US Patent 5,695,741: Scope, Claim Construction, Expiration, and Microbubble Patent Landscape

US Patent 5,695,741 covers dry, soluble microbubble precursor compositions that generate stabilized gas microbubbles when reconstituted in a liquid. Its central technical combination is a low-solubility fluorocarbon gas, a solid porous or void-containing carrier with particles generally below 100 micrometers, and a surfactant that stabilizes the resulting microbubbles. The patent also covers spray-drying and imaging methods using the reconstituted microbubbles.

The patent issued on December 9, 1997, and, based on the pre-URAA 17-year patent term applicable to the filing, expired on December 9, 2014, absent an unusual term adjustment. It therefore provides no current U.S. patent exclusionary right. Its commercial relevance is historical and freedom-to-operate related rather than an active blocking right.[1]

What does US Patent 5,695,741 protect?

The patent protects a platform technology for producing microbubble contrast agents from a dry precursor rather than supplying preformed bubbles in a liquid suspension.

The claimed architecture has four recurring elements:

A solid, substantially liquid-soluble structure.
Internal voids or pores generally smaller than about 100 micrometers.
A gas with low water solubility, principally a fluorocarbon.
A surfactant associated with the structure or incorporated into it.

When added to a suitable liquid, the solid structure dissolves and releases the gas. The gas expands or nucleates into microbubbles, while the surfactant forms or supports the bubble interface.

The claims cover compositions, imaging methods, gas mixtures, and the manufacturing process used to make the precursor.

Core patent data

Item	Information
U.S. patent	US 5,695,741
Issue date	December 9, 1997
Patent title	Microbubble precursor compositions and methods of making and using same
Technology	Dry microbubble precursor and ultrasound or MRI contrast imaging
Principal structural limitation	Solid, substantially liquid-soluble void-containing structures
Particle limitation	Average void or microsphere diameter below about 100 micrometers
Gas limitation	Fluorocarbon gas osmotic agent or qualifying low-solubility gas
Surfactant limitation	Phospholipids, fatty acids, block copolymers, sugar esters and related classes
Manufacturing route	Spray-drying followed by gas permeation or loading
Patent term	Expired in the United States in December 2014
Current blocking status	No live U.S. exclusionary term under this patent

How are the 76 claims organized?

The claim set contains four principal claim groups.

Claims 1 to 10: spray-dried microsphere compositions

Claim 1 is directed to a microbubble precursor containing:

A fluorocarbon gas osmotic agent;
Spray-dried microspheres;
An average microsphere diameter below about 100 micrometers;
A surfactant; and
Starch, derivatized starch, dextran, or a sugar ester with a hydrophilic/lipophilic balance component below about 8.

Claims 2 through 10 narrow the composition by adding voids, specified fluorocarbons, surfactant classes, non-Newtonian surfactants, proteinaceous microspheres, and additional carbohydrates.

Claim 1 is comparatively narrow because it requires both spray-dried microspheres and the specified carrier chemistry. A product using a non-spray-dried porous carrier would not literally satisfy this claim unless the carrier also fell within the claim construction of “spray dried microspheres.”

Claims 11 to 24: broader void-containing precursor compositions

Claim 11 is one of the broader composition claims. It requires:

Solid, substantially liquid-soluble void-containing structures;
Voids with an average diameter below about 100 micrometers;
A gas osmotic agent with water solubility of not more than about 0.5 mM at 25°C and one atmosphere;
A surfactant associated with the structures; and
Adaptation to form microbubbles on addition to a dissolving liquid.

Unlike claim 1, claim 11 does not expressly require spray-drying. It can potentially reach other porous or void-containing soluble structures if they satisfy the remaining limitations.

Claims 12 through 24 specify fluorocarbons, surfactants, carbohydrate carriers, proteinaceous structures, powders, sugar crystals, spray-dried sugar, dried lactose microspheres, and structures that themselves comprise the surfactant.

From an infringement perspective, claim 11 is more important than claim 1 because it does not depend on a particular manufacturing process. Its risk profile turns on whether the accused product has internal voids, whether the void dimensions are within the claimed range, and whether the carrier is substantially soluble in the reconstitution liquid.

