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 .
Claim Status
Applicant’s amendment filed 1/14/2026 has been entered. Claims 1-131 are cancelled. Claims 132-159 are new. Claims 132-159 are pending and examined herein.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-4, 6, 14-15, 78, 80, and 124), in the reply filed on 1/14/2026 is acknowledged.
Claims 21-25, 28-30, 32-34, 37-38, 48-50, 72-75, 84, 107, 111-112, 114, 121, and 127 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 1/14/2026.
Claims 1-131 are cancelled and new claims 132-159 are encompassed within elected Group I, drawn to a method of increasing gene editing efficiency.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 90 (paragraph 270). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claims 141, 146, and 157 are objected to because of the following informalities:
claims 141 and 146 do not end in a period. MPEP 608.01(m) states, “Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations.”
claim 157, line 2, appears to have a typo where “one of more” should read “one or more”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112 – Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 147 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The method of claim 147 in part (v) comprises “a small molecule SAMDH1 inhibitor”, in part (vi) comprises “a small molecule SAMDH1 inhibitor comprising pppCH2dU, or a salt thereof”, and in part (vii) comprises “a small molecule SAMDH1 inhibitor comprising dGMPNPP, or a salt thereof”.
The specification at paragraph 0004 teaches inhibiting SAMHD1 comprises contacting the SAMHD1 with a Vpx protein, or expressing the Vpx protein in the cell, inhibiting SAMHD1 comprises contacting the SAMHD1 with a BGLF4 protein, or expressing the BGLF4 protein in the cell, inhibiting SAMHD1 comprises contacting an mRNA encoding the SAMHD1 with a microRNA or siRNA that hybridizes to the mRNA, or expressing the microRNA or siRNA in the cell and inhibiting SAMHD1 comprises contacting the SAMHD1 with a small molecule SAMHD1 inhibitor. The specification at paragraph [0196] teaches small molecule inhibitors of SAMHD1 pppCH2dU and dGMPNPP, or salts thereof.
Due to the fact that “a small molecule inhibitor” of SAMHD1 encompasses any organic/inorganic molecule, protein, nucleic acid or chemical structure in the genus of “a small molecule inhibitor” that leads to inhibition of SAMHD1 and the lack of description of any additional species by any relevant, identifying characteristics or properties, one of skill in the art would not recognize from the disclosure that Applicant was in possession of the claimed invention.
There is no working example of small molecule inhibitors other than pppCH2dU and dGMPNPP themselves. There are no working examples of other small molecule inhibitors comprising pppCH2dU or dGMPNPP.
Furthermore, Majer et al. (2019; see PTO-892) teaches that the activity of SAMHD1 is thought to be regulated by dephosphorylation at residue threonine-592 (p. 515, left column, para 2). Herold et al. (2017; see PTO-892) teaches the SAMHD1 can be regulated during cell cycle and by promoter methylation (Fig. 1; p. 33, left column, para 2). Accordingly, any small molecule upstream of the phosphorylation or promoter methylation of SAMDH1 is encompassed in the claim, but not described in the specification.
Given the complex nature of the invention, since the claims encompass a method of increasing gene editing efficiency in a cell having low dNTP concentration with small molecule inhibitors of SAMHD1, and since there is a lack of description presented in the specification to overcome the obstacles disclosed in the prior art (in the working examples or otherwise), it would require further experimentation to determine what molecule is considered a SAMHD1 inhibitor the claimed invention.
Claim 149 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 149 is drawn to a method of increasing gene editing efficiency in a cell having low dNTP concentration comprising treating the cell with a DNA polymerase that is a reverse transcriptase. The claim is directed to a genus of fragments of reverse transcriptases having at least 80% through 100% sequence identity to SEQ ID NO: 3-22 or SEQ ID NO: 40-80. As indicated in MPEP § 2163, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show that Applicant was in possession of the claimed genus. In addition, MPEP § 2163 states that a representative number of species means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
In the instant case, the claims encompass a genus of fragments of reverse transcriptases having at least 80% through 100% sequence identity to SEQ ID NO: 3-22 or SEQ ID NO: 40-80 lacking structural limitations. The specification does not describe the length or sequence identity of any of the “fragments” of the reverse transcriptases. The specification at paragraphs 0113 indicates that the fragment may be fused to a Cas nickase, but fails to describe any specific fragments. The specification at paragraph 0105 teaches that “Some embodiments include a functional fragment of the reverse transcriptase”. However, the specification fails to describe any additional species by any relevant, identifying characteristics or properties.
