MERIAL, INC. et al.

Patent Trials and Appeals Board

Feb 3, 2022

2021002287 (P.T.A.B. Feb. 3, 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. 15/763,892 03/28/2018 Natalia Ines Bomchil MER 15-269 1998 33928 7590 02/03/2022 BOEHRINGER INGELHEIM ANIMAL HEALTH USA INC. AH PATENT DEPARTMENT 3239 SATELLITE BLVD. BLDG. 500 DULUTH, GA 30096 EXAMINER LYONS, MARY M ART UNIT PAPER NUMBER 1645 NOTIFICATION DATE DELIVERY MODE 02/03/2022 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): docket.ip@boehringer-ingelheim.com tiki.cantrell@boehringer-ingelheim.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ________________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ________________ Ex parte NATALIA INES BOMCHIL, LIONEL PIERRE CUPILLARD, CELIA FONTANA, PIERRE-MICHEL GUIGAL, JEROME BOUVET, MATHIEU PICARDEAU, and ANGELI KODJO1 ________________ Appeal 2021-002287 Application 15/763,892 Technology Center 1600 ________________ Before RICHARD M. LEBOVITZ, JEFFREY N. FREDMAN, and JOHN G. NEW, Administrative Patent Judges. NEW, Administrative Patent Judge. DECISION ON APPEAL 1 We use the term “Appellant” to refer to the “applicant” as defined in 37 C.F.R. § 1.142. Appellant identifies Boehringer Ingelheim Animal Health USA Inc. as the real party-in-interest. App. Br. 2. Appeal 2021-002287 Application 15/763,892 2 SUMMARY Appellant files this appeal under 35 U.S.C. § 134(a) from the Examiner’s Non-Final Rejection of claims 1-6, 8-14, and 26. Specifically, claims 1, 8, and 9 stand rejected as unpatentable under 35 U.S.C. §§ 102(a)(1) and/or 103 as being anticipated by and/or obvious over Ko et al. (WO 2015/138549 A1, September 15, 2015) (“Ko”). Claims 1-6, 8-14, and 26 stand rejected as unpatentable under 35 U.S.C. § 103 as being obvious over Ko, S-X Ren et al., Unique Physiological and Pathogenic Features of Leptospira interrogans Revealed by Whole-Genome Sequencing, 422 NATURE 888-93 (2003) (“Ren”), J.M. Hardham et al., Identification and Sequences of the Treponema pallidum fliM, fliY, fliP, fliQ, fliR and flhB Genes, 166 GENE 57-64 (1995) (“Hardham”), A. Lambert et al., FlaA Proteins in Leptospira interrogans are Essential for Motility and Virulence but are not Required for Formation of the Flagellum Sheath, 80(6) INFECT. AND IMMUN. 2019-25 (2012) (“Lambert”), and A.S. Toker et al., Deletion Analysis of the FliM Flagellar Switch Protein of Salmonella typhimurium, 178(24) J. BACTERIOL. 7069-79 (“Toker”). We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. NATURE OF THE CLAIMED INVENTION Appellant’s claimed invention is directed to compositions that contain a recombinant or an attenuated Leptospira interrogans. Spec., Abstr. Appeal 2021-002287 Application 15/763,892 3 REPRESENTATIVE CLAIM Independent claim 1 is representative of the claims on appeal and recites: 1. A composition comprising a recombinant or an attenuated Leptospira interrogans, wherein the Leptospira interrogans comprises a mutated non-functional fliM gene. App. Br. 18. ISSUE AND ANALYSIS We agree with and adopt the Examiner’s findings, reasoning, and conclusion that the claims on appeal are obvious over the combined cited prior art. We decline, however, to adopt the Examiner’s conclusion that claims 1, 8, and 9 are anticipated by Ko. We address below the arguments raised by Appellant. A. Claims 1, 8, and 9 The Examiner’s Findings and Conclusions The Examiner finds that Ko teaches vaccine compositions comprising a pharmaceutically acceptable carrier and attenuated, Fcp1-deficient, Leptospira interrogans that is further deficient in a wild-type motility protein, including the motility protein encoded by the fliM gene. Non-Final Act. 5 (citing Ko, 3, 10, 16, Fig. 2, claims 33, 34). The Examiner also finds that Ko teaches that leptospirosis, which is induced by Leptospira infection, is a life-threatening disease that can occur in a diverse range of epidemiological situations, and which is considered the most widespread zoonosis due to the pathogen’s ability to induce a carrier state in a wide range of wild and domestic animals. Non-Final Act. 5 (citing Appeal 2021-002287 Application 15/763,892 4 Ko 1-2). The Examiner finds that Ko further teaches that Leptospira bacteria are highly motile, and can penetrate abraded skin and mucous membranes, crossing tissue barriers and causing a systemic infection in a short period of time by and dissemination, and move efficiently in both viscous and low-viscosity environments. Id. The Examiner finds that Ko teaches the desirability of “motility- deficient” Leptospira, which