Details for Patent: 5,681,588

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Summary for Patent: 5,681,588

Title:	Delayed release microtablet of β-phenylpropiophenone derivatives
Abstract:	A cylindrical delayed release tablet with a convex or flat upper side and lower side is provided, along with a method for its production and a gelatin capsule containing 3-200 tablets of the same having identical or different release rates, wherein the tablet if made of β-phenylpropiophenone derivatives of the formula I as active ingredient ##STR1## where R is n-propyl or 1,1-dimethylpropyl, and their pharmacologically acceptable salts, wherein the tablet has a height and diameter that are both, independently of one another, 1-3 mm, the active ingredient content is in the range from 81-99.9% of the weight of the microtablet, (but not taking into account the weight of any coating which is present, the active ingredient density is greater than 1, the release of active ingredient in the USP paddle method at 50 rpm is 80% as a maximum after 3 hours and as a minimum after 24 hours, the release rate is virtually independent of the pressure when compressing the tablets, and the tablet contains no release-delaying ancillary substance but can contain 0.1-5% by weight of a lubricant and 0-18.9% by weight of other conventional ancillary substances.
Inventor(s):	Karl Kolter, Helmut Fricke, Volker Buehler, Herbert Mueller-Peltzer
Assignee:	GlaxoSmithKline LLC
Application Number:	US08/525,749
Patent Claim Types: see list of patent claims	Composition; Process; Dosage form;

United States Patent 5,681,588: Scope, Claims, Expiration, and Propafenone Microtablet Patent Landscape

U.S. Patent No. 5,681,588 protects a delayed-release multiparticulate dosage form built from high-drug-load cylindrical microtablets, particularly propafenone hydrochloride. The patent does not claim propafenone itself, a new chemical entity, or a broad controlled-release formulation using conventional polymers. Its protection is concentrated on the physical architecture, composition, dissolution profile, and manufacturing process of the microtablets.

The patent issued on October 28, 1997. Its enforceable term has expired under the ordinary U.S. patent-term framework based on a pre-June 8, 1995 filing regime or, depending on the relevant priority and filing dates, no later than the applicable 20-year term from the earliest nonprovisional filing. The patent therefore has no current blocking effect against generic manufacture, subject to separate patents, regulatory exclusivity, and other intellectual-property rights.

What does U.S. Patent 5,681,588 protect?

The patent protects a delayed-release dosage form containing cylindrical microtablets with tightly defined physical and dissolution characteristics.

The central protected combination includes:

Claim element	Limitation
Dosage form	Cylindrical delayed-release microtablet
Tablet geometry	Convex or flat upper and lower surfaces
Diameter and height	Each independently 1 to 3 mm
Active ingredient loading	81% to 99.9% by weight
Active ingredient density	Greater than 1
Release profile	No more than 80% released after 3 hours and at least 80% released after 24 hours in the USP paddle method at 50 rpm
Compression behavior	Release rate virtually independent of compression pressure
Release mechanism	No release-delaying ancillary substance
Lubricant	0.1% to 5% by weight
Other excipients	0% to 18.9%, provided they are conventional excipients that do not delay release

Claim 1 is the principal product claim. It is a combination claim, meaning that an accused product must satisfy the limitations collectively. A product with a different geometry, lower active loading, a polymeric release coating, or a substantially different dissolution result may fall outside the literal scope of claim 1 even if it is designed for the same therapeutic purpose.

Which claims are commercially important?

Claims 1, 3, 5, and 6 carry the greatest commercial importance.

Claim 1: Microtablet dosage form

Claim 1 requires a specific high-drug-load tablet structure. The absence of a release-delaying excipient is central. The delayed release is achieved through the physical properties of the compacted active ingredient and the dimensions of the microtablets rather than through a conventional matrix or coating system.

The claim is narrow in formulation terms but potentially meaningful for a product that reproduces the patented microtablet architecture.

Claim 2: In vivo plasma profile

Claim 2 adds a pharmacokinetic limitation. The dosage form must produce a pronounced plasma-level plateau, have a PTF below 75%, and maintain food-independent bioavailability.

PTF is generally understood as a measure of peak-to-trough fluctuation. A limitation requiring PTF below 75% may create infringement questions that depend on the testing protocol, patient population, dosing conditions, and statistical treatment of pharmacokinetic data.

Claim 2 is narrower than claim 1 and is less likely to be the primary basis for a product-by-product infringement case unless the accused product has a closely matching clinical or pharmacokinetic profile.

Claim 3: Propafenone hydrochloride

Claim 3 limits the active ingredient to propafenone hydrochloride. This is the most relevant claim for Rythmol SR-type products and other extended-release propafenone hydrochloride formulations.

The claim does not cover every propafenone hydrochloride product. It depends on the product also satisfying claim 1's microtablet requirements.

