DETAILED CORRESPONDENCE
Application Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s amendment to the claims filed on 04/28/2026 in response to the Non-Final Rejection mailed on 01/28/2026 is acknowledged. This listing of claims replaces all prior listings of claims in the application.
3. Claims 2 and 4-6 are cancelled.
4. New claims 13-16 are added.
5. Claims 1, 3, and 7-16 are pending.
6. Claims 7-12 stand withdrawn pursuant to 37 CFR 1.142(b).
7. Applicant’s remarks filed on 04/28/2026 in response to the Non-Final Rejection mailed on 01/28/2026 have been fully considered and are deemed persuasive to overcome at least one of the rejections and/or objections as previously applied.
The text of those sections of Title 35 U.S. Code not included in the instant action can be found in the prior Office Action.
Nucleotide and/or Amino Acid Sequence Disclosure Objections
8. The objection to the Nucleotide and Amino Acid sequence disclosures under 37 CFR 1.831 is withdrawn in view of the replacement drawings, sequence listing and CRF filed on 04/28/2026 and 05/11/2026, respectively.
Claim Rejections - 35 USC § 112(a)
9. The written description rejection of claims 1-6 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is withdrawn in view of applicants’ amendment to the claims to recite “a hepatic growth factor, A83-01 and CHIR99021” and “using an adenine base editor or a prime editor”.
10. The scope of enablement rejection of claims 1-6 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is withdrawn in view of applicants’ amendment to the claims to recite “a hepatic growth factor, A83-01 and CHIR99021” and “using an adenine base editor or a prime editor”.
Claim Rejections - 35 USC § 103
11. The rejection of claims 1-6 under 35 U.S.C. 103 as being unpatentable over Choi et al. (WO2018/221904 A2; cited on PTO-892 mailed on 01/28/2026 with US Patent Application Publication 2020/0147143 A1, cited on PTO-892 mailed on 01/28/2026, serving as a translation) in view of Yu et al. (Human Gene Therapy, 2016; cited on IDS filed on 02/13/2023) and Musunuru et al. (WO 2019/213183 A1; cited on PTO-892 mailed on 01/28/2026) is withdrawn in view of applicants’ amendment to the claims to recite “selecting a clonal cell line or cell population having the corrected mutant gene and lacking an off-target effect” and amendment to cancel claims 2 and 4-6.
12. Claims 1, 3, 13-14, and 16 are newly rejected under 35 U.S.C. 103 as being unpatentable over Choi et al. (WO2018/221904 A2; cited on PTO-892 mailed on 01/28/2026 with US Patent Application Publication 2020/0147143 A1, cited on PTO-892 mailed on 01/28/2026, serving as a translation) in view of Yu et al. (Human Gene Therapy, 2016; cited on IDS filed on 02/13/2023) Musunuru et al. (WO 2019/213183 A1; cited on PTO-892 mailed on 01/28/2026), and Liu et al. (WO 2020/191249 A1, priority to 03/19/2019; examiner cited). This new ground of rejection is necessitated by applicants’ amendment to the claims to recite “selecting a clonal cell line or cell population having the corrected mutant gene and lacking an off-target effect”.
13. Claims 1, 3, 13-14, and 16 are drawn to a method of preparing mutant gene-corrected cells, comprising: (a) isolating primary hepatocytes from a subject; (b) treating the isolated cells with a compound comprising a hepatic growth factor (HGF), A83-01 and CHIR99021 to prepare chemically-derived hepatic progenitor cells; (c) correcting a mutant gene of the chemically-derived progenitor cells ex vivo using an adenine base editor (ABE) or a prime editor (PE); and (d) selecting a clonal cell line or a cell population having the corrected mutant gene and lacking an off-target effect.
14. With respect to claims 1, 3, 13-14 and 16, Choi et al. teach methods for treating liver disease by reprogramming primary human adult hepatocytes by isolating the cells from a subject, and treating the isolated cells with a chemical compound such as HGF, A83-01 and CHIR99021 to produce chemically-derived progenitor cells [see Abstract; paragraphs 0005-0014].
However, Choi et al. does not teach the method of claim 1 of correcting a mutant gene of the chemically-derived progenitor cells ex vivo wherein the correcting of a gene is to correct a gene by an adenine base editor or prime editing and selecting a clonal cell line or cell population having the corrected mutant gene and lacking an off-target effect; the method of claim 3, wherein the corrected gene is fumarylacetoacetate hydrolase (Fah); the method of claim 13, further comprising expanding the corrected chemically-derived hepatic progenitor cells and selecting a cell clone that does not have an off-target mutation; the method of claim 14, wherein the correcting of the mutant gene is performed using prime editing (PE) such that a target base is converted without bystander base conversion; and the method of claim 16, wherein the mutant gene is selected from the group consisting of ATPase copper transporting beta and cystic fibrosis transmembrane conductance (CFTR).
Yu et al. teach that progenitor cells have great therapeutic potential because of their ability to self-renew and differentiate, and targeted gene editing technologies using engineered nucleases such as zinc finger nucleases, TALENs, and CRISPR/Cas9 show great clinical promise allowing for the site-specific correction of diseases causing mutations [see Abstract; p. 732-734]. Yu et al. further teach the specificity and off-target effects of gene-editing systems must be key considerations in their development, particularly in terms of the potential clinical applications of these methods in human stem and progenitor cells [see p. 736, column 2]. Yu et al. teach modification of the Cas9 component so that two gRNA/Cas9 complexes are necessary to cleave DNA, achieved either via conversion to a nickase or through fusion of a dead Cas9 with FokI, to greatly decrease off-target editing [see p. 736, column 2].
