Patents 165

Web site: http://www.delphion.com/details?pn=US06610679__

Patent Applications on Macular Degeneration

As of December 2000, U.S. patent applications are open to public viewing.10 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to macular degeneration:

•Amine salt of an integrin receptor antagonist

Inventor(s): Humphrey, Guy R.; (Hillsborough, NJ), Xu, Wei; (North Wales, PA) Correspondence: Merck And CO Inc; P O Box 2000; Rahway; NJ; 070650907 Patent Application Number: 20030004171

Date filed: June 18, 2002

Abstract: The tris(hydroxymethyl)aminomethane ("TRIS") salt of 3-(pyrimidin-5-yl)-9- (5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoi- c acid is a potent antagonist of the integrin.alpha.v.beta.3 receptor and is useful for the prevention and/or treatment of osteoporosis and vascular restenosis, as well as conditions associated with excessive angiogenesis, such as macular degeneration, diabetic retinopathy, atherosclerosis, inflammatory arthritis, cancer, and metastatic tumor growth. The invention also relates to a process for the preparation of the novel salt as well as pharmaceutical compositions containing the salt and methods of using the salt.

Excerpt(s): The present invention is related to U.S. provisional application Serial No. 60/299,344, filed Jun. 19, 2001, the contents of which are hereby incorporated by reference. The present invention relates to a novel amine salt of an integrin receptor antagonist. More particularly, the invention relates to the tris(hydroxymethyl)aminomethyl ("TRIS") salt of 3-(pyrimidin-5-yl)-9-(5,6- ,7,8- tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid, which is a potent integrin.alpha.sub.v.beta.sub.3 receptor antagonist. The "TRIS" salt of the present invention is therefore useful for the treatment and prevention of diseases and conditions for which an antagonist of the integrin.alpha.sub.v.beta.sub.3 receptor is indicated. Integrin.alpha.sub.v.beta.sub.3 receptor antagonists have been described as being of use for the prevention and/or treatment of osteoporosis, vascular restenosis, macular degeneration, diabetic retinopathy, atherosclerosis, inflammatory arthritis, cancer, and metastatic tumor growth [see, for example, M. E. Duggan, et al., "Ligands to the integrin receptor.alpha.sub.v.beta.sub.3, Exp. Opin. Ther. Patents, 10: 1367-1383 (2000); M. Gowen, et al., "Emerging therapies for osteoporosis," Emerging Drugs, 5: 1-43 (2000); J. S. Kerr, et al., "Small molecule.alpha.sub.v integrin antagonists: novel anticancer agents," Exp. Opin. Invest. Drugs, 9: 1271-1291 (2000); and W. H. Miller, et al., "Identification and in vivo efficacy of small-molecule antagonists of integrin.alpha.sub.v.beta.sub.3 (the vitronectin receptor)," Drug Discovery Today, 5: 397-408 (2000)].

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10 This has been a common practice outside the United States prior to December 2000.

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•Antisense oligonucleotide directed toward mammalian vegf receptor genes and uses thereof

Inventor(s): Sirois, Martin G.; (Quebec, CA)

Correspondence: Marshall Gerstein & Borun; Sears Tower Suite 6300; 233 South Wacker Drive; Chicago; IL; 60606-6357; US

Patent Application Number: 20030186920 Date filed: April 10, 2003

Abstract: The present invention provides antisense oligonucleotides that target the genes and mRNAs encoding mammalian VEGF receptors. Also provided are methods for designing and testing the antisense oligonucleotides. Such oligonucleotides can be used to reduce VEGF-induced inflammation and angiogenesis, for example, pathological angiogenesis, in mammals. Thus, the present invention also pertains to pharmaceutical compositions and formulations used in the treatment of mammals having a disease or disorder characterised by inflammation and/or pathological angiogenesis; including tumour growth and metastasis, ocular diseases (diabetic and perinatal hyperoxic retinopathies, age-related macular degeneration), arthritis, psoriasis and atherosclerosis.

Excerpt(s): This application is a continuation in part of U.S. application Ser. No. 09/687,239, filed Oct. 13, 2000, which is hereby incorporated in its entirety. The present invention pertains to the field of antisense oligonucleotides for mammalian VEGF receptor genes and their use as anti-angiogenics and/or anti-inflammatory agents. Angiogenesis is a process by which new capillary vessels sprout from pre-existing ones, and can be summarised as the culmination of i) increased endothelial cell permeability to plasma proteins; ii) transmigration of inflammatory cells into extracellular matrix; iii) synthesis and release of degrading matrix molecules; iv) release of growth factors; v) migration and proliferation of endothelial cells to distant sites; and vi) capillary tube formation and vascular wall remodelling. Physiological angiogenesis is a highly coordinated process that exclusively occurs in healthy individuals under specific conditions, such as during wound healing, ovulation and pregnancy. At other times, the vasculature is extremely stable, with very low rates of new blood vessels (Fan et al., (1995) Trends Phaimacol. Sci. 16:57-66).

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•Apparatus and method for alleviation of symptoms by application of tinted light

Inventor(s): Anderson, John Douglas; (Cambridge, GB), Jordan, Ian; (Ely, GB), Street, Graham Stewart Brandon; (Reading, GB), Thornton, Shane William; (Cambridge, GB)

Correspondence: Birch Stewart Kolasch & Birch; PO Box 747; Falls Church; VA; 220400747; US

Patent Application Number: 20030223036 Date filed: June 19, 2003

Abstract: Apparatus and a corresponding method for the diagnosis and alleviation of symptoms of visually induced physiological defects and/or pathological conditions is provided. A plurality of narrow-band light sources are combined to constitute a colour controllable lamp. A method for adjusting the settings of this lamp permits the optimum illumination for a particular subject to be found, whilst the latter carries out a task such

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as reading or writing. By use of the lamp to simulate the expected visual stimulus, to which the subject would be exposed if provided with viewing aids such as tinted spectacles and the like, an optimal selection from a database of such aids may be made or a new formulation defined. Inter alia, the symptoms of visual dyslexia, macular degeneration and visually induced migraine may be alleviated.

Excerpt(s): The current invention is concerned with the provision or filtration of the illumination for a given task, such as reading or writing, and, specifically, with helping to alleviate the symptoms of certain physiological defects, such as dyslexia, or pathological conditions, such as migraine or macular degeneration, which may be suffered by the subject undertaking the task. It is known that the response of the visual system is affected by the stimuli, which it receives. The threshold for such stimulation varies between individuals and, under adverse conditions, can significantly reduce performance. When the visual system is over stimulated, it reacts in a number of ways. Amongst a variety of undesirable effects, which can be caused, two examples include a drop in convergence sufficiency and a reduction in the ability to accommodate or fuse images. In addition, visual dyslexia may become apparent and migraines can be caused. Visual dyslexia is a condition of impaired reading and writing ability due to visual perception or visualisation problems. It is apparent therefore that for some it is necessary to modify the visual stimulus by changing the spectral distribution in a specific task e.g. reading and writing in school. In summary, it is well established that the colour of ambient lighting has a major influence on the effects of disorders such as dyslexia, epilepsy and migraine. In the case of dyslexia some sufferers can alleviate their reading problems by covering the page with a transparent coloured overlay in order to block out those wavelengths of light which give rise to an aspect of their problem. These overlays typically remove various amounts of simple primary colours, such as red, green or blue light and whilst they may assist with reading, they are of no value for writing. In U.S. Pat. No. 5,855,428 (Wilkins) apparatus is described in which the spectral distribution of light from a fluorescent lamp to illuminate a surface to support reading material is altered by the interposition of specifically selected broadband filters. By adjustment of the position of the selected filter or filters different colours and saturation thereof can be selected.

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•Apparatus and methods for prevention of age-related macular degeneration and other eye diseases

Inventor(s): Lin, J.T.; (Oviedo, FL)

Correspondence: J.T. Lin; 4532 Old Carriage Trail; Oviedo; FL; 32765; US Patent Application Number: 20030105456

Date filed: December 4, 2001

Abstract: Surgical apparatus and surgical methods are proposed for the prevention of age-related macular degeneration (AMD) and choroidal neovascularization (CNV), and other eye diseases such as glaucoma by removal of the sclera tissue to reduce its rigidity and increase the flood flow and decrease pressure in the choriocapillaris. The disclosed preferred embodiments of the system consists of a tissue ablation means and a control means of ablation patterns and a fiber delivery unit. The basic laser beam includes UV lasers and infrared lasers having wavelength ranges of (0.15-0.36) microns and (0.5-3.2) microns and diode lasers of about 0.98, 1.5 and 1.9 microns. AMD and CNV are prevented, delayed or reversed by using an ablative laser to ablate the sclera tissue in a

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predetermined patterns outside the limbus to increase the elasticity of the sclera tissue surrounding the eye globe The surgery apparatus also includes non-laser device of radio frequency wave, electrode device, bipolar device and plasma assisted device

Excerpt(s): The present invention relates to methods and apparatus for the prevention of age-related macular degeneration and other eye diseases. Age-related macular degeneration (AMD) is the leading cause of central visual loss in patients older than 50 years of age in the United States. The 10% of patients with wet degeneration accounts for 90% of the patients with severe vision loss to 20/200 or worse. The majority of eyes suffer severe visual loss of a result of Choroidal neovascularization (CNV), which is the formation of new blood vessels either between the retinal pigment epithelium and Bruch membrance or the subretinal space. CNV is a common manifestation of a variety of macular diseases and can result in severe vision loss. Typically, CNV complicates AMD, but it also can be seen in pathologic myopia, ocular histoplasmosis, angioid streaks, and ocular inflammatory diseases, and as an idiopathic condition. See Atlas of Ophthalmic Surgery, Chapt. 8, ed. by N. Jaffe, (Mosby-Wolfe, 1996).

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•Composition for the treatment and/or prevention of macular degeneration, method for its manufacture, and its use for treating the eye

Inventor(s): Gazzotti, Paolo; (Geroldswil, CH), Richter, Christoph; (Zurich, CH), Shaban, Hamdy; (Dottikon, CH)

Correspondence: Womble Carlyle Sandridge & Rice, Pllc; P.O. Box 7037; Atlanta; GA; 30357-0037; US

Patent Application Number: 20030050283 Date filed: July 1, 2002

Abstract: Negatively charged phospholipids, as well as compositions including negatively charged phospholipids and possibly carotenoids and/or antioxidants, for treating the eye are disclosed. In a preferred embodiment, a composition comprising at least one negatively charged phospholipid except cardiolipin is used to treat age-related macular degeneration. Methods for producing the negatively charged phospholipids, as well as methods for producing the compositions including negatively charged phospholipids and possibly carotenoids and/or antioxidants for treating age-related macular degeneration, are also disclosed.

