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 .
Election/Restrictions
Applicant's election with traverse of Group I (claims 1-8, 11-17, 19, 21-23, 63-66, and 83) in the reply filed on 11/25/2025 is acknowledged. The traversal is on the grounds that each of the claims incorporates in entirety the limitations of the fusion protein of claim 1 and further that no unity objection was raised in the PCT or in related EP applications comprising the same subject matter. This is not found persuasive because while each of the claims incorporates in entirety the limitations of the fusion protein of claim 1, this fusion protein is not novel over the prior art. As set forth in the restriction requirement dated 09/25/2025, WO 2020/047124 A1 (hereinafter Rubens; of record) discloses a system for modifying DNA, said system comprising a polypeptide (or a nucleic acid encoding the same), wherein the polypeptide comprises a target DNA binding domain, a reverse transcriptase domain, and an endonuclease domain (page 3, lines 1-4; figure 17). Rubens further discloses that the DNA binding domain may be a CRISPR-related protein such as Cas9 that retains its endogenous endonuclease activity in addition to its targeted DNA binding activity (page 52, line 19-page 53, line 17). Additionally, these modular DNA binding domains are disclosed to be fused to the reverse transcriptase and endonuclease modules taught therein (page 44, lines 14-20). Thus, Rubens discloses a fusion protein comprising a Cas nuclease and a reverse transcriptase, wherein the Cas nuclease is capable of generating a double-stranded polynucleotide cleavage, as is instantly claimed. Accordingly, the shared technical feature of the fusion protein of claim 1 is not a special technical feature and does not link Groups I and II so as to form a single general inventive concept. While no unity objection was raised in the PCT or in related EP applications comprising the same subject matter, it nonetheless stands that the shared technical feature of the instant claim set is not a special technical feature and therefore does not link Groups I and II so as to form a single general inventive concept, as set forth above.
The requirement is still deemed proper and is therefore made FINAL.
Claims 24, 43 and 68 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 11/15/2025.
Accordingly, claims 1-8, 11-17, 19, 21-23, 63-66, and 83 are pending and under consideration.
The Examiner further acknowledges that Applicant properly and timely elected a species of sequences as set forth in the restriction requirement dated 09/25/2025. Applicant elected a fusion protein comprising a DNA or RNA binding protein of SEQ ID NO: 8 (claim 21) and a fusion protein comprising a sequence having at least 90% identity to SEQ ID NO: 18 (claim 23).
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The earliest effective filing date to which the instant application is entitled is 04/08/2020.
Information Disclosure Statement
Receipt of an information disclosure statements on 04/24/2024 is acknowledged. The signed and initialed PTO-1449 has been mailed with this action.
Drawings
The drawings are objected to because:
Figure 16 purportedly depicts microscopy images of the cells transfected with a Cas9-RT fusion (PE0), Cas9, or Cas9 nickase-RT fusion (PE2) and three different guide RNAs per paragraph [0051] of the specification. However, the images shown in Figure 16 are of insufficient quality for one of ordinary skill in the art to interpret the images shown therein, even in view of the disclosure of the specification. It would be remedial to increase the image quality of Figure 16 such that one of ordinary skill in the art can readily see and interpret the data conveyed therein.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). See Figures 13, 26A, and 26B. Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
Claims 3, 7, 21, 23, and 83 are objected to because of the following informalities:
Claims 3, 7, 21, and 23 all recite selection of sequences from indicated sequence identifiers (SEQ ID NOs). However, each of these claims recites selection from “SEQ ID NOS” (bolded emphasis added). Conventionally, multiple sequence identifiers are written as “SEQ ID NOs” (bolded emphasis added). In order to be consistent with these conventions, it would be remedial to amend the instant claim language to recite “SEQ ID NOs” (bolded emphasis added) instead of “SEQ ID NOS” (bolded emphasis added).
Furthermore, the recitation of claim 23 is not punctuated by a period at the end of the sentence. In order to comport with standard grammatical and/or linguistic conventions, it would be remedial to amend the instant claim language such that the recited sentence of claim 23 is properly punctuated by a period.
Claim 83 recites “a kit comprising the fusion protein of any one of claims 1-8, 11-17, or 21 to 23” (bolded emphasis added). The bolded recitation of “21 to 23” is not internally consistent with the recitations of “1-8” or “11-17,” both of which indicate the claimed range with intervening dashes rather than the verbiage “to.” For purposes of internal consistency, it would be remedial to amend the instant claim language to recite “a kit comprising the fusion protein of any one of claims 1-8, 11-17, or 21-23” (bolded emphasis added).
