(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
`
`1111111111111111 IIIIII IIIII 111111111111111 II Ill 111111111111111 lllll lllll 11111111111111111111111
`
`(10) International Publication Number
`WO 2012/097019 Al
`
`(43) International Publication Date
`19 July 2012 (19.07.2012) WIPO I PCT
`
`~ ~
`
`(51) International Patent Classification:
`A61K 38/18 (2006.01)
`A61P 27/00 (2006.01)
`
`(21) International Application Number:
`
`(22) International Filing Date:
`
`(25) Filing Language:
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`(26) Publication Language:
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`PCT/US2012/020855
`
`l l January 2012 (I 1.01.2012)
`
`English
`
`English
`
`(84)
`
`(30)
`
`Priority Data:
`61/432,245
`61/434,836
`61/561,957
`
`13 January 201 l (13.01.2011)
`21 January 201 l (21.01.2011)
`21 November20ll (21.ll.2011)
`
`us
`us
`us
`(71) Applicant (for all designated States except US): REGEN(cid:173)
`ERON PHARMACEUTICALS, INC. [US/US]; 777 Old
`Saw Mill River Road, Tarrytown, NY 10591 (US).
`
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA,CH,CL,CN,CO,CR,CU,CZ,DE,DK,DM,DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN,
`HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME,
`MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ,
`OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, TZ, VA, VG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ,
`UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU,
`TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE,
`DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU,
`LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK,
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`with international search report (Art. 21(3))
`
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments (Rule 48.2(h))
`
`with sequence listing part of description (Rule 5.2(a))
`
`(72) Inventor; and
`(75) Inventor/Applicant (for US only): YANCOPOULOS,
`George D. [US/US]; 1519 Baptist Church Road, Yorktown
`Heights, NY 10598 (US).
`
`(74) Agent: COTTINGHAM, Frank; Regeneron Pharmaceut(cid:173)
`icals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY
`10591 (US).
`
`;;;;;;;;;;;;;;
`;;;;;;;;;;;;;; (81) Designated States (unless otherwise indicated, for every
`-
`kind of national protection available): AE, AG, AL, AM,
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`,-.-1 <
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`O'I
`,-.-1
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`t--(cid:173)
`O'I
`~
`(54) Title: USE OF A VEGF ANTAGONIST TO TREAT ANGIOGENIC EYE DISORDERS
`M
`,-.-1
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`(57) Abstract: The present invention provides methods for treating angiogenic eye disorders by sequentially administering multiple
`doses of a VEGF antagonist to a patient. The methods of the present invention include the administration of multiple doses of a
`VEGF antagonist to a patient at a frequency of once every 8 or more weeks. The methods of the present invention are useful for the
`treatment of angiogenic eye disorders such as age related macular degeneration, diabetic retinopathy, diabetic macular edema, central
`retinal vein occlusion and corneal neovascularization.
`
`Mylan Exhibit 1062
`Mylan v. Regeneron, IPR2021-00881
`Page 1
`
`Joining Petitioner: Apotex
`
`

`

`PCT/US2012/020855
`WO 2012/097019
`USE OF AVEGF ANTAGONIST TO TREAT ANGIOGENIC EYE DISORDERS
`
`FIELD OF THE INVENTION
`
`f0001J 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
`
`[0002J Severa! eye disorders are associated with pathological angiogenesis. For example,
`the development of age-related macular degeneration (AMD) is associated with a process
`called choroida! neovascularization (CNV). Leakage from the CNV causes macular edema and
`collection of fluid beneath the macula resulting in vision loss. Diabetic rnacular ederna (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 the blood vessels of the retina. Clinically significant DME
`occurs when fluid leaks into the center of the macu!a, the light-sensitive part of the retina
`responsible for sharp, direct vision. Fluid in the macula can cause severe vision loss or
`blindness. Yet another eye disorder associated with abnormal angiogenesls 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 vesseis 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 vessei growth. Thus, inhibiting the
`angiogenic-promoting properties of VEGF appears to be an effective strategy for treating
`
`angiogenic eye disorders.
