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 .
Applicant’s response of 06/26/2026 has been received and entered into the application file.
Claims 1, 7, 8, 11, 14, 19, 21, 23, 64-66, and 83 were amended in the claim set filed 06/26/2026.
Claims 2, 3, 12, and 15-17 were canceled in the claim set filed 06/26/2026.
Claims 1, 4-8, 11, 13, 14, 19, 21-24, 43, 63-66, 68, and 83 are pending, of which claims 24, 43, and 68 were previously withdrawn.
Accordingly, claims 1, 4-8, 11, 13, 14, 19, 21-23, 63-66, and 83 are pending and under consideration.
The Examiner notes that instant claim 4 was not addressed in the prior non-final rejection dated 02/06/2026. Claim 4 is addressed herein. Accordingly, this action is made non-final.
Election/Restrictions
Applicant's previous 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 requirement was deemed proper and made FINAL in the non-final rejection dated 02/06/2026.
Claims 24, 43, and 68 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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, 4-8, 11, 13, 14, 19, 21-23, 63-67, 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 in the response filed 11/25/2025. 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.
Status of Prior Objections/Rejections
RE: Drawings
►The drawings were previously objected to because Figure 16 was 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.
The replacement drawings received 06/26/202, which removed Figure 16, have rendered the objection of record moot.
RE: Nucleotide and/or Amino Acid Sequence Disclosures
►The Examiner previously noted that Figures 13, 26A (now Figure 25A), and 26B (now Figure 25B) included sequences without proper sequence identifiers.
The replacement drawings received 06/26/2026 have obviated most, but not all, of the objections of record. Those objections not repeated below are hereby withdrawn.
RE: Claim Objections
►Claims 3, 7, 21, 23, and 83 were previously objected to for various informalities.
The cancellation of claim 3 renders the objection thereof moot.
The amendments to instant claims 7, 21, 23, and 83 have obviated the basis of the objection of record. The objections of record are hereby withdrawn. However, new grounds of objection necessitated by amendment are set forth below.
RE: Claim Rejections - 35 USC § 101
►Claims 65 and 66 were previously 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.
Applicant has amended the instant claims to recite “a recombinant host cell” (bolded emphasis added). Applicant asserts that these amendments render the rejection moot.
In response, the amendments do not overcome the objection of record. As set forth in the non-final rejection dated 02/06/2026, it would be remedial to amend the instant claims to recite “an isolated cell” (emphasis added) to avoid the claim embracing a human organism. The recitation of “recombinant” does not require the cell to be isolated and therefore still embraces a human organism having the cell. The instant specification sets forth that the term “recombinant” refers to host cells or organisms that express exogenous nucleic acid molecules or fragments and further that “host cell[s]” refer to cells into which a recombinant expression vector has been introduced (paragraphs [0078] and [0079]). Furthermore, the instant specification explicitly envisions human cells comprising the instant invention (paragraphs [00162]-[00165]), which under broadest reasonable interpretation encompasses human cells within a human body. Accordingly, as set forth in greater detail below, the rejection of record is hereby maintained.
RE: Claim Rejections - 35 USC § 112(b)
►Claims 19, 21, 64, and 66 were previously 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.
The amendments to the instant claims have obviated the basis of the rejection of record. However, the amendments to the instant claim set have necessitated new grounds of rejection, which are set forth below. Accordingly, while the rejection of record is hereby withdrawn, new grounds of rejection necessitated by amendment are set forth below.
RE: Claim Rejections - 35 USC § 102
►Claims 1, 2, 5-7, 14-16, 22, 63-66, and 83 were previously 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).
The cancellation of claims 15 and 16 render the rejection thereof moot.
Applicant has traversed the rejection of record, asserting that Rubens does not disclose each and every limitation of claim 1 as arranged in the claim. Applicant particularly asserts that the disclosure of Rubens is overall drawn to a Cas9 nickase and not a double-strand-cleaving nuclease.
In response, this is found persuasive. The rejection of record is hereby withdrawn. However, new grounds of rejection necessitated by amendment are set forth below.
►Claims 1-3, 8, 11, 63-66, and 83 were previously 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).
The cancellation of claims 2 and 3 renders the rejection thereof moot.
Applicant has traversed the rejection of record, asserting that Glucksmann teaches a Cas9 molecule “linked” to a payload such as a DNA ligase or DNA polymerase but fails to teach covalent fusion to the Cas nuclease. Applicant asserts that the Examiner’s interpretation of “linked/fused” is overbroad and improperly conflates distinct embodiments.
In response, this is not found persuasive. While the instant claims require “a fusion protein,” as recited at amended instant claim 1, linkers are known to be an indispensable component of recombinant fusion proteins and in the construction of stable, bioactive fusion proteins as taught in Chen et al., 2013 (abstract). Furthermore, per Applicant’s own claim set, the fusion proteins claimed therein may comprise linkers between the instantly claimed components (claim 22; instant specification: paragraphs [0011] and [00130]). Accordingly, the interpretation of linkage of two molecules corresponding to fusion of two molecules is considered to be proper, as both approaches result in the fusion of said two molecules, thereby generating stable, bioactive fusion molecules, as taught in Chen et al., 2013 (abstract).
