United States Patent 6,068,859: Azithromycin Controlled-Release Dosage Forms, Claim Scope and Patent Landscape

US 6,068,859 covers oral azithromycin dosage forms engineered to reduce early gastrointestinal exposure and control release over approximately six hours. Its claims span release-rate profiles, diffusion and erosion matrices, coated tablets, multiparticulates, enteric protection, osmotic systems, swellable systems, enzyme-degradable systems, porous membranes, and manufacturing processes.

The patent was granted on May 30, 2000, and its ordinary 20-year patent term expired in October 2017, based on the relevant October 3, 1997 nonprovisional filing date. Any six-month pediatric exclusivity associated with an approved azithromycin product would not revive the patent after expiration. The patent therefore does not currently block generic or other commercial development on an infringement basis, although its disclosure remains relevant prior art for later patentability analysis. (U.S. Patent No. 6,068,859, 2000; 35 U.S.C. § 154.)

What does US Patent 6,068,859 protect?

US 6,068,859 protects controlled-release azithromycin products defined primarily by performance rather than by a single formulation composition.

The patent has four principal claim groups:

Claim group	Claims	Primary subject matter
Weight-based release profile	1, 63-71	Release limits expressed in mg/kg of mammal weight
Fixed-dose release profile	2-25, 56, 59-62, 72-76	Release limits expressed in absolute milligrams
Gastric and duodenal protection	26-55, 67	Limited release in the stomach and early duodenum
Manufacturing process	23-25	Granulation and staged polymer coating of azithromycin particles

The independent claims are broad in intended commercial coverage. They do not require a specific polymer, tablet geometry, membrane technology, or manufacturing process unless a dependent claim adds that limitation.

The central inventive concept is controlled gastrointestinal delivery of azithromycin at a slower rate than a conventional bolus dose, with the objective of reducing gastrointestinal adverse effects while maintaining therapeutic exposure.

What are the key release-rate limitations in the patent?

Claims 1 and 2 define cumulative release ceilings at five time points.

Claim 1: weight-based release limits

Claim 1 requires that the dosage form release no more than approximately:

Time after ingestion	Maximum cumulative release
15 minutes	4 mg/kg
1 hour	10 mg/kg
2 hours	20 mg/kg
4 hours	30 mg/kg
6 hours	40 mg/kg

For a 70-kg human, these limits correspond to approximately 280 mg, 700 mg, 1,400 mg, 2,100 mg, and 2,800 mg, respectively.

Claim 2: absolute release limits

Claim 2 requires that the dosage form release no more than approximately:

Time after ingestion	Maximum cumulative release
15 minutes	200 mg
1 hour	500 mg
2 hours	1,000 mg
4 hours	1,500 mg
6 hours	2,000 mg

Claim 2 is more directly aligned with a single-dose human product, particularly a 2-gram azithromycin extended-release formulation. It is also easier to apply to a commercial product because it avoids patient-weight calculations.

The claims use “about,” creating a tolerance question in claim construction. In an infringement dispute, the court would likely examine the specification, prosecution history, dissolution methodology, and the technical meaning of “about” at each time point. A product that exceeds a numerical limit by a small amount could present a doctrine-of-equivalents issue, but the analysis would depend on prosecution-history estoppel and the role of the numerical limitation during examination.

How strong are the independent claims?

The strongest commercial claims are likely claims 2, 26, and 56, but each has a different enforcement profile.

Claim 2: functional controlled-release claim

Claim 2 covers any dosage form containing azithromycin and a pharmaceutically acceptable carrier that meets the specified cumulative release profile.

Its breadth is substantial because the claim does not require:

A particular dosage strength
A specific polymer
A tablet, capsule, or multiparticulate format
A particular coating thickness
A particular dissolution apparatus
A particular release mechanism

The main vulnerability is proof. The patent owner would need to establish that the accused dosage form meets all five release ceilings under an appropriate testing protocol. The claim also raises potential enablement and indefiniteness questions because the release profile is defined by in vivo gastrointestinal delivery, while commercial products are usually characterized through in vitro dissolution testing.

