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 .
Claim Status
Claims 1, 3, 9-12 and 14-18, 21 and 22 are pending and examined. Claims 2, 4-8, 13, 19, 20 and 23-26 have been cancelled.
The rejection of claims 1, 3, 6-12 and 14-26 under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement for introducing new matter is withdrawn in light of the amendments to the claims.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 17 November 2025 has been entered.
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.
Claim(s) 1, 3, 9-12 and 14-18, 21 and 22 REMAIN rejected under 35 U.S.C. 103 as being unpatentable over Senis et al (2016, Nucleic Acids Research, 45:1-17) in view of Maori et al (Patent No. US 11,555,199 B2) and Gurumurthy et al (Pub. No. US 2018/0127787 A1) and Zhao et al (2016, Scientific Reports, 6:1-11), and in further view of Mitter et al (2015, Virus Research, 211:151-158) and Thomas et al (2004, Australasian Plant Pathology, 33:597-599).
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Instant claims 1, 3, 9-12 and 14-18, 21 and 22 are drawn to a method of reducing expression of a viral target gene in a tomato plant cell by introducing a ZFN, TALEN or nuclease that cleaves a native tomato pre-miRNA and making at least two double stranded DNA breaks at said site and selecting for a cell where the breaks have been repaired with intervening DNA encoding an amiRNA comprising a core sequence complementary to the target viral gene resulting in a tomato plant cell comprising the amiRNA comprising the core sequence and wherein the plant is heterozygous, wherein the target is a Bunyavirales gene or a tomato spotted wilt virus gene, wherein the genomic site comprises SEQ ID NO: 6 or 7 and the intervening DNA comprises SEQ ID NO: 2 and a method of producing tomato plant seeds by crossing a plant comprising said cell with another plant.
The specification teaches that SEQ ID NO: 2 is the TSWV sequence of amiTSWV and is embedded within the tomato sequence of miR156b scaffold SEQ ID NO: 6 and is encompassed by SEQ ID NO: 9 (p. 5).
Senis et al teach introducing an amiRNA into a miRNA gene using a sequence specific nuclease such as Cas9 or TALEN to reduce expression of a target gene without perturbing endogenous gene expression (e.g. see Abstract; see also p. 2; see p. 13). The amiRNA is embedded in a miRNA scaffold that is also the scaffold of the native pre-miRNA (see Abstract; see also p. 5, ¶ 1 and 2).
Senis et al teach the importance of keeping at least one allele intact when introducing intervening DNA as the miRNA being altered may play an essential physiological role (p. 13, col. 2, last ¶ bridging p. 14). Therefore, Senis et al reasonably provides motivation for cells being heterozygous for modified pre-miRNAs.
Senis et al teach that this method of linking exogenous to endogenous RNAi triggers to precisely engineer and harness miRNA loci for expression of detectable foreign RNA sequences should prove valuable and can include replacement of a target miRNA with another artificial or natural miRNA (p. 14, col. 2, ¶ 2). Thus, Senis et al reasonably teach replacing rather than inserting intervening DNA into a native pre-miRNA.
However, because Senis et al does not teach practicing this method in plants, the issue is whether one of ordinary skill in the art would have found it obvious to do so while making at least two double strand DNA breaks, and whether one would target a Bunyavirales gene or SEQ ID NO: 2.
To this point, Maori et al teach one of ordinary skill in the art was aware of introducing modified miRNAs/amiRNAs into a plant genome in order to silence a target gene of interest using TALENs or CRISPR (see claims 1, 2, 9 and 10, see also col. 3 and 4; see col. 10; see also col. 16; col. 24 and 26). The method is applicable to any plant, and includes targeting genes of pathogens/exogenous targeting genes affecting tomato or biotic stresses (col. 11 and 12; see col. 49 and 54).
