US Patent 10,472,365: Remimazolam Besylate Claims, Expiration, Orange Book Status and Generic Risk

US Patent 10,472,365 protects a lyophilized remimazolam besylate product when it is reconstituted and administered to produce procedural sedation. The patent does not claim remimazolam itself as a chemical compound. Its principal protection is a method-of-treatment combination requiring:

A lyophilized composition containing remimazolam besylate and a pharmaceutical carrier, excipient or diluent.
Reconstitution with an aqueous solution.
Stability of at least 96.7% of the original remimazolam amount after storage at 40°C and 75% relative humidity for one to four weeks.
HPLC measurement of the remimazolam amount.
Administration to produce sedation.

The patent is associated with Byfavo, the U.S. remimazolam besylate product approved for procedural sedation. Public Orange Book data identifies US 10,472,365 as a listed patent with an expiration date in March 2036. The patent creates a formulation-linked method-of-use barrier rather than a broad chemical-composition monopoly.

What drug and formulation does US Patent 10,472,365 protect?

The compound of formula (I) in the claims is remimazolam. The claimed salt is remimazolam besylate, the active pharmaceutical ingredient in Byfavo.

Remimazolam is an ultra-short-acting benzodiazepine used for intravenous procedural sedation. Byfavo is supplied as a lyophilized powder for reconstitution before intravenous administration. The FDA-approved product is indicated for induction and maintenance of procedural sedation in adults undergoing procedures lasting 30 minutes or less. The product is administered by a health-care professional with appropriate monitoring and resuscitation capability (FDA, 2020).

Core technical limitations

Claim element	Scope
Active ingredient	Besylate salt of remimazolam
Dosage form	Lyophilized composition
Pharmaceutical ingredients	At least one carrier, excipient or diluent
Preparation step	Reconstitution with an aqueous solution
Diluent	Saline or dextrose under dependent claims
Administration routes	Subcutaneous, intramuscular, intradermal or intravenous
Preferred intravenous use	Bolus injection or continuous infusion
Clinical setting	Diagnostic, operative or endoscopic procedure
Stability requirement	At least 96.7% of original compound retained
Stress condition	40°C and 75% relative humidity
Stress duration	One to four weeks
Analytical method	High-performance liquid chromatography
Claimed therapeutic result	Sedation

What is the scope of independent claim 1?

Claim 1 is a multi-element method claim. A potentially infringing product or use must satisfy the full combination, not merely contain remimazolam besylate.

The claim requires both a pharmaceutical-product condition and a clinical-use condition. The composition must be lyophilized and must meet the specified accelerated-stability result. The composition must then be reconstituted and administered in an amount effective to produce sedation.

The claim does not expressly require:

A particular remimazolam dose.
A particular vial size.
A specific excipient.
A specific concentration after reconstitution.
Intravenous administration.
A particular procedure type.
A specific bolus or infusion rate.

Those limitations appear in dependent claims or are absent from the claim.

Why the 96.7% stability limitation matters

The 96.7% threshold is a material narrowing limitation. It distinguishes the claimed composition from a lyophilized remimazolam product that contains the same active ingredient but fails the specified accelerated-stability test.

The measurement must be made by HPLC. A generic manufacturer would need to assess:

The initial amount of remimazolam in the lyophilized product.
The amount remaining after storage.
The exact storage temperature and humidity.
Whether the tested batch falls within the one-to-four-week period.
The HPLC method and calculation used to establish retention.

The claim is not limited to a particular impurity profile in the wording supplied. It focuses on the percentage of the original amount of compound remaining. That creates potential claim-construction issues over assay variability, sampling, degradation products and whether the stability test must be performed on every commercial batch or can be established through representative batch data.

How do claims 2 through 20 narrow the patent?

Claims 2 through 20 define the diluent, route, administration mode and procedure setting.

