DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1, 4, 6, 9, 14, 15, 18, 28 and 35-44 are pending and under examination.
Objections to Specification
The objections to the specification are withdrawn in view of Applicant’s amendments to the Specification.
Objections to Drawings
The objections to the specification are withdrawn in view of Applicant’s submission of a replacement drawing for Figure 11.
35 USC § 103 rejections withdrawn
The rejection of claims 4 and 14 under 35 U.S.C. 103 as being unpatentable over Taylor et al (Current Cancer Drug Discovery 12:197-209, 2012) in view of Pi et al (WO 2015/009879, published January 22, 2015, IDS) in further view of Kankia et al (Oxidative Medicine and Medicine and Cellular Longevity, ID 1864578, pages 1-19, 2017, IDS), Zhang et al (Bioscience Hypotheses, 2:261-263, 2009, IDS) and Ma et al (Med Oncol 32:1-6, 2015) are withdrawn in view of Applicant’s arguments.
35 USC § 103 rejections maintained
The rejections of claims 1, 6, 9, 15, 18, 28 and 35-44 under 35 U.S.C. 103 as being unpatentable over Taylor et al (Current Cancer Drug Discovery 12:197-209, 2012) in view of Pi et al (WO 2015/009879, published January 22, 2015, IDS) in further view of Kankia et al (Oxidative Medicine and Medicine and Cellular Longevity, ID 1864578, pages 1-19, 2017, IDS), Zhang et al (Bioscience Hypotheses, 2:261-263, 2009, IDS) and Ma et al (Med Oncol 32:1-6, 2015) are maintained.
The claims are drawn to a method for treating glioma comprising administering an agent that modulates epidermal growth factor receptor (EGFR) signaling, and an agent that modulates Nrf2 signaling wherein the agent that modulates EGFR signaling is erlotinib and the Nrf2 inhibitor is isoniazid.
Taylor discloses the treatment of malignant glioma with EGFR-targeted therapies including erlotinib. (page 201; Table 1). Taylor discloses that EGFR-targeted agents hold great potential, however, successful treatment of malignant gliomas continues to be a major therapeutic challenge due to both inherent and acquired resistance (page 202-203).
Taylor does not discloses the treatment of malignant glioma with an agent that modulates Nrf2 signaling.
Pi discloses the treatment of cancer comprising the administration of an agent that modulates Nrf2 signaling (page 3, lines 29-31) Pi discloses that constitutive activation of Nrf2 has been observed in many human solid nonlymphoid tumors, including gliomas cancer (page 2, lines 4-8). Pi discloses that inhibitors of Nrf2-
Nrf2 inhibitors may result in enhancing the effectiveness of other agents (e.g., therapeutic agents) or treatment modalities (e.g. radiation treatment for cancer) that would otherwise be less effective or ineffective for treating cancer characterized by constitutive activation of Nrf2 (page 3, line 32 to page 7). Pi discloses that Nrf2 inhibitors include isoniazid (page 4, lines 14-27). Pi disclose that two therapeutic agents may be administered simultaneously or sequentially (page 6, line 29 to page 7, line 5; page 15, lines 5-19). Pi discloses oral administration and injections (page 14, line 27 to page 16, line 4).
One of ordinary skill in the art would have been motivated to apply Pi’s method of treating glioma with an agent that modulates Nrf2 signaling with Taylor discloses the treatment of malignant glioma with EGFR-targeted therapies including erlotinib because both Pi and Taylor disclose the treatment of glioma with agent that modulates Nrf2 signaling and erlotinib, respectively. it must be remembered that “[w]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious.” KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. A.G. Pro, 425 U.S. 273, 282 (1976)). “[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious,” the relevant question is “whether the improvement is more than the predictable use of prior art elements according to their established functions.” (Id.). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 “need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.” KSR at 1741. The Court emphasized that “[a] person of ordinary skill is… a person of ordinary creativity, not an automaton.” Id. at 1742.
