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`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
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`(19) World Intellectual Property
`QUANTTAU ATAAA
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`Orvanization
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`International Bureau.
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`(10) International Publication Number
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`(43) International Publication Date
`WO 2012/097019 Al
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`19 July 2012 (19.07.2012)
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`International Patent Classification:
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`AGIP 27/400 (2006.01)
`AGI 38/78 (2006.015
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`International Application Number:
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`21
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`PCT/US20 12020855
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`UG, 42M, ZW), Burasian (AM, AZ, BY, Kar, RZ, MD, RU,
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`TJ, TM), Purepean (AL, AT, BE, Bor, CH, CY, CZ, DE,
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`OR, ERIS, FE PR, GB, GR, EDR, EIU, IE IS. IT, LT, LU,
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`SM, TR), OAPT (BE, BJ, CF, CG, CT, OM, GA, GN, GQ,
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`GW, ML, MR, NI SN, TD, TG).
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`Published:
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`English
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`English
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`11 January 2012 (11.00.2012)
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`(71)
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`Priority Data:
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`61437245
`61/434,836
`6I/S61957
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`US
`13 January 2011 (13.01.2011)
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`US
`21 January 2011 (21.01.2011)
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`Us
`21 November 20) 1 (21.11.2011)
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`Applicant ¢for afi designated States except US): REGEN-
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`ERON PHARMACEUTICALS, INC. [US/US |, 777 Old
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`Saw Mill River Road, Tarytown, NY 10541 (US).
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`Inventor; and
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`Inventor/Applicant
`‘fur US oni: YANCOPOULOS,
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`George D. |US/US |; 1519 Baptst Church Road, Yorktown
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`Heights, NY 10598 (US).
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`Agent): COTTINGHAM, Frank; Regeneron Phannaceut-
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`jeals, Inc. 777 Old Saw Mill River Road, Tarrylown, NY
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`10591 (US).
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`Designated States fiarless vtenvise trndicated, far every
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`kind of national protection availablesy, AL, AG, AL, AM,
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`with international search report (rt. 2ht3y)
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`before the expiration ofthe time fimit far cmeneing the
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`cloims aad to be republished tt the event of receipt of
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`amendments (Rude 48. 2th)
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`with sequencefisting part ofdescription (Rate 3. 2faj)
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`(34) Title: UST: OF A VIGGEF ANTAGONIST TO TREAT ANGIOGLNIC EYE DISORDERS
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`(37) Abstract: The present invention provides methods for trealing angiogenic eye disorders by sequentially administering multiple
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`doses ofa VEGF antagonist to a patient. The methods of the present Invention include the administration of mulliple doses of a
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`VEGFanlagonist toa patient ata trequeney of once every 8 or more weeks. The methods ofthe present invention ate useful for the
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`treatinent of angiogenic cye diserders such as age related macular degeneration, diabetic retinopathy, diabetic macular edema, central
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`relinal vein ecclusion and comeal neovascularization.
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`CELLTRION- EXHIBIT 1062
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`wo2012/097019AX[IMBINIUMTIATATMATREYA
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`CELLTRION - EXHIBIT 1062
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`WO 2012/097019
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`USE OF A VEGF ANTAGONIST TO TREAT ANGIOGENIC EYE DISORDERS
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`PCT/US2012/020855
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`FIELD OF THE INVENTION
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`foogi] The oresent invention relates to the field of therapautic treatments of eye disorders.
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`More specifically, the invention relates to the administration of VEGF aniagonisis fo treat eye
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`disorders caused by or associated with angiogenesis.
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`BACKGROUND
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`BRIEF SUMMARY OF THE INVENTION
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`The oresent invention provides methodsfer treating angiogenic eye disorders. The
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`methods of the Invention cornprise sequentially administering multiple doses of a VEGF
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`antagonist to a patient over time.
