Details for Patent: 5,686,060

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Summary for Patent: 5,686,060

Title:	Stable microbubble suspensions comprising saturated phospholipids for ultrasound echography
Abstract:	Disclosed are injectable suspensions of gas filled microbubbles in an aqueous carrier liquid usable as contrast agents in ultrasonic echography. The suspensions comprise amphipathic compounds of which at least one may be a laminarized phospholipid as a stabilizer of the microbubbles against collapse with time and pressure. The concentration of phospholipids in the carrier liquid is below 0.01% wt but is at least equal to or above that at which phospholipid molecules are present solely at the gas microbubble-liquid interface. Also disclosed is a method of preparation of the stable suspensions of air or gas filled microbubbles.
Inventor(s):	Michel Schneider, Jean Brochot, Jerome Puginier, Feng Yan
Assignee:	Bracco Suisse SA
Application Number:	US08/420,677
Patent Claim Types: see list of patent claims	Composition; Compound;

United States Patent 5,686,060: Claim Scope, Expiration, and Ultrasound Contrast-Agent Patent Landscape

United States Patent No. 5,686,060 covers injectable ultrasound contrast suspensions containing a high concentration of microbubbles stabilized by a very low concentration of saturated phospholipid. The independent claim requires a specific combination of microbubble density, phospholipid chemistry, and phospholipid concentration. The patent is directed to suspension stability and echogenic performance rather than to a particular drug substance alone.

The patent’s enforceable term has expired under the standard 20-year patent-term rule. It therefore does not currently block manufacture, approval, sale, or use of an ultrasound contrast agent that falls within the former claim scope. Its technical disclosures remain relevant as prior art and as a marker for the development of phospholipid-stabilized microbubble products. [1], [2]

What does United States Patent 5,686,060 cover?

The patent covers an injectable suspension for ultrasonic echography with four central elements:

1. A liquid carrier.
2. At least 10^7 microbubbles per milliliter.
3. At least one saturated phospholipid.
4. A total phospholipid concentration below 0.01% by weight.

The claim is composition-focused. It does not require a particular diagnostic indication, injection route beyond the injectable nature of the suspension, device, imaging protocol, or manufacturing process.

Independent claim 1

Claim 1 is the principal scope-defining claim:

An injectable suspension for ultrasonic echography comprising a carrier liquid containing at least 10^7 microbubbles per milliliter and at least one saturated phospholipid, wherein the phospholipid concentration is below 0.01% by weight.

The claim requires all limitations to be present. A suspension containing microbubbles but no saturated phospholipid would not satisfy the claim. A phospholipid-stabilized suspension with a concentration of 0.01% by weight or higher would fall outside the literal concentration limitation.

The claim does not expressly limit:

• The identity of the gas;
• The bubble size;
• The identity of the liquid carrier;
• The specific saturated phospholipid;
• The method used to generate the bubbles;
• The indication, provided the suspension is injectable and intended for ultrasonic echography.

The claim is therefore broad at the level of formulation architecture but narrow at the level of quantitative thresholds.

How do the dependent claims narrow the patent scope?

The dependent claims add concentration ranges, stabilizers, phospholipid classes, manufacturing forms, particle-size characteristics, surfactants, and gas compositions.

Claim	Added limitation	Practical effect
1	At least 10^7 microbubbles/mL; saturated phospholipid below 0.01% by weight	Core composition claim
2	10^8 to 10^10 microbubbles/mL	Higher bubble-density embodiment
3	Phospholipid above 0.00013% by weight	Narrow range from above 0.00013% to below 0.01%
4	Stabilizer selected from sugars, oligosaccharides, polysaccharides, or hydrophilic polymers	Adds suspension-stability excipient
5	Hydrophilic polymer is polyethylene glycol	PEG-specific version of claim 4
6	Lamellar or laminar phospholipid forms and listed lecithins	Narrows phospholipid identity and physical form
7	Property-modifying substances such as cholesterol, sterols, tocopherol, antioxidants, or phosphatidylglycerol	Adds membrane or oxidation-modifying components
8	Phospholipid powder obtained by freeze-drying or spray-drying	Adds a preparation or storage form
9	Approximately 10^8 to 10^9 bubbles/mL, 0.5 to 10 micrometers, little or no storage variation	Adds particle-size and stability limitations
10	Up to 50% non-laminar surfactants	Permits a substantial additional surfactant fraction
11	Bubbles filled with SF6, CF4, freons, or air	Narrows the gas composition

Because these claims depend from claim 1, every dependent claim retains the core limitations of claim 1. For example, claim 11 does not cover any gas-filled microbubble suspension. It requires a gas listed in claim 11, a saturated phospholipid below 0.01% by weight, and at least 10^7 microbubbles per milliliter.

