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 .
This action is in response to the amendment filed 05/11/2026, in which claims 1, 9, 10, 21, 22, 25, 27-31 and 36 were amended, claims 13, 18 and 26 was previously presented, claims 55-58 were newly added and claims 18, 53 and 54 were withdrawn in a previous office action.
Claims 1, 9, 10, 13, 18, 19, 21, 22, 25-31, 36 and 53-58 are currently pending.
Applicant’s arguments have been thoroughly reviewed, but are not persuasive for the
reasons that follow. Any rejection and objections not reiterated in this action have been
withdrawn.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Acknowledgment is made of applicant’s claim for priority based on the instant application being a continuation of an application filed as PCT/CN2023/140808 on 12/22/2023.
Acknowledgment is made of applicant’s request for priority to two foreign applications filed as CN202311453875.2 on 11/02/2023 and CN202211663018.0. However, due to the foreign priority documents are not in English, all claims are given the priority date of the PCT 371 application filed as PCT/CN2023/140808 on 12/22/2023.
Receipt is acknowledged of the English translation filed on 05/11/2026 and 05/20/2026. However, Applicant cannot rely upon the certified copy of the foreign priority application because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216. A statement that the translation of the certified copy is accurate was not provided.
Therefore, all claims are given the priority date of 12/22/2023.
Election/Restrictions
Applicant’s election of Group I, drawn to claims 1, 3, 4, 6, 7, 9, 10, 13, 18, 19, 21, 22, 25-31 and 36 in the reply filed on 12/31/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 53 and 54 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 12/31/2025.
Claims 13 and 18 were previously withdrawn from consideration as being drawn to the non-elected species of a Cas9 protein. Examination of claim 13 and 18 was found not to cause a burden on search and therefore will be examined.
Claims 1, 9, 10, 13, 18, 19, 21, 22, 25-31, 36 and 55-58 are currently under consideration.
Oath/Declaration
The Declaration under 37 CFR 1.132 filed 05/11/2026 is insufficient to overcome the rejection of claims 1, 9, 10, 19, 21, 22, 25-31, 36 and 55-58 based upon 35 U.S.C. 103 as set forth in the last Office action. All statements and arguments filed in the Declaration are acknowledged and addressed in the response to Arguments in regards to the 103 rejections below.
Nucleotide and/or Amino Acid Sequence Disclosures
The previous objection to the specification has been withdrawn in view of Applicant’s amendments and new sequence listing filed on 05/11/2026.
Claim Objections
The previous objection of claim 10 has been withdrawn in view of Applicant’s amendments to the claims filed on 05/11/2026.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 22, 25, 28, 30, 31 and 36 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a NEW Rejection.
Claims 22 and 25 are drawn to a genus of sequences for a DNA methyltransferases and functionally active fragments thereof. Claim 25 recites, “an amino acid sequence set forth in any one of SEQ ID Nos: 19-22,” which reads on any two or more consecutive amino acids selected from the recited sequence identifiers. The rejected claims thus comprise a genus of sequences for a DNA methyltransferase domain that encompass a partial sequence or a functional fragment thereof.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification describes the full sequences of the DNMT3A, DNMT3L and human DNMT3L DNA methylation domains that were used within the fusion protein constructs (Page 33, Line 24 Bridging Page 34, Lines 5; Page 74, Lines 8-22; Page 75 Bridging Page 76 Table and Page 77 Table). No description is provided of functional fragments of the DNA methyltransferase domains capable of the functions of the full sequences.