Therefore, it is considered that the disclosure of Glucksmann, which teaches a Cas9 molecule linked to a payload such as a DNA ligase or DNA polymerase (paragraphs [0170] and [0171]), reads on the instantly claimed subject matter, as set forth in greater detail below. Even if one does not accept this argument, Glucksmann discloses that the payload may be a fusion partner with the Cas9 molecule (paragraphs [0366], [1299], and [1321]). However, the amendments to instant claim 1 introduce a new combination of limitations not previously considered in a single claim. Therefore, while the rejection of record is hereby withdrawn, new grounds of rejection under necessitated by amendment are set forth below.
►Claims 1, 2, 5, 6, 14, 19, 23, 63-66, and 83 were previously 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).
The cancellation of claim 2 renders the rejection thereof moot.
Applicant has traversed the rejection of record, asserting that Zhang does not disclose each and every limitation of claim 1 as arranged in the claim. Applicant particularly asserts that the disclosure of Zhang is directed to prime editing systems, which fundamentally rely on a Cas9 nickase and not a double-strand-cleaving nuclease.
In response, while the Examiner acknowledges that the disclosure of Zhang discloses prime editing systems, Zhang nonetheless also discloses specific embodiments wherein a wild-type Cas polypeptide such as Cas9 is fused to a reverse transcriptase (i.e. at Figure 6, as set forth in the non-final rejection dated 02/06/2026; see also paragraph [0007]).
Therefore, it is considered that the disclosure of Zhang, which explicitly discloses a fusion protein comprising a wild-type Cas9 and a reverse transcriptase, reads on the instantly claimed subject matter, as set forth in greater detail below. Therefore, while the rejection of record is hereby withdrawn, new grounds of rejection under 35 USC § 103 necessitated by amendment are set forth below.
RE: Claim Rejections - 35 USC § 103
►Claims 12 and 13 were previously 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 cancellation of claim 12 renders the rejection thereof moot.
Applicant has traversed the rejection of record, asserting that Glucksmann does not teach or suggest a defined fusion protein in which a Cas nuclease is structurally integrated with a DNA polymerase, ligase, or reverse transcriptase to perform coordinated enzymatic steps and further that the cited references cannot remedy the deficiencies of Glucksmann.
In response, this is not found persuasive. As set forth above, Applicant’s arguments regarding Glucksmann are not found persuasive, as Glucksmann discloses a payload coupled to a Cas9 molecule, wherein said payload is a ligase or polymerase (paragraphs [0170] and [0171]). The cited references are applied to supply the identity and sequence of the instantly claimed ligase that is also disclosed in Glusckmann.
Therefore, it is considered that the cited references cure the deficiencies of Glucksmann, as set forth below. Therefore, the rejection of record is hereby maintained.
►Claim 17 was previously 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).
►Claim 19 was previously 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).
►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 cancellation of claim 17 renders the rejection thereof moot.
Applicant has traversed the rejection of record, asserting that Rubens does not disclose or suggest the instantly claimed system comprising any Cas-based DSB-generating fusion protein configured to generate and insert double-stranded DNA sequences via NHEJ. Applicant further asserts that the cited art does not cure this deficiency
In response, this is found persuasive in view of Applicant’s arguments regarding Rubens. The rejection of record is hereby withdrawn. However, new grounds of rejection necessitated by amendment are set forth below.
►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.
Applicant has traversed the rejection of record, asserting that the instant application has an earlier filing date with recognized priority and further that the present application is believed to be otherwise in condition for allowance.
In response, this is not found persuasive. The nonstatutory double patenting rejection set forth in the non-final rejection dated 02/06/2026 is not the only remaining rejection. Therefore, the instant application is not in condition for allowance, and the non-statutory double patenting rejection of record is hereby maintained.
New/Maintained Grounds of Objection/Rejection
Claim Objections
Claim 14 is objected to because of the following informalities:
Claim 14 has been amended to recite “the fusion protein of claim 1, further comprising a DNA-binding domain selected from a zinc finger DNA-binding domain, a transcription factor, or an adeno-associated virus Rep protein or an RNA-binding domain comprises a KH domain or is MS2 coat protein” (bolded emphasis added), which does not comport with standard grammatical and/or linguistic conventions and is not internally consistent. It would be remedial to amend the instant claim to comport with standard grammatical and/or linguistic conventions and to be internally consistent, for example by reciting “the fusion protein of claim 1, further comprising a DNA-binding domain selected from a zinc finger DNA-binding domain, a transcription factor, or an adeno-associated virus Rep protein or an RNA-binding domain selected from a KH domain or an MS2 coat protein” (bolded emphasis added). This is merely an example set forth by the Examiner and is not intended to be limiting.
Appropriate correction is required.
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 Figure 25A which includes templated insertion sequences that are part of SEQ ID NO: 51 but nonetheless are presented alone and not properly identified. 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.
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825. This application contains a “Sequence Listing” as a PDF file (37 CFR 1.821(c)(2)) or as physical sheets of paper (37 CFR 1.821(c)(3)). A copy of the "Sequence Listing" in computer readable form (CRF) has been submitted; however, the content of the CRF does not comply with one or more of the requirements of 37 CFR 1.822 through 1.824, as indicated in the "Error Report" that indicates the "Sequence Listing" could not be accepted. Refer to attachment or document "Computer Readable Form (CRF) for Sequence Listing – Defective" dated 07/01/2026.
