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 .
Priority
Applicant’s claim for the benefit of a prior-filed application no. JP2023-036941 filed March 9th, 2023, and PCT/JP2024/009165 filed March 8th, 2024 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Thus, the earliest possible priority for the instant application is March 9th, 2023.
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.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on September 8th, 2025, was considered, initialed, and attached hereto. A signed copy of the list of references cited is included with this Office Action.
Status of Claims
Claims 1-10 filed September 8th, 2025 are pending and examined herein.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see, for example, paragraph 29). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the trademark BLAST® (e.g., at paragraphs 14, 18, 25, 29, 47, 49-50, 52, and 54) has been noted in this application. The Basic Local Alignment Search Tool (BLAST)® is a registered trademark of the National Library of Medicine. The registered trademark symbol ® should be included following the trademarks wherever they appear, and the trademarks should be accompanied by the generic terminology.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings. Specifically, Figures 7-1 to 7-3 provide a sequence identifier for one sequence in the Brief Description of the Drawings, but do not provide a sequence identifier for both sequences shown in the figures to illustrate the comparison recited in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Interpretation
The claims collectively recite the terms “cytoplasmic male sterile line”, “maintainer line”, and “restorer line”. In the instant specification, the term "three-line method" refers to a method utilizing: a cytoplasmic male sterile line serving as a line carrying a male sterile cytoplasm; a fertility restorer line carrying, in its nucleus, a restorer-of-fertility gene corresponding to the male sterile cytoplasm; and a maintainer line serving as a line, whose nuclear gene is identical to that of the sterile line and which does not carry any sterile cytoplasm. In the art, the three-line system in hybrid rice production consists of:
CMS line: A male-sterile line that cannot produce viable pollen, used as the female parent in hybrid seed production.
Maintainer line: Genetically identical to the A-line but fertile. It is used to maintain the CMS trait in the A-line.
Restorer line: A fertile line that carries restorer genes to restore pollen fertility in the F1 hybrid generation (Whitney, B. 2024. “Understanding the Three-Line CMS System in Hybrid Rice Breeding.” Texas A&M AgriLife Organic. Research/Extension) [pg. 2].
Claim 6 recites an F1 hybrid plant, which is produced through use of the combination of plants of three lines of claim 5 and a combination of plants of three lines of other varieties by a three-line method. The “plants of three lines of other varieties” is taken to mean a CMS line, maintainer line, and restorer line created in a different plant variety.
Claim Objections
Claim 6 is objected to for the recitation of “[t]he combination of plants of three lines of claim 5…” As this limitation refers back to the three lines as recited in claim 5, the claim should read “[t]he combination of plants of the three lines of claim 5…” Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 4, 6, 8, and 10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 4, 8, and 10 contains the trademark/trade name BLAST®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe sequence identity analysis and, accordingly, the identification/description is indefinite.
Claim 6 recites an F1 hybrid plant which is produced through use of the combination of plants of three lines of claim 5 and a combination of plants of three lines of other varieties by a three-line method. Claim 6 does not limit the varieties of the plants of three lines. It is unclear if the Applicant intends to claim that different plant varieties may be combined, irrespective of the plant species. For example, it is unclear if an F1 hybrid could be produced through the use of any line of soy (CMS, maintainer, or restorer) in combination with any line of corn (CMS, maintainer, or restorer).
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Claims 1-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant disclosure describes:
Narrowing down of restorer-of-fertility gene candidates for orf288 to PPR461, PPR782, and PPR794.
Using the target sequence for knocking out the three PRR genes (SEQ ID NO: 20) in a Cas9, gRNA integrated binary vector (pZH_OsU6gRNA_MMCas9) introduced into Asian japonica rice cultivar (Oryza sativa L.) ‘Taichung 65’ by Agrobacterium-mediated transformation to obtain an individual showing male sterility.
Mito-Talen disruption of the CMS-causing gene candidate orf288 introduced into Taichung 65.
That knockout of orf288, PPR461, PPR782, and PPR794 in Taichung 65 does not show any male sterility.
The instant disclosure does not describe:
A method of producing any CMS line plant.
A method of producing a CMS line plant comprising a step of knocking out a singular PPR gene in the nuclear genomic DNA.
A method comprising knocking out of the orf288 gene by means other than mito-TALEN.
The orf288 gene including a base sequence encoding an amino acid set forth having a similarity of 80% to the amino acid sequence as set forth in SEQ ID NO: 3.
The Applicant describes knocking out three PPR genes in Taichung 65 [Example 1]. The Applicant describes identifying PPR461, PPR782, and PPR794 and using the target sequence common to the three genes to knockout the combination. The Applicant describes that the expression of orf288 was detected with knockout of the three combined genes [Fig. 8], thus releasing the suppression of the expression of the orf288 gene. The Applicant does not reduce to practice that a singular undefined PPR gene was able to release suppression of the orf288 gene or that a singular PPR gene selected from PPR461, PPR782, and PPR794 functioned to release suppression when individually knocked out.
