U.S. Patent 5,529,766: Scope, Claims, Expiration and Ultrasound Contrast-Agent Patent Landscape

U.S. Patent No. 5,529,766 covers protein-shelled gas microbubbles for diagnostic ultrasound, including bubbles containing sulfur hexafluoride or low-molecular-weight fluorinated hydrocarbons. The claims extend to perfluorinated gases, albumin and human serum albumin shells, biodegradable protein crosslinking, aqueous dispersions, manufacturing processes and vascular ultrasound imaging.

The patent was granted July 2, 1996. Because it is a pre-June 8, 1995 application, its principal U.S. term was generally 17 years from grant under the transitional patent-term rules. Its statutory term therefore expired in 2013, subject to any applicable term adjustment or terminal disclaimer. It does not provide a current blocking right against generic or branded ultrasound contrast products.

What does U.S. Patent 5,529,766 cover?

The patent has five principal claim groups:

Claim group	Claims	Subject matter
Gas-filled protein microbubbles	1-4, 12-15	Protein microbubbles containing sulfur hexafluoride or low-molecular-weight fluorinated hydrocarbon gases
Aqueous dispersions	5-8, 16	Water-based compositions containing the claimed microbubbles
Biodegradably crosslinked microbubbles	9-11, 14-18	Protein shells crosslinked through biodegradable chemical linkages
Manufacturing processes	20-29	Shaking, sonication and chemical crosslinking processes
Ultrasound imaging method	17-19, 30	Diagnostic ultrasound contrast agents and administration into a vascular system

The independent claims are claims 1, 5, 9, 17, 20 and 24. Claim 30 is also an independent method claim in practical scope because it recites the use of the claimed contrast agent for vascular imaging.

The claims use the transitional term "comprising." That language generally permits the presence of additional components or process steps, provided the accused product or process contains every required limitation.

What products and technologies fall within the patent’s core scope?

The commercial center of gravity is a protein-shell ultrasound contrast agent containing a fluorinated gas.

A product would most directly implicate claim 1 if it has:

Gas-containing microbubbles.
A protein capable of forming the bubble shell.
Sulfur hexafluoride or a low-molecular-weight fluorinated hydrocarbon in the gas phase.

Claims 2-4 narrow the protein/gas combination:

Claim 2 requires a perfluorinated hydrocarbon.
Claim 3 requires albumin, gelatin or gamma-globulin.
Claim 4 requires human serum albumin.

The claims do not require a particular therapeutic indication, commercial brand, vial format or route of administration. The product claims are therefore technically broad within the defined composition space.

Gas limitations

The independent gas limitation covers either:

Sulfur hexafluoride; or
A low-molecular-weight fluorinated hydrocarbon.

The fluorocarbon language potentially reaches gases such as perfluoropropane, perfluorobutane and related low-molecular-weight fluorinated hydrocarbons, subject to the patent’s specification and the ordinary meaning applied by a court.

Claim 2 adds the requirement that the hydrocarbon be perfluorinated. A product using sulfur hexafluoride remains within claim 1 without needing to satisfy claim 2.

The wording "gas comprising" is broader than a requirement that the gas consist solely of the specified compound. A mixed gas containing sulfur hexafluoride or a qualifying fluorinated hydrocarbon could fall within the claim if the other limitations are met.

Protein-shell limitations

Claim 1 does not limit the protein to albumin. It covers any protein capable of forming gas-containing microbubbles. Claim 3 narrows the scope to albumin, gelatin or gamma-globulin, and claim 4 narrows further to human serum albumin.

This creates a nested scope structure:

Scope level	Required protein
Claim 1	Any protein capable of forming gas-containing microbubbles
Claim 3	Albumin, gelatin or gamma-globulin
Claim 4	Human serum albumin

The phrase "capable of formation" is functional. It may create claim-construction disputes over whether a particular protein must itself form the shell under the claimed process or merely be suitable for shell formation under some process conditions.

How do the aqueous-dispersion claims operate?

Claims 5-8 and 16 cover aqueous dispersions containing the claimed microbubbles. These claims are composition claims, not merely product-by-process claims.

The aqueous-dispersion claims are commercially important because ultrasound contrast agents are commonly supplied as:

A liquid dispersion;
A vial requiring agitation before administration;
A lyophilized or otherwise prepared product reconstituted into an aqueous suspension; or
A ready-to-use aqueous product.

Claims 5-8 track the un-crosslinked product hierarchy. Claim 16 covers an aqueous dispersion of the biodegradably crosslinked bubbles of claim 9.

A formulation that uses an aqueous carrier, buffer, stabilizer, salt or other excipient may still fall within a "comprising" claim. The presence of additional excipients would not, by itself, avoid infringement.

What protection do the biodegradable crosslinking claims provide?