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claims 65 and 66 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
With regard to claims 65 and 66, which respectively recite “a cell comprising the fusion protein of claim 1,” and “a cell comprising the polynucleotide encoding the fusion protein of claim 1, or the vector of claim 64,” the broadest reasonable interpretation of the term “cell” embraces a human having the cell. Neither the instant claim language nor the disclosure of the instant specification precludes this interpretation. It would be remedial to amend the instant claim to recite “an isolated cell” to avoid the claim embracing a human organism.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 19, 21, 64, and 66 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 19 depends from claim 12 and recites the limitation "the DNA-binding domain" in line 2. There is insufficient antecedent basis for this limitation in the claim. Neither the fusion protein of claim 12 nor of claim 1 is recited to comprise a DNA-binding domain. For purposes of examination, the Examiner has interpreted claim 19 to depend from instant claim 14 rather than from instant claim 12, as claim 14 recites that the fusion protein of claim 1 “further compris[es] a DNA-binding…domain.” It would be remedial to amend the instant claim language such that there is sufficient antecedent basis for the limitation “the DNA-binding domain.”
Claim 21 depends from claim 12 and recites the limitation "the DNA-binding domain" in line 1 and “the RNA-binding domain” in lines 1-2. There is insufficient antecedent basis for these limitations in the claim. Neither the fusion protein of claim 12 nor of claim 1 is recited to comprise a DNA-binding domain or an RNA-binding domain. For purposes of examination, the Examiner has interpreted claim 21 to depend from instant claim 14 rather than from instant claim 12, as claim 14 recites that the fusion protein of claim 1 “further compris[es] a DNA-binding or and RNA-binding domain.” It would be remedial to amend the instant claim language such that there is sufficient antecedent basis for the limitations “the DNA-binding domain” and “the RNA-binding domain.”
Claims 64 and 66 recite the limitation "the polynucleotide encoding the fusion protein of claim 1" in lines 1-2 of each claim. There is insufficient antecedent basis for this limitation in the claim. While a polynucleotide encoding the fusion protein of claim 1 is recited at instant claim 63, claims 64 and 66 do not depend from or otherwise require the recitation of instant claim 63. As such, there is insufficient antecedent basis for this limitation. It would be remedial to amend the instant claim language such that there is sufficient antecedent basis for the limitation "the polynucleotide encoding the fusion protein of claim 1."
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2, 5-7, 14-16, 22, 63-66, and 83 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by WO 2020/047124 A1 (hereinafter Rubens; of record).
With regard to claim 1, which recites “a fusion protein comprising: (i) a Cas nuclease and (ii) a reverse transcriptase, a DNA polymerase, a DNA ligase, or a combination thereof, wherein the Cas nuclease is capable of generating a double-stranded polynucleotide cleavage,” Rubens discloses a system for modifying DNA, said system comprising a polypeptide (or a nucleic acid encoding the same), wherein the polypeptide comprises a target DNA binding domain, a reverse transcriptase domain, and an endonuclease domain (page 3, lines 1-4; figure 17). Rubens further discloses that the DNA binding domain may be a CRISPR-related protein such as Cas9 that retains its endogenous endonuclease activity of double-strand cleavage in addition to its targeted DNA binding activity (page 52, line 19-page 53, line 17). Additionally, these DNA binding modular domains are disclosed to be fused to the reverse transcription and endonuclease modules taught therein (page 44, lines 14-20). Thus, Rubens discloses a fusion protein comprising a Cas nuclease and a reverse transcriptase, wherein the Cas nuclease is capable of generating a double-stranded polynucleotide cleavage, as instantly claimed. Accordingly, it is considered the Rubens anticipates each and every limitation of instant claim 1.
With regard to claim 2, which recites “the Cas nuclease [of the fusion protein of claim 1] is Cas9, Cas12, or Cas14,” as set forth above, the system for modifying DNA disclosed in Rubens comprises a fusion polypeptide comprising a Cas9 nuclease and a reverse transcriptase (page 3, lines 1-4; figure 17; page 52, line 19-page 53, line 17; page 44, lines 14-20). Thus, Rubens anticipates each and every limitation of instant claim 2.
With regard to claim 5, which recites “the fusion protein of claim 1…comprises a Cas nuclease and a reverse transcriptase,” as set forth above, the system for modifying DNA disclosed in Rubens comprises a fusion polypeptide comprising a Cas9 nuclease and a reverse transcriptase (page 3, lines 1-4; figure 17; page 52, line 19-page 53, line 17; page 44, lines 14-20). Thus, Rubens anticipates each and every limitation of instant claim 5.