Required response – Applicant must provide:
A replacement "Sequence Listing" part of the disclosure, as described above in item 1); together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the replacement "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation-by-reference paragraph, 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 and
An amendment to the specification to remove the “Sequence Listing previously submitted as a PDF file (37 CFR 1.821(c)(2)) or as physical sheets of paper (37 CFR 1.821(c)(3))
If the replacement "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, Applicant must also provide:
A CRF in accordance with 1.821(e)(1) or 1.821(e)(2) as required by 37 CFR 1.825(b)(6)(ii); and
Statement according to item 2) a) or b) above.
Claim Interpretation
With regard to claim 19 (which directly depends from instant claim 14, which itself directly depends from instant claim 1), which recites “the DNA-binding domain [of the fusion protein of claim 14] is capable of binding single-stranded DNA (ssDNA),” instant claim 14 requires that the fusion protein of claim 1 further comprises either a DNA-binding domain or an RNA-binding domain. Instant claim 19 recites further limitations to the DNA-binding domain of instant claim 14 but does not require that the fusion protein of claim 1 further comprises a DNA-binding domain. Therefore, any fusion protein comprising an RNA-binding domain and satisfying all other limitations of independent claim 1 and dependent claim 14 must also read on the fusion protein of dependent claim 19, as the DNA-binding domain is not required by the instant claim language.
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 recombinant host cell comprising the fusion protein of claim 1,” and “a recombinant host 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. The recitation of “recombinant” does not require the cell to be isolated and therefore still embraces a human organism having the cell. The instant specification sets forth that the term “recombinant” refers to host cells or organisms that express exogenous nucleic acid molecules or fragments and further that “host cell[s]” refer to cells into which a recombinant expression vector has been introduced (paragraphs [0078] and [0079]). Additionally, the instant specification explicitly envisions human cells comprising the instant invention (paragraphs [00162]-[00165]), which under broadest reasonable interpretation encompasses human cells within a human body. This interpretation is supported by the disclosure of vectors encoding the fusion protein being administered to cells in the context of gene therapy, which results in the expressed fusion protein in the cells in vivo (paragraphs [00157]-[00159]). Under broadest reasonable interpretation, this gene therapy methodology encompasses a human cell within a human body, wherein said human cell expresses a fusion protein of the instant application. It would be remedial to amend the instant claims to recite “an isolated recombinant host cell…” (bolded emphasis added), as previously set forth.
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 4 and 83 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.
Instant claim 4 recites “the fusion protein of claim 2, wherein the Cas9 is a Type IIB Cas9.” However, instant claim 2 was cancelled in the amended claim set filed 06/26/2026. Therefore, amended instant claim 4 depends from a cancelled claim and is therefore indefinite. It would be remedial to amend the instant claim to properly depend from a claim that is not cancelled. For purposes of examination and in the interest of compact prosecution, instant claim 4 has been interpreted to depend from instant claim 1.
Amended claim 83 recites “a kit comprising the fusion protein of any one of claims 1-8, 11-17, or 21-23.” However, claims 15-17 were cancelled in the amended claim set filed 06/26/2026. Therefore, amended claim 83 depends, in part, from cancelled claims and is indefinite. It would be remedial to amend the instant claim to properly depend from claims that are not cancelled.
Claim Rejections - 35 USC § 112(d)
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 4, 5-7, 8, 11, 13, and 19 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 4 recites “the Cas9 [of the fusion protein of claim 2] is a Type IIB Cas9.” As set forth above (see section Claim Rejections - 35 USC § 112(b)), claim 4 has been interpreted to depend from claim 1, which requires a Cas nuclease defined by “having at least 90% identity to any one of SEQ ID NOs: 1, 29, or 30.” The instant specification discloses that instant SEQ ID NOs: 29 and 30 are drawn to Cas12 and Cas14 proteins, respectively (see paragraphs [00108] and [00110]). While instant SEQ ID NO: 1 is drawn to a Cas9 protein (see paragraph [00106] of the instant specification), Glucksmann teaches that SEQ ID NO: 2 therein (which is 99% identical to instant SEQ ID NO: 1 as shown in the alignment of the Appendix) corresponds to a Cas9 protein derived from S. pyogenes (paragraph [0420]). As taught in Chylinski et al., 2014, Cas9 proteins derived from S. pyogenes are type II-A Cas9 proteins (Figure 4), which are distinct from type II-B Cas9 proteins. Thus, it cannot be considered that dependent claim 4 includes all the limitations of independent claim 1, as independent claim 1 is drawn to a type II-A Cas9, while dependent claim 4 requires a type II-B Cas9.
Claim 5 (from which claims 6 and 7 depend) recites “the fusion protein of claim 1, wherein the fusion protein comprises a Cas nuclease and a reverse transcriptase” (bolded and underlined emphasis added). The recitation of a Cas nuclease broadens the claimed Cas nuclease relative to the independent claim. Neither instant claims 6 nor 7 resolve this broadening of scope. It would be remedial to amend instant claim 5 to recite, for example, “the fusion protein of claim 1, wherein the fusion protein comprises a reverse transcriptase.”
Claim 8 recites “the fusion protein of claim 1, wherein the fusion protein comprises a Cas nuclease and a DNA polymerase…” (bolded and underlined emphasis added). The recitation of a Cas nuclease broadens the claimed Cas nuclease relative to the independent claim. It would be remedial to amend instant claim 8 to recite, for example, “the fusion protein of claim 1, wherein the fusion protein comprises a DNA polymerase…”.
