Details for Patent: 6,340,475

Summary for Patent: 6,340,475

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:	US09/282,233
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,340,475
Patent Claim Types: see list of patent claims	Use; Formulation; Dosage form;

United States Drug Patent 6,340,475: Claim Scope, Expiration, Orange Book Status, and Patent Landscape

U.S. Patent No. 6,340,475 is a foundational Depomed patent covering gastroretentive, controlled-release oral dosage forms. Its claims target swellable polymer matrices that remain in the stomach during the fed state and release highly soluble drugs over approximately eight to ten hours. The broadest commercial relevance is metformin hydrochloride, including the Glumetza extended-release product.

The patent issued January 22, 2002, from an application filed in 1999. Its ordinary 20-year patent term expired in approximately 2019, subject to any patent-term adjustment shown in the USPTO record. The patent is therefore no longer an enforceable barrier to generic entry. Its historical importance remains substantial because it established claim language later used across Depomed's gastroretentive product portfolio and related patent families.

What does U.S. Patent 6,340,475 protect?

The patent protects a dosage-form architecture rather than a new active pharmaceutical ingredient. The core technology combines:

1. A highly water-soluble drug.
2. A solid polymeric matrix.
3. A specified drug-to-polymer ratio.
4. Swelling after contact with gastric fluid.
5. Gastric retention during the fed mode.
6. Controlled dissolution, diffusion, or matrix erosion.
7. A minimum one-hour drug-retention threshold.
8. Substantially complete release within eight or ten hours.
9. Substantial structural integrity until drug release is complete.

The central inventive concept is a gastric-retentive matrix that expands after ingestion, remains sufficiently large to resist passage through the pylorus, and releases drug in the stomach before substantial delivery to the intestine.

The claims cover both dosage forms and methods of administration. Claims 1 through 18 primarily address dosage-form structure and performance. Claims 19 through 67 and 68 through 89 address methods, specific drugs, matrix materials, viscosity ranges, polymer molecular weights, and metformin tablets.

How many independent claims does Patent 6,340,475 have?

The patent has multiple independent claim groups. The principal independent claims are claims 1, 19, 22, 24, 27, 28, 29, 30, 32, 33, 34, 37, 38, 39, 40, 42, 43, 44, 68, and 79.

Claim group	Claim type	Principal subject
1	Dosage form	Controlled-release dosage form for highly soluble drugs
19	Administration method	Avoiding intestinal-flora alteration
22	Treatment method	Treating bacterial infections while reducing intestinal-flora effects
24	Administration method	Avoiding colonic enzyme degradation
27	Treatment method	Cyclosporine for transplant patients
28	Treatment method	Digoxin for heart disease
29	Treatment method	Doxifluridine for cancer
30	Administration method	Avoiding lower-GI drug transporter inactivation
32	Treatment method	Cyclosporine and P-glycoprotein
33	Treatment method	Paclitaxel and P-glycoprotein
34	Administration method	Maintaining drugs in an acidic gastric environment
37-39	Treatment methods	Ampicillin esters, iron salts, and ketoconazole
40	Administration method	Protecting drugs from alkaline degradation
42	Treatment method	Nelfinavir mesylate
43	Administration method	Drugs with ionized groups at pH 5 to 8
44	Administration method	Protecting acid-sensitive drugs inside the matrix
68	Dosage form	Metformin hydrochloride
79	Dosage form	Metformin hydrochloride matrix tablet

Claims 68 and 79 are especially significant because they recite metformin hydrochloride directly and do not depend on claim 1.

What are the key limitations of claim 1?

Claim 1 is the principal broad dosage-form claim. A product must satisfy every material limitation.

Drug-solubility limitation

The drug must have water solubility greater than one part drug in ten parts water. Claim 2 narrows this to greater than one part drug in five parts water.

This limitation excludes poorly soluble drugs from the literal scope of claim 1, although other independent method claims cover drugs selected for different pharmacokinetic or stability characteristics.

Drug-to-polymer ratio

The claimed drug-to-polymer weight ratio is approximately 15:85 to 80:20. The range is broad and permits formulations containing from 15% to 80% drug by weight relative to the drug-polymer combination.