Indeed, in a paper published by common inventors Toriyama, K., Iwai, Y., Takeda, S., Takatsuka, A., Igarashi, K., and Kazama, T., the inventors teach orf288-depleted T65 plants using Mito TALEN (2026. “Non-functional allele of RESTORER OF FERTILITY 4 is functional for the reduction of orf288 RNA in japonica rice.” Plant Biotechnology. 43:63-88) [pg. 83, col. 1, ¶2]. Although the knockout of PPR782/rf4 allows for the accumulation of orf288 RNA, the level of orf288 RNA, lower than that in TGA, was insufficient for the CMS induction (see Fig. 3 below) [pg. 5, col. 1, ¶2]. Figure 3 indicates that knockout of PPR461, 782, or 994 were not sufficient alone for releasing the suppression of the expression of the orf288 gene. Toriyama teaches that CRISPR/Cas9-mediated knockout of an additional gene, for which identification efforts are currently in progress, as well as PPR782 may allow for the establishment of a CMS line of T65 [pg. 87, col. 1, ¶4].
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Thus, although the Applicant recites that an individual obtained by knocking out the PPR gene in nuclear genomic DNA can be expected to show male sterility [pg. 22, ln. 6], one of ordinary skill in the art would not predict that a singular PPR gene would provide sufficient structure to perform eh function of releasing the suppression of the expression of the orf288 gene. Further, as the inventors themselves concede in a publication after the instant application, even the PPR genes describes in the instant disclosure would not be sufficient to produce a line showing male sterility that could be classified as a CMS line plant.
Additionally, Toriyama teaches that establishment of orf288-mediated CMS lines of other japonica rice varieties would be feasible, as all previously investigated japonica cultivars carry orf288 in their mitochondrial genome. The instant specification does not teach the production of any CMS line plant other than ‘Taichung 65’, a rice cultivar. Every plant species does not have an orf288 within the mitochondrial genomic DNA and thus the method of producing a CMS line plant would necessarily not include plant species without an orf288. The Applicant describes NCBI search strategies for homologous gene produces, but does not provide any other plants produced in the method claimed. Thus, the Applicant has not reduced to practice a method of producing a CMS line of any plant.
The Applicant describes knockout of the orf288 gene using mito-TALEN genetically introduced into ‘Taichung 65’ to provide lines from which orf288 had been deleted [Example 2]. The Applicant does not describe any other structure that could provide the function of knocking out the orf288. The art teaches that reliable methods for direct mitochondrial transformation in plants have not yet been successful, primarily due to the lack of selection markers and effective macromolecule delivery methods (Zhang, Y. et al. 2026. “Current advances in plant mitochondria: Application revolution of cytoplasmic male sterility.” New Crops. 3. https://doi.org/10.1016/j.ncrops.2025.100081) [pg. 3, col. 2, ¶3], demonstrating unpredictability within available genetic engineering methodologies. mitoTALENs, with an MTS at the amino termini of TALENs, have been successfully used to precisely knock out specific mitochondrial genes in several plants, such as knockout of orf352 (WA352) in rice RT102-type CMS and orf138 in radish CMS-ogu, restoring pollen development [pg. 4, col. 1, ¶1].
However, there is limited successful evidence of the mito-CRISPR/Cas9 system in plants. Although one study has optimized the mito-CRISPR/Cas9 system with a type II Cas protein using plant-biased codons to target the mitochondrial ATP9 gene (mtATP9) in tobacco, there is a risk that this genome editing may not be maintained due to rapid recombination [pg. 3, col. 1, ¶5]. Thus, due to the variability amongst the genus claim of the step of knocking out the orf288 gene in the mitochondrial genomic DNA and the singular species of mito-TALEN provided, which has been demonstrated as the effective knockout method for direct mitochondrial transformation, the Applicant has not reduced to practice the genus of knocking out the orf288 gene as claimed.
The claims recite that the orf288 gene includes a base sequence encoding an amino acid sequence having 80% or more similarity to the amino acid sequence as set forth in SEQ ID NO: 3 in BLAST analysis. For just substitutions with any of the other 19 standard amino acids, there are
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ways to choose which of the 62 to 63 out of 314 positions are changes with 19 possible alternative amino acids, wherein N is the total sequence length and K is the number of changed nucleotides. This results in around 1096 possible unique sequences. A BLAST analysis revealed numerous hypothetical proteins within the 80% or more requirement, such as hypothetical protein (mitochondrion) [Oryza rufipogon], GenBank: AOT98979.1, which is annotated as an orf310. It is not clear that this structure would perform the same function in the method as claimed as it is not annotated as an orf288 and does not provide any relation to orf288. Applicants fail to describe structural features common to the members of the broad genus. Undue experimentation would be required to ensure that another sequence falling within the broad scope of the invention may perform the function as claimed.
As such, claims 1-10 fail to meet the written description requirement.
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.
Claims 1 and 3 are rejected under 35 U.S.C. 103 as being unpatentable over Wang, H., et al. (2021). “A mitochondria-localized pentatricopeptide repeat protein is required to restore hau cytoplasmic male sterility in Brassica napus.” Theor Appl Genet 134, 1377–1386. https://doi.org/10.1007/s00122-021-03777-3 (as cited in IDS filed 09/08/2025), in view of Zheng P. et al. (2021). "OsPPR939, a nad5 splicing factor, is essential for plant growth and pollen development in rice." Theor Appl Genet. 134(3):923-940. doi: 10.1007/s00122-020-03742-6 (as cited in IDS filed 09/08/2025).
