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 Group I (claims 1-3,7,11,13,14,19,21 and 23-29) in the reply filed on 04/17/2026 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Claims 30-33 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 04/17/2026.
Claims 1-3,7,11,13,14,19,21 and 23-29 are under examination.
Priority
This application is a 371 of PCT/US2022/015822, filed 02/09/2022 which claims benefit of 63/147,729, filed 02/09/2021 and claims benefit of 63/153,894, filed 02/25/2021 and claims benefit of 63/240,640, filed 09/03/2021 as reflected by the most recent filing receipt.
Claim Objections
Claims 21,24,26 and 27 are objected to because of the following informalities:
Regarding claim 21, there is an extra comma in line 3 following “a donor sequence” which should be removed in order for the sentence to flow appropriately.
Regarding claim 24, line 2 recites “fused to a 3’ of the nucleic acid component” and is missing “end” after “3’”.
Regarding claims 26 and 27, line 2 of each claim recites “encoding the polypeptide and/or nucleic acid components of paragraphs (a), (b), (c), and/or (d) of claim 14. The term “paragraphs” should be removed. Claims 26 and 27 depend on claim 14 which depends on claim 1. Claim 1 recites “a., b., c.”, while claim 14 uses (d), and claims 26 and 27 recite “(a), (b), (c), and/or (d)”. Therefore, consistent recitation of each component is needed.
Appropriate correction is required.
Specification
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. See at least pages 108,119,148, 173,174,211,219 and 223 which include browser-executable code.
Drawings
The drawings are objected to because FIGs.11A,11B,14,38A,38B,38C,38D,38E and 38F are not clear and legible. 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 § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claims 28 and 29 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
Claim 28 recites “a cell or progeny thereof transiently or non-transiently transfected with the vector system of claim 27”. Claim 29 recites “an organism comprising the cell or progeny thereof of claim 27”. Based on the broadest reasonable interpretation of claim 28, a cell or progeny thereof reads on a human cell within a human organism, as the claim does not recite the cell is isolated. Likewise, claim 29 which recites “an organism comprising the cell or progeny…” also encompasses a human organism.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 11,13,14,19 and 29 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 11 recites the limitation, “wherein the non-LTR retrotransposon is R2” in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. Claim 11 depends on claim 1 which recites “a first non-LTR retrotransposon polypeptide”, and therefore claim 11 is missing “polypeptide” after “non-LTR retrotransposon”, and since claim 1 recites “a first non-LTR retrotransposon polypeptide” there is ambiguity as to if claim 11 is referring to the first non-LTR retrotransposon polypeptide or a different non-LTR retrotransposon.
In addition, claim 11 recites, "optionally a non-LTR retrotransposon polypeptide selected from the group consisting of Table 1" in lines 3-4. See MPEP 2173.05(s). “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted)”.
Claim 13 recites the limitation, “wherein the non-LTR retrotransposon is fused…” in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 13 depends on claim 1 which recites “a first non-LTR retrotransposon polypeptide”, and therefore claim 13 is missing “polypeptide” after “non-LTR retrotransposon”, and since claim 1 recites “a first non-LTR retrotransposon polypeptide” there is ambiguity as to if claim 13 is referring to the first non-LTR retrotransposon polypeptide or a different non-LTR retrotransposon.
Regarding claim 14, line 2 recites “wherein the first and second site-specific nickases are a paired set…”. There is no prior recitation of any site-specific nickases in claim 14 or claim 1, only site-specific nucleases. There is insufficient antecedent basis for this limitation in the claim.
Regarding claim 19, line 1 recites “the donor”. Claim 19 depends on claim 1 which recites both “a donor construct” and “a donor polynucleotide sequence”, so claim 19 should be specific as to what it is referring to. There is insufficient antecedent basis for this limitation in the claim.
Regarding claim 29, the claim recites dependency on claim 27 which does not recite a cell or progeny thereof and therefore there is insufficient antecedent basis for this limitation in the claim. Claim 29 should recite “comprising the cell or progeny thereof of claim 28”.
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.
Claims 1-3,7,11,13,14,23 and 26-28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Emendobio (WO 2020252361, Published 17 Dec 2020), cited on an IDS.
Claim Interpretation: Regarding the claims that recite “optionally”, any optional limitations are not being treated as required limitations.