Claims 19 and later method claims use a much broader range of approximately 0.01:99.99 to 80:20. This creates a significant distinction between the dosage-form claims and method claims.

Swellable matrix

The matrix must swell after imbibing water or gastric fluid. It must become sufficiently large to promote stomach retention during the fed mode.

The claim does not require one specific polymer. Claim 8 identifies poly(ethylene oxide), cellulose, alkyl-substituted celluloses, crosslinked polyacrylic acids, and xanthan gum. This open-ended functional construction potentially covers other polymers if they perform the recited swelling and gastric-retention functions.

Release profile

The matrix must:

• Retain at least approximately 40% of the drug one hour after immersion in gastric fluid.
• Release substantially all drug within approximately eight hours.
• Release drug through dissolution and diffusion.
• Remain substantially intact until all drug is released.

Claims 13 through 15 increase the one-hour retention threshold to approximately 50%, 60%, and 80%.

Which drugs are expressly covered?

The patent lists a large number of drug candidates. The principal drug categories are set out below.

Drug or class	Relevant claims	Therapeutic or technical rationale
Metformin hydrochloride	3, 4, 45-47, 53, 56, 59, 60, 63-65, 68-89	Highly soluble antidiabetic drug
Sertraline hydrochloride	3, 5	Soluble antidepressant
Captopril	3, 6	Gastrically absorbed drug
Vancomycin hydrochloride	3, 7	Local gastrointestinal antibiotic activity
Amoxicillin and cephalosporins	20-23	Reduction of intestinal-flora exposure
Clindamycin and macrolides	20-23	Antibiotic delivery
Cyclosporine	25, 27, 31, 32	Avoidance of lower-GI degradation and P-glycoprotein effects
Digoxin	25, 28, 35	Gastric absorption and transporter-related limitations
Doxifluridine	25, 26, 29	Avoidance of intestinal enzyme degradation
Paclitaxel	31, 33	Avoidance of P-glycoprotein inactivation
Ketoconazole	35, 39	Improved absorption in an acidic environment
Nelfinavir mesylate	41, 42	Protection from intestinal degradation and transporters
Lisinopril, bupropion, ganciclovir, iron salts	52	Gastric absorption or ionization
Ampicillin esters	35-37	Acidic gastric environment
Iron salts	35, 38, 52	Improved gastric bioavailability

The drug lists appear in dependent claims, but the independent claims can reach other drugs if the required solubility, gastric retention, release, and treatment limitations are met.

What formulations are protected by Patent 6,340,475?

The patent expressly covers several polymer systems.

Polymer system	Claims	Limitation
Poly(ethylene oxide)	8, 10-12, 47-49, 54-56, 76-78, 87-89	Molecular weight generally at least 4 million
Cellulose derivatives	8, 9, 45, 50, 51, 57-65, 69-73, 80-84	Includes hydroxypropylmethylcellulose
Crosslinked polyacrylic acids	8, 69, 80	Functional swellable matrix
Xanthan gum	8, 69, 80	Spelled "xanthum gum" in the supplied claim text
Glyceryl monostearate	16	Additional release-retarding agent
Sodium myristate	16	Additional release-retarding agent

Claims 62, 63, 66, and 67 specify hydroxypropylmethylcellulose with a viscosity of approximately 11,000 to 110,000 centipoise, measured in a 2% solution at 20°C. Claims 10 through 12 and related claims specify high-molecular-weight poly(ethylene oxide), including ranges of approximately 4.5 million to 10 million and 5 million to 8 million.

These limitations create potential design-around paths. A competitor could evaluate non-listed polymers, different molecular-weight grades, different viscosity grades, altered tablet geometry, or release profiles that fail the literal one-hour retention or complete-release limitations.

Does the patent cover Glumetza and metformin extended-release tablets?

Yes, the patent is directed in substantial part to metformin hydrochloride gastric-retentive dosage forms. Claims 68 through 89 specifically cover metformin hydrochloride in a swellable polymer matrix.

The most commercially relevant limitations are:

• Metformin hydrochloride as the active ingredient.
• Drug-to-polymer ratio of approximately 15:85 to 80:20.
• Swelling sufficient to promote gastric retention.
• At least approximately 40% metformin retention after one hour in gastric fluid.
• Hydroxypropylmethylcellulose or high-molecular-weight poly(ethylene oxide).
• Tablet dosage forms under claim 79 and its dependents.