With regard to claim 6, which recites “the reverse transcriptase [of the fusion protein of claim 5] is MMLV reverse transcriptase or R2 reverse transcriptase,” Rubens further discloses that the reverse transcriptase of the system for modifying DNA taught therein comprises reverse transcriptase from the non-LTR retrotransposon R2 (page 50, lines 21-24). Thus, Rubens anticipates each and every limitation of instant claim 6.
With regard to claim 7, which recites “the reverse transcriptase [of the fusion protein of claim 5] comprises a polypeptide sequence having at least 90% identity to any one of SEQ ID NO[s]: 2-3,” SEQ ID NO: 1394 of Rubens (disclosed at Table 3) corresponds to an R2 element, which itself comprises a reverse transcriptase domain, as disclosed at page 50, lines 21-24. Furthermore, SEQ ID NO: 1394 of Rubens comprises instant SEQ ID NO: 3, as shown in the alignment of Appendix I. Thus, Rubens anticipates each and every limitation of instant claim 7.
With regard to claim 14, which recites “the fusion protein of claim 1 further compris[es] a DNA-binding or an RNA-binding domain,” Rubens further discloses that the system for modifying DNA taught therein and set forth above may also comprise an additional RNA-binding domain (page 45, line 7) or an additional DNA binding domain (page 45, lines 15-19). Thus, Rubens anticipates each and every limitation of instant claim 14.
With regard to claim 15, which recites “the DNA-binding domain [of the fusion protein of claim 14] is a zinc finger DNA-binding domain, a transcription factor, or an adeno-associated virus Rep protein,” Rubens further discloses that the additional DNA binding domain of the system for modifying DNA taught therein and set forth above may be a zinc finger DNA binding domain (page 45, line 21). Thus, Rubens anticipates each and every limitation of instant claim 15.
With regard to claim 16, which recites “the RNA-binding domain [of the fusion protein of claim 14] is MS2 coat protein (MCP2),” Rubens further discloses that the additional RNA binding domain of the system for modifying DNA taught therein and set forth above may be MS2 coat protein (page 45, lines 8-10). Thus, Rubens anticipates each and every limitation of instant claim 16.
With the regard to claim 22, which recites “the fusion protein of claim 1 further compris[es] a polypeptide linker between (i) and (ii),” Rubens further discloses that the components of the system for modifying DNA taught therein and set forth above may be joined by peptide linkers of multiple residues (page 534, lines 8-19). These peptide linkers of multiple residues read on the instantly claimed “polypeptide linker,” as supported by paragraph [00130] of the instant specification, which discloses that linkers for use in the instant invention comprise about 3 to about 100 amino acids in length. Thus, Ruben anticipates each and every limitation of instant claim 22.
With regard to claim 63, which recites “a polynucleotide encoding the fusion protein of claim 1,” Rubens further discloses a polynucleotide encoding the system for modifying DNA taught therein and set forth above at embodiment 164 (page 26, line 30). Thus, Rubens anticipates each and every limitation of instant claim 63.
With regard to claim 64, which recites “a vector comprising the polynucleotide encoding the fusion protein of claim 1,” Rubens further discloses a vector comprising a polynucleotide encoding the system for modifying DNA taught therein and set forth above at embodiment 165 (page 27, line 1; see also page 556, lines 3-4). Thus, Rubens anticipates each and every limitation of instant claim 64.
With regard to claim 65, which recites “a cell comprising the fusion protein of claim 1,” Rubens further discloses a cell comprising the system for modifying DNA taught therein and set forth above at embodiment 167 (page 27, line 5). Thus, Rubens anticipates each and every limitation of instant claim 65.
With regard to claim 66, which recites “a cell comprising the polynucleotide encoding the fusion protein of claim 1, or the vector of claim 64,” Ruben further discloses a cell comprising a polynucleotide encoding the system for modifying DNA taught therein and set forth above at embodiment 166 (page 27, line 3) as well as a cell comprising the vector comprising a polynucleotide encoding the system for modifying DNA taught therein and set forth above at embodiment 168 (page 27, line 7). Thus, Rubens anticipates each and every limitation of instant claim 66.
With regard to claim 83, which recites “a kit comprising the fusion protein of any one of claims 1-8, 11-17, or 21 to 23,” as set forth above, Rubens anticipates the fusion protein of instant claims 1, 2, 5-7, 16-16, and 22. Furthermore, the recited preamble of “a kit” does not generate or otherwise result in a structural difference of the product claimed therein, meaning the claim body recites a structurally complete invention, while the preamble only states a purpose or intended use for the invention and is thus not a claim limitation given patentable weight (see MPEP § 2111.02(II)). Accordingly, while Rubens does not explicitly disclose a kit comprising the claimed fusion protein, Rubens does disclose the claimed fusion protein, which is the only recited claim limitation with patentable weight at instant claim 83. Thus, Rubens anticipates each and every limitation of instant claim 83.
