US Patent 5,585,112: Scope, Claims, Expiration, and Gas-Filled Liposome Patent Landscape

US Patent 5,585,112 covers fluorine-containing gas-filled liposomes made by shaking lipids in an aqueous medium below the lipid’s gel-to-liquid-crystalline phase-transition temperature. The claims require a temperature-activated gaseous precursor, a fluorine-containing gas, and liposomes containing at least approximately 90% gas by internal volume. The patent is expired and does not present a current US enforcement barrier.

What does US Patent 5,585,112 protect?

US Patent 5,585,112, titled “Gaseous precursor-filled liposomes,” protects a combination of composition and manufacturing limitations rather than a pharmaceutical active ingredient.

The central claim concept is:

A lipid-containing aqueous suspension is prepared.
The suspension is shaken in the presence of a temperature-activated gaseous precursor.
Shaking occurs below the lipid’s gel-to-liquid-crystalline phase-transition temperature.
The precursor is fluorine-containing.
The resulting liposomes contain at least approximately 90% gas internally after activation.

The patent therefore targets gas-filled liposomes produced through a low-temperature, gel-state shaking process. It is directed primarily to ultrasound contrast-agent technology, although claim 20 also reaches nebulizer use and lung targeting.

Core technical limitations

Limitation	Claims affected	Scope
Lipid added to aqueous solution or suspension	1, 2	Required
Shaking-based gas instillation	1, 2	Required
Temperature below gel-to-liquid-crystalline transition	1, 2	Required
Temperature-activated gaseous precursor	1, 2	Required
Fluorine-containing gas	1, 2	Required
At least approximately 90% internal gas volume	1, 2	Required
Specific lipid classes	3, 21	Narrower dependent claims
Polymer-bearing lipid	4-9	Narrower dependent claims
Polymer content of approximately 1-20 mol%	10	Narrower dependent claim
Defined fluorinated gas lists	11-19	Narrower dependent claims
Nebulizer and lung targeting	20	Narrower use limitation

The broadest practical protection is in claims 1 and 2. Claim 1 is framed around “gaseous precursor-filled liposomes prepared by” the process. Claim 2 is framed around “gas-filled liposomes” that are prepared by the same process.

How should claims 1 and 2 be interpreted?

Claims 1 and 2 are product-by-process claims with overlapping technical scope.

Claim 1

Claim 1 requires gaseous precursor-filled liposomes made by the specified gel-state shaking process. It also requires use of a fluorine-containing precursor selected from:

Perfluorocarbons
Fluorohydrocarbons
Sulfur hexafluoride

The claim requires that activation produce liposomes with at least approximately 90% gas by volume inside the liposome.

The phrase “for use with a nebulizer” does not appear until claim 20, so nebulizer use is not required for claim 1.

Claim 2

Claim 2 covers gas-filled liposomes comprising a lipid and a fluorine-containing gas. It incorporates the same process limitations as claim 1.

Claim 2 is potentially broader in product terminology because it refers to “gas-filled liposomes,” but it remains limited by the recited preparation method. A product made by a different process may not fall within the literal scope of claim 2, even if it has a similar lipid shell, fluorinated gas, and internal gas volume.

Product-by-process significance

The process language is material. A competing product may be structurally similar but outside the literal claim scope if it is made by:

Mechanical agitation above the phase-transition temperature
Sonication
Extrusion
Microfluidic formation
Pressure-driven gas loading
Spray drying or lyophilization followed by reconstitution
A process that does not use a temperature-activated precursor
A process using a nonfluorinated gas

The enforceability of a product-by-process claim generally turns on whether the claimed product characteristics are distinguishable and whether the accused product was made by the claimed process. The patent’s expiration makes that distinction commercially relevant only for historical analysis or foreign jurisdictions with different term dates.

What fluorinated gases are covered by US 5,585,112?

Claims 11 through 19 define progressively narrower fluorinated-gas groups.

The broad gas categories in claims 1 and 2 include perfluorocarbons, fluorohydrocarbons, and sulfur hexafluoride. Claim 11 contains a very large Markush list, including perfluoroalkanes, cyclic perfluorocarbons, fluorinated hydrocarbons, fluorinated ethers and related compounds.

The narrower claims focus on gases commonly associated with ultrasound contrast applications.

Claim	Gas limitation
11	Extensive fluorine-containing gas Markush group
12	Includes perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, perfluorocyclobutane, sulfur hexafluoride and other listed gases
13	Perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, perfluorocyclobutane or sulfur hexafluoride
14	Perfluoropropane, perfluorocyclobutane or perfluorobutane
15	Perfluoropropane
16	Any perfluorocarbon gas
17	Perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane or perfluorocyclobutane
18	Perfluoropropane, perfluorocyclobutane or perfluorobutane
19	Perfluoropropane

Claims 15 and 19 are the narrowest and most commercially intelligible species claims because each is limited to perfluoropropane.