Claim 26: gastric and duodenal protection

Claim 26 requires that the dosage form:

Release no more than 10% of incorporated azithromycin into the stomach; and
Release no more than an additional 10% during the first 15 minutes after entering the duodenum.

This claim targets site-specific protection rather than a six-hour cumulative release curve. It may cover enteric-coated tablets and multiparticulates, but it is not limited to an enteric polymer. Any technology meeting the stomach and duodenal release limits could potentially fall within the claim.

The claim has a difficult evidentiary feature: stomach and duodenal release must be measured by a method that credibly models gastrointestinal transit and local exposure. A standard dissolution test may not directly establish literal infringement unless the specification or prosecution history supports the testing approach.

Claim 56: reduced gastrointestinal side effects

Claim 56 covers a method of treating a mammal with an azithromycin dosage form according to claim 2, where the treatment has a reduced incidence of gastrointestinal side effects relative to a bolus oral dose.

This claim contains both structural and result-oriented limitations. It incorporates claim 2’s release profile and adds a clinical result. The “reduced incidence” limitation could complicate enforcement because it may require comparative clinical evidence or a showing that the claimed formulation is designed to produce the stated result.

What formulation technologies are covered?

The dependent claims create a wide formulation perimeter around the release-rate limitations.

Matrix systems

Claims 3-9, 63, 72, and 76 cover azithromycin embedded in a matrix. The matrix may release drug by diffusion or erosion.

Specified materials include:

Hydroxypropyl methylcellulose
Hydroxypropyl cellulose
Polyethylene oxide
Polyacrylic acid
Wax-based multiparticulate matrices
Hydroxypropyl methylcellulose combined with lactose

Claim 4 covers a substantially intact matrix during drug release. Claims 5-9 focus on eroding matrices. Claim 72 narrows the matrix to wax particles smaller than 400 micrometers.

These claims are compositionally narrower than claim 2 but may be easier to evaluate analytically because the relevant polymer or matrix material can be identified from a product’s formulation or manufacturing records.

Reservoir and membrane systems

Claims 10-12 and 64-65 cover:

A reservoir of azithromycin encased in a diffusion-limiting membrane
A coated tablet
Multiparticulates in which individual particles have release-controlling membranes

Claim 74 narrows the multiparticulate to particles containing azithromycin and methyl cellulose with an ethylcellulose membrane. Claim 75 adds a pH-sensitive outer coating.

This claim group reaches products made from coated drug-loaded pellets, beads, granules, or microtablets. It is particularly relevant to multiparticulate products in which each particle independently controls release.

Partial impermeable coatings and geometric delivery systems

Claims 13-21 cover matrix devices with selected portions of the exterior surface covered by an impermeable coating and other portions left open. The claims identify several geometries:

Cylinders with coated flat faces
Cylinders with coated radial surfaces
Tablets with openings
Through-passageways
Slits or removed strips
Cones with an opening near the apex
Hemispheres with an opening near the flat face
Half-cylinders with slits near the centerline

These claims are technically specific and have limited relevance to a product that uses conventional full-surface polymer coating. They could be relevant to specialized osmotic or controlled-orifice designs.

Enteric and pH-sensitive coatings

Claims 24-25, 31-36, and 73-75 cover dosage forms protected in the stomach and released in the small intestine or colon.

The listed polymers include:

Cellulose acetate phthalate
Polyvinyl acetate phthalate
Hydroxypropyl methylcellulose phthalate
Copolymers of acrylic acid and acrylic acid esters
Methacrylic acid and methyl methacrylate copolymers

Claim 25 specifically combines ethylcellulose as the sustained-release polymer with a pH-sensitive polymer. This creates a two-stage system: sustained release is controlled by the inner coating, while gastric protection or delayed release is supplied by the outer pH-sensitive layer.