The claims encompass a large genus of fragments of reverse transcriptases having at least 80% through 100% sequence identity to SEQ ID NO: 3-22 or SEQ ID NO: 40-80 lacking structural limitations. A sufficient written description of a fragments of reverse transcriptases having at least 80% through 100% sequence identity to SEQ ID NO: 3-22 or SEQ ID NO: 40-80 lacking structural limitations may be achieved by a recitation of a representative number of fragments, or a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus. However, in the instant case, there is no structural feature which is representative of all the members of the genus of fragments of reverse transcriptases having at least 80% through 100% sequence identity to SEQ ID NO: 3-22 or SEQ ID NO: 40-80 and there is no information as to a correlation between structure and function.
Because the specification only discloses reverse transcriptases having at least 80% through 100% sequence identity to SEQ ID NO: 3-22 or SEQ ID NO: 40-80, lacking structural limitations and no examples of fragments of the genus and the lack of description of any additional species by any relevant, identifying characteristics or properties, one of skill in the art would not recognize from the disclosure that Applicant was in possession of the claimed invention.
Claims 132-159 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of increasing gene editing in a cell having a low dNTP concentration, the method comprising treating the cell with a construct comprising (a), (b), and (d) and administering (c) to the cell or administering directly (a)-(d) to the same cell, does not reasonably provide enablement for treating the cells with a)-d) using a genus of administration routes or at different points. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The claimed invention broadly reads on treating cells (in vivo or in vitro) with items (a)-(d) of instant claims 132 and claims dependent therefrom at different time points or at the same time. With respect to claim 132 and claim dependent therefrom, the claim embraces using any delivery route in treating step.
The specification, at paras 4 and 211-213, teaches methods of treatment and administering viral vectors to deliver nucleic acids to a subject comprising a cell by injection or oral administration. The specification at paras 169-173 teaches gene editing methods comprising administering GPS-assisted reachover gRNAs (GARGs) via virus particle/particles such as an AAV. The specification, at paras 187-214 and Example 11, further teaches administering dNTPs or nuclesides to a subject or to a cell and that inhibiting SAMHD1 can be used for this purpose. The specification describes in vitro transfections into HEK293T cells with AAV vectors (paras 264-266; Examples 1-14).
There is no working example of delivery to any subject, orally or by injection.
The prior art in Chuang (Approach for in vivo delivery of CRISPR/Cas system: a recent update and future prospect. Cell Mol Life Sci. 2021 Mar;78(6):2683-2708) teaches gene editing activity of the CRISPR/Cas system largely depends on the efficiency of introducing the system into cells or tissues, an efficient and specific delivery system is critical for applying CRISPR/Cas technology and further that some hurdles remain for the translatability of CRISPR/Cas system. Chuang further teaches that an obstacle due to the size of the components in the system, which are all macromolecules is that they are unable to spontaneously enter the cytosol and then the nucleus, which are essential for successful gene modification. In addition, the large size of the CRISPR/Cas system may also make it difficult to package into delivery vehicles such as viral vectors. Another aspect of the difficulty of the CRISPR/Cas system is that it needs to be highly stable and functional; otherwise, it will be degraded or eliminated during circulation in the targeted organs or tissues in different biological systems, including mammals and aquacultures (p. 2684). Chuang warns that viral delivery methods are more complicated that most of the nonviral methods under in vivo conditions (Figure 2 and Table 1). There is further unpredictability in the delivery of how gRNA would get to the same cell in a subject if it was not part of the CRISPR-Cas complex or co-delivered with the complex.
With respect to claim 158(i), the claims depends on claim 133 and the claim does not recite any therapeutic materials just a generic CRISPR-Cas complex with a SAMHD1 inhibitor. It is not apparent how any CRISPR-Cas complex with the inhibitor could treat a genetic disease if there is no nexus between the target sequence of the gRNA in the CRISPR-Cas complex and the genetic disease.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 132-159 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (US20220356469A1; published 11/10/2022; with priority to 8/21/2019; cited in the IDS filed 10/12/2023), in view of Pai et al. (2017. A Critical Balance: dNTPs and the Maintenance of Genome Stability. Genes, 8(2), 57; cited in the PTO-892).
