DETAILED ACTION
Applicants' arguments, filed 11/13/2025, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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 .
Election/Restrictions
Applicant’s election without traverse of Group 1, claims 1-12 in the reply filed on 06/25/2025 is acknowledged.
Priority
The instant application claims foreign priority to KR10-2019-0108278 filed 09/02/20219. The instant application is a 371 of PCT/KR2020/011712 filed 09/02/2020.
Claim Interpretation
With regards to claims 1, the instant claim is directed to an immune-microbubble complex, comprising microbubbles and an antibody conjugated to the microbubble. The term “in an environment in which an immune response is boosted by ultrasound sonophoresis” is considered intended use and is not considered further limiting the composition an immune-microbubble.
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.
A) Claims 1-2, 7-8, and 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (KR20140018150A, provided in the IDS filed 03/01/2022, full English translation from Google Patent added) in view of Campbell et al (US Patent Application Publication 20070088414A1).
Lee recites that the present invention relates to a microbubble-nanoliposome complex capable of diagnosing and treating cancer cells and a method of preparing the same. More specifically, the present invention relates to a microbubble- Since the bubble-nanoliposome complex can carry one or more additional hydrophobic or hydrophilic fluorescent substances as well as one or more therapeutic agents in the complex structure and exhibits excellent target specificity including an external targeting moiety, Cancer, breast cancer, brain cancer, stomach cancer, lung cancer, esophageal cancer, colon cancer, and the like can be diagnosed through the multiple image analysis using specific ultrasound or fluorescence imaging, and at the same time, one or more therapeutic agents can be effectively delivered to the target cancer cells, Cancer, prostate cancer, kidney cancer, ovarian cancer May be useful to take advantage of the development of effective diagnostic and treatment of cancer (Lee at Abstract). Lee recites a microbubble-nanoliposomal complex comprising a hydrophobic microbubble and a hydrophilic nanoliposome covalently bonded to each other. (Lee at claim 1). Lee recites wherein the therapeutic agent is a microbubble-nanoliposomal complex, characterized in that selected from therapeutic genes and drugs. (Lee at claim 2). Lee recites wherein the therapeutic gene is a microbubble-nanoliposomal complex, characterized in that at least one selected from DNA and RNA including an antagonist of expression plasmid, siRNA, shRNA, microRNA and microRNA. (Lee at claim 3). Lee recites wherein the drug is a microbubble-nanoliposomal complex, characterized in that at least one selected from anticancer agents, including doxorubicin, paclitaxel (paclitaxel), docetaxel (docetaxel) (Lee at claim 4). Lee recites wherein the targeting moiety is a microbubble, characterized in that at least one selected from the group consisting of biotin, streptavidin, avidin, antibodies, aptamers, polypeptides, peptides, ligands, receptors, lectins, sugars, lipids, glycolipids and nucleic acids nanoliposome complexes (Lee at claim 5). Lee recites wherein the microbubble-nanoliposomal complex, characterized in that for carrying one or more additional hydrophobic or hydrophilic fluorescent material in the complex structure. (Lee at claim 6). Lee recites wherein the hydrophobic or hydrophilic fluorescent substance is a microbubble-nanoliposomal complex, characterized in that at least one selected from the group comprising FITC, Texas-red, RITC, Cy3, Cy5 and Cy7 (Lee at claim 7). Lee recites wherein the microbubble is a microbubble-nanoliposomal complex, characterized in that it comprises a film-forming material, a phospholipid, a negatively charged compound, a compound having an amine group and a compound having a disulfide group (Lee at claim 8). Lee recites wherein the film forming material is DPPC (1,2-dipalmitory-sn-glycero-3-phosphatidylcholine), DDPC (1,2-didecanoyl-sn-glycero-3-phosphocholine), DEPC (1,2-didecanoyl-sn-glycero -3-phosphocholine), DLOPC (1,2-dilinoleoyl-sn-glycero-3-phosphocholine), DLPC (1,2-dilauroyl-sn-glycero-3-phosphocholine), DMPC (1,2-dimyristoyl-sn- glycero-3-phosphocholine), DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine) and DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine); The phospholipid is cholesterol; The negatively charged compound is DCP (dicetyl phosphate), DEPA (1,2-dierucoyl-sn-glycero-3-phosphate), DLPA (1,2-dilauroyl-sn-glycero-3-phosphate), DMPA (1,2- dimyristoyl-sn-glycero-3-phosphate) and DOPA (1,2-dioleoyl-sn-glycero-3-phosphate); Compounds having an amine group include DPPE (1,2-dipalmitory-sn-glycero-3-phosphoethanolamine), DEPE (1,2-dierucoyl-sn-glycero-3-phosphoethanolamine), and DLPE (1,2-dilauroyl-sn- glycero-3-phosphoethanolamine), DMPE (1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine) and DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine); And the compound having a disulfide group is a DSP-PEG-SPDP 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [PDP (polyethylene glycol) -2000] (Lee at claim 9). Lee recites wherein the nano liposome is a microbubble-nanoliposomal complex, characterized in that it comprises a film-forming substance, a phospholipid, a negatively charged compound and a compound having an amine group (Lee at claim 10). Lee recites wherein the film forming material is DPPC (1,2-dipalmitory-sn-glycero-3-phosphatidylcholine), DDPC (1,2-didecanoyl-sn-glycero-3-phosphocholine), DEPC (1,2-didecanoyl-sn-glycero -3-phosphocholine), DLOPC (1,2-dilinoleoyl-sn-glycero-3-phosphocholine), DLPC (1,2-dilauroyl-sn-glycero-3-phosphocholine), DMPC (1,2-dimyristoyl-sn- glycero-3-phosphocholine), DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine) and DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine); The phospholipid is cholesterol; The negatively charged compound is DCP (dicetyl phosphate), DEPA (1,2-dierucoyl-sn-glycero-3-phosphate), DLPA (1,2-dilauroyl-sn-glycero-3-phosphate), DMPA (1,2- dimyristoyl-sn-glycero-3-phosphate) and DOPA (1,2-dioleoyl-sn-glycero-3-phosphate); And the compound having an amine group is DPPE (1,2-dipalmitory-sn-glycero-3-phosphoethanolamine), DEPE (1,2-dierucoyl-sn-glycero-3-phosphoethanolamine), DLPE (1,2-dilauroyl-sn -glycero-3-phosphoethanolamine), DMPE (1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine) and DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) Microbubble-nanoliposomal complex (Lee at claim 11). Lee recites wherein a film is formed by reacting a film-forming substance, a phospholipid, a negative charge compound, a compound having an amine group and a compound having a disulfide group in an organic solvent and reacting the resultant with a hydrophobic gas in an organic mixed solvent, Producing a bubble; 2) preparing a film by reacting a film-forming substance, a phospholipid, a negative charge compound and a compound having an amine group in an organic solvent to prepare a film, adding the resulting film to water, and dispersing and filtering the nanoliposome by ultrasonic dispersion; 3) reacting the nanoliposome obtained in the step 2) with a therapeutic agent to support the therapeutic agent in the nanoliposome structure;
4) mixing the microbubbles obtained in the step 1) and the nanoliposome obtained in the step 3) and shaking them to prepare a microbubble-nanoliposome complex; and 5) reacting the complex prepared in step 4) with a targeting moiety to bind the targeting moiety to the outside of the complex, the method of preparing the microbubble-nanoliposomal complex (Lee at claim 12).
Lee recites wherein the step (1) or (2) further comprises a step of reacting the microbubble or nanoliposome with a fluorescent substance to form a microbubble or nanoliposome structure, followed by supporting the fluorescent substance in the microbubble or nanoliposome structure (Lee at claim 13). Lee recites wherein a contrast agent composition for cancer cell-specific ultrasound, magnetic resonance imaging or fluorescence analysis comprising the microbubble-nanoliposomal complex (Lee at claim 14). Lee recites a microbubble-nanoliposomal complex, and an anticancer pharmaceutical composition comprising an anticancer agent or anticancer gene as an active ingredient (Lee at claim 15). Lee teaches the use of DSPE-PEG-SPDP {1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [PDP (polyethylene glycol) -2000]} (Lee at page 5).
