Transcript 786_Intro
US 6,743,786 Vanadium Compounds for Treating Cancer Chrissy Brown (PO) Lisa Perlson (AI) November 15, 2006 PO Claimed Invention: VCp2(bpy)OTf2 Abbreviations V – Vanadium(IV) Cp – Cyclopentadienyl Ring Bpy – 2,2’-Bipyridine OTf2 – Triflate (CF3SO3- ) Used to treat Leukemia, Hodgkin’s Lymphoma, non-Hodgkin’s Lymphoma, Multiple Myeloma, Testicular Cancer, Brain Tumor, Breast Cancer and Prostate Cancer PO Anticancer Activity of VCp2Cl2 VCp2Cl2 and TiCp2Cl2 are well known anti-cancer agents. Comparable activity in mammary, lung, colon and skin cancer For testicular, brain and leukemia cancers, only V showed anticancer activity (Unexpected Result) In Vitro Cytotoxicity of Vanadocene Compounds Against Human Cancer VDC = VCp2Cl2 PO Monodentate v. Bidentate VCp2 Ligands Monodenate Ligands Single Coordination to Metal Ex: Cl, CN, SCN Bidentate Ligands Double Coordination to Metal Ex: Bipyridine V Proposed Binding of VCp2X2 to DNA VCp2 have loose interaction with PO4 Group VCp2(bpy) dissociates differently than VCp2Cl2 VCp2(bpy) binds DNA differently leading to a different mode of activity? PO Anticancer Activity of VCp2(bpy) Many VCp2(chelator) compounds synthesized in 1960-1975. No Reported Biological Activity First Reported Synthesis of VCp2(byp) compound VCp2(byp) has high efficacy with low dosage (Unexpected Result) In Vitro Cytotoxicity of Vanadocene Compounds Against Human Cancer PO Claimed Invention: VCp2(bpy)OTf2 Patentability of Claim 5 In certain tumors, VCp2Cl2 is the only Metal-Cp2Cl2 complex to demonstrate anti-cancer activity. This unexpected result implies a new reactivity for V complexes toward these cancer and nullifies any previous assumptions about other ligands. Synthesis of VCp2(bpy)OTf2 was previously unreported in the literature VCp2(bpy)OTf2 shows high efficacy of cancer cell death with low doses compared to other VCp2(chelator) ligands. AI Claimed Invention: VCp2(bpy)OTf2 Invalidity of Claim 5: Obviousness Synthesis of VCp2(bpy)OTf2 was obvious to POSITA from published analogous synthesis of TiCp2(bpy)OTf2. Substitution of V for Ti is common in studies of metallocene complexes, so there is motivation to combine in the prior art. TiCp2(bpy)OTf2 showed anti-cancer activity, so it is not an unexpected result for VCp2(bpy)OTf2 to show anticancer activity. AI Synthesis of VCp2(bpy)OTf2 2 step synthesis of TiCp2(bpy)OTf2 published in 1986 (J. Organometallic Chem. 1986, 302, 193.) Patent acknowledges using “modified” TiCp2(bpy)(OTf2)2 synthesis VCp2X2 and TiCp2X2 are commonly made using the same procedure, as would be known by POSITA. VCp2Cl2 and TiCp2Cl2 are commercially available. TiCp2(bpy)(OTf2)2 AI Metallocenes with Antitumor Activity X M X Cl Ti Br Ti Cl Br Cl V Cl Cl Cl N3 NCS Mo Br N3 Nb NCS Br Mo N3 NCS Nb Br Cl Mo N3 V NCS Br Nb N3 NCS V Br Cl N3 Ti NCS Br V Nb NCS Ti N3 Mo NCS Examiner failed to take into account prior art for VCp2X2 compounds when considering application. N3 AI Activity Against Fluid Ehrlich Ascites Tumor Cl Cl Ti V Cl Optimum Dose Range = 40 – 60 mg/kg Cure Rate = 100% Cl Optimum Dose Range = 80 – 90 mg/kg Cure Rate = 100% N Ti N V N Optimum Dose Range = 140 – 220 mg/kg Cure Rate = 100% N Optimum Dose Range = ? Cure Rate = ?