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 )  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 VCp 2 Cl 2  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) In Vitro Cytotoxicity of Vanadocene Compounds Against Human Cancer  VDC = VCp 2 Cl 2

PO Monodentate v. Bidentate VCp 2 Ligands  Monodenate Ligands Single Coordination to Metal Ex: Cl, CN, SCN  Bidentate Ligands Double Coordination to Metal Ex: Bipyridine V Proposed Binding of VCp 2 X 2 to DNA  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?

PO  Anticancer Activity of VCp 2 (bpy) 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

PO Claimed Invention: VCp 2 (bpy)OTf 2 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 in the literature was previously unreported  VCp 2 (bpy)OTf 2 shows high efficacy of cancer cell death with low doses compared to other VCp 2 (chelator) ligands.

AI 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 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

Metallocenes with Antitumor Activity

M X X Ti Cl Cl Ti Br Br Ti NCS NCS Ti N 3 N 3 V Cl Cl Nb Cl Cl V Br Br Nb Br Br V NCS NCS Nb NCS NCS V N 3 N 3 Nb N 3 N 3 Mo Cl Cl Mo Br Br Mo NCS NCS  Examiner failed to take into account prior art for VCp 2 X 2 compounds when considering application.

Mo N 3 N 3

AI

Activity Against Fluid Ehrlich Ascites Tumor

Ti Cl Cl V Cl Cl Optimum Dose Range = 40 – 60 mg/kg Cure Rate = 100% Optimum Dose Range = 80 – 90 mg/kg Cure Rate = 100% N Ti N Optimum Dose Range = 140 – 220 mg/kg Cure Rate = 100% N V N Optimum Dose Range = ?

Cure Rate = ?