Details for Patent: 5,378,474
Summary for Patent: 5,378,474
| Title: | Sustained release pharmaceutical composition | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Abstract: | The present invention relates to a pharmaceutical pellet composition having a core element including at least one highly soluble active ingredient and a core coating which is partially soluble at a highly acidic pH. The pharmaceutical composition provides a slow release of active ingredient at a highly acidic pH and provides a constant, relatively faster rate of release at a more alkaline pH such as that of the intestine. Oral administration of the pharmaceutical pellet composition of the present invention to a patient is effective to deliver to the blood levels of active ingredient within the therapeutic range and to maintain such levels over an extended period of time. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inventor(s): | Angelo M. Morella, Mark C. Fisher | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Assignee: | Alpharma Pharmaceuticals LLC | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Application Number: | US08/021,276 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Patent Claim Types: see list of patent claims | Composition; Formulation; Compound; Dosage form; | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Patent landscape, scope, and claims: | US Patent 5,378,474: Scope, Claims, Expiration, and Sustained-Release Morphine Patent LandscapeUS Patent 5,378,474 protects a multiparticulate sustained-release pellet platform combining three coating functions: an insoluble rate-controlling polymer, an enteric polymer, and an acid-soluble pore-forming or release-initiating compound. The claims cover high-solubility active ingredients generally and morphine salts specifically. The patent issued on January 3, 1995, and its ordinary pre-Uruguay Round patent term expired on January 3, 2012. The claims therefore no longer create an enforceable US exclusion right. The patent remains commercially relevant as prior art for sustained-release pellet, morphine, opioid, and pH-responsive coating technologies. It does not protect morphine itself, morphine sulfate as a molecule, or every extended-release morphine product. What does US Patent 5,378,474 protect?The patent claims a sustained-release pellet composition with a core and a multipart coating. The core contains a therapeutically effective amount of an active ingredient with aqueous solubility of at least 1 part in 30 parts of water. The coating must include:
The formulation must be capable of maintaining the active ingredient at a steady-state blood level of at least 75% of maximum for more than approximately four hours. The time to maximum concentration must be between approximately four and 30 hours. The invention is therefore defined by a combination of:
A formulation that uses only an insoluble polymer matrix, without the claimed enteric and acid-soluble components, would generally fall outside the literal scope of claim 1. How many independent claims does US 5,378,474 have?The patent has five independent claims: claims 1, 11, 18, and 20 appear as composition claims, while claim 5 is formally dependent on claim 1 but introduces a separate dissolution-profile limitation. The principal independent claim groups are:
Claims 2, 12, 19, and 21 narrow the time to maximum concentration to approximately four to 12 hours. Claims 3 and 4 narrow the active ingredient to specified therapeutic categories and opioid agonists. Claims 13 and 14 specifically address morphine sulfate and plasma-concentration fluctuations. Claims 7 through 10 and 15 through 17 narrow the polymer system, coating percentages, plasticizers, fillers, or particular ethylcellulose, PEG, and methacrylic copolymer combinations. What are the key limitations of claim 1?Claim 1 is broad in the identity of the active ingredient but narrow in formulation structure and performance. A potentially infringing product would need to satisfy all material limitations. Core limitationThe core must contain at least one therapeutically effective active ingredient having aqueous solubility of at least 1 in 30. The claim does not require morphine. Claim 3 lists broad therapeutic categories, including antihistamines, antibiotics, antihypertensives, nonsteroidal anti-inflammatory agents, opiate agonists, sedatives, and vitamins. The solubility limitation excludes poorly soluble compounds unless the claimed solubility test or interpretation supports inclusion. This limitation is important because many modern extended-release products use poorly soluble active ingredients and would not automatically fall within claim 1. Coating limitationThe coating must contain all three components:
The percentages are calculated against the combined weight of components (a), (b), and (c), not necessarily against the full coating weight when plasticizers and fillers are added. The claimed ranges are:
Because the claim uses functional language, the selected materials must also perform the stated release functions. Merely including a polymer from the listed class may not be sufficient if the formulation does not control release or produce the required pH response. Pharmacokinetic limitationThe formulation must maintain blood levels at or above 75% of maximum for more than approximately four hours, with maximum concentration reached between approximately four and 30 hours. This limitation creates potential enforcement complexity. It requires evidence from pharmacokinetic testing, dosing conditions, patient population, and interpretation of “steady state” and “maximum blood level.” A product could use similar polymers but avoid literal infringement if it fails the claimed pharmacokinetic profile. What additional protection do claims 18 and 20 provide?Claims 18 and 20 require at least 35% of the coating composition to be component (a), the insoluble matrix polymer. They also restrict component (a) to ethyl cellulose, quaternary ammonium acrylic or methacrylic polymers, acrylic or methacrylic ester copolymers, or mixtures of those materials. These claims are narrower than claim 1 but more technically concrete. They are directed to formulations in which the insoluble matrix polymer is a dominant coating constituent. Claim 20 applies the same structure to an acid-addition salt of morphine. It does not require morphine sulfate specifically, although claim 13 narrows the salt to morphine sulfate. Which claims are directed specifically to morphine?Claims 11 through 17 and 20 through 21 are morphine-focused.
Claim 17 is the most formulation-specific morphine claim. It requires a particular three-polymer balance:
A morphine pellet product that uses a different enteric polymer, a different plasticizer, or materially different proportions would require a separate infringement analysis. What is the patent’s legal status and expiration date?US Patent 5,378,474 issued on January 3, 1995. Because it belongs to the pre-Uruguay Round patent-term era, its ordinary term ran for 17 years from issue. The resulting expiration date was January 3, 2012, absent a term adjustment or other unusual term event. The patent is therefore expired and cannot presently support an injunction, damages claim for current conduct, or a new Paragraph IV challenge.
The expiration of the patent does not establish that every related family member expired on the same date. Foreign family members may have had different term calculations, maintenance requirements, supplementary protection rules, or national outcomes. US Patent 5,378,474 itself, however, is no longer enforceable. Source: United States Patent and Trademark Office, Patent No. 5,378,474. What is the Orange Book status of US 5,378,474?US Patent 5,378,474 is not an active Orange Book barrier. The patent claims a formulation platform and does not identify a current FDA-approved reference product in the claim language provided. Orange Book relevance depends on whether a patent is submitted by an approved drug sponsor for a specific product and listed against that product in FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations. A patent’s existence does not independently create Orange Book status. For a generic applicant, an expired patent would not ordinarily require a Paragraph IV certification as a basis for early market entry. The applicant would instead address any currently listed, unexpired patents for the relevant reference product. Sources: Food and Drug Administration, Approved Drug Products with Therapeutic Equivalence Evaluations; 21 U.S.C. § 355(j). Does US 5,378,474 create biosimilar risk?No. Biosimilar regulation applies to biological products under the Public Health Service Act. The patent claims a small-molecule oral pellet composition containing active pharmaceutical ingredients such as morphine salts. A biosimilar pathway is not relevant. The relevant competitive pathways are:
A generic applicant could still face other formulation, abuse-deterrence, manufacturing, or method-of-use patents even though US 5,378,474 is expired. How strong was the patent estate technically?The patent was technically stronger against formulations that closely reproduced its three-polymer architecture than against all sustained-release opioid products. StrengthsThe claims combine structural and functional limitations. This can make design-around analysis more difficult where a product uses:
The morphine claims also create a product-specific sub-portfolio, particularly claims 13, 17, and 20. WeaknessesThe patent has several limiting features:
The functional pharmacokinetic limitations could also create proof issues. Infringement would require reliable evidence that the accused product meets the specified release and blood-level profile under the relevant conditions. How does this patent compare with other extended-release morphine estates?US 5,378,474 should be viewed as an early multiparticulate coating patent, not as a complete extended-release morphine estate.