Excerpt(s): The present invention relates to negatively charged phospholipids, as well as compositions including negatively charged phospholipids and possibly carotenoids and/or antioxidants, for treating the eye. In a preferred embodiment, the present invention relates to the use of negatively charged phospholipids for treating age-related macular degeneration. It also relates to methods for producing the negatively charged phospholipids, as well as methods for producing the compositions including negatively charged phospholipids and possibly carotenoids and/or antioxidants for treating agerelated macular degeneration. Age-related macular degeneration (AMD) affects 10 to 20% of the population over 65 years old and represents one of the main causes of serious vision damage and/or vision problems of older people in the industrial nations (Klein, R., Klein, B. E., and Linton, K. L. (1992) Ophthalmology 99, 933-943). One differentiates between the wet form of macular degeneration, which affects approximately 20% of the patients and is treatable using photodynamic therapy, and the dry form of AMD, which affects approximately 80% of the patients. The dry form of AMD typically has a slow

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course and has not been treatable until now. The molecular causes of this illness, which is particularly significant in geriatrics, have not been well researched. The newest investigations have shown that a pigment (A2E, N-retinyl-N-retinylidene ethanolamine), which forms naturally in the eye during the seeing process and increases tenfold with progressing age (Eldrid, G. E., Lasky, M. R. (1993) Nature 361, 724-726; Parish, C. A., Hashimoto, M., Nakanishi, K., Dylon, J., Sparrow, J. (1998) Proc. Natl. Acad. Sci. USA 95, 14609-14613), causes the death of pigment epithelial cells of the retina (Suter, M., Rem, C. E., Grimm, C., Wenzel, A., J{umlaut over (aa)}ttela, M., Esser, P., Kociok, N., Leist, M. and Richter, C. (2000) J. Biol. Chem. 275, 39625-39630). There are some indications that A2E is partially responsible for the dry form of AMD.

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•Compositions and methods for inhibiting endothelial cell proliferation and regulating angiogenesis using cancer markers

Inventor(s): Fortier, Anne H.; (Germantown, MD), Holaday, John W.; (Bethesda, MD)

Correspondence: John S. Pratt, Esq; Kilpatrick Stockton, Llp; 1100 Peachtree Street; Suite 2800; Atlanta; GA; 30309; US

Patent Application Number: 20030012792 Date filed: April 25, 2002

Abstract: Compositions and methods for regulating angiogenesis wherein the compositions comprise cancer markers are provided. Serine proteases and kallikreins exhibit potent antiangiogenic activity on human and other animal cells, particularly endothelial cells. More particularly, the use of a cancer marker, such as PSA, CEA, HCG, NSE, or CA19-9, to inhibit or ameliorate angiogenesis and angiogenesis-related diseases such as cancer, arthritis, macular degeneration, and diabetic retinopathy is disclosed.

Excerpt(s): This application claims priority to U.S. patent application Ser. No. 09/413,049, filed Oct. 6, 1999, which claims priority to U.S. application Ser. No. 09/316,802, filed May 21, 1999, which claims priority to U.S. Provisional Application Serial No. 60/086,586, filed May 22, 1998, each of which is incorporated herein by reference in its entirety. This invention relates to a novel use of cancer markers for preventing, ameliorating or treating a cell proliferative disease or disorder. The invention further relates to novel compositions and methods for treating angiogenesisrelated diseases such as angiogenesis-dependent cancer. Cancer markers are not cancerspecific but rather cancer-associated substances that can be elevated in sera from healthy individuals under various conditions and from patients with benign tumors. The discovery of cancer markers has significantly enhanced not only diagnosis of cancer but has also contributed to the monitoring of cancer patients for assessing disease progression. A rise in cancer markers is a yardstick with which benign diseases can be distinguished from metastatic disease and can also be used to evaluate the efficacy of treatments. A decline in cancer markers is often a predictor of possible residual disease if the timing of blood sampling is soon after therapy.

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•Compositions and methods for prevention and treatment of chronic diseases and disorders including the complications of diabetes mellitus

Inventor(s): Kosbab, John V.; (Dillon, CO)

Correspondence: Greenlee, Winner And Sullivan, P.C.; Suite 201; 5370 Manhattan Circle; Boulder; CO; 80303; US

Patent Application Number: 20030108624 Date filed: June 28, 2002

Abstract: This invention relates to nutrient and therapeutic compositions for treatment and prevention of symptoms and disease conditions associated with microangiopathy and macroangiopathy and to methods using the compositions. In particular, the invention relates to compositions useful in the treatment of diabetic retinopathy and nephropathy, to compositions useful in the treatment of other retinal disorders including macular degeneration and cataracts, to compositions useful in wound healing, to compositions useful for treatment and prevention of neuropathy, to compositions useful for treatment and prevention of cardiovascular disease and to compositions useful for the treatment and prevention of dental and periodontal disorders.

Excerpt(s): The application is a continuation of U.S. patent application Ser. No. 09/827,251, filed Apr. 5, 2001, which is a continuation of U.S. patent application Ser. No. 09/018,273, filed Feb. 4, 1998, which claims priority to U.S. Provisional Application Serial No. 60/037,084, filed Feb. 4, 1997, and No. 60/043,262, filed Apr. 17, 1997, all of which are incorporated by reference in their entirety herein to the extent not inconsistent with the disclosure herein. This invention relates to the use of nutrient and therapeutic compositions to ameliorate the disease symptoms and conditions associated with vascular and capillary disorders: microangiopathy and macroangiopathy. Compositions of this invention include antioxidants, neovascular regulators, promoters or cofactors involved in collagen synthesis, as well as vitamins and minerals to supplement deficiencies. Vascular degeneration, both macroangiopathy and microangiopathy (capillary degeneration), is believed to be the root cause of a variety of degenerative disease conditions that affect a substantial portion of the population. Vascular degeneration is directly associated with cardiovascular disease, atherosclerosis and plaque deposition and indirectly associated with degenerative conditions of the retina (including retinopathy), kidney (nephropathy) and nervous system (neuropathy), as well as skin ulcers.

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•Diagnostics and therapeutics for arterial wall disruptive disorders

Inventor(s): Hageman, Gregory S.; (Coralville, IA)

Correspondence: Townsend And Townsend And Crew Llp; Two Embarcadero Center, 8th Floor; San Francisco; CA; 94111-2422; US

Patent Application Number: 20030149997 Date filed: February 22, 2000

Abstract: The invention provides diagnostics, therapeutics and drug screening assays for arterial wall disruptive disorders, based on the discovery of a high level of correlation between the incidence of arterial wall disruptive disorders and the incidence

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of Age Related Macular Degeneration (AMD). In one embodiment, the arterial wall disruptive disorder is an aortic aneurysm.

Excerpt(s): The invention relates to diagnostics, therapeutics and animal models for arterial wall disruptive disorders, including arterial aneurysmal disease. Disorders of the peripheral arterial system cause their pathological effects by two general mechanisms: obstruction of the arterial lumen or disruption of the vessel wall. Arterial obstruction most commonly results from atherosclerosis, although other causes of luminal blockage may be identified, including inflammatory conditions, external compression, emboli, thrombi or fibromuscular dysplasia. Arterial obstructive disorders typically affect multiple sites within the arterial tree. Disruption of the arterial wall results in aneurysm formation, arterial wall dissection or frank arterial rupture. Arterial aneurysm formation is most commonly related to atherosclerosis. Aneurysms may also result from infections, cystic medial necrosis, congenital anomalies or trauma. As used herein, trauma shall include both non-iatrogenic and iatrogenic processes. Arterial wall dissection may arise as a complication of an aneurysm or as an independent event. Arterial wall dissection in the absence of a pre-existing aneurysm may occur spontaneously, or it may result from trauma. Frank arterial rupture may result from the progressive expansion of an arterial aneurysm beyond a certain critical diameter. If no aneurysm is present, the most common cause of arterial rupture is some type of arterial trauma. Artery wall disruption may affect multiple sites, or may be localized to only one location. Aneuysmal disorders or aneurysmal diseases, as these terms are used herein, include those processes that result in aneurysm formation in a segment of at least one artery. An aneurysm is understood to be a permanent localized dilatation of an artery with increase in diameter of 1.5 times normal, recognizing that values for normal arterial diameter vary with age, sex and blood pressure. (Vermilion B D et al., "A review of one hundred forty-seven popliteal aneurysms with long-term follow-up," Surgery 90:1009, 1981). Aneurysms cause symptoms by rupturing, by compressing adjacent structures, by leaking, by obstructing flow to vessels that arise from the segment of artery affected by the aneurysm, and by accumulating thrombus within the vessel lumen at the site of the aneurysm, said thrombus being capable of suddenly occluding the vessel or of sending smaller emboli into the distal arterial tree.

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•Differentially-expressed genes and polypeptides in angiogenesis

Inventor(s): Jay, Gilbert; (North Bethesda, MD), Sun, Zairen; (Rockville, MD)

Correspondence: Origene Technologies, Incorporated; 6 Taft Court; Suite 100; Rockville; MD; 20850; US

Patent Application Number: 20030148334 Date filed: October 11, 2002

Abstract: The present invention relates to all facets of polynucleotides, the polypeptides they encode, antibodies and specific binding partners thereto, and their applications to research, diagnosis, drug discovery, therapy, clinical medicine, forensic science and medicine, etc. The polynucleotides are expressed during angiogenesis and are therefore useful in variety of ways, including, but not limited to, as molecular markers, as drug targets, and for detecting, diagnosing, staging, monitoring, prognosticating, preventing or treating, determining predisposition to, etc., diseases and conditions, such as abnormal, insufficient, excessive, etc., angiogenesis, such as inflammatory diseases, such as rheumatoid arthritis, osteoarthritis, asthma, pulmonary fibrosis, age-related macular

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degeneration (ARMD), diabetic retinopathy, macular degeneration, and retinopathy of prematurity (ROP), endometriosis, cancer, Coats' disease, peripheral retinal neovascularization, neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, etc

Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/328,395, filed Oct. 12, 2002, which is hereby incorporated by reference in its entirety. Angiogenesis, the process of blood vessel formation, is a key event in many physiological processes that underlie normal and diseased tissue function. During ontogeny, angiogenesis is necessary to establish to the network of blood vessels required for normal cell, tissue and organ development and maintenance. In the adult organism, the production of new blood vessels is needed for organ homeostasis, e.g., in the cycling of the female endometrium, for blood vessel maturation during wound healing, and other processes involved in the maintenance of organism integrity. It also is important in regenerative medicine, including, e.g., in promoting tissue repair, tissue engineering, and the growth of new tissues, inside and outside the body.

