THE GOVERNORS OF THE UNIVERSITY OF ALBERTA

Patent Trials and Appeals Board

Jan 26, 2022

2020005535 (P.T.A.B. Jan. 26, 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. 14/783,699 10/09/2015 Michael Houghton UALB-017 1021 24353 7590 01/26/2022 BOZICEVIC, FIELD & FRANCIS LLP BOZICEVIC, FIELD & FRANCIS 201 REDWOOD SHORES PARKWAY SUITE 200 REDWOOD CITY, CA 94065 EXAMINER ZOU, NIANXIANG ART UNIT PAPER NUMBER 1648 NOTIFICATION DATE DELIVERY MODE 01/26/2022 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@bozpat.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte MICHAEL HOUGHTON, DARREN HOCKMAN, JOHN L. LAW, MICHAEL LOGAN, and D. LORNE TYRRELL Appeal 2020-005535 Application 14/783,699 Technology Center 1600 Before JEFFREY N. FREDMAN, TAWEN CHANG, and TIMOTHY G. MAJORS, Administrative Patent Judges. CHANG, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s decision to reject claims 52-86. 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 The Governors of the University of Alberta. Appeal Br. 3. Appeal 2020-005535 Application 14/783,699 2 STATEMENT OF THE CASE “Hepatitis C virus (HCV) is a blood-borne pathogen that is estimated to infect 150-200 million people worldwide.” Spec. ¶ 3. “The structural proteins [of the HCV virus] comprise a core protein forming the viral nucleocapsid and two envelope glycoproteins, E1 and E2.” Id. According to the Specification, “[t]here is a need in the art for immunogenic compositions that induce an immune response to HCV in an individual so as to provide induction of an immune response effective against multiple HCV genotypes found around the world, e.g., genotypes 1 and 3.” Id. ¶ 5. CLAIMED SUBJECT MATTER The claims are directed to an immunogenic composition and a method of inducing an immune response in an individual. Claim 52 is illustrative: 52. An immunogenic composition comprising: a) a hepatitis C virus (HCV) E1 polypeptide, E2 polypeptide, or E1/E2 heterodimeric polypeptide from a first HCV genotype, wherein the first HCV genotype is genotype 1; b) an HCV E1 polypeptide, E2 polypeptide, or E1/E2 heterodimeric polypeptide from a second HCV genotype, wherein the second HCV genotype is genotype 2; c) an HCV E1 polypeptide, E2 polypeptide, or E1/E2 heterodimeric polypeptide from a third HCV genotype, wherein the third HCV genotype is genotype 3; wherein the composition does not include an HCV E1E2 polypeptide, and E1 polypeptide, or an E2 polypeptide of any genotype other than HCV genotype 1, HCV genotype 2, and HCV genotype 3; d) a pharmaceutically acceptable excipient; and e) an immune-stimulating amount of an adjuvant. Appeal Br. 30 (Claims App.). Appeal 2020-005535 Application 14/783,699 3 REJECTION(S) A. Claims 52-86 are rejected under 35 U.S.C. § 103 as being unpatentable over Choo,2 Houghton,3 Simmonds,4 Alexopoulou,5 and Narahari.6 B. Claims 52-86 are rejected on the ground of nonstatutory obviousness- type double patenting as being unpatentable over claims 1-3 of U.S. patent 6,121,020 (’020 patent) in view of Choo, Houghton, Simmonds, Alexopoulou, and Narahari. OPINION A. Obviousness rejection over Choo, Houghton, Simmonds, Alexopoulou, and Narahari (claims 52-86) 1. Issue The Examiner finds that Choo teaches the need for a vaccine to control the spread of HCV. Ans. 4. The Examiner finds that Choo teaches using an E1/E2 heterodimer from HCV-1 to immunize chimpanzees. Id. The Examiner finds that Choo teaches that “multivalent vaccines may be 2 Q.-L. Choo et al., Vaccination of Chimpanzees against Infection by the Hepatitis C Virus, 91 PROC. NAT’L ACAD. SCI. USA 1294-1298 (1994). 3 Houg[h]ton et al., US 2009/0258033 A1, published Oct. 15, 2009. 4 P. Simmonds et al., Classification of Hepatitis C Virus into Six Major Genotypes and a Series of Subtypes by Phylogenetic Analysis of the NS-5 Region, 74 J. GENERAL VIROLOGY 2391-2399 (1993). 5 Alexandra Alexopoulou, Genetic Heterogeneity of Hepatitis C Virus and Its Clinical Significance, 14 ANNALS OF GASTROENTEROLOGY 261-272 (2001). 