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 .
Status of the Claims
Claims 6-7, 13, 16, and 21 are canceled.
Claims 1-5, 8-12, 14-15, 17-20, and 22-23 are pending.
Claims 1-5, 8-12, 14-15, 17-20, and 22-23 are examined herein.
The previous objections to claims 11-12 have been withdrawn in view of Applicant’s amendments.
The previous rejections to claims 2-4 under 35 USC 112(b) have been withdrawn in view of Applicant’s amendments.
The previous rejections to claims 1-3, 5, 7-9, 17, 22, and 23 under 35 USC 102 have been withdrawn in view of Applicant’s amendments to the claims and cancellation of claim 7. However, in view of Applicant’s amendments, the claims are now rejected under 35 USC 103.
Claims 1-5, 8-12, 14-15, 17-20, and 22-23 are rejected.
Priority
As stated in the prior Office Action dated 06/13/2025:
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Application No. 18/548,008 filed on 08/25/2023 is a 371 of PCT Application No.
PCT/JP2022/008035 filed on 02/25/20322, and also claims foreign priority to Japanese
Application No. JP2021-030805 filed on 02/26/2021.
A certified English translation has not been provided for neither PCT Application
No. PCT/JP2022/008035, nor Japanese Application No. JP2021-030805.
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.
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 22-23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Nishida (US Patent Application No. US-20170321210-A1, published 11/09/2017).
This is a maintained rejection from the previous Office Action.
Claim 22 is drawn to a method for producing a cell modified at a targeted site of a double-stranded DNA, comprising (i) a step of providing a cell comprising the double-stranded DNA of interest, (ii) a step of providing a complex in which a nucleic acid sequence-recognizing module that specifically binds to a target nucleotide sequence in the double-stranded DNA and a DNA glycosylase with sufficiently low reactivity with the double-stranded DNA are bound, (iii) a step of placing the complex in a condition under which the cell is transfected,(iv) a step of placing the transfected cell in a condition that induces modification of the targeted site, without cleaving at least one strand of the double-stranded DNA in the targeted site, and(v) a step of selecting a cell into which the complex has been introduced and/or a cell into which the modification has been introduced, wherein the modification in the cell is maintained for at least the primary transformant.
Claim 23 is drawn to a method for producing a plant cell having a desired property, comprising (i) a step of providing a plant cell comprising a double-stranded DNA related to the desired property, (ii) a step of providing a complex in which a nucleic acid sequence-recognizing module that specifically binds to a target nucleotide sequence in the double-stranded DNA and a DNA glycosylase with sufficiently low reactivity with the double-stranded DNA are bound, (iii) a step of placing the complex in a condition under which the plant cell is transfected, (iv) a step of placing the transfected plant cell in a condition that induces modification of the targeted site, without cleaving at least one strand of the double-stranded DNA in the targeted site, (v) a step of selecting a cell into which the complex has been introduced and/or a cell into which the modification has been introduced, and (vi) a step of selecting the cell having the desired property from the introduced cells.
Regarding claims 22-23, Nishida discloses a method of modifying a targeted site of a double stranded DNA in a plant cell, comprising a step of contacting a complex wherein a nucleic acid sequence-recognizing module that specifically binds to a target nucleotide sequence in a given double stranded DNA and DNA glycosylase with sufficiently low reactivity with a DNA having an unrelaxed double helix structure (unrelaxed DNA) are bonded, with said double stranded DNA, to convert one or more nucleotides in the targeted site to other one or more nucleotides or delete one or more nucleotides, or insert one or more nucleotides into said targeted site, without cleaving at least one strand of said double stranded DNA in the targeted site (claims 1 and 21 of Nishida). Nishida further discloses that the double stranded DNA is contacted with the complex by introducing a nucleic acid encoding the complex into a cell having the double stranded DNA (claim 17 of Nishida). Because Nishida discloses introducing the complex into the cell and altering a target site without cleaving at least one strand of said double stranded DNA in the targeted site, it is reasonably interpreted that Nishida discloses the steps of (iii) and (iv) that is placing the complex in a condition under which the plant cell is transfected and placing the transfected plant cell in a condition that induced modification of a target site, without cleaving at least one strand of the double- stranded DNA in the targeted site. Nishida also discloses wherein the cell is a polyploid cell, and all of the targeted sites in alleles on a homologous chromosome are modified (claim 26 of Nishida), which is reasonably interpreted to encompass the step of selecting the cell in which the complex or modification has been introduced because the cell must be selected to determine the limitations discloses by Nishida. Furthermore, because Nishida discloses all of the targeted sites in alleles on a homologous chromosome are modified (claim 26 of Nishida) and does not disclose anywhere in the publication that the mutation is temporary, the invention of Nishida is also reasonably interpreted to encompass wherein the modification in the cell is maintained for at least the primary transformant, especially without evidence to the contrary.
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.
Claims 1-5, 8-12, 14-15, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Nishida (US Patent Application No. US-20170321210-A1, published 11/09/2017).
This is a modified rejection necessitated by Applicant’s amendments.
Claim 1 is drawn to a method for producing a plant cell modified at a targeted site of a double-stranded DNA, comprising (i) a step of providing a plant cell comprising the double-stranded DNA of interest, (ii) a step of providing a complex in which a nucleic acid sequence-recognizing module that specifically binds to a target nucleotide sequence in the double-stranded DNA and a DNA glycosylase with sufficiently low reactivity with the double-stranded DNA are bound, wherein the DNA glycosylase is a mutant whose reactivity with double-stranded DNA is attenuated as compared with wild-type DNA glycosylase, (iii) a step of placing the complex in a condition under which the plant cell is transfected, wherein the transfection is performed through delivery of the complex to separated plant callus or by Floral dip method, (iv) a step of placing the transfected plant cell in a condition that induces modification of the targeted site, without cleaving at least one strand of the double-stranded DNA in the targeted site, and (v) a step of selecting a cell into which the complex has been introduced and/or a cell into which the modification has been introduced.
Claim 2 is drawn to the method according to claim 1, wherein the nucleic acid sequence-recognizing module is selected from the group consisting of a CRISPR-Cas system wherein the Cas nuclease is inactive for cleavage of at least one strand of double- stranded DNA, a zinc finger motif, a TAL effector and a PPR motif.
Claim 3 is drawn to the method according to claim 1, wherein the nucleic acid sequence-recognizing module is a CRISPR-Cas system in which Cas nuclease is inactive for cleavage of at least one strand of double-stranded DNA.
Claim 4 is drawn to the method according to claim 1, wherein the nucleic acid sequence-recognizing module is a CRISPR-Cas system in which Cas nuclease is inactive for cleavage of both strands of double-stranded DNA.
Claim 5 is drawn to the method according to claim 1, wherein the modification comprises substitution or deletion of one or more nucleotides in the targeted site, or insertion of one or more nucleotides in the targeted site, and/or wherein the modification dominantly occurs on the PAM sequence side of the targeted site.
Claim 8 is drawn to the method according to claim 1, wherein the DNA glycosylase has cytosine-DNA glycosylase (CDG) activity or thymine-DNA glycosylase (TDG) activity.
Claim 9 is drawn to the method according to claim 8, wherein the DNA glycosylase having CDG activity or TDG activity is a mutant of uracil-DNA glycosylase (UDG).
Claim 10 is drawn to the method according to claim 1, wherein the DNA glycosylase is a mutant of uracil-DNA glycosylase (UDG) derived from a yeast and having CDG activity or TDG activity.
Claim 11 is drawn to the method according to claim 1, wherein the plant cell is derived from rice, Arabidopsis thaliana, bean, maize, cotton, safflower, sunflower, tobacco, wheat, barley, hemp, rose, Japanese yew, banana, coffee, sesame, buckwheat, or lettuce.
Claim 12 is drawn to The method according to claim 1, wherein the plant cell is derived from rice or Arabidopsis thaliana.
Claim 14 is drawn to the method according to claim 1,wherein the transfection is performed through delivery using an Agrobacterium method.
Claim 15 is drawn to the method according to claim 1, further comprising a step of producing a plant body from the cell and/or a step of clonally separating the obtained cell.
