|
Patent landscape, scope, and claims: |
US Patent 5,605,673 Microbubble Method Claims and Patent Landscape (Scope, Claim Strength, and Freedom-to-Operate Considerations)
US 5,605,673 is a process patent centered on producing stabilized gas microbubbles for ultrasound and/or MRI imaging using (i) specific gas combinations defined by molar ratios and vapor pressure criteria, (ii) membrane-forming materials that can be surfactants (including non-Newtonian surfactants), (iii) optional shrink-then-stabilize regimens, and (iv) multiple alternative architectures for microbubble formation and in-vial half-life using gas-osmotic agents and spray-dried/starch or surfactant-containing solids.
High-level scope answer (what the claims cover): the claims are not limited to a single active gas or a single formulation “shell.” They broadly cover microbubble production methods where the bubble contains a “first gas” and a second volatile component (not water vapor) satisfying (a) a strict molar ratio window (generally 1:100 to 1,000:1 or other subranges), and (b) a vapor-pressure threshold at 37°C, and the bubble is surrounded by a membrane-forming material. The later dependent claim set expands coverage to halogenated gases in void structures, imaging use with the claimed microbubble preparations, and spray-dried/in-vial stable microbubble-generation approaches using gas osmotic agents (often fluorocarbons) and film-forming carbohydrate or protein materials.
High-level strength answer (where infringement risk concentrates): infringement risk concentrates where a competitor uses the same “core mechanics” the claims require: membrane formation around gas pairs with the same vapor-pressure/molar-ratio constraints; gas-osmotic agents and permeation through a film/surfactant-containing matrix; and spray-dried microsphere powders that reconstitute to microbubbles with specified or implied residence time/half-life improvements. Designs that substitute a different second component outside the specified vapor-pressure criterion, use water vapor as the second component, or omit the gas-osmotic stabilization pathway can reduce direct claim coverage.
What is missing for a complete legal landscape: the prompt provides only the claim text for US 5,605,673 and not the patent bibliographic data (publication number, filing date, issue date confirmation, jurisdiction-specific status, prosecution history) or a list of other related patents (continuations/divisionals, family members, assignees, or competing estates). Without that, a complete “landscape” cannot be produced without inventing facts. The analysis below therefore stays within the provided claim scope and derives enforceable coverage boundaries, design-around levers, and risk mapping that apply directly to US 5,605,673.
What microbubble formation steps are claimed in US 5,605,673?
Core claim 1 sets the “first gate” and the “second gate.”
It requires:
- A first gas and a second component.
- A molar ratio of first gas to second component of about 1:100 to about 1,000:1.
- The second component comprises vapor of a compound that:
- is liquid at 37°C and 760 mm Hg, and
- has vapor pressure ≥ 75 mm Hg at 37°C, and
- the first gas and second component are not water vapor.
- Membrane forming material surrounding the first gas + second component to form microbubbles in a liquid.
Claim 1 scope implications
- The “second component” is not generic; it is constrained by state at physiological conditions (liquid at 37°C/760 mm Hg) plus minimum vapor pressure at 37°C.
- The claim is written to cover vapor-phase delivery of that second component inside the bubble environment. Competitors using gases that do not meet the vapor-pressure threshold at 37°C fall outside the literal language.
- The “not water vapor” proviso is a direct exclusion. Using water vapor as the vapor component is designed out, at least for literal coverage.
Dependent claim anchor points
- Claim 2: membrane forming material is a surfactant.
- Claim 3: surfactant can be non-Newtonian.
- Claim 33-36: second component comprises gas osmotic agent, including fluorocarbons; claim 36 specifies perfluorohexane.
- Claims 38 and 39-41: the membrane forming material is enumerated broadly, including phospholipids, block copolymers, sugar esters, fatty alcohols, amine oxides, hyaluronic acid esters/salts, poly(ethyleneoxy)ethanol, derivatized starches and dextrans, sorbitol derivatives, gelatin/serum albumin, and combinations.
H2: What membrane materials (surfactant vs polymer vs protein) trigger direct coverage?
Direct coverage is satisfied when the method uses the claimed membrane forming material as the “surrounding” material. The membrane forming material is not limited to one chemistry family in claim 38.
- Surfactant route:
- Non-Newtonian surfactant: claims 3, 45, 64, 78, 79, 56/57/58 (via surfactant selection).
- Broad membrane-formers:
- Phospholipids, block copolymers, sugar esters, fatty alcohols, aliphatic amine oxides, hyaluronic acid derivatives, PEO-ethanol and nonylphenoxy PEG analogs, derivatized starches, hydroxyethyl starch fatty acid esters, food vegetable starch, dextrans/dextrin fatty acid esters, sorbitol/sorbitol fatty esters, gelatin, serum albumin.