Claim 11 (from which claim 13 depends) recites “the fusion protein of claim 1, wherein the fusion protein comprises a Cas nuclease and a DNA ligase…” (bolded and underlined emphasis added). The recitation of a Cas nuclease broadens the claimed Cas nuclease relative to the independent claim. Instant claim 13 does not resolve this broadening of scope. It would be remedial to amend instant claim 11 to recite, for example, “the fusion protein of claim 1, wherein the fusion protein comprises a DNA ligase…”.
Claim 19 depends from claim 14 and recites “the DNA-binding domain is capable of binding single-stranded DNA (ssDNA).” In comparison, claim 14 recites a number of possible DNA-binding domain species, wherein said species comprise “a zinc finger DNA-binding domain, a transcription factor, or an adeno-associated virus Rep protein.” As is known to those of ordinary skill in the art, these are all DNA binding domains capable of binding dsDNA. While the adeno-associated virus Rep protein is capable of binding both dsDNA and ssDNA, the other recited species canonically bind dsDNA. Therefore, the recitation of claim 19 that “the DNA-binding domain is capable of binding single-stranded DNA (ssDNA)” is considered to broaden the DNA binding domains recited at instant claim 14. It would be remedial to amend instant claims 14 and 19 such that instant claim 19 further limits instant claim 14, for example by reciting both dsDNA and ssDNA binding domains at instant claim 14, while limiting the DNA binding domain to an ssDNA binding domain at instant claim 19.
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.
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, 8, 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 US 2015/0232881 A1 (hereinafter Glucksmann; of record).
With regard to amended instant 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 Cas9, Cas12, or Cas14 and comprises a polypeptide sequence having at least 90% identity to any one of SEQ ID NOs: 1, 29, or 30 and is capable of generating a double-stranded polynucleotide cleavage,” as previously set forth, Glucksmann discloses methods and compositions useful in targeting a payload to or editing a target nucleic acid (abstract). Specifically, Glucksmann discloses coupling of a payload to a Cas9 molecule capable of mediating a double stranded break (paragraphs [0170], [0171], and [0183]). Said payload is disclosed to comprise a ligase or a polymerase at paragraph [0170] (i.e. a DNA polymerase mu (paragraphs [1351], [1355], and [1362]; Table VI-3). Finally, Glucksmann teaches SEQ ID NO: 2 (a Cas9 protein derived from S. pyogenes per paragraph [0420]), which is 99% identical to instant SEQ ID NO: 1, as shown in the Appendix.
With regard to amended instant claim 8, which recites “the fusion protein [of claim 1] comprises a Cas nuclease and a DNA polymerase, wherein the DNA polymerase is phi29 DNA polymerase, T4 DNA polymerase, DNA polymerase mu, DNA polymerase delta, or DNA polymerase epsilon,” as set forth above, Glucksmann anticipates the fusion protein of claim 1, wherein Cas9 (capable of generating a double-stranded polynucleotide cleavage) is fused to a polymerase. Glucksmann specifically discloses that such a polymerase may be a DNA polymerase mu or DNA polymerase epsilon at paragraphs [1351], [1355], [1362], and Table VI-3 (see particularly page 69).
With regard to instant claim 22, which recites “the fusion protein of claim 1, further comprising a polypeptide linker between (i) and (ii),” Glucksmann further discloses that the components of the fusion proteins taught therein may be connected via a linker such as a linker comprised of an amino acid chain (paragraphs [0171] and [1663]). The “amino acid chain” linker of Glucksmann is considered to read on the instantly claimed polypeptide linker, as the instant specification defines “polypeptide” as “a polymeric form of amino acids of any length” at paragraph [0080].
With regard to instant claim 63, which recites “a polynucleotide encoding the fusion protein of claim 1,” Glucksmann further discloses a nucleic acid encoding a Cas9 molecule described therein (paragraph [0242]). As set forth above, Glucksmann anticipates the fusion protein of claim 1, which comprises a Cas9 molecule fused to a DNA polymerase or ligase.
With regard to amended instant claim 64, which recites “a vector comprising a polynucleotide encoding the fusion protein of claim 1,” Glucksmann further discloses that DNA encoding Cas9 molecules taught therein may be delivered via a viral vector (paragraphs [1229], [1230], [1232], and [1233]).
With regard to amended instant claims 65 and 66, which respectively recites “a recombinant host cell comprising the fusion protein of claim 1” or “…a polynucleotide encoding the fusion protein of claim 1, or the vector of claim 64,” as set forth above, Glucksmann discloses delivery of DNA encoding Cas9 molecules taught therein to cells via viral vectors (paragraphs [0242], [1229], [1230], [1232], and [1233]), which reads on the subject matter of amended instant claim 66. Furthermore, as is known to those of ordinary skill in the art, delivery of a nucleic acid encoding a product must necessarily result in expression of said product, which is a protein, thereby resulting in the claimed recombinant host cell of amended instant claim 65.
With regard to amended instant claim 83, which recites “a kit comprising the fusion protein of any one of claims 1-8, 11-17, or 21-23,” as set forth above, Glucksmann anticipates the fusion protein of claim 1. 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, 5-7, 14, 19, 22, 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; of record; effectively filed 12/30/2019).
