Dow AgroSciences LLC et al.

Patent Trials and Appeals Board

Mar 22, 2022

2021003219 (P.T.A.B. Mar. 22, 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. 14/979,181 12/22/2015 Kenneth E. Narva P12360.1US(75977- US-NP) 2197 80834 7590 03/22/2022 Magleby Cataxinos & Greenwood/Dow AgroSciences LLC 170 S. Main Street Suite 1100 Salt Lake City, UT 84101 EXAMINER UYENO, STEPHEN G ART UNIT PAPER NUMBER 1662 NOTIFICATION DATE DELIVERY MODE 03/22/2022 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): ptomail@mcgiplaw.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte KENNETH E. NARVA, SARAH WORDEN, MEGHAN FREY, CHAOXIAN GENG, MURUGESAN RANGASAMY, KANIKA ARORA, BALAJI VEERAMANI, PREMCHAND GANDRA, ANDREAS VILCINSKAS, and EILEEN KNORR Appeal 2021-003219 Application 14/979,181 Technology Center 1600 ____________ Before RICHARD M. LEBOVITZ, JEFFREY N. FREDMAN, and JOHN G. NEW, Administrative Patent Judges. LEBOVITZ, Administrative Patent Judge. DECISION ON APPEAL The Examiner rejected claims 1-4, 6, 7, 10-19, 21-23, and 43-48 under 35 U.S.C. § 103 as obvious. Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s decision to reject the claims. 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 Corteva Agriscience. Appeal Br. 2. Appeal 2021-003219 Application 14/979,181 2 REJECTION Claims 1-4, 6, 7, 10-19, 21-23, and 43-48 stand rejected by the Examiner in the Final Office Action under 35 U.S.C. § 103 as obvious in view of Baum,2 Coelho,3 Kelly,4 Stam,5 and Ruvkun.6 Final Act. 2-3. Claim 1, the only independent claim on appeal, is reproduced below: 1. An isolated nucleic acid comprising a polynucleotide operably linked to a heterologous promoter, wherein the polynucleotide encodes a double-stranded ribonucleic acid (dsRNA) molecule that kills a Diabrotica virgifera insect when ingested by the insect, the polynucleotide comprising at least a first nucleotide sequence selected from the group consisting of: at least 19 contiguous nucleotides of SEQ ID NO:77, and the complement of at least 19 contiguous nucleotides of SEQ ID NO:77. STATEMENT OF THE CASE Claim 1 is directed to an isolated polynucleotide operably linked to a heterologous promoter. The polynucleotide encodes a double-stranded ribonucleic acid (dsRNA). The polynucleotide sequence comprises “at least 19 contiguous nucleotides of SEQ ID NO:77, and the complement of at least 19 contiguous nucleotides of SEQ ID NO:77.” SEQ ID NO: 77 is the nucampholin gene (“ncm”). Spec. ¶ 18. The dsRNA “kills a Diabrotica virgifera insect when ingested by the insect.” Diabrotica virgifera is the 2 Baum et al., US 2012/0164205 A1, published June 28, 2012. 3 Carmen M. A. Coelho et al., A Genetic Screen for Dominant Modifiers of a Small-Wing Phenotype in Drosophila melanogaster Identifies Proteins Involved in Splicing and Translation, 171 Genetics 597-614 (2005). 4 William G. Kelly et al., Distinct Requirements for Somatic and Germline Expression of a Generally Expressed Caenorhabditis elegans Gene, 146 Genetics 227-238 (1997). 5 Stam et al., US 2007/0003926 A1, published Jan. 4, 2007. 6 Ruvkun et al., US 2006/0178292 A1, published Aug. 10, 2006. Appeal 2021-003219 Application 14/979,181 3 western corn rootworm (“WCR”). Spec. ¶ 2 (May 8, 2019). WCR is described in the Specification as “one of the most devastating corn rootworm species in North America and is a particular concern in corn-growing areas of the Midwestern United States.” Id. The Specification that “[m]ost of the rootworm damage in corn is caused by larval feeding” on corn and other species of grass. Id. ¶¶ 4, 5. The Examiner found that Baum describes a dsRNA molecule produced by a recombinant DNA construct under control of a heterologous promoter, which controls “pests” when ingested. Final Act. 3-5. The Examiner found that Baum does not disclose that the dsRNA comprises nucleotides sequences from nucampholin or SEQ ID NO:77. Id. at 5. However, the Examiner found that Stam used dsRNA from Drosophila nucampholin to show that nucampholin is essential for Drosophila viability. Id. The Examiner also found that Stam teaches that such dsRNA sequences can be used as insecticides, the same purpose of the dsRNA of claim 1. Id. at 5-6. The Examiner found that Kelly and Ruvkun describes orthologs of nucampholin from C. elegans which