Ex Parte Ostroff et alDownload PDFPatent Trial and Appeal BoardDec 8, 201712615040 (P.T.A.B. Dec. 8, 2017) Copy Citation 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. 12/615,040 11/09/2009 Gary R. Ostroff 2732.1047-012 9741 26813 7590 12/12/2017 MUETING, RAASCH & GEBHARDT, P.A. P.O. BOX 581336 MINNEAPOLIS, MN 55458-1336 EXAMINER FINN, MEGHAN R ART UNIT PAPER NUMBER 1629 NOTIFICATION DATE DELIVERY MODE 12/12/2017 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): ptodocketing @ mrgs .com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte GARY R. OSTROFF and GORDON D. ROSS Appeal 2016-000477 Application 12/615,040 Technology Center 1600 Before JEFFREY N. FREDMAN, ULRIKE W. JENKS, and RACHEL H. TOWNSEND, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal1 under 35U.S.C. § 134 involving claims to a method of suppressing or eliminating tumor cells. The Examiner rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. Statement of the Case Background “Beta glucan is a complex carbohydrate” (Spec. 1:15). “Beta glucan’s activity as an immune adjuvant and hemopoietic stimulator compares to that of more complex biological response modifiers” {id. at 2:25—26). “The potential antitumor activity of [3-glucans has been under investigation for 1 Appellants identify the Real Party in Interest as Biothera, Inc. {see App. Br. 3). Appeal 2016-000477 Application 12/615,040 about 30 years” (id. at 3:21—22). Separately, “subtle changes associated with cancer development can lead to different expression of surface proteins . . . These changes in surface antigen expression also provide a target for treatment using selective monoclonal antibodies (mAbs)” (id. at 4:12—15). “The present application discloses a method of antitumor therapy in which insoluble [3-glucan is used with complement activating antibodies directed to tumor antigens to provide an antitumor effect” (Spec. 5:11—13). The claims Claims 1—9, 17, and 18 are on appeal.2,3 Claim 1 is representative and reads as follows: 1. A method of suppressing or eliminating tumor cells, comprising: administering to a subject that comprises tumor cells a therapeutically effective amount of insoluble P( 1,3; 1,6) whole glucan particles and at least one complement activating anti-tumor antibody; wherein the glucan and antibody suppresses or eliminates tumor cells. 2 We note that the Examiner required a species election on Sept. 14, 2011 and Appellants elected trastuzumab as the species for examination on Mar. 14, 2012. We therefore limit our consideration of the merits of the appealed rejection to the elected species. See Ex parte Ohsaka, 2 USPQ2d 1460, 1461 (BPAI 1987). 3 The Examiner appears to have withdrawn the obviousness rejections relying upon Jamas and Goldenberg (see Ans. 10-11), but then the Examiner mailed a PTO-90 form indicating that every ground of rejection is maintained (see Misc. Comm, dated Aug. 25, 2015). As Appellants’ Reply Brief dated Oct. 9, 2015 appears to treat the Jamas and Goldenberg rejections as withdrawn, and given the ambiguity engendered by the Examiner, we will treat these rejections as withdrawn from appeal. 2 Appeal 2016-000477 Application 12/615,040 The issue The Examiner rejected claims 1—9, 17, and 18 under 35 U.S.C. § 103(a) as obvious over Vetvicka,4 Asp,5 Mathiowitz,6 and Miller7 (Non- Final Act.8 3—8). The Examiner finds Vetvicka teaches “insoluble P(1,3;1,6) whole glucan . . . inhibited the growth of cancer cells in vivo” (Non-Final Act. 5). The Examiner finds Vetvicka teaches P(l,3;l,6) glucan “slowed down the progression of tumor growth in a colon cancer model” {id. at 6). The Examiner finds “a synergy between oral pi,3-glucan immunotherapy and traditional chemotherapeutic treatments” {id. at 7). The Examiner finds Asp teaches “a monoclonal antibody that has been shown to inhibit the proliferation of tumor cells from sources expressing HER2 as well as a synergist result with trastuzumab and several chemotherapeutic agents” (Non-Final Act. 7). The Examiner finds Mathiowitz teaches “treatment of cancer by targeting antigens specific to that cancer (page 9, [0077]) including specifically identifying colon carcinoma was having ‘HER2/neu’ as an antigen” (id. at 8). The Examiner finds Miller teaches “antibody 4D5 was found to sensitize breast tumor cell lines to the cytotoxic effects of TNFa” (id. at 8). 