DETAILED ACTION Notice of Pre-AIA or AIA Status The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Priority The present application, filed December 13, 2022, is a national stage application of PCT/GB2021/051621 , filed June 25, 2021, and claims priority to foreign priority application GB2009764.8 , filed June 26, 2020. Election/Restrictions Applicant’s election without traverse of Group I, claims 1-18, in the reply filed on December 1, is acknowledged. Claims 19-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on December 1, 2025. Status of the Application Claims 1-20 are pending and examined on the merits herein. Claims 19 and 20 are withdrawn as directed to a non-elected invention with this Office action. Claims 1-18 are examined on the merits herein. Information Disclosure Statement The information disclosure statement filed February 19, 2025 fails to comply with 37 CFR 1.98(a)(3) (i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. No explanation of relevance for citation no. 017 has been provided. This reference has been placed in the application file, but the information referred to therein has not been considered. Claim Objections Claim 14 is objected to because of the following informalities: Claim 14 recites methotrexate twice, once on line 3 of the claim and once on line 4 of the claim. In addition, claim 14 recites the cytotoxic agent idealisib, which the examiner believes should read as i delalisib . Appropriate correction is required. Claim Rejections - 35 USC § 102 In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention. (a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention. Claims 2 -4 , 8 - 11, 16, and 17 are rejected under 35 U.S.C. 102(a)(1) as being FILLIN "Insert either—clearly anticipated—or—anticipated—with an explanation at the end of the paragraph." \d "[ 3 ]" anticipated by Padda (Padda, S. K.; et al. Cancer Chemotherapy an d Pharmacology 2012, vol. 69, pp. 1013-1020; cited in PTO-892), as evidenced by Wang (Wang, Z.; et al. International Journal of Oncology 2016, vol. 48, pp. 2558-2566; cited in PTO-892) . Claim 1 is drawn to a method for increasing the sensitivity of a subject to a cytotoxic agent, the method comprising administering a PKC inhibitor and a cytotoxic agent to the subject, wherein the PKC inhibitor reaches a peak concentration in the subject prior to the cytotoxic agent reaching a peak concentration. Claim 2 is drawn to a method for treating cancer or an autoimmune disease in a subject, the method comprising administering a PKC inhibitor and a cytotoxic agent to the subject, wherein the PKC inhibitor reaches a peak concentration in the subject prior to the cytotoxic agent reaching a peak concentration. Claims 3-5 require the method is for treating cancer and specific types of cancer, and claims 6-7 require the method is for treating an autoimmune disease and specific type of autoimmune disease. Claim 8 requires the peak concentration of the PKC inhibitor is the maximum concentration that the PKC inhibitor reaches in the blood, cerebrospinal fluid, a target organ or a tumor after administration to the subject and the peak concentration of the cytotoxic agent is the maximum concentration that the cytotoxic agent reaches in the blood, cerebrospinal fluid, the target organ or the tumor after administration to the subject. Claim 9 requires the PKC inhibitor is a PKC- β inhibitor , claim 10 requires the PKC inhibitor is enzastaurin, sotrastaurin, midostaurin, ruboxistaurin, or a pharmaceutically acceptable salt or solvate thereof , and claims 11-12 require the PKC inhibitor is enzastaurin or ruboxistaurin, respectively. Claims 13-15 further limit the cytotoxic agent, claim s 16 -18 require the PKC inhibitor reaches the peak concentration in the subject between 30 minutes and 12 hours prior to the cytotoxic agent reaching the peak concentration , 1 and 8 hours or between 2 and 6 hours prior to the cytotoxic agent reaching the peak concentration , or between 3 and 5 hours prior to the cytotoxic agent reaching the peak concentration . Padda teaches a clinical trial in which patients with advanced solid tumors, including non-small cell lung cancer (NSCLC) , are administered enzastaurin and erlotinib daily. Padda teaches that all patients in the tri al received oral enzastaurin and erlotinib daily. Padda teaches that cycles in the trial were 28 days long, and in the first cycle, enzastaurin was taken 30 min after a meal and erlotinib was taken 1 h before a meal. However , Padda teaches that in subsequent cycles, erlotinib could be taken 2 h after a meal , as long as the timing of dosing was consistent. Padda teaches that all cohorts received erlotinib 150 mg daily, the standard dose given as a single agent for advanced-stage NSCLC (p. 1014, Study design and treatment plan section, third paragraph, lines 1-9). Moreover, Padda teaches that c ohort 1 in their study was designed to include three patients at dose level 1 , which included enzastaurin 250 mg daily with a loading dose of 500 mg on day 1 (given as 250 mg two times a day). Padda teaches that a ll three patients had to complete cycle 1 of dose level 1 without a DLT before enrolling an additional three patients at dose level 2, the full enzastaurin dose of 500 mg daily with a loading dose of 1125 mg on day 1 (given as 375 mg three times a day) (pp. 1014-1015, Study design and treatment plan section, fourth paragraph , lines 1-8). Padda further teaches the pharmacokinetics of both enzastaurin and erlotinib in their clinical trial. Padda teaches the t max for enzastaurin is 4 hours and 4.04 hours for doses of 250 and 500 mg doses of enzastaurin (p. 1017, Table 