US Patent 5,798,091: Scope, Claims, Expiration, and Ultrasound-Contrast Patent Landscape

US Patent 5,798,091 covers gas-emulsion ultrasound contrast media made from a non-lamellar surfactant composition that forms gas bubbles in an aqueous phase. Its core technical combination is a relatively water-insoluble phospholipid, a more water-soluble second surfactant, and a fluorocarbon-containing gas. The claims also cover reconstitution methods and ultrasound imaging methods.

The patent is now expired under the standard US patent-term framework. Its historical importance is greater than its current blocking value. It helped define an early formulation platform for ultrasound contrast agents, but it does not presently create an enforceable US barrier to products such as Definity, Optison, or Lumason.

What invention does US Patent 5,798,091 cover?

The patent protects a formulation and manufacturing concept for producing a gas emulsion substantially free of lamellar surfactant structures.

The central architecture has four elements:

A first surfactant consisting of a phospholipid or phospholipid mixture with at least one acyl chain containing at least 10 carbon atoms.
A first surfactant concentration of at least about 5% by weight of total surfactant.
A second surfactant that is more water-soluble than the first surfactant.
Gas bubbles dispersed in an aqueous continuous phase, with the bubbles surrounded by the surfactant layer.

The claims also require, in several embodiments, a fluorocarbon gas or fluorocarbon-containing gas mixture. Specific dependent claims identify perfluorohexane, nitrogen, air, oxygen, and carbon dioxide.

The claimed formulation is not limited to a single commercial product. It covers a genus of gas emulsions defined by surfactant composition, gas composition, and the absence of lamellar surfactant structures.

What are the independent claims in US Patent 5,798,091?

The patent contains independent claims directed to preparation methods, imaging methods, composition claims, and a specific dimyristoyl phosphatidylcholine formulation.

Claim	Claim category	Principal subject matter
1	Preparation method	Reconstituting a substantially non-lamellar microspherical material with an aqueous liquid
13	Imaging method	Imaging after administration of a gas emulsion made under claim 1
14	Imaging method	Imaging using a gas emulsion containing a gas osmotic agent and modifier gas
15	Imaging method	Imaging using a gas emulsion containing a listed fluorocarbon
16	Imaging method	Imaging using perfluorohexane and nitrogen
17	Composition	Aqueous gas-emulsion contrast medium with fluorocarbon gas and two surfactants
23	Imaging method	Imaging with the claim 17 contrast medium
32	Preparation method	Dissolving a substantially non-lamellar composition in aqueous liquid
33	Preparation method	Making a medium containing perfluorohexane and a modifier gas
34	Imaging method	Imaging with a medium made under claim 33
35	Composition	Gas-emulsion contrast medium using dimyristoyl phosphatidylcholine and a more water-soluble second surfactant

Claims 1 and 17 are the principal broad platform claims. Claim 32 is a second manufacturing route that removes some of the container and microspherical-material language present in claim 1. Claim 35 is narrower because it expressly requires dimyristoyl phosphatidylcholine, commonly abbreviated DMPC.

How broad is claim 1?

Claim 1 is a process claim with several cumulative limitations. A practicing party would need to satisfy all of the following limitations:

provide a container;
place in the container a substantially non-lamellar, approximately microspherical material;
include at least a first and second surfactant;
include a hydrophilic monomer, polymer, or combination;
include a gas or gas mixture;
use a first surfactant containing phospholipid with at least one acyl chain of at least 10 carbon atoms;
have that first surfactant comprise at least about 5% by weight of total surfactant;
use a second surfactant more water-soluble than the first;
add an aqueous liquid;
substantially dissolve the microspherical material;
form gas bubbles surrounded by the two-surfactant layer;
produce an emulsion substantially free of lamellar surfactant structures.

The claim is broad with respect to the identity of the second surfactant. Claims 2 and 3 divide the principal alternatives into two groups.

Claim 2 covers more water-soluble surfactants such as fatty acids, fatty-acid salts, sugar esters, poloxamers, alkyl glucosides, and polysorbates. Claim 3 covers shorter-chain phospholipids, phosphocholines, and lysophospholipids.