lack the ability to move or swim in solutions having a certain viscosity, and explicitly identifies the genes that effect motility in Leptospira, including the fliM gene. Non-Final Act. 5 (citing Ko, 10-11. The Examiner finds that Ko teaches that mutated genes are changes in nucleotide sequences that cause the expression of the gene to be altered, decreased, or not expressed at all. Id. (citing Ko, 11). The Examiner further finds that Ko teaches that motility is essential for penetration into a host mucosa for Leptospira to establish an infection. Id. (citing Ko, 15). The Examiner notes that Ko teaches that motility-deficient Leptospira can induce an immune response without producing disease. Id. (citing Ko, 17). The Examiner concludes that a person of ordinary skill in the art would quickly, easily, and immediately understand that the teachings of Ko encompass compositions comprising L. interrogans bacteria comprising a mutated fliM gene such that the mutated fliM gene resulted in the altered expression of the fliM motility protein, thereby anticipating the instant claims. Non-Final Act. 6. Alternatively, the Examiner concludes that it would have been prima facie obvious to a skilled artisan to mutate the fliM gene, thereby arriving at the claimed invention, because the compositions taught by Ko encompass L. interrogans that were deficient in motility, and because Ko expressly teaches Appeal 2021-002287 Application 15/763,892 5 that the fliM gene affects motility. Non-Final Act. 6. The Examiner also notes that Ko provides examples in which other motility-related genes are mutated so as to render Leptospira deficient in motility-related proteins FlaA1 and FlaA2. Id. The Examiner reasons that mutating the fliM gene to achieve the same end amounts to no more than a predictable use of prior art elements according to their established functions, i.e., mutating the fliM gene would render the Leptospira deficient in the corresponding fliM protein. Id. The Examiner reasons that a person of ordinary skill in the art would have been motivated to make the modification, and with a reasonable expectation of success, because Ko teaches that motility was essential for penetration into a host’s mucosa for Leptospira to establish an infection, and because Ko teaches that motility-deficient Leptospira can stimulate an immune response without producing disease. Id. The Examiner further observes that Ko identifies the fliM gene as being related to the motility of Leptospira. Id. at 6-7. Analysis Anticipation Appellant points to Ko’s use of the term “fliM” in defining the term “motility deficient”: By “motility-deficient” is meant the inability of a Leptospira bacterium to move or swim in a solution having a certain viscosity. Examples of genes that affect motility in Leptospira bacterium include, but are not limited to, flbB, flbD, flgA, flgB, flgC, flgD, flgG, flgH, flgl, flgM, flbA, flhB, flhF, flhX, fliA, fliE, fliF, fliG, fliGl, fliG3, fliH, flil, fliJ, fliL, fliM, fliN, fliO, flip, fliQ, fliR, motA, motAl, motB, motB, flgE, figj, flgK, figL, fihO, fiiD, fliK, fcpl, fcp2, flaAl, fiaA2, fiaBl, fiaB2, flaB3, flaB4, fliS, and any combination thereof. Appeal 2021-002287 Application 15/763,892 6 App. Br. 4 (quoting Ko 10-11) (emphasis added). Appellant contends that the second sentence in the quoted passage purports to provide an exemplary list of genes that affect Leptospira motility; however, it does not affirmatively describe Leptospira having a mutated non-functional fliM gene. Id. According to Appellant, this paragraph, standing alone, cannot therefore support a finding of express anticipation. Id. (citing Wasica Fin. GmbH v. Cont’l Auto. Sys., Inc., 853 F.3d 1272, 1284 (Fed. Cir. 2017). Appellant asserts that the Examiner’s finding of anticipation relies upon Ko’s statement that Leptospira of one embodiment can be deficit in a wild-type protein selected from the quoted list that includes fliM. App. Br. 5 (citing Non-Final Act., 5-6). Appellant contends that the Examiner reasons that a mutated fliM gene would be the first in a list of many possible reasons explaining how Ko’s Leptospira can have a fliM protein deficit. Id. (citing Non-Final Act., 11). Appellant argues that the Examiner’s finding cannot sustain a finding of inherent anticipation because the missing descriptive matter, i.e., a mutated fliM gene causing a fliM protein deficiency, is not necessarily present. Id. (citing, e.g., Transclean Corp. v. Bridgewood Servs., Inc., 290 F.3d 1364, 1373 (Fed. Cir. 2002). Consequently, Appellant