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•Endothelial-cell binding peptides for diagnosis and therapy

Inventor(s): Gyuris, Jeno; (Winchester, MA), Lamphere, Lou; (Newton, MA), Morris, Aaron J.; (Brighton, MA), Tsaioun, Katherine; (Belmont, MA)

Correspondence: Ropes & Gray; One International Place; Boston; MA; 02110-2624; US Patent Application Number: 20030166004

Date filed: November 1, 2002

Abstract: The present invention relates to peptides and their derivatives which bind to endothelial cells and inhibit their proliferation in in vitro assays, e.g., also referred to herein as endothelial cell binding peptide (ECBP) or ECBP sequence. These compositions may be combined with a pharmaceutically acceptable excipient or carrier and used to inhibit angiogenesis and angiogenesis-related diseases such as cancer, arthritis, macular degeneration, and diabetic retinopathy.

Excerpt(s): This application claims priority to U.S. Provisional Application No. 60/334,822, filed on Nov. 1, 2001, the entire contents of which are incorporated herein by reference. Angiogenesis, the process by which new blood vessels are formed, is essential for normal body activities including reproduction, development and wound repair. Although the process is not completely understood, it is believed to involve a complex interplay of molecules which regulate the growth of endothelial cells (the primary cells of capillary blood vessels). Under normal conditions, these molecules appear to maintain the microvasculature in a quiescent state (i.e. one of no capillary growth) for prolonged periods which may last for as long as weeks or, in some cases, decades. When necessary (such as during wound repair), these same cells can undergo rapid proliferation and turnover within a 5 day period (Folkman, J. and Shing, Y., The Journal of Biological Chemistry, 267(16), 10931-10934, and Folkman, J. and Klagsbrun, M., Science, 235, 442-447 (1987). Although angiogenesis is a highly regulated process under normal conditions, many diseases (characterized as angiogenic diseases) are driven by persistent unregulated angiogenesis. Otherwise stated, unregulated angiogenesis may either cause a particular disease directly or exacerbate an existing pathological condition. For example, ocular neovascularization has been implicated as the most common cause of blindness and dominates approximately 20 eye diseases. In certain

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existing conditions, such as arthritis, newly formed capillary blood vessels invade the joints and destroy cartilage. In diabetes, new capillaries formed in the retina invade the vitreous, bleed, and cause blindness. Growth and metastasis of solid tumors are also dependent on angiogenesis (Folkman, J., Cancer Research, 46, 467-473 (1986), Folkman, J., Journal of the National Cancer Institute, 82, 4-6 (1989). It has been shown, for example, that tumors which enlarge to greater than 2 mm must obtain their own blood supply and do so by inducing the growth of new capillary blood vessels. Once these new blood vessels become embedded in the tumor, they provide a means for tumor cells to enter the circulation and metastasize to distant sites such as liver, lung or bone (Weidner, N., et al., The New England Journal of Medicine, 324(1), 1-8 (1991).

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•Eyeglass manufacturing method using variable index layer

Inventor(s): Dreher, Andreas W.; (Escondido, CA)

Correspondence: Knobbe Martens Olson & Bear Llp; 2040 Main Street; Fourteenth Floor; Irvine; CA; 92614; US

Patent Application Number: 20030081172 Date filed: October 25, 2001

Abstract: An Eyeglass Manufacturing Method Using Epoxy Aberrator includes two lenses with a variable index material, such as epoxy, sandwiched in between. The epoxy is then cured to different indexes of refraction that provide precise corrections for the patient's wavefront aberrations. The present invention further provides a method to produce an eyeglass that corrects higher order aberrations, such as those that occur when retinal tissue is damaged due to glaucoma or macular degeneration. The manufacturing method allows for many different applications including, but not limited to, supervision and transition lenses.

Excerpt(s): The present invention relates generally to an eyeglass manufacturing method using a layer with a variable index of refraction. More specifically, the present invention pertains to patient-specific spectacle lenses manufactured with an variable index aberrator in order to more accurately correct lower order aberrations and additionally correct higher order aberrations. The present invention also provides a means for correcting vision problems caused by retinal dysfunction. Present manufacturing techniques for eyeglass lenses are capable of producing lenses that correct only the lower order (sphere and cylinder) aberrations. Customarily, lens blanks are available in discrete steps of refractive power of 0.25 diopters. In most cases, these steps are too large to create optimum vision for a patient's eye. Current manufacturing techniques do not effectively treat vision problems resulting from retinal dysfunction. For example, in macular degeneration, patients suffer from vision loss in selective areas of the fundus, typically close to the center of vision. Laser treatment of the affected areas further destroys retinal tissue, causing blindness at the treated areas. Clinical studies have shown that the human eye and brain are capable of switching to other areas of the retina to substitute the damaged area with an undamaged area. In other words, damaged areas in the retina are essentially bypassed by the brain. Ultimately, vision loss will occur as a portion of an image falls on the damaged retina. Consequently, there is a need to manufacture an eyepiece such that the image may be "warped" around the dysfunctional tissue in order to allow the entire image to focus on the remaining healthy tissue.

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•Guide means for intraocular injection

Inventor(s): Billson, Francis Alfred; (Sydney, AU), Gillies, Mark Cedric; (Randwick, AU), Penfold, Philip Leslie; (Sydney, AU)

Correspondence: Ladas & Parry; 26 West 61st Street; New York; NY; 10023; US Patent Application Number: 20030060763

Date filed: September 12, 2002

Abstract: This invention relates to the art of intraocular injection as a means of treating various conditions of the eye. In particular it relates to a plaque containing guide means for location of a needle entry point into the eye which thereby facilitates such injection. The invention also relates to a kit which includes (1) an intraocular composition containing an active compound able to treat the particular condition; (2) a syringe for dispensing the composition through a needle coupled to the syringe, the syringe having dimensions such that blockage of the needle is minimised; and (3) a plaque containing guide means for location of the needle entry points into the eye. In one form, it provides for a kit which includes (i) an anti-inflammatory steroid which is the active agent in treating the macular degeneration; (ii) a syringe need for the delivery of that steroid through a needle coupled to the syringe, and (iii) a plaque which facilitates correct positioning of the needle.

Excerpt(s): In one form, it provides for a kit which includes (i) an anti-inflammatory steroid which is the active agent in treating the macular degeneration; (ii) a syringe used for the delivery of that steroid through a needle coupled to the syringe, and (iii) a plaque which facilitates correct positioning of the needle. Intraocular injection is known. For example, it is known to inject antibodies to treat intraocular infection. However, various problems may arise when using this technique. For example, if a constituent of the composition is present as sufficiently large particles, it may settle out in the vial before being drawn up into the syringe, thereby providing a non-uniform concentration of that constituent compared to its concentration in the vial.

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•Hydroxamic and carboxylic acid derivatives

Inventor(s): Baxter, Andrew Douglas; (Cambridge, GB), Dyke, Hazel Joan; (Cambridge, GB), Hannah, Duncan Robert; (Cambridge, GB), Keily, John Fraser; (Cambridge, GB), Watson, Robert John; (Cambridge, GB)

Correspondence: Saliwanchik Lloyd & Saliwanchik; A Professional Association; 2421 N.W. 41st Street; Suite A-1; Gainesville; FL; 326066669

Patent Application Number: 20030092727 Date filed: October 25, 2002

Abstract: Pharmacologically active compounds are provided as well as pharmaceutical compositions and methods for treating cancer; inflammation; an autoimmune, infectious or ocular disease; or age-related macular degeneration in a mammal.

Excerpt(s): This invention relates to hydroxamic and carboxylic acid derivatives, and to their use in medicine. Metalloproteinases, including matrix metalloproteinase (I),

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collagenase, gelatinase and TNF.alpha. convertase (TACE), and their modes of action, and also inhibitors thereof and their clinical effects, are described in WO-A-96/11209, WO-A-97/12902 and WO-A-97/19075, the contents of which are incorporated herein by reference. MMP inhibitors may also be useful in the inhibition of other mammalian metalloproteinases such as the ADAM or ADAM-TS families. Compounds which have the property of inhibiting the action of metalloproteinases involved in connective tissue breakdown, such as collagenase, stromelysin and gelatinase, have been shown to inhibit the release of TNF.alpha. both in vitro and in vivo See Gearing et al (1994), Nature 370:555-557; McGeehan et al (1994), Nature 370:558-561; GB-A-2268934, and WO-A- 93/20047. All of these reported inhibitors contain a hydroxamic acid zinc-binding group, as do the imidazole-substituted compounds disclosed in WO-A-95/23790. Other compounds that inhibit MB and/or TNF.alpha. are described in WO-A-95/13289, WO- A-96/11209, WO-A-96/035687, WO-A-96/035711, WO-A-96/035712 and WO-A- 96/035714.

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•Increasing growth factor production by cells

Inventor(s): Chaum, Edward; (Germantown, TN)

Correspondence: Margaret J. Mclaren, PH.D., ESQ.; Akerman Senterfitt; Suite 400; 222 Lakeview Avenue; West Palm Beach; FL; 33402-3188; US

Patent Application Number: 20030186918 Date filed: March 26, 2003

Abstract: Disclosed are methods and compositions for growth factor gene therapy for conditions involving degeneration or injury of cells of the retina, including age-related macular degeneration. Included in the invention are non-viral vectors for delivery of growth factor fusion proteins, cells transduced with such vectors, and methods of treatment using these vectors.

Excerpt(s): This application claims priority from U.S. Provisional Application Serial No. 60/367,873 filed Mar. 27, 2002. The foregoing is incorporated herein by reference. This invention relates generally to the fields of molecular biology and medicine. More particularly, the invention relates to methods of gene therapy for eye diseases using growth factors. The retinal pigment epithelium (RPE) serves many critical functions in maintaining the health of the neurosensory retina. One of these functions is the production of growth factors (also known as cytokines, neurotrophic factors, and trophic hormones), that have both paracrine and autocrine activity in the RPE (Waldbillig R J, et al. J Neurochem 1991, 57:1522-1533; Takagi H, et al., Invest Ophthalmol Vis Sci 1994, 35:916-923; Schweigerer I, et al., Biochem Biophys Res Commun 1987, 143:934-940; Martin D M et al., Brain Res Mol Brain Res 1992, 12:181186).

