Details for Patent: 8,999,393

Which drugs does patent 8,999,393 protect, and when does it expire?

Patent 8,999,393 protects LOREEV XR and is included in one NDA.

This patent has thirty-six patent family members in thirty-one countries.

Summary for Patent: 8,999,393

Title:	Sustained release formulations of lorazepam
Abstract:	A pharmaceutical composition for delivering lorazepam in a prolonged fashion is achieved with prolonged release lorazepam pharmaceutical beads. The composition typically contains sustained release lorazepam beads and delayed sustained release lorazepam beads. The composition can provide once daily dosing that maintains 24 hour therapeutic effect under steady state conditions.
Inventor(s):	Douglas A. Saltel, Michael Vachon
Assignee:	Edgemont Pharmaceuticals Liquidating Trust LLC
Application Number:	US14/150,375
Patent Claim Types: see list of patent claims	Use; Composition; Formulation; Dosage form;

US Patent 8,999,393: Lorazepam Sustained-Release Patent Scope, Claims, Expiration, and Competitive Landscape

US Patent 8,999,393 protects once-daily oral lorazepam formulations using two bead populations: sustained-release beads and delayed sustained-release beads. The patent focuses on pharmacokinetic performance, dissolution behavior, bead architecture, HPMC matrices, enteric protection, and 24-hour therapeutic coverage. Its broadest enforceable commercial relevance is directed to dual-population bead formulations corresponding to the technology used in Loreev XR.

The principal infringement risk is a once-daily lorazepam product containing both immediate sustained-release and delayed, pH-triggered sustained-release beads within the 0.5 mg to 10 mg dosage range, particularly where the product is designed to approximate twice-daily immediate-release lorazepam exposure.

What does US Patent 8,999,393 protect?

The patent protects pharmaceutical compositions and treatment methods that combine:

1. Lorazepam sustained-release beads.
2. Lorazepam delayed sustained-release beads.
3. A total lorazepam dose of 0.5 mg to 10 mg.
4. Once-daily administration.
5. Pharmacokinetic exposure broadly comparable to twice-daily immediate-release lorazepam.
6. At least 24 hours of therapeutic effect.

The claims are not limited to a particular capsule shell, tablet, excipient ratio, bead size, coating thickness, or manufacturing process. The technical limitations are imposed primarily through:

• Release timing.
• Dissolution performance.
• Polymer matrix composition.
• Enteric coating behavior.
• Plasma Cmax and Cmin.
• Tmax and continued drug release.
• Therapeutic duration.

The patent therefore combines structural claims with performance-based claims. A formulation can fall within the claims even if its commercial presentation, excipient composition, or manufacturing process differs from the disclosed examples.

How many independent claims does US 8,999,393 contain?

The supplied claims contain three independent claims:

Claim	Claim type	Principal subject matter
1	Composition	Dual-population sustained-release and delayed sustained-release lorazepam beads
16	Composition	Lorazepam prolonged-release beads with defined pharmacokinetic characteristics
20	Method of treatment	Once-daily treatment of a lorazepam-treatable condition for 24-hour therapeutic effect

Claims 2 through 15 depend from claim 1. Claims 17 through 19 depend from claim 16.

Claims 1 and 16 create separate composition-based infringement paths. A competing product that avoids one independent claim may still implicate the other if its pharmacokinetic profile and dosage form satisfy the relevant limitations.

What is the scope of claim 1?

Claim 1 is the central formulation claim. It requires:

• A pharmaceutical composition.
• Lorazepam sustained-release beads.
• Lorazepam delayed sustained-release beads.
• Total lorazepam content of 0.5 mg to 10 mg.
• Once-daily administration.
• A steady-state Cmax and/or Cmin within 35% of the corresponding values produced by twice-daily immediate-release tablets containing the same total daily lorazepam dose.

The use of "and/or" materially broadens the claim. A formulation may satisfy the pharmacokinetic limitation through:

• Cmax alone;
• Cmin alone; or
• Both Cmax and Cmin.

The comparator is not an arbitrary reference product. It is immediate-release lorazepam administered twice daily at the same total daily dose. The comparison is therefore dose-normalized and regimen-specific.