6 Shobha Narahari et al., Prevalence and Geographic Distribution of Hepatitis C Virus Genotypes in Indian Patient Cohort, 9 INFECTION, GENETICS & EVOLUTION 643-645 (2009). Appeal 2020-005535 Application 14/783,699 4 required for global protection” against HCV, because there are at least six distinct HCV genotypes, some of which are composed of more than one subtype, and “the primary amino acid sequences of the putative envelope glycoprotein domains differ by up to 50% (at least).” Id. at 5. The Examiner finds that Houghton teaches “HCV E1E2 compositions comprising E1E2 antigens and adjuvants to be used in stimulating immune response in a vertebrate subject.” Ans. 5. The Examiner finds that Houghton teaches that its invention “encompass[es] E1 and E2 polypeptides from any of the various HCV strains and isolates including isolates having any of the 6 genotypes of HCV described in Simmonds,” which teaches “different genotypes of HCVs, including genotypes 1, 2 and 3 as well as sub-genotypes,” “as well as newly identified isolates, and subtypes of these isolates.” Id. at 5-6. The Examiner finds “Alexopoulou teaches that there are differences in the relative prevalence of genotypes and subtypes in distinct geographic areas” and that, for example, “1a, 1b, 2a, 2b and 3a are the most prevalent types in Western Europe and North America.” Ans. 6. The Examiner finds that Narahari similarly teaches that, for example, “HCV genotype distribution in [] 2118 Indian patients demonstrated prevalence of HCV3 (3a/3b primarily) in 62% and HCV1 (1a/1b primarily) in 31% patients,” whereas HCV types 2, 4, 5, and 6 were detected only in 0.05%-4.5% of the patient group. Id. at 7. The Examiner finds that, accordingly, Alexopoulou and Narahari “provid[e] a motivation and guidance on selecting HCV genotypes to be targeted if a multivalent vaccine [is] to be developed for populations in a specific geographic region.” Id. Appeal 2020-005535 Application 14/783,699 5 The Examiner asserts that a skilled artisan would have been motivated to produce a vaccine composition comprising E1, E2, or E1/E2 polypeptide from genotypes 1-3 of HCV in order to produce a multivalent vaccine for, e.g., Western Europe and North America. Ans. 7. The Examiner asserts that [t]here is reasonable expectation of success that such E1/E2 complex from various HCV types may be produced and combined, as already being shown in Choo et al. and Houghton et al., and that the combination of E1/E2 polypeptides from different genotypes would provide protection against infection of the respective types. Id. Appellant contends that the cited prior art does not disclose or suggest all of the elements of the claims. Appeal Br. 8, 10-12. Appellant contends that the Examiner has not articulated reasoning why a skilled artisan would have combined the cited prior art so as to arrive at the claimed invention, that the prior art teaches away from the claimed invention, and that the rejection is based on impermissible hindsight reconstruction. Id. at 11-14, 22-23. Finally, Appellant contends that the claimed subject matter exhibits unexpected results and satisfies a long-felt, unmet need. Id. at 8-10, 23-24. Appellant does not separately argue the claims. We, therefore, focus our analysis on claim 52 as representative. The issues with respect to this rejection are (1) whether the cited prior art combination discloses or suggests all elements of claim 52; (2) whether a skilled artisan would have had reason to combine the cited prior art so as to arrive at the invention of claim 52; and (3) whether Appellant has provided evidence of unexpected results or long- felt, unmet need that, when considered together with the evidence of obviousness, shows claim 52 to be non-obvious. Appeal 2020-005535 Application 14/783,699 6 2. Analysis Unless otherwise noted, we adopt the Examiner’s findings of fact and reasoning regarding the scope and content of the prior art (Final Act. 2-7, 9- 25; Ans. 3-8, 9-25) and agree with the Examiner that claim 52 would have been obvious over Choo, Houghton, Simmonds, Alexopoulou, and Narahari. We address Appellant’s arguments below. Only those arguments timely made by Appellant in the Appeal Brief have been considered (no Reply Brief was submitted); arguments not so presented in the Appeal Brief are waived. See 37 C.F.R. § 41.37(c)(1)(iv) (2020); see also Ex parte Borden, 93 USPQ2d 1473, 1474 (BPAI 2010) (informative) (“Any bases for asserting error, whether factual or legal, that are not raised in the principal brief are waived.”). Appellant contends that the cited art fails to disclose or suggest all elements of the claims on appeal. Appeal Br. 8, 10-12. In particular, citing to the declarations of Dr. Amy Weiner,7 Dr. Peter Palese,8 and Dr. Charles Rice,9 Appellant contends that “[a]n essential goal in developing a vaccine against a virus that comprises multiple genotypes is to produce a vaccine composition that: a) includes the fewest possible components (e.g., viruses, or components of viruses, of different viral genotypes); while at the same time b) induces the broadest cross-protection possible.” Appeal Br. 7; see also id. at 24-25. 