Liu’s disclosure is directed to compositions and methods for conducting prime editing of a target DNA molecule (e.g., a genome) that enables the incorporation of a nucleotide change and/or targeted mutagenesis (entire document). Liu further discloses methods that leverage prime editing, including treating trinucleotide repeat contraction diseases, installing targeted peptide tags, treating prion disease through the installation of protection mutations, manipulating RNA-encoding genes for the installation of RNA tags for controlling the function and expression of RNA, using prime editing to construct sophisticated gene libraries, using prime editing to insert immunoepitopes into proteins, use of prime editing to insert inducible dimerization domains into protein targets, and delivery methods, among others (abstract).
Regarding claim 132, Liu teaches methods of gene editing comprising treating a cell with fusion proteins comprising nucleic acid programmable DNA binding proteins (napDNAbp) (e.g., Cas9) and a polymerase (e.g., reverse transcriptase), which is guided to a specific DNA sequence by a modified guide RNA, named an PEgRNA (abstract and Fig. 14). Liu teaches that the Cas9 protein can be nCas9 (paras 0014, 0061-0062, 0143, 0228, 0308, 0312, 0347). Liu teaches optimizing parameters for high editing efficiency (paras 1204 and Example 20).
However, Liu does not specifically teach a method of increasing the gene editing efficiency in a cell having low dNTP concentrations by treating the cell with a SAMHD1 inhibitor.
Pai‘s disclosure is directed to the importance of dTNP levels and genome stability in cells (entire document). Pai teaches that cellular dNTP concentrations affect genome integrity by affecting DNA replication which depends on chromosomal activities, such as DNA repair, recombination, and chromatin assembly (Introduction).
Regarding claim 132, Pai teaches that low dNTP conditions affect DNA polymerase function (Fig. 1; pp. 4-5, Section 4). Pai further teaches that even intermediate levels of dNTP starvation, while not imposing a global block to DNA synthesis, can have a more pronounced effect on specific genomic regions such as hard-to-replicate sequences, fragile sites, and regions of low sequence complexity, all of which can effect gene editing efficiency (p. 4, para 3). Pai teaches that DNA replication under low dNTP levels exacerbates the rates of misincorporation of rNMPs by Pol α, δ, and ε in vitro (p. 4, para 4). Pai further teaches that SAMHD1 regulates dNTP levels in mammalian cells by maintaining low levels of dNTPs outside of S phase, that high dNTP levels can arise from defects in SAMHD1, and that inactivating one allele of SAMHD1 can significantly increase dNTP pools (p. 2, para 2; Fig. 2; p.6, para 2). Pai teaches Samhd1 is the dendritic-and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx (p. 14, reference 55). Pai teaches that imbalances in dNTP levels can lead to polymerase errors and that it is crucial to maintain a balance (pp. 5-6; and Fig. 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the Liu’s method of genome editing with nCas9-RT fusions and guide RNAs by adding a SAMHD1 inhibitor to a cell having a low dNTP concentration in order to improve editing efficiency. Liu teaches compositions and methods to increase efficiency of gene editing using nCas9-RT fusion proteins with guide RNAs (paras 0010-0011, 0014-0015, 0044, 0061, and 0313). Pai teaches that dNTP concentration affects DNA polymerase function, high dNTP levels can arise from defects in SAMHD1, and inactivating one allele of SAMHD1 can significantly increase dNTP pools (p.6, para 2). One of ordinary skill in the art would have been motivated to optimize gene editing efficiency in cells having low dNTP concentration by inhibiting SAMHD1 with an inhibitor such as Vpx, as described by Pai. One would have had a reasonable expectation of success because both Liu and Pai are directed to improving methods of DNA repair and gene editing. Thus, the claimed invention as a whole is prima facie obvious.
Regarding claim 133, Liu teaches administering to a subject the genome editing cas9-RT fusion proteins and guide RNA (paras 0270, 1139, and 1324).
Regarding claims 134-135, Liu teaches that the DNA polymerase comprises a reverse transcriptase (paras 0010-0019, 0027-0028, 0046-0054, 0061-0063, 0070-0073; Example 1). Liu further teaches that nCas9 and the DNA polymerase are separate polypeptide chains and the nCas9 and the DNA polymerase form a Cas-DNA polymerase heterodimer (paras 0045-0047, 0161, 0184, 0198, 0393-0396, 0425, 0919-0928, 0947-1139, 1162, and 1324). Liu further teaches that the Cas-RT heterodimer comprises a first heterodimer fused to the nCas9 and a second heterodimer fused to the DNA polymerase (RT), where the first heterodimer domain binds the second heterodimer domain to form a heterodimer (paras 0195, 0393-0396, and 0411-0422).