argues, the Examiner has failed to establish a prima facie case of anticipation. Id. at 6. We agree with Appellant, insofar as the Examiner has failed to establish a prima facie case of either express or inherent anticipation. Independent claim 1 requires that “the Leptospira interrogans comprises a mutated non-functional fliM gene.” Ko teaches that live or heat-inactivated Leptospira can have attenuated bacterial virulence when they are deficient in Appeal 2021-002287 Application 15/763,892 7 one of a number of wild-type proteins that are known in the art to be associated with bacterial motility, including fliM. See Ko, 3, 16. Ko teaches that such a protein deficiency can be achieved by mutation, which Ko defines thus: By “mutant” or “mutated” is meant a change of the nucleotide sequence in a gene of a Leptospira bacterium, such as a flagellar- coiling protein 1 (Fcp1) gene. The mutant or mutated gene can result in several different types of change in sequences, such as altering the Fcp1 protein, or preventing a gene from functioning properly or completely. Mutations can also occur in nongenic regions of a gene, such that expression of a gene is altered, decreased, or not expressed. Id. at 11 (emphasis added). Ko does not expressly teach a fliM-deficient Leptospira in which the fliM gene is mutated and non-functional; rather Ko is limited to teaching fliM-deficient Leptospira. Furthermore, we agree with Appellant that Ko does not inherently anticipate the claims. As Appellant points out, inherency can only be established when “prior art necessarily functions in accordance with, or includes, the claimed limitations.” In re Cruciferous Sprout Litig., 301 F.3d 1343, 1349 (Fed. Cir. 2002). Consequently, the Leptospira of Ko would necessarily have to be rendered fliM-deficient via a “mutated non-functional fliM gene.” However, Ko expressly discloses that “[m]utations can also occur in nongenic regions of a gene, such that expression of a gene is altered, decreased, or not expressed [e.g., at a regulatory gene]. Ko, 11. Because fliM-deficient Leptospira could thus be achieved by means other than a mutated, non-functional fliM gene, we agree with Appellant that Ko does not inherently anticipate claims 1, 8, and 9. Appeal 2021-002287 Application 15/763,892 8 Obviousness With respect to the Examiner’s rejection of the claims as being obvious, Appellant argues that the motility-related protein Fcpl is the only protein taught with particularity throughout each section of Ko, and that the majority of Ko’s experimental data is specific to Fcp1. App. Br. 7. Appellant asserts that the only flagellar proteins other than Fcp1 mentioned in Ko’s working examples are the filament proteins FlaB1, FlaA1, and FlaA2. Id. (citing Ko, 25, 37-38). Appellant contends that Ko does not mention fliM or any other basal body complex proteins in its working examples. Id. Appellant acknowledges that Ko lists fliM among 50 different motility genes and proteins, Ko’s allegedly vague and speculative statements about fliM neither adequately disclose nor place in the public’s possession Leptospira having a mutated fliM protein or gene. Id. (citing Ko, 3, 10-11). Appellant alleges that the Examiner, impermissibly relied upon hindsight reconstruction in concluding that an artisan of ordinarily skill would have found it obvious to derive the claimed invention by: (1) focusing on Ko’s mention that Leptospira of one embodiment could be deficit in any combination of 50 different proteins, (2) selecting fliM from among the many options; and (3) determining to introduce fliM protein deficiency by knocking out the fliM gene rather than introducing a different genetic mutation having a similar effect. App. Br. 9 (citing Non-Final Act. 5-8, 11- 16). Appellant argues that the Examiner’s analysis, rather than showing what a person of ordinary skill in the art would have done in the normal course of research and development, calls upon the skilled artisan to make a series of arbitrary choices in concert from countless combinations without Appeal 2021-002287 Application 15/763,892 9 any guidance to do so. Id. (citing, e.g., Unigene Labs., Inc. v. Apotex, Inc., 655 F.3d 1352, 1360-61 (Fed. Cir. 2011)). Appellant next disputes the Examiner’s finding that a person of ordinary skill in the artisan would have obviously derived Leptospira with a mutated fliM gene based on an obvious-to-try theory. App. Br. 9. Appellant argues that the Examiner supports this finding by noting that Ko’s purported disclosure of Leptospira deficit