United States Drug Patent 6,500,454: Claim Scope, Expiration, Orange Book Status, and Generic Entry Risk

U.S. Patent No. 6,500,454 protects a specific multiparticulate propranolol dosage form, not propranolol, propranolol salts, or sustained-release propranolol generally. Its central limitation is a two-membrane bead: an inner ethylcellulose membrane that slows release and an outer ethylcellulose-enteric-polymer membrane that creates a gastrointestinal lag period. The claims also require defined two-stage dissolution behavior.

The patent estate is narrow from a formulation-design perspective but potentially strong against products that reproduce the claimed bead architecture and release profile. The patent’s enforceable term has ended. It therefore presents historical infringement significance but no current U.S. blocking right against generic propranolol products. The patent is not relevant to biosimilar analysis because propranolol is a small-molecule active ingredient.

What does U.S. Patent 6,500,454 protect?

The patent protects a pharmaceutical dosage form containing timed sustained-release propranolol beads. The independent product claim, claim 1, requires all of the following:

Required element	Claim requirement
Active ingredient	Propranolol or a pharmaceutically acceptable salt
Core	A propranolol-containing core particle
Inner membrane	Ethylcellulose surrounding the core and sustaining release
Outer membrane	Mixture of ethylcellulose and an enteric polymer
Functional purpose	Outer membrane provides a lag time before drug release
Dissolution test	USP Type II apparatus, 50 rpm, two-stage medium
Release profile	Defined release ranges at 2, 4, 6, 10 and 16 hours

The claim is a combination claim. A product must contain the claimed active ingredient, core, coating sequence and release performance to fall within the literal scope of claim 1. A propranolol formulation using a single extended-release membrane, a pH-independent polymer, or a different release profile would not literally satisfy every limitation of claim 1.

The patent is directed to chronotherapy. Claims 21 through 25 cover administration of the dosage form to provide delayed and sustained propranolol exposure, including evening administration and therapeutic availability by early morning.

How are the claims organized?

Claims 1, 18 and 21 are the principal independent claims.

Claim	Category	Subject matter
1	Product	Dosage form containing timed sustained-release propranolol beads
18	Manufacturing method	Preparation of the coated beads and capsule filling
21	Treatment method	Providing timed sustained release of propranolol to a patient

The remaining claims narrow those independent claims.

Product claim hierarchy

Claims 2 and 3 narrow claim 1 by imposing progressively tighter dissolution windows. Claim 3 is the narrowest release-profile claim and requires:

0% to 5% release after two hours;
5% to 15% after four hours;
25% to 35% after six hours;
55% to 70% after ten hours; and
at least 75% after 16 hours.

Claims 4 through 12 narrow the materials and construction:

claim 4 addresses non-pareil seeds, granulated and milled cores, and extrusion-spheronized cores;
claims 5 and 6 define eligible enteric polymers;
claims 7 and 8 cover plasticizers;
claims 9 through 12 define ethylcellulose-to-enteric-polymer ratios;
claim 12 specifies an approximately 1:1 ethylcellulose-to-hydroxypropyl methylcellulose phthalate ratio.

Claims 13 and 14 add immediate-release propranolol beads that provide a loading dose within the first hour. Claims 15 and 16 define coating-weight ranges. Claim 17 limits the total propranolol content to 80 mg to 160 mg.

Manufacturing claims

Claim 18 requires:

preparation of a propranolol-containing core;
coating with plasticized ethylcellulose;
coating with plasticized ethylcellulose mixed with an enteric polymer; and
filling capsules with the resulting beads.

Claims 19 and 20 broaden the permitted core-production methods to include coating non-pareil seeds or buffer crystals, granulation and milling, and extrusion-spheronization.

Method-of-use claims

Claims 21 through 25 cover administration rather than manufacture. The most commercially relevant limitations are:

oral administration;
late-evening dosing;
effective propranolol exposure by early morning;
continued sustained release; and
a claimed Tmax at approximately 12 hours.

A manufacturer could avoid some method claims by labeling a product without the claimed evening or chronotherapy instructions. That strategy would not necessarily avoid the product claims if the dosage form itself meets claim 1.

What formulation architecture is required?

The patent requires a sequential coating architecture.

