UNITED STATES PATENT AND TRADEMARK OFFICE
`
`APPLICATION
`NUMBER
`61/434,836
`
`FILING or
`37l(c)DATE
`01/21/2011
`
`GRPART
`UNIT
`
`FIL FEE REC'D
`220
`
`26693
`REGENERON PHARMACEUTICALS, INC
`777 OLD SAW MILL RIVER ROAD
`TARRYTOWN, NY 10591
`
`Ul\TfED STATES DEPA RTME'IT OF COMMERCE
`United States Patent and Trademark Office
`Adiliess. COMMISSIO'JER FOR PATENTS
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`\VVi\V.USpto.gov
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`TOT CLAIMS IND CLAIMS
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`CONFIRMATION NO. 3424
`FILING RECEIPT
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`111111111111111111111111]~!1]!~1!~1!~11~~ !1!1~!~1111111111111111111111111
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`Date Mailed: 02/01/2011
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`Receipt is acknowledged of this provisional patent application. It will not be examined for patentability and will
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`Applicant( s)
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`George D. Yancopoulos, Yorktown Heights, NY;
`Power of Attorney:
`Frank Cottingham--50437
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`If Required, Foreign Filing License Granted: 01/28/2011
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`The country code and number of your priority application, to be used for filing abroad under the Paris Convention,
`is US 61 /434,836
`Projected Publication Date: None, application is not eligible for pre-grant publication
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`Early Publication Request: No
`Title
`
`USE OF A VEGF ANTAGONIST TO TREAT ANGIOGENIC EYE DISORDERS
`
`PROTECTING YOUR INVENTION OUTSIDE THE UNITED STATES
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`effect as a regular national patent application in each PCT-member country. The PCT process simplifies the filing
`of patent applications on the same invention in member countries, but does not result in a grant of "an international
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`patent" and does not eliminate the need of applicants to file additional documents and fees in countries where patent
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`Security, Department of Commerce (15 CFR parts 730-774); the Office of Foreign AssetsControl, Department of
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`page 3 of 3
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`USE OF A VEGF ANTAGONIST TO TREAT ANGIOGENIC EYE DISORDERS
`
`FIELD OF THE INVENTION
`
`[0001] The present invention relates to the field of therapeutic treatments of eye disorders. More
`
`specifically, the invention relates to the administration of VEGF antagonists to treat eye disorders
`
`caused by or associated with angiogenesis.
`
`BACKGROUND
`
`[0002] Several eye disorders are associated with pathological angiogenesis. For example, the
`
`development of age-related macular degeneration (AMO) is associated with a process called
`
`choroidal neovascularization (CNV). Leakage from the CNV causes macular edema and collection
`
`of fluid beneath the macula resulting in vision loss. Diabetic macular edema (DME) is another eye
`
`disorder with an angiogenic component. DME is the most prevalent cause of moderate vision loss
`
`in patients with diabetes and is a common complication of diabetic retinopathy, a disease affecting
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`the blood vessels of the retina. Clinically significant DME occurs when fluid leaks into the center of
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`the macula, the light-sensitive part of the retina responsible for sharp, direct vision. Fluid in the
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`macula can cause severe vision loss or blindness. Yet another eye disorder associated with
`
`abnormal angiogenesis is central retinal vein occlusion (CRVO). CRVO is caused by obstruction of
`
`the central retinal vein that leads to a back-up of blood and fluid in the retina. The retina can also
`
`become ischemic, resulting in the growth of new, inappropriate blood vessels that can cause further
`
`vision loss and more serious complications. Release of vascular endothelial growth factor (VEGF)
`
`contributes to increased vascular permeability in the eye and inappropriate new vessel growth.
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`Thus, inhibiting the angiogenic-promoting properties of VEGF appears to be an effective strategy
`
`for treating angiogenic eye disorders.
`
`[0003] Current FDA-approved treatments of angiogenic eye disorders such as AMO and CRVO
`
`include the administration of an anti-VEGF antibody called ranibizumab (Lucentis®, Genentech,
`
`Inc.) on a monthly basis by intravitreal injection.
