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Patent landscape, scope, and claims: |
Scope, claim architecture, and US patent landscape for US Drug Patent 6,033,645
What does US 6,033,645 claim protect?
US 6,033,645 claims methods for ultrasound imaging using a contrast composition built around aqueous delivery of gas (or gas precursor) plus lipid-based carriers, with a rate control parameter designed to “substantially eliminate ultrasound artifacts.” The claim set is dominated by a single inventive theme:
- Administer (or flush) an aqueous vesicle/lipid-gas composition
- Use ultrasound scanning to form a “visible image” of an internal region or diseased tissue
- Maintain a delivery regime that includes continuous infusion
- Use specific quantitative administration/flush rate windows (vesicles/Kg-sec, and gas volume equivalents/Kg-sec; plus mL/sec flushing rates)
- Constrain composition specifics through nested dependent limitations: liposomes/micelles, phospholipid identities, PEG/hydrophilic polymer, and fluorinated gases/perfluorocarbons and/or specific precursor boiling point
The independent claim family is not limited to a particular anatomy beyond dependent claims that include heart region.
What are the core independent claim “pillars”?
The claim set contains multiple independent “method for providing an image” and “method for diagnosing” formulations that vary by (1) whether the composition is administered vs flushed, and (2) whether the carrier is framed as vesicle composition vs broader lipid composition vs surfactant composition.
Pillar A: Administration with continuous infusion (vesicle/lipid + gas)
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Claim 1: method for imaging internal region
- administer vesicle composition in aqueous carrier comprising gas (or gaseous precursor) + lipid vesicles
- scan with ultrasound imaging
- administer at a rate that substantially eliminates artifacts
- administration rate comprises continuous infusion
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Claim 37: method for imaging internal region
- administer lipid composition in aqueous carrier comprising lipid + gas/precursor
- similar artifact-eliminating continuous infusion rate concept
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Claim 123: diagnosing diseased tissue by imaging
- administer vesicle composition
- scan for diseased tissue with the same artifact-elimination continuous infusion rate
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Claim 124: diagnosing diseased tissue using lipid composition
- lipid + gas with continuous infusion artifact-elimination rate concept
Pillar B: Flushing regime with continuous infusion (vesicle/lipid + gas)
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Claim 50: method for imaging internal region
- administer vesicle composition
- flush the composition
- scan with ultrasound imaging
- flushing rate substantially eliminates artifacts and includes continuous infusion
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Claim 76: similar flushing but framed as lipid composition
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Claim 125 and Claim 126: diagnosing diseased tissue with administered + flushed compositions (vesicle vs lipid)
Pillar C: Rate-control method as the invention target
- Claim 88: “substantially eliminating ultrasound artifacts” by regulating the rate at which a contrast agent is administered
- administration is continuous infusion
- contrast agent defined via vesicle composition with gas + lipid vesicles (dependent coverage expands)
This is important for landscape analysis because it captures method infringement even where a court interprets composition terms narrowly, as long as the accused system matches the rate control and includes the defined contrast agent structure.
Pillar D: Non-vesicle carrier embodiments (surfactants)
The claim set also extends beyond lipid vesicles:
- Claim 205: vesicle composition comprising gas + vesicles comprising surfactants
- Claim 209: composition comprising surfactant and gas/precursor (no explicit vesicle structure required in the base statement, though further dependent claims can narrow it)
- Claims 213, 217: analogous “administer + flush” and “flush with continuous infusion” structures using surfactant-based compositions
- Corresponding diagnosing claims: 225, 229, 233, 237 and similar dependents
This broadens the field of potentially infringing modalities from lipid vesicles to surfactant-based ultrasound contrast formulations under the same continuous infusion + artifact-elimination rate concept.
What are the major claim terms that define scope?
1) Contrast composition elements
Across the principal claim sets, the contrast agent is characterized by:
- Aqueous carrier
- Gas or gaseous precursor
- A carrier phase, depending on claim group:
- vesicles comprising lipids (Claims 1, 50, 88, 89, 123, 125, etc.)
- lipid composition comprising lipid (Claims 37, 76, 124, 126, etc.)
- vesicles comprising surfactants (Claim 205)
- surfactant + gas/precursor composition (Claims 209, 217, 229, etc.)
