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 .
Claim Objections
Claim 8 is objected to because of the following informalities: wrong unit recited in line 3 of the claim. In particular line 3 of claim 8 recites, “- valproic acid at a concentration ranging from about 16 mm to about 0.5 mM;” however, “16 mm” should be “16 mM.” Appropriate correction is required.
Claim 13 is objected to because of the following informalities: spelling issue. In particular, line 13 of claim 13 recites, “a pancreas endrocrine tumor, and a pancreatic neuroendrocrine tumor;” however, “endrocrine” should be “endocrine,” and “neuroendrocrine,” should be “neuroendocrine.” Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 10 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 10 recites, the method of claim 4, wherein the further anti-cancer agent is selected from a group that includes doxorubicin (neutral). Regarding claim 10, the use of parenthesis in this instance in the claim renders the claim indefinite because it is unclear whether the recitation within the parenthesis is a definition or a preferred embodiment. For example, the claim recites doxorubicin (neutral), does the method require doxorubicin in the neutral form or can the doxorubicin be administered in the protonated form? As a consequence, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Specifically one of ordinary skill in the art would not be reasonably apprised of what form of doxorubicin can be administered in the method of treating pancreatic cancer. Therefore, given the uncertainty around the terms within the parenthesis claim 10 is rejected under 35 U.S.C. 112(b).
Claim Rejections - 35 USC § 103
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 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.
Claims 1 – 6, and 10 – 16 are rejected under 35 U.S.C. 103 as being unpatentable over Yin et. al. ((2018), Simvastatin inhibits sonic hedgehog signaling and stemness features of pancreatic cancer, Cancer Letter, 426, 14 – 24) in view of Blaauboer et. al. ((2022), The Class I HDAC Inhibitor Valproic Acid Strongly Potentiates Gemcitabine Efficacy in Pancreatic Cancer by Immune System Activation, Biomedicines, 10, 1 – 16).
Regarding claims 1 – 6, and 10 – 16, Yin et. al. teach that pancreatic ductal adenocarcinoma (PDA) is a disease with an exceptionally poor prognosis, high therapy resistance, and early metastasis. See page 14 column 1 paragraph 1. Moreover, Yin et. al. teach that more effective therapeutic options are urgently needed to enhance the survival of patients. See page 14 column 1 paragraph 1. Additionally, Yin et. al. teach that the statin family consists of eight unique compounds as follows: pravastatin, simvastatin and lovastatin are naturally derived from fungal fermentation; and fluvastatin, atorvastatin, cerivastatin, rosuvastatin and pitavastatin are synthetic compounds. See page 15 column 1 paragraph 2. Yin et. al. teach that statins have become of interest for prevention and treatment of cancer because they inhibit inflammation, angiogenesis, and proliferation and are pro-apoptotic. See page 15 column 1 paragraph 2. Furthermore, Yin et. al. teach that even though results in pancreatic cancer were inconsistent, the latest studies, which include one retrospective cohort US study on 2142 PDA patients, a case-control Italian study on 408 PDA patients, and a retrospective Korean study on 1761 PDA patients, have revealed that statin use is associated with lower risk and mortality as well as a longer survival of PDA patients with non-metastatic disease. See page 15 column 1 paragraph 2.
