DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim(s) 1-6, 8-16, 19-40, 42, 45-63, 65, and 67-70 are pending.
Preliminary Amendments
Applicant’s preliminary amendment filed on 07/11/2023 is acknowledged. The specification was amended to update paragraphs [0001] (cross-reference information) and [0002] (Government Support).
Applicant’s preliminary amendment filed on 01/29/2024 is acknowledged. The claims were amended (1) cancel 7, 17-18, 41, 43-44, 64, and 66; and (2) amend 1, 5-6, 8-10, 12-14, 16, 20-21, 24, 26-27, 29-30, 36, 39-40, 42, 45, 47, 49, 52, 55, 57, 59, 63, and 65.
Applicant’s preliminary amendment filed on 09/03/2024 is acknowledged. The specification was amended to correct various typographical errors. A substitute specification, clean and marked up, with a statement of no new matter was filed.
Applicant’s preliminary amendment filed on 03/06/2026 is acknowledged. The following were submitted: (1) a replacement sequence listing; (2) replacement drawings; and (3) substitute specifications, clean and marked, with a statement of no new matter.
Applicant’s preliminary amendment filed on 03/27/2026 is acknowledged. The following were submitted: (1) a replacement sequence listing; and (3) substitute specifications, clean and marked, with a statement of no new matter.
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 08/05/2026 is acknowledged.
Claim(s) 14-16, 19-20, 27-30, 34-36, 47-49, 57-63, 65, and 67-70 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups II-V, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/05/2026.
Applicant’s election without traverse of Species of (a) a TnpB polypeptide and a Ruv-C nuclease domain, a nucleobase deaminase (of claim 11), and the exemplary TnpB polypeptide of Actinoplanes lobatus strain DSM 43150 (TnpB-1) in the reply filed on 08/05/2026 is acknowledged.
Claim(s) 21-26, 31-33, 37-40, 42, 45-46, and 50-56 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/05/2026.
Claim(s) 1-6 and 8-13 are under consideration.
Priority
Acknowledgement is made that this application is a 371 of PCT/US2022/013710 filed 01/25/2022 and claims priority based on provisional application(s) filed as 63/141,371 on 01/25/2021, 63/195,610 on 06/01/2021, 63/210,860 on 06/15/2021, and 63/282,352 on 11/23/2021
All claims are given the priority date of 01/25/2021.
Information Disclosure Statement
Receipt of the information disclosure statement(s) on 07/11/2023, 08/30/2023, and 12/13/2024 are acknowledged. The signed and initialed PTO-1449 form(s) has/have been mailed with this action.
It is of note that the “Foreign Patent Document” cited at #1 on IDS filed 12/13/2024 recited the wrong Foreign Document number and Country Code despite having the publication date and Applicant cited properly. The document number and country code has been marked through with the proper number and code cited above it.
Drawings
The drawings were received on 03/06/2026. These drawings are entered.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Minor informalities
The disclosure is objected to because of the following informalities:
See paragraphs [0717] through [0724], there are multiple recitations of “system,(s) . . .”, it would be remedial to amend this to recite “system(s), . . .”.
Paragraph [1115] recites “(Supplementary Table XXX)”, however, there is no “Supplementary Table XXX” disclosed in the application.
Paragraph [1131] recites “(see Supplementary Table ukreP)”, however, there is no “Supplementary Table ukreP” disclosed in the application.
Paragraph [1133] recites “(Fig. S#KnIchC).”, however, there is no “Fig. S#KnIchC” disclosed in the application.
Appropriate correction is required.
Trademarks/Tradenames
The use of the following term(s), which is/are a trade name or a mark used in commerce, has been noted in this application:
SYBR [0534], [1122];
Triton [0930], [1001], [1125];
Tween [0963];
Q5 [1001], [1121];
Quick Extract [1076 (multiple times)], [1130];
Direct-zol [1111];
RNA Clean & Concentrator [1111], [1113], [1118], [1121];
Ribominus [1111];
NEBNext [1111], [1113],[1114],[1115], [1119], [1127], [1131];
StepOne Plus [1111], [1119];
RNAClean XP [1113];
FastAP [1114];
GlycoBlue [1114];
Nucleobond [1114];
Endura [1114], [1115];
Qubit [1115];
HiScribe [1116], [1121], [1126];
Novex [1116], [1122];
E-gel [1116], [1126];
PURExpress [1119], [1122];
MiSeq [1119], [1127], [1128], [1131];
ChemiDoc [1122], [1126];
GlutaMAX [1123];
Lipofectamine [1124];
OptiMEM [1124];
(aa) cOmplete [1125];
(ab) Phusion [1129];
The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Browser-executable code
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. 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.
