United States Patent 5,573,751: Claim Scope, Expiration, and Ultrasound Contrast-Agent Patent Landscape

U.S. Patent No. 5,573,751 covers fluorinated-gas ultrasound contrast agents, including perfluoropropane, perfluorobutane, sulfur hexafluoride, and related fluorine-containing gases used in microbubbles, liposomes, microspheres, crystals, emulsions, and aqueous suspensions. The patent issued November 12, 1996, and its enforceable term expired in November 2013 under the pre-1995 patent-term rules. It therefore presents no current U.S. blocking risk, although it remains relevant as prior art and as a historical foundation for products such as Optison, Definity, Lumason, and other ultrasound contrast agents.

What does U.S. Patent 5,573,751 cover?

The patent claims ultrasound contrast media that use fluorinated gases to improve acoustic persistence, gas stability, or image contrast relative to conventional air-filled agents.

The claims fall into five technical groups:

Claim group	Claims	Principal subject matter
Broad fluorinated-gas microbubbles	1-3	Microbubbles containing specified fluorinated gases
Perfluoropropane and perfluorobutane agents	4-11	Biocompatible agents, aqueous carriers, and sub-8-micron bubbles
Gas-filled liposomes	12-14	Liposomes containing fluorinated gases
Protein or polymer microspheres	15-18	Air replacement with fluorinated gases in encapsulated microspheres
Crystals, emulsions, and air-filled suspensions	19-22	Fluorinated gases incorporated into other contrast-agent platforms

The patent is directed principally to composition claims. It does not depend on a particular imaging machine, ultrasound frequency, imaging protocol, injection rate, or diagnostic indication.

What fluorinated gases are claimed?

Claim 1 recites a Markush group covering seven specified compounds:

Hexafluoropropylene
Octafluoropropane
Octafluoro-2-butene
Hexafluoro-2-butyne
Hexafluorobuta-1,3-diene
Octafluorocyclobutane
Decafluorobutane

Claims 2 and 3 narrow claim 1 to octafluoropropane and decafluorobutane, respectively.

Claims 4 through 11 separately claim perfluoropropane and perfluorobutane. In commercial ultrasound terminology:

Perfluoropropane is commonly called octafluoropropane or perflutren gas.
Perfluorobutane is commonly called decafluorobutane when referring to the linear C4F10 compound.
Octafluorocyclobutane is a different cyclic C4F8 compound.

This distinction matters. The claim set includes both linear and cyclic fluorocarbon species, and “perfluorobutane” should not automatically be treated as synonymous with octafluorocyclobutane.

How broad is claim 1?

Claim 1 is the broadest claim in the patent. It requires:

Contrast media for ultrasound imaging;
Gaseous microbubbles; and
At least one gas selected from the seven listed fluorine-containing compounds.

The claim does not expressly require:

A lipid shell;
A protein shell;
A polymer shell;
An aqueous carrier;
A particular bubble diameter;
Intravenous administration;
A particular concentration;
A defined gas-to-liquid ratio; or
A specific therapeutic or diagnostic use.

The principal limitation is the closed chemical selection. A composition using a fluorinated gas outside the listed group would not literally satisfy claim 1, although it could implicate another claim or raise an equivalents issue in a live patent dispute.

Claims 2 and 3 are narrower species claims. They offer no additional structural limitation beyond the specific gas selection.

Which claims cover perflutren and perfluorobutane?

Claims 4 through 11 are directed to perfluoropropane and perfluorobutane agents.

Claims	Scope
4	Biocompatible ultrasound agent comprising perfluoropropane
5-6	Perfluoropropane in gaseous microbubbles suspended in a carrier, including an aqueous liquid
7	Perfluoropropane bubbles with a portion below 8 microns
8	Biocompatible ultrasound agent comprising perfluorobutane
9-10	Perfluorobutane in gaseous microbubbles suspended in a carrier, including an aqueous liquid
11	Perfluorobutane bubbles with a portion below 8 microns

Claims 4 and 8 are composition claims with relatively limited express structural detail. The word “comprising” makes them open-ended. A formulation containing perfluoropropane plus additional gases, excipients, shells, or stabilizers could fall within the claims if the remaining limitations were satisfied.

