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 .
Restrictions/Elections
Applicant’s amendment of claims submitted on 12/29/2025 has been acknowledged. Claims 1, 4-8, 11-16, 18-20 are pending.
Claims 4, 5, 7, 12-15, 18-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 07/18/2025.
Therefore, claims 1, 6, 8, 11 and 16 along with elected species of SEQ ID NO: 2, the amino acid sequence of Beta vulgaris Pol θ are examined in this office action.
Objections/Rejections that are withdrawn
Objection to specification has been withdrawn in light of applicant’s amendment of specification to delete the embedded hyperlink and/or other form of browser-executable codes and applicant’s inclusion of proper symbol indicating use in commerce in the terms used in commerce.
Objection to claim 1 has been withdrawn in light of applicant’s amendment of claim 1 to delete the duplicate term “for.
Objection to drawing for lacking Nucleotide and/or Amino Acid Sequence Disclosures is withdrawn in light of applicant’s amendment of specification by submitting substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings (see clean substitute specification, page 9, lines 12-16).
35 U.S.C. 112 102 rejection over Gomez et al. has been withdrawn in light of applicant’s amendment of claim 1 to recite the method is in plant and the method comprise the Pol θ sequence, or a POLQ sequence encoding the same is SEQ ID NO:2, which is as a protein sequence from Beta vulgaris subsp. vulgaris (see alignment above). Since there are many polymerase theta sequences and for example Kamoen et al. (Published: 2025, Journal: PNAS Nexus 4 (6) 1-9) teaches their finding of the Polymerase theta (Polθ)-mediated end joining (TMEJ) in Arabidopsis showed species-specific functionality of the Polθ . Kamoen et al. point to functional divergence in TMEJ across species (page 1, abstract), there is no predictability that the promotion or upregulation or overexpression of Polθ as SEQ ID NO:2 would increase targeted insertion in any plant cells (see scope of enablement rejection below).
Claim Rejections - 35 USC § 112 – written description requirements
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 6, 8, 11 and 16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Analysis of Breadth of Claims
Genetically modified material (claim 16) would encompass material obtained after genetic modification that would have any structure or function.
Specific Pol θ as SEQ ID NO:2 is required to increase targeted insertion of a DNA insert in any plant cell or in the broad genus of plants recited in claim 11.
What is Described in the Specification
Applicant describes the following:
Applicant describes SEQ ID NO: 2 is a Beta vulgaris amino acid sequence (see sequence listing).
Difference Between What was described and What is Claimed
Applicant has not described Pol θ as SEQ ID NO:2 would increase targeted insertion of a DNA insert in any plant cell or in the broad genus of plants recited in claim 11.
Applicant has not described any genetically modified material (claim 16).
Analysis
The purpose of the written description is to ensure that the inventor had possession at the time the invention was made, of the specific subject claimed. For a broad generic claim, the specification must provide adequate written description to identify the genus of the claim.
Applicant has not described Pol θ as SEQ ID NO:2 would increase targeted insertion of a DNA insert in any plant cell or in the broad genus of plants recited in claim 11. Jing et al. teaches in the sample of 68 protein sequences of DNA polymerase theta comprising different eukaryotes, three distinct clades of plant, animal and fungal species were found (page 6, Figure 1). Therefore, there is large variation in the structures and function of the Pol θ proteins in different eukaryotic species.
Furthermore, Sfeir et al. (Published: 2015, Journal: Trends in Biochemical Sciences, 40 (11): 1-14) (Included in IDS submitted on 01/12/2024) teaches various protein effecting eukaryotic end joining (page 703, see Table 1 below) that are involved in the end joining pathway. Therefore, there is dearth of description of Pol θ as SEQ ID NO:2 in would increase targeted insertion of a DNA insert in any plant cell or in the broad genus of plants recited in claim 11.
Genetically modified material (claim 16) would encompass material obtained after genetic modification that would have any structure or function. Therefore, there is dearth of description of genetically modified material.
Given the large structural variable associated with these embodiments, the claims read on an extremely broad and highly diverse structures that would require to lead to increased targeted insertion in a genome editing system in any plant cell. Thus, in view of the analysis presented above, a skilled artisan would appreciate that the claims are directed to extremely broad and highly diverge genus of plants the method needs to have increased increase targeted insertion of a DNA insert.
Given the large size and structural diversity associated with the claimed genus, Applicant’s disclosure is not representative of the claimed genus as a whole. This point is particularly relevant because, as discussed above, the prior art speaks to the disconnection between the structure of the broadly claimed method steps in any plants and the recited specific function.
"The test for sufficiency is whether the disclosure of the application relied upon reasonably conveys to one skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Ariad Pharm, Inc, v EH Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010). To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Lockwood v. Amer. Airlines, ina, 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). "An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations. Lockwood, 107 F.3d at 1572, 41 USPG2d at 1966". While the written description requirement does not demand either examples or an actual reduction, actual "possession" or reduction to practice outside of the specification is not enough. Ariad Pharm, Inc. v. Eli Lilly & Co., 598 F,3d 1336,1352 (Fed. Cir. 2010). Rather, it is the specification itself that must demonstrate possession. Id.
