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 .
Application Status
This action is written in response to applicant’s correspondence received Dec 18, 2025. Claims 1-36, and 38-39 are currently pending and under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/274,483, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Support for the recitation of “at least a first integrase” in instant independent claims 1, 36, and 38-39 is not found in ‘483. Thus, this Application fails to disclose the structures of the nucleic acid construct of claims 1, 36, and 38-39 and the limitations thereof as recited in the dependent claims.
The disclosure of the prior-filed application, Application No. 63/282,055, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Support for the recitation of “at least a first integrase” in instant independent claims 1, 36, and 38-39 is not found in ‘055. Thus, this Application fails to disclose the structures of the nucleic acid construct of claims 1, 36, and 38-39 and the limitations thereof as recited in the dependent claims.
The disclosure of the prior-filed application, Application No. 63/282,055, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Support for the recitation of “at least a first integrase” in instant independent claims 1, 36, and 38-39 is not found in ‘055. Thus, this Application fails to disclose the structures of the nucleic acid construct of claims 1, 36, and 38-39 and the limitations thereof as recited in the dependent claims.
The disclosure of the prior-filed application, Application No. 63/298,941, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Support for the recitation of “at least a first integrase” in instant independent claims 1, 36, and 38-39 is not found in ‘055. Thus, this Application fails to disclose the structures of the nucleic acid construct of claims 1, 36, and 38-39 and the limitations thereof as recited in the dependent claims.
The disclosure of the prior-filed application, Application No. 63/318,344, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Support for the recitation of “at least a first integrase” in instant independent claims 1, 36, and 38-39 is not found in ‘055. Thus, this Application fails to disclose the structures of the nucleic acid construct of claims 1, 36, and 38-39 and the limitations thereof as recited in the dependent claims.
The disclosure of the prior-filed application, Application No. 63/352,897, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Support for the recitation of “at least a first integrase” in instant independent claims 1, 36, and 38-39 is not found in ‘055. Thus, this Application fails to disclose the structures of the nucleic acid construct of claims 1, 36, and 38-39 and the limitations thereof as recited in the dependent claims.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Claims 1-36, and 38-39 are granted priority to the International Patent Application PCT/US2022/079035 filed on Nov 01, 2022.
Information Disclosure Statement
The listing of references in the specification (e.g., [0078], [0082]) is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink ([0080]) 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.
Claim Objections
Claims 4 and 24-25 are objected to because of the following informalities: the quoted recitation is redundant because the language is already included in the claim from which it depends. Appropriate correction is required.
Claim 4 recites wherein the first integrase "that is encoded by a nucleotide sequence in the nucleic acid construct". It would be remedial to delete this recitation from the claim.
Claim 24 recites the nucleic acid construct of claim 1 further comprising a sub-sequence “of the nucleic acid construct”. It would be remedial to recite the nucleic acid construct of claim 1 further comprising a sub-sequence that is capable of self-circularizing to form a self-circular nucleic acid.
Claim 25 recites wherein the sub-sequence “of the nucleic acid construct that is capable of self-circularizing”. It would be remedial to recite wherein the sub-sequence includes the nucleic acid cargo.
Claims 5, 35-36, and 38 are objected to because of the following informalities: An acronym should be defined the first time it appears in an independent claim or in the group of claims under an independent claim. Appropriate correction is required.
In claim 5, line 5, the acronym “RT” is defined as being “reverse transcriptase”. However, this term has previously been recited in claim 1.
In claim 35, line 2, the acronym “ITR” is defined as being “inverted terminal repeat”. However, this term has previously been recited in claim 34.
In claims 36 and 38, the acronym “atgRNA” is defined as being “attachment site-containing guide RNA, and the acronym “ngRNA” is defined as being “nickase guide RNA”. However, these terms have previously been recited in claim 1.
Claim 33 is objected to because of the following informalities: a comma is missing preceding “and integration of the self-circular nucleic acid”. It is recommended that the claim reads “wherein self-circularization to form the self-circular nucleic acid is effected by the first integrase, and integration of the self-circular nucleic acid is effected by the second integrase”. Appropriate correction is required.
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 3-4, 7, 9-10, 12, 16, 18, 25-30, 32-33 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. Those claims included in the statement of rejection but not otherwise discussed are rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
Claim 3 recites "the gene editor system" in line 3. There is insufficient antecedent basis for this limitation in the claim. There is no prior recitation of the term "gene editor system". Rather, claim 3 depends on claim 2 that recites "the prime editor system" in line 1. It is unclear how the gene editor system of claim 3 relates to the prime editor system of claim 2. It is unclear if they are referring to the same editor system or not.
Claim 4 recites "wherein the first integrase...is fused to the primer editor system, the nickase, or the reverse transcriptase by a linker" (emphasis added). Claim 4 depends on claim 1, and there is insufficient antecedent basis for the limitations of "the nickase" and "the reverse transcriptase" in the claim. It is noted that the first recitations of these two limitations are in claim 2. It is unclear how the nickase and reverse transcriptase of claim 2 relates to the nickase and reverse transcriptase of claim 4. It is not clear if they are referring to the same proteins or different proteins encoded in the nucleic acid construct.
Claim 7 recites "the target sequence" in line 3-4. There is insufficient antecedent basis for this limitation in the claim. There is no prior recitation of a target sequence in claim 1 from which it depends. Claim 7 previously depends on claim 5, which provides the first recitation of "a target sequence". It is unclear whether the target sequence of claim 7 refers to the same target sequence of claim 5 or to a different target sequence.