cause a lethal phenotype. Id. The Examiner found that Coelho also discloses that nucampholin is an embryonic lethal in Drosophila and that its sequence is evolutionary conserved across multiple species. Id. at 5. Based on the teachings of Coelho, Kelly, and Stam that nucampholin is a lethal and essential to viability, the Examiner determined it would have been obvious to one of ordinary skill in the art on the effective date of the invention, to have cloned the nucampholin gene of WCR (namely, SEQ ID NO: 77 of claim 1) and substituted it as the target dsRNA of Baum to produce the claimed dsRNA that kills WCR “when ingested by the insect.” Appeal 2021-003219 Application 14/979,181 4 Final Act. 6. The Examiner found that Baum provides the motivation to have cloned the nucampholin gene of WCM to control it from damaging crop plants: The ordinary artisan would have been motivated to isolate nucampholin from Diabrotica virgifera insect pests because Baum teaches that WCR damages crop plants and leads to yield losses. See paragraph 0103. Thus, in an effort to control a pest that affects crop plants such as corn, the ordinary artisan would have turned to previously identified RNAi targets in other organisms, including nucampholin taught by the combination of Coelho, Kelly, Stam, and Ruvkun. Final Act. 7. The Examiner also found there would have been a reasonable expectation of success in cloning WCR nucampholin using “standard molecular cloning techniques known to those of ordinary skill in the art,” using degenerate primers or nucleic acid hybridization, because Coelho teaches that nucampholin sequences are evolutionarily conserved. Final Act. 7. Appellant contends that the cited disclosure from Coelho, Kelly, and Ruvkun do not “establish a foundation for showing that a person of ordinary skill in the art would identify SEQ ID NO:77 as a useful target for RNAi [the claimed dsRNA] in WCR, as claimed.” Appeal Br. 9. Appellant argues that the first error is that SEQ ID NO: 77 “was not known in the prior art” and thus it would not have been used as claimed. Id. at 10. Appellant argues that the second error is “the Examiner’s unsupported conclusion that SEQ ID NO:77 would inherently be identified by designing degenerate primers from D. melanogaster or C. elegans ‘nucampholin’ sequences.” Appeal Br. 10. Appellant argues that “the only fact or reasoning provided to support the inherency of SEQ ID NO:77 being returned by the Appeal 2021-003219 Application 14/979,181 5 proposed nucampholin cloning experiment is the Examiner’s unsupported notice that SEQ ID NO:77 is a nucampholin.” Id. at 11. Appellant contends that sequence identity between Drosophila nucampholin and the claimed SEQ ID NO:77 is less than 70% “to only 1,609 of the 2,681 nucleotides in SEQ ID NO:77” which is “hardly sufficient to establish that designing degenerate primers from D. melanogaster nucampholin would necessarily identify SEQ ID NO:77 under the unspecified hybridization conditions supposed by the Examiner.” Id. at 13 (footnote and emphasis omitted). Appellant further argues that without the knowledge “that SEQ ID NO:77 existed as a sequence” in WCR “with some homology to D. melanogaster CGl2750 and C. elegans let-858, or that it was part of some unbounded genus of nucampholin molecules, all that was obvious from the combination of Baum, Kelly, Stam, and Ruvkun was an invitation to clone an unknown sequence” from WCR using primers from the nucampholin sequences of D. melanogaster or C. elegans. Appeal Br. 14. Appellant states there is no guidance in Baum as to what primers or hybridization conditions could be used to isolate SEQ ID NO:77. Id. ANALYSIS The threshold issue in this rejection is whether the Examiner established it would have been reasonably expected by one of ordinary skill in the art that the western corn worm genome has a nucampholin gene sequence. We turn to the disclosures in Kelly, Coelho, and Ruvkun relied upon by the Examiner to establish this fact. Nucampholin was identified by Kelly in C. elegans as essential in early development and whose depletion causes Appeal 2021-003219 Application 14/979,181 6 lethality in early embryos. Kelly 227 (Abstract). Kelly further disclosed that “Closely homologous” sequences of nucampholin “in yeast, plants, and mammals