Claims	Added limitation
2	Aqueous solution contains dextrose or saline
3	Aqueous solution contains saline
4	Aqueous solution contains dextrose
5	Subcutaneous, intramuscular, intradermal or intravenous administration
6	Intravenous administration
7	Intravenous bolus or continuous infusion
8	Intravenous bolus
9	Continuous infusion
10	Administration during diagnostic, operative or endoscopic procedure
11	Diagnostic procedure
12	Operative procedure
13	Endoscopic procedure
14	Intravenous administration during one of the listed procedures
15	Dextrose or saline, listed administration routes and listed procedure setting
16	Intravenous administration under claim 15
17	Intravenous bolus or continuous infusion under claim 16
18	Saline, intravenous administration and bolus or continuous infusion
19	Saline and intravenous bolus
20	Saline and continuous infusion

Claims 15 through 20 are combination claims. They are narrower than claim 1 because they combine formulation, route and clinical-use limitations.

What do claims 21 through 24 protect?

Claims 21 through 24 isolate the stability period:

Claim	Stability period
21	One week
22	Two weeks
23	Three weeks
24	Four weeks

Each claim retains the 96.7% HPLC stability requirement. These claims provide separate fallback positions if the broader one-to-four-week language in claim 1 is narrowed or challenged.

The dependent claims may also create distinct infringement positions. For example, a product that satisfies the stability requirement after one week but not after four weeks may still fall within claim 21 while avoiding claim 24.

What is the patent expiration date for US 10,472,365?

Public patent and Orange Book records identify an expiration date in March 2036, commonly reported as March 5, 2036, for the patent family associated with the remimazolam lyophilized formulation and sedation claims (FDA, Approved Drug Products with Therapeutic Equivalence Evaluations; USPTO, Patent Center).

Milestone	Date
U.S. patent grant	November 12, 2019
FDA approval of Byfavo	July 2, 2020
Reported patent expiration	March 5, 2036
FDA five-year NCE exclusivity	July 2, 2025

The five-year new chemical entity exclusivity period is separate from patent protection. FDA approval occurred in 2020, so the statutory NCE exclusivity period generally blocked an ANDA submission relying on the reference product until 2025. The patent can continue to block or complicate commercial entry after regulatory exclusivity expires.

Patent-term calculations should be confirmed against the current USPTO record, including any patent-term adjustment, disclaimer or terminal-disclaimer information.

What is the Orange Book status of US Patent 10,472,365?

US 10,472,365 has been associated with Byfavo in Orange Book patent listings. The listing is significant because an ANDA applicant seeking approval of a remimazolam product must address listed patents through the statutory certification framework.

For an ANDA applicant, the principal options are:

Paragraph III certification, accepting approval after patent expiration.
Paragraph IV certification, asserting that the patent is invalid, unenforceable or not infringed.
A section VIII statement, where the applicant omits a protected method of use from its labeling, if the remaining label and product use are legally sufficient.

Because US 10,472,365 includes formulation and method-of-use limitations, a section VIII strategy may be difficult if the proposed generic label reproduces the procedural-sedation use and relies on the same lyophilized remimazolam presentation.

Which parts of the Byfavo product are protected by this patent?

The patent protects the combination of product format and use rather than every remimazolam product.

Protected or potentially protected

Lyophilized remimazolam besylate.
Reconstitution with saline.
Reconstitution with dextrose.
Intravenous bolus administration.
Continuous intravenous infusion.
Sedation during diagnostic procedures.
Sedation during operative procedures.
Sedation during endoscopic procedures.
Products meeting the 96.7% accelerated-stability threshold.

Not necessarily protected by this patent alone

Remimazolam as a chemical entity.
Every remimazolam salt.
Oral remimazolam.
A non-lyophilized remimazolam formulation.
A formulation that does not meet the 96.7% stability limitation.
A use unrelated to producing sedation.
A product used outside the claimed clinical settings, depending on the applicable claim.
A product that is not reconstituted before administration.

The patent therefore has meaningful commercial relevance for a Byfavo-like generic but does not necessarily prevent all alternative remimazolam formulations or delivery systems.

How strong is the patent estate for remimazolam?

US 10,472,365 is strongest against a conventional generic that copies the commercial product presentation and approved procedural-sedation use. It is less comprehensive against non-infringing formulation designs.

