Details for Patent: 5,874,104
Summary for Patent: 5,874,104
| Title: | Treatment of systemic fungal infections with phospholipid particles encapsulating polyene antibiotics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Abstract: | Formulations consisting of phospholipid small unilamellar particles encapsulating polyene antifungal antibiotics and methods for using such compositions to treat systemic fungal infections are described. In a preferred embodiment, the particles are in the form of vesicles which comprise a polyene antifungal antibiotic, preferably amphotericin B and/or nystatin, egg phosphatidylcholine and cholesterol, preferably in the molar ratio of about 0.2 (AMB):2(PL):1(CHOL). These vesicles may also have an amine modified surface. The vesicles are suspended in a low isonic strength saccharide/tris solution at a pH of from about 6.0 to about 8.0 and may be administered to deliver the antifungal antibiotic to treat systemic fungal infections. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inventor(s): | Jill Adler-Moore, Ronald C. Gamble, Richard T. Proffitt | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Assignee: | Nexstar Pharmaceuticals Inc | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Application Number: | US08/467,864 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Patent Claim Types: see list of patent claims | Use; Composition; | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Patent landscape, scope, and claims: | US Patent 5,874,104: Scope, Claims, Expiration, and Amphotericin B Patent LandscapeUS Patent 5,874,104 protects a liposomal injectable formulation of a polyene antifungal, principally amphotericin B, characterized by small unilamellar vesicles, phospholipid-cholesterol composition, low-ionic-strength saccharide hydration media, high drug encapsulation, storage stability, and reduced acute intravenous toxicity. The patent is associated with the formulation technology used for AmBisome, Gilead Sciences’ liposomal amphotericin B product. The patent’s enforceable US term has expired. Its commercial importance now lies in defining the technical architecture of liposomal amphotericin B and in assessing whether a competing product would have historically practiced the patent or could still implicate related, later-expiring formulation, manufacturing, or regulatory rights. What does US Patent 5,874,104 cover?US 5,874,104, titled "Liposomal Formulations of Polyene Antibiotics," covers injectable liposomal formulations and methods for treating systemic fungal infections. The core claim requires the simultaneous presence of several features:
The claim is cumulative. A formulation that satisfies only the lipid composition and drug encapsulation requirements does not necessarily fall within claim 1 if it lacks the specified vesicle size, saccharide-based low-ionic-strength aqueous phase, stability characteristic, or toxicity threshold. The use of "comprising" makes the claim open-ended. Additional excipients, buffers, lipid components, or processing aids may be present, provided the claimed elements remain in the product. How strong is the independent composition claim?Claim 1 is technically detailed but legally narrow. Its strength depends on whether the accused product satisfies each limitation, especially the functional and analytical limitations. Claim 1 limitation analysisSmall unilamellar vesiclesThe vesicles must be "small unilamellar vesicles" with a diameter below 2,000 Å. The size threshold corresponds to approximately 200 nanometers. Multilamellar liposomes, nonvesicular lipid complexes, colloidal dispersions, and substantially larger vesicles are outside the literal scope of this limitation. This distinction separates the claimed technology from several amphotericin B products:
Particle-size testing, cryo-electron microscopy, dynamic light scattering, and vesicle morphology data would be material to infringement analysis. Polyene loading of about 4 to 12 mole percentThe drug must be present at approximately 4 to 12 mole percent. Claim 5 expands the formulation definition with a broader component ratio:
The word "about" introduces ordinary claim-construction flexibility, but the claim does not cover every amphotericin-to-lipid ratio. A formulation materially below or above the claimed loading range would have a substantial noninfringement position, subject to equivalents analysis. Low ionic strength and saccharide phaseClaim 1 requires hydration in a low-ionic-strength aqueous phase composed of a mono- or disaccharide. Claim 6 narrows ionic strength to less than 20 mM. Claims 7 through 9 further specify:
A formulation using a materially higher ionic-strength buffer or a non-saccharide hydration medium may avoid the narrower claims. Claim 1 itself remains broader than claims 6 through 9 because it does not expressly state the less-than-20 mM threshold, exact pH, Tris buffer, or listed saccharides. Acute toxicity limitationClaim 1 requires a mouse intravenous LD50 greater than approximately 21.2 mg/kg of polyene antibiotic. This is a functional product limitation, not merely a statement of intended use. The patent therefore links claim scope to a comparative safety result. That limitation creates both strength and vulnerability:
What do the dependent claims add?The dependent claims create several distinct protection clusters.
