Details for Patent: 5,965,156
Summary for Patent: 5,965,156
| Title: | Amphotericin B liposome preparation | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Abstract: | A novel composition and method for solubilizing amphiphilic drugs in a small amount of organic solvent for use in improved liposomes is disclosed. A phosphatidylglycerol is acidified in a small amount of organic solvent. The amphiphilic drug, such as Amphotericin B, suspended in organic solvent is then added to the acidified phosphatidylycerol and a soluble complex is formed between the phosphatidylglycerol and the amphiphilic drug. When the liposome composition incorporating the soluble complex is hydrated, the final pH of the hydrating aqueous buffer is carefully controlled. The Amphotericin B liposomes formed have markedly reduced toxicity. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inventor(s): | Richard T. Proffitt, Jill Adler-Moore, Su-Ming Chiang | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Assignee: | Nexstar Pharmaceuticals Inc | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Application Number: | US08/469,251 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Patent Claim Types: see list of patent claims | Use; Process; Dosage form; | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Patent landscape, scope, and claims: | United States Drug Patent 5,965,156: Scope, Claims, Expiration, and Amphotericin B Patent LandscapeU.S. Patent No. 5,965,156 protects a manufacturing process for solubilizing polyene antibiotics, especially amphotericin B, with phosphatidylglycerol in an acidified organic solvent. Its strongest protection is directed to the combination of four technical elements: an amphotericin-polyolipid soluble complex, an organic solvent maintained at pH 4.5 or below, removal of the solvent, and hydration into sub-2.0-micron liposomes. The patent does not broadly cover every liposomal amphotericin B product. It does not claim amphotericin B as a molecule, phosphatidylglycerol as a general excipient, or all liposomal formulations. The enforceable term of the patent has ended, eliminating current U.S. infringement exposure from the issued claims. What does U.S. Patent 5,965,156 cover?U.S. Patent 5,965,156, titled “Process for Solubilizing Polyene Antibiotics and Liposomes Containing Same,” covers processes and an intermediate soluble complex used to prepare liposomal polyene antibiotics. The claims focus on process conditions rather than a broad final-product composition.
The patent is relevant to lipid-based amphotericin B products, including the technology associated with liposomal amphotericin B products such as AmBisome. The patent itself does not establish that every AmBisome manufacturing step practices every issued claim. How are the 16 claims organized?The claims divide into four groups:
Claims 1-6: Solubilization processClaim 1 is the principal process claim. It requires:
Claim 2 narrows claim 1 to an organic solvent with a pH of approximately 1.0 to 3.0. Claim 3 limits the phosphatidylglycerol to:
Claim 4 limits the polyene antibiotic to amphotericin B. Claim 5 combines the species limitation in claim 3 with amphotericin B. Claim 6 further limits the lipid to DSPG. Claim 6 is therefore a narrow species claim covering amphotericin B solubilized with DSPG under the claimed acidic conditions. Claims 7-11: Liposome formationClaim 7 adds three manufacturing steps to the solubilization process:
This claim is narrower than claim 1 because it requires a specific solvent-removal and hydration sequence and imposes a particle-size limitation. Claims 8 and 9 repeat the acidic pH and specified phosphatidylglycerol limitations. Claims 10 and 11 add a sterol to the complex. Claims 14 and 15 specify cholesterol as the sterol. The practical infringement significance of claim 7 is substantial. A process that creates amphotericin-containing liposomes without forming and drying the claimed soluble complex, or that produces particles outside the claimed size range, would not satisfy every express limitation of claim 7. Claims 12-13: Soluble-complex intermediateClaim 12 is a product-by-process-style claim directed to:
Claim 13 requires the antibiotic concentration to exceed 25 mg per milliliter of solvent. The concentration threshold is important because it excludes lower-concentration complexes from claim 13, even if the other claim elements are present. Claim 12 remains broader than claim 13 because it does not require the greater-than-25-mg/mL concentration. Claim 16: Therapeutic-use claimClaim 16 covers a method for treating disseminated fungal infection by administering a therapeutically effective amount of liposomes prepared according to claim 7. The claim is dependent on the manufacturing limitations of claim 7. It therefore requires more than administration of any liposomal amphotericin B product. The administered liposome must have been prepared by the claimed acidified-solvent, drying, hydration, and sub-2.0-micron process. What process elements are required for infringement?A process must satisfy every limitation of an asserted claim. The key limitations are summarized below.
