US Patent 10,583,208: Claim Scope, Definity Patent Landscape, and Generic Entry Risk

US Patent No. 10,583,208 covers ultrasound contrast imaging methods using lipid-encapsulated perfluorocarbon gas microspheres made from a highly specific phospholipid formulation with controlled calcium and magnesium impurities. The claims are directed to the manufacturing-and-use combination, not to every ultrasound contrast agent or every formulation containing DPPC.

The claim set appears directed to the formulation and manufacturing process used for perflutren lipid microspheres, commercially associated with Lantheus Medical Imaging’s Definity product. The most important limitations are the DPPA/DPPC/MPEG5000-DPPE composition, perfluorocarbon gas activation, stringent metal-ion specifications, and, in claims 10-18, the exclusion of methanol, toluene, and methyl-tert-butyl ether from suspension formation.

What does US Patent 10,583,208 cover?

The patent covers a method with three principal stages:

Combining an aqueous solvent with a phospholipid solution.
Activating the resulting suspension with a perfluorocarbon gas to form lipid-encapsulated gas microspheres.
Administering the microspheres and obtaining an ultrasound image.

Independent claim 1 requires all of the following:

Claim element	Required limitation
Imaging method	Ultrasound contrast imaging of a subject
Lipid components	DPPA, DPPC, and MPEG5000-DPPE
Additional solvent component	Propylene glycol
Manufacturing step	Aqueous solvent combined with phospholipid solution
Gas phase	Perfluorocarbon gas
Product	Lipid-encapsulated gas microspheres
MPEG5000-DPPE purity	Combined calcium and magnesium below 115 ppm
Phospholipid solution purity	Combined calcium and magnesium below 0.7 ppm
Use step	Administration to a subject followed by ultrasound imaging

Claim 10 contains the same core limitations but adds a process restriction: the phospholipid suspension must be formed under conditions free of methanol, toluene, methyl-tert-butyl ether, or MTBE.

The claims therefore combine product composition, raw-material quality, process conditions, and clinical use. A product that merely contains DPPC or perflutren would not necessarily fall within the claims.

How do the dependent claims narrow the patent scope?

Claims 2-9 and 11-18 add narrower formulation, purity, solvent, and composition limitations.

Phospholipid composition

Claims 2 and 11 require the following molar ranges:

DPPA: 5% to 15%
DPPC: 77% to 90%
MPEG5000-DPPE: 5% to 15%

Claims 3 and 12 narrow that formulation to approximately:

10% DPPA
82% DPPC
8% MPEG5000-DPPE

This composition is commercially significant because it resembles the phospholipid mixture used in Definity-type perflutren lipid microspheres.

Perfluorocarbon gas

Claims 4 and 13 specify perfluoropropane gas. Perfluoropropane is the gaseous component associated with perflutren lipid microspheres. These claims are narrower than claims 1 and 10, which use the broader term “perfluorocarbon gas.”

A competing product using sulfur hexafluoride, perfluorobutane, or another gas may avoid these narrower claims, although it would still need to be assessed against the broader independent claims if the remaining limitations are met.

Metal-ion specifications

Claims 5 and 14 impose component-level impurity limits:

Component	Combined calcium and magnesium limit
MPEG5000-DPPE	Less than 115 ppm
DPPA	Less than 780 ppm
DPPC	Less than 90 ppm
Propylene glycol	Less than 0.7 ppm
Phospholipid solution	Less than 0.7 ppm

These limitations create a substantial evidentiary issue. A patent owner would need to establish the relevant concentrations in the accused formulation or input material. A generic applicant could challenge infringement through batch-specific analytical testing, supply-chain records, certificates of analysis, or an argument that the claim’s measurement methodology is indefinite or not satisfied.

Solvent system

Claims 6 and 15 require a system containing:

Water
Glycerol
Propylene glycol
DPPA
DPPC
MPEG5000-DPPE

Claims 7 and 16 specify an approximate 8:1:1 ratio of water, glycerol, and propylene glycol.

