Ex Parte Sampson et alDownload PDFPatent Trial and Appeal BoardSep 16, 201512092180 (P.T.A.B. Sep. 16, 2015) 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. 12/092,180 11/21/2008 John H. Sampson 000250.00067 9232 22907 7590 09/17/2015 BANNER & WITCOFF, LTD. 1100 13th STREET, N.W. SUITE 1200 WASHINGTON, DC 20005-4051 EXAMINER DUFFY, BRADLEY ART UNIT PAPER NUMBER 1643 MAIL DATE DELIVERY MODE 09/17/2015 PAPER 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. PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE PATENT TRIAL AND APPEAL BOARD __________ Ex parte JOHN H. SAMPSON, DARELL D. BIGNER, DUANE MITCHELL, and AMY HEIMBERGER __________ Appeal 2013-001941 Application 12/092,180 Technology Center 1600 __________ Before DEMETRA J. MILLS, JEFFREY N. FREDMAN, and ROBERT A. POLLOCK, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal1 under 35 U.S.C. § 134 involving claims to a method of treating a tumor expressing EGFRvIII. The Examiner rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm-in-part. 1 Appellants identify the Real Party in Interest as Duke University, which licensed the invention to Celldex Therapeutics (see App. Br. 2). Appeal 2013-001941 Application 12/092,180 2 Statement of the Case Background “[I]mmunotherapy trials suggest that despite the inherent immunosuppression of malignant glioma patients, efficacious immune responses can be generated. However, there is reluctance to not treat GBM [glioblastoma] patients with some form of chemotherapy given the recently established standard of care and the overall poor prognosis” (Spec. ¶ 4). The Claims Claims 1, 3, 4, 7–11, 13, 18, 19, 23, and 44–55 are on appeal.2 Independent claim 1 is representative and reads as follows: 1. A method of treating a tumor expressing EGFRvIII in a subject, comprising the steps of: administering to the subject an amount of an EGFRvIII peptide effective to induce an IgG response to EGFRvIII peptide or to induce EGFRvIII peptide-specific - IFN producing CD8+ T cells, after administering an amount of temozolomide or a pharmaceutically acceptable salt thereof effective to induce lymphopenia of CD8+ T cells; wherein the combined administration of the peptide and the temozolomide or pharmaceutically acceptable salt thereof increases immunotherapeutic efficacy. The Issues A. The Examiner rejected claims 1, 3, 4, 7, 10, 11, 13, 18, 19, 23, and 44–55 under 35 U.S.C. § 103(a) as obvious over Heimberger,3 Moscatello,4 Terando,5 and Su6 (Ans. 2–7). 2 The Examiner withdrew the rejection with regard to claims 5, 6, 12, 15–17, 20–22, and 24 (see App. Br. 2). Appeal 2013-001941 Application 12/092,180 3 B. The Examiner rejected claims 8 and 9 under 35 U.S.C. § 103(a) as obvious over Heimberger, Moscatello, Terando, Su, Salceda,7 and Carter8 (Ans. 7–8). A. 35 U.S.C. § 103(a) over Heimberger, Moscatello, Terando, and Su The Examiner finds that Heimberger teaches “a method of treating a subject having an intracerebral tumor, comprising administering an EGFR peptide vaccine which is effective to produce an IgG response” (Ans. 3). The Examiner acknowledges that Heimberger “does not teach that further administration of a second chemotherapeutic agent which induces CD8+ lymphopenia such as temozolomide in combination with the EGFR peptide vaccine” (Ans. 4). The Examiner finds that Su teaches “a method of treating cancer in a patient comprising administering TMZ, i.e., temozolomide[,] a DNA 3 Heimberger et al., Epidermal Growth Factor Receptor VIII Peptide Vaccination Is Efficacious against Established Intracerebral Tumors, 9 Clinical Cancer Research 4247–4254 (2003). 4 Moscatello et al., A Naturally Occurring Mutant Human Epidermal Growth Factor Receptor as a Target for Peptide Vaccine Immunotherapy of Tumors, 57 Cancer Research 1419– 1424 (1997). 5 Terando et al., On combining antineoplastic drugs with tumor vaccines, 52 Cancer Immunol. Immunother. 680–685 (2003). 6 Su et al., Selective CD4+ Lymphopenia in Melanoma Patients Treated With Temozolomide: A Toxicity With Therapeutic Implications, 22 J. Clinical Oncology 610–616 (2004). 7 Salceda et al., US 2002/0155464 A1, published Oct. 24, 2002. 