# US 11,998,443 B2 · Method for stimulating retinal cells and treating vision loss > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,998,443 B2 - Document ID: US11998443B2 - Status: Granted - Kind: B2 - Application number: 16/611,095 - Filed: 2018-05-08 - Published: 2020-02-20 - Granted: 2024-06-04 - Earliest claimed: 2017-05-08 - Assignees: LambdaVision Incorporated - Applicants: LambdaVision Incorporated - Inventors: Robert R Birge; Nicole Wagner; Jordan A Greco - Web page: https://patentgrep.com/patent/US11998443B2 ## CPC - A61F 2/14: Eye parts, e.g. lenses or corneal implants; Artificial eyes - A61F 9/0017: {implantable in, or in contact with, the eye, e.g. ocular inserts} - A61K 38/164: {from bacteria} - A61L 27/227: {Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24} - A61L 27/50: Materials characterised by their function or physical properties {, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials} - A61L 27/54: Biologically active materials, e.g. therapeutic substances {(A61L27/227 takes precedence)} - A61N 1/36046: {of the eye} - A61N 5/0603: {for treatment of body cavities} - A61N 5/0622: {Optical stimulation for exciting neural tissue} - B29D 11/0073: {Optical laminates} - B32B 7/023: Optical properties - A61F 2009/00863: {Retina} - A61L 2300/252: Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines - A61L 2430/16: for reconstruction of eye parts, e.g. intraocular lens, cornea - A61N 2005/0648: {the light being directed to the eyes} - A61N 2005/0663: {Coloured light} - B32B 2535/00: Medical equipment, e.g. bandage, prostheses or catheter - A61F: FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS (dental prosthetics A61C) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61L: METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K) - A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B) - B29D: PRODUCING PARTICULAR ARTICLES FROM PLASTICS OR FROM SUBSTANCES IN A PLASTIC STATE (making granules B29B9/00; making preforms B29B11/00) - B32B: LAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM ## Abstract Protein-based subretinal implants offer a new approach to restoring vision for patients blinded by conditions such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). The present invention relates to bacteriorhodopsin-based (BR-based) retinal implants that can be implanted in a subretinal position to replace degenerated photoreceptor cells. ## Claims ### Claim 1 A method for treating a patient having loss of vision caused by loss of retinal cells, comprising, (a) implanting into an eye of the patient a bacteriorhodopsin-based retinal implant, and (b) activating the implant with a light source, wherein the implant stimulates retinal cells such that the stimulation is provided at a resolution with pixel dimensions less than about 500 μm, or less than about 350 μm, or less than about 250 μm, or less than about 200 μm, or less than about 150 μm, or less than about 100 μm, or less than about 75 μm, or less than about 50 μm, or less than about 40 μm, or less than about 30 μm, or less than about 25 μm. ### Claim 2 (depends on 1) The method according to claim 1, wherein the bacteriorhodopsin-based retinal implant, comprises at least one substrate layer and a bacteriorhodopsin film, wherein the bacteriorhodopsin film comprises a plurality of individual layers of a native bacteriorhodopsin or a bacteriorhodopsin mutant, wherein each individual layer of the native bacteriorhodopsin or bacteriorhodopsin mutant alternates with a layer of a cationic polymer, and wherein the bacteriorhodopsin mutant is selected from the group consisting of a chloride pump mutant, a dipole mutant, a photocycle mutant, a gold-binding mutant, an ion pump mutant, a Q-state mutant, and combinations thereof. ### Claim 3 (depends on 2) The method according to claim 2, wherein the light source is a light source emitting human visible wavelengths, i.e. about 400 to about 700 nm. ### Claim 4 (depends on 3) The method according to claim 3 wherein the light source is a pulsed light source. ### Claim 5 (depends on 3) The method according to claim 3 wherein the light source is a continuous light source. ### Claim 6 (depends on 2) The method according to claim 2 wherein the light source has an intensity less than about 100 mW/cm2, 50 mW/cm2, 