University of Florida Research Foundation, Inc

Patent Trials and Appeals Board

Jan 12, 2022

2021004771 (P.T.A.B. Jan. 12, 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. 15/306,163 10/24/2016 Brad E. HOFFMAN U1202.70019US01 1910 23628 7590 01/12/2022 WOLF GREENFIELD & SACKS, P.C. 600 ATLANTIC AVENUE BOSTON, MA 02210-2206 EXAMINER NGUYEN, QUANG ART UNIT PAPER NUMBER 1633 NOTIFICATION DATE DELIVERY MODE 01/12/2022 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): Patents_eOfficeAction@WolfGreenfield.com WGS_eOfficeAction@WolfGreenfield.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte BRAD E. HOFFMAN Appeal 2021-004771 Application 15/306,163 Technology Center 1600 ____________ Before RICHARD M. LEBOVITZ, JEFFREY N. FREDMAN, and ULRIKE W. JENKS, Administrative Patent Judges. JENKS, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s decision to reject claims directed to a recombinant adeno- associated viral (rAAV) particle encoding a full-length myelin 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 University of Florida Research Foundation, Inc. Appeal Br. 3. An oral hearing was held on December 15, 2021 and a transcript is entered into the record. (“Tr.”). Appeal 2021-004771 Application 15/306,163 2 oligodendrocyte glycoprotein (MOG) as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. STATEMENT OF THE CASE Claims 1, 3, 8-12, 20, 22, and 28 are on appeal, and can be found in the Claims Appendix of the Appeal Brief. Claim 1, the sole independent claim, and claims 22 and 28 are reproduced below: 1. A recombinant adeno-associated viral (rAAV) particle comprising a nucleic acid vector, the nucleic acid vector comprising: a polynucleotide that includes a nucleic acid segment that encodes a full-length myelin oligodendrocyte glycoprotein (MOG) operably linked to a hepatocyte-specific promoter, wherein the rAAV particle is an AAV serotype 8 particle, and wherein an infection of hepatocytes by the rAAV particle provides for presentation of the encoded MOG to an immune cell in a manner capable of evading or abrogating a cytotoxic T cell response. 22. The rAAV particle of claim 1, wherein the nucleic acid segment encodes human myelin oligodendrocyte glycoprotein (MOG) comprising the amino acid sequence of SEQ ID NO: 15. 28. A composition comprising the rAAV particle of claim 1 in an amount of at least 1011 vector genomes/ml. Appeal Br. 26-28 (Claims Appendix). REJECTIONS Appellant requests review of the following grounds of rejection made by Examiner: I. Claims 1, 3, 8-12, and 20 under 35 U.S.C. § 103 as obvious Appeal 2021-004771 Application 15/306,163 3 over High2 in view of Luth,3 Kerlero de Rosbo,4 Fissolo,5 and Cooper;6 II. Claim 22 under 35 U.S.C. § 103 as obvious over High in view of Luth, Kerlero de Rosbo, Fissolo, Cooper, and Devaux;7 and III. Claim 28 under 35 U.S.C. § 103 as obvious over High in view of Luth, Kerlero de Rosbo, Fissolo, Cooper, and Boye.8 IV. Claims 1, 3, 8−12, 20, 22, and 28 rejected under 35 U.S.C. § 112(a) first paragraph, as failing to comply with the written description requirement. 2 High et al., US 2003/0130221 A1, pub. July 10, 2003. 3 Luth et al., Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs, The Journal of Clinical Investigation 118 (3403- 3410) (2008). 4 Kerlero de Rosbo et al., Predominance of the autoimmune response to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis: reactivity to the extracellular domain of MOG is directed against three main regions Eur. J. Immunol. 27 (1997). 5 Fissolo et al., Treatment with MOG-DNA vaccines induces CD4+ CD25+FoxP3+ regulatory T cells and up-regulates genes with neuroprotective functions in experimental autoimmune encephalomyelitis, Journal of Neuroinflammation, 139 (2012), http://www.jneuroinflammation.com/content/9/1/139 (last visited Dec. 29, 2021). 6 Cooper et al., Improved Induction of Immune Tolerance to Factor IX by Hepatic AAV-8 Gene Transfer, Human Gene Therapy 20 (767−776) (2009). 7 Devaux et al., WO 95/06727, pub. Mar. 9, 1995. 8 Boye et al., 9,816,108 B2, iss. Nov. 14, 2017. Appeal 2021-004771 Application 15/306,163 4 I.-III. Obviousness over High, Luth, Kerlero de Rosbo, Fissolo, and Cooper The issue is whether the preponderance of evidence of record supports Examiner’s conclusion that the claims directed to a recombinant AAV particle encoding myelin oligodendrocyte glycoprotein (MOG) are obvious based on the combined teachings of the references? And if so, whether Appellant has provided sufficient evidence of secondary considerations that outweighs the conclusion of obviousness. We consider the rejections I.-III. together because they rely on the same underlying references. A. Findings of Fact (FF) FF1. High teaches “a vector and a polynucleotide encoding a therapeutic polypeptide to which the subject is immunologically competent, and administering the composition to the subject, such that the therapeutic polypeptide is expressed selectively in hepatocytes of the subject.” High ¶ 20, see also id. claims 1, 5. The method “can induce immune tolerance to a transgene product in a human without eliciting a medically significant immune response.” Id. ¶ 19, see id. ¶ 39 (“‘tolerance’ connotes a state characterized by the absence of a medically significant immune response, in an immunologically competent subject, to a therapeutic polypeptide.”). FF2. High teaches that “[a] therapeutic polypeptide as described herein can be a biologically active peptide, protein fragment or full-length