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 .
Amendments
In the reply filed 12/22/2025, Applicant has amended Claims 47, 49, 50, 58, and 66.
Claims 54-66 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 47-53 are under consideration.
Withdrawn 35 USC § 112(b)
The prior rejection of Claim 50 under 35 U.S.C. § 112(b) pre-AIA 2nd paragraph as being indefinite is withdrawn in light of Applicant’s arguments that “guide RNA” is a term of the art, and at the time of filing one of ordinary skill in the art would have understood that gRNAs can target a gene or its RNA product.
Withdrawn Claim Rejections - 35 USC § 102
The prior rejection of Claims 47-49 and 51-53 under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Esvelt et al., (WO2017/196858, filed 5/09/2017, published 11/16/2017, see IDS filed10/02/2020) is withdrawn in light of Applicant’s amendments to limit the claimed system to specific combinations of breeding pairs that only comprise the target recognition or modifier protein.
Withdrawn 35 USC § 103
The prior rejection of Claims 47-53 under 35 U.S.C. 103 as being unpatentable over Esvelt et al. (WO2017/058839, filed 9/28/2016, see IDS filed 2/02/2022) is withdrawn in order to incorporate the prior art of Bier et al. (WO2018/035300, filed 8/17/2017, published 2/22/2018) in light of Applicant’s amendments to limit the claimed system to specific combinations of breeding pairs, which requires a modification of the grounds of rejection.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 47-53 are rejected under 35 U.S.C. 103 as being unpatentable over Esvelt et al. (WO2017/058839, filed 9/28/2016, see IDS filed 2/02/2022), in view of Bier et al. (WO2018/035300, filed 8/17/2017, published 2/22/2018)
.
In regard to claim 47, Esvelt (WO2017) teaches CRISPR Cas-based gene drive systems comprising male (i.e., heterogametic organism) and female (i.e., homogametic organism) transgenic organisms that comprise gene drive components comprising at least one target recognition element (guide RNA) and at least one nucleic acid modifier protein (Cas9) integrated into one or more of their chromosomes (Abstract, Summary).
Esvelt (WO2017) teaches the scientific concept of a gene-drive system for biasing the sex ratio of a population using a first sex chromosome that encodes an RNA guided nuclease (Cas9) and also expresses a gRNA that targets the opposite sex chromosome, thereby producing gametes predominantly containing the first sex chromosome (Summary, p.9, 3rd para.). Specifically in regard to modifying sex chromosomes, Esvelt (WO2017) teaches a genus of systems comprising at least one component of the CRISPR-Cas gene drive integrated into either the Y chromosome (i.e., “Y-drives”) or the X chromosome (i.e.,“X-drives”), and tracts their effects on sex ratio during zygote formation when sperm of the heterogametic organism fertilize the oocytes from the homogametic organism (Examples V, Fig. 4C & 4D).
Secondly, in regard to only one of the components of the gene-drive being integrated into one of the chromosomes, while the other component is integrated into another chromosome, Esvelt (WO2017) teaches the scientific concept of [AltContent: textbox ([img-media_image1.png])]“split drive” systems, which comprise the Cas9 protein and guide RNAs on separate chromosomes and are especially advantageous because they allow containment of the genetically modified organism by avoiding gene drive escape into wild populations (see p. 71-72, Example XIV “Dependent Gene Drives”, Figs. 16 & 17). Specifically, Esvelt teaches the system comprises transgenic organisms comprising (A) comprising (a)(i) at least one nucleic acid encoding a target recognition element (“Heterozygous sgRNA”), and transgenic organisms comprising (B) comprising (a)(i) at least one nucleic acid encoding a nucleic acid modifier protein (“Heterozygous Cas9”) (see excerpt from Fig. 17 is adjacent).
However, although Esvelt (WO2017) teaches systems of transgenic heterogametic organisms and homogametic organism comprising both components of a Cas9/gRNA gene drive integrated into one of their sex chromosomes (i.e., X-drives and Y-drives), and although Esvelt (WO2017) teaches the scientific concept of “split gene” drives where only one component of a Cas9/gRNA gene drive is integrated into one of their chromosomes, Esvelt (WO2017) is silent to a split-gene drive system comprising only one component of a Cas9/gRNA gene drive integrated into one of the sex chromosomes (i.e., heterozygous split X-drive or heterozygous split Y-drive).