`In particular, the methods of {he Invention comprise
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`sequentially administering to the patient a singie initial dose of a VEGFantagonist, followed by
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`~4-
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`Several eye disorders are associated with pathological angiogenesis. For example,
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`the development of age-related macular degeneration (AMD) is associated with a process
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`calied choroidal neovascularization (CNV). Leakage from the CNV causes macular edema and
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`collection of fluid beneath the macula resuiting in vision loss. Diabetic macular edema (DME) is
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`another eye disorder with an angiogenic component. DME is the most prevalent cause of
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`moderate vision loss in patients with diabetes and is a common complication of diabetic
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`retinopathy, a disease affecting the blood vessels of the retina. Clinically significant DME
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`occurs when fluid leaks into the center of the macula, the light-sensitive part of the retina
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`responsibie for sharp, direct vision. Fluid in the macuia can cause severe vision loss or
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`blindness. Yet another eye disorder associaied with abnormal angiogenesis is central retinal
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`vein occlusion (CRVO}. CRVO is caused by obstructicn of the central retinal vein that leads ic
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`a back-up of blood and fluid in the retina. The retina can also become ischemic, resuilling in the
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`growth of new, inappropriate blood vesseis that can cause further vision loss and more serious
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`complications. Release of vascular endothelial growth factor (VEGF) contributes to increased
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`vascular permeability in the eye and inappropriate new vessel growth. Thus, inhibiting the
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`angiogenic-promoting properties of VEGF appears to be an effective strategyfor treating
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`angiogenic eye disorders.
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`FDA-approved treatments of angiogenic eye disorders such as AMD and CRVO
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`include the administration of an anti-VEGF antibody calied ranibizumab (Lucentis®, Genentech,
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`inc.) on a monthly basis by intravitreal injection.
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`jage4]
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`7,303,746; US 7,306,799, US 7,300,863; US 7,303,748: and US 2007/0190058, Nonetheless,
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`there remains a need in the art for new administration regimens for angiogenic eye disorders,
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`especially those which allow for less frequent dosing while maintaining a high level of efficacy.
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`WO 2012/097019
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`one or mere secondary doses of the VEGF antagonist, followed by one or moretertiary doses of
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`the VEGF antagonists. The present inventors have surprisingly discovered that beneficial
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`therapeutic effects can be achieved in patients suffering from angiogenic eye disorders by
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`administering a VEGF artagonisi to a patient at a frequency of once every 8 or more weeks,
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`especially when such doses are preceded by aboul three doses administered fo the patient af a
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`frequency of about 2 to 4 weeks. Thus, according ic the mefhads of the present invention, each
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`secondary dose of VEGF antagonist is adrninistered 2 to 4 weeks after the immediately
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`preceding dose, and each tertiary dose is administered at least 8 weeks after the immediately
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`preceding dose. An example of a dosing regimen of the present inveniton is shown in Figure 1.
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`One advantage of such a dosing regimen is that, for most of the course of ireaiment (Ae., the
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`tertiary doses), il allows for less frequent dosing (e.g., ance every 8 weeks} compared to prior
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`administration regimens for angiogenic eye disorders which require monthly administrations
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`throughout the entire course of treatment. (See, e.g., prescribing information for Lucentisd>
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`franibizurmab}, Genentech, inc.).
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`The methods of the present invention can be used to treat any angiogenic eye
`9006}
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`gisorder, inciuding, @.g., age related macular degeneration, diabetic retinopathy, diabetic
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`macular edema, central retinal vein occlusion, comeai neovascularization, etc.
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`The methods of the present invention comprise administering any VEGF antagonist to
`fs007]
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`In one embadiment, ihe VEGF antagonist comprises one or more VEGF receptor
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`based chimeric rnolecule(s), (alsa referred to herein as a “VEOF-Trap” or "VEGFT"} An
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`exemplary VEGF antagonist that can be used in the contexi of the present invention is a
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`multimeric VEGF-Dinding protein comprising iwo or more VEGF receptor-based chimeric
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`molecules referred to herein as "VEGFRtiR2-FcAC ila} or "atitbercept.”
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`fo008}] Various administration rovtes are contemplated for use in the methods of the prasent
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`invention, including, é.g¢., topical administration or iniraocular administration (e.g¢.. intravitreai
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`administration}.
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`foooe}6Afflbercept (EYLEA™, Regeneron Pharmaceuticals, inc} was approved by the FDA in
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`November 2011, for the treatment of patients with neovascular (wel) age-related macular
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`degeneration, with a recommended dose of 2 mg administered by intravitreal injection avery 4
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`weeks for the first three months, followed by 2 mg administered by intravitreal injection once
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`every & weeks.
