US Patent 7,544,372: Cyclobenzaprine Extended-Release Bead Claims, Exclusivity and Patent Landscape

US Patent 7,544,372 protects a once-daily cyclobenzaprine dosage form based on extended-release beads coated with a water-insoluble polymer membrane. Its claims combine formulation structure, dissolution performance, pharmacokinetics, dose proportionality, and treatment of painful musculoskeletal conditions.

The patent was relevant to Amrix extended-release capsules and related cyclobenzaprine hydrochloride products. The patent’s FDA-listed term expired in September 2023, eliminating the principal remaining US patent barrier created by this patent. The claims remain important for historical infringement analysis, generic litigation review, and freedom-to-operate assessments involving older products, but they no longer provide current US exclusionary rights after expiration.

What does US Patent 7,544,372 protect?

The patent protects a method of relieving muscle spasms by administering a pharmaceutical dosage form containing cyclobenzaprine extended-release beads.

The independent claim requires all of the following:

Required element	Scope
Therapeutic use	Treatment of muscle spasm associated with painful musculoskeletal conditions
Active ingredient	Cyclobenzaprine, its pharmaceutically acceptable salts or derivatives, or mixtures
Dosage form	A pharmaceutical dosage form containing a population of extended-release beads
Core	An active-containing core particle
Coating	A water-insoluble polymer membrane surrounding the core
Dissolution	Defined release pattern in USP Apparatus 2, 50 rpm, 900 mL of 0.1N HCl at 37°C
Clinical performance	Therapeutically effective plasma concentrations over 24 hours
Coating composition	Specified water-insoluble polymers and plasticizers

The patent is therefore narrower than a general claim to extended-release cyclobenzaprine. A potentially infringing product must satisfy the structural coating limitations, the dissolution limitations, and the claimed treatment method.

The patent does not claim every cyclobenzaprine extended-release formulation. A tablet, matrix formulation, osmotic system, multiparticulate system with a materially different coating, or product with a different release profile may fall outside claim 1, subject to equivalents and other claims or patents.

How are the claims structured?

Claim 1: The principal combination claim

Claim 1 is a combination claim with both structural and functional limitations. It requires:

A method of treating muscle spasms.
Administration of a skeletal-muscle-relaxant dosage form.
Extended-release beads.
Cyclobenzaprine-containing core particles.
A water-insoluble polymer membrane.
A specified dissolution profile.
A 24-hour therapeutically effective plasma concentration.
A listed polymer and plasticizer combination.

The claim’s polymer Markush group includes ethyl cellulose, cellulose derivatives, polyvinyl acetate, neutral methacrylate copolymers, ammonio methacrylic acid copolymers, and mixtures. Listed plasticizers include triacetin, tributyl citrate, triethyl citrate, acetyl tributyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, castor oil, and acetylated glycerides.

Claims 2 and 8: Cyclobenzaprine hydrochloride

Claims 2 and 8 narrow the active ingredient to cyclobenzaprine, with claim 2 specifically identifying cyclobenzaprine hydrochloride.

Claim 3: Pharmacokinetic target

Claim 3 requires a 30-mg dosage form with:

Parameter	Claimed reference value	Permitted range
Cmax	About 20 ng/mL	80% to 125%, approximately 16 to 25 ng/mL
AUC0-168	About 740 ng·hr/mL	80% to 125%, approximately 592 to 925 ng·hr/mL
Tmax	About 7 hours	80% to 125%, approximately 5.6 to 8.75 hours

These limitations introduce a substantial evidentiary issue. Infringement analysis would require reliable pharmacokinetic testing under conditions corresponding to the claim, including dose, patient population, sampling period, and statistical treatment.

Claim 4: Dose proportionality

Claim 4 requires that the adjusted mean ratio between 30-mg and 15-mg products exceed approximately 2 for AUC0-168, AUC0-∞, and Cmax, with p<0.001.

This claim is unusually dependent on comparative clinical or pharmacokinetic data. It does not merely require a 30-mg product. It requires a relationship between the 30-mg and 15-mg dosage forms.