4 Vetvicka et al., Pilot Study: Orally-Administered Yeast J31,3-glucan Prophylactically Protects Against Anthrax Infection and Cancer in Mice, 5 J. Am. Nutraceutical Ass’n 5-9 (2002). 5 Asp et al., US 2003/0096823 Al, published May 22, 2003. 6 Mathiowitz et al., US 2001/0043914 Al, published Nov. 22, 2001. 7 Miller et al., US 2002/0004587 Al, published Jan. 10, 2002. 8 We refer to the Non-Final Action mailed Jan. 30, 2014. 3 Appeal 2016-000477 Application 12/615,040 The Examiner finds it obvious to combine the whole glucan from Vetvicka with the Herceptin of Miller or Asp to treat a patient with colon cancer that overexpresses HER2. Those patients would have tumor cells and read upon the claimed patient population and there is a reasonable expectation of success in inhibiting the tumor growth since both treatments have been individually shown to be effective against that type of cancer. (Non-Final Act. 9). The issues with respect to this rejection are: (i) Does the evidence of record support the Examiner’s conclusion that Vetvicka, Asp, Mathiowitz, and Miller render claim 1 obvious? (ii) If so, have Appellants presented evidence of secondary considerations, that when weighed with the evidence of obviousness, is sufficient to support a conclusion of non-obviousness? Findings of Fact 1. Vetvicka teaches a “highly purified particulate yeast-derived P1,6-branched [31,3 glucan . . . was used in all experiments” (Vetvicka 6, col. 1). 2. Vetvicka teaches “[o]ral WGP Beta Glucan treatment also reduces the threat of cancer, slowing down the progression of tumor growth in a preclinical colon cancer model” (Vetvicka 8, col. 1). 3. Vetvicka teaches a large body of preclinical and clinical work done in Japan demonstrating the oral anti-tumor activity of mushroom pi,3- glucans to yeast pi,3-glucan. These published studies have demonstrated that pi,3-glucan immunotherapy leads to the activation of the innate immune cells (macrophages, neutrophils (PMN) and natural killer (NK) cells), the stimulation of tumoricidal activities, production of cytokines, and the 4 Appeal 2016-000477 Application 12/615,040 generation of enhanced cell-mediated responses. Suzuki and colleagues have reported the stimulation of activated macrophages by the administration of SSG and NK-type lymphokine-activated killer cells by the combined administration of lentinan and IL-2. The stimulation of tumoricidal activities in PMN by a linear bacterial [31,3-glucan has also been reported. (Vetvicka 8, col. 1; citations omitted). 4. Vetvicka teaches a “number of clinical studies have demonstrated synergy between oral [31,3-glucan immunotherapy, and traditional radiation and chemotherapeutic cancer treatment options” (Vetvicka 8, col. 1). 5. Asp teaches: “Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody that selectively binds with a high affinity in cell-based assays (Kd: 5 nM) to the extracellular domain of the human epidermal growth factor receptor 2 protein, HER2” (Asp 12). 6. Asp teaches: “Trastuzumab has been shown, in both in vitro assays and animal models, to inhibit the proliferation of human tumor cells from different sources overexpressing HER2. Furthermore, nonclinical studies have shown additive and synergistic effects of trastuzumab when given in combination with several chemotherapeutic agents” (Asp 14). 7. Mathiowitz teaches: “Antibody-based immunotherapies may function by binding to the cell surface of a cancer cell and thereby stimulate the endogenous immune system to attack the cancer cell” (Mathiowitz 174). 8. Mathiowitz teaches “synergistic combinations of IL-12 and cytokines that augment antigen processing and presentation” (Mathiowitz 189). 5 Appeal 2016-000477 Application 12/615,040 9. Miller teaches “a panel of anti-HER2 antibodies . . . The antibody 4D5 was further found to sensitize HER2-overexpressing breast tumor cell lines to the cytotoxic effects of TNF-alpha” (Miller 130). 