Lee teaches it was confirmed that ultrasonic analysis, MRI analysis and fluorescence analysis were easily performed using a microbubble-nanoliposome complex carrying a fluorescent substance, a target gene, an antibody, etc. (Lee at page 5).
Lee teaches that in addition, the step of bonding a targeting moiety such as the antibody of step 5) to the outside of the conjugate may be carried out by a conventional reaction in which the targeting moiety is directly or indirectly bonded to the surface of the conjugate of the present invention in a covalent or non- And can be carried out, for example, by bonding through ionic bonds, electrostatic bonds, hydrophobic bonds, hydrogen bonds, covalent bonds, hydrophilic bonds, or van der Waals bonds. In this case, in the case of the indirect coupling, an intervening agent such as a binder may be used. As the intermediate agent, sulfosuccinimidyl-4- (N-maleimidomethyl) cyclohexane- 4- (N-maleimidomethyl) cyclohexane-1-carboxylate). (Lee at page 5). Lee teaches the use of DSPE-PEG-SPDP {1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [PDP (polyethylene glycol) -2000]} (Lee at page 5). Lee recites the use of DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine) (Lee at claim 9).
The teachings of Lee differ from instant claim 1 insofar as they do not specifically teach the use of B7-1 or CD80, as the antibody used. The teachings of Campbell cure this deficit.
Campbell teaches microbubbles specifically as ultrasound contrast agents (Campbell at [0185]) and as particles carrying an active agent (Campbell at [0045]). Campbell teaches CD80 (aka B7-1) as an active agent (Campbell at [0124]). Campbell teaches a composition comprising small non-specific microbubbles and a method for delivering the composition using intradermal methods to a particular tissue, e.g., lymphatic tissue, or a particular organ. Although not intending to be bound by a particular mechanism of action, microbubbles are rapidly transported through the lymphatic circulation and may be detected using for example ultrasonic imaging. The invention thus provides improved methods for detecting cancer cells and metastases within the lymphatic system for example to sentinel lymph nodes, and/or improved methods for evaluating lymphedema, e.g., a common morbidity associated with extensive axillary lymph node dissection. The methods of the invention are improved over conventional cancer diagnostics (Campbell at [0149]). Campbell teaches microbubble ultrasound contrast agent is delivered as described herein. An ultrasound probe is positioned either at the injection site or at a regional lymph node site. Although not intending to be bound by a particular mechanism of action the contrast agent is delivered to the intradermal compartments and immediately travels through the lymphatic vessels and to the lymph node. The ultrasound probe detects the contrast agent as it passes beneath the probe. Both diagnostic flow rate and architecture information, including obstructions, can be obtained. In this embodiment, the images can be obtained continuously (real time) or in an episodic manner (Campbell at [0186]). Campbell further teaches therapeutic agents that may be used in the compositions of the invention include but are not limited to chemotherapeutic agents, radiation therapeutic agents, hormonal therapeutic agents, immunotherapeutic agents, immunomodulatory agents, anti-inflammatory agents, antibiotics, anti-viral agents, and cytotoxic agents (Campbell at [0127]). Campbell teaches the use of streptavadin-biuotin conjugation (Campbell at [0178]). Campbell teaches the use of streptavadin-biuotin conjugation (Campbell at [0178]). Campbell teaches the use of DSPC, DSPE-MPEG2000, DSPE-PEG350 and DSPE (Campbell at ([0086]).
The teachings of Campbell differ from the instant claims insofar as it does not specifically teach the details of producing microbubbles. The teachings of Lee cure this deficit.
It would be prima facie obvious to have added the CD80 antibody to the microbubble of Lee for the predictable result of a microbubbles complexed with antibodies to treat and image cancer. See MPEP 2144.06(I).
Regarding instant claim 1, Lee recites that the present invention relates to a microbubble-nanoliposome complex capable of diagnosing and treating cancer cells and a method of preparing the same. (Lee at Abstract). Lee teaches it was confirmed that ultrasonic analysis, MRI analysis and fluorescence analysis were easily performed using a microbubble-nanoliposome complex carrying a fluorescent substance, a target gene, an antibody, etc. (Lee at page 5). Campbell teaches microbubbles specifically as ultrasound contrast agents (Campbell at [0185]) and as particles carrying an active agent (Campbell at [0045]). Campbell teaches CD80 (aka B7-1) as an active agent (Campbell at [0124]). Lee teaches the use of DSPE-PEG-SPDP {1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [PDP (polyethylene glycol) -2000]} (Lee at page 5). Lee recites the use of DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine) (Lee at claim 9).