With regard to amended instant 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 Cas9, Cas12, or Cas14 and comprises a polypeptide sequence having at least 90% identity to any one of SEQ ID NOs: 1, 29, or 30 and is capable of generating a double-stranded polynucleotide cleavage,” as previously set forth, Zhang discloses systems and methods for targeted gene modification and targeted insertion (abstract), said compositions comprising a wild-type Cas polypeptide connected to a reverse transcriptase polypeptide (paragraph [0007]). An exemplary fusion polypeptide is disclosed to be Cas9-M-MLV_RT (wildtype Cas9) corresponding to SEQ ID NO: 1 (paragraph [0051]). As shown in the alignment in the Appendix, SEQ ID NO: 1 of Zhang comprises 99% identity to instant SEQ ID NO: 1.
With regard to instant claim 5, which recites “the fusion protein [of claim 1] comprises a Cas nuclease and a reverse transcriptase,” as set forth above, Zhang discloses systems and methods for targeted gene modification and targeted insertion (abstract), said compositions comprising a wild-type Cas polypeptide connected to a reverse transcriptase polypeptide (paragraph [0007]).
With regard to instant claim 6, which recites “the reverse transcriptase [of the fusion protein of claim 5] is MMLV reverse transcriptase or R2 reverse transcriptase,” as set forth above, an exemplary fusion polypeptide of Zhang is disclosed to be Cas9-M-MLV_RT (wildtype Cas9) corresponding to SEQ ID NO: 1 (paragraph [0051]), which comprises an M-MLV reverse transcriptase per paragraph [0050].
With regard to amended instant claim 7, which recites “the reverse transcriptase [of the fusion protein of claim 5] comprises a polypeptide sequence having at least 90% identity to SEQ ID NO: 2 or SEQ ID NO: 3,” as set forth above, an exemplary fusion polypeptide of Zhang is disclosed to be Cas9-M-MLV_RT (wildtype Cas9) corresponding to SEQ ID NO: 1 (paragraph [0051]), which comprises the entirety of instant SEQ ID NO: 2 (see Appendix).
With regard to amended instant claim 14, which recites “the fusion protein of claim 1, further comprising a DNA_binding domain selected from a zinc finger DNA-binding domain, a transcription factor, or an adeno-associated virus Rep protein or an RNA-binding domain compris[ing] a KH domain or…MS2 coat protein (MCP2),” Zhang further discloses that the compositions taught therein further comprise an aptamer sequence capable of tethering an adaptor protein to the CRISPR complex taught therein, specifically wherein the aptamer sequence is an MS2 loop that binds to an MS2 bacteriophage coat protein (paragraphs [0048] and [0049]), thereby tethering said MS2 bacteriophage coat protein to the CRISPR complex taught therein.
With regard to amended instant claim 19, which recites “the DNA-binding domain [of the fusion protein of claim 14] is capable of binding single-stranded DNA (ssDNA),” as set forth above (see section Claim Interpretation), any fusion protein comprising an RNA-binding domain and satisfying all other limitations of independent claim 1 and dependent claim 14 must also read on the fusion protein of dependent claim 19, as the DNA-binding domain is not required by the instant claim language. As set forth above, Zhang anticipates the fusion protein of instant claim 14. Accordingly, it is considered that Zhang also anticipates instant claim 19.
With regard to claim 22, which recites “the fusion protein of claim 1, further comprising a polypeptide linker between (i) and (ii),” Zhang further discloses that the composition components taught therein may be connected via a linker such as a peptide linker (paragraphs [0120] and [0121]).
With regard to amended instant claim 23, which recites “the fusion protein of claim 1, comprising a polypeptide sequence having at least 90% identity to any one of SEQ ID NOs: 18-26,” as set forth above, Zhang discloses an exemplary fusion polypeptide, which is Cas9-M-MLV_RT (wildtype Cas9) corresponding to SEQ ID NO: 1 (paragraph [0051]). As shown in the alignment in the Appendix, SEQ ID NO: 1 of Zhang comprises instant SEQ ID NO: 18.
With regard to instant claim 63, which recites “a polynucleotide encoding the fusion protein of claim 1,” Zhang further discloses nucleic acids encoding the Cas and reverse transcriptase taught therein, wherein said nucleic acids are packaged into expression vectors introduced into host cells to produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described therein (paragraphs [0225] and [0226]).
With regard to amended instant claim 64, which recites “a vector comprising a polynucleotide encoding the fusion protein of claim 1,” Zhang further discloses nucleic acids encoding the Cas and reverse transcriptase taught therein, wherein said nucleic acids are packaged into expression vectors introduced into host cells to produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described therein (paragraphs [0225] and [0226]).
With regard to amended instant claims 65 and 66, which respectively recites “a recombinant host cell comprising the fusion protein of claim 1” or “…a polynucleotide encoding the fusion protein of claim 1, or the vector of claim 64,” as set forth above, Zhang discloses nucleic acids encoding the Cas and reverse transcriptase taught therein, wherein said nucleic acids are packaged into expression vectors introduced into host cells to produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described therein (paragraphs [0225] and [0226]).