Claim 1 recites a method of producing a cytoplasmic male sterile line plant, comprising a step of knocking out, in a plant having an orf288 gene in mitochondrial genomic DNA thereof and having a pentatricopeptide repeat protein (PPR) gene in nuclear genomic DNA thereof, the PPR gene in the nuclear genomic DNA.
Claim 3 recites the method according to claim 1 or 2, wherein the PPR gene satisfies all of the following requirements: (1) the PPR gene is expressed in an anther of the plant; (2) the PPR gene has a mitochondrial targeting signal; and (3) the PPR gene has 10 or more PPR motifs.
Wang teaches a mitochondria-localized pentatricopeptide repeat (PPR) protein identified by positional cloning and transferred into the hau cytoplasmic male sterility (CMS) line, where it successfully restored fertility in Brassica plants [Abstract]. Wang teaches that CMS is subject to dual regulation by restorer-of-fertility (Rf) genes in the nuclear genome and CMS genes in the mitochondrial genome [pg. 1377, col. 2, ¶1]. Wang teaches that the three-line hybrid system was created based on the CMS/Rf genes and used for the production of major crops.
The hau CMS was identified as a new form of CMS associated with the mitochondrial transcript orf288. Orf288, a chimeric gene downstream of atp6, has been found to be related to the male sterility of hau CMS line [pg. 1377, col. 2, ¶2]. The Rf gene was in clusters of PPR genes on the chromosomal region of A09 [pg. 1383, col. 2, ¶2]. The amino acids at positions 5 and 35 of the PPR motifs were found to be responsible for the RNA sequence recognition, which showed that PPR proteins could directly process transcripts that are transcribed from the mitochondrial or chloroplast genome, and other evidence has shown that RF complexes were observed in vivo, demonstrating that PPR proteins have cofactors involved in the processing of CMS RNA [pg. 1378, col. 1, ¶3].
The Rf locus of the nuclear restorer gene is likely to be generated by gene duplication; that is, it contains several closely linked genes in the same chromosomal region, which simultaneously code for the PPR repeat motif protein and recombine during the replication process [pg. 1384, col. 1, ¶1]. All 59-amino acid residue differences found between RFH and rfh are located in the PPR domains (3rd, 4th, 5th, 6th, and 10th), suggesting that these domains may be involved in the fertile phenotype [pg. 1384, col. 1, ¶2]. Wang additionally teaches that the characteristics of the Rf genes in almost all CMS lines share structural characteristics [pg. 1378, col. 1, ¶2]. Examples across Petunia, B. napus, and rice indicate that restoration genes are structurally conserved and that there are functional similarities.
Wang teaches that the long-term use of a single sterile cytoplasmic genetic background has always been a potential risk. For example, in the 1970s, the United States only used corn T cytoplasmic genetic backgrounds in corn breeding, which caused a large outbreak of T-shaped spot disease and huge economic losses [pg. 1383, col. 1, ¶1]. Thus, there is a need to discover or create a stable new CMS/Rf system that could not only provide basic materials for the utilization of heterosis of crops but also reduce the potential risks caused by the long-term use of a single cytoplasmic genetic background [pg. 1383, col. 1, ¶1].
Wang does not teach a method of producing a CMS line plant comprising knocking out the PPR gene in the nuclear genomic DNA, however, Zheng teaches that complete knockout or partial disruption of the function of a PPR protein in rice (OsPPR939) results in different degrees of growth retardation and pollen sterility [Abstract]. Zheng teaches that the P-subfamily PPR protein OsPPR939 is required for cis-splicing of nad5 intron 1 and transsplicing of nad5 introns 2 and 3 in rice mitochondria [pg. 935, col. 1, ¶2. Zheng teaches that amino acids at specific positions in each PPR motif ensure that a given PPR protein can bind to single-stranded RNA in a sequence-specific fashion [pg. 935, col. 2, ¶2]. Specifically, Zheng teaches that the CRISPR/Cas9-mediated osppr939-1 mutant produces a truncated OsPPR939 protein with only three intact PPR motifs, which is not sufficient to allow the protein to recognize and splice the RNA sequence of nad5. As a result, no mature nad5 RNA accumulates, leading to a complete loss of complex I activity, thereby resulting in pollen death [pg. 935, col. 2, ¶2]. Nad5 is one of nine Nad subunits of respiratory complex I (NADH:ubiquinone oxidoreductase) encoded by the mitochondrial genome, the lack or deficiency of which in the mutants results in pollen death or sterility [pg. 935, col. 2, ¶3].
Zheng teaches that the results show that it is possible to obtain completely male sterile rice plants by knocking out OsPPR939 to some extent [pg. 935, col. 2, ¶1]. In a phylogenetic analysis, OsPPR939 shared high sequence similarities with orthologues in other species [pg. 930, col. 1, ¶2]. Zheng teaches that the results provide a basis for chemically induced male sterile line [pg. 938, col. 1, ¶2].
