The United States of America, as represented by the Secretary, Dept. of Health and Human Services

Patent Trials and Appeals Board

Feb 18, 2022

2021003532 (P.T.A.B. Feb. 18, 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. 15/694,567 09/01/2017 Christopher B. Buck 4239-87376-08 3073 36218 7590 02/18/2022 KLARQUIST SPARKMAN, LLP (OTT-NIH) 121 S.W. SALMON STREET SUITE #1600 PORTLAND, OR 97204-2988 EXAMINER KINSEY WHITE, NICOLE ERIN ART UNIT PAPER NUMBER 1648 NOTIFICATION DATE DELIVERY MODE 02/18/2022 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): docketing@klarquist.com ks-nih@klarquist.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte CHRISTOPHER B. BUCK and DIANA V. PASTRANA Appeal 2021-003532 Application 15/694,567 Technology Center 1600 Before DEBORAH KATZ, ULRIKE W. JENKS, and TAWEN CHANG, Administrative Patent Judges. JENKS, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from Examiner’s decision to reject claims directed to an immunogenic composition. 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(a). Appellant identifies the real party in interest as The United States of America, as represented by the Secretary, Department of Health and Human Services and BioE Holdings Inc. Appeal Br. 2. Appeal 2021-003532 Application 15/694,567 2 STATEMENT OF THE CASE According to the Specification, BKV is a ubiquitous DNA virus and up to 90% of healthy individuals are seropositive. This virus is believed to initiate infection in the urinary tract and then remain latent without disturbing its host, with occasional reactivation in the form of low-level shedding of virions in the urine (viruria). However, in immunocompromised individuals BKV (and the related JC polyomavirus) can cause significant morbidity or even mortality. Spec. 7:23-28. “Polyomavirus-associated pathologies such as PVAN or progressive multifocal leukoencephalopathy (PML) also cause significant morbidity or even mortality in other patients receiving immunosuppressive therapy (for example, for auto-immune disorders [or kidney transplant]).” Spec. 2:12-15. CLAIMED SUBJECT MATTER The claims 1-6, 10-15, and 17-192 are directed to a multivalent BK polyomavirus (BKV) immunogenic composition. Claim 1, reproduced below, is illustrative of the claimed subject matter: 1. A multivalent BK polyomavirus (BKV) immunogenic composition comprising: a virus-like particle comprising at least one BKV serotype IV VP1 polypeptide; a virus-like particle comprising at least one BKV serotype Ib2 VP1 polypeptide; a pharmaceutically acceptable carrier; and an adjuvant. Appeal Br. 12 (Claims Appendix). 2 Claims 20 and 21 are withdrawn from consideration as being directed to a non-elected invention. Non-Final Act. 3. Appeal 2021-003532 Application 15/694,567 3 Claim 11, the only other independent claim, also recites an immunogenic composition but includes sequence identifiers. Id. at 13. REJECTIONS Grounds of rejection before this Panel for review: I. Claims 1, 3-6, 8, 10, 11, 13, 15, and 17-19 under 35 U.S.C. § 103(a) as unpatentable over Franzén,3 in view of Krumbholz,4 Zhong,5 Knowles,6 and Vlastos;7 II. Claim 14 under 35 U.S.C. § 103(a) as unpatentable over Franzén, in view of Krumbholz, Zhong, Knowles, Vlastos, and further in view of Mueller;8 and III. Claims 2 and 12 under 35 U.S.C. § 103(a) as unpatentable over Franzén, in view of Krumbholz, Zhong, Knowles, Vlastos, and further in view of GenBank Accession No. BAG84476 (2008) and GenBank Accession No. BAF03085 (2006). 3 Vlastos Franzén, Murine polyomavirus VP1 virus-like particles as vectors for gene therapy and as vaccines against polyomavirus infection and tumors, Abstract (2004) (“Franzén”). 4 Krumbholz et al., Evolution of four BK virus subtypes, 8 Infection, Genetics and Evolution 632-43 (2008). 5 Zhong et al., Distribution patterns of BK polyomavirus (BKV) subtypes and subgroups in American, European and Asian populations suggest co- migration of BKV and the human race, 90 J. Gen. Virol. 144-152 (2009). 6 Knowles et al., Serological Typing Scheme for BK ... Like Isolates of Human Polyomavirus, 28 J. Med. Virol. 