10. Miller teaches a “recombinant humanized IgGl version of the murine anti-HER2 antibody 4D5 ... is clinically active in patients with HER2-overexpressing metastatic breast cancers that have received extensive prior anti-cancer therapy” (Miller 131). Principles of Law “The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSRInt’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). Analysis We adopt the Examiner’s findings of fact and reasoning regarding the scope and content of the prior art (Non-Final Act. 3—8; FF 1—10) and agree that the claims are obvious over Vetvicka, Asp, Mathiowitz, and Miller. We address Appellants’ arguments below. Prima Facie Obviousness Appellants contend the Examiner provided no rationale unmotivated by hindsight bias why a person having skill in the art would have selected these two anti-cancer treatments. Given all of the treatments known to be effective against colon cancer at the time of the invention, this purported motivation is little more than an invitation to experiment. (App. Br. 10). We are not persuaded. Vetvicka evidences that [31,6-branched pi,3 glucan (FF 1) was a known cancer chemotherapeutic agent (FF 2—3) and was 6 Appeal 2016-000477 Application 12/615,040 combined with other traditional cancer treatment options (FF 4), while Asp, Mathiowitz, and Miller each teach cancer treatments comprising anti-tumor antibodies (FF 5, 7, 10) and each recognizes combinations of the anti-tumor antibodies with other therapeutic agents (FF 6, 8, 9). The flexible analysis set out by the Supreme Court in KSR recognizes the obviousness of pursuing known options within the technical grasp of the skilled artisan, e.g., known equivalents. See KSR, 550 U.S. at 421. Here, it is fair to say that given the prior art teaches certain antibodies were known to treat certain cancers, and to do so in concert with other known knowon antitumor agents (FF 5—10), and that the claimed glucan was known to have demonstrated anti-tumor activity (FF 1—4), the combination of two known anit-tumor antibodies with the claimed glucan was the “product not of innovation but of ordinary skill and common sense.” See Wm. Wrigley Jr. Co. v. Cadbury Adams USALLC, 683 F.3d 1356, 1364—65 (Fed. Cir. 2012 {citing KSR, 550 U.S. at 421). Appellants contend the Examiner used the claims as a template by which to assemble the invention and that “the ‘known options’ in the prior art were not ‘finite, identified, and predictable’ ... and are identified only with hindsight knowledge” of the inventors’ formulation and its properties. Abbott Laboratories v. Sandoz, Inc., 544 F. 3d 1341 (Fed. Cir. 2008). Given the number of cytokines [3-glucan affects and the number of treatments known to affect cytokine sensitivity, Appellant respectfully submits that the Examiner improperly used the claim to assist in finding the rationale to combine its elements. (App. Br. 10). We are not persuaded. While we are fully aware that hindsight bias may plague determinations of obviousness, Graham v. John Deere Co., 383 7 Appeal 2016-000477 Application 12/615,040 U.S. 1,36 (1966), we are also mindful that the Supreme Court has clearly stated that the “combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR, 550 U.S. at 416. In the instant case, Vetvicka teaches “synergy between oral pi,3- glucan immunotherapy, and traditional radiation and chemotherapeutic cancer treatment options” (FF 4); Asp teaches “additive and synergistic effects of trastuzumab when given in combination with several chemotherapeutic agents” (FF 6); and Miller teaches the “antibody 4D5 was further found to sensitize HER2-overexpressing breast tumor cell lines to the cytotoxic effects of TNF-alpha” (FF 9); the ordinary artisan would have reasonably expected the combination of these known chemotherapeutic agents to demonstrate at least additive effects for cancer treatment. See In re Kerkhoven, 626 F.2d 846, 850 (CCPA 1980) (“It is prima facie obvious to combine two 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.”). These expected additive and synergistic effects would have provided reasons for the ordinary artisan to have chosen to combine these chemotherapy treatments. Appellants contend “the Examiner failed to provide any evidence that would have provided a skilled artisan would [sic] a reasonable expectation that the combination would have worked in vivo” (App. Br. 11). We are not persuaded. Our reviewing Court has stated: “Responding to concerns about uncertainty in the prior art influencing the purported success of the claimed combination, this court [in O’Farrell] stated: ‘ [o]bviousness does not require absolute predictability of success ... all that 8 Appeal 2016-000477 Application 12/615,040 is required is a reasonable expectation of success’”. In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009) {citingIn re OTarrell, 853 F.2d 894, 902 (Fed. Cir. 1988)). Here, Vetvicka evidences efficacy of [31,6-branched [31,3 glucan in “a large body of preclinical and clinical work” (FF 3) while Asp, Mathiowitz, and Miller