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176 Macular Degeneration

•Indocyanine green (ICG) compositions and related methods of use

Inventor(s): Alam, Abu; (Lake Forest, IL), Chavan, Ashok J.; (Bloomington, IL), Flower, Robert W.; (Hunt Valley, MD)

Correspondence: Leydig Voit & Mayer, Ltd; Two Prudential Plaza, Suite 4900; 180 North Stetson Avenue; Chicago; IL; 60601-6780; US

Patent Application Number: 20030060718 Date filed: December 27, 2001

Abstract: Aqueous indocyanine green (ICG) composition exhibiting enhanced stability, as well as enhanced ICG concentration, as compared to presently available ICG products. The composition comprises an aqueous ICG composition comprising ICG at a concentration of at least about 10 mg/ml and an aqueous diluent, wherein the composition is stable for at least 24 hours. Diagnostic and therapeutic methods for using these aqueous compositions are also contemplated, e.g., angiography, dye-enhanced photocoagulation, photodynamic therapy, for a variety of conditions, including AgeRelated Macular Degeneration (ARMD), lesions and tumors.

Excerpt(s): This application is a continuation-in-part of co-pending U.S. patent application Ser. No. 09/393,456, filed Sep. 10, 1999, which is incorporated by reference. The present invention generally concerns indocyanine green compositions useful in the diagnosis of organ function and disease in animals, e.g., humans. Indocyanine green (ICG) is a well-known fluorsecent dye. The dye is presently marketed by Akorn, Inc. (Buffalo Grove, Ill.) under the trademark IC GREEN.TM. ICG is presently supplied as a lyophilized powder (25 mg) for reconstitution with 5 ml sterile water for injection (WFI). The reconstituted ICG composition (at 5 mg/ml) should be used within 10 hours, with any unused portion being discarded.

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•Macular degeneration diagnostics and therapeutics

Inventor(s): Sheffield, Val C.; (Coralville, IA), Stone, Edwin M.; (Iowa City, IA)

Correspondence: Needle & Rosenberg P C; 127 Peachtree Street N E; Atlanta; GA; 303031811; US

Patent Application Number: 20030138798 Date filed: July 8, 2002

Abstract: Therapeutics and diagnostics based on the identification of genetic mutations, which cause Macular Degeneration (MD) is disclosed.

Excerpt(s): Macular degeneration is a clinical term that is used to describe a variety of diseases that are all characterized by a progressive loss of central vision associated with abnormalities of Bruch's membrane and the retinal pigment epithelium. These disorders include very common conditions that affect older patients (age related macular degeneration or AMD) as well as rarer, earlier-onset dystrophies that in some cases can be detected in the first decade of life.sup.1-18. The genes associated with some of these dystrophies have been mapped,.sup.5-14 and in three cases, blue-cone monochromasy,.sup.15 pattern dystrophy,.sup.16-17 and Sorsby fundus dystrophy,.sup.18 actually identified. However, none of the latter genes has been found to be responsible for a significant fraction of typical late-onset macular degeneration. In developed countries, AMD is the most common cause of legal blindness in older

Patents 177

patients.sup.19 The hallmark of this condition is the presence of drusen, which are ophthalmoscopically visible, yellow-white hyaline excrescences of Bruch's membrane. In some families, drusen are heritable in an autosomal dominant fashion. Currently, there is no therapy that is capable of significantly slowing the degenerative progression of AMD, and treatment is limited to laser photocoagulation of the subretinal neovascular membranes that occur in 10-15% of affected patients.

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•Materials and methods for treating ocular-related disorders

Inventor(s): Brough, Douglas E.; (Gaithersburg, MD), Kovesdi, Imre; (Rockville, MD), McVey, Duncan L.; (Derwood, MD), Wei, Lisa; (Gaithersburg, MD)

Correspondence: Leydig Voit & Mayer, Ltd; Two Prudential Plaza, Suite 4900; 180 North Stetson Avenue; Chicago; IL; 60601-6780; US

Patent Application Number: 20030045498 Date filed: August 2, 2002

Abstract: The present invention is directed to a method of prophylactically or therapeutically treating an animal for at least one ocular-related disorder, e.g., ocular neovascularization or age-related macular degeneration. The method comprises contacting an ocular cell with an expression vector comprising a nucleic acid sequence encoding an inhibitor of angiogenesis and the same or different nucleic acid sequence encoding a neurotrophic agent. The method also can comprise contacting an ocular cell with different expression vectors, each comprising a nucleic acid sequence encoding an inhibitor of angiogenesis and/or a nucleic acid sequence encoding a neurotrophic agent. In addition, the present invention provides a viral vector comprising a nucleic acid sequence encoding pigment epithelium-derived factor (PEDF) or a therapeutic fragment thereof.

Excerpt(s): This patent application is a continuation of International Patent Application No. PCTIUS01/04203, filed Feb. 9, 2001, which designates the U.S., and which claims the benefit of U.S. Provisional Patent Application No. 60/228,337, filed Aug. 28, 2000, and which also claims the benefit of U.S. Provisional Patent Application No. 60/181,743, filed Feb. 11, 2000, and which also is a continuation-in-part of U.S. patent application Ser. No. 09/599,997, filed Jun. 23, 2000, which claims the benefit of U.S. Provisional Patent Application No. 60/181,743, filed Feb. 11, 2000. The present invention relates to a method of prophylactically or therapeutically treating an ocular disorder as well as materials useful for treating an ocular disorder. An overwhelming majority of the world's population will experience some degree of vision loss in their lifetime. Vision loss affects virtually all people regardless of age, race, economic or social status, or geographical location. Ocular-related disorders, while often not life threatening, necessitate life-style changes that jeopardize the independence of the afflicted individual. Vision impairment can result from most all ocular disorders, including diabetic retinopathies, proliferative retinopathies, retinal detachment, toxic retinopathies, retinal vascular diseases, retinal degenerations, vascular anomalies, agerelated macular degeneration and other acquired disorders, infectious diseases, inflammatory diseases, ocular ischemia, pregnancy-related disorders, retinal tumors, choroidal tumors, choroidal disorders, vitreous disorders, trauma, cataract complications, dry eye, and inflammatory optic neuropathies.

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178 Macular Degeneration

•Method for treating visual impairment through the prophylactic administration of a Morinda citrifolia-based naturaceutical

Inventor(s): Ocampo, Enrique; (El Paso, TX), Jensen, Claude Jarakae; (Cedar Hills, UT)

Correspondence: Kirton & Mcconkie; 1800 Eagle Gate Tower; 60 East South Temple; Salt Lake City; UT; 84111; US

Patent Application Number: 20030134002 Date filed: November 1, 2002

Abstract: Implementation of the present invention takes place in association with the utilization of one or more processed products produced from the Indian Mulberry plant, scientifically known as Morinda citrifolia L., to treat one or more eye disorders that affect vision, such as glaucoma, diabetic retinopathy, retinitis pigmentosa, cataracts, agerelated macular degeneration, night blindness, color blindness, and other related conditions. The processed Morinda citrifolia products from the Indian Mulberry plant may be in the form of a dietary supplement, eye drops, or in another suitable form.

Excerpt(s): The present invention relates to methods and naturaceutical formulations and substances for treating and preventing ocular or visual impairments. Specifically, the present invention relates to Morinda citrifolia-based methods and naturaceutical formulations and substances for treating pre-existing ocular impairments, as well as to Morinda citrifolia-based methods and naturaceutical formulations and substances for preventing the onset or reducing the onset potential of future or additional ocular impairments. The present invention is particularly suited for treatment and prevention of ocular impairments as commonly experienced in mammals, and particularly humans. The eye is an organ that collects light and turns it into electronic messages that are sent to the brain. The brain then turns those signals into a picture for an individual to see. Since individuals have two eyes, two pictures are usually created, which accounts for depth of vision. Most of depth of vision occurs from judging the relative size of the objects seen. The eye includes several intricate parts or components. The eyelids hold the lashes, keep the eye moist, and shield it from intense light. The conjunctiva is a membrane that covers most of the eyeball and allows the lids to gently glide over the eye. The clear cornea covers the iris, and works like a watch-face for the eye. It allows a small amount of light to enter the eye through the pupil. Then, along with the natural lens, it acts like a camera-lens and focuses the image onto the retina. The retina is like the film in a "ocular" camera. It lines the inside of the eye, and is mostly clear. The retina has very few blood vessels that would disturb the retinal picture. Since the retina has so few blood vessels and does a lot of work, it needs to be nourished by a blood vessel layer beneath it. This sub-layer blood vessel is called the choroid or uvea.

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•Method of treating angiogenesis-related disorders

Inventor(s): Bingaman, David P.; (Fort Worth, TX), Gamache, Daniel A.; (Arlington, TX), Graff, Gustav; (Cleburne, TX), Kapin, Michael A.; (Arlington, TX), Yanni, John M.; (Burleson, TX)

Correspondence: Alcon Research, LTD.; R&d Counsel, Q-148; 6201 South Freeway; Fort Worth; TX; 76134-2099; US

Patent Application Number: 20030187072 Date filed: February 14, 2003

Patents 179

Abstract: The use of 3-benzolphenylacetic acids and derivatives, including nepafenac, to treat angiogenesis-related disorders, including ophthalmic angiogenesis-related disorders such as diabetic retinopathy and exudative macular degeneration, is disclosed.

Excerpt(s): 3-benzolphenylacetic acid and certain of its derivatives are known to possess anti-inflammatory activity. U.S. Pat. Nos. 4,254,146, 4,045,576, 4,126,635, and 4,503,073, and U.K. Patent Application Nos. 2,071,086A and 2,093,027A disclose various 3- benzolphenylacetic acids, salts and esters, and hydrates thereof, having antiinflammatory activity. U.S. Pat. No. 4,568,695 discloses 2-amino-3-benzoylphenylethyl alcohols having anti-inflammatory activity. U.S. Pat. No. 4,313,949 discloses 2-amino-3- benzoyl-phenylacetamides having anti-inflammatory activity. This invention relates to the use of certain 3-benzolphenylacetic acids and derivatives to treat or prevent angiogenic diseases. Certain derivatives of 2-amino-3-benzoylbenzeneacetic acid (amfenac) and 2-amino-3-(4-chloro-benzoyl)benzeneacetic acid have also been evaluated by Walsh et al., J. Med Chem., 33:2296-2304 (1990), in an attempt to discover nonsteroidal anti-inflammatory prodrugs with minimal or no gastrointestinal side effects upon oral administration.