Claims 25 to 39: imaging methods

Claim 25 covers a method comprising:

Providing a precursor within claim 11;
Dissolving at least part of the precursor in liquid;
Forming microbubbles surrounded by surfactant;
Introducing the microbubbles into a vertebrate; and
Imaging the microbubbles.

Claim 38 identifies ultrasound and magnetic resonance imaging. The method claims narrow the technology by specifying phospholipids, fluorocarbons, carbohydrates, proteins, spray-dried microspheres, and particular surfactant classes.

These claims are use claims rather than composition claims. They would have been relevant to a diagnostic contrast-agent manufacturer, imaging provider, or sponsor using the precursor in a vertebrate imaging protocol. Because the patent has expired, these claims no longer create current U.S. method-of-use exclusivity.

Claims 40 to 65: gas mixtures with modifier gases

Claim 40 covers a stable precursor containing:

Solid, substantially liquid-soluble void-containing structures;
At least one surfactant;
Voids below about 100 micrometers;
A gas mixture containing a fluorocarbon gas osmotic agent and a modifier gas.

Claim 46 defines the modifier gas as a nonfluorocarbon gas other than water vapor. Claim 47 requires a nonfluorocarbon-to-fluorocarbon molar ratio of approximately 1:10 to 1000:1.

This group is directed to controlling bubble formation, stability, dissolution behavior, or imaging performance through a mixed-gas system. It potentially covers formulations using nitrogen, oxygen, carbon dioxide, or other nonfluorocarbon gases, subject to the claim limitations and specification support.

There is a drafting defect in claim 41. It states, “The composition of claim 46,” even though claim 41 appears to depend substantively from claim 40. The claim also contains apparent typographical errors in chemical names, including “perfluoromethylcycopentane” and “perfluoromethylcyclohoxane.” Those defects could complicate claim construction and prosecution-history analysis. They do not revive the expired patent.

Claims 66 to 73: manufacturing process

Claim 66 covers a method of making the precursor by:

Spray-drying a liquid formulation;
Producing solid, substantially liquid-soluble microspheres;
Forming voids below about 100 micrometers; and
Permeating the microspheres with a fluorocarbon gas osmotic agent.

Claims 67 through 73 add surfactants, fluorocarbons, nonfluorocarbon gases, and storage in a container.

These claims focus on process steps rather than the final diagnostic use. A modern product could avoid literal infringement during the patent term by using a different particle-formation process, loading gas before drying, using preformed lipid vesicles, or employing a nonporous shell architecture.

Claims 74 to 76: dependent spray-dried microsphere claims

Claims 74 through 76 narrow claim 24 by specifying starches, derivatized starches, sugar esters, and surfactants such as phospholipids, block copolymers, fatty acids, and sugar esters.

These claims are chemically and structurally narrower than claim 11. They are more vulnerable to design-around strategies based on alternative excipients or carrier materials.

What technical features define the patent’s claim scope?

The patent’s claim scope is controlled by a combination of composition, particle, gas, surfactant, and functional limitations.

Void-containing solid structures

The “void-containing structures” limitation is central to claims 11, 24, 40, and 66. The claimed structure must be solid and substantially liquid-soluble, and it must define multiple voids. A conventional liquid-filled liposome, a preformed gas-filled microsphere, or a non-soluble polymer shell may fall outside the literal scope depending on its construction.

The claims do not require a particular void shape. They do require the claimed average diameter limitation. The distinction between “average diameter of the microspheres” and “average diameter of the voids” matters. Claim 1 focuses on microsphere diameter, while claim 11 focuses on void diameter.

Fluorocarbon gas osmotic agents

The fluorocarbon Markush lists include perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, perfluorohexane, cyclic fluorocarbons, and perfluorotriethylamine.

The broader functional gas limitation in claim 11 requires water solubility of not more than approximately 0.5 mM at 25°C and one atmosphere. A gas outside the listed fluorocarbons could potentially satisfy the broader limitation if it meets the solubility threshold and all other limitations.