In addition, the court has held that it is obvious to combine two compositions, in order to form a third composition, when each of the two compositions is taught by the prior art to be useful for the same purpose. (In re Kerkhoven, 626, F.2s 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). The idea of combining them flows logically from their having been individually taught in the prior art (MPEP 2144.06). Combining prior art elements according to known methods to yield predictable results is an exemplary rationale for a prima facie case of obviousness. MPEP2143. Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to combine Taylor disclosure of the treatment of malignant glioma with EGFR-targeted therapies including erlotinib with Pi’s method of treating glioma with an agent that modulates Nrf2 signaling because the prior art teaches that both an Nrf2 inhibitor and erlotinib are useful for the treatment of malignant glioma.
Furthermore, Pi discloses that Nrf2 inhibitors may enhance the effectiveness of other therapeutic agents for treating cancer that would otherwise be less effective or ineffective for treating cancer characterized by constitutive activation of Nrf2. Kankia discloses that erlotinib have been in clinical use over the last decade but the efficacy of these drugs is potentially reduced due to frequent emergence of resistance (page 15). Kankia discloses that studies have implicated NRF2 in promoting resistance to chemotherapeutic agents (page 2, 1st column). Kankia suggests that manipulating Nrf2 may enhance the effectiveness of RTK inhibition (Id). Kankia discloses that there was a significant increased cytotoxicity of erlotinib in ovarian cancer cells following the pharmacological inhibition of NRF2 (Figure 9).
Zhang discloses that EGFR-Nrf2 pathway plays a role in cancer cells’ chemoresistance (Abstract). Zhang discloses that Nrf2 is upregulated in resistant cancer cells and is thought to be responsible for acquired chemoresistance (page 262, 2nd column). Further, Zhang disclose that RNAi-mediated silencing of Nrf2 gene expression in non-small cell lung cancer can inhibit tumor growth and increase efficacy of chemotherapy (Id).
Ma discloses that overexpression of Nrf2 in the glioma treated with the combination of TMZ and irradiation was shown to play an important role in the acquisition of drug resistance (page 4, 2nd column). Ma demonstrated that TMZ is sufficient to induce the expression of Nrf2, and this event renders the insensitivity of glioma to TMZ (page 5, 2nd column). Ma discloses that that p38 MAPK signaling mediates the promoting effect of TMA on Nrf2 abundance in glioma cells (Id).
Thus, Kankia, Zhang and Ma all disclose that expression of Nrf2 correlated with chemoresistance. As stated in KSR International Co. v. Teleflex., 82 USPQ2d 1385 (US 2007)
"When a person of ordinary skill is faced with "a finite number of identified,
predictable solutions" to a problem and pursues "the known options within his or her technical grasp," the resulting discovery "is likely the product not of innovation but of ordinary skill and common sense." KSR, 127 S. Ct. at 1742. So too, "[glranting patent protection to advances that would occur in the ordinary course without real innovation retards progress."
Given the disclosure that overexpresson of Nrf2 in cancer including glioma correlates with chemoresistance, given that EGFR-targeted therapies including erlotinib are used in the treatment of malignant glioma and given that resistance frequently occurs during treatment of glioma with EGFR-targeted therapies, it would have been obvious to administer both an agent that modulates EGFR signaling and an agent that modulates Nrf2 signaling for the treatment of malignant glioma.
One of ordinary skill in the art would have had a reasonable expectation of success given the role of overexpresson of Nrf2 in chemoresistance and the treatment of glioma with EGFR-targeted therapies. Furthermore, the art discloses that both EGFR-targeted therapies and agent that modulates Nrf2 signaling may be used for the treatment of glioma.