8 Carter, J., Conjugation of Peptide to Carrier Proteins via m- Maleimidobenzoyl-N-Hydroxysuccinimide Ester (MBS) in The Protein Protocols Handbook 689–692 (J.M. Walker Ed. 1996). Appeal 2013-001941 Application 12/092,180 4 alkylating agent[,] and that TMZ is FDA approved to treat brain tumors” (Ans. 4). The Examiner finds that Su teaches that the “treatment regimen can result in a reduction of CD8+ cells, i.e., CD8+ lymphopenia is observed” but that Su also “makes the observation that TMZ reduces CD4+CD25+ regulatory T cells and suggest that TMZ might offer a pharmacologic strategy that could actually lead to augmented immune results previously observed in mouse models” (Ans. 4–5). The Examiner finds that Terando teaches “how the effectiveness of immunotherapeutic techniques, including adoptive T-cell transfer immunotherapy and vaccine strategies, can be enhanced when used in concert with lymphopenia-inducing chemotherapy” (Ans. 5). The Examiner finds it obvious to combine because “Su et al establish that TMZ is a DNA alkylating agent that induces lymphopenia, including CD8+ cell lymphopenia and Terando provide motivation to combine chemotherapy-induced lymphopenia with peptide vaccines and Heimberger et al teach an EGFRvIII peptide that can induce an IgG response to treat cancers expressing EGFRvIII” (Ans. 10–11). The issue with respect to this rejection is: Does the evidence of record support the Examiner’s conclusion that Heimberger, Su, Moscatello, and Terando render the claims obvious? Findings of Fact 1. Heimberger teaches that the “EGFR gene is often amplified and mutated in human neoplasms. The most common mutation, EGFRvIII, enhances tumorigenicity and occurs in a large proportion of malignant brain tumors and tumors that commonly metastasize to the brain, such as breast Appeal 2013-001941 Application 12/092,180 5 and non-small cell lung carcinomas” (Heimberger 4247, col. 2; references omitted). 2. Heimberger teaches that the mutation “encodes a tumor-specific protein sequence that is expressed on the surface of tumor cells but is not present in normal tissues, making it an ideal target for antitumor immunotherapy” (Heimberger 4247, col. 2). 3. Heimberger teaches that: Tumors developed in all of the C57BL/6J mice vaccinated with KLH in Freund’s adjuvant, and there were no long- term survivors. In contrast, in two separate experiments, tumors never developed in 70% of the PEP-3-KLH- vaccinated mice (n = 10 mice/experiment). In addition, in the PEP-3-KLH-vaccinated mice in which tumors did develop, the volume was significantly less than that in the KLH-vaccinated control mice. (Heimberger 4249, col. 2). 4. Heimberger teaches that: we performed in vivo depletion studies of granulocytes, CD4+ T cells, CD8+ T cells, and NK cells in C57BLl6J mice vaccinated with PEP-3-KLH 3 days before tumor challenge to determine which cell subsets were involved in the effector function. . . . Depletion of CD4+ T cells (n = 10) or granulocytes (n = 4) did not alter the efficacy of the PEP-3-KLH vaccinations. However, depletion of CD8 + T cells (n = 10) diminished the efficacy of the PEP-3-KLH vaccination. Additionally, depletion of the NK cells led to a significant decrease in the efficacy of the PEP-3-KLH vaccinations, with 30% of the mice showing long-term survival and no increase in the median survival time compared with that in the KLH-vaccinated mice (P = 0.44). Furthermore, the efficacy of the PEP-3-KLH vaccination in suppressing tumor volume was abrogated when NK or Appeal 2013-001941 Application 12/092,180 6 CD8+ T cells were depleted . . . To determine whether vaccination with PEP-3-KLH protected against the formation of intracerebral tumors in this model, C57BL/6J mice received three vaccinations. (Heimberger 4250, col. 1–2). 5. Su teaches that “TMZ [temozolomide] has been approved by the US Food and Drug Administration for treatment of anaplastic astrocytoma at a dose of 150 to 200 mg/m2 orally (PO) daily for 5 days every 4 weeks” (Su 610, col. 2). 6. Su teaches that in “patients receiving TMZ according to the standard dose and schedule, lymphopenia seems to be uncommon. For example, in the randomized phase III trial in which 156 patients were treated with TMZ, lymphopenia was not reported” (Lu 615, col. 2). 7. Su teaches that, using their extended administration protocol, in “all 11 patients, the absolute CD4+ T -cell counts were depressed (median CD4+ lymphocyte nadir, 150/µl; range, 44 to 346); the absolute CD8+ T-cell counts were also decreased in five of the patients” (Su 613, col. 1). 8. Su teaches that: The CD4+ lymphopenia induced by TMZ may have complex implications for experimental vaccine therapy. CD4+ T-cell help is very important for immunity against melanoma in mouse models. Vaccines meant to induce T - cell responses might be compromised by CD4+ lymphopenia induced by TMZ and patients who have been treated with TMZ may be poor vaccine candidates. Alternatively, our observation that TMZ depleted CD4+ CD25+ regulatory T cells suggests that TMZ might offer a pharmacologic strategy that could actually lead to an augmented immune responses. For instance, selective depletion of CD4+ CD25+ Appeal 2013-001941 Application 12/092,180 7 T cells enhances immunity induced by vaccine in mouse models (Su 616, cols. 1–2). 