Claims 8, 9, 17, and 18 permit salts or buffers in the aqueous solvent. These claims expand the permitted excipient system but remain dependent on the other required formulation and processing limitations.

What is the technical significance of the calcium and magnesium limitations?

The patent’s central technical distinction is control of divalent-metal impurities in the lipid and solvent system. Calcium and magnesium can affect phospholipid behavior, suspension properties, microsphere formation, stability, or product performance. The claims convert those process-quality requirements into legally enforceable limitations.

The most restrictive numerical requirement is the phospholipid-solution threshold of less than 0.7 ppm combined calcium and magnesium. That requirement applies in both independent claims. It is narrower and more difficult to verify than the 115-ppm limit assigned to MPEG5000-DPPE.

The claims do not state merely that the final microspheres must have low metal content. They specify the impurity concentration of the MPEG5000-DPPE and phospholipid solution. This distinction may matter in litigation because testing the finished drug product may not establish the condition of the starting material or intermediate solution.

How does claim 10 differ from claim 1?

Issue	Claim 1	Claim 10
Core formulation	DPPA, DPPC, MPEG5000-DPPE, propylene glycol	Same
Metal limits	Required	Required
Perfluorocarbon gas	Required	Required
Methanol exclusion	Not expressly required	Required
Toluene exclusion	Not expressly required	Required
MTBE exclusion	Not expressly required	Required
Dependent composition claims	Claims 2-9	Claims 11-18

Claim 10 is narrower because it includes negative process limitations. It may be more difficult to assert against a process that uses one of the excluded solvents. At the same time, a generic manufacturer using a solvent-free process could still face the claim if all other limitations are present.

What products are most exposed to US Patent 10,583,208?

The highest-risk products are perflutren lipid microsphere products that use the following combination:

DPPA, DPPC, and MPEG5000-DPPE
Perfluoropropane
Propylene glycol, glycerol, and water
Similar lipid molar ratios
Low calcium and magnesium raw materials
A solvent-free or restricted-solvent manufacturing process
Ultrasound imaging administration

Definity is the principal commercial reference point. Definity is an FDA-approved ultrasound contrast agent containing perflutren gas encapsulated in a lipid shell. The product is manufactured and marketed by Lantheus Medical Imaging. The FDA describes Definity as a perflutren lipid microsphere injectable suspension used for contrast-enhanced echocardiography and other ultrasound imaging applications.[1]

A product using a different lipid shell, different gas, or substantially different excipient system may present lower literal-infringement risk.

What is the likely patent landscape around Definity and perflutren lipid microspheres?

The relevant landscape includes several patent categories:

Patent category	Typical subject matter	Relevance to US 10,583,208
Lipid microsphere composition	Lipid shell and perfluorocarbon gas	Background and potential blocking rights
Manufacturing process	Mixing, activation, filling, and lyophilization	Directly relevant
Raw-material purity	Metal-ion, solvent, and impurity control	Core subject of US 10,583,208
Imaging use	Echocardiography, perfusion, and diagnostic imaging	Relevant to method claims
Stability and storage	Shelf life, reconstitution, and product performance	Potential continuation or related-family rights
Device and administration	Vial, activation system, injection, or delivery method	Separate infringement layer
Regulatory exclusivity	FDA drug listing and approved-use protection	Commercial entry issue, separate from patent validity

The patent should be analyzed together with earlier Lantheus patents covering lipid-encapsulated gas microspheres and methods for preparing perflutren products. It should also be compared with patents owned by Bracco for SonoVue, GE Healthcare for Optison, and other ultrasound contrast developers. Those products use different formulations and gases, reducing direct overlap in some cases.

What is the Orange Book status of US Patent 10,583,208?

The patent’s Orange Book relevance cannot be determined from the claims alone. Orange Book listing depends on whether the patent was submitted to FDA for an approved drug product and whether FDA accepted the patent for listing.

For an approved drug, a listed patent may be relevant to an Abbreviated New Drug Application through:

Paragraph IV certification, if the applicant asserts that the patent is invalid, unenforceable, or not infringed.
Paragraph III certification, if the applicant accepts delayed approval until patent expiration.
A section viii statement, if the applicant omits a patented method of use.