Osmotic and swellable systems

Claims 37-48, 57-62, and 68-71 address osmotic, swelling, porous, and perforated devices.

Covered structures include:

Tablets or multiparticulates containing osmagents
Semipermeable membranes permeable to water but substantially impermeable to azithromycin
Swellable materials that generate delivery pressure
pH-sensitive trigger mechanisms that cause bursting
Microporous hydrophobic membranes
Hydrophobic liquids that change permeability
Porous coatings that permit both water and azithromycin transport
Coated bilayer tablets with water-swellable and dispensable drug layers
Perforated or passageway-containing coatings

Claims 41-44 require a pH-sensitive trigger that activates between pH 3 and 9. Claims 45-48 use a microporous hydrophobic support containing a hydrophobic liquid. Claims 57 and 58 cover membranes with pores or water-soluble porosigens.

These claims show that the patent was drafted to capture multiple controlled-release platforms, including systems that were not limited to conventional hydrophilic matrix tablets.

Colon-triggered systems

Claims 49-54 cover membranes that are substantially impermeable to azithromycin but labile to enzymes produced by bacteria inhabiting the colon.

Claim 51 specifies polymers containing ethylenically unsaturated monomers crosslinked by substituted or unsubstituted divinylazobenzene. Claims 53 and 54 cover polysaccharide-containing membranes.

These claims are directed to bacterial-enzyme-triggered delivery rather than ordinary pH-dependent enteric release.

What does claim 23 cover?

Claim 23 covers a process for preparing an azithromycin multiparticulate dosage form. The process requires:

Granulating azithromycin bulk drug with a binder;
Producing granules with an average particle size of approximately 50 to 300 micrometers;
Substantially immediately coating the granules with a sustained-release membrane-forming material;
Applying an initial coating amount of approximately 5% to 30% of the coated product’s total weight;
Applying additional polymer until the total polymer coating reaches approximately 25% to 70% of the coated product’s total weight.

Claim 24 adds a pH-sensitive polymer coating. Claim 25 specifies ethylcellulose as the sustained-release polymer and a methacrylic acid/methyl methacrylate copolymer or cellulose acetate phthalate as the pH-sensitive polymer.

The process claims may be more practical to enforce against a manufacturer than product claims if manufacturing evidence is available. They do not, however, cover every controlled-release azithromycin multiparticulate. The accused process must satisfy the particle-size, sequencing, coating-percentage, and polymer limitations.

What is the Orange Book status of US 6,068,859?

US 6,068,859 was associated with the azithromycin extended-release product Zmax, marketed by Pfizer-related entities. Zmax was approved by the FDA as an extended-release oral suspension administered as a single 2-gram dose. (U.S. Food and Drug Administration, 2005.)

The patent’s term expired in 2017 based on the ordinary term calculation. An Orange Book listing does not extend the underlying patent term. Once the patent expired, the listing no longer created a live patent barrier to an ANDA applicant.

The regulatory and patent positions should be separated:

Issue	Assessment
FDA product	Zmax extended-release azithromycin oral suspension
Regulatory pathway	NDA approval
Patent relevance	Controlled-release azithromycin dosage form
Patent expiration	October 2017, subject to the official patent-term record
Current patent exclusion	None after expiration
Pediatric exclusivity	Could have delayed approval timing but did not extend the patent term
Biosimilar pathway	Not applicable; azithromycin is a small molecule
Generic pathway	ANDA pathway, subject to product-specific requirements

When did azithromycin lose exclusivity?

Azithromycin’s original compound and basic product exclusivity expired years before US 6,068,859. The commercial protection for the controlled-release product depended on formulation-specific patent coverage and FDA exclusivity.