In response to Applicant’s argument that Applicant argues that the cited art, individually and collectively, fails to establish such a reasonable expectation of success for the claimed combination of an EGFR inhibitor selected from erlotinib, afatinib, gefitinib, lapatinib, and osimertinib and an agent that modulates Nrf2 signaling selected from isoniazid, ML385, ethionamide, sulfasalazine, and erastin in the treatment of glioma, Taylor discloses the treatment of malignant glioma with EGFR-targeted therapies including erlotinib while Pi discloses the treatment of cancer, including glioma, comprising the administration of an agent that modulates Nrf2 signaling. Given that EGFR inhibitors and Nrf2 inhibitors were well known in the art and have been used to treat cancer it is unclear why there would not be a reasonable expectation of success of treating glioma in a subject with known EGFR inhibitors and Nrf2 inhibitors. It is noted that the specification does not disclose the treatment of glioma in any subject with the known EGFR inhibitors and Nrf2 inhibitors.
Applicant argues that Taylor documents the consistent clinical failure of EGFR-targeted therapies in glioma treatment and attributes this failure to multiple, complex resistance pathways that do not include Nrf2. Applicant argues that even one of skill believed that Nrf2 overexpression contributes to chemoresistance in some contexts the skilled artisan would also recognize that addressing only one of the many documented resistance pathways in a glioma would be highly unlikely to produce a meaningful therapeutic benefit. Applicant argues that this is especially true where the resistance mechanisms of the primary cited reference (e.g., PTEN loss, RTK co-activation, cancer stem cells, BBB limitations) would remain unaddressed by Nrf2 modulation. Applicant argues that because the dominant resistance mechanisms would persist regardless of Nrf2 status, the skilled artisan would not have reasonably expected the claimed combination therapy to be successful.
Applicant further argues that Pi cannot cure the deficiencies of Taylor because Pi also does not teach or suggest that Nrf2 modulators can circumvent the established resistance mechanisms associated with EGFR-targeted therapies. Applicant argue that Pi's disclosures fall far short of creating a reasonable expectation of success for the specific combination claimed here because Pi does not provide any experimental data involving glioma cells. Applicant argues that while glioma is listed amongst the many alternative cancers theorized by Pi to exhibit constitutive Nrf2 activation, Pi's working examples (Examples 1-3) are confined to 3T3-Ll preadipocytes, HepG2 hepatocellular carcinoma cells, THP-1 leukemia cells, U937 leukemia cells, A549 lung carcinoma cells, and HaCaT keratinocytes. Applicant argues that there is not a single experiment in Pi using glioma cells and no data in Pi to suggest that combining inhibition of EGFR and Nrf2 may be successful.
Applicant also argue that Pi's list of therapeutic agents with which Nrf2 inhibitors might be combined encompasses virtually every class of anticancer drug in existence - alkylating agents, antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors, mitotic inhibitors, corticosteroids, proteosome inhibitors, immunotherapeutics (including gefitinib), differentiating agents, and hormonal agents. Applicant argues that this vast breadth of disclosure falls far short of providing a reasonable expectation of success for any one drug class combination in particular.
Applicant’s arguments have been considered but are not persuasive. In response to applicant's arguments against Taylor and Pi, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Taylor discloses the treatment of malignant glioma with EGFR-targeted therapies including erlotinib while Pi discloses the treatment of cancer, including glioma, comprising the administration of an agent that modulates Nrf2 signaling. As discussed above, there was ample motivation to combine Taylor with Pi. In addition, a prior art reference is relevant for all its teachings, not only its examples. Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989) (holding that both preferred and unpreferred embodiments must be considered). In addition, Applicants point to narrow embodiments which are not the sum total of information conveyed by each. Art is art, not only for what it expressly teaches, but also for what it would reasonably suggest to the skilled artisan, including alternative or non-preferred embodiments. MPEP § 2123.