Regarding claim 136, Liu teaches that the DNA polymerase is fused to the nCas9 (paras 0014, 0061, 0237, 0308, 0328, and 2013).
Regarding claim 137, Liu teaches the DNA polymerase can comprise virtually any DNA polymerase, including mammalian non-LTR retrotransposons and bacterial Group II introns (paras 0010, 0079, 0245, 0424, and 0692).
Regarding claim 138, Liu teaches the nCas9 and the DNA polymerase are separate polypeptide chains and the nCas9 and the DNA polymerase are not engineered to heterodimerize (they can be engineered to homodimerize) (para 0047, 0184, 0195, 0243, 0919-0922 and 0938).
Regarding claim 139, Liu teaches that the nCas9 and the RT are separate polypeptide chains and the guide nucleic acid binds to the nCas9 and the RT (paras 0009, 0045-0049, 0061, 0079, and 0185-0186).
Regarding claim 140, Liu teaches that the guide nucleic acid complexes with nCas9 and the DNA polymerase (RT) and wherein, upon complex formation, the nCas9 is capable of introducing a single-strand break at a target site in a target nucleic acid (paras 0009-0010, 0020-0025, and 0079).
Regarding claim 141, Liu teaches dual split-intein prime editing lentivirus system with at least part of the nCas9 and the DNA polymerase are included in at least 2 separate polypeptide chains comprising separate polypeptide chains comprising inteins that bind one another (paras 0129, 0154-0157, 0167-0169, 0729-0736; Example 20).
Regarding claim 142, Liu teaches prime editing systems with at least part of the nCas9 and the DNA polymerase are included in at least 2 separate polypeptide chains, the at least 2 separate polypeptide chains comprise the separate polypeptide chains comprising heterodimer domains that bind one another, and the heterodimer domains comprise streptavidin and streptavidin binding protein, hydrophobic polypeptides, an antibody that binds the Cas nickase, or an antibody that binds the reverse transcriptase, or one or more binding fragments thereof, including MS2 hairpins/aptamers (paras 0084, 0087, 0163, 0165, 0222-0226, 0372, 0605, and 0892-0921).
Regarding claims 143-144, Liu teaches Cas9 and RT fusion proteins may comprise a protein located at the N-terminal or the C-terminal portion of the fusion protein (para 0129, 0205, 0237 and 0154-0155). Therefore, Liu teaches that a first heterodimer domain can be fused to an amino end of the nCas9 and a second heterodimer domain is fused to a carboxy end of the DNA polymerase (RT) and wherein the first heterodimer domain and the second heterodimer domain bind one another, and teaches a first heterodimer domain is fused to a carboxy end of the nCas9 and a second heterodimer domain is fused to an amino end of the DNA polymerase, and the first heterodimer domain and the second heterodimer domain bind one another.
Regarding claim 145, Liu teaches an NLS fused to the nCas9 and the WT MMLV RT (paras 0230, 0237, 0548, 0560-0570).
Regarding claim 146, Liu teaches administering at least one polynucleotide encoding the nCas9 and RT (paras 0046-0050 and 0824-0839).
Regarding claims 147 and 148, Pai teaches the SAMHD1 inhibitor Vpx protein (p. 14, reference 55).
Regarding claim 149, Liu teaches the DNA polymerase comprising a reverse transcriptase, including WT RT enzymes, including geobacillus stereothermophilus RT (GsI-IICRT), Eubacterium Rectale RT (ErRT), rsv RT, HIV RT, and variants of MMLV RT (paras 0446-0452; SEQ ID NOs: 89-100). Liu further teaches: SEQ ID NO: 100 encoding geobacillus stereothermophilus (GsI-IICRT) having 98% sequence identity to Applicant’s SEQ ID NO: 3, SEQ ID NO: 99 encoding Eubacterium Rectale (ErRT) having 99.8% sequence identity to SEQ ID NO: 4 and having 98.4% sequence identity to Applicant’s SEQ ID NO: 5 (See attached OA.Appendices for sequence alignments). Liu further teaches SEQ ID NO: 89 encoding MMLV RT having 99.8% sequence identity to Applicant’s instant SEQ ID NO: 14. (See alignment below). Liu teaches nucleic acid sequences encoding variants of MMLV RT comprising one or more of the following substitutions: P51L, S67K, E69K, L139P, T197A, D200N, H204R, F209N, E302K, E302R, T306K, F309N, W313F, T330P, L345G, L435G, N454K, D524G, E562Q, D583N, H594Q, L603W, E607K, or D653N in the wild type M-MLV RT of SEQ ID NO: 89 or at a corresponding amino acid position in another wild type RT polypeptide sequence (para 0476) and accordingly teaches sequences having at least 97% sequence identity to SEQ ID NOs: 40-80, which are 678 aa variants of the MMLV RT (See OA.Appendices for sequence alignments for SEQ ID NO: 40, 50, 60, 70, and 80).