Claim-drafting issues in claim 11

Claim 11 contains repeated compounds, inconsistent naming conventions and apparent chemical nomenclature errors. Examples include repeated references to 1-fluorobutane and perfluoro-1-butene, duplicated entries for several fluorinated compounds, and nonstandard compound descriptions.

Those defects do not automatically invalidate the claim. The legal effect would depend on claim construction, specification support, prosecution history and whether a skilled person could identify the intended compounds with reasonable certainty. The large Markush list also creates potential written-description, enablement and indefiniteness issues, particularly for compounds that are chemically unstable, toxic, impractical or inadequately supported by working examples.

What lipid formulations are protected?

Claim 3 covers broad lipid classes, including:

Fatty acids
Lysolipids
Sphingolipids
Glycolipids
Sulfatides
Glycosphingolipids
Ether- and ester-linked lipids
Polymerized lipids
Short-chain phospholipids
Synthetic phospholipids with asymmetric acyl chains

Claim 21 provides a detailed species list. It includes phosphatidylcholines, phosphatidylethanolamines, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, sphingomyelin, gangliosides, cholesterol derivatives, fatty acids, cationic surfactants, polymer-bearing lipids and fluorinated lipids.

Relevant named lipid species include:

Dioleoylphosphatidylcholine
Dimyristoylphosphatidylcholine
Dipalmitoylphosphatidylcholine
Distearoylphosphatidylcholine
Phosphatidylethanolamine
Phosphatidylserine
Phosphatidylglycerol
Sphingomyelin
Ganglioside GM1
Cholesterol
Cholesterol sulfate
Stearylamine
Cardiolipin
N-succinyldioleoylphosphatidylethanolamine
Lipids bearing polyethylene glycol
Lipids bearing polyvinylpyrrolidone

The formulation scope is broad at the class level but becomes more specific through the claim dependency structure. A product using a phosphatidylcholine shell and perfluoropropane could satisfy the lipid and gas limitations, but it would still need to meet the claimed process and internal gas-volume limitations.

What polymer-containing liposomes are covered?

Claims 4 through 9 focus on lipids bearing covalently bound polymers.

The claimed polymer molecular-weight ranges are:

Claim	Polymer molecular weight
4	400 to 200,000
5	1,000 to 20,000
6	2,000 to 8,000

Claim 8 identifies:

Polyethylene glycol
Polyvinylpyrrolidone
Polyvinyl alcohol
Polypropylene glycol

Claim 9 narrows the polymer to polyethylene glycol. Claim 10 requires the polymer-bearing lipid to comprise approximately 1 mole% to 20 mole% of the lipid composition.

These claims appear directed to stabilization, circulation behavior, surface modification or control of liposome properties. They are narrower than claims 1 and 2 because they require particular polymer or lipid characteristics.

Antecedent and dependency concerns

Claims 4 through 10 contain drafting issues. Claim 4 refers to “said polymer” even though claim 3 lists lipid classes and does not clearly introduce a polymer-bearing lipid in all alternatives. Claim 7 also uses a formula that is difficult to parse as written:

“XCHY--(CH2)n--O--(CH2)n--YCHX”

The scope would depend heavily on the specification and prosecution record. The claims should not be treated as independently covering every polymer-containing liposome without confirming the intended antecedent basis and construction.

What is the scope of claim 20 for nebulizer and lung applications?

Claim 20 depends on claim 1 and requires gaseous precursor-filled liposomes:

Prepared by the claimed gel-state shaking method
Containing a qualifying fluorine-containing precursor
Having at least approximately 90% internal gas volume
Intended for use with a nebulizer
Targeted to the lung

Claim 20 is narrower than the core claims. It does not cover every pulmonary liposomal aerosol or every fluorinated-gas pulmonary formulation. The process limitations of claim 1 remain present.

The claim is technically relevant to pulmonary delivery and inhaled ultrasound contrast research, but it is not a general patent on nebulizers, inhaled liposomes or lung-targeted particles.

When did US Patent 5,585,112 lose exclusivity?

US Patent 5,585,112 is expired.

Event	Date or status
Earliest priority	1993, according to the patent family record
US filing	1994
Patent grant	December 17, 1996
Nominal patent term	17 years from grant under the pre-URAA term regime
Nominal expiration	December 17, 2013
Current status	Expired
Current US enforcement value	None

The patent was filed before the 20-year term regime applied to most later-filed US applications. For a pre-June 8, 1995 application, the applicable term generally used the longer of 17 years from grant or 20 years from the relevant filing date. The 17-year issue-date term produced the later date in this case. The patent is therefore well beyond its enforceable term. [1]

No current US generic-launch restriction should be attributed to Patent 5,585,112.