Furthermore, prior art is presumed to be operable/enabling MPEP 2121. The specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908, 164 USPQ 642, 645 (CCPA 1970). Furthermore, MPEP 2121, part III states A prior art reference provides an enabling disclosure and thus anticipates a claimed invention if the reference describes the claimed invention in sufficient detail to enable a person of ordinary skill in the art to carry out the claimed invention; "proof of efficacy is not required for a prior art reference to be enabling for purposes of anticipation." Impax Labs. Inc. v. Aventis Pharm . Inc., 468 F.3d 1366, 1383, 81 USPQ2d 1001, 1013 (Fed. Cir. 2006). See also MPEP § 2122.
Applicant is reminded that when the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. Once such a reference is found, the burden is on applicant to provide facts rebutting the presumption of operability. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980). Objective evidence which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Thus, Applicants’ arguments that the disclosures of Taylor and Pi are nonenabling (e.g., inoperable) are not found persuasive in the absence of objective evidence.
Furthermore, Applicant appears to be arguing that the mechanisms of actions for the EGFR inhibitors and the Nrf2 inhibitors were not specifically known in the prior art. However, the claims are drawn to a method of treating glioma in a subject. Given that EGFR inhibitors and Nrf2 inhibitors were taught to treat glioma, it would have been obvious to combine Taylor with Pi to treat glioma. Applicant appears to be arguing why the results of such a combination would be unexpected.
It is noted, as stated above, that that the specification does not disclose the treatment of glioma in any subject with the known EGFR inhibitors and Nrf2 inhibitors.
In addition, Applicant argues that Kankia's results were obtained exclusively in
human ovarian cancer cell lines (PEOl, SKOV3, and OVCAR3) (not glioma cancer cell lines), using bexarotene (not isoniazid, ML385, sulfasalazine, or erastin) as the Nrf2
inhibitor. Applicant argues that a person of ordinary skill would not reasonably extrapolate the results in Kankia from ovarian cancer to predict therapeutic success in glioma - a distinct cancer type characterized by intratumoral heterogeneity and a uniquely immunosuppressive microenvironment that requires drugs that cross the blood-brain barrier, none of which features are present in ovarian cancer.
Applicant argues that Zhang merely discloses a hypothesis that EGFR stimulates cancer cells' defense against cytotoxic drugs through the Nrf2 pathway, proposing that "EGFR targeted drugs should act synergistically with conventional chemotherapy in clinic, especially for the platinum-based chemotherapy drugs, which can generate ROS that activates Nrf2." Applicant argues that Zhang provides no experimental data
testing this hypothesis and, in fact, explicitly states that the hypothesis remains to be tested. Applicant argues that to the extent Zhang discloses that "EGFR targeted drugs" should be used in combination with additional active agents, Zhang only suggests that synergism may be achieved with "conventional chemotherapy" (i.e., cytotoxic agents such as platinum drugs) - not with Nrf2 modulators to overcome resistance to a specific EGFR inhibitor in a specific tumor type.
Applicant argues that Ma demonstrates that Nrf2 contributes to temozolomide (TMZ) resistance in glioma, but TMZ is a DNA-alkylating agent with a fundamentally different mechanism of action from the EGFR inhibitors recited herein. Applicant argues that the fact that Nrf2 mediates resistance to one class of drug does not create a reasonable expectation that modulating Nrf2 will overcome resistance to a mechanistically unrelated drug in the same disease. Applicant argues that this drug-specific induction mechanism cannot simply be extrapolated to EGFR inhibitors such as erlotinib, afatinib, gefitinib, lapatinib, and osimertinib. Ma shows only that "TMZ is sufficient to induce the expression of Nrf2, and this event renders the insensitivity of glioma to TMZ." Applicant argues that there is no evidence in Ma that EGFR inhibitor treatment induces Nrf2 in glioma cells.
