PIONEER HI-BRED INTERNATIONAL, INC.

Patent Trials and Appeals Board

Jan 28, 2022

2021000830 (P.T.A.B. Jan. 28, 2022)

UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 15/323,772 01/04/2017 HUIRONG GAO BB2394-US-PCT 7057 27310 7590 01/28/2022 PIONEER HI-BRED INTERNATIONAL, INC. 7250 NW 62ND AVENUE PO BOX 552 JOHNSTON, IA 50131-0552 EXAMINER COLLINS, CYNTHIA E ART UNIT PAPER NUMBER 1662 NOTIFICATION DATE DELIVERY MODE 01/28/2022 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): IPsupport@corteva.com sue.smith@corteva.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte HUIRONG GAO, XIAOMU NIU, and JINRUI SHI ____________ Appeal 2021-000830 Application 15/323,772 Technology Center 1600 ____________ Before DONALD E. ADAMS, RICHARD M. LEBOVITZ, and TAWEN CHANG, Administrative Patent Judges. ADAMS, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from Examiner’s decision to reject claims 44-46 (Appeal Br. 3). We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 1 We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appellant identifies the real party in interest as “Pioneer Hi- Bred International, Inc. (‘Pioneer’)[, which] is a subsidiary of Corteva AgriscienceTM” (Appellant’s April 27, 2020, Appeal Brief (Appeal Br.) 3). Appeal 2021-000830 Application 15/323,772 2 STATEMENT OF THE CASE Appellant’s disclosure “relates to the field of plant molecular biology, in particular, to methods for altering the genome of a plant cell” (Spec.2 1). Appellant’s only independent claim, claim 44, is reproduced below: 44. A method for replacing a first regulatory sequence in a plant cell, the method comprising introducing a guide RNA, a polynucleotide modification template, and a Cas endonuclease into said plant cell, wherein said guide RNA and Cas endonuclease are capable of forming a complex that enables the Cas endonuclease to introduce a double strand break at a target site in the genome of said plant cell, wherein said polynucleotide modification template comprises a second promoter or second promoter fragment that is different from said first regulatory sequence, wherein the first regulatory sequence modulates the expression of a gene involved in an agronomic trait. (Appeal Br. 17.) Claims 44-46 stand rejected under 35 U.S.C. § 103 as unpatentable over the combination of Archibald,3 Yang I,4 Chai,5 Li I,6 Cong,7 Yang II,8 and Li II.9 2 Appellant’s January 4, 2017, Specification. 3 Archibald et al., WO 2013/066805 A1, published May 10, 2013. 4 Yang et al., Constitutive expression of human coagulating factor IX in HeLa cells by homologous recombination of the promoter, Science in China (Series C) 44(1):18-24 (Feb. 2001). 5 Chai et al., ß-Glucan Synthase Gene Overexpression and ß-Glucans Overproduction in Pleurotus Ostreatus Using Promoter Swapping, PLOS One 8(4):e61693 (Apr. 2013). 6 Li et al., High-efficiency TALEN-based gene editing produces disease resistant rice, Nat. Biotechnol. 30(5):390-92 (May 2012). 7 Cong et al., US 8,871,445 B2, issued Oct. 28, 2014. 8 Yang et al., US 2015/0067922 A1, published Mar. 5, 2015. 9 Li et al., Multiplex and homologous recombination-mediated genome editing in Arabidopsis and Nicotiana benthamiana using guide RNA and Cas9, Nat. Biotechnol. 31(8):688-91 (Aug. 2013). Appeal 2021-000830 Application 15/323,772 3 ISSUE Does the preponderance of evidence relied upon by Examiner support a conclusion of obviousness? ANALYSIS Appellant’s claim 44, reproduced above, is directed to a method of using a guide RNA, polynucleotide modification template, and Cas endonuclease to replace a first regulatory sequence with a second promoter, or second promoter fragment, that modulates the expression of a gene involved in an agronomic trait in a plant, where the second promoter is different from the first regulatory sequence (see Appeal Br. 17; see also Spec. 1-2 (Appellant discloses “methods . . . [that] employ a guide RNA/Cas endonuclease system to provide for an effective system for modifying or altering target sites and nucleotide of interest within the genome of a plant, plant cell or seed”)). The use of heterologous regulatory sequences, e.g., promoter elements, to regulate the expression of polynucleotides of interest was known in this art before the effective filing date of Appellant’s