USOO9254338B2
`
`(12) United States Patent
`Yancopoulos
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 9.254.338 B2
`Feb. 9, 2016
`
`(54) USE OF A VEGF ANTAGONIST TO TREAT
`ANGIOGENC EYE DISORDERS
`
`(71) Applicant: REGENERON
`PHARMACEUTICALS, INC.,
`Tarrytown, NY (US)
`(72) Inventor: George D. Yancopoulos, Yorktown
`Heights, NY (US)
`(73) Assignee: Regeneron Pharmaceuticals, Inc.,
`Tarrytown, NY (US)
`
`(*) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 132 days.
`(21) Appl. No.: 13/940,370
`
`(22) Filed:
`
`Jul. 12, 2013
`
`(65)
`
`Prior Publication Data
`US 2013/O295094A1
`Nov. 7, 2013
`
`Related U.S. Application Data
`(63) Continuation-in-part
`of
`application
`PCT/US2012/020855, filed on Jan. 11, 2012.
`(60) Provisional application No. 61/432.245, filed on Jan.
`13, 2011, provisional application No. 61/434,836,
`filed on Jan. 21, 2011, provisional application No.
`61/561,957, filed on Nov. 21, 2011.
`
`No.
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`(51) Int. Cl.
`A6 IK38/8
`C07K I4/7
`A6 IK 47/48
`A6 IK38/17
`C07K 6/22
`A61 K39/00
`(52) U.S. Cl.
`CPC ......... A61K 47/48415 (2013.01); A61 K38/179
`(2013.01); C07K 14/71 (2013.01); C07K 16/22
`(2013.01); A61 K 2039/505 (2013.01)
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`7,396,664 B2
`2003/0171320 A1
`2005, 0163798 A1
`2005/0260203 A1
`2006, OO58234 A1
`2006/0172944 A1
`2007/O190058 A1
`
`7/2008 Daly et al.
`9/2003 Guyer
`7/2005 Papadopoulos et al.
`1 1/2005 Wiegand et al.
`3/2006 Daly et al.
`8/2006 Wiegand et al.
`8, 2007 Shams
`
`FOREIGN PATENT DOCUMENTS
`
`JP
`WO
`WO
`
`2010-509369
`OOf75319
`2008/063932
`
`3, 2010
`12/2000
`5, 2008
`
`OTHER PUBLICATIONS
`Anonymous "Lucentis (rangibizymab injection) Intravitreal Injec
`tion' pp. 103 (Jun. 2006).
`Do et al., “An exploratory study of the safety, tolerability and
`bioactivity of a single intravitreal injection of vascular endothelial
`growth factor Trap-Eye inpatients with diabetic macular oedema” Br
`J Opthamol. 93(2): 144-1449 (Feb. 2009).
`Do et al., “The DAVINCI Study: phase 2 primary results of VEGF
`Trap-Eye in patients with diabetic macular edema' Opthamology
`118(9): 1819-1826 (Sep. 2011).
`The Eyetech Study Group, "Anti-Vascular Endothelial Growth Fac
`tor Therapy for Subfoveal Choroidal Neovascularization Secondary
`to Age-related Macular Degeneration’ American Academy of
`Ophthamology, 110 (5):979-986 (May 2003).
`Heieret al., "rhufab V2 (anti-VEGF Antibody) for Treatment of
`Exudative AMD' Symposium 8:Experimental and Emerging Treat
`ments for Choroidal Neovascularization, 10 pp (2002).
`Heier et al., “RhuFab V2 in Wet AMD 6 Month Continued
`Improvement Following Multiple Intravitreal Injections' Invest
`Ophthalmol Vis Sci., 44:E-Abstract 972 (2003).
`Krzystolik et al., “Prevention of Experimental Choroidal
`NEovascularization With Intravitreal Anti-Vascular Endothelial
`Growth Factor Antibody Fragment' Arch Ophthamol. 120:338-346
`(Mar. 2002).
`Nguyen et al., “A Phase I Study of Intravitreal Vascular Endothelial
`Growth Factor Trap-Eye in Patients with Neovascular Age-Related
`Macular Degeneration' Opthamology, J.B. Lippincott Co., Philadel
`phia, PA, US, 116(11):2141-2148 (Nov. 1, 2009).
`Nichols, Earl R. “AAO: Ranibizumab (rhuRab) May Improve Vision
`in Age-Related Macular Degeneration' Doctor's Guide Global Edi
`tion, www.pslgroup.com/dg/23f2aa.htm. pp. 1-2 (Nov. 24, 20013).
`Pai et al., "Current concepts in intravitreal drug therapy for diabetic
`retinopathy Saudi Journal of Opthamology 24(4): 143-149 (Jun. 30,
`2010).
`Stewart, “THe expanding role of vascular endothelial growth factor
`inhibitors in opthamology' Mayo Clin Proc. 87 (1):77-88 (Jan.