118-123 (1989). 7 Vlastos et al., VP1 Pseudocapsids, But Not a Glutathione-S-Transferase VPl Fusion Protein, Prevent Polyomavirus Infection in a T-Cell Immune Deficient Experimental Mouse Model, 70 J. Med. Virol. 293-300 (2003). 8 Mueller et al., BK-VP3 as a New Target of Cellular Immunity in BK Virus Infection, 91 Transplantation 100-107 (2011). Appeal 2021-003532 Application 15/694,567 4 OPINION I. Obviousness over Franzén, Krumbholz, Zhong, Knowles and Vlastos The issue is whether the preponderance of evidence of record supports Examiner’s conclusion that the claims directed to an immunogenic composition are obvious. A. Finding of Fact FF1. Franzén teaches using “murine polyomavirus VP1 virus-like particles (MPyV-VLPs) . . . as vaccines against both MPyV infection and MPyV induced tumors.” Franzén 1. “[S]ubcutaneus (s.c.) vaccination with MPyV-VLPs induced a complete protection of both normal and T-cell deficient mice against MPyV infection whereas s.c. vaccination with GST-VP1 protected normal mice, but not all (60%) T-cell deficient mice.” Franzén 2. FF2. Krumbholz teaches that “BK viruses (BKV) comprise four subtypes that are distinguishable by serological and molecular methods with the latter indicating up to four subgroups within subtype I.” Krumbholz, Abstract. “Epidemiological studies revealed that up to 90% of the adult population worldwide is seropositive for BKV. . . . Primary BKV infection occurs early in childhood and appears to be asymptomatic.” Id. at 632. Krumbholz teaches that “[t]he late region of the BKV genome codes for the structural proteins VP1, VP2, and VP3 as well as for the agnoprotein (VPx). . . . The major capsid protein VP1 is responsible for the antigenic variability among BKV isolates.” Id. “Subtype I is most prevalent, followed by subtype IV, with subtypes II and III occurring less frequently.” Id. at 635. Krumbholz teaches that the predominant subtype I can be further Appeal 2021-003532 Application 15/694,567 5 divided into subgroups Ia, Ib-1, Ib-2, and Ic, with subgroup Ib widespread in Germany and other European countries. Id. FF3. Zhong teaches that [t]he frequency of subtype I was always the highest throughout the populations, but that of subtype IV was variable among populations. A subgroup of subtype I (I/b- 2) was detected primarily in all of the European and American populations, whereas subgroup I/c was predominant in the Asian populations (the observed difference was statistically significant). Zhong, Abstract. Zhong teaches “[t]he GenBank/EMBL/DDBJ accession numbers for the sequences reported in this paper are AB369087-AB369101 (complete genomes) and AB369216- AB369245 (typing regions).” Id. at 144. “After primary infection in early childhood, BKV persists in individuals throughout their lives . . . ; thus, the current observations suggest that BKV strains accompanied European emigrants to the USA.” Id. at 150-151. FF4. Knowles teaches that Several BK-like isolates were purified and rabbit antisera raised. The isolates were compared with each other and with BK and JC viruses by haemagglutination-inhibition (HI) and by neutralisation. JC virus was serologically distinct, but all the other isolates showed some cross- reactivity. Two subgroups were again evident: GS and PG were with prototype BK in subgroup 1, and MG and IV were in subgroup 2. Knowles, Abstract. FF5. Vlastos teaches that VP1-ps (1 or 10 μg) were administered subcutaneously, alone or together with Freund’s complete and incomplete Appeal 2021-003532 Application 15/694,567 6 adjuvant, to CD4-/-8-/- T-cell deficient or normal C57B1/6 mice on four occasions. . . . Only immunisation with VP1- ps resulted in haemagglutination inhibition. Complete protection against polyomavirus infection in the T-cell deficient context was obtained with VP1-ps, but not with GST-VP1, immunisation using the present vaccination protocol. Vlastos, Abstract. “VP1-ps administered subcutaneously can induce a protective response against a primary polyomavirus infection in both T-cell immune deficient and normal immune contexts.” Vlastos, 299. B. Analysis