DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Application
Claims 1-14, 17-19, and 21-23 are under examination.
Drawings
The drawings are objected to because of the following reasons:
Figures 5A, 5B, 5C, 7B, 7C, 8C, 9C and 10C, 13E, 14A, 14B, 14C, 16A, and 16B have grayscale that does not sufficiently detail to correlate the graph to the legends.
Figures 7A, 7C, 11C, 11D, 12, and 17 images are blurry and difficult to read.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The abstract of the disclosure does not commence on a separate sheet in accordance with 37 CFR 1.52(b)(4) and 1.72(b). A new abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text.
Claim Objections
Claim 11 is objected to because of the following informalities: grammar, the phrase “average pore diameter than the porous membrane” in line 3 should read “average pore diameter of the porous membrane” or similar. Appropriate correction is required.
Claim Interpretation
Claims 1-3, 6, 21, and 23 recite “extruder” and/or “depot”. The examiner notes that the term extruder refers to a syringe as in figure 3 and depot refers to the internal space in the syringe. For the purposes of examination, the examiner interprets any art with syringes as reading on “extruder” and “depot”.
Claim 9 recites optional language. The phrase following “optionally” is not required by the claim. For the purposes of examination, the examiner interprets any art, regardless of whether it comprises centrifuging step following “optionally” as reading on this claim limitation.
Claim 9 recites the phrase, “to remove foam”. The examiner notes that this phrase is an intended use. The examiner further notes that the specification does not provide additional information as to what the requirements are for a filter to remove foam. Therefore, for the purposes of examination, any prior art containing a filter that could be used to remove foam, even if it is not used to remove foam, reads on this claim limitation.
Claim 11 recites a porous filter average pore diameter similar to or less than the average pore diameter [of] the porous membrane. The examiner notes that the membrane can be any diameter around or less than 0.1-2 µm. The specification states filter pore sizes may be 10 nm to 1 µm (pg 28, para [00117, lines 3-5). For the purposes of examination, the examiner interprets the size of the filter to be around or less than 2 µm and any prior art containing filters with pore sizes around or less than 2 µm reads on this claim limitation.
Claim 23 recites the phrase “configured to”. The examiner notes that no nonce terms are used. The examiner notes that the specification, Figure 3, describes the system. For the purposes of examination, any prior art containing a system which can do what the system is configured to reads on the claim limitations following the phrases, “configured to”.
Claim Rejections - 35 USC § 112(a) – Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 1-14, 17-19, and 21-23 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims teach a protein and polymer nanobubbles and/or microbubbles. However, the instant specification does not offer sufficient description of the common structural elements or identifying characteristics that constitute protein and polymer nanobubbles and/or microbubbles. There is no description of structural elements of protein and polymer nanobubbles and/or microbubbles that are sufficient to distinguish the claimed protein and polymer nanobubbles and/or microbubbles from other types of protein and polymer nanobubbles and/or microbubbles. Furthermore, the instant specification does not indicate that the inventors have possession of the details of the structural elements that would comprise these distinguishing characteristics.
A person of ordinary skill in the art would appreciate that there are many different structural elements that would constitute the protein and polymer nanobubbles and/or microbubbles to facilitate the functions recited in the instant claims. However, the instant specification is silent as to which structural elements the inventor has determined to be sufficient to characterize protein and polymer nanobubbles and/or microbubbles. Therefore, the instant specification does not provide a disclosure of corresponding structure in sufficient detail to demonstrate to one of ordinary skill in the art that the inventor possessed the invention including how the inventor intended what features constitute the protein and polymer nanobubbles and/or microbubbles to allow the function recited in the instant claims.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-3, 6-9, 13-14, 19, 21, and 23 is/are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Robinson, S. P.; U.S. 10,583,207 B2.
Robinson, S. P.; et al. (hereafter referred to as Robinson) teaches lipid-shelled gas-filled microbubbles and their uses (title; abstract). Robinson teaches lipid-based formulations for ultrasound contrast agents, kits comprising them, and gas-filled cores (col 1, lines 17-37). Robinson teaches lipids DPPA, DPPC, mPEG-DPPE, in propylene glycol, glycerol, and a buffer (col 1, lines 34-37). Robinson teaches weight ratios of lipids (col 2, lines 1-25) a container for mixing involving two chambers with lipids in one chamber and the gas in the second chamber (col 3, lines 11-14). Robinson teaches that the concentration of the lipids in solution can be varied from 0.1 mg to 10 mg lipid per mL of solution (col 13, lines 49-55) and can be diluted up to 100-fold (col 14, lines 23-29). Robinson teaches methods of making microbubbles through any type of motion that agitates the lipid solution and results in the introduction of gas with the shaking (col 21, lines 29-35) such as microemulsifying, microfluidizing, manual or mechanical shaking (col 21, lines 42-49).