Claims 9-11 and 14-18 add a chemically crosslinked protein shell. The crosslinking groups must contain biodegradable linkages.

Claim 10 identifies permitted linkage classes, including:

Amide;
Imide;
Imine;
Ester;
Anhydride;
Acetal;
Carbamate;
Carbonate;
Carbonate ester; and
Disulfide.

Claim 11 narrows the scope to a defined linkage formula:

--(Y)n--CO--O--C(R1R2)--O--CO--(Z)n--

The formula permits oxygen, sulfur or nitrogen-containing spacer atoms through the variables Y and Z. It also permits hydrogen, organic substituents or a divalent organic group at the carbon center.

The crosslinking claims are technically narrower than claim 1 but can be commercially significant because crosslinking may affect:

Shell rigidity;
Acoustic response;
In-vivo persistence;
Gas retention;
Mechanical stability;
Clearance and biodegradation; and
Storage stability.

Claim 17 specifically recites a diagnostic ultrasound contrast agent comprising the crosslinked microbubbles. Claim 18 adds an in-vivo half-life of no more than 48 hours, and claim 19 requires dispersion in an aqueous carrier.

The 48-hour limitation is a relatively broad physiological limitation. It may be difficult to use as a practical design-around unless the product has a demonstrated in-vivo persistence exceeding 48 hours. It also creates potential proof issues because half-life depends on the measured analyte, imaging method, population and pharmacokinetic protocol.

What manufacturing processes are protected?

Claims 20-23 cover generation of the microbubbles by shaking or sonicating a protein-containing mixture in the presence of sulfur hexafluoride or a low-molecular-weight fluorinated hydrocarbon.

The process sequence is materially narrower than the product claims. A manufacturer could potentially avoid these claims by using a different bubble-generation technology, such as:

Membrane emulsification;
Pressure-based gas loading;
Microfluidic generation;
Mechanical homogenization;
Spray drying or related particle-forming processes; or
A process that introduces gas after shell formation.

That alternative would not automatically avoid the product claims. Product-by-process differences generally do not eliminate infringement where the resulting product independently satisfies a product claim.

Claims 24-29 cover chemical crosslinking after or during bubble formation. Claim 25 requires a crosslinking agent of formula:

A1-X-A2

where A1 and A2 are protein-reactive functional groups and X contains one or more biodegradable linkages.

Claims 27 and 28 specify aldehyde groups at both reactive ends. A bifunctional dialdehyde or related reagent would be the clearest target of those claims, provided the intervening group satisfies the biodegradable-linkage limitations.

Process-claim design-around considerations

A manufacturer seeking to avoid the process claims would focus on:

Using a non-protein shell.
Using a gas outside the specified gas classes.
Avoiding shaking or sonication in the claimed gas environment.
Avoiding the specified biodegradable crosslinking chemistry.
Using a non-aldehyde crosslinking system where claims 27-28 are at issue.
Producing a product that does not satisfy the product claims even if the process is similar.

The strongest design-around is usually a change in shell chemistry, because it can remove the product, dispersion and method claims at the same time.

What is the scope of claim 30 for vascular imaging?

Claim 30 covers a method of enhancing ultrasound images of a vascular system by administering a diagnostic ultrasound contrast agent according to claim 17.

The claim requires:

An ultrasound contrast agent meeting claim 17;
Administration to the vascular system; and
Use for enhancement of ultrasound images.

It does not expressly limit the imaging target to a particular organ, vessel, disease or imaging protocol. The method can therefore reach broad vascular-imaging use of a qualifying crosslinked protein microbubble agent.

The method claim is narrower than the general product claims because it requires the crosslinked-agent architecture of claim 17. A non-crosslinked albumin microbubble product may implicate claim 1 or claims 5-8 but not claim 30 unless it independently satisfies the incorporated limitations of claim 17.

When did U.S. Patent 5,529,766 lose exclusivity?

Event	Date or status
U.S. patent grant	July 2, 1996
Principal statutory term for pre-1995 filing	Generally 17 years from grant
Expected ordinary expiration	2013
Current enforceability	Expired by statutory term
Current Paragraph IV exposure	None for this patent
Current injunction risk based solely on this patent	None
Current Orange Book exclusivity from this patent	None

The patent’s expiration means that its claims can still be relevant to historical freedom-to-operate analysis, prior-art review, prosecution strategy and validity assessments, but they cannot ordinarily support a new infringement action for post-expiration conduct.

A patent expiration does not eliminate other patents in the same technical field. Later patents could have separately covered:

Specific shell compositions;
Particle-size distributions;
Lyophilized products;
Vial and reconstitution systems;
Manufacturing controls;
Specific imaging indications;
Dosing regimens;
Combination imaging protocols; or
Particular gas and excipient combinations.

