Details for Patent: 6,635,280

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, and US Landscape for Fed-Mode, Stomach-Retentive, Controlled-Release Oral Matrices

United States Patent 6,635,280 claims an oral controlled-release dosage form and associated administration methods that use a solid polymeric matrix engineered to swell to a size exceeding the pyloric diameter in the fed mode, retaining at least about 40% of drug after 1 hour in gastric fluid, and releasing substantially all of the drug within about 10 hours. The core scope is anchored to (1) drug solubility classes, (2) drug-to-polymer ratios, (3) matrix polymer identity and grade ranges (notably high-MW poly(ethylene oxide)), and (4) functional performance criteria in gastric fluid, with further claim layering for (5) drug-specific examples and (6) mechanism-driven avoidance of lower-GI contact and enzyme/transport-mediated degradation or inactivation.

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What is the invention scope in 1 page?

Core technology concept

The patent claims dimensionally unrestricted swelling of a polymeric matrix in gastric fluid to create stomach retention during the fed mode while the matrix releases drug through dissolution and diffusion (and/or erosion).

Performance-defined matrix envelope (claim 1 baseline)

For a dosage form releasing a water-soluble drug (threshold defined on solubility), the matrix must satisfy:

• Drug solubility in water
  • Claim 1: solubility > 1 part drug / 10 parts water
  • Claim 2: solubility > 1 part drug / 5 parts water
• Drug to polymer weight ratio
  • Claim 1: 15:85 to 80:20
  • Claim 19 and later method claims: 0.01:99.99 to 80:20
• Matrix swelling for gastric retention
  • Matrix swells dimensionally unrestricted upon imbibition and becomes larger than pyloric diameter in fed mode
• Release mechanism
  • Drug releases into gastric fluid by dissolution and diffusion out of matrix (claim 1) and by dissolution plus either erosion or diffusion (methods)
• Retention and release timing in gastric fluid
  • Retains at least about 40% of drug at 1 hour
  • Releases substantially all after immersion (explicitly ~10 hours in the method claims)
• Integrity
  • Matrix remains substantially intact until substantially all of drug is released

Claim architecture

• Claims 1-18: dosage form claims (composition + functional gastric-fluid behavior + matrix polymer options + example geometries and polymers).
• Claims 19-44: method claims tying fed-mode gastric retention to avoiding intestinal flora contact, and avoiding degradation/inactivation by enzymes and transporters (including p-glycoprotein).
• Claims 45-70: further dosage-form refinements, including specific release endpoints and polymer grades/viscosity where stated, plus drug/polymers recitations.

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What exactly do the key independent claims cover?

Claim 1 (independent dosage form)

A controlled-release oral dosage form comprising:

• A drug with solubility > 1:10 (w/w drug:water)
• One or more polymers forming a solid polymeric matrix with drug incorporated at drug:polymer = 15:85 to 80:20
• Matrix swelling dimensionally unrestricted to exceed pyloric diameter in fed mode to promote stomach retention
• Release into gastric fluid via dissolution and diffusion out of matrix
• After immersion in gastric fluid:
  • ≥ 40% drug retained at 1 hour
  • substantially all drug released (timing not fixed in claim 1, but locked to about 10 hours in later claims)
• Matrix remains substantially intact until most/all drug released

Scope implication: The claim is functional and performance-defined, with polymer identity defined later. It is not restricted to a single polymer, but it is constrained to an engineered swelling-retention behavior and a release-retention profile in gastric fluid.

Claim 19 (independent method; broader matrix ratio)

A method of administering a drug that is therapeutically absorbed in the stomach but can alter intestinal flora, using:

• Oral dosing while subject is in fed mode
• Dosage form with drug in polymeric matrix
• Drug:polymer = 0.01:99.99 to 80:20 (wider than claim 1)
• Matrix behavior:
  • Swells to > pyloric diameter in fed mode
  • Releases in gastric fluid by dissolving and either erosion or diffusion
  • ≥ 40% retained at 1 hour
  • Releases substantially all within about 10 hours
• Functional target: extend release during fed mode while releasing in stomach and substantially avoiding contact with intestinal flora

Scope implication: Method claims expand the quantitative matrix loading range and hard-wire the ~10 hour “substantially all” requirement.

