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 .
Claims 1, 9, 10, and 13 are amended.
Claims 1-2, 9-10, and 13-20 are pending.
Claims 3-8, 11-12 and 21-51 are cancelled.
Claim 20 is withdrawn.
Note, rejections and objections not reiterated from previous office actions are hereby withdrawn. The following rejections or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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, 9, 13 and 14 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 EXNER (WO 2017/210612) and BORDEN (Influence of Lipid Shell Physicochemical Properties on Ultrasound-Induced Microbubble Destruction. IEEE Trans Ultrason Ferroelectr Freq Control. 2005.).
Regarding claim 1, WU teaches a method of inducing cell death (abstract). The method comprising:
administering nanobubbles which are then destroyed using ultrasound (abstract and page 239, paragraph 2), which reads on administering to the subject a plurality of nanobubbles and insonating nanobubbles with ultrasound energy
The nanobubbles comprise a membrane that surrounds an internal void with a gas (page 228, paragraph 4) and the nanobubbles comprise a lipid membrane (page 238, paragraph 4), which reads on each nanobubble having a lipid membrane that defines at least one internal void, which includes at least one gas, and
The nanobubbles were conjugated to a targeting agent, A10-3.2 aptamer, which binds to prostate-specific membrane antigen (PSMA), which rads on the targeted cell is a prostate cancer cell and the targeting moiety binds to prostate-specific membrane antigen (PSMA);
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) (page 238, paragraph 4).
WU does not teach using dibehenoylglycerophosphocoline (DBPC).
EXNER teaches nanobubbles that target cancerous tumors and are used with ultrasound (page 1, paragraph 0004 and page 41, paragraph 0150). The nanobubbles are destroyed by ultrasound (page 5, paragraph 0028). EXNER teaches that switching DPPC to DBPC, with a molar ratio of at least 50%, which resulted fourfold improvement in half-life of the nanobubbles (page 14, paragraph 1). The mass ratio of the lipids in the nanobubble is 6.1:2:1:1 DBPC:DPPE:DPPA:PEG (page 41, paragraph 00148).
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).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate DBPC. The person of ordinary skill in the art would have been motivated to make those modifications, because it resulted fourfold improvement in half-life of the nanobubbles, and reasonably would have expected success because the references are in the same field of endeavor, such as lipid nanobubbles that are affected by ultrasound. Furthermore, DPPC and DBPC are functional equivalents of lipids used to form nanobubbles that are destroyed by ultrasound.
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 and improved half-life. 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. Furthermore, EXNER teaches the ratio as claimed.
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. Furthermore, WU teaches the composition can achieve ultrasound-mediated nanobubble destruction which causes cell apoptosis (abstract).
Regarding claim 9, EXNER teaches a triblock polymer, such as Pluronic L10 which is a poloxamer, is also added to control the size of the nanobubble and impart the nanobubble with in vitro and in vivo echogenicity (page 25, paragraph 0096).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate Pluronic L10. The person of ordinary skill in the art would have been motivated to make those modifications, because it controls the size of the nanobubble and impart the nanobubble with in vitro and in vivo echogenicity, and reasonably would have expected success because the references are in the same field of endeavor, such as lipid nanobubbles that are destroyed by ultrasound.
Regarding claim 13, WU teaches 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 9, EXNER teaches a triblock polymer, such as PLURONIC L10 which is a poloxamer, is also added to control the size of the nanobubble and impart the nanobubble with in vitro and in vivo echogenicity (page 25, paragraph 0096).
Claims 1, 2, 9, 10, 13 and 14 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.), EXNER (WO 2017/210612) and BORDEN (Influence of Lipid Shell Physicochemical Properties on Ultrasound-Induced Microbubble Destruction. IEEE Trans Ultrason Ferroelectr Freq Control. 2005.) 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, EXNER and BORDEN teach Applicant’s invention as discussed above.
WU, EXNER and BORDEN do 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 diameter 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, 9-10, and 13-19 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.), EXNER (WO 2017/210612), BORDEN (Influence of Lipid Shell Physicochemical Properties on Ultrasound-Induced Microbubble Destruction. IEEE Trans Ultrason Ferroelectr Freq Control. 2005.), 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 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, EXNER, BORDEN, and YU teach Applicant’s invention as discussed above.
WU, EXNER, BORDEN, and YU 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.
Response to Arguments
Applicant argues, the references do not teach including at least one of glycerol, propylene glycol, or poloxamer.
The Examiner does not find the argument persuasive because as discussed above, EXNER teaches a triblock polymer, such as Pluronic L10 which is a poloxamer, is also added to control the size of the nanobubble and impart the nanobubble with in vitro and in vivo echogenicity (page 25, paragraph 0096).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate Pluronic L10. The person of ordinary skill in the art would have been motivated to make those modifications, because it controls the size of the nanobubble and impart the nanobubble with in vitro and in vivo echogenicity, and reasonably would have expected success because the references are in the same field of endeavor, such as lipid nanobubbles that are destroyed by ultrasound.
Applicant argues, the references do not teach using DBPC or that the lipid membrane should comprise a mixture of lipids having at least 50% by weight of DBPC as in claim 1.