`
`[0003J 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 rernains a need in the art for new administration regimens for angiogenic eye disorders,
`especially those which allow for less frequent dosing while maintaining a hlgh level of efficacy,
`
`BRIEF SUMMARY OF THE INVENTION
`
`[0005] The present invention provides methods for treating angiogenic eye disorders, Tile
`methods of the invention comprise sequentially administering multiple doses of a VEGF
`
`antagonist to a patient over time. in particular, the meU1ods of the invention comprise
`sequentia!ly administering to the patient a single initial dose of a VEGF antagonist, followed by
`
`Mylan Exhibit 1062
`Mylan v. Regeneron, IPR2021-00881
`Page 2
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`Joining Petitioner: Apotex
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`PCT/0S2012/020855
`WO 2012/097019
`one or more secondary doses of the VEGF antagonist, followed by one or more tertiary doses of
`
`the VEGF antagonists. The present inventors haw.: surprisingly discovered that beneficiai
`
`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 a!!ows 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
`
`macu!ar edema, central retina! vein occlusion, corneal neovascu!arization, etc,
`
`[0007] The methods of the present invention comprise administering any VEGF antagonist to
`
`the patient !none embodiment, the VEGF antagonist comprises one or more VEGF receptor(cid:173)
`
`based chimeric molecu!e(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
`
`multimerk.~ VEGF-binding protein comprising two or more VEGF receptor-based chimeric
`
`molecules referred to herein as "VEGFR1R2-Fcl\C1(a)" or "af!ibercept"
`
`[OO<Hs] Various administration routes .are contemplated for use in t!1e methods of the present
`
`invention, including, e.g., topical administration or intraocu!ar administration (e.g., intravitreal
`
`administration).
`
`[0009] AfHbercept {EYLEA rM, Regeneron Pharmaceuticals, inc) was approved by the FDA in
`
`November 2011, for the treatment of patients with neovascular (wet) age-related macular
`
`degeneration, with a recommended dose of 2 mg administered by intravitreal injection every 4
`
`weeks for the first three months, followed by 2 mg administered by intravitrea! injection once
`
`every 8 weeks.
`
`[0010] Other embodiments of the present invention will become apparent from a review of the
`
`ensuing detailed description.
`
`BRIEF DESCRIPTION OF THE FIGURE
`
`[0011] Figure i shows an exemplary dosing regimen of the present invention. In this regimen,
`
`a single "initial dose" of VEGF antagonist {"VEGFT') is administered at the beginning of the
`
`treatment regimen (i,e. at "week O"), two "secondary doses" are administered at weeks 4 and 8,
`
`Mylan Exhibit 1062
`Mylan v. Regeneron, IPR2021-00881
`Page 3
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`Joining Petitioner: Apotex
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`WO 2012/097019
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`PCT/0S2012/020855
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`respectively, and at !east six "tertiary doses" are administered once every 8 weeks thereafter,
`
`i,e., at weeks 16, 24, 32, 40, 48, 56, etc.).
`
`DETAILED DESCmPT!ON
`
`[0012] Before the present invenUon 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 termino!ogy used herein is for the
`
`purpose of describing particular embodiments on!y, and is not intended to be limiting, sirn.~e the
`
`scope of the present invention will be limited only by the appended claims.
`
`[0013] Unless defined otherwise, ail technical and scientific terms used herein have the same
`
`rneaning 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 rnay vary from the recited value by no more than 1%.
`
`For example, as used herein, the expression "about 100" includes 99 and 101 and al! values in
`
`between (e.g., 99.1, 99.2, 99,3, 99.4, etc.).
`
`[0014] 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.
`
`DOSING REGIMENS
`
`[0015} 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 admin1stered to the patient at a different point in tirne, 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
`
`[0016] The terms "initial dose," "secondary doses," and "tertiary doses," refer to the ternporal
`
`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 reforred 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 tr1e same amount of VEGF antagonist, but will
`
`generally differ from one another in terms of frequency of administration. In certain
`
`embodiments, however, the amount of VEGF antagonist contained in the initial, secondary
`
`and/or tertiary doses wil! vary from one another (e.g., adjusted up or down as appropriate)
`
`during the course of treatment.