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims with regard to structure and function, the examples are only representative of the full sequences of the DNA methyltransferase domains that would be capable of functioning successfully due to the entirety of their sequence and structure being present. The results are not necessarily predictive of functional fragments of the DNA methyltransferase domains capable of the functions of the full sequences. Thus, it is impossible for one to extrapolate from the few examples described herein those fragments of DNA methyltransferase domains that would necessarily meet the structural/functional characteristics of the rejected claims.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of functional fragments of the DNA methyltransferase domains capable of the functions of the full sequences. For some relevant background, Dhe-Paganon et al (Int J Biochem Mol Biol 2011;2(1):58-66) teaches the primary establishment of methylation patterns on the genome following embryonic fertilization requires DNMT3a and DNMT3b enzymes which have high affinity for non-methylated DNA wherein knock out of these enzymes proved to be fatal at the embryonic stage, suggesting that any overlapping functions of other variants of DNMT are not sufficient in establishing de novo methylation patterns (Page 58, Column 2), therefore any variation or fragment thereof would not be capable of the same function of DNMT3a and DNMT3b in specific situations.
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 22 and 25.
Claim 28 is drawn to a genus of sequences for transcriptional repressor domains. The rejected claims thus comprise a genus of sequences for a transcriptional repressor domain that encompass a partial sequence.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification describes the full sequences of the ZIM3 transcriptional repressor domain that was used within the fusion protein constructs (Page 7, Line 7-8; Page 75 Bridging Page 76 Table and Page 77 Table). No description is provided of functional fragments of the transcriptional repressor domains capable of the functions of the full sequences.
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims with regard to structure and function, the examples are only representative of the full sequences of the transcriptional repressor domains that would be capable of functioning successfully due to the entirety of their sequence and structure being present. The results are not necessarily predictive of functional fragments of the transcriptional repressor domains capable of the functions of the full sequences. Thus, it is impossible for one to extrapolate from the few examples described herein those fragments of transcriptional repressor domains that would necessarily meet the structural/functional characteristics of the rejected claims.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of functional fragments of the transcriptional repressor domains capable of the functions of the full sequences. For some relevant background, Stoll et al (EMBO J. 2022 Dec 15;41(24); Pgs 1-16) teaches that transcriptional repressor domains such as KRAB and ZFN transcriptional repressor domains, such as ZIM3, have highly conserved sequences (Page 6, Column 1). Stoll teaches that even point mutations to the KRAB sequences resulted in loss of silencing function (Page 6, Column 1 bridging Column 2), thus showing the sequence encoding these domains cannot be altered in specific ways or made into fragments without risk of loss of function from the mutations made.
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claim 28.
Claims 30, 31 and 36 are drawn to a genus of sequences for a fusion protein. Claim 30 recites, “wherein the first fusion and/or the second fusion comprises an amino acid sequence as set forth any one of SEQ ID NOs: 53, 361 and 362.” Claim 31 recites, “an amino acid sequence as set forth in any one of SEQ ID NOs: 345 and 346.” Thus, claims 30 and 31 require any two or more amino acid selected from the recited sequence identifiers, which must maintain the function of each of the component parts of the fusion protein. Claim 36 recites, “a nucleic acid sequence as set forth in any one of SEQ ID NOs: 353 and 354.” Thus, claim 36 includes any two or more consecutive nucleotides of the recited sequence identifier, which must encode a fusion protein that maintains the function of each of the component parts of the fusion protein. The rejected claims thus comprise a genus of sequences that encompass fragments of the fusion protein sequences capable of functioning as the full sequence as the fusion protein.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification describes the full sequences of the fusion protein constructs, specifically that the complex formed by combining a first fusion having an amino acid sequence as set forth in SEQ ID NO: 51 (DNMT3A(CD)-DNMT3L(CD)-dCas9-10xGCN4) with a second fusion having an amino acid sequence as set forth in SEQ ID NO: 52 (scFv-KRAB) achieved higher or substantial inhibition efficiency for gRNAs targeting PTP1b gene (Page 74, Lines 8-22; Page 75 Bridging Page 76 Table and Page 77 Table). No description is provided of fragments of the fusion protein sequences capable of functioning as the full sequence as the fusion protein.
