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 03/24/2026 in response to the Non-Final Rejection mailed on 09/25/2025 is acknowledged. This listing of claims replaces all prior listings of claims in the application.
3. Claims 8 and 16 are cancelled.
4. Claims 1, 7, 9-11, and 17 are pending.
5. Claims 10-11 stand withdrawn pursuant to 37 CFR 1.142(b).
6. Applicant’s remarks filed on 03/24/2026 in response to the Non-Final Rejection mailed on 09/25/2025 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.
Information Disclosure Statement
7. The IDS filed on 12/16/2025 has been considered by the examiner and a copy of the Form PTO/SB/08 is attached to the office action.
Claim Rejections - 35 USC § 103
8. The rejection of claims 1, 7-9 and 16-17 under 35 U.S.C. 103 as being unpatentable over Brouns et al. (WO 2013/098244; cited on PTO-892 mailed on 06/04/2021) in view of Liu et al. (WO 2015/089406 A1; cited on IDS filed on 06/01/2018) and Guo et al. (Nature, 2009; cited on PTO-892 mailed 05/03/2023) is withdrawn in view of applicants’ amendment to the claims to recite “wherein temperature-sensitive repressor/operator or temperature-sensitive replication origin is used” and amendment to cancel claims 8 and 16.
9. Claims 1, 7, 9 and 17 are newly rejected under 35 U.S.C. 103 as being unpatentable over Brouns et al. (WO 2013/098244; cited on PTO-892 mailed on 06/04/2021) in view of Liu et al. (WO 2015/089406 A1; cited on IDS filed on 06/01/2018), Guo et al. (Nature, 2009; cited on PTO-892 mailed 05/03/2023), and Boorsma et al. (Nature Biotechnology, 2000; examiner cited). This new grounds of rejection is necessitated by applicants’ amendment to the claims to recite “wherein temperature-sensitive repressor/operator or temperature-sensitive replication origin is used”.
10. With respect to claim 1, Brouns et al. teach a method of modifying a targeted site of double stranded DNA in a host cell by introducing into a host cell a DNA encoding a crRNA crRNA comprising a sequence complementary to a target strand of a target nucleotide sequence in the given double stranded DNA, and (b) a DNA encoding a protein group constituting Cascade wherein the Cascade protein is Cse1, Cse2, Cas7, Cas5, Cas6 and/or Cas6e (synonymous with CasA, CasB, CasC, CasD, and CasE) [see p. 12] and a nucleic acid base converting enzyme, in which the nucleic acid base converting enzyme is constituted in a form capable of forming a complex with any protein in the protein group into the host cell to methylate the target DNA sequence (interpreted as converting one or more nucleotide to other one or more nucleotides without cleaving the double stranded DNA) [see Abstract; p. 3-6; p. 13; p. 26, top]. Brouns et al. further teach that the functional moiety (nucleic acid base converting enzyme) is fused or linked to at least one region of the N terminus and/or the region of the C terminus of at least one of a Cse1, Cse2, Cas7, Cas5, Cas6, or Cas6e subunit [see p. 12, top]. In other words, Brouns et al. structurally envisages an embodiment wherein the nucleic acid base converting enzyme is fused downstream of CasE. Brouns et al. teach the method wherein said Cascade is derived from E. coli [see p. 7, lines 20-22]. Brouns et al. further teach that the functional moiety (nucleic acid base converting enzyme) is fused or linked to at least one region of the N terminus and/or the region of the C terminus of at least one of a Cse1, Cse2, Cas7, Cas5, Cas6, or Cas6e subunit [see p. 12, top; p. 20]. In other words, Brouns et al. structurally envisages an embodiment wherein the nucleic acid base converting enzyme is fused or linked downstream (C-terminus) of CasE. Brouns et al. further teach that the linker peptide is preferably designed to obtain the correct spacing and position of the fused functional moiety and the subunit of Cascade to which the moiety is fused to allow proper interaction with the target nucleotide [see p. 20, lines 11-18]. Brouns et al. teach target nucleotide sequences that are adjacent to a PAM sequence of AAG and wherein the nucleotides used for targeting is 32 to 33 residues long and target sites that are with the claimed range downstream of the PAM sequences [see p. 16, lines 12-16, p. 52-53]. Brouns et al. teach the method comprising a step of introducing an expression vector comprising the DNA encoding the crRNA and Cascade protein group and inducing expression for a period necessary for fixing the modification of the targeted site [see Examples; p. 24, bottom to top of p. 26].