40 mW/cm2, or less than about 30 mW/cm2, or less than about 20 mW/cm2, or less than about 10 mW/cm2, or less than about 5 mW/cm2, or less than about 1 mW/cm2. ### Claim 7 (depends on 2) The method according to claim 2 wherein the substrate layer is an ion permeable layer and is on one or both sides of the implant. ### Claim 8 (depends on 7) The method according to claim 7, wherein the substrate layer is selected from polyethylene terephthalate (PET), 2-hydroxyethyl methacrylate (HEMA), 2-phenylethyl methacrylate (PEM), polyethylene glycol (PEG), methyl methacrylate (MMA), polydimethylsiloxane (PDMS) macromer, poly(vinyl pyrrolidone) (PVP), poly(p-xylylene) (also known as parylene), polyvinyl alcohol (PVA) hydrogel, and combinations thereof. ### Claim 9 The method according to 7 wherein the substrate layer is less than 100 μm in thickness and contains an evenly distributed array of apertures of a diameter less than about 100 μm. ### Claim 10 (depends on 1) The method according to claim 1 wherein the implant is a biocompatible, ion permeable retinal implant. ### Claim 11 (depends on 1) The method according to claim 1 wherein the implant is implanted in a position selected from a subretinal position or an epiretinal position. ### Claim 12 (depends on 1) The method according to claim 1 wherein the retinal cells are selected from retinal ganglion cells, retinal bipolar cells, retinal photoreceptor cells, and combinations thereof. ### Claim 13 (depends on 1) The method according to claim 1 wherein the retinal implant comprises at least about 100 layers of a native bacteriorhodopsin or a bacteriorhodopsin mutant, or at least about 150 layers of a native bacteriorhodopsin or a bacteriorhodopsin mutant, or at least about 200 layers of a native bacteriorhodopsin or a bacteriorhodopsin mutant. ### Claim 14 (depends on 1) The method according to claim 1 wherein the retinal implant further provides a temporal resolution of at least about 30 milliseconds. ### Claim 15 (depends on 1) The method according to claim 1, wherein the retinal implant initiates to the cells an action potential of about 40 μV. ### Claim 16 (depends on 1) The method according to claim 1 wherein the retinal implant provides a unidirectional proton gradient. ### Claim 17 (depends on 16) The method according to claim 16 wherein the bacteriorhodopsin-based retinal implant comprises bacteriorhodopsin molecules such that they are uniformly oriented. ### Claim 18 (depends on 1) The method according to claim 1 wherein the vision loss is caused by loss of retinal photoreceptor cells. ### Claim 19 (depends on 1) The method according to claim 1 wherein the bacteriorhodopsin-based retinal implant is based on native bacteriorhodopsin. ### Claim 20 (depends on 1) The method according to claim 1 wherein the bacteriorhodopsin-based retinal implant is based on a bacteriorhodopsin mutant. ### Claim 21 (depends on 20) The method according to claim 20 wherein the mutant is a Q-state mutant. ### Claim 22 A method for treating a patient having loss of vision caused by loss of retinal cells, comprising, (a) implanting into an eye of the patient a bacteriorhodopsin-based retinal implant, and (b) activating the implant with a light source, wherein the implant stimulates retinal cells such that the stimulation is provided at a resolution limited by (i) the diffraction limit of the light source or (ii) when the retinal implant further comprises an ion-permeable substrate, the aperture diameter and density of the ion-permeable substrate. ### Claim 23 A method for treating a patient having loss of vision caused by loss of retinal cells, comprising, (a) implanting into an eye of the patient a bacteriorhodopsin-based retinal implant, and (b) activating the implant with a light source, wherein the implant stimulates retinal cells such that the stimulation is provided at a resolution with a pixel density of about 4 pixels/mm2 and pixel dimension of about 500 μm, or with a pixel density of about 8 pixels/mm2 and pixel diameter of about 350 μm, or with a pixel density of about 16 pixels/mm2 and pixel diameter of about 250 μm, or with a pixel density of about 25 pixels/mm2 and pixel diameter of about 200 μm, or with a pixel density of about 44 pixels/mm2 and pixel diameter of about 150 μm, or with a pixel density of