Beijing Advanccine Biotechnology Co., Ltd,

Patent Trials and Appeals Board

Feb 24, 2022

2020006741 (P.T.A.B. Feb. 24, 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. 14/394,051 12/08/2014 Bin Wang 3725118.00002 1021 24573 7590 02/24/2022 K&L Gates LLP-Chicago P.O. Box 1135 Chicago, IL 60690 EXAMINER EWOLDT, GERALD R ART UNIT PAPER NUMBER 1644 NOTIFICATION DATE DELIVERY MODE 02/24/2022 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): USpatentmail@klgates.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE _________________ BEFORE THE PATENT TRIAL AND APPEAL BOARD _________________ Ex parte BIN WANG, GUOXING ZHENG, SHUANG GENG, YIZHONG WANG, and QINGLING YU _________________ Appeal 2020-006741 Application 14/394,051 Technology Center 1600 _________________ Before RAE LYNN P. GUEST, DEBORAH KATZ, and TIMOTHY G. MAJORS, Administrative Patent Judges. KATZ, Administrative Patent Judge. DECISION ON APPEAL Appeal 2020-006741 Application 14/394,051 2 Appellant1 seeks our review2, under 35 U.S.C. § 134(a), of the Examiner’s decision to reject claims 12, 18-22, 273, and 31. We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. Appellant’s Specification is directed to treatments for type 1 diabetes (“T1D”). (Spec. 1.) Appellant’s claim 12 recites: A composition for treating type 1 diabetes (T1D) which is capable of eliciting a suppressive immune response against type 1 diabetes (T1D) by increasing the ratio of CD4+CD25+ Treg to CD4+ T cells, enhancing proliferation of CD4+CD25+ Treg population and inhibiting the cytotoxicity effect of auto reactive CD8+ T cells, comprising Mixture (1) or (2) as the active ingredient of the composition, (1) Mixture of a protein antigen and immune suppressive agent(s), wherein the weight ratio of the protein antigen and the immune suppressive agent(s) is 1:20 to 20:1, (2) Mixture of epitope peptides of the protein antigen and immune suppressive agent(s), wherein the weight ratio of the epitope peptides and the immune suppressive agent(s) is 1:1, wherein the protein antigen is selected from the group consisting of insulin, glutamic acid decarboxylase (GAD65) and islet amyloid polypeptide (IAPP), or a fragment thereof, and 1 We use the word “Appellant” as defined in 37 C.F.R. § 1.42. Appellant identifies the real party-in-interest as Beijing Advaccine Biotechnology Co., Ltd. (Appeal Br. 2.) 2 We consider the Final Office Action issued January 3, 2020 (“Final Act.”), the Appeal Brief filed May 27, 2020 (“Appeal Br.”), the Examiner’s Answer issued on July 28, 2020 (“Ans.”), and the Reply Brief filed September 28, 2020 (“Reply Br.”). 3 Claim 27 was omitted from the Claims Appendix, but does not seem to have been canceled by Appellant. It reads: “The composition of Claim 12, wherein the weight ratio of the antigen to the immunosuppressive agent is about 1:20 to about 20:1.” (Response to Final Office Action and A.F.C.P. [After Final Consideration Pilot Program] Request, filed February 7, 2019.) Appeal 2020-006741 Application 14/394,051 3 wherein the immunosuppressive agent is selected from the group consisting of dexamethasone (Dex), cyclosporine (CsA) and a combination thereof. (Appeal Br. 22.) In response to a restriction requirement, Appellant elected the species of a peptide antigen comprising an epitopic sequence from insulin, specifically SEQ ID NO: 2. (See Amendment and Response to Restriction Requirement filed November 22, 2016, 6.) SEQ ID NO: 2 corresponds to the sequence of the human insulin epitope peptide B15-23. (See Spec. 4.) The Examiner rejects claims 12, 18-22, 27, and 31 under 35 U.S.C. § 103(a) over Bresson,4 Wong,5 and Pershadsingh.6 (Ans. 3-5.) The Examiner finds that Bresson teaches a composition including an “islet autoantigen” and anti-CD3 antibodies that elicits an immunosuppressive response against type 1 diabetes (“T1D”). (See Final Act. 2, citing Bresson 1372, Table 1.) Bresson teaches the “advantages from combining antigen-specific induction of Tregs with a suitable systemically acting drug such as anti-CD3 for the treatment of recent-onset diabetes and maybe other autoimmune disorders.” (Bresson 1379; see Final Act. 2.) According to the Examiner, Bresson teaches “the concept of a composition 4 Bresson et al., “Anti-CD3 and nasal proinsulin combination therapy enhances remission from recent-onset autoimmune diabetes by inducing Tregs,” 116 J. CLIN. INVEST. 1371-81 (2006). 5 Wong et al., “Analysis of structure and function relationships of an autoantigenic peptide of insulin bound to H-2Kd that stimulates CD8 T cells in insulin-dependent diabetes mellitus,” 99 PROC. NAT’L ACAD. SCI. 5551- 56 (2002). 