The claim is narrower than a generic "lipid-coated microbubble" claim because it requires a specific reconstitution process and a substantially non-lamellar starting material.

What formulations are protected by the surfactant claims?

The surfactant limitations create a two-component formulation system.

Component	Required feature	Examples identified in the claims
First surfactant	Phospholipid with at least one acyl chain of at least 10 carbon atoms; at least about 5% of total surfactant	Long-chain phospholipids; phosphatidylcholine
Second surfactant	More water-soluble than the first surfactant	Fatty acid, fatty-acid salt, sugar ester, poloxamer, alkyl glucoside, polysorbate
Alternative second surfactant	Shorter-chain phospholipid or related compound	Phosphocholine, lysophospholipid, phospholipid with acyl chains no longer than 14 carbons
Preferred pair	First phosphatidylcholine with a 12- to 18-carbon chain and second phosphatidylcholine with a 6- to 12-carbon chain	Long-chain/short-chain phosphatidylcholine combinations
Narrow embodiment	DMPC as first surfactant plus a more water-soluble second surfactant	Claim 35

The claims do not require a specific phospholipid head group in every embodiment. They do, however, require the first surfactant to be a phospholipid or phospholipid mixture. A formulation using only a non-phospholipid surfactant would fall outside the express first-surfactant requirement.

What gas compositions are covered?

The patent claims gas compositions in two principal ways.

First, claims 1 and 17 broadly cover a gas or gas mixture, with claim 17 requiring a fluorocarbon or mixture of fluorocarbons having at least four carbon atoms.

Second, claims 6 through 12 and 21 through 31 identify gas osmotic agents and modifier gases. The listed gas osmotic agents include:

perfluoropropane;
perfluorobutane;
perfluorocyclobutane;
perfluoromethylcyclobutane;
perfluoropentane;
perfluorocyclopentane;
perfluorohexane;
perfluorocyclohexane;
perfluoroheptane;
perfluorocycloheptane;
substituted perfluorocyclic compounds; and
perfluorotriethylamine.

The modifier gas can be nitrogen, oxygen, carbon dioxide, air, or combinations of those gases.

The most specific gas embodiment is perfluorohexane with nitrogen. Claims 11, 12, 26, 29, 30, and 31 focus on that combination.

The gas language is technically important because low-solubility, high-molecular-weight fluorocarbons can improve bubble persistence relative to ordinary air or oxygen. The claims characterize the fluorocarbon as a gas osmotic agent when its vapor pressure is below 760 mm Hg at 37 degrees C.

Does the patent cover a finished ultrasound contrast product?

Yes, claims 17 and 35 are composition claims. They cover the gas-emulsion medium itself rather than only the steps used to make it.

A potential composition must include:

an aqueous continuous phase;
a plurality of gas bubbles;
a fluorocarbon with at least four carbon atoms in the claim 17 embodiment;
a surfactant layer;
a first phospholipid surfactant with an acyl chain of at least 10 carbons;
at least about 5% of that first surfactant by weight of total surfactant;
a more water-soluble second surfactant; and
an aqueous phase substantially free of lamellar surfactant structures.

The phrase "substantially free of lamellar surfactant structures" is a material limitation. It distinguishes the claimed emulsion from conventional liposome or multilamellar-vesicle systems. In an enforcement dispute, the parties would likely contest the analytical meaning of "substantially free," the test used to detect lamellar structures, and whether transient or residual lamellar material is legally material.

How do the method-of-use claims operate?

Claims 13 through 16, 23, 24, 28, 29, 31, and 34 require:

introducing the claimed gas emulsion or contrast medium into an object or body; and
ultrasonically imaging at least part of that object or body.

These are method-of-use claims, not claims to diagnosis as such. They could theoretically be asserted against performance of the claimed imaging method, subject to the patent's expiration and the ordinary requirements for proving direct or induced infringement.