Thus, based on the analysis above, Applicant has not met either of the two elements of the written description requirement as set forth in the court's decision in Eli Lilly. As a result, it is not clear that Applicant was has described the structure of claimed genus to have application as recited function at the time this application was filed.
Claim Rejections - 35 USC § 112 –Scope of Enablement
In following analysis previous enablement rejection has been modified and reanalyzed to a scope of enablement in light of applicant’s amendment of claim 1 to recite Pol θ as SEQ ID NO:2 and the eukaryotic cell to be a plant cell.
Claims 1, 6, 8 and 11 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method comprising providing the at least one plant cell to be modified, upregulating or overexpressing Pol θ as SEQ ID NO:2, introducing at least one genome editing system and a double stranded DNA insert and cultivating the plant cell, does not reasonably provide enablement for the method would increase targeted insertion of any DNA insert in at least one target genomic sequence in any plant cell and the promotion of Pol θ activity increases the DNA insertion efficiency. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
An “analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.” MPEP 2164.01. “A conclusion of lack of enablement means that. . . the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention [i.e. commensurate scope] without undue experimentation.” In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); MPEP 2164.01.
In In re Wands, 858 F.2d 731,8 USPQ2d 1400 (Fed. Cir. 1988), several factors implicated in determination of whether a disclosure satisfies the enablement requirement and whether any necessary experimentation is “undue” are identified. These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 858 F.2d 731,737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). No single factor is independently determinative of enablement; rather “[i]t is improper to conclude that a disclosure is not enabling based on an analysis of only one of the above factors while ignoring one or more of the others.” MPEP 2164.01. Likewise, all factors may not be relevant to the enablement analysis of any individual claim.
The Breadth of the Claims and nature of invention:
Claim 1 is drawn to a method of increasing targeted insertion in any plant cells by promoting, upregulating or overexpressing Pol θ or a POLQ sequence encoding the same as consisting of SEQ ID NO:2.
Claim 111 recite a large genus of plants in which the method is required to increase targeted insertion.
The state of the prior art:
Mara et al. (Published: 2019, Journal: New Phytologist (2019) 222: 1380–1391 doi: 10.1111/nph.15680) teaches POLQ effecting Alt-EJ are involved in the repair of CRISPR-Cas9- induced DSBs in plants (page 1389, right paragraph 2).
Mara et al. teaches sequence homology searches of the P. patens genome identified putative homologs for the P. patens POLQ gene different species (Fig. S2) (Phytozome #Pp3c5_12930).
Tol et al. (Published: 2022, The Plant Journal 109: 112–125) teaches Pol θ deficiency also prevented ectopic gene targeting (GT) events, suggesting that the sequence of events leading up to this outcome requires TMEJ (page 112, Summary).
Sharief et al. teaches there are at least eight human DNA polymerase θ (page 90, Abstract).
Jing et al. teaches in the sample of 68 protein sequences of DNA polymerase theta comprising different eukaryotes, three distinct clades of plant, animal and fungal species were found (page 6, Figure 1). Therefore, there is large variation in the structures and function of the Pol θ proteins in different eukaryotic species.
Kamoen et al. teaches their finding of the Polymerase theta (Polθ)-mediated end joining (TMEJ) in Arabidopsis showed species-specific functionality of Polθ and point to functional divergence in TMEJ across species (page 1, abstract). Kamoen et al. teaches Polθ-independent MMEJ occur, often requiring longer microhomologies referred to as extended microhomology (eMH) (page 2, left paragraph 3, page 4, left paragraph 5). Kamoen et al. teaches, in plants, the helicase domain can also function independently to facilitate eMMEJ wherein when the flanking sequences contain sufficient homology, Polθ’s polymerase activity is not required when flanking sequences contain sufficient homology (page 5, right paragraph 4, Figure 5). Kamoen et al. teaches Polθ’s polymerase activity becomes obsolete when primer already exist for polymerase delta in TMEJ process (page5, right paragraph 2).
Sfeir et al. (Published: 2015, Journal: Trends in Biochemical Sciences, 40 (11): 1-14) (Included in IDS submitted on 01/12/2024) teaches various protein effecting eukaryotic end joining (page 703, see Table 1 below) that are involved in the end joining pathway. This showed various mechanism of targeted insertion. Therefore, the specific effect of the upregulating or overexpression of Pol θ proteins would also depend on other pathways in end joining mechanisms.
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Therefore, there is no predictability that the upregulation or overexpression of Pol θ or a POLQ sequence encoding the same as consisting of SEQ ID NO:2 would increase the targeted insertion in any plant cell.
Alignment of applicant’s elected SEQ ID NO:2 to the uniport database showed the sequence has 100% sequence identity to the locus A0A0J8CX06_BETVV as
Helicase and polymerase-containing protein TEBICHI disclosed (see alignment below) disclosed by Dohm et al. (see below).
