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 .
The Reply filed by Applicants on 08/21/2025 is hereby acknowledged.
Claim Rejections - 35 USC § 101
The rejection of claims 29 and 30 are rendered moot by the cancellation of claims 29 and 30.
Claim Rejections - 35 USC § 112
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 rejection of claims 29 and 30 are rendered moot by the cancellation of claims 29 and 30.
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)(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.
The rejection of claims 29 and 30 are rendered moot by the cancellation of claims 29 and 30.
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 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 1-2, 6-8, 10, 12-14, 16-18, 20, 24, 26 and 28-32 remain rejected and claims 33-34 are rejected under 35 U.S.C. 103 as being unpatentable over Bundock et al (USPGPUB 20150351340) in view of Brooks et al (2014 Plant Physiology 166:1292-1297) in view of Cermak et al (2015 Genome Biology 1-14) in view of Sadhu et al (2016 Science 353:1113-1116).
The claims are drawn to methods of targeting DNA recombination between homologous chromosomes in a plant cell comprising expressing a nuclease system wherein the nuclease system includes CRISPR-Cas and wherein the Cas protein is Cas9, and wherein the system is targeted to a preselected endogenous target site comprising polymorphic alleles wherein upon expression of said nuclease system the DNA of at least one of said allele is cleaved wherein the nuclease cleaves the DNA creating a double stranded break, analyzing the progeny for homologous recombination and selecting progeny wherein homologous recombination has occurred wherein only one of the parent comprises the nuclease system wherein the traits comprise increased drought resistance improved nutrient content or any trait of benefit for the plant cell (see claim 18) wherein the somatic plant cell comprises a protoplast or a crop plant cell and plants therefrom.
Bundock et al teach a method for removing genetic linkage between a first locus A and a second locus B present on a first plant chromosome in a plant or plant cell wherein the plant cell comprises a first chromosome and a second chromosome that are homologous or homologues (which would include heterozygous and/or hybrid cells), introducing a double strand break in the first and second chromosomes wherein recombination is induced between the chromosomes resulting in the breaking of linkage wherein the DNA is rearranged on the resulting chromosome after recombination using Crispr/Cas (see claims 20-24) wherein the plant is a somatic plant cell from a hybrid and wherein the event is carried out in a crop plant and results in a beneficial trait (see claims 31-32 and Examples 3, 4, and 5).
Brooks et al teach methods of targeting DNA recombination in tomato plants which are a crop species and therefore comprise a crop plant cell using CRISPR/Cas9 which is a nuclease system by expression CRISPR-Cas in a plant cell wherein endogenous target sites were chosen and used to direct homologous recombination (see page 1295 in particular).
Cermak et al teaches methods of targeting DNA recombination in tomato somatic cells comprising delivering TALENS and CRISPR-Cas systems via geminivirus delivery targeting an endogenous gene for anthocyanin formation allowing selection of callus culture using color determination which may be considered an additional benefit of tomato since color factors into consumer preference wherein the cells are protoplasts (see Talent Activity in protoplasts in Materials and Methods for example) wherein the progeny are screened using PCR (see materials and methods under PCR genotyping). Cermak et al states “We show that geminivirus vectors are efficient tools for GT in tomato, and coupled with TALENs or CRISPR/Cas9 reagents, they allow targeting of virtually any sequence in a given genome, making it possible to extend this technology to other crop species to create valuable traits” (see end of page 10 and beginning paragraph of page 11).
CRISPR/Cas9 inherently induces a double strand break as normal part of its operation and accordingly meets the limitation of the instant claims. Likewise, chromosomes inherently are made up of both euchromatin and heterochromatin such that literally any position on a chromosome would be in a stretch of euchromatin or heterochromatin. Therefore the cited art by using a target site inherently meets this limitation of the claims.
