Royalty Report: Drugs, Disease, cardiac – Collection: 286027

License Grant

Licensor hereby grants to Koran Licensee a sole and exclusive right and license in the Territory to use and sell any of the Products for the indications as specified herein.

License Property

Product means (a) TBC-11251, the lead candidate for Licensors Endothelin Receptor Antagonist (TBC-11251 is more particularly described hereto), and/or (b) TBC-1269, the lead candidate for Licensors Selectin Antagonist (TBC-1269 is more particularly described hereto).

TBC11251 is a sulfonamide based antagonist of endothelin binding to its receptors. The compound exhibits selectivity for binding to the A subtype of the endothelin receptors relative to the B subtype. The chemical structure of TBC11251 is 4-chloro-3-methyl-5-(2-(2-(6-methylbenzo[d][1.3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazole (it is also referred to by N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5- (methylenedioxy)phenylacetyl]thiophene-3-sulfphonamide). The compound is also referred to as various salt forms which include, but are not limited to, the sodium phosphate salt (TBC11251Z) and the sodium salt (TBC11251Na).

Application 1 PCT/US94/05755 'Sulfonamides and derivatives thereof that modulate the activity of endothelin' filed April 4, 1994.

Application 2 PCT/US96/04759 'Thienyl-, furyl, pyrrolyl-, and biphenylsulfonamides and derivatives thereof that modulate the activity of endothelin' filed April 4, 1996.

TBC1269 is a mannosylated biphenyl based selectin antagonist which is capable of blocking the binding of E-,P-, and L- selectin to their respective ligands. The compound is also referred to as various sale forms which include, but are not limited to, the sodium salt (TBC1269Na).

Patents covering TBC1269 in the Territories
Application PCT/US96/11032 entitled 'Binding of E-selecting, P-selectin or L-selectin to Sialyl-Lewis or Sialyl-Lewis' filed June 26, 1996.
Application 08/655 entitled 'High yield stereospecific mannosylation' filed May 20, 1996.

Endothelin Receptor Antagonist means a molecular compound under development by Licensor which inhibits the binding of endothelin to a distinct cell surface receptor.

Novastan(R) means a non-protein, synthetic small molecule thrombin inhibitor developed by Licensor that directly and selectively binds to and inactivates thrombin in the blood plasma.

Selectin Antagonist means a molecular compound under development by Licensor which inhibits the selectin-mediated adhesion of inflamed endothelium to the surface of white blood cells.

Endothelin receptors are G protein-coupled receptors whose activation result in elevation of intracellular-free calcium,[2] which constricts the smooth muscles of the blood vessels, raising blood pressure, or relaxes the smooth muscles of the blood vessels, lowering blood pressure, among other functions.

Field of Use

This agreement pertains to the drug industry relating to indications of congestive heart failure , chronic obstructive pulmonary disease, primary pulmonary hypertension, asthma and psoriasis.

License Grant

Licensor grants an exclusive license or sublicense even as to Licensor, with the right to grant sublicenses pursuant to Licensor Patent Rights and Know-How to research, develop, make, have made, use, sell, offer to sell, supply, cause to be supplied, import and have imported Licensed Product in the Field in the Territory.

With the Reciprocal Non-Exclusive Research License for Disclosed Know-How and Confidential Information, Licensor grants a non-exclusive, irrevocable, perpetual, worldwide license, with the right to sublicense to Licensee Affiliates, to use only for research purposes any and all Licensor Know-How or Confidential Information of Licensor disclosed to Licensee during the Term but not any Licensor Patent Rights, it being understood and agreed that neither Licensee nor any of its Affiliates will have any right or license to use any such Licensor Know-How or Licensor Confidential Information with respect to Compound or Licensed Product after termination of this Agreement and/or in connection with obtaining Regulatory Approval of a pharmaceutical product and/or the sale or manufacture for sale of any pharmaceutical product.

License Property

Compound means Licensors-1070 and all modifications, enhancements, improvements and backups which result in a heterobifunctional, pan selectin antagonist comprised of a selectin antagonist linked to a benzy amino sulfuric acid (BASA)  and mimicking the native glycosulfopeptide ligand for E and P – selectins and all isomers, tautomers, enantlomers, hydrates, esters, racemates, polymorphs, metabolites, prodrugs and salts of any of the compounds that are a heterobifunctional, pan selectin antagonist comprised of a selectin antagonist linked to a benzy amino sulfuric acid (BASA)  and mimicking the native glycosulfopeptide ligand for E and P – selectins.

1070 is a rationally designed glycomimetic inhibitor of E-, P- and L-selectins that interferes in a key early step in the inflammatory process leading to leukocyte adhesion and recruitment to inflamed tissue.

Field of Use

1070 is initially being developed for the treatment of vaso-occlusive crisis associated with sickle cell disease.

License Grant

The German Licensor grants an exclusive right and license in the Territory, under Licensors Technology, for all Pharmaceutical Uses, with the right to grant sublicenses, to research, develop, modify and improve Compound and Product;  apply for and obtain Regulatory Approvals; and use, import/export, market, offer to sell and sell, Product and Compound.

License Property

The Compound means the endothelin receptor antagonist compound identified as BSF 208075 (ambrisentan) and the chemical name, (+)-(S)-2-(4,6-Dimethyl-pyrimidin-2-yloxy)-3-methoxy-3,3- diphenyl propionic acid, its racemates, isomers, Prodrugs, active metabolites and any pharmaceutically acceptable salt or complex thereof, in its current and any other formulation.