in any combination of fifty different motility-related proteins represents a limited number of well-defined solutions. Id. at 9-10 (citing Non-Final Act., 14-15). Appellant contends that Ko’s disclosure of 1.13 x 1015 different combinations of mutant Leptospira is not a limited number. Id. at 10. Appellant argues further that the record is replete with evidence showing that genetically manipulating Leptospira is quite difficult given the lack of adequate and efficient genetic tools, Leptospira’s fastidious cultivation requirements, and Leptospira’s slow growth rate. App. Br. 10 (citing Spec., 1, 15; Ko, 2; Lambert, 2019, 2022; Ren, 889). Appellant contends that there is thus no factual basis to support finding either a small or an easily traversed number of options, both preconditions to any obvious-to-try theory. Id. (citing Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc., 520 F.3d 1358, 1364 (Fed. Cir. 2008). Appellant also takes issue with the Examiner’s conclusion that an artisan of ordinary skill would obviously derive Leptospira having a mutated fliM gene in view of Ko’s disclosure of a genus of motility-deficient Leptospira and a collection of statements regarding Leptospira motility having general applicability. App. Br. 10 (citing Final Act., 5-8, 11, 14-16). Appellant contends that these considerations are general in nature, and do Appeal 2021-002287 Application 15/763,892 10 not show a specific suggestion in the art to achieve Leptospira having a mutant fliM protein (or gene) above and beyond any other motility protein (or gene) disclosed by Ko. Id. (citing Unigene, 655 F.3d at 1361). We are not persuaded by Appellant’s arguments. As an initial matter, and in contrast to our anticipation analysis, although Ko does not expressly teach “a mutated non-functional fliM gene,” as recited in claim 1, we agree with the Examiner that a person of ordinary skill in the art would have understood that mutating the fliM gene so as to render it nonfunctional would have been one obvious way to create an fliM deficiency in Leptospira, although not the only way of doing so. Claim 33 of Ko recites: “A composition for stimulating an immune response in a subject in need thereof comprising an effective amount of a motility-deficient Leptospira bacteria.” Claim 34 depends upon claim 33, and recites: The composition of claim 33, wherein the Leptospira bacteria is deficit in a wild-type protein selected from the group consisting of flbB, flbD, flgA, flgB, flgC, flgD, flgG, flgH, flgI, flgM, flhA, flhB, flhF, flhX, fliA, fliE, fliF, fliG, fliG1, fliG3, fliH, fliI, fliJ, fliL, fliM, fliN, fliO, flip, fliQ, fliR, motA, motA1, motB, motB, flgE, flgJ, flgK, flgL, flhO, fliD, fliK, fcpl, fcp2, flaA1, flaA2, flaB1, flaB2, flaB3, flaB4, fliS, and any combination thereof. All of these recited proteins are disclosed by Ko to affect motility in Leptospira. Ko, 10. A person of ordinary skill in the art would understand that creating a deficiency of any of these proteins, including fliM, would satisfy the requirements of claim 34 and have the desired effect of decreasing the virulence of Leptospira. Appellant accuses the Examiner of impermissibly employing hindsight reconstruction in the obviousness analysis. However: Appeal 2021-002287 Application 15/763,892 11 Any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made and does not include knowledge gleaned only from applicant's disclosure, such a reconstruction is proper. In re McLaughlin, 443 F.2d 1392, 1395 (C.C.P.A. 1971). Appellant points to no evidence that the Examiner relied exclusively upon that could have been gleaned only from Applicant’s Specification and not from the evidence of record. Appellant’s allegation of hindsight analysis is consequently without merit. With respect to Appellant’s arguments concerning the Examiner’s “obvious to try: conclusion: The … “obvious to try” [error typically occurs in one of two contexts: (1) when it would have been] “obvious to try” to vary all parameters or try each of numerous possible choices until one possibly arrived at a successful result, where the prior art gave either no indication of which parameters were critical or no direction as to which of many possible choices is likely to be successful[; or (2) ] to explore a new technology or general approach that seemed to be a promising field of experimentation, where the prior art gave only general guidance as to the particular form of the claimed invention or how to achieve it. In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988). The