7 Declaration of Amy Weiner under 37 C.F.R. § 1.132 (Feb. 13, 2019) (“Weiner Declaration”). 8 Declaration of Peter Palese under 37 C.F.R. § 1.132 (Feb. 12, 2019) (“Palese Declaration”). 9 Declaration of Charles M. Rice under 37 C.F.R. § 1.132 (Feb. 15, 2019) (“Rice Declaration”). Appeal 2020-005535 Application 14/783,699 7 Appellant contends that only data regarding the cross-neutralization patterns of the different virus genotypes, and not the “geographic distribution of HCV genotypes,” provides the information necessary to determine “which virus genotypes to include, and which could be excluded, in order to achieve the goals mentioned above.” Id. at 7-8; see also id. at 24-25. Accordingly, Appellant contends that “[t]he inclusion of HCV envelope proteins of genotypes 1, 2, and 3 in an immunogenic composition as claimed is not a reflection of the prevalence of these genotypes in any given population or geographic area” but, rather, is “based on the pattern of cross-neutralization, as determined for the first time by the inventors of the instantly claimed invention.” Id. at 7. We are not persuaded because Appellant has not pointed to any specific limitations in claim 52 not suggested by the combination of cited prior art. That is, although Appellant contends that the cited prior art combination does not disclose the “cross-neutralization patterns of the different virus genotypes” and the alleged goal of “a vaccine composition that[] a) includes the fewest possible components . . . while at the same time b) induces the broadest cross-protection possible,” Appeal Br. 7; see also id. at 24-25, claim 52 does not contain limitations regarding either the cross- neutralization pattern or the goal of the invention. See In re Hiniker Co., 150 F.3d 1362, 1369 (Fed. Cir. 1998) (stating that “the name of the game is the claim”). Appellant contends that, to the extent the Examiner relies on inherency, [t]he Examiner has provided no basis in fact and/or technical reasoning to reasonably support the assertion that immunization with HCV E1/E2 of genotype 2 induces Appeal 2020-005535 Application 14/783,699 8 neutralizing antibody to HCV of genotype 2 and to HCV of genotype 6, but not to HCV genotypes 3, 4, or 5, was an outcome that was “necessarily present,” not merely probably or possibly present, in the prior art. Appeal Br. 18. We are not persuaded. As discussed above, at least as to claim 52, there are no functional limitations regarding cross-neutralization patterns. Thus, the Examiner’s rejection does not need to rely on inherency. Moreover, as discussed below, we find that the Examiner has established a prima facie case of obviousness with respect to an immunogenic composition meeting the limitations of claim 52. As our reviewing court has explained, [w]here . . . the claimed and prior art products are identical or substantially identical . . . the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product. Whether the rejection is based on ‘inherency’ under 35 U.S.C. § 102, on ‘prima facie obviousness’ under 35 U.S.C. § 103, jointly or alternatively, the burden of proof is the same, and its fairness is evidenced by the PTO’s inability to manufacture products or to obtain and compare prior art products. In re Best, 562 F.2d 1252, 1255 (CCPA 1977) (citations and footnote omitted). Appellant has not provided any persuasive evidence that the immunogenic composition suggested by the combination of the cited references, which is identical or substantially identical to the claimed composition, does not necessarily or inherently possess the cross neutralization properties alleged to be possessed by the claimed composition. Appeal 2020-005535 Application 14/783,699 9 Appellant contends that “the problem to be solved is to develop a global HCV vaccine using HCV E1/E2 from the fewest possible different HCV genotypes, where