Regarding claim 1, Nishida discloses a method of modifying a targeted site of a double stranded DNA in a plant cell, comprising a step of contacting a complex wherein a nucleic acid sequence-recognizing module that specifically binds to a target nucleotide sequence in a given double stranded DNA and DNA glycosylase with sufficiently low reactivity with a DNA having an unrelaxed double helix structure (unrelaxed DNA) are bonded, with said double stranded DNA, to convert one or more nucleotides in the targeted site to other one or more nucleotides or delete one or more nucleotides, or insert one or more nucleotides into said targeted site, without cleaving at least one strand of said double stranded DNA in the targeted site (claims 1 and 21 of Nishida). Nishida teaches the DNA glycosylase is a mutant having reduced reactivity with a DNA having an unrelaxed double helix structure (unrelaxed DNA) as compared to a wild-type one (claim 13 of Nishida). Nishida further discloses that the double stranded DNA is contacted with the complex by introducing a nucleic acid encoding the complex into a cell having the double stranded DNA (claim 17 of Nishida). Because Nishida discloses introducing the complex into the cell and altering a target site without cleaving at least one strand of said double stranded DNA in the targeted site, it is reasonably interpreted that Nishida discloses the steps of (iii) and (iv) that is placing the complex in a condition under which the plant cell is transfected and placing the transfected plant cell in a condition that induced modification of a target site, without cleaving at least one strand of the double- stranded DNA in the targeted site. Nishida also discloses wherein the cell is a polyploid cell, and all of the targeted sites in alleles on a homologous chromosome are modified (claim 26 of Nishida), which is reasonably interpreted to encompass the step of (v) that is selecting the cell in which the complex or modification has been introduced because the cell must be selected to determine the limitations discloses by Nishida.
Regarding claim 2, Nishida discloses wherein the nucleic acid sequence- recognizing module is selected from the group consisting of a CRISPR-Cas system wherein at least one DNA cleavage ability of Cas is inactivated, a zinc finger motif, a TAL effector and a PPR motif (claim 2 of Nishida).
Regarding claim 3, Nishida discloses wherein the nucleic acid sequence- recognizing module is a CRISPR-Cas system wherein at least one DNA cleavage ability of Cas is inactivated (claim 3 of Nishida).
Regarding claim 5, Nishida discloses convert one or more nucleotides in the targeted site to other one or more nucleotides or delete one or more nucleotides, or insert one or more nucleotides into said targeted site (claim 1 of Nishida).
Regarding claim 8, Nishida discloses the DNA glycosylase has cytosine- DNA glycosylase (CDG) activity or thymine-DNA glycosylase (TDG) activity (claim 7 of Nishida).
Regarding claim 9, Nishida discloses wherein the DNA glycosylase having CDG activity or TDG activity is a mutant of uracil-DNA glycosylase (UDG) (claim 8 of Nishida).
Regarding claim 17, Nishida discloses the method of producing the plant cell comprising the nucleic acid sequence and mutations described in claim 1 (claims 1, 17, 21, and 26 of Nishida), therefore Nishida also discloses a transformed plant cell obtained by the method of claim 1.
However, Nishida does not teach in a single embodiment:
wherein the transfection is performed through delivery of the complex to separated plant callus or by Floral dip method (remaining limitation of claim 1).
wherein the nucleic acid sequence-recognizing module is a CRISPR-Cas system in which Cas nuclease is inactive for cleavage of both strands of double-stranded DNA (claim 4).
wherein the DNA glycosylase is a mutant of uracil-DNA glycosylase (UDG) derived from a yeast and having CDG activity or TDG activity (claim 10).
wherein the plant cell is derived from rice, Arabidopsis thaliana, bean, maize, cotton, safflower, sunflower, tobacco, wheat, barley, hemp, rose, Japanese yew, banana, coffee, sesame, buckwheat, or lettuce (claim 11).
wherein the plant cell is derived from rice or Arabidopsis thaliana (claim 12).
the transfection is performed through delivery using an Agrobacterium method (claim 14).
the method according to claim 1, further comprising a step of producing a plant body from the cell and/or a step of clonally separating the obtained cell (claim 15).
Regarding the remaining limitation of claim 1, Nishida teaches in an alternative embodiment a complex of a nucleic acid sequence-recognizing module and a DNA glycosylase can be intracellularly expressed by introducing an expression vector containing a DNA encoding a nucleic acid sequence-recognizing module and/or a DNA glycosylase into a host cell, and culturing the host cell (¶0117), and teaches the plant host cell may be callus (¶0125).
Regarding claim 4, Nishida teaches in an alternative embodiment the nucleic acid sequence-recognizing module is a CRISPR-Cas system wherein at least one DNA cleavage ability of Cas is inactivated (claim 3 of Nishida). Nishida also teaches in an alternative embodiment introducing mutations using a CRSIPR-mutant Cas comprising a mutant Cas protein (dCas) wherein cleavage ability of both strands of a double stranded DNA is inactivated (¶0020).
Regarding claim 10, Nishida teaches in an alternative embodiment an enzyme having CDG activity or TDG activity, which is a mutant of yeast mitochondrial uracil-DNA glycosylase (UNG 1), as an enzyme that performs such base excision reaction (¶0018, Fig. 4 and 6).
Regarding claims 11 and 12, Nishida teaches in an alternative embodiment a complex of a nucleic acid sequence-recognizing module and a DNA glycosylase can be intracellularly expressed by introducing an expression vector containing a DNA encoding a nucleic acid sequence-recognizing module and/or a DNA glycosylase into a host cell, and culturing the host cell (¶0117), and teaches the plant host cell may be rice or Arabidopsis thaliana (¶0125).
Regarding claim 14, Nishida teaches in an alternative embodiment an expression vector can be introduced by a known method such as by Agrobacterium (¶0127).
Regarding claim 15, Nishida teaches in an alternative embodiment the expression vector may contain a selection marker such as drug resistance or auxotrophic complementary gene (¶0115), and teaches in an alternative embodiment a working example of using an auxotrophic medium to select surviving cells with mutations (¶0169-0170) (i.e. reasonably interpreted as clonally separating the obtained cell).
Nishida teaches all of the limitations of the rejected claims in alternative
embodiments, but does not disclose a single embodiment having all the limitations. As
such, the claims are not rejected as anticipated under 35 USC 102 but are instead
rejected as obvious under 35 USC 103. One of ordinary skill in the art would have
been motivated to combine the limitations as taught by Nishida into a single
embodiment to arrive at Applicant's claimed inventions because each limitation is explicitly taught as an alternative embodiment of the invention. It would therefore have been obvious to combine the limitations taught by Nishida to arrive at the instantly claimed methods with a reasonable expectation of success because Nishida teaches the same method of modifying plant cells as instantly claimed, and explicitly suggests in an alternative embodiment that the plant cells can be modified by introducing an expression vector containing a DNA encoding a nucleic acid sequence-recognizing module and/or a DNA glycosylase into a host cell (i.e. transfecting), and culturing the host cell (¶0117), and teaches the plant host cell may be callus (¶0125). In addition to this explicit suggestion, transformation of callus cells is a routine and well understood method that does not present any special technical obstacles. One having ordinary skill in the art would have been motivated to combine the teachings for the purpose of obtaining plant cells with modified nucleotides introduced without causing double stranded breaks as explicitly taught by Nishida (claim 1, ¶0005), and specifically in plant callus cells as suggested by Nishida (¶0125).
Claims 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over
Nishida as applied to claims 1 and 17 above, and further in view of Hiroshi (WO-
2018143477-A1, published on 08/09/2018).
This is a modified rejection necessitated by Applicant’s amendments.
Claim 18 is drawn to a transformed plant comprising the plant cell according to
claim 17.
Claim 19 is drawn to a seed obtained from the plant according to claim 18.
Claim 20 is drawn to the plant according to claim 18, wherein the transformed
trait is expressed only in the primary transgenic generation, and/or wherein the
expression of the transformed trait is inherited across generations.
Regarding claims 18-20, Nishida teaches the limitations of claims 1 and 17 as set forth in the previous obviousness rejection. The teachings of Nishida
as they are applied to claims 1 and 17 are set forth previously herein and are
incorporated by reference.
However, Nishida does not explicitly teach:
a transformed plant comprising the plant cell according to claim 17 (claim 18).
a seed obtained from the plant according to claim 18 (claim 19)
the plant according to claim 18, wherein the transformed
trait is expressed only in the primary transgenic generation, and/or wherein the expression of the transformed trait is inherited across generations (claim 20).
In analogous art, Hiroshi also teaches an invention related to altering the DNA of
plant cells using a CRISPR-Cas system in which at least one DNA cleavage ability of
Cas is inactivated (claims 1-4 of Hiroshi).