Regarding claim 1, Emendobio recites a gene editing composition comprising an RNA template molecule, at least one fusion protein, and at least one RNA guide molecule, the RNA template molecule comprising a) an insert template portion; and b) at least one retrotransposon-encoded protein binding site, and the at least one fusion protein comprising c) at least one retrotransposon-encoded protein portion; and d) a CRISPR nuclease portion (claim 1); wherein the retrotransposon- encoded protein of the first or second fusion protein is derived from a non-LTR retrotransposon-encoded protein (claim 15). Emendobio teaches the gene editing complex has four biochemical activities including 1) DNA target site binding mediated by, for example, a CRISPR nuclease; 2) DNA target site cleavage mediated by, for example, a CRISPR nickase, a modified CRISPR nuclease, or a retrotransposon-encoded protein; 3) Binding of an RNA template molecule by a retrotransposon-encoded protein, for example, at binding sites adopted from 5’ and 3’ elements of a R2 RNA; and 4) Reverse transcription, for example, mediated by a retrotransposon-encoded protein (paragraph 0058), and that the fusion protein compositions described herein may be used for introduction of an insert template nucleic acid sequence to a targeted genomic locus in a site-specific manner, which process is completed in several steps:
1) Formation of a complex comprising a fusion protein bound to an RNA molecule comprising an RNA template portion;
2) Introduction of the complex to a cell; and
3) Activity of the complex in the cell occurring in the following steps:
a) Binding of the complex to a genomic target site;
b) First strand nicking of the genomic target site;
c) Target primed reverse transcription of the RNA template;
d) Second strand nicking of the genomic target site; and
e) Second strand synthesis (paragraph 0059).
Regarding claims 2-3, Emendobio teaches the RNA-guided DNA nuclease is a CRISPR nuclease derived from a type II CRISPR system (e.g., Cas9) (paragraphs 0086-0087) and therefore teaches the site specific nuclease is a Type II Cas polypeptide. Regarding the nucleic acid component capable of forming a complex with a Cas polypeptide and directed binding of the complex to the target sequence recited in claim 2, as stated above regarding claim 1, Emendobio recites the composition comprises an RNA guide molecule (claim 1), and recites the first RNA guide molecule targets the CRISPR nuclease portion of the first fusion protein to a first CRISPR nuclease DNA target site (claim 7). Emendobio teaches the retrotransposon-encoded protein portion of the fusion protein complexes with the RNA template molecule and the CRISPR nuclease portion of the fusion protein complexes with the RNA guide molecule (paragraph 0008).
Regarding claim 7, Emendobio teaches the composition further comprises an additional retrotransposon-encoded protein capable of forming a dimer and performing functions of the gene editing process with the retrotransposon-encoded protein of the first fusion protein (paragraph 0100).
Regarding claim 11, Emendobio recites wherein the retrotransposon- encoded protein of the first or second fusion protein is derived from an R2 retrotransposon-encoded protein (claim 16). See also paragraphs 0054-0055, and Fig. 1A and 1B teaching a fusion protein comprising an R2 retrotransposon-encoded protein fused to a Cas9 nickase unit or dead Cas9.
Regarding claim 13, Emendobio recites wherein the first or second fusion protein comprises the retrotransposon-encoded protein portion linked to the N-terminus of the CRISPR nuclease portion (claim 24) or wherein the first or second fusion protein comprises the retrotransposon-encoded protein portion linked to the C-terminus of the CRISPR nuclease portion (claim 25).
Regarding claim 14, Emendobio recites the gene editing composition further comprising a second fusion protein, the second fusion protein comprising a) a retrotransposon-encoded protein portion; and b) a CRISPR nuclease protein portion (claim 9). Emendobio recites the CRISPR nuclease of the first or second fusion protein is a nickase (claim 18), or is a catalytically inactive dead CRISPR nuclease (claim 19).
Regarding claim 23, Emendobio recites wherein the RNA template molecule is linked to the first RNA guide molecule (claim 8), and therefore teaches the donor construct (RNA template molecule) is fused to either a 3’ or a 5’ end of the nucleic acid component (guide RNA molecule).
Regarding claim 26, Emendobio recites a polynucleotide molecule which expresses the gene editing composition of any one of claims 1-26, or a component thereof, in a cell (claim 27).
Regarding claim 27, Emendobio teaches the RNA and protein components are encoded on two separate vectors, and teaches an R2 retrotransposon inserted into a vector and RNA template constructs inserted into a vector (Example 1, paragraphs 0149-0154).
