DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05/04/206 has been entered.
Applicants’ amendments to the claims filed on May 4, 2026, have been received and entered. Claims 1-61, 63-69, 71-87, 93, 96-119, 123-128 and 131-158 have been canceled, while claims 62, 70, 95, 130 have been amended. Claims 62, 67, 69-70, 88-92, 94-95, 120-122, 129 and 130 are pending in the instant application.
Priority
This application is a continuation of application no 15/560,968 filed on 09/22/2017, which is a 371 of PCT/US2016/024353 filed on 03/25/2016, which claims priority from US provisional applications 62/244,572 filed on 10/21/2015; 62/220,815 filed on 09/18/2015; 62/210,392 filed on 08/26/2015; 62/184,103 filed on 06/24/2015; 62/159,932 filed on 05/11/2015; 62/141,810 filed on 04/01/2015; 62/138,939 filed on 03/26/2015; and 62/138,273 filed on 03/25/2015.
It is noted that the amended claim 62 now recites gRNA molecule comprises a 3' polyA tail consisting of 10 or 20 adenine nucleotides. The disclosure of the prior-filed application, US provisional Application no. 62/220,815; 62/210,392; 62/184,103; 62/159,932; 62/141,810; 62/138,939; and 62/138,273, fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for amended claim 1 of this application.
The provisional application no62/220,815; 62/210,392; 62/184,103; 62/159,932; 62/141,810; 62/138,939; and 62/138,273 discloses a similar strategy to add polyA tail to the 3’ end of the gRNA but does not describe using a 3’ polyA tail consisting of 10 or 20 adenine nucleotides. Consequently, there is no written description for this limitation in the above-mentioned provisional application. In case applicants have evidence to support otherwise, applicants are invited to indicate page and line number for the written support specifically for using a 3’ polyA tail consisting of 10 or 20 adenine nucleotides as recited in amended claim 62 of the instant application. It is noted that subject matter of claim 62 is explicitly disclosed in US provisional application no 62/244,572, dated 10/21/2015. Therefore, the effective filing date for instant claims 62, 70, 88-92, 94-95, 120-122, 129 and 130 is 10/21/2015.
Claims 62, 70, 88-92, 94-95, 120-122, 129 and 130 are under consideration.
Withdrawn-Claim Rejections - 35 USC § 103
Claims 62, 69, 129 and 130 are rejected under 35 U.S.C. 103 as being unpatentable over Jinek et al (WO/2013/176772, dated 11/23/2013) as evidenced by Jinek et al (eLife, 2013, e00471, 1-9, IDS) and Janicke et al (RNA, 2012, 18:1289–1295, IDS)/Meissner (US20160348073, EFD 3/27/2015) in view of Epicenter poly(A) polymerase kit, (lit 251, cat.# PAP5104H, 10/2012, 1-5, IDS). In view of Applicants’ amendment of base claims 62, introducing the limitation “gene expressed in a human hematopoietic stem cell (HSC) or a human T cell”, gRNA molecule (i) comprises a 3' polyA tail consisting of 10 or 20 adenine nucleotides,(ii) includes a 5' cap and wherein the composition is capable of editing the gene in the human HSC or human T cell, the previous rejections of claims are hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot. The claims are, however, subject to new rejections over the prior art of record, as set forth below.
Claims 62, 67, 69-70, 119, 129 and 130 are rejected under 35 U.S.C. 103 as being unpatentable over Jinek et al (WO/2013/176772, dated 11/23/2013) as evidenced by Jinek et al (eLife, 2013, e00471, 1-9) and Janicke et al (RNA, 2012, 18:1289–1295, art of record)/ Meissner (US20160348073, EFD 3/27/2015), Epicenter poly(A) polymerase kit, (lit 251, cat.# PAP5104H, 10/2012, 1-5) and further in view of Kim et al (Nature Biotechnology, 2004, 22, 3, 321-325, IDS) and Church et al (WO2015/013583, EFD 07/26/2013). The rejection is withdrawn for the reasons discussed above.