Claims 1-3, 8, 11, 63-66, and 83 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by US 2015/0232881 A1 (hereinafter Glucksmann).
With regard to claim 1, which recites “a fusion protein comprising: (i) a Cas nuclease and (ii) a reverse transcriptase, a DNA polymerase, a DNA ligase, or a combination thereof, wherein the Cas nuclease is capable of generating a double-stranded polynucleotide cleavage,” Glucksmann discloses methods and compositions useful in targeting a payload to or editing a target nucleic acid (abstract). The compositions disclosed in Glucksmann comprise a Cas9 molecule mediating a double stranded break (paragraphs [0168] and [0183]) linked/fused to a payload comprising a modulator, said modulator being a DNA ligase or a DNA polymerase (paragraphs [0171], [1337], and [1351]). Thus, Glucksmann discloses each and every limitation of instant claim 1.
With regard to claim 2, which recites “the Cas nuclease [of the fusion protein of claim 1] is Cas9, Cas12, or Cas14,” as set forth above, the compositions disclosed in Glucksmann comprise a Cas9 molecule mediating a double stranded break (paragraphs [0168] and [0183]). Thus, Glucksmann discloses each and every limitation of instant claim 2.
With regard to claim 3, which recites “the Cas nuclease [of the fusion protein of claim 2] comprises a polypeptide sequence having at least 90% identity to any one of SEQ ID NOS: 1, 29, or 30,” Glucksmann further discloses that SEQ ID NO: 2 taught therein corresponds to Cas9 derived from S. pyogenes (paragraph [0420]). As shown in the alignment of Appendix II, instant SEQ ID NO: 1 is 99.9% identical to SEQ ID NO: 2 of Glucksmann. Thus, Glucksmann discloses each and every limitation of instant claim 3.
With regard to claim 8, which recites “the fusion protein [of claim 1] comprises a Cas nuclease and a DNA polymerase,” as set forth above, the compositions disclosed in Glucksmann comprise a Cas9 molecule mediating a double stranded break (paragraphs [0168] and [0183]) linked/fused to a payload comprising a modulator, said modulator being a DNA ligase or a DNA polymerase (paragraphs [0171], [1337], and [1351]). Thus, Glucksmann discloses each and every limitation of instant claim 8.
With regard to claim 11, which recites “the fusion protein [of claim 1] comprises a Cas nuclease and a DNA ligase,” as set forth above, the compositions disclosed in Glucksmann comprise a Cas9 molecule mediating a double stranded break (paragraphs [0168] and [0183]) linked/fused to a payload comprising a modulator, said modulator being a DNA ligase or a DNA polymerase (paragraphs [0171], [1337], and [1351]). Thus, Glucksmann discloses each and every limitation of instant claim 11.
With regard to claim 63, which recites “a polynucleotide encoding the fusion protein of claim 1,” Glucksmann further discloses nucleic acids encoding the Cas9 molecules taught therein (paragraph [0242]). As set forth above, the Cas9 molecules disclosed in Glucksmann mediate double-stranded breaks and are linked/fused to a payload comprising a modulator, said modulator being a DNA ligase or a DNA polymerase (paragraphs [0168], [0171], [0183], [1337], and [1351]). Thus, Glucksmann anticipates each and every limitation of instant claim 63.
With regard to claim 64, which recites “a vector comprising the polynucleotide encoding the fusion protein of claim 1,” as set forth above, Glucksmann discloses nucleic acids encoding the Cas9 molecules set forth above and taught therein (paragraphs [0168], [0171], [0183], [0242], [1337], and [1351]). Glucksmann further discloses that the nucleic acids taught therein may be packaged into a vector, such as a viral AAV vector (paragraph [0070]). Thus, Glucksmann anticipates each and every limitation of instant claim 64.
With regard to claim 65, which recites “a cell comprising the fusion protein of claim 1,” Glucksmann further discloses that the payloads taught therein may be delivered to a cell by contacting said cell with the payloads fused to the Cas9 molecules taught therein and set forth above (paragraphs [0348]-[0367]). Thus, Glucksmann anticipates each and every limitation of instant claim 65.