Practical scope read: a product shell that is a surfactant-based film is the most direct fit; a polymer film also can fit if it functions as “membrane forming material” under claim 38’s enumerated list.
H2: Are the vapor-pressure and “not water vapor” constraints absolute?
Yes on the face of claim 1. Literal infringement requires:
- the second component vapor comes from a compound meeting the liquid and vapor pressure criteria at 37°C, and
- neither first gas nor second component is water vapor.
How does claim 4’s microbubble shrink-and-stabilize regimen expand the protected process?
Claim 4 builds an additional procedural stage beyond the initial formation of microbubbles.
It requires:
- Initially forming microbubbles with a first average diameter.
- Initial ratio of first gas to second component in those microbubbles is at least about 1:1.
- Contacting the microbubbles with a liquid medium.
- Shrinking microbubbles as a result of loss of the first gas through the membrane.
- Stabilizing the microbubbles at a second average diameter of less than about 75% of the first diameter for at least one minute.
Claim 5 adds a specific stabilization physics test
Stabilization is by providing a gas osmotic pressure differential across the membrane such that:
- the tension of gas(s) dissolved in the medium is equal to or greater than the partial pressure of the same gas(s) inside the microbubbles.
Claim 6 sets a first diameter floor
- first diameter is at least about 5 μm.
H2: What design choices reduce exposure to claim 4/5?
- If a process does not include the shrink step driven by loss of the first gas through the membrane, claim 4’s multistep regimen is not met.
- If stabilization is not based on the osmotic differential relationship in claim 5, the process may avoid that dependent set.
- If the bubble size evolution does not reach a second diameter <75% of initial diameter or the stabilization time is <1 minute, claim 4 can be bypassed.
What halogenated-gas void-structure microbubble method is claimed in claims 7–9?
Claim 7 introduces a second formation architecture: dissolve solid/semi-solid void-containing structures in a liquid where they are soluble.
Requirements:
- Provide solid or semi-solid substantially liquid-soluble void-containing structures defining plurality of voids each with diameter < 100 μm.
- Provide a halogenated gas in voids.
- Provide a surfactant.
- Put void structures + halogenated gas + surfactant into admixture with a liquid in which void-containing structures are soluble.
- Dissolve the void-containing structures in the liquid so the halogenated gas forms microbubbles surrounded by surfactant.
Claim 8 and 9 specify preferred void structures and gas ratios
- Claim 8: void structures are microspheres.
- Claim 9: microbubbles contain a first gas and a second halogenated gas with molar ratio 1:100 to 1000:1.
H2: Which halogenated gases are within the claim set?
- Claim 42/43/44 and parallel dependent sets restrict halogenated gas embodiment to fluorocarbons, including (as listed) perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethylcyclobutane, perfluoropentane, perfluorocyclopentane, perfluoromethylcyclopentane, perfluorodimethylcyclobutane(s), perfluorohexane and others, perfluorotriethylamine.
- Claim 44: perfluorocarbon includes perfluorohexane.
H2: What surfactants are encompassed in the void-structure embodiment?
- Claim 45/46: surfactant can be non-Newtonian and includes nonionic, neutral, anionic, neutral fluorinated, anionic fluorinated surfactants and combinations.
- Claim 47: surfactant can be among the same broad enumerated set (phospholipids, block copolymers, sugar esters, fatty alcohols, aliphatic amine oxides, hyaluronic acid esters/salts, PEO-ethanol and nonylphenoxy PEG, derivatized starches, hydroxyethyl starch fatty acid esters, vegetable starches, dextrans/dextrin fatty acid esters, sorbitol and sorbitol fatty acid esters, gelatin, serum albumin).
Practical exposure read: if a competitor dissolves a solid or semi-solid void-containing microsphere with fluorocarbon gas loaded into the voids, and uses surfactant to stabilize the microbubbles on dissolution, they are close to direct literal coverage.
Does US 5,605,673 cover ultrasound/MRI imaging uses?
Yes, claim 10 is a method-of-use claim.
Claim 10 requires:
- Introducing a microbubble preparation according to claim 1.
- Then imaging at least a portion of the body by ultrasound or magnetic resonance (MRI).
Dependent claims on anatomical target and preparation type
- Claim 11: body is a vertebrate and introduced into vasculature or body cavity.
- Claims 12–14: preparation is as defined in claims 2, 7, or 8 respectively.
- Claims 15–18: further require preparing the microbubble preparation prior to introduction according to the specified method (claim 1, 4, 5, or 7 respectively).