Claim 4: Approximately equal dimensions

Claim 4 narrows the microtablet geometry by requiring height and diameter to be approximately the same. This limitation supports a substantially equidimensional microtablet, rather than an elongated cylinder.

Claim 5: Gelatin capsule containing multiple microtablets

Claim 5 covers a gelatin capsule containing 3 to 200 microtablets. The tablets may have identical or different release rates.

This claim is directed to a multiparticulate capsule system. The ability to use microtablets with different release rates gives the dosage form flexibility in constructing an overall release curve. A capsule containing fewer than three or more than 200 tablets would not satisfy the numerical limitation literally.

Claim 6: Manufacturing process

Claim 6 covers production using:

• 81% to 99.9% granulated active ingredient;
• active-ingredient particles below 1 mm;
• 0.1% to 5% lubricant;
• 0% to 18.9% other non-release-delaying excipients;
• compression in a cylindrical mold;
• a mold height and diameter of 1 to 3 mm; and
• removal of the compressed microtablet from the mold.

Claim 6 creates process risk for manufacturers using substantially the same direct-compression or granulation-and-compression approach, even if the final capsule is not marketed in exactly the same configuration.

How broad is the independent product claim?

Claim 1 is technically narrow but commercially focused.

It does not require:

• a particular capsule shell;
• a particular brand;
• a particular dosage strength;
• a particular tablet coating;
• a particular tablet hardness;
• a particular compression force;
• a particular release-delaying polymer;
• a specific number of microtablets; or
• propafenone hydrochloride specifically.

The claim covers the listed beta-phenylpropiophenone derivatives, including compounds in which R is n-propyl or 1,1-dimethylpropyl, and pharmacologically acceptable salts. Claim 3 then narrows the scope to propafenone hydrochloride.

The claim's principal limitations are quantitative. In litigation, disputes would likely focus on:

1. whether the accused particles are cylindrical;
2. whether their dimensions fall within 1 to 3 mm;
3. whether the active ingredient constitutes at least 81% by weight;
4. whether the formulation contains a release-delaying excipient;
5. how "virtually independent" compression behavior is measured;
6. whether the USP paddle test was performed under comparable conditions; and
7. whether the release limits are met at both the three-hour and 24-hour time points.

What formulation technology does the patent cover?

The patent covers a high-drug-load, uncoated microtablet formulation in which delayed release results from the physical compact rather than an added release-controlling polymer.

This distinction separates the patent from three common controlled-release approaches:

Formulation approach	Likely relationship to claim 1
High-drug-load uncoated microtablets with the claimed dimensions and dissolution profile	Potentially within scope
Polymer-matrix tablet	May avoid the "no release-delaying ancillary substance" limitation
Coated pellets or coated microtablets	May avoid the claimed uncoated composition, depending on construction
Osmotic tablet	Generally outside the claimed microtablet architecture
Ion-exchange resin system	Generally outside the claimed composition unless the product also satisfies every limitation
Conventional immediate-release propafenone tablet	Outside the delayed-release limitations
Multiparticulate capsule containing non-tablet pellets	Outside the microtablet limitations

The absence of a release-delaying excipient is important for design-around analysis. A competitor using a polymer coating or matrix may avoid literal infringement, although the doctrine of equivalents could become relevant if the alternative performs substantially the same function in substantially the same way.

When did U.S. Patent 5,681,588 expire?

The patent issued in 1997 and is expired. The relevant expiration date depends on the patent's priority and filing history, including whether the patent was governed by the former 17-year-from-issue term or the 20-year-from-filing term.

Event	Date or status
U.S. patent issued	October 28, 1997
Patent type	Pharmaceutical formulation and manufacturing patent
Current enforceability	Expired
Current generic blocking effect	None from this patent alone
Possible historical regulatory relevance	Orange Book listing and Paragraph IV activity, if listed for the relevant NDA

A patent expiration analysis must distinguish patent term from FDA exclusivity. Even after the patent expired, a product could have remained protected by regulatory exclusivity, separate formulation patents, or litigation settlements. Those protections do not revive U.S. Patent 5,681,588.

What was the Orange Book status of the patent?

The patent's relevance to the Orange Book depends on whether it was submitted for listing against a propafenone hydrochloride extended-release product, particularly Rythmol SR or a related NDA.

Orange Book listing is product-specific. A patent may be listed only if it claims the approved drug, a method of using it, or a drug product, as required by the Hatch-Waxman framework. A process-only claim is generally not independently eligible for Orange Book listing as a drug product patent.

For a propafenone extended-release capsule, the most likely listing relevance would have been:

• claim 3, because it expressly identifies propafenone hydrochloride;
• claim 5, because it covers a gelatin capsule containing multiple microtablets; and
• claim 1, because it defines the underlying microtablet product.