2) Artifact elimination through administration/flush “rate windows”
This is the strongest claim-scoping lever.
A. Vesicle administration rate windows (vesicles/Kg-sec)
- Claim 23: about 1×10^6 to less than 8×10^6 vesicles/Kg-sec
- Claim 24–28 narrow to bands such as:
- 1×10^6 to 7×10^6
- 1.5×10^6 to 6×10^6
- 2×10^6 to 5.5×10^6
- 2.5×10^6 to 5×10^6
- 3×10^6 to 4.5×10^6
B. Gas administration rate windows (cc gas/Kg-sec)
- Claim 29: about 1×10^-7 to about 3×10^-3 cc gas/Kg-sec
- Narrowed by dependents (Claims 30–36), including:
- 3×10^-6 to 3×10^-3
- 4×10^-6 to 2×10^-3
- 8×10^6(?) to 2×10^-3 cc gas/Kg-sec (claim text appears internally inconsistent in exponent notation; however the presence of the dependent windows is still part of the claim architecture)
- 1×10^-5 to 1×10^-3
- 4×10^-5 to 1×10^-3
- 8×10^-5 to <1×10^-3
- 1×10^-4 to 9×10^-4
C. Flush rate windows (mL/sec)
- Claim 70: about 0.01 to 2.4 mL/sec
- Claims 71–75 provide nested narrowing to:
- 0.05 to 2
- 0.07 to 1.8
- 0.09 to 1.6
- 0.1 to 1.5
- 0.3 to 1.3
D. Continuous infusion
Continuous infusion appears as a mandatory element of the administration/flush rate for independent claims (1, 37, 50, 76, 88, 123, 124, 125, 126, etc.) and also recurs in artifact-eliminating subclaims.
3) Vesicle structure granularity (unilamellar/oligolamellar/multilamellar)
The claims push composition specificity down to vesicle architecture and bilayer count:
- Claims 127–129: lipid-coated bubbles; vesicles selected from unilamellar/olig( o )lamellar/multilamellar
- Claims 130–133: unilamellar with one monolayer; one bilayer; with perfluoropropane (for certain dependent branches)
- Mirror sets appear for alternative claim branches (Claims 135–138, 141–144, 146–149, 151–157, 159–163, 165–170, etc.)
This structure-specific layering narrows infringement for products that use mixed-size or structurally heterogeneous carriers without the defined lamellarity.
4) Lipid chemistry and substitutions
A nested set of dependents specify phospholipids and even individual molecular species:
Phospholipid backbone class (Claims 4–6 etc.)
- phospholipids include phosphatidylcholine, phosphatidylethanolamine, phosphatidic acid
Specific phosphatidylcholine species (Claim 6)
- dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine
and dpalmitoylphosphatidylcholine singled out (Claim 7)
Specific phosphatidylethanolamine species (Claim 8)
- dipalmitoylphosphatidylethanolamine, dioleoylphosphatidylethanolamine, N-succinyldioleoylphosphatidylethanolamine, 1-hexadecyl-2-palmitoylglycerophosphoethanolamine
and dipalmitoylphosphatidylethanolamine singled out (Claim 9)
Specific phosphatidic acid species (Claim 10)
- dipalmitolylphosphatidic acid
5) Polymer/PEG inclusion
- Claim 11–13: lipid further comprises a polymer; polymer comprises hydrophilic polymer such as polyethylene glycol (PEG)
Other claim branches replicate PEG inclusion (Claims 163–164).
6) Gas scope: fluorinated gases/perfluorocarbons and defined boiling point
- Claim 14–17: fluorinated gas; includes perfluorocarbon, sulfur hexafluoride, heptafluoropropane
- Claim 17 expands perfluorocarbon selections to perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, perfluorocyclobutane
- Claim 18: gaseous precursor boiling point > about 37° C
- Claim 19–21: gaseous precursor includes fluorinated compound, perfluorocarbon
- Claim 21: perfluoropentane and perfluorohexane (note these additions widen beyond early perfluoromethane/perfluoroethane lists)
Later dependents (Claims 179, 182, 185, 188, etc.) expand gas/precursor coverage broadly to:
- nitrogen
- sulfur hexafluoride
- perfluoromethane through perfluorononane (multiple perfluoroalkanes and rings)
And include combination gas:
- nitrogen + perfluoropropane (e.g., Claims 180, 183, 186, 189, 192, etc.)