Claims 5 through 7 and 9 through 21: Formulation fallbacks

The dependent claims add the following limitations:

A single extended-release bead population.
Polymer coating at approximately 7% to 12% by weight.
Water-soluble polymers such as hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, polyethylene glycol, or polyvinylpyrrolidone.
An additional 12-hour dissolution endpoint.
Ethyl cellulose as the water-insoluble polymer.
Diethyl phthalate as the plasticizer.
A total daily dose of 15 mg or 30 mg cyclobenzaprine hydrochloride.

Claims 15 through 18 create a particularly specific formulation chain: hydroxypropyl methylcellulose, cyclobenzaprine hydrochloride, 7% to 12% membrane weight, and the specified 12-hour release profile.

What dissolution profile does the patent require?

The central release profile is:

Testing time	Required release
2 hours	No more than approximately 40%
4 hours	Approximately 40% to 65%
8 hours	Approximately 60% to 85%
12 hours, where required by dependent claims	Approximately 75% to 85%

Testing must use USP Apparatus 2, paddles at 50 rpm, 900 mL of 0.1N hydrochloric acid, and 37°C.

The profile is not a generic “extended release” requirement. It imposes four-hour and eight-hour release windows and, in certain dependent claims, a 12-hour window. Small differences in coating weight, polymer permeability, plasticizer concentration, bead size, or aqueous pore formation could change whether a product falls within the claimed profile.

A design-around strategy could target a materially different release curve, a different dosage architecture, or a different mechanism of release. Such a strategy would require testing against every limitation, including the 24-hour plasma-concentration limitation.

When did US Patent 7,544,372 lose exclusivity?

The US Orange Book-listed expiration date for US 7,544,372 was September 27, 2023. The patent therefore no longer blocks US generic marketing after that date, assuming no separate unexpired patent, regulatory exclusivity, injunction, or other legal restriction applies.

Milestone	Date or status
Patent issued	June 9, 2009
FDA product association	Amrix extended-release cyclobenzaprine capsules
Listed patent expiration	September 27, 2023
Current patent status	Expired by stated term
Patent term extension	No current extension generally associated with the listed expiration
Regulatory exclusivity	Separate from patent term and not a continuing barrier after patent expiration

Patent expiration does not retroactively eliminate liability for conduct occurring before expiration. It also does not eliminate potential claims based on other patents, confidential know-how, trade secrets, or manufacturing processes.

What was the Orange Book status of US 7,544,372?

The patent was historically listed in the FDA Orange Book for Amrix, a once-daily extended-release cyclobenzaprine hydrochloride product. Orange Book listing connected the patent to an approved drug product and supported the Hatch-Waxman certification process for ANDA applicants.

The listing was commercially significant because an ANDA applicant seeking approval for a therapeutically equivalent extended-release cyclobenzaprine product could face:

A Paragraph IV certification alleging that the patent was invalid, unenforceable, or not infringed.
Patent litigation by the NDA holder or patent owner.
A potential 30-month stay of approval under the Hatch-Waxman framework if litigation was timely initiated.
A first-applicant 180-day exclusivity issue, depending on the ANDA filing history and other applicants.

After patent expiration, the patent no longer creates a prospective Orange Book-based approval block. The FDA Orange Book remains the relevant historical source for listed patent data and patent-expiration information.[1]

Which companies challenged or competed with Amrix?

The commercial field included the original Amrix product and generic cyclobenzaprine hydrochloride extended-release capsules. Cephalon was associated with Amrix commercialization, while Eurand was associated with the multiparticulate controlled-release technology used in the product and patent family.

Public Hatch-Waxman activity around Amrix involved generic applicants seeking approval for 15-mg and 30-mg extended-release capsules. The commercial competitive set included generic manufacturers such as Actavis and other ANDA sponsors that entered or prepared to enter the market after patent and regulatory barriers were addressed.

The material legal question for each applicant was not simply whether its product contained cyclobenzaprine. The relevant questions included whether the proposed product used:

A bead-based dosage form.
A water-insoluble polymer membrane.
A claimed polymer-plasticizer combination.
A release profile within the claimed ranges.
A 15-mg or 30-mg dose producing the claimed pharmacokinetic characteristics.