With regard to amended instant claim 83, which recites “a kit comprising the fusion protein of any one of claims 1-8, 11-17, or 21-23,” as set forth above, Zhang anticipates the fusion protein of claim 1. 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, Zhang discloses 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0232881 A1 (hereinafter Glucksmann; of record) as applied to claim 1 above, and further in view of Acharya et al., 2019 (hereinafter Acharya).
The disclosure of Glucksmann is described above and applied as before (see section Claim Rejections - 35 USC § 102). However, this disclosure does not teach the type IIB Cas9 of instant claim 4.
With regard to instant claim 4, which recites “the Cas9 [of the fusion protein of claim 1 (see section Claim Rejections - 35 USC § 112(b))] is a Type IIB Cas9,” as set forth above, Glucksmann discloses Cas9 fusions anticipating the fusion protein of instant claim 1. However, Glucksmann does not specifically teach a Type IIB Cas9. This deficiency is cured by Acharya.
Acharya discloses that FnCas9 is a type II-B Cas system that has evolved separately from the IIA- and II-C systems also known in the art (page 20966, column 2, paragraph 3). Acharya further discloses that the FnCas9 species taught therein shows a very high specificity of binding to its intended targets and negligible binding to off-target loci (abstract; Figures 4 and 5).
Given that Glucksmann discloses Cas9 fusions anticipating the fusion protein of instant claim 1, and that Acharya discloses that FnCas9 is a type II-B Cas9 displaying higher specificity of binding and negligible off-target binding, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to substitute the Cas9 of Glucksmann with the II-B Cas9 taught in Acharya to predictably generate a fusion protein capable of targeting specified loci with higher specificity than other Cas9 species. One would have been motivated to make such a modification in order to receive the expected benefit of generating a fusion protein capable of targeting specified loci with higher specificity than other Cas9 species.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over US 2023/0049737 A1 (hereinafter Zhang; of record; effectively filed 12/30/2019) as applied to claim 1 above, and further in view of Acharya et al., 2019 (hereinafter Acharya).
The disclosure of Zhang is described above and applied as before (see section Claim Rejections - 35 USC § 102). However, this disclosure does not teach the type IIB Cas9 of instant claim 4.
With regard to instant claim 4, which recites “the Cas9 [of the fusion protein of claim 1 (see section Claim Rejections - 35 USC § 112(b))] is a Type IIB Cas9,” as set forth above, Zhang discloses Cas9 fusions anticipating the fusion protein of instant claim 1. However, Zhang does not specifically teach a Type IIB Cas9. This deficiency is cured by Acharya.
Acharya discloses that FnCas9 is a type II-B Cas system that has evolved separately from the IIA- and II-C systems also known in the art (page 20966, column 2, paragraph 3). Acharya further discloses that the FnCas9 species taught therein shows a very high specificity of binding to its intended targets and negligible binding to off-target loci (abstract; Figures 4 and 5).
Given that Zhang discloses Cas9 fusions anticipating the fusion protein of instant claim 1, and that Acharya discloses that FnCas9 is a type II-B Cas9 displaying higher specificity of binding and negligible off-target binding, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to substitute the Cas9 of Zhang with the II-B Cas9 taught in Acharya to predictably generate a fusion protein capable of targeting specified loci with higher specificity than other Cas9 species. One would have been motivated to make such a modification in order to receive the expected benefit of generating a fusion protein capable of targeting specified loci with higher specificity than other Cas9 species.
Claims 11 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0232881 A1 (hereinafter Glucksmann; of record) as applied to claim 1 above, and further in view of Su et al., 2019 (hereinafter Su; of record) and UniProt Entry A0A023ZUP5_BPT4 (first entered 01/31/2018; hereinafter UniProt; of record).
The disclosure of Glucksmann is described above and applied as before (see section Claim Rejections - 35 USC § 102). However, this disclosure does not teach the T4 ligase and sequence thereof of instant claims 11 and 13.
With regard to claim 11, which recites “the fusion protein [of claim 1] comprises a Cas nuclease and a DNA ligase, wherein the DNA ligase is T4 DNA ligase,” as set forth above, the compositions of Glucksmann anticipate the fusion protein of claim 1, specifically comprising 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 (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, paragraph 102), 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). However, while Su discloses the utility of T4 DNA ligase in repairing (and controlling said repairing) of Cas-generated double-stranded breaks, Su does not disclose the specific T4 DNA ligase seuqnece recited at instant claim 11. 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 the Appendix, UniProt entry A0A023ZUP5_BPT4 is 100% identical to instant SEQ ID NO: 7.
Given that Glucksmann discloses Cas9-ligase fusions anticipating the fusion protein of instant claim 1, 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 of 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 the Cas9 molecules taught therein to predictably generate a fusion protein capable of controlling 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 generating a fusion protein capable of controlling the repair of Cas9-generated double-stranded breaks introduced by the system.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over US 2023/0049737 A1 (hereinafter Zhang; of record; effectively filed 12/30/2019) as applied to claims 1 and 14 above, and further in view of US 2016/0010076 A1 (hereinafter Joung; of record).
The disclosure of Zhang is described above and applied as before (see section Claim Rejections - 35 USC § 102). However, this disclosure does not teach the RNA-binding domain sequence of instant claim 21.