Regarding claim 18, Hiroshi teaches a plant produced from the plant cell whose
genome has been modified (abstract).
Regarding claim 19, Hiroshi teaches a progeny plant produced from the plant
(abstract) (i.e. reasonably interpreted to encompass a seed to produce the progeny
plant), and also teaches a part of a plant that is a seed (claim 35 of Hiroshi).
Regarding claim 20, Hiroshi teaches a genome modification that enables DNA
conversions inheritably by progeny (abstract) (i.e. expression of the transformed trait is
inherited across generations).
It would therefore have been obvious to a person of ordinary skill in the art to
modify the invention of Nishida to include the limitations of Hiroshi to arrive at the
instantly claimed method with a reasonable expectation of success because Nishida
and Hiroshi both teach altering plant cell genomes using similar methodology, and
producing a plant, seed, and progeny that have inherited the genomic alteration is a
routine method in plant biotechnology and could be achieved without encountering any
special technical obstacles. One having ordinary skill in the art would have been
motivated to do so because Hiroshi teaches a similar method, as well as generating a
whole plant and seed/ progeny plants comprising the genetic mutations (abstract).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-5, 8-12, 14-15, 17, and 22-23 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-5, 9-10, and 12 of U.S. Patent No. 11041169 in view of Nishida (US Patent Application No. US-20170321210-A1, published 11/09/2017).
This is a modified rejection necessitated by Applicant’s amendments.
Regarding claims 1, 22, and 23, 11041169 teaches a method for modifying a
targeted site of a double-stranded DNA of a plant cell, comprising a step of bringing a complex in which a nucleic acid sequence- recognizing module that specifically binds to
a selected target nucleotide sequence in a double-stranded DNA and a nucleic acid
base converting enzyme or DNA glycosylase are linked, and a donor DNA containing an
insertion sequence into contact with said double- stranded DNA, to substitute the
targeted site with the insertion sequence, or to insert the insertion sequence into said
targeted site, without cleaving at least one strand of said double- stranded DNA in the
targeted site (claims 1, 10, and 12). 11041169 further teaches wherein the double-
stranded DNA is contacted with the complex by introducing a nucleic acid encoding the
complex into the cell (claim 9).
Regarding claim 2, 11041169 teaches wherein the nucleic acid sequence-
recognizing module is selected from the group consisting of a CRISPR-Cas system in
which at least one DNA cleavage ability of Cas effector protein is inactivated, a zinc
finger motif, a TAL effector and a PPR motif (claim 3).
Regarding claim 3, 11041169 teaches wherein the nucleic acid sequence-
recognizing module is a CRISPR-Cas system in which only one of the two DNA
cleavage abilities of the Cas effector protein is inactivated (claim 4).
Regarding claim 4, 11041169 teaches wherein the nucleic acid sequence-
recognizing module is a CRISPR-Cas system in which both DNA cleavage abilities of
the Cas effector protein are inactivated (claim 5).
Regarding claim 5, 11041169 teaches a donor DNA containing an insertion
sequence into contact with said double- stranded DNA, to substitute the targeted site
with the insertion sequence, or to insert the insertion sequence into said targeted site
(claim 1).
However, 11041169 does not explicitly teach:
The DNA glycosylase has sufficiently low reactivity with the double-stranded DNA; wherein the DNA glycosylase is a mutant whose reactivity with double-stranded DNA is attenuated as compared with the wild type; wherein the transfection is performed through delivery of the complex to separated plant callus or by the Floral dip method; and a step of selecting a cell into which the complex has been introduced and/or a cell into which the modification has been introduced (remaining limitations of claim 1).
The DNA glycosylase has sufficiently low reactivity with the double-stranded DNA (remaining limitation of claims 22-23).
the method according to claim 1, wherein the DNA glycosylase has cytosine-DNA glycosylase (CDG) activity or thymine- DNA glycosylase (TDG) activity (claim 8).
the method according to claim 8, wherein the DNA glycosylase having
CDG activity or TDG activity is a mutant of uracil-DNA glycosylase (UDG) (claim 9).
The method according to claim 1, wherein the DNA glycosylase is a mutant of uracil-DNA glycosylase (UDG) derived from a yeast and having CDG activity or TDG activity (claim 10).
The method according to claim 1, wherein the plant cell is derived from rice, Arabidopsis thaliana, bean, maize, cotton, safflower, sunflower, tobacco, wheat, barley, hemp, rose, Japanese yew, banana, coffee, sesame, buckwheat, or lettuce (claim 11).
The method according to claim 1, wherein the plant cell is derived from rice or Arabidopsis thaliana (claim 12).
The method according to claim 1, wherein the transfection is performed through delivery using an Agrobacterium method (claim 14).
The method according to claim 1, wherein further comprising a step of producing a plant body from the cell and/or a step of clonally separating the obtained cell (claim 15).
A transformed plant cell obtainable by the method according to claim 1 (claim 17).
Regarding claims 1, 22, and 23, Nishida teaches a method of modifying a targeted site of a double stranded DNA in a plant cell, comprising a step of contacting a complex wherein a nucleic acid sequence-recognizing module that specifically binds to a target nucleotide sequence in a given double stranded DNA and DNA glycosylase with sufficiently low reactivity with a DNA having an unrelaxed double helix structure (unrelaxed DNA) are bonded, with said double stranded DNA, to convert one or more nucleotides in the targeted site to other one or more nucleotides or delete one or more nucleotides, or insert one or more nucleotides into said targeted site, without cleaving at least one strand of said double stranded DNA in the targeted site (claims 1 and 21 of Nishida). Nishida teaches the DNA glycosylase is a mutant having reduced reactivity with a DNA having an unrelaxed double helix structure (unrelaxed DNA) as compared to a wild-type one (claim 13 of Nishida). Nishida further teaches that the double stranded DNA is contacted with the complex by introducing a nucleic acid encoding the complex into a cell having the double stranded DNA (claim 17 of Nishida). Nishida teaches in an alternative embodiment a complex of a nucleic acid sequence-recognizing module and a DNA glycosylase can be intracellularly expressed by introducing an expression vector containing a DNA encoding a nucleic acid sequence-recognizing module and/or a DNA glycosylase into a host cell, and culturing the host cell (¶0117), and teaches the plant host cell may be callus (¶0125). Because Nishida teaches introducing the complex into the cell and altering a target site without cleaving at least one strand of said double stranded DNA in the targeted site, it is reasonably interpreted that Nishida teaches the steps of (iii) and (iv) that is placing the complex in a condition under which the plant cell is transfected and placing the transfected plant cell in a condition that induced modification of a target site, without cleaving at least one strand of the double- stranded DNA in the targeted site. Nishida also teaches wherein the cell is a polyploid cell, and all of the targeted sites in alleles on a homologous chromosome are modified (claim 26 of Nishida), which is reasonably interpreted to encompass the step of (v) that is selecting the cell in which the complex or modification has been introduced because the cell must be selected to determine the limitations teaches by Nishida.
Regarding claim 8, Nishida teaches the DNA glycosylase has cytosine- DNA glycosylase (CDG) activity or thymine-DNA glycosylase (TDG) activity (claim 7 of Nishida).
Regarding claim 9, Nishida teaches wherein the DNA glycosylase having CDG activity or TDG activity is a mutant of uracil-DNA glycosylase (UDG) (claim 8 of Nishida).
Regarding claim 10, Nishida teaches in an alternative embodiment an enzyme having CDG activity or TDG activity, which is a mutant of yeast mitochondrial uracil-DNA glycosylase (UNG 1), as an enzyme that performs such base excision reaction (¶0018, Fig. 4 and 6).
Regarding claims 11 and 12, Nishida teaches in an alternative embodiment a complex of a nucleic acid sequence-recognizing module and a DNA glycosylase can be intracellularly expressed by introducing an expression vector containing a DNA encoding a nucleic acid sequence-recognizing module and/or a DNA glycosylase into a host cell, and culturing the host cell (¶0117), and teaches the plant host cell may be rice or Arabidopsis thaliana (¶0125).
Regarding claim 14, Nishida teaches in an alternative embodiment an expression vector can be introduced by a known method such as by Agrobacterium (¶0127).
Regarding claim 15, Nishida teaches in an alternative embodiment the expression vector may contain a selection marker such as drug resistance or auxotrophic complementary gene (¶0115), and teaches in an alternative embodiment a working example of using an auxotrophic medium to select surviving cells with mutations (¶0169-0170) (i.e. reasonably interpreted as clonally separating the obtained cell).