Alignment of SEQ ID NO: 2 to uniport database:
RESULT 1
A0A0J8CX06_BETVV
ID A0A0J8CX06_BETVV Unreviewed; 2133 AA.
AC A0A0J8CX06;
DT 14-OCT-2015, integrated into UniProtKB/TrEMBL.
DT 14-OCT-2015, sequence version 1.
DT 02-APR-2025, entry version 48.
DE RecName: Full=Helicase and polymerase-containing protein TEBICHI {ECO:0008006|Google:ProtNLM};
GN ORFNames=BVRB_2g031660 {ECO:0000313|EMBL:KMT18137.1};
OS Beta vulgaris subsp. vulgaris (Beet).
OC Eukaryota; Viridiplantae; Streptophyta; Embryophyta; Tracheophyta;
OC Spermatophyta; Magnoliopsida; eudicotyledons; Gunneridae; Pentapetalae;
OC Caryophyllales; Chenopodiaceae; Betoideae; Beta.
OX NCBI_TaxID=3555 {ECO:0000313|EMBL:KMT18137.1, ECO:0000313|Proteomes:UP000035740};
RN [1] {ECO:0000313|EMBL:KMT18137.1, ECO:0000313|Proteomes:UP000035740}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC TISSUE=Taproot {ECO:0000313|EMBL:KMT18137.1};
RX PubMed=24352233; DOI=10.1038/nature12817;
RA Dohm J.C., Minoche A.E., Holtgrawe D., Capella-Gutierrez S., Zakrzewski F.,
RA Tafer H., Rupp O., Sorensen T.R., Stracke R., Reinhardt R., Goesmann A.,
RA Kraft T., Schulz B., Stadler P.F., Schmidt T., Gabaldon T., Lehrach H.,
RA Weisshaar B., Himmelbauer H.;
RT "The genome of the recently domesticated crop plant sugar beet (Beta
RT vulgaris).";
RL Nature 505:546-549(2014).
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DR EMBL; KQ090038; KMT18137.1; -; Genomic_DNA.
DR EnsemblPlants; KMT18137; KMT18137; BVRB_2g031660.
DR Gramene; KMT18137; KMT18137; BVRB_2g031660.
DR KEGG; bvg:104884718; -.
DR eggNOG; KOG0950; Eukaryota.
DR OMA; FHNMCQQ; -.
DR OrthoDB; 2320933at2759; -.
DR Proteomes; UP000035740; Chromosome 2.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0003677; F:DNA binding; IEA:InterPro.
DR GO; GO:0003887; F:DNA-directed DNA polymerase activity; IEA:InterPro.
DR GO; GO:0051301; P:cell division; IEA:EnsemblPlants.
DR GO; GO:0006261; P:DNA-templated DNA replication; IEA:InterPro.
DR GO; GO:0006302; P:double-strand break repair; IEA:TreeGrafter.
DR GO; GO:1990067; P:intrachromosomal DNA recombination; IEA:EnsemblPlants.
DR GO; GO:0009933; P:meristem structural organization; IEA:EnsemblPlants.
DR GO; GO:0009640; P:photomorphogenesis; IEA:EnsemblPlants.
DR GO; GO:2000011; P:regulation of adaxial/abaxial pattern formation; IEA:EnsemblPlants.
DR GO; GO:1902749; P:regulation of cell cycle G2/M phase transition; IEA:EnsemblPlants.
DR GO; GO:0010468; P:regulation of gene expression; IEA:EnsemblPlants.
DR CDD; cd18026; DEXHc_POLQ-like; 1.
DR CDD; cd08638; DNA_pol_A_theta; 1.
DR CDD; cd18795; SF2_C_Ski2; 1.
DR FunFam; 1.10.150.20:FF:000002; DNA polymerase I; 1.
DR FunFam; 1.10.3380.20:FF:000003; Helicase and polymerase-containing protein TEBICHI; 1.
DR FunFam; 1.20.1060.10:FF:000003; Helicase and polymerase-containing protein TEBICHI; 1.
DR FunFam; 3.40.50.300:FF:000968; Helicase and polymerase-containing protein TEBICHI; 1.
DR FunFam; 3.40.50.300:FF:001000; Helicase and polymerase-containing protein TEBICHI; 1.
DR Gene3D; 1.10.3380.20; -; 1.
DR Gene3D; 3.30.70.370; -; 1.
DR Gene3D; 1.10.150.20; 5' to 3' exonuclease, C-terminal subdomain; 1.
DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 2.
DR Gene3D; 3.30.420.10; Ribonuclease H-like superfamily/Ribonuclease H; 1.
DR Gene3D; 1.20.1060.10; Taq DNA Polymerase, Chain T, domain 4; 1.
DR InterPro; IPR011545; DEAD/DEAH_box_helicase_dom.
DR InterPro; IPR001098; DNA-dir_DNA_pol_A_palm_dom.
DR InterPro; IPR043502; DNA/RNA_pol_sf.
DR InterPro; IPR002298; DNA_polymerase_A.
