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 of claims 1, 3, 6-8, 21, 23, 25, 35, 37, 38, 41-44, 46, 47, and 51 (Group I) in the reply filed on 02/17/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 60 and 99 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 02/17/2026, as set forth above.
Accordingly, claims 1, 3, 6-8, 21, 23, 25, 35, 37, 38, 41-44, 46, 47, and 51 are pending and under consideration.
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 05/11/2020.
Information Disclosure Statement
Receipt of an information disclosure statement on 11/10/2022 is acknowledged. The signed and initialed PTO-1449 has been mailed with this action.
Drawings
The drawings are objected to because:
37 CFR 1.84 (u)(1) states “View numbers must be preceded by the abbreviation "FIG."” In the current case, the view numbers for the drawings are preceded by the word "Figure" instead of the abbreviation "FIG.". It would be remedial to amend the drawings such that the view numbers are preceded by the abbreviation “FIG.” in place of “Figure.”.
With regard to Figures 2-6, 7A, 8A, and 10-12, all of these figures include labels “W2,” “W6,” and “W10,” which are not clearly defined either in the figures themselves or in the associated brief description of the drawings. The brief descriptions disclose analysis at 2-, 6-, or 10-weeks post-injection, the designations of which are presumed to correspond to W2, W6, and W10. However, in the absence of a clear designation, this presumption cannot be assumed to be accurate. For purposes of clarity, it would be remedial to clearly define all labels in the instant drawings, either in the drawings themselves or in the associated brief descriptions.
With regard to Figure 9, the depicted gels include labels “TS1” and “TS3,” which are not clearly defined either in the figure itself or in the associated brief description of the drawings. For purposes of clarity, it would be remedial to clearly define all labels in the instant drawings, either in the drawings themselves or in the associated brief descriptions.
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.
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.
Claims 1, 3, 6-8, 21, 23, 25, 35, 37, 38, 41-43, and 51 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2016/205825 A1 (hereinafter Precision; as cited in the IDS filed 11/10/2022; of record) in view of US 2019/0153440 A1 (hereinafter Casebia; as cited in the IDS filed 11/10/2022; of record) and WO 2020/214724 A1 (hereinafter Wilson; effectively filed 04/15/2019; as cited in the IDS filed 11/10/2022), as evidenced by Kraunus et al., 2004 (hereinafter Kraunus; of record).
With regard to claim 1, which recites “a recombinant DNA construct comprising a polynucleotide, wherein said polynucleotide comprises:
a first nucleic acid sequence encoding a first engineered nuclease;
a first promoter operably linked to said first nucleic acid sequence encoding said first engineered nuclease, wherein said promoter is positioned 5’ upstream of said first nucleic acid sequence and drives expression of said first engineered nuclease in a target cell; and
two or more engineered nuclease construct recognition sequences,
wherein said polynucleotide comprises a nuclear localization signal that is positioned 5’ upstream of said first nucleic acid sequence encoding said first engineered nuclease;
wherein said polynucleotide comprises an intron that is positioned 3’ downstream of said nuclear localization signal and 5’ upstream of said first nucleic acid sequence encoding said first engineered nuclease,”
Precision discloses self-limiting viral vectors encoding nucleases (or endonucleases) and comprising recognition sequences for said nucleases such that the nucleases cleave the viral vector and limit its persistence (abstract), as well as recombinant DNA constructs encoding the same (paragraph [0091]). The endonuclease taught therein may be an engineered ZFN, TALEN, or CRISPR/Cas9 (paragraph [0031]), which is considered to read on the instantly claimed engineered nuclease. The expression of this engineered endonuclease is disclosed to be under the control of a promoter placed 5' upstream of said engineered endonuclease (paragraph [0046]), as instantly claimed. Precision further discloses that the vectors taught therein may comprise two recognition sequences placed in any position to be recognized by the associated endonuclease (paragraph [0032], [0048], [0073], and [0075]-[0077]), as instantly claimed. While Precision does disclose the inclusion of an intron in the self-limiting viral vector taught therein, Precision is silent as to the instantly claimed intron placement. Additionally, Precision is silent as to the instantly claimed nuclear localization sequence.
These deficiencies are cured by Casebia, Wilson, and Kraunus, as set forth below.
Casebia discloses nucleic acids encoding a self-inactivating CRISPR-Cas system (abstract; paragraphs [0380]-[0382]) as depicted in Figures 5A and 5B. The self-inactivating CRISPR-Cas systems depicted in Figures 5A and 5B comprise an sEF1α promoter positioned 5’ upstream of a sequence encoding Cas9, wherein expression of the encoded Cas9 is driven by said sEF1α promoter (paragraphs [0385], [0502], and [0728]). These systems are disclosed to further comprise a 5’ and a 3’ P23H target site (also referred to as SIN sites) that are targeted by the Cas9 (paragraphs [0141], [0142], and [0793]) and are therefore considered to read on the instantly claimed “two or more engineered nuclease construct recognition sequences.” Finally, the systems of Casebia are disclosed to comprise two nuclear localization signals (NLS) positioned 5’ upstream and 3’ downstream of the nucleic acid sequence encoding Cas9 (paragraph [0321]; Figures 5A and 5B), as instantly claimed. However, while Casebia discloses an intron as part of the self-inactivating system taught therein, the intron of Casebia is placed within the ORF encoding the Cas9 (paragraphs [0511] and [0512]; Figures 5A and 5B) rather than 3’ downstream of the nuclear localization signal and 5’ upstream of the nucleic acid sequence encoding the engineered nuclease, as instantly claimed.
This deficiency is cured by Wilson, which discloses a gene editing nuclease expression cassette (Figure 1), wherein a nuclease coding sequence is operably linked to regulatory sequences such as a promoter directing expression of the same (abstract). These cassettes are further disclosed to comprise nuclease modulating sequences selected from the target sequence for the nuclease or a mutated target sequence which is recognized by the nuclease following its expression (abstract). These nuclease modulating sequences are disclosed to be located in tandem or to be separated by an intron (page 12, lines 7-9), which may be located 3’ downstream of the nuclear localization signal and 5’ upstream of the nucleic acid sequence encoding the engineered nuclease (Figure 1), as instantly claimed. Per the instant specification, this location corresponds to the 5’ UTR (page 52, paragraph 1). Similar to Casebia and Wilson, Kraunus discloses self-limiting vectors and sequences thereof (abstract), wherein an intron is placed in the 5’ UTR of the construct to control (i.e. increase) the expression of the encoded transgene (abstract). Given this disclosure, it is considered that placing an intron in the 5’ UTR (as taught in Kraunus and disclosed in Wilson) of the construct of Casebia would predictably facilitate control of expression of the nuclease within said construct.