Perfluoropropane and perfluorobutane are gaseous fluorocarbons commonly associated with ultrasound contrast-agent technology. Perfluorohexane is separately recited in claim 54.

Surfactant limitations

The surfactant provisions cover broad categories:

Nonionic surfactants;
Neutral and anionic surfactants;
Fluorinated surfactants;
Phospholipids;
Fatty acids;
Block copolymers;
Sugar esters; and
Non-Newtonian surfactants.

The HLB limitation of less than about 8 narrows certain claims. HLB is a formulation parameter rather than a single molecular identity. Its application may depend on the component being measured, the test method, and whether the claim requires the surfactant itself or a component of the surfactant to meet the threshold.

The term “non-Newtonian surfactant” is unusual. It may create construction issues because non-Newtonian behavior is ordinarily associated with the rheology of a formulation or suspension, not a surfactant molecule in isolation.

When did US Patent 5,695,741 lose exclusivity?

The patent lost enforceable U.S. exclusivity in December 2014 under the 17-year term applicable to the pre-June 8, 1995 filing framework. The patent issued in 1997, so the nominal term ran 17 years from issuance.[1]

Milestone	Date or status
Application filed	Before issuance in 1997, with priority in the mid-1990s
Patent issued	December 9, 1997
Nominal term	17 years from issue
Expiration	December 9, 2014
Current status	Expired
Paragraph IV relevance today	None under this patent
Current Orange Book blocking effect	None from this expired patent

The patent’s expiration eliminates both composition and method-of-use exclusivity. It also eliminates the practical value of a Paragraph IV challenge directed solely to this patent.

What is the Orange Book status of US Patent 5,695,741?

US Patent 5,695,741 is not a current Orange Book barrier because it expired in 2014. Any historical listing would no longer support a 30-month stay or other current statutory enforcement consequence.

The relevant contrast-agent products are approved under different FDA regulatory records:

Product	Active contrast material	Sponsor or manufacturer	FDA use
Optison	Perflutren protein-type A microspheres	GE Healthcare	Ultrasound contrast imaging
Definity	Perflutren lipid microspheres	Lantheus Medical Imaging	Ultrasound contrast imaging
Lumason	Sulfur hexafluoride lipid-type A microspheres	Bracco Diagnostics	Ultrasound contrast imaging

Optison was approved before Definity and Lumason. Definity and Lumason use lipid-based or lipid-associated microbubble systems, while Optison uses a proteinaceous shell architecture. Their approved products illustrate different technical approaches to stabilized ultrasound contrast agents.[2-4]

The FDA approvals do not establish infringement or noninfringement under the claims of US 5,695,741. They show that the commercial market developed around several different shell, gas, and manufacturing platforms.

Which companies challenged or competed against the patented technology?

The principal commercial competitors have been Lantheus, Bracco, and GE Healthcare.

Lantheus and Definity

Definity uses perflutren gas encapsulated in lipid microspheres. The product is supplied as a vial that is activated before administration. Its principal commercial value is ultrasound enhancement in echocardiography and other imaging applications.[2]

The product has conceptual overlap with the patent’s emphasis on fluorocarbon gases, surfactants, and microbubble formation. The disclosed and marketed product architecture is not enough to establish that it practices the claimed spray-dried, soluble, void-containing precursor.

Bracco and Lumason

Lumason uses sulfur hexafluoride in lipid-type A microspheres. It is supplied as a kit requiring reconstitution before injection. Its gas is not one of the fluorocarbons expressly listed in claims 3, 13, 28, 53, or 71. The broader gas-solubility limitation in claim 11 is also directed to a gas osmotic agent with very low water solubility, so a literal analysis would require product-specific data and claim construction.[3]

GE Healthcare and Optison

Optison uses perflutren gas in human serum albumin microspheres. The proteinaceous shell has a conceptual relationship to claims 8, 21, 36, 49, and 62, which recite proteinaceous microspheres or void-containing structures.[4]

The patent claims, however, generally require a substantially liquid-soluble solid precursor structure. A preformed albumin microsphere suspension may differ materially from the dry, dissolving, void-containing precursor required by claims 11, 25, 40, and 66.