As to claim 1, Robinson teaches a method of generating a plurality of gas-core, lipid shelled microbubbles comprising reversibly transferring a dispersion of at least one lipid and a gas through a porous membrane between a first depot and a second depot to provide a dispersion of lipid shelled microbubbles (col 41, lines 1-10).
As to claim 2, Robinson teaches a method wherein the dispersion of at least one lipid and gas is reversibly transferred through the membrane using a first extruder and a second extruder (col 41, lines 1-10).
As to claim 3, Robinson teaches the first extruder and the second extruder define, respectively, the first depot and the second depot (col 41, lines 1-10).
As to claim 6, Robinson teaches method wherein the first depot includes the dispersion of the at least one lipid and gas and the second depot includes a gas prior to reversible transferring of the dispersion through the membrane (col 41, lines 1-10).
As to claim 7, Robinson teaches the method wherein the dispersion is reversibly transferred through the porous membrane 50 times (col 41, lines 1-10). "[W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated’ if one of them is in the prior art. MPEP 2131.03(I).
As to claim 8, Robinson teaches a method wherein the porous membrane has an average pore diameter of 0.4 or 1.0 µm (col 41, lines 41-51). "[W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated’ if one of them is in the prior art. MPEP 2131.03(I).
As to claim 9, Robinson teaches a method according to claim 1 wherein the dispersion of lipid microbubbles are reversibly transferred through a porous membrane (col 41, lines 1-10).
As to claim 13, Robinson teaches a method wherein the at least one lipid includes a mixture of phospholipids having varying acyl chain lengths (col 41, lines 1-10).
As to claim 14, Robinson teaches a method wherein the mixture of phospholipids includes at least DPPA, DPPC, mPEG-DPPE (col 8, lines 60-63).
As to claim 19, Robinson teaches the gas is a perfluorocarbon (col 41, lines 1-10).
As to claim 21, Robinson teaches a method wherein the gas of the dispersion in the first depot is the same as the gas in the second depot (col 41, lines 1-10).
As to claim 23, Robinson teaches a system for performing the method recited in claim 1, the system comprising a first extruder and a second extruder with a channel permitting reversible fluid flow between the extruders and contains a porous membrane to provide a dispersion of lipid microbubbles (col 41, lines 1-10).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 4-5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Robinson, S. P.; U.S. 10,583,207 B2 and Bispo de Jesus, M.; et al. Microemulsion extrusion technique: a new method to produce lipid nanoparticles, 2013, 15, 1960. The teachings of Robinson as applied in the previous rejection are incorporated in this rejection.
Robinson, S. P.; et al. (hereafter referred to as Robinson) teaches lipid-shelled gas-filled microbubbles and their uses (title; abstract). Robinson teaches lipid-based formulations for ultrasound contrast agents, kits comprising them, and gas-filled cores (col 1, lines 17-37). Robinson teaches lipids DPPA, DPPC, mPEG-DPPE, in propylene glycol, glycerol, and a buffer (col 1, lines 34-37). Robinson teaches weight ratios of lipids (col 2, lines 1-25) a container for mixing involving two chambers with lipids in one chamber and the gas in the second chamber (col 3, lines 11-14). Robinson teaches that the concentration of the lipids in solution can be varied from 0.1 mg to 10 mg lipid per mL of solution (col 13, lines 49-55) and can be diluted up to 100-fold (col 14, lines 23-29). Robinson teaches methods of making microbubbles through any type of motion that agitates the lipid solution and results in the introduction of gas with the shaking (col 21, lines 29-35) such as microemulsifying, microfluidizing, manual or mechanical shaking (col 21, lines 42-49).
As to claim 4, Robinson teaches the lipids can be warmed to achieve complete dissolution (col 10, lines 42-50).
Robinson does not explicitly teach a temperature so that the lipid is in fluid state.
