Details for Patent: 6,635,280

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Summary for Patent: 6,635,280

Title:	Extending the duration of drug release within the stomach during the fed mode
Abstract:	Drugs are formulated as unit oral dosage forms by incorporating them into polymeric matrices comprised of hydrophilic polymers that swell upon imbibition of water to a size that is large enough to promote retention of the dosage form in the stomach during the fed mode. The oral formulation is designed for gastric retention and controlled delivery of an incorporated drug into the gastric cavity, and thus administered, the drug is released from the matrix into the gastric fluid by solution diffusion. The swollen polymeric matrix, having achieved sufficient size, remains in the gastric cavity for several hours if administered while the patient is in the fed mode, and remains intact long enough for substantially all of the drug to be released before substantial dissolution of the matrix occurs. The swelling matrix lowers the accessibility of the gastric fluid to the drug and thereby reduces the drug release rate. This process, together with diffusion retardation by selection of specific polymers, polymer molecular weights, and other variables, results in a sustained and controlled delivery rate of the drug to the gastric cavity.
Inventor(s):	John W. Shell, Jenny Louie-Helm, Micheline Markey
Assignee:	Assertio Therapeutics Inc
Application Number:	US10/045,823
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,635,280
Patent Claim Types: see list of patent claims	Use; Formulation; Dosage form;

United States Patent 6,635,280: Scope, Claims, Expiration, Orange Book Status, and Competitive Patent Landscape

U.S. Patent No. 6,635,280 covers a gastroretentive, controlled-release oral dosage form that swells in the stomach, exceeds the fed-state pyloric diameter, remains substantially intact, and releases drug over approximately eight to ten hours. Its broadest commercial relevance is metformin hydrochloride, particularly extended-release products based on a hydrophilic polymer matrix. The patent has expired, eliminating current infringement risk from the patent itself, although related continuation, formulation, and product-specific patents may have had different terms.

What does U.S. Patent 6,635,280 protect?

The patent protects two related subject matter groups:

1. A dosage form defined by physical, compositional, and dissolution characteristics.
2. Methods of treating patients by administering gastroretentive dosage forms for drugs affected by intestinal degradation, bacterial flora, pH, or transporters.

The central invention is a swelling matrix tablet administered in the fed state. The matrix absorbs gastric fluid, expands beyond the pyloric diameter, remains in the stomach, and releases the incorporated drug through matrix erosion, drug dissolution, or diffusion.

The independent claim architecture is as follows:

Claim group	Independent claim	Principal subject matter
Dosage form	1	Highly water-soluble drug in a swellable polymer matrix
Antibacterial administration	19	Gastric delivery to avoid intestinal flora
Antibacterial treatment	22	Treatment of bacterial infections
Colonic enzyme avoidance	24	Drugs degraded by colonic bacterial enzymes
Cyclosporine	27	Transplant immunosuppression
Digoxin	28	Heart disease treatment
Doxifluridine	29	Cancer treatment
Transporter avoidance	30	Drugs affected by lower-GI transporters
Cyclosporine and paclitaxel	32-33	Avoidance of P-glycoprotein in the lower GI tract
Acidic gastric environment	34	Drugs with greater bioavailability in acid
Ampicillin esters	37	Bacterial infection treatment
Iron salts	38	Anemia treatment
Ketoconazole	39	Systemic fungal infection
Alkaline degradation	40	Drugs degraded in alkaline conditions
Nelfinavir mesylate	42	HIV treatment
Ionized drugs	43	Gastric absorption of ionizable drugs
Acid degradation	44	Protection of unreleased drug in the matrix

Claim 1 is the principal platform claim. Claims 19 through 44 extend the platform into drug-specific and physiological-use categories.

What are the key limitations of claim 1?