Regarding claim 28, Emendobio recites a modified cell having a sequence that has been modified by the method of any one of claims 28-30, and wherein the cell is a plant cell or a mammalian cell (claim 31).
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.
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 19,21,24 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Emendobio as applied to claims 1-3,7,11,13,14,23 and 26-28 above.
The teachings of Emendobio as applied to claims 1-3,7,11,13,14,23 and 26-28 have been described above.
Emendobio does not explicitly teach the exact cited order of the donor construct recited in claims 19 and 21.
However, Emendobio recites the RNA template molecule comprises at least one region having sequence homology to a DNA target site (claim 2) and wherein the region having sequence homology to a DNA target site flanks a retrotransposon-encoded protein binding site (claim 3) and wherein the RNA template molecule comprises a first retrotransposon-encoded protein binding site flanking the 5’ end of the insert template portion, and a second retrotransposon-encoded protein binding site flanking the 3’ end of the insert template portion (claim 4), and wherein a first region having sequence homology to a first DNA target site flanks the 5’ end of the first retrotransposon-encoded protein binding site, and a second region having sequence homology to a second DNA target site flanks 3’ end of the second retrotransposon-encoded protein binding site (claim 5). Emendobio teaches the RNA molecule comprises (1) a RNA guide portion that targets the fusion protein to a target site in the genome; and (2) an RNA template portion (paragraph 0014). Emendobio teaches as an example, an RNA template molecule includes secondary RNA structures upstream and downstream of an RNA insert template portion. Such RNA structures are used for proper binding of a retrotransposon-encoded protein to the RNA template molecule, and thus serve as retrotransposon-encoded protein binding sites (paragraph 0056) and a synthetic RNA template molecule comprises R2 protein binding sites flanking an RNA insert template sequence. The R2 protein binding sites are RNA sequences that form secondary structures which allow R2 protein binding and ribozyme activity. These R2 binding sites are termed the R2 5’ pseudoknot and R2 3’ structured regions. The synthetic RNA template molecule may further comprise one or two homology arms, which are complementary to sequences in a targeted genomic locus and facilitate accurate priming of an RNA template molecule at the genomic locus. The one or two homology arms may be upstream and/or downstream of an R2 protein binding site (paragraph 0057). In some embodiments, the gene editing composition further comprises an RNA molecule which comprises an RNA template portion, wherein the RNA template portion comprises at least one retrotransposon-encoded protein binding site flanking an RNA insert template portion. In some embodiments, the RNA molecule further comprises at least one homology arm flanking the retrotransposon-encoded protein binding site (paragraph 0133).
It would have been obvious to one of ordinary skill in the art before the effective filing date to have provided a donor construct comprising the recited components and order of claims 19 and 21 based on the teachings of Emendobio with a reasonable expectation of success. There would be a reasonable expectation of success as Emendobio teaches RNA template molecules comprising the recited components and various arrangements of the components and an ordinary artisan would be able to arrange the recited components based on known techniques to provide the recited donor construct and yield predictable results. One of ordinary skill in the art would have been motivated to do so based on the teachings of Emendobio regarding an RNA template molecule includes secondary RNA structures upstream and downstream of an RNA insert template portion. Such RNA structures are used for proper binding of a retrotransposon-encoded protein to the RNA template molecule, and thus serve as retrotransposon-encoded protein binding sites (paragraph 0056) and a synthetic RNA template molecule comprises R2 protein binding sites flanking an RNA insert template sequence. The R2 protein binding sites are RNA sequences that form secondary structures which allow R2 protein binding and ribozyme activity. The synthetic RNA template molecule may further comprise one or two homology arms, which are complementary to sequences in a targeted genomic locus and facilitate accurate priming of an RNA template molecule at the genomic locus. The one or two homology arms may be upstream and/or downstream of an R2 protein binding site (paragraph 0057).
Emendobio does not explicitly teach that the donor construct is fused to a 3’ end of the nucleic acid component.
However, Emendobio teaches the RNA-guided DNA nuclease is a CRISPR nuclease derived from a type II CRISPR system (e.g., Cas9) (paragraphs 0086-0087) as cited above for claim 3. Emendobio teaches there is a provided an RNA molecule comprising (1) a RNA template portion, e.g. for editing or correction of an allele; and (2) a retrotransposon protein recruiting portion, which encodes at least one sequence that recruits an endogenous retrotransposon-encoded component (e.g. an LI protein) reverse-transcribe an RNA template sequence for insertion at a target DNA site. The RNA molecule may further comprise an RNA guide portion (the nucleic acid component) which complexes with an RNA-guided DNA nuclease to target the RNA molecule to a target sequence (paragraph 0013), and in some embodiments, the RNA molecule comprises (1) a RNA guide portion that targets the fusion protein to a target site in the genome; and (2) an RNA template portion (paragraph 0014).
