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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 27 April 2026 has been entered.
Priority
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Application Status
This action is written in response to applicant’s correspondence received 27 April 2026. Claims 1-2 and 4-15 are currently pending. Claims 11-15 are withdrawn from prosecution as being drawn to non-elected subject matter. Accordingly, claims 1-2 and 4-10 are examined herein. The restriction requirement mailed 22 May 2025 is still deemed proper. Applicant's elected Group I without traverse in the reply filed 10 June 2025.
Any rejection or objection not reiterated herein has been overcome by amendment.
Applicant' s amendments have been thoroughly reviewed, but are not persuasive to place the
claims in condition for allowance for the reasons that follow.
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.
Claim(s) 1-2 and 4-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (US Patent No. 9,790,490 B2, published 17 October 2017).
Regarding claim 1, Zhang is drawn to an invention concerned with methods and compositions for targeting nucleic acids (Abstract). Zhang teaches the use of an inducible Cpf1 CRISPR-Cas system, termed “Split-Cpf1”, that comprises the following: a first Cpf1 fusion construct attached to a first half of an inducible dimer and a second Cpf1 fusion construct attached to a second half of the inducible dimer that, in the presence of an inducer energy, form a functional Cpf1 protein (Col. 78, lines 41-48). Zhang teaches that the first Cpf1 fusion construct that comprises FKBP fused to C terminal part of the split CPf1 (i.e., a C-terminal side fragment of a split Cpf1 protein) via a GlySer linker while the second Cpf1 fusion construct comprises FRB fused with the N terminal part of the split CPf1 (i.e., an N-terminal side fragment of a split Cpf1 protein) via a GlySer linker (Col. 95, lines 55-67). Zhang teaches the use of an LbCpf1 protein having 100% identity to the claimed SEQ ID NO: 2 (Col. 535; see SEQ ID NO: 242 in previously attached sequence alignment). Zhang teaches that the LbCpf1 protein can be split at positions 566-571 in order to create the split CPf1 protein (Col. 93, lines 12-23).
Zhang does not explicitly disclose that the combination of the two polypeptides are obtained by cutting the claimed SEQ ID NO: 2 at any position selected from position 69 to position 73, position 83 to position 89, position 131 to position 138, position 244 to position 252, position 265 to position 296, position 309 to position 312, position 371 to position 387, position 404 to position 409, position 437 to position 445, position 549 to position 552, position 574 to position 577, position 606 to position 609, position 619 to position 628, position 727 to position 736, position 802 to position 811, position 1037 to position 1042, position 1140 to position 1148, position 1155 to position 1161, and position 1163 to position 1178 (Claim 1).
However, Zhang further teaches that preferably, the split position occurs where an interruption of the amino acid sequence does not result in the partial or full destruction of a structural feature (e.g. alpha-helixes or beta-sheets) (Col. 92, lines 31-40). Zhang teaches that unstructured regions (i.e., regions that do not show up in the crystal structure because these regions are not structured enough to be “frozen” in a crystal) are often preferred options for the split site (Col. 92, lines 31-40). Zhang further teaches that splits which keep the two parts (either side of the split) roughly the same length may be advantageous for packing purposes (Col. 94, lines 14-18). As shown in FIGs. 105A-B of Zhang, reproduced below, at the claimed positions 69-73, 83-89, 244-252, 309-312, 404-409, 549-552, 606-609, 1037-1042, and 1155-163, there is neither an alpha helix nor a beta sheet in the secondary structure in a species of LbCpf1 (Col. 24, lines 14-26; see FIGs. 105A-B).