demonstrate strong evolutionary conservation in eukaryotes.” Id. Subsequently, Coelho identified nucampholin in Drosophila. Coelho also described “the strong evolutionary conservation between the different Ncm proteins.” Coelho 609. Coelho explained that this strong sequence conservation between different nucampholins “suggests that they play a critical role in [RNA] splicing.” Id. Coelho also found “that CG12750 is most similar to a distinct class of proteins that is found across species and includes Caenorhabditis elegans Nucampholin/LET-858.” Id. (emphasis omitted). Ruvkun also lists “counterparts” to nucampholin in other species. Ruvkun 20 (Table 4C). Ruvkun identified nucampholin in C. elegans (also called let-858 or F33A8.1). Ruvkun found that nucampholin is a member of a class of genes which, when disrupted, lead to defects in “Ecdysozoan molting,” making it useful as an insecticide. Ruvkun Abstract, ¶¶ 16, 39; page 11 (Table 1A listing F33A8.1 as an RNAi (the same function provided by the claimed dsRNA) producing molt defects in larvae). The Examiner found that it is known that Ecdysozoans include arthropods, such as Diabrotica virgifera, the Western Corn Worm. Final Act. 6. Based on the disclosure in Coelho that nucampholin is “found across species,” its evolutionary conservation in different species as described by Kelly, and Ruvkun, and WCR being an Ecdysozoan, the Examiner had reasonable basis to find that nucampholin would also exist in WCR. Appellant does not provide persuasive evidence to rebut this finding by the Examiner. Appellant contends that the Examiner did not establish that “SEQ Appeal 2021-003219 Application 14/979,181 7 ID NO:77 existed as a sequence in D. virgifera with some homology to D. melanogaster CG12750 and C. elegans let-858,” but did not offer any evidence that a copy of nucampholin did not exist in D. virgifera, the Western Corn Rootworm, or that one of ordinary skill in the art would have doubted its existence. Appeal Br. 14. The next issue in this appeal is whether the Examiner established that there would have been a reasonable expectation of success in identifying and cloning nucampholin from WCR. Appellant states that the Examiner erred by making the “unsupported conclusion that SEQ ID NO:77 would inherently be identified by designing degenerate primers from D. melanogaster or C. elegans ‘nucampholin’ sequences.” Appeal Br. 10. Appellant is referring to the statement by the Examiner in the Advisory Action, subsequent to the Final Action, that a BLAST search was “performed simply to identify inherent properties of SEQ ID NO:77” which “necessarily possesses the property of being nucampholin from Diabrotica virgifera.” Advisory Action 2 (dated July 20, 2020). The Examiner did not base the rejection on “inherency” in the Final Office Action. The Examiner determined in the Final Office Action that it would have been obvious to one of ordinary skill in the art to clone nucampholin from WCR with a reasonable expectation of success based on the conservation of the nucleotide sequence of nucampholin across species. Final Act. 6-7. The discussion of inherency in the Advisory Action was a response by the Examiner to Appellant’s argument that their own BLAST search of sequences did not contain the same results shown by the Examiner. Appeal 2021-003219 Application 14/979,181 8 Advisory Action 2.7 The Examiner stated that the BLAST search is not “part of the rejection of record.” Id. at 3. Consequently, the Examiner’s characterization of the BLAST search as identifying “inherent properties of SEQ ID NO: 77” is inconsequential to the rejection. Appellant does not dispute that knocking out the nucampholin gene in the Western Corn Rootworm would be useful for pest control. Appellant’s principal contention is that the SEQ ID NO:77 was not known in the prior art before the effective date of the invention and that it would not have been obvious to clone it. Appeal Br. 10, 13. Appellant argues: It should be a matter of judicial notice that when conditions are adjusted to isolate sequences with less identity, non-specific, off-target results are obtained. For example, if the conditions are adjusted such that all sequences having 70% identity hybridize to the primers, the experiment may return any and all