Ex Parte Baker et alDownload PDFPatent Trial and Appeal BoardJun 23, 201612281129 (P.T.A.B. Jun. 23, 2016) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 12/281,129 11/21/2008 35151 7590 06/27/2016 Pepper Hamilton LLP/Kilburn&Strode 400 Berwyn Park 899 Cassatt Road Berwyn, PA 19312-1183 FIRST NAMED INVENTOR Matthew Baker 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 ATTORNEY DOCKET NO. CONFIRMATION NO. KIST0127PUSA 8076 EXAMINER TIJEDES, AMYE ART UNIT PAPER NUMBER 1644 NOTIFICATION DATE DELIVERY MODE 06/27/2016 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): bwdocket@pepperlaw.com bwdocket@pepeprlaw.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte MATTHEW BAKER, FRANCIS J. CARR, ALYSON RUST, and LAURA DA VIES 1 Appeal2014-007616 Application 12/281, 129 Technology Center 1600 Before DEMETRA J. MILLS, ULRIKE W. JENKS, and RACHEL H. TOWNSEND, Administrative Patent Judges. TOWNSEND, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 involving claims to a method for measuring immunogenicity in humans by assaying T cell response to a test substance, which have been rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. 1 Appellants identify the Real Party in Interest as Antitope Ltd. (Appeal Br. 1.) Appeal2014-007616 Application 12/281, 129 STATEMENT OF THE CASE T cell assays are used to measure T cell responses to test substances. (Spec. 1: 18-21.) According to Appellants, human T cell assays have been used to "detect human T cell epitopes for several purposes including evaluating the potential immunogenicity of [the test substance] ... defining T cell epitopes within a protein sequence for subsequent inclusion in vaccines, and defining T cell epitopes within a protein sequence for subsequent removal in order to avoid immunogenicity." (Spec. 1:21-27 .) Appellants note that "[ c ]urrent T cell assay methods to detect T cell epitopes are limited by one or both of poor sensitivity and/or by interference due to immunomodulatory or toxic samples which inhibit, stimulate or otherwise modify either APCs, T cells or both APCs and T cells." (Spec. 2:8-11.) The invention seeks to provide a "more sensitive" T cell assay "for optimal detection ofimmunogenicity." (Spec. 3:27--4:7.) Claims 1-8, 11, 12, 14--18, 21, 22, 24--26, and 28 are on appeal. Claim 1 is illustrative and reads as follows: 1. A method for measuring immunogenicity in humans of a test substance which is tested in order to assess immunogenicity using the following steps: (a) isolating antigen-presenting cells (APCs) and T cells from a human blood sample obtained from a healthy human subject; (b) depleting CD25+ and CD8+ T cells from the isolated cells; ( c) incubating said APCs and CD25+ and CD8+ depleted T cell-depleted cells obtained in (b) with the test substance for a period of 4 to 9 days; and ( d) assaying T cell responses to the test substance as a measure of immunogenicity. (Appeal Br. App. 1.) 2 Appeal2014-007616 Application 12/281, 129 The following ground of rejection by the Examiner is before us on review: Claims 1-8, 11, 12, 14--18, 21, 22, 24--26, and 28 under 35 U.S.C. § 103(a) as unpatentable over Scott,2 Levings,3 Danke,4 and Jones. 5 DISCUSSION The Examiner finds that Scott teaches a method of determining the immunogenicity of a peptide or protein antigen [including human therapeutic cytokines and cytokine receptors] comprising isolating APCs[( antigen presenting cells)] and CD4+ T cells from a single human peripheral blood sample, culturing the CD4+ T cells with the APCs and the antigen, and detecting T cell proliferation to the antigen. (Final Action 26; Ans. 2.) According to the Examiner the T cell response is a measure of the immunogenicity of antigen epitopes. (Final Action 2-3; Ans. 3.) Regarding the specifics of the process, the Examiner finds Scott teaches enriching the CD4+ T cells using a kit from Dynal, which removes CD8+ T cells. (Final Action 2; Ans. 3.) The Examiner also finds that Scott 2 Scott et al., US 2005/0220800 Al, published Oct. 6, 2005. 3 Megan K. Levings et al., Human CD25+cn4+ T Regulatory Cells Suppress Naive and Memory T Cell Proliferation and Can Be Expanded in Vitro without Loss of Function, 193(11) J. Exp. Med., 1295-1301 (2001). 4 Nancy A. Danke et al., Autoreactive T Cells in Healthy Individuals, 172 J. Immunol., 5967-5972 (2004). 5 Tim D. Jones et al., The Development of a Modified Human IFN-a2b Linked to the FC Portion of Human IgG 1 as a Novel Potential Therapeutic for the Treatment of Hepatitis C Virus Infection, 24 J. Interferon & Cytokine Res., 560-572 (2004). 6 Final Action mailed July 9, 2013. 