H2: What imaging modalities and routes are explicitly included?
- Imaging: ultrasound or MRI.
- Administration: via vasculature or body cavity in vertebrates (for claim 11).
Scope implication: even if a competitor argues about formation method differences, an imaging method that uses microbubble preparations made by the claimed methods can still implicate method-of-use coverage.
What in-vial stability and spray-dried microbubble methods are claimed (claims 19–32, 28–31, 29–32)?
This is the largest “commercially relevant” portion of the claim set for product design. It ties microbubble stability and half-life to spray-dried powders, gas osmotic agents, and specific film-forming components.
Claim 19: spray drying + gas osmotic agent + reconstitution
Requires:
- Spray dry a liquid formulation containing a biocompatible film-forming material to form microsphere powder.
- Combine microspheres with a gas osmotic agent and store in a container with the agent.
- Mix aqueous phase with powder; powder substantially dissolves to form microbubbles.
Claim 20–22: film-former is starch/derivative and parameters
- Film-forming material comprises starch or derivatized starch (claim 20).
- Starch/derivative has:
- molecular weight > 500,000 or
- dextrose equivalency value < 12 (claim 21).
- Starch can be hydroxyethyl starch (claim 22).
Claim 23: non-Newtonian surfactant can be the film-former
- Film-forming material comprises non-Newtonian surfactant.
Claim 24: gas osmotic agent comprises fluorocarbon
Claim 25–27: sugar ester options
- Film-forming material can comprise a sugar ester (claim 25).
- Sugar ester component has hydrophilic-lipophilic balance < 8 (claim 26).
- Sugar ester includes sucrose tristearate (claim 27).
Claim 28: gas osmotic agent-permeated surfactant-containing powder
- Provide a gas osmotic agent-permeated surfactant-containing powder.
- Combine with an aqueous phase.
Claim 29: spray dried starch/dextrin + gas osmotic agent + half-life requirement
Requires:
- Provide spray dried formulation comprising starch, derivatized starch or dextrin.
- Provide gas osmotic agent that permeates the formulation.
- Combine with aqueous phase to form microbubbles with in vivo half-life ≥ 20 seconds.
Claims 30–31: spray dried microspheres with inflating agent
- Claim 30: spray dried in combination with an inflating agent to form spray dried microspheres.
- Claim 31 inflating agent examples:
- methylene chloride, Freon 113, perfluorohexane, carbon dioxide.
Claim 32: add sugar polyester
- Spray dried formulation further comprises a sugar polyester.
H2: Which fluorocarbons are expressly used as gas osmotic agents?
A long dependent list is provided under claims 35/43/54/67/81 and others. The set includes perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethylcyclobutane, perfluoropentane, perfluorocyclopentane, perfluoromethylcyclopentane, perfluorodimethylcyclobutanes, perfluorohexane, perfluorocyclohexane, perfluoroheptane, perfluorocycloheptane, perfluoromethylcyclohexane, perfluorodimethylcyclopentane, perfluorotrimethylcyclobutane, and perfluorotriethylamine.
H2: How does claim 29’s “half-life ≥ 20 seconds” constrain scope?
Direct coverage for claim 29 depends on achieving an in vivo half-life at or above 20 seconds after reconstitution. Competitors can lower exposure by:
- using different film-formers outside claim 29’s categories, or
- using gas osmotic agents that do not permeate as required, or
- failing to meet the in vivo half-life threshold.
How broad is US 5,605,673 in terms of “what exactly must be inside the microbubble”?
Claim architecture coverage map
- Claim 1: first gas + second component defined by vapor pressure/liquid state and molar ratio + membrane surrounding.
- Claim 7: halogenated gas loaded into void structures; dissolution forms bubbles in surfactant.
- Claims 19 and 29: powders and agents engineered to yield microbubbles after reconstitution with stability/half-life outcomes.
H2: Are “molar ratio windows” consistent across embodiments?
Yes, the claim set repeatedly uses molar ratio constraints:
- Claim 1: about 1:100 to about 1,000:1.
- Claim 4: initial microbubbles have first gas:second component ≥ 1:1.
- Claim 9: first gas:second halogenated gas 1:100 to 1000:1.
- The same ratio window appears in the dependent family logically aligned with the gas-combination embodiments.
H2: What is the key “negative limitation”?
- Both first gas and second component are not water vapor (claim 1). That single proviso can matter in any formulation strategy using water vapor generation to supply the “second component.”
How strong is the patent estate around this claim set (claim strength and obvious design-arounds)?