each teach efficacy of antibodies in cancer treatment (FF 5—9) including a commercially available anti-HER2 antibody (FF 10). Moreover, each reference suggests combination therapies (FF 4, 6, 8, 9). Consequently, there is a reasonable expectation of success in applying these combined therapies to cancer treatment. Appellants provide no evidence, as opposed to attorney argument, rebutting this expectation of success. See In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974) (“Attorney’s argument in a brief cannot take the place of evidence.”). Appellants contend In Takeda Chem. Indus, v. Alphapharm Pty., the Federal Circuit noted the importance of a starting point for an obviousness analysis. 492 F.3d 1350, 1358 (Fed. Cir. 2007). In Takeda, Alphapharm asserted that “the prior art would have led one of ordinary skill in the art to select “compound b as a lead compound.” Id. at 1357. The court disagreed, holding that when the “prior art disclosed a broad selection of compounds any one of which could have been selected” and provided nothing to “narrow the possibilities” to a particular compound, selection of a compound b from that list was not obvious. Id. at 1359-60. Similarly, at the time of the invention, the literature related to cancer treatment - and even colon cancer treatment - identified hundreds, if not thousands, of potential agents that have an effect against cancer in vitro and provided nothing to narrow the choice of agents to those identified by the Examiner. (Reply Br. 3). 9 Appeal 2016-000477 Application 12/615,040 We are not persuaded. First Takeda involves a wholly different factual scenario concerning structurally similar compounds, where the question was whether a compound having a particular chemical structure was obvious from a chemically similar structure. Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd, 492 F.3d 1350, 1353—54 (Fed. Cir. 2007). The obviousness question turned on the selection of a lead compound that the infringer contended would have been obvious to modify to arrive at the claimed invention. Id. at 1357. The Federal Circuit agreed with the District Court that there was no reason to select the lead compound because there was no experimental data or test results in one reference for any of the fifty- four compounds synthesized that included the “lead compound” that would suggest its selection as a “target[] for modification to seek improved properties.” Id. In the second reference that disclosed the “lead compound,” that particular compound was “not identified as ont of the three most favorable compounds,” and, in fact, was “singled out” as having negative activities. Id. at 1358. The Court further noted that none of the species in the prior art genus fell within the scope of the claim, since “[pjioglitazone differs from compound b in two respects, and one would have to both homologate the methyl group of compound b and move the resulting ethyl group to the 5-position on the pyridyl ring in order to obtain pioglitazone.” Id. at 1360. To the extent that Takeda may be relevant here, at all, we find it supports the Examiner’s conclusion of obviousness. In the instant case, all of the prior art compounds of Vetvicka, Asp, Mathiowitz, and Miller fall within the scope of the claim (FF 1, 5, 7, 9, 10), and each has positive data and/or test results which would recommend their use in suppressing or 10 Appeal 2016-000477 Application 12/615,040 eliminating tumor cells. See Merck & Co., v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989) (“That the [prior art] discloses a multitude of effective combinations does not render any particular formulation less obvious.”) Secondary Considerations Appellants contend “the Examiner failed to give adequate weight to the unexpected result9 reported by Appellant in the Specification that the combination of [3-glucan and complement-activating monoclonal antibodies is synergistic” (App. Br. 12). Appellants contend “Figures 9-11 of the specification, [show] the combination of [3-glucan and monoclonal antibodies is more efficient at suppressing or eliminating tumor cells than either [3-glucan or monoclonal antibodies administered alone” (id.). We find these arguments unpersuasive. As indicated above, due to the election of species, the claims are limited to the antibody trastuzumab, identified by the Specification as Herceptin™ (see Spec. 23:21), an antibody targeted to extracellular domain of