Regarding instant claim 2, Lee teaches that in addition, the step of bonding a targeting moiety such as the antibody of step 5) to the outside of the conjugate may be carried out by a conventional reaction in which the targeting moiety is directly or indirectly bonded to the surface of the conjugate of the present invention in a covalent or non- And can be carried out, for example, by bonding through ionic bonds, electrostatic bonds, hydrophobic bonds, hydrogen bonds, covalent bonds, hydrophilic bonds, or van der Waals bonds. In this case, in the case of the indirect coupling, an intervening agent such as a binder may be used. As the intermediate agent, sulfosuccinimidyl-4- (N-maleimidomethyl) cyclohexane- 4- (N-maleimidomethyl) cyclohexane-1-carboxylate). (Lee at page 5). Campbell teaches the use of streptavadin-biuotin conjugation (Campbell at [0178]).
Regarding instant claim 7, Campbell teaches CD80 (aka B7-1) as an active agent (Campbell at [0124]).
Regarding instant claim 8, Lee teaches the use of DSPE-PEG-SPDP {1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [PDP (polyethylene glycol) -2000]} (Lee at page 5). Lee recites the use of DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine) (Lee at claim 9). Lee teaches 1) A film is formed by reacting a film-forming substance, a phospholipid, a negative charge compound, a compound having an amine group and a compound having a disulfide group in an organic solvent and reacting the resultant with a hydrophobic gas in an organic mixed solvent, Producing a bubble;2) preparing a film by reacting a film-forming substance, a phospholipid, a negative charge compound and a compound having an amine group in an organic solvent to prepare a film, adding the resulting film to water, and dispersing and filtering the nanoliposome by ultrasonic dispersion; 3) reacting the nanoliposome obtained in step 2) with one or more therapeutic agents to carry one or more therapeutic agents in the nanoliposome structure; 4) mixing the microbubbles obtained in the step 1) and the nanoliposome obtained in the step 3) and shaking the microbubbles to prepare a microbubble-nanoliposome complex; and 5) A method for producing the microbubble-nanoliposome complex of the present invention, comprising reacting the complex prepared in step 4) with a targeting moiety to bind the targeting moiety to the outside of the complex to provide (Lee at page 5).
Regarding instant claim 11, Lee recites a microbubble-nanoliposomal complex, and an anticancer pharmaceutical composition comprising an anticancer agent or anticancer gene as an active ingredient (Lee at claim 15).
Regarding instant claim 12, Lee recites that the present invention relates to a microbubble-nanoliposome complex capable of diagnosing and treating cancer cells and a method of preparing the same. (Lee at Abstract). Lee teaches it was confirmed that ultrasonic analysis, MRI analysis and fluorescence analysis were easily performed using a microbubble-nanoliposome complex carrying a fluorescent substance, a target gene, an antibody, etc. (Lee at page 5).
B) Claims 3-5 and 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (KR20140018150A, provided in the IDS filed 03/01/2022, full English translation from Google Patent added) and Campbell et al (US Patent Application Publication 20070088414A1) as applied to claims 1-2, 7-8, and 11-12 above, and in further view of Kim et al (US Patent Application Publication 20170080114A1).
The teachings of Lee and Campbell are discussed above.
The teachings of Lee and Campbell differ from instant claim 3 insofar as they do not specifically teach the use of specifically DSPE-PEG2000-NHS. The teachings of Kim cure this deficit.