It would have been obvious to one of ordinary skill in the art before the effective filing date that the RNA template of Emendobio is fused to a 3’ end of the RNA guide portion (the nucleic acid component of instant claims) as there are only two options of being fused to either the 3’ end or the 5’ end of the RNA guide portion, and therefore fusing to the 3’ end or 5’ end is equally obvious. One of ordinary skill in the art would have been motivated to provide the donor construct fused to a 3’ end of the RNA guide portion because Emendobio teaches an RNA molecule comprising an RNA template portion which may further comprise an RNA guide portion which complexes with an RNA-guided DNA nuclease to target the RNA molecule to a target sequence, and teaches an RNA molecule comprises (1) a RNA guide portion that targets the fusion protein to a target site in the genome; and (2) an RNA template portion (paragraph 0014).
Emendobio does not explicitly teach an organism per se comprising the cell or progeny thereof transiently or non-transiently transfected with the vector system.
However, Emendobio teaches the gene editing compositions described herein may be delivered to a target cell by any suitable means and the target cell may be any type of cell e.g., eukaryotic or prokaryotic, in any environment e.g., isolated or not, maintained in culture, in vitro, ex vivo, in vivo or in planta (paragraph 0062). Emendobio teaches any suitable viral vector system may be used to deliver the compositions disclosed herein. Conventional viral and non-viral based gene transfer methods can be used to introduce the composition in cells (e.g., mammalian cells, plant cells, etc.) and target tissues. Such methods can also be used to administer nucleic acids encoding the composition or the composition itself to cells in vitro. In certain embodiments, the nucleic acids encoding the composition or the composition itself is administered for in vivo or ex vivo gene therapy uses (paragraph 0063). Emendobio teaches ex vivo cell transfection for diagnostics, research, or for gene therapy (e.g., via re infusion of the transfected cells into the host organism) is well known to those of skill in the art. In a preferred embodiment, cells are isolated from the subject organism, transfected with an RNA composition, and re-infused back into the subject organism (e.g., patient) (paragraph 0075).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to provide a subject organism that comprise cells that have been transfected with a vector system encoding the composition disclosed by Emendobio with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to do so because Emendobio taught the nucleic acids encoding the composition or the composition itself is administered for in vivo or ex vivo gene therapy uses (paragraph 0063). Emendobio teaches ex vivo cell transfection for diagnostics, research, or for gene therapy (e.g., via re infusion of the transfected cells into the host organism) is well known to those of skill in the art…in a preferred embodiment, cells are isolated from the subject organism, transfected with an RNA composition, and re-infused back into the subject organism (e.g., patient) and therefore the subject organism is an obvious product of the disclosed ex vivo gene therapy method.
Accordingly, the limitations of claims 19,21,24 and 29 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Emendobio as applied to claims 1-3,7,11,13,14,23 and 26-28 above and further in view of Yan et al. (Science 363, 88-91 (2019)).
The teachings of Emendobio as applied to claims 1-3,7,11,13,14,23 and 26-28 have been described above.
Emendobio teaches there is a provided an RNA molecule comprising (1) a RNA template portion, e.g. for editing or correction of an allele; and (2) a retrotransposon protein recruiting portion, which encodes at least one sequence that recruits an endogenous retrotransposon-encoded component (e.g. an LI protein) reverse-transcribe an RNA template sequence for insertion at a target DNA site. The RNA molecule may further comprise an RNA guide portion which complexes with an RNA-guided DNA nuclease to target the RNA molecule to a target sequence (paragraph 0013), and in some embodiments, the RNA molecule comprises (1) a RNA guide portion that targets the fusion protein to a target site in the genome; and (2) an RNA template portion (paragraph 0014).
Emendobio does not teach the site-specific nuclease is a TnpB or a Type V Cas or that the donor construct is fused to a 5’ end of the nucleic acid component.