DR InterPro; IPR014001; Helicase_ATP-bd.
DR InterPro; IPR001650; Helicase_C-like.
DR InterPro; IPR046931; HTH_61.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR048960; POLQ-like_helical.
DR InterPro; IPR012337; RNaseH-like_sf.
DR InterPro; IPR036397; RNaseH_sf.
DR PANTHER; PTHR10133; DNA POLYMERASE I; 1.
DR PANTHER; PTHR10133:SF62; DNA POLYMERASE THETA; 1.
DR Pfam; PF00270; DEAD; 1.
DR Pfam; PF00476; DNA_pol_A; 1.
DR Pfam; PF00271; Helicase_C; 1.
DR Pfam; PF20470; HTH_61; 1.
DR Pfam; PF21099; POLQ_helical; 1.
DR PRINTS; PR00868; DNAPOLI.
DR SMART; SM00487; DEXDc; 1.
DR SMART; SM00490; HELICc; 1.
DR SMART; SM00482; POLAc; 1.
DR SUPFAM; SSF56672; DNA/RNA polymerases; 1.
DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1.
DR SUPFAM; SSF53098; Ribonuclease H-like; 1.
DR SUPFAM; SSF158702; Sec63 N-terminal domain-like; 1.
DR PROSITE; PS51192; HELICASE_ATP_BIND_1; 1.
DR PROSITE; PS51194; HELICASE_CTER; 1.
PE 4: Predicted;
KW ATP-binding {ECO:0000256|ARBA:ARBA00022840};
KW Nucleotide-binding {ECO:0000256|ARBA:ARBA00022741};
KW Reference proteome {ECO:0000313|Proteomes:UP000035740}.
FT DOMAIN 501..693
FT /note="Helicase ATP-binding"
FT /evidence="ECO:0000259|PROSITE:PS51192"
FT DOMAIN 733..925
FT /note="Helicase C-terminal"
FT /evidence="ECO:0000259|PROSITE:PS51194"
FT REGION 1..42
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 138..187
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1304..1332
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1311..1323
FT /note="Low complexity"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
SQ SEQUENCE 2133 AA; 234489 MW; 5260825D4DB7B510 CRC64;
Query Match 100.0%; Score 10944; Length 2133;
Best Local Similarity 100.0%;
Matches 2133; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MDSDEPQTRIDQFFASKKKRALSPKTAKDSSPSAKGSLENYLVTSQNDSVKRSLALEIDL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MDSDEPQTRIDQFFASKKKRALSPKTAKDSSPSAKGSLENYLVTSQNDSVKRSLALEIDL 60
Qy 61 SSKNEKKEIFLPSDGATRGLILPEAIPVDKYGAGNVGGAGNRDNSDQVQEIENVGLKQFA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 SSKNEKKEIFLPSDGATRGLILPEAIPVDKYGAGNVGGAGNRDNSDQVQEIENVGLKQFA 120
Qy 121 LDFLSLYCRRIQTSSLSEHKTHEHKRCGSPSVLAVEGTPSKRRHFVADKENSQPGQETPS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 LDFLSLYCRRIQTSSLSEHKTHEHKRCGSPSVLAVEGTPSKRRHFVADKENSQPGQETPS 180
Qy 181 SDKGDSDLVLCSNVTQKVERDVNSALGPQISLRKCSKVTNSTSLVDECSTPAAICKSSSA 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SDKGDSDLVLCSNVTQKVERDVNSALGPQISLRKCSKVTNSTSLVDECSTPAAICKSSSA 240
Qy 241 RETPVSTRGSSIFSPGEAFWNEAIQVVDGLFPQTGNNFFQVAEDTGISKTQVVEVFSHCG 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 RETPVSTRGSSIFSPGEAFWNEAIQVVDGLFPQTGNNFFQVAEDTGISKTQVVEVFSHCG 300
Qy 301 EGSSNNKCDVPVGIYASNTKQAEFTITSPKTHKGILEREASPLPVKHFDFSCDDKNLDES 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 EGSSNNKCDVPVGIYASNTKQAEFTITSPKTHKGILEREASPLPVKHFDFSCDDKNLDES 360
Qy 361 MPGRVSSGNREDYRDASERAVCNVDHKRPLDDNAVLIGSDVQSHALALKVLDETAPVFGA 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 MPGRVSSGNREDYRDASERAVCNVDHKRPLDDNAVLIGSDVQSHALALKVLDETAPVFGA 420
Qy 421 EKMRHSVVGPDTDNNISASPNRKNANFVAPGMFDGNSTPSSSMPLEDRLNLSNWLPPAIC 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 EKMRHSVVGPDTDNNISASPNRKNANFVAPGMFDGNSTPSSSMPLEDRLNLSNWLPPAIC 480
Qy 481 SIYRRKGIAKLYPWQVDCLQMDGVLQKRNLVYCASTSAGKSFVAEILMLRRVIDSGKIAL 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 SIYRRKGIAKLYPWQVDCLQMDGVLQKRNLVYCASTSAGKSFVAEILMLRRVIDSGKIAL 540