With respect to claim 7, Brouns et al. teach the method wherein the host cell is a prokaryotic cell [see p. 24, bottom; p. 26, top].
With respect to claim 9, Brouns et al. teach a method of modifying a targeted site of double stranded DNA in a host cell by introducing into a host cell a DNA encoding a crRNA crRNA comprising a sequence complementary to a target strand of a target nucleotide sequence in the given double stranded DNA, and (b) a DNA encoding a protein group constituting Cascade and a nucleic acid base converting enzyme, in which the nucleic acid base converting enzyme is constituted in a form capable of forming a complex with any protein in the protein group into the host cell to methylate the target DNA sequence (interpreted as converting one or more nucleotide to other one or more nucleotides without cleaving the double stranded DNA) [see Abstract; p. 3-6; p. 13; p. 26, top].
With respect to claim 17, Brouns et al. teach a method of modifying a targeted site of double stranded DNA in a host cell by introducing into a host cell a DNA encoding a crRNA crRNA comprising a sequence complementary to a target strand of a target nucleotide sequence in the given double stranded DNA, and (b) a DNA encoding a protein group constituting Cascade and a nucleic acid base converting enzyme, in which the nucleic acid base converting enzyme is constituted in a form capable of forming a complex with any protein in the protein group into the host cell to methylate the target DNA sequence (interpreted as converting one or more nucleotide to other one or more nucleotides without cleaving the double stranded DNA) [see Abstract; p. 3-6; p. 13; p. 26, top].
However, Brouns et al. does not teach the method comprising a cytidine deaminase, wherein the cytidine deaminase is PmCDA1 and converting one or more nucleotides occurs primarily at cytosine residues and wherein temperature-sensitive repressor/operator or temperature-sensitive replication origin is used.
Liu et al. teach similar methods of modifying a targeted site of a double stranded DNA in a host cell by introducing a DNA encoding a crRNA and a DNA encoding a Cas9 protein fused to a cytidine deaminase to institute site specific nucleotide change at a particular location in a genome as a potential approach to gene editing based therapeutics and research tool [see Abstract; p. 1 to top of p. 2; paragraphs 0009-0011]. Liu et al. further teach that the cytidine deaminase can be fused to the C-terminus of the Cas9 protein (downstream) [see p. 15, bottom]. Liu et al. further teach wherein the cytidine deaminase is a APOBEC family or AID family cytidine deaminase for targeted deamination of cytosine using suitable guide RNA sequences that are complementary to a nucleic acid sequence within 50 nucleotides upstream or downstream of the target nucleotide to be edited [see paragraphs 0089, 00127].
Guo et al. teach AID/APOBEC cytidine deaminases from sea lampreys, Petromyzon marinus [see Abstract; p. 796, column 2; p. 799, column 2 bridging to column 1, p. 800].
Boorsma et al. teach a temperature regulated alphavirus replicon based DNA expression system for simplifying bioprocess engineering strategies particularly in situations wherein the cloned protein has detrimental effects on host cell metabolism [see Abstract; p. 429, column 2]. Additionally, the precise adjustment of expression levels by temperature should allow development of bioprocess strategies in which the expression level of the product or of a modifying enzyme is precisely modulated to optimize the amount or nature of a product [see p. 431, column 2, bottom]
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 Brouns et al., Liu et al., Guo et al., and Boorsma et al. in a method of modifying a targeted site of a double stranded DNA in a host cell because Brouns et al. teach Cascade fusion proteins for targeted DNA modification. Liu et al. teach Cas-cytidine deaminase fusion proteins, wherein the cytidine deaminase is a APOBEC family or AID family cytidine deaminase to institute site specific nucleotide change at a particular location in a genome as a potential approach to gene editing based therapeutics and research tool. Guo et al. teach AID/APOBEC cytidine deaminases from sea lampreys, Petromyzon marinus. Boorsma et al. teach a temperature regulated alphavirus replicon based DNA expression system for simplifying bioprocess engineering strategies particularly in situations wherein the cloned protein has detrimental effects on host cell metabolism. One of ordinary skill in the art would have had a reasonable expectation of success and a reasonable level of predictability to combine the teachings of Brouns et al., Liu et al., Guo et al., and Boorsma et al. because Liu et al. acknowledges cytidine deaminase fusions with Cas proteins to institute site specific nucleotide change at a particular location in a genome as a potential approach to gene editing based therapeutics and research tool. One of ordinary skill in the art looking for APOBEC and/or AID cytidine deaminase would recognize that the cytidine deaminases of Guo et al. are these types of cytidine deaminase and would have a reasonable expectation of success and a reasonable level of predictability that these Petromyzon marinus cytidine deaminases could be used in the fusions of Brouns et al. and Liu et al. Furthermore, one of ordinary skill in the art would look to Boorsma et al. for use of a temperature regulated replicon because Boorsma et al. acknowledges the precise adjustment of expression levels by temperature should allow development of bioprocess strategies in which the expression level of the product or of a modifying enzyme is precisely modulated to optimize the amount or nature of a product. 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
11. Applicants’ remarks filed on 03/24/2026 have been fully considered by the examiner; however, they are rendered moot in view of the new rejection set forth above which is necessitated by applicants’ amendment to the claims.
