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 .
DETAILED ACTION
Claims 1-18, and 31 are canceled. Claims 34-35 are new. Claims 19-30, and 32-35 are pending. Claims 19-23, and 26-30 are withdrawn as being drawn to a non-elected invention. Claims 24-25, and 32-35 are under consideration in this action.
Priority
The instant claims are entitled to an effective filing date of 02/13/2019.
Response to Amendment filed 10/20/2025
The § 112(a) new matter rejection of claims 1-10, 12, 14, 16-17, 24-25, and 31-33 is withdrawn in light of the amendment.
The §103 rejection of claims 1-5, 7-10, 12, 14, 16-17, 24-25 and 31 over Liu is withdrawn because claims 1-5, 7-10, 12, 14, 16-17, and 31 are canceled and in light of the amendment to claims 24-25.
Claim Objections
Claims 24 and 25 are objected to because of the following informalities:
Claims 24 and 25 depend from subsequent claim 32. As such, claims 24 and 25 are objected to because a claim in dependent form shall contain a reference to a claim previously set forth. To obviate this objection, claims 24 and 25 can be canceled and added as new claims 36 and 37.
New claims 24 and 25 should be renumbered as claims 34 and 35 respectively, because 37 CFR 1.126 requires the original numbering of claims to be preserved throughout prosecution. When new claims are presented, they must be numbered consecutively beginning with the number next following the highest numbered claims previously presented (whether entered or not).
Misnumbered new claims 24 and 25 have been renumbered to claims 34 and 35 respectively.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
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.
(New Rejection) Claims 24-25 and 32-35 are rejected under 35 U.S.C. 103 as being unpatentable over Joung (US 2020/0308571, earliest effective filing date Feb. 4, 2019).
Regarding claims 25 and 32, Joung teaches an adenine base editor (ABE) variant comprising an adenosine deaminase and a programmable DNA binding domain, the adenosine deaminase comprising one or more E. coli TadA monomers, wherein at least one of the one or more E. coli TadA monomers comprise one or more mutations that decrease RNA editing activity while preserving DNA editing activity. See claim 1 of Joung. The one or more mutations comprise one or more mutations at amino acid positions that correspond to residues of wild type (WT) E. coli TadA (SEQ ID NO: 1) or E. coli TadA deaminase monomer with ABE 7.10 mutations (SEQ ID NO: 34) as listed in table A. See claim 4 of Joung. SEQ ID NO: 34 of Joung is 100% identical to instant SEQ ID NO: 4. See the alignment attached in the office action appendix. In table A, Joung teaches amino acid substitutions predicted to generate ABE variants with reduced RNA editing. The table includes reasoning behind the proposed changes. Joung lists I76, D147, and Q154 amongst the residues to change in table A and suggests that the changes are associated with a binding prediction. See table A in paragraph [0066]. Joung teaches that the mutations [of table A] can include substitution with any other amino acid other than the WT amino acid. See [0067]. Joung teaches an ABE variant wherein the programable DNA binding domain is selected from a list that includes CRISPR Cas RNA-guided nucleases, wherein the CRISPR-Cas nuclease is a Cas9 or a Cas12 that has a ssDNA nickase activity or is catalytically inactive. See claims 10-12 of Joung. Joung teaches exemplary Cas9 orthologs including S. pyogenes Cas 9 accession number Q99ZW2.1 with nickase mutations/catalytic residues including D10A, and S. aureus Cas9 accession J7RUA5.1 with nickase mutations/catalytic residues including D10A. See [0076], table C . Furthermore, Joung teaches kits comprising the proteins and nucleic described (relevant to instant claim 25). See [0121].
Joung does not teach a tyrosine at position 76 (I76Y), a threonine at position 147 (D147T), and a serine at position 154 (Q154S) (relevant to instant claim 32).
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to select any non-WT amino acid residue at the I76, D147, and Q154 variable positions taught by Joung including tyrosine at position 76, threonine at position 147 and serine at position 154. One would be motivated to do so, because Joung suggests that such substitutions are predicted to generate ABE variants with reduced RNA editing; and Joung teaches ABE variants that have decreased RNA editing activity and preserved DNA editing activity. There would be a reasonable expectation of success because Joung suggests that the mutations can include substitutions with any other amino acid other than the WT amino acid.