Kim teaches a composition wherein 1,2-disteraoyl-sn-glycero-3-phosphocholine (DSPC), DSPE-PEG2000-NHS (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-n-[poly(ethyleneglycol)] 2000-N-hydroxysuccinimide), and a lipid containing porphyrin (porphyrin-lipid) as the lipids, and polyoxyethylene 40 stearate (POE40s) as an emulsifier were mixed at a molar ratio of 50:15:15:1 and dissolved in chloroform, and then the chloroform was completely evaporated by using a rotary evaporator to form a lipid thin film. Subsequently, distilled water, propylene glycol, and glycerin were mixed at a ratio of 8:1:1, and then the resulting mixture was added to the lipid thin film. The lipid was dissolved while the temperature was maintained at 55 to 60° C. SF6 or C3F8 gas was put into a container containing the mixed solution, the container was filled with the gas at 200 kPa, and then microbubbles (porphyrin-MBs) were prepared through sonication and mechanical agitation (Kim at [0062]).
The teaching of Kim differ from the instant claims insofar as they do not specifically teach the use of CD80.
It would be prima face obvious to have used the more detailed directions of making microbubbles taught by Kim to make the microbubbles of Lee and Campbell. The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). See MPEP 2144.07.
It would have been prima facie obvious to one of ordinary skill in the art to have combined the DSPE-PEG-SPDP of Lee and/or the DSPE-MPEG2000 of Campbell with the DSPE-PEG2000-NHS of Kim for the predictable outcome of a DSPC and DSPE-PEG microbubble used for cancer treatment. See MPEP 2144.06(I).
Regarding instant claim 1, Lee recites that the present invention relates to a microbubble-nanoliposome complex capable of diagnosing and treating cancer cells and a method of preparing the same. (Lee at Abstract). Lee teaches it was confirmed that ultrasonic analysis, MRI analysis and fluorescence analysis were easily performed using a microbubble-nanoliposome complex carrying a fluorescent substance, a target gene, an antibody, etc. (Lee at page 5). Campbell teaches microbubbles specifically as ultrasound contrast agents (Campbell at [0185]) and as particles carrying an active agent (Campbell at [0045]). Campbell teaches CD80 (aka B7-1) as an active agent (Campbell at [0124]). Lee teaches the use of DSPE-PEG-SPDP {1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [PDP (polyethylene glycol) -2000]} (Lee at page 5). Lee recites the use of DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine) (Lee at claim 9).
Regarding instant claim 2, Lee teaches that in addition, the step of bonding a targeting moiety such as the antibody of step 5) to the outside of the conjugate may be carried out by a conventional reaction in which the targeting moiety is directly or indirectly bonded to the surface of the conjugate of the present invention in a covalent or non- And can be carried out, for example, by bonding through ionic bonds, electrostatic bonds, hydrophobic bonds, hydrogen bonds, covalent bonds, hydrophilic bonds, or van der Waals bonds. In this case, in the case of the indirect coupling, an intervening agent such as a binder may be used. As the intermediate agent, sulfosuccinimidyl-4- (N-maleimidomethyl) cyclohexane- 4- (N-maleimidomethyl) cyclohexane-1-carboxylate). (Lee at page 5). Campbell teaches the use of streptavadin-biuotin conjugation (Campbell at [0178]).
Regarding instant claim 4, Lee teaches the use of DSPE-PEG-SPDP {1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [PDP (polyethylene glycol) -2000]} (Lee at page 5). Lee recites the use of DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine) (Lee at claim 9). Kim teaches a composition wherein 1,2-disteraoyl-sn-glycero-3-phosphocholine (DSPC), DSPE-PEG2000-NHS (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-n-[poly(ethyleneglycol)] 2000-N-hydroxysuccinimide), and a lipid containing porphyrin (porphyrin-lipid) as the lipids, and polyoxyethylene 40 stearate (POE40s) as an emulsifier were mixed at a molar ratio of 50:15:15:1 and dissolved in chloroform, and then the chloroform was completely evaporated by using a rotary evaporator to form a lipid thin film. Subsequently, distilled water, propylene glycol, and glycerin were mixed at a ratio of 8:1:1, and then the resulting mixture was added to the lipid thin film. The lipid was dissolved while the temperature was maintained at 55 to 60° C. SF6 or C3F8 gas was put into a container containing the mixed solution, the container was filled with the gas at 200 kPa, and then microbubbles (porphyrin-MBs) were prepared through sonication and mechanical agitation (Kim at [0062]).