Bispo de Jesus, M.; et al. (hereafter referred to as Bispo de Jesus) is drawn to a microemulsion extrusion technique for producing lipid-based nanoparticles that is fast, inexpensive, reproducible, free of organic solvents, and suitable for small volume preparations (title; abstract). Bispo de Jesus teaches small-volume extrusion techniques have been established for liposomal formulations for fast, inexpensive, reproducible, free of organic solvents (pg 2, col 2, para 1, lines 1-9). Bispo de Jesus teaches a lipid system containing EPC, PLF68, mitoxantrone, stearic acid, DOTAP, and glyceryl monostearate for the nanoparticles (pg 2, col 2, para 2, lines 1-11). Bispo de Jesus teaches an adaptation of the microemulsion technique using the Avanti mini-extruder with a 100 nm membrane between the syringes at a temperature above the melting point of the lipid, and the system extruded 0-30 times (pg 3, col 1, para 1, lines 1-10; pg 3, col 1, para 2, lines 1-8; pg 3, col 1, para 3, lines 1-3; Figure 1) with temperatures 5-15 oC above the melting point of the lipid (pg 3, col 2, para 1, lines 1-3) with a lipid concentration of 10 mM (pg 3, col 2, para 2, lines 1-3). Bispo de Jesus teaches lyophilization of the nanoparticles (pg 4, col 1, para 2, lines 1-10) and characterization of the nanoparticles (pg 6, Figure 2; pg 8, Figure 3; pg 9, Table 2).
Regarding a temperature so that the lipid is in the fluid state, Bispo de Jesus teaches the temperature is such that at least one lipid is in a fluid state (pg 3, col 1, para 2, lines 5-7; pg 3, col 2, para 1, lines 1-3).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the method of Robinson to include the temperatures as taught by Bispo de Jesus because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of temperatures so that at least one lipid was in the fluid state.
A person of ordinary skill in the art would have had a reasonable expectation of success in adjusting the temperature so that at least one lipid was in fluid state because the prior art of Robinson disclosed temperatures up to 75oC known to result in dissolved lipids. Additional prior art of Bispo de Jesus suggested using temperature to melt lipids (pg 3, col 1, para 2, lines 5-7) to have similar property of aiding in the dispersion of the lipids.
The skilled artisan would have been motivated to use a temperature to melt the lipids because melted lipids are easier to disperse into a solvent of choice.
As to claim 5, Bispo de Jesus teaches the temperature is higher than the solid to fluid phase transition temperature of at least one lipid (pg 3, col 1, para 2, lines 5-7; pg 3, col 2, para 1, lines 1-3).
Claim(s) 10-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Robinson as applied to claims 1-3, 6-9, 13-14, 19, 21, and 23 above, and further in view of Sheeran, P. S.; et al. Methods of Generating Submicrometer Phase-Shift Perfluorocarbon Droplets for Applications in Medical Ultrasonography. IEEE Trans. Ultrason. Ferroelectr. Freq. Control. 2017, 64, 1, 252-263 (as cited in the IDS filed on 07/08/2024). The teachings of Robinson as applied in the previous rejections are incorporated in this rejection.
As to claim 10, Robinson teaches using a filter during reversible transferring the microbubbles (pg 41, lines 1-10).
Robinson does not teach an additional porous filter after reversible transferring the microbubbles.
Sheeran, P. S.; et al. (hereafter referred to as Sheeran) is drawn to methods of generating ultrasound contrast agents with perfluorocarbon gas cores through various methods (title; abstract). Sheeran teaches microbubbles may be made by a number of microbubble generation techniques (pg 3, para 2, lines 1-5). Sheeran teaches the conditions for acoustic droplet vaporization are governed by the thermodynamics and kinetics of the fluorocarbon core (pg 3, para 3, lines 1-2) and that the instability of the fluorocarbon droplets is done by choice of the acryl chain length improves stabilization (pg 5, para 3, lines 6-7) allowing the lipid layer to buckle and fold, expand and collapse enabling more stable microbubbles (pg 5, para 4, lines 4-7). Sheeran teaches different microbubble generation techniques such as sonication using a probe or tip sonication to generate droplets in a container (pg 6, para 2, lines 1-4) and that the main benefits of using tip sonication are its ease of use and relatively low cost (pg 6, para 3, lines 1-5) and disadvantages include potential destruction of the emulsion components and erosion of the probe tip and increased polydispersity compared to other methods (pg 6, para 4, lines 1-4) and that energy required is very high (pg 6, para 5, lines 1-3). Sheeran teaches extrusion which is commonly used for liposomes but can be adapted for microbubbles (pg 7, para 2, lines 1-2) and is considered gentler than sonication and produces more uniform size distributions depending on the pore size of the membrane used (pg 7, para 2, lines 2-6) and where the solution and gas are loaded and extruded through a 1 µm pore size polycarbonate membrane and then filtered through a 0.4 or 0.2 µm pore size membrane (pg 8, para 1, lines 1-15). Sheeran teaches microbubble condensation (pg 8, para 2, lines 1-10), microfluidics (pg 10, para 3, lines 1-8), homogenization/microfluidization (pg 12, para 2, lines 14). Sheeran teaches characterization by particle size and concentration (pg 12, para 4, lines 1-6) and ultrasound (pg 14, para 1).