Para [0162] page 858;
Para [0177] page 865;
Para [0179] page 865;
Para [0270] page 894;
Para [0321] page 909;
Para [0383] page 929;
Para [0583] page 992;
Para [0604] page 1002;
Para [0622] page 1006;
(10) Para [0796] page 1016-1107;
(11) Para [0801] page 1108;
(12) Para [1076] page 1219;
(13) Para [1111] page 1235;
(14) Para [1113] page 1235;
Claim Objections
Claim 5 is objected to because of the following informalities:
claim 5 recites “The composition of any of claim 1”, it would be remedial to remove the “any of”.
Claim 11 is objected to because of the following informalities:
Integrase is recited twice; it would be remedial to remove one;
“a translation activater” should be “a translation activator”;
It would be remedial to add “a” in front of “phosphatase”, “polymerase”, “ligase”, and “helitron” for consistency.
It would be remedial to add “or” in front of “a nuclease” and after “a histone modifier,”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) – indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 12 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 12 recites the limitation "the ωRNA" in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 12 depends upon claim 1, which does not recite “ωRNA”.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim(s) 1-6, 8, 10, and 12-13 rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more.
Claim 1 recites, “A non-naturally occurring, engineered composition comprising a) a TnpB polypeptide comprising a Ruv-C nuclease domain, the Ruv-C nuclease domain optionally comprising Ruv-CI, Ruv-CII, and Ruv-CIII subdomains, and b) a nucleic acid component comprising a scaffold and a reprogrammable spacer sequence, the nucleic acid component molecule capable of forming a complex with the TnpB polypeptide and directing the TnpB polypeptide to a target polynucleotide.” Claim 2 recites, “wherein the TnpB polypeptide comprises about 200 to about 500 amino acids.” Claim 3 recites, “wherein the reprogrammable space sequence comprises a spacer of 10 nucleotides to 30 nucleotides in length.” Claim 4 recites, “wherein the nucleic acid component molecule comprises a scaffold of about 80 to 200 nucleotides in length.” Claim 5 recites, “wherein the TnpB complex binds a target adjacent motif (TAM) sequence 5' of the target polynucleotide.” Claim 6, dependent upon claim 5, recites, “wherein the TAM sequence comprises TCA, or a TTCAN.” Claim 8 recites, “wherein the target polynucleotide is DNA.” Claim 9 recites, “further comprising a homologous recombination donor template comprising a donor sequence for insertion into a target polynucleotide.” Claim 10 recites, “further comprising a functional domain associated with the TnpB polypeptide.”
Claim(s) 1-6, 8, 10, and 12-13 are not markedly different from the product’s naturally occurring counterpart in the natural state.
Regarding claim 1, 10, and 13, Shmakov et al (Diversity and evolution of class 2 CRISPR-Cas systems, Nat Rev Microbiol, vol 15, iss 3, pages 1-30, published March 2017), “In addition to the RuvC-like nuclease domain, TnpB proteins contain a predicted, positively charged, long α-helix that seems to be the counterpart to the bridge helix, which is a common feature of Cas9 and Cpf1 (FIG. 2). Thus, similar to the class 2 effectors, the TnpB proteins are predicted to bind to RNA. Moreover, it has been reported that a TnpB protein from the haloarchaeon Halobacterium salinarum binds to short overlapping sense transcripts of its own gene46. Biochemical and biological characterization of TnpB should shed light on the evolution of the functions of class 2 CRISPR–Cas effectors”, (p.5, para 1). Further Shmakov et al teaches about citation 46, “This work demonstrates that TnpB proteins bind to RNA, which is compatible with their role as ancestors of class 2 CRISPR–Cas effectors.”, (p.16, see notes of citation 46). Further, merely reciting “non-naturally occurring” or “engineered” does not rise to the level of markedly different without any element in addition to the judicial exception because both of the terms do not provide any significant structural or functional changes relative to the closest nature-based product. Batt (Chapter 14: Genetic Engineering of Food Proteins, Food proteins and their applications, page 425, published in 1997) teaches that “. . .Mother Nature is ultimate and most efficient engineer of protein structure.”, (p. 425, para 1, lines 7-8).