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•Method to treat age-related macular degeneration

Inventor(s): Peyman, Gholam A.; (New Orleans, LA)

Correspondence: Wood, Herron & Evans, Llp; 2700 Carew Tower; 441 Vine Street; Cincinnati; OH; 45202; US

Patent Application Number: 20030093064 Date filed: November 13, 2001

Abstract: Age-related macular degeneration (AMD) results in the formation of new blood vessels in the eye. The walls of these vessels leak fluid, which causes scarring in the surrounding tissue, resulting in reduced vision or loss of vision. Photodynamic therapy (PDT) alone has been used to treat AMD, but many retreatments are needed, which cause further damage to the already diseased area. Laser treatment to coagulate the fluid actually causes additional new vessels to form. However, the inventive method of treating patients with both PDT and laser coagulation surprisingly either improved vision, or prevented further loss of vision. Moreover, the combined treatment eliminated the need for retreatment, and did not generate new vessel growth. Laser coagulation and PDT may be administered within the same treatment session or either may be administered first and the other may be administered within ninety days.

Excerpt(s): The invention is directed generally to an ophthalmological process, and more specifically to a process to improve, maintain, or reduce loss of visual acuity in a patient having or at risk for developing macular degeneration. In the mammalian eye, macular degeneration (also called age related macular degeneration, AMD) is a pathological condition that is the most common cause of legal blindness among individuals over the age of 60, with an incidence ranging from 11% to 18.5% in individuals over the age of 85. In the United States, AMD affects roughly 3.6 million individuals, with over 200,000 new cases developing annually. One type of AMD results in proliferation of new blood vessels in the subretinal area, typically the choroid. In the normal retina, both the large blood vessels and the capillaries have intact vessel walls. In the normal choroid, the large vessels have intact vessel walls, but the capillaries have fenestrations or openings

180Macular Degeneration

in their walls. In patients with AMD, new blood vessels proliferate from the choriocapillaries through defects in Bruch's membrane beneath or on top of retinal pigment epithelium (RPE), and form vascular membranes. The resulting choroidal neovascularizations (new vessels in the choroid) occur in about 8-10% of all patients with AMD, and are also seen in patients with pathologic myopia and presumed ocular histoplasmosis syndrome, as well as other idiopathic conditions.

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•Methods and compositions for treating conditions of the eye

Inventor(s): Gragoudas, Evangelos S.; (Lexington, MA), Miller, Joan W.; (Winchester, MA), Renno, Reem Z.; (Boston, MA)

Correspondence: Testa, Hurwitz & Thibeault, Llp; High Street Tower; 125 High Street; Boston; MA; 02110; US

Patent Application Number: 20030175282 Date filed: May 5, 2003

Abstract: Provided are methods and compositions for the photodynamic therapy (PDT) of ocular conditions characterized by the presence of unwanted choroidal neovasculature, for example, neovascular age-related macular degeneration. The selectivity and sensitivity of the PDT method can be enhanced by combining the PDT with an anti-angiogenesis factor, for example, angiostatin or endostatin, or with an apoptosis-modulating factor. Furthermore, the selectivity and sensitivity of the PDT may be further enhanced by coupling a targeting moiety to the photosensitizer so as to target the photosensitizer to choroidal neovasculature.

Excerpt(s): This application claims priority to U.S. Provisional Application Serial No. 60/181,641, filed Feb. 10, 2000, the disclosure of which is incorporated herein by reference. The invention relates generally to photodynamic therapy-based methods and compositions for treating ocular conditions and, more specifically, the invention relates to photodynamic therapy-based methods and compositions for treating ocular conditions characterized by unwanted choroidal neovasculature. Choroidal neovascularization can lead to hemorrhage and fibrosis, with resulting visual loss in a number of conditions of the eye, including, for example, age-related macular degeneration, ocular histoplasmosis syndrome, pathologic myopia, angioid streaks, idiopathic disorders, choroiditis, choroidal rupture, overlying choroid nevi, and certain inflammatory diseases. One of the disorders, namely, age-related macular degeneration (AMD), is the leading cause of severe vision loss in people aged 65 and above (Bressler et al. (1988) SURV. OPHTHALMOL. 32, 375-413, Guyer et al. (1986) ARCH. OPHTHALMOL. 104, 702-705, Hyman et al. (1983) AM. J. EPIDEMIOL. 188, 816-824, Klein & Klein (1982) ARCH. OPHTHALMOL. 100, 571-573, Leibowitz et al. (1980) SURV. OPHTHALMOL. 24, 335-610). Although clinicopathologic descriptions have been made, little is understood about the etiology and pathogenesis of the disease.

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Patents 181

•Methods and compositions for treatment of ocular neovascularization and neural injury

Inventor(s): DeVries, Gerald W.; (Laguna Hills, CA), Wheeler, Larry A.; (Irvine, CA)

Correspondence: Carlos A. Fisher; Allergan, INC.; T2-7h; 2525 Dupont Drive; Irvine; CA; 92612; US

Patent Application Number: 20030082183 Date filed: April 26, 2002

Abstract: Methods and compositions for the treatment of ocular neovascularization and macular degeneration. The invention includes combining photodynamic therapy with administration of a neuroprotectant and a neovascularization inhibitor.

Excerpt(s): Loss of visual acuity is a common problem associated with aging and with various conditions of the eye. Particularly troublesome is the development of unwanted neovascularization in the cornea, retina or choroid. Choroidal neovascularization leads to hemorrhage and fibrosis, with resultant visual loss in a number of recognized eye diseases, including macular degeneration, ocular histoplasmosis syndrome, myopia, diabetic retinopathy and inflammatory diseases. Age-related macular degeneration (AMD) is the leading cause of new blindness in the elderly, and choroidal neovascularization is responsible for 80% of the severe visual loss in patients with this disease. Although the natural history of the disease is eventual quiescence and regression of the neovascularization process, this usually occurs at the cost of sub-retinal fibrosis and vision loss. Traditional treatment of AMD relies on occlusion of the blood vessels using laser photocoagulation. However, such treatment requires thermal destruction of the neovascular tissue, and is accompanied by full-thickness retinal damage, as well as damage to medium and large choroidal vessels. Further, the subject is left with an atrophic scar and visual scotoma. Moreover, recurrences are common, and visual prognosis is poor.

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•Methods of screening and using inhibitors of angiogenesis

Inventor(s): Baciu, Peter C.; (Laguna Niguel, CA), Manuel, Virna M.; (Lawndale, CA), Zhang, Heying; (Rockville, MD)

Correspondence: Carlos A. Fisher; Allergan, INC.; T2-7h; 2525 Dupont Drive; Irvine; CA; 92623; US

Patent Application Number: 20030171271 Date filed: April 3, 2002

Abstract: A method of screening for agents which are able to inhibit angiogenesis. Such agent have therapeutic application in the treatment of conditions including cancer, macular degeneration and retinopathies. Also included are methods of treating a patient having a pathological condition characterized by an increase in angiogenesis which comprises administering to the patient an agent capable of inhibiting activation of an integrin subunit.

Excerpt(s): This patent application claims benefit of priority under 35 USC.sctn. 119(e) to provisional patent application No. 60/281,512, filed Apr. 4, 2001, which is hereby incorporated by reference herein. Angiogenesis is the method by which new blood vessels form from existing vasculature in an animal. The process is distinct from

182Macular Degeneration

vasculogenesis, in that the new endothelial cells lining the vessel arise from proliferation of existing cells, rather than differentiating from stem cells. The process is invasive and dependent upon proteolyisis of the extracellular matrix (ECM), migration of new endothelial cells, and synthesis of new matrix components. Angiogenesis occurs during embryogenic development of the circulatory system; however, in adult humans, angiogenesis only occurs as a response to a pathological condition (except during the reproductive cycle in women). Thus, in adults, angiogenesis is associated with conditions including wound healing, arthritis, tumor growth and metastasis, as well as in ocular conditions such as retinopathies, macular degeneration and corneal ulceration and trauma. In each case the progression of angiogenesis is similar: a stimulus results in the formation of a migrating column of endothelial cells. Proteolytic activity is focused at the advancing tip of this "vascular sprout", which breaks down the ECM sufficiently to permit the column of cells to infiltrate and migrate. Behind the advancing front, the endothelial cells differentiate and begin to adhere to each other, thus forming a new basement membrane. The cells then cease proliferation and finally define a lumen for the new arteriole or capillary.

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•Methods of treating ophthalmic disorders with epoxy-steroidal aldosterone receptor antagonists

Inventor(s): Aiken, James W.; (Basking Ridge, NJ)

Correspondence: Senniger Powers Leavitt And Roedel; One Metropolitan Square; 16th Floor; ST Louis; MO; 63102; US

Patent Application Number: 20030158162 Date filed: December 12, 2002

Abstract: A method for treating or preventing ophthalmic disorders comprising the administration of one or more aldosterone receptor antagonists that contain a 9,11epoxy moiety, such as eplerenone is disclosed. The method results in a reduction of intraocular pressure which treats or prevents the ophthalmic disorders. Among the disorders are intraocular hypertension, glaucoma, low tension glaucoma, age-related macular degeneration (AMD), macular edema, and diabetic retinopathy.As glucocorticoids and mineralocorticoids also cause the retention of ions, such as sodium and potassium, where aldosterone receptors are located, aldosterone receptor antagonists that contain a 9,11-epoxy moiety, such as eplerenone, also can be administered to modulate the intraocular concentration of ions. Thus, aldosterone receptor antagonists can be administered to maintain an intraocular ionic environment that is beneficial to intraocular cell survival.

Excerpt(s): This application is a complete application based on U.S. provisional application Serial No. 60/341,033, filed Dec. 12, 2001 and the entire disclosure of which is incorporated herein by reference. The present invention relates to novel methods for the treatment or prevention of glaucoma, ocular hypertension, and other ophthalmic disorders exhibiting elevated intraocular pressure, as well as ocular disorders characterized by retinal neurodegeneration or edema including glaucoma, diabetic retinopathy, and adult macular degeneration with one or more epoxy-steroidal aldosterone receptor antagonists. Glaucoma is a group of diseases that can lead to damage to the eye's optic nerve and result in blindness. The optic nerve connects the retina, the light-sensitive layer of nerve cells at the back of the eye, with the brain. A healthy optic nerve is necessary for good vision.