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims with regard to structure and function, the examples are only representative of the full sequenced fusion proteins that would be capable of functioning successfully due to having the full sequence and structure of the fusion protein required. The results are not necessarily predictive of fragments of the fusion protein sequences capable of functioning as the full sequence as the fusion protein. Thus, it is impossible for one to extrapolate from the few examples described herein those fragments of the fusion protein sequences capable of functioning as the full sequence as the fusion protein that would necessarily meet the structural/functional characteristics of the rejected claims.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of fragments of the fusion protein sequences capable of functioning as the full sequence as the fusion protein. The fusion proteins outlined in the instant claims require at least one DNA methyltransferase and at least one transcriptional repressor domain on either fusion protein as well as a recruitment domain on each in order for the first and second fusion proteins to become linked after administration. As previously stated, the prior art does not teach a functional fragment of the DNA methyltransferase domains or the transcriptional repressor domains capable of successfully functioning the same as the full structured fusion proteins comprising the entirety of the sequences claimed.
Dhe-Paganon et al (Int J Biochem Mol Biol 2011;2(1):58-66) teaches the primary establishment of methylation patterns on the genome following embryonic fertilization requires DNMT3a and DNMT3b enzymes which have high affinity for non-methylated DNA wherein knock out of these enzymes proved to be fatal at the embryonic stage, suggesting that any overlapping functions of other variants of DNMT are not sufficient in establishing de novo methylation patterns (Page 58, Column 2), therefore any variation or fragment thereof would not be capable of the same function of DNMT3a and DNMT3b in specific situations.
Stoll et al (EMBO J. 2022 Dec 15;41(24); Pgs 1-16) teaches that transcriptional repressor domains such as KRAB and ZFN transcriptional repressor domains, such as ZIM3, have highly conserved sequences (Page 6, Column 1). Stoll teaches that even point mutations to the KRAB sequences resulted in loss of silencing function (Page 6, Column 1 bridging Column 2), thus showing the sequence encoding these domains cannot be altered in specific ways or made into fragments without risk of loss of function from the mutations made.
Furthermore, with the DNA methyltransferase being the majority of the first fusion protein and the transcriptional repressor domain being the majority of the second fusion protein and neither having a function fragment for use in the fusion protein, it would be even more unlikely that a fragment of the fusion proteins would be capable of the advanced successful functions of the full structured fusion proteins comprising the entirety of the sequences claimed.
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 30, 31 and 36.
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 13 and 18 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. Claim 13 relies on claim 10 and recites “wherein the DNA binding domain is capable of binding to a guide RNA, and the guide RNA is capable of specifically recognizing and hybridizing to the target sequence of the target locus” however claim 10 as currently written does not require a DNA binding domain that would use a guide RNA. Claim 18 relies on claim 10 recites “wherein the Cas protein is a dead Cas9 (dCas9) protein or a dead Cas12 (dCas12) protein”, however claim 10 as currently written does not require the DNA binding domain to be a CRISPR-Cas system or protein. Applicant 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.
Response to Amendments - Claim Rejections - 35 USC § 112
The previous rejections of claims 30, 31 and 36 under 35 U.S.C. 112(b) has been withdrawn in view of Applicant’s amendments to the claims filed on 05/11/2026.
Claim Rejections - 35 USC § 103
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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 9, 13, 18, 21, 22, 25, 26, 30, 31, 36 and 55 are rejected under 35 U.S.C. 103 as being unpatentable over Segal et al (US 2019/0233805 Al) in view of Lanshakov et al (Journal of Biosciences and Medicines, 8, 197-207). This is a NEW Rejection.
Regarding claims 1, 9, 13, 18 and 21, Segal teaches two fusion proteins administered together wherein one fusion comprises a DNMT3a protein fused to the N-terminus of a dCas9 and the second comprises a KRAB protein fused to the N-terminus of a dCas9 along with the administration of a DNMT3L cassette and three sgRNAs into HCT116 cells to target the HER2 gene promotor [0025]. Segal teaches the dual administration of the two fusion proteins achieved long-term gene repression [0025].