Regarding claim 2, Shmakov et al teaches, “Numerous CRISPR-associated TnpB homologues were detected in the size range that is typical of the transposon-encoded TnpB, that is, ~400 amino acids (Supplementary information S2 (box), part a).”, (p.5, para 4).
Regarding claim(s) 3 and 4, despite the lack of a thorough biochemical investigation of TnpB prior to the filing date (as mentioned by Shmakov et al), Nety (Thesis: The Transposon-Endcoded Protein TnpB is an RNA-Guided Nuclease, Suchita P. Nety; Doctor of Philosophy at the Massachusetts Institute of Technology, pages 1-84, published September of 2023) provides evidence that TnpB binds small RNA, specifically, “RNA pulldown revealed a small RNA bound to TnpB, of approximately 190 nucleotides in length and overlapping the TnpB ORF at its 3’ end (Figure 2.1D). Conservation of the 3’ noncoding sequence across this family of TnpBs led us to speculate that the scaffold region of the ωRNA is 173nt long with an approximately 17nt guide region. The ωRNA is predicted to be highly structured with conserved hairpins (Figure 2.1E). The ωRNAs for the remaining 9 orthologs were predicted by aligning their loci to the
PNG
media_image1.png
196
512
media_image1.png
Greyscale
PNG
media_image2.png
156
542
media_image2.png
Greyscale
experimentally determined ωRNA.”, (p.14, para 3; see 2.1 A/B and D/E).
Regarding claim(s) 5-6 and 8, Gomes-Filho et al (Sense overlapping transcripts in IS1341-type transposase genes are functional non-coding RNAs in archaea, RNA Biology, vol 12, iss 5, pages 490-500, published May 6th, 2015) teaches, “These sotRNAs allowed us to find a UUCA tetraloop motif that is present in other archaea (ncRNA family HgcC) and in a H. salinarum intergenic ncRNA derived from a palindrome associated transposable elements (PATE).”, (abstract). Further, Figure 3 demonstrates UUCA-G/C. Despite not explicitly being a TTCAN or annotated as a TAM-specific site, Nety characterized the TAM of naturally occurring TnpB orthologs, “We investigated whether these TnpB orthologs possess Cas-like RNA-guided endonuclease functions, including DNA cleavage, dependence of DNA cleavage on a target-adjacent motif, and reprogrammability of the guide. Based on the evolutionary relationship between TnpB and Cas12, we hypothesized that TnpB would require a TAM 5' to its target sequence, rather than 3’. Using an in vitro TAM screen, we tested 10 TnpB orthologs for cleavage of a reprogrammed target sequence flanked by an 8-nucleotide degenerate TAM library (Figure 2.2A). Out of the 10 orthologs tested, 7 displayed reprogrammable 5' TAM-specific DNA cleavage (Figure 2.2B). These TAMs are almost identical to each other, taking the form 5' TTCAN, which is consistent with the protein sequence similarity of these proteins.”, (p.15, para 2).
Regarding claim 12, the instant specification defines “vector” as “In one embodiment, a vector refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. Vectors include nucleic acid molecules that are single-stranded, double-stranded, or partially double-stranded; nucleic acid molecules that comprise one or more free ends, no free ends (e.g., circular); nucleic acid molecules that comprise DNA, RNA, or both; and other varieties of polynucleotides known in the art.”, (para [0415]). Thus, merely reciting “vector”, which reads on a genome, does not rise to the level of markedly different without any element in addition to the judicial exception.
This judicial exception is not integrated into a practical application because claim(s) 1-6, 8, 10, and 12-13 do not include any element in addition to the judicial exception.
Claim(s) 1-6, 8, 10, and 12-13 are rejected under 35 U.S.C. 101 because no inventive concept is provided or more than what is well-known, routine, and conventional in the art. The claimed invention does not have any elements in addition to the judicial exception, therefore, the claims are not directed to a product of nature without significantly more.
Claim 13 is rejected under 35 U.S.C. 101 because Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim 13 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
Claim 13 does not explicitly recite “human organism”, however the instant specification discloses, “The compositions may be engineered to target genetic loci or loci in HSCs. In one embodiment, the TnpB polypeptide(s) can be codon-optimized for a eukaryotic cell and especially a mammalian cell, e.g., a human cell, for instance HSC, or iPSC and nucleic acid component targeting a locus or loci in HSC, such as circulatory disease, can be prepared.”, (p.994, para [0585]). “In one embodiment, after ex vivo modification the HSCs or iPCS can be expanded prior to administration to the subject.”, (para [0589]).