Thus, it is considered that Precision, Casebia, Wilson, and Kraunus collectively disclose each and every limitation of instant claim 1.
With regard to claim 3, which recites “said polynucleotide [of the recombinant DNA construct of claim 1] comprises a nuclear localization signal that is positioned 3’ downstream of said first nucleic acid sequence encoding said first engineered nuclease,” as set forth above, the systems of Casebia are disclosed to comprise two nuclear localization signals (NLS) positioned 5’ upstream and 3’ downstream of the nucleic acid sequence encoding Cas9 (paragraph [0321]; Figures 5A and 5B), as instantly claimed. Thus, it is considered that Casebia discloses each and every additional limitation of instant claim 3.
With regard to claim 6, which recites “at least one of said two or more engineered nuclease construct recognition sequences [of the recombinant DNA construct of claim 1] is positioned 3’ downstream of said intron,” as set forth above, Precision discloses self-limiting viral vectors comprising genes encoding site-specific endonucleases (abstract). These constructs are depicted in Figures 1A-1D. As shown in Figure 1A, the engineered nuclease construct recognition sequence may be placed 3’ downstream of the ORF encoding the nuclease, which is 3’ downstream of the intron of the construct of instant claim 1, as required by the instant claim language. Thus, it is considered that Precision discloses each and every additional limitation of instant claim 6.
With regard to claim 7, which recites “at least one of said two or more engineered nuclease construct recognition sequences [of the recombinant DNA construct of claim 1] is positioned 5’ upstream of said intron,” as set forth above, Precision discloses self-limiting viral vectors comprising genes encoding site-specific endonucleases (abstract). These constructs are depicted in Figures 1A-1D. As shown in Figure 1B, the engineered nuclease construct recognition sequence may be placed 5’ upstream of the promoter operably linked to the encoded nuclease, which is 5’ upstream of the intron of the construct of instant claim 1, as required by the instant claim language. Thus, it is considered that Precision discloses each and every additional limitation of instant claim 7.
With regard to claim 8, which recites “at least one of said two or more engineered nuclease construct recognition sequences [of the recombinant DNA construct of claim 1] is positioned within said intron,” as set forth above, Precision discloses self-limiting viral vectors comprising genes encoding site-specific endonucleases (abstract). These constructs are depicted in Figures 1A-1D. As shown in Figures 1C and 1D, the engineered nuclease construct recognition sequence may be placed within the intron of the construct (Figure 1C) or within the 5’ UTR of the construct (Figure 1D). As set forth above, Wilson discloses gene editing nuclease expression cassettes comprising nuclease modulating sequences that may be separated by an intron, which may be placed in the 5’ UTR (abstract; page 12, lines 7-9; Figure 1). Therefore, while Wilson does not disclose placement of the recognition sequence within the intron of the construct, Wilson does disclose that the intron may be placed in the 5’ UTR, and Precision discloses that the recognition sequence may be placed within the intron of the construct as well as within the 5’ UTR of the construct. Thus, it is considered that Precision and Wilson collectively disclose each and every additional limitation of instant claim 8.
With regard to claim 21, which recites “said two or more engineered nuclease construct recognition sequences [of the recombinant DNA construct of claim 1] are non-identical,” as set forth above, Wilson discloses a gene editing nuclease expression cassette, wherein said cassette comprises a nuclease coding sequence is operably linked to regulatory sequences such as a promoter directing expression of the same and nuclease modulating sequences selected from the target sequence for the nuclease or a mutated target sequence which is recognized by the nuclease following its expression (abstract; Figure 1). Wilson further discloses that these cassettes may comprise multiple modulating sequences, which may be the same or different from each other (page 12, lines 1-19). Thus, it is considered that Wilson discloses each and every additional limitation of instant claim 21.
With regard to claim 23, which recites “said first engineered nuclease [of the recombinant DNA construct of claim 1] binds and cleaves a genomic recognition sequence in a target cell and at least one of said two or more engineered nuclease construct recognition sequences, wherein said genomic recognition sequence is identical to at least one of said two or more engineered nuclease construct recognition sequences,” as set forth above, Precision discloses self-limiting viral vectors comprising genes encoding site-specific endonucleases as well as recognition sequences for said site-specific endonucleases (abstract). Per Precision, the endonuclease expressed from the vector taught therein recognizes and cuts both the genome and the vector genome (paragraph [0034]), as instantly claimed. Thus, it is considered that Precision discloses each and every additional limitation of instant claim 23.
With regard to claim 25, which recites “said first engineered nuclease [of the recombinant DNA construct of claim 1] binds and cleaves a genomic recognition sequence in a target cell and at least one of said two or more engineered nuclease construct recognition sequences, wherein said genomic recognition sequence is identical to at least one of said two or more engineered nuclease construct recognition sequences, and wherein one or more second engineered nucleases binds and cleaves at least one or said two or more engineered nuclease construct recognition sequences,” Precision discloses that the vectors and constructs taught therein may further comprise a second nucleic acid sequence encoding a second engineered nuclease, the expression of which is driven by a second promoter (paragraphs [0068] and [0070]). Precision further discloses that the second engineered nuclease taught therein can recognize and cleave a second chromosomal recognition sequence present in the genome of the target cell (paragraph [0073]). Per Precision, in embodiments comprising a second endonuclease sequence, the endonuclease recognition site of the construct and shared by the genome is recognized by one of the expressed endonucleases, which identifies said recognition site in the construct and in the genome, and subsequently introduces a break in the genome at the targeted site of interest (paragraphs [0035] and [0089]). Thus, it is considered that Precision discloses each and every additional limitation of instant claim 25.
With regard to claim 35, which recites “said recombinant DNA construct [of claim 1] further comprises a protein degradation peptide encoding sequence positioned 3’ downstream of said first nucleic acid sequence encoding said first engineered nuclease,” as set forth above, Wilson discloses a gene editing nuclease expression cassette, wherein said cassette comprises a nuclease coding sequence is operably linked to regulatory sequences such as a promoter directing expression of the same and nuclease modulating sequences selected from the target sequence for the nuclease or a mutated target sequence which is recognized by the nuclease following its expression (abstract; Figure 1). As depicted in Figure 1 of Wilson, the cassettes taught therein may further comprise a PEST sequence, which is a protein degradation sequence of about 42 amino acids in length (Figure 1; page 1, lines 27-31). As shown in Figure 1, this PEST sequence is positioned 3’ downstream of the first nucleic acid sequence encoding the first engineered nuclease, as instantly claimed. Thus, it is considered that Wilson discloses each and every additional limitation of instant claim 35.