Regarding claim 17, Nishida teaches the method of producing the plant cell comprising the nucleic acid sequence and mutations described in claim 1 (claims 1, 17, 21, and 26 of Nishida), therefore Nishida also discloses a transformed plant cell obtained by the method of claim 1.
It would therefore have been obvious to a person of ordinary skill in the art to modify the invention of as taught by U.S. Patent No. 11041169 to include the limitations of Nishida to arrive at the instantly claimed method with a reasonable expectation of success because Nishida teaches the same method but applies the method to plant cells. One having ordinary skill in the art would have been motivated to do so because Nishida teaches successful genome modification of plant cells using the same method of U.S. Patent No. 11041169.
Claims 18-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-5, 9, 10, and 12 of U.S. Patent No. 11041169 in view of Nishida (US Patent Application No. US-20170321210-A1, published 11/09/2017) as applied to claims 1 and 17 above, and further in view of Hiroshi (WO- 2018143477-A1, published on 08/09/2018).
This is a modified rejection necessitated by Applicant’s amendments.
11041169 and Nishida teach the limitations of claims 1 and 17 described above, and are incorporated herein by reference.
However, 11041169 and Nishida do not explicitly teach:
A transformed plant comprising the plant cell according to claim 17 (claim 18).
A seed obtained from the plant according to claim 18 (claim 19).
The plant according to claim 18, wherein the transformed trait is expressed only in the primary transgenic generation, and/or wherein the expression of the transformed trait is inherited across generations (claim 20).
In analogous art, Hiroshi also teaches an invention related to altering the DNA of plant cells using a CRISPR-Cas system in which at least one DNA cleavage ability of Cas is inactivated (claims 1-4 of Hiroshi).
Regarding claim 18, Hiroshi teaches a plant produced from the plant cell whose genome has been modified (abstract).
Regarding claim 19, Hiroshi teaches a progeny plant produced from the plant (abstract) (i.e. reasonably interpreted to encompass a seed to produce the progeny plant), and also teaches a part of a plant that is a seed (claim 35 of Hiroshi).
Regarding claim 20, Hiroshi teaches a progeny plant having a mutation is selected by selecting a progeny plant having a mutation (abstract) (i.e. expression of the transformed trait is inherited across generations).
It would therefore have been obvious to a person of ordinary skill in the art to modify the invention of 11041169 and Nishida to include the limitations of Hiroshi to arrive at the instantly claimed method with a reasonable expectation of success because 11041169, Nishida, and Hiroshi all teach altering plant cell genomes using similar methodology, and producing a plant, seed, and progeny that have inherited the genomic alteration is a routine method in plant biotechnology and could be achieved without encountering any special technical obstacles. One having ordinary skill in the art would have been motivated to do so because Hiroshi teaches a similar method, as well as generating a whole plant and seed/ progeny plants comprising the genetic mutations (abstract).
Claims 1-5, 8-12, 14-15, 17, and 22-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 7, 17, and 21 of copending Application No. 17/175,245 in view of Nishida (US Patent Application No. US-20170321210-A1, published 11/09/2017).
This is a modified rejection necessitated by Applicant’s amendments.
Regarding claims 1, 22, and 23, copending Application No. 17/175,245 teaches modifying a double stranded DNA in a cell by contacting it with a complex comprising a nucleic acid sequence-recognizing module bonded to a DNA glycosylase to bind a targeted site, wherein the DNA glycosylase has reduced reactivity with a DNA (claim 1). Copending Application No. 17/175,245 teaches the DNA glycosylase is a mutant that has reduced reactivity with a DNA as compared to a wild- type DNA glycosylase (claim 1). Copending Application No. 17/175,245 further teaches one or more nucleotides in the target site are modified without a double-stranded break in the targeted site (claim 1).
Regarding claim 2, copending Application No. 17/175,245 teaches wherein the nucleic acid sequence-recognizing module is selected from the group consisting of a clustered regularly interspaced short palindromic repeats (CRISPR)-associated (CRISPR-Cas) system wherein at least one DNA cleavage ability of Cas nuclease is inactivated, a zinc finger motif, a transcription activator-like (TAL) effector and a pentatricopeptide repeat (PPR) motif (claim 2).
Regarding claim 3, copending Application No. 17/175,245 teaches wherein the nucleic acid sequence-recognizing module is a CRISPR-Cas system wherein at least one DNA cleavage ability of Cas nuclease is inactivated (claim 3).
Regarding claim 5, copending Application No. 17/175,245 teaches converting one or more nucleotides in the targeted site to other one or more nucleotides, or deleting one or more nucleotides, or inserting one or more nucleotides into said targeted site (claim 1).
Regarding claims 8 and 9, copending Application No. 17/175,245 teaches wherein the DNA glycosylase is a mutant of uracil-DNA glycosylase (UDG) and has cytosine-DNA glycosylase (CDG) activity or thymine-DNA glycosylase (TDG) activity (claim 7).
Regarding claim 10, copending Application No. 17/175,245 teaches the DNA glycosylase is a mutant of uracil-DNA glycosylase (UDG) derived from a yeast and having CDG activity or TDG activity (claim 7 and 21).
However, copending Application No. 17/175,245 does not explicitly teach:
Wherein transfection is performed through delivery of the complex to separated plant callus or by Floral dip method (remaining limitation of claim 1)
the cell is a plant cell; and a step of selecting a cell into which the complex has been introduced and/or a cell into which the modification has been introduced (remaining limitations of claim 1, 22, and 23).
the method according to claim 1, wherein the nucleic acid sequence recognizing module is a CRISPR-Cas system in which Cas nuclease is inactive for cleavage of both strands of double-stranded DNA (claim 4).
The method according to claim 1, wherein the plant cell is derived from rice, Arabidopsis thaliana, bean, maize, cotton, safflower, sunflower, tobacco, wheat, barley, hemp, rose, Japanese yew, banana, coffee, sesame, buckwheat, or lettuce (claim 11).
The method according to claim 1, wherein the plant cell is derived from rice or Arabidopsis thaliana (claim 12).
the method according to claim 1, wherein the transfection is performed through delivery using an Agrobacterium method (claim 14).
The method according to claim 1, further comprising a step of producing a plant body from the cell and/or a step of clonally separating the obtained cell (claim 15).
A transformed plant cell obtained by the method of claim 1 (claim 17).
Regarding claims 1, 22, and 23, in analogous art Nishida teaches a method of modifying a targeted site of a double stranded DNA in a plant cell, comprising the method of copending Application No. 17/175,245. Nishida teaches a complex of a nucleic acid sequence-recognizing module and a DNA glycosylase can be intracellularly expressed by introducing an expression vector containing a DNA encoding a nucleic acid sequence-recognizing module and/or a DNA glycosylase into a host cell, and culturing the host cell (¶0117), and teaches the plant host cell may be callus (¶0125). Nishida also teaches wherein the cell is a polyploid cell, and all of the targeted sites in alleles on a homologous chromosome are modified (claim 26 of Nishida), which is reasonably interpreted to encompass the step of (v) that is selecting the cell in which the complex or modification has been introduced because the cell must be selected to determine the limitations discloses by Nishida.
Regarding claim 4, Nishida teaches the nucleic acid sequence-recognizing module is a CRISPR-Cas system wherein at least one DNA cleavage ability of Cas is inactivated (claim 3 of Nishida). Nishida also teaches in an alternative embodiment introducing mutations using a CRSIPR-mutant Cas comprising a mutant Cas protein (dCas) wherein cleavage ability of both strands of a double stranded DNA is inactivated (¶0020).
Regarding claims 11 and 12, Nishida teaches a complex of a nucleic acid sequence-recognizing module and a DNA glycosylase can be intracellularly expressed by introducing an expression vector containing a DNA encoding a nucleic acid sequence-recognizing module and/or a DNA glycosylase into a host cell, and culturing the host cell (¶0117), and teaches the plant host cell may be rice or Arabidopsis thaliana (¶0125).
Regarding claim 14, Nishida teaches an expression vector can be introduced by a known method such as by Agrobacterium (¶0127).
Regarding claim 15, Nishida teaches the expression vector may contain a selection marker such as drug resistance or auxotrophic complementary gene (¶0115), and teaches in an alternative embodiment a working example of using an auxotrophic medium to select surviving cells with mutations (¶0169-0170) (i.e. reasonably interpreted as clonally separating the obtained cell).