4). Padda teaches the t max for erlotinib is 2 hours when administered with a 250 mg enzastaurin dose and 4 hours when administered with 500 mg enzastaurin dose . As evidence that erlotinib i s a cytotoxic agent, Wang teaches a study in which autophagy inhibition facilitates erlotinib cytotoxicity in lung cancer cells (p. 2558, Title). Want teaches that inhibition of autophagy significantly enhanced cytotoxicity of erlotinib in TKI-resistant cancer cells via modulation of endoplasmic reticulum (ER) stress induced apoptosis (p. 2558, Abstract, lines 12-15). Therefore, erlotinib is a cytotoxic agent because it has its own cytotoxic effect that may be enhanced by inhibition of autophagy, as taught by Wang. Regarding claim 8, plasma is interpreted herein as part of blood, and thus satisfies the limitations of claim 8. As evidence that enzastaurin is a PKC-β inhibitor, the instant spe cification provides that PKC-β-inhibitors act synergistically with venetoclax. In Example 3, enzastaurin, sotrastaurin and midostaurin are used with venetoclax, and thus enzastaurin, sotrastaurin and midostaurin are inhibitors of PKC-β (p. 25, lines 21-34). Therefore, the administration of enzastaurin 30 minutes after a meal and erlotinib 2 hours after a meal, wherein each shows a time to maximal plasma concentration of approximately 4 hours (e.g., for the 500 mg dose of enzastaurin) , as taught by Padda for subsequent cycles of treatment, would satisfy the requirements of present claims 2 - 4, 8 - 11, 16, and 17. Thus Padda anticipates claims 2 - 4, 8 - 11, 16, and 17. Claims 2 - 4 , 8 -11, and 13 are rejected under 35 U.S.C. 102(a)(1) as being FILLIN "Insert either—clearly anticipated—or—anticipated—with an explanation at the end of the paragraph." \d "[ 3 ]" anticipated by Hanauske (Hanauske, A.-R.; et al. Annals of Oncology 2009, vol. 20, pp. 1565-1575; cited in PTO-892) , as evidenced by Carducci (Carducci, M. A.; et al. Journal of Clinical Oncology 2006, vol. 24, pp. 4092-4099; cited in PTO-892) and Kim (Kim, J. H.; et al. Cancer Science 2005, vol. 96, pp. 365-371; cited in PTO-892). Hanauske teaches a phase Ib study that evaluated the safety, pharmacokinetics, and activity of enzastaurin either 500 mg once daily (QD) or 250 mg twice daily (b.i.d.) in combination with pemetrexed for treating advanced/metastatic cancer (p. 1565, Abstract, Background section, lines 1-2) . Hanauske teaches that p emetrexed 500 mg/m 2 with folic acid and vitamin B12 was given on day 1 every 21 days with enzastaurin 500 mg orally QD starting on day 5 of cycle 1 after a loading dose of 400 mg thrice daily on day 4. To evaluate whether a b.i.d. regimen results in higher enzastaurin exposures, the study was amended , and a fter amendment , in cycle 1, patients received 500 mg enzastaurin QD on days 1–15 without initial loading dose and 250 mg b.i.d. on days 16–30; in subsequent cycles, patients received pemetrexed on day 1 every 21 days with enzastaurin b.i.d ( p. 1565, Abstract, Patients and methods section, lines 1- 5 ) (emphasis added). Hanauske teaches that the cohort of patients following study amendment included dose with histological diagnosis of lung cancer (p. 1568, Table 1). As evidence of the time that enzastaurin reaches a peak concentration, Carducci teaches the median plasma t max of dosing enzastaurin was between approximately 1 and 4 hours, depending on dose (p. 4096, Table 4; p. 4095, right column, Pharmacokinetics section, lines 5-7). Therefore, in considering a combination treatment of enzastaurin and pemetrexed , wherein enzastaurin is administered , for example, on day 1 , and pemetrexed administered on day 1 of cycle 2 (i.e., 31 days after beginning the study) , enzastaurin would reach a peak concentration in the plasma prior to administration of pemetrexed , and thus prior to pemetrexed reaching a peak concentration. As evidence that pemetrexed is a cytotoxic agent, Kim teaches pemetrexed is a newly developed multitargeted antifolate with promising clinical activity in many solid tumors , including gastric cancer (p. 365, Abstract, lines 1-3). Kim teaches that pemetrexed was more cytotoxic than 5-fluorouracil, with IC 50 between 17 and 310 nM in most of the gastric cancer cell lines examined (p. 365, Abstract, lines 13-15). Thus pemetrexed is a cytotoxic agent. In addition, in view of Kim, pemetrexed is reasonably considered a folate antagonist, as recited in claim 13 . Regarding claim 8, plasma is interpreted herein as part of blood, and thus satisfies the limitations of claim 8. As evidence that enzastaurin is a PKC-β inhibitor, the instant specification provides that PKC-β-inhibitors act synergistically with venetoclax. In Example 3, enzastaurin, sotrastaurin and midostaurin are used with venetoclax, and thus enzastaurin, sotrastaurin and midostaurin are inhibitors of PKC-β (p. 25, lines 21-34). Thus Hanauske anticipates claims 2- 4 , 8 -11, and 13. Claims 2-5, 8, and 13-15 are rejected under 35 U.S.C. 102(a)(1) as being FILLIN "Insert either—clearly anticipated—or—anticipated—with an explanation at the end of the paragraph." \d "[ 3 ]" anticipated by Roberts (Roberts, J. D.; et al. Clinical Cancer Research 2006, vol. 12, pp. 5809-5816; cited in PTO-892), as evidenced by Kortmansky (Kortmansky, J.; Schwartz, G. K. Cancer Investigation 2003, vol. 21, pp. 924-936; cited in PTO-892) and Nelson ( Nelson , T . J. ; et al. Journal of Alzheimer’s Research 2017 , vol. 5 8 , pp. 521 - 535 ; cited in PTO-892). Roberts teaches a clinical trial in which p atients with chronic lymphocytic leukemia (CLL) or indolent lymphoma received fludarabine daily for 5 days and a single dose of bryostatin - 1 via a 24-hour continuous infusion either before or after the fludarabine course (p. 5809, Abstract, Experimental Design section, lines 1-3). Roberts teaches that b ryostatin - 1 can be administered safely and tolerably with full dose fludarabine (25 mg/m 2 /d x 5) , and that the recommended bryostatin - 1 phase II dose is 50 μ g/m 2 for both sequences, b ryostatin - 1 → fludarabine and fludarabine → bryostatin -1 (p. 5809, Abstract, Results section, lines 1-3). Roberts teaches t he combination is active against both CLL and indolent lymphomas with responses seen in patients who had been previously treated with fludarabine (p. 5809, Abstract, Results section, lines 3-5). Regarding the specific schedule of administration, Roberts teaches Arm 1 of their study included a 24 hour infusion of bryostatin-1, and followed one hour later by a 30 minute daily infusion of fludarabine for 5 days (p. 5811, Figure 1). Fludarabine is a nucleoside analog, and thus satisfies the limitations of claim 13. Roberts concludes from their study that b ryostatin - 1 can be administered with full dose fludarabine, and the combination is moderately active in patients with persistent disease following prior treatment (p. 5809, Conclusions section, lines 1-2). As evidence that bryostatin-1 is an inhibitor of PKC, Kortmansky teaches that b ryostatin-1 is a macrocyclic lactone derived from a marine invertebrate that binds to the regulatory domain of protein kinase C , and s hort-term exposure to bryostatin-1 promotes activation of PKC, whereas prolonged exposure promotes significant downregulation of PKC (p. 924, Abstract, lines 3-4) (emphasis added). Therefore, bryostatin-1 is an inhibitor of PKC. Roberts does not teach the peak concentrations of fludarabine and bryostatin-1 in their study. However, based on the above schedule of administration, the limitations of claim 1 are believed to be satisfied by the schedule of Roberts. As evidenced by Nelson, an IV dose of bryostatin-1 showed a peak bryostatin 1 plasma concentration at approximately 1 hour following infusion, after which the concentration rapidly decreased (p. 525, Figure 1). MPEP 2112.01 (especially at I) citing In re Best , 562 F.2d 1252, 195 USPQ 430 (C.C.P.A. 1977) and In re Spada , 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990) discusses the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions or characteristics that are newly recited or identical to an invention as instantly claimed. In such a situation the burden is shifted to the applicants to show the invention of the applicant and the prior art are not the same or that the prior art products do not necessarily possess the characteristics of the claimed invention. In this instance, bryostatin-1 reaches a peak concentration during infusion of Arm 1 of the study of Roberts, which is prior to fludarabine being administered and thus prior to a peak concentration of fludarabine administration. Regarding claim 8, plasma is interpreted herein as part of blood, and thus satisfies the limitations of claim 8. Thus Roberts, as evidenced by Kortmansky and Nelson , anticipates 2-5, 8, and 13-15. Claims 2-5 and 8 are rejected under 35 U.S.C. 102(a)(1) as being FILLIN "Insert either—clearly anticipated—or—anticipated—with an explanation at the end of the paragraph." \d "[ 3 ]" anticipated by Monnerat (Monnerat, C.; et al. Annals of Oncology 2004, vol. 15, pp. 316-323; cited in PTO-892 ), as evidenced by Siddik (Siddik, Z. H.; et al. Oncogene 2003, vol. 22, pp. 7265-7279; cited in PTO-892). Monnerat teaches that PKC412 is an oral inhibitor of protein kinase C (p. 316, Abstract, Background section, line 1). Monne rat teaches that e scalating doses of PKC412 were given every day of a 4 week cycle with cisplatin 100 mg/m 2 on day 2 and gemcitabine 1000 mg/m 2 on days 1, 8 and 15 in patients with non-small-cell lung cancer (p. 316, Abstract, Patients and Methods section, lines 1-3). Monnerat teaches the PKC412 pharmacokinetic profile was assessed in four patients at the 50 mg dose level (p. 320, right column, Pharmacokinetics section, lines 1-2). Based on this assessment, Monnerat teaches PKC412 reaches a maximum plasma concentration at approximately 4 hours after dosing (p. 322, Figure 2). Therefore, in considering a combination treatment of PKC412 and cisplatin, wherein PKC412 is administered on day 1 and cisplatin on day 2, PKC412 reaches a peak concentration in the plasma prior to administration of cisplatin, and thus prior to cisplatin reaching a peak concentration. In addition, a plasma concentration is interpreted as satisfying claim 8, because plasma is part of blood. As evidence that c isplatin i s a cytotoxic agent , Siddik teaches that cisplatin is one of the most potent antitumor agents known, displaying clinical activity against a wide variety of solid tumors. Siddik teaches its cytotoxic mode of action is mediated by its interaction with DNA to form DNA adducts, primarily intrastrand crosslink adducts, which activate several signal transduction pathways, including those involving ATR, p53, p73, and MAPK, and culminate in the activation of apoptosis (p. 7265, Abstract, lines 1-8). Therefore, cisplatin is a cytotoxic agent. Regarding claim 8, plasma is interpreted herein as part of blood, and thus satisfies the limitations of claim 8. Thus Monnerat anticipates claims 2- 5 and 8. Claims 2 , 6, 8-10, and 16 -17 are rejected under 35 U.S.C. 102(a)(1) as being FILLIN "Insert either—clearly anticipated—or—anticipated—with an explanation at the end of the paragraph." \d "[ 3 ]" anticipated by Merani ( Merani , S .; et al. Transplantation 2009, vol. 87, pp. 59-65; cited in