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`Form Revision Date: February 8, 2006
`
`1
`Samsung Bioepis Exhibit 1065
`Page 1
`
`Samsung Bioepis Exhibit 1065
`Page 1
`
`

`

`PTO/AIA/15 (03-13)
`Approved for use through 01/31/2014. OMB 0651-0032
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`Samsung Bioepis Exhibit 1065
`Page 2
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`Samsung Bioepis Exhibit 1065
`Page 2
`
`

`

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`Samsung Bioepis Exhibit 1065
`Page 3
`
`Samsung Bioepis Exhibit 1065
`Page 3
`
`

`

`Electronic Patent Application Fee Transmittal
`
`Title of Invention:
`
`USE OF A VEGF ANTAGONIST TO TREAT ANGIOGENIC EYE DISORDERS
`
`a
`
`Utility under 35 USC 111(a) Filing Fees
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`omen
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`Description
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`Quantity
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`Sub-Total in
`USD(S$)
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`Miscellaneous-Filing:
`
`Samsung Bioepis Exhibit 1065
`Page 4
`
`

`

`so
`
`.
`
`Sub-Total in
`
`Post-Allowance-and-Post-Issuance:
`
`1600
`
`Miscellaneous:
`
`Total in USD (S$)
`
`Samsung Bioepis Exhibit 1065
`Page 5
`
`Samsung Bioepis Exhibit 1065
`Page 5
`
`

`

`
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`i a
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`Electronic AcknowledgementReceipt
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`Title of Invention:
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`USE OF A VEGF ANTAGONIST TO TREAT ANGIOGENIC EYE DISORDERS
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`Charge any Additional Fees required under 37 C.F.R. Section 1.16 (National application filing, search, and examination fees)
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`Samsung Bioepis Exhibit 1065
`Page 6
`
`

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`Charge any Additional Fees required under 37 C.F.R. Section 1.19 (Document supply fees)
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`725A1_Specification.pdf
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`Image File Wrapper and mayaffect subsequent processing
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`1255991
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`eee33322201e20b1 idB
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`725A1_SeqListStatement.pdf
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`Information:
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`725A1_AppDataSheet.pdf
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`Samsung Bioepis Exhibit 1065
`Page 7
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`

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`Information:
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`Information:
`
`Transmittal of New Application
`
`.
`ae
`725A1_ApplicationTransmittal.
`pdf
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`276559
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`1f3a69d8d94bef563f27d2443e5 18e782b1
`8cb70
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`Fee Worksheet (SB06)
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`fee-info.pdf
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`1e8c487df991d67f0cd6fb4c4f879022d7ef9
`49a
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`Samsung Bioepis Exhibit 1065
`Page 8
`
`Samsung Bioepis Exhibit 1065
`Page 8
`
`

`

`USE OF A VEGF ANTAGONIST TO TREAT ANGIOGENIC EYE DISORDERS
`
`CROSS-REFERENCE TO RELATED APPLICATIONS
`
`[0001]
`
`This application is a continuation-in-part of International Patent Application No.
`
`PCT/US2012/020855, filed on January 11, 2012, which claims the benefit of US Provisional
`
`Application Nos. 61/432,245, filed on January 13, 2011, 61/434,836, filed on January 21, 2011, and
`
`61/561 ,957, filed on November 21, 2011, the contents of which are hereby incorporated by
`
`referencein their entireties.
`
`FIELD OF THE INVENTION
`
`[0002]
`
`The presentinvention 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
`
`[0003]
`
`Several eye disorders are associated with pathological angiogenesis. For example, the
`
`development of age-related macular degeneration (AMD) 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 mostprevalent 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 macula, 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 angiogenesis is central retinal vein occlusion (CRVO). CRVOis causedby 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.
`
`Thus, inhibiting the angiogenic-promoting properties of VEGF appears to be an effective strategy
`
`for treating angiogenic eye disorders.
`
`[0004]
`
`FDA-approved treatments of angiogenic eye disorders such as AMD and CRVOinclude
`
`the administration of an anti-VEGF antibody called ranibizumab (Lucentis®, Genentech, Inc.) ona
`
`monthly basis by intravitreal injection.
`
`[0005] Methods fortreating eye disorders using VEGF antagonists are mentionedin, e.g., US
`
`7,803,746; US 7,306,799; US 7,300,563; US 7,303,748; and US 2007/0190058. Nonetheless,
`
`-1-
`
`Samsung Bioepis Exhibit 1065
`Page 9
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`Samsung Bioepis Exhibit 1065
`Page 9
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`