Why the pharmacokinetic limitation matters

The Cmax and Cmin limitations create both a technical requirement and an evidentiary issue. In an infringement dispute, the patent holder would likely need pharmacokinetic data showing that the accused product, when administered once daily, produces the required steady-state exposure relative to the specified twice-daily immediate-release comparator.

A product may contain sustained-release beads and delayed-release beads but avoid claim 1 if its steady-state Cmax and Cmin fall outside the claimed range. Conversely, a formulation with different excipients may still raise risk if its pharmacokinetic profile meets the claim.

What do claims 2 through 15 add?

The dependent claims narrow claim 1 through therapeutic, dissolution, structural, and pharmacokinetic limitations.

Claims	Added limitation	Commercial significance
2	At least 24-hour therapeutic effect	Links the formulation to once-daily clinical duration
3	All lorazepam is contained in the two bead populations	Excludes separate uncoated or immediate-release lorazepam fractions
4	Sustained-release beads release 20% to 70% in two hours under specified two-media testing	Defines early release behavior
5	50% release within one to five hours	Narrows the sustained-release profile
6	At least 90% remains unreleased before 10 hours	Requires prolonged release
7	Delayed sustained-release beads release 90% after 10 hours	Protects a late-release bead population
8	pH-dependent delay coating and 20% to 80% release in four hours	Targets enteric or pH-triggered release
9-10	Lorazepam-polymer matrix and enteric-coated delayed-release core	Protects bead architecture
11	HPMC in both polymer matrices	Narrows the matrix chemistry
12	Enteric coating releases at pH 7 or higher	Narrows the pH trigger
13	Cmax not greater than 12 ng/mL per 1 mg and/or Cmin at least 5 ng/mL per 1 mg	Adds absolute exposure thresholds
14	Cmax and/or Cmin within 20% of twice-daily immediate-release exposure	Tighter pharmacokinetic target
15	Continued lorazepam release for at least 24 hours in a single-dose pharmacokinetic study	Links release duration to clinical testing

Claims 9 through 12 are particularly important for formulation analysis because they describe the likely physical implementation of the claimed product: HPMC-containing lorazepam matrices combined with an enteric-coated delayed-release bead population.

What formulations are protected by the bead claims?

The protected formulation architecture has two functional populations.

Sustained-release beads

The sustained-release beads contain lorazepam dispersed in a polymer matrix. The claims identify HPMC as an example of the matrix material. These beads begin releasing drug earlier and provide the initial portion of the 24-hour exposure profile.

Claims 4 through 6 define a release pattern that includes:

• 20% to 70% release during the early portion of the test;
• 50% release within one to five hours under the additional limitation;
• Less than 90% total release before 10 hours.

Delayed sustained-release beads

The delayed sustained-release beads contain:

• A core with lorazepam dispersed in a polymer matrix; and
• An enteric or pH-dependent coating surrounding the core.

The coating delays release through the acidic stage of the dissolution test and permits release after exposure to phosphate buffer at pH 7.4. Claim 12 further specifies a coating designed to release drug at pH 7 or greater.

This architecture separates the dose into an earlier sustained-release component and a later delayed-release component. The combination is intended to reduce peak-trough fluctuation while extending exposure beyond the normal duration of immediate-release lorazepam.

How do claims 16 through 19 differ from claim 1?

Claim 16 is an independent composition claim with a different center of gravity. It requires:

• A sustained-release lorazepam composition.
• Lorazepam prolonged-release beads.
• Tmax of at least four hours.
• Continued release beyond 20 hours.
• An oral dosage form containing 0.5 mg to 10 mg of lorazepam.
• At least 24 hours of therapeutic effect after once-daily administration.

Unlike claim 1, claim 16 does not expressly require both sustained-release beads and delayed sustained-release beads. It also does not expressly require an enteric coating, HPMC, or the Cmax/Cmin comparison to immediate-release tablets.

That makes claim 16 potentially broader in formulation design but narrower in its pharmacokinetic requirements.

Claims 17 and 18 increase the continued-release requirement:

• Claim 17: release for at least 24 hours.
• Claim 18: release for at least 28 hours.

Claim 19 adds an AUC distribution requirement: 40% to 60% of total AUC during the first 24 hours, measured against AUC over 120 hours. This limitation is directed to an extended, relatively even exposure profile rather than rapid early release.