protein that can bring forth a desired therapeutic response.” Id. ¶ 50. FF3. High teaches that suitable vectors include AAV vectors that “can be produced in a helper virus-free system, are devoid of any viral gene products, and have reduced immunogenicity Appeal 2021-004771 Application 15/306,163 5 compared with other viral vectors.” Id. ¶ 62. High exemplifies the use of AAV-2 vector using “a helper virus-free system, which utilizes two helper plasmids to supply adenoviral gene functions (E2A, E4, and VA) and the AAV2 rep/cap genes.” Id. ¶ 76. The vector was able to provide sustained the expression of hF.IX after administration mice. Id. ¶¶ 84-91 (Example 3). High notes that “C3H mice injected with a higher vector dose (5x1011 vg) continue to express 30-200 ng/ml hF.IX.” Id. ¶ 89. High teaches that higher levels of transgene expression favor tolerance. See id. ¶¶ 92-110 (Example 4). FF4. Cooper teaches induction of immune tolerance to factor IX by hepatic AAV-8 gene transfer. “Compared with AAV-2, AAV-8 was more efficient in transgene expression and induction of tolerance to F.IX in three different strains of wild-type mice. At equal vector doses, AAV-8 induced transgene product-specific regulatory CD4+CD25+FoxP3+T cells at significantly higher frequency.” Cooper, Abstract. Cooper acknowledges that it is not yet been established whether AAV-8 would be superior for immune tolerance induction in humans, but improvements in expression of gene transfers to liver rhesus and cynomolgus macaques have been reported. Id. at 773. “For example, increased transgene expression from the AAV-8 vector correlated with a higher frequency of induced transgene product specific Tregs, supporting the hypothesis that tolerance induction is facilitated by optimal induction of Tregs.” Id. FF5. Luth teaches that “[o]ur findings indicate that autoantigen Appeal 2021-004771 Application 15/306,163 6 expression in the liver may generate autoantigen-specific Tregs. Thus, targeting of autoantigens to hepatocytes may be a novel approach to prevention or treatment of autoimmune diseases.” Luth, abstract. “Expression of the neural autoantigen myelin basic protein (MBP) in the liver was accomplished stably in liver-specific MBP transgenic mice and transiently using gene transfer to liver cells in vivo. Such ectopic MBP expression induced protection from autoimmune neuroinflammation in a mouse model of multiple sclerosis.” Id. “We found that hepatic tolerance induced generation of MBP specific Tregs and protection from EAE. Treg generation was thymus independent, required ectopic expression of MBP in the liver, and occurred by conversion from conventional CD4+CD25-T cells.” Id. at 3404. Luth teaches that “targeting of autoantigen expression to the liver may indeed be an attractive approach to induce active tolerance to autoantigens and protect from autoimmune disease, and the usefulness of this approach to serve as therapy for human autoimmune disease should be explored.” Id. at 3409. FF6. Kerlero de Rosbo teaches that “the autoimmune response to myelin oligodendrocyte glycoprotein (MOG) predominates in MS over that to myelin basic protein (MBP).” Kelero de Rosbo, abstract, see also id. at 3066 (“the predominance of auto reactivity to MOG in MS, thereby showing unequivocally that the autoimmune response to MOG has a prevalent role in the pathogenesis of the disease”). “One such CNS- specific myelin component, myelin oligodendrocyte glycoprotein (MOG), as in the last few years attracted a lot of interest as a possible Appeal 2021-004771 Application 15/306,163 7 primary target antigen in MS.” Id. at 3060. Kerlero de Rosbo teaches that “MOG-reactive T cells themselves can transfer disease to naïve syngeneic recipients.” Id. FF7. Kerlero de Rosbo teaches that experimental autoimmune encephalomyelitis (EAE) is a well-known and well-accepted model for studying MS. Id. at 3059. FF8. Fissolo teaches using MOG-DNA vaccines to induce CD4+CD25+FoxP3+ regulatory T cells. Fissolo, Title. “[B]y treating EAE mice with a DNA vaccine encoding the oligodendrocyte glycoprotein (MOG), and exploring the therapeutic effects on the disease-induced inflammatory and neurodegenerative changes.” Fissolo, Abstract. Fissolo teaches that “a DNA vaccine encoding the myelin oligodendrocyte glycoprotein (MOG) induces immune regulation and efficiently suppresses experimental autoimmune encephalomyelitis (EAE) in both prophylactic and therapeutic settings.” Id. at 2. Specifically, Fissolo teaches that “[f]or prophylactic treatment, 100 μg DNA/mouse in phosphate-buffered saline (PBS) was injected intramuscularly in the tibialis anterior muscle at 28 and 14 days before EAE induction. For therapeutic: treatment, mice received intramuscular (i.m.) injections of DNA (100 μg/mouse) at days 10 and 24 postimmunization (p.i.).” Id. at 2. FF9. Fissolo’s Figures 1A-1C, repoduced below show the effect of prophylactic treatment with DNA vaccine. Appeal 2021-004771 Application 15/306,163 8 Figure 1A-1C, shows prophylactic of EAE with MOG-DNA vaccination ameliorates the clinical signs of the disease. Fissolo 4. EAE was induced in female C57BL6/J mice with MOG35-55 peptide in CFA. Mice were vaccinated with i.m. injections of 100 μg of DNA according to prophylactic (A) protocols. Two groups of mice (n = 5) were subjected to DNA treatment with the full-length MOG-DNA construct (□) or plasmid control (■) in prophylactic (B) settings. Disease parameters in mice treated prophylactically