Qy 541 LVLPYVSICVEKAEHLEVLLEPLGKQVRSYYGNQGGGTLPKDTSVAVCTIEKANSLVNRL 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 LVLPYVSICVEKAEHLEVLLEPLGKQVRSYYGNQGGGTLPKDTSVAVCTIEKANSLVNRL 600
Qy 601 LEEDRLSEVGIIVIDELHMVADPSRGYLLELLLTKLRYGAGEGNGESHSGDSSATSSGKG 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 LEEDRLSEVGIIVIDELHMVADPSRGYLLELLLTKLRYGAGEGNGESHSGDSSATSSGKG 660
Qy 661 DLTQGLQIVGMSATMPNVAAVADWLHAALYQTEFRPVPLEEFIKVGNNIYDKKMEIVRTV 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 DLTQGLQIVGMSATMPNVAAVADWLHAALYQTEFRPVPLEEFIKVGNNIYDKKMEIVRTV 720
Qy 721 PKLANLGGKDPDHVVELCNEVVEDGHSVLIFCSSRKGCESTARHISMYLKKFSAKIQEES 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 PKLANLGGKDPDHVVELCNEVVEDGHSVLIFCSSRKGCESTARHISMYLKKFSAKIQEES 780
Qy 781 SEFADVFSAIDSLRRCPVGLDPVLEETLPSGVAYHHAGLTVEEREIVETCYRKGLVRVLT 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 781 SEFADVFSAIDSLRRCPVGLDPVLEETLPSGVAYHHAGLTVEEREIVETCYRKGLVRVLT 840
Qy 841 ATSTLAAGVNLPARRVIFRQPKIGRDFIDGTRYRQMSGRAGRTGIDAKGESVLICRPEEV 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 841 ATSTLAAGVNLPARRVIFRQPKIGRDFIDGTRYRQMSGRAGRTGIDAKGESVLICRPEEV 900
Qy 901 KRIKALLNDSCPPLQSCLSEDKNGMTHAILEVVAGGIVQTANDIHRYVRCTLLNSTKPFE 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 901 KRIKALLNDSCPPLQSCLSEDKNGMTHAILEVVAGGIVQTANDIHRYVRCTLLNSTKPFE 960
Qy 961 DVVKSAQDSLRWLCHKKFLEWNDDTKLYSTTPLGRAAFGSSLSPEESLIVLDDLSRAREG 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 961 DVVKSAQDSLRWLCHKKFLEWNDDTKLYSTTPLGRAAFGSSLSPEESLIVLDDLSRAREG 1020
Qy 1021 FVLASDLHLVYLATPINVEVEPDWELFYERFMELSSLDQSVGNRVGVIEPFLMRMAHGAP 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1021 FVLASDLHLVYLATPINVEVEPDWELFYERFMELSSLDQSVGNRVGVIEPFLMRMAHGAP 1080
Qy 1081 VRTASRSRNAIKGLHSRLDFQLGVSKSNTLSDEQSLRVCRRFYVALILSRLVQELPVGEV 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1081 VRTASRSRNAIKGLHSRLDFQLGVSKSNTLSDEQSLRVCRRFYVALILSRLVQELPVGEV 1140
Qy 1141 CAAFKVARGMVQSLQENAGRFASMVSLFCERLGWFDLEGLVAKFQNRVSFGVRAEIVELT 1200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1141 CAAFKVARGMVQSLQENAGRFASMVSLFCERLGWFDLEGLVAKFQNRVSFGVRAEIVELT 1200
Qy 1201 TIPYVKGSRARALFKAGLRTPLAIA EASVTEIAKALFESLSWAQEDLAQRRVQLGIAKKI 1260
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1201 TIPYVKGSRARALFKAGLRTPLAIA EASVTEIAKALFESLSWAQEDLAQRRVQLGIAKKI 1260
Qy 1261 KNAARKIVLDKAEEARVAAFSAFQSLGLNVPQLSRPVLLPASGIPIDNDESTPSSGEDST 1320
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1261 KNAARKIVLDKAEEARVAAFSAFQSLGLNVPQLSRPVLLPASGIPIDNDESTPSSGEDST 1320
Qy 1321 SSSFHQKRKHMSVELVERQGNEGDPGTDAGRPAKKLVTSLEISTERKAVNTLPSGVGVIR 1380
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1321 SSSFHQKRKHMSVELVERQGNEGDPGTDAGRPAKKLVTSLEISTERKAVNTLPSGVGVIR 1380
Qy 1381 DSSTPIQDSVPVGVMTLSPCLGQSASVASVGIVNKEDQRWETNNAGSDGNKKLSNDKGPI 1440
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1381 DSSTPIQDSVPVGVMTLSPCLGQSASVASVGIVNKEDQRWETNNAGSDGNKKLSNDKGPI 1440
Qy 1441 NIASTSGLESLLDLWESVGEFYFDIHFNKKSEANSLLAYEVHGLAICWEDSRVYYVNLAK 1500
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1441 NIASTSGLESLLDLWESVGEFYFDIHFNKKSEANSLLAYEVHGLAICWEDSRVYYVNLAK 1500
Qy 1501 ILQNSNFGSCNIECSGHVNPIDANNLLFTENLLWNRISRLLGRVGVRKFTWNLKLQVKVL 1560
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1501 ILQNSNFGSCNIECSGHVNPIDANNLLFTENLLWNRISRLLGRVGVRKFTWNLKLQVKVL 1560
Qy 1561 KNAVLSLNKNNLSQTLKSTTIEVADGSFCKLPQVILQDGIDLSIVAWILWPDEERSSNPS 1620
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1561 KNAVLSLNKNNLSQTLKSTTIEVADGSFCKLPQVILQDGIDLSIVAWILWPDEERSSNPS 1620