6 U.S. Patent 7,232,828 B2, issued June 19, 2007. Appeal 2020-006741 Application 14/394,051 4 employing an immunodominant autoantigen peptide and an immunosuppressive for the treatment of T1D.” (Ans. 5.) The Examiner finds that Wong teaches the insulin B15-23 peptide is a CD8+ T cell immunodominant epitope and would have been considered to be an obvious candidate for the autoantigen portion of a composition as taught in Bresson. (See Final Act. 2, citing Wong 5551, 5555.) The Examiner finds further that Pershadsingh teaches many immunosuppressive agents that are interchangeable with anti-CD3 antibody used in Bresson, including dexamethasone and cyclosporine. (See Final Act. 3, citing Pershadsingh 34:53-64, 6:50.) According to the Examiner, one of ordinary skill in the art would have considered it obvious to use the B15-23 peptide (SEQ ID NO: 2) of Wong, because it is a CD8+ T cell immunodominant epitope, and would have used dexamethasone, because it is interchangeable with anti-CD3, in a composition as taught in Bresson. (See Final Act. 3.) The Examiner concludes that the teachings of Wong and Pershadsingh, in light of the teachings of Bresson, render the claimed composition obvious. (See id.) Appellant argues that instead of encouraging the use of the epitope peptide B15-23, Bresson teaches away from the claimed composition. (See Appeal Br. 7-12; see Reply Br. 2-9.) Specifically, Appellant argues that Bresson teaches the epitope peptide B9-23 is not useful in an immunosuppressive composition for treatment of T1D and, thus, one of ordinary skill in the art would not have looked to the shorter epitope peptide B15-23 for use in a composition. (See Appeal Br. 7-12.) Appellant points to the experimental results reported in Table 1 and Figure 4 of Bresson for support. Appeal 2020-006741 Application 14/394,051 5 Table 1 of Bresson describes an experiment, wherein two mouse models of T1D (NOD and H-2d RIP-LCMV-nucleoprotein [RIP-LCMV-NP] mice) were treated with a combination of anti-CD3 and various islet antigens, including human proinsulin II B24-C36 peptide (“hpIIp”) and peptide B9-23 of insulin. (See Bresson 1372.) Bresson reports that hpIIp exhibited the best synergy and it became the focus of the rest of the investigation. (See Bresson 1372.) Table 1 reports further results and is reproduced below. (Bresson 1372.) Table 1 reports that the efficacy improvement of anti-CD3 plus hpIIp peptide compared to anti-CD3 alone was 28% in NOD mice, whereas with anti-CD3 plus “InsB9-23” peptide compared to anti-CD3 Appeal 2020-006741 Application 14/394,051 6 provided only 2% improvement. (See Table 1.) Appellant argues that the epitope peptide B9-23 is similar to the epitope peptide B15-23, because it includes all of the amino acids of the former and that one of ordinary skill in the art would not have modified the composition of Bresson by substituting hpIIp with either epitope peptide B9-23 or B15-23. (See Appeal Br. 7-12.) The Examiner disputes Appellant’s interpretation of Table 1, asserting that “the authors did nothing with the B9-23 peptide” and that they “used the B24-C36 peptide [hpIIp] exclusively.” (Ans. 5, 7.) The Examiner cites to the Methods section of Bresson on page 1380, which mentions only the hpIIp peptide, to support the finding that no animals were actually treated with the B9-23 peptide. (See Ans. 5-6.) According to the Examiner, no response would have been expected with the B9-23 peptide because it was never used. (See id.) We disagree with the Examiner because the text in Bresson explains that anti-CD3 was combined “with various islet antigens given by various means.” (Bresson 1372.) The results in Table 1 list “hpIIp (i.n.)” as well as “InsB9-23 (i.n.).” (See Reply Br. 6-7.) The Examiner overlooks these indications that the proinsulin hpIIp peptide was compared with the insulin B9-23 peptide in Bresson. Whether or not the authors provided a complete explanation of the methods, Bresson makes it clear that the B9-23 peptide was used in a combination therapy with anti-CD3 in at least in the experiment reported in Table 1. Thus, we agree with Appellant that Bresson teaches the B9-23 peptide works poorly as a combination therapy with anti-CD3. Figure 4 provides similar results. Nevertheless, we disagree that one of ordinary skill in the art would not have considered the B15-23 peptide in a composition as suggested by Bresson. Appeal 2020-006741 Application 14/394,051 7 Specifically, we are not persuaded by Appellant’s argument that the B9-23 peptide used in Bresson is necessarily similar enough to the B15-23 peptide to have discouraged use of the latter. (See Appeal Br. 8-9; see Reply Br. 4.) Appellant argues