With regard to claim 37, which recites “said protein degradation peptide encoding sequence [of the recombinant DNA construct of claim 35] is positioned 5’ upstream of at least one of said two or more engineered nuclease construct recognition sequences,” as set forth above, Figure 1 of Wilson depicts that the cassettes taught therein may further comprise a PEST sequence, which is a protein degradation sequence of about 42 amino acids in length (Figure 1; page 1, lines 27-31). As shown in Figure 1, this PEST sequence may be positioned 5’ upstream of one of the two target sequences of the cassettes taught therein, as instantly claimed. Thus, it is considered that Wilson discloses each and every additional limitation of instant claim 37.
With regard to claim 38, which recites “said protein degradation peptide encoding sequence [of the recombinant DNA construct of claim 35] is positioned 3’ downstream of at least one of said two or more engineered nuclease construct recognition sequences,” as set forth above, Figure 1 of Wilson depicts that the cassettes taught therein may further comprise a PEST sequence, which is a protein degradation sequence of about 42 amino acids in length (Figure 1; page 1, lines 27-31). As shown in Figure 1, this PEST sequence may be positioned 3’ downstream of one of the two target sequences of the cassettes taught therein, as instantly claimed. Thus, it is considered that Wilson discloses each and every additional limitation of instant claim 38.
With regard to claim 41, which recites “the recombinant DNA construct of claim 1…comprises a polynucleotide, wherein said polynucleotide comprises from 5’ to 3’:
a first promoter sequence, wherein said first promoter sequence is operably linked to a first nucleic acid sequence encoding a first engineered nuclease and drives expression of said first engineered nuclease in a target cell;
a first engineered nuclease construct recognition sequence positioned 3’ downstream of said first promoter;
a nuclear localization signal positioned 3’ downstream of said first engineered nuclease construct recognition sequence;
an intron positioned 3’ downstream of said nuclear localization signal and 5’ upstream of said first nucleic acid sequence encoding said first engineered nuclease;
a second engineered nuclease construct recognition sequence positioned 3’ downstream of said first nucleic acid sequence encoding said first engineered nuclease; and
a polyA sequence positioned 3’ downstream of said second engineered nuclease construct recognition sequence,”
as set forth above, Precision, Casebia, Wilson, and Kraunus collectively disclose the recombinant DNA construct of claim 1, which encodes a viral vector as taught therein (Precision: paragraph [0090]). Regarding the specified order of the claimed construct, Precision, Casebia, and Wilson disclose each and every component, as set forth below. Furthermore, according to MPEP § 2144.04(VI)(C), when all the parts of a claimed invention (i.e. the claimed construct) are disclosed in the art, rearrangement of those parts is considered an obvious variation of the invention as disclosed in the art.
With specific regard to the construct of instant claim 41, Figure 5B of Casebia depicts a self-limiting Cas9 system (abstract) wherein a first promoter sequence is operably linked to a first nucleic acid sequence encoding a first engineered nuclease (SaCas9) to drive expression thereof, as in (i). Casebia further discloses a first engineered nuclease construct recognition sequence (i.e. P23H target site) positioned 3’ downstream of said first promoter, as in (ii). As set forth above, Casebia also discloses an NLS positioned 3’ downstream of said first engineered nuclease construct recognition sequence, as in (iii). Regarding the intron placement of (iv), the introns of Casebia are not positioned as claimed. However, Wilson also discloses a self-inactivating/self-modulating gene editing nuclease expression cassette (abstract; Figure 1), wherein said system comprises an intron placed 3’ downstream of said NLS and 5’ upstream of said first nucleic acid sequence encoding said first engineered nuclease, as in (iv). Regarding the claimed second engineered nuclease construct recognition sequence, Precision discloses that the self-limiting constructs taught therein may comprise two or more recognition sequences which are recognized by the first engineered nuclease and/or any additional engineered nucleases encoded by the viral vector (paragraph [0089]). These recognition sequences may be placed in any position where it will be recognized by the expressed nuclease and result in termination of transcription of the viral genome (paragraph [0032]). One such position is disclosed to be placement 3’ downstream of the first engineered nuclease and before the promoter of the second engineered nuclease (paragraph [0035]), as in (v). Finally, regarding the claimed polyA sequence, the self-limiting Cas9 construct of Casebia (abstract) depicted in Figure 5B comprises a polyA sequence derived from SV40, as in (vi).
Thus, not only does the prior art disclose each and every component of the claimed construct, but the prior art supports the claimed placement of each and every component of the claimed construct. Accordingly, it is considered that Casebia, Wilson, and Precision disclose each and every additional limitation of instant claim 41.
With regard to claim 42, which recites “the recombinant DNA construct of claim 1…comprises a polynucleotide, wherein said polynucleotide comprises from 5’ to 3’:
a first promoter sequence, wherein said first promoter sequence is operably linked to a first nucleic acid sequence encoding a first engineered nuclease and drives expression of said first engineered nuclease in a target cell;
a first engineered nuclease construct recognition sequence positioned 3’ downstream of said first promoter;
a nuclear localization signal positioned 3’ downstream of said first engineered nuclease construct recognition sequence;
an intron positioned 3’ downstream of said nuclear localization signal and 5’ upstream of said first nucleic acid sequence encoding said first engineered nuclease;
a protein degradation peptide encoding sequence positioned 3’ downstream of said first nucleic acid sequence encoding said first engineered nuclease;
a second engineered nuclease construct recognition sequence positioned 3’ downstream of said first nucleic acid sequence encoding said first engineered nuclease; and
a polyA sequence positioned 3’ downstream of said second engineered nuclease construct recognition sequence,”
as set forth above, Precision, Casebia, Wilson, and Kraunus collectively disclose the recombinant DNA construct of claim 1, which encodes a viral vector as taught therein (Precision: paragraph [0090]). Regarding the specified order of the claimed construct, Precision, Casebia, and Wilson disclose each and every component, as set forth below. Furthermore, according to MPEP § 2144.04(VI)(C), when all the parts of a claimed invention (i.e. the claimed construct) are disclosed in the art, rearrangement of those parts is considered an obvious variation of the invention as disclosed in the art.