The current Orange Book status should be treated as historical if the patent has expired. An expired listing does not provide a current basis for an infringement suit or a Paragraph IV certification directed to an unexpired patent.

Did the patent create Paragraph IV risk for generic propafenone?

Yes, while unexpired, the patent could create Paragraph IV risk for an ANDA applicant seeking approval of a therapeutically equivalent extended-release propafenone hydrochloride product.

An ANDA applicant could have used one of four principal certification strategies:

Certification	Effect
Paragraph I	No patent information listed
Paragraph II	Patent has expired
Paragraph III	Applicant will wait until patent expiration
Paragraph IV	Patent is invalid, unenforceable, or not infringed

For this patent, a Paragraph IV position could have challenged:

• the scope of "cylindrical" microtablets;
• the numerical dimensions;
• the active-ingredient percentage;
• the interpretation of "release-delaying ancillary substance";
• the USP dissolution limitations;
• the compression-pressure limitation;
• the validity of the claims over prior art; or
• the applicability of the claims to the proposed generic capsule.

Because the patent has expired, a current ANDA applicant would ordinarily rely on a Paragraph II certification for this patent rather than face a live Paragraph IV dispute.

What prior-art and validity issues affect patent strength?

The patent's strength is mixed.

Strengths

The claims contain multiple measurable limitations. Specific dimensions, active-loading ranges, dissolution endpoints, and excipient restrictions can make anticipation more difficult if no single prior-art reference discloses the complete combination.

The product claims also link formulation structure to a defined release profile. That relationship may have supported nonobviousness if conventional delayed-release technology generally relied on polymers, coatings, or matrix-forming excipients.

Weaknesses

The claims are vulnerable to combination-based obviousness arguments. A challenger could combine prior art relating to:

• propafenone sustained release;
• high-drug-load compacts;
• microtablets or minitablets;
• multiparticulate gelatin capsules;
• granulated active ingredients;
• lubricant-containing tablet blends; and
• dissolution-controlled dosage forms.

The terms "virtually independent of the pressure" and "pronounced plasma level plateau" may also present indefiniteness or enablement issues if the patent does not establish clear testing boundaries.

Claim 6 is narrower than claim 1 because it requires a particular particle-size and manufacturing sequence. That may improve clarity but gives competitors more opportunities to design around the process.

How does this patent compare with conventional propafenone patents?

U.S. Patent 5,681,588 is a formulation-and-process patent, not a compound patent.

Patent category	Typical protection	Relationship to U.S. 5,681,588
Compound patent	Propafenone or a chemical genus	Separate and broader at the molecular level
Salt patent	Propafenone hydrochloride or another salt	Potentially separate
Immediate-release formulation patent	Conventional propafenone tablet or capsule	Separate dosage-form protection
Extended-release formulation patent	Release-controlled propafenone product	May overlap commercially
Microtablet patent	Physical microtablet architecture	Core subject of U.S. 5,681,588
Method-of-use patent	Treatment of arrhythmia or dosing regimen	Separate therapeutic-use protection
Manufacturing patent	Granulation, compression, or encapsulation	Claim 6 is within this category

The patent has limited scope against unrelated propafenone products but could have had substantial value against a generic that copied the branded extended-release microtablet design.

What biosimilar risk applies?

No biosimilar pathway is relevant. Propafenone hydrochloride is a chemically synthesized small-molecule active ingredient, not a biologic subject to the Public Health Service Act.

Competition would proceed through the ANDA pathway under section 505(j) of the Federal Food, Drug, and Cosmetic Act rather than through a 351(k) biosimilar application. Relevant regulatory issues include:

• pharmaceutical equivalence;
• bioequivalence;
• extended-release pharmacokinetic comparability;
• dissolution similarity;
• capsule or multiparticulate composition; and
• any applicable product-specific guidance.

The patent does not create a biologic exclusivity period, interchangeability issue, or Purple Book listing.

What generic launch scenarios existed?

Three generic strategies were available after patent expiry.

Microtablet replication

A generic could reproduce the claimed high-drug-load microtablet design. After expiration, the patent would no longer block that approach, although other unexpired patents could still matter.

Formulation design-around

A generic could use coated pellets, a polymer matrix, osmotic technology, or another multiparticulate system. This approach could reduce historical infringement exposure but would require separate bioequivalence development.

Alternative immediate-release product

A manufacturer could pursue immediate-release propafenone hydrochloride, which would not target the same extended-release product profile. That route would involve different labeling, dosing, and therapeutic-substitution considerations.

What manufacturing and intellectual-property barriers remain?

The patent's expiration removes one barrier but not all barriers to market entry.

A generic manufacturer still must address:

• formulation reproducibility at very small tablet dimensions;
• uniformity across thousands of microtablets;
• capsule filling accuracy;
• dissolution control across production lots;
• high active-ingredient loading;
• lubricant distribution;
• stability of the extended-release profile;
• bioequivalence for a multiparticulate dosage form;
• freedom to operate under later patents; and
• regulatory requirements for labeling and substitution.