Claim 9 recites "the first integration site" in lines 6, 8, and 10. There is insufficient antecedent basis for this limitation in the claim. There is no prior recitation of “a first integration site” in the instant claim or the claim from which it depends. Thus, it is unclear which element is instant claim referring to. It is noted the first recitation of "first integration site" is in claim 5, but instant claim does not depend on claim 5. It is unclear whether the first integration site of claim 9 is related to claim 5. It is unclear whether they are referring to the same or different first integration site.
Claim 12 recites "the first integration site" in line 2. There is insufficient antecedent basis for this limitation in the claim. There is no prior recitation of “a first integration site” in the instant claim or the claim from it depends. Thus, it is unclear which element is instant claim referring to. It is noted the first recitation of "first integration site" is in claim 5. It is unclear how whether the first integration site of claim 12 is related to claim 5. It is unclear whether they refer to the same or different first integration site.
Claim 16 recites “wherein the second cognate pair has a faster integration rate than the first cognate pair” (emphasis added). There is insufficient antecedent basis for these two limitations in the claim. There is no prior recitation of these two limitations in the instant claim or the claim from which it depends. It is noted that the recitation of “any one of claims 10-15” is deleted from instant claim 16, which would provide antecedent basis for the recited first and second cognate pairs. It is also noted the first recitation of “a second cognate pair” is in claim 15. It is unclear whether the second cognate pair of 16 is related to claim 15. It is unclear whether they are referring to the same or different second cognate pair. Similarly, the first recitation of “a first cognate pair” is in claim 12. It is unclear how the first cognate pair of claims 12 and 16 are related. It is unclear whether they are referring to the same or different first cognate pair.
Claim 18 recites “the second integrase”, in line 2. There is insufficient antecedent basis for this limitation in the claim. There is no prior recitation of “a second integrase” in the instant claim or any claim from it depends. It is noted that the recitation of “any one of claims 1-17” is deleted from instant claim 18, which would provide antecedent basis for the recited second integrase. It is also noted the first recitation of “a second integrase” is in claim 17. It is unclear how the second integrase of claims 17 and 18 are related. It is unclear whether they are referring to the same or different second integrase.
Claim 25 recites wherein the sub-sequence of the nucleic acid construct that is capable of self-circularizing includes the nucleic acid cargo (emphasis added), which indicates the nucleic acid cargo is present in the sub-sequence regardless of whether the sub-sequence is self-circularized or not as the claim is limited to the sub-sequence of the nucleic acid construct with the capabilities of self-circularizing. However, the subsequent recitation, “whereby upon self-circularizing the self-circular nucleic acid comprises the nucleic acid cargo”, creates ambiguity and renders the claim indefinite. It is unclear whether this recitation requires that the nucleic acid cargo be present in the sub-sequence because of self-circularization or is merely stating the presence of the nucleic acid cargo before self-circularization.
The recitation of “self-circularizing the self-circular nucleic acid” in claim 25 also renders the determination of the scope of the claim difficult. The claim from which it depends, claim 24, recites the sub-sequence is capable of self-circularizing to form a self-circular nucleic acid, which suggests that the self-circular nucleic acid is obtained after self-circularization. However, the recitation of “self-circularizing the self-circular nucleic acid” makes it unclear whether the self-circular nucleic acid undergoes a further self-circularization. It is unclear how the self-circular nucleic acid of claim 25 relates to the self-circular nucleic acid of claim 24. It is unclear whether claim 25 intends to refer to the self-circular nucleic acid of claim 24 and further limit it to comprise the nucleic acid cargo of claim 1.
Claims 26 and 28 recites “the third integrase recognition site” and “the fourth integrase recognition site”. There is insufficient antecedent basis for these two limitations in the claims. There is no prior recitation of these two limitations in the instant claims or the claims from which they depend. It is noted the first recitation of “a third integrase recognition site” is in claim 13. It is unclear how the third integrase recognition site of claims 13, 26, and 28 are related. It is unclear whether they are referring to the same or different third integrase recognition site. Similarly, the first recitation of “a fourth integrase recognition site” is in claim 14. It is unclear how the fourth integrase recognition site of claims 14, 26, and 28 are related. It is unclear whether they are referring to the same or different fourth integrase recognition site.
Claim 27 recites “the second integrase recognition site”. There is insufficient antecedent basis for this limitation in the claim. There is no prior recitation of this limitation in the instant claim or the claim from which it depends. It is noted the first recitation of “a second integrase recognition site” is in claim 11. It is unclear whether the second integrase recognition site of claim 27 is related to the second integrase recognition site of claim 11. It is unclear whether they are referring to the same or different second integrase recognition site.
Claim 29 recites “the first recombinase recognition site” and “the second recombinase recognition site”. There is insufficient antecedent basis for these two limitations in the claims. There is no prior recitation of these two limitations in the instant claim or the claim from which it depends. It is noted the first recitation of “a first recombinase recognition site” is in claim 20. It is unclear whether the first recombinase recognition site of claim 29 is related to the first recombinase recognition site of claim 20. It is unclear whether they are referring to the same or different first recombinase recognition site. Similarly, the first recitation of “a second recombinase recognition site” is in claim 21. It is unclear whether the second recombinase recognition site of claims 21 and 29 are related. It is unclear whether they are referring to the same or different second recombinase integrase recognition site.