In response to Applicant’s argument that a person of ordinary skill would not reasonably extrapolate the results in Kankia from ovarian cancer to predict therapeutic success in glioma - a distinct cancer type characterized by intratumoral heterogeneity and a uniquely immunosuppressive microenvironment that requires drugs that cross the blood-brain barrier, none of which features are present in ovarian cancer, Kankia discloses that studies have implicated NRF2 in promoting resistance to chemotherapeutic agents. Kankia suggests that manipulating Nrf2 may enhance the effectiveness of RTK inhibition. Thus, Kankia was referring to a variety of cancers in which it has been found that NRF2 may inhibit the effectiveness to various tyrosine kinases. Given that Kankia was discussing the use of Nrf2 inhibitors for cancer treatment Kankia was clearly an analogous art. MPEP 2141.01(a) I recites that a reference is analogous art to the claimed invention if: (1) the reference is from the same field of endeavor as the claimed invention (even if it addresses a different problem); or (2) the reference is reasonably pertinent to the problem faced by the inventor (even if it is not in the same field of endeavor as the claimed invention). See Bigio, 381 F.3d at 1325, 72 USPQ2d at 1212.
Furthermore, Kankia was only being used to support the treatment of glioma with Nrf2 inhibitors and EGFR inhibitors as was Ma. Ma discloses that overexpression of Nrf2 in the glioma treated with the combination of TMZ and irradiation was shown to play an important role in the acquisition of drug resistance. Even without Kankia and Ma there would have been motivated to combine Taylor and Pi. Taylor discloses the treatment of malignant glioma with EGFR-targeted therapies including erlotinib while Pi discloses the treatment of cancer, including glioma, comprising the administration of an agent that modulates Nrf2 signaling. Thus, both Taylor and Pi disclose the treatment of glioma with different anti-cancer agents.
In addition, most tumors exhibit intratumoral heterogeneity and both Kankia and the present specification use cell lines so it is not clear the relevance of the requirement that the drugs cross the blood-brain barrier.
In response to Applicant’s arguments that Zhang provides no experimental data testing this hypothesis and, in fact, explicitly states that the hypothesis remains to be tested, the specification, prior art is presumed to be operable/enabling MPEP 2121. The specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908, 164 USPQ 642, 645 (CCPA 1970). Furthermore, MPEP 2121, part III states
A prior art reference provides an enabling disclosure and thus anticipates a claimed invention if the reference describes the claimed invention in sufficient detail to enable a person of ordinary skill in the art to carry out the claimed invention; "proof of efficacy is not required for a prior art reference to be enabling for purposes of anticipation." Impax Labs. Inc. v. Aventis Pharm . Inc., 468 F.3d 1366, 1383, 81 USPQ2d 1001, 1013 (Fed. Cir. 2006). See also MPEP § 2122.
Applicant is reminded that when the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. Once such a reference is found, the burden is on applicant to provide facts rebutting the presumption of operability. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980). Objective evidence which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Thus, Applicants’ arguments that Zhang et al provides no experimental data testing there hypothesis is not found persuasive in the absence of objective evidence. Further, Zhang was only being used to support the treatment of glioma with Nrf2 inhibitors and EGFR inhibitors. Even without Zhang there would have been motivated to combine Taylor and Pi. Taylor discloses the treatment of malignant glioma with EGFR-targeted therapies including erlotinib while Pi discloses the treatment of cancer, including glioma, comprising the administration of an agent that modulates Nrf2 signaling. Thus, both Taylor and Pi disclose the treatment of glioma with different anti-cancer agents.
In addition, Applicant argues that it has been surprisingly found that EGFR inhibition itself triggers activation of the Nrj2 signaling pathway as an adaptive survival mechanism in glioma cells, and, as such, combination treatments using an EGFR inhibitor and a Nrf2 modulator are significantly better than one of skill would have expected. Applicant argues that the data contained in the application as originally filed support that the combination of EGFR inhibition and Nrf2 modulation results in a synergistic effect over administration of either agent in isolation. Applicant argues that as detailed in the instant application, transcriptome analysis of GBM12 cells treated with erlotinib revealed 3,635 upregulated genes, with 40 Nrf2 pathway/target genes significantly enriched. Applicant argues that his Nrf2 activation was confirmed in multiple patient-derived xenograft (PDX) lines and involves increased nuclear localization ofNrf2 and increased transcriptional activity of an Nrf2 reporter.