Regarding claim 17, Nishida teaches the method of producing the plant cell comprising the nucleic acid sequence and mutations described in claim 1 (claims 1, 17, 21, and 26 of Nishida), therefore Nishida also discloses a transformed plant cell obtained by the method of claim 1.
It would therefore have been obvious to a person of ordinary skill in the art to modify the invention of as taught by copending Application No. 17/175,245 to include the limitations of Nishida to arrive at the instantly claimed method with a reasonable expectation of success because Nishida teaches the same method but applies the method to plant cells. One having ordinary skill in the art would have been motivated to do so because Nishida teaches successful genome modification of plant cells using the same method of copending Application No. 17/175,245.
This is a provisional nonstatutory double patenting rejection.
Claims 18-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 7, 17, and 21 of copending Application No. 17/175,245 in view of Nishida (US Patent Application No. US- 20170321210-A1, published 11/09/2017) as applied to claims 1 and 17 above, and further in view of Hiroshi (WO-2018143477-A1, published on 08/09/2018).
This is a modified rejection necessitated by Applicant’s amendments.
Copending Application No. 17/175,245 and Nishida teach the limitations of claims 1 and 17 described above, and are incorporated herein by reference. However, Copending Application No. 17/175,245 and Nishida do not explicitly teach:
A transformed plant comprising the plant cell according to claim 17 (claim 18).
A seed obtained from the plant according to claim 18 (claim 19).
The plant according to claim 18, wherein the transformed trait is expressed only in the primary transgenic generation, and/or wherein the expression of the transformed trait is inherited across generations (claim 20).
In analogous art, Hiroshi also teaches an invention related to altering the DNA of
plant cells using a CRISPR-Cas system in which at least one DNA cleavage ability of
Cas is inactivated (claims 1-4 of Hiroshi).
Regarding claim 18, Hiroshi teaches a plant produced from the plant cell whose
genome has been modified (abstract).
Regarding claim 19, Hiroshi teaches a progeny plant produced from the plant
(abstract) (i.e. reasonably interpreted to encompass a seed to produce the progeny
plant), and also teaches a part of a plant that is a seed (claim 35 of Hiroshi).
Regarding claim 20, Hiroshi teaches a progeny plant having a mutation is
selected by selecting a progeny plant having a mutation (abstract) (i.e. expression of the
transformed trait is inherited across generations).
It would therefore have been obvious to a person of ordinary skill in the art to
modify the invention of Copending Application No. 17/175,245 and Nishida to include
the limitations of Hiroshi to arrive at the instantly claimed method with a reasonable
expectation of success because Copending Application No. 17/175,245 , Nishida, and
Hiroshi all teach altering plant cell genomes using similar methodology, and producing a
plant, seed, and progeny that have inherited the genomic alteration is a routine method
in plant biotechnology and could be achieved without encountering any special technical
obstacles. One having ordinary skill in the art would have been motivated to do so
because Hiroshi teaches a similar method, as well as generating a whole plant and
seed/ progeny plants comprising the genetic mutations (abstract).
This is a provisional nonstatutory double patenting rejection.
Claims 1-5, 7-15, 17 and 22-23 are provisionally rejected on the ground of
nonstatutory double patenting as being unpatentable over claims 1, 3 and 10 of
copending Application No. 18/539,833 in view of Nishida (US Patent Application No.
US-20170321210-A1, published 11/09/2017).
This is a modified rejection necessitated by Applicant’s amendments.
Regarding claims 1, 22, and 23, copending Application No. 18/539,833 teaches
a complex comprising a nucleic acid sequence-recognizing module specifically binding
to a target nucleotide sequence in a DNA and a DNA modifying enzyme-binding module
bonded to each other, wherein the nucleic acid sequence-recognizing module is a
CRISPR-Cas system, wherein at least one DNA cleavage ability of Cas is inactivated,
and wherein the complex converts one or more nucleotides in the targeted site to other
one or more nucleotides or deletes one or more nucleotides, or inserts one or more
nucleotides into the targeted site, wherein the targeted site is altered without cleaving at
least one strand of the DNA (claims 1 and 10).
Regarding claims 2-3, copending Application No. 18/539,833 teaches wherein
the nucleic acid sequence-recognizing module is a CRISPR-Cas system wherein at
least one DNA cleavage ability of Cas is inactivated (claim 1).
However, copending Application No. 18/539,833 does not explicitly teach:
wherein the DNA glycosylase is a mutant whose reactivity with double-stranded DNA is attenuated as compared with the wild type; and wherein the transfection is performed through delivery of the complex to separated plant callus or by the Floral dip method (remaining limitations of claim 1).
providing a plant cell comprising the double-stranded DNA of interest and a step of selecting a cell into which the complex has been introduced and/or a cell into which the modification has been introduced (remaining limitations of claims 1, 22, and 23).
the method according to claim 1, wherein the nucleic acid sequence recognizing module is a CRISPR-Cas system in which Cas nuclease is inactive for cleavage of both strands of double-stranded DNA (claim 4).
the method according to claim 1, wherein the modification comprises substitution or deletion of one or more nucleotides in the targeted site, or insertion of one or more nucleotides in the targeted site, and/or wherein the modification dominantly occurs on the PAM sequence side of the targeted site (claim 5)
the method according to claim 1, wherein the DNA glycosylase has cytosine-DNA glycosylase (CDG) activity or thymine- DNA glycosylase (TDG) activity (claim 8).
the method according to claim 8, wherein the DNA glycosylase having CDG activity or TDG activity is a mutant of uracil-DNA glycosylase (UDG) (claim 9).
The method according to claim 1, wherein the DNA glycosylase is a mutant of uracil-DNA glycosylase (UDG) derived from a yeast and having CDG activity or TDG activity (claim 10).
The method according to claim 1, wherein the plant cell is derived from rice, Arabidopsis thaliana, bean, maize, cotton, safflower, sunflower, tobacco, wheat, barley, hemp, rose, Japanese yew, banana, coffee, sesame, buckwheat, or lettuce (claim 11).
The method according to claim 1, wherein the plant cell is derived from rice or Arabidopsis thaliana (claim 12).
The method according to claim 1, wherein the transfection is performed through delivery using an Agrobacterium method (claim 14).
The method according to claim 1, further comprising a step of producing a plant body from the cell and/or a step of clonally separating the obtained cell (claim 15).
a transformed plant cell obtainable by the method according to claim 1 (claim 17).
Regarding claims 1, 22, and 23, in analogous art Nishida teaches Nishida
teaches a method of modifying a targeted site of a double stranded DNA in a plant cell, comprising the method of copending Application No. 18/539,833. Nishida teaches a complex of a nucleic acid sequence-recognizing module and a DNA glycosylase can be intracellularly expressed by introducing an expression vector containing a DNA encoding a nucleic acid sequence-recognizing module and/or a DNA glycosylase into a host cell, and culturing the host cell (¶0117), and teaches the plant host cell may be callus (¶0125). Nishida also teaches wherein the cell is a polyploid cell, and all of the targeted sites in alleles on a homologous chromosome are modified (claim 26 of Nishida), which is reasonably interpreted to encompass the step of (v) that is selecting the cell in which the complex or modification has been introduced because the cell must be selected to determine the limitations discloses by Nishida.
Regarding claim 4, Nishida teaches the nucleic acid sequence-recognizing
module is a CRISPR-Cas system wherein at least one DNA cleavage ability of Cas is
inactivated (claim 3 of Nishida). Nishida also teaches in an alternative embodiment
introducing mutations using a CRSIPR-mutant Cas comprising a mutant Cas protein
(dCas) wherein cleavage ability of both strands of a double stranded DNA is inactivated
(¶0020).
Regarding claim 5, Nishida teaches convert one or more nucleotides in the
targeted site to other one or more nucleotides or delete one or more nucleotides, or
insert one or more nucleotides into said targeted site (claim 1 of Nishida).
Regarding claim 8, Nishida teaches the DNA glycosylase has cytosine-
DNA glycosylase (CDG) activity or thymine-DNA glycosylase (TDG) activity (claim 7 of
Nishida).
Regarding claim 9, Nishida teaches wherein the DNA glycosylase having CDG
activity or TDG activity is a mutant of uracil-DNA glycosylase (UDG) (claim 8 of
Nishida).