(Qy: Applicant’s SEQ ID NO: 14)
Qy 1 TLNIEDEHRLHETSKEPDVSLGSTWLSDFPQAWAETGGMGLAVRQAPLIIPLKATSTPVS 60
|||||||:||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 TLNIEDEYRLHETSKEPDVSLGSTWLSDFPQAWAETGGMGLAVRQAPLIIPLKATSTPVS 60
Qy 61 IKQYPMSQEARLGIKPHIQRLLDQGILVPCQSPWNTPLLPVKKPGTNDYRPVQDLREVNK 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 IKQYPMSQEARLGIKPHIQRLLDQGILVPCQSPWNTPLLPVKKPGTNDYRPVQDLREVNK 120
Qy 121 RVEDIHPTVPNPYNLLSGLPPSHQWYTVLDLKDAFFCLRLHPTSQPLFAFEWRDPEMGIS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 RVEDIHPTVPNPYNLLSGLPPSHQWYTVLDLKDAFFCLRLHPTSQPLFAFEWRDPEMGIS 180
Qy 181 GQLTWTRLPQGFKNSPTLFDEALHRDLADFRIQHPDLILLQYVDDLLLAATSELDCQQGT 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 GQLTWTRLPQGFKNSPTLFDEALHRDLADFRIQHPDLILLQYVDDLLLAATSELDCQQGT 240
Qy 241 RALLQTLGNLGYRASAKKAQICQKQVKYLGYLLKEGQRWLTEARKETVMGQPTPKTPRQL 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 RALLQTLGNLGYRASAKKAQICQKQVKYLGYLLKEGQRWLTEARKETVMGQPTPKTPRQL 300
Qy 301 REFLGTAGFCRLWIPGFAEMAAPLYPLTKTGTLFNWGPDQQKAYQEIKQALLTAPALGLP 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 REFLGTAGFCRLWIPGFAEMAAPLYPLTKTGTLFNWGPDQQKAYQEIKQALLTAPALGLP 360
Qy 361 DLTKPFELFVDEKQGYAKGVLTQKLGPWRRPVAYLSKKLDPVAAGWPPCLRMVAAIA VLT 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 DLTKPFELFVDEKQGYAKGVLTQKLGPWRRPVAYLSKKLDPVAAGWPPCLRMVAAIA VLT 420
Qy 421 KDAGKLTMGQPLVILAPHAVEALVKQPPDRWLSNARMTHYQALLLDTDRVQFGPVVALNP 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 KDAGKLTMGQPLVILAPHAVEALVKQPPDRWLSNARMTHYQALLLDTDRVQFGPVVALNP 480
Qy 481 ATLLPLPEEGLQHNCLDILAEAHGTRPDLTDQPLPDADHTWYTDGSSLLQEGQRKAGAAV 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 ATLLPLPEEGLQHNCLDILAEAHGTRPDLTDQPLPDADHTWYTDGSSLLQEGQRKAGAAV 540
Qy 541 TTETEVIWAKALPAGTSAQRAELIALTQALKMAEGKKLNVYTDSRYAFATAHIHGEIYRR 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 TTETEVIWAKALPAGTSAQRAELIALTQALKMAEGKKLNVYTDSRYAFATAHIHGEIYRR 600
Qy 601 RGLLTSEGKEIKNKDEILALLKALFLPKRLSIIHCPGHQKGHSAEARGNRMADQAARKAA 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 RGLLTSEGKEIKNKDEILALLKALFLPKRLSIIHCPGHQKGHSAEARGNRMADQAARKAA 660
Qy 661 ITETPDTSTLLIENSSP 677
|||||||||||||||||
Db 661 ITETPDTSTLLIENSSP 677
(Db: Liu’s SEQ ID NO: 89)
Regarding claim 150, Liu teaches that the nCas9 can be an S. pyogenes Cas9 nickase (paras 0014, 0061-0062, 0143, 0145, and 0228).