Applicant further argues that combination treatments for glioma involving
an EGFR inhibitor and a Nrf2 modulator were not merely additive; the results were synergistic. As illustrated by Figures 5A-D of the instant application, ''Nrf2 inhibition alone does not affect viability of glioma cells." Figures 5A-D. In all cases, a "significant
synergistic effect" was found using the recited combination.
Applicant argues that the observed synergistic effect was further confirmed in vivo in multiple orthotopic glioma models. In the GBM6 orthotopic model, for example, the combination of erlotinib plus INH significantly prolonged survival compared to erlotinib alone (p = 0.0046), while erlotinib alone or INH alone was ineffective. See as filed application at paragraph [00401] and Figure 6A and 6B). Applicant argues that the erlotinib plus INH combination was more effective than temozolomide (TMZ), the current standard of care, which was completely ineffective in this GBM6 model with unmethylated MGMT.
Applicant argues that these results are unexpected for at least two reasons. First, erlotinib alone has consistently failed in GBM clinical trials, as the Office Action's own primary reference Taylor recognizes, documenting only a "modest effect over placebo" in Phase II trials. Applicant argues that a person of ordinary skill would not have expected that adding a Nrf2 modulator such as isoniazid - a tuberculosis drug-would transform erlotinib from an ineffective agent into one that outperforms the standard of care. Second, none of the cited references provide any evidence to demonstrate that pharmacological Nrf2 modulation enhances EGFR-inhibitor efficacy in any cancer type, let alone in glioma specifically. Pi's experimental data involves sensitizing cancer cells to arsenic trioxide, not an EGFR inhibitor. Kankia used bexarotene (not isoniazid, ML385, ethionamide, sulfasalazine, or erastin) in ovarian cancer (not glioma). Applicant argues that the combination of EGFR inhibition and Nrf2 modulation even exceeded TMZ efficacy- a result no reference predicts - further underscores the unexpected nature of these results.
Applicant’s arguments have been considered but are not persuasive. Applicant has not demonstrated that co-treatment with the erlotinib and different Nrf2 had synergistic effects in suppressing glioma cell proliferation. The specification appears to show that only one dose of erlotinib and one dose of the different Nrf2 inhibitors decreased the viability of several glioblastoma cell lines. The specification also disclose that 50 mg/kg erlotinib plus 25 mg/kg INH was more effective than temozolomide and each of erlotinib and INH alone in the survival of gliobastoma cells in an animal model for gliobastoma.
Wiesenthal, (Human Tumor Assay Journal, on-line at (http://weisenthal.org/synergy1.htm, March 14, 2012) discusses the question of synergy between drug combinations and diseases.
Most "classic" drug combinations are only additive or are, at most, minimally synergistic. Examples of merely additive drug combinations are cisplatin/5FU, cisplatin/Taxol, and cisplatin/etoposide. However, some newer combinations show greater degrees of synergy, including cisplatin/topotecan, gemcitabine/platinum, and gemcitabine/alkylators. The profound synergy between gemcitabine/platinum in vitro has now been confirmed in the clinic in a number of settings. The similar degree of synergy between gemcitabine and alkylating agents suggest that these combinations should be explored in clinical settings in which alkylating agents are known to be important, particularly higher dose regimens with growth factor and/or stem cell support.