Segal does not teach the use of a two-part recruitment domain or that the KRAB is attached to a two-part recruitment domain, such as a suntag.
Lanshakov teaches improved dCas9 vectors with Suntag system to suppress gene expression and enhance methylation of CpG islands, such as 10 times repetitive GCN peptide that were fused to dCas9 and single chain antibody against GCN4 peptide was fused to KRAB repressor or Dnmt3a catalytic domain (Page 197, Abstract). Lanshakov teaches the use of dCas9-10xGCN +scfv-Krab wherein the usage of the Suntag system with KRAB repressor led to significant improvement in transcription decrease (Page 201, Paragraph 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Segal to include the two part recruitment domain, such as suntag, fused to a repressor domain, such as the KRAB, as taught by Lanshakov because Segal teaches it is within the ordinary skill in the art to use two fusion proteins administered together wherein one fusion comprises a DNMT3a protein fused to the N-terminus of a dCas9 and the second comprises a KRAB protein fused to the N-terminus of a dCas9 along with the administration of a DNMT3L cassette and three sgRNAs for long-term repression of genes and Lanshakov teaches the use of dCas9-10xGCN +scfv-Krab wherein the usage of the Suntag system with KRAB repressor led to significant improvement in transcription decrease.
One would have been motivated to make such a modification in order to receive the expected benefit of effective and long-term repression of genes as taught by Segal and Lanshakov, respectively.
Regarding claims 22, 25 and 26, the phrase “an amino acid sequence” is interpreted as two or more consecutive amino acids with 100% identity and does not require the entire length of the sequence.
Segal teaches the DNMT3A-dCas9 is co-administrated with DNMT3L as both being the DNA methylation domain [0025], therefore, indirectly linked. Segal teaches the sequence of DNMT3A as SEQ ID NO: 6 which is 100% identical to instant SEQ ID NO: 19 (Page 29; See NEW Appendix I).
Regarding claims 30 and 31, the phrase “an amino acid sequence” is interpreted as two or more consecutive amino acids with 100% identity and does not require the entire length of the sequence.
Segal teaches the DNMT3A-dCas9 is co-administrated with DNMT3L as both being the DNA methylation domain [0025], therefore, indirectly linked. Segal teaches the sequence of DNMT3A as SEQ ID NO: 86 which is 100% identical to two or more consecutive amino acid of instant SEQ ID NO: 346 and instant SEQ ID NO: 362 (Page 37 bridging Page 38; See NEW Appendix II and III, respectively).
Regarding claims 36 and 55, the phrase “a nucleic acid sequence” is interpreted as two or more consecutive nucleic acids with 100% identity and does not require the entire length of the sequence.
Segal teaches the DNMT3A-dCas9 is co-administrated with DNMT3L as both being the DNA methylation domain [0025], therefore, indirectly linked. Segal teaches the sequence of DNMT3A as SEQ ID NO: 86 which was translated to the nucleic acid sequence and found to be 100% identical to two or more consecutive nucleic acid of instant SEQ ID NO: 353 (Page 37 bridging Page 38; See NEW Appendix IV).
Claims 27, 28 and 56-58 are rejected under 35 U.S.C. 103 as being unpatentable over Segal et al (US 2019/0233805 Al) in view of Lanshakov et al (Journal of Biosciences and Medicines, 8, 197-207) as applied to claims 1, 9, 13, 18, 21, 22, 25, 26, 30, 31, 36 and 55, and further in view of Replogle et al (Elife. 2022 Dec 28; 11:e81856; pgs. 1-32) as evidenced by Uniprot Q96PE6 (ZIM3, Human; Pgs. 1/3-3/3; Dec. 2022). This is a NEW rejection.
The teachings of Segal and Lanshakov are as described and applied above.
Regarding claims 27 and 28, the phrase “an amino acid sequence” is interpreted as two or more consecutive amino acids with 100% identity and does not require the entire length of the sequence.