Glumetza was developed as a once-daily extended-release metformin product based on Depomed's gastric-retentive technology. The patent's metformin claims are historically relevant to the product's intellectual-property position, although expiration of the patent term removes it as a current blocking right.

What is the Orange Book status of U.S. Patent 6,340,475?

The patent was historically associated with metformin extended-release products, including Glumetza-related regulatory protection. FDA Orange Book listings must be distinguished from enforceability:

• An Orange Book listing identifies a patent submitted by an NDA holder.
• Listing does not extend the patent term.
• Listing does not establish validity or infringement.
• An expired patent cannot ordinarily block approval or commercial launch after expiration.

The relevant FDA product context is NDA 021748 for Glumetza, a metformin hydrochloride extended-release product. Any historical Orange Book listing should be checked against the FDA's current and archived Orange Book records because patent listings, delistings, and expiration entries can change over time (FDA, n.d.-a; FDA, n.d.-b).

When did Patent 6,340,475 lose exclusivity?

The patent's ordinary 20-year term ran from the relevant nonprovisional filing date, not from the issue date. Based on the 1999 filing chronology, the patent expired in approximately 2019, subject to any patent-term adjustment reflected in the USPTO patent record.

The key dates are:

Event	Date
Earliest priority and application history	1998-1999 period
U.S. filing	1999
Patent issue	January 22, 2002
Ordinary 20-year term endpoint	Approximately 2019
Current enforceability	Expired by ordinary term

Patent expiration is separate from FDA market exclusivity. Metformin is a small-molecule drug, so there is no biosimilar pathway or biologic reference-product exclusivity issue. Generic approval proceeds through the ANDA pathway, typically with Paragraph IV or other certification analysis where unexpired listed patents remain relevant.

Which companies challenged the Glumetza patent estate?

Generic competition to Glumetza involved ANDA applicants and litigation concerning the broader Depomed and successor-company patent estate. The relevant commercial parties have included Depomed, Santarus, Valeant Pharmaceuticals, Bausch Health, and generic manufacturers such as Lupin and other ANDA applicants.

The litigation risk was not limited to Patent 6,340,475. Related patents covering controlled-release metformin, gastric-retentive formulations, tablet geometry, and manufacturing details could create separate litigation exposure. A complete defendant-by-defendant Paragraph IV chronology requires review of individual FDA certifications, district-court dockets, Federal Circuit decisions, and settlement agreements. The supplied claim text alone does not establish which specific ANDA applicants challenged this patent or whether a particular settlement included a licensed launch date.

What patent landscape surrounds Patent 6,340,475?

The surrounding landscape includes four overlapping technology groups.

Foundational gastroretentive patents

These patents claim swellable dosage forms that remain in the stomach and release drug over a controlled period. They may overlap on:

• Gastric retention.
• Expandable matrix systems.
• Fed-state administration.
• Polymer swelling.
• Drug diffusion and matrix erosion.

Metformin formulation patents

These patents focus on metformin hydrochloride extended release, including:

• Polymer composition.
• Tablet size and shape.
• Drug loading.
• Release kinetics.
• Manufacturing process.
• Combination with other antidiabetic agents.

Product-specific Orange Book patents

NDA holders can list patents directed to the product, formulation, method of use, or manufacturing process. These patents may have expiration dates later than Patent 6,340,475 and can remain commercially relevant after the foundational patent expires.

Generic formulation and process patents

Generic manufacturers may rely on alternative polymers, compression conditions, tablet dimensions, or dissolution profiles to avoid later patents. The commercial question is therefore the full remaining estate, not Patent 6,340,475 in isolation.

How strong is the patent estate?

Patent 6,340,475 had broad historical scope but limited current strength because its statutory term has expired.

