Royalty Report: Drugs, Therapeutic, cardiac – Collection: 3467

License Grant

The Licensor receives royalties from the Licensee on 6R-BH4 product sold in Japan. Additionally in 2008, 6R-BH4 royalty revenues included a $1.5 million milestone payment related to the Japanese approval of biopterin, which contains the same active ingredient as Kuvan, for the treatment of patients with PKU.  Phenylketonuria (PKU) is a rare condition in which a baby is born without the ability to properly break down an amino acid called phenylalanine.

License Property

6R-BH4, commonly known as BH4 or tetrahydrobiopterin, is a naturally occurring enzyme cofactor that is required for numerous biochemical and physiologic processes, including the synthesis of nitric oxide (NO). NO has been shown to play a key protective role throughout the cardiovascular system and produces multiple positive effects, such as relaxing smooth muscle, reducing blood pressure, controlling inflammation and reducing platelet aggregation.

Researchers have demonstrated that a deficiency of BH4 can disrupt NO synthesis, resulting in a loss of normal endothelial NO production. This loss of endothelial NO production, commonly referred to as endothelial dysfunction, has been associated with many cardiovascular diseases, including hypertension, diabetic vascular disease, peripheral arterial disease, coronary arterial disease and pulmonary hypertension, and has been shown to be a strong predictor of cardiovascular adverse events in a number of clinical studies.

Field of Use

The rights granted apply to the healthcare industry.

License Grant

The Licensor entered into an Agreement with the German Licensee for the further development and commercialization of Kuvan and PEG-PAL for PKU and 6R-BH4, the active ingredient in Kuvan, for other diseases such as cardiovascular indications including those associated with endothelial dysfunction. Through the Agreement, the Licensee acquired exclusive rights to market these products in all territories outside the U.S. and Japan, and the Licensor retained exclusive rights to market these products in the U.S.  On December 8, 2007, the Licensor announced that we re-acquired Canadian rights for BH4 from the Licensee.

License Grant

Pursuant to the attached term sheet between the Swiss Licensor and the Licensee, the agreement is for the exclusive manufacturing of prespecified amounts of API for commercial sales and distribution in Licensees Field of Use.

License Property

The API or Product means (6R)-5,6,7,8-Tetrahydro-L-biopterin dihydrochloride (Tetrahydrobiopterin, BH4) intended for use as an active pharmaceutical ingredient.

Phenoptinâ„¢ is a proprietary oral form of tetrahydrobiopterin (6R-BH4), for the treatment of moderate to mild forms of phenylketonuria (PKU). PKU is a genetic disorder caused by a deficiency of an enzyme, phenylalanine hydroxylase (PAH), which is required for the metabolism of phenylalanine (Phe), an amino acid found in most protein-containing foods.

Field of Use

Licensees Field of Use means use of the Product in the field of single gene disorders, including the indication of phenylketonuria (PKU). Specifically excluded is any single-gene disorder based on mutation or deletion of the nitric oxide synthase gene.

Phenylketonuria (commonly known as PKU) is a rare inherited disorder that increases the levels of a substance called phenylalanine in the blood. Phenylalanine is a building block of proteins (an amino acid) that is obtained through the diet. It is found in all proteins and in some artificial sweeteners.  PKU is caused by a defect in the gene that helps create the enzyme needed to break down phenylalanine.