Segal and Lanshakov do not specifically teach the KRAB repressor domain is a ZIM3.
Replogle teaches generating K562, RPE1, Jurkat, HT29, HuTu-80, and HepG2 cell lines engineered to stably express Zim3-dCas9 and demonstrate robust on-target knockdown across these cell lines (Page 3, Paragraph 1). Replogle teaches Zim3-dCas9 provides the best balance between strong on-target knockdown and minimal non-specific effects, specifically the KRAB domain from ZIM3, which was recently reported to mediate stronger knockdown than KRAB(KOX1) (Page 3, Paragraph 1 and Page 6, Paragraph 1). The uniprot submission is cited as evidenced to show that the ZIM3 protein used within Replogle comprising the KRAB domain is 100% identical to instant SEQ ID NO: 26 (See NEW Appendix V).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Segal and Lanshakov to include the specific use of the ZIM3 KRAB domain as taught by Replogle because Segal teaches it is within the ordinary skill in the art to use two fusion proteins administered together wherein one fusion comprises a DNMT3a protein fused to the N-terminus of a dCas9 and the second comprises a KRAB protein fused to the N-terminus of a dCas9 along with the administration of a DNMT3L cassette and three sgRNAs for long-term repression of genes, Lanshakov teaches the use of dCas9-10xGCN +scfv-Krab wherein the usage of the Suntag system with KRAB repressor led to significant improvement in transcription decrease and Replogle teaches Zim3-dCas9 provides the best balance between strong on-target knockdown and minimal non-specific effects, specifically the KRAB domain from ZIM3, which was recently reported to mediate stronger knockdown.
One would have been motivated to make such a modification in order to receive the expected benefit of the KRAB domain from ZIM3, which was recently reported to mediate stronger knockdown as taught by Replogle.
Regarding claims 56-58, Segal and Lanshakov do not teach using a cleavable peptide linker, e.g., a T2A peptide, a p2A peptide.
Replogle teaches lentiviral vectors expressing the corresponding effectors linked via a P2A ribosome skipping sequence (Page 13, Paragraph 2) due to P2A ribosomal skipping sequences enabling translation of multiple proteins from a single open reading frame (Page 5, Paragraph 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Segal and Lanshakov to include the P2A cleavable peptide linker within a fusion protein as taught by Replogle because Segal teaches it is within the ordinary skill in the art to use two fusion proteins administered together wherein one fusion comprises a DNMT3a protein fused to the N-terminus of a dCas9 and the second comprises a KRAB protein fused to the N-terminus of a dCas9 along with the administration of a DNMT3L cassette and three sgRNAs for long-term repression of genes, Lanshakov teaches the use of dCas9-10xGCN +scfv-Krab wherein the usage of the Suntag system with KRAB repressor led to significant improvement in transcription decrease and Replogle teaches lentiviral vectors expressing the corresponding effectors linked via a P2A ribosome skipping sequence (Page 13, Paragraph 2) due to P2A ribosomal skipping sequences enabling translation of multiple proteins from a single open reading frame.
One would have been motivated to make such a modification in order to receive the expected benefit of enabling translation of multiple proteins from a single open reading frame as taught by Replogle.
Claims 10, 19 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Segal et al (US 2019/0233805 Al) in view of Lanshakov et al (Journal of Biosciences and Medicines, 8, 197-207, 2020) as applied to claims 1, 9, 13, 18, 21, 22, 25, 26, 30, 31, 36 and 55, and further in view of Naldini et al (US 2019/0032049 Al). This is a NEW rejection to address the amendment to the claims in the reply filed 05/11/2026.
The teachings of Segal and Lanshakov as described and applied above.
Regarding claims 10, 19 and 29, the phrase “an amino acid sequence” is interpreted as two or more consecutive amino acids with 100% identity and does not require the entire length of the sequence.
Segal and Lanshakov do not teach the specific use of a TALE nuclease protein as the DNA binding domain and therefore, do not teach an amino acid sequence of instant SEQ ID NO: 343.