Because US 10,583,208 claims a method involving formulation, administration, and ultrasound imaging, its Orange Book treatment would depend on the scope of the approved labeling and the type of patent information submitted. A method-of-use patent does not automatically block all generic versions of the drug. Its effect depends on the approved use and the labeling proposed by the applicant.[2]

When does US Patent 10,583,208 lose exclusivity?

The patent issued on March 10, 2020. The enforceable expiration date is determined by the earliest effective nonprovisional filing date in the patent family, adjusted for patent-term adjustment and any applicable terminal disclaimer. The issue date alone does not establish the expiration date.

The USPTO Patent Center record and the front page of the issued patent control the continuity, priority, patent-term-adjustment, and terminal-disclaimer analysis.[3] A commercial freedom-to-operate opinion should therefore use the recorded expiration data rather than calculate term solely from the March 2020 issue date.

Regulatory exclusivity is separate. FDA exclusivity may expire before or after patent protection and is not extended merely because this patent remains enforceable.

Which generic entry scenarios create the greatest risk?

Scenario 1: Same formulation and same gas

A generic manufacturer using DPPA, DPPC, MPEG5000-DPPE, propylene glycol, glycerol, water, and perfluoropropane faces the highest risk. If the raw materials satisfy the claimed metal limits, the product could meet claims 1 and 2-9.

Scenario 2: Same formulation with higher metal impurities

A manufacturer could attempt to use materials exceeding one or more claimed thresholds. That approach creates potential noninfringement, but it may create regulatory, stability, or product-performance problems. It also requires reliable batch-level evidence.

Scenario 3: Different gas

Using sulfur hexafluoride or another gas could avoid claims 4 and 13, but not necessarily claims 1 and 10, which broadly recite perfluorocarbon gas. Whether the substitute gas is a perfluorocarbon would require chemical classification.

Scenario 4: Different lipid composition

Changing DPPA, DPPC, or MPEG5000-DPPE levels may avoid the narrower percentage claims. The independent claims still require all three lipids, however, so removing one component could provide a stronger design-around.

Scenario 5: Different manufacturing solvents

Claims 10-18 can be avoided if the process uses methanol, toluene, or MTBE, assuming the limitation is interpreted as requiring the absence of each listed solvent. That design-around would not avoid claim 1 and its dependents.

Scenario 6: Alternative imaging indication

Because the claims require administering the microspheres and obtaining an ultrasound image, a product used outside the claimed imaging context may raise different issues. Induced infringement risk can still arise if labeling, marketing, or instructions encourage the claimed use.

How strong is the patent estate?

The patent has moderate-to-strong commercial relevance but a narrower enforcement profile than a basic composition patent.

Strengths include:

Direct alignment with a commercially important perflutren lipid-microsphere formulation.
Quantitative impurity limitations that can distinguish manufacturing processes.
Independent claims covering both formulation and clinical use.
Dependent claims that capture a specific 10:82:8 lipid ratio and an 8:1:1 solvent ratio.
A second independent claim directed to restricted-solvent processing.

Potential weaknesses include:

The claims require multiple formulation and process facts to be proven simultaneously.
The low metal thresholds may create claim-construction and analytical-testing disputes.
Method claims require administration and imaging, not merely manufacture.
A competitor may design around the gas, lipid ratio, excipient system, solvent conditions, or impurity profile.
Patent validity may turn on prior art involving lipid microsphere formulations, purification, metal control, and solvent removal.

The patent is most valuable as part of a broader product-specific estate. Its commercial leverage is weaker if it is the only patent covering the product and stronger if related composition, manufacturing, formulation, and use patents remain enforceable.

What patent litigation and Paragraph IV risks should be evaluated?

A Paragraph IV challenger would likely focus on:

Anticipation by earlier perflutren lipid-microsphere formulations.
Obviousness of using low-metal phospholipid materials.
Whether the impurity thresholds are inherent in prior-art formulations.
Written-description support for the precise ppm limits.
Enablement of producing and measuring the claimed purity levels.
Indefiniteness of “about,” “free condition,” and combined calcium and magnesium measurements.
Whether the accused generic product performs every claimed method step.