Claim 30 recites “a second recombinase recognition site”, but claim 29 from which claim 30 depends recites “the second recombinase recognition site”. It is unclear whether claim 30 is introducing an additional second recombinase recognition site or it is referring to the second recombinase recognition site of claim 29. It is unclear whether the self-circularizing is mediated by recombination of the first and the second recombinase recognition sites flanked in the sub-sequence of claim 29. It is unclear whether the self-circularizing is mediated by recombination of the first recombinase recognition site flanked in the sub-sequence of claim 29 and an second recombinase recognition site, in addition to the second recombinase recognition site already flanked in the sub-sequence of claim 29.
Claim 32 recites “the second integrase recognition site” and “the first integrase recognition site”. There is insufficient antecedent basis for these two limitations in the claim. There is no prior recitation of these two limitations in the instant claim or any of the claims from which it depends. It is noted the first recitation of “a second integrase recognition site” is in claim 11. It is unclear whether the second integrase recognition site of claims 32 and 11 are related. It is unclear whether they are referring to the same or different second integrase recognition site. Similarly, the first recitation of "first integration site" is in claim 5. It is unclear whether the first integration site of claims 32 and 5 are related. It is unclear whether they refer to the same or different first integration site.
Claim 32 also recites "the target sequence" in line 5. There is insufficient antecedent basis for this limitation in the claim. There is no prior recitation of this limitation in the instant claim or any claims from which it depends. It is noted the first recitation of "target sequence" is in claim 5. It is unclear whether the target sequence of claim 32 is related to the target sequence of claim 5. It is unclear whether they are referring to the same or different target sequence.
Claim 33 recites “the second integrase” which lacks antecedent basis in the claim. There is no prior recitation of this limitation in the instant claim or any claims from which it depends. It is noted the first recitation of “a second integrase” is in claim 17. It is unclear whether the second integrase of claim 17 is related to the second integrase of claim 33. It is unclear whether they are referring to the same or different second integrase.
Claim 33 recites “wherein self-circularization…is effected by the first integrase and integration of the self-circular nucleic acid is effected by the second integrase”, which renders the claim indefinite. The specification does not provide guidance regarding the scope of “effected by”, including the degree in which the integrases contribute to the claimed reactions. It is unclear whether the claim requires the integrase to complete the entire reaction or not. It is unclear whether the claim requires (i) the integrase to initiate the reactions and (ii) one or more additional enzymes to complete the reactions. It is unclear whether “effected by” requires the integrases to be solely responsible for the reactions, or merely a necessary component. Without clarity, one ordinary skilled in the art could not reasonably determine the metes and bounds of the claim.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 30 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 30 depends on claim 29, which further depends on claim 28. Claim 30 requires self-circularizing to be mediated by recombination of a first recombination recognition site and a second recombinase recognition site by a recombinase, which substitutes the self-circularizing requirements of claim 28 where recombination occurs between the third integrase recognition and the fourth integration recognition site by the first integrase. Thus, dependent claim 30 fails to include all of the limitations of the claim from which it depends and further limit that claim.
Claim Interpretation
Claims 5 and 9 recite “at least a portion” of a first integration recognition site. The recitation of “at least a portion” is interpreted to encompass at least one nucleotide of the first integration site and up to the full-length integration recognition site.
Claims 6 and 9 recite “entirety of the first integration recognition site”. The recitation of “entirety” is interpreted to encompass the full-length of the integration recognition site, with or without nucleotides at both ends.
Claim 16 recites “wherein the second cognate pair has a faster integration rate than the first cognate pair”, which renders the claim indefinite due to lack of antecedent basis (see discussion above in 112(b)). The specification discloses the nucleic acid construct includes a first cognate pair (e.g., a first integrase recognition site and a second recognition site) and a second cognate pair (e.g., a third integrase recognition site and a fourth recognition site); in addition, the first cognate pair and the second cognate pair have different integration rates, e.g., the second cognate pair has a faster integration rate whereby self-circularization occurs prior to integration into the genome ([0174]). In view of these teachings and the deleted recitation of “any one of claims 10-15” indicating that claim 16 was previously dependent of claim 15, claim 16 is interpreted to refer to the second cognate pair recited in claim 15 in the interest of compact prosecution.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-8, 11-15, 23, 34-36, and 38 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Abudayyeh (WO 2022087235A1; Published Date: Apr 28, 2022; Filling Date: Oct 21, 2021; IDS received on 04/26/2024, Cite No. B1). The rejection of claims 34-35 is evidenced by Earley (Human Gene Therapy; 2020, 31: 151-162).
Regarding claim 1, Abudayyeh teaches a vector (i.e., nucleic acid construct) comprising a) a nucleotide sequence encoding a DNA binding nuclease comprising a nickase activity that is C-terminally linked to a reverse transcriptase (i.e., a prime editor system); b) a nucleotide sequence encoding a gRNA comprising a primer binding sequence, an integration sequence, and a guide sequence (i.e., at least a first attachment site-containing guide RNA: atgRNA); c) a nucleotide sequence encoding an integration enzyme linked to the reverse transcriptase (i.e., at least a first integrase); d) a DNA minicircle (i.e., a nucleic acid cargo) (claim 54). Abudayyeh further teaches all these nucleotide sequences can be packaged into one vector ([307]).