Furthermore, Yin et. al. teach that the ASAN-PaCa, BxPc-3 (less aggressive), MIA-PaCa2 and PANC-1 (highly aggressive) PDA cell lines were treated with gemcitabine for 72 h followed before the cells were then treated with simvastatin in concentrations ranging from 2 to 40 mM to mimic plasma concentrations, which can vary from 1 nM to 2mM. See page 16 column 1 paragraph 5. Additionally, Yin et. al. teach that tumor xenotransplantation was performed on fertilized eggs from genetically identical hybrid Lohman Brown (LB) chickens using established human pancreatic cell line MIA-PaCa2 cells on day 9 of development. See page 15 column 1 paragraph 4 and column 2 paragraph 8. Additionally, Yin et.al. teach that before harvesting the tumors on day 18, on days 12 and 15 the embryos were treated with 20 mL of saline alone (CO) or 20 mL of saline with 60 mg of simvastatin (SIM), 75 mg of gemcitabine (GEM) or both in a volume of 20 mL (SIM + GEM) were injected into the CAM vessels that directly supplied the tumor xenografts. See page 21 Figure 4A. See claim 1 limitation for a method for treating pancreatic cancer comprising administering a statin. See claim 2 limitation for a method of claim 1 where the statin selected is simvastatin. See claim 3 limitation for a method of claim 2 where the statin is simvastatin. See claim 4 limitation for a method of claim 1 where at least in further anti-cancer agent is administered. See claim 5 limitation for a method of claim 1 where the subject has responded to a first line therapy. See claim 6 limitation for a method of claim 5 where the first line therapy comprises administering gemcitabine. See claim 10 limitation for a method of claim 4 where the further anti-cancer agent selected is gemcitabine. See claim 11 limitation for a method of claim 4 where the further anti-cancer agent is gemcitabine. See claim 13 limitation for a method of claim 1 where the pancreatic cancer selected is pancreatic ductal adenocarcinoma. See claim 14 limitation for a method of claim 1 where the statin is administered separately. See claim 15 limitation for a method of claim 15 where the single dosage form unit comprise at least one pharmaceutically acceptable excipient, saline. See claim 16 limitation for a method of claim 14 where the statin is administered in a separate dosage form for parenteral administration.
Additionally, Yin et.al. teach that treatment with simvastatin, gemcitabine and both together reduced the tumor take rate and tumor size compared to the control xenografts. See page 20 column 1 paragraph 1. Importantly, Yin et. al. teach that the tumor take rate and size were significantly lower after the combined treatment compared to each single drug treatment. See page 20 column 1 paragraph 1. Furthermore, Yin et. al. teach that their results reveal that simvastatin significantly enhanced the ability of gemcitabine to reduce the cell viability, colony formation and spheroid formation. See page 23 column 1 paragraph 2. Moreover, Yin et. al. teach that unlike the single treatment, the combination of simvastatin with gemcitabine potentiated the effect and led to a complete inhibition of tumor growth, engraftment and metastasis of PDA xenografts on chicken eggs. See page 23 column 1 paragraph 2.
However, while Yin et. al. taught a method for treating pancreatic ductal adenocarcinoma (PDA) comprising administering the statin, simvastatin, and gemcitabine; Yin et. al. fail to teach a method of treatment further comprising administering a HDAC inhibitor. See claim 1 limitation. Moreover, Yin et. al. fail to each a method where the HDAC inhibitor and the statin are administered separately. See claim 14 limitation.
Nevertheless, Blaauboer et. al. teach that pancreatic cancer represents the fourth most lethal cancer in the Western world, with a 5-year survival rate of 8.5%. See page 1 paragraph 1. Additionally, Blaauboer et. al. teach that the incidence rate of pancreatic cancer is slowly rising and, as a consequence, it is expected to be the second leading cause of cancer-related death by 2030. See page 1 paragraph 1. Moreover, Blaauboer et. al. teach that to increase survival rates following surgery, gemcitabine (2’,2’-difluoro2’deoxycytidine, dFdC) has long been the standard first-line chemotherapy for patients with resectable disease. See page 1 paragraph 2. Unfortunately, Blaauboer et. al. teach that gemcitabine therapeutic value is substantially limited due to treatment resistance. See page 1 paragraph 2 and page 2 paragraph 1. Moreover, Blaauboer et. al. teach that despite the introduction of other more effective chemotherapeutic regimens, such as FOLFIRINO.X.; gemcitabine/nab-paclitaxel and gemcitabine/capecitabine, gemcitabine alone is still recommended for (elderly) patients with comorbidities, as it is much better tolerated with less toxicity compared to the other chemotherapeutic agents. See page 2 paragraph 1. See claim 12 limitation for a method of claim 11 where the further anti-cancer agent is a combination of gemcitabine/nab-paclitaxel.