PTO-892), as evidenced by Weckbecker (Weckbecker, G.; et al. Transplant International 2010, vol. 23, pp. 543-552; cited in PTO-892 ), Ferjani ( Ferjani , H. ; et al. Human and Experimental Toxicology 2015 , vol. 34 , pp. 1119 - 1132 ; cited in PTO-892) , and Inoue (Inoue, H.; et al. International Journal of Urology 1997, vol. 4, pp. 279-284; cited in PTO-892) . Merani teaches a study in which AEB-071 (AEB) is administered in combination with CTLA4-Ig, mycophenolate mofetil (MMF) , or cyclosporine A (CsA) to prevent rejections of rodent allogeneic islet transplant s (p. 59, Abstract, Background and Methods sections, lines 1-6). Merani teaches that a llogeneic islet transplant recipients treated with oral dose of AEB twice daily (30 mg/kg per dose, group 2 in Table 1) exhibited delayed allograft rejection, with median survival time (MST) of 24 days compared with a vehicle treated group ( MST 7 days ) (p. 61, right column, results section, first paragraph, lines 1-5). Merani further teaches the efficacy of AEB when combined with sub-optimal doses of CTLA4-Ig, MMF, and CsA (p. 61, right column, Results section, second paragraph, lines 1-4). Merani teaches transplant recipients were treated with combinations of sub-therapeutic CTLA4-Ig, MMF , or CsA plus 30 mg/kg po bid of AEB . Merani teaches t he morning dose of AEB was administered concurrently with the morning dose of the partnered immunosuppressive agent, with the noted exception in the combination arm of MMF and AEB, in which MMF was administered 1 hour after AEB to avoid previously observed drug-drug interaction (p. 61, right column, Results section, lines fourth paragraph, lines 1-8) (emphasis added). Merani teaches that t ransplantation of pancreatic islets is an emerging therapy for selected patients with type 1 diabetes. Merani teaches that a fter initial success in seven consecutive patients and in a recent multicenter trial, there is now strong evidence that islet graft failure occurs over time , and this loss of beta-cell function after transplantation is likely a combination of allo-rejection, autoimmune diabetes recurrence, and beta-cell senesce or immunosuppressive toxicities on the islet cell (p. 59, left column, lines 1-8) (emphasis added). Therefore, treating islet rejection is reasonably considered as treating an autoimmune disease. Merani targets PKC-β1, and is thus an inhibitor of PKC-β (p. 59, fight column, first full paragraph, lines 1-3). As evidence that AEB - 071 is sotrastaurin , Weckbecker teaches that NVP-AEB071 (AEB, sotrastaurin), an oral inhibitor of protein kinase C (PKC), effectively blocks T-cell activation (p. 543, Summary, lines 1-2). Weckbecker further teaches that oral administration of 20 mg/kg AEB results in a T max of 0.5 hours (p. 546, Table 1). As evidenced that mycophenolate mofetil is a cytotoxic agent, Ferjani teaches mycophenolate mofetil (M MF ) over 200 μ M presents a cytotoxic effect on the HCT116 cell line (p. 1123, right column, Results section, lines 27-28). Therefore, mycophenolate mofetil is a cytotoxic agent. Regarding the pharmacokinetics of MMF, Inoue teaches pharmacokinetic studies of mycophenolate mofetil in rat kidney allograft recipients (p. 279, Title). Inoue teaches that rats were given mycophenolate mofetil (abbreviated as MPM by Inoue; see p. 279, Introduction section) orally at a variety of doses and then subjected to the pharmacokinetic s tudies (p. 280, right column, Results section, first paragraph, lines 1-3). Inoue teaches the MPM plasma concentration increased rapidly in a dose-dependent manner, and peaked at 15 to 30 minutes after the drug administration (p. 280, right column, Results section, first paragraph, lines 5-8; data shown on p. 281, Figure 1). Therefore , in considering the combination treatment of AEB-071 and MMF taught by Merani , wherein MMF is administered one hour after AEB-071 , AEB-071 would reach a peak plasma concentration approximately 0.5 hours after administration, and thus prior to MMF being administered and reaching a peak concentration. In addition, because each of AEB-071 and MMF show T max values of approximately 0.5 hours, the difference in time between peak concentrations would be about one hour, which satisfies claim s 16 and 17. MPEP 2112.01 (especially at I) citing In re Best , 562 F.2d 1252, 195 USPQ 430 (C.C.P.A. 1977) and In re Spada , 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990) discusses the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions or characteristics that are newly recited or identical to an invention as instantly claimed. In such a situation the burden is shifted to the applicants to show the invention of the applicant and the prior art are not the same or that the prior art products do not necessarily possess the characteristics of the claimed invention. In this instance, the pharmacokinetic data for each of AEB-071 and MMF are believed to satisfy the peak concentration requirements recited in claims 2 and 16-17, absent evidence to the contrary. Regarding claim 8, plasma is interpreted herein as part of blood, and thus satisfies the limitations of claim 8. As evidence that enzastaurin is a PKC-β inhibitor, the instant specification provides that PKC-β-inhibitors act synergistically with venetoclax. In Example 3, enzastaurin, sotrastaurin and midostaurin are used with venetoclax, and thus enzastaurin, sotrastaurin and midostaurin are inhibitors of PKC-β (p. 25, lines 21-34). Thus Merani , as evidenced by Weckbecker, Ferjani, and Inoue, anticipates claims 2, 6, 8-10, and 16 -17 . Claim Rejections - 35 USC § 103 The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action: A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows: 1. Determining the scope and contents of the prior art. 2. Ascertaining the differences between the prior art and the claims at issue. 