Claims 62, 88-92, 94 and 95 are rejected under 35 U.S.C. 103 as being unpatentable over Jinek et al (WO/2013/176772, dated 11/23/2013) as evidenced by Jinek et al (eLife, 2013, e00471, 1-9, IDS) and Janicke et al (RNA, 2012, 18:1289–1295, IDS)/ Meissner (US20160348073, EFD 3/27/2015), Epicenter poly(A) polymerase kit, (lit 251, cat.# PAP5104H, 10/2012, 1-5, IDS) as applied above for claim 62 and further in view of Zhang et al (WO2014093712, dated 6/19/2014, IDS)/O’Connell et al (US20180002736, EFD1/28/2015). The rejection is withdrawn for the reasons discussed above.
Claims 62, 119-122 are rejected under 35 U.S.C. 103 as being unpatentable over Jinek et al (WO/2013/176772, dated 11/23/2013) as evidenced by Jinek et al (eLife, 2013, e00471, 1-9, IDS) and Janicke et al (RNA, 2012, 18:1289–1295, IDS)/ Meissner (US20160348073, EFD 3/27/2015) in view of Epicenter poly(A) polymerase kit, (lit 251, cat.# PAP5104H, 10/2012, 1-5, IDS). as applied above for claim 62 and further in view of Liu et al (EP3842063, dated 06/30/2021, filed on 9/5/2014, EFD9/6/2013). The rejection is withdrawn for the reasons discussed above.
New Claim Rejections - 35 USC § 103- necessitated by amendments
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.
Claims 62, 70, 129 and 130 are rejected under 35 U.S.C. 103 as being unpatentable over Jinek et al (WO/2013/176772, dated 11/23/2013) as evidenced by Jinek et al (eLife, 2013, e00471, 1-9, (2) IDS), Meissner (US20160348073, EFD 3/27/2015, IDS), Von Der Mulbe (U.S. 2016/0326575 05/08/2015), Chen (U.S. 2016/0017366; 01/21/ 2016), Mali et al (Science, 2013; 339, 823-826).
Claims are directed to a composition comprising a gRNA molecule comprising a targeting domain that is complementary to a target domain from a gene expressed in a human hematopoietic stem cell (HSC) or a human T cell, wherein the gRNA molecule (i) comprises a 3' polyA tail consisting of 10 or 20 adenine nucleotides,(ii) includes a 5' cap,[[;]] and (iii) is complexed with a Cas9 protein, and wherein the composition is capable of editing the gene in the human HSC or human T cell.. claims 129-130 are interpreted as composition for an intended use that must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
With respect to claims 62, 70, inek et al teach a composition comprising a complex comprising: (i) a Cas9 protein and tracrRNA: crRNA duplex (50-500 nM, 1:1) in a buffer (see para. 520, 524). It is relevant to note that the gRNA prepared by Jinek uses RNA was in vitro transcribed through run-off reactions by T7 RNA polymerase and then resulting transcribed RNA (see para. 517). It is disclosed that DNA-targeting RNA and a variant Cas9 site-directed polypeptide form a complex. The DNA-targeting RNA (gRNA, para. 130) provides target specificity to the complex by comprising a nucleotide sequence that is complementary to a sequence of a target DNA (see para. 20, 449, 493-494, 533-534, 553, 631). Jinek further teaches that DNA-targeting RNA may include a 5' cap (e.g., a 7-methylguanylate cap (m7G)) and a 3' polyadenylated tail (i.e., a 3' poly (A) tail) (see para. 133, 134, 386, 387, 426, 444). Jinek teaches a composition comprising DNA-targeting RNA polynucleotide provides target specificity to the complex by comprising a nucleotide sequence that is complementary to a sequence of a target DNA and a polynucleotide encoding the same site-directed modifying polypeptide, wherein the site-directed modifying polypeptide comprises an amino acid of Cas9 as set forth in figure 3 (see para. 20 and 192).
Regarding claims 129, Jinek teaches use of the composition for gene editing or to treat a disease (see para. 261). It is further disclosed that the DNA-targeting RNA provide specificity by hybridizing to target DNA, a mitotic and/or post-mitotic cell of interest in the disclosed methods may include a cell from any organism including any somatic or human stem cell (hematopoietic cell) (see para. 274). Jinek (2) publication teaches an in vitro transcription to produce sgRNA molecules, whereby their sgRNA lacked a 5’ cap and a 3’ polyadenylation sequence that have reduced the sgRNA stability in vivo; whereas, providing such 5’ and 3’ modifications may enhance the Cas9::sgRNA assembly and activity in cells (page 5). Jinek teaches modifying the sgRNA coding sequence to further comprise a polyA-encoding sequence (Figure 3a).