The dependent claims add practical formulation limitations. They are more relevant to commercial products because ultrasound contrast agents generally contain gas within a carrier and have particle distributions below the pulmonary capillary size range.

What formulations are protected by claims 12 through 22?

Gas-filled liposomes

Claims 12 through 14 cover gas-filled liposomes in which at least one fluorine-containing gas is included. Claim 13 identifies:

Perfluoroethane;
Perfluoropropane;
Perfluorobutane;
Sulfur hexafluoride; or
Mixtures of those gases.

Claim 14 limits the liposomes to less than eight microns in diameter.

These claims are directed to a platform rather than a single marketed product. They combine the gas-containing liposome structure with fluorinated gas chemistry.

Encapsulated microspheres

Claims 15 through 18 cover encapsulated air-filled microspheres in which all or part of the air is replaced by a fluorinated gas. Claim 16 specifies microspheres measuring 2 to 4 microns. Claim 18 specifies microspheres formed from denatured proteins.

This group is particularly relevant to protein-shell products. The claims focus on gas composition and particle structure, not on a particular protein sequence or manufacturing process.

Crystals in saccharide diluents

Claims 19 and 20 cover a contrast agent containing crystals suspended in a saccharide diluent, with microbubbles of perfluoroethane, perfluoropropane, perfluorobutane, or sulfur hexafluoride. Claim 20 recites crystals ranging from 5 to 10 microns.

These claims are narrower and structurally distinct from the broad microbubble claims.

Emulsions

Claim 21 covers an emulsion of highly fluorinated organic compounds that also provides microbubbles of at least one gaseous fluorine-containing chemical.

The claim could reach formulations combining fluorinated liquid-phase materials with a gas-containing microbubble population. It is not limited to a specific emulsifier, droplet size, shell material, or route of administration.

Air-filled microbubble suspensions

Claim 22 covers an air-filled microbubble suspension in which the bubbles contain perfluoroethane, perfluorobutane, perfluoropropane, or sulfur hexafluoride.

This claim is broader in formulation architecture than claims 12 and 15 because it does not expressly require liposomes, denatured proteins, or a specified encapsulating material.

What was the patent’s expiration date?

U.S. Patent 5,573,751 issued on November 12, 1996. Because the application was filed before the June 8, 1995 transition to the modern twenty-year term, the applicable term generally ran for the longer of:

Seventeen years from the issue date; or
Twenty years from the relevant filing date.

On that basis, the patent expired in November 2013, subject to any patent-term adjustment, terminal disclaimer, or other recorded event. Public patent records identify no current enforceable term for the issued claims.

Event	Date
U.S. application filing period	Pre-June 8, 1995
Patent issued	November 12, 1996
Nominal seventeen-year term from issue	November 12, 2013
Current status	Expired

The expiration eliminates present infringement liability under the issued U.S. claims. The patent remains relevant for prior-art analysis, freedom-to-operate history, validity review, and interpretation of later patents.

Is U.S. Patent 5,573,751 listed in the Orange Book?

A patent does not receive Orange Book protection merely because it covers a pharmaceutical or diagnostic composition. Listing depends on an approved drug product, the holder’s submission to FDA, and whether the patent claims an approved product or an approved method of use under FDA listing rules.

U.S. Patent 5,573,751 should not be treated as an active Orange Book barrier for current ultrasound contrast products. Its 2013 expiration independently removes any current exclusivity even if it was historically associated with a product or patent-family strategy.

