United States Drug Patent 5,639,443: Claim Scope, Expiration, and Ultrasound Microbubble Patent Landscape

United States Patent No. 5,639,443 covers ultrasound contrast-agent preparations, kits, and manufacturing concepts based on microbubbles containing a relatively mobile gas and a low-solubility, higher-molecular-weight vapor component. The claims emphasize fluorocarbon vapors, gas-exchange-driven bubble shrinkage, surfactant or protein membranes, and in-container sonication.

The patent issued on June 17, 1997. Its ordinary 20-year term from the earliest effective nonprovisional filing date appears to have expired in approximately 2015. The patent therefore does not present a current U.S. exclusion right unless an unusual patent-term adjustment or extension applied. The claims remain relevant as prior art and as technical indicators of the technology used in later ultrasound contrast agents, including products based on perfluorobutane, perfluoropentane, perfluorohexane, sulfur hexafluoride, and perflutren.

What does U.S. Patent 5,639,443 cover?

The patent covers compositions and kits that generate or contain ultrasound-responsive microbubbles. Its core technical concept is a bubble containing:

A first gas;
A second component that is the vapor of a compound liquid at 37°C and 760 mm Hg;
A second-component vapor pressure of at least 75 mm Hg at 37°C;
A defined molar ratio between the first gas and the second component;
A membrane surrounding the gas mixture.

Claim 1 is the principal composition claim. It requires the first gas and second component to be present in a molar ratio from approximately 1:100 to 1000:1. Water vapor is expressly excluded.

The specification and dependent claims target a physical mechanism in which the more soluble first gas diffuses out of the bubble more rapidly than the less soluble fluorocarbon vapor. The bubble initially shrinks, then stabilizes because the remaining vapor produces an osmotic pressure differential. Claims 4 through 6 and 27 through 29 define this behavior in quantitative terms.

The patent is broader than a claim directed to a specific marketed product. It claims a class of microbubble preparations, membranes, gas mixtures, prepackaged kits, and bubble-generation systems.

How are the 52 claims organized?

The claims divide into four principal groups.

Claim group	Claims	Primary subject matter
Core microbubble preparations	1-14	Gas mixture, vapor component, ratios, solubility, permeability, shrinkage and stabilization
In-container generation	15-16	Liquid, container and ultrasonic transmission membrane
Membrane materials	17-26	Surfactants, carbohydrates, phospholipids, solid or semisolid membranes and albumin
In vivo preparations	27-38	Blood-compatible bubble shrinkage, fluorocarbons and specified fluorocarbon combinations
Microbubble kits	39-52	Sealed containers, ultrasonic generation, dried void-containing structures and spray-dried microspheres

Claims 9 and 2 are materially similar. Claim 9 repeats the fluorocarbon/nonfluorocarbon relationship already introduced in claim 2. This repetition does not create an independent claim; it narrows claim 1 in the same general direction.

What elements must be present for infringement of claim 1?

A product would need to satisfy every limitation of claim 1. The key elements are:

Claim 1 limitation	Scope
Aqueous medium	The preparation must contain water-based liquid
Plurality of microbubbles	The product must contain multiple microbubbles
Generally spherical membrane	The bubbles must have a surrounding membrane
First gas	A gas component distinct from the second component
Second component	Vapor of a compound that is liquid at 37°C and 760 mm Hg
Vapor pressure	At least 75 mm Hg at 37°C
Molar ratio	First gas to second component from approximately 1:100 to 1000:1
Exclusion	Neither component may be water vapor

The claim does not require that the second component be a fluorocarbon. That limitation appears in dependent claims 2 and 9. Claim 1 could therefore encompass certain nonfluorocarbon volatile liquids if they meet the temperature, vapor-pressure and ratio limitations.

The claim also does not expressly require a particular membrane chemistry. The membrane may be a surfactant, protein, carbohydrate, phospholipid, solid material or semisolid material under the dependent claims.

What fluorocarbon microbubbles are protected by the patent?

Claims 2, 9-14 and 27-38 concentrate on fluorocarbon systems.

The principal combinations are:

A nonfluorocarbon first gas with a fluorocarbon second component;
At least two fluorocarbons as the second component;
A perfluorocarbon as the second component;
Fluorocarbons as both the first gas and second component;
A low-water-solubility second component;
A first gas with at least ten times the water solubility of the second component;
A membrane at least five times more permeable to the first gas than to the second component.

Claims 36 and 37 specifically identify gaseous perfluorobutane, perfluorohexane and perfluoropentane in ratios from approximately 1:10 to 10:1.