`
`[0004] Methods for treating eye disorders using VEGF antagonists are mentioned in, e.g., US
`
`7,303,746; US 7,306,799; US 7,300,563; US 7,303,748; and US 2007/0190058. Nonetheless,
`
`there remains a need in the art for new administration regimens for angiogenic eye disorders,
`
`especially those which allow for less frequent dosing while maintaining a high level of efficacy.
`
`BRIEF SUMMARY OF THE INVENTION
`
`[0005] The present invention provides methods for treating angiogenic eye disorders. The
`
`methods of the invention comprise sequentially administering multiple doses of a VEGF antagonist
`
`to a patient over time. In particular, the methods of the invention comprise sequentially
`
`-1-
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`administering to the patient a single initial dose of a VEGF antagonist, followed by one or more
`
`secondary doses of the VEGF antagonist, followed by one or more tertiary doses of the VEGF
`
`antagonists. The present inventors have surprisingly discovered that beneficial therapeutic effects
`
`can be achieved in patients suffering from angiogenic eye disorders by administering a VEGF
`
`antagonist to a patient at a frequency of once every 8 or more weeks, especially when such doses
`
`are preceded by about three doses administered to the patient at a frequency of about 2 to 4
`
`weeks. Thus, according to the methods of the present invention, each secondary dose of VEGF
`
`antagonist is administered 2 to 4 weeks after the immediately preceding dose, and each tertiary
`
`dose is administered at least 8 weeks after the immediately preceding dose. An example of a
`
`dosing regimen of the present invention is shown in Figure 1. One advantage of such a dosing
`
`regimen is that, for most of the course of treatment (i.e., the tertiary doses), it allows for less
`
`frequent dosing (e.g., once every 8 weeks) compared to prior administration regimens for
`
`angiogenic eye disorders which require monthly administrations throughout the entire course of
`
`treatment. (See, e.g., prescribing information for Lucentis® [ranibizumab], Genentech, Inc.).
`
`[0006] The methods of the present invention can be used to treat any angiogenic eye disorder,
`
`including, e.g., age related macular degeneration, diabetic retinopathy, diabetic macular edema,
`
`central retinal vein occlusion, corneal neovascularization, etc.
`
`[0007] The methods of the present invention comprise administering any VEGF antagonist to the
`
`patient. In one embodiment, the VEGF antagonist comprises one or more VEGF receptor-based
`
`chimeric molecule(s), (also referred to herein as a "VEGF-Trap" or "VEGFT"). An exemplary VEGF
`
`antagonist that can be used in the context of the present invention is a multimeric VEGF-binding
`
`protein comprising two or more VEGF receptor-based chimeric molecules referred to herein as
`
`"VEGFR1 R2-Fc~C1 (a)."
`
`[0008] Various administration routes are contemplated for use in the methods of the present
`
`invention, including, e.g., topical administration or intraocular administration (e.g., intravitreal
`
`administration).
`
`[0009] Other embodiments of the present invention will become apparent from a review of the
`
`ensuing detailed description.
`
`BRIEF DESCRIPTION OF THE FIGURE
`
`[001 0] Figure 1 shows an exemplary dosing regimen of the present invention. In this regimen, a
`
`single "initial dose" of VEGF antagonist ("VEG FT") is administered at the beginning of the treatment
`
`regimen (i.e. at "week O"), two "secondary doses" are administered at weeks 4 and 8, respectively,
`and at least six "tertiary doses" are administered once every 8 weeks thereafter, i.e., at weeks 16,
`
`24, 32, 40, 48, 56, etc.).
`
`-2-
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`DETAILED DESCRIPTION
`
`[0011] Before the present invention is described, it is to be understood that this invention is not
`
`limited to particular methods and experimental conditions described, as such methods and
`
`conditions may vary. It is also to be understood that the terminology used herein is for the purpose
`
`of describing particular embodiments only, and is not intended to be limiting, since the scope of the
`
`present invention will be limited only by the appended claims.
`
`[0012] Unless defined otherwise, all technical and scientific terms used herein have the same
`
`meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
`
`As used herein, the term "about," when used in reference to a particular recited numerical value,
`
`means that the value may vary from the recited value by no more than 1 %. For example, as used
`
`herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2,
`
`99.3, 99.4, etc.).