Regarding claim 10, Nishida teaches an enzyme having CDG activity
or TDG activity, which is a mutant of yeast mitochondrial uracil-DNA glycosylase (UNG
1), as an enzyme that performs such base excision reaction (¶0018, Fig. 4 and 6).
Regarding claims 11 and 12, Nishida teaches a complex of a nucleic acid
sequence-recognizing module and a DNA glycosylase can be intracellularly expressed by introducing an expression vector containing a DNA encoding a nucleic acid
sequence-recognizing module and/or a DNA glycosylase into a host cell, and culturing
the host cell (¶0117), and teaches the plant host cell may be rice or Arabidopsis
thaliana (¶0125).
Regarding claim 14, Nishida teaches an expression vector can be introduced by
a known method such as by Agrobacterium (¶0127).
Regarding claim 15, Nishida teaches the expression vector may contain a
selection marker such as drug resistance or auxotrophic complementary gene (¶0115),
and teaches in an alternative embodiment a working example of using an auxotrophic
medium to select surviving cells with mutations (¶0169-0170) (i.e. reasonably
interpreted as clonally separating the obtained cell).
Regarding claim 17, Nishida teaches the method of producing the plant cell
comprising the nucleic acid sequence and mutations described in claim 1 (claims 1, 17,
21, and 26 of Nishida), therefore Nishida also discloses a transformed plant cell
obtained by the method of claim 1.
It would therefore have been obvious to a person of ordinary skill in the art to modify the invention of as taught by copending Application No. 18/539,833 to include the limitations of Nishida to arrive at the instantly claimed method with a reasonable expectation of success because Nishida teaches the same method but applies the method to plant cells. One having ordinary skill in the art would have been motivated to do so because Nishida teaches successful genome modification of plant cells using the same method of copending Application No. 18/539,833.
This is a provisional nonstatutory double patenting rejection.
Claims 18-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3,and 10 of copending Application No. 18/539,833 in view of Nishida (US Patent Application No. US-20170321210-A1, published 11/09/2017) as applied to claims 1 and 17 above, and further in view of Hiroshi (WO-2018143477-A1, published on 08/09/2018).
This is a modified rejection necessitated by Applicant’s amendments.
Copending Application No. 18/539,833 and Nishida teach the limitations of claims 1 and 17 described above, and are incorporated herein by reference.
However, Copending Application No. 18/539,833 and Nishida do not explicitly teach:
A transformed plant comprising the plant cell according to claim 17 (claim 18).
A seed obtained from the plant according to claim 18 (claim 19).
The plant according to claim 18, wherein the transformed trait is expressed only in the primary transgenic generation, and/or wherein the expression of the transformed trait is inherited across generations (claim 20).
In analogous art, Hiroshi also teaches an invention related to altering the DNA of
plant cells using a CRISPR-Cas system in which at least one DNA cleavage ability of
Cas is inactivated (claims 1-4 of Hiroshi).
Regarding claim 18, Hiroshi teaches a plant produced from the plant cell whose
genome has been modified (abstract).
Regarding claim 19, Hiroshi teaches a progeny plant produced from the plant
(abstract) (i.e. reasonably interpreted to encompass a seed to produce the progeny
plant), and also teaches a part of a plant that is a seed (claim 35 of Hiroshi).
Regarding claim 20, Hiroshi teaches a progeny plant having a mutation is
selected by selecting a progeny plant having a mutation (abstract) (i.e. expression of the
transformed trait is inherited across generations).
It would therefore have been obvious to a person of ordinary skill in the art to
modify the invention of Copending Application No. 18/539,833 and Nishida to include
the limitations of Hiroshi to arrive at the instantly claimed method with a reasonable
expectation of success because Copending Application No. 18/539,833, Nishida, and
Hiroshi all teach altering plant cell genomes using similar methodology, and producing a
plant, seed, and progeny that have inherited the genomic alteration is a routine method
in plant biotechnology and could be achieved without encountering any special technical
obstacles. One having ordinary skill in the art would have been motivated to do so
because Hiroshi teaches a similar method, as well as generating a whole plant and
seed/ progeny plants comprising the genetic mutations (abstract).
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant argues beginning on p. 8 of remarks dated 12/01/2025 the
following arguments:
Without acquiescing to any rejection and merely to expedite prosecution, Applicant has amended claim 1 to recite that "the DNA glycosylase is a mutant whose reactivity with double-stranded DNA is attenuated as compared with wild-type DNA glycosylase" and "the transfection is performed through delivery of the complex to separated plant callus or by Floral dip method." (canceled claims 7 and 13 have been incorporated into claim 1).
Nishida et al. describes genome editing using Cas proteins fused to DNA-modifying enzymes, including base editors. However, Nishida et al. does not recite the features that the DNA glycosylase is a mutant whose reactivity with double-stranded DNA is attenuated as compared with wild-type DNA glycosylase and the transfection is performed through delivery of the complex to separated plant callus or by Floral dip method, as recited in claim 1. While Nishida et al. discloses DNA glycosylases as potential fusion partners, Nishida et al. does not disclose the specific combination of features required by the pending claims.
Nishida et al. does not disclose a mutant glycosylase with attenuated reactivity toward double-stranded DNA as a design parameter. The present invention, as defined by the pending claims, specifically requires selection of a DNA glycosylase mutant whose reactivity with double-stranded DNA is attenuated as compared with wild-type DNA glycosylase, which is a functional requirement that defines the enzyme's behavior. Nishida et al. discloses the general use of DNA glycosylases without any disclosure of attenuating their dsDNA reactivity to reduce cytotoxicity or improve precision.
Furthermore, while Nishida et al. discloses that plant cells may be targets, Nishida et al. does not disclose specific transformation methods for plants. In particular, Nishida et al. does not disclose transfection through delivery to separated plant callus tissue or by the Floral dip method. The working examples, i.e., Examples 1-5, in Nishida et al. are restricted to mammalian systems with no practical demonstration in plants. Therefore, a person of ordinary skill in the art would have understood that the pending claims are not anticipated by Nishida et al., which only discloses generic statements about potential applicability to plants, without specific disclosure of delivery methods.
The present invention as defined by the pending claims has a specific requirement for "selecting a cell into which the complex has been introduced and/or a cell into which the modification has been introduced." This selection step is critical for isolating successfully modified plant cells and initiating regeneration. However, Nishida et al. does not clearly disclose such a selection as an intentional process step.
Therefore, a person of ordinary skill in the art would have understood that Nishida et al. fails to disclose the specific combination of (1) a DNA glycosylase mutant with attenuated dsDNA reactivity, (2) plant-specific transfection methods (e.g., delivery of the complex to separated plant callus or the Floral dip method), and (3) the selection step for modified cells, as recited in the pending claims. Accordingly, claims 1-3, 5, 8, 9, 17, 22, and 23 are not anticipated by Nishida et al., and the anticipation rejection of claims 1-3, 5, 8, 9, 17, 22, and 23 based on Nishida et al. should be withdrawn.
This argument has been fully considered and is found not persuasive for the following reason(s):
Claims 22 and 23 remain rejected under 35 USC 102 because these claims have not been amended.
In view of the currently amended claims, the previous rejections to pending claims 1-3, 5, 8, 9, and 17 under 35 USC 102 have been withdrawn. However, in view of Applicant’s amendments, the claims are now rejected under 35 USC 103.
Applicant’s first argument is Nishida et al. does not disclose a mutant glycosylase with attenuated reactivity toward double-stranded DNA as a design parameter. This argument is not persuasive because Nishida does in fact teach the DNA glycosylase is a mutant having reduced reactivity with a DNA having an unrelaxed double helix structure (unrelaxed DNA) as compared to a wild-type one (claim 13 of Nishida).
Applicant’s second argument is that while Nishida et al. discloses that generic statements that plant cells may be targets, Nishida et al. does not disclose specific transformation methods for plants. This argument is not persuasive because Nishida explicitly states in claim 21 that method may be a applied to a plant cell, and Nishida also teaches in the specification that a complex of a nucleic acid sequence-recognizing module and a DNA glycosylase can be intracellularly expressed by introducing an expression vector containing a DNA encoding a nucleic acid sequence-recognizing module and/or a DNA glycosylase into a host cell, and culturing the host cell (¶0117), and teaches the plant host cell may be callus (¶0125). Both floral dip methods and transformation of callus are common, routine methods well understood in the art for introducing an expression vector into a plant cell, and Nishida explicitly suggests transformation of callus cells (¶0117 and 0125). Therefore, it would be obvious to use plant callus cells for transformation in the method described by Nishida. For this reason, this argument is not found persuasive.