Regarding an additional filtration step to remove the foam, Sheeran teaches a filter a stage of reversible transferring the microbubbles (pg 8, para 1, lines 1-15; pg 14, para 2, lines 11-14).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the method of Robinson to include an additional filter as taught by Sheeran because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of additional filtration steps after initial reversible transfer of the microbubble solution.
A person of ordinary skill in the art would have had a reasonable expectation of success in adding additional porous filters because the prior art of Robinson disclosed porous membranes are compatible with microbubbles (col 41, lines 1-10). Additional prior art of Sheeran suggested additional filters help reduce the size of the microbubbles (pg 8, para 1, lines 3-15) and can be used to filter off microscale content (pg 14, para 2, lines 11-14) and that the microbubbles have similar behavior because of the overlap of the thermodynamics and kinetics of the core gas and lipid shell.
The skilled artisan would have been motivated to add additional filters because they can reduce the microbubble size and remove microparticles from the microbubbles.
As to claim 11, Sheeran teaches subsequent porous filters have a smaller average pore diameter compared to the initial porous diameter (pg 8, para 1, lines 1-15; pg 14, para 2, lines 11-14).
As to claim 12, Robinson teaches a lipid concentration range of about 0.1-10 mg/mL. This prior art range overlaps with the claimed range of 1-20 mg/mL. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
Claim(s) 17-18 and 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Robinson as applied to claims 1-3, 6-9, 13-14, 19, 21, and 23 above, and further in view of Abenojar, E. C.; et al. Theoretical and Experimental Gas Volume Quantification of Micro- and Nanobubble Ultrasound Contrast Agents, 2020, 12, 3, 208. The teachings of Robinson as applied in the previous rejection are incorporated in this rejection.
As to claim 17, Robinson teaches propylene glycol, glycerol and a buffer (col 1, lines 34-37).
Robinson does not explicitly teach PBS.
Abenojar, E. C.; et al. (hereafter referred to as Abenojar) is drawn to theoretical and experimental quantification of microbubble ultrasound contrast agents (title; abstract). Abenojar teaches ultrasound is a noninvasive, safe, accessible, and inexpensive medical imaging modality for improving soft tissue contrast which can be protein or lipid shelled with gas cores (pg 2, para 1, lines 1-8). Abenojar teaches that the shell composition and gas used are important factors acoustic response and longevity of the bubbles (pg 2, para 2, lines 1-4). Bubbles filled with hydrophobic gases are more stable than microbubbles filled with air (pg 2, para 2, lines 8-11) and perfluorocarbons are especially good (pg 2, para 2, lines 14-18). Abenojar teaches microbubbles made from DBPC, DPPA, DPPE, mPEG-DSPE, propylene glycol, glycerol, PBS, and perfluoropropane (pg 2, para 3, lines 1-8; pg 2, para 4, lines 1-5) through a sonication method. The bubbles were then centrifuged for isolation, redispersed, purged, and stored at 4oC (pg 4, para 1, lines 2-12). The bubbles were characterized with four techniques of RMM, DLS, NTA, and coulter counter (pg 4, para 2, lines 1-3).
Regarding PBS, Abenojar teaches propylene glycol, glycerol and PBS (pg 3, para 3, lines 5-8; pg 3, para 4, lines 1-5).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the buffer of Robinson with the specific buffer as taught by Abenojar because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of a lipid solution including propylene glycol, glycerol, and PBS.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting PBS for a generic buffer because the prior art of Robinson disclosed buffers known to work well with microbubble solutions (col 1, lines 46-50), including phosphate buffers (col 10, lines 10-12). Additional prior art of Abenojar suggested PBS as the buffer with the lipid solution has similar microbubble properties because of the lipids, gas core, and solution.
The skilled artisan would have been motivated to substitute a generic buffer of Robinson with PBS of Abenojar because PBS is a widely studied buffer and is compatible for use in humans and other animals.