Qy 1621 LEKEVKRRLSSEAAGAANQSGRWKNQMRRAAHNGCCRRAAQTRALHSVLWKLLVSEELVE 1680
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1621 LEKEVKRRLSSEAAGAANQSGRWKNQMRRAAHNGCCRRAAQTRALHSVLWKLLVSEELVE 1680
Qy 1681 ALLGVELPLVHVLADMEDQGIGVDMEGCLKARHVLSKKLKILEKEAYKLAGMMFSLYMPA 1740
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1681 ALLGVELPLVHVLADMEDQGIGVDMEGCLKARHVLSKKLKILEKEAYKLAGMMFSLYMPA 1740
Qy 1741 DIANVLYGHLKLPIPEGHNKGKQHASTDKHCLDLLRLEHPIVPVIKEHRTLAKLLNCTLG 1800
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1741 DIANVLYGHLKLPIPEGHNKGKQHASTDKHCLDLLRLEHPIVPVIKEHRTLAKLLNCTLG 1800
Qy 1801 SICSLAKLSMRTQRYTVHGRWLQTSTATGRLSMEEPNLQCVEHMVEFRMHQNGDAQCDSD 1860
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1801 SICSLAKLSMRTQRYTVHGRWLQTSTATGRLSMEEPNLQCVEHMVEFRMHQNGDAQCDSD 1860
Qy 1861 GTDYKINARDFFIPTEENWLLVTADYSQIELRLMAHFSKDPSLIELLTDPHGDAFTMIAS 1920
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1861 GTDYKINARDFFIPTEENWLLVTADYSQIELRLMAHFSKDPSLIELLTDPHGDAFTMIAS 1920
Qy 1921 RWTGKLESVVSSQERDQTKRLVYGILYGMGANTLAEQLNCSADEAKAKIQSFKNSFPGVA 1980
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1921 RWTGKLESVVSSQERDQTKRLVYGILYGMGANTLAEQLNCSADEAKAKIQSFKNSFPGVA 1980
Qy 1981 SWLHEAVAFCRQHGYVQTLKGRKRFLSKIKIGDSKEKAKAQRQAVNSICQGSAADIIKIA 2040
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1981 SWLHEAVAFCRQHGYVQTLKGRKRFLSKIKIGDSKEKAKAQRQAVNSICQGSAADIIKIA 2040
Qy 2041 MINIYSVIAGCETRSSNDALVAKFSTLKGHCRILLQVHDELVMEVDPSVLGEAGLLLKTC 2100
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2041 MINIYSVIAGCETRSSNDALVAKFSTLKGHCRILLQVHDELVMEVDPSVLGEAGLLLKTC 2100
Qy 2101 MESAASLSVPLQVKVKFGRTWGSLEPFNVNDLR 2133
|||||||||||||||||||||||||||||||||
Db 2101 MESAASLSVPLQVKVKFGRTWGSLEPFNVNDLR 2133
The amount of direction provided by the inventor:
Applicant describes SEQ ID NO: 2 is a Beta vulgaris amino acid sequence (see sequence listing).
The existence of working examples:
The Specification or state of the art does not teach a person with skill in the art how to make and/or use the subject matter within the full scope of these claims because:
Applicant fails to teach promoting or upregulating or overexpression of Pol θ as SEQ ID NO: 2 as a Beta vulgaris amino acid sequence would increase targeted insertion in any plant cells.
Applicant fails to teach promoting or upregulating or overexpression of Pol θ as SEQ ID NO: 2 as a Beta vulgaris amino acid sequence would increase targeted insertion in any cells of the recited genus of plants claimed in claim 11.
Applicant has zero example of upregulating or overexpression of Pol θ as SEQ ID NO: 2 as a Beta vulgaris amino acid sequence or any other Pol θ would increase targeted insertion in any cells of the recited genus of plants claimed in claim 11 or in any other plants.
Lack of a working example is a critical factor to be considered, especially in a case involving an unpredictable and undeveloped art. See MPEP § 2164. Genetech, 108 F.3d at 1366, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”.
In the absence of guidance from either the instant disclosure or the art, it would require undue trial and error experimentation for a skilled artisan to make and use the Pol θ as SEQ ID NO: 2 to know whether it will increase targeted insertion of a DNA insert, with no reasonable expectation of success in arriving at the invention of the method leading to the increased targeted insertion in any plant cells or genus of plant cells recited in claim 11.