Additionally, Blaauboer et. al. teach that epi-drugs have emerged as a novel and promising approach to reactivate gene expression. See page 2 paragraph 3. Blaauboer et. al. teach that epi-drugs are chemical compounds that target specific enzymes, which are necessary for the maintenance and establishment of epigenetic modifications, with the main strategy being the inhibition of DNA methyltransferases (DNMTs) and histone deacetylates (HDACs). See page 2 paragraph 3. Furthermore, Blaauboer et. al. teach that valproic acid (VPA) has a IC50 of 1098 µM, that is 1.098mM, for cell proliferation against mouse pancreatic cancer KPC3 cell line, derived from a primary tumor of a female KrasG12D/+;Trp53R172H/+;Pdx-1-Cre (KPC) mouse. See page 2 paragraph 6 and page 4 paragraph 4.
Specifically, Blaauboer et. al. teach that C57BL/6 8 – 10 week aged male mice were subcutaneously injected in the flank with 100.000 KPC3 cells (passage number 3), a mouse pancreatic cell line) in 100 µL PBS/0.1% BSA. See page 2 paragraph 6 and 3 paragraphs 4 – 5. Furthermore, Blaauboer et. al. teach that the mice were randomized into four groups where one group received the vehicle control; one group received the VPA as a monotherapy through intraperitoneal (i.p.) injection of 100 µL of distilled water or 500 mg/kg VPA daily; on group received the gemcitabine monotherapy through an i.p. injection of 50 mg/kg gemcitabine two times a week (days two and five); and one group received a combination injection of 500 mg/kg VPA i.p. upon start of the treatment, and on days two and five they received an i.p. injection of 50 mg/kg gemcitabine. See page 3 paragraph 5. See claim 2 limitation for a method of claim 1 where the HDAC inhibitor selected is valproic acid. See claim 3 limitation for a method of claim 2 where HDAC inhibitor is valproic acid. See claim 4 limitation for a method of claim 1 where at least in further anti-cancer agent is administered. See claim 5 limitation for a method of claim 1 where the subject has responded to a first line therapy. See claim 6 limitation for a method of claim 5 where the first line therapy comprises administering gemcitabine. See claim 10 limitation for a method of claim 4 where the further anti-cancer agent selected is gemcitabine. See claim 11 limitation for a method of claim 4 where the further anti-cancer agent is gemcitabine. See claim 14 limitation for a method of claim 1 where the statin is administered separately. See claim 15 limitation for a method of claim 15 where the single dosage form unit comprise at least one pharmaceutically acceptable excipient, distilled water. See claim 16 limitation for a method of claim 14 where the statin is administered in a separate dosage form for intraperitoneal administration.
Moreover, Blaauboer et. al. teach that the combination therapy resulted in significant tumor growth control over time and smaller tumor volumes when compared with untreated mice, while monotherapy with VPA or gemcitabine did not. See page 7 paragraph 1. Additionally, Blaauboer et. al. teach that the after 21 days of treatment, tumor volume was reduced by 74% compared to vehicle-treated mice (1239 vs. 324 mm3; p = 0.003). See page 7 paragraph 1 and Figures 5B–D. Blaauboer et. al. teach that in the end, total body weight was reduced by 7% in combination-treated mice (p < 0.05 compared to control). See page 7 paragraph 1 and Figure 5E. Furthermore, Blaauboer et. al. teach that a low concentration VPA, which is a well-tolerated class I HDACi, strongly potentiated the antitumor effect of gemcitabine in vitro and in vivo. See page 11 paragraph 1. Blaauboer et. al. teach that the class I HDACi VPA strongly potentiated the antitumor response of gemcitabine in pancreatic cancer in vitro and in vivo. See page 13 paragraph 4. See claim 1 limitation for a method for treating pancreatic cancer comprising administering a HDAC inhibitor.