Regarding claim 151, Liu teaches that the dNTP concentration comprises a dATP concentration, a dCTP concentration, a dGTP concentration, or a dTTP concentration, or any combination thereof (para 0131).
Regarding claim 152, Liu teaches administering rAAV constructs comprising a nucleotide sequence encoding the guide nucleic acid and the DNA polymerase (paras 0824, 0837, 0970-0974).
Regarding claims 153-154, Liu teaches administering rAAV constructs comprising one or more of the components of the prime editing system, including DNA polymerase (RT), nCas9, and the SAMHD1 inhibitor Vpx (heterologous polypeptides of interest) (paras 0206, 0599-0601, and 0823-0827).
Regarding claim 155, Liu teaches the guide nucleic acid (PEgRNA) comprising a DNA nucleobase and/or an RNA nucleobase (paras 0009-0011, 0071, and 0207).
Regarding claim 156, Liu teaches administering can be oral or by injection (paras 0825, 0946, and 1118-1119).
Regarding claim 157, Liu teaches administering a composition comprising a administering a composition comprising a pharmaceutical carrier and one of more of: administering a composition comprising a pharmaceutical carrier and one of more of: (i) the DNA polymerase or the at least one polynucleotide sequence encoding a DNA polymerase; (ii) the Cas9 nickase (nCas9) or the at least one polynucleotide sequence encoding a nCas9; (iii) the SAMHD 1 inhibitor or the at least one polynucleotide sequence encoding a SAMHD1 inhibitor; and/or (iv) the guide nucleic acid or the at least one polynucleotide sequence encoding a guide nucleic acid (para 0824-0829, and 1115-1261).
Regarding claim 158, Liu teaches that the subject has a genetic disorder;(ii) the subject is a vertebrate;(iii) the subject is a mammal; and/or (iv) the subject is a human
(para 0060, 0107, 0270, 0284-0285, 0708-0711, and 1053).
Regarding claim 159, Liu teaches that administering corrects a disease-causing gene mutation in the cell of a subject (paras 0060, 0107, 0284-0285, and 0708-0711).
Therefore the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
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 132-159 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 11352623 in view of Liu et al. (US20220356469A1; published 11/10/2022; with priority to 8/21/2019; cited in the IDS filed 10/12/2023) and Pai et al. (2017. A Critical Balance: dNTPs and the Maintenance of Genome Stability. Genes, 8(2), 57; cited in the PTO-892).
Claims 1-27 of U.S. Pat No. 11352623 teach compositions comprising a Cas9 nickase and RT and polynucleotides encoding the nCas9 and RT (together or separately) further comprising a guide nuclease that binds to the Cas nickase or the RT (claims 132, 136, 139, 152, and 155), comprising fusion proteins comprising leucine zippers (claims 134-135, 142-144), inteins (claim 141), that the RT is WT mlvRT or mlvRT variants having point mutations (claim 149), and S. pyogenes Cas9 nickase (claim 150).
However, the combined teachings of Liu and Pai are discussed above, particularly regarding a method of increasing gene editing efficiency in a cell have low dNTP concentrations by using a SAMHD1 inhibitor, such as Vpx (claims 132 and 153-154), administering the composition to a subject (claim 133), wherein the subject has a genetic disorder, is a mammal, and the administering corrects a disease-causing gene mutation in the cell of a subject (claims 156 and 158-159), pharmaceutical compositions (claim 157), DNA polymerase comprising non-long terminal repeat retrotransposable element or bacterial group II intron fused to nCas9 (claim 137), can be engineered not to heterodimerize (claim 138), nCas9 is capable of introducing a single-strand break at a target site in a target nucleic acid (claim 140), NLS (claim 145),
It would have been obvious to one of ordinary skill in the art to have modified the product of the copending claims with the SAMHD1 inhibitor as taught by Pai because Pai also teaches improving compositions and methods of DNA repair and gene editing.
Conclusion
No claim is allowed.
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/KHALEDA B HASAN/Examiner, Art Unit 1636
/BRIAN WHITEMAN/Primary Examiner, Art Unit 1636
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