Jinek differs from claimed invention by not disclosing 3’ end PolyA tail consisting of 10 or 20 adenine nucleotides.
Meissner et teaches a method of producing primary human T cells [0014, 114], using the CRISPR/Cas system to inactivate PD-1 ([0016], as illustrated in Figure 13A), wherein the CRISPR/Cas system is introduced into the cell as a gRNA/Cas complex [0210, 228]. Meissner teaches that the RNAs may be modified to comprise a 5' cap (para. 303) and a 3' polyA tail (307). Meissner teaches that the polyA tail may be of 5, 10 or 20 adenine nucleotides (see para. 307). It is disclosed that composition may be for use in editing human T cells (see fig. 13, 14) (limitation of claim 130).
While Jinek (133, 134, 386, 387, 426, 444, page 5 of publication) and Meissner teach that the RNAs may be modified to comprise a 5’ cap, e.g. an anti-reverse cap analog (e. 0303) and a 3’ polyA tail (0307), The combination of references do not reduce to practice of modifying a guide RNA (gRNA) comprising both a 5’ cap and a 3’ polyA tail.
Von Der Mulbe teaches an in vitro synthesis of RNA molecules, wherein the RNA molecule includes CRISPR guide RNAs (e.g. [0042], wherein the RNA molecules comprise a 5’ cap and a polyA sequence (para, 42), and wherein the 5’ cap includes a m7G cap (para. 40, 98, 265). Chen et al is considered relevant prior art for having disclosed a vector encoding a guide RNA and/or a Cas9 nuclease and a polyA sequence (para. 89) and in vitro synthesis of a mRNA encoding a Cas9 protein, wherein the Cas9 mRNA comprises a 5’ cap and a 3’ polyA tail (para. 89, 124, 169, Table 7). Chen teaches an in vitro transcription of a CRISPR gRNA (163) but does not disclose wherein the IVT gRNA comprises a 3’ polyA tail.
Mali teaches a method of editing a target gene in a human host cell using the CRISPR/Cas9 system the method comprising the step of expressing a guide RNA from an expression vector, wherein said guide RNA encoded by the expression vector comprises a polyT tail (Figure 1A, U6 promoter-target-gRNA scaffold-polyT), and thus upon transcription comprises a polyA tail.
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teaching of prior art to modify the composition comprising a complex comprising IVT sgRNA by adding polyA tail of varying length of 5, 10 or 20 adenine nucleotides at 3’-terminal as suggested by Meissner, with a reasonable expectation of success, before the effective filing date of instant invention, to enhance stability and efficiency of sgRNA as suggested by Jinek, Meissner (see above). Said modification amounting to combining prior art elements according to known methods to yield predictable results.
One of ordinary skill in the art would be motivated to do so because prior art recognized that (a) the addition of a 5’ cap and a 3’ polyA tail may enhance sgRNA stability in vivo, thereby enhancing assembly and activity of Cas9::sgRNA ribonucleoprotein complexes in cells, whereby the sgRNA coding sequence was modified to further encode a polyA tail (Jinek et al); (b) CRISPR guide RNAs may comprise a 5’ cap, and a polyA sequence (Von Der Mulbe et al; Chen et al). 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). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I). One of ordinary skill in the art would have been expected to have a reasonable expectation of success in adding polyA tail at 3’terminal of sgRNA because prior art successfully reported polyadenylation at 3’ terminal of RNA as evident from the teaching of Meissner. It should he noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, USPQ2d , slip op. at 20, (Bd, Pat, App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (www.uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
Claims 62, 88-92, 94 and 95 are rejected under 35 U.S.C. 103 as being unpatentable over Jinek et al (WO/2013/176772, dated 11/23/2013) as evidenced by Jinek et al (eLife, 2013, e00471, 1-9, IDS), Meissner (US20160348073, EFD 3/27/2015), Von Der Mulbe (U.S. 2016/0326575 05/08/2015), Chen (U.S. 2016/0017366; 01/21/ 2016), Mali et al (Science, 2013; 339, 823-826) as applied above for claim 62 and further in view of Zhang et al (WO2014093712, dated 6/19/2014, IDS)/O’Connell et al (US20180002736, EFD1/28/2015).