about 100 pixels/mm2 and pixel diameter of about 100 μm, or with a pixel density of about 178 pixels/mm2 and pixel diameter of about 75 μm, or with a pixel density of about 400 pixels/mm2 and pixel diameter of about 50 μm, or with a pixel density of about 625 pixels/mm2 and pixel diameter of about 40 μm, or with a pixel density of about 1111 pixels/mm2 and pixel diameter of about 30 μm, or with a pixel density of about 1600 pixels/mm2 and pixel diameter of about 25 μm. ### Claim 24 A method for stimulating retinal cells comprising, (a) contacting the retinal cells with a bacteriorhodopsin-based retinal implant, (b) activating the implant with a light source, wherein (i) wherein the implant stimulates retinal cells such that the stimulation is provided at a resolution with pixel dimensions less than about 500 μm, or less than about 350 μm, or less than about 250 μm, or less than about 200 μm, or less than about 150 μm, or less than about 100 μm, or less than about 75 μm, or less than about 50 μm, or less than about 40 μm, or less than about 30 μm, or less than about 25 μm; or (ii) wherein the implant stimulates retinal cells such that the stimulation is provided at a resolution limited by (a) the diffraction limit of the light source or (b) when the retinal implant further comprises an ion-permeable substrate, the aperture diameter and density of the ion-permeable substrate; or (iii) wherein the implant stimulates retinal cells such that the stimulation is provided at a resolution with a pixel density of about 4 pixels/mm2 and pixel dimension of about 500 μm, or with a pixel density of about 8 pixels/mm2 and pixel diameter of about 350 μm, or with a pixel density of about 16 pixels/mm2 and pixel diameter of about 250 μm, or with a pixel density of about 25 pixels/mm2 and pixel diameter of about 200 μm, or with a pixel density of about 44 pixels/mm2 and pixel diameter of about 150 μm, or with a pixel density of about 100 pixels/mm2 and pixel diameter of about 100 μm, or with a pixel density of about 178 pixels/mm2 and pixel diameter of about 75 μm, or with a pixel density of about 400 pixels/mm2 and pixel diameter of about 50 μm, or with a pixel density of about 625 pixels/mm2 and pixel diameter of about 40 μm, or with a pixel density of about 1111 pixels/mm2 and pixel diameter of about 30 μm, or with a pixel density of about 1600 pixels/mm2 and pixel diameter of about 25 μm. ### Claim 25 A retinal implant for treating a patient having loss of vision caused by loss of retinal cells, comprising, (i) a retinal implant that when activated by a light source stimulates retinal cells such that the stimulation is provided at a resolution with pixel dimensions less than about 500 μm, or less than about 350 μm, or less than about 250 μm, or less than about 200 μm, or less than about 150 μm, or less than about 100 μm, or less than about 75 μm, or less than about 50 μm, or less than about 40 μm, or less than about 30 μm, or less than about 25 μm, or (ii) a retinal implant for treating a patient having loss of vision caused by loss of retinal cells, comprising, a retinal implant that when activated by a light source stimulates retinal cells such that the stimulation is provided at a resolution limited by (a) the diffraction limit of the light source or (b) when the retinal implant further comprises an ion-permeable substrate, the aperture diameter and density of the ion-permeable substrate, or (iii) a retinal implant for treating a patient having loss of vision caused by loss of retinal cells, comprising, a retinal implant that when activated by a light source stimulates retinal cells such that the stimulation is provided at a resolution with a pixel density of about 4 pixels/mm2 and pixel dimension of about 500 μm, or with a pixel density of about 8 pixels/mm2 and pixel diameter of about 350 μm, or with a pixel density of about 16 pixels/mm2 and pixel diameter of about 250 μm, or with a pixel density of about 25 pixels/mm2 and pixel diameter of about 200 μm, or with a pixel density of about 44 pixels/mm2 and pixel diameter of about 150 μm, or with a pixel density of about 100 pixels/mm2 and pixel diameter of about 100 μm, or with a pixel density of about 178 pixels/mm2 and pixel diameter of about 75 μm, or with a pixel density of about 400 pixels/mm2 