3. Resolving the level of ordinary skill in the pertinent art. 4. Considering objective evidence present in the application indicating obviousness or nonobviousness. This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention. Claims 2 -4 , 8 - 11, 16, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Padda (Padda, S. K.; et al. Cancer Chemotherapy an d Pharmacology 2012, vol. 69, pp. 1013-1020; cited in PTO-892), as evidenced by Wang (Wang, Z.; et al. International Journal of Oncology 2016, vol. 48, pp. 2558-2566; cited in PTO-892) . The examiner believes that claims 2-4, 8-11, 16, and 17 are anticipated by Padda with evidence from Wang , as described in the above rejection under 35 U.S.C. § 102 . However, for the sake of argument, if there is any uncertainty about whether patients in the study of Padda participated in the dosing schedule wherein erlotinib is dosed after enzastaurin, then claims 2-4, 8-11, 16, and 17 would have been obvious over Padda, with evidence from Wang. Padda teaches as described in the above rejection under 35 U.S.C. § 102. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to practice the method of Padda administering enzastaurin 30 minutes after a meal and erlotinib 2 hours after a meal. One of ordinary skill in the art would have been motivated to practice the method of Padda administering enzastaurin 30 minutes after a meal and erlotinib 2 hours after a meal because Padda teaches this dosing schedule as one potential dosing schedule of their method, and thus one of ordinary skill in the art would have considered this schedule when administering enzastaurin and erlotinib for the purposes of treating NSCLC. Given the t max values for enzastaurin and erlotinib disclosed by Padda, such an administration schedule would satisfy the peak concentration time requirements recited in claims 2 and 16 - 17. As evidence that erlotinib i s a cytotoxic agent, Wang teaches a study in which autophagy inhibition facilitates erlotinib cytotoxicity in lung cancer cells (p. 2558, Title). Want teaches that inhibition of autophagy significantly enhanced cytotoxicity of erlotinib in TKI-resistant cancer cells via modulation of endoplasmic reticulum (ER) stress induced apoptosis (p. 2558, Abstract, lines 12-15). Therefore, erlotinib is a cytotoxic agent because it has its own cytotoxic effect that may be enhanced by inhibition of autophagy, as taught by Wang. Regarding claim 8, plasma is interpreted herein as part of blood, and thus satisfies the limitations of claim 8. As evidence that enzastaurin is a PKC-β inhibitor, the instant specification provides that PKC-β-inhibitors act synergistically with venetoclax. In Example 3, enzastaurin, sotrastaurin and midostaurin are used with venetoclax, and thus enzastaurin, sotrastaurin and midostaurin are inhibitors of PKC-β (p. 25, lines 21-34). Therefore the invention taken as a whole is prima facie obvious. Claims 1-3 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Abe (Abe, S.; et al. Japan Journal of Cancer Research 2000, vol. 91, pp. 1192-1198, cited in PTO-892) in view of Kurata (Kurata, N.; et al. Cancer Chemotherapy Pharmacology 1999, vol. 44, pp. 12-18 ; cited in PTO-892 ) . Abe teaches UCN-01 (7-Hydroxystaurosporine) enhances 5- f luorouracil cytotoxicity through down-regulation of thymidylate synthetase messenger RNA (p. 1192, Title). Abe teaches that 7-Hydroxystaurosporine (UCN-01) is a new antitumor agent that was isolated as a selective inhibitor of Ca 2+ and phospholipid-dependent protein kinase C (PKC) (p. 1192, left column, second paragraph, lines 1-3). Abe teaches that sequential administration of UCN-01 and 5-FU to CRL 1420 human pancreatic carcinoma cells, wherein UCN-01 was followed by 5-FU, achieved higher inhibition, particularly at concentrations of less than 1 μg/ml (p. 1194, right column, Results section, first paragraph, lines 4-6; results shown on 1195, Figure 2). For the schedule of administration of UNC-01 and 5-FU, Abe teaches cells were treated for 36 hours with UCN-01, followed by 36 hours with 5-FU (p. 1193, Figure 1 caption). Moreover, Abe teaches that at 0.01 μg/ml concentration, the inhibition rates of 5-FU, UCN-01, and UCN-01/5-FU were 6.5%, 16.3%, and 46%, respectively, suggesting that the antitumor activities of UCN-01 and 5-FU in UCN-01/5-FU were synergistic (p. 1194, right column, Results section, first paragraph, lines 6-10). 5-FU is a nucleoside analog, as recited in claim 13. Abe does not teach administering a PKC inhi b itor and a cytotoxic agent to a subject , wherein the PKC inhibitor reaches a peak concentration in the subject prior to the cytotoxic agent reaching a peak concentration , for the purposes of increasing sensitivity of a subject to a cytotoxic agent of for treating cancer or an autoimmune disease, as required by claims 1 and 2. Kurata teaches the p harmacokinetics and pharmacodynamics of the protein kinase inhibitor, UCN-01 (p. 12, Title). Kurata teaches the plasma concentration versus time profiles for UCN-01 after i.v. administration to mice at doses of 1, 3, and 9 mg/kg, to rats at doses of 0.35, 1, and 3.5 mg/kg, and to dogs at a dose of 0.5 mg/kg (p. 15, Figures 2a-c). In each of these instances, the plasma concentration of UCN-01 peaks shortly after i.v. administration and decreases over the course of 12-72 hours, depending on the specific sample. It would have been prima facie obvious to administer to a subject the PKC inhibitor UCN-01 prior to the cytotoxic