Risk factor	Assessment
Product overlap with Byfavo	High
Relevance to lyophilized injectable generics	High
Coverage of remimazolam molecule itself	Low under the supplied claims
Coverage of alternative dosage forms	Limited
Dependence on analytical testing	High
Method-of-use exposure	High for procedural sedation
Design-around potential	Moderate
Biosimilar relevance	None
Orange Book relevance	High if listed against the reference product

The principal vulnerability is claim dependency on the stability assay. A challenger may dispute whether the patent claims a reproducible product characteristic, whether the test method is sufficiently defined, or whether the stability result is inherent in the accused product. The patent owner would likely respond that the claimed stability performance is an objective limitation demonstrated by the specified HPLC test.

What Paragraph IV challenges could generic manufacturers bring?

A generic applicant could challenge US 10,472,365 on several grounds.

Invalidity theories

Potential arguments include:

Lack of enablement if the specification does not enable the full breadth of lyophilized compositions, excipients, reconstitution solutions, routes and procedures covered by the claims.
Lack of written description if the claims cover stability combinations not adequately described across their full scope.
Obviousness based on known lyophilized benzodiazepine formulations, remimazolam salt forms, standard saline or dextrose reconstitution and routine stability testing.
Indefiniteness involving the meaning of “original amount,” the one-to-four-week period or the HPLC measurement conditions.
Anticipation by an earlier remimazolam formulation or method reference.

Non-infringement theories

A generic applicant could argue that its product:

Is not lyophilized.
Does not use remimazolam besylate.
Does not retain at least 96.7% under the claimed test.
Uses a different reconstitution process.
Is labeled only for an unclaimed use.
Does not instruct administration during a diagnostic, operative or endoscopic procedure.
Uses a formulation with a different stability profile.

The most difficult design-around path is likely a conventional lyophilized remimazolam product intended for the same U.S. procedural-sedation market. That product would need to address both the product limitation and the treatment-use limitation.

Is there biosimilar risk for remimazolam?

No. Remimazolam is a chemically synthesized small molecule, not a biologic. The relevant competitive pathway is an ANDA for a generic drug, not a biosimilar application under the Public Health Service Act.

The principal regulatory issues are pharmaceutical equivalence, bioequivalence, labeling, manufacturing controls and patent certification. FDA-approved injectable generics would need to demonstrate compatibility with the proposed route and dosage form and satisfy applicable quality requirements.

What generic launch scenarios exist?

Launch after patent expiration

A Paragraph III applicant can accept the reported March 2036 expiration date. This is the lowest litigation-risk route but delays entry.

Paragraph IV challenge

A Paragraph IV applicant could seek approval before expiration by challenging validity or infringement. If the patent owner sues within the statutory period, FDA approval may be subject to a 30-month stay, subject to statutory exceptions and litigation developments.

Carved-out labeling

A section VIII strategy may be possible only if the generic label omits the protected procedural-sedation use and does not otherwise encourage the patented method. This route is commercially limited because procedural sedation is the core clinical use of Byfavo.

Formulation design-around

A manufacturer could explore:

A ready-to-use liquid formulation.
A different salt or chemical form.
A non-lyophilized presentation.
A formulation that fails the claimed stability threshold.
A delivery system that does not require reconstitution.

Each design-around must be assessed against other remimazolam patents, FDA product requirements and induced-infringement risks.

What licensing and commercial relationships affect the patent landscape?

Remimazolam was developed by PAION. U.S. commercialization of Byfavo has involved licensing and commercial arrangements with U.S. partners, including Acacia Pharma. Eagle Pharmaceuticals acquired Acacia Pharma in 2023, making Eagle a significant commercial participant in the U.S. Byfavo business.

The relevant commercial rights should be separated from patent ownership:

Entity	Role
PAION	Original developer and remimazolam rights holder in the global development history
Acacia Pharma	U.S. commercialization partner for Byfavo before acquisition
Eagle Pharmaceuticals	Acquired Acacia Pharma and assumed its commercial position
FDA	Regulatory authority for Byfavo approval and generic applications

A licensee may enforce or participate in enforcement only to the extent permitted by the license and applicable standing rules. The patent owner, listed drug sponsor and commercial distributor may not be the same entity.