Therefore, claim 13 encompasses a human cell that can be modified ex vivo and reintroduced into a human, which encompasses cells in vivo in a human (i.e., a human organism), which is excluded from the scope of patentable subject matter.
Limiting claim 13 to “an isolated cell” would obviate the rejection.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-6, 8-10, and 12-13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chittoor and Nagy (US 2019/0093090 A1, published March 28th, 2019; effective filing date of December 29th, 2015).
Regarding claims 1 and 10, Chittoor and Nagy teach, “Some embodiments relate to a composition for cleaving a target DNA comprising a CRISPR-associated transposase as described herein, and the use thereof. In some embodiments, the CRISPR-associated transposase is selected from the group consisting of SEQ ID NOs: 124-246 and 275-287, homologs thereof and orthologs thereof. In some embodiments, a complex comprising CRISPR-associated transposase and a guide RNA specific for a target DNA is described.”, (para [0064]; also see Figure 10).
More specifically, “. . .(a) a guide RNA or a DNA encoding a guide RNA where the guide RNA further comprises: (i) a first segment comprising a nucleotide sequence that is complementary to the target DNA; and (ii) a second segment that interacts with a CRISPR-associated transposase; and (b) an polynucleotide encoding the CRISPR-associated transposase, wherein the CRISPR-associated transposase comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% homology to a sequence selected from the group consisting of SEQ ID NOs: 124-246 and 275-287, where components (a) and (b) are located on same or different vectors, where the guide RNA and the CRISPR-associated transposase form a complex in the eukaryotic cell, and where the complex selectively modulates transcription of the target DNA.”, (see para [0011]).
Lastly, “The Insertion Element (IS) 605 or TnpB contains a split RuvC endonuclease domain and is considered a progenitor of Cpf1 and C2C1 proteins (Kapitonov, 2016). The RuvC domain provides the endonuclease activity of these enzymes. Proteins containing Zn-ribbon domains are thought to bind DNA. The CRISPR-associated transposases were analyzed for the presence of RuvC catalytic domains based on sequence alignment with split RuvC regions described in literature. Using the CRISPR-associated transposase of SEQ ID NO: 136 (DNA: SEQ ID NO: 304) as an example, a RuvC I and RuvC III regions with conserved catalytic “D” amino acids (position 233 and 408) and the RuvC II region with a conserved ‘E” amino acid (position 354) were identified, and these three conserved residues are indicated in FIG. 4.”, (see para [0190]).”
Wherein “RuvC endonuclease domain” reads on a functional domain associated with the TnpB polypeptide.
Wherein, “sequence that is complementary to the target DNA”, reads on spacer, and a “second segment that interacts with the CRISPR-associated transposase”, reads on scaffold
Regarding claim 2, Chittoor and Nagy teach SEQ ID NO: 136, which is 451 amino acids.
Regarding claim 3, Chittoor and Nagy teach spacer sequences in Figure 2 of 17 nucleotides. Further, “A guide-RNA sequence can also be generated based on the fragment of the repeat sequence and the spacer sequence. A guide-RNA sequence may be designed to comprise at least 20 nucleotides from a spacer sequence.”, (para [0189]).
Regarding claim 4, Chittoor and Nagy teach repeat sequences and full CRISPR guide sequences corresponding to each transposase in table 9. More specifically that the repeat sequences correspond to five locations on SEQ ID NO: 662, i.e., 42-71, 107-136, 174-203, 239-268, and 304-333. Thus, the repeat sequence, i.e., the interacting portion with the transposase, comprises five segments of 29 nucleotides which is 145 nucleotides.
Moreover, Chittoor and Nagy teach, spacer sequences and full CRISPR guide sequences corresponding to each transposase in table 10teach, “The guide-RNA sequences for a transposase can be designed to comprise at least one of the associated repeat sequences (R) and at least one of the associated spacer sequences (S), including but not limited to the combinations and orientations such as R+S, antisense sequence of R+S, S+R, and antisense sequence of S+R.”, (see para [0189]).
Regarding claim(s) 5 and 6, Chittoor and Nagy teach predicted PAM motifs for the transposases in paragraph [0187]. More specifically, “This alignment suggested a PAM motif of nucleotide triplet 5′-TCA-3′ is present at the 5′ end of the spacer.” Also see Figure 2 which teaches “TCA” and TTCAG”.