Given that Wang teaches a plant having an orf88 gene in mitochondrial genomic DNA and a PPR gene in nuclear genomic DNA, teaches the benefits of developing CMS lines, and teaches that a PPR gene added to a line restored fertility in the plant line; and given that Zheng teaches knocking out of a PPR gene for the creation of male sterile plants; it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to knock out other known PPR genes such as one in a plant having an orf288 gene to reduce suppression on the CMS-causing ORF to produce a cytoplasmic male sterile line plant. The construction of CMS systems comprising a CMS line with manipulated CMS and Rf genes was well known in the prior art. One would have had reasonable expectation of success in following the methodology of Zheng in CRISPR/Cas9-mediated knock out of a known PPR gene as taught by Wang, as both Wang and Zheng teach that restoration genes are structurally and functionally similar across different species. One would have been motivated to do so as Wang teaches the importance of developing multiple sterile cytoplasmic genetic backgrounds to prevent disease outbreak in monocultured crops.
Regarding claim 3, Wang teaches that when the rfh promoter was fused with GUS to determine the spatial and temporal expression patterns of rfh, the GUS activity was mainly detected in the anthers from the flower buds and hardly observed in other tissues (i.e., (1) the PPR gene is expressed in an anther of the plant) [pg. 1384, col. 1, ¶3]. Wang teaches that the PPR protein selected as the gene candidate was suspected to be involved in the processing of mitochondrial RNA transcripts due to the mitochondrial localization signals at its N-terminus (i.e., (2) the PPR gene has a mitochondrial targeting signal) [pg. 1381, col. 1, ¶1]. Zheng further teaches that most PPR proteins are targeted to mitochondria and/or plastids and that OsPPR969 is suggested to localize to mitochondria and contains a mitochondrion-targeting peptide at its N-terminus [pg. 929, col. 1, ¶2; col. 2, ¶1]. Wang teaches that the 59-amino acid residue differences between RFH and rfh are located in the PPR domains (3rd, 4th, 5th, 6th, and 10th) [pg. 1384, col. 1, ¶2], suggesting that the PPR gene as 10 or more PPR motifs (i.e., (3) the PPR gene has 10 or more PPR motifs).
Claims 2, 5, and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Wang and Zheng as applied to claims 1 and 3 above, and further in view of Takatsuka, A. et al. (Published online February, 25, 2022). “TALEN-mediated depletion of the mitochondrial gene orf312 proves that it is a Tadukan-type cytoplasmic male sterility-causative gene in rice.” Plant J. 110(4):994-1004. doi: 10.1111/tpj.15715.
Examiner notes that although the Takatsuka reference shares common inventors, it was first published and publicly available February 25th, 2022. As such, the Takatsuka reference qualifies as prior art under 102(a)(1) and does not qualify for an exception under 102(b)(1)(A) as it is outside of the one-year grace period disclosure by inventor.
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Claim 2 recites a method of producing a maintainer line plant, comprising the steps of: knocking out, in a plant having an orf288 gene in mitochondrial genomic DNA thereof and having a PPR gene in nuclear genomic DNA thereof, the PPR gene in the nuclear genomic DNA; and knocking out the orf288 gene in the mitochondrial genomic DNA.
Claim 5 recites a combination of plants of three lines, comprising: a restorer line plant, which is a plant having an orf288 gene in mitochondrial genomic DNA thereof and having a pentatricopeptide repeat protein (PPR) gene in nuclear genomic DNA thereof; a cytoplasmic male sterile line plant obtained by knocking out, in the restorer line plant, the PPR gene in the nuclear genomic DNA; and a maintainer line plant obtained by knocking out, in the restorer line plant, the PPR gene in the nuclear genomic DNA and the orf288 gene in the mitochondrial genomic DNA.
Claim 7 recites the combination according to claim 5 or the plant according to claim 6, wherein the PPR gene satisfies all of the following requirements: (1) the PPR gene is expressed in an anther of the plant; (2) the PPR gene has a mitochondrial targeting signal; and (3) the PPR gene has 10 or more PPR motifs.
Regarding claim 2, Wang teaches that CMS is a maternal genetic trait subject to dual regulation by restorer-of-fertility (Rf) genes in the nuclear genome and CMS genes in the mitochondrial genome [pg. 1377, col. 2, ¶1]. Wang teaches that the three-line hybrid system was created based on the CMS/Rf genes and is commonly used for the production of major crops. Wang teaches CMS associated with the mitochondrial transcript orf288, which is related to male sterility in the hau CMS line (i.e., a plant having an orf288 gene in mitochondrial DNA) [pg. 1377, col. 2, ¶2]. Wang teaches identification and characterization of Rf genes in CMS lines and the use of CMS/Rf genes in the creation of CMS plant lines. Zheng teaches that complete knockout or partial disruption of the function of a PPR protein in rice (OsPPR939) results in different degrees of growth retardation and pollen sterility (i.e., knocking out the PPR gene in nuclear genomic DNA) [Abstract]. Zheng teaches that PPR knockout is useful for the development of CMS plant lines and teaches the functional and structural similarities in PPR proteins of different species.
Although Wang teaches that CMS is dually regulated by Rf and CMS genes, Wang and Zheng do not explicitly teach a method of producing a maintainer line plant comprising knocking out both the orf288 gene and the PPR gene. However, Takatsuka teaches that CMS is considered to be caused by the expression of a unique mitochondrial open reading frame referred to as a CMS-associated gene [Abstract]. Under a loss-of-function approach, mitochondria-targeted transcription activator-like effector nucleases (mitoTALEN) designed to knockout orf312 in a rice Tadukan-type CMS (TAA) proved that orf312 is a CMS-causative gene. Further, all orf312-depleted plants exhibited recovery of anther dehiscence and seed setting, which was maintained into the next generation as compared to sterile orf312-retaining plants (i.e., knocking out the orf gene in the mitochondrial genomic DNA).
