Details for Patent: 6,350,468

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Summary for Patent: 6,350,468

Title:	Double capsule for the administration of active principles in multiple therapies
Abstract:	A pharmaceutical dosage form particularly suitable for the administration of active principles in multiple therapies is disclosed. The pharmaceutical dosage form is a double capsule where in an internal capsule is placed inside an external one. Each internal and external capsule includes one or more active principles. A double capsule according to the invention is preferably used in triple or quadruple therapies against the microorganisms Helicobacter Pylori. Advantages of this pharmaceutical dosage form consist in providing a simple posology for administration of two and more active principles, allowing the active principles to activate at the right intervals of time and in the preestablished quantities, and preventing interactions between active principles. In a preferred embodiment of the invention, the pharmaceutical dosage form has an external capsule containing bismuth subcitrate and metronidazole, and an internal capsule containing tetracycline and optionally omeprazole, which is used in therapy for eradication of Helicobacter pylori.
Inventor(s):	Giovanni Sanso
Assignee:	Aptalis Pharma Canada ULC
Application Number:	US09/581,721
Patent Claim Types: see list of patent claims	Composition; Compound; Dosage form;

United States Drug Patent 6,350,468: Claim Scope, Expiration, Orange Book Status, and H. pylori Patent Landscape

U.S. Patent No. 6,350,468 protects a capsule-in-capsule dosage form combining bismuth, a nitroimidazole antibiotic, and a second antibiotic for treating Helicobacter pylori. The patent also covers quadruple-therapy versions containing a proton-pump inhibitor or H2 antagonist. Its principal commercial embodiment is the bismuth subcitrate, metronidazole, and tetracycline combination associated with Pylera.

The patent was granted on February 26, 2002, from an application filed June 18, 1998. Based on the statutory 20-year term for post-June 8, 1995 applications, the ordinary expiration date was June 18, 2018, subject to any applicable patent-term adjustment or extension. The patent is therefore no longer an enforceable U.S. exclusion right. The historical Orange Book relevance was directed to the capsule formulation and associated H. pylori treatment regimen, not to the individual active ingredients as new chemical entities.

What does U.S. Patent 6,350,468 protect?

The patent has two principal claim groups:

1. Method claims covering oral administration of the combined therapy to a mammal.
2. Pharmaceutical dosage-form claims covering the physical capsule configuration.

The core structural limitation is an internal capsule placed inside an external capsule. The external capsule contains a soluble bismuth salt and a first antibiotic. The internal capsule contains a second antibiotic.

The broadest independent claims are:

Claim	Category	Core subject matter
1	Method	Oral administration of nested capsules containing bismuth plus two antibiotics
21	Dosage form	Nested capsule product containing the same therapeutic components

The claims do not merely cover simultaneous administration of three known drugs. They require a particular dosage-form architecture in which one capsule is placed inside another.

How broad are the independent claims?

Claim 1: method of treatment

Claim 1 requires all of the following:

• A mammalian patient.
• Treatment directed against H. pylori.
• Oral administration.
• A pharmaceutical dosage form.
• An internal capsule inside an external capsule.
• A soluble bismuth salt and first antibiotic in the external capsule.
• A second antibiotic in the internal capsule.

A product administered as separate tablets or separate conventional capsules would not literally meet the nested-capsule limitation. A single conventional capsule containing all active ingredients also would not literally meet the claim unless it contained a separately identifiable internal capsule.

The claim does not expressly require:

• A specific dose.
• A specified dosing frequency.
• A specified treatment duration.
• A specific ratio between the active ingredients.
• A particular release profile.
• An enteric coating.
• A particular capsule shell material.
• A particular order of administration beyond oral administration of the claimed dosage form.

Those omissions expand the potential scope, but the capsule-in-capsule limitation remains central.

Claim 21: pharmaceutical dosage form

Claim 21 is an apparatus or composition-style claim directed to the dosage form itself. It does not require proof that the dosage form was administered to a patient. The claim requires:

• An internal capsule.
• An external capsule surrounding or containing the internal capsule.
• A soluble bismuth salt and first antibiotic in the external capsule.
• A second antibiotic in the internal capsule.
• Suitability for oral triple therapy against H. pylori.

This claim creates the principal product infringement risk for a competing capsule-in-capsule product, while claim 1 creates method-of-treatment exposure when the dosage form is used for H. pylori therapy.

