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 .
Receipt is acknowledged of IDS filed on 12/15/2022, 02/24/2025, and 05/28/2025.
Claims 1-2, 8-20 and 22 are pending.
Claims 3-7, 21, and 23-51 are cancelled.
Claim 20 are withdrawn.
Election/Restrictions
Applicant’s election without traverse of Species A, B and C in the reply filed on 10/22/2025 is acknowledged.
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.
Claims 1, 8, 9, 11, 13, 14 and 22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WU (Ultrasound-mediated nanobubble destruction (UMND) facilitates the delivery of A10-3.2 aptamer targeted and siRNA-loaded cationic nanobubbles for therapy of prostate cancer. Drug Delivery. 2018.).
Regarding claim 1, WU teaches a method of inducing cell death (abstract). The method comprises administering nanobubbles which are then destroyed using ultrasound (abstract and page 239, paragraph 2), which reads on insonating nanobubbles with ultrasound. The nanobubbles comprise a membrane that surrounds an internal void with a gas (page 228, paragraph 4). The nanobubbles were conjugated to a targeting agent, A10-3.2 aptamer, which binds to prostate-specific membrane antigen (PSMA).
Note, since the nanobubbles are comprised of the same components, used for the same method, and no specific size and/or diameter is listed in claim 1, the nanobubbles of the prior art would be of a size and/or diameter that facilitates internalization of the nanobubble by the target cell upon binding of the targeting moiety to the cell surface molecule and upon application of ultrasound energy be able to promote inertial cavitation of the internalized nanobubbles and apoptosis and/or necrosis of the target cell.
Regarding claim 8, 9 and 11, the nanobubbles comprise a lipid membrane made of 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE-PEG2000-COOH), and 3b-[N-(N0,N0-dimethylaminoethane)-carbamoyl]-cholesterol hydrochloride (DC-cholesterol)
Regarding claim 13, the nanobubbles are filled with perfluoropropane gas (page 228, paragraph 4), which is a perfluorocarbon gas (Applicant’s specification, page 14, paragraph 0071).
Regarding claim 14, note, since the nanobubbles are comprised of the same components and used for the same method it would be inherent that the isnonation would induce cell death without adversely effecting normal cells and tissues. Furthermore, the nanobubbles of the prior art showed low toxicity after injection (page 239, paragraph 3).
Regarding claim 22, the nanobubbles further encapsulate siRNA (abstract and page 227, paragraph 3), which is used as a therapeutic agent.
Claim Rejections - 35 USC § 103
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.
Claims 1, 2, 8-11, 13, 14 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over WU (Ultrasound-mediated nanobubble destruction (UMND) facilitates the delivery of A10-3.2 aptamer targeted and siRNA-loaded cationic nanobubbles for therapy of prostate cancer. Drug Delivery. 2018.) in view of YU (G250 Antigen-Targeting Drug-Loaded Nanobubbles Combined with Ultrasound Targeted Nanobubble Destruction: A Potential Novel Treatment for Renal Cell Carcinoma. International Journal of Nanomedicine. 2020.).
WU teaches Applicant’s invention as discussed above.
WU does not teach a diameter of between 50 nm to 400 nm.
Regarding claim 2, YU teaches nanobubbles with a targeting agent conjugated to the surface with a therapeutic agent encapsulated that are destroyed using ultrasound that are made using a lipid membrane with a perfluoropropane gas interior (abstract). The nanobubbles have a diameter of 368 nm (abstract). YU teaches that nanobubbles with small diameters have enhanced permeability and retention (page 82, paragraph 3).
Regarding claim 10, the nanobubbles have a lipid concentration of 11 mg/mL which was used to create the membrane of the nanobubble (page 83, paragraph 2).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate a dimeter of 368 nm. The person of ordinary skill in the art would have been motivated to make those modifications, because it allows for enhanced permeability, and reasonably would have expected success because the references are in the same field of endeavor such as nanobubbles with a targeting agent conjugated to the surface with a therapeutic agent encapsulated that are destroyed using ultrasound that are made using a lipid membrane with a perfluoropropane gas interior.
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate a lipid concentration of 11 mg/mL. The person of ordinary skill in the art would have been motivated to make those modifications, because it allows for the lipid membrane to be formed, and reasonably would have expected success because the references are in the same field of endeavor such as nanobubbles with a targeting agent conjugated to the surface with a therapeutic agent encapsulated that are destroyed using ultrasound that are made using a lipid membrane with a perfluoropropane gas interior.
Claims 1, 2, 8-12, 13, 14 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over WU (Ultrasound-mediated nanobubble destruction (UMND) facilitates the delivery of A10-3.2 aptamer targeted and siRNA-loaded cationic nanobubbles for therapy of prostate cancer. Drug Delivery. 2018.) and YU (G250 Antigen-Targeting Drug-Loaded Nanobubbles Combined with Ultrasound Targeted Nanobubble Destruction: A Potential Novel Treatment for Renal Cell Carcinoma. International Journal of Nanomedicine. 2020.) in view of BORDEN (Influence of Lipid Shell Physicochemical Properties on Ultrasound-Induced Microbubble Destruction. IEEE Trans Ultrason Ferroelectr Freq Control. 2005.).