`
`--3-
`
`Mylan Exhibit 1062
`Mylan v. Regeneron, IPR2021-00881
`Page 4
`
`Joining Petitioner: Apotex
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`

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`WO 2012/097019
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`PCT/0S2012/020855
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`[0017]
`
`!n 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, 10½, 11, 11½, 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.
`
`[00181
`
`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),
`
`fo!lowed 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.
`
`[0019] 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 ceriain 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.
`
`[0020]
`
`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 invo!ving 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 initiai dose of a VEGF
`
`antagonist, followed by one or more secondary doses of the VEGF antagonist, foliowed 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, 8"½, 9, 9½, 10, 10½, 11, 11½, 12} weeks after
`
`the immediately preceding dose. The frequency of administration may aiso be adjusted during
`
`the course of treatment by a physician depending on the needs of the individual patient
`
`following ciinicai examination.
`
`Mylan Exhibit 1062
`Mylan v. Regeneron, IPR2021-00881
`Page 5
`
`Joining Petitioner: Apotex
`
`

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`WO 2012/097019
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`PCT/0S2012/020855
`
`VEGF ANTAGONISTS
`
`[0021] The methods of the present invention comprise administering to a patient a VEGF
`
`antagonist according to spE.'.:clfied dosing regimens. As used herein, the expression "VEGF
`
`antagonist" means any molecule that blocks, reduces or interferes with the normal biological
`
`activity of VEGF.
`
`[0022] VEGF antagonists include moiecules which interfere with the interaction between
`
`VE.GF and a natural VEGF receptor, e.g., moiecules 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 antiNEGF antibodies, anti-VEGF receptor antibodies, and
`
`VEGF receptor--based chimeric molecules (also referred to herein as "VEGF-Traps").
`
`[0023J 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 Flt'l) and/or VEGFR.2 (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 VEGFR1R2 .. FcliC1(a} which is encoded by the
`
`nucleic add sequence of SEQ lD N0:1. VEGFR1 R2-FcnC1(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 adds 130 to 231 of SEQ iD N0:2; and (3) a muitimerization
`component ("FcnC1 (a)") comprising amino acids 232 to 457 of SEQ ID N0:2 (the C-terminal
`amino acid of SEQ ID N0:2 [i.e., K458J may or may not be included in the VEGF antagonist
`
`used in the methods of the invention; see e.g., US Patent 7,:196,664). Amino acids 1--26 of SEQ
`ID N0:2 are the signal sequence.
`
`[0024] The VEGF antagonist used in the Examples set forth herein below is a dimeric
`
`molecule comprising two VEGFR1R2-Fc.l\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
`
`[0025]
`
`The methods of the present invention can be used to treat any angiogenlc 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 angiogenlc eye disorders that are treatable
`
`using the methods of the present invention include choroidal neovascularization, age-related
`
`macular degeneration (AMD), diabetic retinopathies, diabetic macu!ar edema (DME), central
`
`retinal vein occlusion (CRVO), corneal neovascuiarization, and retina! neovascu!arization,
`
`Mylan Exhibit 1062
`Mylan v. Regeneron, IPR2021-00881
`Page 6
`
`Joining Petitioner: Apotex
`
`

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`WO 2012/097019
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`PHARMACEUTICAL FORMULATIONS
`
`PCT/0S2012/020855
`
`[00261 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 antagonfst 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 formu!ary known to
`
`all pharmaceutical chemists: Remington's Pharmaceutical Sciences (15th ed, Mack Publishing
`
`Company, Easton, Pa., 1975), particularly Chapter 87 by B!aug, Seymour, therein. These
`
`formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid
`
`(cationic or anionic) containing vesicles (such as UPOFECTIN™), 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 physiologicaliy compatible and tolerable \Nith the route of administration.
`
`See also Powell et a!. 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.
`
`[0027] 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 polyalcohoi (e.g., propylene
`
`glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50
`
`(poiyoxyt~thylene (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
`
`solubiiizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared
`
`can be filled in an appropriate ampoule if desired.
`
`MODES OF ADMINISTRATION
`
`[0028] 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.