claimed invention (see Ans.10 5-9 (citing Archibald 30, 68:Example 6, 94:Example 30, 95-98:Examples 34-38, and 40; Yang I 18; , Chai 1; Li I 390; Cong 6:23, 31:57, 34:35-43, 34:64-35:57, 36:49-56, 137:Claims 11 and 13; Yang II 13-24:Examples 1-3; Li II 690-691)). In particular, Examiner finds that Archibald discloses “maize plants transgenic for an overexpression transgene comprising a constitutive ubiquitin promoter operably linked to a polynucleotide encoding 10 Examiner’s September 18, 2020, Answer. Appeal 2021-000830 Application 15/323,772 4 ZmARGOS8 exhibit increased yield under a variety of different growth conditions, as compared to control plants” (Ans. 5 (citing Archibald 68:Example 6, 94:Example 30, 95-98:Examples 34-38, and 40)). Examiner further finds that Archibald discloses “that the Zea mays GOS2 promoter is a suitable alternative promoter for the constitutive expression of ZmARGOS transgenes” (Ans. 5 (citing Archibald 30)). Examiner recognizes that Archibald does not disclose “introducing a guide RNA, a polynucleotide modification template, and a Cas endonuclease into a cell in order to replace a Zea mays ARGOS8 promoter with a Zea mays GOS2 promoter” (Ans. 5). Cong “relates to systems, methods and compositions used for the control of gene expression involving sequence targeting, such as genome perturbation or gene-editing, that may use vector systems related to Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and components thereof” (Cong 1:56-62). Cong discloses “methods of directing CRISPR complex formation in eukaryotic cells and methods for selecting specific cells by introducing precise mutations utilizing the CRISPR/Cas system” (Cong, Abstract). Cong discloses “[m]ethods for producing transgenic plants,” which “begin[s] with a method of cell transfection” (Cong 34:39-43; see also Cong 6:18-23 (Cong “provides a eukaryotic organism; preferably a multicellular eukaryotic organism, comprising a eukaryotic host cell,” wherein the “organism . . . may be a plant”); Ans. 6). Cong discloses a method comprising the delivery of “a CRISPR enzyme in combination with (and optionally complexed with) a guide sequence . . . to a cell” (Cong 31:57-60; see Ans. 6). Appeal 2021-000830 Application 15/323,772 5 Cong discloses that, “[w]ith recent advances in crop genomics, the ability to use CRISPR-Cas systems to perform efficient and cost effective gene editing and manipulation will allow the rapid selection and comparison of single and multiplexed genetic manipulations to transform such genomes for improved production and enhanced traits” (Cong 34:64-35:2; see Ans. 6). Cong discloses: The target polynucleotide of a CRISPR complex can be any polynucleotide endogenous or exogenous to the eukaryotic cell. For example, the target polynucleotide can be a polynucleotide residing in the nucleus of the eukaryotic cell. The target polynucleotide can be a sequence coding . . . a non-coding sequence (e.g., a regulatory polynucleotide . . .). (Cong 36:49-56; see Ans. 6.) Based on the combination of Archibald, Yang I, Chai, Li I, Cong, Yang II, and Li II, Examiner concludes that, before the effective filing date of Appellant’s claimed invention, it would have been prima facie obvious to use “a guide RNA, a polynucleotide modification template, and a Cas endonuclease . . . to replace the promoter that regulates the expression of a eukaryotic animal, fungal or plant cell cellular gene with a different promoter” (Ans. 7-8). According to Examiner, The use of a guide RNA, a polynucleotide modification template, and a Cas endonuclease would have been a simple substitution of equivalent elements (a guide RNA, a polynucleotide modification template, and a Cas endonuclease for a gene targeting vector or a homologous recombination fragment) to obtain predictable results (the replacement of a promoter that Appeal 2021-000830 Application 15/323,772 6 regulates the expression of a eukaryotic animal cell, fungal cell or plant cell cellular gene with a different promoter). (Id. at 8.) More specifically, Examiner concludes that before the effective filing date of Appellant’s claimed invention, it would have been prima facie obvious “to replace the native promoter that regulates the expression of a ZmARGOS8 maize plant gene with a constitutive