In particular, Weisenthal states that combination chemotherapy frequently, but not always, has produced greater degrees of clinical benefit than single agent therapy.” Wiesenthal further states that most “classic” drug combinations are only additive or are at most, minimally synergistic. Berenbaum (Clin exp Immunol, 1997, 28:1-18) disclose that to demonstrate the synergistic effect of two treatment agents, one must first prepare a dose-response curve for each agent alone (see Fig. 1 of Berenbaum). One must also prepare a number of combination treatments containing varying amounts of each agent. The results of all the treatments, each agent alone and the various combinations must be compared and analyzed quantitatively and statistically. The discussion on p. 2 of Berenbaum describes how the value obtained by measuring a response achieved by administering two pharmaceutical treatment agents is often mistaken for synergy when in reality it is the same as the effect obtained by using either agent alone. That is, the effect produced by administering agent A in a particular amount (e.g., x mg) and agent B in a particular amount (e.g., y mg) is the same as the one obtained by administering that total amount of agent A (x + y mg). Berenbaum also provides an algebraic method and a geometric method for determining the nature of the interaction of two agents (see pp. 3-5). To produce a graph such as Fig. 2 (p. 5), a particular response (effect) must be achieved by administering each agent alone. Different doses of agent A and different doses of agent B create the axes. A line is drawn between the two intercepts (the additivism line). A number of combinations of agent A and agent B, containing varying amounts of A and varying amounts of B, are tested, and the response is measured. The combinations producing the response achieved in the amount equal to that of the intercept points are determined and plotted as data points on the graph. If these data points fall below the additive line, the effect of the combination is considered to be synergistic.
In addition, Chou et al (Cancer Res, 70:440-446, 2010 states that “most clinical synergy claims thus far are not supported by the available data”. (page 441, 2nd column, heading 6). Chou also states that “synergism is more than an additive effect” (page 440, 2nd column). Chou suggests that the term “synergism” is frequently misused and that a particular method should be used to demonstrate synergism. Chou goes on to state that "faulty or unsubstantiated synergy claims are pervasive”. (page 440, 1st column). Chou further states that “most clinical synergy claims thus far, to my knowledge, are not supported by the available data”. (page 441, 2nd column, heading 6). Chou et al goes on to state that synergism needs to be determined with a combination index (CI) using the Chou-Talalay Method (Abstract, page 440, 1st column, heading 8).
Applicants have not demonstrated that co-treatment with erlotinib and the different Nrf2 inhibitors had synergistic effects in suppressing glioma cell proliferation. The specification appears to show that only one dose of erlotinib and one dose of the different Nrf2 inhibitors decreased the viability of several glioblastoma cell lines. The specification also disclose that 50 mg/kg erlotinib plus 25 mg/kg INH was more effective than temozolomide and each of erlotinib and INH alone in the survival of gliobastoma cells in an animal model for gliobastoma. Chou et al goes on to state that synergism needs to be determined with a combination index (CI) using the Chou-Talalay Method
In addition, MPEP 716.02(d) states
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at “elevated temperatures” using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110C and 130C. The court affirmed the rejection of claims 1-7 and 9-10 because the term “elevated temperatures” encompassed temperatures as low as 60C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.).
The specification appears to show that only one dose of erlotinib and one dose of the different Nrf2 inhibitors decreased the viability of several glioblastoma cell lines. The specification also disclose that 50 mg/kg erlotinib plus 25 mg/kg INH was more effective than temozolomide and each of erlotinib and INH alone in the survival of gliobastoma cells in an animal model for gliobastoma. Thus, the unexpected results claimed by Applicant does not demonstrate that the Nrf2 inhibitors could enhance the effect by afatinib, gefitinib, lapatinib, and osimertinib on the growth of glioblastoma cancer cells.
Double Patenting rejections maintained
The rejections of claims 1, 4, 6, 9, 14, 15, 18, 28 and 35-44 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 22, 23, 25 and 45-50 of copending Application No. 17/609757 are maintained.
Applicant requests that this provisional rejection be held in abeyance until the Examiner finds allowable subject matter in this case.
Summary
Claims 1, 4, 6, 9, 14, 15, 18, 28 and 35-44 stand rejected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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