The claims do not limit the imaging target to a particular organ, blood vessel, cardiac chamber, or disease. They therefore have broad use coverage, but their scope depends on the underlying medium satisfying the formulation limitations.

When did US Patent 5,798,091 expire?

US Patent 5,798,091 is expired. The patent issued in 1998, and its enforceable term ran from the applicable US filing-date framework for a pre-1995 or transition-era application. The public patent record should be used for the exact patent-term calculation, including any terminal disclaimer or adjustment recorded by the USPTO.

The practical business conclusion is unchanged: US Patent 5,798,091 is no longer an enforceable patent blocking manufacture, sale, or use of a product that falls within its claims.

Event	Date or status
US patent number	5,798,091
Issue year	1998
Technology	Fluorocarbon gas-emulsion ultrasound contrast media
Primary claim categories	Composition, preparation, and ultrasound imaging
Current US enforceability	Expired
Current Paragraph IV relevance	None for this patent because it is expired
Current Orange Book relevance	No identified active Orange Book exclusivity based on this patent
Current biosimilar relevance	None; this is a small-molecule/device-like contrast-agent technology, not a biologic patent

A patent's expiration does not eliminate other risks. Later patents may cover a particular lipid ratio, vial system, lyophilization method, gas-loading process, particle-size distribution, administration protocol, or manufacturing control.

Does US Patent 5,798,091 have Orange Book listings?

The patent itself does not operate as a current Orange Book barrier. FDA Orange Book listing applies to patents submitted by an NDA holder for an approved drug product. A patent can be technically relevant to a drug without appearing as an Orange Book-listed patent.

The key distinction is:

an expired patent has no current exclusionary term;
an Orange Book-listed patent may support a Paragraph IV notice while active;
a patent not listed in the Orange Book can still be relevant in ordinary patent litigation if it remains enforceable;
a patent covering a manufacturing process or method of use may not necessarily block an ANDA product in the same way as a composition claim.

The principal FDA-approved ultrasound contrast agents are associated with later product-specific regulatory and patent estates, not with an active exclusivity position under US Patent 5,798,091.

What FDA-approved products should be compared with this patent?

The principal US ultrasound contrast products include:

Product	Active gas or gas source	Sponsor or manufacturer	General formulation class
Definity	Perflutren gas	Lantheus Medical Imaging	Lipid-shelled microspheres
Optison	Perflutren gas	GE Healthcare	Human serum albumin microspheres
Lumason, marketed as SonoVue outside the US	Sulfur hexafluoride	Bracco	Phospholipid-shelled microspheres
SonoVue	Sulfur hexafluoride	Bracco	Not originally approved under that name in the US

These products do not automatically fall within claim 17 merely because they are ultrasound contrast agents. Claim analysis requires product-specific information about:

the identity and acyl-chain length of the phospholipids;
the amount of the first phospholipid relative to total surfactant;
the identity and relative water solubility of any second surfactant;
the gas composition;
the presence or absence of lamellar structures; and
the manufacturing and reconstitution process.

Definity and Lumason are technically closer to the patent's lipid-shell concept than Optison, but technical similarity does not establish infringement. The patent is expired in any event.

Which patents and technology areas followed this patent?

The broader ultrasound-contrast patent landscape developed around several distinct claim families.

Lipid-shelled microbubble compositions

These patents claim phospholipid mixtures, lipid ratios, particle sizes, shell structures, and gas compositions. Later products generally use highly controlled lipid systems rather than the broad surfactant combinations stated in the 5,798,091 claims.

Lyophilized or dry-powder reconstitution systems

US Patent 5,798,091 places substantial emphasis on a substantially non-lamellar material that dissolves in water to create the gas emulsion. Later patent families commonly focus on:

lyophilized cakes;
vial-headspace gas loading;
reconstitution time;
shaking or agitation requirements;
particle-size consistency; and
storage stability.

These process and presentation claims can remain relevant after the expiration of an earlier composition patent.

Gas-selection patents

Later families address perfluorobutane, perflutren, sulfur hexafluoride, octafluoropropane, and other low-solubility gases. They may claim gas mixtures, gas-to-lipid ratios, shell permeability, acoustic response, or circulation persistence.