Relevant competing opioid products have historically included extended-release morphine products such as MS Contin, Kadian, Avinza, and other modified-release morphine formulations. Their patent positions depended on formulation, dosage form, labeling, abuse-deterrence technology, and product-specific Orange Book submissions rather than on this patent alone. What manufacturing and formulation barriers did the patent create?The claims require more than mixing three excipients. A commercial product would need to control:
Ethylcellulose and acrylic or methacrylic polymers can produce different permeability, film strength, and pH responses depending on molecular weight, substitution, particle size, plasticizer, curing temperature, and coating process. Those variables may affect whether a formulation satisfies the functional language even when it uses a named polymer. The patent also lists fillers and plasticizers. Claims 9 and 10 permit up to 50% plasticizer and up to 75% filler based on total coating weight, with narrower ranges in claim 10. These provisions expand the formulation space but do not eliminate the need to satisfy the core three-component structure. What generic launch risks exist today?US 5,378,474 presents no current US launch block because it expired in 2012. A generic or 505(b)(2) applicant would instead evaluate:
A product that copied the disclosed technology could still encounter commercial or regulatory risk, but not an enforceable infringement claim based solely on US 5,378,474. What litigation or settlement issues affect the patent?The supplied record identifies no current litigation or settlement that could preserve enforceability after expiration. Any historical litigation, licensing arrangement, or settlement involving a related morphine product would need to be analyzed separately from the patent’s present legal status. An expired patent cannot support a new Paragraph IV litigation strategy. Historical settlements may still matter for commercial history, but they do not extend the statutory term of the patent. What is the geographic coverage of the patent family?US 5,378,474 provides protection only in the United States. Any corresponding foreign applications or granted patents would require separate review. Foreign rights may have expired on different dates and may have been narrowed, abandoned, opposed, or revoked. For current freedom-to-operate work, the relevant geographic questions are:
The US patent itself cannot block manufacturing, sale, or importation in another country after expiration. Key Takeaways
FAQs About US Patent 5,378,474Does US 5,378,474 cover all extended-release morphine products?No. It covers specific pellet compositions containing a morphine salt and a coating with the claimed insoluble, enteric, and acid-soluble components, together with defined release-performance limitations. Is morphine sulfate itself patented by US 5,378,474?No. Claim 13 identifies morphine sulfate as an active ingredient in a claimed sustained-release pellet formulation. It does not claim morphine sulfate as a chemical compound. Can a generic manufacturer launch a morphine pellet product without challenging this patent?Yes, because the patent expired on January 3, 2012. The manufacturer must still evaluate active patents covering the selected reference product and formulation. Does using ethylcellulose alone create infringement risk under this patent?Not ordinarily. The claims require additional enteric and acid-soluble coating components, as well as the claimed dosage-form and release characteristics. Could a tablet infringe US 5,378,474?The claims expressly require a pellet composition with a core element and coating. A conventional matrix tablet would generally not satisfy the pellet limitation, although the full product and claim construction would control any specific analysis. References
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Drugs Protected by US Patent 5,378,474
| 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 |
Foreign Priority and PCT Information for Patent: 5,378,474
| Foriegn Application Priority Data | ||
| Foreign Country | Foreign Patent Number | Foreign Patent Date |
| Australia | PJ2192 | Jan 06, 1989 |
International Family Members for US Patent 5,378,474
| Country | Patent Number | Estimated Expiration | Supplementary Protection Certificate | SPC Country | SPC Expiration |
|---|---|---|---|---|---|
| Austria | 133862 | ⤷ Start Trial | |||
| Austria | 167629 | ⤷ Start Trial | |||
| Australia | 4773290 | ⤷ Start Trial | |||
| Australia | 617573 | ⤷ Start Trial | |||
| Canada | 2007181 | ⤷ Start Trial | |||
| Germany | 69025208 | ⤷ Start Trial | |||
| Germany | 69032445 | ⤷ Start Trial | |||
| >Country | >Patent Number | >Estimated Expiration | >Supplementary Protection Certificate | >SPC Country | >SPC Expiration |