Regarding claims 2-3, Abudayyeh further teaches wherein the prime editor system comprises nucleotide sequences encoding a nickase that is C-terminally linked to a reverse transcriptase (claim 54). Thus, Abudayyeh teaches the nucleotide sequences encoding these two enzymes are positioned in the construct such that when expressed, the prime editor system comprises a fusion protein comprising the nickase and the reverse transcriptase.
Regarding claim 4, Abudayyeh further teaches wherein the first integrase is linked to the reverse transcriptase via a linker (claim 54).
Regarding claim 5, Abudayyeh further teaches the gRNA (i.e., atgRNA) discussed in instant claim 1 can also be refer to as prime-editing guide RNA (pegRNA) ([264]), which comprises (i) a guide sequence (i.e., a domain) that can interact with the encoded nickase and guide it to a DNA target site (claim 54, [260]); and (ii) a reverse transcriptase template sequence comprising and an integration site sequence (i.e., a first integration recognition site) that can be recognized by recombinases, integrases or transposases ([265], FIG. 2, FIG. 29E).
Regarding claim 6, Abudayyeh further teaches the pegRNA comprises an integration site sequence that can be recognized by recombinases, integrases or transposases ([265], FIG. 2) (i.e., wherein the RT template comprises the entirety of the first integration recognition site).
Regarding claim 7, Abudayyeh further teaches the first integrase recognition site (e.g., lox71 or lox66) are incorporated into the cell’s genome at a target site by the atgRNA upon transfection of plasmids encoding prime editing construct (i.e., the nucleic acid construct of claim 1) ([319], FIG. 4).
Regarding claim 8, Abudayyeh further teaches the nucleic acid construct further comprises a nicking guide RNA (i.e., a second atgRNA ) (claim 54).
Regarding claim 11, Abudayyeh further teaches the nucleic acid construct, particularly the nucleic acid cargo, further comprises a second integrase recognition site (FIG. 6).
Regarding claim 12, Abudayyeh further teaches wherein the second and first integrase recognition sites are a first cognate pair, for example, attB and attP sites (FIG. 6) or attPTT and attBTT sites comprising two central nucleotides changed from GA to TT ([328], FIG. 13).
Regarding claims 13-15, Abudayyeh further teaches the nucleic acid construct, particularly the nucleic acid cargo, further comprises a third and a fourth integrase site that is a second cognate pair (FIG. 13, reproduced below). Abudayyeh teaches that modifying the central dinucleotide of attB and attP sites generate a series of orthogonal integrase recognition sites that allow site-specific integration of multiple genes into a cell ([328]-[332], FIG. 16A, 16B).
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Regarding claim 23, Abudayyeh further teaches wherein the nucleic acid cargo comprises a gene, particularly green fluorescent protein or mCherry ([329]).
Regarding claim 34-35, Abudayyeh further teaches the nucleic acid construct is delivered via adeno-associated virus (AAV) in vivo ([367), which indicates the nucleic acid construct comprises a 5’ and a 3’ inverted terminal repeat (ITR). As evidenced by Earley, “96% of the AAV genome is replaced with a gene cassette of interest, leaving only the 145bp ITR sequences” flanking the ends of the genome (i.e., 5’ and 3’ ITRs) (abstract; pg. 151, introduction, left-column).
Regarding claim 36, Abudayyeh teaches a vector comprising the recited nucleic acid construct as discussed above as applied to claim 1 (claim 54).
Regarding claim 38, Abudayyeh teaches preparing the nucleic acid construct in a pharmaceutically acceptable carrier for in vitro, ex vivo, or in vivo delivery to the carrier including a cell, a tissue, an organ, or a subject ([305]). Thus, Abudayyeh teaches a pharmaceutical composition comprising the recited nucleic acid construct.
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.
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 8-10, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Abudayyeh (cited supra) as applied to claims 1 and 8 above, and further in view of Zhang (WO 2021/138469 A1 Pub Date: July 08, 2021; IDS received 04/26/2024, Cite No. B2).
Regarding claims 8-9, Abudayyeh is applied to relevant teachings of claim 1 as discussed above and are incorporated herein by reference. Abudayyeh teaches wherein the nucleic acid construct comprises (i) a first atgRNA comprising a reverse transcriptase (RT) template encoding a first integration recognition site, and (ii) a second atgRNA (e.g., nicking guide RNA) (claim 54). Abudayyeh teaches the first atgRNA is capable of inserting sequences up to 56 base pairs at a specific genomic site, “with higher efficiency at lengths below 31 bp” ([346], FIGs 29A-B).
However, Abudayyeh does not teach the second atgRNA includes a second RT template that comprises at least a portion of the first integration recognition site.