Examiner finds that Franzén teaches “subcutaneous (s.c.) vaccination with MPyV-VLPs induced complete protection of both normal and T-cell deficient mice against MPyV infection whereas s.c. vaccination with GST- VP1 protected normal mice, but not all (60%) T-cell deficient mice. MPyV- VLPs were also shown to induce antibody titers in normal and T-cell deficient mice.” Non-Final Act. 6; 9 FF1. Examiner acknowledges that Franzén “does not teach that the VP1 capsid proteins are from subtype Ib2 or IVc2.” Non-Final Act. 6. Examiner relies on Krumbholz for teaching that “human BK polyomavirus, subtype I is most prevalent, followed by subtype IV, with subtypes II and III occurring less frequently.” Non-Final Act. 7; FF2. Examiner relies on Zhong for teaching that “subtype I (l/b-2) was detected primarily in all of the European and American populations . . . 9 We have considered, and herein refer to, the Specification of September 1, 2017 (“Spec.”); Non-Final Office Action of June 9, 2020 (“Non-Final Act.”); Appeal Brief of November 9, 2020(“Appeal Br.”); Examiner's Answer of March 12, 2021 (“Answer”); and Reply Brief of May 11, 2021 (“Reply Br.”). An oral hearing was held on January 24, 2022 and a transcript is entered in the record (“Tr.”). Appeal 2021-003532 Application 15/694,567 7 [and] fully sequenced subtype IV isolates from the American and European populations belonged to subgroup IV/c-2.” Non-Final Act. 7. Examiner relies on Zhong for teaching SEQ ID No: 27 (GenBank Accession No. AB369087). Id.; FF3. Examiner concludes that it would be obvious for one of ordinary skill in the art to vaccinate, particularly in America and Europe, with a composition comprising JCV VLPs and VLPs composed of VP1 capsid proteins from human BK polyomavirus serotypes I, II, III and IV, particularly, I/b-2 from serotype I and IV/c-2 from serotype IV. One of ordinary skill in the art would be motivated to do so given the teachings of Vlastos Franzen (BKV and JCV are associated with severe and lethal diseases) and given the findings of Vlastos Franzen (VLPs composed of VP1 protect against polyomavirus infection in mice by inducing antibodies). There would be a reasonable expectation of success given the vaccination data presented by Vlastos Franzen. Non-Final Act. 8 (emphasis added) (footnote omitted). We agree with and adopt the findings concerning the scope and content of the prior art as well as conclusion as set forth in Examiner’s Answer and the Non-Final Office Action. The findings of fact reproduced above are referenced to highlight certain pertinent evidence. Appellant contends that there is no motivation to combine the references as proposed by Examiner. Appeal Br. 4. According to Appellant, they “discovered that renal transplant patients who have serum antibodies capable of neutralizing BKV-I fail to neutralize BKV-IV.” Id. at 5. Appellant contends that “neutralizing titers of ≥40 are considered by the field to correlate with protective responses against viruses.” Id. at 6. Appellant contends that Knowles demonstrates the previously accepted model is that one BKV infection can produce antibodies that can cross- neutralize between all types of BKVs, therefore concluding that there is “no Appeal 2021-003532 Application 15/694,567 8 motivation to include more than one BKV genotype in a vaccine.” Id. (citing Decl.-110). According to Dr. Buck’s declaration it is now been observed that “some individuals who have effective neutralizing antibody responses against BKV-Ib1 remain unable to neutralize BKV-Ib2.” Decl.-1 ¶ 4. Thus, some kidney transplant recipients who lack antibodies capable of neutralizing a specific BKV genotype are at risk for de novo infection. Decl.-1 ¶ 6; see also Tr. 11, 1-3 (Appellant’s counsel emphasized that the inventors “identified a previously unrecognized problem in the field, and as you know, the In re Omeprazole Patent Litigation case, I feel, is directly on point here.”). Appellant contends that the use of capsid polypeptides of BKV-Ib2 and BKV-IV were shown to be effective at inducing high titer are broadly cross-reacting antibodies. “Unexpectedly, this immunogenic composition will be effective even in those individuals known to be seropositive for BKV-1a antibodies.” Appeal Br. 8 (citing Decl.