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`ther embodiments of the present invention will become apparent from a review of the
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`ansuing detated description.
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`{0021}
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`SRIEF DESCRIPTION OF THE FIGURE
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`In this regimen,
`Figure4 shows an exemplary dosing regimen of the present invention.
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`a single “initial dose” of VEGF antagonist (VEGFT") is administered at the beginning of the
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`treatment regimen (Le. atweek O°}, fwo "secondary doses" are administered at weeks 4 and 8,
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`WO 2012/097019
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`respectively, and al least six “tertiary doses” are administered once every 8 weeks thereafier,
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`ia, alweeks 16, 274, 32, 40, 48, 56, eic.).
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`PCT/US2012/020855
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`BETAILED DESCRIPTION
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`Invention is described, it is to be understood that this invention is
`[6012] Before the present
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`not lirnited to particular methods and experimental conditions described, as such methods and
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`conditions may vary.
`itis also to be understood that the terminaiogyused herein is for the
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`purpose of describing paricular embodiments only, and is net intended to be Hmiting, since the
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`scope of the present invention wil be limited only by the appended claims.
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`0013] Unless defined otherwise, all technical and scientific terms used herein have the same
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`meaning as commoniy understood by one of ordinary skil in the art to which this invention
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`belongs. As used herein, the term “about,” when used in reference to a particular recited
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`numerical value, means that the value may vary frora the recited value by no more than 1%,
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`For example, as used herein, the expression “about 100” inchides 99 and 107 and all values in
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`between (e.g, 90.1, 99.2, 99.3, 99.4, atc}
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`fogie4l Although any methods and materials similar or equivalent fo those described herein
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`can be used in the practice cr testing of the present invention, the preferred methods and
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`materials are naw described.
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`DOSING REGIMENS
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`fo025} The present invention provides methods fortreating angiogenic eye disorders. The
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`methods of the invention comprise sequentially administering to a patient multiple doses of a
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`VEGFantagonist. As used hereiri, “sequentially administering" means that each dose of VEGF
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`antagonist is adrninistered to the catienf at a different pointin time, e.g., on different days
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`separated by a predeterminedinterval {e.g., hours, days, weeks or months}. The presenti
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`invention includes methods which comprise sequentially administering to the patient a single
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`intial dase of a VEGF antagonist, followed by one or more secondary doses of the VEGF
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`antagonist, followed by one or more tertiary doses of the VEGF antagonist,
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`The terms “initial dose," “secondary doses,” and “tertiary doses,” refer io the temporai
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`sequence of administration of the VEGF antagonist. Thus, the “iiitial dose" is ine dose which is
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`administered at the beginning of the treatment regimen(also referred to as the "baseline dose");
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`the “secondary doses" are the doses which are administered after the initial dasa; and the
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`“tertiary deses” are the doses which are administered aller the secondary doses. The initial,
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`secondary, and tertiary doses may all contain the same amount of VEGF antagonist, but will
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`in certain
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`embodirnents, however, the amount of VEGF antagonist contained in the initial, secondary
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`and/or tertiary doses wil vary from one another (e.g., adjusted up ar down as appropriate)
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`during the course of treatment.
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`f0016]
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`WO 2012/097019
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`PCT/US2012/020855
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`in one exemplary embodiment of the present invention, each secondary doseis
`[e017}
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`adminisierad 2 to 4 {e.g 2, 24, 3, Y4, or 4) weeks afer the immediately preceding dose, and
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`each tertiary dose is administered at least 8 fe.g., 8, 874, 8, 9%4, 10, 10%, 14, 11%, 12, 12%, 43,
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`13%, 14, 144, or more) weeks after the immediately preceding dose. The phrase “the
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`immediately preceding dose," as used herein, means, in a sequence of multiple administrations,
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`the dose of VEGF antagonist which is administered fo a patient prior to the administration of the
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`very next dese in the sequence with no intervening doses.