Regarding instant claim 5, Campbell recites wherein in the forming of the lipid thin film, the emulsifier:porphyrin-lipid:lipid:lipid comprising NHS are added at a molar ratio of 5 to 10:15 to 30:60 to 75:15 to 30 (Campbell at claim 12). It would be prima facie obvious to have optimized the molar ratios of the lipids used in the microbubble to optimize the bubble properties. See MPEP2144.05(II).
Regarding instant claim 7, Campbell teaches CD80 (aka B7-1) as an active agent (Campbell at [0124]).
Regarding instant claim 8, Lee teaches the use of DSPE-PEG-SPDP {1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [PDP (polyethylene glycol) -2000]} (Lee at page 5). Lee recites the use of DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine) (Lee at claim 9). Lee teaches 1) A film is formed by reacting a film-forming substance, a phospholipid, a negative charge compound, a compound having an amine group and a compound having a disulfide group in an organic solvent and reacting the resultant with a hydrophobic gas in an organic mixed solvent, Producing a bubble;2) preparing a film by reacting a film-forming substance, a phospholipid, a negative charge compound and a compound having an amine group in an organic solvent to prepare a film, adding the resulting film to water, and dispersing and filtering the nanoliposome by ultrasonic dispersion; 3) reacting the nanoliposome obtained in step 2) with one or more therapeutic agents to carry one or more therapeutic agents in the nanoliposome structure; 4) mixing the microbubbles obtained in the step 1) and the nanoliposome obtained in the step 3) and shaking the microbubbles to prepare a microbubble-nanoliposome complex; and 5) A method for producing the microbubble-nanoliposome complex of the present invention, comprising reacting the complex prepared in step 4) with a targeting moiety to bind the targeting moiety to the outside of the complex to provide (Lee at page 5).
Regarding instant claim 10, Campbell recites wherein in the forming of the lipid thin film, the emulsifier:porphyrin-lipid:lipid:lipid comprising NHS are added at a molar ratio of 5 to 10:15 to 30:60 to 75:15 to 30 (Campbell at claim 12). It would be prima facie obvious to have optimized the molar ratios of the lipids used in the microbubble to optimize the bubble properties. See MPEP2144.05(II).
Regarding instant claim 11, Lee recites a microbubble-nanoliposomal complex, and an anticancer pharmaceutical composition comprising an anticancer agent or anticancer gene as an active ingredient (Lee at claim 15).
Regarding instant claim 12, Lee recites that the present invention relates to a microbubble-nanoliposome complex capable of diagnosing and treating cancer cells and a method of preparing the same. (Lee at Abstract). Lee teaches it was confirmed that ultrasonic analysis, MRI analysis and fluorescence analysis were easily performed using a microbubble-nanoliposome complex carrying a fluorescent substance, a target gene, an antibody, etc. (Lee at page 5).
C) Claims 1-2, 5, 7, and 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Campbell et al (US Patent Application Publication 20070088414A1).
Campbell teaches microbubbles specifically as ultrasound contrast agents (Campbell at [0185]) and as particles carrying an active agent (Campbell at [0045]). Campbell teaches CD80 (aka B7-1) as an active agent (Campbell at [0124]). Campbell teaches a composition comprising small non-specific microbubbles and a method for delivering the composition using intradermal methods to a particular tissue, e.g., lymphatic tissue, or a particular organ. Although not intending to be bound by a particular mechanism of action, microbubbles are rapidly transported through the lymphatic circulation and may be detected using for example ultrasonic imaging. The invention thus provides improved methods for detecting cancer cells and metastases within the lymphatic system for example to sentinel lymph nodes, and/or improved methods for evaluating lymphedema, e.g., a common morbidity associated with extensive axillary lymph node dissection. The methods of the invention are improved over conventional cancer diagnostics (Campbell at [0149]). Campbell teaches microbubble ultrasound contrast agent is delivered as described herein. An ultrasound probe is positioned either at the injection site or at a regional lymph node site. Although not intending to be bound by a particular mechanism of action the contrast agent is delivered to the intradermal compartments and immediately travels through the lymphatic vessels and to the lymph node. The ultrasound probe detects the contrast agent as it passes beneath the probe. Both diagnostic flow rate and architecture information, including obstructions, can be obtained. In this embodiment, the images can be obtained continuously (real time) or in an episodic manner (Campbell at [0186]). Campbell further teaches therapeutic agents that may be used in the compositions of the invention include but are not limited to chemotherapeutic agents, radiation therapeutic agents, hormonal therapeutic agents, immunotherapeutic agents, immunomodulatory agents, anti-inflammatory agents, antibiotics, anti-viral agents, and cytotoxic agents (Campbell at [0127]). Campbell teaches the use of streptavadin-biuotin conjugation (Campbell at [0178]). Campbell teaches the use of DSPC, DSPE-MPEG2000, DSPE-PEG350 and DSPE (Campbell at ([0086]).