Claim 24 / 27 / 28 / 29 (lower-GI enzyme/transport avoidance variants)

These method claims further narrow by adding specific biological avoidance targets:

• Claim 24: avoid degradation by colonic bacterial enzymes and contact with intestinal enzymes and drug transporters
• Claim 27: cyclosporine; avoid substantial degradation by colonic bacterial enzymes
• Claim 28: digoxin; avoid substantial degradation by colonic bacterial enzymes
• Claim 29: doxifluridine; avoid degradation by intestinal enzymes and inactivation by transporters

Claims 32 and 33 (explicit p-glycoprotein inactivation avoidance)

• Claim 32: cyclosporine; avoid inactivation by p-glycoprotein in lower GI
• Claim 33: paclitaxel; avoid inactivation by p-glycoprotein in lower GI

Scope implication: The patent’s landscape relevance for oncology and transplant drug formulations is amplified by p-gp-specific language, which can be used to argue functional equivalence to known transporter-mediated inactivation concerns.

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What polymers and polymer grades are explicitly within claim scope?

Polymer family (claim 8 and downstream)

Claim 8 recites polymers for the solid matrix, specifically:

• poly(ethylene oxide)
• cellulose
• alkyl-substituted celluloses
• crosslinked polyacrylic acids
• xanthan gum

Claim 9 narrows alkyl-substituted celluloses to:

• hydroxymethyl-cellulose
• hydroxyethyl-cellulose
• hydroxypropyl-cellulose
• hydroxypropylmethyl-cellulose
• carboxymethyl-cellulose

High molecular weight poly(ethylene oxide) limitations

• Claim 10: PEO molecular weight ≥ 4,000,000
• Claim 11: PEO MW 4,500,000 to 10,000,000
• Claim 12: PEO MW 5,000,000 to 8,000,000

Metformin-specific retention and polymer grades

• Claims 52-56: specific metformin hydrochloride retention thresholds and PEO MW ranges
  • Claim 52: retains ≥ 50% at 1 hour for metformin HCl
  • Claim 53: retains ≥ 60% at 1 hour for metformin HCl
  • Claims 54-56: PEO MW ≥ 4,000,000, 4,500,000 to 10,000,000, 5,000,000 to 8,000,000

Cellulose-derivative grade/viscosity (claim 51)

• Claim 51: hydroxypropylmethyl-cellulose with viscosity 11,000 to 110,000 centipoise (2% solution at 20°C)

Matric geometry (dosage form shape constraints)

• Claim 17: two cylindrical tablets, each about
  • 9-12 mm length
  • 6.5-7 mm diameter
• Claim 18: one elongated tablet about
  • 18-22 mm length
  • 6.5-7.8 mm width
  • 6.2-7.5 mm height

Landscape implication: For design-around and freedom-to-operate analysis, the claim set is not confined to mucoadhesive or bioerodible paradigms. It is tied to a swelling-to-pylorus-crossing requirement, plus explicit retention/release metrics. The polymer lists are broad but still enumerated.

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How broad is the drug scope in the claims?

The claims repeatedly use formula-like inclusion lists that function as coverage hooks for formulation competitors.

Explicit drug examples in dosage-form claims

Claim 3 lists drugs (example set) including:

• metformin hydrochloride
• vancomycin hydrochloride
• captopril
• erythromycin lactobionate
• ranitidine hydrochloride
• sertraline hydrochloride
• tramadol
• ticlopidine hydrochloride

Claim 4-7 and 8-12 then focus:

• Claim 4: metformin hydrochloride (explicit metformin dosage form)
• Claim 5: sertraline hydrochloride
• Claim 6: captopril
• Claim 7: vancomycin hydrochloride

Explicit drugs expanded in method claims

Method claims (19 onwards) expand the covered therapeutic context and included drug lists:

