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 1-4, 6 and 9-16 are pending.
Claims 5, 7, 8 are cancelled.
Claims 14-16 are withdrawn.
Claims 1, 14, and 15 and 16 are amended.
Note, rejections and objections not reiterated from previous office actions are hereby withdrawn.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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/12/2026 has been entered.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4, 6 and 9-13 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 7, and 14 of U.S. Patent No. 12178981B2 in view of XIAO (The effect of surface charge on in vivo biodistribution of PEG-oligocholic acid based micellar nanoparticles. Biomaterials. 2011.) and IRUDAYARAJ (US 2016/0166716 A1).
The patent recites: A method for increasing blood-brain barrier permeability of a drug, the method comprising using (a) nano-bubble water or a nano-bubble aqueous solution, said nano- bubble water or said nano-bubble aqueous solution comprising nano-bubbles with an average diameter of not more than 200 nm, and (b) an ultrasound. Wherein the nano-bubbles consist of a gas, and a non-ionic surfactant (claim 1), wherein the nano-bubbles do not contain a phospholipid (claim 14), and the ultrasound generating apparatus has an ultrasound output intensity of 50-500 mW/cm2 (claim 7). The nano-bubbles in the nano-bubble water or the nano-bubble aqueous solution have a density of not less than 2.0×108 bubbles/mL (claim 5).
The patent does not recite the ultrafine bubble water to be negatively charged or the diameter claimed by applicant.
XIAO teaches that nanoparticles that are negatively charged do not show obvious hemolytic and cytotoxic properties due to their ability to be cleared by the liver more efficiently (abstract). Thus, negatively charged nanoparticles have better blood compatibly and less toxic effects.
IRUDAYARAJ teaches a nanobubble solution (paragraph 0056), which reads on ultrafine bubble aqueous solution, with average diameters less than about 200 nm (Claim 4), the bubbles have polyethylene glycol (claim 3), which reads on not a phospholipid and is a non-ionic surfactant, and uses ultrasound to burst the nanobubbles (paragraph 0065), also called sonoporation (paragraph 0062). The nanobubble solution was neutralized to a pH of 7 (Page 4, paragraph 0060-0061). IRUDAYARAJ teaches the nanobubbles can deliver a biomolecule, such as a polynucleotide (claim 7 and paragraph 0042). IRUDAYARAJ teaches the size of the nanobubbles can be tuned to initiate bursting at different frequencies, power or intensity (paragraph 0054).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate having negatively charged nanoparticles. The person of ordinary skill in the art would have been motivated to make those modifications, because negatively charged nanoparticles have better blood compatibility and less toxic effects, and reasonably would have expected success because the references are in the same field of endeavor, such as nanoparticles for drug delivery.
The references do not specifically teach the average diameter of the bubbles as claimed by the Applicant. The diameter 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 diameter in order to best achieve desired results, such as tuning the diameter to initiate bursting at different frequencies, power or intensity. Thus, absent of some demonstration of unexpected results from the claimed parameters, this optimization of diameter would have been obvious at the time of Applicant’s invention.
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.
Claims 1-4, 6, 9, 10, 12 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over IRUDAYARAJ (US 2016/0166716 A1) in view of TLAXCA (ANALYSIS OF IN VITRO TRANSFECTION BY SONOPORATION USING CATIONIC AND NEUTRAL MICROBUBBLES. Ultrasound Med Biol. 2010.).
Regarding claim 1, IRUDAYARAJ teaches a nanobubble solution (paragraph 0056), which reads on ultrafine bubble aqueous solution, with average diameters less than about 200 nm (Claim 4), the bubbles have polyethylene glycol (claim 3), which reads on not a phospholipid and is a non-ionic surfactant, and uses ultrasound to burst the nanobubbles (paragraph 0065), also called sonoporation (paragraph 0062). The nanobubble solution was neutralized to a pH of 7 (Page 4, paragraph 0060-0061). IRUDAYARAJ teaches the nanobubbles can deliver a biomolecule, such as a polynucleotide (claim 7 and paragraph 0042).
