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 .
Continued Examination Under 37 CFR 1.114
1. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/13/2026 has been entered.
Upon further considerations, the restriction requirement between the inventions of Groups I and IV as set forth in the Office action mailed on 08/28/3034 is withdrawn.
In view of the above noted withdrawal of the restriction requirement, applicant is advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Once a restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claims 4-6, 8, 10-12, 16, 18, 20, 22-40, 45-58, 61-71, 73, 75, 77, and 79-122 have been cancelled. Claims 59, 60, and 72 have been withdrawn. Claims 1, 15, 17, 41, and 78 have been amended. Claims 123 and 124 are new.
Claims 1-3, 7, 9, 13-15, 17, 19, 21, 41-44, 74, 76, 78, 123, and 124 are under examination.
2. The objections to claims 15 and 41 are withdrawn in response to the amendments filed on 01/13/2026.
The rejection of claims 1-3, 7, 9, 13, 15, 17, 19, 21, 41-44, and 78 as being unpatentable over Shen et al. (WO 17/165862), in view of both Kim et al. (Nat. Biotechnology) and Kim et al. (BBRC, 2006, 343: 295-302) is withdrawn in response to the amendment introducing the limitation of two UGI domains in claims 1, 17, and 41.
Claim Objections
3. Claim 76 is objected to because of the recitation “a guide RNA”. Correction to “the guide RNA” is required.
Claim Rejections - 35 USC § 103
4. 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.
5. Claims 1-3, 7, 9, 13-15, 17, 19, 21, 41-44, 78, and 124 are rejected under 35 U.S.C. 103 as being unpatentable over Shen et al. (WO 17/165862), in view of both Liu et al. (WO 18/176009) and Kim et al. (BBRC, 2006, 343: 295-302).
The claims recite a method for editing a SERPIN A1 polynucleotide comprising introducing the E264V mutation in the encoded protein The term “comprising” is reasonably interpreted as encompassing introducing point mutations other than E264V.
Shen et al. teach a method for treating a subject affected by A1AD associated with the E264V point mutation in the SERPINA1 gene (S-type SERPINA1) causing the aggregation of the encoded S-type A1AT within the hepatocytes of the subject (such as a human); the method comprises using an sgRNA/Cas9 to correct the mutation via HDR, where the sgRNA comprises a targeting domain complementary to the targeted portion of SERPINA1; the method comprises contacting the hepatocytes of the subject with the gRNA/Cas9 either in vivo or ex vivo (claims 1-3, 7, and 42-44) (see Abstract; p. 2, first three paragraphs; p. 3, first full and second to last paragraphs; p. 5, third and fourth paragraphs; p. 6, second full paragraph; p. 7, last paragraph; p. 9, second to last paragraph; p. 15, fourth paragraph; p. 20, first two paragraphs; paragraph bridging p. 23 and 24; paragraph bridging p. 35 and 36; p. 36, second full paragraph; p. 45, fourth paragraph; p. 142, last two paragraphs; p. 143, first paragraph; p. 173, second paragraph).
Shen et al. do not teach a base editor (BE) as recited in claims 1, 9, 13-15, 17, 41, and 78). Liu et al. teach a fourth generation BE4 capable of efficiently deaminate cytidine to convert C:G to T:A and correct for the presence of disease relevant point mutations; B4 is set forth by SEQ ID NO: 167 and has the structure NH2-APOBEC1-linker-dCas9-UGI-UGI-NLS-COOH; dCas9 is nuclease inactive SpCas9 and NLS comprises the sequence KRTADGSEFEPKKKRKV (i.e., identical to the claimed SEQ ID NO: 39, see the Sequence Listing). Liu et al. teach that using a third generation base editor (BE3) results in permanent correction of up to 37% of the cellular DNA with less than 1% indel formation, while HDR yielded only 0.7% correction with 4% indel formation. Liu et al. teach that BE4 is even more efficient than BE3 with respect to C:G to T:A base editing and product purity (see [0006]; [0024]-[0025]; [0151]; [0210]; [0221]; [0346]; [0400]; [0407]; [0488]-[0489]; [0532]; [0614]; [0618]; [0629]-[0630]; p. 305; claim 159; Fig. 109).