-211 ¶ 6). According to the declarant Dr. Buck, “the unexpected finding [is] that a single-genotype natural BKV infection or a single-genotype vaccine immunogen may not elicit detectable cross-neutralizing antibody responses against noncognate BKV genotypes. This teaching could not have been predicted based on Knowles et al. or any other literature cited in the Office action.” Decl.-2 ¶ 7. As discussed in the “Appeal Brief, prior to the effective filing date of the present application, the field believed that vaccination with a single BKV subtype was sufficient for eliciting an immune response to all subtypes.” 10 Declaration under 37 C.F.R. § 1.132 by Dr. Christopher B. Buck signed November 28, 2016 (“Decl.-1”). 11 Declaration under 37 C.F.R. § 1.132 by Dr. Christopher B. Buck signed March 5, 2020 (“Decl.-2”). Appeal 2021-003532 Application 15/694,567 9 Reply Br. 2-3. Appellant contends that “one of ordinary skill in the art would not have had any motivation to include both BKV IV and BKV I VP1 polypeptides in an immunogenic composition, as it would have been viewed as unnecessary or redundant.” Id. at 3. Appellant contends that the declaration evidence has not been given fair weight by Examiner. Id. at 5. We begin with claim interpretation because before a claim is properly interpreted, its scope cannot be compared to the prior art. We agree with Examiner that the claims are directed to a composition and not “a method of eliciting cross-reactive, neutralizing antibodies.” Ans. 7. In this case, the preamble recites “[a] multivalent BK polyomavirus (BKV) immunogenic composition comprising. . . .” “‘Comprising’ is a term of art used in claim language which means that the named elements are essential, but other elements may be added and still form a construct within the scope of the claim.” Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501 (Fed. Cir. 1997). “In the patent claim context, the term ‘comprising’ is well understood to mean ‘including but not limited to’.” CIAS, Inc. v. Alliance Gaming Corp., 504 F.3d 1356, 1360 (Fed. Cir. 2007). We are not persuaded by Appellant’s contention that Examiner has not articulated a sufficient motivation for concluding that the claims are obvious. “The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). “[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious,” the answer depends on “whether the improvement is more than the predictable use of prior art elements according to their established functions.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 417 (2007). Appeal 2021-003532 Application 15/694,567 10 Examiner finds that Franzén teaches “human polyomaviruses BKV and JCV are associated with severe and lethal diseases in immune deficient individuals and that there are no commonly used vaccines against these human pathogens.” Ans. 6 (emphasis omitted). Examiner explains that it was known that different BKV subtypes are prevalent in different populations. [T]he teachings of Zhong et al. [show] (BKV subtype I is prevalent throughout the world, subtype IV is prevalent in Asia and part of Europe, and subtypes II and III are rare throughout the world), one of ordinary skill in the art desiring to produce a BKV immunogenic composition, particularly for Americans and Europeans, is motivated to include at least BKV types I and IV (the top two prevalent BKV types) in the composition. One of ordinary skill in the art is further motivated to include subtype Ib2, which is the most prevalent in European and American populations, and subtype I/c which is most prevalent in Asian populations. Ans. 9 (emphasis added). It is prima facie obvious to combine two [or more] compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. . . . [T]he idea of combining them flows logically from their having been individually taught in the prior art. In re Kerkhoven, 626 F.2d 846, 850 (CCPA 1980). In other words, knowing that different BKV subtypes are prevalent in different parts of the world, we agree with Examiner’s position that it would have been obvious to combine various subtypes in order to create a composition that will provide broadest immunogenic protection to the patient population receiving the vaccine. We are also not persuaded by Appellant’s contention that Examiner has not given the declarations fair weight. The second declaration by Appeal 2021-003532 Application 15/694,567 11 Dr. Buck explains that, for viruses, neutralizing titers ≥40 correlate with protection from disease. Decl.