agent 5-FU for the purposes of treating cancer . One of ordinary skill in the art would have been motivated to administer to a subject the PKC inhibitor UCN-01 prior to the cytotoxic agent 5-FU because Abe teaches synergistic activity between the UCN-01 and 5-FU, with sequential administration of UCN-01 and 5-FU to CRL 1420 human pancreatic carcinoma cells, wherein UCN-01 was followed by 5-FU, achieved higher inhibition, particularly at concentrations of less than 1 μg/ml. Accordingly, one of ordinary skill in the art would have considered the sequence of administration of UCN-01 and 5-FU, and in view of Abe, would have staggered administration such that UCN-01 was administered prior to 5-FU. Regarding the specific peak concentrations required by the present claims, one of ordinary skill in the art would have considered the schedule of administration disclosed by Abe, wherein UCN-01 is administered for 36 hours followed by administration of 5-FU for 36 hours. As taught by Kurata, the plasma concentration of UCN-01 peaks shortly after i.v. administration and then decreases over several hours, and thus extending the method of treating cancer, including the dosing of UCN-01 prior to dosing with 5-FU, to a subject would be expected to provide a peak plasma concentration of UCN-01 prior to a peak plasma concentration of 5-FU . In addition, because Abe teaches that UCN-01 and 5-FU show synergistic activity, UCN-01 would have been expected to increase the sensitivity of a subject to the cytotoxic agent 5-FU when administered to a subject, as observed in Abe’s cell culture studies. Therefore the invention taken as a whole is prima facie obvious. Claims 1 -11, 13-14 , and 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Song (Publication no. WO 2020055698 A1; cited in PTO-892) in view of Cook (Cook, N.; et al. Molecular Oncology 2015, vol. 9, pp. 997-1007; cited in PTO-892) , as evidenced by Rushworth (Rushworth, S. A.; et al. Cellular Signalling 2013, vol. 25, pp. 106-112; cited in PTO-892) . Song teaches and claims a method for treatment or prevention of lymphoma, or for reduction of risk of metastasis or relapse in a subject having been treated for lymphoma, wherein the method comprises administering to a subject in need thereof, enzastaurin, or a pharmaceutically acceptable salt thereof, and an inhibitor of BTK (p. 56, claim 14) . Song further claims the inhibitor of BTK is selected from a group that includes ibrutinib , acalabrutinib, and zanubrutinib (p. 56, claims 15 and 16). Song further teaches and claims wherein enzastaurin, and the inhibitor of BTK are administered separately (p. 57, claim 19), and wherein enzastaurin and the inhibitor of BTK are administered on a schedule which causes both to be present in the blood or plasma of the treated subject together (p. 57, claim 20). Song teaches that e nzastaurin and an inhibitor of Bruton' s tyrosine kinase (BTK) may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g., synergistic effect (p. 17, [0068], line 2 to p. 18, line 3). Song teaches the term "non-fixed combination" means that e nzastaurin and an inhibitor of Bruton's tyrosine kinase (BTK) are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two substances in the body of the patient (p. 18, first paragraph, lines 12-16). Song further claims wherein the lymphoma is Hodgkin lymphoma or Non-Hodgkin lymphoma (p. 57, claim 21), w herein lymphoma is non-Hodgkin lymphom a (p. 57, claim 22), and wherein the lymphoma is selected from a group that includes Burkitt's lymphoma (p. 57, claim 23). As evidenced that , for example, ibrutinib is a cytotoxic agent, Rushworth teaches that the BTK inhibitor ibrutinib is cytotoxic to chronic lymphocytic leukemia (CLL) cells (p. 106, right column, second paragraph, lines 11-12) and to myeloma (p. 106, Title). Therefore, ibrutinib is a cytotoxic agent. Moreover, because Song teaches this combination as achieving a cooperative or synergistic effect, this method would reasonably be interpreted as increasing the sensitivity of a subject to a cytotoxic agent , as required by claim 1. In addition, Song teaches their methods may be applied to immunological disorders, including graft versus host disease (GVHD), rheumatoid arthritis, and systemic lupus erythematosus (p. 5, [0014], lines 1-3). Song does not teach wherein the PKC inhibitor reaches a peak concentration in t he subject prior to the cytotoxic agent reaching a peak concentration , as required by the present claims. Cook teache s that the purpose of early stage clinical trials is to determine the recommended dose and toxicity profile of an investigational agent or multi-drug combination. Cook teaches molecularly targeted agents (MTAs) and immunotherapies have distinct toxicities from chemotherapies that are often not dose dependent and can lead to chronic and sometimes unpredictable side effects , and t herefore utilizing a dose escalation method that has toxicity based endpoints may not be as appropriate for determination of recommended dose, and alternative parameters such as pharmacokinetic or pharmacodynamic outcomes are potentially appealing options. Cook teaches that ap proaches to enhance safety and optimize dosing include improved preclinical models and assessment, innovative model based design and dose escalation strategies, patient selection, the use of expansion cohorts and extended toxicity assessments (p. 997, Abstract, lines 1-11). Cook further teaches that pharmacokinetic studies examining different formulations or dosing schedules of drugs should be encouraged as they may reveal a more optimal route or administration frequency that yields biologically relevant exposures (p. 1004, right column, first full paragraph, lines 1-4). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to sequentially administer the combination therapy of enzastaurin and the BTK inhibitor ibrutinib for the purposes of treating a lymphoma, such as Burkitt’s lymphoma. One of ordinary skill in the art would have been motivated to sequentially administer the combination therapy of enzastaurin and the BTK inhibitor ibrutinib for the purposes of treating a lymphoma, such as Burkitt’s lymphoma, because Song teaches a method of treating Burkitt’s lymphoma by administration of enzastaurin and BTK inhibitors such as ibrutinib , and teaches that these agents may be administered separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative or synergistic effect . Accordingly, when contemplating the method of Song, one of ordinary skill in the art would have considered both simultaneous administration and separate administration to achieve a synergistic effect, including a schedule in which enzastaurin is administered prior to the BTK inhibitor . Moreover, because Cook teaches that pharmacokinetic studies examining different formulations or dosing schedules of drugs should be encouraged as they may reveal a more optimal route or administration frequency that yields biologically relevant exposures , one of ordinary skill in the art would have recognized the dosing schedule of enzastaurin and BTK inhibitor as a result-effective variable, and would have adjusted the dosing schedule by routine experimentation to identify the optimal dosing schedule for treating lymphoma . MPEP 2144.05 (II) at A states: "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). In this instance, because Song expressly teaches compounds administered as part of their method may be administered sequentially, one of ordinary skill in the art would have contemplated a dosing schedule with sequential administration. Moreover, because Song teaches the compounds separately within time intervals that allow that the combination partners to show a cooperative effect , and because Cook suggests studies examining different formulations or dosing schedules of drugs to identify a more optimal route or administration frequenc y, one of ordinary skill in the art would have recognized the administration schedule as a result effective variable, and would have engaged in experimentation to identify the optimal dosing schedule and administration frequency for the enzastaurin and BTK inhibitors administered as part of the method of Song. Regarding the specific time between the PKC inhibitor reaching the peak concentration and the cytotoxic agent reaching the peak concentration, because one of ordinary skill in the art would have recognized the schedule of sequential administration as a result-effective variable and engaged in experimentation to identify the optimal dosing schedule for treating cancer by administering enzastaurin and, for example, ibrutinib, as part of the method of Song, this optimal dosing would have considered administration in which the PKC inhibitor reached a peak concentration prior to the cytotoxic agent reaching a peak concentration, with the times separating the peak concentrations as recited in claims 16-18, absent evidence of non-obviousness for the specific combination of enzastaurin and BTK inhibitor s taught by Song. Regarding the autoimmune disease of claims 2 and 6-7, because Song teaches their method may be practiced for treating the immunological disorders recited above, including rheumatoid arthritis and systemic lupus erythematosus, one of ordinary skill in the art would have contemplated the combination therapy taught by Song for treating these diseases, because such a combination may provide an effective treatment. In addition, one of ordinary skill in the art would have similarly contemplated the schedules of administration taught by Song for treating said autoimmune diseases. Therefore the invention taken as a whole is prima facie obvious. Claims 1 -3 , 9, 10, 12 , and 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Porter (Publication no. US 2015/0306101 A 1 ; cited in PTO-892 ) in view of Cook (Cook, N.; et al. Molecular Oncology 2015, vol. 9, pp. 997-1007; cited in PTO-892 ), as evidenced by Litvin (Litvin, O.; et al. Molecular Cell 2015, vol. 57, pp. 784-796; cited in PTO-892) and Joy (Joy, S. V.; et al. Annals of Pharmacotherapy 2005, vol. 10, pp. 1693-1699; cited in PTO-892). Porter teaches and claims a pharmaceutical combination comprising or consisting of: (a) a protein kinase C (PKC) inhibitor compound, or a pharmaceutically acceptable salt thereof, and (b) a mitogen activated protein kinase (MEK) inhibitor compound, or a pharmaceutically acceptable salt thereof (p. 15, claim 1), and further claims the PKC inhibitor is selected from a group that includes ruboxistaurin (p. 15, claim 2). Porter also claims the MEK inhibitor is selected from the group that includes PD325901 (p. 15, claim 3). In addition, Porter claims a method for treating a proliferative disease, comprising the simultaneous, separate or sequential administration of a therapeutically effective amount of a PKC inhibitor compound, or a pharmaceutically acceptable salt thereof, in combination with at least one MEK inhibitor compound, to a patient in need thereof having a proliferative disease (p. 15, claim 14), and further claims the proliferative disease is melanoma (p. 15, claim 16). Melanoma is a type of cancer, as required by claims 2-3. Regarding sequential administration of the combination of Porter, Porter teaches the combinatio n may be administered simultaneously, independently