Campbell differs from the instant claims in this rejection insofar as it does not teach the combination of the instantly recited components with sufficient specificity for anticipation. Campbell teaches the components of the instant recited composition and uses each component of their established function in the art but does not explicitly combine the components together into a single embodiment or a preferred composition. However, given the disclosure of each component individually, it would have been prima facie obvious to a person having ordinary skill in the art at a time prior to the filing of the present patent application and following the teachings of Campbell to have selected and combined known components for their established functions with predictable results. MPEP §2143 and §2144.06(I).
Regarding instant claim 1, Campbell teaches microbubbles specifically as ultrasound contrast agents (Campbell at [0185]) and as particles carrying an active agent (Campbell at [0045]). Campbell teaches CD80 (aka B7-1) as an active agent (Campbell at [0124]). Campbell teaches the use of streptavadin-biuotin conjugation (Campbell at [0178]). Campbell teaches the use of DSPC, DSPE-MPEG2000, DSPE-PEG350 and DSPE (Campbell at ([0086]).
Regarding instant claim 2, Campbell teaches the use of streptavadin-biuotin conjugation (Campbell at [0178]).
Regarding instant claim 5, Campbell recites wherein in the forming of the lipid thin film, the emulsifier:porphyrin-lipid:lipid:lipid comprising NHS are added at a molar ratio of 5 to 10:15 to 30:60 to 75:15 to 30 (Campbell at claim 12). It would be prima facie obvious to have optimized the molar ratios of the lipids used in the microbubble to optimize the bubble properties. See MPEP2144.05(II).
Regarding instant claim 7, Campbell teaches CD80 (aka B7-1) as an active agent (Campbell at [0124]).
Regarding instant claim 11, Campbell teaches microbubbles specifically as ultrasound contrast agents (Campbell at [0185]) and as particles carrying an active agent (Campbell at [0045]). Campbell teaches CD80 (aka B7-1) as an active agent (Campbell at [0124]). Campbell further teaches therapeutic agents that may be used in the compositions of the invention include but are not limited to chemotherapeutic agents, radiation therapeutic agents, hormonal therapeutic agents, immunotherapeutic agents, immunomodulatory agents, anti-inflammatory agents, antibiotics, anti-viral agents, and cytotoxic agents (Campbell at [0127]).
Regarding instant claim 12, Campbell teaches microbubbles specifically as ultrasound contrast agents (Campbell at [0185]) and as particles carrying an active agent (Campbell at [0045]). Campbell teaches CD80 (aka B7-1) as an active agent (Campbell at [0124]).
Response to Arguments
Applicant's arguments filed 11/13/2025 have been fully considered but they are not persuasive.
Applicant argues that Lee and Kim recite to many possible components for it to be obvious to have selected the DSPC and DSPE of the amended claims and therefore the obviousness rejection should be withdrawn.