With specific regard to the construct of instant claim 42, Figure 5B of Casebia depicts a self-limiting Cas9 system (abstract) wherein a first promoter sequence is operably linked to a first nucleic acid sequence encoding a first engineered nuclease (SaCas9) to drive expression thereof, as in (i). Casebia further discloses a first engineered nuclease construct recognition sequence (i.e. P23H target site) positioned 3’ downstream of said first promoter, as in (ii). As set forth above, Casebia also discloses an NLS positioned 3’ downstream of said first engineered nuclease construct recognition sequence, as in (iii). Regarding the intron placement of (iv), the introns of Casebia are not positioned as claimed. However, Wilson also discloses a self-inactivating/self-modulating gene editing nuclease expression cassette (abstract; Figure 1), wherein said system comprises an intron placed 3’ downstream of said NLS and 5’ upstream of said first nucleic acid sequence encoding said first engineered nuclease, as in (iv). Wilson further discloses that the cassettes taught therein comprise a PEST sequence, which is a protein degradation sequence of about 42 amino acids in length (Figure 1; page 1, lines 27-31). As shown in Figure 1, this PEST sequence is positioned 3’ downstream of the first nucleic acid sequence encoding the first engineered nuclease, as in (v). Regarding the claimed second engineered nuclease construct recognition sequence, Precision discloses that the self-limiting constructs taught therein may comprise two or more recognition sequences which are recognized by the first engineered nuclease and/or any additional engineered nucleases encoded by the viral vector (paragraph [0089]). These recognition sequences may be placed in any position where it will be recognized by the expressed nuclease and result in termination of transcription of the viral genome (paragraph [0032]). One such position is disclosed to be placement 3’ downstream of the first engineered nuclease and before the promoter of the second engineered nuclease (paragraph [0035]), as in (vi). Finally, regarding the claimed polyA sequence, the self-limiting Cas9 construct of Casebia (abstract) depicted in Figure 5B comprises a polyA sequence derived from SV40, as in (vii).
Thus, not only does the prior art disclose each and every component of the claimed construct, but the prior art supports the claimed placement of each and every component of the claimed construct. Accordingly, it is considered that Casebia, Wilson, and Precision disclose each and every additional limitation of instant claim 42.
With regard to claim 43, which recites “the recombinant DNA construct of claim 1…comprises a polynucleotide, wherein said polynucleotide comprises from 5’ to 3’:
a first promoter sequence, wherein said first promoter sequence is operably linked to a first nucleic acid sequence encoding a first engineered nuclease and drives expression of said first engineered nuclease in a target cell;
a nuclear localization signal positioned 3’ downstream of said first promoter;
an intron positioned 3’ downstream of said nuclear localization signal and 5’ upstream of said first nucleic acid sequence encoding said first engineered nuclease;
a first engineered nuclease construct recognition sequence positioned within said intron;
a protein degradation peptide encoding sequence positioned 3’ downstream of said first nucleic acid sequence encoding said first engineered nuclease;
a second engineered nuclease construct recognition sequence positioned 3’ downstream of said protein degradation peptide encoding sequence; and
a polyA sequence positioned 3’ downstream of said second engineered nuclease construct recognition sequence,”
as set forth above, Precision, Casebia, Wilson, and Kraunus collectively disclose the recombinant DNA construct of claim 1, which encodes a viral vector as taught therein (Precision: paragraph [0090]). Regarding the specified order of the claimed construct, Precision, Casebia, and Wilson disclose each and every component, as set forth below. Furthermore, according to MPEP § 2144.04(VI)(C), when all the parts of a claimed invention (i.e. the claimed construct) are disclosed in the art, rearrangement of those parts is considered an obvious variation of the invention as disclosed in the art.
With specific regard to the construct of instant claim 43, Figure 5B of Casebia depicts a self-limiting Cas9 system (abstract) wherein a first promoter sequence is operably linked to a first nucleic acid sequence encoding a first engineered nuclease (SaCas9) to drive expression thereof, as in (i). Casebia further discloses a first engineered nuclease construct recognition sequence (i.e. P23H target site) positioned 3’ downstream of said first promoter, as in (ii). Regarding the claimed intron placement, as set forth above, this placement corresponds to the 5’ UTR per the instant specification (page 52, paragraph 1). Kraunus discloses self-limiting vectors and sequences thereof (abstract), wherein an intron is placed in the 5’ UTR of the construct to control (i.e. increase) the expression of the encoded transgene (abstract), as in (iii). Furthermore, Wilson also discloses placement of the claimed intron in the 5’ UTR (Figure 1), ad in (iii). Regarding the first engineered nuclease construct recognition sequence, Precision discloses that the engineered nuclease construct recognition sequence may be placed within the intron of the construct (Figure 1C) or within the 5’ UTR of the construct (Figure 1D). As set forth above, Wilson discloses gene editing nuclease expression cassettes comprising nuclease modulating sequences that may be separated by an intron, which may be placed in the 5’ UTR (abstract; page 12, lines 7-9; Figure 1). Therefore, while Wilson does not disclose placement of the recognition sequence within the intron of the construct, Wilson does disclose that the intron may be placed in the 5’ UTR, and Precision discloses that the recognition sequence may be placed within the intron of the construct as well as within the 5’ UTR of the construct, as in (iv). Wilson further discloses that the cassettes taught therein comprise a PEST sequence, which is a protein degradation sequence of about 42 amino acids in length (Figure 1; page 1, lines 27-31). As shown in Figure 1, this PEST sequence is positioned 3’ downstream of the first nucleic acid sequence encoding the first engineered nuclease, as in (v). Regarding the claimed second engineered nuclease construct recognition sequence, while Precision discloses that the self-limiting constructs taught therein may comprise two or more recognition sequences which are recognized by the first engineered nuclease and/or any additional engineered nucleases encoded by the viral vector (paragraph [0089]). These recognition sequences may be placed in any position where it will be recognized by the expressed nuclease and result in termination of transcription of the viral genome (paragraph [0032]). One such position is disclosed to be placement 3’ downstream of the first engineered nuclease and before the promoter of the second engineered nuclease (paragraph [0035]), as in (vi). Finally, regarding the claimed polyA sequence, the self-limiting Cas9 construct of Casebia (abstract) depicted in Figure 5B comprises a polyA sequence derived from SV40, as in (vii).
Thus, not only does the prior art disclose each and every component of the claimed construct, but the prior art supports the claimed placement of each and every component of the claimed construct. Accordingly, it is considered that Casebia, Kraunus, Wilson, and Precision disclose each and every additional limitation of instant claim 43.
With regard to claim 51, which recites “a recombinant adeno-associated virus (AAV) comprising the recombinant DNA construct of claim 1,” as set forth above, Precision, Casebia, Wilson, and Kraunus collectively disclose each and every limitation of instant claim 1. Casebia further discloses that the constructs taught therein may be delivered via rAAV particles comprising the same (paragraph [0476]). Thus, it is considered that Precision, Casebia, Wilson, and Kraunus collectively disclose each and every limitation of instant claim 51.