Inner ethylcellulose membrane

The first membrane surrounds the propranolol core. Ethylcellulose is a water-insoluble film former that limits aqueous penetration and drug diffusion. Claims 7 and 8 permit plasticizers such as triethyl citrate, triacetin, dibutyl sebacate, polyethylene glycol and related materials.

Claim 16 places the first membrane at approximately 1.5% to 4% of the total bead weight. This limitation narrows the claim and may create design-around opportunities through materially different inner-coating weights.

Outer ethylcellulose-enteric membrane

The second membrane combines ethylcellulose with an enteric polymer. The claim requires that this membrane provide a lag time. The relevant enteric polymers include:

cellulose acetate phthalate;
hydroxypropyl methylcellulose phthalate;
hydroxypropyl methylcellulose succinate;
polyvinyl acetate phthalate;
shellac; and
pH-sensitive methacrylic acid-methyl methacrylate copolymers.

Claims 9 through 12 impose polymer-ratio limitations. Claim 9 allows a broad 10:1 to 1:2 ethylcellulose-to-enteric-polymer range. Claims 10 through 12 narrow the ratio to 2:1 to 1:1, with claim 12 specifying approximately 1:1 when hydroxypropyl methylcellulose phthalate is used.

Bead and capsule format

The claims contemplate multiparticulate beads filled into capsules. The patent does not require one exclusive core-manufacturing process. It covers layered cores made on sugar seeds, as well as matrix-type cores produced by granulation, milling or extrusion-spheronization.

A tablet containing compressed coated beads could raise a claim-construction issue. The independent claims require a "pharmaceutical dosage form" comprising TSR beads, not necessarily a capsule. Claim 18 expressly recites capsule filling, but that limitation does not automatically restrict claim 1.

How important is the dissolution profile?

The dissolution profile is a central claim limitation, not merely an experimental description.

The required test uses:

a USP Type II apparatus;
50 rpm;
700 mL of 0.1N hydrochloric acid for the first two hours;
transition to pH 6.8 after addition of 200 mL of pH modifier; and
release measurements through 16 hours.

Claim 1 allows relatively broad release ranges:

Time	Claim 1 release range
2 hours	0% to 20%
4 hours	5% to 35%
6 hours	10% to 60%
10 hours	40% to 90%
16 hours	At least 60%

The nested claims impose narrower profiles. A competing product may use the same polymers yet avoid claims 2 or 3 if its measured release falls outside those narrower ranges. It may still infringe claim 1 if it falls within the broader ranges and satisfies the structural limitations.

The wording "substantially corresponding" creates a factual issue. In litigation, the parties would likely contest:

acceptable variation around each percentage range;
batch-to-batch variability;
sampling and assay methodology;
the exact pH transition procedure;
whether all time points must fall within the ranges;
whether the test must be performed on the marketed dosage form; and
whether release from an alternative apparatus is comparable.

The functional release limitation may make the claims harder to invalidate for lack of written description if the specification provides representative formulations and test data. It also gives an accused manufacturer a meaningful noninfringement position where its formulation has a different lag period or release curve.

What are the strongest and weakest parts of the patent estate?

Strengths

The strongest features are the combination of structure and performance:

two distinct membranes;
ethylcellulose in both membranes;
an enteric polymer in the outer membrane;
a delayed release period in acid followed by sustained release at higher pH; and
quantified release behavior over 16 hours.

A generic that copies the reference product’s bead technology may face substantial infringement risk even if it changes excipients that are not expressly claimed.

The method claims also create potential exposure for a manufacturer that uses the claimed coating sequence, even if its labeling avoids chronotherapy language.

Weaknesses

The estate has several limitations:

It is restricted to propranolol formulations.
It requires ethylcellulose in the inner membrane.
It requires an ethylcellulose-enteric-polymer mixture in the outer membrane.
It depends on a specific dissolution test and release pattern.
Several dependent claims require particular coating weights or polymer ratios.
It does not broadly cover all delayed-release, extended-release or pulsatile propranolol systems.
The patent term has expired.

The use of ethylcellulose in both membranes gives formulation scientists several potential design-around paths. Possible alternatives include:

replacing the inner membrane with a different rate-controlling polymer;
using a distinct enteric barrier rather than a mixed outer membrane;
using a pH-sensitive capsule shell or osmotic system;
changing the coating sequence;
using a matrix tablet rather than coated beads; or
engineering a release profile outside claim 1.