Zhang teaches nucleic acid constructs comprising nucleotide sequences encoding (a) a Cas polypeptide connected or otherwise capable of forming a complex with a reverse transcriptase (i.e., a prime editor system), (b) a guide molecule capable of forming a complex with the Cas polypeptide, comprising a sequence capable of directing site-specific binding of Cas complex to a target sequence, comprising a binding site region, and a RT template, (c) a recombinase (i.e., a first integrase), and (d) a donor template (i.e., nucleic acid cargo) (claim 1, [0223], [0054]). Zhang further teaches the guide molecule is also referred to as pegRNA, and that the nucleic acid construct comprises two pegRNAs (i.e., a pair of atgRNA) ([0136]). Zhang teaches each of the two pegRNAs include RT template containing desired 3’ overhangs or extended regions (i.e., a first and second RT template) complementary to each other and introduce a serine integrase recombination site (i.e., entirety of the first integration recognition site) ([0136], [0014]). In other words, Zhang teaches using a pair of pegRNAs, each carrying an RT template comprising extended regions in such way that two extended regions cooperate to introduce one integration recognition site. Zhang further teaches this strategy enables introduction of integration recognition sites up to 50 bp as recognition sites identified by serin integrases have a minimal length of approximately 34-40 bp ([0056], pg. 18).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified Abudayyeh’s atgRNAs to include a second atgRNA that comprises an RT template encoding at least a portion of the integration recognition site as taught by Zhang because it would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. Each component in the combination performs the same function as they do separately: each atgRNA comprises an RT template that encodes at least a portion of the integration recognition site. One would have been motivated to have done so for the advantage of using two atgRNAs to distribute the sequence of the integration recognition site for prime editing, particularly sequences which length exceed optimal prime editing efficiency of below 31 bp as demonstrated by Abudayyeh; thereby enabling incorporation of diverse integration recognition sites not restricted by length. One would have had a reasonable expectation of success in doing so because Zhang demonstrates paired atgRNAs can generate complementary extended regions that collectively introduce a serine integrase recognition site.
Regarding claim 10, the obviousness to modify Abudayyeh’s nucleic acid construct to comprise a second atgRNA comprising recited limitation is discussed above as applied to claims 8-9. Zhang further teaches the composition comprising nucleotide sequences encoding the aforementioned components target a polynucleotide sequence in the genome of a cell ([0043], and the Cas complexes comprising the pair of atgRNAs are capable of inserting a recombination site in the DNA loci of interest ([0052]). Accordingly, Zhang teaches the recited limitation of instant claim 10.
Regarding claim 39, the obviousness to modify Abudayyeh’s nucleic acid construct to comprise a second atgRNA comprising recited limitation is discussed above as applied to claims 8-9. Abudayyeh teaches a pharmaceutical composition comprising the recited nucleic acid construct ([305]) as discussed above as applied to claim 38.
However, Abudayyeh does not teach a method comprising administering to a patient in need thereof an effective amount of the pharmaceutical composition.
Zhang teaches a pharmaceutical composition comprising the nucleic acid construct, and it is delivered to the tissues of interest of a patient via various delivery strategies and dosages known to one skilled in the art ([0295]-[0296], [0830]) for gene therapy treatments associated with a wide range of genetic diseases ([0973]).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have delivered Abudayyeh’s pharmaceutical composition to a patient in need thereof as taught by Zhang because it would have merely amounted to a simple combination of prior art elements to yield predictable results. Abudayyeh teaches delivery of pharmaceutical composition in vivo to a tissue or an organ ([305]), and Zhang teaches the pharmaceutical composition can be delivered in vivo to a patient’s tissue of interest for gene therapy treatments. Accordingly, one would have been motivated to have done so for the advantage administering the pharmaceutical composition to a patient to correct defects associated with genetic diseases as taught by Zhang. One would have had a reasonable expectation of success in doing so because both Abudayyeh and Zhang teach (i) pharmaceutical compositions comprising the recited limitations, and (ii) delivery in vivo to a tissue.
Claims 20-22, 24-28, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Abudayyeh (cited supra) as applied to claim 1 above, and further in view of Lamb (US 10,793,867 B2; Published Date: Oct 06, 2020).
Regarding claim 24, Abudayyeh is applied to relevant teachings of claim 1 as discussed above and are incorporated herein by reference. In summary, Abudayyeh teaches a nucleic acid construct comprising a prime editor system and a nucleic acid cargo that is a minicircle DNA (claim 54), in which all undesired bacterial components are removed and allowing only the desired gene to be integrated into the host cell genome along with minimal scars from the integration sites ([337]).
However, Abudayyeh does not teach the nucleic acid construct further comprises a sub-sequence that is capable of self-circularizing to form a self-circular nucleic acid.
Lamb teaches a “linear donor DNA construct” (i.e., nucleic acid construct) comprising a nucleotide sequence encoding (i) a TALER target sequence, (ii) a nucleic acid cargo or exogenous DNA sequence, and (iv) integrase recognition sites (e.g., Lox sites) (claim 1; FIG. 3 annotations are underlined below). Lamb further teaches the integrase recognition sites “cause the formation of a circular intermediate” comprising the nucleic acid cargo and the TALER target sequence (claim 1; Example 2, para. 2). Thus, Lamb teaches a sub-sequence that is capable of self-circularizing to form a self-circular nucleic acid (referred to as circular intermediate). Lamb further teaches upon formation of the sub-sequence, a TALER recombinase subsequently mediates recombination between the TALER target sequence encoded in the self-circular nucleic acid and another TALER target sequence located in a host cell genome, resulting in integration of the self-circular nucleic acid at a selected genomic locus and an intended integration site (Example 2, para. 2; FIG. 3). Lamb also explains that recombination between a circular donor DNA molecule and a genomic site results in integration of the entire donor DNA molecule at the genomic site, including undesired DNA sequences in the donor DNA molecule (Example 2, para. 1), whereas recombination between a linear donor DNA molecule and a genomic site results in a chromosomal break. Thus, the strategy of forming a circular intermediate from a linear donor DNA molecule avoids these disadvantages.