Given the large variations of pathways leading to targeted insertion of a DNA insert in a plant and various effects of specific Pol θ genes and their effects in any plants for increasing targeted insertion of a DNA insert and specificity of the Pol θ genes, specifically, does not provide predictability in increasing targeted insertion in any plant cells by a method of promoting or upregulating or overexpressing Pol θ as SEQ ID NO: 2 as a Beta vulgaris amino acid sequence. Instead, applicant has zero example of such increased targeted insertion by promoting or upregulating or overexpressing Pol θ as SEQ ID NO: 2 as a Beta vulgaris amino acid sequence or by any other Pol θ in any plant.
Thus, in view of the unpredictability associated with the effect of the Pol θ as SEQ ID NO: 2 as a Beta vulgaris amino acid sequence for increasing targeted insertion in any plants and also in sugar beet (Beta vulgaris) itself, the lack of enabling guidance from either the instant disclosure or the art, and breath and diversity of the embodiments encompassed by the claimed genus, the lack of sufficient working examples, and the level of the art at the time of the invention, one of ordinary skill in the art must rely on undue trial and error experimentation to make and test the numerous polypeptides encompassed by the broad genera, in order to make and/or use the invention within the full scope of these claims.
For at least this reason, the Specification does not teach a person with skill in the art how to make and/or use the subject matter within the full scope of these claims.
Response to Argument
Applicant's arguments filed 12/29/2025 have been fully considered but they are not persuasive.
Applicant argues claim 1 now recites the method is performed in plant cells, provides further details of the promotion of Pol θ activity, provides a comparator for increased targeted insertion, and includes sequences for Pol θ. Applicant submits claimed method is applicable to a variety of plant species and target genomic sequences, and that one of ordinary skill in the art would be able to develop suitable genome editing systems to make desired insertions into preferred target genomic sequences. Applicant argues it is the combination with increased Pol 8 activity, by way of upregulation or overexpression, that the targeted insertion is unexpectedly increased. See, e.g., [0018]-[0020] of the Application as published (Response to Rejection, page 10, paragraph 3).
Applicant's arguments have been fully considered but they are not persuasive since there is no evidence that promotion of Pol θ activity would be useful for method of targeted integration of DNA insert in any plants. Paragraph [0018]-[0020] of the Application as published only states the finding of Pol θ activation was surprising without any evidence the activation of SEQ ID NO:2 would have any surprising results. Therefore the part of written description rejection has been maintained and enablement rejection has been modified to scope of enablement rejection, see above.
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.
Anticipated by Mara et al.
Claim 16 is rejected under 35 U.S.C. 102 (a) (1) as being anticipated by Mara et al. (Published: 2019, Journal: New Phytologist (2019) 222: 1380–1391 doi: 10.1111/nph.15680).
Claims is drawn a plant cell produced by the method for increasing targeted insertion of a DNA insert in a plant cell and by introducing gene editing system in the cell and cultivating the plant cell.
The claim is interpreted as “product by process claim”. Following analysis based on the In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) which states “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” Thus, a product-by-process claim may be properly rejectable over prior art teaching the same product produced by a different process, if the process of making the product fails to distinguish the two products. In instant claim the product of the plant cell of claim 16 would require a plant cell with CRISPR mediated integration of any nucleotide sequences.
Regarding claim 16, Mara et al. discloses POLQ plays a key role in the repair of CRISPR/Cas9-induced double-stranded breaks in the moss Physcomitrella patens from plant kingdom wherein POLQ is competitor and inhibitor of the homolog directed repair (HR) repair pathway (page 1380, Summary) wherein the non-homologous end joining (NHEJ) is increased when POLQ is active in wildtype plants than in the mutant plant with mutant polq genes for editing of APT locus (page 1387, Figure 5 and 6).
Applicant defines “A "DNA insert" as used herein in the context of the methods of the present invention is to be distinguished from a repair template (RT), which understanding is closely related to the naturally occurring Pol 8 repair pathway, which is used herein in a modified manner to optimize GE outcomes. The pronounced functional difference is that for HDR, the repair template serves as a template, which means that the DNA strand is synthesized based on the sequence of the RT (recombination), whereas for MMEJ/HMEJ the DNA insert is itself inserted (except for the homology arm (for MMEJ <25 nt and for HMEJ 25 - 2,000 nt)). The methods of the present invention, therefore, exploit the naturally occurring MMEJ/HMEJ pathways to provide improved GE strategies. In certain embodiments, a DNA insert may also be understood as an RNA insert, or as an insert comprising RNA and DNA portions, as long as this DNA and/or RNA insert is intended to be inserted during MMEJ/HM EJ, or wherein the RNA insert serves as template for the DNA insert. (Spec, page 24 and 25, last and first paragraph).