first context is relevant to our present analysis, and we find that the Examiner’s findings and conclusion are not error in this context. We acknowledge Appellant’s point that Ko teaches a genus of 50 possible proteins (and their relevant structural genes) that affect the motility of Leptospira. See, e.g., Ko, 10. However, it is not the case that Ko teaches “either no indication of which parameters were critical or no direction as to which of many possible Appeal 2021-002287 Application 15/763,892 12 choices is likely to be successful.” O’Farrell, 853 F.2d at 903. To the contrary, Ko repeatedly teaches that a mutation that creates a deficiency of any of these motility-related proteins is likely to produce the desired effect successfully. See Ko, 3, 10, 16-17, claims 25, 33, 34, 42. We note that “specific disclosure, even in a list, makes this case different from cases involving disclosure of a broad genus without reference to the potentially anticipating species.” Perricone v. Medicis Pharm. Corp., 432 F.3d 1368, 1377 (Fed. Cir. 2005). This is not, therefore, a situation where “a defendant merely throws metaphorical darts at a board filled with combinatorial prior art possibilities,” but rather reflects circumstances where “a skilled artisan merely pursues ‘known options’ from a ‘finite number of identified, predictable solutions.’” In re Kubin, 561 F.3d 1351, 1359 (Fed. Cir. 2009); KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007). Under the latter circumstances, obviousness under § 103 arises. KSR, 550 U.S. at 421. All of the listed proteins (and their genes) are described by Ko as affecting affect motility in Leptospira and Ko teaches that creating a deficiency of any of the proteins via genetic mutation would yield decreased motility, decreasing the virulence of Leptospira. See Ko 1, 3, 10-11. We acknowledge Appellant’s argument that Leptospira may be a demanding organism in which to induce genetic mutations. However, Ko expressly teaches making mutations to create a deficiency of the disclosed motility proteins (see Ko, 11), and Appellant has adduced no direct evidence to overcome the rebuttable presumption that the claims of Ko are enabled in this respect. See Amgen Inc. v. Hoechst Marion Roussel, Inc., 314 F.3d 1313, 1354-55 (Fed. Cir. 2003). Appeal 2021-002287 Application 15/763,892 13 In summary, we conclude that Appellant has failed to overcome the Examiner’s prima facie case that the claims 1, 8, and 9 are obvious over the cited prior art. B. Claims 1-6, 8-14, and 26 Issue 1 Appellant makes additional arguments with respect to claims 1-6, 8- 14, and 26. Appellant first argues that the Examiner erred by failing to provide a reasoned rationale for deriving a Leptospira having a mutated non- functional fliM gene Analysis Appellant again alleges that the Examiner impermissibly used hindsight reconstruction, because Toker and Hardham are non-analogous art that the Examiner has impermissibly employed to reconstruct Appellant’s claims. App. Br. 11. According to Appellant, Toker and Hardham concern phylogenetically different bacteria that are not probative of Leptospira, and they discuss flagellar proteins that are not germane to Fcp1 or Ko’s Fcp1- deficient Leptospira. Id. Specifically, Appellant asserts that Lambert teaches that Salmonella is an enterobacterium, and although Treponema, as taught by Ren, is a spirochete like Leptospira, the former differs extensively from the latter. Id. (citing Lambert, 2019, Ren, Abstr.). Appellant also points to E.A. Wunder Jr. et al., A Novel Flagellar Sheath Protein, FcpA, Determines Filament Coiling, Translational Motility and Virulence for the Leptospira Spirochete, 101(3) MOL. MICROBIOL. 457-70 (2016) (“Wunder”) as teaching that Leptospira are unique and markedly different from other Appeal 2021-002287 Application 15/763,892 14 spirochetes. Id. (citing Wunder, 457). Appellant asserts that a person of ordinary skill in the art, starting with Ko’s Fcp1-deficient Leptospira, would have been dissuaded from studies concerning phylogenetically different bacteria because the gene encoding Fcp1 is highly conserved among Leptospira but is not found in other bacteria. App. Br. 11 (citing Ko, 3; Wunder, Abstr., 460). Appellant next argues that Toker, Hardham, and Lambert report various investigations in the field of bacteria motility, but do not teach or suggest a vaccine or a fliM-deficient Leptospira, or suggest that a fliM- deficient Leptospira would be desirable and suitable for use in a vaccine. App. Br. 11-12. Appellant argues