Regarding claim 8, Chittoor and Nagy teach, “The CRISPR-associated transposase complexed with the guide RNA cleaves the genomic DNA at the target site and indel mutations are created by improper repair. Mutations are detected by sequencing.”, (para [0197]).
Regarding claim 9, Chittoor and Nagy teach, “The CRISPR-associated transposase complexed with the guide RNA cleaves the genomic DNA at the target site and the donor polynucleotide is incorporated by non-homologous end-joining or homologous recombination. Integrations are detected by sequencing amplicons spanning the chromosome-oligo junctions (e.g., FIG. 10).”, (para [0198]).
Regarding claim 12, Chittoor and Nagy teach, “. . .(a) a guide RNA or a DNA encoding a guide RNA where the guide RNA further comprises: (i) a first segment comprising a nucleotide sequence that is complementary to the target DNA; and (ii) a second segment that interacts with a CRISPR-associated transposase; and (b) an polynucleotide encoding the CRISPR-associated transposase, wherein the CRISPR-associated transposase comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% homology to a sequence selected from the group consisting of SEQ ID NOs: 124-246 and 275-287, where components (a) and (b) are located on same or different vectors, where the guide RNA and the CRISPR-associated transposase form a complex in the eukaryotic cell, and where the complex selectively modulates transcription of the target DNA.”, (see para [0011]).
Regarding claim 13, Chittoor and Nagy teach, “A eukaryotic cell is transformed with an expression vector comprising a heterologous promoter operably linked to a sequence encoding one of the CRISPR-associated transposases selected from SEQ ID NOs: 124-246, 275-287, and a sequence encoding a RNA guide comprising a sequence targeting an endogenous genomic sequence of the eukaryotic cell.”, (para [0197]).
Accordingly, claim(s) 1-6, 8-10, and 12-13 are anticipated by Chittoor and Nagy.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Chittoor and Nagy (supra) as applied to claim(s) 1-6, 8-10, and 12-13 above, and in view of Gaudelli et al (Programmable base editing of A*T to G*C in genomic DNA with DNA cleavage, Nature, vol 551, pages 464-471, published November 1st, 2017; IDS filed 08/30/2023 as NPL #15).
Despite Chittoor and Nagy teaching, “In some embodiments, the nucleic acid-targeting system comprises a CRISPR-associated transposase with a heterologous functional domain.”, (para [0013]).
Chittoor and Nagy do not teach wherein the heterologous functional domain is a nucleobase deaminase.
Regarding claim 11, Gaudelli et al teaches, “Here we describe adenine base editors (ABEs) that mediate the conversion of A•T to G•C in genomic DNA. We evolved a transfer RNA adenosine deaminase to operate on DNA when fused to a catalytically impaired CRISPR–Cas9 mutant.”, (abstract). See figure 1C below.
PNG
media_image5.png
248
350
media_image5.png
Greyscale
Further, “ABEs introduce point mutations more efficiently and cleanly, and with less off-target genome modification, than a current Cas9 nuclease-based method, and can install disease-correcting or disease-suppressing mutations in human cells. Together with previous base editors, ABEs enable the direct, programmable introduction of all four transition mutations without double-stranded DNA cleavage.”, (abstract). Lastly, “The development of ABEs greatly expands the capabilities of base editing and the fraction of pathogenic SNPs that can be addressed by genome editing without introducing DSBs (Fig. 1a). Together with BE33 and BE45, these ABEs advance the field of genome editing by enabling the direct installation of all four transition mutations at target loci in living cells with a minimum of undesired byproducts.”, (p.471, col 1, para 1).
Therefore, it would have been obvious to one of skill in the art before the effective filing date of the claimed invention to modify the teachings of Chittoor and Nagy, i.e., a Crispr-associated transposes with a nucleic acid component, with the teachings of Gaudelli et al, i.e., adding a deoxyadenosine deaminase to a Crispr system, to yield the predictable results of a Crispr-associated transposes fused to a nucleobase deaminase with a nucleic acid component. One of skill would be motivated to modify Chittoor and Nagy because the disclosure suggests that in some embodiments the nucleic-targeting system comprises a CRISPR-associated transposase with a heterologous functional domain, and Gaudelli et al teaches adding a heterologous functional domain, i.e., adenosine deaminase, into a nucleic-targeting CRISPR system. Further, one would be motivated to make such a modification because Gaudelli et al teaches that ABEs (a) can introduce point mutations more efficiently and cleanly, and with less off-target genome modification, than a current Cas9 nuclease-based method, (b) can install disease-correcting or disease-suppressing mutations in human cells, i.e., pathogenic SNPS, without DSBs, and (3) can enable, together with other nucleobase deaminases, e.g., BE3 and BE4, direct installation of all four transition mutations at target loci. One of skill could have looked to the teachings of Chittoor and Nagy and Gaudelli et al and arrived at the claimed invention with a high likelihood of success.