The relevant sequence was:

Event	Date or period
Azithromycin compound and early product patents	Primarily expired before the controlled-release patent
US 6,068,859 filing	October 3, 1997
US 6,068,859 grant	May 30, 2000
Zmax FDA approval	2005
US 6,068,859 ordinary expiration	October 2017
Post-expiration position	No continuing patent-based exclusivity

The precise commercial launch date of a generic extended-release product would depend on FDA approval, formulation equivalence, manufacturing capability, and any separate patents or regulatory exclusivities tied to a particular NDA.

Which companies challenged or could challenge the patent?

The patent’s 2017 expiration substantially reduces the present value of Paragraph IV litigation concerning this patent. A Paragraph IV certification would have been commercially relevant before expiration if an ANDA applicant sought approval for an equivalent extended-release azithromycin product.

The likely competitive groups were:

Generic manufacturers of azithromycin immediate-release tablets, capsules, and suspensions
Manufacturers evaluating an extended-release suspension or multiparticulate product
Contract manufacturers with polymer-coating and multiparticulate capabilities
Brand or authorized-generic suppliers linked to Pfizer’s azithromycin franchise

No biosimilar challenge is relevant because FDA biosimilar law applies to biological products, not azithromycin.

A patent-expired product can still face regulatory barriers. An ANDA applicant may need to demonstrate pharmaceutical equivalence, bioequivalence, dose uniformity, dissolution comparability, stability, and, depending on the reference product and dosage form, additional clinical or pharmacokinetic support.

What patent litigation and settlements affect US 6,068,859?

The supplied claim set does not establish a litigation history, and the patent record alone does not establish a settlement agreement. The patent expired before a current infringement action could create meaningful forward-looking exclusion.

The practical litigation risk today is therefore limited to:

Historical damages claims for pre-expiration conduct
Contractual disputes involving old licenses or settlements
Ownership or assignment disputes
Allegations concerning later patents that are not part of US 6,068,859
Regulatory disputes over product sameness or approval timing

A settlement involving this patent would not restore exclusivity after expiration unless it imposed independent contractual restrictions. Any such restriction would arise from the agreement, not from the patent.

How does the patent compare with competing azithromycin patent estates?

Estate type	Typical subject matter	Current risk from US 6,068,859
Original azithromycin compound patents	Active ingredient	Expired
Immediate-release azithromycin patents	Tablets, capsules, suspensions	Generally expired or product-specific
US 6,068,859	Controlled-release dosage forms and methods	Expired
Later formulation patents	New polymers, delivery platforms, dosing regimens	Must be assessed separately
Manufacturing patents	Particle engineering, coating, scale-up	Potentially relevant if later-issued
Regulatory exclusivity	NDA, pediatric, orphan, or other FDA exclusivity	Product- and date-specific

US 6,068,859 is unusually broad in technology coverage but old in priority. Its principal commercial value was the ability to cover multiple controlled-release architectures through functional release limits and dependent formulation claims. Its present value is primarily historical and blocking-prior-art value.

What generic launch risks exist for an extended-release azithromycin product?

After expiration, the main risks are technical and regulatory rather than patent-based.

Formulation and manufacturing barriers

An applicant may need to control:

Azithromycin particle size
Drug loading
Polymer coating weight
Coating uniformity
Enteric dissolution behavior
Multiparticulate size distribution
Dose dumping risk
Suspension reconstitution and stability
Taste and palatability
Scale-up reproducibility

Azithromycin’s high dose and gastrointestinal tolerability profile make release-rate control commercially important. A formulation that releases too rapidly may fail performance testing or produce greater gastrointestinal exposure.

Regulatory barriers

The applicant must address the reference product’s dosage form and labeling. A product intended to substitute for an extended-release oral suspension may not qualify merely by matching the active ingredient and total dose. The release mechanism, pharmacokinetics, dissolution profile, and administration instructions may be material to FDA’s determination of equivalence.

