1. US 6,743,786 Vanadium Compounds for Treating Cancer Chrissy Brown (PO) Lisa Perlson (AI) November 15, 2006

2. 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 - ) PO  Used to treat Leukemia, Hodgkin’s Lymphoma, non-Hodgkin’s Lymphoma, Multiple Myeloma, Testicular Cancer, Brain Tumor, Breast Cancer and Prostate Cancer

3. Anticancer Activity of VCp 2 Cl 2 In Vitro Cytotoxicity of Vanadocene Compounds Against Human Cancer  VDC = VCp 2 Cl 2 PO  VCp 2 Cl 2 and TiCp 2 Cl 2 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)

4. Monodentate v. Bidentate VCp 2 Ligands  Monodenate Ligands Single Coordination to Metal Ex: Cl, CN, SCN  Bidentate Ligands Double Coordination to Metal Ex: Bipyridine Proposed Binding of VCp 2 X 2 to DNA PO  VCp 2 have loose interaction with PO 4 Group  VCp 2 (bpy) dissociates differently than VCp 2 Cl 2  VCp 2 (bpy) binds DNA differently leading to a different mode of activity? V

5. Anticancer Activity of VCp 2 (bpy) PO  Many VCp 2 (chelator) compounds synthesized in 1960-1975.  No Reported Biological Activity  First Reported Synthesis of VCp 2 (byp) compound  VCp 2 (byp) has high efficacy with low dosage (Unexpected Result) In Vitro Cytotoxicity of Vanadocene Compounds Against Human Cancer

6. Claimed Invention: VCp 2 (bpy)OTf 2 PO Patentability of Claim 5  In certain tumors, VCp 2 Cl 2 is the only Metal-Cp 2 Cl 2 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 VCp 2 (bpy)OTf 2 was previously unreported in the literature  VCp 2 (bpy)OTf 2 shows high efficacy of cancer cell death with low doses compared to other VCp 2 (chelator) ligands.

7. Claimed Invention: VCp 2 (bpy)OTf 2 Invalidity of Claim 5: Obviousness  Synthesis of VCp 2 (bpy)OTf 2 was obvious to POSITA from published analogous synthesis of TiCp 2 (bpy)OTf 2.  Substitution of V for Ti is common in studies of metallocene complexes, so there is motivation to combine in the prior art.  TiCp 2 (bpy)OTf 2 showed anti-cancer activity, so it is not an unexpected result for VCp 2 (bpy)OTf 2 to show anti- cancer activity. AI

8. Synthesis of VCp 2 (bpy)OTf 2  2 step synthesis of TiCp 2 (bpy)OTf 2 published in 1986 (J. Organometallic Chem. 1986, 302, 193.)  Patent acknowledges using “modified” TiCp 2 (bpy)(OTf 2 ) 2 synthesis  VCp 2 X 2 and TiCp 2 X 2 are commonly made using the same procedure, as would be known by POSITA.  VCp 2 Cl 2 and TiCp 2 Cl 2 are commercially available. TiCp 2 (bpy)(OTf 2 ) 2 AI

9. Metallocenes with Antitumor Activity AI  Examiner failed to take into account prior art for VCp 2 X 2 compounds when considering application.

10. Optimum Dose Range = 40 – 60 mg/kg Cure Rate = 100% Optimum Dose Range = 80 – 90 mg/kg Cure Rate = 100% Optimum Dose Range = 140 – 220 mg/kg Cure Rate = 100% Optimum Dose Range = ? Cure Rate = ? Activity Against Fluid Ehrlich Ascites Tumor AI