are shown in table (C). Mean clinical scores Appeal 2021-004771 Application 15/306,163 9 are plotted against the number of days after EAE induction. Disease scores are expressed as mean values (SEM). Indicates cumulative disease scores at 30 days p.i.; statistically significant differences obtained by Student’s t-tests. Fissolo 4. FF10. Fissolo’s Figures 1D-1F, reproduced below, show the effect of therapeutic treatment with DNA vaccine. Figure 1D-1F shows therapeutic treatment of EAE with MOG- DNA vaccination ameliorates the clinical signs of the disease. EAE was induced in female C57BL6/J mice with MOG35-55 Appeal 2021-004771 Application 15/306,163 10 peptide in CFA. Mice were vaccinated with i.m. injections of 100 μg of DNA according to therapeutic (D) protocols. Two groups of mice (n = 5) were subjected to DNA treatment with the full-length MOG-DNA construct (□) or plasmid control (■) in therapeutic (E) settings. Disease parameters in mice treated therapeutically are shown in table (F). Mean clinical scores are plotted against the number of days after EAE induction. Disease scores are expressed as mean values (SEM) indicates cumulative disease scores at 30 days p.i.; statistically significant differences obtained by Student’s t-tests. FF11. Devaux teaches “the complete nucleotide sequence (SEQ ID NO:1) and deduced amino acid sequence (SEQ ID NO: 2) of DNA encoding human MOG protein. Devaux 4:10-11, see id. 32-34 (Sequence Listing). FF12. Examiner finds that: Devaux et al already disclosed a nucleic acid molecule having a nucleotide sequence encoding human MOG, an autoantigen related to demyelinating autoimmune diseases, having SEQ ID NO: 2 that is 100% identical to the sequence of SEQ ID NO: 15 of the present application for preparation of recombinant human MOG and/or antigenic fragments that are useful in the treatment of autoimmune diseases (see at least the abstract; SEQ ID NOs. 1-2; and attached sequence search). Final Act. 14. FF13. Boye teaches using AAV mediated gene therapy for restoring visual function. “[T]iters were 4.69x1012 viral genomes per mL (vg/mL) and 4.12x1013 vg/mL for AAV5-smCBAmGC1 Appeal 2021-004771 Application 15/306,163 11 andAAV5-hGRK1-mGC1.” Boye 37:35-37, see also id. at 48:50-52 (expressing viral titer in vg/ml) B. Analysis Examiner finds that High teaches hepatic/liver-directed expression of therapeutic genes that induces immunological tolerance to the expression product of the therapeutic gene. Final Act. 7; FF1-FF3. Examiner finds that High teaches competent AAV vector/particles comprising a transgene operably linked to a liver-specific promoter. Final Act. 7; FF1. Examiner finds that the therapeutic polypeptide can be any polypeptide or protein that can elicit a desired therapeutic effect. Final Act. 7; FF2. Examiner acknowledges that High does not teach using a recombinant AAV-8 vector/particle, or that the therapeutic transgene encodes myelin oligodendrocyte glycoprotein (MOG) that is operably linked to a hepatocyte- specific promoter. Final Act. 8; FF3. Examiner relies on Cooper for teaching an AAV-8 vector system that has been shown to be more efficient for transgene expression and induction of tolerance than AAV-2. Final Act. 10; FF4. Based on the combination of High and Cooper, Examiner concludes that one of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to utilize AAV-8 particles for the expression of a transgene because Cooper teaches that transgene expression using AAV-8 particles provides an even distribution for the expression of the transgene. Final Act. 11. Examiner relies on Luth for teaching the expression of neural autoantigens in the liver. Specifically, Examiner finds that Luth: already demonstrated that ectopic expression of neural Appeal 2021-004771 Application 15/306,163 12 autoantigen myelin basic protein (MBP) in a transgenic mouse liver suppresses experimental autoimmune neuroinflammation in a mouse model for the human neuroinflammatory disease multiple sclerosis EAE by inducing MBP-specific CD4+CD25+Foxp3+ Tregs which are important mediators of immune tolerance to self-antigens and Treg inactivation may cause autoimmune disease. Final Act. 11 (emphasis removed); see FF5. Luth suggests that “targeting of autoantigen expression to the liver may indeed be an attractive approach to induce active tolerance to autoantigens and protect from autoimmune disease, and the usefulness of this approach to serve as therapy for human autoimmune disease should be explored.” FF5; Final Act. 9. Examiner looks to Kerlero de Rosbo for teaching an autoimmune response to myelin oligodendrocyte glycoprotein (MOG) in patients having multiple sclerosis (MS). Final Act. 9-10. Kerlero de Rosbo teaches that experimental autoimmune encephalomyelitis (EAE) is a well-accepted model for studying MS. FF7. Examiner relies on Fissolo for teaching the use of MOG-DNA vaccines to induce regulatory T cells and to protect against EAE induction. Final Act. 10; FF8-FF10. Examiner concludes that based on the combined teachings it would have been obvious as to prepare: a recombinant AAV-8 vector/particle comprising at least a therapeutic transgene encoding a full-length myelin oligodendrocyte glycoprotein (MOG) operably linked to a liver- specific/hepatocyte-specific promoter for inducing immunological tolerance at least to MOG and/or for inducing MOG-specific CD4+CD25+FoxP3+ Tregs in the liver to suppress autoimmune neuroinflammation associated with MS in a patient, as well as the same modified recombinant AAV vector that further comprises a second therapeutic trans gene encoding myelin basic protein (MBP). . . . Final Act. 11. Appeal 2021-004771 Application 15/306,163 13 We agree with Examiner’s fact finding, statement of the rejection and responses to Appellant’s arguments as set forth in the Final Office Action and Answer. The findings of fact reproduced above are referenced to highlight certain pertinent evidence. We find that Examiner has provided evidence to support a prima facie case of obviousness. If we do not mention specifically separately argued claims below, we agree with and adopt Examiner’s conclusions with respect to those claims. We provide the following additional comment to arguments set forth in the Appeal Brief. 