DETAILED ACTION
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 .
1. Claims 2, 3, 5-12, 15, 17, 18, 21-24, 27-31, 36, 38-43, 48, and 49 have been cancelled. Claim 1 has been amended.
Claims 1, 4, 13, 14, 16, 19, 20, 25, 26, 32-35, 37, and 44-47 are pending and under examination.
Claim Rejections - 35 USC § 103
2. 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 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.
3. Claims 1, 4, 13, 14, 16, 19, 25, 26, 32-34, 37, 44, 45, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Jain et al. (Mol. Pharmaceutics, 2013, 10: 2416-2425), in view of both Foster et al. (Adv. Healthcare Mater., first published on 22 December 2014, 4: 760-770) and Kozielski et al. (ACS Nano, 2014, 8: 3232-3241).
Jain et al. teach a stabilized lipid-polymer hybrid nanoplex for improved transfection efficiency, where the nanoplex has a size of about 242.6 nm and comprises a pDNA encapsulated within a DOTAP liposome electrostatically coated with a first layer of anionic PAA and a second PEI layer; Jain et al. use the nanoplex to transfect human cells in vitro (claims 1, 4, 16, 19, 25, and 32) (see Abstract; p. 2418, column 1, second to last paragraph; p. 2422, Fig. 9; Fig. 2423, Fig. 10).
Jain et al. do not teach the light-responsive mPEG-b-P(APNBMA) nor do they teach siRNA (claims 1, 4, 13, 14, 25, and 37). Foster et al. teach inefficient silencing when PEI is used due to limited siRNA cytoplasmic release. Foster et al. teach mPEG-b-P(APNBMA)23.6 nanoparticles for light-controlled siRNA release and using these nanoparticles to deliver active siRNA to cells for on/off control of target gene silencing; Foster et al. teach that the siRNA remains bound to the nanoparticles in the cells in the absence of stimulation with light and is efficiently delivered to the cytoplasm upon light stimulation (claims 1, 4, 13, 14, 32, 34, and 37) (see Abstract; p. 761; p. 762, paragraph bridging columns 1 and 2; paragraph bridging p. 765 and 766; p. 767, paragraph bridging columns 1 and 2). Based on these teachings, one of skill in the art would have found obvious to modify Jain et al. by replacing PEI with mPEG-b-P(APNBMA)23.6 and further testing the resulting nanoplex for siRNA delivery to the human cells with the reasonable expectation that doing so would result in light-controlled silencing of target genes in the human cells (claim 32).
With respect to claims 26 and 33, based on Foster et al. teaching that the siRNA remains bound to the nanoparticles in the cells in the absence of stimulation with light and is efficiently delivered to the cytoplasm upon light stimulation, one of skill in the art would have reasonably expected the nanoplexes to be stable and not release the siRNA for at least one week in the absence of light-stimulation.
With respect to limitation of primary human cells (claims 44, 45, and 47), one of skill in the art would have found obvious to use any cell of interest, including primary human cell (i.e., isolated from a subject) when silencing genes in primary human cells was needed (see Kozielski et al., Abstract).
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
4. Claims 1, 4, 13, 14, 16, 19, 20, 24-26, 32-34, 37, 44, 45, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Jain et al. taken with both Foster et al. and Kozielski et al., in further view of both Liao et al. (Biomaterials, 2010, 31: 8780-8799) and Bekale et al. (Colloids and Surfaces B: Biointerfaces, online December 2014, 125: 309-317).
The teachings of Jain et al., Foster et al., and Kozielski et al. are applied as above for claims 1, 4, 13, 14, 16, 19, 24-26, 32-34, 37, 44, 45, and 47. Jain et al., Foster et al., and Kozielski et al. do not teach a PAA having a MW of 250 kDa (claim 20). Liao et al. teach that anionic polymers assist in the intracellular siRNA release and enhance gene silencing effectiveness by weakening the strength of the interaction between the cationic carrier and the siRNA (see Abstract; p. 8780, column 2; p. 8781, column 2, fourth full paragraph; p. 8782, Fig. 1). Bekale et al. teach that MW affects the binding affinity between cationic and anionic polymers (see Abstract). Based on these teachings, one of skill in the art would have reasonably concluded that PAA MW is a result-effective variable with respect to siRNA transfection efficiency. One of skill in the art would have found obvious to use routine experimentation and vary the PAA MW with the reasonable expectation that doing so would identify the MW resulting in the strength of electrostatic interactions leading to optimal transfection efficiency. Routine optimization is not considered inventive and no evidence has been presented that the selection the claimed MW was other than routine or that the results should be considered unexpected in any way as compared to the closest prior art (see MPEP 2144.05 II).