Claim 1 requires every one of the following elements:

• An oral controlled-release dosage form.
• A drug with water solubility greater than one part drug to ten parts water.
• One or more polymers forming a solid polymeric matrix.
• Drug-to-polymer weight ratio from 15:85 to 80:20.
• Swelling under unrestricted conditions after water imbibition.
• A swollen size exceeding the pyloric diameter in the fed state.
• Gastric release through dissolution and diffusion.
• Retention of at least approximately 40% of the drug after one hour in gastric fluid.
• Release of substantially all drug after immersion.
• Substantial structural integrity until substantially all drug is released.

This is a combination claim rather than a simple polymer or formulation claim. Infringement requires a competing product to satisfy the dosage-form composition, drug loading, swelling behavior, gastric-retention theory, dissolution profile, and integrity limitations.

The claim does not require a particular tablet shape, manufacturing process, polymer concentration, drug dose, coating, or commercial brand. Those features are introduced through dependent claims.

How broad is the drug coverage?

The patent names a large group of active ingredients. The principal drug categories are:

Drug or category	Relevant claims	Commercial or technical rationale
Metformin hydrochloride	3, 4, 47-56	Highly soluble drug requiring prolonged gastric delivery
Sertraline hydrochloride	3, 5	Soluble active in a matrix system
Captopril	3, 6	Gastric absorption and controlled release
Vancomycin hydrochloride	3, 7	Local or gastric delivery concept
Ciprofloxacin	57-63	Antibacterial delivery
Amoxicillin	20-23	Avoidance of intestinal flora effects
Cefuroxime axetil	20-23	Antibacterial delivery
Cefaclor	20-23	Highly soluble antibacterial
Clindamycin	20-23	Reduction of intestinal-flora exposure
Clarithromycin	20-23	Gastric antibacterial delivery
Azithromycin	20-23	Gastric antibacterial delivery
Ceftazidime	20-23	Antibacterial delivery
Cyclosporine	25, 27, 31-32	Avoidance of intestinal enzymes and P-glycoprotein
Digoxin	25, 28, 35	Acidic gastric absorption concept
Doxifluridine	25-26, 29	Avoidance of intestinal degradation and transporters
Paclitaxel	31, 33	Avoidance of P-glycoprotein
Ketoconazole	35, 39	Greater bioavailability in an acidic environment
Nelfinavir mesylate	41-42	Avoidance of alkaline degradation and intestinal inactivation
Iron salts	35, 38, 64-70	Maintenance in an acidic gastric environment
Ampicillin esters	35-37	Acid-dependent bioavailability

The claims do not protect every oral controlled-release product containing one of these drugs. They protect only products and methods that also meet the gastric-retention and matrix-performance limitations.

What polymers are protected?

Claim 8 identifies five polymer families:

• Polyethylene oxide.
• Cellulose and alkyl-substituted celluloses.
• Crosslinked polyacrylic acids.
• Xanthan gum.

Claim 9 identifies specific cellulose derivatives:

• Hydroxymethyl cellulose.
• Hydroxyethyl cellulose.
• Hydroxypropyl cellulose.
• Hydroxypropylmethyl cellulose.
• Carboxymethyl cellulose.

Claims 10 through 12 narrow the polyethylene oxide molecular weight to at least approximately 4 million, with preferred ranges of 4.5 million to 10 million and 5 million to 8 million.

Claims 47 through 56 provide a more specific metformin formulation position. They identify hydroxypropylmethyl cellulose, including grades with a viscosity of 11,000 to 110,000 centipoise in a 2% solution at 20°C, and high-molecular-weight polyethylene oxide.

The polymer limitations are important because a conventional hypromellose matrix may fall within the claim scope only if the finished dosage form also swells beyond the fed-state pyloric diameter and satisfies the release and integrity criteria. Polymer identity alone is insufficient.

What dosage-form characteristics are required?

The patent uses performance limitations that distinguish the claimed product from ordinary extended-release tablets.