Applicant’s third argument is that Nishida et al. does not clearly disclose such a selection as an intentional process step. This argument is not found persuasive because as described in the rejections previously herein, Nishida also discloses wherein the cell is a polyploid cell, and all of the targeted sites in alleles on a homologous chromosome are modified (claim 26 of Nishida), which is reasonably interpreted to encompass the step of selecting the cell in which the complex or modification has been introduced because the cell must be selected to determine the limitations discloses by Nishida.
For the reasons above and those set forth in the obviousness rejection above, claims 1-3, 5, 8, 9, and 17 are rejected under 35 USC 103.
Applicant argues beginning on p. 10 of remarks dated 12/01/2025 the
following arguments:
The Office rejects claims 4 and 10-15 as allegedly obvious over Nishida et al. and claims 18-20 as allegedly obvious over Nishida et al. in view of Hiroshi et al.
The Office alleges that Nishida et al. discloses the limitations of claim 1, upon which claims 4, 10-15, and 18-20 depend, as discussed above with respect to the anticipation rejection. The Office admits that Nishida et al. does not teach in a single embodiment with the features of claims 4, 10-15, and 18-20. However, the Office asserts that Nishida et al. teaches all of the features of claims 4 and 10-15 in alternative embodiments and that a person of ordinary skill in the art would have been motivated to combine the features as taught by Nishida et al. into a single embodiment to arrive at the methods defined by claims 4 and 10- 15, such that the methods of claims 4 and 10-15 would have been obvious in view of Nishida et al. In addition, the Office contends that Hiroshi et al. teaches an invention related to altering the DNA of plant cells using a CRISPR-Cas system in which at least one DNA cleavage ability of Cas is inactivated as recited in claims 18-20 and that it would have been obvious to a person of ordinary skill in the art to modify the invention of Nishida et al. to include the features disclosed in Hiroshi et al. so as to arrive at the methods of claim 18-20, such that the methods of claims 18-20 would have been obvious in view of the combination of Nishida et al. and Hiroshi et al.
Without acquiescing to any rejection and merely to expedite prosecution, Applicant has amended claim 1 to recite that "the DNA glycosylase is a mutant whose reactivity with double-stranded DNA is attenuated as compared with wild-type DNA glycosylase" and that "the transfection is performed through delivery of the complex to separated plant callus or by Floral dip method."
As discussed above with respect to the anticipation rejection, Nishida et al. does not disclose or suggest combining a mutant glycosylase with attenuated dsDNA reactivity with plant-specific delivery methods, namely delivery of the complex to separated plant callus or by the Floral dip method. The Office's assertion that "alternative embodiments can be combined" to arrive at the present invention is based on impermissible hindsight reconstruction of the present invention. There must be some teaching or suggestion in the prior art that would have motivated a skilled person to make the specific combination, and Nishida et al. provides no such teaching or suggestion.
Nishida et al. discloses Examples 1-5 which focus exclusively on mammalian cells. It is well understood in the art that the specific challenges of plant transformation are fundamentally different from mammalian cell culture. Specifically, plant callus tissue is highly sensitive to DNA damage and oxidative stress, plant cell walls require specialized delivery methods, and plant regeneration from callus depends on maintaining cell viability. Nishida et al. does not disclose that it is necessary to attenuate glycosylase dsDNA reactivity, which feature needs to be combined with plant-specific delivery methods to provide the present invention. A person of ordinary skill in the art would have had no motivation to attenuate glycosylase dsDNA reactivity and combine such a feature with plant-specific delivery methods based on the disclosure of Nishida et al.
In addition, a person of ordinary skill in the art would not have had a reasonable
expectation of success using the presently claimed methods based on the disclosures of the cited references because the specific combination of features involves technical interactions that are not predictable, such as enzyme delivery method compatibility and plant-specific factors.
In that regard, the effectiveness of an attenuated glycosylase mutant depends critically on the delivery method and target tissue. Callus transformation and Floral dip, as well as, more specifically, Agrobacterium delivery, create different cellular environments with varying levels of stress and DNA repair activity. The art does not teach which enzyme characteristics work best with which delivery methods.
Different plant species respond differently to transformation stress and the optimal level of glycosylase attenuation varies by species and tissue type. This unpredictability is reflected in the extensive optimization required, as shown in the working examples of the present application.
The art also recognizes significant challenges with the technical obstacles of
maintaining enzyme activity after attenuation while reducing cytotoxicity, achieving efficient delivery to callus or floral tissue, and balancing editing efficiency with plant cell viability and regeneration. A person of ordinary skill in the art would have understood that overcoming these challenges would require substantial experimentation and could not be overcome by routine optimization.
Therefore, the methods of claims 4 and 10-15 would not have been obvious in view of Nishida et al.
While the Office also relies upon Hiroshi et al., Hiroshi et al. merely discloses general CRISPR-Cas systems for plants. Hiroshi et al. does not disclose DNA glycosylase mutants with attenuated dsDNA reactivity and does not teach the specific combination of features in the pending claims. Hiroshi et al. merely confirms that transformed plants can be produced and that traits can be inherited, which are well-known principles in plant biotechnology. Hiroshi et al. does not provide any teaching that would have motivated a person of ordinary skill in the art to combine the system disclosed by Nishida et al. with the specific enzyme attenuation and delivery methods recited in the pending claims. As such, the transformed plant and seed obtained therefrom as defined by claims 18-20 would not have been obvious in view of Nishida et al. alone or in combination with Hiroshi et al.
Neither Nishida et al. alone nor in combination with Hiroshi et al. provides any teaching or suggestion toward such advantages, which further evidences the non-obviousness of the present invention as defined by the pending claims over the disclosure of Nishida et al. alone or in combination with Hiroshi et al.
For at least the foregoing reasons, the present invention as defined by any of claims 4, 10-12, 14, 15, and 18-20 are not obvious over Nishida et al. alone or in combination with Hiroshi et al., and the obviousness rejection of claims 4, 10-12, 14, 15, and 18-20 based thereon should be withdrawn.
This argument has been fully considered and is found not persuasive for the following reason(s):
In sum, Applicant has argued that Nishida et al. does not disclose or suggest combining a mutant glycosylase with attenuated dsDNA reactivity with plant-specific delivery methods, namely delivery of the complex to separated plant callus or by the Floral dip method, and that "alternative embodiments can be combined" to arrive at the present invention is based on impermissible hindsight reconstruction of the present invention. Applicant essentially argues that because claim 1 is not obvious, the obviousness rejections should be withdrawn from 4, 10-12, 14, 15, and 18-20.
This argument is not found persuasive because, as described above, Nishida does in fact teach the argued limitations (see previous argument response), therefore claim 1 is obvious. The obviousness rejections to claims 4, 10-12, 14, 15, and 18-20 are not withdrawn in view of Applicant’s amendments to claim 1, and have been modified in view of Applicant’s amendments.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). The teachings in the argument relied upon by the Applicant (i.e., Nishida et al. does not disclose or suggest combining a mutant glycosylase with attenuated dsDNA reactivity with plant-specific delivery methods, namely delivery of the complex to separated plant callus or by the Floral dip method) are knowledge which was within the level of ordinary skill at the time the claimed invention was made. The teachings are also both described in the disclosure of Nishida. As previously stated, Nishida does in fact teach the DNA glycosylase is a mutant having reduced reactivity with a DNA having an unrelaxed double helix structure (unrelaxed DNA) as compared to a wild-type one (claim 13 of Nishida). Nishida also claims the method of Nishida can be applied to plant cells (claim 21 of Nishida), and suggests that a complex of a nucleic acid sequence-recognizing module and a DNA glycosylase can be intracellularly expressed by introducing an expression vector containing a DNA encoding a nucleic acid sequence-recognizing module and/or a DNA glycosylase into a host cell, and culturing the host cell (¶0117), and teaches the plant host cell may be callus (¶0125). In addition to these teachings, both floral dip methods and transformation of callus are common, routine methods well understood in the art for introducing an expression vector into a plant cell. Based on the teachings in the prior art, one of ordinary skill would have been motivated to use the invention of Nishida in plant callus cells and use the known, routine transformation methods to introduce an expression vector containing a DNA encoding a nucleic acid sequence-recognizing module and a mutant glycosylase with attenuated dsDNA reactivity into the cell(s) for the purpose of modifying a target site in the cells as taught by Nishida (claim 1, abstract, entire document).