There is an important claim-construction issue. Claim 1 defines the second component as the vapor of a compound that is liquid at 37°C. Perfluoropentane and perfluorohexane have materially different boiling points and physical states at 37°C. A fluorocarbon that is gaseous at 37°C may not satisfy the second-component limitation of claim 1, although it may be used as the first gas or fall within the separate wording of claims 36 and 37. The interaction between claims 1, 36 and 37 would require analysis of the specification, prosecution history and claim-dependency rules.

How does the shrinkage and stabilization mechanism work?

Claims 4 through 6 and 27 through 29 require a specific performance profile.

The bubble must:

Begin at a first average diameter;
Have a first-gas-to-second-component ratio of at least 1:1;
Lose the first gas through the membrane;
Shrink to less than approximately 75% of its original diameter;
Remain stabilized at or near the reduced diameter for at least one minute;
Stabilize because of a gas osmotic pressure differential.

Claims 5 and 28 add a high gas-tension environment, including dissolved gas tension of at least approximately 700 mm Hg. Claims 6 and 29 specify an initial diameter of at least 10 micrometers and a final diameter between approximately 1 and 6 micrometers.

These limitations are narrower than ordinary claims to an ultrasound contrast agent. A product would not fall within these claims merely because its bubbles shrink in blood. The accused product would need to satisfy the stated size, ratio, shrinkage and stabilization conditions.

What membrane materials are covered?

Claims 17 through 26 cover a broad range of membrane materials.

Surfactant membranes

Claims 17 through 23 cover membranes formed from:

Surfactants generally;
Non-Newtonian viscoelastic surfactants;
Carbohydrates;
Polysaccharides;
Fatty-acid esters of sugars;
Sucrose stearate;
Phospholipids.

The phospholipid language is significant because modern ultrasound contrast agents commonly use phospholipid shells. The claim, however, does not cover every phospholipid microbubble automatically. The gas mixture and other limitations of the parent claim must also be met.

Protein and albumin membranes

Claims 24 through 26 cover solid or semisolid membranes and proteinaceous membranes, including albumin. These claims are technically relevant to protein-shelled ultrasound agents such as Optison, although product coverage would require satisfaction of the parent gas and vapor limitations.

Carbohydrate and polymer systems

The claims extend to carbohydrate membranes, fatty-acid sugar esters and other surfactant systems. This language creates potential historical overlap with early spray-dried or reconstituted microbubble technologies.

What do claims 39 through 52 cover?

Claims 39 through 52 are kit claims rather than direct claims to a preformed microbubble preparation.

Sealed-container kits

Claim 39 covers a sealed container containing:

A liquid;
A surfactant;
A fluorocarbon gas;
Components adapted to form microbubbles after energy is applied.

Claims 40 and 41 require a structure that transmits external ultrasonic energy through a flexible polymer membrane less than approximately 0.5 mm thick.

Claim 42 adds a nonfluorocarbon gas and a molar ratio between the nonfluorocarbon and fluorocarbon gases from approximately 1:10 to 1000:1.

Dried void-containing structures

Claim 43 covers a kit containing:

Dried, liquid-soluble, void-containing structures;
Voids with an average diameter below approximately 100 micrometers;
A liquid suitable for in vivo injection;
A gas in the voids;
A surfactant.

The gas must be the vapor of a nonaqueous material that is liquid at 37°C. Claims 44 through 52 narrow the system to surfactant-containing structures, non-Newtonian surfactants, sugar esters, phospholipids, proteins, carbohydrates, fluorocarbons, perfluorohexane and spray-dried microspheres.

These claims are directed to reconstitution and in situ bubble generation. They are relevant to products supplied as dry formulations or as systems that generate bubbles immediately before administration.

When did U.S. Patent 5,639,443 lose exclusivity?

The patent issued June 17, 1997, and appears to derive from an early-1990s priority chain. Under the post-1995 U.S. patent-term regime, the ordinary term is 20 years from the earliest effective nonprovisional filing date, not 17 years from issuance. On that basis, the patent’s ordinary term ended in approximately 2015. The U.S. Patent and Trademark Office patent record is the controlling source for the exact expiration date and any patent-term adjustment or disclaimer (U.S. Patent No. 5,639,443).

The patent is therefore expired and cannot ordinarily support a new U.S. infringement action against current products. Its claims can still matter in:

Prior-art analysis;
Invalidity and obviousness reviews;
Freedom-to-operate histories;
Patent-family landscaping;
Identification of technical disclosure dates;
Analysis of later patents claiming improved microbubble formulations.

What is the Orange Book status of Patent 5,639,443?

Patent 5,639,443 is not known as a current Orange Book-listed patent for Definity, Optison or Lumason. The Orange Book generally lists patents submitted by sponsors for approved drug products, including drug-substance, drug-product and method-of-use patents. A broad, expired platform patent is not itself a current Orange Book barrier unless it was properly submitted and remains within its enforceable term (FDA, 2025a).