Nevertheless, it would have been obvious to one having ordinary skill in the art at the time the invention was filed to prepare said system comprising a heterozygous split X-drive or a heterozygous split Y-drive because each of the individual elements of the instant claim are independently presented by Esvelt (WO2017) as embodiments and are taught that they can be combined in various embodiments; therefore a combination of all the elements into a single embodiment would be apparent to an artisan skilled in transgenic animals in light of the Supreme Court’s KSR decision (see MPEP 2143 Exemplary Rationale (A)). Regarding the rationale for combining prior art elements according to known methods to yield predictable results, as stated supra, Esvelt (WO2017) teaches the advantages of split-gene drive systems for avoiding gene drive escape, and sex chromosome based gene drives for biasing sex ratio in a population.
However, Esvelt (WO2017) is silent to a split drive system that is integrated into a sex chromosome, which is in a breeding pair such that when one member of the breeding pair comprises one of the separated components of the split drive, the other member has the other component.
Bier et al. (WO2018) teaches a breeding pair comprising a split-gene drive comprising an Cas9 on one chromosome and at least one gRNA on a different chromosome, wherein the two transgenic organisms of the breeding pair carry only one of these two elements of the split-drive system, when crossed result in progeny carrying both elements in the same individual that cause active genome modification ([0025] Autocatalytic genome editing using trans-complementation). Bier goes on to teach that since the two separate elements (i.e., Cas9 or gRNA) can each be propagated safely as neither alone can create a full gene-drive. Also, neither element alone can create off-target mutagenesis in the stocks of transgenic organisms, until they are crossed resulting in progeny with both elements and a full gene-drive [0026]. Bier also teaches husbandry advantages since neither of the two constructs alone constitute a full-gene drive, each single element can be propagated safely as separate stock [0034].
Accordingly, it would have been predictably obvious to use only one component of a split-gene drive system for incorporation into one of the sex chromosomes of the heterogametic organism of a breeding pair and the other component for incorporation into a chromosome of the homogametic transgenic organism of the breeding pair with a reasonable expectation of success.
In regard to claim 48, as stated supra, the modifier protein is Cas9.
In regard to claims 49 and 51, as stated supra, the CRISPR-based gene split drives comprise a Cas9 nuclease and at least one gRNA target recognition element.
In regard to claim 50, as stated supra, Esvert (WO2017) suggests a transgenic heterogametic eukaryotic organism of a breeding pair comprising at least one gRNA integrated into its sex chromosome. In regard to claim 50(i), as per the nature of the at least one gRNAs, Esvelt teaches at least two guide RNAs are used which comprise those that are responsible for the drive to copy itself and those that are responsible for targeting an undesired trait such as a fertility gene (p. 8, 2nd para., p. 14, 2nd & 3rd para., see Fig. 11A, & 12). In regard to claim 50(ii), in the “sgRNA-only split drive” embodiment of Esvelt in view of Bier, one option is that the heterogametic male of the breeding pair would have only the sgRNAs in a first sex chromosome (i.e., split Y-sgRNA drive or split X-sgRNA drive); however, since the sgRNAs are sex chromosome linked, it would have been understood by one of ordinary skill in the art that the sperm of the transgenic heterogametic male would have had only the transgenic Y chromosome or X chromosome, wherein ½ of the sperm would not have had the sgRNA transgene and could not contribute to the split-drive system if the sgRNAs were only in the Y chromosome or X chromosome.
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to prepare the sgRNA-only split drive system comprising said sgRNAs in one sex chromosome of a transgenic heterogametic organism of a breeding pair as suggested by Esvelt (WO2017) in view of Bier, and further include the sgRNAs in the other sex chromosome of the sgRNA-only split drive transgenic heterogametic organism with a reasonable expectation of success. One of ordinary skill would have been motivated to do so in order to ensure that all of the sperm (both X and Y carrying) were sgRNA-drive transgenics.