What does claim 20 protect?

Claim 20 is a method-of-treatment claim covering:

• A patient with a lorazepam-treatable condition.
• Once-daily administration.
• A composition according to claim 1.
• A sufficient dose to provide a 24-hour therapeutic effect during steady-state conditions.

The claim requires use of a composition that already falls within claim 1. It does not independently cover every once-daily lorazepam treatment. The composition must satisfy the dual-bead and pharmacokinetic requirements of claim 1.

Potentially relevant conditions include anxiety disorders, insomnia-related conditions, seizure-related indications, and other conditions for which lorazepam is clinically used. The breadth of "lorazepam-treatable condition" is limited by the incorporated composition requirements and the need to establish a 24-hour therapeutic effect.

When does US Patent 8,999,393 lose exclusivity?

The patent issued on April 7, 2015. Its term is generally calculated from the earliest effective nonprovisional priority date, subject to patent-term adjustment, patent-term extension, terminal disclaimers, and any applicable pediatric extension. Public patent records identify the expected nominal expiration as occurring in 2029, subject to the recorded term calculation. [1]

A practical exclusivity timeline is:

Event	Date or period
Patent issued	April 7, 2015
Nominal patent term endpoint	2029, subject to adjustment
FDA approval of Loreev XR	2020
Possible pediatric extension	Up to six additional months if statutory requirements were satisfied
Earliest ordinary post-patent entry window	2029, subject to Orange Book and litigation status

Patent expiration does not itself establish immediate generic market entry. A generic applicant must also address any other listed patents, regulatory exclusivity, settlement restrictions, manufacturing issues, and court-ordered injunctions.

What is the Orange Book status of US 8,999,393?

US Patent 8,999,393 has been associated with the Orange Book patent protection for Loreev XR, an extended-release lorazepam product marketed by Almatica Pharma. Loreev XR was approved by the FDA in September 2020 as an extended-release capsule for once-daily administration. [2,3]

The relevant regulatory distinction is:

• Patent protection: primarily formulation and pharmacokinetic protection.
• Regulatory exclusivity: separate from patent rights and dependent on the approval pathway and FDA exclusivity designation.
• Orange Book listing: relevant to abbreviated new drug application certification and potential 30-month stay litigation.

The patent does not protect immediate-release lorazepam tablets generally. Immediate-release lorazepam products have long been marketed by multiple manufacturers and are subject to a substantially different patent position.

Which companies are challenging the patent?

A complete current list of Paragraph IV filers, ANDA applicants, litigation defendants, and settlement participants cannot be established from the claim text alone. The relevant sources for a live challenge assessment are:

• FDA Orange Book patent listings;
• FDA Paragraph IV notice information;
• PACER and district court dockets;
• ANDA litigation filings under the Hatch-Waxman Act;
• Patent assignment and maintenance records.

The existence of an ANDA filing would not by itself establish commercial launch timing. A generic applicant may file a Paragraph IV certification, settle the litigation, receive a licensed entry date, or remain subject to an injunction.

What generic entry risks exist?

A generic or follow-on product would face several design and regulatory routes.

Route 1: Avoid the dual-bead architecture

A product could attempt to use:

• A single sustained-release bead population;
• A multiparticulate system with a different delayed-release mechanism;
• A matrix tablet;
• An osmotic system;
• A coated tablet;
• A liquid or implantable delivery system.

This strategy may reduce risk under claim 1 but would still require analysis under claim 16, particularly if the product has a Tmax of at least four hours and release beyond 20 hours.

Route 2: Avoid the claimed dose range

The claims specify 0.5 mg to 10 mg. A product outside that range could avoid literal infringement of claims requiring the dosage limitation, but a commercial lorazepam product would need to remain clinically useful and meet FDA labeling requirements. Dose variation alone may not avoid claims that use broader dosage or method language elsewhere in the patent family.

Route 3: Avoid the pharmacokinetic profile

A product may seek to avoid:

• Cmax within 35% or 20% of twice-daily immediate-release exposure;
• Cmin within the claimed ranges;
• Tmax of four hours or longer;
• Release beyond 20, 24, or 28 hours.

This strategy creates regulatory risk because the product must still demonstrate the intended once-daily therapeutic performance.