A product could be therapeutically equivalent to Amrix for FDA purposes while presenting a different patent-infringement position. FDA equivalence and patent infringement are separate analyses.

What patent litigation affected the patent?

The patent was part of the Hatch-Waxman dispute environment surrounding Amrix and generic extended-release cyclobenzaprine. ANDA litigation would have focused on validity, enforceability, infringement, and the scope of the formulation and method claims.

The strongest litigation issues would likely have included:

Infringement

A patent owner would need to establish that the accused product or use satisfied the required bead structure, coating composition, dissolution profile, and treatment limitations. Method-of-use claims can create complications because the accused party may not directly administer the product. Liability may instead depend on inducement, labeling, prescribing instructions, or commercial conduct.

Claim construction

Disputed terms could include:

“Population of extended release beads.”
“Water insoluble polymer membrane.”
“Substantially corresponding.”
“Therapeutically effective plasma concentration.”
“Provides a maximum blood plasma concentration.”
“Sufficient amount.”
“About 7% to 12%.”

The word “about” does not create an unlimited range. Its scope depends on the specification, prosecution history, technical context, and expected measurement variability.

Validity

Potential validity challenges would focus on:

Obviousness over prior controlled-release cyclobenzaprine formulations.
Written description and enablement for the broad polymer and plasticizer groups.
Definiteness of the dissolution and pharmacokinetic limitations.
Anticipation by prior bead-based drug delivery systems.
Double-patenting issues within the patent family.

The combination of known polymers with a particular release profile can create an obviousness dispute, but unexpected pharmacokinetic behavior or clinically meaningful performance may support non-obviousness.

How strong was the patent estate?

US 7,544,372 was strongest against products that closely replicated the Amrix architecture: cyclobenzaprine hydrochloride beads, ethyl-cellulose-based coatings, diethyl phthalate or similar plasticizers, hydrophilic pore-forming polymers, and the claimed dissolution profile.

Its principal limitations were:

It was a method claim rather than a broad composition claim.
It required multiple technical elements in combination.
Several dependent claims required difficult-to-prove pharmacokinetic outcomes.
The dissolution limitations could be designed around.
The patent expired in 2023.

The estate was more commercially meaningful when combined with related formulation patents, regulatory exclusivity, manufacturing know-how, and litigation timing. US 7,544,372 alone did not necessarily cover every extended-release cyclobenzaprine product.

What manufacturing and intellectual-property barriers existed?

The formulation uses multiparticulate processing rather than a simple immediate-release tablet. Relevant manufacturing barriers included:

Uniform drug loading onto core particles.
Consistent bead size distribution.
Controlled polymer-coating thickness.
Stable plasticizer incorporation.
Prevention of dose dumping.
Reproducible dissolution across manufacturing lots.
Encapsulation or final dosage-form uniformity.
Stability of cyclobenzaprine hydrochloride during coating and storage.

These process requirements can create practical barriers even after patent expiration. They are not necessarily patent barriers. Manufacturing know-how, equipment qualification, process validation, and regulatory comparability can delay entry without creating a continuing right to exclude.

How does this patent compare with competing cyclobenzaprine products?

Product type	Likely relationship to US 7,544,372
Immediate-release cyclobenzaprine tablets	Generally outside the extended-release bead limitations
Generic extended-release capsules using similar beads	Highest historical infringement exposure
Matrix tablets	Potential design-around, depending on other patents
Osmotic or membrane-controlled systems	Potential design-around if not bead-based
Different polymer or plasticizer system	May avoid dependent claims but not necessarily claim 1
Different dissolution profile	Potentially avoids the release limitation
Other skeletal muscle relaxants	Outside the cyclobenzaprine active-ingredient limitation
Biosimilar products	Not relevant because cyclobenzaprine is a small-molecule drug

Cyclobenzaprine extended-release capsules competed primarily with immediate-release cyclobenzaprine products, generic extended-release capsules, and alternative muscle relaxants such as tizanidine, baclofen, methocarbamol, and carisoprodol. Those products generally do not practice the specific cyclobenzaprine bead claims.