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`{6018]
`in one exemplary embodiment of the present invention, a single initial dase of a VEGF
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`antagonist is administered to a patient on the first day of the treatment regimen{.¢., al week 0},
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`followed by two secondary doses, each administered four weeks after the immediately
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`preceding dose (,¢., at week 4 and at week 8), followed by ai least 5 tertiary doses, each
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`administered eight weeks after the immediately preceding dose {1e., ai weeks 16, 24, 32, 40
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`and 48}. Thetertlary doses may continue (at intervals of 8 or more weeks}indefinitely during
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`ihe course of the treatment regimen. This exemplary administration regimenis depicted
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`graphically in Figure 4.
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`The methods of the invention may comprise administering to a patent any number of
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`secondary and/or tertlary doses of a VEGF aniagonist. For exampie, in certain embacimenis,
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`only a single secondary dose is administered to the patient.
`in other embodirnents, two or rnore
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`(e.g., 2, 3, 4, 5, 8, 7, 8, or more) secondary doses are administered io the patient. Likewise, in
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`certain embodiments, only a single terlary cose is adrnirustered to the patient.
`In other
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`ambodirnents, two or more (e.g, 2,3, 4, 5, 6, 7, 8, ar mare} teriary doses are administered to
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`jG029}
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`the patient.
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`in embodiments involving muilipie secondary doses, each secondary dase may be
`i96206)
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`administered at the sarne frequency as the olher secondary doses. For example, each
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`secondary dose may be administered to the patient 4 weeks after the immedialely preceding
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`dose. Similarly, in erbodiments inveiving mulliple tertiary doses, each tertiary dose may he
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`administered al the same frequency as ihe other tertiary doses. For example, each tertiary
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`dose may be administered to the patient 8 weeks after the immediately preceding dose.
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`Alternatively, the frequency at which the secondary and/ortertiary doses are administered to a
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`patient can vary over the course of the treatment regimen. Far example, the present invention
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`includes methods which comprise administering to the patient a single iniial dose of a VEGF
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`antagonist, followed by one or more secondary doses of the VEGF antagonist, followed by at
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`least 5 tertiary doses of the VEGF antagonist, wherein the first four tertiary doses are
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`administered 8 weeks afler the immediately preceding dose, and wherein each subsequent
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`tertiary dose is administered from 8 to 12 (e.g., 8, 8%, 9, 94, 10, 1044, 11, 11%, 42) weeke after
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`the immediately preceding dose. The frequency of administration may aiso be adjusted during
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`the course of treatment by a physician depending on the neads of the individual patient
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`following clinical examination.
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`ade
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`WO 2012/097019
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`PCT/US20 12020835
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`VEGF ANTAGONISTS
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`The methods of the present invenhon comprise administering to 4 patient a VEGF
`{0022}
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`antagonist according to specified dosing regimens. As used herein, the expression “VEGF
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`antagonist” means any rnolecule that blocks, reduces or interferes with the narmal biolagical
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`activity of VEGF.
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`{0022} VEGF antagonists include molecules which interfere with ihe inieraction between
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`VEGF and a natural VEGF receptor, e.g., molecules which bind to VEGF or a VEGF receptor
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`and prevent or ctherwise hinder ine interaction between VEGF and a VEGF receptor. Specific
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`exemplary VEGF antagonists include anti-VEGF antibodies, antl-VEGF receptor antibodies, and
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`VEGF receptor-based chimeric molecules (also referred to herein as “VEGF-Traps"}.
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`{0025} VEGF recepter-based chirneric molecules inciude chimeric polypeptides which
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`comprise two or more immunogiobulln (Ig)-like domains of a VEGF receptor such as VEGFR?
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`falso referred to as Fit?) and/or VEGFRe {also referred io as Fiki or KDR), and may also
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`contain a multimerizing domain (e.g., an Fe domain which facilitates the multimerization fe.g.,
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`dimerization! of iwo or more chimeric polypeptides}. An exemplary VEGF receptor-based
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`chimeric molecule is a molecule referred fo as VEGFRIR2-FcAC ia} which is enceded by ihe
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`nucleic acid sequence of SEQ ID NOct. VEGFRIR2-FeAC1(a) comprises three components:
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`(4) a VEGFR1 component comprising amino acids 27 io 129 of SEQ ID NO:2: (2) a VEGFR2
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`component comprising amino acids 130 to 241 of SEQ iD NO-2: and (3) a multimerization
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`component ('FcAC 1(a}"} comprising amino acids 232 to 467 of SEQ iD NO:2 (the C-terminal
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`amino acid of SEQ iD NO:2 [Le., K458] may or may not be included in the VEGF antagonist
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`used in the methods of ihe invention: see e.g., LIS Patent 7,396,664), Amino acids 1-26 of SEQ
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`i NO:2 are the signal sequence.