the vaccine would induce neutralizing antibody to the largest number of different HCV genotypes” and that “[t]he cited art does not provide any information as to which E1/E2 genotypes to include and which to exclude in order to solve the problem.” Appeal Br. 13. Accordingly, Appellant contends that the Examiner has not provide a reason for a skilled artisan to combine the cited references in such a way as to arrive at the claimed invention. Id. We are not persuaded. Assuming that the problem the inventor was trying to solve is as described, “[i]n determining whether the subject matter of a patent claim is obvious, neither the particular motivation nor the avowed purpose of the patentee controls. . . . [A]ny need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 419-20 (2007). In this case, the Examiner has articulated a reason for a skilled artisan to arrive at an immunogenic composition comprising the E1, E2, or E1/E2 heterodimeric polypeptides from only HCV genotypes 1, 2, and 3, a pharmaceutically acceptable excipient, and an immune-stimulating amount of an adjuvant, as recited in claim 52, namely to provide a HCV vaccine for populations in Western Europe and North America where HCV genotypes 1, 2, and 3 are the most prevalent types.10 Ans. 6. 10 Appellant contends that the claimed invention is not “merely a ‘substitution of one element for another known in the field to have the same function.’” Appeal Br. 18 (emphasis omitted). We do not find this Appeal 2020-005535 Application 14/783,699 10 Appellant contends that “Alexopoulou does not suggest that one should develop an HCV vaccine only for Western Europe and North America” and the Examiner provides “no rationale” as to why a skilled artisan “would be motivated to develop an HCV vaccine for genotypes prevalent in Western Europe and North America, to the exclusion of genotypes prevalent in the Middle East, Central Africa, and Southern Africa.” Appeal Br. 14-15. We are not persuaded. The Examiner cites to Gersch,11 which supports the Examiner’s position that “it is a common practice in the field of vaccine development to produce multivalent viral vaccines by including antigens from prevalent virus types and excluding non-prevalent types,” as well as the proposition that multiple versions of vaccines may be developed against the same virus to protect different populations. Ans. 17. For example, Gersch teaches that Cervarix™, a currently available HPV vaccine, “protects against HPV16 and 18, the high-risk types associated with 70% of cervical cancer,” while Gardasil™, another available HPV vaccine, “protects against HPV16 and 18 as well as HPV6 and 11, the types responsible for 90% of genital warts.” Gersch 426, left col. Appellant has not provided persuasive evidence to the contrary. argument persuasive, because, as discussed above, the Examiner has articulated a rationale for combining the teachings of the prior art to arrive at the claimed invention. 11 Elizabeth D. Gersch et al., New Approaches to Prophylactic Human Papillomavirus Vaccines for Cervical Cancer Prevention, 17 ANTIVIRAL THERAPY 425 (2012). Appeal 2020-005535 Application 14/783,699 11 In this regard, we acknowledge the declarations Appellant submitted from Drs. Weiner, Palese, Rice, and Houghton.12 The declarations from Drs. Weiner, Palese, and Rice are substantially identical, and state that “[a] goal in developing a vaccine against a virus that comprises multiple genotypes is to include in the vaccine the fewest possible genotypes that would provide protection against the largest number of genotypes”; that development of a vaccine for a such a virus “requires knowledge of cross- neutralization patterns of those genotypes” in order to achieve the goals mentioned above; and that, accordingly, when making a vaccine to such a virus it is necessary to determine “the number of cross-protective serotypes” and not merely “the number and diversity of genotypes.” See, e.g., Weiner Decl. ¶¶ 3-5. The Houghton Declaration similarly states that, “[i]n designing a vaccine, it is vital to determine how many different strains need to be represented in a vaccine in order to protect the global community.” Houghton Decl. ¶ 5. Nevertheless, although these declarations suggest that development of a “global” vaccine is a desirable goal, they do not persuade us that a skilled artisan would not have found it obvious to also develop vaccines that protect against only the most prevalent genotypes of a virus and/or a subset of the global population, or that a skilled artisan would have been motivated to only develop a single, most “optimal” vaccine for any particular virus.13 As our reviewing court has explained, the question in an 12 Declaration of Michael Houghton under 37 C.F.R. § 1.132 (July 11, 2018) (“Houghton Declaration”). 