9. Terando teaches that: With the advent of the increasing use of immunotherapy in the clinical setting, investigators have sought to determine ways in which to combine accepted chemotherapeutic regimens with innovative immunotherapeutic techniques, and have discovered that the lymphodepletion that results from antineoplastic drug administration may be, in some cases, advantageous in eliciting clinically relevant responses to cancer immunotherapy. As well, several of these drugs have been found, paradoxically, to actually augment antitumor immunity. (Terando 680, col. 1). 10. Terando teaches that “it may ultimately be found that chemotherapy combined with vaccine therapy offers therapeutic advantages over single-modality treatment” (Terando 680, co. 1). 11. Terando teaches that: Nigam and colleagues vaccinated BALB-C mice with a GM-CSF-secreting cancer cell vaccine followed 1 week later by intraperitoneal administration of one of a variety of anticancer drugs. . . . Of the 11 agents tested, doxorubicin was the only drug that increased effector cell activity. While nine of the remaining 10 drugs resulted in either no change or a decrease in effector T-cell function, cyclophosphamide appeared to be the only agent that reduced effector function to the level of the unvaccinated controls. Based on previous studies of the positive immunomodulatory effects of cyclophosphamide, this was somewhat surprising. (Terando 682, col. 2). Appeal 2013-001941 Application 12/092,180 8 12. Terando teachs that: When neu-transgenic mice were given chemotherapy (with cyclophosphamide, doxorubicin, or paclitaxel) prior to vaccine administration, it was found that the animals pretreated with cyclophosphamide and paclitaxel both exhibited an increase in neu-specific T cells as determined by ELISpot analysis . . . cyclophosphamide and paclitaxel were found to augment tumor protection from neu- and GMCSF- expressing whole tumor vaccines in neu- transgenic animals when given prior to vaccination. (Terando 683, col. 1). 13. Terando teaches that “two studies demonstrate that active immunization strategies are significantly more successful when they are employed in a lymphopenic host” (Terando 684, col. 1). 14. Terando teaches that: Berd et al. in 1986 published the first trial of combined cyclophosphamide and vaccine therapy to treat human patients with melanoma. This study treated 19 patients with metastatic melanoma with an autologous melanoma cell vaccine either alone, or preceded by cyclophosphamide, and demonstrated in vivo immunopotentiation by cyclophosphamide as shown through increased DTH responses from vaccine administration in the cyclophosphamide pre-treatment group. (Terando 683, col. 1; reference omitted). 15. Terando teaches that “[i]f a lymphopenic environment is conducive to the proliferation of tumor-specific T cells, then it would follow that active immunization strategies employed in a lymphopenic setting may be more effective than those administered to an immunocompetent host” (Terando 683, col. 2). Appeal 2013-001941 Application 12/092,180 9 16. Terando teaches that “[t]his is the first study in which lymphodepletion has been used successfully to augment adoptive immunotherapy in humans, and future studies are needed to test whether the inclusion of vaccines in this setting provide additional therapeutic benefit” (Terando 684, col. 2). 17. Moscatello teaches that the “fact that this mutant EGF receptor is tumor specific and at least capable of eliciting a humoral response in animals raises the possibility that a vaccine based on this alteration could be used as a peptide vaccine against tumors” (Moscatello 1419, col. 2). Principles of Law “Obviousness does not require absolute predictability of success . . . all that is required is a reasonable expectation of success.” In re O’Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988). Analysis Claim 1 We adopt the Examiner’s findings of fact and reasoning regarding the scope and content of the prior art (Ans. 2–7; FF 1–17) and agree that claim 1 is obvious over Heimberger, Moscatello, Terando, and Su. Terando suggests that cancer “chemotherapy combined with vaccine therapy offers therapeutic advantages over