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Details for Patent: 5,723,147
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Summary for Patent: 5,723,147
| Title: | Multivesicular liposomes having a biologically active substance encapsulated therein in the presence of a hydrochloride | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Abstract: | Disclosed are multivesicular liposomes containing biologically active substances, the multivesicular liposomes having defined size distribution, adjustable average size, adjustable internal chamber size and number, and a modulated rate of the biologically active substance in contrast to the previous art. The process comprises dissolving a lipid component in volatile organic solvents, adding an immiscible aqueous component containing at least one biologically active substance to be encapsulated, and adding to either or both the organic solvents and the lipid component, a hydrochloride effective to control the release rate of the biologically active substance from the multivesicular liposome, making a water-in-oil emulsion from the two components, immersing the emulsion into a second aqueous component, dividing the emulsion into small solvent spherules which contain even smaller aqueous chambers, and then removing the solvents to give an aqueous suspension of multivesicular liposomes encapsulating biologically active substances. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inventor(s): | Sinil Kim, Stephen B. Howell | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Assignee: | Pacira Pharmaceuticals Inc | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Application Number: | US08/472,126 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Patent Claim Types: see list of patent claims | Use; Composition; Dosage form; | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Patent landscape, scope, and claims: | US Patent 5,723,147 covered a multivesicular liposome platform in which hydrohalide concentration was used to modulate drug release. Its broadest claims reached compositions containing a biologically active substance, amphipathic lipid, neutral lipid, and 10-500 mM hydrochloric acid or selected hydrochloride salts. The patent also claimed therapeutic methods and narrower formulations for cytarabine, morphine sulfate, hydromorphone, amikacin, methotrexate, and iohexol. The patent issued on March 3, 1998, and its 20-year statutory term expired in 2016, subject to any recorded patent-term adjustment. It therefore presents no current U.S. blocking right. Its historical importance is greater in the DepoFoam and DepoCyt patent families, where later or separate patents could have provided product-specific protection. US Drug Patent 5,723,147: Claim Scope, Expiration, and Multivesicular Liposome Patent LandscapeWhat does US Patent 5,723,147 protect?US 5,723,147 protects a release-controlled multivesicular liposome, or MVL, that contains a hydrohalide at a concentration of approximately 10 mM to 500 mM. The hydrohalide must be present in an amount sufficient to modulate release of the encapsulated active ingredient. The core claim requires four technical elements:
The patent is therefore a platform patent rather than a conventional compound patent. It does not claim cytarabine, morphine, amikacin, or another active ingredient in isolation. Infringement requires practice of the specified MVL architecture and hydrohalide-controlled formulation conditions. The claims are composition, method-of-treatment, and formulation-specific claims. They do not require a particular injection route, dose, particle size, lipid identity, encapsulation efficiency, or release profile unless those limitations are introduced through a dependent claim. How broad is claim 1 of US 5,723,147?Claim 1 is the principal composition claim and has four substantial limitations. First, the carrier must be a multivesicular liposome with multiple non-concentric chambers and membranes distributed in a matrix. This excludes ordinary unilamellar liposomes, simple multilamellar liposomes, polymeric microspheres, solid lipid particles, and non-liposomal depot systems. Second, the formulation must contain an amphipathic lipid and a neutral lipid lacking a hydrophilic head group. The claim is directed to a two-component lipid system, not merely any lipid nanoparticle. The neutral lipid limitation is important because many modern lipid nanoparticles use ionizable lipids, cholesterol, phospholipids, and polyethylene glycol lipids without necessarily satisfying the claimed structural description. Third, the formulation must contain one of the recited hydrohalides:
Fourth, the hydrohalide concentration must fall within approximately 10 mM to 500 mM and must be sufficient to modulate release. The concentration range alone is not the entire limitation. The formulation must also have the claimed release-modulating function. The active-ingredient list is unusually broad. It includes small molecules, nucleic acids, proteins, peptides, vaccines, hormones, radionuclides, pesticides, and herbicides. Claims 4 and 5 expressly extend the platform to pesticide and herbicide formulations, while claims 7 and 8 identify protein and hormone subcategories. What formulations are protected by US 5,723,147?The patent covers formulations in which hydrohalide concentration changes the release behavior of the encapsulated material. The specification and dependent claims distinguish between conditions that increase and decrease release rates. The most commercially relevant narrow formulations are:
Claims 13 and 14 create a concentration-dependent split for cytarabine. A cytarabine MVL containing 10 mM to less than approximately 70 mM hydrochloric acid is directed toward increased release, while a formulation containing approximately 70 mM to 500 mM is directed toward decreased release. The boundary at approximately 70 mM creates potential claim-construction and testing issues. A product near that boundary would require precise measurement of the encapsulation-phase concentration and analysis of whether the formulation produces the claimed release effect. How do claims 6 and 12 cover treatment methods?Claim 6 covers administering a biologically active substance encapsulated in an MVL when encapsulation occurred in the presence of one of the specified hydrohalides at 10-500 mM. Claim 12 narrows the active ingredient to cytarabine, morphine sulfate, hydromorphone, amikacin, or methotrexate. The method claims require more than administration of the active ingredient. They require:
Claims 3 and 10 add a therapeutic-effect limitation requiring a rate sufficient to ameliorate disease in a living mammal. These limitations may narrow infringement but can create evidentiary disputes because they depend on the clinical and pharmacokinetic behavior of the formulation. Claims 6 and 12 also contain drafting inconsistencies. Claim 6 refers to "a hydrochloride" while listing hydrochloric acid and hydrochloride salts. Claim 12 uses similar terminology. The terminology would likely be interpreted in the context of the specification and claim set rather than according to strict chemical nomenclature alone. When did US 5,723,147 lose exclusivity?US 5,723,147 lost its U.S. patent exclusivity in 2016. The patent issued March 3, 1998, under the post-1995 patent-term regime, which generally provides a term of 20 years from the earliest effective U.S. nonprovisional filing date under 35 U.S.C. § 154.
The patent is not a live U.S. exclusion right. Patent-term adjustment, if any, would be reflected in the USPTO record. No patent-term extension under the pharmaceutical regulatory extension statute should be assumed for this platform patent without a specific extension record. The expiration of US 5,723,147 does not eliminate later patents covering particular MVL products, manufacturing processes, lipid combinations, formulations, or drug-specific delivery systems. What is the Orange Book status of US 5,723,147?US 5,723,147 is a platform patent and is not inherently an Orange Book-listed patent. The FDA Orange Book lists patents associated with approved drug products when the NDA holder submits them and the listing meets the applicable statutory and regulatory categories. Platform patents may be listed for a drug product, but a patent number does not become an Orange Book patent merely because it concerns drug delivery. For a product such as liposomal cytarabine, Orange Book analysis must distinguish:
The relevant FDA regulatory pathway for a generic equivalent would depend on whether the reference product is treated as an eligible reference listed drug and whether the proposed product can demonstrate pharmaceutical equivalence, bioequivalence, and equivalent clinical performance. Complex liposomal products can require a more extensive analytical and clinical package than conventional immediate-release small-molecule products. FDA, “Approved Drug Products with Therapeutic Equivalence Evaluations.” [2] Which products are most closely associated with this patent?The most relevant commercial connection is the DepoFoam MVL technology and DepoCyt, a liposomal formulation of cytarabine. DepoCyt used multivesicular liposomes to provide sustained release of cytarabine after intrathecal administration. Its formulation and regulatory history are separate from the legal scope of US 5,723,147, but cytarabine is expressly identified in claims 9, 11, 12, 13, and 14.