How strong was the patent estate during its term?

During its term, the estate had meaningful breadth at the platform level but several limitations reduced practical enforcement strength.

Strengths

Claim 11 did not require spray-drying.
The claims covered both compositions and imaging methods.
The gas limitation included a functional low-solubility test.
The surfactant language reached phospholipids, block copolymers, fatty acids, sugar esters, and fluorinated surfactants.
Claim 40 added mixed fluorocarbon and modifier-gas systems.
Claim 66 targeted manufacturing, creating possible process-based infringement exposure.

Weaknesses

The 100-micrometer average-diameter requirement required reliable particle or void characterization.
“Substantially liquid-soluble” could create factual disputes for partially soluble or crosslinked materials.
“Adapted to form microbubbles” is functional language that may depend on performance testing.
“Non-Newtonian surfactant” is potentially ambiguous.
Claim 41 contains an incorrect dependency reference.
The Markush lists do not automatically cover every fluorinated gas.
The claims focus on dry soluble precursors and may not reach conventional preformed liquid microbubble products.
The patent expired before the modern commercial expansion of several ultrasound contrast products.

The strongest historical claims were likely claim 11, directed to the broad void-containing precursor, and claim 66, directed to spray-drying and gas permeation. Claim 1 was narrower because it required the specified spray-dried microsphere and excipient combination.

What manufacturing and intellectual-property barriers remain?

US Patent 5,695,741 no longer creates a manufacturing barrier. Current barriers arise from formulation know-how, regulatory approval, manufacturing validation, and later patent families.

Important technical barriers include:

Maintaining controlled void size and particle distribution;
Loading a low-solubility gas without premature loss;
Achieving reproducible reconstitution;
Preventing aggregation during storage;
Controlling bubble size after activation;
Maintaining sterility and container-closure integrity;
Demonstrating safety after intravenous administration; and
Validating imaging performance across ultrasound platforms.

Later patents may cover lipid compositions, activation devices, vial designs, excipient ratios, gas-shell interactions, dosing, imaging protocols, or manufacturing controls. Those rights must be reviewed separately from the expired '741 patent. An analysis limited to US 5,695,741 cannot establish freedom to operate for a current product against later-filed patents.

What generic-entry risks exist for products covered by this technology?

Traditional generic substitution is less direct for ultrasound contrast agents than for ordinary oral small-molecule drugs. These products are injectable diagnostic agents supplied with specialized preparation, activation, storage, and administration instructions.

Potential entrants may use:

A different gas;
A preformed liquid microsphere suspension;
A lipid shell instead of a carbohydrate or protein precursor;
A non-spray-dried manufacturing process;
A carrier that is not substantially liquid-soluble;
A particle or void size outside the claimed range; or
A different FDA approval pathway, including a 505(b)(2) application where appropriate.

Because the patent expired, US 5,695,741 does not delay a generic, follow-on, or competing contrast-agent launch. The principal risks are later active patents, FDA requirements, clinical comparability, manufacturing scale-up, and market access.

Does this patent create biosimilar risk?

No. The patent does not claim a biologic therapeutic, antibody, recombinant protein, or biosimilar reference product. Its claims cover microbubble precursor compositions and imaging methods.

Optison contains a proteinaceous microsphere component, but that does not make US 5,695,741 a biologic exclusivity patent. A follow-on Optison-type product would face product-specific FDA, manufacturing, clinical, and patent issues rather than biosimilar risk under this patent.

How does US 5,695,741 compare with modern ultrasound contrast-agent patents?