sequences in the organism that have such low identity to the primer over the sequence of the primer. Furthermore, D. melanogaster nucampholin is only even somewhat identical to 60% of SEQ ID NO:77 (1,609 of 2,681 nucleotides). If primers were designed to hybridize anywhere in the remaining 40% of the gene, they would not isolate SEQ ID NO:77 even if they were reduced to the lowest stringency suggested in Baum. Though its sequence is understandably not explicitly given by the Examiner, the C. elegans let-858 discussed by Kelly is only homologous to SEQ ID NO:77 over a mere 44 out of its 2,681 nucleotides, and it is only 75% identical over this small segment. Id. at 13. This argument does not persuade us that the Examiner erred. 7 The pages of the Advisory Action are not numbered. We numbered them, beginning at 1 for the first page of text written by the Examiner. Appeal 2021-003219 Application 14/979,181 9 “[O]n examination the PTO bears the initial burden of presenting a prima facie case of unpatentability. If that burden is not met, patentability is established. If it is met, the burden shifts to the applicant, to come forward with evidence and argument to rebut the prima facie case. In re Piasecki, 745 F.2d 1468, 1472 (Fed. Cir. 1984).” In re Huping Hu, 848 F. App’x 416, 423 (Fed. Cir. 2021). The Examiner, to establish prima facie obviousness of claim 1, provided evidence that nucampholin is conserved across species. Final Act. 5-6 (citing Coelho, Kelly, Ruvkun). Appellant did not provide persuasive objective evidence to rebut the Examiner’s finding. Appellant argues that primers designed over certain regions of the nucampholin Drosophila and C. elegans sequences would not hybridize to SEQ ID NO: 77 even at the lowest stringency. Appeal Br. 13. We are not persuaded by this argument. Appellant did not provide sufficient objective evidence that the identified prior art nucampholin sequences would be unable to hybridize and select nucampholin from WCR using Drosophila, C. elegans, or any of the nucampholin sequences which were known before the effective date of the application. Appellant describes problems of designing primers to hybridize to SEQ ID NO:77, but this is not supported by objective evidence, such as a declaration by an expert, that primers could not be designed, for example, to identified conserved regions of the nucampholin sequence. Appellant states that “C. elegans let-858 discussed by Kelly is only homologous to SEQ ID NO:77 over a mere 44 out of its 2,681 nucleotides, and it is only 75% identical over this small segment.” Appeal Br. 13 (emphasis omitted). But Appellant fails to address the statement in Kelly that let-858/nucampholin is Appeal 2021-003219 Application 14/979,181 10 “evolutionary conserved” (Kelly 237) (emphasis omitted) or the statement in Coelho of “strong evolutionary conservation between the different Ncm proteins” (Coelho 609). In other words, if Kelly and Coelho could use this degree of conservation to identify other members of the nucampholin family in different species,8 why did the Examiner err in finding that it similarly could use to identify the nucampholin in WCR? Appellant did not refute this published evidence relied upon by the Examiner in finding there was a reasonable expectation of success in isolating WCR nucampholin. Appellant argues that the hybridization conditions are not described, but does not specifically identify the deficiency in the references cited by the Examiner for this purpose nor explain why this lack of guidance would have led to a lack of a reasonable expectation of success when considered from the viewpoint of one of ordinary skill in the art. “[A]ttorney argument [is] not the kind of factual evidence that is required to rebut a prima facie case of obviousness.” In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997). Appellant also focused on the alleged inability of primers to identify nucampholin in WCR, but the Examiner also points to the description in Stam of identifying “homologous sequences by hybridization,” a disclosure not even addressed by Appellant. Final Act. 7 (citing Stam ¶ 61). Stam addresses the specific question at issue in teaching “sets of hybridization/ 8 Coelho 609 (“BLAST searches show that CG12750 is most similar to a distinct class