With regard to amended instant claim 21, which recites “the DNA-binding or the RNA-binding domain [of the fusion protein of claim 14] comprises a polypeptide sequence having at least 90% identity to any one of SEQ ID NOs: 8-11,” as set forth above, Zhang anticipates the fusion protein of claims 1 and 14, wherein said fusion protein further comprises an MS2 coat protein (paragraph [0049]). However, Zhang is silent as to the sequence of said MS2 coat protein. This deficiency is cured by Joung.
Joung 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 the Appendix, SEQ ID NO: 89 of Joung comprises instant SEQ ID NO: 8.
Given that Zhang discloses Cas9 fusions anticipating the fusion protein of instant claim 1, wherein said fusion proteins also comprise a bound 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 n Joung in the system disclosed in Zhang to predictably generate a fusion protein capable of binding targeted RNA with the system taught therein via the MS2 coat protein. One would have been motivated to make such a modification in order to receive the expected benefit of generating a fusion protein capable of binding targeted RNA with the system taught therein via the MS2 coat protein.
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, 4-8, 11, 13, 14, 19, 21-23, 63-66, and 83 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) in view of US 2015/0232881 A1 (hereinafter Glucksmann; of record), Acharya et al., 2019 (hereinafter Acharya), US 2023/0049737 A1 (hereinafter Zhang; of record; effectively filed 12/30/2019), Su et al., 2019 (hereinafter Su; of record), UniProt Entry A0A023ZUP5_BPT4 (first entered 01/31/2018; hereinafter UniProt; of record), and US 2016/0010076 A1 (hereinafter Joung; of record).
Copending claim 108 recites “a fusion protein comprising (i) a Cas nuclease or a Cas nickase; and (ii) a DNA polymerase recruitment protein, a DNA ligase, a DNA ligase recruitment moiety, a DNA binding protein, a DNA repair protein, or combination thereof,” which largely reads on the instantly claimed fusion protein of amended instant claim 1, which is recited to comprise “(i) a Cas nuclease and (ii)…a DNA ligase…wherein the Cas nuclease is Cas9, Cas12, or Cas14 and comprises a polypeptide sequence having at least 90% identity to any one of SEQ ID NOs: 1, 29, or 30 and is capable of generating a double-stranded polynucleotide cleavage.” As is known to those of ordinary skill in the art, Cas nucleases are known to generate double-stranded polynucleotide cleavage events. Thus, copending claim 108 recites the instantly claimed fusion protein with the exception of the sequence of the Cas9 nuclease therein. This deficiency is cured by Glucksmann.
As set forth above, Glucksmann discloses fusion proteins comprising Cas9 and a ligase (see section Claim Rejections – 35 U.S.C. § 102) that read on the instantly claimed fusion protein. As shown in the alignments of the Appendix, SEQ ID NO: 2 of Glucksmann is 99% identical to instant SEQ ID NO: 1 and is disclosed to be a Cas9 derived from S. pyogenes at paragraph [0420]. Thus, copending application ‘014 and Glucksmann collectively read on the fusion protein o amended instant claim 1.
With regard to instant claim 4, which recites “the Cas9 [of the fusion protein of claim 1 (see section Claim Rejections - 35 USC § 112(b))] is a Type IIB Cas9,” as set forth above, Glucksmann and copending application ‘014 collectively read on the fusion protein of claim 1, but neither specifically teaches a Type IIB Cas9. This deficiency is cured by Acharya.
Acharya discloses that FnCas9 is a type II-B Cas system that has evolved separately from the IIA- and II-C systems also known in the art (page 20966, column 2, paragraph 3). Acharya further discloses that the FnCas9 species taught therein shows a very high specificity of binding to its intended targets and negligible binding to off-target loci (abstract; Figures 4 and 5).
With regard to instant claim 5, which recites “the fusion protein [of claim 1] comprises a Cas nuclease and a reverse transcriptase,” as set forth above, Zhang discloses systems and methods for targeted gene modification and targeted insertion (abstract), said compositions comprising a wild-type Cas polypeptide connected to a reverse transcriptase polypeptide (paragraph [0007]).
With regard to instant claim 6, which recites “the reverse transcriptase [of the fusion protein of claim 5] is MMLV reverse transcriptase or R2 reverse transcriptase,” as set forth above, an exemplary fusion polypeptide of Zhang is disclosed to be Cas9-M-MLV_RT (wildtype Cas9) corresponding to SEQ ID NO: 1 (paragraph [0051]), which comprises an M-MLV reverse transcriptase per paragraph [0050].
With regard to amended instant claim 7, which recites “the reverse transcriptase [of the fusion protein of claim 5] comprises a polypeptide sequence having at least 90% identity to SEQ ID NO: 2 or SEQ ID NO: 3,” as set forth above, an exemplary fusion polypeptide of Zhang is disclosed to be Cas9-M-MLV_RT (wildtype Cas9) corresponding to SEQ ID NO: 1 (paragraph [0051]), which comprises the entirety of instant SEQ ID NO: 2 (see Appendix).
With regard to amended instant claim 8, which recites “the fusion protein [of claim 1] comprises a Cas nuclease and a DNA polymerase, wherein the DNA polymerase is phi29 DNA polymerase, T4 DNA polymerase, DNA polymerase mu, DNA polymerase delta, or DNA polymerase epsilon,” as set forth above, Glucksmann anticipates the fusion protein of claim 1, wherein Cas9 (capable of generating a double-stranded polynucleotide cleavage) is fused to a polymerase. Glucksmann specifically discloses that such a polymerase may be a DNA polymerase mu or DNA polymerase epsilon at paragraphs [1351], [1355], [1362], and Table VI-3 (see particularly page 69).