Route 4: Use a non-enteric delayed-release mechanism

A coating triggered by enzyme activity, time-dependent erosion, osmotic pressure, or mechanical rupture could avoid the specific pH-dependent and enteric-coating limitations in claims 8, 9, 10, and 12. The product could nevertheless remain exposed to claim 1 if it retains the required two bead populations and pharmacokinetic profile.

How strong is the patent estate?

The patent has meaningful commercial strength because claim 1 combines a recognizable product architecture with clinically relevant performance limitations. The strongest features are:

• A specific dual-population bead system;
• Once-daily administration;
• A defined dose range;
• Comparison to twice-daily immediate-release lorazepam;
• 24-hour therapeutic coverage;
• Detailed dissolution and pharmacokinetic dependent claims.

The main validity and enforcement vulnerabilities are claim construction and proof.

Potential validity pressure points

The key issues likely to arise in validity proceedings include:

• Whether the claimed pharmacokinetic ranges are adequately supported and enabled across the full dose range;
• Whether the dissolution limitations are sufficiently reproducible;
• Whether the claimed combination would have been obvious from prior sustained-release benzodiazepine formulations;
• Whether the specification provides enough guidance to achieve the claimed Cmax, Cmin, Tmax, and AUC profiles;
• Whether "therapeutic effect for at least 24 hours" is definite and objectively measurable;
• Whether the comparison to twice-daily immediate-release tablets creates an objective infringement standard.

Enforcement strength

Claims 9 through 12 may be easier to analyze structurally because they identify HPMC matrices and enteric coatings. Claims 1, 2, 13, 14, 15, and 16 through 19 depend more heavily on clinical, dissolution, and pharmacokinetic testing.

A formulation may be difficult to clear solely through label review because several claims concern product characteristics rather than express treatment instructions. A non-infringing label does not necessarily eliminate product-by-process or pharmacokinetic exposure.

What patent litigation affects Loreev XR?

The relevant litigation question is whether an ANDA applicant has certified Paragraph IV against the listed patent and whether the patent holder filed an infringement action within the statutory period. A complete litigation conclusion requires current docket and Orange Book data. The supplied claims establish the technical scope but do not establish whether any active case, settlement, covenant not to sue, or launch license exists.

For transaction, launch, or investment analysis, the critical legal facts are:

Issue	Relevance
Orange Book listing	Determines whether an ANDA applicant must certify against the patent
Paragraph IV notice	Can trigger patent litigation
30-month stay	May delay FDA approval
Settlement agreement	May establish an earlier licensed entry date
Patent-term adjustment	Can move the actual expiration date
Pediatric extension	Can add up to six months
Continuation patents	May preserve additional claim coverage after the parent patent expires

How does US 8,999,393 compare with immediate-release lorazepam patents?

Issue	Immediate-release lorazepam	US 8,999,393
Dosage frequency	Usually multiple daily doses	Once daily
Release mechanism	Rapid dissolution	Sustained and delayed bead release
Primary protection	Historical compound, formulation, or method rights	Extended-release delivery system
Cmax control	Less controlled	Explicitly claimed
Cmin control	Less controlled	Explicitly claimed
Therapeutic duration	Typically shorter	At least 24 hours
Generic competition	Established	Dependent on formulation patents and FDA pathway
Biosimilar risk	Not applicable	Not applicable because lorazepam is a small molecule

Biosimilar risk is not relevant to this patent. Lorazepam is a small-molecule active pharmaceutical ingredient, so competing products would generally proceed through the ANDA pathway rather than the biosimilar pathway under the Biologics Price Competition and Innovation Act.

What licensing and manufacturing barriers matter?

The principal manufacturing barrier is reproducible production of two bead populations with different release profiles. A commercial manufacturer must control:

• Lorazepam loading;
• Polymer dispersion;
• HPMC grade and concentration;
• Bead size distribution;
• Coating weight gain;
• Enteric coating uniformity;
• Acid-stage resistance;
• pH-triggered release;
• Batch-to-batch Cmax, Cmin, Tmax, and AUC performance.

A licensee would need rights covering the patent claims, any continuation patents, formulation know-how, analytical methods, coating technology, and commercial manufacturing process. Patent clearance without access to the originating know-how may not provide an efficient path to an equivalent product.