-2 ¶ 6. Giving this cut-off for neutralizing titers, the declarant Dr. Buck asserts that Knowles teaches “that vaccinating rabbits with a single BKV genotype II immunogen elicits antibody responses that cross-neutralize BKV genotypes I, III, and IV at potentially protective levels.” Id. As Examiner explains, the declaration is not persuasive because its focus on “eliciting cross-reactive, neutralizing antibodies in humans by administering a combination of BKV IV and BKV Ib2 VP1 proteins” when the claims are directed to a composition. Ans. 7. Furthermore, Knowles’ disclosure shows that as expected the best reactivity is always against the isolate to which the antiserum was raised. See Knowles 121-122 (Tables III-V); Ans. 8 “(Table V of Knowles et al. merely shows that different strains/genotypes of BKV can elicit sera that can cross-neutralize other BKV strains/genotypes to varying degrees.”). We not persuaded by Appellant’s contention that one of ordinary skill in the art would not include multiple immunogens or VLPs in the composition, unless they were deemed to be required. Appeal Br. 6-7 (citing Decl.-1 ¶¶8-912); see also Tr. 11, 13-15 (counsel asserting that there is no reason to “incur additional expense, time, effort to make a modification that was - you know, didn’t have a recognized reason to be made”), 17, 6-16, 24:3-5. Even if it is more expensive, time consuming, or incurs greater regulatory hurdles to include multiple immunogens, this does not persuade us that Examiner is in error. As Examiner points out, one of ordinary skill in the art desiring to produce a BKV immunogenic composition, particularly for Americans and 12 We note that the Declaration-1 does not contain paragraphs 8 and 9, but instead lists two paragraphs 6. Appeal 2021-003532 Application 15/694,567 12 Europeans, is motivated to include at least BKV types I and IV (the top two prevalent BKV types [if not all subtypes]) in the composition. One of ordinary skill in the art is further motivated to include subtype Ib2, which is the most prevalent in European and American populations, and subtype I/c which is most prevalent in Asian populations. Ans. 9. Examiner finds, and we agree, that Appellant’s “unexpectedly superior results” argument is not persuasive. Ans. 9; Appeal Br. 7 (“some BKV-Ia/Ib1-neutralizing sera failed to neutralize BKV-Ib2” (citing Decl.-2 ¶¶ 4-5)), see id. at 8 “it is only the present specification that provides the information that a VP1 polypeptide vaccine immunogen based on BKV-Ib2 induces a humoral immune response that is non-equivalent to a BKV-Ia/Ib1 immunogen. These findings are unexpected in light of the high degree of sequence similarity between BKV-Ia/Ib1 and BKV-Ib2 VP1 capsid polypeptides.” The observation that “[n]early every human subject has neutralizing antibodies for BKV-Ib1 . . . [and that] some individuals who have effective neutralizing antibody responses against BKV-Ib1 remain unable to neutralize BKV-Ib2” (Decl.