What is the Orange Book status of US 5,585,112?

US Patent 5,585,112 is not an Orange Book patent for an approved drug product.

The patent covers a liposomal gas-delivery platform. It does not claim an FDA-approved active pharmaceutical ingredient, a drug substance, or a specific approved drug product. Orange Book listing is tied to patents submitted for approved new drug applications and to the statutory categories recognized by FDA regulations. Platform patents are not automatically listed merely because an approved product may use a technically related formulation. [2]

The patent should therefore not be treated as an Orange Book-listed patent supporting a Paragraph IV challenge.

Does US 5,585,112 create Paragraph IV risk?

No current Paragraph IV risk arises directly from this patent because it is expired and is not an Orange Book-listed drug patent.

A Paragraph IV certification applies when an ANDA applicant asserts that a patent listed for the reference listed drug is invalid, unenforceable or will not be infringed. Patent 5,585,112 does not provide a current Orange Book barrier for an ANDA. [3]

For historical products, the patent could have been relevant to a formulation or manufacturing analysis if the product and process met the claims. That relevance ended when the patent expired.

How does this patent compare with FDA-approved ultrasound contrast agents?

The technical subject matter overlaps with modern ultrasound contrast-agent platforms, but the product categories are not identical.

Product	US FDA status	Gas or active component	Shell or carrier	Relationship to US 5,585,112
Definity	FDA-approved	Perflutren	Lipid microspheres	Technical overlap in fluorinated gas and lipid shell; product-specific patent estate is separate
Lumason	FDA-approved	Sulfur hexafluoride	Phospholipid microspheres	Technical overlap in SF6 and lipid-based microspheres; no current risk from the expired patent
Optison	FDA-approved	Perflutren	Human albumin microspheres	Different shell technology
Sonazoid	FDA-approved in the US	Perfluorobutane	Lipid-based microspheres	Technical overlap with perfluorobutane and lipid shells, but later product-specific rights govern

Definity and Lumason are described by FDA as microsphere products rather than being automatically characterized as the specific “liposomes” claimed in Patent 5,585,112. Structural terminology matters. A lipid-shelled microsphere may be technically similar to a liposome in some respects but still require separate analysis of shell morphology, internal composition, manufacturing process and claim construction. [4][5]

What patent landscape surrounds gas-filled liposomes?

The relevant patent landscape has several layers:

Early liposome and ultrasound-contrast patents

The earliest platform patents generally addressed:

Gas-containing liposomes
Echogenic liposome compositions
Ultrasound imaging using gas-filled carriers
Methods of producing lipid-shelled gas structures
Stabilization of gas-containing vesicles

US Patent 5,585,112 occupies the process and fluorinated-gas portion of that landscape. Related early patents from the same technical field may contain composition, imaging-method and formulation claims that are not coextensive with the claims of the ’112 patent.

Later microsphere patents

Later patent families moved toward:

Perfluoropropane and perfluorobutane microspheres
Phospholipid monolayer shells
Freeze-dried or lyophilized formulations
Reconstitution before administration
Targeted microspheres
Drug-loaded and ligand-bearing ultrasound agents
Controlled particle-size distributions
Injectable and intravascular products

These later patents often claim microsphere size, shell composition, gas loading, excipients, reconstitution performance, storage stability or clinical imaging methods rather than the exact low-temperature shaking method in the ’112 patent.

Manufacturing and know-how barriers

Even after patent expiration, practical barriers may remain in:

Sterile lipid handling
Gas precursor containment
Particle-size control
Residual solvent removal
Shelf-life and container-closure systems
Freeze-drying and reconstitution
Endotoxin control
In-process gas-volume measurement
Nebulization performance
Batch consistency

Those are regulatory and manufacturing barriers, not continuing rights under Patent 5,585,112.

Are there licensing deals associated with US 5,585,112?

The patent record identifies institutional ownership associated with the University of Texas system, but the patent itself does not establish the terms of any commercial license, sublicense, royalty arrangement or field-of-use restriction.

A patent assignment is not proof of a licensing transaction. Any historical licensing relationship would need to be evaluated from separate agreements, SEC filings, university technology-transfer records or litigation documents. The expiration of the patent eliminates the need for a current license to practice the expired US claims.

Which companies are challenging the patent?

No current Paragraph IV challenge is relevant because the patent is expired and is not an Orange Book-listed drug patent.