However, Emendobio teaches there is a provided an RNA molecule comprising (1) a RNA template portion, e.g. for editing or correction of an allele; and (2) a retrotransposon protein recruiting portion, which encodes at least one sequence that recruits an endogenous retrotransposon-encoded component (e.g. an LI protein) reverse-transcribe an RNA template sequence for insertion at a target DNA site. The RNA molecule may further comprise an RNA guide portion which complexes with an RNA-guided DNA nuclease to target the RNA molecule to a target sequence (paragraph 0013), and in some embodiments, the RNA molecule comprises (1) a RNA guide portion that targets the fusion protein to a target site in the genome; and (2) an RNA template portion (paragraph 0014).
Before the effective filing date, Yan et al. taught Class 2 CRISPR-Cas systems are of particular interest, because their programmable single-effector nucleases have enabled genome engineering and nucleic acid detection tools, and that Class 2 systems include types II, V, and VI, which are based on Cas9, Cas 12, and Cas13 effectors, respectively. Yan et al. taught Cas9 contains an HNH nuclease domain inserted into a RuvC nuclease domain, and the two domains together cleave double-stranded DNA, Cas12 contains a single RuvC nuclease domain that cleaves dsDNA adjacent to protospacer adjacent motif (PAM) sequences and single-stranded DNA (ssDNA) nonspecifically (page 88, left column). Yan et al. taught a framework for systematic discovery, screening, and characterization of class 2 CRISPR-Cas systems, and demonstrated a range of activities for four type V CRISPR-Cas subtypes, including target and collateral cleavage of ssRNA and ssDNA as well as dsDNA nicking and cleavage (Fig. 4C). These findings reveal the transition in the properties of Cas12 proteins along the proposed evolutionary path from TnpB to large type V effectors. Additionally, future applications could include expanded genomic targeting via the minimal Cas12c2 PAM, high-fidelity genome editing using Cas12i nicking or sensitive and durable nucleic acid detection via collateral cleavage by the thermostable Cas12g1 (pages 90-91).
It would have been obvious to one of ordinary skill in the art before the effective filing date to substitute the CRISPR endonuclease of Emendobio with a Type V Cas of Yan et al., and that the RNA template of Emendobio is fused to a 5’ end of the RNA guide portion as there are only two options of being fused to either the 3’ end or the 5’ end of the RNA guide portion. This would amount to substituting one type of site-specific nuclease for another site-specific nuclease to yield predictable results. One of ordinary skill in the art would have been motivated to substitute the CRISPR endonuclease of Emendobio with a Type V Cas because Yan et al. taught Class 2 CRISPR-Cas systems are of particular interest, because their programmable single-effector nucleases have enabled genome engineering and nucleic acid detection tools, and that Class 2 systems include types II, V, and VI, which are based on Cas9, Cas 12, and characterization of class 2 CRISPR-Cas systems demonstrated a range of activities for four type V CRISPR-Cas subtypes, including target and collateral cleavage of ssRNA and ssDNA as well as dsDNA nicking and cleavage (Fig. 4C). These findings reveal the transition in the properties of Cas12 proteins along the proposed evolutionary path from TnpB to large type V effectors, and that future applications could include expanded genomic targeting via the minimal Cas12c2 PAM and high-fidelity genome editing using Cas12i nicking. One of ordinary skill in the art would have been motivated to provide the donor construct fused to a 5’ end of the RNA guide portion as there are only two options, either fusing to the 3’ end or 5’ end and either is equally obvious and because Emendobio teaches an RNA molecule comprising an RNA template portion which may further comprise an RNA guide portion which complexes with an RNA-guided DNA nuclease to target the RNA molecule to a target sequence, and teaches an RNA molecule comprises (1) a RNA guide portion that targets the fusion protein to a target site in the genome; and (2) an RNA template portion (paragraph 0014).
Accordingly, the limitations of claim 25 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 1-3,7,11,13,14,19,21 and 23-29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1,3,6,7,9,12,13,17,18,41-44,46,47,50,52,53,57,62,68,71-74 and 76-89 of copending Application No. 17/778,192.
Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1,3,6,12,13,17,18,41-44,46,47,50,52,53,57,62,68,71-74 and 76-89 of copending application ‘192 recite an engineered or non-naturally occurring composition comprising a site-specific nuclease polypeptide (such as TpnB, as recited at claim 41), a non-LTR retrotransposon polypeptide (such as R2 as recited in claim 13) connected to the site-specific nuclease polypeptide, a guide molecule capable of forming a complex with the site-specific nuclease polypeptide and directing site-specific binding to a target sequence, and a polynucleotide encoding a retrotransposon RNA, wherein the retrotransposon RNA is capable of forming a complex with the non-LTR retrotransposon polypeptide (as recited in claim 3) and comprises or encodes a donor polynucleotide for insertion at a target sequence (as recited in claim 6). The site-specific nuclease polypeptide of is further recited to lack nuclease activity or be a nickase in claim 7. Claim 9 further recites that the non-LTR retrotransposon polypeptide taught therein is a dimer, wherein the dimer subunits are connected or form a tandem fusion.