Patents 183

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•N-aryl (thio) anthranilic acid amide derivatives, their preparation and their use as VEGF receptor tyrosine kinase inhibitors

Inventor(s): Altmann, Karl-Heinz; (Reinach, CH), Bold, Guido; (Gipf-Oberfrick, CH), Ferrari, Stefano; (Muttenz, CH), Furet, Pascal; (Thann, FR), Haberey, Martin; (Berlin, DE), Hofmann, Francesco; (Bottmingen, CH), Huth, Andreas; (Berlin, DE), Kruger, Martin; (Berlin, DE), Manley, Paul William; (Arlesheim, CH), Menrad, Andreas; (Oranienburg, DE), Mestan, Jurgen; (Denzlingen, DE), Seidelmann, Dieter; (Berlin, DE), Thierauch, Karl-Heinz; (Berlin, DE), Wood, Jeanette Marjorie; (Biel-Benken, CH)

Correspondence: Thomas Hoxie; Novartis Corporation; Patent And Trademark Dept; 564 Morris Avenue; Summit; NJ; 079011027

Patent Application Number: 20030064992 Date filed: June 26, 2002

Abstract: 1Described are compunds of formula (I), wherein W is O or S; X is NR.sub.8; Y is CR.sub.9R.sub.10--(CH.sub.2)n wherein R.sub.9 and R.sub.10 are independently of each other hydrogen or lower alkyl, and n is an integer of from and including 0 to and including 3; or Y is SO.sub.2; R.sub.1 is aryl; R.sub.2 is a monoor bicyclic heteroaryl group comprising one or more ring nitrogen atoms with the exception that R.sub.2 cannot represent 2-phthalimidyl, and in case of Y=SO.sub.2 cannot represent 2,1,3- benzothiadiazol-4-yl; any of R.sub.3, R.sub.4, R.sub.5 and R.sub.6, independently of the other, is H or a substituent other than hydrogen; and R.sub.7 and R.sub.8, independently of each other, are H or lower alkyl; or a N-oxide or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical product for the treatment of a neoplastic disease which responds to an inhibition of the VEGF receptor tyrosine kinase activity. The compounds of formula (I) can be used for the treatment e.g. of a neoplastic disease, such as a tumor disease, of retinopathy and age-related macular degeneration.

Excerpt(s): The invention relates to new benzamide derivatives, processes for the preparation thereof, the application thereof in a process for the treatment of the human or animal body, the use thereof--alone or in combination with one or more other pharmaceutically active compounds--for the treatment especially of a neoplastic disease, such as a tumor disease, of retinopathy and age-related macular degeneration; a method for the treatment of such a disease in animals, especially in humans, and the use of such a compound--alone or in combination With one or more other pharmaceutically active compounds--for manufacture of a pharmaceutical preparation (medicament) for the treatment of a neoplastic disease, of retinopathy and age-related macular degeneration. Certain diseases are known to be associated with deregulated angiogenesis, for example diseases caused by ocular neovascularisation, such as retinopathies (including diabetic retinopathy), age-related macula degeneration, psoriasis, haemangioblastoma, haemangioma, arteriosclerosis, an inflammatory disease, such as a rheumatoid or rheumatic inflammatory disease, especially arthritis, such as rheumatoid arthritis, or other chronic inflammatory disorders, such as chronic asthma, arterial or post-transplantational atherosclerosis, endometriosis, and especially neoplastic diseases, for example so-called solid tumours and liquid tumours (such as leucemias). According to recent findings, at the centre of the network regulating the growth and differentiation of the vascular system and its components, both during embryonic development and normal growth and in a wide number of pathological

184Macular Degeneration

anomalies and diseases, lies the angiogenic factor known as "Vascular Endothelial Growth Factor" (=VGEF; originally termed "Vascular Permeability Factor", =VPF), along with its cellular receptors (see Breier, G., et al., Trends in Cell Biology 6, 454-6 [1996] and references cited therein).

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•Novel integrin ligand ITGL-TSP

Inventor(s): Fornwald, James A.; (Norristown, PA), Hastings, Gregg A.; (Westlake Village, CA), Jonak, Zdenka L.; (Devon, PA), Terrett, Jonathon A.; (Oxfordshire, GB), Trulli, Stephen H.; (Havertown, PA)

Correspondence: Human Genome Sciences Inc; 9410 Key West Avenue; Rockville; MD; 20850

Patent Application Number: 20030166065 Date filed: April 4, 2002

Abstract: ITGL-TSP polypeptides and polynucleotides and methods for producing such polypeptides by recombinant techniques are disclosed. Also disclosed are methods for utilizing ITGL-TSP polypeptides and polynucleotides in the design of protocols for the treatment of, angiogenic diseases (cancer, cancer metastasis, chronic inflammatory disorders, rheumatoid arthritis, atherosclerosis, macular degeneration, diabetic retinopathy), restenosis, Alzheimer's disease and tissue remodeling, among others, and diagnostic assays for such conditions.

Excerpt(s): This application is a continuation of U.S. patent application Ser. No. 08/845,496, filed Apr. 24, 1997, which is herein incorporated by reference. This invention relates to newly identified polynucleotides, polypeptides encoded by them and to the use of such polynucleotides and polypeptides, and to their production. More particularly, the polynucleotides and polypeptides of the present invention relate to thrombospondin-metalloproteinase family, hereinafter referred to as ITGL-TSP. The invention also relates to inhibiting or activating the action of such polynucleotides and polypeptides. ITGL-TSP is a novel thrombospondin (metalloproteinase)-like gene which could have multifunctional activity in normal and disease states. The homology to the thrombospondin type 1 (TSP-1) would "predict" that ITGL-TSP could have similar functions such as TSP-1. TSP-1 modulates aggregation of platelets, formation and lysis of fibrin, adhesion and migration of cells and progression of cells through the growth cycle. TSP-1 is implicated as a potential regulator of tumor growth and metastasis. Conflicting observations suggest that overexpression of TSP-1 causes "increased or suppressed" tumor growth. TSP-1 is a homotrimer with different functional domains, some of which serve as receptor recognizing regions. One of the important functions has been its ability to bind to integrins, such as a Vb3, aIIbb3 and other unknown integrin receptors. Integrins are a large family of cell surface receptors that mediate cell to cell as well as cell to matrix adhesion. Structurally, integrins consist of a heterodimer of an a and b chain. Each subunit has a large N-terminal extracellular domain followed by a transmembrane domain and a short C-terminal cytoplasmic region. Some receptors share a common b chain while having different a chains. ITGL-TSP could be a such novel ligand which could play an important role in different diseases.

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Patents 185

•Novel retina-specific human proteins C7orf9, C12orf7, MPP4 and F379

Inventor(s): Stoehr, Heidi; (Wuerzburg, DE), Weber, Bernard H. F.; (Wuerzburg, DE)

Correspondence: Burns Doane Swecker & Mathis L L P; Post Office Box 1404; Alexandria; VA; 22313-1404; US

Patent Application Number: 20030054446 Date filed: November 29, 2001

Abstract: The present invention relates to the novel human retina-specific proteins called C7orf9, C12orf7, MPP4 and F379, and isolated nucleic acid molecules encoding said proteins. Also provided are vectors, host cells, antibodies and recombinant methods for producing these human proteins. The invention further relates to diagnostic and therapeutic methods useful for diagnosing and treating macular degeneration, e.g. AMD.

Excerpt(s): The present invention relates to gene expression in human retinal tissue and particularly to the novel retina-specific proteins C7orf9, C12orf7, MPP4 and F379 associated with macular degeneration including age-related macular degeneration

(AMD) and the genes encoding C7orf9, C12orf7, MPP4 and F379. First described in 1855, age-related macular degeneration (AMD) is now recognized as the most common cause of visual morbidity in the developed world The prevalence of AMD in persons over 52 was found to be 9% increasing to more than 25% in persons over the age of 75. Projected estimates indicate that by the year 2020 as many as 7.5 million individuals over 65 years may suffer from central vision loss due to AMD. As the population of older people in industrialized countries increases, the associated social and economic consequences of AMD are destined to increase in the next millenium unless preventive or therapeutic treatments can be devised. Histologically, an increasing accumulation of yellowish lipofuscin-like particles within the retinal pigment epithelium (RPE) can be observed with age. This likely represents an early stage in the evolution of AMD which is followed by secondary complications frequently associated with loss of visual acuity. It is thought that the lipofuscin-like deposits represent remnants of undigested phagocytosed photoreceptor outer segment membranes which, in the normal physiological processes, are excreted basally through Bruch's membrane into the choriocapillaris. Over time, incomplete digestion and accumulation of lipofuscin-like particles affect Bruch's membrane and lead to its progressive destruction as seen by electron microscopy as an abnormal thickening of the inner collagenous layer of the membrane. The deposits in the RPE and Bruch's membrane consist largely of lipids although their exact composition may vary between individuals with some deposits revealing more polar phospholipids while others contain predominantly apolar neutral lipids.

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186 Macular Degeneration

•Nucleic acid and amino acid sequences for ATP-binding cassette transporter and methods of screening for agents that modify ATP-binding cassette transporter

Inventor(s): Allikmets, Rando; (Frederick, MD), Anderson, Kent L.; (Houston, TX), Dean, Michael; (Frederick, MD), Leppert, Mark; (Salt Lake City, UT), Lewis, Richard A.; (Houston, TX), Li, Yixin; (Houston, TX), Lupski, James R.; (Houston, TX), Nathans, Jeremy; (Baltimore, MD), Rattner, Amir; (Baltimore, MD), Shroyer, Noah F.; (Houston, TX), Singh, Nanda; (Salt Lake City, UT), Smallwood, Philip; (Woodbine, MD), Sun, Hui; (Baltimore, MD)

Correspondence: Woodcock Washburn Llp; One Liberty Place, 46th Floor; 1650 Market Street; Philadelphia; PA; 19103; US

Patent Application Number: 20030162276 Date filed: January 10, 2003

Abstract: The present invention provides nucleic acid and amino acid sequences of an ATP binding cassette transporter and mutated sequences thereof associated with macular degeneration. Methods of detecting agents that modify ATP-binding cassette transporter comprising combining purified ATP binding cassette transporter and at least one agent suspected of modifying the ATP binding cassette transporter an observing a change in at least one characteristic associated with ATP binding cassette transporter. Methods of detecting macular degeneration is also embodied by the present invention.