the human epidermal growth factor receptor 2 protein, HER2 (FF 5). However, the data presented in figures 9 to 11 of the Specification is drawn to the anti-GD2 ganglioside antibody, 3F8 (see Spec. 30:18—19) or anti murine mammary tumor virus membrane antigen antibody, 11C1 (see Spec. 37:13—14). Neither antibody tested shares the same binding to the target antigen as trastuzumab or the same structure as trastuzumab, and therefore the evidence of figures 9-11 was not compared to the closest prior art of Asp who teaches trastuzumab (FF 5—6) or even Miller who teaches a more 9 We note that the Examiner found, in the Answer, that unexpected results “is a new argument that appellant did not raise previously” (Ans. 14). 11 Appeal 2016-000477 Application 12/615,040 general anti-HER2 antibody that sensitizes tumor cells to TNF-a (FF 9). See In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) (“when unexpected results are used as evidence of nonobviousness, the results must be shown to be unexpected compared with the closest prior art.”). In addition, to the extent that Appellants are ignoring the species election and reading claim 1 to encompass any complement activating anti tumor antibody, the evidence is not commensurate in scope with this broad genus because only two species were tested. Unexpected results must be “commensurate in scope with the degree of protection sought by the claimed subject matter.” In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005). Here, to the extent that any results are unexpected, they are not commensurate in scope with the much broader recitations of claim 1. Finally, we find unpersuasive, Appellants’ contention that “none of the cited documents, either alone or in combination, teach or suggest a synergistic effect would be achieved when treating with trastuzumab and a [3-glucan” (Reply Br. 6). In contrast, Vetvicka teaches “synergy between oral pi,3-glucan immunotherapy, and traditional. . . chemotherapeutic cancer treatment options (FF 4); Asp teaches “synergistic effects of trastuzumab when given in combination with several chemotherapeutic agents” (FF 6); and Miller teaches that the anti-HER2 antibody 4D5 was “found to sensitize HER2-overexpressing breast tumor cell lines to the cytotoxic effects of TNF-alpha” (FF 9). Thus, three separate references provide some evidence that the ordinary artisan would have expected synergistic results between P-glucan therapy and other known therapies and between trastuzumab and other known therapies, thereby providing support for the Examiner’s finding that 12 Appeal 2016-000477 Application 12/615,040 “there is teaching that one agent would increase the effectiveness of the other agent and thus the prior art directly suggests the synergistic effect.” (Ans. 17). See In re Skoner, 517 F.2d 947, 950 (CCPA 1975) (“Expected beneficial results are evidence of obviousness of a claimed invention. Just as unexpected beneficial results are evidence of unobviousness”). Therefore, as we balance the evidence as a whole, including the Examiner’s prima facie case of obviousness, Appellants’ rebuttal arguments, and Appellants’ asserted unexpected results, we conclude that the method of claim 1 is obvious over the teachings of Vetvicka, Asp, Mathiowitz, and Miller (FF 1—10). In particular, we find that even if the Specification evidence demonstrates some unexpected results for two antibodies other than trastuzumab, that showing does not support the breadth of claim 1 or the election to trastuzumab and is insufficient to overcome the Examiner’s showing of obviousness in this case, where Vetvicka teaches synergies in tumor cell treatment with a [3-glucan and other chemotherapeutic agents (FF 4) and similar teachings in Asp (FF 6), Mathiowitz (FF 8), and Miller (FF 9). Conclusions of Law (i) The evidence of record supports the Examiner’s conclusion that Vetvicka, Asp, Mathiowitz, and Miller render claim 1 obvious. (ii) Appellants have not presented evidence of secondary considerations, that when weighed with the evidence of obviousness, is sufficient to support a conclusion of non-obviousness. 13 Appeal 2016-000477 Application 12/615,040 SUMMARY In summary, we affirm the rejection of claim 1 under 35 U.S.C. § 103(a) as obvious over Vetvicka, Asp, Mathiowitz, and Miller. Claims 2— 9, 17, and 18 fall with claim 1. 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 14 Copy with citationCopy as parenthetical citation