`
`-6-
`
`Mylan Exhibit 1062
`Mylan v. Regeneron, IPR2021-00881
`Page 7
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`Joining Petitioner: Apotex
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`

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`PCT/0S2012/020855
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`In certain ernbodimenls, the VEGF antagonist ls administered to the patient by ocuiar,
`intraocular, intravitreal or subconjunctiva! 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 OFVEGF ANTAGONIST ADMINISTERED
`
`[0029] Each dose of VEGF antagonist administered to the patient over the c;ourse 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 ofVEGF
`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 !ast), 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,
`roo30] The amount of VEGF antagonist administered to the patient in each dose ls, 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 symptoms or indicia of an angiogenic eye disorder, or a dose of VEGF antagonist that
`inhibits, prevents, lessens, or delays the progression of an angiogenic eye disorder. In the case
`of an anti-VEGF antibody or a VEGF receptor-based chimeric molecule such as VEGFR1R2-
`FcAC1 (a), a therapeutically effective amount can be from about0.05 rng to about 5 m g, e,g.,
`about 0.05 mg, 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 OA 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, about 0.75 mg, abowt 0.8 mg, about 0.85 mg, about 0.9 mg,
`about 1.0 rng, about 1.05 mg; about 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, 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 1. 75 mg,. about ·1.a mg, about 1.85 mg,
`about 1.9 mg , about 2.0 mg , about 2.05 mg, about 2. 1 mg, 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 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, 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 mg, or about 5.0 mg of the
`antibody or recc➔pt.or-based chimeric molecule .
`
`.. 7 ..
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`Mylan v. Regeneron, IPR2021-00881
`Page 8
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`WO 2012/097019
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`PCT/0S2012/020855
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`{0031} The amount of VEGF antagonist contained within the individual doses may be
`
`expressed in terms of milligrams of antibody per kilogram of patient body weight (i.e., mg/kg).
`
`For example, the VEGF antagonist may be administered to a patient ata dose of about 0.0001
`to about 1 O mg/kg of patient body weight
`
`TREATMENT POPULATION AND EFFICACY
`
`[0032] The methods of the present invention are useful for treating angiogenic eye disorders
`
`in patients that have been diagnosed with or are at risk of being afflicted with an angiogenic eye
`
`disorder. Generally, the methods of the present invention demonstrate efficacy within 104
`weeks of the initiation of the treatment regimen (with the initial dose administered at "week O"),
`e.g., by the 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 week 48, by the end of week 56, etc. In the context of methods for treating
`
`angiogenic eye disorders such as AMO, CRVO, and DME, "efficacy" means that, from the
`
`initiation of treatment, the patient exhibits a loss of 15 or fewer letters on the Early Treatment
`
`Diabetic Retlnopathy Study (ETDRS) visual acuity chart !n certain embodiments,. "efficacy"
`means a gain of one or more (e.g., ·1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or more) letters on the ETDRS
`chart from the time of initiation of treatment
`
`EXAMPLES
`l 0033] The following exam pies are put forth so as to provide those of ordina1y skill in the art
`with a 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, Efforts have been made to ensure accuracy with respect to numbers
`used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be
`
`accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is
`average molecular weight, temperature is in degrees Centigrade, and pressure is at or near
`atmospheric.
`
`[0034] The exemplary VEGF antagonist used in ail Examples set forth below is a dimeric
`
`molecule having two functional VEGF bindin9 units . Each functionai b inding unit is comprised
`of lg domain 2 from VEGFR1 fused to lg domain 3 from VEGFR2, which in turn is fused to the
`
`hinge region of a human !gG1 Fe domain (VEGFR1 R2-Fc11G1 (a); encoded by SEQ ID N0:1 ).
`
`This VEGF antagonist is referred to in the examples beiow as "VEGFT". For purposes ofthe
`
`fol!owing Examples, "monthly" dosing is equivalent to dosing once every four weeks.
`
`Example 1: Phase I Clinical Trial of lntravitreally Administered VEGF Receptor~Based
`Chimeric Molecule (VEGFT} in Subjects with Neovascular AMD
`
`[0035]
`
`In this Phase I study, 21 subjects vvith neovascular AMO received a single intravitrea!