A patent owner would likely emphasize the combination of formulation, impurity control, solvent restrictions, and imaging use rather than any single ingredient.

No settlement agreement, Paragraph IV notice, or litigation outcome can be attributed to US 10,583,208 from the claim text alone. Those issues must be confirmed through USPTO litigation records, FDA Paragraph IV notices, PACER, and the patent’s prosecution history.

Key Takeaways

US 10,583,208 is a formulation-process-use patent for lipid-encapsulated perfluorocarbon ultrasound microspheres.
The principal commercial target is a Definity-type perflutren formulation.
The critical limitations are DPPA, DPPC, MPEG5000-DPPE, propylene glycol, perfluorocarbon gas, and strict calcium/magnesium thresholds.
Claims 10-18 add solvent exclusions for methanol, toluene, and MTBE.
The 10:82:8 phospholipid ratio and 8:1:1 water/glycerol/propylene glycol ratio create narrower but commercially focused claim positions.
A generic using the same lipid system and perfluoropropane faces the highest infringement risk.
A different lipid, gas, solvent system, or metal profile may provide a design-around.
Exact patent expiration and Orange Book status require the official USPTO and FDA records, respectively.
The patent’s practical value depends on related composition, process, method-of-use, and regulatory exclusivity rights.

FAQs

Does US 10,583,208 cover all ultrasound contrast agents?

No. It covers methods using the specified phospholipid components, impurity limits, perfluorocarbon gas, microsphere formation process, administration, and ultrasound imaging steps.

Does using DPPC alone infringe this patent?

Not on the face of the asserted claims. The claims require DPPA, DPPC, and MPEG5000-DPPE together, plus the other listed limitations.

Can a generic avoid the patent by using sulfur hexafluoride?

It may avoid the narrower perfluoropropane claims, but sulfur hexafluoride is not automatically outside the broader “perfluorocarbon gas” language. The chemical identity and full formulation must be assessed.

Are manufacturing-only activities enough to infringe the independent claims?

The claims require administration to a subject and obtaining an ultrasound image. Manufacturing alone does not satisfy those express method steps, although induced or contributory infringement theories may present separate issues.

Is this patent a biosimilar patent?

No. It concerns a chemically defined ultrasound contrast agent and microsphere formulation, not a biologic reference product or biosimilar pathway.

References

U.S. Food and Drug Administration. (n.d.). Definity prescribing information. FDA.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA.
United States Patent and Trademark Office. (2020). U.S. Patent No. 10,583,208. USPTO Patent Center.

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Lantheus Medcl	DEFINITY	perflutren	INJECTABLE;INTRAVENOUS	021064-001	Jul 31, 2001		RX	Yes	Yes	10,583,208	⤷ Start Trial				METHOD OF USING THE DRUG SUBSTANCE/DRUG PRODUCT FOR ULTRASOUND IMAGING	⤷ Start Trial
Lantheus Medcl	DEFINITY RT	perflutren	INJECTABLE;INTRAVENOUS	021064-002	Nov 17, 2020		RX	Yes	Yes	10,583,208	⤷ Start Trial				METHOD OF USING THE DRUG SUBSTANCE/DRUG PRODUCT FOR ULTRASOUND IMAGING	⤷ Start Trial
>Applicant	>Tradename	>Generic Name	>Dosage	>NDA	>Approval Date	>TE	>Type	>RLD	>RS	>Patent No.	>Patent Expiration	>Product	>Substance	>Delist Req.	>Patented / Exclusive Use	>Submissiondate

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2017291815	⤷ Start Trial
Brazil	112018074469	⤷ Start Trial
Canada	3025580	⤷ Start Trial
China	109562194	⤷ Start Trial
China	116370659	⤷ Start Trial
Eurasian Patent Organization	201892568	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 10,583,208

Which drugs does patent 10,583,208 protect, and when does it expire?

Summary for Patent: 10,583,208