With regard to claim 66, which recites “a cell comprising the polynucleotide encoding the fusion protein of claim 1, or the vector of claim 64,” as set forth above, Glucksmann discloses nucleic acids encoding the Cas9 molecules set forth above and taught therein (paragraphs [0168], [0171], [0183], [0242], [1337], and [1351]). Glucksmann further discloses that the nucleic acids taught therein may be packaged into a vector, such as a viral AAV vector (paragraph [0070]). Additionally, Glucksmann discloses that the payloads taught therein may be delivered to a cell by contacting said cell with a nucleic acid encoding a Cas9 molecule as taught therein (paragraphs [0348]-[0367]). Thus, Glucksmann anticipates each and every limitation of instant claim 66.
With regard to claim 83, which recites “a kit comprising the fusion protein of any one of claims 1-8, 11-17, or 21 to 23,” as set forth above, Glucksmann anticipates the fusion protein of instant claims 1-3, 8, and 11. Furthermore, the recited preamble of “a kit” does not generate or otherwise result in a structural difference of the product claimed therein, meaning the claim body recites a structurally complete invention, while the preamble only states a purpose or intended use for the invention and is thus not a claim limitation given patentable weight (see MPEP § 2111.02(II)). Accordingly, while Glucksmann does not explicitly disclose a kit comprising the claimed fusion protein, Glucksmann does disclose the claimed fusion protein, which is the only recited claim limitation with patentable weight at instant claim 83. Thus, Glucksmann anticipates each and every limitation of instant claim 83.
Claims 1, 2, 5, 6, 14, 19, 23, 63-66, and 83 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 2023/0049737 A1 (hereinafter Zhang; effectively filed on 12/30/2019).
With regard to claim 1, which recites “a fusion protein comprising: (i) a Cas nuclease and (ii) a reverse transcriptase, a DNA polymerase, a DNA ligase, or a combination thereof, wherein the Cas nuclease is capable of generating a double-stranded polynucleotide cleavage,” Zhang discloses systems and methods for targeted gene modification, targeted insertion, perturbation of gene transcripts, and nucleic acid editing, said systems comprising components of CRISPR systems and reverse transcriptases (abstract). These systems include a Cas nuclease capable of generating double strand breaks (i.e. Cas9) fused to a reverse transcriptase domain (Figure 6; paragraphs [0025] and [0040]). Thus, Zhang anticipates each and every limitation of instant claim 1.
With regard to claim 2, which recites “the Cas nuclease [of the fusion protein of claim 1] is Cas9, Cas12, or Cas14,” as set forth above, the systems for gene editing disclosed in Zhang include a Cas nuclease capable of generating double strand breaks (i.e. Cas9) fused to a reverse transcriptase domain (Figure 6; paragraphs [0025] and [0040]). Thus, Zhang anticipates each and every limitation of instant claim 2.
With regard to claim 5, which recites “the fusion protein of claim 1…comprises a Cas nuclease and a reverse transcriptase,” as set forth above, the systems for gene editing disclosed in Zhang include a Cas nuclease capable of generating double strand breaks (i.e. Cas9) fused to a reverse transcriptase domain (Figure 6; paragraphs [0025] and [0040]). Thus, Zhang anticipates each and every limitation of instant claim 5.
With regard to claim 6, which recites “the reverse transcriptase [of the fusion protein of claim 5] is MMLV reverse transcriptase or R2 reverse transcriptase,” Zhang further discloses that the reverse transcriptases of the systems taught therein may be derived from M-MLV reverse transcriptase (paragraph [0050]), as instantly claimed. Thus, Zhang anticipates each and every limitation of instant claim 6.
With regard to claim 14, which recites “the fusion protein of claim 1 further compris[es] a DNA-binding or an RNA-binding domain,” Zhang further discloses that the fusion proteins taught therein may further comprise ssDNA annealing proteins (paragraphs [0088] and [0089]), which read on the instantly claimed DNA-binding domain, as annealing reads on binding under broadest reasonable interpretation. Thus, Zhang anticipates each and every limitation of instant claim 14.
With regard to claim 19, which recites “the DNA-binding domain [of the fusion protein of claim 14 (see section Claim Rejections - 35 USC § 112(b))] is capable of binding single-stranded DNA (ssDNA),” as set forth above, Zhang further discloses that the fusion proteins taught therein may further comprise ssDNA annealing proteins (paragraphs [0088] and [0089]). Examples of such ssDNA annealing proteins are disclosed at paragraphs [0073]-[0076]. As set forth above, under broadest reasonable interpretation, annealing reads on binding. Thus, Zhang anticipates each and every limitation of instant claim 19.
With regard to claim 23, which recites “the fusion protein of claim 1 compris[es] a polypeptide sequence having at least 90% identity to any one of SEQ ID NOS: 18-26,” Zhang discloses SEQ ID NO: 1, which comprises instant SEQ ID NO: 18, as shown in the alignment of Appendix III. Zhang discloses that SEQ ID NO: 1 taught therein comprises a wild-type Cas9 fusion with a reverse transcriptase derived from M-MLV (paragraphs [0050] and [0051]). Thus, Zhang anticipates each and every limitation of instant claim 23.
