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 1-5, 14, 16, 20, 23-39, 42-43, and 49 have been cancelled. Claims 6, 8, 9, 13, 15, 17, 18, 21, 22, 40, 41, 48, and 50 have been amended.
Claims 6-13, 15, 17-19, 21, 22, 40, 41, 44-48, 50, and 51 are pending and under examination.
Claim Objections
2. Claims 21 and 40 should recite “the nanoparticle” in lines 1 and 2-3, respectively.
3. Claim 41 should recite “the cytosol” in line 2.
Claim Rejections - 35 USC § 112(b)
4. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
5. Claims 18, 41, and 44-47 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “substantially” in claim 18 is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim or specification. Neither the specification nor the art provides a standard for ascertaining the intended degree, and thus, one of skill in the art would not be reasonably apprised of the scope of the invention. The metes and bounds of the claim cannot be determined and the claim is indefinite.
Claim 41 recites the limitation “the at least one disulfide bond” in clause (b). There is insufficient antecedent basis for this limitation in the claim. Claim 41 also recites (a), (b), and/or (c), i.e., encompassing (a) and (c) or only (c). Clause (c) recites the limitation "the at least one disulfide bond”. There is insufficient antecedent basis for this limitation in clause (a) or the parent claim 40.
Claim 44 recites the limitation "the pharmaceutical formulation" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
Claim 45 recites the limitation "the one or more nanoparticles" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claims 46 and 47 are rejected for being dependent from the rejected claim 45 and also for failing to further clarify the basis of the rejection.
Claim Rejections - 35 USC § 103
6. 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.
7. Claims 6-13, 15, 17, 18, 21, 22, 40, 41, 44-48, 50, and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Green et al. (WO 14/066811; cited on the IDS filed on 10/31/2023), in view of Krasnici et al. (Int. J, Cancer, 2003, 105: 561-567)
Green et al. teach the bioreducible poly(β-aminoesters) (PBAEs) R647 and R64Ac, having the structures:
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91
462
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R647
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R64Ac
(claims 6-12) (see paragraph bridging p. 8 and 9; p. 9, Scheme 1).
Green et al. teach that R647 is suitable for obtaining nanoparticles encapsulating an siRNA (see Example 4).
Green et al. also teach a diblock copolymer of R647 and R64Ac (R647-R64Ac), having a R647 to R64Ac ratio of 1:3 (claim 13). Green et al. use R64Ac and R647-R64Ac to encapsulate siRNA into R64Ac or R647-R64Ac nanoparticles, followed by crosslinking the R64Ac acrylate groups via adding the photoinitiator Irgacure 2959 and exposing the nanoparticles/Irgacure 2959 mixture to UV light; crosslinking enhances stability and transfection efficiency compared to the non-crosslinked nanoparticles (claims 6, 15, and 22) (see Examples 7 and 8; Fig. 14 and 20). As demonstrated by Fig. 14, the R64Ac and the R647-R64Ac nanoparticles exhibit the same efficiency for siRNA delivery.
Green et al. teach encapsulating the siRNA in R647-R64Ac, not in a mixture of R647 and R64Ac (R647 + R64Ac) (claim 6 and 22). However, based on the teachings in Green et al., one of skill in the art would have known that nanoparticle stability and enhanced transfection efficiency are provided by the crosslinking of R64Ac. One of skill in the art would have reasonably concluded that crosslinking R647 + R64Ac would achieve the same result as crosslinking R647-R64Ac, and would have viewed using R647 + R64Ac as an obvious variant. One of skill in the art would have found obvious to obtain the stabilized nanoparticles by encapsulating the siRNA in R647 + R64Ac (at a weight ratio of 1:3), and further crosslinking the nanoparticles as taught by Green et al., to achieve the predictable result of obtaining a stable composition mediating enhanced transfection efficiency.
With respect to claims 17 and 18, Green et al. teach optimization by varying the R647:siRNA weight ratio from 37.5 to 600 (see p. 4, lines 22-24; Fig. 5). Green et al. also teach that the R647:siRNA ratio is a result-effective variable with respect to the zeta potential (see p. 4, lines 25-29; Fig. 6). Furthermore, Krasnici et al. teach that a neutral charge is optimal for the delivery of therapeutic agents to tumors (see Abstract). One of skill in the art would have found obvious to vary the ratio (R64 + R64A):siRNA by starting with the range taught by Green et al., with the reasonable expectation that doing so would identifying the optimal ratio resulting in a neutral bioreducible nanoparticle suitable for the delivery of the siRNA to tumors, when delivery to tumors was desired. Doing so would have only entailed routine experimentation. Routine optimization is not considered inventive and no evidence has been presented that the selection the claimed range 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).
With respect to claims 40, 50, and 51, Green et al. teach a method for treating glioblastoma or lung cancer by administering the nanoparticles to a subject, i.e., Green et al. also teach a pharmaceutical composition as recited in claims 21 and 44 (see Abstract; p. 3, lines 1-6; p. 21, lines 1-9).
With respect to claim 41, Green et al. teach that the bioreducible nanoparticles are degraded by the cytosolic glutathione to release the encapsulated siRNA into the cytosol (see paragraph bridging p. 7 and 8).
With respect to claims 45-47, since Green et al. teach treating glioblastoma or lung cancer and, since Krasnici et al. teach that a neutral charge is optimal for tumor delivery, one of skill in the art would have found obvious to administer neutral bioreducible nanoparticle with the reasonable expectation that doing so would result in the preferential siRNA delivery to the glioblastoma or lung cancer cells.
With respect to claim 48, Green et al. teach that the efficacy of the crosslinked nanoparticles remains constant over 5 h in serum, while the efficacy of the non-crosslinked nanoparticles decreased (see p. 53, lines 27-34; Fig. 20). Based on these teachings, one of skill in the art would have reasonably concluded that the crosslinked nanoparticles would exhibit enhanced stability in blood compared to the non-crosslinked nanoparticles.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
8. Claims 6-13, 15, 17-19, 21, 22, 40, 41, 44-48, 50, and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Green et al. taken with Krasnici et al., in further view of Rodrigues et al. (Carbohydrate Polymers, 2012, 89: 282-289).
The teachings of Green et al. and Krasnici et al. are applied as above for claims 6-13, 15, 17, 18, 21, 22, 40, 41, 44-48, 50, and 51.
With respect to claim 19, Green et al. teach that the R647 nanoparticles have a diameter of 111-118 nm (see p. 39, lines 8-15; Fig. 13). Furthermore, Rodrigues et al. teach that crosslinking reduces the size of the nanoparticles (see Abstract). Thus, one of skill in the art would have reasonably expected a nanoparticle size of less than 111-118 nm after crosslinking. This range overlaps with the claimed range 50-500 nm. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
8. No claim is allowed. No claim is free of prior art.
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/ILEANA POPA/Primary Examiner, Art Unit 1633