power |
High |
| Current generic risk |
None from this patent |
| Biosimilar risk |
Not applicable |
| Formulation protection |
Not shown in supplied claims |
| Manufacturing protection |
Not shown in supplied claims |
| Licensing leverage |
None based on patent term |
What manufacturing and IP barriers remain?
Patent 4,316,839 does not create a current manufacturing barrier. A present-day manufacturer would instead need to address:
- FDA approval of flumazenil injection;
- Active pharmaceutical ingredient specifications;
- Sterile manufacturing and aseptic processing;
- Stability and container-closure requirements;
- Bioequivalence or pharmaceutical equivalence;
- Controlled quality systems;
- Supply of qualified flumazenil API;
- Any current FDA-listed patents unrelated to Patent 4,316,839;
- Trade secrets covering manufacturing processes, if used by a supplier.
Process know-how may remain commercially valuable even after the composition patent expires. Trade secrets do not appear in the patent claims and cannot be assessed from the claim language.
How does this patent compare with a modern drug patent?
Patent 4,316,839 differs from current pharmaceutical patent portfolios in three important respects:
| Issue |
Patent 4,316,839 |
Modern drug patent portfolio |
| Core protection |
Broad chemical genus and species |
Composition, formulation, methods, salts, polymorphs, devices, processes |
| Patent term |
17 years from grant |
Generally 20 years from earliest nonprovisional filing |
| Regulatory linkage |
Limited compared with current Orange Book practice |
Often integrated with Orange Book-listed patents |
| Litigation strategy |
Focused on chemical identity and analogs |
Often includes formulation, dosing, and method claims |
| Current value |
Expired |
Depends on remaining term and claim validity |
The patent was commercially important because it claimed flumazenil as a molecule. It did not create the layered formulation and method-of-use estate commonly used to extend exclusivity for modern products.
Key Takeaways
- U.S. Patent 4,316,839 covers flumazenil and multiple related imidazobenzodiazepine analogs.
- Claims 10 and 17 are the most direct flumazenil claims.
- Claim 1 is a broad Markush genus covering carbonyl, thiocarbonyl, ester, cyano, halogenated, fused-ring, and stereochemically defined analogs.
- The patent was granted on February 23, 1982 and expired on February 23, 1999.
- The patent cannot support current U.S. infringement litigation or delay generic entry.
- It is a small-molecule compound patent, so biosimilar analysis does not apply.
- The supplied claims do not show formulation, manufacturing-process, or method-of-use protection.
- Any current flumazenil patent risk would have to arise from a separate later patent or regulatory issue.
FAQs
Is U.S. Patent 4,316,839 still enforceable?
No. The patent expired on February 23, 1999 under the pre-1995 U.S. 17-year-from-grant patent term.
Does Patent 4,316,839 cover the flumazenil injection product?
It covers the flumazenil active ingredient and, in claim 17, its pharmaceutically acceptable acid-addition salts. It does not, based on the supplied claims, independently claim the injection formulation.
Can a generic company file an ANDA for flumazenil?
Yes. Patent 4,316,839 does not prevent an ANDA filing or approval. The applicant must still satisfy FDA requirements for the injectable dosage form.
Is flumazenil subject to biosimilar competition?
No. Flumazenil is a chemically synthesized small molecule. Generic competition proceeds through the ANDA or, in some cases, 505(b)(2) pathway rather than the biosimilar pathway.
Does claim 16 cover every analog listed in claim 1?
No. Claim 16 is a closed list of specifically identified compounds. Claim 1 is the broader genus claim, while claim 16 covers only the enumerated species.
References
- U.S. Patent No. 4,316,839. (1982). Imidazobenzodiazepines. United States Patent and Trademark Office.
- U.S. Food and Drug Administration. (1992). Romazicon (flumazenil) injection prescribing information. FDA.
- U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA.
- Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 355.