What generic entry risks existed?

Before September 2023, generic entry risk depended on the ANDA applicant’s certification and litigation posture. The main scenarios were:

Scenario	Commercial consequence
Paragraph III certification	Approval delayed until patent expiration
Paragraph IV certification without timely suit	Possible approval before expiration
Timely patent litigation	Potential 30-month approval stay
Successful invalidity or non-infringement position	Earlier approval possible
Settlement agreement	Entry date governed by settlement terms
Post-expiration entry	No continuing barrier from this patent

Following expiration, the principal risks shifted from patent exclusion to FDA approval, formulation development, manufacturing scale-up, bioequivalence, supply, and market pricing.

What licensing deals were associated with the technology?

The commercial history of Amrix involved collaboration and commercialization arrangements among the developers and marketing parties, including Eurand and Cephalon. The existence of a commercial partnership does not establish that every related patent was assigned to the same entity. Patent ownership, exclusive licensing, NDA rights, and commercialization rights must be distinguished.

No current exclusionary licensing right can extend the expired term of US 7,544,372. A private license may continue to allocate royalties or contractual rights, but it cannot revive the patent’s expired exclusionary power.

Key Takeaways

US 7,544,372 covers a method of treating muscle spasms with cyclobenzaprine extended-release beads.
The claim scope depends on bead structure, water-insoluble polymer coating, plasticizer, dissolution profile, and 24-hour therapeutic exposure.
Claims 3 and 4 add demanding pharmacokinetic and dose-comparison requirements.
Claims 11 through 18 focus on ethyl cellulose, diethyl phthalate, hydroxypropyl methylcellulose, coating weight, and the 12-hour release profile.
The patent was historically associated with Amrix extended-release cyclobenzaprine capsules.
The FDA-listed patent term expired on September 27, 2023.
Generic competition is now governed primarily by FDA approval, formulation capability, manufacturing, and commercial economics rather than this patent.
The patent did not cover all cyclobenzaprine products or all extended-release technologies.
Biosimilar analysis is inapplicable because cyclobenzaprine is a small-molecule active ingredient.
Historical infringement analysis remains relevant for pre-expiration sales and ANDA litigation.

FAQs About US Patent 7,544,372

Was US 7,544,372 a composition patent or a method patent?

It was primarily a method-of-treatment patent. The claims require administering the specified extended-release cyclobenzaprine dosage form to relieve muscle spasms.

Did the patent cover immediate-release cyclobenzaprine tablets?

No. The claims require extended-release beads with a water-insoluble polymer membrane and a specified release profile.

Could a matrix tablet avoid US 7,544,372?

Potentially. A matrix tablet may avoid the “population of extended release beads” limitation, although infringement would require reviewing the full patent family and any other applicable patents.

Did expiration of US 7,544,372 eliminate all Amrix patent risk?

No. Expiration eliminated this patent’s exclusionary effect. Other patents, contractual rights, manufacturing know-how, regulatory issues, or separate litigation could have created different risks.

Is a generic cyclobenzaprine extended-release capsule automatically infringing?

No. FDA therapeutic equivalence does not determine patent infringement. The product must be compared against each claim limitation, including coating composition, bead architecture, dissolution, pharmacokinetics, and method-of-use requirements.

References

U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
United States Patent and Trademark Office. (2009). U.S. Patent No. 7,544,372: Extended release dosage forms of cyclobenzaprine.
U.S. Food and Drug Administration. (2016). Amrix prescribing information.
U.S. Food and Drug Administration. (2024). Approved drug product labeling for cyclobenzaprine hydrochloride extended-release capsules.
U.S. Code, 35 U.S.C. §§ 154, 271, 281-285.
U.S. Code, 21 U.S.C. § 355(j).

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
World Intellectual Property Organization (WIPO)	2005048996	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 7,544,372

Summary for Patent: 7,544,372