Note, Applicant’s specification states that to make an ultrafine bubble aqueous solution negatively-charged, the pH of the ultrafine bubble aqueous solution is preferably 7-14 (Page 18, paragraph 2). Therefor since the solution in the prior art is at a pH of 7, it is inherently negatively charged. Furthermore, the specification does not provide a clear explanation on how the solution is created to be negatively charged apart from the above mentioned pH conditions.
Note, since applicant’s claims are towards a system and not a method the limitation of “wherein an ultrasound output intensity of the ultrasound generator is not more than 720 mW/cm2”, any ultrasound generator that has the capability of producing any value under 720 mW/cm2 would read on the claim, such as a broken ultrasound generator which would produce 0 mW/cm2.
Regarding claim 2 and 3, IRUDAYARAJ teaches the nanobubbles have polyethylene glycol (claim 3), which reads on not a phospholipid and is a non-ionic surfactant.
Regarding claim 4, IRUDAYARAJ teaches the nanobubbles are filled with oxygen (claim 9), which reads on air.
Regarding claim 6, The d90/d10 ratio is a ratio between larger and smaller nanoparticles within the solution, this is a common ratio used in the art. IRUDAYARAJ teaches that the size of the nanobubbles can be tuned to initiate bursting at different frequencies, power or intensity (paragraph 0054), including creating a solution where a percentage of the nanobubbles burst at one frequency, while the other percentage bursts at a higher frequency (paragraph 0055).
Regarding claim 9, IRUDAYARAJ teaches the nanobubbles burst at a frequency of 1.1 MHz (claim 10).
Regarding claim 10, IRUDAYARAJ teaches the nanobubbles can deliver a biomolecule, such as a polynucleotide (claim 7 and paragraph 0042), which reads on nucleic acid.
Additional disclosures: IRUDAYARAJ teaches the frequency or power or intensity at which the nanobubble bursts may be tuned and is controlled in part by the polymer material and number and type of cross links (page 3, paragraph 0055) and the size of the nanobubbles can be tuned to initiate bursting at different frequencies, power or intensity (paragraph 0054). The composition can be further used for imaging (Page 3, paragraph 0052 and page 4, paragraph 0058).
IRUDAYARAJ does not teach the density of microbubbles as claimed by Applicant.
TLAXCA teaches a method of delivering a material into cells using a microbubble solution (abstract). The higher the concentration, also called density, of the microbubbles the higher the transfection efficiency (page 6, paragraph 5).
The references do not specifically teach the microbubble density as claimed by the Applicant. The microbubble density 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 microbubble density in order to best achieve desired results, such as increasing the transfection efficiency for the delivery of a material into the target cell. Thus, absent of some demonstration of unexpected results from the claimed parameters, this optimization of the microbubble density would have been obvious at the time of Applicant’s invention.
The reference does not specifically teach the average diameter of the bubbles as claimed by the Applicant. The diameter 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 diameter in order to best achieve desired results, such as tuning the diameter to initiate bursting at different frequencies, power or intensity. Thus, absent of some demonstration of unexpected results from the claimed parameters, this optimization of diameter would have been obvious at the time of Applicant’s invention.
Note, with regard to claims 12 and 13, the intended use of delivery of a nucleic acid into an immune cell or T cell in the product claims is met by the prior art, because the prior art compositions would be at least capable of performing said use. As the prior art teaches the same product, it would in turn be able to perform the same function.
The reference does not specifically teach the ultrasound output intensity as claimed by the Applicant. The ultrasound output intensity 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 ultrasound output intensity in order to best achieve desired results, such as having an appropriate intensity to burst the nanobubble being administered. Thus, absent of some demonstration of unexpected results from the claimed parameters, this optimization of the ultrasound output intensity would have been obvious at the time of Applicant’s invention.
The reference does not specifically teach d90/d10 size ratio or the ultrasound output intensity as claimed by the Applicant. The d90/d10 size ratio and the ultrasound output intensity 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 d90/d10 size ratio and ultrasound output intensity in order to best achieve desired results, such as changing the size of the nanobubbles to allow bursting at various frequencies, power or intensity and changing the output intensity to allow for complete bursting of the nanobubbles. Thus, absent of some demonstration of unexpected results from the claimed parameters, this optimization of the d90/d10 size ratio and the ultrasound output intensity would have been obvious at the time of Applicant’s invention.