further that the Examiner’s treatment of Ko’s fifty listed proteins as obvious variants constitutes an arbitrary agency action under 5 U.S.C. § 706(2). App. Br. 12 (citing Non-Final Act., 6-7, 14-16). According to Appellant, during prosecution of the Ko applicant’s corresponding U.S. national phase application, the Patent Office issued a restriction requirement requiring the Ko applicant to select one of the 50 proteins for examination. Id. (citing US Appl. Ser. No. 15/124,633 (the “’633 application”), Office Action, 2-4, November 13, 2017). Appellant asserts that this restriction requirement was never rescinded. Id. (citing ’633 application, Response, 2, Jan. 8, 2018, pg. 2 (electing group IV and the Fcp1 gene), also citing Notice of Allowance, 2, August 3, 2018, (cancelling claims 1-31 and 41-17 for being drawn to a non-elected invention)). Appellant notes that restriction is only appropriate where a single application provides two or more independent and distinct inventions, and inventions are distinct if at least one invention is novel and nonobvious over Appeal 2021-002287 Application 15/763,892 15 the other. App. Br. 12 (citing 35 U.S.C. § 121; MPEP § 802.01). Appellant therefore argues that, by the Patent Office’s own admission, Ko’s fifty proteins were nonobvious variants of one another as of Ko’s priority date. Id. (citing ’633 application, 4, November 13, 2017) (emphasis omitted): ([T]here are patentably distinct products contained within each Group III and Group IV, e.g., bacteria with deficits in different wild-type proteins are structurally distinct chemical compounds and are unrelated to one another. These sequences are thus deemed to normally constitute independent Examination. It is additionally noted that this sequence election requirement is a restriction requirement and not a species election requirement)). Appellant argues that the additional cited references, each of which predates Ko and was publically available at the time of Ko’s priority date, do not provide a basis for reaching a contrary result . Id. at 13. Appellant asserts that the preclusive effect of the Patent Office’s prior determination that the proteins of Ko are allegedly nonobvious variants, coupled with the absence of any competent evidence post-dating Ko that would justify reaching a contrary result, requires finding that the Examiner’s treatment of Ko’s fifty proteins as obvious variants to be arbitrary agency action. App. Br. 13-14 (citing 5 U.S.C. § 706(2); Innovad Inc. v. Microsoft Corp., 260 F.3d 1326, 1334 (Fed. Cir. 2001); In re Kahn, 441 F. 3d 977, 988 (Fed. Cir. 2006)). We are not persuaded by Appellant’s arguments. As an initial matter, we fail to see the relevance of Appellant’s argument that the restriction requirement placed upon Ko’s ’633 application somehow renders the Examiner’s conclusion of obviousness an arbitrary agency action. The question squarely before us is whether the Ko reference cited by the Examiner, a prior printed publication, would have rendered Appellant’s Appeal 2021-002287 Application 15/763,892 16 claims obvious to a person of ordinary skill in the art at the time of invention. We agree with the Examiner that it does, for the reasons we have explained in the preceding section. With respect to Appellant’s argument that Toker and Hardham are non-analogous art: Two separate tests define the scope of analogous prior art: (1) whether the art is from the same field of endeavor, regardless of the problem addressed and, (2) if the reference is not within the field of the inventor’s endeavor, whether the reference still is reasonably pertinent to the particular problem with which the inventor is involved. In re Bigio, 381 F.3d 1320, 1325 (Fed. Cir. 2004). Toker teaches investigating the function of the fliM protein in two species of non- spirochete bacteria, and its interactions with fliG and fliN. Toker, Abstr. Toker teaches engineering a series of 34 fliM deletion mutant proteins, each lacking a different 10-amino-acid segment, and that deletions at the N- terminus produced a counterclockwise switch bias, deletions in the central region of the protein produced poorly motile, or non-flagellate cells, and deletions near the C-terminus produced only non-flagellate cells. Id. The fliM protein, therefore, is involved in flagellar function and motility across a range of flagellated bacteria, including Leptospira, as taught by Ko. See Ko 1. The Examiner relies upon Toker as teaching methods for the deletion of the fliM gene, which resulted in fliM protein deficient