License Grant

As part of Licensee's acquisition of the Licensor's portfolio of cardiovascular growth factor therapeutic assets, pursuant to a Technology Transfer Agreement entered into between the Licensor and the Licensee, Licensee acquired a portfolio of methods and compositions directed at the treatment of cardiovascular diseases. Licensee also has exclusive licenses to methods for introducing DNA to the heart and for improving heart muscle function, as well as to various biologics. The Licensee's resulting portfolio of cardiovascular product candidates and associated intellectual property include methods and genes applicable to the treatment of heart diseases, the promotion of healing, and the treatment of peripheral vascular disease. Among the product candidates we acquired  are Generx and Corgentin. Generx (alferminogene tadenovex) is a DNA-based, myocardial-derived growth factor therapeutic being developed for potential use by interventional cardiologists as a one-time treatment to promote and stimulate the growth of collateral circulation in the hearts of patients with ischemic conditions such as recurrent angina. Angina, which is often felt as severe chest pain, can significantly limit patients’ mobility and quality of life and is a disorder that affects millions of adults in the United States and elsewhere.  In addition, we have secured the rights to Genvascor, a pre-clinical, DNA-based, endothelial nitric oxide synthase (eNOS) therapeutic.

License Property

Genvascor is being designed to induce production of nitric oxide and is directed at mediating the effects of multiple growth factors to enhance neovascularization and increased blood flow for the potential treatment of patients with critical limb ischemia due to advanced peripheral arterial occlusive disease (PAOD).

Field of Use

Licensee may elect to develop Genvascor alone or in collaboration with a development partner.

License Grant

Seller shall sell, transfer, assign, convey, deliver, license or sublicense, as specified below, to Buyer, or shall cause to be sold, transferred, assigned, conveyed, delivered, licensed or sublicensed, as specified below, to Buyer, and Buyer shall acquire all of Seller’s right, title and interest in and to the properties and assets of Seller.

Field of Use

The Licensee would acquire all rights to the cardiovascular products, including related trademarks, patents, intellectual property, product inventory and other related assets consisting of Cardene® I.V. (nicardipine hydrochloride), Cardene SR® and new formulations of Cardene in development, as well as Retavase® (reteplase) and the development product ularitide.  Cardene®  is for the short-term treatment of hypertension when oral therapy is not feasible or desirable. Cardene I.V. is the only intravenous calcium channel blocker (calcium ion influx inhibitor) for this indication.  Cardene I.V. offers rapid, precise blood pressure control and has been proven to be as effective as sodium nitroprusside with fewer dose adjustments (1).  Cardene I.V. prevents calcium ions from entering cardiac and vascular smooth muscle cells (the cells that line the arteries) through specific ion channels in the cell membrane. When these channels are blocked, calcium cannot enter the cell, thereby preventing the vascular smooth muscle from contracting.  Retavase® (reteplase) is a fibrinolytic agent for the management of acute myocardial infarction (AMI) or heart attack in adults for the improvement of ventricular function following AMI, the reduction of the incidence of congestive heart failure and the reduction of mortality associated with AMI. Treatment. Retavase, a recombinant plasminogen activator, works by generating plasmin, an enzyme produced naturally by the body’s blood plasma. Plasmin breaks down fibrin, a major constituent of blood clots, thereby helping to dissolve the clots.

License Grant

The parties have entered into a worldwide alliance. The Licensor has Agreements for the codevelopment and cocommercialization of AVAPRO/AVALIDE (irbesartan), an angiotensin II receptor antagonist indicated for the treatment of hypertension and diabetic nephropathy, which is copromoted in certain countries outside the U.S. under the tradename APROVEL/COAPROVEL and comarketed in certain countries outside the U.S. by the Licensor under the tradename KARVEA/KARVEZIDE; and PLAVIX (clopidogrel), a platelet aggregation inhibitor, which is copromoted in certain countries outside the U.S. under the tradename PLAVIX and comarketed in certain countries outside the U.S. by the Company under the tradename ISCOVER.

License Property

Clopidogrel bisulfate is a platelet aggregation inhibitor, which is approved for protection against fatal or non-fatal heart attack or stroke in patients with a history of heart attack, stroke, peripheral arterial disease or acute coronary syndrome.

AVAPRO/AVALIDE is an angiotensin II receptor blocker for the treatment of hypertension.

Field of Use

The rights granted apply to the healthcare industry.

License Grant

Licensor grants to the Swiss Licensee a license under the Licensors IP and Licensor’s interest in Joint Project Technology to use, sell, offer to sell, and import each Licensed Product for each Indication solely within the Field and the Territory during the Royalty Term.