that because B9-23 includes all of the amino acids of B15-23 one of ordinary skill in the art would have expected them to work similarly. (See id.) In support, Appellant presents a declaration by inventor Dr. Wang. (See Declaration Under 37 C.F.R. § 1.132, filed December 17, 2019 (“Wang Decl.”).) Dr. Wang testifies that hpIIp is “significantly different” from the insulin peptides recited in Appellant’s claims. (See Wang Decl. ¶ 5.) Dr. Wang testifies that the B15-23 peptide would not have been expected to have a better fit with the CD8+ MHC class I binding site than the B9-23 peptide merely because of its length. (See Wang Decl., ¶ 6.) Instead, Dr. Wang asserts that the additional amino acids (serine, lysine, histidine, and glutamic acid) of the B9-23 peptide indicates it “might have better binding affinity to the MHC II molecule than insulin peptide B15-23.” (See Wang Decl. ¶ 6.) Dr. Wang cites data from an analysis using “IEDB Analysis Resource.” (See Wang Decl., ¶ 7.) Dr. Wang reports that the analysis shows “insulin peptide B9-23 (SHLVEALYLVCGERG) can bind with different human MHC II molecules (HLA-DR/DP/DQ) with various binding affinities, indicating that insulin peptide B9-23 has more potential to bind and activate MHC II expressing CD4+ Tregs.” (Wang Decl. ¶ 7.) Dr. Wang also reports that insulin peptide B15-23 (noted with red box) not only binds with few MHC-1 allele (interaction with DC8 T cells) but also shows less binding affinity, whereas the sequence of insulin peptide B9-23 covered more epitopes with higher binding affinity to MHC-1.” (Wang Decl. ¶ 7.) Dr. Appeal 2020-006741 Application 14/394,051 8 Wang concludes that “the insulin peptide B9-23 might have better binding affinity to the MHC-1 molecule than insulin peptide B15-23.” (Wang Decl. ¶ 7.) It is not clear what the “IEDB Analysis Resource” Dr. Wang presents is or how it supports Dr. Wang’s conclusions because little explanation is given and the figures in the declaration are illegible. (See Ans. 7.) There is no requirement that a fact finder must credit the inadequately explained testimony of an expert witness. Rohm and Haas Co. v. Brotech Corp., 127 F.3d 1089, 1092 (Fed. Cir. 1997). Furthermore, Dr. Wang’s conclusions are only that the B9-23 peptide might have had better characteristics than the B15- 23 peptide. Although Appellant presents Dr. Wang’s testimony to support the argument that the B15-23 epitope peptide would have been considered to be an even poorer candidate than the B9-23 epitope peptide for the claimed composition, it also tends to support the Examiner’s finding that those of ordinary skill would not necessarily have considered the B15-23 epitope peptide to be so similar to the B9-23 epitope peptide to have the same properties. (See Ans. 6.) As the Examiner finds, and Dr. Wang’s testimony tends to support, “[a] single amino acid difference can enable or negate MHC binding. Peptides of different lengths can have vastly different properties, particularly in regards to MHC class I or class II binding” because it highlights differences between the epitope peptides. (Ans. 6.) The teachings of the cited art, such as Wong, also support the uniqueness of each peptide and disparate effects that peptide length can have. Specifically, in regard to the B15-23 epitope peptide as an MHC class I allele and autoantigen for CD8+ T cells, Wong teaches: Appeal 2020-006741 Application 14/394,051 9 Although both the B15-23 nonamer and the B15-24 decamer were able to induce cytotoxicity, it was unlikely that the decamer was the cognate peptide for the clone, because the stimulation occurred at 100-fold lower concentration with the nonamer in both cytotoxicity and production of IFN-γ. It is possible that the decamer stimulates less well because the nonamer binds in register and the presence of the F residue in the decamer interferes with TCR recognition. Indeed, such peptides that extend by one or more residues out of the carboxyl-terminal pocket of an MHC class I molecule have been identified by pool sequencing and x-ray crystallography . . . However, the universal mode of TCR binding to MHC I- peptide complexes would be considerably disturbed by the presence, at the carboxyl terminus of the insulin peptide, of the bulky and inflexible phenylalaine residue protruding out of the p9 pocket. This amino acid protrusion would certainly cause rearrangement of nearby H-2Kd heavy chain residues and perhaps instability of the complex, as observed in the HLA-A2- calreticulin decamer peptide complex [added pl0Gly . . .]; thus, such a complex would most probably not be recognized by the cognate TCR. Alternatively, the decamer preparations