A design-around must be assessed against the full claim language and the doctrine of equivalents. Simply changing a trade name, plasticizer or bead size would rarely be sufficient if the same claimed functions and relationships remain.

When did U.S. Patent 6,500,454 lose exclusivity?

U.S. Patent No. 6,500,454 is expired. Its effective patent term ended after the applicable 20-year term measured from the relevant U.S. filing framework, subject to any recorded patent-term adjustment. The patent no longer provides an enforceable U.S. exclusionary right in 2026. [1][4]

The patent’s expiration removes the principal patent barrier created by the claimed two-membrane propranolol formulation. It does not eliminate other possible barriers, including:

separate patents on a marketed product;
regulatory exclusivity;
manufacturing know-how;
trade secrets;
product-specific formulation patents;
facility qualification;
supply agreements; and
FDA approval requirements.

What is the Orange Book status of propranolol products?

Propranolol is an approved small-molecule drug with multiple generic products. FDA Orange Book analysis is product-specific. A patent may be listed against one NDA product and absent from another. Listing status also does not extend an expired patent’s enforceable term. [2]

The relevant regulatory framework includes:

Issue	Propranolol implication
FDA approval	Generic propranolol products may be approved through an ANDA where the reference product and dosage form permit
Patent listing	Depends on the specific reference NDA and listed patent
Paragraph IV	Historically relevant if an ANDA applicant challenged an unexpired listed patent
30-month stay	Available only under the statutory conditions and timing rules
Current blocking effect	None from an expired patent
Regulatory exclusivity	Separate from patent term and must be assessed by NDA and dosage form

The FDA’s Orange Book should be used to verify historical listing, delisting and expiration information for any particular propranolol reference product. The patent itself does not establish Orange Book listing status. [2]

Which companies challenged the propranolol patent?

The supplied claims do not establish the identity of any ANDA applicants, Paragraph IV challengers, litigation defendants or settlement counterparties. Patent claims alone cannot substantiate those procedural facts.

A reliable challenge analysis must distinguish among:

a Paragraph IV certification;
an ANDA filing;
a patent-infringement complaint;
a declaratory-judgment action;
a consent judgment;
a license;
a covenant not to sue; and
a commercial launch before or after patent expiration.

Those events are documented through FDA records, district-court dockets, Federal Circuit opinions and settlement filings. The patent text does not identify them. [2][5]

What patent litigation and settlement issues affect this patent?

A historical dispute involving this patent would likely focus on four issues.

Infringement

The claimant would need to show that the accused dosage form has the required core and coating structure and meets the dissolution limitations. Discovery would likely include formulation records, coating-process parameters, polymer ratios, coating weights, dissolution data and ANDA exhibit batches.

Claim construction

Likely disputes would include the meaning of:

"outer membrane";
"mixture of ethylcellulose and an enteric polymer";
"providing a lag time";
"substantially corresponding";
"about";
"approximately"; and
"Tmax at about 12 hours."

Validity

Potential validity challenges could involve:

anticipation by earlier delayed-release propranolol systems;
obviousness based on ethylcellulose and enteric-polymer coating technology;
written-description support for the broad dissolution ranges;
enablement across the full polymer and ratio ranges; and
indefiniteness of "substantially corresponding" and "about."

The patent’s layered dependent claims may have different validity profiles. The broad claim 1 is more commercially important but potentially more vulnerable to prior art. Narrow claims 10 through 12 may be harder to read on a generic formulation but can gain strength from specific polymer-ratio limitations.

Settlement

A settlement could permit an earlier launch through a date-certain license, a supply arrangement or a nonexclusive formulation license. It could also restrict launch by dosage form, indication, market or manufacturing site. No settlement terms should be inferred from the patent claims.

Is biosimilar risk relevant?

No. Propranolol is a chemically synthesized small molecule, not a biologic. The relevant competitive pathway is generic substitution under the ANDA framework, not biosimilar approval under the Biologics Price Competition and Innovation Act.

The principal regulatory and commercial questions are bioequivalence, dosage-form equivalence, labeling, dissolution, manufacturing consistency and any remaining product-specific patents. [2][5]

What generic launch scenarios exist?