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`jo024]
`The VEGF antagonis! used in the Examples set forth herein belowis a dimeric
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`molecule comprising fwo VEGFRIR2-FcAC 1 {a} raoiecules and is referred to herein as
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`“VEGFT.” Additional VEGF receptor-based chimeric molecules which can be used in the
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`context of the creseni invention are disclosed in US 7,396,664, 7,303,746 and WO 00/75319,
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`{0025}
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`ANGHIGENIC EYE DISORDERS
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`The methods of the present invention can be used fo treal any angiogenic eye
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`disorder. The exprassion "angiogenic eye disorder,” as used herein, means anydisease of the
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`eye which is caused by or associates with the growth or prailferation of blood vesseis or by
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`blood vessel leakage. Non-limifing examples of angiogenic eye disorders that are treatabie
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`using fhe methods of the present invention include choroidal! neovascularization, age-related
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`macular degeneration (AMD), diabetic retincpathies, diabetic macular edema (OME), certral
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`retinal vein occlusion (CRVO}, corneal neovascuiarization, and retinal neovascuiarization.
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`a
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`

`WO 2012/097019
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`PHARMACEUTICAL FORMULATIONS
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`The present invention includes methods in which the VEGF antagonist thatis
`i026]
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`administered to the patient is cantained within a pharmaceutical formulation. The
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`pharmaceutical formulation may comprise the VEGF antagonist along with at ieast one inactive
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`ingredient such as, ¢.g., a pharmaceutically acceptable carrier, Other agents may be
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`incorporated into the pharmaceutical composition to provide improved transfer, delivery,
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`folerance, anc the like. The term "pharmaceutically acceptable” means approved by a
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`regulatory agency of fhe Federal or a state government or jisted in the U.S. Pharmacapeia or
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`other generally recognized pharmacopeia for use in animals, and more particularly, in humans.
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`The tearm “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the antibody is
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`administered. A multitude of appropriate formulations can be found in the formulary known to
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`all pharmaceutical chemists: Remington's Pharmaceutical Sciences (15th ed, Mack Publishing
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`Company, Easton, Pa., 1975), particularly Chapter 87 by Blaug, Seymour, therein. These
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`formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid
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`{cationic or anionic} comtairuing vesicles (such as LIPOFECTIN™}. DNA conjugates, anhydrous
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`absorption pastes, of-in-waier and water-in-oil emulsions, emulsions carbowax (polyethylene
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`gfycois of various molecular weights), semi-solid geis, and semi-solid mixtures containing
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`carbowax, Any of the foregoing mixtures may be appropriate in the context of the methods of
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`the present invertion, provided that ne VEGF antagonis! is not inactivated by the formulation
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`and the formulation is physiologically compatible and tolerable with ine route of administration.
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`See also Powell et al. PDA (1998) J Pharm Sci Technol. 52:238-311 and the citations therein
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`for additional information related to excipients and carriers well known to pharmaceutical
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`chemists,
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`Pharmaceutical formulations useful for administration by injection in the contex! of the
`10027]
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`present invention ray be orepared by dissolving, suspending or emuisifying a VEGF antagonist
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`in a sterile aqueous medium or an oily medium conventionally used for injections. As the
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`aqueous medium for injections, there are, for example, ohysiologicai saline, an isotonic solution
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`conlaining giucose and other auxiliary agents, etc., which may be used in combination with an
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`appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene
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`giycoi, polyethylene glycol}, a nonionic surfactant [e.g., polysorbate 80, HCO-50
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`{polyoxyethylene (50 mol} adduct of hydrogenated castorofl)f, etc. As the cily medium, there
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`may be employed, e.g., sesame off, soybean oll, eic., whicn may be used in combination with a
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`solubilizing adeni such as benzyl senzoate, berzy!l aicohal, etc. The injection thus prepared
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`can be filled in an appropriate ampoule if desired.
