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 26 June 2025. Claims 1, 3, 6, 9, 12, 14-16, 20, 22, and 26-33 are pending. Claims 15-16, 20, 22, and 27-30 are amended. Claims 1-3, 6, 9, 12, 14, 26, and 31-33 remain withdrawn from consideration as being drawn to a non-elected invention. Accordingly, claims 15-16, 20, 22, and 27-30 are currently under examination.
Applicant’s amendments, filed 26 June 2025, have been fully considered and are deemed persuasive. Accordingly, the previously filed 35 USC 102 and 103 rejections of record have been withdrawn.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 16 May 2025 has been considered.
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.
Claim(s) 15-16, 20, 22, and 28-30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Govindaraju (Nucleic acids research 44.7 (2016): 3276-3287) in view of Waryah (Epigenome editing: methods and protocols (10 March 2018): 19-63). This is a new rejection necessitated by Applicant’s amendments.
Regarding claim 15, Govindaraju is drawn towards a study concerned with modeling an R2Bm endonuclease (Abstract). Govindaraju teaches that R2Bm RNA comprises a zinc finger (i.e., a DNA binding domain), a “basic region” that is involved in RNA binding, a CCHC motif (i.e., a linker domain), and a reverse transcriptase domain (pg. 3276-3277; see Figure 1A). Govindaraju teaches that R2Bm endonucleases function via a process called target-primed reverse transcription (i.e., TPRT) (pg. 3276). Govindaraju teaches that TPRT requires that the R2Bm endonuclease cleaves a host chromosome (i.e., the R2Bm is able to bind to DNA at a DNA target site) to generate a free 3’ OH, such that the reverse transcriptase present in the R2Bm can bind to an RNA component and reverse transcribe the RNA (i.e., generating cDNA) such that the reverse transcribed product is inserted at the cleavage site (pg. 3276). Govindaraju teaches that the R2Bm RNA binds to two R2Bm protein subunits have been shown to be involved in the TPRT reaction: one bound to the 5’ end of the R2Bm RNA and one bound to the 3’ end of the R2Bm RNA (pg. 3276-3277; see Figure 1B). Govindaraju teaches that the protein subunit bound to the R2Bm RNA’s 3’ end is a protein binding motif (PBM) that interacts with target DNA upstream of the insertion site (i.e., the 3’ protein subunit comprises a DNA targeting sequence), cleaves a first DNA strand and performs TPRT (pg. 3276-3277; see Figure 1B). Govindaraju teaches that the protein subunit bound to the 5’ end of the R2Bm RNA binds to target DNA downstream of the insertion site, cleaves a second DNA strand and is thought to perform second strand synthesis (pg. 3276-3277; see Figure 1B).
Govindaraju does not teach or suggest that the DNA binding domain is a different DNA binding domain than a parental R2 LINE DNA binding domain (Claim 15). Govindaraju does not teach or suggest that the DNA binding domain is substituted with an alternative DNA binding domain relative to the parental LINE DNA binding domain (Claim 16). Govindaraju does not teach or suggest that the DNA binding domain comprises an RNA-guided domain (Claim 20).
However, one of ordinary skill in the art would have considered the teachings of Waryah as both references are common fields of endeavor pertaining to the study of DNA binding domains.
Waryah is drawn towards a review study concerned with a comparison between zinc fingers, TALEs, and CRISPR systems (Abstract). Waryah teaches that zinc fingers, TALEs, and CRISPR systems all serve as custom DNA-binding domains which can be fused to epigenetic modifying domains to manipulate epigenetic marks at specific sites in the genome (Abstract). Waryah teaches that the mechanisms of DNA binding by zinc fingers, TALEs, and CRISPR systems were known in the art (pg. 24; see Fig. 1). Waryah teaches that CRISPR systems utilize a guide RNA to target and bind to target DNA sequences (pg. 24; see Fig. 1). Waryah teaches that the principles of DNA targeting by CRISPR systems are similar to those that had been found previously with zinc fingers and TALEs (pg. 38).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the zinc finger DNA binding domain of Govindaraju for a CRISPR DNA binding domain, as described by Waryah. A person of ordinary skill in the art would have had a reasonable expectation of success because both Govindaraju and Waryah teach the use of DNA binding domains that can target and bind to DNA sequences of interest. Further, Waryah teaches that both zinc fingers and CRISPR systems were known to bind to target DNA via similar mechanisms.
Regarding claim 22, Govindaraju teaches that that the R2Bm RNA comprises a “basic region” that is involved in RNA binding, a CCHC motif (i.e., a linker domain), and a reverse transcriptase domain that are unmutated and endogenous to the R2Bm system (pg. 3276-3277; see Figure 1A).
Regarding claims 28 and 30, Govindaraju teaches the use of an E. coli codon-optimized R2Bm ORF (i.e., a nucleic acid encoding the R2Bm) that was able to be transformed into a BL21 strain of E. coli such that the R2Bm was expressed within the E. coli (pg. 3278).
Regarding claim 29, Govindaraju teaches that R2Bm is capable of generating a transient 4-way Holliday junction-like nucleic acid structure (i.e., a productive 4-way junction) during TPRT (pg. 3285).
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Govindaraju (Nucleic acids research 44.7 (2016): 3276-3287) in view of Waryah (Epigenome editing: methods and protocols (2018): 19-63) as applied to claims 15-16, 20, 22, and 28-30 above, and further in view of Kudla (Science 324.5924 (2009): 255-258). This is a new rejection necessitated by Applicant’s amendments.
Regarding claim 27, Govindaraju in view of Waryah renders obvious claims 15-16, 20, 22, and 28-30 as described above.
Govindaraju in view of Waryah does not teach or suggest the use of a vector encoding the protein component of claim 15 (Claim 27).
However, one of ordinary skill in the art would have considered the teachings of Kudla as both references are common fields of endeavor pertaining to the use of nucleic acids encoding proteins to be expressed in E. coli cells.
Kudla is drawn towards a study concerned with the successful expression and detection of GFP in E. coli cells (Abstract). Kudla teaches the use of different expression vectors encoding a GFP gene under the control of a T7 promoter that could be expressed within E. coli cells (pg. 255, 257; see Fig. 3).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the expression construct that could express the R2Bm in E. coli cells rendered obvious by Govindaraju in view of Waryah for an expression vector that can be utilized to express proteins in E. coli cells, as described by Kudla. A person of ordinary skill in the art would have had a reasonable expectation of success because both Govindaraju in view of Waryah and Kudla teach the use of nucleic acids that can encode and express proteins of interest within E. coli cells.
Response to Arguments
Regarding the previously pending 35 USC 102 and 103 rejections of record, Applicant’s amendments, filed 26 June 2025, have been fully considered and are deemed persuasive. Accordingly, the previously filed 35 USC 102 and 103 rejections of record have been withdrawn.
Insofar as Applicant’s arguments are applicable to the currently utilized Govindaraju reference, Applicant has not provided any specific arguments pertaining to the Govindaraju reference other than the fact that Govindaraju is directed to a structural and functional analysis of the endonuclease domain of the R2 retrotransposon from Bombyx mori (R2Bm), showing that specific motifs near and/or within the R2 endonuclease are important for DNA binding, cleavage, and target-primed reverse transcription (TPRT) (Remarks; pg. 11). Therefore, the Govindaraju reference is interpreted as being drawn to valid prior art.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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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/KYLE T REGA/Examiner, Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636