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Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified Abudayyeh’s strategy of providing the nucleic acid cargo to a linear donor construct that forms a circular intermediate (i.e., self-circular nucleic acid) in view of Lamb. This modification would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. This modification is (i) a simple substitution of swapping one linear nucleic acid cargo to another that serves the same purpose of encoding a sequence of interest to be integrated into a specific genomic site. One would have been motivated to have done so for the advantage of avoiding chromosomal break as taught by Lamb. Abudayyeh also teaches supplying the nucleic acid cargo as a minicircle DNA devoid of significant bacterial sequences (col. 37, lines 1-10). Thus, this modification would have also merely amounted to (ii) a simple substitution of alternative means of providing a circular nucleic acid cargo for later genomic integration. Lamb teaches the sub-sequence flanking integrase recognition sites is delivered to the host cell and undergoes self-circularization intracellularly to generate the self-circular nucleic acid for subsequence genomic integration. Thus, this modification does not change Abudayyeh’s mechanism of integrating the circular nucleic acid cargo into host cell genome, rather, it modifies the strategy of providing the nucleic acid cargo. One would have been motivated to have done so for the advantage of generating a self-circular nucleic acid intracellularly immediately prior to genomic integration as taught by Lamb, rather than supplying it exogenously. One would have had a reasonable expectation of success in doing so because both Abudayyeh and Lamb teach genomic integration of a circular nucleic acid cargo via recombination between integrase recognition sites located in the circular nucleic acid and a specific genomic site.
Regarding claims 25-28, the obviousness to modify Abudayyeh’s nucleotide sequence encoding the nucleic acid cargo to a sub-sequence capable of self-circularizing as taught by Lamb is discussed above as applied to claim 24. Lamb teaches the sub-sequence is flanked by specific nucleotide sequences recognized by enzymes well known in the art, including integrase phiC31 (Example 2, para. 3) (i.e., a third and a fourth integrase recognition site), and recombination between these two sites result circularization of the sub-sequence comprising the nucleic acid cargo and the TALER target sequence (i.e., second integrase recognition site) by a recombinase (Example 2, para. 2).
Regarding claim 32, the obviousness to modify Abudayyeh’s nucleotide sequence encoding the nucleic acid cargo to a sub-sequence capable of self-circularizing as taught by Lamb is discussed above as applied to claim 24. Lamb further teaches upon transformation of the nucleic acid construct into a cell, and after formation of the circular intermediate (i.e., self-circularizing to form the self-circular nucleic acid), a recombinase subsequently mediates recombination between the TALER target sequence (i.e., the second integrase recognition site) encoded in the circular intermediate and another TALER target sequence (i.e., the first integrase recognition site) located in cell’s genome, resulting in integration of the nucleic acid cargo at a selected genomic locus and an intended integration site (Example 2, para. 2; FIG. 3 annotated above).
Regarding claims 20-22, the obviousness to modify Abudayyeh’s nucleotide sequence encoding the nucleic acid cargo to a sub-sequence capable of self-circularizing as taught by Lamb is discussed above as applied to claim 24. Lamb teaches sub-sequence is flanked with recognition sites, particularly Lox site that are recognized by recombinase Cre to form the self-circular nucleic acid (FIG. 3; Example 2, para. 3). Thus, Lamb teaches the nucleic acid construct further comprises a first and a second recombinase recognition sites, as well as a Cre recombinase.
Claims 29 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Abudayyeh (cited supra) and Lamb (cited supra) as applied to claims 24 and 28 above, and further in view of Ow (US 7,972,857 B2; Published Date: Jul 05, 2011).
Regarding claim 31, the obviousness to modify Abudayyeh’s nucleic acid cargo to a subsequence capable of self-circularizing as taught by Lamb is discussed above as applied to claim 24. Lamb further teaches a method of “stacking transgenic loci” in a host cell comprising (a) transforming the host cell with the nucleic acid construct comprising the sub-sequence, (b) selecting the host cell expressing the nucleic acid cargo integrated at the intended genomic site, particularly an antibiotic resistance gene, and (c) identifying a host cell of a subsequent generation that carries the genomic integration (claim 22). Lamb further teaches repeating steps (a) to (c) to generate host cells comprising “a stack of genetically linked transgenic loci arranged in cis” by integrating the nucleic acid cargo at the same genomic site in subsequent rounds (claim 25).
However, Lamb does not teach wherein the self-circular nucleic acid comprises one or more additional integration recognition sites that enable integration of additional nucleic acid cargo.