GOS2 promoter” using the Cas endonuclease system “in order to increase the yield of the plant under a variety of different growth conditions by constitutively overexpressing the ZmARGOS8 gene” with a reasonable expectation of success, given the success of . . . [Yang I, Chai, and Li I] in altering the expression of eukaryotic animal, fungal and plant cell cellular genes by replacing or by mutating their promoter sequences, and given the success of . . . [Yang II and Li II] in specifically modifying plant cell cellular genes by introducing into a plant cell a guide RNA and a Cas endonuclease, and a guide RNA, a polynucleotide modification template, and a Cas endonuclease. (Id. at 8-9.) For the reasons discussed above, we find that the combination of Archibald, Yang I, Chai, Li I, Cong, Yang II, and Li II makes obvious the use of a Cas system, comprising a guide RNA, polynucleotide modification template, and Cas endonuclease to replace the native, endogenous, ZmARGOS8 promoter with a constitutive promoter, such as the Zea mays GOS2 promoter. As discussed above, maize plants that constitutively express ZmARGOS8 exhibit increased yield under a variety of different growth conditions, as compared to control plants. For the foregoing reasons, we are not persuaded by Appellant’s contention that when viewed in isolation “Archibald’s modulation of gene expression in a transgenic plant does not teach or suggest replacing an Appeal 2021-000830 Application 15/323,772 7 endogenous promoter with a different regulatory sequence because Archibald’s transgenic plant had both the native (endogenous) promoter and the introduced heterologous promoter” (Appeal Br. 5). The evidence relied upon by Examiner establishes that those of ordinary skill in this art used a variety of technologies to modify regulatory elements in eukaryotic organisms, including animal, fungi, and plant, as a matter of routine. In particular, as discussed above, Cong expressly discloses using a Cas system comprising a guide RNA, polynucleotide modification template, and Cas endonuclease to replace the native, endogenous, plant promoter with a heterologous plant promoter. As further discussed above, Cong discloses that, “[w]ith recent advances in crop genomics, the ability to use CRISPR-Cas systems to perform efficient and cost effective gene editing and manipulation will allow the rapid selection and comparison of single and multiplexed genetic manipulations to transform such genomes for improved production and enhanced traits” (Cong 34:64-35:2). In sum, Cong discloses the advantages of using the CRISPR-Cas system to replace native, endogenous, regulatory elements with heterologous regulatory elements. Archibald discloses that the introduction of a promoter that constitutively expresses ZmARGOS8, in maize, results in maize plants that exhibit increased yield under a variety of different growth conditions, as compared to control plants. Thus, the combination of Archibald, Yang I, Chai, Li I, Cong, Yang II, and Li II makes obvious the use of a Cas system, comprising a guide RNA, polynucleotide modification template, and Cas endonuclease to replace the native, endogenous, ZmARGOS8 promoter with a constitutive promoter, such as the Zea mays GOS2 promoter. See KSR Appeal 2021-000830 Application 15/323,772 8 Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (“The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.”). For the foregoing reasons, we are not persuaded by Appellant’s contention that Shi,11 a post-filing publication, highlights the Appellant’s alleged deficiencies in Examiner’s prima facie case of obviousness, because it demonstrated that “genome edited ARGOS8 variants surprisingly demonstrated increased yield in maize” (Appeal Br. 9). Notwithstanding Appellant’s contention to the contrary, Shi, as characterized by Appellant, supports, rather than rebuts, Examiner’s prima facie case of obviousness on this record and confirms exactly what those of ordinary skill in this art would have reasonably expected based on the combination of Archibald, Yang I, Chai, Li I, Cong, Yang II, and Li II. See KSR, 550 U.S. at 416 (“The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.”). Appellant fails to direct attention to an evidentiary basis on this record that