What formulation ranges are protected by Patent 5,686,060?

The most commercially relevant concentration window is the overlap between claims 1, 3, and 9:

• Microbubble concentration: approximately 10^8 to 10^9 per milliliter;
• Bubble diameter: 0.5 to 10 micrometers;
• Saturated phospholipid concentration: greater than 0.00013% and less than 0.01% by weight;
• Storage performance: little or no variation in bubble characteristics;
• Optional gas: SF6, CF4, air, or specified freons.

Claim 3 creates a quantitative lower boundary, but only for the dependent embodiment. Claim 1 remains open to phospholipid concentrations at or below 0.00013%, so long as the concentration remains below 0.01%.

The claims do not establish a single mandatory bubble-size range. Size appears only in claim 9. A product with bubbles outside 0.5 to 10 micrometers could still potentially fall within claim 1 if the other claim 1 requirements were met.

Saturated phospholipids and lecithins

Claim 6 identifies a broad group of phospholipid families, including:

• Phosphatidic acid;
• Phosphatidylcholine;
• Phosphatidylethanolamine;
• Phosphatidylserine;
• Phosphatidylglycerol;
• Phosphatidylinositol;
• Cardiolipin;
• Sphingomyelin.

The claim also requires that the phospholipids be at least partially in lamellar or laminar form. That limitation is more technically specific than claim 1 and would require evidence concerning the physical state of the formulation.

A product using a phospholipid outside the claim 6 list could remain within claim 1 if the material qualifies as a saturated phospholipid. Conversely, a listed phospholipid would not satisfy claim 6 unless the lamellar or laminar-form limitation is met.

How strong were the patent claims?

The strongest historical claim was claim 1 because it combined broad product coverage with measurable thresholds. A formulation provider could potentially avoid literal infringement by changing one central parameter:

• Reducing the bubble concentration below 10^7 per milliliter;
• Increasing the total saturated-phospholipid concentration to 0.01% by weight or higher;
• Using a non-phospholipid stabilizing architecture;
• Using a different formulation that did not contain a saturated phospholipid;
• Demonstrating that the bubbles were not present in the claimed concentration in the injectable carrier.

The principal validity and enforcement risks would have concerned:

1. Anticipation. Earlier ultrasound contrast-agent disclosures may have described gas-filled microbubbles, phospholipid stabilization, and injectable suspensions.
2. Obviousness. The use of phospholipids, sugars, PEG, cholesterol, and related excipients in liposomal or emulsion systems could support an obviousness challenge if the claimed numerical ranges were predictable.
3. Indefiniteness. Terms such as “little or no variation,” “saturated phospholipid,” and “at least partially in lamellar or laminar form” could generate claim-construction disputes.
4. Measurement methodology. Bubble count depends on the analytical method, sampling conditions, dilution, and bubble persistence. The same product could produce different reported concentrations under different testing protocols.
5. Enablement and written description. The patent claims broad classes of phospholipids, gases, stabilizers, and surfactants. The technical disclosure would have been important in assessing whether the full breadth was enabled.

The patent’s current practical strength is zero as an exclusion right because the term has ended.

When did United States Patent 5,686,060 lose exclusivity?

Patent 5,686,060 is expired. Utility patents generally receive a term of 20 years from the earliest effective nonprovisional filing date, subject to patent-term adjustment and limited statutory extensions. [2]

The patent issued in 1997, but its term was governed by the post-1995 20-year rule rather than by the older 17-year-from-issuance rule. On that basis, the patent expired no later than the applicable 20-year term measured from its effective filing date, absent a documented term adjustment or extension.