and pixel diameter of about 50 μm, or with a pixel density of about 625 pixels/mm2 and pixel diameter of about 40 μm, or with a pixel density of about 1111 pixels/mm2 and pixel diameter of about 30 μm, or with a pixel density of about 1600 pixels/mm2 and pixel diameter of about 25 μm, wherein the implant is a bacteriorhodopsin-based retinal implant that comprises at least one substrate layer and a bacteriorhodopsin film, wherein the bacteriorhodopsin film comprises a plurality of individual layers of a native bacteriorhodopsin or a bacteriorhodopsin mutant, wherein each individual layer of the native bacteriorhodopsin or bacteriorhodopsin mutant alternates with a layer of a cationic polymer, and wherein the bacteriorhodopsin mutant is selected from the group consisting of a chloride pump mutant, a dipole mutant, a photocycle mutant, a gold-binding mutant, an ion pump mutant, a Q-state mutant, and combinations thereof. ### Claim 26 (depends on 25) The retinal implant according to claim 25, wherein the light source is a light source emitting human visible wavelengths, i.e. about 400 to about 700 nm. ### Claim 27 (depends on 26) The retinal implant according to claim 26 wherein the light source is selected from a pulsed light source or a continuous light source. ### Claim 28 (depends on 25) The retinal implant according to claim 25 wherein the light source has an intensity less than about 100 mW/cm2, 50 mW/cm2, 40 mW/cm2, or less than about 30 mW/cm2, or less than about 20 mW/cm2, or less than about 10 mW/cm2, or less than about 5 mW/cm2, or less than about 1 mW/cm2. ### Claim 29 (depends on 25) The retinal implant according to claim 25 wherein the implant is a biocompatible, ion permeable retinal implant. ### Claim 30 (depends on 25) The A retinal implant according to claim 25 wherein the implant is implanted in a position selected from a subretinal position or an epiretinal position. ### Claim 31 (depends on 25) The retinal implant according to claim 25 wherein the retinal cells are selected from retinal ganglion cells, retinal bipolar cells, retinal photoreceptor cells, and combinations thereof. ### Claim 32 (depends on 25) The retinal implant according to claim 25 wherein the retinal implant comprises at least about 100 layers of a native bacteriorhodopsin or a bacteriorhodopsin mutant, or at least about 150 layers of a native bacteriorhodopsin or a bacteriorhodopsin mutant, or at least about 200 layers of a native bacteriorhodopsin or a bacteriorhodopsin mutant. ### Claim 33 (depends on 25) The retinal implant according to claim 25 wherein the retinal implant further provides a temporal resolution of at least about 30 milliseconds. ### Claim 34 (depends on 25) The retinal implant according to claim 25, wherein the retinal implant initiates to the cells an action potential of about 40 μV. ### Claim 35 (depends on 25) The retinal implant according to claim 25 wherein the retinal implant provides a unidirectional proton gradient. ### Claim 36 (depends on 35) The retinal implant according to claim 35 wherein the retinal implant comprises bacteriorhodopsin molecules such that they are uniformly oriented. ### Claim 37 (depends on 25) The retinal implant according to claim 25 wherein the vision loss is caused by loss of retinal photoreceptor cells. ### Claim 38 (depends on 25) The retinal implant according to claim 25 wherein the substrate layer is an ion permeable layer and is on one or both sides of the implant. ### Claim 39 (depends on 38) The retinal implant according to claim 38, wherein the substrate layer is selected from polyethylene terephthalate (PET), 2-hydroxyethyl methacrylate (HEMA), 2-phenylethyl methacrylate (PEM), polyethylene glycol (PEG), methyl methacrylate (MMA), polydimethylsiloxane (PDMS) macromer, poly(vinyl pyrrolidone) (PVP), poly(p-xylylene) (also known as parylene), polyvinyl alcohol (PVA) hydrogel, and combinations thereof. ### Claim 40 The retinal implant according to 38 wherein the substrate layer is less than 100 μm in thickness and contains an evenly distributed array of apertures of a diameter less than about 100 μm. ### Claim 41 (depends on 25) The retinal implant according to claim 25 wherein the retinal implant is based on native bacteriorhodopsin. ### Claim 42 (depends on 25) The retinal implant according