Furthermore, Kim et al. teach that the S-type A1AT having the E264V point mutation is conformationally unstable; the destabilizing E264V point mutation can be suppressed by introducing stabilizing mutations (including M374I) in the hydrophobic core (see Abstract; p. 297, paragraph bridging columns 1 and 2; p. 298, paragraph bridging columns 1 and 2 and column 2; p. 300, Table 1; paragraph bridging p. 300 and 301).
Based on the combined teachings of Liu et al. and Kim et al., one of skill in the art would have reasonably concluded that B4 could be used to edit the C:G of the methionine codon 374 and change it to an isoleucine codon. One of skill in the art would have found obvious to modify Shen et al. by using BE4 to edit codon 374 in the S-type SERPINA1 with the reasonable expectation that doing so would change the codon from ATG to ATA and introduce the M374I mutation in S-type A1AT. One of skill in the art would have reasonably expected that doing so would result in therapeutic effect because the prior art teaches that stabilizing mutations in the hydrophobic core compensate for the E264V mutation. By doing so, one of skill in the art would have deaminate the cytosine at position 1455 of the S-type SERPINA1 (claims 1, 17, 41, and 78) and would have obtained a cell as recited in claims 17, 19, 21, and 78.
While SEQ ID NO: 167 taught by the cited prior art may not be identical to the claimed SEQ ID NO: 167 (claimed 124), as per MPEP § 716.02, [a]ny 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). In this case, the prior art teaches the essential elements in the claimed arrangement and there is no evidence that using the claimed SEQ ID NO: 167 leads to unexpected results over the prior art. Specifically using the claimed SEQ ID NO: 167 is not significant if it does not provide a novel feature.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
6. Claims 1-3, 7, 9, 13-15, 17, 19, 21, 41-44, 74, 76, 78, 123, and 124 are rejected under 35 U.S.C. 103 as being unpatentable over Shen et al. taken with both Liu et al. and Kim et al., in further view of Brown et al. (U.S. Patent No. 9,458,457).
The teachings of Shen et al., Liu et al., and Kim et al. are applied as above for claims 1-3, 7, 9, 13-15, 17, 19, 21, 41-44, 78, and 124. Shen et al., Liu et al., and Kim et al. do not specifically teach that the sgRNA comprises the spacer set forth by SEQ ID NO: 3 (claims 74, 76, and 123). Brown et al. teach inhibiting A1AT by using an siRNA having a guide strand identical to the spacer set forth by SEQ ID NO: 3 (see Abstract and column 9, lines 25-35; see the attached Sequence Alignment). Using the sequence taught by Brown et al. as the spacer in the sgRNA of Shen et al., Liu et al., and Kim et al. would have been obvious to one of skill in the art, with the reasonable expectation that doing so would result in therapeutic effect. By doing so, one of skill in the art would have used a complex between BE4 and the sgRNA comprising the sequence set forth by the claimed SEQ ID NO: 3 (claim 76).
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
Response to Arguments
7. The applicant argues that the cited prior art does not teach the recited BE, does not teach using BE to edit SERPINA1, and does not teach introducing the M34I mutation
This is not found persuasive. Liu et al. teach BE4 having the recited NH2-APOBEC1-dCas9-UGI-UGI-NLS-COOH structure, where the NLS is set forth by the claimed SEQ ID NO: 39. Liu teaches that BE4 is more efficient than HDR in correcting mutations. Kim teaches the E264V mutant; Kim teaches compensating for the presence of the E264V mutation by introducing the stabilizing M374I mutation. Liu and Kim together provide the motivation to modify Shen by replacing HDR with BE4 and further use BE4 to change codon 374 of the unstable E264V mutant from ATG to ATA such as to introduce the compensatory M374I mutation.
The argument of lack of reasonable expectation of success is not found persuasive because it is just an argument not supported by any evidence.
8. No claim is allowed. No claim is free of prior art.
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/ILEANA POPA/Primary Examiner, Art Unit 1633