of proteins that is found across species and includes Caenorhabditis elegans Nucampholin/LET-858 (KELLY et al. 1997), Schizosaccharomyces pombe Cwf22p and S. cerevisiae Cwc22p (OHI et al. 2002), and human KIAA1604 protein (Figure 7B). As the C. elegans protein was the first member of this protein family to be named, we have also called the D. melanogaster ortholog ‘Nucampholin’ (Ncm).”). Appeal 2021-003219 Application 14/979,181 11 wash conditions that may be used to clone homologous nucleotide sequences that are substantially identical to reference nucleotide sequences” (Stam ¶ 61). Similarly, Ruvkun discloses: one may readily design gene- or nucleic acid sequence-specific oligonucleotide probes, including degenerate oligonucleotide probes . . . These oligonucleotides are useful . . . for the isolation of virtually any gene listed in Tables IA, IB, 4A-4D, and 7, either through their use as probes capable of hybridizing to a . . . gene, or as complementary sequences or as primers for various amplification techniques, for example, polymerase chain reaction (PCR) cloning strategies. (Ruvkun ¶ 218) Appellant’s statement that there is no evidence that SEQ ID NO: 77 is nucampholin (Appeal Br. 10) misapprehends the rejection. It is true that SEQ ID NO:77 was not known in the prior art. Id. But the rejection is based on the obviousness of cloning it. The Examiner provided sufficient evidence that SEQ ID NO:77 would be obtained “using standard molecular cloning techniques known to those of ordinary skill in the art,” such by hybridization or the creation of degenerate primers. Final Act. 7. SEQ ID NO:77 is therefore an obvious product of these standard molecular cloning techniques. SEQ ID NO: 77 is acknowledged in the Specification to be nucampholin: In specific examples, nucampholin (referred to herein as ncm) may be selected as a target gene for post-transcriptional silencing. In particular examples, a target gene useful for post- transcriptional inhibition is a novel gene referred to herein as a Diabrotica ncm (e.g., SEQ ID NO:1 and SEQ ID NO:77). Spec. ¶ 18 (Dec. 22, 2015). Knowledge of the specific sequence of SEQ ID NO: 77 is not necessary to establish its obviousness as long as it would have been obvious to have obtained it using the conventional cloning techniques described by Appeal 2021-003219 Application 14/979,181 12 the Examiner. In re Kubin, 561 F.3d 1351, 1356-1357 (Fed. Cir. 2009).9 Appellant’s argument that SEQ ID NO: 77 was not known in the prior art is a misapprehension of the law because, under Kubin, it is not necessary that the sequence was “known” for it to have been obvious to one of ordinary skill in the art. See Reply Br. 5-6. CONCLUSION The Examiner’s decision to reject claim 1 as obvious is affirmed. Claims 2-4, 6, 7, 10-19, 21-23, and 43-48 were not argued separately and therefore fall with claim 1. 37 C.F.R. § 41.37(c)(1)(iv). 9 In Kubin, the claim was directed to isolated nucleic acid having at least 80% identity to specifically recited amino acid sequence of SEQ ID NO:2. The amino acid sequence was a portion of the known NAIL or p38 protein. The nucleotide sequence of the NAIL protein, however, was unknown. The Examiner had rejected the claims as obvious based on a known nucleic acid cloning method similar to the rejection in this appeal. The Board, in affirming the Examiner, found that appellant had used conventional techniques to isolate the gene sequence that codes for the known protein. Kubin, 561 F.3d at 1355. The Board found that there was a reasonable expectation of success in doing so. Id. On appeal, the court recognized that the cited prior art publications in the rejection did not disclose the nucleic acid sequence of NAIL. Id. at 1361. The court explicitly acknowledged that Kubin disclosed this sequence for the first time. Id. However, the court found that the gene had been cloned routinely using available starting materials and therefore was obvious. Id. Appeal 2021-003219 Application 14/979,181 13 DECISION SUMMARY Claim(s) Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1-4, 6, 7, 10-19, 21- 23, 43-48 103 Baum, Coelho, Kelly, Stam, Ruvkun 1-4, 6, 7, 10-19, 21- 23, 43-48 TIME PERIOD No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv). See 37 C.F.R. § 1.136(a)(1)(iv) (2013). AFFIRMED