phenotypes. Non- Final Act. 12-13 (citing, e.g. Toker, 7070, 7071). Both Toker and Ko are therefore directed to the molecular basis of flagellar motility in bacteria, and to the genes encoding the proteins involved in basal body direction of the Appeal 2021-002287 Application 15/763,892 17 flagella. Both references are therefore in the same field of endeavor, viz., the molecular basis of bacterial flagellar motility. Although Toker and Ko employ different bacterial species, the fliM gene is present in both species (along with other basal body proteins), and a person of ordinary skill in the art would have understood the relevance of Toker’s teachings to those of Ko. The Examiner has established the pertinency of Toker’s teachings to those of Ko. Similarly, Hardham teaches identification and sequences of genes related to the flagellar motility, including fliM of a spirochete bacterium, Treponema pallidum. Hardham Abstr. The Examiner relies upon Hardham as teaching that Hardham teaches that the fliM gene and its corresponding fliM protein are part of a flagellar switch complex that controls motility. Non-Final Act. 12 (citing, e.g., Hardham, 58, 61, Table 2). The Examiner reasons that Hardham provides evidence that one of ordinary skill in the art, as early as 1995, would have recognized that the fliM gene encodes a flagellar switch protein used in motility by spirochete bacteria. Id. Again, we find that, because Hardham is directed to studies of the molecular and genetic bases of flagellar motility in bacteria and, in this case, a spirochete species like Leptospira, it is in the same field of endeavor as Ko. Similarly, we find that a person of ordinary skill in the art would have found that the teachings of Hardham are pertinent to the problems addressed by Ko, for the reasons set forth by the Examiner. We consequently do not agree with Appellant that Toker and Hardham are non-analogous art. Nor are we persuaded by Appellant’s argument that a person of ordinary skill in the art, starting with Ko’s Fcp1-deficient Leptospira, would have been dissuaded from studies concerning phylogenetically different Appeal 2021-002287 Application 15/763,892 18 bacteria because the gene encoding Fcp1 is highly conserved among Leptospira but is not found in other bacteria. See App. Br. 11 (citing Ko, 3; Wunder, Abstr., 460). We do not find this argument persuasive, because Fcp1 is not the protein at issue in the present claims, it is, rather, fliM, which is present in all of the bacteria taught by the combined references. Indeed, Lambert is expressly relied upon by the Examiner as teaching that one of ordinary skill in the art would have recognized that: (1) Salmonella and Leptospira have homologous genes (including fliM) with respect to their flagella and motility; and (b) the virulence of Leptospira interrogans is dependent upon its motility. See Final Act. 12. We consequently conclude that a person of ordinary skill in the art would have found it obvious to combine the teachings of the references in the manner set forth by the Examiner. Issue 2 Appellant argues that the Examiner erred by failing to demonstrate a reasonable expectation of success in deriving Leptospira having a mutated, non-functional fliM gene. App. Br. 14. Analysis Appellant argues that the record is allegedly replete with evidence showing that genetically manipulating Leptospira is quite difficult and unpredictable given the lack of adequate and efficient genetic tools, Leptospira’s fastidious cultivation requirements and Leptospira’s slow growth rate. App. Br. 14 (citing Spec., 1, 15; Ko, 2; Lambert, 2019, 2022; Ren, 889). Appellant also contends that the record does not contain a single Appeal 2021-002287 Application 15/763,892 19 working example of fliM-mutant Leptospira, or a roadmap for constructing one. Id. (citing Endo Pharm. Inc. v. Actavis LLC, 922 F.3d 1365, 1376-78 (Fed. Cir. 2019)). Appellant disputes the Examiner’s finding that Ko’s working examples of Leptospira with mutant Fcp1 and flaA2 genes confers a reasonable expectation of success in modifying Leptospira’s fliM gene. App. Br. 15 (citing Non-Final Act., 6-7). According to Appellant, Ko acknowledges the lack of genetic tools for manipulating Leptospira and nowhere suggests that its mutagenesis methods are a generally applicable tool suitable for modifying any Leptospira gene, or fliM specifically. Id. (citing Ko, 2; also citing Spec., 1, 15; Lambert, 2019, 2022, Ren, 889). Furthermore, argues Appellant, the Patent Office has previously ruled that Fcp1 and