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
5. Claims 1, 4, 13, 14, 16, 19, 24-26, 32-35, 37, 44, 45, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Jain et al. taken with both Foster et al. and Kozielski et al., in further view of Bartlett et al. (Nucl. Acids Res., 2006, 34: 322-333).
The teachings of Jain et al., Foster et al., and Kozielski et al. are applied as above for claims 1, 4, 13, 14, 16, 19, 24-26, 32-34, 37, 44, 45, and 47. Jain et al., Foster et al., and Kozielski et al. do not teach repeated administration (claim 35). Bartlett et al. teach the need for repeated administration due to the transient nature of gene silencing when using siRNAs (see p. 326, paragraph bridging columns 1 and 2; p. 328-329; p. 332, paragraph bridging columns 1 and 2). Thus, using multiple administrations followed by light-stimulation would have been obvious to one of skill in the art to predictably achieve prolonged gene silencing.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
6. Claims 1, 4, 13, 14, 16, 19, 24-26, 32-34, 37, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Jain et al. taken with both Foster et al. and Kozielski et al., in further view of Schroeder et al. (J. Int. Med., 2009, 267: 9-21).
The teachings of Jain et al., Foster et al., and Kozielski et al. are applied as above for claims 1, 4, 13, 14, 16, 19, 24-26, 32-34, 37, 44, 45, and 47. Jain et al., Foster et al., and Kozielski et al. do not teach administering to humans (claim 46). Schroeder et al. teach ongoing human clinical trials using siRNAs (see paragraph bridging p. 16 and 17; p. 17, Table 2). Thus, modifying Jain et al., Foster et al., and Kozielski et al. by using a therapeutic siRNA and further administering the resulting nanoplex to humans in need of therapy would have been obvious to one of skill in the art with the reasonable expectation that doing so would result in therapeutic effect.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
Response to Arguments
7. The applicant argues that, since Jain selected PEI for its unique ability to undergo endosomal escape and mediate nuclear entry, one of skill in the art would not have been motivated to replace PEI with mPEG-b-P(APNBMA) with a reasonable expectation for successful delivery to the nucleus.
This is not found persuasive because the rejection is based on delivering siRNA to the cytoplasm, not the nucleus. Thus, the argument of lack of reasonable expectation for successful delivery to the nucleus is not material to the rejection.
That siRNAs function in the cytoplasm was common knowledge in the prior art. Foster teaches that PEI mediates low gene silencing because it cannot efficiently release the siRNAs into the cytoplasm. Since Foster teaches that mPEG-b-P(APNBMA) mediates efficient silencing, the siRNA is necessarily released into the cytoplasm, i.e., it escaped from the endosomes. Since siRNAs function in the cytoplasm, there is no need for mPEG-b-P(APNBMA) to mediate nuclear uptake. Only delivery to the cytoplasm is needed, which mPEG-b-P(APNBMA) is able to do.
Thus, Foster provides the motivation to replace PEI with mPEG-b-P(APNBMA) when siRNA delivery was needed and also the reasonable expectation that doing so would result in a composition suitable for silencing mRNAs of interest.
The argument that one of skill in the art would have reasonably expected that the nanoplex would deliver the siRNA to the nucleus is not found persuasive because it is just an argument not supported by any evidence.
Jain specifically teach that it is PEI which mediates nuclear entry (see p. 2417, column 1, first full paragraph). Foster teaches that, unlike PEI, mPEG-b-P(APNBMA) mediates efficient cytoplasmic delivery. Thus, one of skill in the art would have reasonably expected that replacing PEI with mPEG-b-P(APNBMA) would result in a composition suitable for siRNA delivery to the cytoplasm.
For these reasons, the arguments that Jain formulated the nanoplex as a whole for nuclear delivery and that it was unexpected that the modified nanoplex would mediate efficient siRNA delivery to the cytoplasm are not found persuasive. Jain only points to the PEI component for mediating nuclear entry. By reading Jain, one of skill in the art would have reasonable concluded that the nanoplex is capable to enter the nucleus due to the presence of PEI and would have reasonably expected efficient cytoplasmic delivery by replacing PEI (inefficient siRNA cytoplasmic release) with mPEG-b-P(APNBMA).
Example 1 and Fig. 1 were previously addressed.
The argument that Liao, Bekale, Bartlett, and Schroeder do not teach the limitations of claim 1 is not found persuasive because none of Liao, Bekale, Bartlett, and Schroeder has to disclose the limitations recited in claim 1.
The limitations of claim 1 are taught by the combined teachings of Jain and Foster. Liao and Bekale were cited for addressing the limitations of claim 20; Bartlett was cited for addressing the limitations of claim 35; and Schroeder was cited for addressing the limitations of claim 46.
Conclusion
8. THIS ACTION IS MADE FINAL. 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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/ILEANA POPA/Primary Examiner, Art Unit 1633