single-modality treatment” (FF 10). Heimberger and Moscatello teach treatment of certain cancers containing an EGFRvIII mutation with tumor vaccine therapies (FF 1–4, 17). Su teaches the use of temozolomide (TMZ) for cancer treatment (FF 5). Su teaches that “TMZ depleted CD4+ CD25+ regulatory T cells suggests that TMZ might offer a pharmacologic strategy that could actually lead to an Appeal 2013-001941 Application 12/092,180 10 augmented immune responses. For instance, selective depletion of CD4+ CD25+ T cells enhances immunity induced by vaccine in mouse models” (FF 8). We agree with the Examiner that the ordinary artisan, motivated by Terando to combine chemotherapy with vaccine therapy (FF 10, 16), would have reasonably lymphodepleted cancer patients with TMZ as taught by Su (FF 7–8) prior to the EGFRvIII vaccine treatments of Heimberger and Moscatello (FF 1–4, 17) because Terando teaches that “lymphodepletion has been used successfully to augment adoptive immunotherapy” (FF 16) and Su teaches that T cell depletion “enhances immunity induced by vaccine in mouse models” (FF 8). Appellants contend that “[t]aken together, the two references, Heimberger and Su, would lead one of skill in the art to expect that TMZ would diminish and/or abrogate the efficacy of EGFRvIII vaccination” (App. Br. 5). Appellants contend that “Terando teaches that the immunomodulation effects of non-TMZ drugs, cyclophosphamide, adriamycin, and taxanes were varied and unpredictable” (App. Br. 5). We do not find these arguments persuasive because they do not recognize the significance placed by Terando and Su on timing of vaccine treatment relative to chemotherapy. When Appellants note that only one out of eleven drugs tested by Terando increased effector cell activity (see App. Br. 5; FF 11), this result occurred when the tumor vaccine was administered first and the drug was administered second (FF 11), an order that also differs from that required by claim 1 of treating with TMZ first followed by treatment with the EGFRvIII vaccine (see Claim 1). Appeal 2013-001941 Application 12/092,180 11 Terando cites a prior art example of efficacy when the claimed order of administration is used, with chemotherapeutic followed by vaccine, specifically teaching that “cyclophosphamide and paclitaxel were found to augment tumor protection from neu- and GMCSF- expressing whole tumor vaccines in neu-transgenic animals when given prior to vaccination” (FF 12). Terando also cites a prior art human clinical example that “demonstrated in vivo immunopotentiation by cyclophosphamide as shown through increased DTH responses from vaccine administration” (FF 14). That is, Terando teaches that treatment with the chemotherapeutic agent cyclophosphamide enhanced the ability of a vaccine to treat melanoma (FF 14). Su also cites a prior art teaching that “selective depletion of CD4+ CD25+ T cells enhances immunity induced by vaccine in mouse models” (FF 8). Thus, while the evidence of record shows that administering a vaccine first, followed by chemotherapeutic, may reduce vaccine efficacy (FF 11), the evidence of record also demonstrates that administering a chemotherapeutic agent first, followed by vaccine administration, frequently enhances vaccine efficacy (FF 8, 12–16). This evidence therefore supports the Examiner’s finding of a reasonable expectation in success in performing the treatment required by claim 1 in the order required by claim 1 (Ans. 6– 7). Appellants contend that “[i]t is improper according to Gore and Grasseli to make the rejection because at least Heimberger, the primary Appeal 2013-001941 Application 12/092,180 12 reference, and Su teach away from the invention for treating tumors” (App. Br. 7). We do not find Appellants’ teaching away argument persuasive. A teaching away requires a reference to actually criticize, discredit, or otherwise discourage the claimed solution. See In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004). Here, Heimberger teaches that immunodepletion after vaccination reduced vaccine efficacy (FF 4), a finding that differs from the order required by claim 1 and the order suggested by Terando, where chemotherapeutic lymphodepletion occurs first, before vaccination (FF 16). Similarly, Su also teaches that the order of administration may be important and cites a prior art teaching that “selective depletion of CD4+ CD25+ T cells enhances immunity induced by vaccine in mouse models” (FF 8). Therefore, Heimberger and Su are consistent with Terando, that administering a vaccine before lymphodepletion