Given that Precision discloses self-limiting viral vectors (and constructs encoding the same) comprising nucleases and one or two recognition sequences (placed in varying locations) for said nucleases such that the nucleases target a genomic locus and cleave the viral vector to limit its persistence, that Casebia discloses self-inactivating CRISPR-Cas systems comprising two nuclear localization signals (NLS) positioned 5’ upstream and 3’ downstream of the nucleic acid sequence encoding Cas9, and that Wilson discloses self-modulating cassettes comprising an intron placed in the 5’ UTR (which controls (i.e. increases) the expression of the encoded transgene per Kraunus), it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to combine the features of the systems of Precision, Casebia, and Wilson to predictably control expression of the encoded nuclease to regulate cleavage of the targeted genomic site and of the vector itself. One would have been motivated to make such a modification in order to receive the expected benefit of controlling expression of the nuclease encoded within the construct to regulate cleavage of the targeted genomic site and of the vector itself.
Claims 44, 46, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2016/205825 A1 (hereinafter Precision; as cited in the IDS filed 11/10/2022; of record) in view of US 2019/0153440 A1 (hereinafter Casebia; as cited in the IDS filed 11/10/2022 of record) and WO 2020/214724 A1 (hereinafter Wilson; effectively filed 04/15/2019; as cited in the IDS filed 11/10/2022), as evidenced by Kraunus et al., 2004 (hereinafter Kraunus; of record) as applied to claim 1 above, and further in view of WO 2017/075335 A1 (hereinafter Voyager; as cited in the IDS filed 11/10/2022), as evidenced by Yang, 2011 (hereinafter Yang).
The combined disclosures of Precision, Casebia, Wilson, and Kraunus are described above and applied as before. However, these disclosures do not teach the third engineered nuclease construct recognition sequence of instant claims 44, 46, and 47.
With regard to claim 44, which recites “the recombinant DNA construct of claim 1…comprises a first engineered nuclease construct recognition sequence, a seconding engineered nuclease construct recognition sequence, and a third engineered nuclease construct recognition sequence,” as set forth above, Precision discloses that the self-limiting constructs taught therein may comprise two or more recognition sequences which are recognized by the first engineered nuclease and/or any additional engineered nucleases encoded by the viral vector (paragraph [0089]). However, Precision does not disclose a third nuclease construct recognition sequence, as instantly claimed. This deficiency is cured by Voyager.
Voyager discloses self-regulatory viral particles (abstract) comprising one or more recombinase recognition sites that regulate expression of the endonuclease or recombinase encoded therein (paragraphs [00293], [00311]). Voyager explicitly discloses that the constructs taught therein may comprise a first, second, and third recombinase recognition site, wherein the third recombinase recognition site is positioned 3’ downstream of the encoded nuclease (paragraph [00311]). Regarding the instantly claimed nuclease recognition sequence versus the recombinase recognition sequence disclosed in Voyager, the Examiner notes that the instant specification defines a “nuclease” as a naturally-occurring or engineered enzyme that cleaves a phosphodiester bond within a polynucleotide chain. This definition is consistent with that taught in Yang, which discloses that nucleases are a broad class of enzymes that cleave the phosphodiester bonds of nucleic acids and include endonucleases, exonucleases, and recombinases (abstract). Therefore, a recombinase recognition site reads on a nuclease recognition site, as a recombinase is a species of nuclease. Thus, it is considered that Voyager discloses each and every additional limitation of instant claim 44.
With regard to claim 46, which recites “the recombinant DNA construct of claim 1…comprises a polynucleotide, wherein said polynucleotide comprises from 5’ to 3’:
a first promoter sequence, wherein said first promoter sequence is operably linked to a first nucleic acid sequence encoding a first engineered nuclease and drives expression of said first engineered nuclease in a target cell;
a first engineered nuclease construct recognition sequence positioned 3’ downstream of said first promoter;
a nuclear localization signal positioned 3’ downstream of said first promoter;
an intron positioned 3’ downstream of said nuclear localization signal and 5’ upstream of said first nucleic acid sequence encoding said first engineered nuclease;
a second engineered nuclease construct recognition sequence positioned within said intron;
a third engineered nuclease construct recognition sequence positioned 3’ downstream of said first nucleic acid sequence encoding said first engineered nuclease; and
a polyA sequence positioned 3’ downstream of said second engineered nuclease construct recognition sequence,”
regarding the specified order of the claimed construct, Precision, Casebia, Wilson, and Voyager disclose each and every component, as set forth below. Furthermore, according to MPEP § 2144.04(VI)(C), when all the parts of a claimed invention (i.e. the claimed construct) are disclosed in the art, rearrangement of those parts is considered an obvious variation of the invention as disclosed in the art.
With specific regard to the construct of instant claim 46, Figure 5B of Casebia depicts a self-limiting Cas9 system (abstract) wherein a first promoter sequence is operably linked to a first nucleic acid sequence encoding a first engineered nuclease (SaCas9) to drive expression thereof, as in (i). Casebia further discloses a first engineered nuclease construct recognition sequence (i.e. P23H target site) positioned 3’ downstream of said first promoter, as in (ii). As set forth above, Casebia also discloses an NLS positioned 3’ downstream of said first engineered nuclease construct recognition sequence, as in (iii). Regarding the intron placement of (iv), the introns of Casebia are not positioned as claimed. However, Wilson also discloses a self-inactivating/self-modulating gene editing nuclease expression cassette (abstract; Figure 1), wherein said system comprises an intron placed 3’ downstream of said NLS and 5’ upstream of said first nucleic acid sequence encoding said first engineered nuclease, as in (iv). Regarding the claimed second engineered nuclease construct recognition sequence, Precision discloses that the self-limiting constructs taught therein may comprise two or more recognition sequences which are recognized by the first engineered nuclease and/or any additional engineered nucleases encoded by the viral vector (paragraphs [0035] and [0089]). These recognition sequences may be placed in any position where it will be recognized by the expressed nuclease and result in termination of transcription of the viral genome (paragraph [0032]). While Precision discloses that one such position is 3’ downstream of the first engineered nuclease and before the promoter of the second engineered nuclease (paragraph [0035]), as set forth above, Precision discloses that nuclease construct recognition sequences may be placed in any position where it will be recognized by the expressed nuclease and result in termination of transcription of the viral genome (paragraph [0032]), including within an intron (Figure 1C), as in (v).