Similarly, Gurumurthy et al teach modifying gene expression in a cell using nucleases wherein an amiRNA replaces an endogenous target sequence (see Abstract; see also claims 1, 7-9, 14; see Figures 2-5; see also ¶ 0255). The method is applicable to plants (¶ 0041). These amiRNAs are inserted into intronic regions where endogenous miRNAs are present and thus would not affect the expression of the host gene (¶ 0220-0221).
Zhao et al teach the deletion of endogenous miRNAs and their replacement with an intervening DNA corresponding to the TFL1 gene by making two double stranded DNA breaks (see Abstract; see also Figure 1 and 2). This allows for targeted gene replacement intervening DNA in plants such as maize that are transgene free as opposed to inserting intervening DNA (p. 6, ¶ 4).
Mitter et al teach that TSWV is an economically important viral pathogen of a wide range of field and horticultural crops and that amiRNA can be used for broad spectrum resistance to tospoviruses and other viruses (e.g., see Abstract).
Thomas et al teach sequencing and analysis of TSWV within the Bunyaviridae family, and in particular GenBank Accession No. AY611529 having 100% sequence identity to SEQ ID NO: 2 of the instant invention (see Attachment A in the Office action dated 17 August 2023; see also p. 599, col. 1). Viruses are a significant production problem in chickpeas, and TSWV is known to infect them (p. 597).
Therefore, prior to the effective filing date of the instant invention it would have been prima facie obvious to one of ordinary skill in the art to apply the method as taught by Senis et al to silence expression of a target gene of interest, for example, as taught by Maori et al and Zhao et al.
One would have found it obvious to do so because the methods are functionally equivalent to one another in so far as each method is used to silence a gene of interest by insertion or replacement without the need for implementing classical molecular genetics and transgenic tools comprising expression cassettes that have a promoter, terminator and selection markers to produce improved crops or novel non-GMO plants with increased crop yield having protection against stress, pathogens and pests (e.g., see Maori et al, col. 11; see also Zhao et al, Abstract).
Moreover, one would be motivated to do this because when the amiRNAs are inserted into intronic regions where endogenous miRNAs are present the expression of the host genes will not be disturbed (Senis et al, see Abstract; see also p. 2; see p. 13; see also Gurumurthy et al, ¶ 0220-0221).
One would have a reasonable expectation of success in doing so because each of Senis et al and Maori et al and Gurumurthy et al teach the successful inhibition of a gene of interest whereas Zhao et al demonstrate the successful replacement of endogenous miRNA with intervening DNA that functional and expressed.
One would have used the method to target SEQ ID NO: 2 because it is a design choice: TSWV sequences were known in the art (e.g., see Thomas et al), and the specific sequence targeted is inconsequential so long as gene silencing occurs and TSWV resistance is increased, the importance of which is noted above. The same is true for the placement of the intervening DNA: so long as it does not interfere with endogenous gene expression its location is inconsequential.
As this target sequence would be replacing native pre-miRNA in the plant genome, it is necessarily follows that the genomic site would comprise SEQ ID NO: 6 or 7 or that the cell would comprise SEQ ID NO: 2.
Response to Arguments
Applicant traverses the rejection of the claims because of the speculative nature of the cited language in Senis, which fails to provide the requisite reasonable expectation of success.
Applicants claims that conclusive proof is not required but that the present rejection fails to provide any objective evidence that the person of ordinary skill in the art could have had any responsible expectation of success at the earliest priority date in carrying out the presently claimed invention.
Applicant asserts that at most the person of ordinary skill could have tried in the hope that this strategy would be successful but that this "wait and see" mindset does not satisfy the legal requirements for a prima facie case of obviousness under 35 U.S.C. § 103 (Applicant reply dated 17 November 2025, p. 7, ¶ 2).
This argument is not persuasive because even if the teachings of Senis are considered speculative, Zhao clearly teaches the deletion of endogenous miRNAs and their replacement with an intervening DNA corresponding to the TFL1 gene by making two double stranded DNA breaks. When the endogenous miRNA was replaced expression of the gene of interest occurred (p. 6 ¶ 1 and 2; see also supplementary Figure 5). Moreover, Gurumurthy teaches the successful amiRNA replacement of an endogenous target sequence.