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`there remains a needin the art for new administration regimens for angiogenic eye disorders,
`
`especially those whichallow for less frequent dosing while maintaining a high levelof efficacy.
`
`BRIEF SUMMARYOF THE INVENTION
`
`[0006]
`
`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
`
`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 moretertiary doses of the VEGF
`
`antagonists. The present inventors have surprisingly discovered that beneficial therapeutic effects
`
`can be achievedin 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 eachtertiary
`
`doseis 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(/.e., the tertiary doses), it allows for less
`
`frequent dosing (e.g., once every 8 weeks) comparedto 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.).
`
`[0007]
`
`The methods of the present invention can be usedto treat any angiogenic eye disorder,
`
`including, e.g., age related macular degeneration, diabetic retinopathy, diabetic macular edema,
`
`central retinal vein occlusion, corneal neovascularization, etc.
`
`[0008]
`
`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
`
`"VEGFR1R2-FcAC1(a)" or "aflibercept."
`
`[0009] 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).
`
`[0010] Aflibercept (EYLEA™, Regeneron Pharmaceuticals, Inc) was approved by the FDAin
`
`November 2011, for the treatment of patients with neovascular (wet) age-related macular
`
`degeneration, with a recommended dose of 2 mg administeredby intravitreal injection every 4
`
`-2-
`
`Samsung Bioepis Exhibit 1065
`Page 10
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`Samsung Bioepis Exhibit 1065
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`