Regarding claim 24, Joung teaches a deaminase fusion protein embodiment that includes a cell-penetrating peptide (excipient) sequence that facilitates delivery to the intracellular space. See [0099]. Cell penetrating peptides (CPP) are short peptides that facilitate the movement of a wide range of biomolecules across the cell membrane into the cytoplasm or other organelles. Examples of molecules that can be delivered by CPPs include therapeutic drugs. See [0100].
Regarding claim 33 and 35, Joung teaches an adenine base editor (ABE) variant comprising an adenosine deaminase and a programmable DNA binding domain, the adenosine deaminase comprising one or more E. coli TadA monomers, wherein at least one of the one or more E. coli TadA monomers comprise one or more mutations that decrease RNA editing activity while preserving DNA editing activity. See claim 1 of Joung. The one or more mutations comprise one or more mutations at amino acid positions that correspond to residues of wild type (WT) E. coli TadA (SEQ ID NO: 1) or E. coli TadA deaminase monomer with ABE 7.10 mutations (SEQ ID NO: 34) as listed in table A. See claim 4 of Joung. SEQ ID NO: 34 of Joung is 100% identical to instant SEQ ID NO: 4; and SEQ ID NO: 34 of Joung includes a Y123 residue. See the alignment attached in the office action appendix. Joung teaches one or more mutations at amino acid positions corresponding to residues including Y123. See claim 5 of Joung. In table A, Joung teaches amino acid substitutions predicted to generate ABE variants with reduced RNA editing. The table includes reasoning behind the proposed changes. Joung lists I76, V82, H123 [sic. Y123], D147 and Q154 amongst the residues to change in table A. Joung suggests that such substitutions at positions 76, 123, 147 and 154 are associated with a binding prediction and that the V82 change is associated with protein structure. See table A in paragraph [0066]. Joung teaches that the mutations [of table A] can include substitution with any other amino acid other than the WT amino acid. See [0067]. Joung teaches an ABE variant wherein the programable DNA binding domain is selected from a list that includes CRISPR Cas RNA-guided nucleases, wherein the CRISPR-Cas nuclease is a Cas9 or a Cas12 that has a ssDNA nickase activity or is catalytically inactive. See claims 10-12 of Joung. Joung teaches exemplary Cas9 orthologs including S. pyogenes Cas 9 accession number Q99ZW2.1 with nickase mutations/catalytic residues including D10A, and S. aureus Cas9 accession J7RUA5.1 with nickase mutations/catalytic residues including D10A. See [0076], table C . Furthermore, Joung teaches kits comprising the proteins and nucleic described (relevant to instant claim 35). See [0121].
Joung does not teach a tyrosine at position 76 (I76Y), a serine at position 82 (V82S), a histidine at position 123 (Y123H), an arginine at position 147 (D147R), and arginine at position 154 (Q154R) (relevant to instant claim 33).
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to select any non-WT amino acid residue at the I76, V82, Y123, D147 and Q154 variable positions taught by Joung including: tyrosine at position 76, serine at position 82, histidine at position 123, arginine at position 147 and arginine at position 154. One would be motivated to do so, because Joung suggests that such substitutions are predicted to generate ABE variants with reduced RNA editing; and Joung teaches ABE variants that have decreased RNA editing activity and preserved DNA editing activity. There would be a reasonable expectation of success because Joung suggests that the mutations can include substitutions with any other amino acid other than the WT amino acid.
Regarding claim 34, Joung teaches a deaminase fusion protein embodiment that includes a cell-penetrating peptide (excipient) sequence that facilitates delivery to the intracellular space. See [0099]. Cell penetrating peptides (CPP) are short peptides that facilitate the movement of a wide range of biomolecules across the cell membrane into the cytoplasm or other organelles. Examples of molecules that can be delivered by CPPs include therapeutic drugs. See [0100].
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KIMBERLY C BREEN whose telephone number is (571)272-0980. The examiner can normally be reached M-Th 7:30-4:30, F 8:30-1:30 (EDT/EST).
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/K.C.B./Examiner, Art Unit 1657