Claims 18 through 23 are particularly important because they move from a broad liposome concept toward a recognizable amphotericin B formulation. Claim 22 specifies a molar ratio of approximately:
Claim 23 adds hydration in buffered 9% sucrose. These limitations closely track the formulation profile disclosed for liposomal amphotericin B products. What formulations are protected by US 5,874,104?The strongest formulation position is the combination of:
The most commercially relevant specific embodiment is the amphotericin B, distearoylphosphatidylglycerol, soy phosphatidylcholine, and cholesterol formulation in claim 22, hydrated with buffered 9% sucrose under claim 23. The patent does not require every one of these elements in claim 1. Claims 22 and 23 are narrower and require the specific ratio and hydration medium. Does the patent cover AmBisome?AmBisome is a liposomal amphotericin B product approved by the FDA under NDA 050740. The FDA label describes amphotericin B encapsulated in liposomes composed principally of hydrogenated soy phosphatidylcholine, cholesterol, and distearoylphosphatidylglycerol, with a 9% sucrose-containing formulation system.[2] That formulation is technically aligned with the subject matter of claims 19, 21, 22, and 23. The patent’s disclosure and claim structure are consistent with the liposome platform used for AmBisome. A definitive historical infringement conclusion would require the actual product specifications, manufacturing records, claim construction, and litigation positions, but the overlap is direct at the formulation-architecture level. When did US Patent 5,874,104 expire?The patent issued on March 2, 1999. Its US application traces to a November 1994 filing and an earlier November 1993 priority date. Under the modern patent-term framework, the relevant term is generally 20 years from the earliest effective nonprovisional filing date, not 20 years from issuance.[3]
The patent is therefore no longer an active US exclusion right. Any patent-term adjustment or extension would need to appear in the official USPTO record. Public patent records identify the patent as expired by term.[1] What is the Orange Book status of the patent?AmBisome was approved as NDA 050740. Orange Book listing analysis must distinguish between:
US 5,874,104 has reached the end of its patent term. It cannot now block a new ANDA solely through an unexpired patent right. Historical Orange Book listing, if applicable, would have affected earlier ANDA certification obligations but does not restore an expired patent. FDA approval of AmBisome does not itself create continuing market exclusivity. Drug exclusivity periods run separately from patent rights and are generally much shorter than the life of a formulation patent.[4] Were there Paragraph IV challenges or patent litigation?A Paragraph IV certification would have been relevant to an ANDA applicant asserting that a listed AmBisome patent was invalid, unenforceable, or not infringed. The expiration of US 5,874,104 removes the current patent-term barrier, but it does not establish that no historical Paragraph IV notice or litigation occurred. The public-facing risk assessment for this patent is:
Any historical patent litigation must be separated from current freedom to operate. A settlement involving an earlier generic applicant could have delayed launch without extending the patent term for all market participants. How does this patent compare with competing amphotericin B products?