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`weeksforthe first three months, followed by 2 mg administered byintravitreal injection once every
`
`8 weeks.
`
`[0011] Other embodimentsof the present invention will become apparent from a review of the
`
`ensuing detailed description.
`
`BRIEF DESCRIPTION OF THE FIGURE
`
`[0012]
`
`Figure 1 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 0"), two "secondary doses" are administered at weeks 4 and 8, respectively,
`
`and atleast six "tertiary doses" are administered once every 8 weeksthereafter, .e., at weeks 16,
`
`24, 32, 40, 48, 56, etc.).
`
`DETAILED DESCRIPTION
`
`[0013]
`
`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 understoodthat the terminology used herein is for the purpose
`
`of describing particular embodimentsonly, and is not intended to belimiting, since the scope of the
`
`present invention will be limited only by the appended claims.
`
`[0014] 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 usedin reference to a particular recited numerical value,
`
`means that the value mayvary 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.).
`
`[0015] 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
`
`[0016]
`
`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
`
`predeterminedinterval (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
`
`-3-
`
`Samsung Bioepis Exhibit 1065
`Page 11
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`Samsung Bioepis Exhibit 1065
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`antagonist, followed by one or more secondary doses of the VEGF antagonist, followed by one or
`
`moretertiary doses of the VEGF antagonist.
`
`[0017]
`
`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 whichis
`
`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 mayall contain the same amount of VEGF antagonist, but will generally differ
`
`from one anotherin terms of frequency of administration.
`
`In certain embodiments, however, the
`
`amount of VEGF antagonist containedin the initial, secondary and/or tertiary doses will vary from
`
`one another(é.g., adjusted up or down as appropriate) during the course of treatment.
`
`[0018]
`
`In one exemplary embodiment of the present invention, each secondary doseis
`
`administered 2 to 4 (e.g., 2, 2%, 3, 3%, or 4) weeksafter the immediately preceding dose, and each
`
`tertiary dose is administered at least 8 (e.g., 8, 874, 9, 9%, 10, 10%, 11, 11%, 12, 12%, 13, 13%, 14,
`
`14’4, or more) weeksafter 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.
`
`[0019]
`
`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 weeksafter the immediately preceding
`
`dose(/.e., at week 4 and at week 8), followed by at least 5 tertiary doses, each administered eight
`
`weeksafter the immediately preceding dose(/.e., at weeks 16, 24, 32, 40 and 48). The tertiary
`
`doses maycontinue (at intervals of 8 or more weeks)indefinitely during the courseof the treatment
`
`regimen. This exemplary administration regimen is depicted graphically in Figure 1.
`
`[0020]
`
`The methods of the invention may comprise administering to a patient any numberof
`
`secondary and/ortertiary doses of a VEGF antagonist. For example, in certain embodiments, only
`
`a single secondary doseis 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(é.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.
`
`[0021]
`
`In embodimentsinvolving 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 othertertiary doses. For example, each tertiary dose may be administered
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`-4-
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`to the patient 8 weeksafter the immediately preceding dose. Alternatively, the frequency at which
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`the secondary and/ortertiary doses are administered to a patient can vary over the course of the
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`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 subsequenttertiary dose is administered from 8 to 12 (e.g., 8,
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`8’4, 9, 9%, 10, 10%, 11, 11%, 12) weeksafter the immediately preceding dose. The frequencyof
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`administration may also be adjusted during the course of treatment by a physician depending on
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`the needs of the individual patient following clinical examination.
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`VEGF ANTAGONISTS
`
`[0022]
`
`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, reducesor interferes with the normal biological activity
`
`of VEGF.
`
`[0023] VEGF antagonists include molecules whichinterfere 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
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`antagonists include anti-VEGF antibodies, anti-VEGF receptor antibodies, and VEGF receptor-
`
`based chimeric molecules (also referred to herein as "VEGF-Traps").
`
`[0024] VEGF receptor-based chimeric molecules include chimeric polypeptides which comprise
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`two or more immunoglobulin (Ig)-like domains of a VEGF receptor such as VEGFR1 (also referred
`
`to as Fit1) and/or VEGFR2 (also referred to as Flk1 or KDR), and may also contain a multimerizing
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`domain (é.g., an Fc 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-FcAC1(a) which is encodedby the nucleic acid sequence of SEQ ID
`
`NO:1. VEGFR1R2-FcAC1(a) comprises three components: (1) a VEGFR1 component comprising
`
`amino acids 27 to 129 of SEQ ID NO:2; (2) a VEGFR2 component comprising amino acids 130 to
`
`231 of SEQ ID NO:2; and (3) a multimerization component ("FcAC1(a)") comprising amino acids
`
`232 to 457 of SEQ ID NO:2 (the C-terminal amino acid of SEQ ID NO: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 NO:2 are the signal sequence.
`
`[0025]
`
`The VEGF antagonist used in the Examples set forth herein below is a dimeric molecule
`
`comprising two VEGFR1R2-FcAC1(a) molecules and is referred to herein as "VEGFT." Additional
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`-5-
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`VEGF receptor-based chimeric molecules which can be used in the context of the present invention
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`are disclosed in US 7,396,664, 7,303,746 and WO 00/75319.
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`ANGIOGENIC EYE DISORDERS
`
`[0026]=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
`
`the present invention include age-related macular degeneration (e.g., wet AMD, exudative AMD,
`
`etc.), retinal vein occlusion (RVO), central retinal vein occlusion (CRVO; e.g., macular edema
`
`following CRVO), branch retinal vein occlusion (BRVO), diabetic macular edema (DME), choroidal
`
`neovascularization (CNV; e.g., myopic CNV), iris neovascularization, neovascular glaucoma, post-
`
`surgical fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), optic disc neovascularization,
`
`corneal neovascularization, retinal neovascularization, vitreal neovascularization, pannus,
`
`pterygium, vascular retinopathy, and diabetic retinopathies.
`
`PHARMACEUTICAL FORMULATIONS
`
`[0027]
`
`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 maybeincorporatedinto 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
`
`governmentorlisted 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 knownto 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
`
`-6-
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`Technol. 52:238-311 and the citations therein for additional information related to excipients and
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`carriers well known to pharmaceutical chemists.
`
`[0028]
`
`Pharmaceutical formulations useful for administration by injection in the context of the
`
`present invention may be preparedby dissolving, suspending or emulsifying a VEGF antagonistin
`
`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 otherauxiliary 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 castoroil)], 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
`
`benzoate, benzyl alcohol, etc. The injection thus prepared can befilled in an appropriate ampoule if
`
`desired.
`
`MODES OF ADMINISTRATION
`
`[0029]
`
`The VEGF antagonist (or pharmaceutical formulation comprising the VEGF antagoni