Thus, contrary to Applicant’s position that the Office has failed to provide any objective evidence that the person of ordinary skill in the art could have had any responsible expectation of success, the teachings of the prior art demonstrate that one would have a reasonable expectation of success in replacing, rather than inserting, intervening DNA into native pre-miRNA.
Applicant argues that the relevant question is not whether one would have a reasonable expectation of success inhibiting expression of a gene of interest, but that the issue is the references fail provide the ordinarily skilled worker with both the motivation and reasonable expectation of success to modify the teachings of Senis to arrive at the claimed method to achieve gene silencing of a viral target gene in tomato (Applicant reply dated 17 November 2025, p. last ¶).
This argument is not persuasive and has been addressed supra regarding one’s reasonable expectation of success. Regarding the issue of whether there is motivation to modify the teachings of Senis, the Office has explained that one is not motivated to modify the teachings of Senis per se.
Rather, the Office contends that the methods of Senis and those of Maori, Gurumunthy and Zhao are functionally equivalent and may be substituted for one another to predictably lead to the expression of an amiRNA.
However, even in light of this position the Office has provided the requisite motivation for inserting intervening DNA into native tomato pre-miRNA: when the amiRNAs are inserted into intronic regions where endogenous miRNAs are present the expression of the host genes will not be disturbed (Senis et al, see Abstract; see also p. 2; see p. 13; see also Gurumurthy et al, ¶ 0220-0221).
In other words, amiRNAs insertion where endogenous miRNAs are present would not affect the expression of the host gene and allows for targeted gene replacement in plants that are transgene free.
Applicant traverses the rejection because in marked contrast to the speculative statements in Senis, the inventors have exemplified reducing the expression of a viral target gene in a tomato plant cell as recited in claim 1 and because the outcome was not at all obvious based on the combined teachings of the cited references.
This argument is unpersuasive because as noted above, the prior art is not merely speculative but in fact teaches that the deletion of endogenous miRNAs in plants and their replacement with an intervening DNA corresponding to the TFL1 gene by making two double stranded DNA breaks results in the expression of the gene of interest. Thus, one would have a reasonable expectation of success in applying the methods of Senis in a tomato plant to reduce expression of a target viral gene.
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, 3, 9-12, 14-18, 21 and 22 REMAIN provisionally rejected, and claims 19-26 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 9, 11, 12, 13 and 14 of copending Application No. 17/297,527 (referred to herein as ‘527; published as Pub. No. US 2022/0010322 A1). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claims 1, 3, 9-12 and 14-18, 21 and 22 are drawn to a method of reducing expression of a viral target gene in a tomato plant cell by introducing a ZFN, TALEN or nuclease that cleaves a native tomato pre-miRNA and making at least two double stranded DNA breaks at said site and selecting for a cell where the breaks have been repaired with intervening DNA encoding an amiRNA comprising a core sequence complementary to the target viral gene resulting in a tomato plant cell comprising the amiRNA comprising the core sequence and wherein the plant is heterozygous, wherein the target is a Bunyavirales gene or a tomato spotted wilt virus gene, wherein the genomic site comprises SEQ ID NO: 6 or 7 and the intervening DNA comprises SEQ ID NO: 2 and a method of producing tomato plant seeds by crossing a plant comprising said cell with another plant.
‘527 claims a method of reducing expression of a target gene comprising introducing a ZFN or TALEN or nuclease that cleaves a target site that is repaired with intervening DNA and wherein the gene expression modification includes regulation at precursor or mature mRNA level (see claims 1, 2, 9, 11, 12, 13 and 14).
Therefore, prior to the effective filing date of the instant invention it would have been prima facie obvious to arrive at the methods as instantly claimed because they are encompassed by what is claimed by ‘527 (i.e., reducing expression of a target gene by site directed cleavage of genomic DNA in a precursor or mature miRNA; see also ¶ 0142).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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/JASON DEVEAU ROSEN/Primary Examiner, Art Unit 1662