• Claim 20: amoxicillin, cefuroxime axetil, cefaclor, clindamycin, clarithromycin, azithromycin, ceftazidine, ciprofloxacin
• Claim 21: highly soluble drug group: amoxicillin, cefuroxime axetil, cefaclor, clindamycin
• Claim 22: infection treatment claims listing amoxicillin, cefuroxime axetil, cefaclor, clindamycin, clarithromycin, azithromycin, ceftazidine
• Claims 25-26: cyclosporine, digoxin, doxifluridine
• Claims 31-33: cyclosporine and paclitaxel (with explicit p-gp language in 32-33)
• Claims 35-36: esters of ampicillin, iron salts, digoxin, ketoconazole
• Claims 37-39: ampicillin ester, iron salts, ketoconazole
• Claim 41: nelfinar mesylate
• Claim 42: HIV infection method using nelfinar mesylate
• Claim 43: generic class based on ionized group between pH 5 and 8
• Claims 44-45: acid environment and protective release language
• Claim 57 and onward: ciprofloxacin appears in dosage-form refinement
• Claims 64-70: iron salt dosage-form refinements, though certain downstream metformin retention language appears embedded in the claim text provided

Landscape implication: The explicit inclusion lists create practical enforcement leverage against competitors developing stomach-retentive, fed-mode controlled-release formulations for the same chemical entities or close alternatives.

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What performance characteristics define retention and release?

Gastric immersion retention thresholds

Across claims 1 and dependent claims:

• Claim 1: ≥ 40% retained at 1 hour
• Claim 13-15: dependent thresholds:
  • Claim 13: ≥ 50% retained
  • Claim 14: ≥ 60% retained
  • Claim 15: ≥ 80% retained

Release window in method claims

• Claim 19 and downstream: “releases substantially all … within about ten hours after immersion”
• Claim 45-46 then refine dosage-form release endpoints:
  • Claim 45: substantially all within about 10 hours
  • Claim 46: substantially all within about 8 hours

Matrix integrity

• Claim 1: “remains substantially intact until substantially all of said drug is released”
• Method claims: functional equivalent via “releases substantially all within about ten hours” after defined gastric-fluid swelling and release behavior; they preserve the same matrix concept.

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What biological rationale the claims tie to functional outcomes

The claims frame stomach retention as a way to reduce downstream exposure:

• Avoid intestinal flora alteration
  • Claim 19 and 22 explicitly target “substantially avoiding contact … with said intestinal flora.”
• Avoid colonic bacterial enzyme degradation
  • Claim 24 targets colonic bacterial enzymes and the contact with “intestinal enzymes and drug transporters.”
• Avoid transporter-mediated inactivation (p-gp)
  • Claim 32 (cyclosporine) and Claim 33 (paclitaxel): avoid inactivation by p-glycoprotein in lower GI.
• Acidic environment bioavailability maintenance
  • Claim 34: bioavailability substantially greater in acidic environment than alkaline environment.
  • Claims 37-39: maintain maximum bioavailability of ampicillin ester, iron salts, ketoconazole.
  • Claim 44: protects unreleased drug in matrix from gastric fluid and ties to acidic environment.

Landscape implication: The claims map to a specific “stomach-first exposure window” thesis: retention during fed mode reduces both microbial enzyme and transporter-mediated issues that would occur after the dosage form passes into the intestine.

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How does the claim set enable both generic and drug-specific coverage?

Generic method claims

Claims 19, 24, 30, 34, 40, 43 define broad administration methods by:

• feeding state (fed mode),
• swelling-retention,
• drug release profile in gastric fluid,
• avoidance of lower-GI exposure mechanisms,
• and specific broad functional drug categories (solubility, ionization state, pH-dependent bioavailability).

Drug-specific dependent claims

The dependent claims repeatedly lock onto:

• named active pharmaceutical ingredients (APIs),
• specific polymer candidates,
• and measurable gastric-fluid retention outcomes.

This structure makes the patent landscape operationally relevant even where competitors try to position their products as “similar but not the same,” because the independent claims are functionally defined while dependent claims provide enforcement targets tied to marketed-like entities.

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What is the US patent landscape risk profile for this patent?