The teaching of Jinek, Meissner, Von Der Mulbe, Chen and Mali have been described above and relied in same manner here. The combination of references differs from c claimed invention by not teaching that the gRNA molecule lacks a 5' terminal phosphate or a 5’ triphosphate group.
The combination of references differs from the claimed invention by not teaching that the gRNA molecule contains one or more nucleotides that stabilize the gRNA molecule.
Before the effective filing date of instant application, Zhang teaches single guide RNA for sequence manipulations in cells, which have been chemically modified by incorporating 2'-deoxy or 2'-fluoro analogs (para. 29, 35, 37, 73). Zhang teaches modifying gRNA to improve stability by modifying the nucleotide (page 18, para. 37). It is further disclosed that nucleic acid backbone may be modified, for example, a phosphorothioate backbone (see para. 29) (limitation of claims 88-90, 94 and 95). It is further disclosed that modified bases include, but are not limited to, 2-aminopurine, 5-bromo-uridine, pseudouridine, inosine, 7-methylguanosine (see para. 29, 37) (limitation of claim 92). O’Connell teaches gRNA has one or more base modification or a backbone modification (see para. 619) including modified cytidine or adenosine or guanosine (para. 671, 676).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teaching of prior art to modify the composition comprising sgRNA comprising a 3’ polyA tail as disclosed in Jinek, Meissner and others as discussed above by modifying the nucleotide as disclosed and suggested in Zhang/ O’Connell, with a reasonable expectation of success, before the effective filing date of instant invention to improve the stability of gRNA. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to do so because prior art recognized that gRNA backbone and/or nucleotide may be modified to improve the stability of gRNA against nuclease degradation (see Zhang). One of ordinary skill in the art would have been expected to have a reasonable expectation of success in modifying the nucleotide base in gRNA because prior art successfully reported modifying gRNA as evident from the teaching of Zhang to improve the stability of gRNA. It should he noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, USPQ2d , slip op. at 20, (Bd, Pat, App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (www.uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
Claims 62, 120-122 are rejected under 35 U.S.C. 103 as being unpatentable over Jinek et al (WO/2013/176772, dated 11/23/2013) as evidenced by Jinek et al (eLife, 2013, e00471, 1-9, IDS), Meissner (US20160348073, EFD 3/27/2015), Von Der Mulbe (U.S. 2016/0326575 05/08/2015), Chen (U.S. 2016/0017366; 01/21/ 2016), Mali et al (Science, 2013; 339, 823-826) as applied above for claim 62 and further in view of Liu et al (EP3842063, dated 06/30/2021, filed on 9/5/2014, EFD9/6/2013).
Claims interpretation: eiCas9 is interpreted as mutating key residues in both DNA cleavage domains of the Cas9 protein (e.g., the D10A and H840A or N863A mutations) resulting in the generation of a catalytically inactive Cas9 (eiCas9 which is also known as dead Cas9 or dCas9) (see specification para. 985, 1315).
The teaching of Jinek, Meissner, Von Der Mulbe, Chen and Mali have been described above and relied in same manner here. The combination of references differs from the claimed invention by not teaching that Cas is nickase or dCas9.
Before the effective filing date of instant application, Liu teaches engineering variants of Cas9 that cleave only one DNA strand ("nickases") enable double-stranded breaks to be specified by two distinct gRNA sequences (see para. 60, 65-66) or dCas9 containing inactivating mutations D10A and H840A (para. 23, 24, 67, 126)
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teaching of prior art to modify the composition of Jinek, Meissner, Chen and Mali by substituting Cas9 with nickase or dCas9 c as disclosed and suggested in Liu, with a reasonable expectation of success, before the effective filing date of instant invention to enable double-stranded breaks or enable fusion of dCas9-KRAB. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in art would be motivated to do so because prior art recognized that variant of Cas9 for specific use to improve efficiency. One of ordinary skills in the art would have been expected to have a reasonable expectation of success in using variants of Cas9 because prior art successfully reported the use of these Cas9 variants. It should he noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, USPQ2d , slip op. at 20, (Bd, Pat, App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (www.uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
Response to arguments
To the extent that Applicants’ arguments are pertinent to the new rejections, they are addressed as follows:
Applicant argues that claims have been amended to limit the scope to specific cell type and composition capable of editing the gene in the human HSC or T cells.