Licensee expressly acknowledges that the license granted includes a sublicense of certain rights licensed to Licensor pursuant to the Existing Third Party Agreements, and any sublicense of such rights must comply with the requirements set forth in the respective Existing Third Party Agreements regarding sublicenses granted pursuant to such Existing Third Party Agreement.

License Property

Licensor has developed, licensed or acquired certain intellectual property relating to those certain investigational therapies currently referred to by Licensor as Phenoptin and Phenylase.

The Licensed Product means any product incorporating Phenoptin or Phenylase as an active pharmaceutical ingredient, either alone or with one or more other pharmaceutical ingredients, including all additions, mutations, post-translational modifications (e.g., PEGylation), rearrangements, and other modifications thereto and any other pharmaceutical product that the manufacture, use, sale, offer to sell or import thereof, would infringe one or more Patent Claims under any Patents in or to any Licensor IP; or the research, development, formulation, composition or manufacture of which was performed with the use of or incorporates any Licensor IP; or the development of which was in part funded by Licensor under this Agreement. The term Licensed Product shall include Supplied Product.

Phenoptin means tetrahydrobiopterin (6R-BH4).  Phenylase means phenylalanine ammonia lyase.

Licensors IP includes patents for Methods and Compositions for the Treatment of Phenylketonuria, Crystalline Forms of (6R)-L-erythro-tetrahydrtobiopterin dihydrochloride  and Methods for Preparing Tetrahydrobiopterin, and others.

Phenylketonuria also called PKU, is a rare inherited disorder that causes an amino acid called phenylalanine to build up in the body. PKU is caused by a defect in the gene that helps create the enzyme needed to break down phenylalanine.

Without the enzyme necessary to process phenylalanine, a dangerous buildup can develop when a person with PKU eats foods that contain protein or eats aspartame, an artificial sweetener. This can eventually lead to serious health problems.

Field of Use

The Field means all therapeutic, diagnostic or preventative uses, and these ingredients have been developed for the treatment of genetic disorders that are characterized by an inability of the body to metabolize the essential amino acid, phenylalanine (PKU), including, without limitation, phenylketonuria, and also for the treatment of other disorders.

License Grant

The Swiss Licensor hereby grants to the Canadian Licensee a perpetual, world-wide exclusive license, with the right to grant sub-licenses, at the royalty rates set out to the Purchased Assets and the Arising Patents and the know how related thereto for Cardiovascular Indications, which Licensee shall exploit at its own risk and without any possible recourse of whatever nature against Licensor or any of its Affiliates.

License Property

For the purposes of this Agreement, 'Cardiovascular Indications' means heart failure, coronary artery disease, arterial hypertension or systemic hypertension, arrhythmias (including atrial, nodal, and ventricular), hypertension, peripheral vascular disorders, shock, endocarditis, pericardial disease, cardiac tumors, vaivular heart disease and angina only. For the avoidance of doubt, Cardiovascular Indications do not include cerebrovascular diseases, pulmonary hypertension and Chronic Obstructive Pulmonary Disease. Within a reasonable time after the invention or creation of any Arising Patents and the know how related thereto, Licensor will notify and provide reasonable particulars of same to Licensee.

'Existing Patents' means the RSD930 and RSD1236 Patent Families (ApplicationNumbers US 09/328,540; PCT/CA99/00535; US 09/328,541; PCT/CA99/00534; PCT/CA00/01506; PCT/CA00/01507; PCT/CA00/01508; PCT/CA98/00842 and Thailand Patent Appl.# 045858; Taiwan Patent Appl.# 87114395; The Philippines Patent Appl. # 98/2246; and Malaysia Patent Appl. # Pl 9804017 and all patentm applications claiming priority therefrom or sharing at least one common priority therewith).

Field of Use

The rights granted apply to the drug industry in the respiratory field for cardiovascular indications.