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US 6,743,786 Vanadium Compounds for Treating Cancer. Chrissy Brown (PO) Lisa Perlson (AI) November 15, 2006. PO. Claimed Invention: VCp 2 (bpy)OTf 2. Abbreviations V – Vanadium(IV) Cp – Cyclopentadienyl Ring Bpy – 2,2’-Bipyridine OTf 2 – Triflate (CF 3 SO 3 - ).
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US 6,743,786Vanadium 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 anti- cancer 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 Proposed Binding of VCp2X2 to DNA V • 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 anti-cancer 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 • Examiner failed to take into account prior art for VCp2X2 compounds when considering application.
AI Activity Against Fluid Ehrlich Ascites Tumor Optimum Dose Range = 40 – 60 mg/kgCure Rate = 100% Optimum Dose Range = 80 – 90 mg/kg Cure Rate = 100% Optimum Dose Range = ? Cure Rate = ? Optimum Dose Range = 140 – 220 mg/kg Cure Rate = 100%