`2012).
`Thomas Reuters Integrity “VEGF Trap-Eye final phase II results in
`age-related macular degeneration presented at 2008 Retina Society
`Meeting” (Sep. 28, 2008).
`Nguyen et al., “A phase I trial of an IV-administered vascular
`endothelial growth factor trap for treatment in patients with choroidal
`neovascularization due to age-related macular degeneration' Oph
`thalmology (Sep. 2006) 113 (9): 1522e 1-1522e 14 (epub Jul. 28,
`2006).
`Primary Examiner — Christine J Saoud
`Assistant Examiner — Jon M Lockard
`(74) Attorney, Agent, or Firm — Frank Cottingham; Karl
`Bozicevic
`
`ABSTRACT
`(57)
`The present invention provides methods for treating angio
`genic eye disorders by sequentially administering multiple
`doses of a VEGFantagonist to a patient. The methods of the
`present invention include the administration of multiple doses
`of a VEGFantagonist to a patientata 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, dia
`betic macular edema, central retinal vein occlusion, branch
`retinal vein occlusion, and corneal neovascularization.
`26 Claims, 1 Drawing Sheet
`
`Mylan Exhibit 1019
`Mylan v. Regeneron, IPR2021-00880
`Page 1
`
`Joining Petitioner: Apotex
`
`

`

`Feb.9, 2016
`
`US 9.254,338 B2
`US 9,254,338 B2
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`60
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`U.S. Patent
`U.S. Patent
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`Weeks
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`Mylan Exhibit 1019
`Mylan v. Regeneron, IPR2021-00880
`Page 2
`Joining Petitioner: Apotex
`
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`Mylan Exhibit 1019
`Mylan v. Regeneron, IPR2021-00880
`Page 2
`
`Joining Petitioner: Apotex
`
`

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`US 9,254,338 B2
`
`1.
`USE OF A VEGF ANTAGONST TO TREAT
`ANGOGENC EYE DSORDERS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation-in-part of International
`Patent Application No. PCT/US2012/020855, filed on Jan.
`11, 2012, which claims the benefit of U.S. Provisional Appli
`cation Nos. 61/432,245, filed on Jan. 13, 2011, 61/434,836,
`filed on Jan. 21, 2011, and 61/561,957, filed on Nov. 21, 2011,
`the contents of which are hereby incorporated by reference in
`their entireties.
`
`FIELD OF THE INVENTION
`
`The present invention relates to the field of therapeutic
`treatments of eye disorders. More specifically, the invention
`relates to the administration of VEGFantagonists to treat eye
`disorders caused by or associated with angiogenesis.
`
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`15
`
`BACKGROUND
`
`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 most prevalent cause of moderate
`vision loss in patients with diabetes and is a common com
`plication 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). CRVO is caused by
`obstruction of the central retinal vein that leads to a back-up
`of blood and fluid in the retina. The retina can also become
`ischemic, resulting in the growth of new, inappropriate blood
`vessels that can cause further vision loss and more serious
`complications. Release of vascular endothelial growth factor
`(VEGF) contributes to increased vascular permeability in the
`eye and inappropriate new vessel growth. Thus, inhibiting the
`angiogenic-promoting properties of VEGF appears to be an
`effective strategy for treating angiogenic eye disorders.
`FDA-approved treatments of angiogenic eye disorders
`such as AMD and CRVO include the administration of an
`anti-VEGF antibody called ranibizumab (Lucentis(R), Genen
`tech, Inc.) on a monthly basis by intravitreal injection.
`Methods for treating eye disorders using VEGF antago
`nists are mentioned in, e.g., U.S. Pat. Nos. 7.303,746; 7.306,
`799; 7,300,563; 7,303,748; and US 2007/0190058. Nonethe
`less, there remains a need in the art for new administration
`regimens for angiogenic eye disorders, especially those
`which allow for less frequent dosing while maintaining a high
`level of efficacy.
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`single initial dose of a VEGFantagonist, followed by one or
`more secondary doses of the VEGF antagonist, followed by
`one or more tertiary doses of the VEGF antagonists. The
`present inventors have Surprisingly discovered that beneficial
`therapeutic effects can be achieved in patients suffering from
`angiogenic eye disorders by administering a VEGF antago
`nist to a patientata 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 inven
`tion, each secondary dose of VEGF antagonist is adminis
`tered 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 FIG.1. One advantage of
`Such a dosing regimen is that, for most of the course of
`treatment (i.e., the tertiary doses), it allows for less frequent
`dosing (e.g., once every 8 weeks) compared to prior admin
`istration regimens forangiogenic eye disorders which require
`monthly administrations throughout the entire course of treat
`ment. (See, e.g., prescribing information for Lucentis(R)
`Iranibizumab, Genentech, Inc.).