13 Indeed, although Appellant contends that “the data presented in the instant application indicate that, for a global vaccine, one should include HCV E1/E2 of genotypes 1, 2, and 3 . . . and that inclusion of g4, g5, and g6 is not required,” Appeal Br. 25, claim 70 recites a composition comprising E1, Appeal 2020-005535 Application 14/783,699 12 obviousness analysis is “whether there is something in the prior art as a whole to suggest the desirability, and thus the obviousness, of making the combination, not whether there is something in the prior art as a whole to suggest that the combination is the most desirable combination available.” In re Fulton, 391 F.3d 1195, 1200 (Fed. Cir. 2004) (citation omitted). Appellant contends that “[t]he Examiner has engaged in impermissible hindsight reconstruction” and “appears to have selected portions of Alexopoulou and Narahari that fit with the Office Action’s rationale, while ignoring those that do not.” Appeal Br. 14, 22-23. Appellant contends that the cited art in fact teaches away from the claimed invention. Id. at 11-14. We are not persuaded. As the predecessor of our reviewing court has explained: 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 (CCPA 1971). In this case, the Examiner has explained why a skilled artisan would have been motivated to develop the claimed immunogenic composition (i.e., to develop a HCV vaccine against the most prevalent genotypes for use in North America and Western Europe), without taking into account “knowledge gleaned only from applicant’s disclosure.” McLaughlin, 443 F.2d 1395. E2, or E1/E2 heterodimeric polypeptides from only HCV genotypes 1 and 3 (i.e., without polypeptides from genotype 2). Appeal 2020-005535 Application 14/783,699 13 Neither are we persuaded that the Examiner has ignored portions of Alexopoulou and Narahari that do not “fit with the Office Action’s rationale,” or that these references teach away from the claimed invention. Appellant contends that “Alexopoulou states that neutralizing antibody elicited by a specific HCV isolate ‘is isolate-specific and fails to induce a protective immunity against reinfection by heterologous strains” and that, “[t]hus, if anything, Alexopoulou suggests that a vaccine composition should include E1/E2 from all HCV genotypes.” Appeal Br. 11-12. Appellant further contends “Narahari states that the presence of HCV1 and HCV4 in the Indian population is ‘a cause of concern, since these genotypes are relatively resistant to the commonly used interferon therapy’” and that, “[t]hus, if anything, Narahari would suggest that one might want to include E1/E2 of HCV genotype 4 in a vaccine composition” rather than exclude it as required by the claims. Id. at 12. A reference may be said to “teach away” when a skilled artisan, “upon reading the reference, would be discouraged from following the path set out in the reference, or would be led in a direction divergent from the path that was taken by the applicant.” In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994). “[I]n general, a reference will teach away if it suggests that the line of development flowing from the reference’s disclosure is unlikely to be productive of the result sought by the applicant.” Gurley, 27 F.3d at 553. In this case, the passages Appellant cites do not suggest that combining the E1, E2, or E1/E2 heterodimeric polypeptides of only HCV genotypes 1, 2, and 3, together with a pharmaceutically acceptable excipient and an immune-stimulating amount of an adjuvant, would not result in an immunogenic composition against, e.g., the HCV genotypes most prevalent Appeal 2020-005535 Application 14/783,699 14 in Western Europe and North America. Neither do they suggest that any HCV immunogenic composition must contain E1, E2, or E1/E2 heterodimeric polypeptides from other HCV genotypes. See, e.g., In re Fulton, 391 