With regard to claim 11, which recites “the fusion protein [of claim 1] comprises a Cas nuclease and a DNA ligase, wherein the DNA ligase is T4 DNA ligase,” as set forth above, the compositions of Glucksmann and the copending application read on the fusion protein of claim 1. However, Glucksmann neither specifies 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, paragraph 102), 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). However, while Su discloses the utility of T4 DNA ligase in repairing (and controlling said repairing) of Cas-generated double-stranded breaks, Su does not disclose the specific T4 DNA ligase sequence recited at instant claim 11. 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 the Appendix, UniProt entry A0A023ZUP5_BPT4 is 100% identical to instant SEQ ID NO: 7.
With regard to amended instant claim 14, which recites “the fusion protein of claim 1, further comprising a DNA-binding domain selected from a zinc finger DNA-binding domain, a transcription factor, or an adeno-associated virus Rep protein or an RNA-binding domain compris[ing] a KH domain or…MS2 coat protein (MCP2),” as set forth above, Zhang also anticipates the fusion protein of claim 1. Zhang further discloses that the compositions taught therein further comprise an aptamer sequence capable of tethering an adaptor protein to the CRISPR complex taught therein, specifically wherein the aptamer sequence is an MS2 loop that binds to an MS2 bacteriophage coat protein (paragraphs [0048] and [0049]), thereby tethering said MS2 bacteriophage coat protein to the CRISPR complex taught therein.
With regard to amended instant claim 19, which recites “the DNA-binding domain [of the fusion protein of claim 14] is capable of binding single-stranded DNA (ssDNA),” as set forth above (see section Claim Interpretation), any fusion protein comprising an RNA-binding domain and satisfying all other limitations of independent claim 1 and dependent claim 14 must also read on the fusion protein of dependent claim 19, as the DNA-binding domain is not required by the instant claim language. As set forth above, Zhang anticipates the fusion protein of instant claim 14. Accordingly, it is considered that Zhang also anticipates instant claim 19.
With regard to amended instant claim 21, which recites “the DNA-binding or the RNA-binding domain [of the fusion protein of claim 14] comprises a polypeptide sequence having at least 90% identity to any one of SEQ ID NOs: 8-11,” as set forth above, Zhang anticipates the fusion protein of claims 1 and 14, wherein said fusion protein further comprises an MS2 coat protein (paragraph [0049]). However, Zhang is silent as to the sequence of said MS2 coat protein. This deficiency is cured by Joung.
Joung 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 the Appendix, SEQ ID NO: 89 of Joung comprises instant SEQ ID NO: 8.
With regard to instant claim 22, which recites “the fusion protein of claim 1, further comprising a polypeptide linker between (i) and (ii),” Glucksmann further discloses that the components of the fusion proteins taught therein may be connected via a linker such as a linker comprised of an amino acid chain (paragraphs [0171] and [1663]). The “amino acid chain” linker of Glucksmann is considered to read on the instantly claimed polypeptide linker, as the instant specification defines “polypeptide” as “a polymeric form of amino acids of any length” at paragraph [0080].
With regard to amended instant claim 23, which recites “the fusion protein of claim 1, comprising a polypeptide sequence having at least 90% identity to any one of SEQ ID NOs: 18-26,” as set forth above, Zhang discloses an exemplary fusion polypeptide, which is Cas9-M-MLV_RT (wildtype Cas9) corresponding to SEQ ID NO: 1 (paragraph [0051]). As shown in the alignment in the Appendix, SEQ ID NO: 1 of Zhang comprises instant SEQ ID NO: 18.
Copending claims 119-121 respectively recite “a polynucleotide encoding the fusion protein of claim 108,” “a vector comprising the polynucleotide of claim 119,” and “a cell comprising the fusion protein of claim 108, the polynucleotide of claim 119, the vector of claim 120, or a combination thereof,” which respectively read on the limitations of instant claims 63-66.
Finally, as set forth above, with regard to amended instant claim 83, which recites “a kit comprising the fusion protein of any one of claims 1-8, 11-17, or 21-23,” as set forth above, copending application ‘014 and Glucksmann collectively read on the fusion protein of claim 1. 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, the copending application and Glucksmann disclose the claimed fusion protein, which is the only recited claim limitation with patentable weight at instant claim 83.
Given that the copending application discloses the instantly claimed fusion protein with the exception of the sequence of the Cas9 nuclease therein; that Glucksmann discloses the sequence of the claimed Cas9 nuclease; Acharya discloses that Type IIB Cas enzymes exhibit higher specifity; Su discloses that T4 DNA ligase (i.e. the sequence disclosed in UniProt) repairs CRISPR-induced double-stranded breaks; Zhang discloses the utility of including the MS2 coat protein (the sequence of which is disclosed in Joung) in gene editing compositions, 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 of the copending application per the teachings of the various secondary references to predictably generate a gene editing composition with increased specificity that is also capable of repairing the double-stranded breaks induced thereby. One would have been motivated to make such a modification in order to receive the expected benefit of generating a gene editing composition with increased specificity that is also capable of repairing the double-stranded breaks induced thereby.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/SARAH E ALLEN/Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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