Applicant argues beginning on p. 13 of remarks dated 12/01/2025 the
following arguments:
Furthermore, the present invention as defined by the claims provides the unexpected results of reduced cytotoxicity in plant callus, improved regeneration efficiency, enhanced editing precision and stability, and a broader applicability across plant species.
It is well known in the art that plant callus is highly sensitive to DNA damage. Wild- type glycosylases can introduce excessive base excision, leading to double-strand breaks that trigger cell death. However, in the present invention, by attenuating dsDNA reactivity, the claimed mutant glycosylase minimizes collateral damage, thereby maintaining callus viability during transformation, which directly improves the likelihood of regenerating edited plants.
Plant transformation success depends not only on DNA uptake but also on the ability of tissues to regenerate into whole plants. High levels of DNA damage impair regeneration pathways. The attenuated glycosylase mutant, when delivered to separated plant callus or by Floral dip, allows efficient editing without overwhelming the repair machinery, thereby resulting in higher regeneration rates of fertile, stably edited plants.
In contrast to wild-type glycosylases that may attack non-target dsDNA regions, the attenuated mutant glycosylase confines its activity to single-stranded contexts generated by CRISPR/Cas targeting. This leads to fewer off-target mutations and ensures that plant lines obtained after transfection exhibit stable inheritance of precise edits.
Some crop species are notoriously recalcitrant to transformation. Excessive DNA damage during editing is one reason for such recalcitrance. The present invention reduces stress on plant cells, thereby making base-editing applicable to a broader range of economically important plants.
These concrete technical effects-reduced callus necrosis, improved regeneration efficiency, enhanced gene editing precision, and broader species applicability-arise only from the specific combination of attenuated glycosylase mutants with plant-specific delivery methods as recited in the pending claims.
This argument has been fully considered and is found not persuasive for
the following reason(s):
This is not found persuasive. With regard to Applicant’s argument that Applicant has offered evidence of unexpected and unobvious results, pursuant to MPEP 716.02(b), the evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). In the instant case, Applicant alleges delivery of the attenuated glycosylase mutant to separated plant callus or by Floral dip results in higher regeneration rates of fertile, stably edited plants. Applicant has also provided no supporting art for the assertions in the argument above, nor any evidence regarding how the specific combination of an attenuated glycosylase mutant with the callus or floral dip delivery method generates the alleged unexpected results, e.g. as compared to any other transformation method. Regardless, these alleged results do not appear unexpected or unobvious because Nishida teaches when mutant uracil DNA glycosylase is used as DNA glycosylase, the cytotoxicity by the enzyme can be avoided by further introducing a mutation that decreases reactivity with a DNA having an unrelaxed double helix structure to make a base excision reaction by mutant UNG having CDG activity or TDG activity more selective to the region of a relaxed double-stranded or single stranded DNA (see FIG. 1, middle panel) (¶0075). Floral dip and callus methods using, e.g. agrobacterium-mediated transformation, are also known, routine methods in the art for producing stable transgenic plants, and would be expected to have greater transformation and regeneration efficiency of stable transgenic plants compared to other transformation methods that are known to have difficult/ low transformation or regeneration efficiency to produce stable transgenics (e.g., non-agrobacterium-mediated gene transfer or fibre mediated gene delivery, or PEG-mediated transformation) (see Kavipriya, p. 285, Table 2). Therefore, because the recited mutant DNA glycosylase reduces cell cytotoxicity and the recited methods would have increased transformation and regeneration efficiency compared to other methods with reduced transformation and regeneration efficiency, the alleged unexpected results of higher regeneration rates of fertile, stably edited plants do not appear unexpected or unobvious.
Further, even if Applicant can make such a showing, MPEP 716.02(c) provides that the evidence of unexpected results must be weighed against evidence supporting prima facie obviousness in making a final determination of the obviousness of the claimed invention. MPEP 716.02(c) directs the examiner to MPEP 716.01(d), which establishes that although the record may establish evidence of secondary considerations which are indicia of nonobviousness, the record may also establish such a strong case of obviousness that the objective evidence of nonobviousness is not sufficient to outweigh the evidence of obviousness. Newell Cos. v. Kenney Mfg. Co., 864 F.2d 757, 769, 9 USPQ2d 1417, 1427 (Fed. Cir. 1988), cert. denied, 493 U.S. 814 (1989); Richardson-Vicks, Inc., v. The Upjohn Co., 122 F.3d 1476, 1484, 44 USPQ2d 1181, 1187 (Fed. Cir. 1997) (showing of unexpected results and commercial success of claimed ibuprofen and pseudoephedrine combination in single tablet form, while supported by substantial evidence, held not to overcome strong prima facie case of obviousness). The showing, when made, must outweigh the rationale in support of a finding of prima facie obviousness provided in the 103 rejection(s). Here, Nishida teaches nearly all of the limitations of claim 1 in a single embodiment, except teaches in an alternative embodiment that the cell of which the nucleic acid sequence-recognizing module and a DNA glycosylase can be intracellularly expressed may be a plant callus cell (see 103 rejection above). Therefore, Nishida teaches and explicitly suggests all limitations of the instantly claimed invention without the need to reference another document. In view of the foregoing, Applicant’s evidence is not deemed to outweigh the basis for the rejection.
Finally, MPEP 716.02(d) provides that whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). In this case, the scope of the claims does not appear commensurate with the evidence. The claims are broadly drawn to any plant, however Applicant only provides evidence of modifying a target site of DNA in rice cells. Additionally, Applicant has argued unexpected results with regard to floral dip methods, but Applicant fails to describe floral dip methods using the claimed invention and has only provided evidence in working examples using callus derived from rice. For these reasons, the scope of claims does not appear commensurate with the evidence.
Applicant argues beginning on p. 14 of remarks dated 12/01/2025 the
following arguments:
The Office rejects claims 1-5, 7-15, 17-20, 22, and 23 for obviousness-type double patenting over claims 1, 3-5, 9, 10, and 12 of U.S. Patent 11,041,169 in view of Nishida et al. alone or in combination with Hiroshi et al.
Inasmuch as claims 7 and 13 have been canceled, Applicant addresses the
obviousness-type double patenting rejections with respect to claims 1-5, 8-12, 14, 15, 17-20, 22, and 23.
Applicant will file a terminal disclaimer with respect to the '169 patent as an
administrative convenience to render the obviousness-type double patenting rejection moot, upon an indication of the allowability of the pending claims except for the obviousness-type double patenting rejection and to the extent that the obviousness-type double patenting rejection remains applicable to such claims.
The Office provisionally rejects claims 1-5, 7-15, 17-20, 22, and 23 for obviousness- type double patenting over the claims of each of (a) U.S. Patent Application 17/175,245 and (b) U.S. Patent Application 18/539,833, in view of Nishida et al. alone or in combination with Hiroshi et al.
Inasmuch as claims 7 and 13 have been canceled, Applicant addresses the
obviousness-type double patenting rejections with respect to claims 1-5, 8-12, 14, 15, 17-20, 22, and 23.
The obviousness-type double patenting rejections are provisional in nature because the '245 and '833 applications remain pending. Applicant requests that the provisional obviousness-type double patenting rejections be held in abeyance until the present application otherwise is in condition for allowance.
This argument has been fully considered and is found not persuasive for
the following reason(s):
Regarding the nonstatutory double patenting rejections, the rejections are maintained. The rejections may be withdrawn in the event a terminal disclaimer is filed, or the subject matter of the claims is amended in a manner that a nonstatutory double patenting rejection is no longer applicable.
Regarding the provisional nonstatutory double patenting rejections, these rejections are maintained. In the event the provisional nonstatutory patenting rejection is the only rejection remaining in the application, the rejection will be maintained until applicant overcomes the rejection because the instant application has a later patent term filing date (see MPEP 804.I.1(b)(iii)).
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 JESSICA N STOCKDALE whose telephone number is (703)756-5395. The examiner can normally be reached M-F 8:30-5:00 CT.
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JESSICA N. STOCKDALE
Examiner
Art Unit 1663
/JESSICA NICOLE STOCKDALE/Examiner, Art Unit 1663
/CHARLES LOGSDON/Primary Examiner, Art Unit 1662