Attribute	US 5,695,741	Definity-type platform	Lumason-type platform	Optison-type platform
Primary gas concept	Fluorocarbon gas osmotic agent	Perflutren	Sulfur hexafluoride	Perflutren
Carrier emphasis	Soluble void-containing solids and spray-dried microspheres	Lipid microspheres	Lipid-type A microspheres	Proteinaceous microspheres
Reconstitution	Central to claimed precursor system	Activation before use	Reconstitution before use	Product-specific suspension handling
Claimed particle limitation	Generally below 100 micrometers	Product-specific	Product-specific	Product-specific
Imaging focus	Ultrasound and MRI	Ultrasound	Ultrasound	Ultrasound
Current '741 exclusion	None	None from '741	None from '741	None from '741
Main current legal risk	Later patent families	Later lipid and device patents	Later lipid and formulation patents	Later protein-shell and manufacturing patents

The commercial products overlap with the patent’s general objective, but product-level infringement cannot be inferred from therapeutic category, gas identity, or FDA labeling alone.

Key Takeaways

US Patent 5,695,741 covers dry microbubble precursors that dissolve in liquid and generate stabilized gas microbubbles.
Its core limitations are soluble solid structures, internal voids below about 100 micrometers, low-solubility gas, and surfactant stabilization.
Claims 1, 11, 40, and 66 are the main independent claim anchors.
The patent covers compositions, mixed-gas systems, imaging methods, and spray-drying processes.
Claim 11 is broader than claim 1 because it does not expressly require spray-drying.
Claim 66 is the key process claim and requires spray-drying followed by gas permeation.
The patent expired in December 2014 and has no current U.S. blocking effect.
Definity, Lumason, and Optison represent competing commercial architectures but cannot be classified as infringing or noninfringing without product-specific technical evidence.
There is no current Paragraph IV or biosimilar issue under this expired patent.
Current freedom-to-operate analysis must focus on later patents covering lipid shells, protein shells, activation systems, formulations, manufacturing, and imaging methods.

FAQs about US Patent 5,695,741

Does US Patent 5,695,741 cover Definity?

Not automatically. Definity uses perflutren lipid microspheres, but infringement would depend on whether its product and manufacturing process satisfy the specific soluble void-containing structure, particle-size, gas, surfactant, and method limitations. The patent is expired in any event.

Does US Patent 5,695,741 cover Lumason?

Not automatically. Lumason uses sulfur hexafluoride lipid-type A microspheres, while the patent’s principal listed gases are fluorocarbons. The broader gas-solubility claim would require a separate technical and legal analysis, but the patent’s expiration eliminates current enforcement risk.

What claim is broadest in US Patent 5,695,741?

Claim 11 is likely the broadest composition claim because it does not require spray-dried microspheres and instead focuses on soluble void-containing structures, low-solubility gas, surfactant, and microbubble formation upon reconstitution.

Can a company design around US Patent 5,695,741?

Yes, and the patent no longer needs to be designed around in the United States because it expired. Historically, potential design-arounds included preformed liquid microspheres, non-spray-dried carriers, non-soluble shells, alternative gases, and formulations outside the void-size limitation.

Are foreign equivalents of US Patent 5,695,741 still enforceable?

The U.S. expiration date does not determine foreign status. Foreign counterparts require jurisdiction-specific review of grant, maintenance fees, patent-term rules, supplementary protection, and expiration records. No foreign right can be assumed from the U.S. patent alone.

References

United States Patent and Trademark Office. (1997). US Patent No. 5,695,741, Microbubble precursor compositions and methods of making and using same. https://patents.google.com/patent/US5695741A/en
U.S. Food and Drug Administration. (2022). Definity (perflutren lipid microsphere) injectable suspension prescribing information. Lantheus Medical Imaging. https://www.accessdata.fda.gov/drugsatfda_docs/label/
U.S. Food and Drug Administration. (2023). Lumason (sulfur hexafluoride lipid-type A microspheres) prescribing information. Bracco Diagnostics. https://www.accessdata.fda.gov/drugsatfda_docs/label/
U.S. Food and Drug Administration. (2020). Optison (perflutren protein-type A microspheres) injectable suspension prescribing information. GE Healthcare. https://www.accessdata.fda.gov/drugsatfda_docs/label/

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Details for Patent: 5,695,741

Summary for Patent: 5,695,741