`
`[0013] Although any methods and materials similar or equivalent to those described herein can be
`
`used in the practice or testing of the present invention, the preferred methods and materials are
`
`now described. All publications mentioned herein are incorporated herein by reference to describe
`
`in their entirety.
`
`DOSING REGIMENS
`
`[0014] The present invention provides methods for treating angiogenic eye disorders. The
`
`methods of the invention comprise sequentially administering to a patient multiple doses of a VEGF
`
`antagonist. As used herein, "sequentially administering" means that each dose of VEGF antagonist
`
`is administered to the patient at a different point in time, e.g., on different days separated by a
`
`predetermined interval (e.g., hours, days, weeks or months). The present invention includes
`
`methods which comprise sequentially administering to the patient a single initial dose of a VEGF
`
`antagonist, followed by one or more secondary doses of the VEGF antagonist, followed by one or
`
`more tertiary doses of the VEGF antagonist.
`
`[0015] The terms "initial dose," "secondary doses," and "tertiary doses," refer to the temporal
`
`sequence of administration of the VEGF antagonist. Thus, the "initial dose" is the dose which is
`
`administered at the beginning of the treatment regimen (also referred to as the "baseline dose"); the
`
`"secondary doses" are the doses which are administered after the initial dose; and the "tertiary
`
`doses" are the doses which are administered after the secondary doses. The initial, secondary,
`
`and tertiary doses may all contain the same amount of VEGF antagonist, but will generally differ
`
`from one another in terms of frequency of administration. In certain embodiments, however, the
`
`-3-
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`amount of VEGF antagonist contained in the initial, secondary and/or tertiary doses will vary from
`
`one another (e.g., adjusted up or down as appropriate) during the course of treatment.
`
`[0016]
`
`In one exemplary embodiment of the present invention, each secondary dose is
`
`administered 2 to 4 (e.g., 2, 2½, 3, 3½, or 4) weeks after the immediately preceding dose, and each
`
`tertiary dose is administered at least 8 (e.g., 8, 8½, 9, 9½, 10, 1 0½, 11, 11 ½, 12, 12½, 13, 13½, 14,
`
`14½, or more) weeks after the immediately preceding dose. The phrase "the immediately
`
`preceding dose," as used herein, means, in a sequence of multiple administrations, the dose of
`
`VEGF antagonist which is administered to a patient prior to the administration of the very next dose
`
`in the sequence with no intervening doses.
`
`[0017]
`
`In one exemplary embodiment of the present invention, a single initial dose of a VEGF
`
`antagonist is administered to a patient on the first day of the treatment regimen (i.e., at week 0),
`
`followed by two secondary doses, each administered four weeks after the immediately preceding
`
`dose (i.e., at week 4 and at week 8), followed by at least 5 tertiary doses, each administered eight
`
`weeks after the immediately preceding dose (i.e., at weeks 16, 24, 32, 40 and 48). The tertiary
`
`doses may continue (at intervals of 8 or more weeks) indefinitely during the course of the treatment
`
`regimen. This exemplary administration regimen is depicted graphically in Figure 1.
`
`[0018] The methods of the invention may comprise administering to a patient any number of
`
`secondary and/or tertiary doses of a VEGF antagonist. For example, in certain embodiments, only
`
`a single secondary dose is administered to the patient. In other embodiments, two or more (e.g., 2,
`
`3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient. Likewise, in certain
`
`embodiments, only a single tertiary dose is administered to the patient. In other embodiments, two
`
`or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.