The most important technical barrier is control of the cumulative release profile. A capsule containing multiple microtablets can exhibit batch-to-batch variability if tablet dimensions, density, compression behavior, or lubricant distribution change.

What litigation and settlement issues should be reviewed?

A complete historical litigation assessment would focus on:

1. any ANDA notice letters asserting Paragraph IV certifications;
2. district-court complaints under 35 U.S.C. §271(e)(2);
3. patent-term calculations and pediatric extensions;
4. claim-construction rulings involving microtablet dimensions or dissolution;
5. settlements that delayed generic launch;
6. consent judgments or dismissals after patent expiration; and
7. later Orange Book-listed patents for propafenone extended-release capsules.

Because U.S. Patent 5,681,588 is expired, any current litigation value would be historical. A settlement involving this patent could still matter for the timing of a past generic launch, but it would not independently prevent present-day entry.

How strong is the patent estate for propafenone extended-release products?

The estate represented by U.S. Patent 5,681,588 was strongest against a product that copied all of the following:

• a gelatin capsule;
• multiple 1 to 3 mm cylindrical microtablets;
• high propafenone hydrochloride loading;
• no release-delaying excipient;
• the specified dissolution profile; and
• the claimed manufacturing process.

It was weaker against products using a different release technology or different particle geometry.

Risk area	Assessment
Compound protection	Not provided by this patent
Propafenone hydrochloride formulation protection	Meaningful but narrow
Microtablet architecture	Strongest claim focus
Process protection	Narrower and more design-around susceptible
Method-of-use protection	Not provided
Current blocking power	None because the patent is expired
Biosimilar risk	Not applicable
Historical Paragraph IV risk	Material for matching extended-release products

Key Takeaways

• U.S. Patent 5,681,588 covers a specific delayed-release microtablet platform, not propafenone as a molecule.
• Claim 1 requires 1 to 3 mm cylindrical microtablets, 81% to 99.9% active ingredient, no release-delaying excipient, and a defined 3-hour/24-hour dissolution profile.
• Claim 3 narrows the invention to propafenone hydrochloride.
• Claim 5 covers gelatin capsules containing 3 to 200 claimed microtablets.
• Claim 6 protects a granulation-and-compression manufacturing process.
• The patent issued on October 28, 1997, and is expired.
• No current Paragraph IV threat or patent-based launch block arises from this patent alone.
• Propafenone is a small molecule, so biosimilar analysis is not applicable.
• Historical infringement risk was highest for a generic replicating the branded high-drug-load microtablet architecture.
• Current generic risk depends on later patents, Orange Book records, regulatory exclusivity, and the generic's selected formulation technology.

Frequently Asked Questions

Does U.S. Patent 5,681,588 cover all extended-release propafenone products?

No. It covers only products meeting the patent's specific microtablet, composition, dimensional, and dissolution limitations.

Can a generic use a polymer coating after this patent expires?

Yes, subject to any separate unexpired patents and FDA requirements. A polymer-coated formulation would generally differ from the claimed no-release-delaying-excipient structure.

Is propafenone hydrochloride protected by a compound patent in U.S. Patent 5,681,588?

No. The patent claims a dosage form and manufacturing process containing specified beta-phenylpropiophenone derivatives. It does not claim propafenone hydrochloride as a standalone chemical compound.

Does claim 5 cover a capsule containing only one microtablet?

No. Claim 5 requires a gelatin capsule containing 3 to 200 microtablets.

Does the expired patent still affect FDA approval of a generic?

An expired patent may remain relevant to historical patent certifications and regulatory records, but it does not independently block approval or commercial launch. Current approval depends on the applicable NDA, ANDA requirements, labeling, exclusivity, and any unexpired patents.

References

1. United States Patent and Trademark Office. (1997). U.S. Patent No. 5,681,588: Delayed-release microtablets.
2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations.
3. U.S. Food and Drug Administration. (2024). Orange Book: Approved drug products with therapeutic equivalence evaluations.
4. U.S. Food and Drug Administration. (2024). Rythmol SR (propafenone hydrochloride) prescribing information.
5. United States Congress. (1984). Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417.
6. United States Code. 35 U.S.C. §§ 154, 271(e), and 282.

Drugs Protected by US Patent 5,681,588

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

Foreign Priority and PCT Information for Patent: 5,681,588

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Germany	43 10 963.2	Apr 03, 1993

PCT Information
PCT Filed	March 24, 1994	PCT Application Number:	PCT/EP94/00949
PCT Publication Date:	October 03, 1994	PCT Publication Number:	WO94/22434

International Family Members for US Patent 5,681,588

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	148988
Australia	6429594
Australia	678227
Brazil	1100303