As to claim 18, Abenojar teaches DBPC, DPPA, DPPE, PEG-DSPE, propylene glycol, glycerol, and PBS (pg 3, para 3, lines 1-8; pg 3, para 4, lines 1-5).
As to claim 22, Abenojar teaches nanobubbles with a size of 265 ± 116 nm (pg 6, para 2, lines 3-4) which is 0.15-0.38 µm. This range lies inside the claimed range of 0.05 µm to 0.4 µm. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
Pertinent Art
The prior art of Masahito, M.; et al. JP 2019048779 A is deemed pertinent to the application.
Masahito, M.; et al. (hereafter referred to as Masahito) is drawn to a contrast medium for ultrasonic diagnosis and X-ray contrast medium (pg 4, para [0001], lines 1-3). Masahito teaches computed tomography irradiates the human body with X-rays from various directions and the transmitted X-rays are detected, reconstructed, and visualized by the difference in the irradiated and transmitting X-rays from tissues (pg 4, para [0002]) but that tissues with similar densities are difficult to distinguish and contrast agents are very helpful in visualizing the different tissues (pg 4, para [0003]) where these contrast agents can have a high iodine content (pg 4, para [0004]) or they can be sensitive to ultrasonic waves (pg 4, para [0005]). These ultrasound-based contrast agents have a significant design advantage in that their acoustic properties vary depending on the local environment enabling clear diagnostic images of the human body (pg 5, para [0006], lines 1-7) and that microbubbles are especially significant for imaging biological tissues with excellent ultrasound scattering properties (pg 5, para [0006], lines 5-8). Masahito teaches that while the microbubbles can also be loaded with an X-ray contrast agent and administered via a single dose (pg 5, para [0008], lines 1-5). Masahito teaches loading a triiodobenzene dimer compound into the microbubbles (pg 5, para [0010], lines 1-6). Masahito teaches the microbubbles are gas-filled (pg 7, para [0022], pg 12, para [0062]), a temperature above 36oC (pg 7, para [0025]). And Masahito teaches that the microbubbles do not need to be made by ultrasonic vibration to generate or maintain the microbubbles (pg 12, para [0061]) with diameters from 1 nm to 1000 µm (pg 12, para [0063]). Masahito teaches that the microbubbles can be made by ultrasonication (pg 13, para [0067]) or through a dual syringe system where the gas is loaded into one syringe, and the microbubble forming compounds in another syringe connected to each other and reciprocating the two syringes back and forth multiple times at elevated temperatures (pg 13, para [0068]; pg 13, para [0069], lines 1-3) which may then be filtered (pg 14, para [0070]).
The examiner considers the two-syringe extruder system for making microbubbles of Masahito to render this art pertinent to this application.
The prior art of De Leon, A.; et al. Contrast enhanced ultrasound imaging by nature-inspired ultrastable echogenic nanobubbles, Nanoscale, 2019, 11, 15647 is deemed pertinent to the application.
De Leon, A.; et al. (hereafter referred to as de Leon) is drawn to nanobubble ultrasound contrast agents with improved in vivo stability of the shell-stabilized gas bubble (title; abstract). De Leon teaches slight advancement on ultrasound technology can have a potentially large impact in the medical field due to the number of imaging procedures performed worldwide (pg 15647, col 1, lines 1-6) and that signal decay is one of the main limitations of microbubbles (pg 15647, col 1, lines 12-13). De Leon teaches that ultrastable nanobubbles can be designed by engineering the membrane shell to withstand deformations due to ultrasound and flow in vivo (pg 15647, col 2, para 1, lines 13-15) and that bilayer membranes work very well (pg 15647, col 2, para 2, lines 1-6). Additionally, incorporating glycerol and propylene glycol are useful for robustness (pg 15648, col 1, para 2, lines 5-14). De Leon teaches characterization of the nanobubbles (pg 15648, Figure 1; pg 15650, Figure 2; pg 15651, Figure 3; pg 15652, Figure 4; pg 15653, Figure 5). And de Leon teaches preparation and isolation of the nanobubbles where the concentration of the lipid solution is 10 mg/mL (pg 15653, col 2, para 2, lines 1-13).
The examiner considers the lipid composition of the microbubbles to render this art pertinent to this application.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Evan M Lewoczko whose telephone number is (571)272-9830. The examiner can normally be reached Monday-Friday 9-5PM.
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/EVAN M LEWOCZKO/Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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