3 Appeal2014-007616 Application 12/281, 129 "teaches separating the APCs, treating the APCs with cytokines, and adding the antigen to the APCs prior to the addition of the CD4+ T cells (see page 13, in particular)." (Id.) The Examiner explains that Scott does not teach using T-cell populations that are also CD25+ depleted. (Final Action 3; Ans. 3.) According to the Examiner, however, using such a T-cell population would have been obvious in light of Levings and Danke. The Examiner finds that Levings and Danke teach that "CD4+ T cell populations are comprised of a CD4+CD25+ regulatory T cell fraction and a CD4+CD25- fraction." (Ans. 5; Final Action 3.) The Examiner further finds that Levings teaches that CD4+CD25+ regulatory T cells present in human peripheral blood, "suppress proliferation of CD4+CD25- T cells" and "in the absence of CD25+ regulatory T cells, purified CD4+CD25- T cell populations display increase[d] proliferative response[] to antigen." (Final Action 3.) The Examiner finds that Danke has a similar teaching, namely "that CD4+CD25+ regulatory T cells in peripheral blood can suppress the response of CD4+CD25- T cells to self antigens." (Id.) According to the Examiner, Danke further teaches "that depletion of said CD+CD25+ regulatory T cells to yield a CD4+CD25- T cell population can be used to enhance and evaluate proliferative responses of said CD4+CD25- T cells to self antigens in healthy individuals" that "cannot be detected in the presence of CD25+ T cells." (Id.) The Examiner concludes that it would have been obvious to deplete CD25+ regulatory T cells in the Scott method of determining epitope immunogenicity and that the person of ordinary skill "would particularly be motivated to remove such CD25+ T cells to further 4 Appeal2014-007616 Application 12/281, 129 enhance epitope detection to the self therapeutic cytokine and cytokine receptors." (Id.) We adopt as our own the Examiner's findings and reasoning as set out in the Answer and Final Action. We agree with the Examiner's conclusion that modifying Scott to further deplete the T cell population of CD25+ T cells would have been obvious to one having ordinary skill in the art. Appellants first argue that because Scott is directed to enriching for CD4+ "to obtain a pure population of T cells," whereas claim 1 recites depleting CD25+ and CD8+ T cells, Scott "does not teach, suggest, motivate, or make obvious the depletion of CD8+ and CD25+ T cells and incubating the depleted T cells with a test substance." (Appeal Br. 2--4.) We disagree. Regardless of whether Scott "teaches enriching a pure population of CD4+ T cells" (Appeal Br. 4), the enrichment process of Scott using the kit from Dynal to obtain CD4+ cells targets other cells for removal from the cell population. As the Examiner noted, Appellants' Specification discloses that the term "'depletion' means elimination of some of the regulatory T cells. This can be done by physically removing the cells." (Ans. 5; Spec. 5: 1-2.) As the Examiner explained, "[t]he positive enrichment kits used in [Scott] retain those cells that express CD4 via a magnetic bead system, while removing and eliminating (i.e. depleting) all cells that are not CD4+, including CD8+ T cells." (Ans. 5.) Appellants' Specification exemplifies depletion of CD25+ T cells using a magnetic bead system. (Spec. 13: 1-20.) Scott teaches that mature T cells, which the Examiner notes are found in peripheral blood, are "single positive for either CD4 or CD8." (Scott i-f 52; 5 Appeal2014-007616 Application 12/281, 129 Ans. 5.) Thus, Scott's teaching of isolating CD4+ T cells from the peripheral blood samples, necessarily includes targeting unwanted CD8+ T cells for removal. Thus, we agree with the Examiner that Scott's enrichment process by removing CD8+ T cells is a depletion step within the scope of "the CD8 depletion step recited" in claim 1. (Ans. 5.) Appellants' argument that none of the cited references "teach" or "discuss" the depletion of CD8+ and CD25+ T cells (Appeal Br. 4) also does not persuade us the Examiner's rejection is in error. "Non-obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a combination of references." In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). The references must be read, not in isolation, but for what they fairly teach as a whole to one of ordinary skill in the art. (Id.) We agree with the Examiner that Levings and Danke provide motivation to deplete CD25+ cells from the T cell population to be tested in Scott, i.e., a population of T cells depleted of CD8+ T cells. As the Examiner found, these references "teach that depletion of CD25 regulatory T cells enhances the proliferative response of CD4 T cells to a variety of antigens, including self antigens, tumor antigens, and foreign alloantigens." (Ans. 6; Danke 5969-5970 (noting that tested peptides in peptide-dependent proliferation assays included diabetes associated Ag glutamic acid decarboxylase (GAD) 65, the vitiligo and melanoma- associated Ag tyrosinase, and the cancer/testis Ag NY-ES0-1 ), 5968 ("The removal of the CD4 +cn25+ population enabled a rapid expansion of these autoreactive T cells in vitro") (emphasis added); Levings 1298, e.g., Fig. 2, (noting proliferation assay involved alloantigens and that the cn25- 6 Appeal2014-007616 Application 12/281, 129 CD4+cell proliferation is suppressed to a significant degree when CD25+ CD4+cells are present).) In addition, as the Examiner noted, Danke teaches that such removal "enables detection of self antigen specific T cells that could not be detected in the presence of CD25+ regulatory T cells." (Final Action 4--5; Ans. 7; Danke 5968 After 14 days of culture, tetramer-positive T cells could