The FDA approved DepoCyt in 1999 for intrathecal treatment of lymphomatous meningitis. The label described a sustained-release liposomal cytarabine product administered by the intrathecal route. [3] DepoCyt was later withdrawn from the U.S. market for commercial reasons, not because US 5,723,147 remained enforceable. How does US 5,723,147 compare with other multivesicular liposome patents?The patent landscape is divided into five groups. Core MVL architecture patentsThese patents claim the physical structure and preparation of multivesicular liposomes. They are potentially broader than drug-specific formulation patents because they may cover many active ingredients and release profiles. Hydrohalide release-modulation patentsUS 5,723,147 occupies this category. Its distinctive limitation is the use of hydrochloric acid or selected hydrochloride salts during encapsulation to alter release. Drug-specific MVL patentsSeparate patents may claim cytarabine, morphine sulfate, hydromorphone, amikacin, or other actives in an MVL. These patents can create barriers even after expiration of a broader platform patent. Manufacturing patentsMVL manufacturing may involve double-emulsion or multiple-emulsion processes, lipid deposition, solvent removal, aqueous-phase selection, and control of internal chamber composition. A later entrant could avoid US 5,723,147 yet infringe a process patent covering a particular manufacturing sequence. Commercial product patentsCommercial products may have patents directed to dosage, route of administration, treatment schedules, stability, vial composition, or a particular sustained-release profile. These patents are usually more relevant to launch timing than an expired platform patent. Known related patent numbers in the MVL and DepoFoam field include US 5,766,627 and US 5,932,241, which should be reviewed separately for filing dates, continuations, terminal disclaimers, and expiration status. Their relevance cannot be inferred solely from similar titles or shared inventorship. The USPTO patent file and complete family records control. [1] What patent litigation affects US 5,723,147?US 5,723,147 has no current enforcement value because its statutory term expired in 2016. Historical litigation or licensing involving DepoFoam, DepoCyt, or related MVL patents may still matter for:
A Paragraph IV challenge to US 5,723,147 itself is no longer commercially meaningful. Paragraph IV certifications are directed to listed patents associated with an approved drug and are used to challenge patents before expiration. An expired patent cannot ordinarily support a forward-looking launch injunction, although it can remain relevant to historical regulatory records and litigation databases. No current generic-entry risk should be assigned to this patent alone. Risk must be assessed against unexpired patents covering the reference product, formulation, method of use, or manufacturing process. How strong is the patent estate for a competing MVL product?The expired patent is technically broad but legally weak as a current barrier. Its strongest historical features were:
A competing product would face the greatest current risk from later, unexpired patents covering the specific lipid composition, particle architecture, manufacturing process, dosage regimen, or active ingredient. It would not face a live infringement risk from US 5,723,147 after expiration. What generic launch scenarios exist for liposomal cytarabine and similar products?A generic or follow-on entrant could pursue several pathways:
For complex liposomal products, the main barriers are usually formulation comparability, particle-size distribution, internal aqueous-phase characterization, release testing, sterility, stability, and clinical pharmacokinetics. Patent expiry reduces the legal barrier but does not remove the FDA development burden. Does US 5,723,147 create biosimilar risk?No conventional biosimilar pathway is implicated by this patent. The claims cover liposomal formulations of proteins, peptides, vaccines, cytokines, and other biologically active substances, but the patent is not a biologic composition-of-matter patent. A protein product using an MVL delivery system could face:
Those issues arise independently of the expired patent. The patent’s inclusion of interleukin-2, granulocyte colony-stimulating factor, hepatitis B antigen, GM-CSF, IGF-1, and alpha-interferon does not create current biosimilar exclusivity. Key Takeaways
FAQs About US Patent 5,723,147Is US 5,723,147 still enforceable?No. Its standard 20-year patent term ended in 2016, making it unavailable as a current U.S. exclusion right. Does the patent cover ordinary liposomes?No. The claims require a multivesicular liposome with multiple non-concentric chambers and membranes distributed in a matrix. Does the patent cover all liposomal cytarabine products?No. A cytarabine product must also satisfy the MVL structure, lipid requirements, hydrohalide conditions, and release-modulation limitations. Can a company launch a liposomal morphine product without reviewing this patent?Yes as to this expired patent, but later patents covering morphine formulation, manufacturing, dosage, administration, or release characteristics must be assessed. Was US 5,723,147 a composition-of-matter patent for cytarabine?No. It was a delivery-platform and formulation patent. Cytarabine was one of several active ingredients recited in narrower claims. References
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Drugs Protected by US Patent 5,723,147
| 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: 5,723,147
| Foriegn Application Priority Data | ||
| Foreign Country | Foreign Patent Number | Foreign Patent Date |
| United Kingdom | 8704171 | Feb 23, 1987 |
International Family Members for US Patent 5,723,147
| Country | Patent Number | Estimated Expiration | Supplementary Protection Certificate | SPC Country | SPC Expiration |
|---|---|---|---|---|---|
| Austria | 87823 | ⤷ Start Trial | |||
| Australia | 1205588 | ⤷ Start Trial | |||
| Australia | 602190 | ⤷ Start Trial | |||
| >Country | >Patent Number | >Estimated Expiration | >Supplementary Protection Certificate | >SPC Country | >SPC Expiration |