Naldini teaches a bi-partite TALE nuclease fusion complex where each fusion protein is fused to a DNMT3A or KRAB [0193]. Naldini teaches the TALE nuclease amino acid sequence as SEQ ID NO: 43 which is 100% identical to two or more consecutive amino acids of instant SEQ ID NO: 343 (Page 19 bridging Page 20; See New Appendix VI).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the TALE nuclease of Segal for the TALE nuclease as taught by Naldini because Segal teaches it is within the ordinary skill in the art to use two fusion proteins administered together wherein one fusion comprises a DNMT3a protein fused to the N-terminus of a dCas9 and the second comprises a KRAB protein fused to the N-terminus of a dCas9 along with the administration of a DNMT3L cassette and three sgRNAs for long-term repression of genes, Lanshakov teaches the use of dCas9-10xGCN +scfv-Krab wherein the usage of the Suntag system with KRAB repressor led to significant improvement in transcription decrease and Naldini teaches the TALE nuclease amino acid sequence as SEQ ID NO: 43 which is 100% identical to two or more consecutive amino acids of instant SEQ ID NO: 343 successfully used within a bipartite fusion protein.
One would have been motivated to make such a modification in order to receive the expected benefit of the specific TALE nuclease for success use of a bipartite fusion protein as taught by Naldini.
Response to Arguments - Claim Rejections - 35 USC § 103
The previous rejection of claims under 35 U.S.C. 103 has been withdrawn in view of Applicant’s amendments to the claims filed on 05/11/2026. However, Applicant’s declaration has been addressed herein.
Applicant argues the declaration filed provides a direct head-to-head in vivo comparison; taking the same functional effector domains (DNMT3A, hDNMT3A, dCas9 and ZIM3) and delivering them either as the Maeder-style single chain fusion or as the claimed bipartite complex (identified in the instant specification as V15). Applicant argues the bipartite delivery of the complex identified as V15 showed increased efficiency compared to the fusion proteins delivered in the single chain fusion construct.
However, the declaration, as well as the arguments filed in the remarks, are not persuasive. The head-to-head comparison of the inventors claimed invention, DNMT3A-hDNMT3L-dCas9-1xGCN4 and scFv-ZIM3 as two fusion proteins, versus the single fusion construct showing SNMT3A-hDNMT3L-dCas9-ZIM3; showing increase and longer repression of the two-construct model versus the single construct model. However, these results are not unexpected, as previously recited, Segal teaches the dual administration of the two fusion proteins achieved long-term gene repression (specifically DNMT3a and KRAB) [0025] and Lanshakov teaches the use of dCas9-10xGCN +scfv-Krab wherein the usage of the Suntag system with KRAB repressor led to significant improvement in transcription decrease relative to the use of a single fusion protein containing dCas9 and Krab domains (Page 201, Paragraph 3). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Segal to include the two part recruitment domain, such as suntag, fused to a repressor domain, such as the KRAB, as taught by Lanshakov because Segal teaches it is within the ordinary skill in the art to use two fusion proteins administered together wherein one fusion comprises a DNMT3a protein fused to the N-terminus of a dCas9 and the second comprises a KRAB protein fused to the N-terminus of a dCas9 along with the administration of a DNMT3L cassette and three sgRNAs for long-term repression of genes and Lanshakov teaches the use of dCas9-10xGCN +scfv-Krab wherein the usage of the Suntag system with KRAB repressor led to significant improvement in transcription decrease.One would have been motivated to make such a modification in order to receive the expected benefit of effective and long-term repression of genes as taught by Segal and Lanshakov, respectively.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDRA ROSE LIPPOLIS whose telephone number is (703)756-5450. The examiner can normally be reached Monday-Friday, 8:00am to 5:00pm EST.
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, JENNIFER A DUNSTON can be reached at (571) 272-2916. 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.
/ALEXANDRA ROSE LIPPOLIS/Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
Prosecution Insights