The patent does not provide a current barrier to:

• Generic or follow-on ultrasound contrast-agent development;
• Use of SF6, air, CF4, or other gas systems;
• Use of phosphatidylcholine or related phospholipids;
• Commercial formulations meeting the historical claim parameters.

Patent expiration does not remove the relevance of other unexpired patents covering particular products, manufacturing processes, delivery systems, or formulation improvements.

What is the Orange Book status of Patent 5,686,060?

Patent 5,686,060 should not be treated as a current Orange Book barrier solely because it covers an ultrasound contrast suspension. Orange Book listing is product-specific and depends on FDA submission and sponsor listing practices. The Orange Book identifies patents submitted by NDA sponsors for approved drug products; it does not automatically include every patent that technically covers a formulation category. [3]

The principal ultrasound contrast products in the United States have included:

Product	Active gas or imaging component	Sponsor or major commercial party	Regulatory category
Lumason, marketed outside the U.S. as SonoVue	Sulfur hexafluoride microbubbles	Bracco	FDA-approved injectable ultrasound contrast agent
Definity	Perflutren lipid microspheres	Lantheus	FDA-approved injectable ultrasound contrast agent
Optison	Perflutren protein-type microspheres	GE Healthcare	FDA-approved injectable ultrasound contrast agent

FDA labeling describes the formulation, gas, excipients, preparation, administration, contraindications, and handling requirements for each product. [4]-[6]

An Orange Book-listed patent for a specific approved product could create a separate regulatory or litigation issue even if Patent 5,686,060 has expired. A Paragraph IV certification would be relevant only to a current unexpired patent listed against the reference product in an abbreviated application. The expired patent itself cannot support a new Paragraph IV-based launch dispute.

Does the patent create biosimilar risk?

No. Patent 5,686,060 is directed to an injectable microbubble suspension and is not a biologic patent. Biosimilar procedures under the Public Health Service Act do not apply to this patent. [7]

Follow-on products would generally be evaluated through drug approval pathways, including an abbreviated application or a 505(b)(2) application, depending on formulation differences, reference-product status, clinical requirements, and the FDA’s determination of pharmaceutical equivalence and bioequivalence. [8]

The relevant competitive risk is generic or follow-on drug risk, not biosimilar risk.

What manufacturing and intellectual-property barriers remain?

The expired patent did not eliminate other technical barriers. Current developers may still face protection or know-how relating to:

• Microbubble generation and size control;
• Gas loading and retention;
• Lyophilized or spray-dried precursor systems;
• Vial reconstitution;
• Phospholipid film formation;
• Sterility and endotoxin control;
• Particle-size distribution;
• Shelf-life and storage stability;
• Injection-device compatibility;
• Manufacturing scale-up;
• FDA comparability and clinical performance requirements.

The commercial product may be difficult to replicate even when the principal formulation patent has expired. Regulatory approval requires more than matching the broad claim language. The sponsor must establish quality, safety, imaging performance, labeling compliance, and manufacturing control.

Which products are most relevant to the historical claim scope?

Lumason or SonoVue

Lumason uses sulfur hexafluoride, one of the gases expressly identified in claim 11. Its phospholipid-based microbubble architecture makes it technically close to the historical subject matter. That overlap does not create current infringement exposure because Patent 5,686,060 has expired. Current risk would depend on later, unexpired patents directed to the commercial product, manufacturing process, or specific formulation.

Definity

Definity uses perflutren lipid microspheres. Perflutren is not expressly listed in claim 11, which identifies SF6, CF4, freons, and air. A Definity-related analysis would therefore turn on claim 1 and the dependent claims other than claim 11, including whether the product contains a saturated phospholipid below 0.01% by weight and whether the claimed microbubble concentration is present in the relevant suspension.

Optison

Optison uses a protein-based microsphere platform rather than the phospholipid-centered architecture emphasized by the patent. Its technical relationship to claim 1 would depend on the product’s actual excipient composition and whether a saturated phospholipid is present at the claimed concentration. A protein-stabilized product without the claimed phospholipid would generally fall outside the literal scope.

What patent litigation or settlement agreements affect this patent?