Regarding applicants’ remarks that the incorporation of temperature sensitive expression control provides and unexpected and advantageous result by providing a temporal window for editing followed by elimination of the vector is found to be not persuasive in view of the new rejection set forth above. Furthermore, this argument is found to be not persuasive because the argument of unexpected results must be commensurate in scope with the claimed invention. MPEP 716.02(d) states “whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)”. In the instant case, the alleged unexpected result occurred with the cI857/PL system and the pSC101 ts-ori system; however, the claims are unlimited with respect to the temperature-sensitive repressor/operator and/or temperature sensitive replication origin. There is no evidence of record that the alleged unexpected property would occur over all temperature-sensitive repressor/operator and/or temperature sensitive replication origin as encompassed by the claims. Accordingly, the alleged unexpected result is not commensurate in scope with the claims.
Double Patenting
12. The nonstatutory double patenting rejection of claims 8 and 16 over claims 1-6 of U.S. Patent No. 10,655,123 in view of Brouns et al. (WO 2013/098244; cited on PTO-892 mailed on 06/04/2021) is withdrawn in view of the cancellation of claims 8 and 16.
13. The nonstatutory double patenting rejection of claims 8 and 16 over claims 1-12 of U.S. Patent No. 10,767,173 in view of Brouns et al. (WO 2013/098244; cited on PTO-892 mailed on 06/04/2021) is withdrawn in view of the cancellation of claims 8 and 16.
14. The nonstatutory double patenting rejections of claims 1, 7, 9, and 17 over claims 1-6 of U.S. Patent No. 10,655,123 and claims 1-12 of U.S. Patent No. 10,767,173 in view of Brouns et al. (WO 2013/098244; cited on PTO-892 mailed on 06/04/2021) are maintained for the reasons of record set forth in the Non-Final Rejection mailed on 06/10/2024) and the reasons set forth below.
RESPONSE TO REMARKS: Beginning on p. 9 of applicants’ remarks, applicants in summary contend that the claims require the use of temperature-sensitive repressor/operator or temperature-sensitive replication origin which are not disclosed by the claims of the ‘123 and ‘173 patents.
This argument is found to be not persuasive because the claims of both patents recite expression vectors comprising a nucleic acid encoding the complex in a form permitting control of an expression period. The specification defines this control as including temperature sensitive repressors and operators. MPEP 804.II.B.1 states “[t]he specification can be used as a dictionary to learn the meaning of a term in the claim. Toro Co. v. White Consol. Indus., Inc., 199 F.3d 1295, 1299, 53 USPQ2d 1065, 1067 (Fed. Cir. 1999) ("[W]ords in patent claims are given their ordinary meaning in the usage of the field of the invention, unless the text of the patent makes clear that a word was used with a special meaning."); Renishaw PLC v. Marposs Societa' per Azioni, 158 F.3d 1243, 1250, 48 USPQ2d 1117, 1122 (Fed. Cir. 1998)”.
Conclusion
15. Status of the claims:
Claims 1, 7, 9-11, and 17 are pending.
Claims 10-11 stand withdrawn pursuant to 37 CFR 1.142(b).
Claims 1, 7, 9 and 17 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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