Field of Use

The license is for any pharmaceutical use.  The clinical study of the compound is for pulmonary arterial hypertension, Chronic Renal Failure and Chronic Heart Failure.

License Grant

The Licensee entered into a Sublicense Agreement pursuant to which the Licensor agreed to grant a worldwide License for the development, manufacture and commercialization of DARA, an ARB and ERA which the Licensee is initially using in connection with the treatment of focal segmental glomerulosclerosis (or FSGS), and which we refer to as RE-021.  DARA (PS433540) is an Angiotesin Receptor Blocker (ARB) and Endothelin Receptor Antagonist (ERA) .

License Property

RE-021 is a small molecule intended to treat focal segmental glomerulosclerosis (or FSGS), a disease that causes nephrotic syndrome and kidney failure.  RE-021 is a small molecule angiotensin receptor blocker (ARB) and selective endothelin receptor antagonist (ERA). RE-021 has already been demonstrated safe in human clinical studies. RE-021 could be useful as a treatment for other nephropathies and recalcitrant hypertension.

License Grant

The Company and its wholly owned subsidiary entered into a Sublicense Agreement with Licensee for the full world-wide rights to its dual-acting receptor antagonist of angiotensin and endothelin receptors (DARA) to another pharma.

License Property

Licensor acquired the DARA (previous development name, PS433540) in its acquisition of another company in December 2008. The compound possesses two clinically-validated mechanisms of action that selectively block two potent vasoconstrictor and mitogenic agents, angiotensin-II and endothelin 1, at their respective receptors. In previously-completed Phase IIb studies for hypertension, the drug was found to be safe and well tolerated, and demonstrated statistically significantly greater reductions in blood pressure compared with either placebo or irbesartan.

Field of Use

Licensee intends to develop DARA for orphan indications of severe kidney diseases, including focal segmental glomerulosclerosis (FSGS), as well as conduct proof-of-concept studies in resistant hypertension and diabetic nephropathy. The DARA, with its unique dual blockade of angiotensin and endothelin receptors, is expected to provide meaningful clinical benefits in mitigating proteinuria in indications for which there are no approved therapies.

License Grant

The Licensor of Japan grants an exclusive, even as to Licensor, license, including the right to grant sublicenses, under the Licensors Intellectual Property to research, develop, make, have made, use, offer for sale, market, sell, import, export and distribute Compound and/or Product in and throughout the Licensee Territory in the Field.

License Property

The technology is a new chemical class of compounds of integrin alpha Vbeta3 and GPIIbIIIa receptors dual antagonists, including a lead compound known as CP4715, having potential cardio and cerebroprotective activity.

Product shall mean any pharmaceutical composition containing Compound as an active ingredient, in any formulation, delivery system or package configuration.

Compound shall mean the chemical compound, having dual antagonistic activity against both integrin alpha Vbeta3 and GPilbllla receptors which activity substantially contributes to the therapeutic efficacy for its intended use, which is the compound defined as (2S)-benzenesulfonylamino-3-[3-methoxy-4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]propionic acid and designated by the Licensor internal code name of CP4715.

MN-447 and MN-462 are antithrombic (anti-clotting) agents that represent novel approaches to blood clot formation and lysis, respectively, and are expected to treat a variety of thrombotic disorders.

MN-447 is a novel cardioprotective, anti-platelet agent that acts as a potent dual antagonist of glycoprotein (GP) IIbIIIa and integrin alpha-v-beta-3 receptors that play key roles in blood clot formation and various cell behaviors and functions such as leukocyte adhesion. MN-447 acts downstream by inhibiting the final common pathway of platelet aggregation — the cross-linking of platelets via fibrinogen bridges to GP IIbIIIa receptors. Inhibition of integrin alpha-v-beta-3 receptors has been linked to an inhibition of leukocyte adhesion to endothelium (the layer of cells lining blood vessels), reduction of hyperplasia (abnormal cellular proliferation) and lumen stenosis (blood vessel constriction) in response to vascular injury. In animal models of myocardial infarction and unstable angina, the dual inhibitory activity of MN-447 produced superior cardioprotective efficacy, such as reduction in infarct size after reperfusion (restoration of blood flow), compared to inhibition of the GP IIbIIIa receptor alone and showed a low risk of bleeding.

MN-462 is a selective inhibitor of a key enzyme in the intrinsic antifibrinolytic mechanism, plasma carboxypeptidase B (CPB; also called activated thrombin-activatable fibrinolysis inhibitor (TAFIa)), which inhibits physiological fibrinolysis (the lysis or dissolving of blood clots). By enhancing intrinsic fibrinolysis through plasma CPB inhibition, MN-462 has the potential to both reduce and prevent thrombus or blood clot formation as well as to dissolve formed thrombus, and consequently, represents a novel approach to treating various thrombotic disorders. In preclinical studies, MN-462 has demonstrated significant fibrinolytic-enhancing and anti-thrombotic activities as monotherapy in several thrombosis models, as well as activities when used as an adjunct to fibrinolytics such as tissue plasminogen activator (t-PA). The effect of MN-462 in enhancing the intrinsic fibrinolytic process has also been observed to result in a low risk of bleeding.

Field of Use

The Field shall mean any use of Compound or Product in humans.  The patent application includes human platelet aggregation inhibitory activity, and, therapeutic agents for treating cardiovascular diseases, angiogenesis-related diseases, cerebrovascular diseases and the like and for inhibiting platelet aggregation.