`
`(IVT) dose of VEGFT. Five groups of three subjects each received either 0.05, 0.15, 0.5, 2 or 4
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`Mylan v. Regeneron, IPR2021-00881
`Page 9
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`WO 2012/097019
`PCT/0S2012/020855
`mg of VEGFT, and a sixth group of six subjects received 1 mg. No serious adverse events
`
`related to the study drug, and no identifiable intraocular inflammation was reported. Preliminary
`
`results showed that, following injection of VEGFT, a rapid decrease in foveal thickness and
`
`rnacu!ar volume was observed that was maintained through 6 weeks. At Day 43 across ail dose
`
`groups, mean excess retinal thickness [excess retina! thickness ;;; (retina! thickness - 179µ)] on
`optical coherence tomography (OCT) was reduced from 1 i 9µ to 27µ as assessed by Fast
`Macu!ar Scan and from 194µ to 60µ as assessed using a single Posterior Pole. scan. The mean
`
`increase in best corrected visuai acuity (BCVA) was 4.75 letters, and BCVA was stabie or
`
`improved in 95% of subjects. !n the 2 highest dose groups (2 and 4 mg), the mean increase in
`
`BCVA was 13.5 letters, with 3 of 6 subjects demonstrating improvement of~ 3 lines.
`
`Example 2: Phase ii Clinical Trial of Repeated Doses of lntravitreal!y Administered VEGF
`Receptor~Based Chimeric Molecule (VEGFT) in Subjects with Neovascuiar AMO
`
`[0036] This study was a double-masked, randomized study of 3 doses (0.5, 2, and 4 mg) of
`
`VEGFT tested at 4-week and/or 12-week dosing intervals. There were 5 treatment arms in this
`
`study, as follows: 1) 0.5 mg every 4 weeks, 2) 0.5 mg every 12 weeks, 3) 2 mg every 4 weeks,
`
`4) 2 rng every 12 weeks and 5) 4 mg every 12 weeks. Subjects were dosed at a fixed interval
`
`for the first 12 weeks, after which tl1ey were evaluated every 4 weeks for 9 months, during which
`
`additionai doses were administered based on pre-specified criteria. All subjects were then
`
`followed for one year after their last dose of VEG FT. Preliminary data from a pre-planned
`
`interim analysis indicated that VEGFT met its primary endpoint of a statistically significant
`
`reduction 1n retina! thicknt:lss after 12 weeks compared with baseline (a!! groups combined,
`
`decrease of 135µ, p < 0.0001 ). Mean change from base!ine in visual acuity, a key secondary
`
`endpoint of the study, aiso demonstrated statiSticai!y significant improvement (all groups
`combined, increase of 5.9 letters, p < O.OOO'l). Moreover, patients in the dose groups that
`received only a single dose, on average, demonstrated a decrease in excess retina! thickness
`(p < 0.0001) and an increase in visual acuity (p;;; 0.012) at 12 weeks. There were no drug(cid:173)
`
`rt:l!ated serious adverse events, and treatment with the VEGF antagonists was generally we!l(cid:173)
`
`to!erated. The most common adverse events were those typically associated with intravitrea!
`
`injections,
`
`Example 3: Phase I Clinical Trial of Systemically Administered VEGF R.eceptor~Based
`Chimeric Molecule (VEGFT) in Subjects with Naovascular AMO
`
`[0037] This study was a placebo-controlled, sequential-group, dose-escaiating safety,
`
`tolerability and bioeffect study of VEGFT by !V infusion in subjects with neovascu!ar AMO.
`
`Groups of 8 subjects meeting eligibility criteria for subfoveai choroida! neovascularization (CNV)
`
`related to AMO were assigned to receive 4 !V injections of VEG FT or placebo at dose !eve!s of
`
`0.~3, 1, or 3 mg/kg over an 8-week period,
`
`-9-
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`Mylan v. Regeneron, IPR2021-00881
`Page 10
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`Joining Petitioner: Apotex
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`WO 2012/097019
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`[0038] Most adverse events that were attributed