Which active ingredients fall within the patent?

Claims 5 through 16 and 24 through 32 use extensive Markush groups.

Bismuth compounds

The listed bismuth compounds include:

• Bismuth subcitrate.
• Bismuth citrate.
• Bismuth subnitrate.
• Colloidal bismuth subnitrate.
• Bismuth subsalicylate.
• Bismuth aluminate.
• Bismuth carbonate.
• Bismuth oxide.
• Bismuth phosphate.
• Bismuth salicylate.
• Various bismuth oxides, vanadates, and related salts.

Claim 7 narrows the bismuth component to bismuth subcitrate. Claims 10, 13, and 16 further narrow the combination to bismuth subcitrate, metronidazole, tetracycline, and omeprazole.

First antibiotic: nitroimidazoles

The first antibiotic is selected from nitroimidazoles, including:

• Metronidazole.
• Tinidazole.
• Ornidazole.
• Nimorazole.
• Misonidazole.
• Related listed nitroimidazole compounds.

Metronidazole is the commercially important embodiment.

Second antibiotic: macrolides or tetracyclines

The second antibiotic is selected from:

• Macrolides, including clarithromycin, azithromycin, and erythromycin.
• Tetracyclines, including tetracycline, doxycycline, chlortetracycline, lymecycline, methacycline, and sancycline.

Claim 7 narrows the second antibiotic to tetracycline. This is the combination most closely associated with the commercial bismuth-based H. pylori product.

What quadruple-therapy formulations are protected?

Claims 2 through 4 and claims 22 and 23 add a K+/Na+ ATPase inhibitor or H2 antagonist.

The listed compounds include:

• Omeprazole.
• Lansoprazole.
• Pantoprazole.
• Rabeprazole.
• Cimetidine.
• Famotidine.
• Ranitidine.
• Nizatidine.
• Other historical acid-suppression compounds.

The patent covers three alternative placements:

Claim pathway	Placement of acid-suppressing agent
Claims 2 and 22	Inside the internal capsule
Claims 3 and 23	Inside the external capsule
Claim 4	In a second pharmaceutical dosage form

Claims 10, 13, 16, 29, and 32 narrow the quadruple therapy to:

• Bismuth subcitrate.
• Metronidazole.
• Tetracycline.
• Omeprazole.

The alternative in claim 4 is commercially and legally broader because the acid-suppressing agent does not have to be incorporated into either capsule. It can be supplied separately.

What formulation features are protected?

Capsule stability

Claim 17 requires both capsules to be stable at:

• 5°C to 50°C.
• 35% to 65% relative humidity.

This limitation may be useful for distinguishing the claimed dosage form from an unstable or incompatible co-formulation. It also creates a potential proof issue because infringement would require demonstrating the relevant stability characteristics.

Hard gelatin capsules

Claim 18 covers hard gelatin for both capsules. Claim 35 repeats the hard-gelatin limitation for the dosage-form claims.

A non-gelatin capsule could avoid literal infringement of these narrower claims, but it would not necessarily avoid the broader claims 1 or 21 if all other limitations were met.

Capsule sizes

Claims 19, 20, 33, and 34 specify capsule formats:

• Internal capsule: size 2 or 3.
• External capsule: size 0+ or 1.
• Preferred combination: external size 0+ and internal size 3.

These claims narrow the patent to a particular manufacturing and packaging configuration.

Excipients

Claim 36 permits one or more excipients in the internal and external capsules. Claim 37 lists:

• Magnesium stearate.
• Talc.
• Cellulose and derivatives.
• Silica and derivatives.
• Sugars.
• Polyethylene glycols.
• Waxes.
• Mono-, di-, and triglycerides of hydrogenated fatty acids.
• High-molecular-weight alcohols and acids.
• Mixtures of these materials.

The excipient claims are dependent and do not independently protect a formulation lacking the nested-capsule structure.

What are the strongest claims?

The most commercially significant claims are claims 1 and 21, followed by claims 7 and 26.

Claim	Practical significance
1	Broad treatment-method claim for the nested triple-therapy capsule
7	Specific method using bismuth subcitrate, metronidazole, and tetracycline
21	Broad product claim for the nested triple-therapy capsule
26	Specific dosage form using bismuth subcitrate, metronidazole, and tetracycline
10	Specific quadruple-therapy method with omeprazole
29	Specific quadruple-therapy dosage form with omeprazole

Claims 7 and 26 are narrower but easier to map to a specific product. Claims 1 and 21 have greater nominal breadth but depend on the same distinctive capsule-in-capsule architecture.