Patent barriers outside US 6,068,859

Later patents may cover:

Specific extended-release suspensions
Taste-masked azithromycin compositions
New polymer combinations
Stable reconstituted suspensions
Alternative particle-engineering methods
Specific dosing regimens
New indications or patient populations

Those rights require a separate, current patent search. They cannot be inferred from the claims of US 6,068,859.

What is the geographic coverage of US 6,068,859?

US 6,068,859 has territorial effect only in the United States. It does not directly block manufacture, use, sale, or importation in Europe, Canada, Japan, China, or other jurisdictions.

The corresponding international and foreign applications may have produced separate patents with different:

Claim scope
Priority dates
Patent-term calculations
Validity outcomes
Opposition or examination histories
Expiration dates
Enforcement positions

A United States freedom-to-operate conclusion cannot be extended to foreign markets without reviewing the relevant national-phase patents and local prosecution records.

Key Takeaways

US 6,068,859 covers controlled-release azithromycin dosage forms, not azithromycin as a molecule.
Claims 1 and 2 define cumulative release ceilings over 15 minutes, one hour, two hours, four hours, and six hours.
Claims 26-55 focus on limiting gastric and early duodenal release.
Claims 3-21, 57-76 cover matrix, membrane, enteric, osmotic, swellable, porous, multiparticulate, and geometric delivery systems.
Claims 23-25 cover a staged granulation and polymer-coating process.
The patent’s ordinary term expired in October 2017.
No biosimilar pathway applies because azithromycin is a small-molecule drug.
Current commercial risk from this patent is not patent exclusion. It is primarily formulation development, FDA approval, bioequivalence, manufacturing scale-up, and possible later patent coverage.
Historical infringement analysis would require product-specific dissolution data, formulation records, manufacturing evidence, and the patent prosecution history.
Foreign equivalents must be evaluated separately because US 6,068,859 has no direct extraterritorial effect.

FAQs About US 6,068,859 and Azithromycin Controlled Release

Is US 6,068,859 still enforceable against a generic azithromycin product?

No. The patent’s ordinary US term expired in 2017. A later generic product cannot infringe an expired patent, although pre-expiration conduct may raise historical damages issues.

Did US 6,068,859 cover Zithromax immediate-release tablets?

The claims are directed to controlled-release azithromycin dosage forms and specified gastrointestinal release profiles. They would not ordinarily cover a conventional immediate-release Zithromax tablet unless that product satisfied the claimed release limitations.

Can a generic manufacturer use the polymers named in claims 6-9?

Yes, because the patent has expired. Before expiration, use of a named polymer could have created risk if the product also met all limitations of the applicable dependent claim.

Does the patent cover azithromycin extended-release suspension?

Potentially, if the suspension is a “dosage form” containing azithromycin and meets the applicable release-rate or gastrointestinal-release limitations. The claims do not uniformly require a tablet or multiparticulate.

What is the most commercially important claim in US 6,068,859?

Claim 2 is likely the most commercially significant because it defines an absolute release profile applicable to a high-dose human product without requiring a particular delivery technology. Its enforcement would depend heavily on the selected release-testing methodology and proof that every numerical limitation is satisfied.

Sources

U.S. Patent No. 6,068,859. (2000). Controlled release azithromycin dosage forms. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (2005). Zmax (azithromycin) extended-release oral suspension prescribing information. U.S. Department of Health and Human Services.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations. Orange Book. U.S. Department of Health and Human Services.
United States Code. (2023). 35 U.S.C. § 154, contents and term of patents.
United States Code. (2023). 21 U.S.C. § 355, applications for FDA approval of new drugs.

PCT Information
PCT Filed	April 13, 1995	PCT Application Number:	PCT/IB94/00264
PCT Publication Date:	November 16, 1995	PCT Publication Number:	WO95/30422

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
African Regional IP Organization (ARIPO)	548	⤷ Start Trial
African Regional IP Organization (ARIPO)	9500735	⤷ Start Trial
Austria	209497	⤷ Start Trial
Australia	2113195	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 6,068,859