Similarly, instant claims 1-3,13,14,19,21 and 23-29 recite an engineered composition comprising a site-specific nuclease (such as an IscB or a TnpB per copending claim 2), a non-LTR retrotransposon polypeptide fused to said site-specific nuclease, and a donor construct
comprising a donor polynucleotide sequence for insertion into the target polynucleotide and comprising one or more elements capable of forming a complex with the non-LTR
retrotransposon polypeptide. Claim 7 further recites that the non-LTR retrotransposon polypeptide is a dimer, wherein the dimer subunits are connected or form a tandem fusion. Claim 11 further recites that the non-LTR retrotransposon is R2, and claim 19 recites that the donor taught therein comprises first and second homology regions in addition to the donor template for insertion into the target polynucleotide.
This is a provisional nonstatutory double patenting rejection.
Claims 1-3,7,11,13,14,19,21 and 23-29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 39,47,49 and 51 of copending Application No. 18/249,865.
Although the claims at issue are not identical, they are not patentably distinct from each other because claim 39 of copending application '865 recites an engineered, non-naturally occurring composition comprising a Cas protein, a non-LTR retrotransposon associated with the Cas protein, a single guide molecule capable of forming a complex with the Cas protein and directing site-specific binding to a target sequence, and a donor construct for insertion into the targeted sequence. Claims 47 and 49 further recite one or more polynucleotides encoding one or more components of said composition, as well as a method of using said composition to direct the non-LTR retrotransposon protein to the target sequence, thereby facilitating insertion of the donor polynucleotide sequence at the target sequence, optionally introducing one or more base edits. Claim 51 recites an isolated cell or progeny thereof.
Similarly, instant claims 1-3,13,14,19,21 and 23-29 recite an engineered composition comprising a site-specific nuclease, which can be a Cas polypeptide in claims 2,3,14,21,23-29, a non-LTR retrotransposon polypeptide fused to said site-specific nuclease, and a donor construct comprising a donor polynucleotide sequence for insertion into the target polynucleotide and comprising one or more elements capable of forming a complex with the non-LTR retrotransposon polypeptide. Instant claim 28 recites a cell or progeny thereof transfected with the vector system encoding the polypeptide and/or nucleic acid components of claim 14.
This is a provisional nonstatutory double patenting rejection.
Claims 1-3,7,11,13,14,19,21 and 23-29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 37,39,40,42 and 45-48 of copending Application No. 18/271,684.
Claim 37 of copending application '684 recites an engineered, non-naturally occurring composition comprising a TnpB polypeptide, a non-LTR retrotransposon protein associated with said TnpB polypeptide, and an wRNA component (comprising a donor template comprising a homology region (per copending claim 42) located between two binding elements capable of forming a complex with the non-LTR retrotransposon protein) capable of forming a complex with the TnpB protein and directing site-specific binding of the complex to a target sequence of a target polynucleotide. The TnpB polypeptide taught therein may be engineered to have nickase activity per copending claim 39. Additionally, the wRNA component molecule directs the fusion protein to a target sequence 3' of the targeted insertion site per copending claim 40. Claims 45-48 further recite one or more polynucleotides encoding one or more components of said composition (as well as one or more vectors comprising the same), as well as a method of using said composition to direct the non-LTR retrotransposon protein to the target sequence, thereby facilitating insertion of the donor polynucleotide sequence at the target sequence and introducing one or more base edits.
Similarly, instant claims 1-3,7,11,13,14,19,21 and 23-29 recites an engineered composition comprising a site-specific nuclease (such as an IscB or a TnpB per copending claim 2), a non-LTR retrotransposon polypeptide fused to said site-specific nuclease, and a donor construct comprising a donor polynucleotide sequence for insertion into the target polynucleotide and comprising one or more elements capable of forming a complex with the non-LTR retrotransposon polypeptide. Instant claim 27 recites a vector system encoding the polypeptide and/or nucleic acid components of claim 14.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 1-3,7,11,13,14,19,21 and 23-29 are rejected.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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