With regard to claim 63, which recites “a polynucleotide encoding the fusion protein of claim 1,” Zhang further discloses that the systems taught therein may be packaged into a vector comprising a polynucleotide encoding said systems (paragraph [0215]). As set forth above, these systems include a Cas nuclease capable of generating double strand breaks (i.e. Cas9) fused to a reverse transcriptase domain (Figure 6; paragraphs [0025] and [0040]). Thus, Zhang anticipates each and every limitation of instant claim 63.
With regard to claim 64, which recites “a vector comprising the polynucleotide encoding the fusion protein of claim 1,” Zhang further discloses that the systems taught therein may be packaged into a vector comprising a polynucleotide encoding said systems (paragraph [0215]). As set forth above, these systems include a Cas nuclease capable of generating double strand breaks (i.e. Cas9) fused to a reverse transcriptase domain (Figure 6; paragraphs [0025] and [0040]). Thus, Zhang anticipates each and every limitation of instant claim 64.
With regard to claim 65, which recites “a cell comprising the fusion protein of claim 1,” Zhang further discloses that the expression vectors comprising a polynucleotide encoding the systems taught therein are capable of directing expression of said polynucleotide in cells comprising the same, thereby necessarily producing cells comprising the protein of the systems taught therein (paragraph [0231]). Thus, Zhang anticipates each and every limitation of instant claim 65.
With regard to claim 66, which recites “a cell comprising the polynucleotide encoding the fusion protein of claim 1, or the vector of claim 64,” as set forth above, Zhang further discloses that the systems taught therein may be packaged into a vector comprising a polynucleotide encoding said systems (paragraph [0215]) and that these vectors are capable of directing expression of said polynucleotide in cells comprising the same, thereby necessarily producing cells comprising the protein of the systems taught therein (paragraph [0231]). Thus, Zhang anticipates each and every limitation of instant claim 66.
With regard to claim 83, which recites “a kit comprising the fusion protein of any one of claims 1-8, 11-17, or 21 to 23,” as set forth above, Zhang anticipates the fusion protein of instant claims 1, 2, 5, 6, 14, and 23. Furthermore, the recited preamble of “a kit” does not generate or otherwise result in a structural difference of the product claimed therein, meaning the claim body recites a structurally complete invention, while the preamble only states a purpose or intended use for the invention and is thus not a claim limitation given patentable weight (see MPEP § 2111.02(II)). Accordingly, while Zhang does not explicitly disclose a kit comprising the claimed fusion protein, Zhang does disclose the claimed fusion protein, which is the only recited claim limitation with patentable weight at instant claim 83. Thus, Zhang anticipates each and every limitation of instant claim 83.
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.
Claims 12 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0232881 A1 (hereinafter Glucksmann) as applied to claim 11 above, and further in view of Su et al., 2019 (hereinafter Su) and UniProt Entry A0A023ZUP5_BPT4 (first entered 01/31/2018; hereinafter UniProt).
The disclosure of Glucksmann is described above and applied as before. However, this disclosure does not teach the T4 ligase and sequence thereof of instant claims 12 and 13.
With regard to claim 12, which recites “the DNA ligase [of the fusion protein of claim 11] is T4 DNA ligase,” as set forth above, the compositions disclosed in Glucksmann comprise a Cas9 molecule mediating a double stranded break (paragraphs [0168] and [0183]) linked/fused to a payload comprising a modulator, said modulator being a DNA ligase or a DNA polymerase (paragraphs [0171], [1337], and [1351]). However, Glucksmann does not specify that the ligase taught therein is T4 DNA ligase. This deficiency is cured by Su, which discloses that T4 DNA ligase alone is sufficient for repairing chromosomal double-stranded breaks induced by Cas9 in vivo with high efficiency (Section 3.2; Figure 2). Furthermore, Su discloses that T4 DNA ligase-mediated DNA ligation offers the possibility of controlling the size of introduced DNA deletions by regulating RecBCD activity in tandem (page 112, column 1, paragraphs 1-2), thereby suggesting that T4 DNA ligase is a single component non-homologous end joining system that has great potential in genome mutagenesis, genome reduction, and genome editing (abstract). Thus, Su discloses each and every additional limitation of instant claim 12. However, while Su discloses the utility of T4 DNA ligase in repairing (and controlling said repairing) Cas9-generated double-stranded breaks, Su does not disclose the specific T4 DNA ligase sequence recited at instant claim 13. This deficiency is cured by UniProt.