Ow teaches a nucleic acid construct comprising (i) a nucleic acid cargo (e.g., trait 1), (ii) two attB integrase recognition sites, both flanked by a set of inverted recombination sites (e.g., Cre-lox recombinase recognition sites), and (iii) unneeded DNA (FIG. 8A; Example 6, col. 32, lines 7-19). Ow further teaches a recombinase identifies the pair of recombinase recognition sites, and recombines the unneeded DNA to remove it from the nucleic acid construct (FIG. 8B). Subsequently, remaining nucleic acid construct is integrated via one of the two attB sites to a genomic site comprising the corresponding attP integrase recognition site by φC31 (FIG. 8C). The remaining attB at the genomic locus can now serve as a target for another round of site-specific recombination to achieve a stack of integrated nucleic acid cargos in cis (col. 38, lines 55-59). Ow teaches “this recurring pattern can be repeated indefinitely” (col. 39, line 49).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified Lamb’s self-circular nucleic acid to comprise one or more additional integration recognition sites to enable subsequent integration of additional cargos as taught by Ow because it would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. Lamb teaches the self-circular nucleic acid comprise an integrase recognition site for recombination with corresponding integrase recognition site at the genomic site. The combination of an additional integrase recognition site of Ow does not modify the mechanism of genomic integration reaction of Lamb. The modification would merely provide an additional cognate integration site for subsequent integration events. One would have been motivated to have done so for the advantage of site-specific genomic modifications, particularly insertion of a series of genes each appended to the existing site adjacent to the previously inserted DNA as taught by Ow (col. 3, lines 52-53). One would have had a reasonable expectation of success in doing so because Lamb teaches the self-circular nucleic acid enables sequential “stacking” of nucleic acid cargos at a specific genomic site in the cis arrangement, and Ow teaches the inclusion of an additional integration recognition site enables integration of additional nucleic acid cargos in similar arrangement of Lamb.
Regarding claim 29, the obviousness to modify the self-circular nucleic acid of Lamb to comprise an additional integration recognition site as taught by Ow is discussed above as applied to claim 31. Further, Ow teaches the region comprising the nucleic acid cargo (i.e., sub-sequence) is flanked by two recombinase recognition sites to remove unneeded DNA (col. 32, lines 7-19, lines 54-56).
Claims 16-19 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Abudayyeh (cited supra) and Lamb (cited supra) as applied to claims 24 and 32 above, and further in view of Calos (US 8,304,233 B2; Published Date: Nov 06, 2012).
Regarding claim 16, Abudayyeh is applied to relevant teachings of claims 1, and 11-15 as discussed above and are incorporated herein by reference. The obviousness to modify Abudayyeh’s nucleic acid cargo to a sub-sequence capable of self-circularizing as taught by Lamb is discussed above as applied to claim 24.
Lamb teaches the nucleic acid cargo comprising a second cognate pair consisting of a third and fourth integrase recognition sites (e.g., Lox sites) that undergo self-circularization to form the self-circular nucleic acid comprising the second integrase recognition site and nucleic acid cargo (FIG. 3 annotated above). Lamb further upon self-circularization, integrase mediates recombination between a first cognate pair consisting of the second integrase recognition site on the self-circular nucleic acid and a first integrase recognition site in the cell’s genome (FIG. 3, boxed illustration; Example 2, para. 2). Lamb explicitly teaches that self-circularization occurs prior to genomic integration (Example 2, para. 2, lines 27-34), and that these two reactions could be orthogonal when completed with different enzymes (Example 2, para. 3 and 4).
However, Lamb does not explicitly teach wherein the second cognate pair has a faster integration rate than the first cognate pair.
Calos teaches a self-circularization and genomic integration strategy similar to Lamb’s. Calos teaches a vector comprising a nucleic acid cargo flanked by a second cognate pair consisting of a third and fourth integrase recognition site (e.g., attB1 and attP1), which are recognized by an integrase to undergo self-circularization and result in “integrating expression cassette vector” (i.e., self-circular nucleic acid) that is devoid of undesired backbone sequences (FIG. 22A annotations underlined; col. 36, lines 58-65; col. 37, lines 1-10). Calos further teaches the self-circular nucleic acid is integrated into a specific genomic site via recombination between a first cognate pair consisting of a second recognition site (e.g., attB2) and a first integrase recognition site located at the genomic site (col. 37, lines 10-16; FIG. 22B). Calos further teaches utilization of different integrase recognition site pairs and enzymes for the two orthogonal and sequential reactions, self-circularization and genomic integration, because each integrase has distinct recognition sites that do not cross react with each other; therefore using one integrase for self-circularization and another for genomic integration reduces of unwanted recombination between the two reactions (col. 37, lines 62-64; col. 38, lines 3-7; col. 38, lines 21-43).
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Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have employed different integrases for the self-circularization and genomic integration reactions as taught by Calos because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. This substitution would have been swapping one integrase to another that serves the same purpose, recombination via recognition of distinct sequence-specific sites. It would have been obvious to have selected two integrases that perform recombination at different reaction rates, particularly wherein self-circularization (i.e., the second cognate pair) recombines prior to recombination of the first cognate pair (i.e., genomic integration) as taught by both Lamb and Calos. One would have been motivated to have done so for the advantage of obtaining predictable and higher yield of the self-circular nucleic acid as taught by Calos over arrangements in which two recognition sites for the same integrase are present on the sub-sequence (col. 38, lines, 30-35). One would have also been motivated to have done so to ensure self-circularization reaction occurs prior to genomic integration. One would have had a reasonable expectation of success in doing so because both Lamb and Calo teach vectors comprising a cognate pair of recognition sites that undergo self-circularization by an integrase, followed by genomic integration by another integrase that recognizes a different cognate pair of recognition sites, wherein the self-circularization occurs prior to genomic integration.
Regarding claims 17-19, the obviousness to modify the integrase for the self-circularization reaction of Lamb to another integrase in view of Calos is discussed above as applied to claim 16. Lamb teaches wherein the integrase is well known in the art, and one of the examples is phiC31 (Example 2, para. 3, lines 35-37).