What litigation affects US Patent 10,472,365?

The principal litigation risk is future ANDA litigation triggered by a Paragraph IV certification. The claim set is tailored to the Byfavo presentation, so any generic applicant seeking to copy the lyophilized intravenous procedural-sedation product would face a direct patent analysis.

A current litigation conclusion requires review of the USPTO Patent Center record, PACER, FDA Orange Book updates and any district-court docket. The supplied claims alone do not establish that an active infringement action, settlement agreement or authorized generic arrangement exists.

Key Takeaways

US 10,472,365 is a remimazolam besylate formulation-linked method patent.
Its central requirement is a lyophilized composition that retains at least 96.7% of the original remimazolam amount after accelerated storage.
The claims require reconstitution and administration to produce sedation.
Saline, dextrose, intravenous bolus, continuous infusion and procedural sedation are covered through dependent claims.
The patent does not broadly claim remimazolam as a chemical compound.
Public Orange Book information associates the patent with Byfavo and reports expiration in March 2036.
Remimazolam has generic, not biosimilar, competition risk.
A conventional Byfavo-like generic faces substantial formulation and method-of-use exposure.
Potential design-arounds include non-lyophilized products, alternative salts and formulations that do not satisfy the claimed stability threshold.
Paragraph IV litigation is the principal route to earlier generic entry.

FAQs

Does US 10,472,365 cover remimazolam injections that are already in liquid form?

Not on the supplied claim language. Claim 1 requires a lyophilized composition that is reconstituted before administration. A ready-to-use liquid formulation would require analysis under other patents and infringement theories.

Can a generic use saline to reconstitute remimazolam without infringing?

Saline is expressly recited in claims 3 and 18, but infringement depends on every limitation, including the lyophilized presentation, stability threshold, HPLC measurement and sedation use.

Does the patent cover veterinary sedation?

The claims refer to a “subject” and do not expressly limit the subject to humans. The scope would depend on claim construction, specification disclosures, labeling and the accused use.

Is the 96.7% requirement a product limitation or a testing requirement?

It operates as a claim limitation describing the performance of the lyophilized composition under specified storage conditions, with the amount measured by HPLC. Its enforcement would likely focus on validated testing of the accused product.

Can a generic launch before 2036 with a different remimazolam salt?

Possibly, but not solely because the salt differs. The generic would need to avoid the claimed besylate salt limitation and clear any separate patents, regulatory requirements and induced-infringement issues.

References

U.S. Food and Drug Administration. (2020). FDA approves Byfavo for procedural sedation in adults.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. Orange Book.
U.S. Patent and Trademark Office. (2019). U.S. Patent No. 10,472,365, methods of producing sedation using a lyophilized remimazolam besylate composition.
U.S. Food and Drug Administration. (2020). Byfavo (remimazolam) prescribing information.
Eagle Pharmaceuticals, Inc. (2023). Annual report and disclosures concerning the acquisition of Acacia Pharma.

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Acacia	BYFAVO	remimazolam besylate	POWDER;INTRAVENOUS	212295-001	Oct 6, 2020		RX	Yes	Yes	10,472,365	⤷ Start Trial				USE OF REMIMAZOLAM FOR INDUCTION AND MAINTENANCE OF PROCEDURAL SEDATION IN ADULTS UNDERGOING PROCEDURES LASTING 30 MINUTES OR LESS	⤷ Start Trial
>Applicant	>Tradename	>Generic Name	>Dosage	>NDA	>Approval Date	>TE	>Type	>RLD	>RS	>Patent No.	>Patent Expiration	>Product	>Substance	>Delist Req.	>Patented / Exclusive Use	>Submissiondate

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	0613692.3	Jul 10, 2006
United Kingdom	0613694.9	Jul 10, 2006

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	E480532	⤷ Start Trial
Australia	2007274054	⤷ Start Trial
Brazil	PI0714886	⤷ Start Trial
Canada	2657347	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 10,472,365

Which drugs does patent 10,472,365 protect, and when does it expire?

Summary for Patent: 10,472,365