What is the Orange Book status of this patent?

U.S. Patent 5,529,766 is not a current source of Orange Book exclusivity. The Orange Book identifies patents and regulatory exclusivities associated with approved drug products when submitted and listed under FDA rules. A broad platform patent covering ultrasound microbubbles does not automatically appear in the Orange Book merely because a contrast product was approved.

The relevant FDA products have included protein-shell and non-protein-shell ultrasound contrast technologies. The principal U.S. commercial comparators are:

Product	Active gas or gas system	Shell technology	FDA status
Optison	Perflutren	Human serum albumin shell	FDA-approved ultrasound contrast agent
Definity	Perflutren	Phospholipid-based microspheres	FDA-approved ultrasound contrast agent
Lumason	Sulfur hexafluoride	Phospholipid-based microspheres	FDA-approved ultrasound contrast agent

FDA labeling identifies the composition, preparation, administration and safety requirements for these products. Optison is the closest commercial comparator to the protein/HSA/perfluorocarbon subject matter, while Definity and Lumason demonstrate the commercial importance of non-protein shell designs.[2-4]

How does the patent compare with Optison, Definity and Lumason?

5,529,766 versus Optison

Optison is the closest product-level comparison because it uses perflutren gas in human serum albumin microspheres. That combination maps conceptually onto:

Claim 1: protein microbubbles plus a fluorinated hydrocarbon;
Claim 2: perfluorinated hydrocarbon;
Claim 4: human serum albumin;
Claims 5 and 8: aqueous dispersions;
Claim 12 or 13: size-defined microbubbles, depending on the applicable product specification.

Whether a marketed product literally fell within the issued claims would depend on the precise shell structure, production process, gas composition and claim construction. The patent’s expiration removes current enforcement risk.

5,529,766 versus Definity

Definity uses a phospholipid shell rather than the protein shell expressly required by claims 3, 4, 9 and related dependent claims. Its perflutren gas may satisfy the gas portion of claim 1, but claim 1 still requires a protein capable of forming the microbubbles.

A phospholipid-only product would generally present a stronger noninfringement position against the protein limitations. The product could remain exposed to unrelated patents covering phospholipid microspheres, perfluoropropane formulations or vial activation systems.

5,529,766 versus Lumason

Lumason uses sulfur hexafluoride and a phospholipid shell. The sulfur hexafluoride limitation aligns with claim 1, but the protein-shell requirement is a material distinction.

A phospholipid-shell sulfur hexafluoride product would therefore be outside the most natural reading of the protein microbubble claims unless the formulation also includes a protein that performs the claimed shell-forming function. Separate patents and regulatory rights associated with sulfur hexafluoride microspheres remain relevant independently of this expired patent.

How strong was the patent estate?

The patent was structurally strong as a platform patent because it combined several claim categories:

Broad product claims;
Specific protein and HSA claims;
Gas-selection claims;
Aqueous-composition claims;
Crosslinked-shell claims;
Manufacturing claims; and
Vascular-imaging method claims.

Its strongest historical coverage was likely directed to protein-shelled perfluorocarbon microbubbles, particularly human serum albumin microspheres containing perfluorinated gases.

Its principal limitations were:

The protein-shell requirement excluded many phospholipid contrast agents.
The crosslinking claims required specified biodegradable chemistry.
The process claims were limited to recited generation or crosslinking steps.
The patent term ended before the current commercial expansion of several ultrasound contrast products.
The functional phrase "protein capable of formation" could have generated enablement and claim-construction issues across a broad range of proteins.

Patent strength is now historical rather than exclusionary. For current commercial analysis, later patents covering specific products and manufacturing systems are more important than the expired claims of U.S. 5,529,766.

Were there Paragraph IV challenges or patent settlements?

No current Paragraph IV challenge can be directed to U.S. Patent 5,529,766 because the patent has expired. Paragraph IV certifications address patents listed for approved drug products and cannot create an operative challenge to an expired patent.

The patent also does not create a current settlement barrier for generic or follow-on ultrasound contrast development. Any historical litigation or settlement involving protein microspheres, Optison, Albunex, Definity or related products would need to be analyzed separately from the present enforceability of this patent.

The commercially relevant current risk is not this expired patent. It is the existence of unexpired patents covering a particular competitor product, delivery format, manufacturing method or imaging indication.

What generic-entry risks remain after expiration?