may reduce vaccine efficacy (FF 11), and do not teach away from Terando’s teaching that administering a chemotherapeutic causing lymphodepletion first followed by vaccine enhances vaccine efficacy (FF 12–16). Claims 44–49 Appellants contend that none of the cited prior art teach or suggest the particular timing or mode of the administration of the two agents as recited in claims 44–49, namely, after the CD8+ T cells begin to recover from nadir of the induced lymphopenia, after TREG cells in the subject reach a peak and are declining in response to the temozolomide, or repeatedly in a cycle. (App. Br. 6). Appeal 2013-001941 Application 12/092,180 13 The Examiner finds that based on Terando “one of skill in the art would have administered the EGFRvIII peptide after the CD8+ T cells begin to recover from nadir, i.e., low point, of the induced lymphopenia because if the chemotherapy was still reducing the number of T cells then homeostatic proliferation would not be effective” (Ans. 11). The Examiner further finds that Su and Heimberger “administer temozolomide or the peptide repeatedly, so that when administering temozolomide or salt thereof and the peptide after, one of skill in the art would continue cycling the treatments as needed to achieve maximal treatment in the patient” (Ans. 11). We find that Appellants have the better position regarding claims 44 and 45, but that the Examiner has the better position regarding claims 46–49. Specifically, while Terando and Su teach the desirability of lymphodepletion, the Examiner has not identified any specific teaching or suggestion to administer the EGFRvIII peptide vaccine after the CD8+ cells have begun to recover from their lowest level as required by claims 44 and 45. Instead, Terando teaches to administer the vaccine after performing lymphodepletion but without identifying a specific level or degree of lymphodepletion that should be achieved prior to vaccine administration. Further, while the dosing schedule would be subject to optimization, the evidence does not suggest a reason to wait until the CD8+ cells increase from their lowest levels as required by the claims. In contrast, claims 46 and 47 are simply drawn to a decline in TREG cells in a subject, that is, to lymphodepletion (see Ans. 11–12). Because we already agree with the Examiner that Terando and Su suggest lymphodepletion prior to vaccine administration, we agree with the Appeal 2013-001941 Application 12/092,180 14 Examiner that Terando and Su are reasonably understood to suggest administering vaccines after regulatory cells such as CD8+ cells begin declining in number relative to their original starting peak due to the chemotherapeutic agent (FF 8, 12–16). We also agree with the Examiner that claims 48 and 49 are rendered obvious by Heimberger and Su, where Heimberger teaches multiple vaccine treatments (FF 4) and Su teaches cyclic dosing using TMZ (FF 5–6). Therefore combining these two therapies into a cyclic dosing approach reasonably represents routine optimization of the combination suggested by Terando (FF 9). Conclusion of Law The evidence of record supports the Examiner’s conclusion that Heimberger, Su, Moscatello, and Terando render claims 1 and 46–49 obvious. The evidence of record does not support the Examiner’s conclusion that Heimberger, Su, Moscatello, and Terando render claims 44 and 45 obvious. B. 35 U.S.C. § 103(a) over Heimberger, Moscatello, Terando, Su, Salceda, and Carter Appellants do not separately argue the claims in this obviousness rejection. Having affirmed the obviousness rejection of claim 1 over Heimberger, Su, Moscatello, and Terando, we also find that the further combination with Salceda and Carter is sound and fact based and renders the remaining claims obvious for the reasons given by the Examiner (see Ans. 7–8). Appeal 2013-001941 Application 12/092,180 15 SUMMARY In summary, we affirm the rejection of claims 1 and 46–49 under 35 U.S.C. § 103(a) as obvious over Heimberger, Su, Moscatello, and Terando. Pursuant to 37 C.F.R. § 41.37(c)(1), we also affirm the rejection of claims 3, 4, 7, 10, 11, 13, 18, 19, 23, and 50–55, as these claims were not argued separately. We reverse the rejection of claims 44 and 45 under 35 U.S.C. § 103(a) as obvious over Heimberger, Su, Moscatello, and Terando. We affirm the rejection of claims 8 and 9 under 35 U.S.C. § 103(a) as obvious over Heimberger, Moscatello, Terando, Su, Salceda, and Carter. 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-IN-PART dm Copy with citationCopy as parenthetical citation