Regarding the claimed third engineered nuclease construct recognition sequence and placement thereof, as set forth above, Voyager discloses self-regulatory viral particles (abstract) comprising one or more recombinase recognition sites that regulate expression of the endonuclease or recombinase encoded therein (paragraphs [00293], [00311]). Voyager explicitly discloses that the constructs taught therein may comprise a first, second, and third recombinase recognition site, wherein the third recombinase recognition site is positioned 3’ downstream of the encoded nuclease (paragraph [00311]), as in (vi). The Examiner notes that the instant specification defines a “nuclease” as a naturally-occurring or engineered enzyme that cleaves a phosphodiester bond within a polynucleotide chain. This definition is consistent with that taught in Yang, which discloses that nucleases are a broad class of enzymes that cleave the phosphodiester bonds of nucleic acids and include endonucleases, exonucleases, and recombinases (abstract). Therefore, a recombinase recognition site reads on a nuclease recognition site, as a recombinase is a species of nuclease.
Finally, regarding the claimed polyA sequence, the self-limiting Cas9 construct of Casebia (abstract) depicted in Figure 5B comprises a polyA sequence derived from SV40, as in (vii).
Thus, the prior art discloses each and every component of the claimed construct and supports the claimed placement of each and every component of the claimed construct. Accordingly, it is considered that Casebia, Wilson, Precision, and Voyager disclose each and every additional limitation of instant claim 46.
With regard to claim 47, which recites “the recombinant DNA construct of claim 1…comprises a polynucleotide, wherein said polynucleotide comprises from 5’ to 3’:
a first promoter sequence, wherein said first promoter sequence is operably linked to a first nucleic acid sequence encoding a first engineered nuclease and drives expression of said first engineered nuclease in a target cell;
a first engineered nuclease construct recognition sequence positioned 3’ downstream of said first promoter;
a nuclear localization signal positioned 3’ downstream of said first promoter;
an intron positioned 3’ downstream of said nuclear localization signal and 5’ upstream of said first nucleic acid sequence encoding said first engineered nuclease;
a second engineered nuclease construct recognition sequence positioned within said intron;
a protein degradation peptide encoding sequence positioned 3’ downstream of said first nucleic acid sequence encoding said first engineered nuclease;
a third engineered nuclease construct recognition sequence positioned 3’ downstream of said protein degradation peptide encoding sequence; and
a polyA sequence positioned 3’ downstream of said third engineered nuclease construct recognition sequence,”
regarding the specified order of the claimed construct, Precision, Casebia, Wilson, and Voyager disclose each and every component, as set forth below. Furthermore, according to MPEP § 2144.04(VI)(C), when all the parts of a claimed invention (i.e. the claimed construct) are disclosed in the art, rearrangement of those parts is considered an obvious variation of the invention as disclosed in the art.
With specific regard to the construct of instant claim 47, Figure 5B of Casebia depicts a self-limiting Cas9 system (abstract) wherein a first promoter sequence is operably linked to a first nucleic acid sequence encoding a first engineered nuclease (SaCas9) to drive expression thereof, as in (i). Casebia further discloses a first engineered nuclease construct recognition sequence (i.e. P23H target site) positioned 3’ downstream of said first promoter, as in (ii). As set forth above, Casebia also discloses an NLS positioned 3’ downstream of said first engineered nuclease construct recognition sequence, as in (iii). Regarding the intron placement of (iv), the introns of Casebia are not positioned as claimed. However, Wilson also discloses a self-inactivating/self-modulating gene editing nuclease expression cassette (abstract; Figure 1), wherein said system comprises an intron placed 3’ downstream of said NLS and 5’ upstream of said first nucleic acid sequence encoding said first engineered nuclease, as in (iv). Regarding the claimed second engineered nuclease construct recognition sequence, Precision discloses that the self-limiting constructs taught therein may comprise two or more recognition sequences which are recognized by the first engineered nuclease and/or any additional engineered nucleases encoded by the viral vector (paragraphs [0035] and [0089]). These recognition sequences may be placed in any position where it will be recognized by the expressed nuclease and result in termination of transcription of the viral genome (paragraph [0032]). While Precision discloses that one such position is 3’ downstream of the first engineered nuclease and before the promoter of the second engineered nuclease (paragraph [0035]), as set forth above, Precision discloses that nuclease construct recognition sequences may be placed in any position where it will be recognized by the expressed nuclease and result in termination of transcription of the viral genome (paragraph [0032]), including within an intron (Figure 1C), as in (v). Wilson further discloses that the cassettes taught therein comprise a PEST sequence, which is a protein degradation sequence of about 42 amino acids in length (Figure 1; page 1, lines 27-31). As shown in Figure 1, this PEST sequence is positioned 3’ downstream of the first nucleic acid sequence encoding the first engineered nuclease, as in (vi).
Regarding the claimed third engineered nuclease construct recognition sequence and placement thereof, as set forth above, Voyager discloses self-regulatory viral particles (abstract) comprising one or more recombinase recognition sites that regulate expression of the endonuclease or recombinase encoded therein (paragraphs [00293], [00311]). Voyager explicitly discloses that the constructs taught therein may comprise a first, second, and third recombinase recognition site (paragraph [00311]), as in (vii).
Regarding the claimed placement, as set forth above, according to MPEP § 2144.04(VI)(C), when all the parts of a claimed invention (i.e. the claimed construct) are disclosed in the art, rearrangement of those parts is considered an obvious variation of the invention as disclosed in the art. The Examiner notes that the instant specification defines a “nuclease” as a naturally-occurring or engineered enzyme that cleaves a phosphodiester bond within a polynucleotide chain. This definition is consistent with that taught in Yang, which discloses that nucleases are a broad class of enzymes that cleave the phosphodiester bonds of nucleic acids and include endonucleases, exonucleases, and recombinases (abstract). Therefore, a recombinase recognition site reads on a nuclease recognition site, as a recombinase is a species of nuclease; thus, it is considered that the disclosure of Voyager reads on (vii).
Finally, regarding the claimed polyA sequence, the self-limiting Cas9 construct of Casebia (abstract) depicted in Figure 5B comprises a polyA sequence derived from SV40, as in (viii).
Thus, the prior art discloses each and every component of the claimed construct, which may be rearranged by routine experimentation per MPEP § 2144.04(VI)(C). Accordingly, it is considered that Casebia, Wilson, Precision, and Voyager disclose each and every additional limitation of instant claim 47.
Given that Precision, Casebia, Wilson, and Kraunus collectively disclose the construct of claim 1, including the arrangement of the components of said construct, as set forth above, and that Voyager further discloses the inclusion of a third nuclease recognition sequence (per Yang, a recombinase is a species of a nuclease) for purposes of further controlling nuclease expression from the self-limiting vectors/constructs taught therein, 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 construct of Precision, Casebia, Wilson, and Kraunus to further comprise a third nuclease recognition sequence to predictably further control nuclease expression from the self-limiting vector/construct thereof. One would have been motivated to make such a modification in order to receive the expected benefit of further controlling expression from the self-limiting vector/construct thereof.