Applicant in part rely on previous argument in part relying on example 14 to state none of the reference teach alone or together suggest the unexpected editing results from compositions comprising a gRNA molecule comprising a targeting domain that is complementary to a target domain from a gene expressed in a human hematopoietic stem cell (HSC) or a human T cell, wherein the gRNA molecule (i) comprises a 3' polyA tail consisting of 10 or 20 adenine nucleotides, (ii) includes a 5' cap, and (iii) is complexed with a Cas9 protein, and wherein the composition is capable of editing the gene in the human HSC or human T cell, as presently claimed and demonstrated by the present application. Applicants’ arguments have been fully considered but are not found persuasive.
Applicants’ amendment of base claim to recite the specific cell type only in part addresses the previous rejection of record. To the extent, applicants’ argument pertains to unexpected editing results, previous office indicated that figure 48B (see below) of the instant application clearly shows there is no significant difference between percentage indel observed with polyA tail length of 2A, 10A, 15A or 25A. It is unclear from the figure whether level of gene editing is affected by length of the targeting domain, gRNA, method of administering the composition, in human cells, type of Cas9 or something else. The specification describes that the targeting domain comprises 10+/- to 100+/-5 nucleotides in length. In some embodiment, the targeting domain comprises a secondary domain and a core domain (see page 32, lines 18-19). Figure 48A results with polyA tail of 10A and 20A that is strikingly different from percentage indel observed in figure 48B.
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Further, specification teaches CB CD34⁺ cells are electroporated with capped and tailed AAVSI specific gRNA, HBB-specific gRNA, or CXCR4-specific gRNA co-delivered with S. pyogenes Cas9 mRNA-maintained ex vivo hematopoietic colony forming potential (see fig. 25).
These results show an inconsistent pattern, and it is unclear if the results observed with polyA extension as claimed could be extended to a generic gRNA of varying length with a polyA tail, use of any Cas9 or gRNA comprising any other targeting domain of varying length targeting any gene as required by the pending claim. It is further unclear if the composition or method of using composition that uses electroporation method exhibits reduced cell toxicity and improved editing of cells. This is further evidenced by Jung (Anim Cells Syst 2024 Mar 3;28(1):75–83, cited as evidence without relying on rejection) who reported cleavage efficiency could be affected by GC content of PAM proximal and distal region, type of nucleotide according to the sgRNA spacer sequence position affects the cleavage efficiency, and this factor must be adequately considered to avoid low gene-editing efficiency, scaffold of gRNA, secondary structure of the sgRNA significantly impacts the cleavage efficiency of the CRISPR system and chromatin state. It is disclosed that the location of the target DNA sequence in the heterochromatin state negatively affects the cleavage efficiency (see page 77, col. 2, para. 2 to page 80). In view of foregoing, it is apparent that there are multiple factor apart from the adding polyA tail of 10A or 20A to 3’ of gRNA that effect the editing efficiency and therefore a specific composition as set forth in examples of instant specification could not be extended to a generic composition comprising a gRNA molecule comprising any targeting domain of any length that is complementary to any target domain from any gene expressed in a human hematopoietic stem cell (HSC) or a human T cell, wherein the gRNA molecule (i) comprises a 3' polyA tail consisting of 10 or 20 adenine nucleotides,(ii) includes a 5' cap and (iii) is complexed with any Cas9 protein.
In response to applicants’ argument that composition is capable of editing the gene in the human HSC or human T cell, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. In the instant case, prior art of Meissner teaches using the CRISPR/Cas system to inactivate PD-1 ([0016], as illustrated in Figure 13A, 14), wherein the CRISPR/Cas system is introduced into the human T cell as a gRNA/Cas complex (210, 228, claim 1), therefore, it is appliable to the rejection.
It should be further noted that any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). It should be noted that the ultimate goal of adding polyA tails is to provide stability of gRNA in vivo (see page 5, last para. of Jinek). As previously indicated, Jinek teaches a composition comprising a DNA-targeting RNA polynucleotide that provides target specificity to the complex by comprising a nucleotide sequence that is complementary to a sequence of a target DNA, wherein the DNA-targeting RNA (gRNA) may include a 5' cap (e.g., a 7-methylguanylate cap (m7G)) and a 3' polyadenylated tail (i.e., a 3' poly (A) tail) (see para. 133, 134, 386, 387, 426, 444). As discussed above, those of ordinary skill in the art previously recognized the scientific and technical concepts that: i) the addition of a 5' cap and a 3' polyA tail may enhance sgRNA stability in vivo, thereby enhancing assembly and activity of Cas9 sgRNA ribonucleoprotein complexes in cells, whereby the sgRNA coding sequence was modified to further encode a polyA tail (Jinek et al); ii) CRISPR guide RNAs may comprise a 5' cap and a polyA sequence (Von Der Mulbe et al; Chen et al).