Limitation	Claim requirement
Fed-state administration	The patient takes the dosage form while in a fed mode
Swelling	The matrix imbibes gastric fluid and expands
Gastric retention	Swollen dosage form exceeds the pyloric diameter
One-hour retention	At least 40% of drug remains after one hour
Preferred one-hour retention	At least 50%, 60%, or 80% under dependent claims
Complete release	Substantially all drug releases within approximately 10 hours
Preferred release period	Within approximately eight hours under claim 46
Structural integrity	Dosage form remains substantially intact until drug release is substantially complete
Release mechanism	Dissolution, diffusion, and, for method claims, matrix erosion

Claims 17 and 18 add physical dimensions. Claim 17 covers two cylindrical tablets, each approximately 9 to 12 mm long and 6.5 to 7 mm in diameter. Claim 18 covers a single elongated tablet approximately 18 to 22 mm long, 6.5 to 7.8 mm wide, and 6.2 to 7.5 mm high.

These dimensional claims are narrower than claim 1 but may be relevant where a commercial product uses a defined tablet geometry.

How do the method claims differ from the dosage-form claims?

The method claims add a therapeutic or pharmacokinetic purpose. They seek to protect administration of a drug in a gastric-retentive matrix to avoid a specific biological problem.

The principal method theories are:

Avoiding intestinal flora

Claims 19 through 23 address antibiotics that may alter intestinal flora. The claimed method releases substantially all drug in the stomach within approximately ten hours, reducing exposure of the lower intestinal tract.

Avoiding colonic enzymes

Claims 24 through 29 cover drugs that are degraded by bacterial enzymes or intestinal enzymes. Cyclosporine, digoxin, and doxifluridine are expressly identified.

Avoiding P-glycoprotein

Claims 30 through 33 address cyclosporine and paclitaxel. The asserted benefit is delivery and absorption before the drug reaches lower-GI P-glycoprotein transport systems.

Maintaining an acidic environment

Claims 34 through 44 cover drugs with greater bioavailability in acid or degradation in alkaline conditions. The named examples include ketoconazole, iron salts, ampicillin esters, nelfinavir mesylate, and digoxin.

For infringement purposes, these claims require more than use of the same matrix technology. A method claim also requires the claimed drug, administration conditions, physiological purpose, and release behavior.

What are the principal claim-construction and validity issues?

The strongest claim-scope issues are functional and physiological.

Pyloric-diameter limitation

The phrase "exceeding the pyloric diameter in the fed mode" raises questions about how the limitation is measured. The claim refers to a physiological condition rather than a fixed tablet dimension. A product may need evidence showing swelling under unrestricted conditions and retention characteristics in a fed-state stomach.

"Substantially all" release

The claims do not specify a universal numerical threshold for "substantially all." The specification, prosecution history, dissolution method, and expert testimony would likely determine how the term is applied.

"Substantially intact"

This limitation separates the claimed system from an immediately disintegrating or rapidly eroding tablet. Partial erosion is permitted under several method claims, but the matrix must retain sufficient integrity to support gastric retention and prolonged release.

Gastric-fluid test conditions

The one-hour retention requirement depends on the gastric-fluid medium, agitation, pH, temperature, sink conditions, and assay method. A non-infringement or invalidity analysis would focus heavily on the specified test protocol and reproducibility.

Drug-solubility thresholds

Claims 1 through 3 distinguish highly soluble drugs through specified water-solubility ratios. A competing product could avoid a narrow claim by using a drug, salt, polymorph, or formulation state outside the stated solubility threshold, although claims 19 through 44 have different drug and method requirements.

Dependent-claim drafting defects

Claims 62 and 69 refer to retention of "metformin hydrochloride" even though their parent claims identify ciprofloxacin and an iron salt, respectively. Those references create apparent antecedent and consistency problems. They may limit enforceability or create claim-construction disputes, but they do not necessarily invalidate the broader independent claims.

When did U.S. Patent 6,635,280 expire?

The patent issued on October 21, 2003. Its term was governed by the modern 20-year term measured from the applicable nonprovisional filing date, subject to patent-term adjustment and any other statutory adjustment. Public patent records identify the patent as expired, with the effective term ending in 2021 rather than extending into the current decade.[1]

Event	Date
Patent issued	October 21, 2003
Patent family priority period	2000
Expected statutory term endpoint	2021
Current enforceability	Expired
Current standalone infringement exposure	None

Because the patent is expired, claims 1 through 70 cannot presently support an infringement action. Historical infringement, damages, or settlement questions remain separate from current freedom to operate.