WU and YU teach Applicant’s invention as discussed above.
WU and YU do not teach the weight ratio of lipids used in the nanobubble.
Regarding claim 12, BORDEN teaches bursting nanobubbles using ultrasound and that the lipid composition for nanobubbles significantly impacts the properties of the how the nanobubbles burst, such as acoustic dissolution rate, fragmentation propensity, and mechanism of excess lipid shedding (abstract).
The references do not specifically teach the weight ratio of the lipids used as claimed by the Applicant. The weight ratio of the lipids used is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of the ordinary skill to determine the optimal weight ratio of the lipids used in order to best achieve desired results, such as a nanobubble with the desired bursting properties. Thus, absent of some demonstration of unexpected results from the claimed parameters, this optimization of the weight ratio of the lipids used would have been obvious at the time of Applicant’s invention.
Claims 1, 2, 8-19 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over WU (Ultrasound-mediated nanobubble destruction (UMND) facilitates the delivery of A10-3.2 aptamer targeted and siRNA-loaded cationic nanobubbles for therapy of prostate cancer. Drug Delivery. 2018.) and YU (G250 Antigen-Targeting Drug-Loaded Nanobubbles Combined with Ultrasound Targeted Nanobubble Destruction: A Potential Novel Treatment for Renal Cell Carcinoma. International Journal of Nanomedicine. 2020.) and BORDEN (Influence of Lipid Shell Physicochemical Properties on Ultrasound-Induced Microbubble Destruction. IEEE Trans Ultrason Ferroelectr Freq Control. 2005.) in view of SUZUKI (Tumor growth suppression by the combination of nanobubbles and ultrasound. Cancer Science. 2016.) and HERNOT (Microbubbles in Ultrasound-Triggered Drug and Gene Delivery. Adv Drug Deliv Rev. 2008.).
WU, YU and BORDEN teach Applicant’s invention as discussed above.
WU, YU and BORDEN do not teach the ultrasound settings used on the nanobubbles.
Regarding claim 15, SUZUKI teaches using non-focused ultrasound to burst nanobubbles for the treatment of cancer (abstract and page 218, paragraph 4). SUZUKI teaches the ultrasound had a duty cycle of 50% (page 218, paragraph 9) an intensity of 1-3 W/cm2 (figure 3), a frequency of 1 Mhz (page 218, paragraph 4) for 2 minutes (figure 3). These values were used to find the optimal therapeutic behavior for the nanobubble upon being altered using ultrasound.
Regarding claim 19, SUZUKI teaches using non-focused ultrasound to burst nanobubbles for the treatment of cancer (abstract and page 218, paragraph 4). Non-focused ultrasound was used because high intensity focused ultrasound involves multiple long sessions and can cause skin burns around shallow tumors (page 217, paragraph 1).
SUZUKI does not teach the amplitude used on the nanobubbles or using two different amplitudes for two pulses.
Regarding claim 15-17, HERNOT teaches that the behavior of lipid microbubbles/nanobubbles is dependent upon the amplitude of ultrasound to which they are exposed (page 3, paragraph 3). At a lower amplitude nanobubbles can be used for imaging (page 3, paragraph 4), followed by a higher amplitude to burst the nanobubbles (page 3, paragraph 5).
Regarding claim 18, HERNOT teaches a lower amplitude is considered non-inertial cavitation (page 3, paragraph 4), which would read on below the nanobubble pressure threshold for inertial cavitation and the higher amplitude caused inertial cavitation (page 3, paragraph 5), which would read on above the threshold pressure for inertial cavitation.
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate specific ultrasound settings. The person of ordinary skill in the art would have been motivated to make those modifications, because the nanobubbles behavior is dependent upon the ultrasound settings and the ones listed in SUZUKI achieved the desired bursting of the nanobubbles, and reasonably would have expected success because the references are in the same field of endeavor, such as bursting nanobubbles using ultrasound.
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate using a non-focused ultrasound. The person of ordinary skill in the art would have been motivated to make those modifications, because it is an alternative to focused ultrasound and can allow for shorter sessions for patient and lessens the risk of skin burns around shallow tumors, and reasonably would have expected success because the references are in the same field of endeavor, such as bursting nanobubbles using ultrasound for the treatment of cancer.
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate a specific amplitude, as well as two different amplitudes. The person of ordinary skill in the art would have been motivated to make those modifications, because the nanobubbles behavior is dependent upon the amplitude and different amplitudes can be used to achieve different effects, such as imaging or bursting which would allow for one composition to preform multiple functions, and reasonably would have expected success because the references are in the same field of endeavor, such as bursting nanobubbles using ultrasound.
The reference does not specifically teach the amplitude values as claimed by the Applicant. The amplitude values is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of the ordinary skill to determine the optimal amplitude values in order to best achieve desired results, such as achieving the desired effect from the nanobubbles such as imaging or bursting. Thus, absent of some demonstration of unexpected results from the claimed parameters, this optimization of the amplitude values would have been obvious at the time of Applicant’s invention.
Conclusion
No claims are allowable.
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/S.L.M./ Examiner, Art Unit 1618
/Michael G. Hartley/ Supervisory Patent Examiner, Art Unit 1618