Regarding claim 12 limitation for the method according claim 11, where the further anticancer agent is a combination of nab-paclitaxel and gemcitabine; as taught above, Blaauboer et. al. teach alternative chemotherapeutic regimens, such as FOLFIRINO.X.; gemcitabine/nab-paclitaxel and gemcitabine/capecitabine, that was known in the art as first-line chemotherapy for patients with resectable disease. Given that the skill of one of ordinary skill in the oncological arts is relatively high; being that of a Ph.D. or M.D. in would have been within the purview of such artisan the treat pancreatic cancer that has with a combination of gemcitabine/nab-paclitaxel since it was known in the art as taught by Blaauboer et. al.
Therefore it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the method of Yin et. al. for treating pancreatic ductal adenocarcinoma (PDA) comprising administering the statin, simvastatin, and gemcitabine in view of Blaauboer et. al. that is to include the HDAC inhibitor valproic acid either as a single dosage unit or separately. One of ordinary skill in the art would have been motivated to make the modification because both statin and valproic acid have been shown to be effective in treating pancreatic cancer especially when combined with gemcitabine. Thus one of ordinary skill in the art would have had a reasonable expectation of success with the combination therapy because the combination of simvastatin with gemcitabine led to a complete inhibition of tumor growth, engraftment and metastasis of PDA xenografts on chicken eggs and the combination of valproic acid with gemcitabine resulted in significant tumor growth control over time with smaller tumor volumes compared with untreated mice. Moreover, one of ordinary skill in the art would have had a reasonable expectation of success with the combination therapy because the dual therapies where effective thus the combination of all three therapies, that is valproic acid, simvastatin, gemcitabine would have a reasonable expectation of being at least as effective as the dual therapies against pancreatic cancer.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Yin et. al. ((2018), Simvastatin inhibits sonic hedgehog signaling and stemness features of pancreatic cancer, Cancer Letter, 426, 14 – 24) and Blaauboer et. al. ((2022), The Class I HDAC Inhibitor Valproic Acid Strongly Potentiates Gemcitabine Efficacy in Pancreatic Cancer by Immune System Activation, Biomedicines, 10, 1 – 16) as applied to claims 1 – 6, and 10 – 16 above, and further in view of Zhang et. al. ((2022), The Efficacy and Safety of PD-1 Inhibitors Combined with Nab-Paclitaxel Plus Gemcitabine versus Nab-Paclitaxel Plus Gemcitabine in the First-Line Treatment of Advanced Pancreatic Cancer: A Retrospective Monocentric Study, Cancer Management and Research, I4, 535 – 546).
The prior art teachings of Yin et. al. and Blaauboer et. al. as they relate to claims 1 and 4, from which claim 9 depends, is given previously in this office action and are fully incorporated here.
However, Yin et. al. and Blaauboer et. al. does not explicitly teach a method where the further anti-cancer agent selected is a PD-1 inhibitor. See claim 9 limitation.
Nevertheless, Zhang et. al. teach that pancreatic cancer is hidden in a location that makes it difficult to diagnose at an early stage. See page 535 paragraph 1. Moreover, Zhang et. al. teach that about 50% of pancreatic cancer is accompanied by distant metastasis at diagnosis, and the 5-year survival rate is only 9%. See page 535 paragraph 1. Zhang et. al. teach that in a 2017 phase Ib/II study of Pembrolizumab, gemcitabine, and nab-paclitaxel for patients with metastatic pancreatic cancer, the disease control rate (DCR) reached 100%. See page 536 paragraph 2. Furthermore, Zhang et. al. teach that patients with advanced metastatic (stage IV) pancreatic ductal adenocarcinoma were treated with either the chemotherapy of gemcitabine 1000 mg/m2 intravenous drip, nab-paclitaxel 125 mg/m2 intravenous drip (AG), day 1–8, every 3 weeks as a treatment cycle or the combination of Toripalimab 240 mg, Camrelizumab 200 mg; Tislelizumab 200 mg; or Sintilimab 200 mg administered intravenously at day 1, every 3 weeks; and gemcitabine 1000 mg/m2 intravenous drip, nab-paclitaxel 125 mg/m2 intravenous drip (PD-1 + AG), day 1–8, every 3 weeks as a treatment cycle. See page 536 paragraph 5 and page 537 paragraph 1. See claim 9 limitation for a method where the further anti-cancer agent selected is a PD-1 inhibitor. Furthermore, Zhang et. al. teach that in terms of median overall survival (OS), the median OS was 2.8 months longer in the combination therapy group than in the AG group. See page 539 paragraph 1. Moreover, Zhang et. al. teach that compared with the AG chemotherapy regimen, the addition of PD-1 inhibitor effectively prolonged the OS of patients with advanced pancreatic cancer and had good safety and reduced the risk of death by about 20.0% (HR = 0.203, 95% CI, 0.090−0.459, P < 0.001). See page 542 paragraph 1.