1. Claim 1 (a) Claim interpretation We begin with claim interpretation, because before a claim is properly interpreted, its scope cannot be compared to the prior art. Claim 1 is directed a product, specifically, a recombinant adeno- associated viral (rAAV) particle comprising a nucleic acid of interest. The claim describes the product as having the following structural features: (1) a polynucleotide that includes a nucleic acid segment that encodes a full- length myelin oligodendrocyte glycoprotein (MOG), (2) a hepatocyte- specific promoter, and (3) an rAAV particle that is an AAV-8 serotype particle. The claim further requires that the polynucleotide and the hepatocyte-specific promoter are operably linked. We interpret “operably linked” to mean that the promoter can drive the transcription of the MOG nucleic acid into mRNA that is translated into a MOG protein. Because the claim explains that the promoter has to be hepatocyte-specific promoter the transcription would, therefore, only occur if the AAV particle infects liver cells. Appeal 2021-004771 Application 15/306,163 14 Finally, the claim also includes the following wherein clause: “wherein an infection of hepatocytes by the rAAV particle provides for presentation of the encoded MOG to an immune cell in a manner capable of evading or abrogating a cytotoxic T cell response.” The wherein clause requires that the AAV particle having the recited structural features achieves the stated function once the AAV particle infects hepatic cells. “[T]he patentability of apparatus or composition claims depends on the claimed structure, not on the use or purpose of that structure.” Catalina Mktg. Int’l, Inc. v. Coolsavings.com, Inc., 289 F.3d 801, 809 (Fed. Cir. 2002). Merely stating an intended use is not sufficient to structurally distinguish from the prior art. In re Sinex, 309 F.2d 488, 492 (CCPA 1962). A “mere statement of a new use for an otherwise old or obvious composition cannot render a claim to the composition patentable.” In re Zierden, 411 F.2d 1325, 1328 (CCPA 1969). The wherein clause, therefore, is interpreted to be a functional limitation that does not provide further structural details and merely explains how the vector functions when placed into the requisite environment. The structural limitations of the claim include a MOG encoding polynucleotide linked to a hepatic-specific promoter packaged into an AAV-8 particle. Thus, if there is a reason to arrive at the structural limitations of the claim, then the recited functional limitation is necessarily present as well. (b) Lacks reasonable expectation of success Appellant contends that the combination as articulated by Examiner lacks a reasonable expectation of success. See Appeal Br. 11-13. Specifically, Appellant contends that Examiner is dismissing the weight of Appeal 2021-004771 Application 15/306,163 15 Manno,9 Wang,10 and Mingozzi11 cited by Appellant for the position that generic references about AAV vectors says nothing specifically about AAV- mediated hepatic gene therapy. Id. at 12. Appellant contends that Mingozzi specifically casts doubt on the success of AAV-8 therapies. Id. at 13. We are not persuaded by Appellant’s arguments. “Obviousness does not require absolute predictability of success . . . all that is required is a reasonable expectation of success.” In re Droge, 695 F.3d 1334, 1338 (Fed. Cir. 2012) (quoting In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009) (citing In re O’Farrell, 853 F.2d 894, 903-04 (Fed.Cir. 1988)). As Examiner explains, and we agree (see above I.B.1.a), that the claims are directed to a product. Specifically, Examiner finds that the instant claims are directed to a rAAV-8 particle that contains a full-length myelin oligodendrocyte glycoprotein (MOG) operably linked to hepatocyte specific promoter for presentation to the immune cells. Ans. 4. Whatever “cytotoxic T cell response [is] to be eluded or abrogated is one that is directed to [the property of] an encoded MOG that is presented by infected hepatocytes.” Id. In other words, it is a property of the MOG protein when presented by hepatocytes that produces the response of “evading or abrogating a cytotoxic T cell response” as recited in the claim. 9 Manno et al., Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response, 12 Nature Medicine (342-347) (2006), submitted with Supplemental Declaration. 10 Wang et al, Adeno-associated virus vector as platform for gene therapy delivery, 18 Nature Reviews (358-378) (2019), submitted with Supplemental Declaration. 