not be detected from the unfractionated PBMC. However, a population ofDR0401-restricted GAD-reactive T cells was easily detected in the CD4 +CD25- samples with the DR040 II GAD557I tetramers (Fig. IA).) Thus, we agree with the Examiner's conclusion that "the cited references make obvious performing a cell selection process comprising isolating T cells from a blood sample and depleting all cells that are not CD4+ (including CD8+ T cells), followed by further removing (i.e. depleting) the CD25+ cells to yield a pure CD4+CD25-CD8- T cell population." (Ans. 5- ?.. \ v.; Appellants' also argue that the Examiner's rejection is in error because "[n]one of the Examiner's cited art teach, suggest, motivate, or make obvious" that the claimed T cell population "may be used for measuring immunogenicity [of] a test substance." (Appeal Br. 4.) However, Scott teaches that "[t]he immunogenic responses (i.e., T-cell proliferation) to the prepared peptides ... were tallied." (Scott 14 (i-1148).) The Supreme Court in KSR Int'l v. Teleflex Inc., 550 U.S. 398 (2007), held that "neither the particular motivation nor the avowed purpose of the patentee controls" the determination of whether claims have been proved obvious. 550 U.S. at 419. "What matters is the objective reach of the claim" and whether "the combination was obvious to a person with ordinary skill in the art," not the 7 Appeal2014-007616 Application 12/281, 129 patentee. Id. at 420. Appellants' claims are broadly directed to incubating the T cell population claimed, antigen-presenting cells and T cells depleted of CD25+ and CD8+ populations, with "a test substance" and measuring immunogenicity by "assaying T cell responses to the test substance." (Appeal Br. App. 1.) Regardless of whether the references assess T cell proliferation to "measure immunogenicity," they teach measuring T cell proliferation in response to antigen stimulation, which is "assaying T cell responses to the test substance" as claimed. Indeed, Appellants' Specification identifies measuring T cell proliferation as one of the methods contemplated for assaying T cell response and determining immunogenicity. (See, e.g., Spec. 8:17-30; 10:14--19.) Thus, we agree with the Examiner that Scott teaches "a method of determining the immunogenicity of human therapeutic cytokines and cytokine receptors" as claimed. (Ans. 6-7; see also Final Action 3 (noting Scott "teaches evaluating the proliferative response to variant cytokine therapeutic proteins (i.e. different formulations or manufacturing batches, see pages 13-14, in particular)".) Appellants' argument that the claimed depletion step results in a surprising result (Appeal Br. 5, 9) is also not persuasive. We agree with the Examiner that the invention as claimed does not provide an unexpected result. (Ans. 6.) Danke and Levings teach the very thing that Appellants contend is "surprising," namely that depletion of CD25+ cells provides an enhancement of T cell responses to a variety of antigens. (Danke 5967 ("The removal of the CD4+cn25+ population enabled a rapid expansion of these autoreactive T cells in vitro") (emphasis added); Levings 1298, e.g., Fig. 2, (noting proliferation assay involved alloantigens and that the CD25- 8 Appeal2014-007616 Application 12/281, 129 CD4+cell proliferation is suppressed to a significant degree when CD25+ CD4+cells are present).) Appellants criticize the relevance of Danke's and Levings' teachings because Danke concerns "removal of CD25+ regulatory T cells ... for the specific purpose of demonstrating regulation of autoreactive T cells by CD25+ regulatory T cells in healthy individuals," and Levings concerns "suppression of reactivity of CD4+ T cells to alloantigens." (Appeal Br. 6-8.) The claims, however, do not exclude the antigen being an alloantigen; and, regardless of the setting in which Danke and Levings discuss removal of CD25+ regulatory T cells, one of ordinary skill in the art would understand from these references that the presence of CD4+CD25+ T cells inhibit proliferation of T cells, whereas depleting CD25+ T cells enhances T cell responses to a variety of antigens. That Appellants' invention achieves an enhanced T cell response upon depletion of at least CD25+ T cells, therefore, would not be unexpected to one having ordinary skill in the art. "Expected beneficial results are evidence of obviousness of a claimed invention." In re Skoner, 517 F .2d 94 7, 950 ( CCP A 197 5) (emphasis added). For the reasons discussed, Appellants do not persuade us that the Examiner erred in concluding the method recited in claim 1 would have been obvious in view of the cited references. Accordingly, we affirm the Examiner's obviousness rejection of claim 1. Claims 2-8, 11, 12, 14--18, 21, 22, 24--26, and 28 have not been argued separately and, therefore, fall with claim 1. 37 C.F.R. § 41.37(c)(l)(iv). 9 Appeal2014-007616 Application 12/281, 129 SUMMARY We affirm the rejection of claims 1-8, 11, 12, 14--18, 21, 22, 24--26, and 28 as being unpatentable over Scott, Levings, Danke, and Jones. 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 10 Copy with citationCopy as parenthetical citation