Within the claim text, strength is driven by three features:
-
Numeric and functional constraints
- Vapor pressure ≥ 75 mm Hg at 37°C for the second-component precursor (claim 1).
- Bubble diameter reductions and stabilization duration (claim 4).
- In vivo half-life ≥ 20 seconds (claim 29).
- Size limits for void structures (<100 μm) (claim 7).
-
Mechanistic stabilization and permeation concepts
- Claim 5’s gas osmotic pressure differential relationship.
- Claim 29’s “gas osmotic agent permeates” the spray-dried formulation.
-
Broad membrane-forming material universe
- Claim 38 provides extensive membrane-formers. That breadth increases the chance that a competitor’s shell overlaps, even when chemistry differs.
Design-around levers derived directly from claim limitations:
- Remove the vapor-pressure-qualified second component pathway (claim 1).
- Use a second component that is water vapor or otherwise outside claim 1’s “not water vapor” and vapor pressure criteria (claim 1).
- Avoid the shrink-then-stabilize workflow with loss of the first gas through the membrane and stabilization below 75% diameter for ≥1 minute (claim 4/5/6).
- Avoid halogenated gas created by void structure dissolution (claim 7/8/9).
- In in-vial stability products, avoid spray-dried starch/dextrin + permeating gas osmotic agent + reconstitution yielding in vivo half-life ≥20 seconds (claim 29).
- Avoid using gas osmotic agent-permeated surfactant-containing powder architecture (claim 28).
- For imaging claims, ensure the administered microbubble preparation is not made using claim 1/2/7/8 methods and does not meet those preparation definitions before use (claim 10–18).
Which competitive strategies are most likely to overlap the claim scope?
Most overlap (highest risk)
- Microbubble platforms using:
- fluorocarbon osmotic agents (especially perfluorohexane),
- starch or derivatized starch spray-dried microspheres,
- surfactant-containing shells,
- reconstitution to yield microbubbles with meaningful in vivo persistence,
- and optionally a shrink-and-stabilize step with osmotic differential stabilization.
Lower overlap (often safer)
- Systems that:
- do not use the vapor-pressure-defined second component from claim 1,
- do not employ the gas-osmotic permeation and reconstitution schema,
- or omit the specific timing/size evolution required by claim 4/6 or the 20-second in vivo half-life requirement of claim 29.
Key Takeaways
- US 5,605,673 is a multi-pronged microbubble IP document covering gas-pair formation with tight vapor and molar-ratio constraints, membrane/surfactant architectures, optional shrink-and-osmotically stabilize workflows, a void-structure dissolution route using halogenated (fluorocarbon) gases, and a spray-dried powder + gas osmotic agent approach aimed at in-vivo microbubble persistence (half-life ≥20 seconds).
- The claims are most exposed where a competitor uses fluorocarbon gas osmotic agents, permeation through film/surfactant matrices, and starch/dextrin spray-dried powders that reconstitute into microbubbles meeting the stated stability outcomes.
- Strong direct infringement posture is created by numeric thresholds: vapor pressure (claim 1), bubble size/time changes (claim 4), and in vivo half-life (claim 29).
FAQs
-
Does US 5,605,673 require fluorocarbon gases to be used in all embodiments?
No. Fluorocarbons are explicitly tied to gas osmotic agent embodiments (e.g., claim 33-36, 24, 35, 42-44 and related lists) and halogenated gas embodiments (claim 7 and dependent claims), but claim 1’s “second component” is defined by vapor pressure/liquid state rather than exclusively by fluorocarbon identity.
-
Can a competitor infringe claim 10 (imaging) without practicing claim 1?
Claim 10 depends on “a microbubble preparation according to claim 1.” If the administered preparation does not meet the claim 1-defined preparation criteria, direct literal coverage for claim 10 is reduced.
-
What is the most restrictive element of claim 1?
The “second component” vapor must come from a compound that is liquid at 37°C/760 mm Hg and has vapor pressure ≥75 mm Hg at 37°C, with the added exclusion that neither first gas nor second component is water vapor.
-
What does claim 29 add that claim 19 does not?
Claim 29 includes an explicit performance requirement: microbubbles formed after combining the spray-dried formulation with an aqueous phase must have an in vivo half-life of at least about 20 seconds.
-
How can a formulation team reduce risk against claims 28–32?
Avoid a gas osmotic agent-permeated spray-dried starch/dextrin formulation that reconstitutes into microbubbles meeting the claim’s timing and composition constraints, especially where the process aims at the in vivo half-life benchmark tied to claim 29.
References
- United States Patent 5,605,673. “Methods for forming microbubbles” (claims as provided).
More… ↓
⤷ Start Trial
|