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FIG. 105A of Zhang
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Additionally, Zhang teaches that once a potential split site has been identified, a suitable split construct can be designed (Col. 93, lines 60-61). Zhang teaches that in order to create a split construct at a desired potential split site, an NES can be positioned at the N′ terminal end of the first part of the split amino acid (or the 5′ end of nucleotide encoding it) and an NLS that is positioned at the C′ terminal end of the second part of the split amino acid (or the 3′ end of the nucleotide encoding it) such that both constructs can be operably linked to an NES (Col. 93, line 62 to Col. 94, line 5). Zhang teaches that various linkers may be employed to separate the Cpf1 fragments from dimerization domains selected from FRB and FKBP (Col. 94, lines 24-39).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have tried to split the claimed SEQ ID NO: 2 at a position selected from 69-73, 83-89, 244-252, 309-312, 404-409, 549-552, 606-609, 1037-1042, and 1155-1163 because it would have merely amounted to choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success. Zhang teaches that there was a need to generate a split CPf1 protein that could have its activity induced in the presence of an inducer. Additionally, because Zhang teaches that preferred split sites are split sites that keep the fragments roughly the same length, and do not cause the interruption of an alpha helix or beta sheet, one of ordinary skill in the art would have recognized that the potential split sites which fit both criteria are finite across the span of the claimed SEQ ID NO:2. A person of ordinary skill in the art would have also recognized that the list of possible split sites includes at least the claimed residues 606-609, because a split at that region of the protein would not result in the destruction of a structured region and keep the resulting fragments roughly the same length. Because Zhang provides evidence that determining an optimal split site can be accomplished by a person of ordinary skill in the art, followed by method steps on how to generate the split Cpf1 fragments that can be linked to an inducible dimer and an NES, one of ordinary skill in the art could have pursued the potential different split sites across the length of the protein of Zhang and would have expected to be able to generate a functional split Cpf1 protein with a reasonable expectation of success.
Regarding claim 2, Zhang teaches that FKBP and FRB is a dimer that separates the split Cpf1 fusion constructs until rapamycin-induced dimerization (i.e., formation of a dimer with dependence on the presence of a drug) of the FKBP and FRB domains form a set of fused polypeptides that forms a functional full-length Cpf1 nuclease (Col. 89, lines 47-54).
Regarding claim 4, Zhang teaches that the split Cpf1 may be utilized to cleave target nucleic acid sequences (i.e., the split Cpf1 is nuclease-active) (Col. 3, lines 57-63).
Regarding claim 5, Zhang teaches that the Cpf1 may be catalytically inactive (Col. 80, lines 51-59; Col 108, lines 44-67).
Regarding claim 6, Zhang teaches that functional domains may be fused to a functional effector domain (i.e., a functional domain) in order to recruit the functional effector domain to a target region of a gene without inducing cleavage of the target region of the gene (Col. 108, lines 44-67).
Regarding claim 7, Zhang teaches that a heterologous functional domain selected from a transcriptional activator may be located at the amino- or carboxy-terminus and fused to the Cpf1 protein (i.e., a functional domain may be bound to either the N-terminal side fragment or the C-terminal side fragment) (Col. 7, lines 4-5, 33-39).
Regarding claims 9-10, Zhang teaches the use of expression vectors comprising nucleic acids encoding the split Cpf1 protein (Col. 96, line 61 to Col. 97, line 5).
Response to Arguments
Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Applicant alleges that the claimed invention is nonobvious over the disclosure of Zhang because Zhang does not teach or suggest that the split-Cpf1 can “spontaneously” associate without the need for an external stimulation (Remarks; pg. 5-6). Applicant alleges that Zhang teaches the use of inducible associative split Cpf1 proteins that require light or a chemical such as rapamycin for the N- and C-terminal side fragments to form a dimer and a subsequent full-length protein (Remarks; pg. 5-6). Applicant alleges that the disclosure of Zhang does not teach or suggest the specific advantages, namely spontaneous association, as shown in the instant Application in the exemplified N574/C575 split (Remarks; pg. 5).
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., spontaneous association of the side fragments) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Additionally, it is noted that the dependent claims 2 and 7 explicitly recite that the dimer is dependent on light or in the presence of a drug (see Claims 2 and 7). As such, the broadest reasonable interpretation of the claims appear to be directed towards an inducible system that is able to associate two split fragments of a Cpf1 protein in the presence of an external stimulus. Additionally, MPEP 716.01(c) makes clear that arguments of counsel cannot take the place of evidence in the record.
Further, Fig. 3 of the instant application demonstrates that many different split points, including many of those that are claimed, required the presence of rapamycin in order to induce the split Cpf1 fragments to associate with one another (pg. 10-11; see Fig. 3). Accordingly, Applicant’s arguments with respect to the single split point that demonstrated “spontaneous association”, N574/C575, is moot because the claimed advantageous result is not demonstrated by the entirety of the claimed split sites present in claim 1. The number of split sites is much larger than the split sites demonstrated to allow for “spontaneous association” in the instant specification and thus the advantageous result is not commiserate in scope with the entirety of the currently claimed invention.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KYLE T REGA whose telephone number is (571)272-2073. The examiner can normally be reached M-R 8:30-4:30, every other F 8:30-4:30 (EDT/EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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