The relevant FDA-approved ultrasound contrast products include:

Product	Active contrast component	Sponsor or current commercial owner	Shell or formulation type
Definity	Perflutren lipid microspheres	Lantheus Medical Imaging	Lipid-based microspheres
Optison	Perflutren protein-type A microspheres	GE HealthCare	Human serum albumin shell
Lumason/Sonovue	Sulfur hexafluoride lipid microspheres	Bracco	Phospholipid shell

The product labels describe the approved compositions and administration methods, but they do not establish that any product infringes an expired platform claim (FDA, 2024a; FDA, 2024b; FDA, 2024c).

Which current products are technically closest to the patent?

Definity

Definity uses perflutren, also known as octafluoropropane, in lipid microspheres. Its formulation is technically adjacent to the patent’s fluorocarbon and phospholipid concepts. The patent’s claims specifically emphasize mixtures involving a first gas and a volatile fluorocarbon component. Definity’s commercial formulation is not established by its label as the same claimed gas mixture or shrinkage system.

Optison

Optison uses perflutren gas in human serum albumin microspheres. The albumin-shell concept falls within the subject matter addressed by claims 25 and 26 at a high technical level. The product’s approved composition must still be compared against the complete limitations of the applicable claim.

Lumason/Sonovue

Lumason uses sulfur hexafluoride lipid microspheres. Its phospholipid-shell architecture is relevant to claim 23, but sulfur hexafluoride is not a fluorocarbon. The product therefore does not automatically satisfy claims limited to a fluorocarbon second component. The parent claim’s physical-state and vapor-pressure limitations also require separate analysis.

What patent landscape surrounds this technology?

The commercial ultrasound contrast market developed through several overlapping patent areas.

Patent area	Typical claim focus	Commercial relevance
Gas-mixture microbubbles	Volatile fluorocarbon vapor plus a more soluble gas	Early platform technology and bubble persistence
Lipid-shell microspheres	Phospholipid composition, shell architecture and stabilizers	Definity and Lumason-type products
Albumin-shell microspheres	Protein crosslinking and albumin matrix	Optison-type products
Dry powder or spray-dried agents	Reconstitution, porous particles and trapped gas	Manufacturing and point-of-care preparation
Container sonication	Flexible transmission membranes and in-container generation	Kit and device integration
Imaging methods	Organ imaging, perfusion, Doppler and echocardiography	Method-of-use and regulatory protection
Manufacturing processes	Emulsification, lyophilization, spray drying and sterilization	Process barriers and product consistency
Safety and administration	Dose, infusion, contraindications and imaging protocols	Regulatory differentiation rather than composition exclusivity

The most important later patent risk for a new entrant is unlikely to come from Patent 5,639,443 itself. It is more likely to arise from later, unexpired patents covering:

Specific lipid compositions;
Defined particle-size distributions;
Stabilizers and excipients;
Manufacturing conditions;
Dry powder reconstitution;
Device-assisted bubble formation;
Therapeutic or diagnostic uses;
Combination imaging protocols.

Are there Paragraph IV challenges involving this patent?

A Paragraph IV certification is relevant only while a listed patent remains in the Orange Book and is being challenged by an abbreviated new drug application. Patent 5,639,443 appears to be expired and is not a current product-specific Orange Book barrier for the principal ultrasound contrast agents.

Accordingly, there is no meaningful current Paragraph IV launch obstacle associated with this patent. A generic or follow-on ultrasound contrast product would instead face:

FDA requirements for demonstrating pharmaceutical equivalence or an appropriate comparative standard;
Product-specific formulation and manufacturing patents;
Device or container patents;
Clinical and safety requirements;
Patent rights unrelated to Patent 5,639,443.

Does biosimilar risk apply?

Biosimilar risk is limited because the principal products are drug-device or drug-microbubble contrast agents, not biologic medicines in the conventional biosimilar sense.

Optison contains albumin microspheres, but the commercial product is regulated as an ultrasound contrast agent rather than as a biosimilar reference biologic. Definity and Lumason are also not conventional biologic reference products for a biosimilar pathway. A competitor would generally evaluate an abbreviated drug pathway, a 505(b)(2) application, or another product-specific FDA route rather than a standard biosimilar application.

Patent 5,639,443 does not create a current biosimilar exclusion period.

What litigation and settlement issues affect the patent?

The supplied patent claims do not establish litigation history, and the patent’s expiration removes the principal basis for current injunctive enforcement. Historical litigation involving related ultrasound contrast patents may still be relevant, but it should not be attributed to Patent 5,639,443 without a case-specific docket or opinion.

No current settlement agreement can be inferred from the claim text. Any settlement involving Alliance Pharmaceutical, Lantheus, Bracco, GE HealthCare or another party would require a separate agreement, court filing or regulatory record.