What is the revenue exposure from this patent?

The patent’s commercial value is tied primarily to Loreev XR and any once-daily extended-release lorazepam products using comparable bead technology. Immediate-release lorazepam revenue is not dependent on this patent.

Revenue exposure depends on:

• Loreev XR net sales;
• The share of prescriptions converted from immediate-release lorazepam;
• Payer coverage and reimbursement;
• Generic launch timing;
• Any authorized generic;
• The number of competing extended-release products;
• The effective patent expiration date;
• Settlement or license terms.

The patent creates a formulation-specific barrier rather than a market-wide lorazepam monopoly.

Key Takeaways

• US Patent 8,999,393 is directed to once-daily extended-release lorazepam.
• Claim 1 is the principal dual-bead composition claim.
• The claimed product combines sustained-release beads with delayed sustained-release beads.
• The patent claims both physical structure and pharmacokinetic performance.
• Claims 9 through 12 specifically target HPMC matrices and pH-dependent enteric coatings.
• Claim 16 provides a separate composition claim based on Tmax and continued release beyond 20 hours.
• Claim 20 covers once-daily treatment using a claim 1 composition.
• The patent is associated with Loreev XR patent protection.
• The nominal patent term ends in 2029, subject to patent-term adjustment, pediatric extension, and related term calculations.
• Biosimilar competition is not relevant because lorazepam is a small molecule.
• The principal generic design-around options are a different delivery architecture, a different delay mechanism, or a pharmacokinetic profile outside the claimed ranges.
• Current Paragraph IV challenges, settlements, and active litigation require docket-level verification and cannot be determined from the claim text alone.

FAQs

Does US Patent 8,999,393 cover all extended-release lorazepam products?

No. The strongest claims require specified bead populations, release characteristics, pharmacokinetic behavior, or prolonged-release performance. A different delivery system may avoid literal infringement, although claim 16 and related family patents would require separate analysis.

Can a generic lorazepam capsule avoid infringement by changing the coating material?

Possibly, but changing the coating material alone may not be sufficient. Claims 1 and 16 contain functional and pharmacokinetic limitations that can apply regardless of the specific coating chemistry.

Does the patent cover lorazepam tablets?

The claims are directed to pharmaceutical compositions and oral dosage forms containing beads. A tablet containing the claimed bead populations could potentially fall within the claims. A conventional immediate-release tablet would not satisfy the claimed sustained-release architecture.

Is FDA approval of a generic lorazepam product blocked until patent expiration?

Not necessarily. An ANDA applicant may challenge the patent through a Paragraph IV certification, await expiration, negotiate a settlement, or obtain a licensed launch date. FDA approval timing is separate from commercial launch timing.

What is the most important technical limitation for freedom-to-operate analysis?

The highest-value limitation is the combination of two release populations with a once-daily pharmacokinetic profile approximating twice-daily immediate-release lorazepam. A product that meets both the bead architecture and exposure requirements presents the greatest infringement risk.

Drugs Protected by US Patent 8,999,393

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Almatica	LOREEV XR	lorazepam	CAPSULE, EXTENDED RELEASE;ORAL	214826-001	Aug 27, 2021		RX	Yes	No	8,999,393		Y			ONCE DAILY TREATMENT OF ANXIETY DISORDER IN ADULTS
Almatica	LOREEV XR	lorazepam	CAPSULE, EXTENDED RELEASE;ORAL	214826-004	Feb 16, 2022		RX	Yes	No	8,999,393		Y			ONCE DAILY TREATMENT OF ANXIETY DISORDER IN ADULTS
Almatica	LOREEV XR	lorazepam	CAPSULE, EXTENDED RELEASE;ORAL	214826-002	Aug 27, 2021		RX	Yes	No	8,999,393		Y			ONCE DAILY TREATMENT OF ANXIETY DISORDER IN ADULTS
Almatica	LOREEV XR	lorazepam	CAPSULE, EXTENDED RELEASE;ORAL	214826-003	Aug 27, 2021		RX	Yes	Yes	8,999,393		Y			ONCE DAILY TREATMENT OF ANXIETY DISORDER IN ADULTS

International Family Members for US Patent 8,999,393

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	094391
Australia	2014205440
Brazil	112015016304
Canada	2897302
Chile	2015001920