Takatsuka teaches that mitoTALENs have been previously used to disrupt the mitochondrial CMS-associated genes orf79 (involved in BT-type CMS) and orf352 (involved in RT102-type CMS) in rice [pg. 994, col. 2, ¶2], demonstrating orf knockout in the prior art. Molecular genetic analysis identified orf312 as a candidate mitochondrial CMS-associated gene, as it was differentially expressed between TAA and a restorer line, TAR, in anthers at the meiotic and mature stages, with transcript amounts being reduced by the action of an Rf gene [pg. 995, col. 1, ¶2].
Takatsuka teaches that the nucleotide sequence of orf312 is similar to that of the mitochondrial gene orf288 of Nipponbare, which encodes a hypothetical protein, and that of the mitochondrial gene WA352 of WA-CMS, which encodes a CMS associated protein. The C-terminal half of WA352, which shares homology with ORF288 of Nipponbare and ORF312 of Tadukan, has been reported to interact with subunit 11 of cytochrome c oxidase (COX11), resulting in a reactive oxygen species burst and premature programmed cell death of the tapetum, and consequently pollen abortion [pg. 995, col. 1, ¶2].
Wang teaches orf288 in CMS plant lines, that CMS is a maternally inherited trait, and the three-line CMS system for hybridization; Zheng teaches knockout of PPR proteins characterized in rice; and Takatsuka teaches knockout of orf312 to produce non-sterile rice and teaches that orf312 is similar to orf288. As the maintainer line requires the same nuclear DNA as the CMS line, but lacks the male-sterile trait, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to knockout the orf gene in the mitochondrial genomic DNA as taught by Takatsuka in the CMS line with a PPR gene knocked out in the nuclear DNA to create a maintainer line. The male sterile phenotype arises as a result of a mitochondrial CMS gene and a nuclear fertility restoring gene. One would be motivated to do so as the knockout of the orf312 gene resulted in the recovery of anther dehiscence and seed setting, thus resulting in a normal, fertile cytoplasm.
Further, the three-line system is well known in the prior art for the production of CMS lines. As Wang teaches that CMS is a maternally inherited trait encoded in the mitochondrial genome, one would have reasonable expectation of success in using the line with the orf and the PPR genes deleted as the male parent, which would produce pollen with the disruption of the CMS-causing gene as the maintainer line. The female CMS line plant could then use this line as the male maintainer line to pollinate the female CMS line to obtain further CMS lines with the maternally inherited CMS trait.
One would have reasonable expectation of success in knocking out the orf288 gene in the mitochondrial genomic DNA of a Brassica plant as Takatsuka teaches that orf312 is similar to that of the mitochondrial gene orf288 of Nipponbare and Takatsuka demonstrated effective pollen production with orf312 knockout. Further, Wang teaches CMS in Brassica napus but teaches that the Rf genes had structural and functional similarities to those of rice, Zheng teaches a PRR essential for pollen development in rice, and Takatsuka teaches deletion of the mitochondrial orf312 gene in rice. As these are all in rice, or teach functional homologs in rice, one would reasonably combine the inventions of Wang, Zheng, and Takatsuka.
Regarding claim 5, as detailed above, Wang and Zheng render obvious the CMS line plant obtained by knocking out the PPR gene in the nuclear genomic DNA and Wang, Zheng, and Takatsuka render obvious the maintainer line plant obtained by knocking out the PPR gene in the nuclear genomic DNA and the orf288 gene in the mitochondrial genomic DNA. The restorer line plant is a fertility restorer line carrying, in its nucleus, a restorer-of-fertility gene corresponding to the male sterile cytoplasm and is commonly used in the three-line CMS system.
Zheng teaches that the sterile phenotype of CMS lines can be restored by nuclear genes called restorer-of-fertility genes (Rf genes), most of which encode PPR proteins [pg. 923, col. 2, ¶1]. Zheng teaches that PPR proteins are commonly targeted to mitochondria and suppress male sterility by controlling the CMS-associated genes at the transcriptional and translational levels [pg. 924, col. 1, ¶1]. Zheng teaches examples of mitochondrion-localized proteins in rice that restore male fertility by prohibiting ORF production. Zheng additionally teaches that the osppr mutants generated by CRISPR/Cas9-mediated genome editing were recessive, with F1 progeny of the mutants and the wild-type rice plants exhibiting the phenotype of the wild-type plants [pg. 927, col. 2, ¶2]. Thus, one of ordinary skill in the art would use a plant having an orf288 gene and a PPR gene, as collectively taught by all of Wang, Zheng, and Takatsuka, as a restorer line plant. One would have reasonable expectation of success that the restorer line crossed with the CMS line would produce viable, fertile F1 seeds, as Zheng teaches that the mutation of the PPR gene is recessive. Pollen from the restorer line with the dominant fertility-restoring genes could reasonably be used to pollinate the CMS line resulting in the production of normal pollen and viable seeds from the progeny. One would be motivated to create to combination of plants of three lines comprising a restorer, CMS, and maintainer line as Wang teaches the importance of developing multiple sterile cytoplasmic genetic backgrounds to prevent disease outbreak in monocultured crops and teaches that the three-line system (restorer, CMS, maintainer line) is commonly used for the production of crops.