However, Lamb does not teach recited limitations in instant claims 17-19.
Calos teaches different integrases are used for self-circularization and genomic integration, each recognizing distinct integration recognition sites (col. 37, lines 1-19; col. 38, lines 21-43). Calos further teaches wherein the integrases may be derived from different phages, e.g., BxB1 (col. 38, lines 3-7).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have further modified one or both Lamb’s integrases to BxB1 as taught by Calos because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. Each of the substituted component (from one serine integrase phiC31 to another serine integrase BxB1) and its function (recombination of nucleic acid upon recognition of sequence-specific sites) were known in the art. One would have had a reasonable expectation of success in doing so because both Lamb and Calos demonstrate successful self-circularization and genomic integration by two integrases, and Calos teaches these two reactions can be performed using two different integrases, wherein one or both of them are BxB1, that recognize different integrase recognition sites.
Regarding claim 33, the obviousness to modify Abudayyeh’s nucleic acid cargo to a sub-sequence of Lamb is discussed above as applied to claim 24. Lamb teaches wherein self-circularization and genomic integration are effected by the same integrase, or self-circularization is effected by viral replication proteins while genomic integration is effected a integrase (Example 2, para. 4).
However, Lamb does not teach wherein self-circularization and integration are effected by the first and second integrase, respectively.
Calos is applied to teachings of claim 16 as discussed above and are incorporated herein by reference. Calos further teaches wherein self-circularization and genomic integration are effected by different integrases sequentially, and each integrase recognize distinct attachment sites that do not cross react with each other (col. 38, lines 3-7; col. 38, lines 21-43).
Thus, in view of Lamb’s teachings that self-circularization and genomic integration could be completed by different enzymes, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have motivated to configure the self-circularization and genomic integration reactions and have arrived at Calos’ teachings to perform these two reactions with two different enzyme of the same family, integrases. This modification would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. Each of the substituted components (from enzymes that mediates formation of the self-circular nucleic acid based on recognition of specific double-stranded sequences to integrases of Calos, e.g., Bxb1 that recognizes attB/attP sites) and its function (mediating recombination of the self-circular nucleic acid) were known in the art. This substitution would have been swapping similar features that serve the same purpose. Consistent with Lamb’s teachings, Calos discloses the sequential use of different integrases having distinct recognition sites for self-circularization and genomic integration allows separate and orthogonal recombination events. One would have had a reasonable expectation of success in doing so because Both Lamb and Calos teach self-circularization and genomic integration reactions can be performed separately using enzymes that recognize distinct sequences that do not cross react with each other.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-36 and 38-39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 57-60, and 62 of copending Application No. 19/515,777 (claims filed on 03/02/2026) in view of Abudayyeh, Earley, Lamb, Calos, and Ow (cite supra).
Regarding instant claim 1, ‘777 recites a system comprising (a) a gene editor (i.e., a prime editor system) comprising a nickase linked to a reverse transcriptase, (b) at least a first attachment site-containing guide RNA (atgRNA), (c) an integrase, and (d) a donor polynucleotide (i.e., nucleic acid cargo) (claim 57).
Regarding instant claims 2-3, 5, 7-9, ‘777 recites the gene editor comprises a nickase linked to a reverse transcriptase (i.e., fusion protein) (claim 57), the first atgRNA comprises the instantly recited limitations of claim 5 (claim 58), the integration recognition site is integrated into a cell’s genome target sequence upon introducing the first atgRNA into the cell (claim 62), the system further comprises a second atgRNA (claim 59), the first and second atgRNA comprises the instantly recited limitations of claim 9 (claim 60).
However, ‘777 does not recite limitations in instant claims 4, 6, 10-36, and 38-39. The combination of Abudayyeh, Earley, Lamb, Calos, and Ow render obvious instant claims as discussed supra. All obviousness arguments above are incorporated herein. The addition of claims 57-60, and 62 of ‘777 further support this obviousness; thus, the prior art combined with said claims renders the instant claims obvious.
This is a provisional nonstatutory double patenting rejection.
Claims 1-36 and 38-39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 54, and 57-58 of copending Application No. 19/200,601 (claims filed on 09/11/2025) in view of Abudayyeh, Earley, Lamb, Calos, and Ow (cite supra).
Regarding instant claim 1, ‘601 recites a polynucleotide comprising nucleic acid sequences encoding (a) fusion protein (i.e., a prime editor system) comprising a nickase linked to a reverse transcriptase and an integrase (claim 54). ‘601 further recites (b) at least a first attachment site-containing guide RNA (atgRNA), and (c) a donor polynucleotide (i.e., nucleic acid cargo) (claim 57).
Regarding instant claims 2-3, and 5, ‘777 recites the fusion protein comprises a nickase linked to a reverse transcriptase (claim 54), and the first atgRNA comprises the instantly recited limitations of claim 5 (claim 58).
However, ‘601 does not recite limitations in instant claims 4, 6-36, and 38-39. The combination of Abudayyeh, Earley, Lamb, Calos, and Ow render obvious instant claims as discussed supra. All obviousness arguments above are incorporated herein. The addition of claims 54, 57-58 of ‘601 further support this obviousness; thus, the prior art combined with said claims renders the instant claims obvious.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowable.
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/QIWEN SU-TOBON/
Examiner
Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
