Details for Patent: 6,645,988
Summary for Patent: 6,645,988
| Title: | Substituted benzimidazole dosage forms and method of using same | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Abstract: | The present invention relates to pharmaceutical preparations comprising substituted benzimidazole proton pump inhibitors. There is provided a liquid or solid pharmaceutical dosage form that is not enteric coated or delayed released containing a proton pump inhibitor and a Primary Essential Buffer. When the dosage form is placed in a liquid phase the Primary Essential Buffer maintains the pH of the environment at a value greater than the pKa of the proton pump inhibitor for a time sufficient to substantially avoid acid degradation of the proton pump inhibitor in the environment. Also provided is a method for treating acid-related gastrointestinal disorders by administering a solid pharmaceutical dosage form; and a kit for the preparation of a liquid oral pharmaceutical composition. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inventor(s): | Jeffrey O. Phillips | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Assignee: | University of Missouri Columbia | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Application Number: | US09/901,942 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Patent Claim Types: see list of patent claims | Use; Composition; Dosage form; | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Patent landscape, scope, and claims: | United States Drug Patent 6,645,988: Claims, Scope, Expiration, Litigation, and Patent LandscapeUS Patent 6,645,988 protected non-enteric-coated oral dosage forms combining a proton pump inhibitor with a substantial buffering system. The patent covered omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole and several less-commercialized PPIs, including specified solid dosage forms, layered tablets, gastric-pH control methods and manufacturing processes. The patent issued on November 11, 2003, from an application claiming priority to May 17, 1999. Its standard 20-year patent term expired in 2020, subject to any applicable patent-term adjustment or extension. The patent is no longer a blocking patent for current generic development. Its commercial importance was historically tied to Zegerid, the omeprazole/sodium bicarbonate product developed by Santarus. What does US Patent 6,645,988 protect?The patent protects a formulation architecture that replaces enteric coating with an alkaline buffering system. The buffer raises gastric pH and protects the acid-labile PPI after administration. The central limitations are:
The claims do not cover every PPI formulation. A potentially infringing product would generally need to satisfy the specified PPI identity, dose, buffer-equivalent range, non-enteric-coated configuration and dosage-form limitations. How broad are the independent claims?Claims 1, 24, 25 and 29 are the principal scope-defining claims. Claim 1: non-enteric-coated buffered dosage formClaim 1 requires:
The use of "consisting essentially of" narrows the active-ingredient definition. The phrase generally permits additional ingredients that do not materially affect the basic and novel characteristics of the formulation, while excluding additional active ingredients that materially change the claimed composition. The claim is broad across the listed PPIs but narrower than a generic claim to any acid-labile drug combined with an alkaline excipient. Claim 24: outer-layer and inner-core architectureClaim 24 covers a two-region solid dosage form:
This claim is directed to spatial distribution of the buffer rather than merely the presence of buffer in the overall tablet. A product using a buffered outer layer and PPI-containing core could face claim 24 analysis even if its formulation differs from a simple physical blend. Claim 25: gastric-pH methodClaim 25 covers administering the claim 1 dosage form in an amount effective to raise gastric-fluid pH to at least 3.7 from the time the PPI contacts gastric fluid throughout stomach dwell time. Claims 26 to 28 increase the pH threshold to at least 4.6, 4.8 and 5.6. These are functional method claims. In an infringement dispute, gastric-pH performance, formulation behavior and the relevant dwell-time evidence would be central. Claim 29: blending and formulation processClaim 29 independently recites the non-enteric-coated formulation and adds a manufacturing sequence:
Claim 29 is broader in dosage-form coverage than claim 1 because it expressly includes capsules, pellets and granules. It is also operationally important because a product may be evaluated under both product-composition and process theories. Which PPIs and buffers are covered?PPI coverageThe patent’s Markush group includes:
The claims also extend to an enantiomer, isomer, free base or salt of the listed compound. That language creates broader chemical coverage than a claim limited to one named salt or stereoisomer, although claim construction would depend on the particular molecular form and prosecution history. Primary Essential BuffersClaim 10 lists the principal buffer class. It includes:
Claim 11 narrows the buffer to sodium bicarbonate. Claims 12 and 13 specify sodium bicarbonate quantities of approximately 400 mg to 4,000 mg and at least approximately 800 mg. Claim 14 narrows the buffer to calcium carbonate. Claims 15 to 17 specify calcium carbonate quantities ranging from approximately 400 mg to 4,000 mg, approximately 500 mg to 1,000 mg, or at least approximately 700 mg. Claim 23 covers a combination of sodium bicarbonate and calcium carbonate. Secondary Essential BuffersClaim 18 lists:
The claim structure permits a Primary Essential Buffer alone or a Primary Essential Buffer combined with a Secondary Essential Buffer. The total buffer-equivalent amount, rather than only the mass of buffer, is a key limitation. What formulation types are protected?The patent reaches several non-enteric-coated dosage technologies. Suspension and chewable tabletsThese dosage forms are designed to be dispersed or chewed before swallowing. The formulation must still deliver the specified PPI and buffer relationship. A product marketed as a chewable or suspension tablet can fall within claim 1 if the quantitative and chemical limitations are met. Two-part tablets and capsulesThe two-part architecture can separate the PPI from part of the buffer or distribute the buffer between an outer component and an inner core. Claim 24 is particularly relevant to layered or core-shell products. Effervescent productsEffervescent powders and tablets are expressly listed in claim 1. Carbonate and bicarbonate systems may provide both acid neutralization and effervescence, but the product must satisfy the claimed buffer-equivalent range. Flavoring and excipient systemsClaims 19 and 20 cover flavoring agents, including fruit, caramel, chocolate, root beer, coffee, mint, licorice and related flavors. Claim 21 covers anti-foaming agents. Claim 22 lists conventional excipients such as binders, diluents, lubricants, disintegrants, colorants, antioxidants, chelating agents, anti-caking agents, moistening agents, preservatives and coatings. These dependent claims generally add formulation detail. They do not independently rescue a product that fails the core PPI, buffer, dosage-form or non-enteric-coating limitations. What was the commercial product associated with the patent?The principal commercial product was Zegerid, an immediate-release omeprazole and sodium bicarbonate product. The product used sodium bicarbonate to create an alkaline gastric environment and avoid reliance on an enteric-coated PPI pellet system. The FDA approved prescription Zegerid capsules and powder-for-suspension products under NDA 21-302 on September 9, 2004. The product was associated with Santarus, which later became part of the Salix and Valeant, now Bausch Health, corporate history. FDA labeling identifies omeprazole and sodium bicarbonate as the active ingredients and describes the product as an immediate-release formulation rather than a conventional enteric-coated omeprazole product (FDA, 2004; DailyMed, 2024). The patent’s claims are broader than the commercial Zegerid presentation because they cover several PPIs, multiple buffers and multiple solid dosage forms. When did US Patent 6,645,988 expire?The patent’s ordinary term ran approximately 20 years from the earliest effective nonprovisional filing date. Based on the May 17, 1999 priority date and the patent’s prosecution history, the expected expiration was in 2020.
The issue date did not create a 17-year post-issuance term because the application was filed after the 1995 transition to the 20-year-from-filing patent term system. The patent therefore could not remain enforceable merely because it issued in 2003. What was the Orange Book status of US Patent 6,645,988?US Patent 6,645,988 was historically relevant to the Orange Book listing for prescription Zegerid. Orange Book listings identify patents submitted by the NDA holder and do not independently determine infringement, validity or current enforceability. The principal regulatory implications were:
FDA Orange Book records should be read together with the patent register and the patent’s official USPTO status. An Orange Book listing is not a substitute for a current patent-term determination (FDA, 2024; USPTO, 2024). Which companies challenged the patent?The leading reported challenge involved Par Pharmaceutical. Santarus v. Par PharmaceuticalSantarus asserted US Patent 6,645,988 and related US Patent 6,780,882 against Par in Hatch-Waxman litigation involving an ANDA for an omeprazole/sodium bicarbonate product. The dispute examined obviousness, written description, enablement and infringement issues relating to buffered PPI formulations. The Federal Circuit decision in Santarus, Inc. v. Par Pharmaceutical, Inc., 694 F.3d 1344 (Fed. Cir. 2012), upheld the district court’s treatment of the asserted claims and addressed the patentability of the buffered PPI formulation technology. The case is significant because it confirmed that the combination of a PPI with a sufficient alkaline buffer could support patent protection despite earlier PPI products and conventional antacid technologies. The litigation did not extend the patent term. Any settlement or launch restriction ultimately remained bounded by the patent’s statutory expiration and the terms of the parties’ agreement. How strong was the patent estate?The patent estate was commercially meaningful but structurally concentrated.