For products such as Definity, Optison, and Lumason, the operative patent analysis must be conducted against the patents specifically listed for each product and against later patents covering shell composition, manufacturing, dosing, imaging use, or product-specific formulations. The existence of Patent 5,573,751 does not establish that every fluorinated-gas contrast product has the same Orange Book status.

Which commercial products are technically adjacent?

Product	Active gas	Shell or carrier platform	U.S. regulatory status	Relationship to the patent
Optison	Perflutren, principally perfluoropropane	Human serum albumin microspheres	FDA-approved	Technically aligned with claims 4-7 and 15-18
Definity	Perflutren, principally perfluoropropane	Lipid microspheres	FDA-approved	Technically aligned with claims 4-7 and 12-14
Lumason	Sulfur hexafluoride	Phospholipid microspheres	FDA-approved	Technically aligned with claims 12-14 and 22
Sonovue	Sulfur hexafluoride	Phospholipid microspheres	Approved outside the United States; marketed by Bracco	Technically aligned with claims 12-14 and 22
Sonazoid	Perfluorobutane	Lipid microspheres	Approved in selected non-U.S. markets	Technically aligned with claims 8-11 and potentially 12-14

These products may practice the technical concepts described in the patent, but none faces current U.S. infringement exposure from Patent 5,573,751 because the patent has expired.

Did the patent create a blocking position against Optison or Definity?

The claims are broad enough to encompass important product architectures:

Optison-type protein microspheres containing perfluoropropane;
Definity-type lipid microspheres containing perfluoropropane;
Lumason-type lipid microspheres containing sulfur hexafluoride; and
Perfluorobutane-containing microbubble formulations.

That scope does not establish that the patent was the only relevant patent. Commercial products typically depend on layered patent estates covering:

Shell composition;
Lipid or protein constituents;
Particle-size distributions;
Gas-loading methods;
Lyophilization or reconstitution;
Sterilization;
Manufacturing controls;
Dosing and imaging protocols; and
Product-specific clinical uses.

A product could therefore have been covered by the 5,573,751 claims while also relying on separate patents for its commercial implementation.

Were Paragraph IV challenges or settlements associated with this patent?

No current Paragraph IV risk arises from Patent 5,573,751 because the patent expired before the modern generic-entry disputes involving many ultrasound contrast products became commercially significant.

Paragraph IV litigation is product-specific. A generic or competing applicant must challenge patents listed for the reference product, not every patent that broadly describes the same active gas or microbubble concept. The relevant disputes for Optison, Definity, and Lumason must therefore be evaluated through their individual FDA listings, approved labeling, ANDA or 505(b)(2) pathway, and patent-family records.

Patent 5,573,751 does not create a current statutory stay, launch bar, or automatic litigation trigger.

What manufacturing and intellectual-property barriers remain?

The expired patent removed the broadest early composition barrier, but technical entry barriers remain in several areas:

Shell engineering

Commercial products require narrow particle-size distributions, adequate acoustic response, circulation stability, and acceptable pulmonary safety. Lipid, protein, and polymer shells produce different stability and reconstitution profiles.

Gas retention

Perfluoropropane and sulfur hexafluoride have different diffusion and dissolution behavior. Gas retention affects shelf life, circulation time, acoustic persistence, and product handling.

Sterile manufacture

Manufacturers must control aseptic processing, vial filling, lyophilization or suspension stability, particulate burden, and reconstitution performance.

Clinical and regulatory data

FDA approval requires product-specific chemistry, manufacturing, controls, clinical performance, and safety data. A competitor cannot generally rely on the expired patent alone to obtain approval.

Later patent families

The most relevant live rights are likely to be later-generation patents covering:

Lipid mixtures;
PEGylated or charged shell components;
Protein crosslinking or denaturation;
Reconstitution systems;
Manufacturing conditions;
Diagnostic imaging protocols; and
Specific clinical indications.

The commercial strength of a current patent estate therefore depends more on later formulation and manufacturing claims than on the expired broad gas-selection claims in Patent 5,573,751.