With regard to claim 13, which recites “the DNA ligase [of the fusion protein of claim 11] comprises a polypeptide sequence having at least 90% identity to SEQ ID NO: 7,” UniProt discloses that entry A0A023ZUP5_BPT4 is the wild-type DNA ligase derived from bacteriophage T4. As shown in the alignment of Appendix IV, UniProt entry A0A023ZUP5_BPT4 is 100% identical to instant SEQ ID NO: 7. Thus, UniProt discloses each and every additional limitation of instant claim 13.
Given that Glucksmann discloses a Cas9 molecule mediating a double stranded break that is linked/fused to a payload comprising a modulator, said modulator being a DNA ligase or a DNA polymerase (as set forth above), and that Su discloses the utility of T4 DNA ligase (such as the wild-type DNA ligase derived from bacteriophage T4 and set forth by UniProt) in repairing (and controlling said repairing) Cas9-generated double-stranded breaks, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to engineer the system disclosed in Glucksmann to specifically comprise a T4 DNA ligase (such as the wild-type DNA ligase derived from bacteriophage T4 and set forth by UniProt) as the payload fused to the Cas9 molecules taught therein to predictably control the repair of Cas9-generated double-stranded breaks introduced by the system. One would have been motivated to make such a modification in order to receive the expected benefit of controlling the repair of Cas9-generated double-stranded breaks introduced by the system.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/047124 A1 (hereinafter Rubens; of record) as applied to claim 14 above, and further in view of Dedow and Bailey-Serres, 2019 (hereinafter Dedow).
The disclosure of Rubens is described above and applied as before. However, this disclosure does not teach the RNA-binding domain comprising a KH domain of instant claim 17.
With regard to claim 17, which recites “the RNA-binding domain [of the fusion protein of claim 14] comprises a KH domain,” as set forth above, Rubens discloses that the system for modifying DNA taught therein and set forth above may also comprise an additional RNA-binding domain (page 45, line 7). While Rubens does not disclose that this RNA-binding domain comprises a KH domain, this deficiency is cured by Dedow. Dedow discloses that K-homology (KH) domains are highly conserved RNA-binding domains that determine the binding specificity of RNA interaction in eukaryotes (page 1927, column 2, paragraph 2). Thus, Dedow discloses each and every additional limitation of instant claim 17.
Given that Rubens discloses a system for modifying DNA comprising Cas9 fused to a reverse transcriptase and an additional RNA-binding domain, and that Dedow discloses that K-homology (KH) domains are highly conserved RNA-binding domains that determine the binding specificity of RNA interaction in eukaryotes, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the system disclosed in Rubens such that the additional RNA-binding domain taught therein comprises a KH domain to predictably target/bind a specified RNA sequence with said system. One would have been motivated to make such a modification in order to receive the expected benefit of targeting/binding a specified RNA sequence with a system for modifying DNA.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/047124 A1 (hereinafter Rubens; of record) as applied to claim 14 above (see section Claim Rejections - 35 USC § 112(b)), and further in view of Lin et al., 2017 (hereinafter Lin).
The disclosure of Rubens is described above and applied as before. However, this disclosure does not teach that the DNA-binding domain disclosed therein is capable of binding ssDNA, as in instant claim 19.
With regard to claim 19, which recites “the DNA-binding domain [of the fusion protein of claim 14 (see section Claim Rejections - 35 USC § 112(b))] is capable of binding single-stranded DNA (ssDNA),” as set forth above, Rubens discloses that the system for modifying DNA taught therein and set forth above may also comprise an additional DNA-binding domain (page 45, lines 15-19). While Rubens does not disclose that this DNA-binding domain may be capable of binding ssDNA, this deficiency is cured by Lin. Lin discloses that fusion of Cas9 to the ssDNA-binding protein RecA (which is also an ATP-dependent recombinase involved in bacterial homologous recombination) enhances gene knockout and deletion in mammalian cells (Abstract; Section 3.1). Thus, Lin discloses each and every additional limitation of instant claim 19.
Given that Rubens discloses a system for modifying DNA comprising Cas9 fused to a reverse transcriptase and an additional RNA-binding domain, and that Lin discloses that fusion of Cas9 to the ssDNA-binding protein RecA enhances gene knockout and deletion in mammalian cells, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the system disclosed in Rubens such that the additional DNA-binding domain taught therein is ssDNA-binding protein RecA to predictably enhance gene knockout and deletion in mammalian cells treated with the system taught therein. One would have been motivated to make such a modification in order to receive the expected benefit of enhancing gene knockout and deletion in mammalian cells.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/047124 A1 (hereinafter Rubens; of record) as applied to claim 14 above (see section Claim Rejections - 35 USC § 112(b)), and further in view of US 2016/0010076 A1 (hereinafter Joung).