How strong is the patent estate for a new ultrasound contrast product?

As a live U.S. patent, Patent 5,639,443 has no meaningful remaining term. As a prior-art reference, it is technically broad but claim-specific.

Factor	Assessment
Current enforceability	Low to none because the patent appears expired
Breadth of core composition claims	Broad, but constrained by physical-state, vapor-pressure and ratio limitations
Coverage of lipid-shell agents	Potentially relevant through claim 23, but not automatic
Coverage of albumin-shell agents	Potentially relevant through claims 25-26
Coverage of spray-dried products	Expressly addressed by claim 52
Coverage of current sulfur-hexafluoride products	Limited by fluorocarbon requirements in several dependent claims
Litigation leverage	Low after expiration
Prior-art significance	High for gas-exchange and fluorocarbon-vapor concepts
Current launch risk	Primarily from later patents, not this patent

What generic launch scenarios exist?

A competitor could pursue several commercial approaches.

Preformed lipid microspheres

A product using a preformed phospholipid shell and a persistent fluorocarbon gas would be technically close to the patent’s subject matter. Because the patent is expired, the commercial review would focus on later lipid-composition, manufacturing and method-of-use patents.

Albumin-based microspheres

An albumin-shell product would be historically close to claims 25 and 26. The main current barriers would be formulation reproducibility, protein manufacturing, regulatory comparability and later product-specific patents.

Dry reconstitutable kits

A spray-dried or porous-particle kit could implicate the technical concepts in claims 43 through 52. Patent 5,639,443 would not block launch after expiration, but later patents could cover particle morphology, gas loading, reconstitution time and packaging.

Sulfur hexafluoride systems

A sulfur-hexafluoride product is less directly aligned with the fluorocarbon-dependent claims. Its key patent issues would likely concern phospholipid shell composition, particle size, manufacturing and imaging applications.

Key Takeaways

Patent 5,639,443 covers microbubble preparations, fluorocarbon vapor systems, gas-exchange-driven shrinkage, surfactant and albumin membranes, sonication containers and reconstitution kits.
Claim 1 is the core composition claim and requires a first gas, a volatile liquid-at-37°C second component, a vapor pressure of at least 75 mm Hg and a defined molar ratio.
Claims 4 through 6 and 27 through 29 require measurable bubble shrinkage and stabilization behavior.
Claims 36 and 37 specifically address perfluorobutane, perfluoropentane and perfluorohexane combinations.
The patent appears to have expired in approximately 2015 under the 20-year patent-term framework.
It is not a current Orange Book barrier for the principal U.S. ultrasound contrast products.
Definity, Optison and Lumason are technically adjacent but cannot be classified as claim-covered products from product labels alone.
Current launch risk lies primarily in later formulation, manufacturing, device and method-of-use patents.
The patent remains important as prior art for fluorocarbon microbubble design and gas-diffusion stabilization.

FAQs

What is the expiration date of U.S. Patent 5,639,443?

The ordinary patent term appears to have ended in approximately 2015, calculated from the earliest effective nonprovisional filing date. The USPTO patent record controls the precise date and any adjustment.

Does Patent 5,639,443 cover Definity?

Definity is technically related because it uses perflutren in lipid microspheres. The claim text alone does not establish infringement because the complete gas composition, vapor-pressure and ratio limitations must be satisfied.

Does Patent 5,639,443 cover Optison?

Optison is technically relevant to the albumin-shell claims, particularly claims 25 and 26. The patent’s expiration means those claims do not create a current U.S. exclusion right.

Is perfluoropentane liquid at body temperature for purposes of claim 1?

The answer depends on the compound’s physical state and the claim-construction record. Perfluoropentane has a boiling point near body temperature, creating a material issue under claim 1’s requirement that the compound be liquid at 37°C.

Can a company file a Paragraph IV challenge against this patent?

Not as a practical current strategy unless the patent were listed for a relevant product and remained legally enforceable. An expired, nonlisted platform patent does not ordinarily support a Paragraph IV certification challenge.

References

U.S. Patent No. 5,639,443. (1997). Microbubble preparations and methods of use. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (2024a). Definity (perflutren lipid microsphere) injectable suspension prescribing information. Lantheus Medical Imaging.
U.S. Food and Drug Administration. (2024b). Optison (perflutren protein-type A microspheres) injectable suspension prescribing information. GE HealthCare.
U.S. Food and Drug Administration. (2024c). Lumason (sulfur hexafluoride lipid-type A microspheres) prescribing information. Bracco Diagnostics.
U.S. Food and Drug Administration. (2025a). Approved drug products with therapeutic equivalence evaluations. Center for Drug Evaluation and Research.

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

Summary for Patent: 5,639,443