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 1-6 and 9-16 are pending.
Claims 7, 8 are cancelled.
Claims 14-16 are withdrawn.
Claims 1, 14, and 15 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Note, rejections and objections not reiterated from previous office actions are hereby withdrawn.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.
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 1-13 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8 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.).
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 output intensity is not more than 720 mmW/cm2 (claim 8), which reads on the instant claim 1, a system for delivering a target substance into an immune cell, comprising ultrafine bubble water or ultrafine bubble aqueous solution comprising ultrafine bubbles with an average diameter of not more than 200 nm and not containing phospholipid, and an ultrasound generator in combination wherein the ultrasound output intensity is not more than 720 mmW/cm. The solution has a density of not less than 2.0 x 108 bubbles/mL (claim 5).
The patent does not recite the ultrafine bubble water to be 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). Thus, negatively charged nanoparticles have better blood compatibly and less toxic effects.
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.
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 1-6, 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 BLUM (Nanoparticles Formed by Acoustic Destruction of Microbubbles and Their Utilization for Imaging and Effects on Therapy by High Intensity Focused Ultrasound. Theranostics. 2017.).
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).
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 5, IRUDAYARAJ teaches the nanobubbles have an average diameter between 60-80 nm (paragraph 0017).
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.
BLUM teaches a microbubble suspension that is used for imaging and bursts upon ultrasound to release achieve a therapeutic effect (abstract). The nanobubbles had an average size of 164 nm and an average concentration of 1.64 x 109 bubbles/mL (page 695, paragraph 4), which reads on density. BLUM further teaches that the microbubble concentration needs to be high enough so that it can be properly detected (page 698, paragraph 1). 1x108 bubbles/mL showed a high brightness for detection (Figure 3c).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate a density/concentration of 1x108 bubbles/mL. The person of ordinary skill in the art would have been motivated to make those modifications, because the bubble/mL concentration/density needs to be high enough for imaging purposes and a concentration/density 1x108 bubbles/mL showed a high brightness for detection, and reasonably would have expected success because the references are in the same field of endeavor such as nanobubble solutions that are used for imaging and therapeutics and are bursted using ultrasound.
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 1-6, 9, 10, 12 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over IRUDAYARAJ (US 2016/0166716 A1) and BLUM (Nanoparticles Formed by Acoustic Destruction of Microbubbles and Their Utilization for Imaging and Effects on Therapy by High Intensity Focused Ultrasound. Theranostics. 2017.) in view of XIAO (The effect of surface charge on in vivo biodistribution of PEG-oligocholic acid based micellar nanoparticles. Biomaterials. 2011.).
IRUDAYARAJ and BLUM 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 1-6 and 9-13 are rejected under 35 U.S.C. 103 as being unpatentable over IRUDAYARAJ (US 2016/0166716 A1) and BLUM (Nanoparticles Formed by Acoustic Destruction of Microbubbles and Their Utilization for Imaging and Effects on Therapy by High Intensity Focused Ultrasound. Theranostics. 2017.) in view of DUCHATEAU (US 2018/0291343 A1).
IRUDAYARAJ and BLUM teaches Applicant’s invention above.
IRUDAYARAJ and BLUM 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 HARDEE is towards gas filled microbubbles and not ultrafine bubbles.
The examiner does not find this argument persuasive. Applicant’s arguments with respect to claims 1-6 and 9-13 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
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.
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