to claim 25 wherein the retinal implant is based on a bacteriorhodopsin mutant. ### Claim 43 (depends on 42) The retinal implant according to claim 42 wherein the mutant is a Q-state mutant. ### Claim 44 A retinal implant for treating a patient having loss of vision caused by loss of retinal cells, comprising, a retinal implant that when activated by a light source stimulates retinal cells such that the stimulation is provided at a resolution with pixel dimensions less than about 500 μm, or less than about 350 μm, or less than about 250 μm, or less than about 200 μm, or less than about 150 μm, or less than about 100 μm, or less than about 75 μm, or less than about 50 μm, or less than about 40 μm, or less than about 30 μm, or less than about 25 μm, wherein the implant is a bacteriorhodopsin-based retinal implant that comprises at least one substrate layer and a bacteriorhodopsin film, wherein the bacteriorhodopsin film comprises a plurality of individual layers of a native bacteriorhodopsin or a bacteriorhodopsin mutant, wherein each individual layer of the native bacteriorhodopsin or bacteriorhodopsin mutant alternates with a layer of a cationic polymer, and wherein the bacteriorhodopsin mutant is selected from the group consisting of a chloride pump mutant, a dipole mutant, a photocycle mutant, a gold-binding mutant, an ion pump mutant, a Q-state mutant, and combinations thereof. ### Claim 45 A retinal implant for treating a patient having loss of vision caused by loss of retinal cells, comprising, a retinal implant that when activated by a light source stimulates retinal cells such that the stimulation is provided at a resolution limited by (a) the diffraction limit of the light source or (b) when the retinal implant further comprises an ion-permeable substrate, the aperture diameter and density of the ion-permeable substrate, wherein the implant is a bacteriorhodopsin-based retinal implant that comprises at least one substrate layer and a bacteriorhodopsin film, wherein the bacteriorhodopsin film comprises a plurality of individual layers of a native bacteriorhodopsin or a bacteriorhodopsin mutant, wherein each individual layer of the native bacteriorhodopsin or bacteriorhodopsin mutant alternates with a layer of a cationic polymer, and wherein the bacteriorhodopsin mutant is selected from the group consisting of a chloride pump mutant, a dipole mutant, a photocycle mutant, a gold-binding mutant, an ion pump mutant, a Q-state mutant, and combinations thereof. ### Claim 46 A retinal implant for treating a patient having loss of vision caused by loss of retinal cells, comprising, a retinal implant that when activated by a light source stimulates retinal cells such that the stimulation is provided at a resolution with a pixel density of about 4 pixels/mm2 and pixel dimension of about 500 μm, or with a pixel density of about 8 pixels/mm2 and pixel diameter of about 350 μm, or with a pixel density of about 16 pixels/mm2 and pixel diameter of about 250 μm, or with a pixel density of about 25 pixels/mm2 and pixel diameter of about 200 μm, or with a pixel density of about 44 pixels/mm2 and pixel diameter of about 150 μm, or with a pixel density of about 100 pixels/mm2 and pixel diameter of about 100 μm, or with a pixel density of about 178 pixels/mm2 and pixel diameter of about 75 μm, or with a pixel density of about 400 pixels/mm2 and pixel diameter of about 50 μm, or with a pixel density of about 625 pixels/mm2 and pixel diameter of about 40 μm, or with a pixel density of about 1111 pixels/mm2 and pixel diameter of about 30 μm, or with a pixel density of about 1600 pixels/mm2 and pixel diameter of about 25 μm, wherein the implant is a bacteriorhodopsin-based retinal implant that comprises at least one substrate layer and a bacteriorhodopsin film, wherein the bacteriorhodopsin film comprises a plurality of individual layers of a native bacteriorhodopsin or a bacteriorhodopsin mutant, wherein each individual layer of the native bacteriorhodopsin or bacteriorhodopsin mutant alternates with a layer of a cationic polymer, and wherein the bacteriorhodopsin mutant is selected from the group consisting of a chloride pump mutant, a dipole mutant, a photocycle mutant, a gold-binding mutant, an ion pump mutant, a Q-state mutant, and combinations thereof.