In regard to claims 52 and 53, Esvelt (WO2017) teaches the transgenic organisms are rodents pests such as rats (p. 13, 3rd para, p. 38, 1st para., see Fig. 6B). Furthermore, in regard to claim 53, it must be noted that phrase “optionally, wherein said rodent is a mouse and wherein:” is followed by limitations directed to the integration sites of the guide RNA in a mouse. Since these limitations are optional, the only examined limitation for claim 53 is that the mammal of claim 52 is a rodent, which is what is taught by Esvelt (WO2017).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 12/22/2025 are acknowledged.
Applicant argues that instant claim has been amended to a breeding a pair, comprising a transgenic heterogametic organism with only one component of a CRISPR-based system (either gRNA or Cas9) and a transgenic homogametic organism comprising only one complement component (either Cas9 or gRNA, respectively), wherein the complete system becomes functionally reconstituted in the zygote progeny.
Applicant argues that this is fundamentally different from split-drive system of Esvelt. Applicant argues that the split-drives of Esvelt are implemented within one transgenic organism and do not contemplate the segregation of CRISPR. Applicant notes that the cited Example XIV and Fig. 17 of Esvelt depict the split-drive components on separate chromosomes of the same organism. Furthermore, Applicant argues that Esvelt does not teach or suggest splitting the components by sex, nor does it describe a breeding scheme where each parent contributes only Cas9 or gRNA.
Furthermore, Applicant argues that although the secondary reference of Bier teaches a split-drive system with only Cas9 or gRNA integration in separate organisms to reduce off-target effects and enable safer propagation, Bier does not teach integration into sex chromosomes.
Applicant argues neither Esvelt nor Brier teaches integration of only Cas9 or gRNA into a sex chromosome of a parent, thereby preventing drive activity and off-target editing in the parent, yet enabling a zygote progeny to inherit both component and reconstitute drive activity to bias sex or traits. Applicant argues that the claimed breeding pair allows sex-specific segregation of split-drive elements that is not taught or suggested by the cited references, is not an obvious design choice, and represents a novel and non-obvious mechanism to control drive activity.
Applicant’s arguments have been considered but are not found persuasive
Although Esvelt (WO2017) does not provide a preferred embodiment of a single component of a split-drive (i.e., only Cas9 or gRNA) integrated into a sex chromosome,
Esvelt does generally teach “a method of biasing the sex ratio of a population is provided including using a sex chromosome that encodes an RNA guided nuclease” (p.9, 3rd para.), and discloses the scientific concept of Y chromosome (i.e., “Y-drives”) or X chromosome (i.e., “X-drives”) for gene modification in the zygote (Example V, Fig. 4). Furthermore, Esvelt also teaches the scientific concept and advantages of “separating the components of a CRISPR-based gene drive element such that one component does not exhibit drive (referred to herein as a “split drive”) is utilized as a method of preventing the driving element from altering wild populations.” (Example XIV “Dependent Gene Drives”).
MPEP 2123 (I) states a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments, and a person of ordinary skill in the art would have reasonably combined embodiments of Esvelt to produce a heterozygous split-drive system into an X or Y chromosome with a reasonable expectation of success.
Finally, as stated in the pending rejection, Bier et al. (WO2018) teaches a breeding pair comprising split-gene drive elements of either a Cas9 or gRNA, wherein “(w)hen these two elements are carried in the same individual (e.g., in progeny resulting from a cross of two individuals carrying a respective one of the two elements) both elements are actively copied onto their sister chromosomes and any additional gRNAs cause active genome sequence editing.”[0025].
[AltContent: textbox ([img-media_image2.png])]
Thus, it would have been obvious to modify the X or Y integrated heterozygous split-drives of Esvelt into separate individuals of a breeding pair as taught by Bier with a reasonable expectation of success, and one of ordinary skill would have been motivated to do so “(s)ince neither of the two constructs alone constitutes a drive, each single element can be propagated safely as a separate stock” ([0034] of Bier). It must be noted, that Bier implicitly teaches that the these elements would have segregated separately because they were on different chromosomes coming form different individuals.
In regard to the fact that Bier does not teach integration of the split gene-drive elements into sex chromosomes, Applicant is reminded that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In instant case, the primary reference of Esvelt makes obvious the use of a sex chromosome as an integration site for biasing sex ratios of a population.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee 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 date of this final action.
No claims are allowed.
Examiner Contact Information
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/ARTHUR S LEONARD/Examiner, Art Unit 1631
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