supports Appellant’s intimation that Archibald’s results could not have been achieved by replacing the native ZmARGOS8 promoter with a heterologous constitutive promoter, because Archibald discloses expression from “at least two copies of the Argos8 gene itself - one native and one introduced recombinant Argos8,” driven by a native promoter and heterologous promoter, respectively (Appeal Br. 7-8; see id. at 8 (Appellant contends that “Archibald’s results with the recombinant GOS2 promoter 11 Shi et al., ARGOS8 variants generated by CRISPR-Cas9 improve maize grain yield under field drought stress conditions, Plant Biotechnology Journal 1-10 (2016). Appeal 2021-000830 Application 15/323,772 9 provided an alternative to other constitutive promoters to drive ARGOS8 recombinantly, but not a rationale or a motivation to replace the endogenous promoter of ARGOS8, because in Archibald, both the recombinant ARGOS8 and the native ARGOS8 were expressed”); id. at 9-10 (Appellant contends that Examiner failed “to articulate . . . why a person having ordinary skill in the art would be motivated . . . to ignore [Archibald’s] recombinant overexpression data, but instead opt to replace the endogenous promoter with a different regulatory sequence, as claimed”); see also Reply Br.12 9-10). See In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974) (“Attorney’s argument in a brief cannot take the place of evidence.”). For the foregoing reasons, we are not persuaded by Appellant’s contention that Yang I, Yang II, and Chai do not disclose promoter replacement in plant cells, which fails to account for the contributions of Archibald, Li I, Li II, and Cong to the rejection over the combination of Archibald, Yang I, Chai, Li I, Cong, Yang II, and Li II (Appeal Br. 5-6; see also id. at 11-15; Reply Br. 6-8). As discussed above, Cong discloses the replacement of a native plant regulatory element with a heterologous regulatory element. See In re Antor Media Corp., 689 F.3d 1282, 1288 (Fed. Cir. 2012) (“[A] prior art printed publication cited by an examiner is presumptively enabling barring any showing to the contrary by a patent applicant or patentee.”). Therefore, we are not persuaded by Appellant’s contention that “Cong did not mention or perform genome editing in any plant cell, let alone demonstrate the precise replacement of a first regulatory sequence with a different promoter or 12 Appellant’s November 16, 2020, Reply Brief. Appeal 2021-000830 Application 15/323,772 10 promoter fragment to modify an agronomic trait in a plant” (Appeal Br. 6; see id. at 13; Reply Br. 7). See In re Susi, 440 F.2d 442, 446 n.3 (CCPA 1971) (Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or non-preferred embodiments.). We are not persuaded by Appellant’s contention that Li I’s use of “TALEN (not a Cas endonuclease) does not even come close to replacing any genetic sequence, let alone a regulatory sequence, because sequence replacement through homologous recombination is fundamentally different than making a few point mutations,” which fails to account for Cong’s contribution to the combination of Archibald, Yang I, Chai, Li I, Cong, Yang II, and Li II. (Appeal Br. 6; see also id. at 11 and 13-14; Reply Br 7- 8). For the foregoing reasons, we are not persuaded by Appellant’s contention that Examiner’s conclusion of obviousness is based on improper hindsight reconstruction (see Appeal Br. 5 and 10; Reply Br. 5). For the same reasons, we are not persuaded by Appellant’s contention that “Examiner attempts to cherry pick disclosures in the cited references without regard to what the references actually describe and what they do not teach” (Reply Br. 4). CONCLUSION The preponderance of evidence relied upon by Examiner supports a conclusion of obviousness. The rejection of claim 44 under 35 U.S.C. § 103 as unpatentable over the combination of Archibald, Yang I, Chai, Li I, Cong, Yang II, and Li II is affirmed. Claims 45-46 are not separately argued and fall with claim 44. Appeal 2021-000830 Application 15/323,772 11 DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 44-46 103 Archibald, Yang I, Chai, Li I, Cong, Yang II, Li II 44-46 TIME PERIOD FOR RESPONSE No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R. § 1.136(a)(1)(iv) (2019). AFFIRMED