The Examiner does not agree. The amendment to the claims required further search and additional search within Lee, Campbell, and Kim. Lee teaches the use of DSPE-PEG-SPDP {1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [PDP (polyethylene glycol) -2000]} (Lee at page 5) and Lee recites the use of DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine) (Lee at claim 9). Campbell teaches the use of DSPC, DSPE-MPEG2000, DSPE-PEG350 and DSPE (Campbell at ([0086]). Kim teaches the use of DSPC, DSPE, DSPE-PAG and most specifically DSPE-PEG2000-NHS (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-n-[poly(ethyleneglycol)] 2000-N-hydroxysuccinimide). Therefore Lee, Campbell, and Kim all teach DSPC and DSPE. Campbell and Kim further both teach DSPE-PEG compounds. Lee, Campbell, and Kim all teach microbubbles used in the treatment of cancer. It would have been prima facie obvious to one of ordinary skill in the art to have combined the DSPE-PEG compounds of Campbell and Kim for the predictable outcome of a cancer treatment related microbubble comprising DSPE and DSPC. See MPEP 2144.06(I). It would have been obvious to have used the DSPE-PEG compound for its intended purpose as a lipid barrier component in a cancer treatment related microbubble comprising DPSC and DSPE. See MPEP 2144.07. It would have been obvious for one of ordinary skill in the art, an individual with knowledge of making, modifying and optimizing lipid components to create microbubbles to have selected DPSC and DPSE from a finite list of possible lipid components. There would be a reasonable expectation of success because Lee, Campbell, and Kim teach the use of DPSC and DPSE for microbubbles for cancer treatment. See MPEP 2143. Furthermore, the claims comprise DPSC and DPSE, the microbubbles may contain the other often overlapping lipid components taught by Lee, Campbell, and Kim. As such, the applicant’s arguments are not persuasive and the obviousness rejection stands.
Relevant Prior Art
MacDougall (US20120010230A1)
MacDougall teaches that he L3.6pl tumor cell line was injected subcutaneously and treatment with IPI-926 was initiated. IPI-926 or vehicle was administered orally at 40 mg/kg for seven consecutive days. On the eighth day, animals were subjected to ultrasound image capture and analysis using the Vevo 2100 high frequency ultrasound instrument (Visualsonics) in conjunction with contrast enhancement (microbubbles) during the imaging procedure. Contrast agent was administered by iv administration during the imaging procedure and quantified by measuring echogenic signal derived from the contrast agent over time (MacDougall at [0589]). MacDougall teaches that in the composition the antibody is labeled, e.g., a radio-labeled, chromophore-labeled, fluorophore-labeled, or enzyme-labeled antibody. In another embodiment, an antibody derivative (e.g., an antibody conjugated with a substrate or with the protein or ligand of a protein-ligand pair {e.g., biotin-streptavidin}), or an antibody fragment (e.g., a single-chain antibody, an isolated antibody hypervariable domain, etc.) which binds specifically with a protein corresponding to the marker, such as the protein encoded by the open reading frame corresponding to the marker or such a protein which has undergone all or a portion of its normal post-translational modification, is used.
Harlow et al. (US Patent Application 20100272776A1)
Harlow recites wherein one or more of the one or more immunogens or the one or more adjuvants is provided in a form of at least one of at least one of microspheres, macrospheres, micelles, liposomes, nano-capsules, micro-capsules, macro-capsules, microbubbles or encapsulated in polymeric shells (Harlow at claim 124). Harlow teaches that he adjuvant can be one or more biomolecules that stimulate activation, proliferation, and/or differentiation of T cell lymphocytes. Examples of T cell stimulators include, but are not limited to, enterotoxins, MHC-peptide complexes, CD80 (B7-1), B7-2, antibodies to CD2, CD28, CD3; phorbol esters, IL-2, protein kinase C activators such as phorbol myristate acetate, calcium ionophores such as inonmycin, agents that trigger T cell receptor (TCR/CD3) activation, CD86, tumor necrosis factor (ligand) superfamily member 14 (TNFSF14), CD5, and ICOS.
The relevant prior art is presented for completeness of the record and compact prosecution. In selecting the references to be used in rejecting the claims, the examiner should carefully compare the references with one another and with the applicant’s disclosure to avoid an unnecessary number of rejections over similar references. The examiner is not called upon to cite all references that may be available, but only the "best." (See 37 CFR 1.104(c).) Multiplying references, any one of which is as good as, but no better than, the others, adds to the burden and cost of prosecution and should therefore be avoided. See MPEP 904.03, third paragraph in section. The examiner takes the position that Harlow and MacDougall appears to be just as good as Lee. As such, no rejection over Harlow and MacDougall has been written in view of the provisions of MPEP 904.03.
Conclusion
No claims are presently allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA MICHELLE PETRITSCH whose telephone number is (571)272-6812. The examiner can normally be reached M-F 08:30-17:00 EST ALT Fridays.
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/AMANDA MICHELLE PETRITSCH/Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612