FlaA2 are patentably distinct, non-obvious variants of fliM. Id. (citing ’633 application, Office Act. 4, November 13, 2017). Appellant contends that Ko’s working examples, none of which relate to fliM, do not support finding a reasonable expectation of success in view of the technical prejudice in the art against Leptospira genome engineering. Id. Appellant also notes that the Examiner also finds that Toker’s methods for creating S. typhimurium fliM mutants, coupled with the similar flagellar structures of S. typhimurium and L. interrogans, confers a reasonable expectation of success in modifying a Leptospira’s fliM gene. App. Br. 15 (citing Non-Final Act. 13-16). Appellant asserts that Ko’s own disclosure, which postdates Toker by nearly 20 years, considers pre-existing techniques like Toker’s as being ineffective to manipulate Leptospira genetically. Id. (citing Ko, 2). Appeal 2021-002287 Application 15/763,892 20 Appellant also argues that the evidence of record demonstrates that spirochetes are morphologically and structurally unique within the bacteria domain, have an unusual and complex motility system among bacteria, and do not conform to models of flagellar structure used to describe other bacteria motility systems. App. Br. 16 (citing Ko, 42; Ren, 889; Wunder, Abstr., 457, 465). Therefore, Appellant asserts that Toker’s methods for modifying S. typhimurium, an enterobacteria and not a spirochete, would not reasonably lead to an expectation of success in genetically modifying any spirochetes, let alone the difficult Leptospira. Id. (citing Ko, 1; Lambert, 2019). The Examiner responds that that the entire genome of Leptospira was published over 15 years ago (citing, e.g., Ren, 2003); and that Lambert provides detailed methods for culturing and the genetic manipulation of L. interrogans. Ans. 29 (citing, e.g., Lambert, 2020). The Examiner also finds that Ko teaches detailed methods for culturing and genetic manipulation, including art-recognized conventional procedures, in general; and L. interrogans procedures, specifically. Id. (citing Ko 20-26 and references cited therein). The Examiner therefore reasons that the prior art provides sufficient guidance regarding culturing and mutating Leptospira. We find that the preponderance of the evidence supports the Examiner’s position. “Only a reasonable expectation of success, not absolute predictability, is necessary for a conclusion of obviousness.” In re Longi, 759 F.2d 887, 897 (Fed. Cir. 1985). Appellant asserts that the prior art indicates considerable difficulties in the culture and genetic manipulation of Leptospira, however, we find no textual support in the references cited by Appellant, including Wunder, that adequately supports Appellant’s Appeal 2021-002287 Application 15/763,892 21 contention. Furthermore, Ko expressly teaches construction of mutant and complemented strains of Leptospira, in which the Fcp1 gene is mutated and rendered inoperative. Ko, 21-26. Appellant provides inadequare evidence with respect to why similar techniques would not be applicable to mutation of the fliM gene. Similarly, Toker teaches selective inactivation of portions of the fliM gene in Salmonella. Given that Ko teaches inactivation of the Fcp1 gene, and given that the structure and sequence of the fliM gene in spirochetes and other bacteria was well known in the art at the time of invention (see, e.g., Hardham), we agree with the Examiner that a person of ordinary skill in the art, having a knowledge of the teachings of Ko and Toker, would have had a reasonable expectation of success, , in providing a mutated non-functional fliM gene in Leptospira. However, a certainty of success is not necessary to meet the requirements of Section 103, it is only necessary that the expectation of success be reasonable. Longi, 759 F.2d at 897. We are not persuaded by Appellant’s argument that any expectation of success would have been unreasonable to a person of ordinary skill in the art. We consequently affirm the Examiner’s rejection of the claims. CONCLUSION The rejection of claims 1, 8, and 9 as unpatentable under 35 U.S.C. § 102 is reversed. The rejection of claims 1-6, 8-14, and 26 as unpatentable under 35 U.S.C. § 103 is affirmed. 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). Appeal 2021-002287 Application 15/763,892 22 AFFIRMED Claim(s) Rejected 35 U.S.C. § Reference(s)/ Basis Affirmed Reversed 1, 8, 9 102 Ko 1, 8, 9 1, 8, 9 103 Ko 1, 8, 9 1-6, 8-14, 26 103 Ko, Ren, Hardham, Toker, Lambert 1-6, 8-14, 26 Overall Outcome 1-6, 8-14, 26