The disclosure of Rubens is described above and applied as before. However, this disclosure does not teach the RNA-binding domain sequence of instant claim 21.
With regard to claim 21, which recites “the DNA-binding or the RNA-binding domain [of the fusion protein of claim 14 (see section Claim Rejections - 35 USC § 112(b))] comprises a polypeptide sequence having at least 90% identity to any one of SEQ ID NOS: 8-11,” as set forth above, Rubens discloses that the system for modifying DNA taught therein and set forth above may also comprise an additional RNA-binding domain (page 45, line 7) or an additional DNA binding domain (page 45, lines 15-19). Furthermore, as set forth above, Rubens discloses that the additional RNA-binding domain taught therein may be MS2 coat protein (page 45, lines 8-10). However, Rubens does not disclose that the additional RNA-binding domain of an MS2 coat protein taught therein comprises a polypeptide sequence having at least 90% identity to any one of SEQ ID NOs: 8-11. This deficiency is cured by Joung, which discloses that SEQ ID NO: 89 taught therein is MS2 coat protein (paragraph [0105]), which is a fixed RNA binding sequence (paragraph [0049]). As shown in the alignment of Appendix V, SEQ ID NO: 89 of Joung comprises instant SEQ ID NO: 8. Thus, Joung discloses each and every additional limitation of instant claim 21.
Given that Rubens discloses a system for modifying DNA comprising Cas9 fused to a reverse transcriptase and an additional RNA-binding domain such as MS2 coat protein, and that Joung discloses that SEQ ID NO: 89 taught therein is MS2 coat protein, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to utilize the MS2 coat protein sequence disclosed in Joung in the system disclosed in Rubens to predictably bind targeted RNA with the system taught therein. One would have been motivated to make such a modification in order to receive the expected benefit of binding targeted RNA with the system taught therein.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 14, 63, 64, and 66 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 108 and 119-121 of copending Application No. 18/554,014 (reference application; corresponds to US 2024/0182890 A1). Although the claims at issue are not identical, they are not patentably distinct from each other, as set forth below.
Copending claim 108 recites “a fusion protein comprising (i) a Cas nuclease…; and (ii)…a DNA ligase…a DNA binding protein…or combination thereof,” which reads on the recitation of instant claims 1 and 14. Instant claim 1 recites “a fusion protein comprising: (i) a Cas nuclease and (ii)…a DNA ligase…wherein the Cas nuclease is capable of generating a double-stranded polynucleotide cleavage,” while instant claim 14 further recites that the claimed fusion protein also comprises “a DNA-binding…domain.” Although copending claim 108 does not explicitly recite that the Cas nuclease claimed therein is capable of generating a double-stranded polynucleotide cleavage, as instantly claimed, the disclosure of copending application ‘014 teaches that Cas nucleases generate double-stranded cleavage in target DNA (paragraph [0032]). Furthermore, the DNA binding protein of copending application ‘014 reads on the instantly claimed DNA binding domain, as DNA binding proteins must comprise at least one DNA binding domain in order to function properly, as is known to those of ordinary skill in the art. Thus, copending claim 108 is not patentably distinct from instant claims 1 and 14.
Copending claims 119-121 respectively recite “a polynucleotide encoding the fusion protein” set forth above, “a vector comprising the polynucleotide [encoding the fusion protein set forth above],” and “a cell comprising the fusion protein [set forth above], the polynucleotide [encoding the fusion protein set forth above], the vector [comprising the polynucleotide encoding the fusion protein set forth above], or a combination thereof.” In comparison, instant claims 63, 64, and 66 respectively recite “a polynucleotide encoding the fusion protein of [instant] claim 1,” “a vector comprising the polynucleotide encoding the fusion protein of [instant] claim 1,” and “a cell comprising the polynucleotide encoding the fusion protein of [instant] claim 1, or the vector [comprising the polynucleotide encoding the fusion protein of instant claim 1].” Given that the fusion protein of copending claim 108 reads on the fusion protein of instant claim 1, the additional recitations of a polynucleotide encoding said fusion protein, as well as a vector comprising said polynucleotide and a cell comprising the same in both claim sets also read on each other. Thus, copending claims 119-121 are not patentably distinct from instant claims 63, 64, and 66.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Claims 3, 7, 21, 23, and 83 are objected to.
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/SARAH E ALLEN/ Examiner, Art Unit 1637
/J. E. ANGELL/ Primary Examiner, Art Unit 1637