Strength factor	Assessment
Technical breadth	Broad functional coverage of swellable gastric-retentive matrices
Drug coverage	Broad lists spanning antibiotics, cardiovascular drugs, oncology drugs, and metformin
Polymer coverage	Broad, with specific high-molecular-weight and viscosity subranges
Claim redundancy	High, with multiple dosage-form and method claim groups
Vulnerability	Functional language, broad drug lists, performance testing, and potential prior-art overlap
Current blocking value	None after expiration
Historical litigation value	High for Glumetza and related gastric-retentive products
Biosimilar relevance	None
Generic-entry relevance today	Limited to historical validity and prosecution analysis

The method claims are particularly broad in subject matter but may be harder to enforce than the metformin dosage-form claims. They require proof that the accused product is administered in the claimed manner and achieves the specified physiological or therapeutic result. Claims 68 and 79 are more commercially concrete because they focus on metformin dosage forms.

What generic launch risks existed?

Before expiration, generic launch risk depended on four questions:

1. Whether the ANDA product used a swellable gastric-retentive matrix.
2. Whether its metformin-to-polymer ratio fell within the claimed range.
3. Whether its dissolution profile met the one-hour retention and complete-release limitations.
4. Whether later Depomed patents remained unexpired.

Potential design-around approaches included:

• Using a non-swellable extended-release matrix.
• Selecting a different release mechanism.
• Using a drug-to-polymer ratio outside the claimed range.
• Altering the polymer molecular weight or viscosity.
• Designing a tablet that does not promote gastric retention.
• Demonstrating a release profile outside the claimed thresholds.

These strategies would require product-specific testing. A formulation can avoid one claim while still implicating another patent in the broader estate.

Key Takeaways

• U.S. Patent 6,340,475 covers swellable, gastric-retentive controlled-release dosage forms.
• The principal commercial target is metformin hydrochloride, including Glumetza-type tablets.
• Claims 1, 19, 43, 68, and 79 define the most important claim families.
• The patent covers poly(ethylene oxide), hydroxypropylmethylcellulose, other cellulose derivatives, crosslinked polyacrylic acids, and xanthan gum.
• Key technical limitations include drug-to-polymer ratio, gastric swelling, one-hour drug retention, complete release within eight to ten hours, and matrix integrity.
• The patent's ordinary term expired in approximately 2019.
• There is no current biosimilar issue because metformin is a small-molecule drug.
• Historical Orange Book and Paragraph IV relevance does not create current enforceability after expiration.
• Current market risk depends primarily on later Glumetza and metformin formulation patents, not on Patent 6,340,475 itself.

FAQs About U.S. Patent 6,340,475

Is U.S. Patent 6,340,475 still enforceable?

No. Its ordinary patent term expired in approximately 2019, subject to the specific patent-term adjustment shown in the USPTO record.

Does Patent 6,340,475 cover all extended-release metformin tablets?

No. It covers metformin formulations meeting its specific matrix, swelling, drug-loading, gastric-retention, and release limitations. Conventional extended-release metformin products using different technologies may fall outside its claims.

Can a generic manufacturer receive FDA approval despite this patent?

Yes, after patent expiration. Before expiration, an ANDA applicant would have needed an appropriate patent certification and could have faced Paragraph IV litigation.

Is hydroxypropylmethylcellulose required for infringement?

No. The independent claims are not limited to hydroxypropylmethylcellulose. That polymer appears in dependent claims. A product using another polymer could still implicate the broader functional claims if all limitations are met.

Does this patent cover injectable metformin, capsules, or immediate-release tablets?

The claims are directed to oral controlled-release dosage forms and related administration methods. Injectable products and immediate-release tablets generally do not satisfy the claimed swellable gastric-retentive matrix requirements.

References

1. Food and Drug Administration. (n.d.-a). Approved drug products with therapeutic equivalence evaluations. U.S. Department of Health and Human Services.

2. Food and Drug Administration. (n.d.-b). Electronic Orange Book: Patent and exclusivity information. U.S. Department of Health and Human Services.

3. United States Patent and Trademark Office. (2002). U.S. Patent No. 6,340,475, Gastroretentive drug dosage forms.

4. United States Patent and Trademark Office. (n.d.). Patent term adjustment and patent term calculation resources. U.S. Department of Commerce.

5. U.S. Food and Drug Administration. (n.d.-c). Abbreviated new drug application process. U.S. Department of Health and Human Services.

Drugs Protected by US Patent 6,340,475

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 6,340,475

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	302597
Australia	729529
Australia	8138698
Canada	2290624
Canada	2364845