The Examiner does not find the argument persuasive because as discussed above EXNER teaches a mass ratio of the lipids in the nanobubble is 6.1:2:1:1 DBPC:DPPE:DPPA:PEG and that switching DPPC to DBPC, with a molar ratio of at least 50%, which resulted fourfold improvement in half-life of the nanobubbles. BORDEN teaches making nanobubbles using DBPC with DSPE-PEG2000-COOH (figure 2 and table III) which showed stability (page 4, paragraph 4) and did not produce aspherical bubble morphologies or folded shapes (page 5, paragraph 3).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate DBPC. The person of ordinary skill in the art would have been motivated to make those modifications, because it resulted fourfold improvement in half-life of the nanobubbles, and reasonably would have expected success because the references are in the same field of endeavor, such as lipid nanobubbles that are affected by ultrasound. Furthermore, DPPC and DBPC are functional equivalents of lipids used to form nanobubbles that are destroyed by ultrasound.
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 and improved half-life. 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. Furthermore, EXNER teaches the ratio as claimed.
Applicant argues, the references do not teach insonating nanobubbles internalized into the target cell with ultrasound energy effective to promote inertial cavitation of the internalized nanobubbles and promote drug-free apoptosis and/or necrosis of the target cell. Wu does not teach does not teach that the ultrasound therein would promote inertial cavitation. Yu does not teach that the nanobubbles themselves entered the cells or insonating nanobubbles internalized into the target cell with ultrasound energy effective to promote inertial cavitation of the internalized nanobubbles and promote drug-free apoptosis and/or necrosis of the target cell. Yu states that ultrasound increased the permeability of cell membranes and facilitated entry of the drug temsirolimus (TEM) into the cells, pg. 93, right col., but does not teach that the ultrasound mediated cavitation effect was itself sufficient to promote drug-free apoptosis and/or necrosis of the target cells as claimed. Suzuki does not teach that the nanobubbles therein are internalized by target cells or that the ultrasound promotes inertial cavitation of the internalized nanobubbles and drug-free apoptosis and/or necrosis of the target cell. Suzuki instead teaches that the cavitation of the nanobubbles might cause pores in the cell membrane that release tumor-associated antigens that could prime cos+ T cells of the anti-tumor cellular immune system, pg. 221, right col.; abstract, but fails to provide any indication that the nanobubbles therein have been internalized by the cells.
The Examiner does not find the argument persuasive because as discussed above, 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. Furthermore, WU teaches the composition can achieve ultrasound-mediated nanobubble destruction which causes cell apoptosis (abstract).
Applicant argues, Boren investigated the acoustic response of lipid microbubbles to insonification under conditions that did not cause inertial cavitation. Instead, the single cycling pulsing used therein caused DBPC microbubbles to form buds and strings that build up to form large lipid particles several microns in diameter after the gas core had been eliminated, Fig. 5(d), Fig. 6; pg. 6, ,r 2. Borden provides no teachings that would lead one skilled in the art to optimize lipids for preparing nanobubbles that are subjected to ultrasound energy effective to promote inertial cavitation of internalized nanobubbles within target cells and cause drug-free apoptosis and/or necrosis of the target cells as in the present amendment.
The Examiner does not find the argument persuasive because BORDEN is not cited for inertial cavitation. WU, as discussed in the above argument teaches inertial cavitation.
Applicant argues, in Borden the DBPC-containing microbubbles where the largest microbubbles therein, Table II, and Borden does not provide any teaching that would lead one skilled in the art to nanobubbles having a size and/or diameter that facilitates internalization of the nanobubble to a target cell.
The Examiner does not find the argument persuasive because no size and/or diameter is listed in claim 1, where the property of a size that facilitates internalization of the nanobubble to a target cell is recited. Furthermore, as discussed above, YU teaches nanobubbles with a diameter of 368 nm (abstract). YU teaches that nanobubbles with small diameters have enhanced permeability and retention (page 82, paragraph 3).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate a diameter 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.
Applicant argues, the ultrasound parameters in Borden involved single-cycling pulsing that caused DBPC microbubbles to form buds and strings that build up to form large lipid particles several microns in diameter after the gas core had been eliminated, Fig.5(d), Fig. 6; pg. 6, ,r 2. Borden provides no teachings that would lead one skilled in the art to optimize lipids for preparing nanobubbles that are subjected to ultrasound energy effective to promote inertial cavitation of internalized nanobubbles within target cells and cause drug-free apoptosis and/or necrosis of the target cells as in the present amendment.
The Examiner does not find the argument persuasive because BORDEN is not cited for inertial cavitation. WU, as discussed in the above argument teaches inertial cavitation.
Applicant argues, Hernot does not teach to insonate nanobubbles at two different pulses with pulses of different pressure amplitudes as the cited teachings are merely a description of how the strength or intensity of the acoustic power/pressure affects the microbubble and there is no teaching that would lead one skilled in the art to insonate internalized nanobubbles with ultrasound energy effective to promote inertial cavitation of the internalized nanobubbles and drug-free apoptosis and/or necrosis of the target cell.
The Examiner does not find the argument persuasive because as discussed above, 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. Furthermore, WU, as discussed in the above argument teaches inertial cavitation.
Conclusion
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.
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/S.L.M./ Examiner, Art Unit 1618 /JAKE M VU/Primary Examiner, Art Unit 1618
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