What was the FDA and Orange Book relevance?

The patent’s most important FDA-facing relevance was metformin extended-release technology. The claim set is closely aligned with the technical concept used in gastric-retentive metformin products, including the Glumetza product platform associated with Depomed, later Assertio.

The FDA approved Glumetza, an extended-release metformin hydrochloride product, through NDA 021748. Orange Book-listed patents for a drug product are product-specific and do not automatically establish that every claim in a platform patent covers the approved product. Listing also does not extend the patent term.[2]

A patent relevant to an NDA may generate:

• Paragraph IV certifications by generic applicants.
• Patent litigation under Hatch-Waxman.
• A 30-month regulatory stay in qualifying circumstances.
• A statutory 180-day exclusivity period for the first eligible Paragraph IV filer.
• Settlement restrictions governed by the terms of the agreement and antitrust law.

The expired status of U.S. Patent 6,635,280 means it no longer creates a live Orange Book barrier. Current generic risk for metformin extended-release products must instead be assessed against any unexpired patents covering the specific product, formulation, manufacturing process, tablet geometry, or approved labeling.[2,3]

Were there Paragraph IV challenges or litigation risks?

Metformin extended-release products, including Glumetza, were subject to generic competition and patent disputes involving Depomed and generic manufacturers. The relevant litigation landscape included challenges to patents covering the metformin gastric-retentive formulation and related product technology.

The principal potential defendants in the broader Glumetza patent environment included:

• Actavis.
• Lupin.
• Wockhardt.
• Other abbreviated new drug application applicants.

A Paragraph IV challenge to one patent does not necessarily invalidate or clear the entire patent estate. Generic applicants typically address each Orange Book-listed patent separately through certification, litigation, settlement, or launch after expiration.

For U.S. Patent 6,635,280 specifically, the business significance is now historical. The patent may have contributed to a past litigation or settlement position, but its expiration removes the patent as a current launch blocker.

How strong was the patent estate?

The patent was technically broad but legally dependent on difficult-to-measure performance limitations.

Strength factor	Assessment
Platform coverage	Broad
Drug coverage	Broad, with named active ingredients
Polymer coverage	Broad but functionally constrained
Manufacturing coverage	Limited in the stated claims
Product-shape coverage	Narrow dependent claims
Method-of-use coverage	Broad in theory, fact-intensive in enforcement
Design-around exposure	Moderate to high
Current enforceability	None because the patent is expired
Commercial importance	High for historical metformin ER strategy

The strongest historical value was the combination of a platform claim with metformin-specific dependent claims and product-oriented performance requirements. The principal design-around routes were:

• Use of a non-swelling matrix.
• Use of a dosage form that does not exceed the fed-state pyloric diameter.
• Release through the small intestine rather than substantially in the stomach.
• Faster matrix erosion.
• Different drug-to-polymer ratios.
• Different release duration.
• Alternative tablet geometry.
• A formulation that fails the one-hour drug-retention threshold.

How does this patent compare with competing controlled-release technologies?

U.S. Patent 6,635,280 differs from conventional extended-release patents in that its central limitation is gastric retention rather than merely prolonged dissolution.

Technology type	Gastric retention required?	Typical release site	Primary design objective
Conventional hydrophilic matrix	No	Stomach and intestine	Slow release
Enteric-coated tablet	No	Intestine	Acid protection
Osmotic tablet	No	GI tract	Controlled osmotic release
Floating dosage form	Often	Stomach	Buoyancy-based retention
Expandable gastroretentive matrix	Yes	Stomach	Swelling and prolonged gastric residence
Mucoadhesive system	Intended	Stomach or upper GI tract	Adhesion to mucosa
Delayed-release system	No	Distal GI tract	Site-specific release

The patent’s differentiation is the combination of swelling, fed-state pyloric exclusion, prolonged gastric release, and substantial matrix integrity.

What generic launch scenarios existed?