Because U.S. Patent 6,500,454 is expired, a current generic applicant does not need to wait for this patent. The practical scenarios are:

Scenario	Current effect of Patent 6,500,454
Generic immediate-release propranolol	No effect
Generic conventional extended-release propranolol	No effect
Generic delayed and sustained-release beads	No effect from this expired patent
Product copying the claimed bead system	Historical infringement exposure only
Product relying on a different formulation patent	Depends on that separate patent
Product using the same manufacturing process	No current exclusionary right from this patent

The main remaining barrier is regulatory approval and commercial execution. Manufacturing complexity may still matter because two sequential polymer coatings, controlled coating weights and reproducible dissolution performance require specialized multiparticulate processing.

How strong is the patent from a freedom-to-operate perspective?

For current U.S. development, the patent has no blocking strength because it is expired. For historical freedom-to-operate analysis, its claim strength was moderate to high against close copies and lower against alternative delivery systems.

A product would have faced the greatest historical risk if it combined:

propranolol beads;
an inner ethylcellulose membrane;
an outer ethylcellulose-enteric-polymer membrane;
capsule delivery;
80 mg to 160 mg total propranolol; and
a 12-hour delayed-sustained release profile.

Risk would have been lower for a formulation using a matrix tablet, osmotic delivery, a single enteric coat, a different rate-controlling polymer or a materially different release curve.

Key Takeaways

U.S. Patent 6,500,454 covers a specific two-membrane propranolol bead system.
Claim 1 requires an ethylcellulose inner membrane and an ethylcellulose-enteric-polymer outer membrane.
The dissolution profile is a substantive limitation and may be decisive in infringement analysis.
Claims 2 and 3 narrow the release profile; claims 9 through 12 narrow polymer ratios.
Claims 18 through 20 cover manufacturing methods.
Claims 21 through 25 cover timed administration, including evening dosing and early-morning exposure.
The patent is expired and does not create a current U.S. exclusionary right.
Propranolol is not subject to biosimilar competition because it is a small molecule.
Any current generic-entry analysis must focus on remaining patents, Orange Book records, FDA approval requirements and manufacturing capability.
Paragraph IV, litigation and settlement conclusions cannot be derived from the claim text alone.

FAQs

Does U.S. Patent 6,500,454 cover Inderal LA or InnoPran XL broadly?

No. The claims do not broadly cover all sustained-release propranolol products. They cover products that meet the claimed bead structure and dissolution requirements. Product-specific coverage depends on the applicable NDA, formulation and Orange Book records.

Can a generic avoid the patent by using a tablet instead of beads?

Historically, a tablet could avoid literal infringement if it did not contain the claimed TSR beads. The analysis would depend on whether the tablet incorporated coated beads or another structure equivalent to the claimed membranes.

Does using hydroxypropyl methylcellulose phthalate automatically create infringement?

No. HPMCP is one of the claimed enteric polymers, but its use alone is insufficient. The product must also satisfy the claimed ethylcellulose membranes, coating arrangement and applicable release limitations.

Does patent expiration eliminate the need for FDA approval?

No. Expiration removes the patent barrier but does not remove the ANDA, bioequivalence, manufacturing, labeling or quality requirements imposed by FDA law.

Are the method-of-use claims still commercially important after expiration?

No current U.S. exclusivity follows from those claims after expiration. Before expiration, the evening-administration and early-morning-exposure limitations could have created labeling and induced-infringement issues.

References

U.S. Patent No. 6,500,454. (2003). Timed sustained release propranolol pharmaceutical dosage form. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA, Center for Drug Evaluation and Research.
U.S. National Library of Medicine. (2024). DailyMed: Propranolol hydrochloride extended-release capsules. National Library of Medicine.
United States Patent and Trademark Office. (2024). Patent term calculator and patent term adjustment information. U.S. Department of Commerce.
35 U.S.C. §§ 156, 271(e), 282; 21 U.S.C. § 355. (2024). United States Code.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	442134	⤷ Start Trial
Australia	2002330211	⤷ Start Trial
Canada	2462637	⤷ Start Trial
Germany	60233668	⤷ Start Trial
European Patent Office	1432411	⤷ Start Trial
Spain	2333306	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 6,500,454

Summary for Patent: 6,500,454