Regarding claim 7, Wang teaches that when the rfh promoter was fused with GUS to determine the spatial and temporal expression patterns of rfh, the GUS activity was mainly detected in the anthers from the flower buds and hardly observed in other tissues (i.e., (1) the PPR gene is expressed in an anther of the plant) [pg. 1384, col. 1, ¶3]. Wang teaches that the PPR protein selected as the gene candidate was suspected to be involved in the processing of mitochondrial RNA transcripts due to the mitochondrial localization signals at its N-terminus (i.e., (2) the PPR gene has a mitochondrial targeting signal) [pg. 1381, col. 1, ¶1]. Zheng further teaches that most PPR proteins are targeted to mitochondria and/or plastids and that OsPPR969 is suggested to localize to mitochondria and contains a mitochondrion-targeting peptide at its N-terminus [pg. 929, col. 1, ¶2; col. 2, ¶1]. Wang teaches that the 59-amino acid residue differences between RFH and rfh are located in the PPR domains (3rd, 4th, 5th, 6th, and 10th) [pg. 1384, col. 1, ¶2], suggesting that the PPR gene has 10 or more PPR motifs. Wang additionally teaches that the PPR gene family shares structural similarities across different plant species [pg. 1378, col. 1, ¶2]. Additionally, the PPR of Zheng (OsPPR939) contains 22 motifs (i.e., (3) the PPR gene has 10 or more PPR motifs). It would have been prima facie obvious to one of ordinary skill in the art at the time of filing to known rice PPR genes or alternatives thereof that would have structural similarity and thus 10 or more motifs as these were known to one of ordinary skill in the art. As Zheng teaches depletion or knockout of the OsPPR939, one of ordinary skill in the art would arrive at the invention with a reasonable expectation of success, and without any surprising results. As these are characteristics of rice PPR genes, as taught by Zheng, one would have been motivated to use such PPRs with the inherent characteristics in the plant lines of the instant application.
Claims 4 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Wang, Zheng, and Takatsuka as applied to claims 2, 5, and 7 above, and further in view GenBank: AFH75414.1. 2012. cytoplasmic male sterile related protein, partial [Oryza sativa Indica Group] and Song, Y. et al. (2017). “Molecular identification of the cytoplasmic male sterile source from Dongxiang wild rice (Oryza rufipogon Griff.).” Journal of Integrative Agriculture. 16(8): 1669-1675. https://doi.org/10.1016/S2095-3119(16)61505-8.
Claim 4 recites the method according to claim 2, wherein the orf288 gene includes a base sequence encoding an amino acid sequence having a similarity of 80% or more to the amino acid as set forth in SEQ ID NO: 3 in blast analysis.
Claim 8 recites the combination according to claim 5 or the plant according to claim 6, wherein the orf288 gene includes a base sequence encoding an amino acid sequence having a similarity of 80% or more to the amino acid sequence as set forth in SEQ ID NO: 3 in blast analysis.
As detailed above, Wang teaches orf288 in CMS plant lines, that CMS is a maternally inherited trait, and the three-line CMS system for hybridization; Zheng teaches knockout of PPR proteins characterized in rice; and Takatsuka teaches knockout of orf312 to produce non-sterile rice and teaches that orf312 is similar to orf288. Thus, combined, Wang, Zheng, and Takatsuka render obvious the method of producing a maintainer line plant. Wang, Zheng, and Takatsuka do not explicitly teach that the orf288 gene includes a base sequence encoding an amino acid sequence having 80% or more identity to SEQ ID NO: 3 of the instant application in BLAST analysis.
However, a BLAST analysis revealed a partial sequence of a cytoplasmic male sterile related protein (AFH75414.1) with 96% identity to 184 amino acids of SEQ ID NO: 3 of the instant application. Out of the 216 amino acid sequence of SEQ ID NO: 3 of the instant application, SEQ ID NO: AFH75414.1 has 81.9% identity to SEQ ID NO: 3 of the instant application (see alignment below).
Alignment statistics for match #1
Score
Expect
Method
Identities
Positives
Gaps
341 bits(875)
5e-115
Compositional matrix adjust.
177/184(96%)
180/184(97%)
0/184(0%)
Query 131 SSSFQESTGEMDALMASTTPSAPRTPSGGEPSVNQPLPGEQAMPPALPVMQEAANRALPY 190
SSSFQESTGEMDALMASTTPSAPRTPSGGEPSVNQPLPGEQAMPPALPVMQEAANRA PY
Sbjct 33 SSSFQESTGEMDALMASTTPSAPRTPSGGEPSVNQPLPGEQAMPPALPVMQEAANRAPPY 92
Query 191 APYPYPVDEIIGGDCVQSIQRRILGANLNPSAHDMQMSRIQAEDLFELKVQIIRKMATLH 250
APYPYPVDEIIGGD VQSIQRRILGAN NPSAHDMQMSRIQAEDLFELKV+IIRKMA LH
Sbjct 93 APYPYPVDEIIGGDSVQSIQRRILGANWNPSAHDMQMSRIQAEDLFELKVEIIRKMAGLH 152
Query 251 PSGDWMGWGARALDNPRTATGEEDLAKLHKMLDDLQSRNEQSATFWRLVERVRLRADEDQ 310
PSGDWMGWGARALDNPRTATGEEDLA+LH+MLDDLQSRNEQSATFWRLVERVRLRADEDQ
Sbjct 153 PSGDWMGWGARALDNPRTATGEEDLARLHQMLDDLQSRNEQSATFWRLVERVRLRADEDQ 212
Query 311 NSAS 314
NSAS
Sbjct 213 NSAS 216
AFH75414.1 is annotated as the amino acid sequence of a CMS related gene orf216 in Oryza sativa, with the accession no. JN887490.1. Song teaches that orf216 is a chimeric ORF located between two segments of orf224 and orf288 in a CMS-DW line [Abstract]. This ORF was also detected in CMS-HL. Song teaches that, based on sequencing results, orf216 (accession no. JN887490) is derived from orf288, orf224, and a sequence of unknown origin, as shown in Fig. 1 [pg. 1674, col. 1, ¶3] (see Fig. 1 below).