Excerpt(s): This application claims priority to U.S. provisional application serial No. 60/039,388, filed Feb. 27, 1997. Members of the superfamily of mammalian ATP binding cassette (ABC) transporters are being considered as possible candidates for human disease phenotypes. The ABC superfamily includes genes whose products are transmembrane proteins involved in energy-dependent transport of a wide spectrum of substrates across membranes (Childs and Ling, 1994; Dean and Allikmets, 1995). Many disease-causing members of this superfamily result in defects in the transport of specific substrates (CFTR, Riordan et al., 1989; ALD, Mosser et al., 1993; SUR, Thomas et al., 1995; PMP70, Shimozawa et al., 1992; TAP2, de la Salle et al., 1994). In eukaryotes, ABC genes encode typically four domains that include two conserved ATP-binding domains (ATP) and two domains with multiple transmembrane (TM) segments (Hyde et al. 1996). The ATP-binding domains of ABC genes contain motifs of characteristic conserved residues (Walker A and B motifs) spaced by 90-120 amino acids. Both this conserved spacing and the "Signature" or "C" motif just upstream of the Walker B site distinguish members of the ABC superfamily from other ATP-binding proteins (Hyde et al., 1990; Michaelis and Berkower, 1995). These features have allowed the isolation of new ABC genes by hybridization, degenerate PCR, and inspection of DNA sequence databases (Allikmets et al., 1993, 1995; Dean et al., 1994; Luciani et al., 1994). The characterization of twenty-one new members of the ABC superfamily may permit characterization and functions assigned to these genes by determining their map locations and their patterns of expression (Allikmets et al., 1996). That many known ABC genes are involved in inherited human diseases suggests that some of these new loci will also encode proteins mutated in specific genetic disorders. Despite regionally localizing a gene by mapping, the determination of the precise localization and sequence of one gene nonetheless requires choosing the certain gene from about 250 genes, four to about five million base pairs, from within the regionally localized chromosomal site.

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Patents 187

•Objective system and method for evaluating ocular changes including assessment of macular integrity and function

Inventor(s): Grant, Alan; (Chevy Chase, MD)

Correspondence: Jacobson Holman Pllc; 400 Seventh Street N.W.; Suite 600; Washington; DC; 20004; US

Patent Application Number: 20030002014 Date filed: July 2, 2001

Abstract: A system and method for objectively testing for ocular changes including agerelated macular degeneration through reliance on involuntary physical reactions such as the fixation reflex and optokinetic nystagmus. A narrow band of visible blue light is beamed at the patient's eye through alternate apertures in a mask which are separated by a relatively small angle of subtendance at the entrance pupil. In the presence of a healthy macula, the blue light is filtered out and the fixation reflex is absent. Conversely, if the macula is in the process of degenerating by the progressive loss of protective pigments, then the impinging of the narrow band of visible blue light upon the macula, via the alternate apertures, will evoke the fixation reflex.

Excerpt(s): The present invention is related to the field of ocular health, disease and degeneration and, more particularly, to a noninvasive system and objective method for analyzing macular function and thereby detecting macular changes and degradations, which may be predictive of future age-related macular degeneration. Human longevity is extending, and we are increasingly subject to adverse physiological changes which are detrimental to our well-being and independence. Loss of visual acuity, which may or may not lead ultimately to blindness, can be debilitating. The macula lutea, a small area lying slightly lateral to the center of the retina, represents the region of maximum visual acuity in the human eye. While many age-related ocular changes such as cataract formation, adult-onset diabetes, and glaucoma can be reasonably well-managed so that visual self-sufficiency can be maintained, Age-related Macular Degeneration (AMD) impacting the macula lutea is progressively the most debilitating exception. Evaluation of the macula lutea has traditionally been limited to subjective testing. By definition, subjective testing is flawed and individually anecdotal, due to total reliance on patient responses.

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•Substituted benzofurans and benzothiophenes, methods of making and methods of use as integrin antagonists

Inventor(s): Anaclerio, Beth M.; (New Castle, DE), Marder, Victor J.; (Los Angeles, CA), Sanchez, Juan Jose Marugan; (Downingtown, PA), U'Prichard, David C.; (Philadelphia, PA)

Correspondence: Sterne, Kessler, Goldstein & Fox Pllc; 1100 New York Avenue, N.W., Suite 600; Washington; DC; 20005-3934; US

Patent Application Number: 20030018064 Date filed: April 26, 2002

Abstract: The present invention relates to novel substituted benzofurans and

benzothiophenes compounds that are antagonists of alpha V (.alpha.v) integrins, for example.alpha.sub.v.beta.sub.3 and.alpha.sub.v.beta.sub.5 integrins, their

188Macular Degeneration

pharmaceutically acceptable salts, and pharmaceutical compositions thereof. The compounds may be used in the treatment of pathological conditions mediated by.alpha.sub.v.beta.sub.3 and.alpha.sub.v.beta.sub.5 integrins, including such conditions as tumor growth, metastasis, restenosis, osteoporosis, inflammation, macular degeneration, diabetic retinopathy, and rheumatoid arthritis. The compounds have the general formula I: 1where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, m, n, i, j and k are defined herein.

Excerpt(s): This application claims priority to Provisional application No. 60/324,516, filed Oct. 26, 2001, and also claims priority to Provisional application No. 60/286,532, filed on Apr. 27, 2001. The present invention relates to novel substituted benzofurans and benzothiophenes that are antagonists of alpha V (.alpha.v) integrins, for example.alpha.sub.v.beta.sub.3 and.alpha.sub.v.beta.sub.5 integrins, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof. Integrins are cell surface glycoprotein receptors which bind extracellular matrix proteins and mediate cell-cell and cell-extracellular matrix interactions (generally referred to as cell adhesion events) (Hynes, R. O., Cell 69:11-25 (1992)). These receptors are composed of noncovalently associated alpha (.alpha.) and beta (.beta.) chains which combine to give a variety of heterodimeric proteins with distinct cellular and adhesive specificities (Albeda, S. M., Lab. Invest. 68:4-14 (1993)). Recent studies have implicated integrins in the regulation of cellular adhesion, migration, invasion, proliferation, apoptosis and gene expression (Albeda, S. M., Lab. Invest. 68:4-14 (1993); Juliano, R., Cancer Met. Rev. 13:25-30 (1994); Ruoslahti, E. and Reed, J. C., Cell 77:477-478 (1994); and Ruoslahti, E. and Giancotti, F. G., Cancer Cells 1:119-126 (1989)).

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•System and method for full field oscillating stimulus perimeter

Inventor(s): Stewart, Jeffrey L.; (Greenwich, CT)

Correspondence: John DE LA Rosa; Suite 2211; 67 Wall Street; New York; NY; 10005; US Patent Application Number: 20030081176

Date filed: October 1, 2001

Abstract: A novel visual field test utilizing oscillating visual stimuli is proposed, which may be used to diagnose for eye disorders, such as glaucoma or macular degeneration. Such visual stimuli oscillate in color, polarity, saturation, luminance or intensity. Preferably, the visual test pattern consists of oscillating visual stimuli arranged in a pattern, such as a repeating or grid pattern, covering substantially all of the field of vision being tested. And, may include the use of frequency doubling visual stimuli. In use, the visual field test pattern is positioned in front of the patient so as to cover substantially all of the field of vision being tested, typically about a solid angle of 40.degree. or more. The eye under examination is fixated, and the patient asked to indicate areas where the oscillating visual stimuli are dissimilar, such as by outlining those areas different from the rest of the visual field test pattern. This procedure may be repeated for different contrast, saturation, or luminance levels, corresponding to varying degrees of visual sensitivity levels. Areas of dissimilarity correspond to visual field defects. The characteristic locations of the areas of dissimilarity for a particular sensitivity setting will allow clinicians not only to diagnose, but also to determine the severity of the eye disorder.

Patents 189

Excerpt(s): The present invention relates to a visual test system and method for testing the functioning of different parts of the retina and other potions of the visual pathway. A large number of degenerative eye disorders, such as glaucoma and macular degeneration, may be detected by evaluating a patient's visual field, such as through perimetry and campimetry. While the patient's eye is fixated, such visual tests present discrete light stimuli in the patient's field of vision, and then monitor the patient's response to the stimuli, allowing a mapping of the visual field to be obtained. Visual field tests employing test patterns have also been developed for measuring a patient's visual field. One such visual test uses a so-called "Amsler grid" consisting of equally spaced, parallel, horizontal and vertical lines. In use, the grid is positioned about 28-30 cm in front of the patient. With one eye covered, the other eye is fixated on a central point positioned in the grid, such as a dot. The patient is then asked to indicate areas of distortion in the grid by, for example, drawing an outline around the areas of grid distortion, such as, missing squares or wavy lines. Over time, the patient is again asked to note any changes that occur in the severity or location of the grid distortion, typically on a daily or weekly basis.

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•Telomere-encoding synthetic DNA nanocircles, and their use for the elongation of telomere repeats

Inventor(s): Kool, Eric T.; (Stanford, CA)

Correspondence: Howrey Simon Arnold & White Llp; 750 Bering Drive; Houston; TX; 77057; US

Patent Application Number: 20030148988 Date filed: January 3, 2003

Abstract: Telomere-encoding nucleic acid nanocircles, methods for their preparation, and methods for their use are disclosed. The nanocircles can be constructed containing multiple repeats of the complement of telomere repeat sequences. The telomereencoding nanocircles are useful for extending telomeres both in vitro and in vivo, for treating macular degeneration, the effects of skin aging, liver degeneration, and cancer. The nanocircles are further useful for treating cell cultures to produce long-lived noncancerous cell populations. This use has wide applicability in scientific research, tissue engineering, and transplantation.

Excerpt(s): The present application claims priority to U.S. Provisional Patent Application Serial No. 60/345,056 filed Jan. 4, 2002, the contents of all of which are incorporated herein by reference. The invention relates to compositions and methods for the extension of telomere repeat sequences and, more specifically, to the use of synthetic nucleic acid nanocircles for the extension of telomere repeat sequences. The invention further relates to synthetic, diagnostic, and therapeutic uses for the nanocircles. The many potential uses of telomere-encoding nanocircles include their use to enhance the lifespan of non-cancerous cell populations in culture, to treat macular degeneration, to treat skin aging, to treat liver degeneration, and to treat cancer. Additionally, nanocircles can be used to elongate telomeres in vitro, to add synthetic telomeres onto chemicals or biomolecules having a telomere primer, and to add detectable or modified bases into a telomere. Human cell populations typically have a finite lifetime, dividing a number of times before entering a nondividing phase called "replicative senescence". Human chromosomes are capped with repeated sequences called "telomeres". Human telomeres consist of up to about 2500 repeats of the sequence 5'-TTAGGG-3' (SEQ ID NO:1).

190Macular Degeneration

Telomeres in normal non-cancerous cells shorten each time that a cell divides. This has been viewed as a type of `clock`, helping to determine the lifespan of a cell population.