`
`[0019]
`
`In embodiments involving multiple secondary doses, each secondary dose may be
`
`administered at the same frequency as the other secondary doses. For example, each secondary
`
`dose may be administered to the patient 4 weeks after the immediately preceding dose. Similarly,
`
`in embodiments involving multiple tertiary doses, each tertiary dose may be administered at the
`
`same frequency as the other tertiary doses. For example, each tertiary dose may be administered
`
`to the patient 8 weeks after the immediately preceding dose. Alternatively, the frequency at which
`
`the secondary and/or tertiary doses are administered to a patient can vary over the course of the
`
`treatment regimen. For example, the present invention includes methods which comprise
`
`administering to the patient a single initial dose of a VEGF antagonist, followed by one or more
`
`secondary doses of the VEGF antagonist, followed by at least 5 tertiary doses of the VEGF
`
`antagonist, wherein the first four tertiary doses are administered 8 weeks after the immediately
`
`preceding dose, and wherein each subsequent tertiary dose is administered from 8 to 12 (e.g., 8,
`
`8½, 9, 9½, 10, 1 0½, 11, 11 ½, 12) weeks after the immediately preceding dose. The frequency of
`
`-4-
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`administration may also be adjusted during the course of treatment by a physician depending on
`
`the needs of the individual patient following clinical examination.
`
`VEGF ANTAGONISTS
`
`[0020] The methods of the present invention comprise administering to a patient a VEGF
`
`antagonist according to specified dosing regimens. As used herein, the expression "VEGF
`
`antagonist" means any molecule that blocks, reduces or interferes with the normal biological activity
`
`of VEGF.
`
`[0021] VEGF antagonists include molecules which interfere with the interaction between VEGF
`
`and a natural VEGF receptor, e.g., molecules which bind to VEGF or a VEGF receptor and prevent
`
`or otherwise hinder the interaction between VEGF and a VEGF receptor. Specific exemplary VEGF
`
`antagonists include anti-VEGF antibodies, anti-VEGF receptor antibodies, and VEGF receptor(cid:173)
`
`based chimeric molecules (also referred to herein as "VEGF-Traps").
`
`[0022] VEGF receptor-based chimeric molecules include chimeric polypeptides which comprise
`
`two or more immunoglobulin (lg)-like domains of a VEGF receptor such as VEGFR1 (also referred
`
`to as Flt1) and/or VEGFR2 (also referred to as Flk1 or KOR), and may also contain a multimerizing
`
`domain (e.g., an Fe domain which facilitates the multimerization [e.g., dimerization] of two or more
`
`chimeric polypeptides). An exemplary VEGF receptor-based chimeric molecule is a molecule
`
`referred to as VEGFR1 R2-Fc~C1 (a) which is encoded by the nucleic acid sequence of SEQ ID
`
`N0:1. VEGFR1R2-Fc~C1(a) comprises three components: (1) a VEGFR1 component comprising
`
`amino acids 27 to 129 of SEQ ID N0:2; (2) a VEGFR2 component comprising amino acids 130 to
`
`231 of SEQ ID N0:2; and (3) a multimerization component ("Fc~C1 (a)") comprising amino acids
`
`232 to 457 of SEQ ID N0:2 (the C-terminal amino acid of SEQ ID N0:2 [i.e., K458] may or may not
`
`be included in the VEGF antagonist used in the methods of the invention; see e.g., US Patent
`
`7,396,664). Amino acids 1-26 of SEQ ID N0:2 are the signal sequence.
`
`[0023] The VEGF antagonist used in the Examples set forth herein below is a dimeric molecule
`
`comprising two VEGFR1 R2-Fc~C1 (a) molecules and is referred to herein as "VEGFT." Additional
`
`VEGF receptor-based chimeric molecules which can be used in the context of the present invention
`
`are disclosed in US 7,396,664, 7,303,746 and WO 00/75319.
`
`ANGIOGENIC EYE DISORDERS
`
`[0024)
`
`The methods of the present invention can be used to treat any angiogenic eye disorder.
`
`The expression "angiogenic eye disorder," as used herein, means any disease of the eye which is
`
`caused by or associated with the growth or proliferation of blood vessels or by blood vessel
`
`leakage. Non-limiting examples of angiogenic eye disorders that are treatable using the methods of
`
`-5-
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`the present invention include choroidal neovascularization, age-related macular degeneration
`
`(AMO), diabetic retinopathies, diabetic macular edema (DME), central retinal vein occlusion
`
`(CRVO), corneal neovascularization, and retinal neovascularization.