11 Mingozzi et al., CD8+ T-cell responses to adeno-associated virus capsid in humans, 13 Nature Medicine (419-422) (2007), submitted with Supplemental Declaration. Appeal 2021-004771 Application 15/306,163 16 As Examiner notes, there are no limitations in the claim that the product is actually administered to a particular host. Please note that the claimed rAAVS particle with the functional language “wherein an infection of hepatocytes by the rAAV provides for presentation of the encoded MOG to an immune cell in a manner capable of evading or abrogating a cytotoxic T cell response” can be used in a mammal such as mice and dogs, and not necessarily limited to human subjects, let alone human subjects already exposed to previous AAV infections and harboring memory T cells to AAVs. Ans. 6. “Moreover, the functional language for the claimed rAAV8 particle simply requires the cytotoxic T cell response to be eluded or abrogated is one that is directed to an encoded MOG that is presented by infected hepatocytes, and not to adeno-associated virus capsid protein.” Id. at 7. We determine that Examiner has sufficiently articulated why there is a reasonable expectation of successfully producing a recombinant AAV particle as claimed. See Final Act. 6-15; Ans. 3-14; FF1-FF13. We are not persuaded by Appellant’s contention that Wang, Manno, and Mingozzi support the position that the rejection as articulated by Examiner lacks a reasonable expectation of success. Wang teaches that rAAVs are a favorable vector for gene therapy, but because they persist as non-replicating episomes they are gradually lost in mitotic cells. Wang, 365. Manno also supports the position that rAAV-2 vectors can transduce human hepatocytes but it is not clear how long the expression lasts in this system. See Manno, Abstract. Mingozzi’s teaching that “[h]epatic adeno-associated virus (AAV)- serotype 2 mediated gene transfer results in transgene product expression that is sustained in experimental animals but not in human subjects” (Mingozzi, Abstract) does not teach away from the presently claimed Appeal 2021-004771 Application 15/306,163 17 product. All that Mingozzi suggests is that the AAV-2 serotype may not be an ideal platform for human administration of a transgene. Furthermore, the claims are directed to an AAV-8 serotype and not an AAV-2 serotype. Therefore, arguments that the AAV-2 serotype might not be an ideal gene transfer tool does not persuade us that Examiner erred. Examiner relies on Cooper for teaching that AAV-8 vectors show increased transgene expression that “correlated with a higher frequency of induced transgene product specific Tregs, supporting the hypothesis that tolerance induction is facilitated by optimal induction of Tregs.” FF4. Thus, Examiner has good reason why the ordinary artisan would have chosen to replace the AAV-2 vector with the AAV-8 vector. Accordingly, we are not persuaded by Appellant’s contention that Mingozzi’s teaching with respect to AAV-2 supports a position that there is no reasonable expectation of success in arriving at the instantly claimed AAV-8 product. (c) Hindsight We are not persuaded by Appellant’s contention that “Examiner has engaged in a hindsight reconstruction of the claims from an unusually high number of references.” Appeal Br. 8. “The criterion . . . is not the number of references, but what they would have meant to a person of ordinary skill in the field of the invention.” In re Gorman, 933 F.2d 982, 986 (Fed. Cir. 1991) (The use thirteen references to support obviousness rejection does not of itself weigh against conclusion of obviousness). Examiner’s cited references describe using recombinant AAV to target expression of a transgene in the liver while other references discuss expression of certain neuronal proteins as a target for treating MS. See Ans. 3-14; FF1-FF10. Appellant has not directed us to information that could only have been gleaned from Appeal 2021-004771 Application 15/306,163 18 Appellant’s disclosure and would have been necessary to arrive at a conclusion of obviousness. See In re McLaughlin, 443 F.2d 1392, 1395 (CCPA 1971). Accordingly, we are not persuaded by Appellant’s contention that Examiner’s rejection is based on hindsight. (d) Inherency Appellant contends that Examiner’s prima facie case relies on conclusory assertions, and that Examiner’s reliance on inherency based on In re Best is in error. Appeal Br. 10. “No court or tribunal of which Appellant is aware has extended the principle of inherent disclosure to an obviousness rejection that relies on more than three references.” Id. at 11. Appellant contends that they have made a showing by a preponderance of the evidence that one of ordinary skill in the art would have had no reasonable expectation that the alleged prior art composition exhibits this property. Id. (citing Ex Parte Kodas, No. 2017-008945, 2018 WL 4333780, at *7 (P.T.A.B. Aug. 21, 2018) (citing In re Best); see also Honeywell Int'l. v. Mexichem Amanco Holding, 865 F.3d 1348, 1355 (Fed. Cir. 2017) (“What is important regarding properties that may be inherent, but unknown, is whether they are unexpected. All properties of a composition are inherent in that composition, but unexpected properties may cause what may appear to be an obvious composition to be nonobvious.”). We are not persuaded by Appellant’s contention. The issue is whether the property “of evading or abrogating a cytotoxic T cell response” is an unexpected property or merely a by-product of expressing the MOG in hepatic cells. Examiner finds, and we agree, that the combined references would result in a modified recombinant AAV-8 particle encoding full-length MOG that would be structurally indistinguishable from the claimed particle Appeal 2021-004771 Application 15/306,163 19 and thereby would have the same recited property once administered to a patient. Ans. 12. Administering the same composition to the same patient population, including animals, would result in the same presentation of the MOG polypeptide to the immune system. Where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, 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 (C.C.P.A. 1977). Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Prindle, 297 F.2d 251, 254 (CCPA 1962). Here, Examiner explains that: High et al already taught clearly that hepatic/liver-directed expression of a therapeutic transgene induces immunological tolerance (e.g., at the T helper cell level) to the expression product of the therapeutic transgene and it is not broken by challenge, along with a sustained transgene expression in different murine strains without eliciting a neutralizing antibody response; and Luth et al also demonstrated that ectopic expression of neural autoantigen myelin basic protein (MBP) in a transgenic mouse liver suppresses experimental autoimmune neuroinflammation in a mouse model for the human neuroinflammatory disease multiple sclerosis EAE by inducing MBP-specific CD4+CD25+Foxp3+ Tregs which are important mediators of immune tolerance to self-antigens. Ans. 12; see FF1-FF10. We agree with Examiner’s conclusion that expressing MOG in the liver would result in the property “of evading or Appeal 2021-004771 Application 15/306,163 20 abrogating a cytotoxic T cell response” because this is not an unexpected property but rather property of expressing the same protein in the same environment. Appellant has not provided evidence to show that the rAAV particles as articulated by Examiner based on the combination of references are structurally different from the claimed AAV particle. Indeed, Appellant has not provided evidence that expression of MOG in an AAV-8 vectors would fail to result in evading the T-cell response. In contrast, Examiner points to Fissolo as evidencing that an entirely different system expressing MOG suppresses this response. FF8-FF10. The evidence favors the Examiner’s position. Accordingly, we are not persuaded by Appellant’s contention that Examiner’s reliance on inherency is improper. (e) Unexpected results We are not persuaded by Appellant’s contention that “none of the cited references teaches or suggests the evasion of a CTL response, as claimed.” Appeal Br. 8. Appellant contends that Examiner has refused to consider evidence of unexpected results. Id. at 16. “The First Declaration provides experimental data indicating that the claimed rAAV particle may neutralize epitope spreading without provoking an adverse response.” Id. Furthermore, the “Supplemental Declaration (see infra at 18) demonstrates that a single administration of rAAV8-MOG provided efficacy in multiple genetically diverse strains of mice.” Id. Appellant contends that “[t]hroughout prosecution, the Examiner has miscast the proffered objective evidence as relating to specific applications and methods of the claimed composition, rather than composition itself.” Id. at 17. Appellant is arguing functional limitations of the product claim. As discussed above (I.B.1.a), we do not interpret the last wherein clause of the Appeal 2021-004771 Application 15/306,163 21 claim to recite any structural features. Instead, the last wherein clause of the claim describes the function after the vector particle infects a patient’s hepatocyte. We agree with Examiner that the combined references suggest producing a rAAV vector that encodes a transgene for expression in hepatic cells by including a hepatocyte specific promoter linked to the transgene. See Ans. 3-14; FF1-FF10. As Examiner explains, the AAV-8 particle constructed based on the cited references is structurally indistinguishable from the recombinant particle of the present application. Ans. 5, 12. Thus, the particle would necessarily possess the same recited property upon infection of hepatocytes. Ans. 5 (citing In re Best, Bolton, and Shaw, 562 F.2d 1252, 1255 (CCPA 1977); In re Brown, 459 F.2d 531, 535 (CCPA 1972) (“As a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith.”). We find that Examiner has directed us to sufficient teachings in the references to support the expression of neural autoantigens such as myelin basic protein (MBP) as well as myelin oligodendrocyte glycoprotein (MOG) in the liver. See FF5-FF10. The combination as relied on by Examiner starts with High’s teaching of targeting transgene expression to liver cells using rAAV and this is further supported by Luth’s teaching that transgene expression of autoantigens in liver is beneficial. See FF1-FF3, FF5. These teachings when combined with Fissolo teaching that DNA vaccines to MOG are effective not only for prophylactic applications but also for treatment applications in an animal model of multiple sclerosis further support Examiner’s conclusion that one of ordinary skill in the art would have been Appeal 2021-004771 Application 15/306,163 22 motivated to insert MOG encoding nucleic acid into an AAV expression system. FF1-FF10. Accordingly, we agree with Examiner that the combined references are sufficient to suggest the production of an identical recombinant AAV particle as claimed. See Ans. 5. The immunological properties associated with the claimed particle are not