Without searching file histories and family members, the landscape can only be characterized at the claim-scope level provided. The actionable risk profile is driven by whether competitors make and sell formulations that meet the mechanical and performance criteria:

High-risk overlap patterns (likely infringing fact patterns)

• Oral controlled-release formulations designed to:
  • swell in gastric fluid to exceed pyloric diameter in fed mode,
  • retain ≥40% drug at 1 hour,
  • release substantially all by ~8-10 hours,
  • use polymer matrices among the enumerated set (PEO, cellulose derivatives, crosslinked polyacrylic acids, xanthan gum).
• Products that claim or operate for:
  • stomach retention to avoid intestinal flora degradation,
  • avoidance of colonic bacterial enzymatic degradation,
  • avoidance of p-gp mediated inactivation,
  • or retention to maintain acidic-environment bioavailability.

Medium-risk overlap patterns

• Products using the same swelling-retention concept but differing in:
  • drug solubility threshold,
  • drug:polymer ratio outside the recited ranges,
  • retention or release kinetics outside the quantified gastric-fluid criteria,
  • or matrix integrity behavior.

Lower-risk overlap patterns

• Designs that avoid at least one of the hard functional anchors:
  • no pyloric-diameter exceeding swelling,
  • retention below specified thresholds at 1 hour in gastric fluid,
  • release not complete by ~8-10 hours after immersion,
  • or matrix that is not substantially intact until release completion.
• Different polymer chemistry beyond the enumerated families (though “one or more polymers” may still intersect via included classes only).

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Key takeaways on scope and claim leverage

• The invention is defined by functional gastric performance: swelling to exceed pyloric diameter in fed mode, ≥40% retention at 1 hour, and substantially all release by ~10 hours, with matrix integrity maintained.
• Drug solubility and drug:polymer ratio are gating terms: solubility thresholds (>1:10 or >1:5) and drug:polymer ranges (15:85 to 80:20 in dosage form; 0.01:99.99 to 80:20 in method).
• Polymer coverage is meaningful but enumerated: PEO (including specific MW ranges), cellulose and alkyl-substituted celluloses (including HPMCs with specified viscosity), crosslinked polyacrylic acids, and xanthan gum.
• Enforcement leverage comes from layered dependent claims: specific APIs (metformin, sertraline, captopril, vancomycin, amoxicillin family, cyclosporine, digoxin, paclitaxel, ketoconazole, nelfinar mesylate, etc.) and performance cutoffs (50%, 60%, 80% retention at 1 hour; 8-hour complete release option).
• Mechanistic story is explicitly tied to downstream avoidance: reducing intestinal flora contact, avoiding colonic bacterial enzyme degradation, and avoiding p-gp inactivation.

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FAQs

1) What single functional requirement most strongly drives infringement analysis?

The dosage form must swell in gastric fluid in an unrestricted manner to exceed the pyloric diameter in the fed mode, enabling stomach retention.

2) Are drug:polymer ratios treated differently in dosage versus method claims?

Yes. Claim 1 limits drug:polymer to 15:85 to 80:20, while method claims such as claim 19 expand the range to 0.01:99.99 to 80:20.

3) What gastric-fluid metrics are expressly quantified?

The matrix must retain at least ~40% drug at 1 hour and then release substantially all within about 10 hours (with dependent options for ~8 hours in dosage-form claims).

4) Does the patent limit polymer types to PEO alone?

No. PEO is central, but the claims list cellulose, alkyl-substituted celluloses, crosslinked polyacrylic acids, and xanthan gum.

5) Which mechanistic protection concepts appear in the method claims?

Avoiding contact with intestinal flora, avoiding colonic bacterial enzyme degradation, and avoiding p-glycoprotein-mediated inactivation (explicitly for cyclosporine and paclitaxel).

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Key Takeaways

• Patent 6,635,280 claims a stomach-retentive fed-mode controlled-release oral matrix defined by pyloric exceeding swelling, gastric-fluid retention (≥40% at 1 hour), and near-complete release by ~10 hours.
• The scope is broad across APIs via enumerated lists and generic performance-linked claims, while the polymer scope is enumerated and includes specific PEO MW bands and HPMC viscosity.
• The most direct landscape risk is to any competitor formulation that matches the swelling-retention and gastric release kinetics while using polymer classes in the claim set and targeting lower-GI exposure avoidance (flora, enzymes, and p-gp).

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References

1. United States Patent and Trademark Office (USPTO). United States Patent 6,635,280. (Claim text provided in prompt).

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