7) Anatomy
- Claim 22 and corresponding dependents: internal region comprises heart region
All other dependent “diseased tissue” claims are generic for diseased tissue detection.
8) Reconstruction from lyophilized composition
Several claims add:
- composition is reconstructed from a lyophilized composition (Claims 178, 181, 184, 187, 190, 193, 196, 199, 202, etc.)
This adds manufacturing/format specificity, typically relevant to products formulated as freeze-dried contrast components.
How broad is protection vs how quickly does it narrow?
Broadeners
The broadest claim statements are the “rate-regulation + continuous infusion + ultrasound imaging” constructs (e.g., Claims 1, 37, 88, 123, 124, 209), plus the expansion to “surfactant” compositions (Claims 205, 209, 213, 217).
Narrowers
Infringement typically becomes harder when the accused system deviates from the nested dependencies, especially for:
- specific phospholipid species
- specific vesicle lamellarity (monolayer/bilayer counts)
- perfluoropropane-specific branches
- PEG/hydrophilic polymer presence if asserted under those dependent claims
- the specific numeric rate windows, particularly mL/sec flush windows and vesicles/Kg-sec bands
What is the claim-to-infringement “map” used in practice?
In freedom-to-operate and design-around analysis, the easiest match is where an accused product aligns with the rate control first, then overlays composition.
Infringement sequencing that matters
- Is the ultrasound artifact elimination achieved by regulating dose rate with continuous infusion? (Claim 88 is the “rate control” anchor.)
- Does the administered/ flushed contrast contain gas/precursor + vesicles/lipids/surfactant?
- Do the carrier structure and gas types match the dependent subsets?
- Do numeric ranges match (vesicles/Kg-sec, cc gas/Kg-sec, mL/sec flush)?
What is the likely internal patent landscape around US 6,033,645 (claims and continuation effects)?
Within a single US patent document, landscape impact comes from:
- dense dependent claims that cover multiple embodiments (vesicle, lipid, surfactant)
- repeated parallel structures for imaging vs diagnosing
- parallel “administer” vs “flush” versions
- multiple independent-style claim heads across variants
That structure indicates the inventors sought to cover:
- the modality (ultrasound)
- the formulation (gas + lipid/surfactant carriers)
- the operational delivery parameter (continuous infusion rate and flushing regime)
- multiple chemical and structural implementations (phospholipid identities, PEG, lamellarity, gas identity lists, lyophilized format)
Landscape implication for competitors
A competing ultrasound contrast program that:
- uses gas-loaded micro/nano carriers, and
- administers by infusion and attempts to reduce acoustic artifacts via dose ramping/rate control
is exposed if it also falls into the rate windows and continuous infusion requirements.
A program that changes only lipid species may still infringe broader claims that do not require those nested dependencies, particularly where the asserted claim is nearer the independent “composition + rate regulation” anchor. Conversely, if litigation asserts dependent claims with phospholipid identity or vesicle lamellarity, the ability to design around by changing lipid chemistry or lamellarity becomes more meaningful.
Key “design-around levers” implied by the claim text
The claim set implies four principal degrees of freedom for non-infringement strategies:
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Break the continuous infusion requirement
- if dosing is bolus-based or intermittent in a way that does not meet “continuous infusion,” the “rate comprises continuous infusion” language is an attack surface (Claims 1, 37, 50, 76, 88, 123, 124, 125, 126, etc.)
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Target a rate outside the numeric windows
- avoid vesicles/Kg-sec windows (Claims 23–28, 101–106)
- avoid cc gas/Kg-sec windows (Claims 29–36, 107–114, etc.)
- avoid flushing mL/sec windows (Claims 70–75, 82–87, etc.)
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Alter the carrier chemistry class
- if the product uses a contrast mechanism not based on lipid vesicles and not within surfactant compositions as claimed, it can reduce alignment. The patent explicitly includes surfactants, so design-around must address beyond “not lipids.”
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Change vesicle architecture or structure
- where asserted claims require monolayer/bilayer lamellarity and specific perfluoropropane combinations, structural dissimilarity is a stronger lever.