Therefore it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the method of Yin et. al. for treating pancreatic ductal adenocarcinoma (PDA) comprising administering the statin, simvastatin, and gemcitabine in view of Blaauboer et. al. that is to include the HDAC inhibitor valproic acid either as a single dosage unit or separately, in further view of Zhang et. al. to include a PD-1 inhibitor. One of ordinary skill in the art would have been motivated to make the modification because PD-1 inhibitors have been shown to be effective in treating pancreatic cancer especially when combined with gemcitabine and nab-paclitaxel. Thus one of ordinary skill in the art would have had a reasonable expectation of success with the combination therapy because the combination of a PD-1 inhibitor with gemcitabine and nab-paclitaxel led to the median OS increasing by 2.8 months and reduced the risk of death by about 20.0% (HR = 0.203, 95% CI, 0.090−0.459, P < 0.001).
Claims 7 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Yin et. al. ((2018), Simvastatin inhibits sonic hedgehog signaling and stemness features of pancreatic cancer, Cancer Letter, 426, 14 – 24) and Blaauboer et. al. ((2022), The Class I HDAC Inhibitor Valproic Acid Strongly Potentiates Gemcitabine Efficacy in Pancreatic Cancer by Immune System Activation, Biomedicines, 10, 1 – 16) as applied to claims 1 – 6, and 10 – 16 above, in view of Mayer et. al. ((2007), Optimizing Combination Chemotherapy by Controlling Drug Ratios, Molecular Interventions, 7, 216 – 223).
The prior art teachings of Yin et. al. and Blaauboer et. al. as they relate to claim 1, from which claims 7 – 8 depend, is given previously in this office action and are fully incorporated here.
However, Yin et. al. and Blaauboer et. al. does not explicitly teach a method where the ratio of the HDAC inhibitor and the statin is of about 50:50 cytotoxic ratio. See claim 7 limitation. Moreover, Yin et. al. and Blaauboer et. al. does not explicitly teach a method where the HDAC inhibitor selected is valproic acid at a concentration ranging from about 16 mm to about 0.5 mM and the statin selected is simvastatin at a concentration ranging from about 8μM to about 0.06μM. See claim 8 limitation.
Nevertheless, given that the skill of one of ordinary skill in the oncological arts is relatively high; being that of a Ph.D. or M.D. in would have been within the purview of such artisan to take the in vitro and in-vivo teachings of the prior art of Yin et.al. and Blaauboer et. al. to optimize from the IC50 values. Thus, in regards to claim 8 limitation for a method where the statin selected is simvastatin at a concentration ranging from about 8μM to about 0.06μM, as taught above Yin et. al. teach that the ASAN-PaCa, BxPc-3 (less aggressive), MIA-PaCa2 and PANC-1 (highly aggressive) PDA cell lines were treated with gemcitabine for 72 h followed before the cells were then treated with simvastatin in concentrations ranging from 2 to 40 mM to mimic plasma concentrations, which can vary from 1 nM to 2mM. See page 16 column 1 paragraph 5. Thus the prior art of Yin et. al. teach a plasma concentration range of 1 nM to 2 mM, that is 0.001 μM to 2 mM which overlaps with the lower range of 0.06 μM. Furthermore, Blaauboer et. al. teach that valproic acid (VPA) has a IC50 of 1098 µM, that is 1.098mM, which overlaps with claim 8 limitation for a method where the HDAC inhibitor selected is valproic acid at a concentration ranging from about 16 mm to about 0.5 mM. See page 2 paragraph 6 and page 4 paragraph 4. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05 (I).