at the same time or separately within time intervals that allow that the combination partners to show a cooperative, e.g., synergistic, effect. Porter further teaches the term "non-fixed combination" means that the active ingredients are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits , wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient (p. 4, [0048], lines 1-23). As evidence the MEK inhibitors may be cytotoxic agents, Litvin teaches the transcriptional and phenotypic response to MAPK pathway inhibition of both NRAS-mut and BRAF-mut cell lines using a MEK inhibitor (PD325901, 50 nM) that fully inhibits the pathway in all cell lines at 8 hours (p. 785, right column, first full paragraph, liens 1-4). Litvin teaches the cell lines’ phenotypic responses to MEK inhibition , stating the cell lines display a w ide range o f cytotoxic responses, as well as differences in proliferation under MEK inhibition (p. 785, right column, second full paragraph, lines 1-4) (emphasis added) . Therefore, the MEK inhibitor PD325901 is a cytotoxic agent. Moreover, because Porter teaches this combination as achieving a cooperative or synergistic effect, this method would reasonably be interpreted as increasing the sensitivity of a subject to a cytotoxic agent , as required by claim 1. Porter does not teach wherein the PKC inhibitor reaches a peak concentration in t he subject prior to the cytotoxic agent reaching a peak concentration. Cook teaches as described in the above rejection under 35 U.S.C. § 103. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to sequentially administer the combination therapy of ruboxistaurin and a MEK inhibitor , such as the MEK inhibitor PD325901 , for the purposes of treating a proliferative disease, such as cancer. One of ordinary skill in the art would have been motivated to sequentially administer the combination therapy of ruboxistaurin and a MEK inhibitor, such as the MEK inhibitor PD325901 , for the purposes of treating a proliferative disease, such as cancer, because Porter teaches a method of treating a proliferative disease by administration of ruboxistaurin and a MEK inhibitor, and further teaches that these agents may be administered separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g., synergistic effect . Accordingly, when contemplating the method of Porter, one of ordinary skill in the art would have considered both simultaneous administration and separate administration to achieve a synergistic effect, including a schedule in which ruboxistaurin is administered prior to the MEK inhibitor. Moreover, because Cook teaches that pharmacokinetic studies examining different formulations or dosing schedules of drugs should be encouraged as they may reveal a more optimal route or administration frequency that yields biologically relevant exposures , one of ordinary skill in the art would have recognized the dosing schedule of ruboxistaurin and a MEK inhibitor as a result-effective variable, and would have adjusted the dosing schedule by routine experimentation to identify the optimal dosing schedule for treating cancer . MPEP 2144.05 (II) at A states: "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). In this instance, because Porter expressly teaches the compounds administered as part of their method may be administered sequentially, one of ordinary skill in the art would have contemplated the method of Porter with sequential administration of ruboxistaurin and MEK inhibitor. Moreover, because Porter teaches the compounds separately within time intervals that allow that the combination partners to show a cooperative or synergistic effect , and because Cook suggests studies examining different formulations or dosing schedules of drugs to identify a more optimal route or administration frequenc y, one of ordinary skill in the art would have recognized the administration schedule as a result effective variable, and would have engaged in experimentation to identify the optimal dosing schedule and administration frequency for the specific PKC and MEK inhibitors administered as part of the method of Porter. Regarding the specific time between the PKC inhibitor reaching the peak concentration and the cytotoxic agent reaching the peak concentration, because one of ordinary skill in the art would have recognized the schedule of sequential administration as a result-effective variable, one of ordinary skill in the art would have engaged in experimentation to identify the optimal dosing schedule for treating cancer by administering ruboxistaurin and, for example, PD325901 , as part of the method of Porter , and this optimal dosing would have considered administration in which the PKC inhibitor reached a peak concentration prior to the cytotoxic agent reaching a peak concentration, with the times separating the peak concentrations as recited in claims 16-18, absent evidence of non-obviousness for the specific combination of ruboxistaurin and MEK inhibitor taught by Porter . As evidence that ruboxistaurin is a PKC-β inhibitor, Joy teaches ruboxistaurin is a PKC-β inhibitor (p. 1693, Title). Therefore the invention taken as a whole is prima facie obvious. Conclusion No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT BENJAMIN BRANDSEN whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (703)756-4780 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT Monday - Friday from 9:00 am to 5:00 pm . Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, FILLIN "SPE Name?" \* MERGEFORMAT Scarlett Goon can be reached at FILLIN "SPE Phone?" \* MERGEFORMAT (571)270-5241 . The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status