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 4-6, 8, 10-12, 16, 18, 20, 22-40, 45-58, 61-71, 73, 75, 77, and 79-123 have been cancelled. Claims 59, 60, and 72 have been withdrawn. Claims 1, 17, 41, 74, and 78 have been amended
Claims 1-3, 7, 9, 13-15, 17, 19, 21, 41-44, 74, 76, 78, and 124 are under examination.
2. The rejection pertaining to claim 123 is moot because the claim was cancelled with the reply filed on 04/27/2026.
The objection to claim 76 is withdrawn in response to the amendment filed on 04/27/2026.
All obviousness-type rejections are withdrawn in response to the amendment limiting the claims to SEQ IS Nos: 4-9. New grounds of rejection are set forth below.
New Rejections
Claim Rejections - 35 USC § 103
3. 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.
4. Claims 1-3, 7, 9, 13-15, 17, 19, 21, 41-44, 74, 76, 78, and 124 are rejected under 35 U.S.C. 103 as being unpatentable over Shen et al. (WO 17/165862), in view of all Liu et al. (WO 18/176009), Kim et al. (BBRC, 2006, 343: 295-302), and Benchling (2016).
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 subject); 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, 42-44, and 76) (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 correcting by using a base editor (BE) (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 an sgRNA targeting BE4 to 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 to identify the optimal targeting sgRNAs, as doing so would have only entailed routine experimentation (see Benchling). One of skill in the art would also have reasonably expected that introducing the M374I mutation 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.
Shen et al., Liu et al., and Kim et al. do not specifically teach that the sgRNA comprises a spacer set forth by one of SEQ ID NOs: 4-9 (claims 1, 17, 41, 74, and 78). However, it is noted that there is no evidence of record that using any of the spacers set forth by SEQ ID NOs: 4-9 leads to unexpected results. 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, there is no evidence of unexpected results over the prior art. Specifically using the claimed SEQ ID NOs: 4-9 is not significant if it does not provide a novel feature.
Similar considerations apply to the claimed SEQ ID NO: 167 (claim 124). While SEQ ID NO: 167 taught by the cited prior art may not be identical to the claimed SEQ ID NO: 167, 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.
Response to Arguments
5. The arguments are answered below to the extent that they pertain to the new rejection.
The arguments that the cited prior art fails to teach or suggest the recited sgRNAs and lack of reasonable expectation of success in arriving at these sequences are not found persuasive.
As stated in the rejection, designing sgRNAs optimal for editing C at the desired genomic site was routine in the prior art. While the sgRNAs identified by the prior art may not be identical to SEQ ID NOs: 4-9, there is no evidence that using these sequences leads to unexpected results over the prior art. Specifically using the claimed SEQ ID NOs: 4-9 is not significant because there is no evidence that they provide a novel feature.
Conclusion
6. 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 ILEANA POPA whose telephone number is (571)272-5546. The examiner can normally be reached 8:00 am to 4:30 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher Babic can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ILEANA POPA/Primary Examiner, Art Unit 1633
Prosecution Insights