When did U.S. Patent 6,350,468 lose exclusivity?

The ordinary patent term ended June 18, 2018, based on the June 18, 1998 U.S. filing date. The patent therefore does not create a current blocking patent right against generic or competing H. pylori products.

The individual active ingredients were already established drugs. The patent’s value was directed to:

• Combination therapy.
• Capsule architecture.
• Component placement.
• Optional acid suppression.
• Selected capsule dimensions.
• Stability and excipient features.

After expiration, competitors may practice those claimed combinations without a patent-license requirement, subject to other unexpired patents, regulatory exclusivities, trademarks, trade secrets, and manufacturing rights.

What was the Orange Book status of the patent?

The patent was associated with the U.S. regulatory protection for the bismuth-based H. pylori combination marketed as Pylera. FDA product labeling identifies the bismuth subcitrate potassium, metronidazole, and tetracycline hydrochloride combination and its capsule dosage form (FDA, 2023).

The Orange Book listing of a patent does not extend the patent term. Once the patent expired, the listing ceased to create a live patent barrier to an ANDA applicant. A generic applicant could still face regulatory requirements relating to:

• Demonstration of pharmaceutical equivalence.
• Bioequivalence.
• Capsule configuration and release characteristics.
• Labeling differences.
• Manufacturing controls.
• Any other unexpired listed patents or regulatory protections.

Were there Paragraph IV challenges?

A Paragraph IV certification would have been relevant while the patent was listed and unexpired. Such a certification would assert that the patent was invalid, unenforceable, or not infringed.

The commercial importance of a Paragraph IV challenge declined sharply after June 18, 2018 because the patent no longer supported a live infringement action for post-expiration commercial activity. A current generic applicant would generally address the expired patent through a certification reflecting expiration rather than through a litigation-triggering Paragraph IV position.

The historical claim vulnerabilities would have included:

• Obviousness based on known bismuth-based H. pylori triple therapy.
• Obviousness of placing one capsule inside another.
• Written-description support for the very broad lists of bismuth salts, antibiotics, acid suppressants, and excipients.
• Enablement across the full Markush scope.
• Definiteness of terms such as “soluble salt,” “first antibiotic,” “second antibiotic,” and capsule “format.”
• Whether the accused product actually contains an internal capsule rather than a single blended capsule.

A reliable assessment of any historical Paragraph IV litigation requires the prosecution history, ANDA notices, district-court dockets, and Federal Circuit records.

What generic-entry risks remain?

Patent 6,350,468 itself presents no current U.S. patent-term barrier. The principal remaining risks are technical and regulatory rather than exclusivity-based.

Generic product risks

A generic developer may need to resolve:

• Whether the reference product uses a true capsule-in-capsule configuration.
• Whether the active ingredients are released in the same manner.
• Whether the product is eligible for an ANDA or requires a different FDA pathway.
• Whether the formulation has equivalent stability.
• Whether the product can reproduce the commercial capsule size and fill-weight characteristics.
• Whether manufacturing processes are protected by later patents or confidential know-how.

Label and indication risks

A product using the same three active ingredients could avoid the expired patent by using a different dosage form, such as separate tablets or conventional capsules. That design may still need to satisfy FDA requirements for the intended H. pylori indication.

How does the patent compare with competing H. pylori products?

Product or regimen	Core components	Relationship to Patent 6,350,468
Pylera-type bismuth therapy	Bismuth, metronidazole, tetracycline	Closest commercial embodiment
Traditional bismuth quadruple therapy	Bismuth, metronidazole, tetracycline, PPI	Falls within the technical concept when supplied in the claimed configuration
Helidac-type regimen	Bismuth subsalicylate, metronidazole, tetracycline	May overlap active-ingredient selections but generally differs in dosage form
Talicia	Rifabutin, amoxicillin, omeprazole	Outside the claimed antibiotic and bismuth combination
Voquezna-based regimens	Vonoprazan with antibiotics	Outside the patent’s listed active-ingredient combinations

Talicia and vonoprazan-based products compete therapeutically but do not generally practice the specific bismuth-plus-nitroimidazole-plus-second-antibiotic capsule configuration claimed by the patent.

Does the patent create biosimilar risk?