could have smaller amounts of the nonamer as a breakdown product, and this minute amount is in fact stimulating to the T cell clone. Last, but much less likely, both the nonamer and the decamer could stimulate recognition by the TCR if both p9G and p10F are able to act as anchor residues to the MHC, but it would be difficult to explain our peptide substitution data if this were the case. The two peptide-MHC I complexes herein would have distinctly different TCR recognition surfaces, making their nearly equivalent recognition by a single TCR species highly unlikely. (Wong 5554-5555 (citations omitted).) Given that one of ordinary skill in the art would have known there are many reasons why the longer B15-24 peptide induced cytotoxicity less well than the minimally shorter B15-23 peptide, we are not persuaded that the ordinarily skilled artisan would have Appeal 2020-006741 Application 14/394,051 10 concluded that the B15-23 peptide would have the same or worse activity than the B9-23 peptide, as Appellant argues. Instead, on this record, we find that one of ordinary skill in the art would have understood that the affect of each peptide must be determined empirically. Therefore, we are not persuaded that the activity of the B9-23 peptide would have evidenced the expected activity of the B15-23 peptide, much less taught away from the latter’s use. Furthermore, we note that there is no lower limit in Appellant’s claim 12 on the degree to which the composition is capable of “eliciting a suppressive immune response against type 1 diabetes (TlD) by increasing the ratio of CD4+CD25+ Treg to CD4+ T cells, enhancing proliferation of CD4+CD25+ Treg population and inhibiting the cytotoxicity effect of auto reactive CD8+ T cells.” Although Bresson teaches that the hpIIp peptide is superior to the B9-23 peptide, it also teaches that the later has some, if minimal (2%), improvement in efficacy. In light of all the evidence before us, we are not persuaded by Appellant’s argument that an ordinarily skilled artisan would have considered the B9-23 and B15-23 peptides to have necessarily been similar in eliciting a suppressive autoimmune response against T1D as claimed. Dr. Wang’s testimony is contradicted by the discussion in Wong of the disparate effects of nonamer and decamer peptides that differ by only one terminal amino acid and by his own report on the different characteristics of the B9-23 and B15-23 peptides. Accordingly, we are not persuaded that one of ordinary skill in the art would necessarily have been discouraged from using the B15-23 peptide in a composition as taught in Bresson merely because the B9-23 peptide provided minimal efficacy. We are not persuaded that Bresson teaches away from the Appeal 2020-006741 Application 14/394,051 11 claimed composition. See In re Gurley, 27 F3d 551, 553 (Fed. Cir. 1994) (“A reference may be said to teach away when a person of ordinary skill, 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.”) Although Bresson does not teach away from the claimed composition, there must still be a reason why one of ordinary skill in the art would have looked to the teachings of Wong to use the B15-23 epitope peptide in a composition as taught in Bresson. Appellant does not dispute the Examiner’s reasoning that the teaching in Wong of the B15-23 epitope peptide as a CD8+ T cell immunodominant epitope would have indicated to those in the art that it is a candidate for an autoantigen in a composition as taught in Bresson. (See Final Act. 2-3.) In addition, Appellant does not challenge the Examiner’s determination that Pershadsingh suggests dexamethasone could be used as an immune suppressive agent in a composition as taught in Bresson. Because the Examiner’s findings are supported by the cited art, we are persuaded there would have been a reason to use the B15-23 epitope peptide in the composition of Bresson. Appellant argues further that the Specification demonstrates unexpected results achieved by the claimed composition. (See Appeal Br. 12-15; see Reply Br. 10-12.) According to Appellant, the Specification “shows surprisingly that a composition of an immunosuppressive agent (e.g., DEX) and a protein antigen (e.g., rh-insulin) can be used for treating type 1 diabetes (T1D).” (Appeal Br. 13; Reply Br. 11.) In light of the teachings of Bresson, we are not persuaded that this would have been surprising to the Appeal 2020-006741 Application 14/394,051 12 ordinarily skilled artisan. Bresson teaches that “a novel combination treatment with anti-CD3ε-specific antibody and i.n. proinsulin peptide can reverse recent-onset diabetes in 2 murine diabetes models with much