Claims 1-4, 6, 9, 10, 12 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over IRUDAYARAJ (US 2016/0166716 A1) and TLAXCA (ANALYSIS OF IN VITRO TRANSFECTION BY SONOPORATION USING CATIONIC AND NEUTRAL MICROBUBBLES. Ultrasound Med Biol. 2010.) in view of XIAO (The effect of surface charge on in vivo biodistribution of PEG-oligocholic acid based micellar nanoparticles. Biomaterials. 2011.).
IRUDAYARAJ and TLAXCA teach Applicant’s invention above.
IRUDAYARAJ teaches an inherently negatively charged ultrafine bubble water in view of Applicant’s specification, however does not explicitly teach the ultrafine bubble water being negatively charged.
XIAO teaches that nanoparticles that are negatively charged do not show obvious hemolytic and cytotoxic properties due to their ability to be cleared by the liver more efficiently (abstract).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate having negatively charged nanoparticles. The person of ordinary skill in the art would have been motivated to make those modifications, because negatively charged nanoparticles have better blood compatibility and less toxic effects, and reasonably would have expected success because the references are in the same field of endeavor, such as nanoparticles for drug delivery.
Claims 1-4, 6 and 9-13 are rejected under 35 U.S.C. 103 as being unpatentable over IRUDAYARAJ (US 2016/0166716 A1) and TLAXCA (ANALYSIS OF IN VITRO TRANSFECTION BY SONOPORATION USING CATIONIC AND NEUTRAL MICROBUBBLES. Ultrasound Med Biol. 2010.) in view of DUCHATEAU (US 2018/0291343 A1).
IRUDAYARAJ and TLAXCA teaches Applicant’s invention above.
IRUDAYARAJ and TLAXCA do not teach the nucleic acid encoding a chimeric antigen receptor into a T cell.
Regarding claim 11, DUCHATEAU teaches transfecting immune cells, such as T cell, with a chimeric antigen receptor (claim 58) that can be delivered via sonoporation (paragraph 0374). The immune cells transfected with a chimeric antigen receptor enhance the efficiency of immunotherapy (field of invention).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate the nucleic acid encoding a chimeric antigen receptor into a T cell. The person of ordinary skill in the art would have been motivated to make those modifications, because immune cells transfected with a chimeric antigen receptor enhance the efficiency of immunotherapy, and reasonably would have expected success because all references teach delivering a nucleic acid using sonoporation.
Response to Arguments
Applicant argues, Examples 1 and 2 of the present application demonstrate that the presently claimed system and methods remarkably increase the introduction efficiency of a target substance into a cell (see, paragraphs [0087]-[0092] and FIGs. 1 and 2). Such a remarkable effect is not taught or suggested by the cited references and could not have been expected by a person of ordinary skill in the art.
In order to overcome a prima facie case of obviousness, it is incumbent upon the Applicant to provide comparative test evidence that demonstrates unexpected superiority of the claimed compositions versus the closest prior art compositions, and not simply an advantage predictable from the prior art. See In re Chapman, 148 USPQ 711, 715 (CCPA, 1966). Moreover, such proffered comparisons must be commensurate in scope with the breadth of the claims. See In re Clemens, 206 USPQ 289, 296 (CCPA, 1980) and In re Coleman, 205 USPQ 1172, 1175 (CCPA 1980).
In the instant case, the only microbubble density provided in the data is 4 x 108 bubbles/mL (Applicant’s specification example 1). The instant claims however are any density above 1.0 x 108, which is an extremely large range. The claim is not commensurate in scope with the data.
Furthermore, as discussed above, TLAXCA teaches a method of delivering a material into cells using a microbubble solution (abstract). The higher the concentration, also called density, of the microbubbles the higher the transfection efficiency (page 6, paragraph 5). The prior art describes the Applicant’s result of the density for the introduction efficiency of a target substance into a cell, therefor it is simply an advantage predictable from the prior art.
For a complete discussion of unexpected results, Applicants are referred to MPEP 716.02 et seq.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMANTHA L. MEJIAS whose telephone number is (703)756-5666. The examiner can normally be reached M-F.
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/S.L.M./ Examiner, Art Unit 1618 /JAKE M VU/Primary Examiner, Art Unit 1618
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