`
`PHARMACEUTICAL FORMULATIONS
`
`[0025] The present invention includes methods in which the VEGF antagonist that is administered
`
`to the patient is contained within a pharmaceutical formulation. The pharmaceutical formulation
`may comprise the VEGF antagonist along with at least one inactive ingredient such as, e.g., a
`
`pharmaceutically acceptable carrier. Other agents may be incorporated into the pharmaceutical
`
`composition to provide improved transfer, delivery, tolerance, and the like. The term
`
`"pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state
`
`government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use
`
`in animals, and more particularly, in humans. The term "carrier" refers to a diluent, adjuvant,
`
`excipient, or vehicle with which the antibody is administered. A multitude of appropriate
`
`formulations can be found in the formulary known to all pharmaceutical chemists: Remington's
`
`Pharmaceutical Sciences (15th ed, Mack Publishing Company, Easton, Pa., 1975), particularly
`
`Chapter 87 by Blaug, Seymour, therein. These formulations include, for example, powders, pastes,
`
`ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as
`
`LIPOFECTIN™), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil
`
`emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid
`
`gels, and semi-solid mixtures containing carbowax. Any of the foregoing mixtures may be
`
`appropriate in the context of the methods of the present invention, provided that the VEGF
`
`antagonist is not inactivated by the formulation and the formulation is physiologically compatible
`
`and tolerable with the route of administration. See also Powell et al. PDA (1998) J Pharm Sci
`
`Technol. 52:238-311 and the citations therein for additional information related to excipients and
`
`carriers well known to pharmaceutical chemists.
`
`[0026] Pharmaceutical formulations useful for administration by injection in the context of the
`
`present invention may be prepared by dissolving, suspending or emulsifying a VEGF antagonist in
`
`a sterile aqueous medium or an oily medium conventionally used for injections. As the aqueous
`
`medium for injections, there are, for example, physiological saline, an isotonic solution containing
`
`glucose and other auxiliary agents, etc., which may be used in combination with an appropriate
`
`solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol,
`
`polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol)
`
`adduct of hydrogenated castor oil)], etc. As the oily medium, there may be employed, e.g., sesame
`
`oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl
`
`-6-
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`benzoate, benzyl alcohol, etc. The injection thus prepared can be filled in an appropriate ampoule if
`
`desired.
`
`MODES OF ADMINISTRATION
`
`[0027) The VEGF antagonist (or pharmaceutical formulation comprising the VEGF antagonist)
`
`may be administered to the patient by any known delivery system and/or administration method. In
`
`certain embodiments, the VEGF antagonist is administered to the patient by ocular, intraocular,
`
`intravitreal or subconjunctival injection. In other embodiments, the VEGF antagonist can be
`
`administered to the patient by topical administration, e.g., via eye drops or other liquid, gel, ointment
`
`or fluid which contains the VEGF antagonist and can be applied directly to the eye. Other possible
`
`routes of administration include, e.g., intradermal, intramuscular, intraperitoneal, intravenous,
`
`subcutaneous, intranasal, epidural, and oral.
`
`AMOUNT OF VEGF ANTAGONIST ADMINISTERED
`
`[0028] Each dose of VEGF antagonist administered to the patient over the course of the treatment
`
`regimen may contain the same, or substantially the same, amount of VEGF antagonist.
`
`Alternatively, the quantity of VEGF antagonist contained within the individual doses may vary over
`
`the course of the treatment regimen. For example, in certain embodiments, a first quantity of VEGF
`
`antagonist is administered in the initial dose, a second quantity of VEGF antagonist is administered
`
`in the secondary doses, and a third quantity of VEGF antagonist is administered in the tertiary
`
`doses. The present invention contemplates dosing schemes in which the quantity of VEGF
`
`antagonist contained within the individual doses increases over time (e.g., each subsequent dose
`
`contains more VEGF antagonist than the last), decreases over time (e.g., each subsequent dose
`
`contains less VEGF antagonist than the last), initially increases then decreases, initially decreases
`
`then increases, or remains the same throughout the course of the administration regimen.