PNG
media_image4.png
454
929
media_image4.png
Greyscale
As this is the same orf216 accession, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing that the sequence of orf216 with a disclosed accession no. would share identity with the sequence of orf288 as orf216 was derived in part from orf288. Thus, one of ordinary skill in the art could have used the partial annotated orf216 in the invention as taught by Wang, Zheng, and Takatsuka, as claimed as Song teaches that orf216 is derived from orf288 and share sequence similarity, as shown in Fig. 1. One would be motivated to do so as Song teaches that orf288 plays a role in many types of CMS [pg. 1674, col. 2, ¶1] and further that other CMS line gene sequences shared portions of orf288, such as CW-orf307 and WA352 [pg.1674, col. 1, ¶3]. As the BLAST analysis showed over 80% identity to the amino acid sequence as set forth in SEQ ID NO: 3, AFH75414.1 and Song render obvious claims 4 and 8 in combination with the teachings of Wang, Zheng, and Takatsuka.
Claims 6 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Wang, Zheng, and Takatsuka, as applied to claims 2, 5, and 7 above, and further in view of Toriyama, K. et al. 2021. “Molecular basis of cytoplasmic male sterility and fertility restoration in rice.” Plant Biotechnology. 38, 285-295.
Examiner notes that although the Toriyama reference shares a common inventor, the reference has a disclosure with a prior public availability date of 2021. As such, the Toriyama reference qualifies as prior art under 102(a)(1) and does not qualify for an exception under 102(b)(1)(A) as it is outside of the one-year grace period disclosure by inventor
Claim 6 recites an F1 hybrid plant, which is produced through use of the combination of plants of three lines of claim 5 and a combination of plants of three lines of other varieties by a three-line method.
Claim 9 recites the F1 hybrid plant according to claim 6, wherein the PPR gene satisfies all of the following requirements: (1) the PPR gene is expressed in an anther of the plant; (2) the PPR gene has a mitochondrial targeting signal; and (3) the PPR gene has 10 or more PPR motifs.
Regarding claim 6, as detailed above, Wang teaches orf288 in CMS plant lines, that CMS is a maternally inherited trait, and the three-line CMS system for hybridization; Zheng teaches knockout of PPR proteins characterized in rice; and Takatsuka teaches knockout of orf312 to produce non-sterile rice and teaches that orf312 is similar to orf288. Thus, combined, Wang, Zheng, and Takatsuka render obvious the combination of three lines comprising a restorer plant line, maintainer plant line, and CMS plant line comprising a PPR gene and an orf288 gene. Wang, Zheng, and Takatsuka do not explicitly teach that the combination of plants of the three lines are used in combination with plants of three lines of another variety by a three-line method. However, the use of the three-line method for hybridization in breeding efforts is well known in the art.
For example, Toriyama teaches that a CMS line, a maintainer line, and a fertility restorer line are often used for hybrid rice breeding, known as a three-line breeding method [pg. 292, col. 2, ¶2]. The seeds of the CMS lines are multiplied by crossing a CMS line and a maintainer line. F1 hybrid seeds are produced by crossing a CMS line and a restorer line. Hybrid rice cultivars have an average yield advantage of 15 to 50% over inbred cultivars due to heterosis, a hybrid vigor. WA-CMS plants are most widely used as female parents in hybrid rice breeding, which accounts for approximately 90% of the three-line hybrids produced in China and 100% of the hybrids developed outside China [pg. 293, col. 1, ¶1], thus demonstrating the use of combinations of lines from different three-line systems to provide novel hybrids.
Toriyama teaches that a known CMS-associated gene for WA-CMS is WA352, which encodes 352 amino acids [pg. 288, col. 1, ¶2]. The evolution of the WA352 gene has been documented, and orf284 and orf288 have been reported to provide a promoter region active in meiotic anthers and a region responsible for interaction with COX11, respectively. The orf288 gene might also play an important role in the evolution of other CMS genes, because a CMS-associated gene, orf312 of Tadukan-type CMS (TA-CMS), also contains a major part of orf288 [pg. 289, col. 1, ¶2]. As Toriyama teaches that orf288 is a known CMS gene associated with known types of CMS that have been previously used in hybrid breeding. It would have been prima facie obvious and within the scope of ordinary skill in the art at the time of filing to modify three-line methods with known PPR and orf288 genes to result in a combination of lines and to use those lines in combination with other CMS, restorer, or maintainer lines to develop new hybrids as this is a process often used for hybrid rice breeding. One would have been motivated as Toriyama teaches that this process accounts for heterosis in hybrid varieties, a desirable trait in new rice varieties. As these methods are known, as are PPR and orf genes, one would have reasonable expectation of success in modifying the methods to create new lines to be used with other known CMS lines.