How strong is the patent estate today?

As an enforceable U.S. asset, Patent 5,573,751 has no remaining strength because its claims expired in 2013.

As prior art, it is significant. The patent discloses the core proposition that stable fluorinated gases can replace air in ultrasound contrast microbubbles and can be used in liposomes, protein microspheres, emulsions, and related delivery systems. Later applicants seeking patents on fluorinated-gas contrast products must distinguish their inventions through structure, formulation, manufacturing, particle characteristics, therapeutic use, or performance limitations.

Business question	Assessment
Current U.S. blocking risk	None from this patent
Historical composition coverage	Broad
Coverage of perfluoropropane	Direct and substantial
Coverage of perfluorobutane	Direct but dependent on chemical identity
Coverage of sulfur hexafluoride	Claims 13, 17, 19, and 22
Orange Book relevance today	No current exclusivity
Paragraph IV significance	None as an active patent
Prior-art significance	High
Manufacturing protection	Limited; claims are mainly composition-focused
Relevance to current products	Technical and historical, not an active barrier

Key Takeaways

U.S. Patent 5,573,751 claims ultrasound contrast agents containing specified fluorinated gases.
The principal covered gases include perfluoropropane, perfluorobutane, sulfur hexafluoride, perfluoroethane, and related fluorocarbons.
Claims reach lipid liposomes, protein microspheres, aqueous suspensions, emulsions, crystals, and air-filled microbubble systems.
The patent is broadest where it claims a contrast medium containing gaseous microbubbles of a listed fluorinated compound.
The patent issued November 12, 1996, and expired in November 2013.
It creates no current U.S. generic-launch, Paragraph IV, Orange Book, or infringement barrier.
Its primary present value is prior-art and patent-landscape significance.
Current competitive protection for Optison, Definity, Lumason, Sonovue, and Sonazoid depends on later product-specific patents and regulatory exclusivities.

FAQs

Does U.S. Patent 5,573,751 cover Definity?

Its claims are technically broad enough to read on perfluoropropane-containing lipid microspheres, which are the core platform used by Definity. The patent expired in 2013 and therefore cannot currently block Definity or a competing product.

Does the patent cover Lumason?

Claims 12, 13, 17, 19, and 22 expressly identify sulfur hexafluoride or fluorinated-gas microbubbles. Lumason uses sulfur hexafluoride in phospholipid microspheres, making it technically relevant. The patent’s expiration eliminates current U.S. enforcement risk.

Is perfluorobutane the same as octafluorocyclobutane?

No. Perfluorobutane generally refers to a C4F10 compound, while octafluorocyclobutane is a cyclic C4F8 compound. The patent lists both types of fluorinated compounds in different claim language.

Can a company launch a fluorinated-gas ultrasound contrast agent without licensing this patent?

Yes, with respect to Patent 5,573,751, because the U.S. patent expired in 2013. A launch still requires review of later patents, FDA approval requirements, product-specific exclusivities, and third-party rights.

Does the patent protect a method of diagnosing a patient?

The supplied claims are composition claims. They do not expressly claim administering the agent, imaging a patient, or diagnosing a disease. Later patents may separately claim imaging methods or clinical uses.

References

U.S. Patent No. 5,573,751. (1996). Ultrasound contrast agents. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (1997). Optison (perflutren protein-type A microspheres) prescribing information. FDA.
U.S. Food and Drug Administration. (2001). Definity (perflutren lipid microsphere) prescribing information. FDA.
U.S. Food and Drug Administration. (2014). Lumason (sulfur hexafluoride lipid-type A microspheres) prescribing information. FDA.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	191346	⤷ Start Trial
Australia	2550392	⤷ Start Trial
Australia	3995997	⤷ Start Trial
Australia	679428	⤷ Start Trial
Brazil	1100167	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,573,751

Summary for Patent: 5,573,751