The most important claim-construction issues would have involved the meaning of “soluble complex,” “acidified organic solvent,” “maintaining,” and “liposomes having a diameter of less than 2.0 μm.” Those terms define the technical boundary between the claimed process and alternative amphotericin formulation routes. What patents protect liposomal amphotericin B?The relevant patent landscape has several layers: Active pharmaceutical ingredient patentsAmphotericin B is an established polyene antifungal. The molecule is long off patent. U.S. Patent 5,965,156 does not claim the amphotericin B molecule itself. Lipid-complex and liposome patentsThe central technology protected by Patent 5,965,156 is the use of phosphatidylglycerol and acidic organic-solvent conditions to produce a soluble amphotericin complex and then liposomes. The claims are process-centered and include specific lipid, pH, sterol, concentration, and particle-size limitations. Other patent families associated with liposomal amphotericin B may claim:
Those families must be analyzed separately. Patent 5,965,156 should not be treated as a proxy for the entire AmBisome patent estate. Formulation patentsThe patent’s formulation relevance is strongest where the product uses:
A formulation using a different phospholipid, a different solvent system, a different complexation route, or a different particle-size profile could avoid one or more limitations. That conclusion would depend on process records, not only on the final vial composition. Method-of-use patentsClaim 16 is a method-of-use claim for disseminated fungal infection. It is narrower than a general claim to antifungal treatment because it incorporates the preparation requirements of claim 7. The claim does not independently cover all clinical uses of amphotericin B liposomes. It is limited to administration of liposomes made by the specified process. When did U.S. Patent 5,965,156 lose exclusivity?Patent 5,965,156 is expired. Its 1999 grant date does not determine the full term. U.S. patent term is generally calculated from the earliest effective nonprovisional filing date for applications subject to the modern 20-year term rules, subject to patent-term adjustment, terminal disclaimers, and other statutory factors. The issued patent is no longer a current U.S. barrier to generic or alternative manufacturing. Any historical patent protection associated with the patent ended before 2026. The expiration of this patent does not automatically establish that every related patent in the liposomal amphotericin B field has expired. What is the Orange Book status of Patent 5,965,156?The FDA Orange Book is relevant to approved small-molecule drug products, including liposomal amphotericin B products marketed under NDA pathways. Patent listings can change over time through expiration, delisting, corrections, or regulatory updates. Patent 5,965,156 has historically been associated with the liposomal amphotericin B patent landscape. Because the patent is expired, it cannot presently block an ANDA applicant through a live patent term. The Orange Book listing, if retained as a historical record, does not revive an expired patent or extend its enforceability. FDA Orange Book patent listing also does not constitute a final determination of infringement or validity. (FDA, 2024a, 2024b) AmBisome is approved as liposomal amphotericin B injection. It is a chemically synthesized small-molecule drug product, not a biologic. A competing applicant would generally pursue an abbreviated new drug application under section 505(j), rather than a biosimilar application under section 351(k). Are biosimilar challenges relevant to this patent?No. Biosimilar law is not the relevant pathway for amphotericin B liposomal injection. Amphotericin B is a small-molecule active ingredient. A competitor would need to establish pharmaceutical equivalence and bioequivalence, together with compliance with applicable chemistry, manufacturing, and controls requirements. The principal regulatory risk is therefore a generic or hybrid drug application, not biosimilar substitution. The product remains technically difficult to copy because liposomal performance depends on lipid composition, drug loading, particle-size distribution, aggregation control, sterility, reconstitution behavior, and stability. Those barriers are regulatory and manufacturing barriers, not surviving rights under Patent 5,965,156. Which companies are challenging the patent?The expired status of Patent 5,965,156 means that a current Paragraph IV challenge is not required to clear this patent. A Paragraph IV certification is relevant when an applicant seeks approval before expiration of a listed patent and asserts that the patent is invalid, unenforceable, or will not be infringed. No current litigation consequence follows from a Paragraph IV challenge to an expired patent. Historical ANDA activity directed to liposomal amphotericin B would need to be assessed against the complete Orange Book listing and the status of other patents, not Patent 5,965,156 alone. The relevant commercial parties include:
A specific company’s launch risk cannot be determined from Patent 5,965,156 without reviewing its manufacturing process, product specifications, regulatory filing, and the remaining patent families. What generic entry risks remain?The patent presents no current U.S. term-based exclusion risk. Residual entry risks are operational and regulatory:
The strongest continuing barrier is likely manufacturing know-how rather than the expired claims. A competitor can avoid the patent by using a different process, but still face difficulties reproducing the reference product’s clinical and physicochemical profile. How strong was the patent estate?Patent 5,965,156 was technically focused but commercially meaningful during its term. Its strengths were:
Its weaknesses were equally clear:
The estate was stronger against a process that intentionally reproduced the claimed solvent-complex and hydration sequence than against a competitor using a distinct lipid assembly method. What licensing and settlement issues matter?Patent 5,965,156 is expired, so a license under this patent alone has no current U.S. exclusion value. Historical licenses or settlement agreements could still matter for:
No current royalty or settlement obligation can be inferred from the issued claims. Commercial due diligence should separate patent rights from technology-transfer rights and trade-secret restrictions. What is the geographic coverage?U.S. Patent 5,965,156 covers the United States only. Corresponding foreign applications or patents would require separate review. A U.S. expiration does not establish expiration in Europe, Japan, Canada, or other jurisdictions. For global launch planning, the relevant analysis must identify:
The U.S. patent cannot be used to block manufacture, sale, or importation outside the United States. Key Takeaways
FAQsCan a company make liposomal amphotericin B without infringing Patent 5,965,156?Yes, the patent is expired. During its term, a competing process would also need to avoid the specific claimed combination of phosphatidylglycerol, acidified organic solvent, soluble complex, solvent removal, hydration, and particle-size limitations where applicable. Does Patent 5,965,156 cover AmBisome as a product?It primarily covers processes and a soluble intermediate. It does not broadly claim every physical or commercial form of AmBisome. Product coverage depends on the complete patent estate and the specific manufacturing process. Does the patent cover cholesterol-containing amphotericin liposomes?Claims 10, 11, 14, and 15 address inclusion of a sterol, with claims 14 and 15 specifically identifying cholesterol. Those claims also depend on the underlying process limitations. Is a Paragraph IV certification needed for this expired patent?No current Paragraph IV challenge is needed to overcome an expired patent. A generic applicant must still address any other unexpired patents listed for the reference product. Can the same patent block liposomal amphotericin B sales outside the United States?No. U.S. Patent 5,965,156 has territorial effect in the United States only. Foreign patent families must be analyzed separately. References
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Drugs Protected by US Patent 5,965,156
| Applicant | Tradename | Generic Name | Dosage | NDA | Approval Date | TE | Type | RLD | RS | Patent No. | Patent Expiration | Product | Substance | Delist Req. | Patented / Exclusive Use | Submissiondate |
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| >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 5,965,156
| Country | Patent Number | Estimated Expiration | Supplementary Protection Certificate | SPC Country | SPC Expiration |
|---|---|---|---|---|---|
| Austria | 66598 | ⤷ Start Trial | |||
| Australia | 2416188 | ⤷ Start Trial | |||
| Australia | 598958 | ⤷ Start Trial | |||
| >Country | >Patent Number | >Estimated Expiration | >Supplementary Protection Certificate | >SPC Country | >SPC Expiration |