Sadhu et al teach the use of CRISPR to direct mitotic recombination, that is the homologous recombination between chromosomes at particular sites wherein polymorphic alleles are exploited to provide mapping populations (see Figure 1) wherein Manganese sensitivity is targeted. Sadhu et al state “In a heterozygous diploid individual, an LOH event can be generated by cutting only one chromosome, leaving its homolog intact to serve as a template for repair by HR. This is accomplished by using polymorphic heterozygous PAM sites” (see middle of page 1113) thus teaching the element of targeting a polymorphic allele.
The state of the art demonstrates that plant transformation methods for site-specific inductions of recombination between homologous chromosomes to add beneficial traits to plants as taught by Bundock et al and that using CRISPR/Cas9 technology in tomato plants (which are a crop plant) for precise genome editing was known and conducted at the time of filing, and that using this technology for crop trait improvement was predicted and known (see Bundock et al and statements above). Furthermore, the concept of targeting polymorphic alleles and cutting one chromosome for gene conversion was taught and known in the art as taught by Sadhu et al and more so, was taught as a method to generate high resolution genetic maps.
Given the state of the art, the disclosures of Bundock et al, Brooks et al, Cermak et al and Sadhu et al, it would have been obvious to one of ordinary skill in the art to use CRISPR/Cas9 in tomato plants for trait improvement as taught and suggested by Brooks et al and Cermak et al and to modify it by constructing maps as taught and suggest by Sadhu et al and one of ordinary skill in the art would have been motivated to do so for crop trait improvement as taught by Cermak et al, wherein particular traits could be associated with particular variation as according to Sadhu et al. In crop science, both mapping of traits as well as directed precise genomic changes would be of enormous benefit as suggested by both Cermak et al and Sadhu et al and accordingly, one of ordinary skill in the art would have been motivated to use the taught approaches for improvement in crop species as instantly claimed. And as motivated, and practicing all the steps of the claimed invention, the instantly claimed result, the increased percent of allele-dependent homologous automatically follows from this practice.
It is noted that the overall concept of inducing recombination between homologous chromosomes was known at the time of filing and taught, however some of the individual elements that are known tools of molecular biology for use with plants are provided by additional references.
Response to Arguments
Applicant's arguments filed 01/30/2025 have been fully considered but they are not persuasive.
Applicant’s urge that Bundock differs in several elements of the claimed method including (1) disclosing reciprocal chromosome translocation by non-homologous end joining (2) requires cleavage of both alleles, and (3) the production and selection of a plant progeny wherein targeted homologous recombination occurred.
This is not persuasive because Bundock is not relied upon for this teaching which is in fact remedied by Brooks and Cermak. Furthermore, Bundock envisions clearly using the CRISPR/Cas system for generating recombination, and the CRISPR/Cas system uses BOTH homologous recombination and NHEJ in the process as described by Cermak et al and Sadhu et al, with repair mechanisms associated with CRISPR/Cas technology.
Applicants urge that Cernak, similarly differs in several key areas.
This is not persuasive because Sadhu et al remedies these areas as described up above. The technology, particularly of CRISPR/Cas, but also nucleases in general, is known to transfer across species as well as interchange element as conditions demand, and this is demonstrated and evidenced by the statements in Sadhu et al, wherein it is stated “In addition to single-celled organisms, LOH panels could be generated from cultured cells, enabling in vitro genetic dissection of human traits with cellular phenotypes. In multicellular organisms, mapping resolution could be enhanced with CRISPR-directed meiotic recombination events” (see page 1116 3rd full paragraph), and Brooks et al stating “CRISPR/Cas9 has seen a meteoric rise during the past 2 years, with applications to bacterial, animal, human, and, most recently, plant systems” (see first full paragraph). Shared elements of recombination, selecting recombination events and CRISPR/Cas are transferable across species and the statements above give evidence to this. The motivation for combining these elements is described above in the rejection of record.
Applicant’s further urge unexpected results with an unexpected high rate of HR-repair approximately 14% per allele.
This is not persuasive because the cited unexpected result is a necessary result that follows from practicing the invention as claimed.
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.
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/BRENT T PAGE/Primary Examiner, Art Unit 1663