higher efficacy than with mono therapy with anti-CD3 or antigen alone.” (Bresson Abstract.) Thus, as the Examiner finds, the concept of a composition employing an immunodominant autoantigen peptide and an immunosuppressive for the treatment of T1D was known in the art. (See Ans. 5.) Appellant points to several figures of the Specification, which show the results of injecting rh-insulin and dexamethasone on blood glucose, CTL responses, Treg frequency, IL-10 expression, and survival. (See Appeal Br. 13-14.) Appellant cites further to the declaration testimony of Inventor Wang about similar results. (See Appeal Br. 14, citing Wang Decl., ¶ 10.) We note, first, that these results were not obtained with the species elected by Appellant - the B15-23 epitope peptide - but rather with rh-insulin. Thus, the results are not commensurate with the scope of Appellant’s claims and do not address the elected species. Furthermore, given the teachings of Bresson that treatment with an immunodominant autoantigen peptide and an immunosuppressive caused “insulin-specific Tregs producing IL-10, TGF-β, and IL-4 [to be] strongly enhanced” and that treated cells “could transfer dominant tolerance to immunocompetent recent-onset diabetic recipients and suppressed heterologous autoaggressive CDS responses,” we are not persuaded that the results cited by Appellant would have been unexpected. (Bresson Abstract.) Similarly, we are not persuaded by Appellant’s argument and Dr. Wang’s testimony regarding “Appellant’s recent article from Human Appeal 2020-006741 Application 14/394,051 13 Vaccines & Immunotherapeutics DOI: 10.1080/21645515.2019.1616504” (“Article”), given the results reported in Bresson of the induction of Treg and acquisition of a tolerogenic phenotype. (See Appeal Br. 14-15, citing Wang Decl., ¶ 11.) Appellant fails to persuade us that unexpected results indicate the composition of claim 12 would not have been obvious to those of ordinary skill in the art, given the teachings of the prior art. Because we are also unpersuaded that Bresson teaches away from the claimed composition, we are not persuaded that the Examiner erred in rejecting claim 12. Accordingly, we affirm the Examiner’s rejection of claim 12. Appellant argues for the separate patentability of claims 18-22, raising the same arguments discussed above. (See Appeal Br. 15-19.) We are not persuaded by these arguments. Specifically, Appellant argues separately for the patentability of claims 18 and 20, asserting that the Examiner did not address “peptide antigen comprises at least one epitopic sequence from insulin, GAD65, IAPP, or a combination thereof” or that the antigen is a “native protein or peptide.” (See Appeal Br. 15-16, 17.) To the extent claim 18 is not drawn to the elected species, we disagree with Appellant because the epitope peptide B15-23 taught in Wong is a native peptide of insulin. (See Ans. 10.) Appellant also argues separately for the patentability of claim 19, arguing that the Examiner did not address the limitation of an “antigen is from human, dog or cat.” (See Appeal Br. 16.) Because Appellant elected SEQ ID NO: 2, the sequence of human insulin B15-23, for examination, we are not persuaded that the Examiner erred. (See Spec. 4; see Amendment and Response to Restriction Requirement filed November 22, 2016, 6.) Appeal 2020-006741 Application 14/394,051 14 Appellant further argues separately for the patentability of claim 21, arguing that the Examiner did not address the limitation of a chemically synthesized antigen. (See Appeal Br. 18.) Appellant is mistaken because the Examiner addresses this limitation, finding that because the method of synthesis or isolation of the recited epitope peptide would have no patentable effect on the claimed composition and, therefore, would have been obvious. (See Final Act. 3.) Appellant presents no argument to the contrary. Appellant also argues separately for the patentability of claim 22, arguing that the Examiner did not address the recited SEQ ID NOs. (See Appeal Br. 18-19.) Appellant is mistaken because the Examiner’s rejection is based on the teaching of SEQ ID NO:2 in Wong. Appellant fails to persuade us that the Examiner erred in rejecting any of the claims that depend on claim 12. Accordingly, we affirm the rejections of those claims. Conclusion Upon consideration of the record and for the reasons given, we affirm the Examiner’s rejection. In summary: Claims Rejected 35 U.S.C. § Basis Affirmed Reversed 12, 18-22, 27, 31 103 Bresson, Wong, Pershadsingh 12, 18-22, 27, 31 Appeal 2020-006741 Application 14/394,051 15 No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136. AFFIRMED