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•Topical treatment of ocular hypertension, glaucoma, ischemic retinopathy and agerelated macular degeneration with ophthalmic formulation of dopamine antagonists

Inventor(s): Chiou, George C.Y.; (College Station, TX)

Correspondence: Morrison & Foerster Llp; 755 Page Mill RD; Palo Alto; CA; 94304-1018; US

Patent Application Number: 20030069232 Date filed: February 28, 2001

Abstract: This invention provides ocular formulations comprising an ocular drug and a carboxylic acid in an amount sufficient to maintain the pH of the formulation from about 4.5 to about 7.5. The ocular drug may be a dopamine antagonist and the acid may be lactic acid, citric acid or tartaric acid. In some aspects, the pH of the formulation is about 5.5 The ocular formulations of this invention provide enhanced bioavailability which results in increased drug concentrations across the cornea and in the eye ball, i.e., aqueous humor and intraocular organs and chambers. Moreover, the present formulations are non-irritating when applied topically and have a shelf-life of at least fourteen days at 25.degree. C. Methods are also provided to increase ocular blood flow by using present ocular formulations comprising dopamine antagonists or other drugs for the prevention and treatment of ocular hypertension, glaucoma, ischemic retinopathy and age-related macular degeneration (AMD).

Excerpt(s): The present invention relates generally to ocular formulations and methods for using those formulations to improve blood flow to the retina and choroid to halt or reverse the course of visual deterioration. Accordingly, this invention transcends the related disciplines of pharmaceutical sciences, ocular pharmacology and medicine. Several potential drugs have been developed with high anticipation of treating various eye diseases, yet only a few of those potential drugs have reached the clinics because of the problems of drug delivery. Ocular drug delivery faces three major difficulties: first, the ocular bioavailability of the drug is often poor because the drug needs to cross the cornea to enter the eye ball, i.e., the aqueous humor and other interior anatomical organs of the eye; second, very often, the drug formulation is irritable when applied topically to the eye; and third, the ocular formulations are very unstable, i.e., have a short shelf-life, in the order of a few days to few weeks. For example, most, if not all dopamine antagonists do not dissolve in plain aqueous medium and, as a result, their non-aqueous formulations often produce severe eye irritation. Various absorption enhancers and antiirritants have been proposed in the prior art to overcome these difficulties. However, the search for a successful resolution to the problem continues. Accordingly, there is a need for stable ocular formulations that enhance the ocular bioavailability of a drug with reduced ocular irritation when administered topically. As the following description illustrates, the present invention meets this need.

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Patents 191

•Treatment of disease states characterized by excessive or inappropriate angiogenesis

Inventor(s): Payne, J. Donald; (Spring, TX), West, Jennifer L.; (Pearland, TX) Correspondence: Eric P. Mirabel; 3783 Darcus; Houston; TX; 77005; US Patent Application Number: 20030118657

Date filed: December 3, 2002

Abstract: Disclosed is a method for reducing excessive or inappropriate neovasculature, including nevasculature in the eye which interferes with or has potential to interfere with vision, for example, that associated with diabetic retinopathy or macular degeneration. The regions of the neovasculature are targeted with nanoparticles, including metal nanoshells, which are then irradiated, preferably with a laser, to heat them and ablate the undesired blood vessels. The nanoparticles are targeted to the neovasculature by linking them with a targeting agent, including, for example, antibodies, antibody fragments, receptor binding proteins or other proteins or molecules including growth factors.

Excerpt(s): This Application claims the benefit of U.S. Provisional Application No. 60/336,824, filed on Dec. 3, 2001. Certain disease states and conditions, including macular degeneration, diabetic retinopathy, cancer and healing wounds, are characterized by excessive or inappropriate angiogenesis. Macular degeneration and diabetic retinopathy can both lead to blindness or deterioration of vision. In both these conditions, new blood vessels which proliferate in the retina are the main cause of vision impairment. In cancer, the tumor promotes the growth of new blood vessels to support the growth of the tumor. Angiogenesis arising in connection with wounds may impair healing. Macular degeneration relates to a breakdown of the macula, the light-sensitive part of the retina responsible for the sharp, direct vision needed for activities including reading or driving. Macular degeneration is more common in people over age 65, and whites and females are at highest risk. Most cases of macular degeneration are related to aging (age-related macular degeneration), but it also can occur as a side effect of some drugs, and it appears to run in families.

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•Tyrosine kinase inhibitors

Inventor(s): Bilodeau, Mark T.; (Lansdale, PA), Hartman, George D.; (Lansdale, PA), Hungate, Randall W.; (Newbury Park, CA), Manley, Peter J.; (Harleysville, PA), Rodman, Leonard; (New York, NY)

Correspondence: Merck & CO., INC.; Patent Department; P.O. Box 2000 - Ry60-30; Rahway; NJ; 07065-0907; US

Patent Application Number: 20030064996 Date filed: February 1, 2002

Excerpt(s): This application claims priority under 35 U.S.C.sctn.119(e) from U.S. Provisional Application 60/153,348, filed Sep. 10.sup.th, 1999. The present invention relates to compounds which inhibit, regulate and/or modulate tyrosine kinase signal transduction, compositions which contain these compounds, and methods of using them to treat tyrosine kinase-dependent diseases and conditions, such as angiogenesis, cancer, tumor growth, atherosclerosis, age related macular degeneration, diabetic retinopathy, inflammatory diseases, and the like in mammals. Tyrosine kinases are a

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class of enzymes that catalyze the transfer of the terminal phosphate of adenosine triphosphate to tyrosine residues in protein substrates. Tyrosine kinases are believed, by way of substrate phosphorylation, to play critical roles in signal transduction for a number of cell functions. Though the exact mechanisms of signal transduction is still unclear, tyrosine kinases have been shown to be important contributing factors in cell proliferation, carcinogenesis and cell differentiation.

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•Use of melanin for inhibition of angiogenesis and macular degeneration

Inventor(s): D'Amato, Robert J.; (Lexington, MA)

Correspondence: John S. Pratt, Esq; Kilpatrick Stockton, Llp; 1100 Peachtree Street; Suite 2800; Atlanta; GA; 30309; US

Patent Application Number: 20030096735 Date filed: January 9, 2003

Abstract: Composition and methods of using melanin, or melanin-promoting compounds, for inhibiting angiogenesis to treat angiogenesis-dependent diseases, such as macular degeneration and cancer.

Excerpt(s): This application relates to a inhibitor of angiogenesis useful for treating angiogenesis-related diseases, such as macular degeneration and angiogenesisdependent cancers. The invention further relates to novel pharmaceutical compositions and methods for treating and curing macular degeneration, and other angiogenesisdependent diseases. As used herein, the term "angiogenesis" means the generation of new blood vessels into a tissue or organ. Under normal physiological conditions, humans or animals only undergo angiogenesis in very specific restricted situations. For example, angiogenesis is normally observed in wound healing, fetal and embryonal development and formation of the corpus luteum, endometrium and placenta. The control of angiogenesis is a highly regulated system of angiogenic stimulators and inhibitors. The control of angiogenesis has been found to be altered in certain disease states and, in many cases, the pathological damage associated with the disease is related to the uncontrolled angiogenesis. Both controlled and uncontrolled angiogenesis are thought to proceed in a similar manner. Endothelial cells and pericytes, surrounded by a basement membrane, form capillary blood vessels. Angiogenesis begins with the erosion of the basement membrane by enzymes released by endothelial cells and leukocytes. The endothelial cells, which line the lumen of blood vessels, then protrude through the basement membrane. Angiogenic stimulants induce the endothelial cells to migrate through the eroded basement membrane. The migrating cells form a "sprout" off the parent blood vessel, where the endothelial cells undergo mitosis and proliferate. The endothelial sprouts merge with each other to form capillary loops, creating the new blood vessel. In the disease state, prevention of angiogenesis could avert the damage caused by the invasion of the new microvascular system.

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Patents 193

•Vision through photodynamic therapy of the eye

Inventor(s): Fsadni, Mario; (Buelach, CH), Huber, Gustav; (Zurich, CH), Levy, Julia; (Vancouver, CA), Strong, H. Andrew; (North Van, CA)

Correspondence: Morrison & Foerster Llp; 3811 Valley Centre Drive; Suite 500; San Diego; CA; 92130-2332; US

Patent Application Number: 20030149012 Date filed: March 7, 2003

Abstract: Photodynamic therapy of conditions of the eye, especially those conditions characterized by unwanted neovasculature, such as age-related macular degeneration, results in enhanced visual acuity for treated subjects.

Excerpt(s): The invention relates to a method to improve visual acuity by administering photodynamic therapy (PDT) to the eye. Loss of visual acuity is a common problem associated with aging and with various conditions of the eye. Particularly troublesome is the development of unwanted neovascularization in the cornea, retina or choroid. Choroidal neovascularization leads to hemorrhage and fibrosis, with resultant visual loss in a number of recognized eye diseases, including macular degeneration, ocular histoplasmosis syndrome, myopia, and inflammatory diseases. Age-related macular degeneration (AMD) is the leading cause of new blindness in the elderly, and choroidal neovascularization is responsible for 80% of the severe visual loss in patients with this disease. Although the natural history of the disease is eventual quiescence and regression of the neovascularization process, this usually occurs at the cost of sub-retinal fibrosis and vision loss. Current treatment of AMD relies on occlusion of the blood vessels using laser photocoagulation. However, such treatment requires thermal destruction of the neovascular tissue, and is accompanied by full-thickness retinal damage, as well as damage to medium and large choroidal vessels. Further, the subject is left with an atrophic scar and visual scotoma. Moreover, recurrences are common, and visual prognosis is poor.

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•Zeaxanthin formulations for human ingestion

Inventor(s): Garnett, Kevin M.; (Morristown, NJ), Gierhart, Dennis L.; (Chesterfield, MO), Guerra-Santos, Luis H.; (Ballwin, MO)

Correspondence: Patrick D. Kelly; 11939 Manchester #403; ST. Louis; MO; 63131; US Patent Application Number: 20030108598

Date filed: December 17, 2002

Abstract: Preparations are disclosed containing the 3R-3'R stereoisomer of zeaxanthin, packaged for oral ingestion by humans as a therapeutic drug or nutritional supplement. Zeaxanthin is a yellow carotenoid pigment found in the macula (in the center of the human retina), which helps protect retinal cells against phototoxic damage. The R-R stereoisomer can be prepared by fermenting cells, such as Flavobacterium multivorum (ATCC 55238), which do not create any detectable quantity of the undesired and potentially toxic S-S or S-R isomers, and which do not synthesize any other carotenoids. The R-R isomer can be concentrated, in large quantities and at low cost, into a viscous oily fluid containing about 5 to 20% zeaxanthin, by means of a simple solvent extraction process. This oily fluid can be mixed with a carrier such as vegetable oil and enclosed