The patent is not a broad monopoly over amphotericin B. It is a formulation patent directed to a particular delivery system. A non-liposomal amphotericin B product would not ordinarily practice the core vesicle claims. What generic entry risks exist for liposomal amphotericin B?The principal barrier to generic entry is regulatory and technical complexity rather than the expired patent. ANDA and formulation samenessA generic liposomal amphotericin B applicant must address more than active-ingredient identity. Relevant comparability attributes include:
FDA guidance recognizes that liposome drug products require product-specific characterization beyond conventional small-molecule dissolution testing.[5] Manufacturing and process barriersClaim 12 identifies a process using:
Even after patent expiration, manufacturing can remain difficult because the product’s clinical performance may depend on tightly controlled lipid hydration, solvent removal, particle-size reduction, aseptic processing, lyophilization, and reconstitution. The expired process claim does not prevent use of the process today. It does, however, identify the critical unit operations that a generic developer must replicate or replace while preserving product comparability. Is there biosimilar risk?No conventional biosimilar pathway applies. Amphotericin B is a small-molecule antifungal, not a biologic subject to the Public Health Service Act biosimilar framework. The relevant competitive pathway is an ANDA or, depending on the proposed differences, a 505(b)(2) application.[6] The product may still present complex-drug regulatory risk because a liposome is a structured drug-delivery system. That complexity does not convert AmBisome into a biologic. What geographic coverage does the patent provide?US 5,874,104 provides US rights only. Foreign protection depends on separately granted national or regional counterpart patents. A US expiration does not establish that corresponding patents in Europe, Japan, Canada, or other markets expired on the same date. The commercial patent review should therefore distinguish:
The US patent cannot be used to block a product manufactured, sold, or imported solely outside the United States. How strong is the patent estate for liposomal amphotericin B?The estate represented by US 5,874,104 was strong during its term against products that copied the complete liposomal architecture. Its main strengths were the combination of structural and functional limitations, the specific phospholipid-cholesterol system, the high encapsulation requirement, and the low-toxicity performance characteristic. Its limitations were equally clear:
The current commercial value is therefore historical and analytical, not exclusionary. What licensing and ownership issues matter?AmBisome was developed through the liposomal drug-delivery platform associated with Vestar and NeXstar and was later commercialized by Gilead Sciences. Gilead acquired NeXstar in 1999, after the patent issued.[7] Ownership history matters for:
Patent ownership does not necessarily establish ownership of all manufacturing know-how or regulatory data. A competitor may face practical barriers from proprietary process knowledge even where the patent itself has expired. Key Takeaways
FAQsCan a generic amphotericin B product infringe US 5,874,104?A conventional amphotericin B deoxycholate injection would not ordinarily satisfy the core liposome limitations. A liposomal product could historically have raised infringement issues if it met the vesicle, lipid, loading, aqueous-phase, stability, and toxicity limitations. The patent is now expired. Does claim 22 cover every product containing amphotericin B, cholesterol, and phosphatidylglycerol?No. Claim 22 requires the specified component combination and approximately 0.4:0.8:2.0:1.0 molar ratio. It is materially narrower than a general amphotericin B composition claim. Is a lipid-complex amphotericin B product covered by the patent?Not automatically. The patent requires small unilamellar vesicles. A lipid complex with a different particle structure, morphology, or drug-association mechanism may fall outside the literal claim scope. Can an applicant use a different buffer to avoid the patent?A different buffer may avoid narrower claims requiring Tris or particular pH and ionic-strength conditions. It would not necessarily avoid claim 1 if the alternative formulation still satisfies claim 1’s broader limitations. Does patent expiration eliminate all barriers to an AmBisome generic?No. It removes the exclusionary effect of this patent. FDA comparability, liposome characterization, manufacturing control, stability, clinical bridging, and commercial scale-up remain significant development requirements. References
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Drugs Protected by US Patent 5,874,104
| 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 5,874,104
| Country | Patent Number | Estimated Expiration | Supplementary Protection Certificate | SPC Country | SPC Expiration |
|---|---|---|---|---|---|
| Austria | 66597 | ⤷ Start Trial | |||
| Australia | 606880 | ⤷ Start Trial | |||
| Australia | 7716087 | ⤷ Start Trial | |||
| Canada | 1292184 | ⤷ Start Trial | |||
| Germany | 3772498 | ⤷ Start Trial | |||
| Denmark | 168982 | ⤷ Start Trial | |||
| Denmark | 434187 | ⤷ Start Trial | |||
| >Country | >Patent Number | >Estimated Expiration | >Supplementary Protection Certificate | >SPC Country | >SPC Expiration |