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.
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Claims 1, 23, 41-43, and 51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, 10, and 20 of U.S. Patent No. 10,662,440 B2 in view of WO 2016/205825 A1 (hereinafter Precision; as cited in the IDS filed 11/10/2022; of record), US 2019/0153440 A1 (hereinafter Casebia; as cited in the IDS filed 11/10/2022; of record), and WO 2020/214724 A1 (hereinafter Wilson; effectively filed 04/15/2019; as cited in the IDS filed 11/10/2022), as evidenced by Kraunus et al., 2004 (hereinafter Kraunus; of record).
Claim 1 of patent ‘440 recites “a viral vector comprising:
a first nucleic acid sequence encoding a fist engineered nuclease and comprising, from 5’ to 3’, a first exon, an intron, and a second exon;
A first promoter operably linked to said first nucleic acid sequence, wherein said first promoter is positioned 5’ upstream of said first nucleic acid sequence and drives expression of said first engineered nuclease in a target cell; and
A first vector recognition sequence which is recognized and cleaved by said first engineered nuclease, wherein said first vector recognition sequence is positioned within said intron of said first nucleic acid sequence,”
while claim 20 recites “a recombinant DNA construct encoding said viral vector of claim 1.”
While the construct of patent ‘440 is not identical to that of the instant application, the constructs are not patentably distinct. Patent ‘440 does not recite “two or more engineered nuclease construct recognition sequences, wherein [the] polynucleotide comprises a nuclear localization signal that is positioned 5’ upstream of said first nucleic acid sequence encoding said first engineered nuclease; wherein [the] polynucleotide comprises an intron that is positioned 3’ downstream of said nuclear localization signal and 5’ upstream of said first nucleic acid sequence encoding said first engineered nuclease,” as is recited at instant claim 1. However, these deficiencies are cured by Precision, Casebia, Wilson, and Kraunus.
As set forth above, Precision discloses self-limiting viral vectors encoding nucleases (or endonucleases) and comprising recognition sequences for said nucleases such that the nucleases cleave the viral vector and limit its persistence (abstract). Precision further discloses that the vectors taught therein may comprise two recognition sequences placed in any position to be recognized by the associated endonuclease (paragraph [0032], [0048], [0073], and [0075]-[0077]), as instantly claimed.
Additionally, Casebia discloses self-inactivating CRISPR-Cas systems (abstract; Figures 5A and 5B), wherein said self-inactivating CRISPR-Cas systems comprise two nuclear localization signals (NLS) positioned 5’ upstream and 3’ downstream of the nucleic acid sequence encoding Cas9 (paragraph [0321]; Figures 5A and 5B), as instantly claimed.
Finally, Wilson discloses a gene editing nuclease expression cassette (Figure 1), wherein said cassettes comprise nuclease modulating sequences selected from the target sequence for the nuclease, which may be separated by an intron (page 12, lines 7-9) located 3’ downstream of the nuclear localization signal and 5’ upstream of the nucleic acid sequence encoding the engineered nuclease (Figure 1), as instantly claimed. Per the instant specification, this location corresponds to the 5’ UTR (page 52, paragraph 1). Similar to Casebia and Wilson, Kraunus discloses self-limiting vectors and sequences thereof (abstract), wherein an intron is placed in the 5’ UTR of the construct to control (i.e. increase) the expression of the encoded transgene (abstract). Thus, in view of Precision, Casebia, Wilson, and Kraunus, patent ‘440 is not patentably distinct from the instant application.
Claim 2 of patent ‘440 recites “the viral vector of claim 1…comprises a first polyA sequence positioned 3’ downstream of said first nucleic acid sequence.” Instant claims 41-43 all recite recombinant DNA constructs comprising the components set forth above and further comprising a polyA sequence positioned 3’ downstream of the first nucleic acid sequence encoding a first engineered nuclease, as claimed in patent ‘440. Instant claims 42 and 43 further recite “a protein degradation peptide encoding sequence positioned 3’ downstream of said first nucleic acid sequence encoding said first engineered nuclease,” which is disclosed in Wilson. As set forth above, Wilson discloses that the cassettes taught therein comprise a PEST sequence, which is a protein degradation sequence of about 42 amino acids in length (Figure 1; page 1, lines 27-31). As shown in Figure 1, this PEST sequence is positioned 3’ downstream of the first nucleic acid sequence encoding the first engineered nuclease, as instantly claimed. Furthermore, as set forth above, according to MPEP § 2144.04(VI)(C), when all the parts of a claimed invention (i.e. the claimed construct) are disclosed in the art, rearrangement of those parts is considered an obvious variation of the invention as disclosed in the art. Thus, in view of Precision, Casebia, Wilson, and Kraunus, patent ‘440 is not patentably distinct from the instant application.
Claim 4 of patent ‘440 recites the “first vector recognition sequence [of the viral vector of claim 1] is identical to a first chromosomal recognition sequence present in the genome of said target cell.” In comparison, instant claim 23 recites that the “genomic recognition sequence is identical to at least one of said two or more engineered nuclease construct recognition sequences.” Thus, both patent ‘440 and the instant application recite identical targeting of the genome and of the vector/construct itself. Thus, in view of Precision, Casebia, Wilson, and Kraunus, patent ‘440 is not patentably distinct from the instant application.
Claim 10 of patent ‘440 recites “the viral vector of claim 1…is an adeno-associated virus (AAV) vector...”. In comparison, instant claim 51 recites “a recombinant adeno-associated virus (AAV) comprising the recombinant DNA construct of claim 1.” As set forth above, the viral vector and construct thereof of patent ‘440 and the instant application are not patentably distinct. Thus, the AAV vectors comprising the same are also not patentably distinct.
Given that patent ‘440 recites a viral vector and recombinant DNA construct encoding the same comprising all the features of the instant application with the exception of:
Two recognition sequences placed in any position to be recognized by the associated endonuclease (disclosed in Precision);
At least one nuclear localization signals (NLS) positioned 5’ upstream and/or 3’ downstream of the nucleic acid sequence encoding a nuclease (disclosed in Casebia); and
An intron within the 5’ UTR (taught in Kraunus and disclosed in Wilson) and a PEST sequence downstream of the encoded nuclease (disclosed in Wilson),
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 construct of patent ‘440 to further comprise the features disclosed in Precision, Casebia, Wilson, and Kraunus to predictably produce a controllable and self-limiting vector capable of cleaving both genomic targets and itself. One would have been motivated to make such a modification in order to receive the expected benefit of producing a controllable and self-limiting vector capable of cleaving both genomic targets and itself.