F.3d at 1200 (explaining that obviousness does not require the prior art to suggest that a particular combination is the “most desirable” combination available). Appellant contends that data presented in the application regarding cross neutralization is unexpected and could not have been predicted from the cited prior art. Appeal Br. 8-10, 23. In particular, Appellant contends that “[t]he observation that immunization with HCV E1/E2 of genotype 2 induces neutralizing antibody to HCV of genotype 2 and genotype 6 (and not to HCV of genotype 1, 3, 4, or 5) was unexpected.” Id. at 9. We are not persuaded. As an initial matter, “the burden of showing unexpected results rests on he who asserts them. Thus it is not enough to show that results are obtained which differ from those obtained in the prior art: that difference must be shown to be an unexpected difference.” In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972) (citation omitted). Moreover, “[i]t is well settled that unexpected results must be established by factual evidence. Mere argument or conclusory statements in the specification does not suffice.” In re De Blauwe, 736 F.2d 699, 705 (Fed. Cir. 1984) (citation omitted). Although Appellant repeatedly contends in the Appeal Brief that the cross-neutralization pattern presented in Figures 7a and 7b, particularly the observation that HCV E1/E2 of genotype 2 induces neutralizing antibody to HCV of genotypes 2 and 6 but not HCV of genotype 1, 3, 4, or 5, is unexpected, “[a]ttorney’s argument in a brief cannot take the place of Appeal 2020-005535 Application 14/783,699 15 evidence.” In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974) (citation omitted). Similarly, although we acknowledge that Dr. Houghton states that “[t]he data presented in the instant application showed, for the first time ever,” that “immunization with HCV surface glycoproteins of genotype 2” does not “result in cross-neutralization of genotype 3” and that “[t]hese results were unexpected,” Dr. Houghton provided no explanation as to why the results were unexpected. Accordingly, we decline to give significant weight to this conclusory statement. In re Beattie, 974 F.2d 1309, 1313 (Fed. Cir. 1992) (opinion evidence in declarations has little value without factual support). To the extent Appellant relies on Lanford14 or Alexopoulou in its unexpected results argument, see, e.g., Appeal Br. 11-13, 20, we are also unpersuaded. Lanford teaches that infection with the “whole” HCV of genotype 1 (i.e., “where all viral proteins and mRNAs [of HCV of genotype 1] are presented to the immune system, not just E1/E2”) protected chimpanzees against infection with genotype 4, a mixture of genotypes 2 and 3, and an inoculum containing genotypes 1, 2, 3, and 4. Lanford Declaration15 ¶ 7. Appellant contends that “Lanford provides no information regarding [genotype 6]” and that, moreover, “based on the data presented in Lanford, if anything, one might have expected that E1/E2 of g1 would induce a neutralizing Ab response to g2 and g3,” which “supports the non-obviousness of instant claims.” Appeal Br. 20. 14 Robert E. Lanford et al., Cross-Genotype Immunity to Hepatitis C Virus, 78 J. VIROLOGY 1575-1581 (2004). 15 Declaration of Robert E. Lanford under 37 C.F.R. § 1.132 (July 16, 2018) (“Lanford Declaration”). Appeal 2020-005535 Application 14/783,699 16 Appellant does not explain how Lanford shows that the claimed subject matter - which comprises E1, E2, or E1/E2 heterodimer polypeptides from HCV genotypes 1, 2, and 3 and not simply the polypeptides of HCV genotype 1 - exhibits unexpected results. Neither has Appellant explained why, based on Lanford, a skilled artisan would have expected the E1, E2, or E1/E2 heterodimeric polymer of HCV genotype 1 would induce neutralizing response to HCV genotypes 2 and 3, given that in Lanford all the viral proteins and mRNAs of HCV of genotype 1 are presented to the immune system, not just E1/E2. Finally, Appellant has not shown unexpected results as compared to the closest prior art, whether that closest prior art is Lanford or some other reference. In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) (explaining that, “when unexpected results are used as evidence of nonobviousness, the results must be shown to be unexpected compared with the closest prior art” (citation