Regarding claim 9, Wang teaches that when the rfh promoter was fused with GUS the GUS activity was mainly detected in the anthers (i.e., (1) the PPR gene is expressed in an anther of the plant) [pg. 1384, col. 1, ¶3]. Wang teaches mitochondrial localization signals at the N-terminus of the PPR protein (i.e., (2) the PPR gene has a mitochondrial targeting signal) [pg. 1381, col. 1, ¶1]. Zheng further teaches OsPPR939 was highly expressed in anther tissue [pg. 930, col. 1, ¶3], that most PPR proteins are targeted to mitochondria and/or plastids, and that OsPPR969 is suggested to localize to mitochondria and contains a mitochondrion-targeting peptide at its N-terminus [pg. 929, col. 1, ¶2; col. 2, ¶1]. Wang teaches that the PPR gene has 10 or more PPR motifs. Wang additionally teaches that the PPR gene family shares structural similarities across different plant species [pg. 1378, col. 1, ¶2]. The PPR of Zheng (OsPPR939) contains 22 motifs (i.e., (3) the PPR gene has 10 or more PPR motifs). It would have been prima facie obvious to one of ordinary skill in the art at the time of filing to known rice PPR genes or alternatives thereof that would have structural similarity and thus 10 or more motifs as these were known to one of ordinary skill in the art. As Zheng teaches depletion or knockout of the OsPPR939, one of ordinary skill in the art would arrive at the invention with a reasonable expectation of success, and without any surprising results. As these are characteristics of rice PPR genes, as taught by Zheng, one would have been motivated to use such PPRs with the inherent characteristics in the plant lines of the instant application.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Wang, Zheng, Takatsuka, and Toriyama as applied to claims 6 and 9 above, and further in view of GenBank: AFH75414.1 and Song, as applied to claims 4 and 8 above.
Claim 10 recites the F1 hybrid plant according to claim 6, wherein the orf288 gene includes a base sequence encoding an amino acid sequence having a similarity of 80% or more to the amino acid sequence as set forth in SEQ ID NO: 3 in blast analysis.
As detailed above, Wang teaches orf288 in CMS plant lines, that CMS is a maternally inherited trait, and the three-line CMS system for hybridization; Zheng teaches knockout of PPR proteins characterized in rice; and Takatsuka teaches knockout of orf312 to produce non-sterile rice and teaches that orf312 is similar to orf288. Thus, combined, Wang, Zheng, and Takatsuka render obvious the combination of three lines comprising a restorer plant line, maintainer plant line, and CMS plant line comprising a PPR gene and an orf288 gene. Toriyama teaches a combination of plants of three lines used in combination with plants of three lines of another variety by a three-line method, as claimed in claim 6. However, Wang, Zheng, Takatsuka, and Toriyama not explicitly teach that the orf288 gene includes a base sequence encoding an amino acid sequence having 80% or more identity to SEQ ID NO: 3 of the instant application in BLAST analysis.
However, as in the rejection of claims 4 and 8, a BLAST® analysis revealed a partial sequence of a cytoplasmic male sterile related protein (AFH75414.1) 81.9% identity to SEQ ID NO: 3 of the instant application. AFH75414.1 is annotated as the amino acid sequence of a CMS related gene orf216 in Oryza sativa, with the accession no. JN887490.1. Song teaches that, based on sequencing results, orf216 (accession no. JN887490) is derived from orf288, orf224, and a sequence of unknown origin, as shown in Fig. 1 [pg. 1674, col. 1, ¶3] (see Fig. 1 above).
As this is the same orf216 accession (JN887490), it would have been prima facie obvious to one of ordinary skill in the art at the time of filing that the sequence of orf216 with a disclosed accession no. would share identity with the sequence of orf288 as orf216 was derived in part from orf288. Thus, one of ordinary skill in the art could have used the partial annotated orf216 in the invention as taught by Wang, Zheng, and Takatsuka, as claimed as Song teaches that orf216 is derived from orf288 and share sequence similarity, as shown in Fig. 1. One would be motivated to do so as Song teaches that orf288 plays a role in many types of CMS [pg. 1674, col. 2, ¶1] and further that other CMS line gene sequences shared portions of orf288, such as CW-orf307 and WA352 [pg.1674, col. 1, ¶3]. Additionally, Toriyama teaches that CMS types used for hybrid rice breeding include HL-CMS and CMS-WA, both of which include orf216, and thus fragments of orf288, as taught by Song. As the BLAST analysis showed over 80% identity to the amino acid sequence as set forth in SEQ ID NO: 3, AFH75414.1 and Song render obvious claim 10 in combination with the teachings of Wang, Zheng, Takatsuka, and Toriyama.
Conclusion
No claims allowed.
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/EMILY K JOHNSON/Examiner, Art Unit 1662
/BRATISLAV STANKOVIC/Supervisory Patent Examiner, Art Units 1661 & 1662
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