In view of foregoing, it is apparent that Jinek, Meissner, Chan and others explicitly disclose a composition comprising gRNA that is 5 capped and 3′-polyadenylated for higher efficiencies of Cas9-mediated genome targeting. A variety of methods suitable for this purpose (to introduce 5′-cap or 3′-polyadenylation of varying length including 5A, 10A or 20A are well-known in the art, including one disclosed in Meissner. Given that art teaches adding polyA tails to provide stability of IVT gRNA in vivo was known in prior art, thus the relevance of Applicants' arguments with respect to addition of 3polyA tail to gRNA is not apparent. To the extent prior art describe adding polyA tail and/or 5’cap to the gRNA to mimic mRNA structure to stability of gRNA in vivo, the rejection is applicable to the instant case. The fact that 3’polyA tail may be added to the RNA to provide stability of gRNA to a greater extent is an expected result and is the goal behind adding 3’ poly A tail. As indicated in MPEP 716.02(c), Where the unexpected properties of a claimed invention are not shown to have a significance equal to or greater than the expected properties, the evidence of unexpected properties may not be sufficient to rebut the evidence of obviousness. In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977). “Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof.” In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967).
Therefore, in view of the fact patterns of the instant case, and the ground of rejection outlined by the examiner, applicants’ arguments are not compelling and do not overcome the rejection of record.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 129 and 130 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. In the instant case, claims 129 and 130 recite a composition that does not further limit the composition of independent claim 62. Claims merely recites intended use of the composition that is inherent to the composition of claim 1. It is suggested that claim 129 should be amended to a pharmaceutical composition comprising a gRNA… and a pharmaceutical excipient. Applicants may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. Appropriate correction is required.
Obviousness type Double Patenting
Claims 62, 70, 88, 94-95, 120-122, 129 and 130 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 162, 387-393, 396, 398-400, 403, 407-409, 417-419 of copending Application No. 16098845 in view of Church et al (WO2015/013583)/ Zhang et al (WO2014093712) for the reasons of record.
In the instant case, even though the conflicting claims are not the same, they are not patentably distinct from each other because both sets of claims encompass overlapping subject matter directed to a gRNA molecule comprising a 3’ polyA-tail. Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teaching of prior of ‘845 to modify the method of using composition comprising sgRNA by adding polyA tail of varying length from 10 to 20 adenine nucleotides at 3’-terminal using method as disclosed in Janicke and remove 5’-terminal phosphate as disclosed and suggested in Church, with a reasonable expectation of success, before the effective filing date of instant invention, to enhance stability and efficiency of sgRNA as suggested by ‘845. This is a provisional nonstatutory double patenting rejection.
Response to arguments
While Applicant has requested that the rejection be held in abeyance until allowable subject matter can be identified, a request of abeyance does not overcome or address an issue of obvious double patenting between claims in the instant case and application 16098845. It is noted that 16098845 application is still co pending. Thus, the rejection is maintained.
Conclusion
No claims allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Grudzien ( (Synthesis of Anti-Reverse Cap Analogs (ARCAs) and their Applications in mRNA Translation and Stability, Methods in Enzymology 431: 203-227, 2007) teaches replacement of a mRNA 5' m7G cap with an anti-reverse cap analog (ARCA), thereby rendering the artisan's 3' A-containing mRNA more resistant to decapping enzymes and degradation (e.g. Abstract; pages 205-206), resulting in prolonged stability and half-lives (Figure 11.6; Table 11.1).
Duchateau (WO2014/191128) teaches editing the genome of primary human T cells using the CRISPR/Cas9 system (. Figure 4), wherein at least two endogenous genes have been inactivated (page 31, line 24; claim 34).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANOOP K. SINGH whose telephone number is (571)272-3306. The examiner can normally be reached Monday-Friday, 8AM-5PM.
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632
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