Targeted and molecular imaging

Separate patent estates cover ligand-bearing microbubbles, antibody or peptide targeting, endothelial markers, thrombus imaging, drug delivery, and therapeutic ultrasound. Those technologies are outside the principal scope of 5,798,091, which claims general ultrasound imaging.

Manufacturing and quality-control patents

Commercial development also depends on patents and know-how concerning:

sterile production;
controlled particle-size distributions;
vial filling;
gas exchange;
lipid oxidation control;
residual solvent limits;
container closure systems; and
acoustic characterization.

These rights can be more commercially important than the expired foundational patent because they affect reproducibility and regulatory approval.

Are Paragraph IV challenges relevant to this patent?

No current Paragraph IV challenge is relevant to US Patent 5,798,091 because the patent is expired.

Paragraph IV certifications are made against listed patents associated with an approved drug product. A generic applicant may assert that a listed patent is invalid, unenforceable, or will not be infringed. That mechanism is relevant to active Orange Book patents for products such as contrast agents, but not to an expired patent.

For current product-entry analysis, the relevant questions concern later active patents associated with Definity, Lumason, Optison, or other products. The status of those patents must be reviewed separately in FDA Orange Book records, USPTO records, and litigation databases.

Are biosimilar risks relevant?

No. Biosimilar law does not apply to this patent because the claimed technology is a synthetic or formulation-based ultrasound contrast platform, not a biologic active ingredient.

The relevant competitors are:

generic or 505(b)(2) contrast-agent applicants;
branded ultrasound contrast manufacturers;
contract manufacturers with lipid-microsphere capabilities; and
developers of alternative imaging agents.

A product may face FDA regulatory complexity even when the patent barrier has expired. Contrast agents can require substantial comparative characterization, stability data, sterility controls, and clinical or imaging-performance evidence.

How strong was the patent estate?

Historically, the patent had meaningful platform breadth but limited commercial durability.

Strength factor	Assessment
Composition breadth	Moderate to broad
Process coverage	Broad but dependent on non-lamellar and reconstitution limitations
Gas coverage	Broad genus with specific fluorocarbon embodiments
Method-of-use coverage	Broad because no organ or disease limitation is required
Definiteness risk	Potential disputes over "substantially free," "more water soluble," and "approximately microspherical"
Design-around potential	Material, particularly through different shell chemistry, gas selection, or manufacturing process
Current blocking value	None because the patent is expired

The strongest historical claims were likely the composition claims, especially claim 17, because they could reach a finished product without requiring proof of the accused party's manufacturing steps. The process claims could be more difficult to enforce because they require evidence of how the product was made.

Claims 1 and 32 also contain technical terms that could generate claim-construction disputes. "Substantially non-lamellar," "substantially free," and "more water soluble" require context from the specification and testing methods. The meaning of those terms would be assessed against the intrinsic record and, if necessary, technical evidence.

What generic launch risks exist today?

US Patent 5,798,091 does not create a current generic-launch risk or barrier. A competitor can develop a fluorocarbon or sulfur-hexafluoride ultrasound contrast agent without obtaining a license under this patent.

The current launch risks are more likely to arise from:

active product-specific composition patents;
formulation and shell-structure patents;
reconstitution and vial patents;
manufacturing-process patents;
method-of-use patents;
regulatory exclusivity;
clinical bridging requirements;
device compatibility;
supply of pharmaceutical-grade fluorocarbon gas; and
manufacturing know-how.

A design-around strategy can avoid the historical claim set by using a different shell architecture, avoiding the claimed two-surfactant relationship, selecting a different gas, or using a process that does not begin with the claimed non-lamellar microspherical material. Because the patent is expired, design-around analysis is relevant to later patent families rather than to 5,798,091 itself.

What geographic coverage did the patent provide?

US Patent 5,798,091 provided protection only in the United States. Corresponding foreign applications may have existed, but a US patent does not establish rights in Europe, Japan, Canada, China, or other jurisdictions.