`
`[0029] The amount of VEGF antagonist administered to the patient in each dose is, in most
`
`cases, a therapeutically effective amount. As used herein, the phrase "therapeutically effective
`
`amount" means a dose of VEGF antagonist that results in a detectable improvement in one or more
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`symptoms or indicia of an angiogenic eye disorder, or a dose of VEGF antagonist that inhibits,
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`prevents, lessens, or delays the progression of an angiogenic eye disorder. In the case of an anti(cid:173)
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`VEGF antibody or a VEGF receptor-based chimeric molecule such as VEGFR1 R2-Fc6.C1 (a), a
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`therapeutically effective amount can be from about 0.05 mg to about 5 mg, e.g., about 0.05 mg,
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`about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about
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`0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg,
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`about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 1.0 mg, about 1.05 mg, about
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`-7-
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`Regeneron Pharmaceuticals, Inc. Exhibit 2025 Page 10
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`1.1 mg, about 1.15 mg, about 1.2 mg, about 1.25 mg, about 1.3 mg, about 1.35 mg, about 1.4 mg,
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`about 1.45 mg, about 1.5 mg, about 1.55 mg, about 1.6 mg, about 1.65 mg, about 1.7 mg, about
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`1.75 mg, about 1.8 mg, about 1.85 mg, about 1.9 mg, about 2.0 mg, about 2.05 mg, about 2.1 mg,
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`about 2.15 mg, about 2.2 mg, about 2.25 mg, about 2.3 mg, about 2.35 mg, about 2.4 mg, about
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`2.45 mg, about 2.5 mg, about 2.55 mg, about 2.6 mg, about 2.65 mg, about 2.7 mg, about 2.75 mg,
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`about 2.8 mg, about 2.85 mg, about 2.9 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5
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`mg, or about 5.0 mg of the antibody or receptor-based chimeric molecule.
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`[0030] The amount of VEGF antagonist contained within the individual doses may be expressed
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`in terms of milligrams of antibody per kilogram of patient body weight (i.e., mg/kg). For example,
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`the VEGF antagonist may be administered to a patient at a dose of about 0.0001 to about 10 mg/kg
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`of patient body weight.
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`TREATMENT POPULATION AND EFFICACY
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`[0031] The methods of the present invention are useful for treating angiogenic eye disorders in
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`patients that have been diagnosed with or are at risk of being afflicted with an angiogenic eye
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`disorder. Generally, the methods of the present invention demonstrate efficacy within 104 weeks of
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`the initiation of the treatment regimen (with the initial dose administered at "week O"), e.g., by the
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`end of week 16, by the end of week 24, by the end of week 32, by the end of week 40, by the end of
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`week 48, by the end of week 56, etc. In the context of methods for treating angiogenic eye
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`disorders such as AMO, CRVO, and DME, "efficacy" means that, from the initiation of treatment, the
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`patient exhibits a loss of 15 or fewer letters on the Early Treatment Diabetic Retinopathy Study
`
`(ETDRS) visual acuity chart. In certain embodiments, "efficacy" means a gain of one or more (e.g.,
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`1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or more) letters on the ETDRS chart from the time of initiation of
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`treatment.
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`EXAMPLES
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`[0032] The following examples are put forth so as to provide those of ordinary skill in the art with a
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`complete disclosure and description of how to make and use the methods and compositions of the
`
`invention, and are not intended to limit the scope of what the inventors regard as their invention.
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`Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts,
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`temperature, etc.) but some experimental errors and deviations should be accounted for. Unless
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`indicated otherwise, parts are parts by weight, molecular weight is average molecular weight,
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`temperature is in degrees Centigrade, and pressure is at or near atmospheric.
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`[0033] The exemplary VEGF antagonist used in all Examples set forth below is a dimeric
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`molecule having two functional VEGF binding units. Each functional binding unit is comprised of lg
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`-8-
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`Regeneron Pharmaceuticals, Inc. Exhibit 2025 Page 11
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`domain 2 from VEGFR1 fused to lg domain 3 from VEGFR2, which in turn is fused to the hinge
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`region of a human lgG1 Fe domain (VEGFR1R2-FcLiC1(a); enco