omitted)). Appellant points out that Alexopoulou teaches that the “neutralizing antibody elicited by a specific HCV isolate, is isolate specific and fails to induce a protective immunity against reinfection by heterologous strains” and that, “[t]hus, if anything, Alexopoulou suggests that a vaccine composition should include E1/E2 from all HCV genotypes.” Appeal Br. 12-13. We have addressed above Appellant’s arguments regarding Alexopoulou’s alleged teaching away. To the extent Appellant also relies on Alexopoulou for unexpected results, we are likewise unpersuaded. Alexopoulou explicitly suggests that “cross-protective immunity against various HCV genotypes . . . could be achieved either by using antigens from highly conserved regions or by including antigens from different Appeal 2020-005535 Application 14/783,699 17 genotypes.” Alexopoulou 268, left column. Thus, Alexopoulou does not suggests that cross-neutralization would be unexpected among different HCV genotypes. Finally, Appellant contends that the claimed invention addresses a long-felt, unmet need. Appeal Br. 23-24. The entirety of Appellant’s arguments consists of the conclusory statement that “[p]ublications by those in the field of HCV vaccine development underscore the fact that there is a long-felt, unmet need for an HCV vaccine,” citations without analysis to three references as examples of such publications, and another conclusory statement that “[t]he instant invention as claimed addresses this need.” Appeal Br. 23-24. To constitute persuasive evidence of nonobviousness, Appellant must, however, submit “actual evidence of long-felt need, as opposed to [simply] argument.” In re Kahn, 441 F.3d 977, 990 (Fed. Cir. 2006). We agree with the Examiner that Appellant has not provided sufficient evidence persuasive of the existence of a long-felt, unmet need that is allegedly satisfied by the claimed invention. Ans. 24. Accordingly, for the reasons discussed above, we affirm the Examiner’s rejection of claim 52 as obvious over the combination of Choo, Houghton, Simmonds, Alexopoulou, and Narahari. Claims 53-86, which are not separately argued, fall with claim 52. Appeal 2020-005535 Application 14/783,699 18 B. Non-statutory obviousness-type double patenting rejection over the ’020 patent in view of Choo, Houghton, Simmons, Alexopoulou, and Narahari (claims 52-86) The Examiner finds that, although claims 52-86 on appeal are not identical to claims 1-3 of the ’020 patent, they are not patentably distinct from each other: Both sets of claims encompass an immunogenic composition comprising an E1 polypeptide and an E2 polypeptide. The differences between the two sets of claims include: (1) the patented claims require specific E1 and E2 polypeptides with membrane spanning regions deleted for secretion while the instant claims are directed to E1 and E2 polypeptides in general (which encompass the E1, E2 polypeptide of the patented claims); and (2) the instant claims require that the immunogenic composition comprises E1/E2 polypeptides from HCV genotypes 1-3. As indicated in the art rejection above, the cited references combined suggest a multivalent vaccine composition comprising E1 /E2 polypeptides from HCV genotypes 1-3. Ans. 8. Appellant makes the same arguments as in the obviousness rejection, contending that claims 1-3 of the ’020 patent does not recite an immunogenic composition comprising all of the recited elements of claim 52 and that, “[a]s set out above, the composition of a global vaccine that would induce neutralizing antibodies to multiple HCV genotypes is not disclosed in, and could not be determined from, the combination of Choo, Houghton, Simmonds, Alexopoulou, and Narahari.” Appeal Br. 27-28. Accordingly, we affirm the Examiner’s rejection of claim 52 on the ground of nonstatutory obviousness-type double patenting for the same reasons already Appeal 2020-005535 Application 14/783,699 19 discussed. Claims 53-86, which are not separately argued, fall with claim 52. CONCLUSION In summary: Claim(s) Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 52-86 103 Choo, Houghton, Simmonds, Alexopoulou, Narahari 52-86 52-86 Nonstatutory Double Patenting: US 6,121,020, Choo, Houghton, Simmonds, Alexopoulou, Narahari 52-86 Overall Outcome 52-86 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). AFFIRMED