-1 ¶ 4) does not persuade us of any unexpected results for the claimed composition. In formulating the rejection, Examiner relies on including at least those BKV antigens that represent the most prevalent subtypes “to create an immunogenic composition for BKV” effective for a broader population. Ans. 10. As Examiner repeatedly points out, the claims are directed to an immunogenic composition, in a pharmaceutical carrier that can reasonably encompass all BKV VP1 polypeptide subtypes. After all, it is obvious combine multiple compositions each individually known to be effective for the same purpose. Kerkhoven, Appeal 2021-003532 Application 15/694,567 13 626 F.2d at 850; see Knowles 123-124 (Tables III-V showing that the best reactivity is always against the isolate to which the antiserum was raised). Finally, we are not persuaded by Appellant’s contention that In re Omeprazole Patent Litig., 483 F.3d 1364, 1381 (Fed. Cir. 2007), is on point to the facts of the present case. See Tr. 11 (counsel asserting that “it was not obvious because the flaws in the prior art that prompted the modification had not been recognized and so there would have been no reason to modify, even though it could have been done”). Even if the field in the BKV art before the effective filing date of the claimed invention was under the impression that infection with one BKV serotype would provide protection for all known serotypes, this does not persuade us that Examiner erred. We note that the claims recite an immunogenic composition and there is no requirement with regard to any level of protection. Here, Knowles shows that that the best reactivity is always against the isolate to which the antiserum was raised. See Knowles 123-124 (Tables III-V). This provides sufficient motivation to include all known serotypes in a vaccine formulation in order to achieve the broadest protection against BKV for a patient population. See Ans. 8 (citing Krumbholz and Zhang); Non-Final Act. 8. C. Conclusion The preponderance of evidence of record supports Examiner’s conclusion that the subject matter of claim 1 directed to an immunogenic composition is obvious. As Appellant does not argue the claims separately, claims 3-6, 8, 10, 11, 13, 15, and 17-19 fall with claim 1. 37 C.F.R. § 41.37 (c)(1)(iv). Appeal 2021-003532 Application 15/694,567 14 II. Obviousness over Franzén, Krumbholz, Zhong, Knowles Vlastos, and Mueller With respect to this rejection, Appellant relies on the same arguments relied upon with respect to claim 1 discussed in Section I above. Appeal Br. 10 (asserting that Mueller does not remedy the deficiencies of the combination of Franzén, Krumbholz, Zhong, Knowles, and Vlastos). Thus, for the reasons discussed above, we find that the Examiner has established prima facie showing of obviousness with respect to claim 14, which Appellant has failed to rebut. Accordingly, we affirm the rejection of this claim. III. Obviousness over Franzén, Krumbholz, Zhong, Knowles Vlastos, and GenBank Accession No. BAG84476 (2008) and GenBank Accession No. BAF03085 (2006) With respect to this rejection, Appellant relies on the same arguments relied upon with respect to claim 1 discussed in Section I above. Appeal Br. 10 (“The cited GenBank Accession Nos. do not remedy the deficiencies of these references.”). Thus, for the reasons discussed above, we find that the Examiner has established prima facie showing of obviousness with respect to claim 2 and 12, which Appellant has failed to rebut. Accordingly, we affirm the rejection of this claim. CONCLUSION We conclude, considering the totality of the cited evidence and arguments, that the preponderance of the evidence supports Examiner’s conclusion of obviousness with respect to claim 1 (see supra Section I), and Appellant has not provided persuasive rebuttal evidence or evidence of secondary considerations that, when considered together with the evidence of obviousness, shows the claim to be non-obvious. Claims 3-6, 8, 10, 11, Appeal 2021-003532 Application 15/694,567 15 13, 15, and 17-19, which are not separately argued, fall with claim 1. We further affirm the rejections of claims 2, 12, and 14 for the same reasons. DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1, 3-6, 8, 10, 11, 13, 15, 17-19 103 Franzén, Krumbholz, Zhong, Knowles Vlastos, 1, 3-6, 8, 10, 11, 13, 15, 17-19 14 103 Franzén, Krumbholz, Zhong, Knowles Vlastos, Mueller 14 2, 12 103 Franzén, Krumbholz, Zhong, Knowles Vlastos, GenBank Accession No. BAG84476 (2008) and GenBank Accession No. BAF03085 (2006) 2, 12 Overall Outcome 1-6, 8, 10- 15, 17-19 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