No. Biosimilar law is not the relevant framework because the covered products are small-molecule drug combinations, not biologics. Competitive entry would occur through generic-drug pathways, primarily an ANDA or, depending on product differences, another FDA application route.

What licensing deals affect the patent?

The patent record and FDA labeling establish the patent’s technical relationship to the bismuth-based H. pylori product. They do not, by themselves, establish the full chain of commercial licenses, assignments, or royalty arrangements.

Because the patent expired in 2018, any historical license would generally have commercial significance only for:

• Accrued royalties.
• Past sales.
• Territory-specific rights.
• Manufacturing know-how.
• Trademark or brand rights.
• Related unexpired patents.

The expired patent itself is not a current licensing gate for U.S. market entry.

How strong was the patent estate?

The estate was commercially meaningful before expiration because it combined:

• A product claim.
• A method-of-treatment claim.
• Specific active-ingredient combinations.
• A distinctive capsule-in-capsule configuration.
• Optional quadruple therapy.
• Stability, capsule-material, size, and excipient limitations.

Its principal weakness was concentration around a specific physical dosage form. A competitor using separate dosage units, a single conventional capsule, a different active-ingredient combination, or a non-nested delivery system could have had substantial noninfringement arguments.

The patent’s current strength is effectively zero as an exclusion right because its ordinary term has ended. Its continuing value is historical, evidentiary, and potentially relevant to prosecution or litigation concerning related patent families.

Key Takeaways

• U.S. Patent 6,350,468 covers a nested capsule containing bismuth plus two antibiotics for H. pylori therapy.
• The core commercial combination is bismuth subcitrate, metronidazole, and tetracycline.
• Claims 2 through 4 and related claims add a PPI or H2 antagonist for quadruple therapy.
• Claims 1 and 21 are the principal broad method and dosage-form claims.
• Claims 7 and 26 are the key narrow claims for the bismuth subcitrate, metronidazole, and tetracycline embodiment.
• The ordinary patent term ended June 18, 2018.
• The patent no longer blocks U.S. generic entry.
• The main residual barriers are formulation development, bioequivalence, manufacturing capability, later patents, and regulatory compliance.
• Biosimilar analysis is not applicable because the products are small-molecule combinations.

FAQs About U.S. Patent 6,350,468

Does Patent 6,350,468 cover Pylera?

It covers the claimed capsule-in-capsule formulation and related H. pylori treatment methods corresponding to the bismuth, metronidazole, and tetracycline combination. The patent expired in 2018.

Can a generic manufacturer launch a bismuth, metronidazole, and tetracycline product?

The expired patent does not prevent launch. The manufacturer must still satisfy FDA requirements and avoid infringement of any later, unexpired patents covering formulation, manufacturing, packaging, or labeling.

Does the patent cover separate tablets administered together?

Not literally under the principal claims, because claims 1 and 21 require an internal capsule placed inside an external capsule. Separate tablets may implicate other patents but do not meet that limitation by themselves.

Is omeprazole required by the patent?

No. Omeprazole is required only in the narrow claims directed to the specific quadruple-therapy embodiment. The broader claims permit other listed PPIs or H2 antagonists and, in some claims, separate administration of the acid-suppressing agent.

Does an expired Orange Book patent still block an ANDA?

No. An expired patent does not provide a current basis for an injunction against post-expiration commercial activity. The applicant must still address the patent in its FDA certification strategy and evaluate other listed or unlisted intellectual-property rights.

References

1. U.S. Patent and Trademark Office. (2002). U.S. Patent No. 6,350,468: Pharmaceutical composition for the treatment of Helicobacter pylori infections.
2. U.S. Food and Drug Administration. (2023). Pylera prescribing information.
3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
4. U.S. Code, 35 U.S.C. § 154. Patent term.
5. U.S. Code, 21 U.S.C. § 355(j). Abbreviated new drug applications and patent certifications.

Drugs Protected by US Patent 6,350,468

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: 6,350,468

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Italy	MI97A2788	Dec 17, 1997

PCT Information
PCT Filed	December 14, 1998	PCT Application Number:	PCT/EP98/08167
PCT Publication Date:	June 24, 1999	PCT Publication Number:	WO99/30693

International Family Members for US Patent 6,350,468

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	014126
Austria	254910
Australia	2413599
Australia	743090
Brazil	9812803
Canada	2315408