Accordingly, claim 11 is unpatentable over Chittoor and Nagy in view of Gaudelli et al
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.
Claim(s) 1, 8, and 10-13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 5, 19, and 20 of copending Application No. 19/120,257 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following:
Claim 5 of 257 recites, “A composition comprising, “a recombinant TnpB polypeptide having one or more catalytic rearrangements relative to a reference TnpB polypeptide, and an engineered nucleic acid components comprising a scaffold and a reprogrammable spacer sequence, the engineered nucleic acid component capable of forming a complex with the TnpB and directing sequence-specific binding of the complex to a target DNA sequence.”, “further comprises a functional domain associated with the recombinant TnpB polypeptide”, “wherein the functional domain is a transposase, an integrase, a nucleobase deaminase, a reverse transcriptase, a recombinase, an integrase, a topoisomerase, a retrotransposon, a phosphatase, a polymerase, a ligase, a helitron, a helicase, a methylase, a demethylase, a translation activator, a translation repressor, a transcription activator, a transcription repressor, a transcription release factor, a chromatin modifier, a histone modifier, or a nuclease.””
Claim 5 of 257 anticipates instant claim(s) 1, 8, 10, and 11.
Claim 19 of 257 recites, “A vector system comprising one or more vectors encoding the recombinant TnpB polypeptide, and the nucleic acid component of claim 1.”
Claim 19 of 257 anticipates instant claim 12.
Claim 20 of 257 recites, “An engineered cell comprising the composition of claim 1.”
Claim 20 of 257 anticipates instant claim 13.
Accordingly, claim(s) 1, 8, and 10-13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 5, 19, and 20 of copending Application No. 19/120,257.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim(s) 1-6 and 8-12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 2, 9, and 13 of copending Application No. 19/176,309 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following:
Claim 2 of 309 recites, ““A non-naturally occurring, engineered composition comprising a) a TnpB polypeptide,b) a MazE polypeptide or domain, and c) a nucleic acid component comprising a scaffold and a reprogrammable spacer sequence, wherein the nucleic acid component is capable of forming a complex with the TnpB polypeptide and directing sequence-specific binding of a target polynucleotide, and wherein the MazE polypeptide or domain is linked to or otherwise capable of complexing with the TnpB polypeptide nucleic acid component.”, wherein the TnpB polypeptide comprises about 200 to about 500 amino acids, wherein the reprogrammable spacer sequence comprises a spacer of 10 nucleotides to 30 nucleotides in length, wherein the nucleic acid component comprises a scaffold of about 80 to 200 nucleotides in length, wherein the target polynucleotide is DNA, wherein the complex binds a target adjacent motif (TAM) sequence 5' of the target polynucleotide, wherein the TAM sequence comprises a nucleotide sequence of TCA or TTCAN, or wherein the amino acid sequence of TnpB polypeptide and MazE polypeptide are selected from those presented in Table 1.”
Claim 2 of 309 anticipates instant claim(s) 1-6, and 8.
Claim 9 of 309 recites, “wherein the composition further comprises a homologous recombination donor template comprising a donor sequence for insertion into a target polynucleotide, or a functional domain associated with the TnpB polypeptide, wherein the functional domain is a transposase, an integrase, a nucleobase deaminase, a reverse transcriptase, a recombinase, an integrase, a topoisomerase, a retrotransposon, phosphatase, polymerase, ligase, helitron, a helicase, a methylase, a demethylase, a translation activator, a translation repressor, a transcription activator, a transcription repressor, a transcription release factor, a chromatin modifier, a histone modifier or, a nuclease.”
Claim 9 of 309 anticipates instant claims 9-11.
Claim 13 of 309 recites, “A vector system comprising one or more vectors encoding the TnpB polypeptide, and the nucleic acid component of claim 1.”
Claim 13 of 309 anticipates instant claim 12.
Accordingly, claim(s) 1-6, 8, and 9-12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 2, 9, and 13 of copending Application No. 19/176,309.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LEXUS M TATGE whose telephone number is (571)272-0061. The examiner can normally be reached Monday-Friday: 8:30am to 5:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/L.M.T./Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
Prosecution Insights