The patent also does not present a current litigation threat against manufacturers of fluorinated-gas microspheres, liposomal ultrasound agents or inhaled lipid formulations. Historical litigation involving related gas-filled liposome patents would not automatically establish liability under the ’112 patent because claim language, patent term, accused process and product structure would differ.

How strong is the patent estate for current commercial products?

The current strength of Patent 5,585,112 is zero as an enforceable US right because the patent expired in 2013. Its historical technical breadth was substantial, but its practical claim scope was narrowed by several cumulative limitations:

The gel-state temperature condition
The shaking-based preparation method
The temperature-activated precursor
Fluorine-containing gas selection
At least approximately 90% internal gas volume
Liposome characterization
Product-by-process language

A commercial product using a lipid shell and perfluoropropane would not necessarily have infringed even during the patent term. The manufacturer would also have needed to use the claimed preparation method and satisfy the internal gas-volume limitation.

What generic launch risks exist?

There is no current generic-launch risk from US 5,585,112. The patent cannot block:

Generic ultrasound contrast development
Biosimilar development
Liposomal drug development
Fluorinated-gas microsphere manufacture
Pulmonary nebulizer formulations
Research use of the claimed process

A modern competitor would still need to evaluate active patents covering the specific marketed product, including formulation, particle size, lyophilization, container, method of imaging, manufacturing process and regulatory exclusivity. Those rights are separate from the expired ’112 patent.

Key Takeaways

US Patent 5,585,112 covers fluorine-containing gas-filled liposomes made by low-temperature gel-state shaking.
Claims 1 and 2 are the principal claims and use product-by-process language.
The required elements include a temperature-activated precursor, fluorinated gas, below-transition-temperature processing and at least approximately 90% internal gas volume.
Claims 3 through 21 narrow the scope through lipid classes, PEG and other polymers, gas species, pulmonary nebulizer use and named lipid compounds.
Perfluoropropane, perfluorobutane, perfluorocyclobutane and sulfur hexafluoride are central claimed gases.
The patent expired on or about December 17, 2013.
It is not an Orange Book-listed patent and does not create current Paragraph IV risk.
FDA-approved products such as Definity, Lumason, Optison and Sonazoid require separate product-specific patent analysis.
The patent has no current US enforcement value, although its technical disclosures remain relevant to historical patent landscaping and prior-art analysis.
Manufacturing know-how and later patents may still affect commercial entry, but those barriers do not arise from the expired ’112 patent.

FAQs about US Patent 5,585,112

Is perfluoropropane covered by US Patent 5,585,112?

Yes. Claims 14, 15, 18 and 19 specifically identify perfluoropropane, subject to the remaining process, lipid and gas-volume limitations.

Does the patent cover sulfur hexafluoride liposomes?

Yes. Sulfur hexafluoride is included in claims 1, 2, 12 and 13. A product would still need to satisfy the claimed preparation method and internal gas-volume requirement.

Does the patent cover Definity?

The patent’s fluorinated gas and lipid-shell concepts overlap technically with Definity, but the expired patent does not establish current infringement. Definity’s product structure, manufacturing process and later patent rights require separate analysis.

Does claim 20 cover all inhaled liposomes?

No. Claim 20 is limited to the claim 1 liposomes and adds nebulizer use and lung targeting. It does not cover every inhaled liposome or pulmonary lipid formulation.

Can a company practice the claimed method in the United States today?

Yes, from a Patent 5,585,112 perspective. The patent is expired. Other unexpired patents, FDA requirements, trade secrets and product-specific regulatory obligations may still affect commercialization.

References

United States Patent and Trademark Office. (1996). Gaseous precursor-filled liposomes (U.S. Patent No. 5,585,112).
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA.
U.S. Food and Drug Administration. (2024). Abbreviated new drug application submissions: Refuse-to-receive standards. FDA.
U.S. Food and Drug Administration. (2024). Definity prescribing information. Lantheus Medical Imaging, Inc.
U.S. Food and Drug Administration. (2024). Lumason prescribing information. Bracco Diagnostics Inc.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0712293	⤷ Start Trial	91325	Luxembourg	⤷ Start Trial
European Patent Office	0712293	⤷ Start Trial	CA 2007 00027	Denmark	⤷ Start Trial
European Patent Office	0712293	⤷ Start Trial	300267	Netherlands	⤷ Start Trial
European Patent Office	0712293	⤷ Start Trial	SPC018/2007	Ireland	⤷ Start Trial
European Patent Office	0712293	⤷ Start Trial	SPC/GB07/031	United Kingdom	⤷ Start Trial
European Patent Office	0712293	⤷ Start Trial	0790017-8	Sweden	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,585,112

Summary for Patent: 5,585,112