A generic or follow-on manufacturer faces several distinct risks:

Risk category	Relevance to U.S. 5,529,766
Direct infringement	No current risk from the expired patent
Product similarity	High historical relevance, especially for HSA/perfluorocarbon bubbles
Regulatory equivalence	Significant; ultrasound contrast agents may require complex comparative characterization
Manufacturing know-how	Potentially significant even after patent expiration
Later patents	Potentially material and product-specific
Trade secrets	Possible for shell formation, vial preparation and stability controls
Clinical differentiation	Relevant where indications, safety data or imaging performance differ
Biosimilar risk	Not applicable in the ordinary biologic-biosimilar sense

Ultrasound contrast agents are not ordinarily analyzed as biosimilars merely because they contain albumin or another biological material. The principal regulatory issue is pharmaceutical equivalence, product performance, safety, imaging comparability and manufacturing consistency.

What licensing and commercial rights are relevant?

The patent’s commercial value would historically have depended on ownership and licensing within the ultrasound contrast sector, particularly for albumin-shell and fluorocarbon-gas products. The patent itself does not establish the existence, scope or continuing status of any license agreement.

After expiration, any historical license to the patent generally cannot preserve patent exclusivity against new entrants. Contractual obligations, know-how rights, trademarks and confidential manufacturing information can survive separately, but they are not rights created by the expired patent.

What geographic coverage did the patent have?

U.S. Patent 5,529,766 provided rights only in the United States. Related foreign applications or national-stage patents may have covered corresponding technology in Europe and other jurisdictions, but those rights had separate:

Filing dates;
Prosecution histories;
Claim scopes;
Maintenance requirements;
Patent-term calculations; and
Expiration dates.

A U.S. expiration does not establish that every corresponding foreign patent expired on the same date. A country-by-country freedom-to-operate review must examine the related family and national records.

Key Takeaways

U.S. Patent 5,529,766 covers protein-shelled gas microbubbles for ultrasound imaging.
Its principal gas scope includes sulfur hexafluoride and low-molecular-weight fluorinated hydrocarbons.
Claims 2-4 narrow the invention to perfluorinated hydrocarbons, albumin-class proteins and human serum albumin.
Claims 9-18 add biodegradably crosslinked protein shells, aqueous dispersions and diagnostic-agent limitations.
Claims 20-29 cover shaking, sonication and specified biodegradable crosslinking processes.
Claim 30 covers vascular ultrasound imaging using the claimed crosslinked contrast agent.
The patent’s ordinary U.S. term expired in 2013.
Optison is the closest commercial comparator because it uses human serum albumin microspheres and perflutren.
Definity and Lumason use phospholipid shells and provide stronger distinctions from the protein-shell limitations.
The patent creates no current Paragraph IV, Orange Book or injunction risk.
Current freedom-to-operate analysis must focus on later patents, regulatory requirements, manufacturing know-how and product-specific rights.

FAQs

Does U.S. Patent 5,529,766 cover perflutren?

Potentially, if the perflutren is contained in protein microbubbles satisfying the remaining claim limitations. Perflutren alone does not satisfy the claims because the claims also require a protein capable of forming the gas-containing microbubbles.

Does the patent cover sulfur hexafluoride contrast agents?

It can cover sulfur hexafluoride contrast agents with protein shells. A sulfur hexafluoride product with only a phospholipid shell would have a substantial distinction from the patent’s protein limitation.

Is Optison blocked by U.S. Patent 5,529,766?

The patent’s claim structure is technically relevant to Optison because Optison uses human serum albumin and perflutren. The patent expired, so it no longer blocks Optison, a generic, or a competing product.

Are ultrasound contrast agents biologics subject to biosimilar approval?

Not automatically. The regulatory pathway depends on the product’s classification, formulation, manufacturing process and FDA requirements. Albumin-containing microspheres are not automatically treated as biosimilars to a reference biologic.

Can a manufacturer avoid the patent by changing only the bubble-generation process?

That may avoid the process claims but not necessarily the product claims. A product with the same protein shell and qualifying gas could remain within the composition claims regardless of how it was manufactured.

References

U.S. Patent No. 5,529,766. (1996). Microbubbles. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (2023). Optison (perflutren protein-type A microspheres) injectable suspension: Prescribing information. FDA.
U.S. Food and Drug Administration. (2023). Definity (perflutren lipid microsphere) injectable suspension: Prescribing information. FDA.
U.S. Food and Drug Administration. (2023). Lumason (sulfur hexafluoride lipid-type A microspheres) for injectable suspension: Prescribing information. FDA.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA.
Leahy-Smith America Invents Act, Pub. L. No. 112-29, 125 Stat. 284 (2011).
35 U.S.C. §§ 154, 156, 271, 282.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	9106686	Mar 28, 1991

PCT Information
PCT Filed	March 28, 1992	PCT Application Number:	PCT/EP92/00716
PCT Publication Date:	October 15, 1992	PCT Publication Number:	WO92/17213

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	133158	⤷ Start Trial
Austria	134668	⤷ Start Trial
Austria	157547	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,529,766

Summary for Patent: 5,529,766