A global freedom-to-operate review would require separate analysis of:

PCT applications;
European patent family members;
national-phase prosecution;
granted claims;
terminal disclaimers;
maintenance fees;
opposition proceedings;
national expiration dates; and
abandoned or lapsed family members.

The US expiration does not establish that all foreign counterparts have expired, although patents from the same early-1990s priority period are generally also likely to be expired under ordinary national terms.

What is the commercial significance of US Patent 5,798,091?

The commercial value of the patent was as an early platform right covering reconstituted gas emulsions for ultrasound imaging. Its claims reached the interface between formulation chemistry and clinical imaging use.

Its current value is primarily historical and analytical:

it identifies an early lipid-shell microbubble design;
it illustrates the use of fluorocarbon gases for bubble persistence;
it shows the importance of non-lamellar dry formulations;
it provides prior art against later broad claims to related gas-emulsion systems; and
it may help identify the origin of related patent families and licensing positions.

It should not be treated as an active US exclusivity asset, a current Orange Book blocker, or a basis for a present-day Paragraph IV strategy.

Key Takeaways

US Patent 5,798,091 covers gas-emulsion ultrasound contrast media, reconstitution methods, and ultrasound imaging methods.
The core formulation uses a long-chain phospholipid first surfactant, a more water-soluble second surfactant, and gas bubbles in an aqueous phase.
The claims emphasize a substantially non-lamellar starting material and an emulsion substantially free of lamellar surfactant structures.
Perfluorohexane with nitrogen is the most specific gas embodiment.
Claim 17 is the principal composition claim; claim 35 narrows the first surfactant to DMPC.
The patent is expired and has no current US blocking effect.
It is not a current Orange Book or Paragraph IV barrier.
Biosimilar law is not relevant.
Later patent risks should be assessed around lipid-shell composition, dry-powder reconstitution, gas selection, manufacturing, targeting, and product-specific FDA filings.
A product's status as an ultrasound contrast agent does not establish infringement of this patent without matching the detailed surfactant, gas, structural, and process limitations.

FAQs

Does US Patent 5,798,091 cover Definity?

Not as a currently enforceable patent. Definity uses lipid-shelled perflutren microspheres, but infringement would require matching the patent's specific surfactant, structural, gas, and process limitations. The patent is expired.

Does US Patent 5,798,091 cover Lumason?

The patent does not create a current blocking right against Lumason. Lumason uses sulfur hexafluoride and a phospholipid shell. Its technical formulation and later product-specific rights must be analyzed separately.

Can a company license US Patent 5,798,091 for a new ultrasound contrast agent?

A license is not required for current US practice because the patent has expired. Commercial licensing may still be relevant to later patents, know-how, trademarks, manufacturing processes, or foreign family members.

What is the most important limitation in claim 17?

The central limitations are the long-chain phospholipid first surfactant, its minimum proportion of total surfactant, the more water-soluble second surfactant, fluorocarbon-containing gas, and aqueous emulsion substantially free of lamellar surfactant structures.

Does the patent cover therapeutic ultrasound or drug delivery?

No express independent claim is directed to therapeutic ultrasound, drug delivery, or molecular targeting. The use claims are directed to introducing the contrast medium into an object or body and ultrasonically imaging at least part of that object or body.

References

United States Patent and Trademark Office. (1998). US Patent No. 5,798,091, gas emulsions for ultrasonic imaging.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations.
U.S. Food and Drug Administration. (n.d.). Orange Book: Approved drug products with therapeutic equivalence evaluations.
U.S. Food and Drug Administration. (n.d.). Definity prescribing information. Lantheus Medical Imaging.
U.S. Food and Drug Administration. (n.d.). Optison prescribing information. GE Healthcare.
U.S. Food and Drug Administration. (n.d.). Lumason prescribing information. Bracco Diagnostics.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	281183	⤷ Start Trial
Australia	4922196	⤷ Start Trial
Australia	5199701	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,798,091

Summary for Patent: 5,798,091