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`MODES OF ADMINISTRATION
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`10028] The VEGF antagonist (or pharmaceutical formulation comprising the VEGF antagonist)
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`may be administered to the patient by any known delivery system and/or adrrsnistration method.
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`6.
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`WO 2012/097019
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`incerlain embodiments, the VEGFantagonist is administered to the patient by ocular,
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`intraocular, intravitreal or subconjunctival injection.
`In other embociments, the VEGF antagonisi
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`can be administered to the patient by topical administration, e.g., via eye drops or other liquid,
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`ge!, ointment or fluid which contains the VEGF antagonist and can be applied directlyto the
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`eye. Other possible routes of administration include, e.g., intradermal, intramuscutar,
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`infraperitorieal, intravenous, subcutaneous, intranasal, epidural, and oral.
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`PCT/US2012/020855
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`fog29]
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`AMOUNT OF VEGF ANTAGONIST ADMINISTERED
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`Each dose of VEGF antagonist administered to the patient over the course of the
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`treatment regimen may conlain the same, or substantially the same, amount of VEGF
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`aniagonisi. Alternatively, ihe quantify of VEGF antegonisi contained within the individual doses
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`may vary over the course of the treatmert regimen. For example, in certain embodiments, a
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`first quantity of VEGF antagonist is administered in the initial dose, a second quantity of VEGF
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`antagonist is administered in the secondary doses, and a third quantity of VEGF antagonistis
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`administered in the tertiary doses. The present invention contemplates dosing schemes in
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`which the quanlily of VEGF antagonist contained within ihe individual doses increases over time
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`{e.g., each subsequenl dose contains more VEGF antagonist than the last), decreases over
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`time (e.g, each subsequent dose contains lese VEGF antagonist than the jasi), initially
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`increases then decreases, initially decreases then increases, or remains the samethroughout
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`the course of the administration regimen.
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`foo30) The amourt of VEGF antagonist administered to fhe patient in each dose is, in most
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`cases, a therapeutically effective amount. As used herein, the phrase “therapeutically effective
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`amount’ means a dose of VEGF anlaganist that results in a detectable improvement in one or
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`more sympicme or indicia of an angiagenic eye disorder, or a dose of VEGF antagonist that
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`inhibiis, prevenis, lessens, or delays ihe progression of an angiogenic eye disorder.
`In the case
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`ofan ant-VEGF antibody or a VEGF receptor-based chimeric molecule such as VEGFRIR2-
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`FeAC (a), a therapeutically effective arnount can be from about 0.08 mg to abouf 5 mg, e.g.,
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`about 0.05 mg, aboul 0.7 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 6.3 mg,
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`about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.56 mg, about 0.6 mg,
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`about 0.65 mg, about 0.7 mg, about 0.75 mg, about 6.8 mg, about 0.86 mg, about 0.9 mg,
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`about 1.0 mg, about 1.05 mg, about 1.1 mg, about 1.15 mg, about 1.2 mg, about 1.25 mg,
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`about 1.3 mg, about 1.35 mg, about 1.4 mg, about 1.45 mg, about 1.5 mg, about 7.55 rng,
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`about 1.8 mg, about 1.95 mg, about 1.7 mg, about 1.75 mg, about 1.8 mg, about 7.85 mg,
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`about 1.9 mg, about 2.0 mg, about 2.05 mg, about 2.1 mg, about 2.45 mg, about 2.2 mg, aboul
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`2.25 mg, aboul 2.3 mg, about 2.35 mg, about 2.4 mg, about 2.45 mg, about 2.5 mg, about 2.55
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`mg, about 2.6 mg, aboul 2.65 mg, about 2.7 mg, about 2.75 ma, about 2.6 mq. about 2.85 mg,
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`about 2.9 mg, about 3.0 mg, aboul 3.5 ma, about 4.0 mg, about 4.6 mg, or about 5.0 mg ofthe
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`antibody or receptor-based chimeric molecule.
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`WO 2012/097019
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`{0033}
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`PCT/US2012/020855
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`The amount of VEGF antagonist contained within the individual doses maybe
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`expressed in terms of milligrams of antibody per kilogram of patient body weight {7.6., mg/kg}.
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`For example, the VEGF antagonist may be administered to a patient at a d