Claims 1, 23, 41-43, and 51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, and 50 of copending Application No. 18/058,260 (corresponds to US 2023/0193318 A1; claims amended 08/16/2026) in view of WO 2016/205825 A1 (hereinafter Precision; as cited in the IDS filed 11/10/2022; of record), US 2019/0153440 A1 (hereinafter Casebia; as cited in the IDS filed 11/10/2022; of record), and WO 2020/214724 A1 (hereinafter Wilson; effectively filed 04/15/2019; as cited in the IDS filed 11/10/2022), as evidenced by Kraunus et al., 2004 (hereinafter Kraunus; of record).
Copending claim 1 recites “an adeno-associated viral (AAV) vector comprising a polynucleotide, wherein said polynucleotide comprises:
a 5’ inverted terminal repeat (ITR);
a nucleic acid sequence encoding an engineered nuclease and an intron that prevents expression of said engineered nuclease in a packaging cell;
a promoter operably linked to said nucleic acid sequence, wherein said promoter is positioned 5’ upstream of said nucleic acid sequence and drives expression of said engineered nuclease in a target cell;
a vector recognition sequence which is recognized and cleaved by said engineered nuclease, wherein said vector recognition sequence is identical to a chromosomal recognition sequence present in the genome of said target cell, or wherein said vector recognition sequence is a sub-optimal recognition sequence which is recognized and cleaved by said engineered nuclease; and
a 3’ ITR;
wherein said polynucleotide does not comprise more than one promoter.”
Copending claim 2 recites that “the AAV of claim 1…further comprises a polyA sequence positioned 3’ downstream of said nucleic acid sequence.”
Copending claim 50 recites “a recombinant DNA construct encoding said AAV of claim 1.”
While the copending construct is not identical to that of the instant application, the constructs are not patentably distinct. The copending application does not recite “two or more engineered nuclease construct recognition sequences, wherein [the] polynucleotide comprises a nuclear localization signal that is positioned 5’ upstream of said first nucleic acid sequence encoding said first engineered nuclease; wherein [the] polynucleotide comprises an intron that is positioned 3’ downstream of said nuclear localization signal and 5’ upstream of said first nucleic acid sequence encoding said first engineered nuclease,” as is recited at instant claim 1. However, these deficiencies are cured by Precision, Casebia, Wilson, and Kraunus.
As set forth above, Precision discloses self-limiting viral vectors encoding nucleases (or endonucleases) and comprising recognition sequences for said nucleases such that the nucleases cleave the viral vector and limit its persistence (abstract). Precision further discloses that the vectors taught therein may comprise two recognition sequences placed in any position to be recognized by the associated endonuclease (paragraph [0032], [0048], [0073], and [0075]-[0077]), as instantly claimed.
Additionally, Casebia discloses self-inactivating CRISPR-Cas systems (abstract; Figures 5A and 5B), wherein said self-inactivating CRISPR-Cas systems comprise two nuclear localization signals (NLS) positioned 5’ upstream and 3’ downstream of the nucleic acid sequence encoding Cas9 (paragraph [0321]; Figures 5A and 5B), as instantly claimed.
Finally, Wilson discloses a gene editing nuclease expression cassette (Figure 1), wherein said cassettes comprise nuclease modulating sequences selected from the target sequence for the nuclease, which may be separated by an intron (page 12, lines 7-9) located 3’ downstream of the nuclear localization signal and 5’ upstream of the nucleic acid sequence encoding the engineered nuclease (Figure 1), as instantly claimed. Per the instant specification, this location corresponds to the 5’ UTR (page 52, paragraph 1). Similar to Casebia and Wilson, Kraunus discloses self-limiting vectors and sequences thereof (abstract), wherein an intron is placed in the 5’ UTR of the construct to control (i.e. increase) the expression of the encoded transgene (abstract).
Instant claims 41-43 all recite recombinant DNA constructs comprising the components set forth above and further comprising a polyA sequence positioned 3’ downstream of the first nucleic acid sequence encoding a first engineered nuclease, as claimed at claim 2 of the copending application. Instant claims 42 and 43 further recite “a protein degradation peptide encoding sequence positioned 3’ downstream of said first nucleic acid sequence encoding said first engineered nuclease,” which is disclosed in Wilson. As set forth above, Wilson discloses that the cassettes taught therein comprise a PEST sequence, which is a protein degradation sequence of about 42 amino acids in length (Figure 1; page 1, lines 27-31). As shown in Figure 1, this PEST sequence is positioned 3’ downstream of the first nucleic acid sequence encoding the first engineered nuclease, as instantly claimed. Furthermore, as set forth above, according to MPEP § 2144.04(VI)(C), when all the parts of a claimed invention (i.e. the claimed construct) are disclosed in the art, rearrangement of those parts is considered an obvious variation of the invention as disclosed in the art.
Instant claim recites that the “genomic recognition sequence is identical to at least one of said two or more engineered nuclease construct recognition sequences,” as in (d) of copending claim 1.
Finally, instant claim 51 recites “a recombinant adeno-associated virus (AAV) comprising the recombinant DNA construct of claim 1.” As set forth above, the viral vector and construct thereof of the copending and instant applications are not patentably distinct. Thus, the AAV vectors comprising the same are also not patentably distinct.
Thus, in view of Precision, Casebia, Wilson, and Kraunus, the copending application is not patentably distinct from the instant application.
Given that the copending application recites a viral vector and recombinant DNA construct encoding the same comprising all the features of the instant application with the exception of:
Two recognition sequences placed in any position to be recognized by the associated endonuclease (disclosed in Precision);
At least one nuclear localization signals (NLS) positioned 5’ upstream and/or 3’ downstream of the nucleic acid sequence encoding a nuclease (disclosed in Casebia); and
An intron within the 5’ UTR (taught in Kraunus and disclosed in Wilson) and a PEST sequence downstream of the encoded nuclease (disclosed in Wilson),
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 construct of the copending application to further comprise the features disclosed in Precision, Casebia, Wilson, and Kraunus to predictably produce a controllable and self-limiting vector capable of cleaving both genomic targets and itself. One would have been motivated to make such a modification in order to receive the expected benefit of producing a controllable and self-limiting vector capable of cleaving both genomic targets and itself.
Conclusion
No claims are allowed.
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/SARAH E ALLEN/ Examiner, Art Unit 1637
/J. E. ANGELL/ Primary Examiner, Art Unit 1637
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