Before expiration, a generic applicant could pursue several routes:

1. File an ANDA with a Paragraph IV certification against the patent.
2. File with a Section viii statement carving out method claims where legally permissible.
3. Develop a non-infringing formulation that does not satisfy the gastric-retention limitations.
4. Wait for patent expiration.
5. Challenge only product-specific patents while accepting or designing around broader platform patents.

After expiration, a generic metformin manufacturer can develop an extended-release product without infringing this patent. Regulatory approval still requires demonstration of bioequivalence or satisfaction of the applicable FDA pathway, and other live patents may remain relevant.

What geographic coverage did the patent provide?

U.S. Patent 6,635,280 provided protection only in the United States. Corresponding international applications or national-phase patents may have protected related technology in Europe, Canada, Japan, or other jurisdictions, but foreign rights required separate prosecution and separate validity analysis.

Expiration in the United States did not automatically determine foreign expiration. A global freedom-to-operate review must examine:

• Patent family members.
• National-phase grants.
• Patent-term adjustments or extensions.
• Supplementary protection certificates.
• Local maintenance fees.
• Claim amendments during prosecution.
• Local litigation and settlement agreements.

Key Takeaways

• U.S. Patent 6,635,280 covers expandable, gastroretentive controlled-release matrix dosage forms.
• Claim 1 requires a highly soluble drug, polymer matrix, specified drug-to-polymer ratio, fed-state gastric retention, one-hour drug retention, prolonged release, and substantial matrix integrity.
• Metformin hydrochloride is the most commercially important claimed drug.
• The patent also covers method-of-use concepts involving intestinal flora, colonic enzymes, P-glycoprotein, acidic gastric conditions, and alkaline degradation.
• Polyethylene oxide, hypromellose and other cellulose derivatives, crosslinked polyacrylic acids, and xanthan gum are expressly identified.
• The patent issued on October 21, 2003 and is expired.
• It no longer creates a current U.S. infringement barrier or Orange Book exclusivity barrier.
• Historical Glumetza generic competition and Paragraph IV activity must be analyzed together with related metformin patents, not this patent in isolation.
• Claims 62 and 69 contain apparent dependent-claim reference errors that could have affected their litigation value.
• Current generic launch risk depends on unexpired product, formulation, manufacturing, labeling, and regulatory exclusivities.

FAQs

Does U.S. Patent 6,635,280 still block generic metformin extended-release products?

No. The patent has expired. Current blocking risk must be assessed against other unexpired patents and regulatory exclusivities associated with the specific metformin product.

Is every hydroxypropylmethylcellulose metformin tablet covered by this patent?

No. The product must also satisfy the claim’s swelling, gastric-retention, release, drug-loading, and matrix-integrity limitations.

Does the patent cover ordinary sustained-release tablets?

Not automatically. Ordinary sustained-release tablets that do not swell beyond the fed-state pyloric diameter or do not remain substantially intact through release may fall outside the claims.

Can an expired patent support a Paragraph IV lawsuit?

No prospective infringement claim can be based on an expired patent. Historical damages or disputes may remain relevant, but expiration removes the patent as a current launch prohibition.

Are cyclosporine and paclitaxel products covered as active-ingredient patents?

No. The patent does not claim cyclosporine or paclitaxel compositions generally. It claims their use in a specific gastroretentive matrix dosage form with defined release and gastric-retention characteristics.

References

1. United States Patent and Trademark Office. (2003). U.S. Patent No. 6,635,280, Gastroretentive controlled-release oral drug dosage forms.
2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
3. U.S. Food and Drug Administration. (2024). Abbreviated new drug application approvals and patent certification requirements.
4. Depomed, Inc. (2005). Glumetza, metformin hydrochloride extended-release tablets, NDA 021748. U.S. Food and Drug Administration.

Drugs Protected by US Patent 6,635,280

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

International Family Members for US Patent 6,635,280

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	302597
Australia	729529
Australia	8138698
Canada	2290624
Canada	2364845
Germany	69831335
European Patent Office	0998271