The main vulnerability was that the claims required a defined relationship between PPI quantity and buffer capacity. A competing product using a different PPI, a different buffer system, a materially different buffer-equivalent ratio or an enteric-coated delivery system could avoid at least some claims. How does this patent compare with other PPI patent strategies?Buffered immediate-release strategyUS 6,645,988 focuses on gastric pH control through alkaline buffering. Its commercial advantage was avoidance of an enteric-coated PPI delivery system. Enteric-coated PPI strategyMany conventional omeprazole, lansoprazole, pantoprazole and rabeprazole products use enteric-coated pellets, granules or tablets. Those patents typically focus on:
An enteric-coated product ordinarily does not satisfy the express non-enteric-coated limitation in claims 1, 24 and 29, although other patents may apply. Combination-product strategyA product combining a PPI with an analgesic, prokinetic agent or other active ingredient could raise issues under "consisting essentially of" language. The analysis would turn on whether the additional active ingredient materially changes the claimed formulation and whether the product still satisfies the other limitations. What generic entry risks existed?Before expiration, generic developers faced four principal risks:
After expiration, the patent-specific risk became negligible. Current generic products must still satisfy FDA quality, bioequivalence, labeling and manufacturing requirements, but US 6,645,988 no longer prevents approval or launch. What biosimilar risk applies?No biosimilar pathway applies. Omeprazole and sodium bicarbonate are small-molecule active ingredients regulated through the ANDA pathway under section 505(j) of the Federal Food, Drug, and Cosmetic Act. The relevant competitive products are generics, not biosimilars under section 351(k) of the Public Health Service Act. The commercial barriers are therefore formulation development, bioequivalence, stability, manufacturing scale, supply reliability and regulatory approval rather than biologic similarity or interchangeability. What manufacturing and geographic barriers remain?The patent was a US patent. Its expiration removed the US patent barrier, but corresponding foreign family members would have required separate review in each jurisdiction. Patent expiration in the United States does not automatically establish freedom to operate in Europe, Canada, Japan, China or other markets. Current manufacturing barriers are primarily technical:
These barriers can affect launch timing and cost without creating patent exclusivity. Key Takeaways
FAQs About US Patent 6,645,988Does US 6,645,988 cover Zegerid?Yes. Zegerid’s immediate-release omeprazole/sodium bicarbonate formulation was within the commercial field addressed by the patent, although the patent’s claim language extends beyond the marketed product. Can a generic omeprazole product infringe this patent today?US 6,645,988 is expired, so it cannot currently be asserted to block a US generic launch. A generic product may still implicate other unexpired patents or regulatory exclusivities. Does an enteric-coated omeprazole tablet infringe claim 1?Ordinarily, the express "not enteric-coated" limitation would make an enteric-coated product outside claim 1. The product would require separate analysis under other claims, patents or claim-construction positions. Why was sodium bicarbonate important to the claimed invention?Sodium bicarbonate supplied alkaline buffering capacity, neutralized gastric acid and raised gastric pH when the PPI contacted gastric fluid. The claims quantify the required buffer relationship in milliequivalents per milligram of PPI. Are the listed flavors independently patent-protected?No. Claims 19 and 20 make flavors dependent formulation limitations. They do not create a separate patent right after expiration and do not independently protect the listed flavors as such. References
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Drugs Protected by US Patent 6,645,988
| Applicant | Tradename | Generic Name | Dosage | NDA | Approval Date | TE | Type | RLD | RS | Patent No. | Patent Expiration | Product | Substance | Delist Req. | Patented / Exclusive Use | Submissiondate |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| >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 6,645,988
| Country | Patent Number | Estimated Expiration | Supplementary Protection Certificate | SPC Country | SPC Expiration |
|---|---|---|---|---|---|
| Argentina | 038157 | ⤷ Start Trial | |||
| Austria | 340574 | ⤷ Start Trial | |||
| Australia | 1907100 | ⤷ Start Trial | |||
| Australia | 2002330863 | ⤷ Start Trial | |||
| Australia | 2003214858 | ⤷ Start Trial | |||
| Australia | 2005229686 | ⤷ Start Trial | |||
| Australia | 3276701 | ⤷ Start Trial | |||
| >Country | >Patent Number | >Estimated Expiration | >Supplementary Protection Certificate | >SPC Country | >SPC Expiration |