unexpected, aside from any arguments regarding inherency. Luth specifically suggests that “targeting of autoantigen expression to the liver may indeed be an attractive approach to induce active tolerance to autoantigens and protect from autoimmune disease, and the usefulness of this approach to serve as therapy for human autoimmune disease should be explored.” FF5. When Luth’s suggestion that expressing autoantigens in the liver is combined with the teachings Fissolo that suggests MOG expression using a DNA vaccine leads to prophylactic as well as therapeutic treatments in a multiple sclerosis model the reasonable conclusion is that expression of MOG protein in the liver would be beneficial for developing tolerance. See FF5, FF8-FF10. We are also not persuaded by Appellant’s contention that the evidence provided in the declarations is sufficient to overcome Examiner’s strong prima facie case of obviousness of the product. As Examiner notes, and we agree, that the examined claims are not method claims. See Ans. 11. A showing that AAV-MOG provides prophylactic or therapeutic treatment with the administration of only a single dose of the AAV construct is not sufficiently persuasive to establish unexpected results with respect to the claimed AAV particle. See First Declaration ¶¶ 13-16, see also id. Appendix B; Supplemental Dec. ¶¶6-11, see also id. Appendix A. Appeal 2021-004771 Application 15/306,163 23 Contrary to Appellant’s contentions, the induction of treatment or prophylaxis using MOG-DNA is not unexpected. Fissolo suggests achieving prophylactic or therapeutic treatment of EAE using a MOG-DNA vaccine. FF9-FF10. Admittedly, Fissolo’s DNA vaccine is administered twice, at 28 and 14 days, prior to EAE induction or at 10 and 24 days after EAE induction. FF9-FF10. Fissolo’s MOG-DNA vaccine encodes the same full- length MOG but is missing the recombinant AAV construct as well as the hepatic promoter. Luth teaches that transient expression of myelin basic protein (MBP) using adenoviral gene transfer for expressing MBP suppressed EAE induction and mice. FF5; Luth 3404 (Figure 1), see also id. at 3409 (“even transient hepatic expression of autoantigen induced robust control of autoreactive lymphocytes (Figure 1, F and G)”). Thus, based on the prior art teachings, we find there is nothing surprising with respect expressing MOG-DNA for the treatment of prophylaxis of EAE. Because the claims are not directed to a method of using the rAAV particle, we agree with Examiner that the discussion in the Declarations of a single dose protocol versus a multi-dose protocol is not sufficient to overcome the obviousness rejection is articulated by Examiner that is directed to the rAAV particle. See Ans. 11-12. Here, there is a strong prima facie case of obviousness based on the combined references as articulated by Examiner in the Final Office action and Answer. Appellant adduces no persuasive evidence to demonstrate that the allegedly unexpected and beneficial properties of their composition would have been unexpected and different in kind from those properties of compositions taught by the prior art. See Iron Grip Barbell Co. v. USA Sports, Inc., 392 F.3d 1317, 1322 (Fed. Cir. 2004) (holding that unexpected results that are probative of Appeal 2021-004771 Application 15/306,163 24 nonobviousness are those that are “different in kind and not merely in degree from the results of the prior art”). (f) Industry praise Appellant contends that Examiner is ignoring the proffered evidence of industry praise for the invention. Appeal Br. 14. “In particular, the First Declaration establishes industry praise of the invention in a commentary in a neurology medical publication.” Id. at 15 (citing first declaration paragraph 18 (“for example, in a recently published commentary, “experts praise the results” published in Keeler.”); Reply Br. 3; First Declaration ¶ 19 (“For example, Dr. Bellur Prabhakar, head of the department of microbiology and immunology at the University of Illinois, stated, ‘The findings in this study are quite exciting . . . [and] very encouraging.’”). There are numerous cases in which objective considerations of nonobviousness, including unexpected results, substantial evidence of commercial success, praise, copying, and licensing were inadequate to overcome a strong case of prima facie obviousness. See e.g., Leapfrog Enters. Inc. v. Fisher-Price, Inc., 485 F.3d 1157, 1162 (Fed. Cir. 2007); Iron Grip Barbell Co., Inc. v. USA Sports, Inc., 392 F.3d 1317, 1324 (Fed. Cir. 2004); Richardson-Vicks Inc. v. Upjohn Co., 122 F.3d 1476, 1483-1484 (Fed. Cir. 1997); Asyst Techs., Inc. v. Emtrak, Inc., 544 F.3d 1310, 1316 (Fed. Cir. 2008) (“[E]vidence of secondary considerations does not always overcome a strong prima facie showing of obviousness.”). Appeal 2021-004771 Application 15/306,163 25 Here, the recognition of the inventor’s work in a publication (see First Dec. ¶¶ 17-18 (citing Robinson12) and encouraging words by Dr. Bellur Prabhakar (see First Dec. ¶¶ 19-20) does not convince us of industry praise. Indeed, we note that in Robinson the positive commentary is also attributed to Dr. Prabhakar. Robinson, however, also cites commentary by Dr. Hafler, another expert in the field, who questions the fundamental role of MOG in human MS, and finds that even if MOG is relevant “it’s not clear that a virally delivered gene for a self-antigen to induce tolerance is likely to find clinical utility.” Robinson. It is also not apparent that Dr. Prabhakar considered all the evidence provided by Examiner before providing their opinion. On balance, therefore, we are not persuaded that encouraging words by a single expert in the field is sufficiently convincing evidence of industry praise to overcome Examiner’s strong prima facie case of obviousness with respect to the claimed product. 