Therefore, any DNA insert that serves as template for the insertion of any potion of DNA is considered as DNA insert. The DNA portion found in the plasmid of the Gomez et al. encompass the DNA insert. A DNA portion would mean as small as one nucleotide as a template for repair wherein there are several such small insert were found in Gomez et al. screened edited cells (see Figure 4 below).
Mara et al. discloses method comprise insertion of concatenated copies of the donor cassettes was frequent in gene targeting experiments in P. patents (page 1387, left paragraph 3).
Mara et al. discloses in the method number of clones with single copy insertion of the donor cassette at the targeted locus is not significantly different (Fisher’s exact test P = 0.09) between wild-type and the polq mutant (Fig. 6b) (page 1387, left paragraph 3).
Mara et al. discloses in their method they have evaluated CRISPR-induced gene targeting (GT) by targeting the APT reporter gene with a donor template presenting homology to the target (page 138, left paragraph 2). Mara et al. discloses the method showed importance of Alt-EJ for the repair of CRISPR-Cas9-induced DSBs which was observed in the moss P. patens (page 1389, right paragraph 2).
Mara et al. discloses the potential role of Alt-EJ repair in the formation of the concatenated copies of the donor cassettes, they compared the nature of the HR repair events observed at the APT locus in the wild-type and polq mutant (page 1387, left paragraph 3). Therefore Mara et al. discloses method comprise introducing donor template and inserting the portion of the template.
Mara et al. discloses when short microhomologies are present near the cleavage site, the main pathway involved could be Alt-EJ and Alt-EJ has been described to be a back-up repair system when other DNA repair pathways are compromised which is more pre-eminent and POLQ is involved in Alt EJ-mediated DNA repair (page 1387, second to last paragraph and page 1388, first left paragraph).
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Therefore Mara et al. anticipate the claim.
Anticipated by Shen et al.
Claim 16 is rejected under 35 U.S.C. 102 (a) (1) as being anticipated by Shen et al. (Published 2017, G3 Genes Genomes Genetics, 7:193-202).
Claims is drawn a plant seed produced by the method for increasing targeted insertion of a DNA insert in a plant cell and by introducing gene editing system in the cell and cultivating the plant cell.
The claim is interpreted as “product by process claim”. Following analysis based on the In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) which states “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” Thus, a product-by-process claim may be properly rejectable over prior art teaching the same product produced by a different process, if the process of making the product fails to distinguish the two products. In instant claim the product of the plant seed of claim 16 would require a plant seed with CRISPR mediated integration of any nucleotide sequences.
Regarding claims 16, Shen et al. discloses method using a CRISPR/Cas9 for DSB induction at the Arabidopsis cruciferin 3 (CRU3) and protoporphyrinogen oxidase (PPO) genes wherein NHEJ analysis in wild-type plants and plants deficient in key factors of c-NHEJ (ku80), b-NHEJ (parp1 parp2), or both (ku80 parp1 parp2) showed, microhomologies and templated insertions were observed at the repair junctions in the wild type and all mutants, and the mutation have promoted the Polymerase θ -mediated DSB repair (page 193, Abstract). Shen et al. discloses the templated insertions resulted from a KU80- and PARPs-independent alternative end-joining mechanism, such as that mediated by Pol θ (page 199, left paragraph 1, see Figure 2).
Shen et al. discloses T1 and T2 seeds of the edited plants (page 195, paragraphs 2 and 3).
Therefore Shen et al. anticipate the claim.
Response to Argument
Applicant's arguments filed 12/29/2025 have been fully considered but they are not persuasive.
Applicant argues Applicant herein amends claim 1 to incorporate the subject matter of claim 3, which is not rejected over either of Gomez or Mara for this reason Gomez or Mara fails to anticipate the claim.
Applicant's arguments have been fully considered but they are not persuasive since the amendment of claim 1 does not change the rejection on claim 16 which is a product of a plant cell that would not require the method steps since the claim has been analyzed as product by process, see above.
Summary
No claim is allowed.
Claims 1, 6, 8 and 11 are free of a prior art. The closest prior art is Mara et al. that discloses a method of producing P. patens plants produced by the method for increasing targeted insertion of a DNA insert by promoting DNA polymerase theta (Pol θ) activity in the plant cell and by introducing gene editing system CRISPR/Cas9 in the plant cell and regenerating the plant cell. Mara et al. does not specifically teach increasing targeted insertion by promoting protein of amino acid sequence of SEQ ID NO:2, as a protein sequence from Beta vulgaris subsp. vulgaris (see alignment above). Since there are many polymerase theta sequences and for example Kamoen et al. teaches their finding of the Polymerase theta (Polθ)-mediated end joining (TMEJ) in Arabidopsis showed species-specific functionality of the Polθ and Kamoen et al. point to functional divergence in TMEJ across species (page 1, abstract), there is no predictability that the promotion of Polθ as SEQ ID NO:2 would increase targeted insertion in any plant cells (see Scope of enablement rejection above).
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.
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/SANTOSH SHARMA/Examiner, Art Unit 1663
/DAVID H KRUSE/Primary Examiner, Art Unit 1663
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