However, Yin et. al. and Blaauboer et. al. does not explicitly teach a method where the ratio of the HDAC inhibitor and the statin is of about 50:50 cytotoxic ratio. See claim 7 limitation.
Nevertheless, Mayer et. al. teach that drug combinations have played a particularly prominent role in the treatment of cancer. See page 217 column 1 paragraph 1. Furthermore, Mayer et.al. teach that despite these advances, the fundamentals of combination chemotherapy development have remained largely unchanged from those originally pioneered by Frei and coworkers in the 1960s which has been to: 1) use drugs with non-overlapping toxicities so that each drug in the combination can be administered at near-maximal dose; 2) combine agents with different mechanisms of action in order to inhibit the emergence of broad spectrum drug resistance; and 3) administer the full combination as early as possible in the disease. See page 217 column 1 paragraph 2. Additionally, Mayer et. al. teach that the evaluation of synergistic drug combinations is frequently conducted in cell culture, where the concentration and duration of administered drug(s) can be tightly controlled, and the inhibition of tumor cell growth can be readily measured. See page 217 column 2 paragraph 4 and page 218 column 1 paragraph 1.
Moreover, Mayer et.al. teach that ideally, a systematic evaluation of drug combinations should examine a series of fixed drug ratios, with each fixed ratio diluted over a range of concentrations that elicits a broad spectrum of the biological response [e.g., ranging from less than 10% to greater than 90% inhibition of tumor cell growth. See page 219 column 1 paragraph 2. Furthermore, Mayer et. al. teach that the above approach is capable of revealing common trends in drug ratio dependency among different tumor types, and we have found that many commonly used drug combinations, representing a wide range of drug classes with disparate chemical and functional properties, exhibit striking drug ratio-dependent synergy with certain ratios consistently display synergy across a panel of tumor cell types, whereas other ratios can be strongly antagonistic which suggests that the phenomenon of drug ratio-dependent tumor cell growth inhibition is mechanistically unbiased and of widespread importance to combination chemotherapy. See page 219 column 1 paragraph 2. Given that the skill of one of ordinary skill in the oncological arts is relatively high; being that of a Ph.D. or M.D. in would have been within the purview of such artisan to take the in vitro and in-vivo teachings of the prior art of Yin et.al., Blaauboer et. al., and Mayer et. al. to optimize the combination treatment regimen from the IC50 values to get a cytotoxicity ratio of 50: 50 HDAC inhibitor: statin.
Therefore it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the method of Yin et. al. for treating pancreatic ductal adenocarcinoma (PDA) comprising administering the statin, simvastatin, and gemcitabine in view of Blaauboer et. al. that is to include the HDAC inhibitor valproic acid either as a single dosage unit or separately in further view of Mayer et. al., that is to administer the HDAC inhibitor and the statin is of about 50:50 cytotoxic ratio. One of ordinary skill in the art would have been motivated to make this modification to: 1) use drugs with non-overlapping toxicities so that each drug in the combination can be administered at near-maximal dose; 2) combine agents with different mechanisms of action in order to inhibit the emergence of broad spectrum drug resistance; and 3) administer the full combination as early as possible in the disease. One of ordinary skill in the art would have had a reasonable expectation of success because the prior art taught that systematic evaluation of drug combinations over a series of fixed drug ratios is capable of revealing common trends in drug ratio dependency among different tumor types, and many commonly used drug combinations.
Conclusion
Claims 1 – 16 are rejected.
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/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627
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