What are the practical claim scope boundaries? (Summary table)
| Dimension |
What the claims require |
Key claim ranges/windows |
| Modality |
ultrasound imaging to obtain “visible image” of internal region/diseased tissue |
Claims 1, 37, 50, 76, 123–126, etc. |
| Core contrast |
aqueous carrier + gas/precursor + vesicles comprising lipids (or lipid composition; or surfactant compositions) |
Claims 1, 37, 50, 76; 205, 209, 213, 217 |
| Rate control |
artifact elimination via administration/flush rate that “comprises continuous infusion” |
independent claim heads (1, 37, 50, 76, 88, 123, 124, 125, 126, etc.) |
| Vesicle dose rate |
vesicles/Kg-sec |
~1×10^6 to <8×10^6 (Claim 23); multiple narrowed bands (24–28; 101–106) |
| Gas dose rate |
cc gas/Kg-sec |
~1×10^-7 to ~3×10^-3 (Claim 29); nested windows (30–36; 107–114) |
| Flush rate |
mL/sec flushing |
~0.01 to 2.4 mL/sec (Claim 70); nested bands (71–75; 82–87) |
| Lipid chemistry |
phospholipid class and species |
Claims 4–10 and dependents; phosphatidylcholine species and phosphatidylethanolamine species |
| Polymer |
hydrophilic polymer such as PEG |
Claims 11–13; 163–164 |
| Gas type |
fluorinated gases, perfluorocarbons, sulfur hexafluoride, heptafluoropropane; plus broad perfluoroalkane range; nitrogen combinations |
Claims 14–21; 179, 182, 185, 188, 191, 194, 197, 200, 203, 207, 208, etc. |
| Vesicle architecture |
unilamellar/oligolamellar/multilamellar; monolayer/bilayer |
Claims 127–149; 150–176; etc. |
| Formulation |
reconstituted from lyophilized composition |
Claims 178–203, 206–204, 214–240 style dependents |
| Anatomy |
heart region |
Claims 22 and 81/69/122 equivalents |
Key Takeaways
- US 6,033,645 is anchored on ultrasound artifact elimination through controlled delivery rate with continuous infusion of a gas/precursor-loaded aqueous contrast carried by lipid vesicles/lipids or surfactant-based compositions.
- Scope is broad at the top level (imaging and diagnosis; administration vs flushing; vesicles vs lipid vs surfactant carriers), then narrows via explicit nested limitations covering:
- numeric delivery/flush rate windows
- phospholipid classes and specific species
- PEG inclusion
- gas identity lists
- vesicle lamellarity and monolayer/bilayer structure
- lyophilized reconstitution format
- The rate-regulation independent claim (Claim 88) is a principal landscape risk driver for competing products that attempt to solve artifact artifacts by controlling infusion rate rather than changing chemistry alone.
FAQs
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Which element most directly governs whether a competing ultrasound contrast regimen infringes US 6,033,645?
The method claims repeatedly require an administration or flushing regimen whose rate substantially eliminates ultrasound artifacts and comprises continuous infusion, with multiple numeric windows tied to vesicle dose, gas dose, or flush volume.
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Does the patent require lipid vesicles specifically?
Many claims require vesicles comprising lipids (and phospholipid sub-sets), but the claim set also includes surfactant-based compositions (e.g., surfactant vesicles and surfactant + gas compositions), expanding coverage beyond purely lipid systems.
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How do the numeric rate ranges affect freedom-to-operate?
They create clear factual thresholds. If accused dosing does not meet the recited bands (vesicles/Kg-sec, cc gas/Kg-sec, or mL/sec flush), it is less likely to fall within those dependent claim scopes.
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Can changing the phospholipid avoid infringement?
It may avoid narrower dependent claims that specify phosphatidylcholine/phosphatidylethanolamine/phosphatidic acid species. However, broader independent claim heads that do not include those specific lipid identities can still be asserted if the accused system meets the rate/continuous infusion and carrier composition requirements.
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Is the heart region a required limitation?
No. Heart imaging appears as a dependent anatomical limitation (e.g., “heart region”), while the principal imaging claims cover internal regions generally and diseased tissue generally.
References
[1] US Patent No. 6,033,645, “Method for providing an image of an internal region of a patient using ultrasound and gas-containing vesicles with controlled infusion rates.” (Claim text provided in prompt).
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