No current enforcement or settlement right can arise from Patent 5,686,060 because the patent has expired. The provided record does not establish a historical litigation docket, Paragraph IV case, or settlement agreement specifically tied to this patent. Those matters should not be inferred from the existence of the patent or from later litigation involving Lumason, Definity, Optison, or other ultrasound contrast products.

The more relevant present-day litigation questions concern later patents owned by Bracco, Lantheus, GE Healthcare, or other developers. Those patents may cover particular lipid mixtures, gas compositions, lyophilized products, vial systems, manufacturing methods, or clinical uses.

How should a competitor assess generic launch risk?

A competitor can use Patent 5,686,060 as expired prior art, but should separate three issues:

1. Patent freedom to operate. The patent itself does not block launch.
2. Regulatory pathway. A follow-on product still requires FDA approval and may need clinical or comparative imaging data.
3. Later patent exposure. Unexpired patents covering a reference product, process, formulation, or method of use may remain relevant.

For a proposed SF6 phospholipid microbubble product, the highest historical overlap would be with claims 1, 2, 3, 6, 9, and 11. For a perflutren lipid product, claims 1, 2, 3, 6, and 9 would be more relevant than claim 11. For a protein-stabilized product, claim 1 may be avoidable if no saturated phospholipid is used.

Key Takeaways

• Patent 5,686,060 covers injectable ultrasound contrast suspensions with at least 10^7 microbubbles per milliliter and saturated phospholipid below 0.01% by weight.
• Claims 2 through 11 narrow the invention through bubble density, phospholipid concentration, stabilizers, phospholipid classes, particle size, surfactants, and gas identity.
• SF6 is expressly covered by claim 11, while perflutren is not expressly listed in that claim.
• The patent’s term has expired under the 20-year utility-patent term framework.
• The patent creates no current blocking right and cannot independently support a new Paragraph IV challenge or infringement action.
• The relevant current risks are later patents, FDA requirements, manufacturing know-how, and product-specific Orange Book listings.
• Biosimilar procedures do not apply because the patent covers a drug formulation rather than a biologic.
• Product-level analysis must distinguish Lumason, Definity, Optison, and later follow-on formulations.

Frequently Asked Questions

Does Patent 5,686,060 cover all ultrasound contrast agents?

No. It covers a defined subset of injectable microbubble suspensions containing a saturated phospholipid below 0.01% by weight and at least 10^7 microbubbles per milliliter.

Is sulfur hexafluoride protected by Patent 5,686,060?

Sulfur hexafluoride is expressly identified in claim 11. The claim also requires the other limitations inherited from claim 1.

Can an expired patent still block FDA approval?

No. An expired patent cannot block approval on patent-enforcement grounds. FDA may still require evidence of quality, safety, efficacy, and manufacturing control.

Does changing the phospholipid concentration avoid the claims?

Increasing the concentration to 0.01% by weight or higher would avoid the literal concentration limitation of claim 1. A complete freedom-to-operate analysis would still need to assess later patents and possible equivalents issues.

Is a follow-on ultrasound contrast product a biosimilar?

No. Ultrasound contrast agents are regulated as drugs, and a follow-on product would generally be assessed under an applicable drug approval pathway rather than the biosimilar pathway.

References

1. United States Patent and Trademark Office. (1997). United States Patent No. 5,686,060: Ultrasound contrast agents.

2. United States Code. (2023). 35 U.S.C. § 154: Contents and term of patent; provisional rights.

3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations [Orange Book].

4. U.S. Food and Drug Administration. (2024). Lumason (sulfur hexafluoride lipid-type A microspheres) prescribing information.

5. U.S. Food and Drug Administration. (2024). Definity (perflutren lipid microsphere) prescribing information.

6. U.S. Food and Drug Administration. (2024). Optison (perflutren protein-type A microspheres) prescribing information.

7. Public Health Service Act, 42 U.S.C. § 262.

8. Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 355.

Drugs Protected by US Patent 5,686,060

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

International Family Members for US Patent 5,686,060

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0619743		C300061	Netherlands
European Patent Office	0619743		29/2001	Austria
European Patent Office	0619743		SPC/GB01/043	United Kingdom