2. Claims 10 and 11 Appellant contends that Examiner fails to articulate any rationales underpinning and motivation to combine the references in order to arrive at recombinant AAV particles that encodes two distinct therapeutic molecules. Appeal Br. 21. We are not persuaded by Appellant’s contention. Examiner is relying on the teachings of High for expressing “[t]he polynucleotide encoding one or more proteins of interest can be operatively associated with a variety of different promoter/regulator sequences.” Final Act. 3 (emphasis omitted) 12 Robinson, Inducing Tolerance to a Myelin Protein Reverses MS Symptoms in a Mouse Model. Will the Gene Therapy Translate to Human Trials? NeurologyToday (2019), submitted with the First Declaration. Appeal 2021-004771 Application 15/306,163 26 (citing High ¶ 57 (“The polynucleotide encoding one or more proteins of interest can be operatively associated with a variety of different promoter/regulator sequences”)); Ans. 13. Particularly the primary High reference already taught the polynucleotide encoding one or more proteins of interest, coupled with the successful demonstration by Luth et al that ectopic MBP (myelin basic protein) expression in the liver in the form of MBP-encoding vector and/or adenoviral gene transfer of MBP suppresses experimental autoimmune encephalomyelitis (EAE) along with the Kerlero de Rosbo reference disclosing and suggesting a prevalent role for the autoimmune response to MOG (myelin oligodendrocyte glycoprotein) in the pathogenesis of MS (multiple sclerosis) and Fissolo’s showing that vaccination with DNA encoding MBP was also associated with a significant reduction in EAE disease severity, although to a lesser degree compared with MOG-encoding DNA vaccines. Ans. 13-14 (emphasis omitted). We agree with Examiner that based on the combined teachings in the references it would have been obvious to include multiple target proteins associated with the autoimmune response in multiple sclerosis (FF6) and there would have been reasonable expectation that the proteins would be successfully expressed using an AAV construct. See FF1- FF10; see Droge, 695 F.3d at 1338 (absolute predictability of success is not required only reasonable expectation is needed for a finding of obviousness). 3. Claim 20 Appellant contends that Examiner fails to articulate rationales underpinning the motivation to arrive at nucleic acid segments that encode two therapeutic molecules. Appeal Br. 21. For the reasons discussed above, with respect to claims 10 and 11, we are not persuaded by Appellant’s contention that Examiner has failed to articulate a sufficient rationale that the claims are rendered obvious. Appeal 2021-004771 Application 15/306,163 27 4. Claim 28 Appellant contends that the teachings of Boye fails to remedy the deficiencies of the other references. Appeal Br. 22. We are not persuaded by Appellant’s contention that Examiner has failed to articulate a sufficient rationale to support a conclusion of obviousness. Having found no deficiency based on the combination of High, Luth, Kerlero, de Rosbo, Fissolo, and Cooper (see above I.B.1) with respect to the limitations of claim 1, we are not persuaded by Appellant’s contention that Boye is insufficient to reach the vector particle titers as recited in claim 28. Examiner relies on Boye for teaching the application of certain AAV titers for therapeutic purposes. See FF13. We agree with Examiner that AAV titers would be recognized as a result effective variable that may be adjusted to within the claimed range of in order to achieve optimal levels of expression of the therapeutic protein from the AAV particle construct. See Ans. 16-17; In re Applied Materials, Inc., 692 F.3d 1289, 1295 (Fed. Cir. 2012) (overlap of prior art range with claimed range “provides sufficient motivation to optimize the ranges”); In re Boesch, 617 F.2d 272, 276 (CCPA 1980) (“discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art”). IV. Written description (new matter) Appellant disagrees with the rejection but does not argue the merits of the rejection, instead Appellant notes proposed amendments to overcome the new matter rejection. Appeal Br. 24 (If prosecution is reopened, Appellant will make this amendment to place these claims in better position for allowance.”). We therefore summarily affirm this rejection. See MPEP § 1205.02 (“If a ground of rejection stated by the examiner is not addressed Appeal 2021-004771 Application 15/306,163 28 in the appellant’s brief, appellant has waived any challenge to that ground of rejection and the Board may summarily sustain it, unless the examiner subsequently withdrew the rejection in the examiner’s answer.”). DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1, 3, 8-12, 20 103 High, Luth, Kerlero de Rosbo, Fissolo, Cooper 1, 3, 8-12, 20 22 103 High, Luth, Kerlero de Rosbo, Fissolo, Cooper, Devaux 22 28 103 High, Luth, Kerlero de Rosbo, Fissolo, Cooper, Boye 28 1, 3, 8−12, 20, 22, 28 112 Written Description 1, 3, 8−12, 20, 22, 28 Overall Outcome 1, 3, 8-12, 20, 22, 28 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). AFFIRMED