Musunuru et al. teach ex vivo methods of correcting mutant gene mutations in hepatic cells comprising a site specific mutation in fumarylacetoacetate hydrolase using adenosine deaminase base editors such as ABE7.1, ABEmax and ABE6.3 as high efficient low off-target effect editors to treat the hereditary disorder tyrosinemia type I [see p. 20, bottom; p. 25; p. 29, bottom; p. 30-31; p. 54]. Musunuru et al. further teach selecting a clonal cell line or cell population having the corrected mutant gene [see p. 55].
Liu et al. teach prime editor compositions and methods for conducting prime editing of a target DNA molecule that enables the incorporation of a nucleotide change and/or targeted mutagenesis for modifying progenitor cells to build a cell-fate map for single cells in a whole organism that lack off-target effects [see Abstract; paragraph 0950], and teach the improvement of the prime editor gRNA scaffold for reducing off-target activities [see paragraph 0672]. Liu et al. also teach the functional correction of CFTR for cystic fibrosis patients [see paragraphs 1058 and 1153].
Before the effective filing date of the claimed invention, it would have been obvious for one of ordinary skill in the art to combine the teachings of Choi et al., Yu et al., Musunuru et al., and Liu et al. to use the hepatic progenitor cells of Choi et al. to correct a mutant gene using an adenine base editor and a prime editor because Choi et al. teach methods for preparing chemically-derived hepatic progenitor cells from primary hepatocytes for treatment of various liver diseases. Yu et al. teach that progenitor cells hold clinical promise for site specific correction of mutations that cause diseases. Musunuru et al. teach that base editors can be designed to target mutant gene mutations in hepatic cells to treat hereditary disorder tyrosinemia type I. Liu et al. teach prime editor compositions and methods for conducting prime editing of a target DNA molecule that enables the incorporation of a nucleotide change and/or targeted mutagenesis for modifying progenitor cells to build a cell-fate map for single cells in a whole organism that lack off-target effects, and teach the improvement of the prime editor gRNA scaffold for reducing off-target activities One of ordinary skill in the art would have had a reasonable expectation of success, a reasonable level of predictability, and would have been motivated to combine the teachings of Choi et al., Yu et al., Musunuru et al., and Liu et al because Yu et al. acknowledges that progenitor cells hold clinical promise for site specific correction of mutations that cause diseases, and Musunuru et al. acknowledges that base editors can be designed to target mutant gene mutations in hepatic cells to treat hereditary disorder tyrosinemia type I. Liu et al. acknowledge the advantage of prime editors in reducing off target effect of modifications to cells such as progenitor cells. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
15. Claim 15 is newly rejected under 35 U.S.C. 103 as being unpatentable over Choi et al. (WO2018/221904 A2; cited on PTO-892 mailed on 01/28/2026 with US Patent Application Publication 2020/0147143 A1, cited on PTO-892 mailed on 01/28/2026, serving as a translation) in view of Yu et al. (Human Gene Therapy, 2016; cited on IDS filed on 02/13/2023) Musunuru et al. (WO 2019/213183 A1; cited on PTO-892 mailed on 01/28/2026), and Liu et al. (WO 2020/191249 A1, priority to 03/19/2019; examiner cited) as applied to claims 1, 3, 13-14, and 16 above and further in view of Huang et al. (Cell Press, 2019; examiner cited). This new grounds of rejection is necessitated by applicants’ amendment to the claims to add new claim 15.
16. The relevant teachings of Choi et al., Yu et al., Musunuru et al., and Liu et al. as applied to claims 1, 3, 13-14, and 16 are set forth above.
However, the combination of Choi et al., Yu et al., Musunuru et al. and Liu et al. do not teach the method of claim 15, wherein the adenine base editor is selected from the group consisting of NG-ABEmax and NG-ABE8e.
Huang et al. teach the development of ABEmax-NG to induce A to G conversion with expanded editing scope and high precision [see Abstract; p. 647]. Huang et al. further teach that ABEmax-NG is a versatile editor for targeting most human pathogenic splice sites both in vitro and in vivo [see p. 647].
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to combine the teachings of Choi et al., Yu et al., Musunuru et al., Liu et al., and Huang et al. according to the teachings of Huang et al. to substitute the adenine base editors with an ABEmax-NG in the methods of Choi et al., Yu et al., Musunuru et al. and Liu et al. because Huang et al. teach that ABEmax-NG is a versatile editor for targeting most human pathogenic splice sites both in vitro and in vivo. One of ordinary skill in the art would have had a reasonable expectation of success, a reasonable level of predictability and would have been motivated to combine the teachings of Choi et al., Yu et al., Musunuru et al., Liu et al., and Huang et al. because Huang et al. acknowledges that ABEmax-NG is a versatile editor for targeting most human pathogenic splice sites both in vitro and in vivo. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Response to Remarks Regarding Prior Art Rejections
17. Applicants’ remarks filed on 04/28/2026 have been fully considered by the examiner; however, they are rendered moot in view of the new rejections set forth above, which are necessitated by applicants’ amendment to the claims.
Conclusion
18. Status of the claims:
Claims 1, 3, and 7-16 are pending.
Claims 7-12 stand withdrawn pursuant to 37 CFR 1.142(b).
Claims 1, 3, and 13-16 are rejected.
No claims are in condition for an allowance.
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 PAUL J HOLLAND whose telephone number is (571)270-3537. The examiner can normally be reached Monday to Friday from 8AM to 5PM.
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/PAUL J HOLLAND/Primary Examiner, Art Unit 1656
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