`The methods of the present invention can be used to treat
`any angiogenic eye disorder, including, e.g., age related
`macular degeneration, diabetic retinopathy, diabetic macular
`edema, central retinal vein occlusion, corneal neovascular
`ization, etc.
`The methods of the present invention comprise adminis
`tering any VEGF antagonist to the patient. In one embodi
`ment, 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 “afliber
`cept.”
`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).
`Aflibercept (EYLEATM, Regeneron Pharmaceuticals, Inc)
`was approved by the FDA in November 2011, for the treat
`ment of patients with neovascular (wet) age-related macular
`degeneration, with a recommended dose of 2 mg adminis
`tered by intravitreal injection every 4 weeks for the first three
`months, followed by 2 mg administered by intravitreal injec
`tion once every 8 weeks.
`Other embodiments of the present invention will become
`apparent from a review of the ensuing detailed description.
`
`BRIEF DESCRIPTION OF THE FIGURE
`
`FIG. 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 at least
`six “tertiary doses' are administered once every 8 weeks
`thereafter, i.e., at weeks 16, 24, 32, 40, 48, 56, etc.).
`
`DETAILED DESCRIPTION
`
`BRIEF SUMMARY OF THE INVENTION
`
`The present invention provides methods for treating angio
`genic eye disorders. The methods of the invention comprise
`sequentially administering multiple doses of a VEGFantago
`nist to a patient over time. In particular, the methods of the
`invention comprise sequentially administering to the patienta
`
`65
`
`Before the present invention is described, it is to be under
`stood 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
`
`Mylan Exhibit 1019
`Mylan v. Regeneron, IPR2021-00880
`Page 3
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`Joining Petitioner: Apotex
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`3
`terminology used herein is for the purpose of describing
`particular embodiments only, and is not intended to be limit
`ing, since the scope of the present invention will be limited
`only by the appended claims.
`Unless defined otherwise, all technical and scientific terms 5
`used herein have the same meaning as commonly understood
`by one of ordinary skill in the art to which this invention
`belongs. As used herein, the term “about when used in
`reference to a particular recited numerical value, means that
`the value may vary from the recited value by no more than 10
`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.).
`Although any methods and materials similar or equivalent
`to those described herein can be used in the practice or testing 15
`of the present invention, the preferred methods and materials
`are now described.
`Dosing Regimens
`The present invention provides methods for treating angio
`genic eye disorders. The methods of the invention comprise 20
`sequentially administering to a patient multiple doses of a
`VEGF antagonist. As used herein, “sequentially administer
`ing' means that each dose of VEGF antagonist is adminis
`tered to the patient at a different point in time, e.g., on differ
`ent days separated by a predetermined interval (e.g., hours, 25
`days, weeks or months). The present invention includes meth
`ods which comprise sequentially administering to the patient
`a single initial dose of a VEGFantagonist, followed by one or
`more secondary doses of the VEGF antagonist, followed by
`one or more tertiary doses of the VEGF antagonist.
`The terms “initial dose.” “secondary doses.” and “tertiary
`doses.” refer to the temporal sequence of administration of the
`VEGFantagonist. Thus, the “initial dose' is the dose which is
`administered at the beginning of the treatment regimen (also
`referred to as the “baseline dose'); the “secondary doses’ are 35
`the doses which are administered after the initial dose; and the
`“tertiary doses’ are the doses which are administered after the
`secondary doses. The initial, secondary, and tertiary doses
`may all contain the same amount of VEGF antagonist, but
`will generally differ from one another in terms of frequency 40
`of administration. In certain embodiments, however, the
`amount of VEGFantagonist contained in the initial, second
`ary and/or tertiary doses will vary from one another (e.g.,
`adjusted up or down as appropriate) during the course of
`treatment.
`45
`In one exemplary embodiment of the present invention,
`each secondary dose is administered 2 to 4 (e.g., 2, 2/2, 3,3/2.
`or 4) weeks after the immediately preceding dose, and each
`tertiary dose is administered at least 8 (e.g., 8, 8/2, 9, 9/2, 10,
`10/2, 11, 1 1/2, 12, 12/2, 13, 13/2, 14, 14%, or more) weeks 50
`after the immediately preceding dose. The phrase “the imme
`diately 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 55
`doses.
`In one exemplary embodiment of the present invention, a
`single initial dose of a VEGFantagonist is administered to a
`patient on the first day of the treatment regimen (i.e., at week
`O), followed by two secondary doses, each administered four 60
`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 65
`during the course of the treatment regimen. This exemplary
`administration regimen is depicted graphically in FIG. 1.
`
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`US 9,254,338 B2
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`4
`The methods of the invention may comprise administering
`to a patient any number of secondary and/or tertiary doses of
`a VEGF antagonist. For example, in certain embodiments,
`only a single secondary dose is administered to the patient. In
`other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or
`more) secondary doses are administered to the patient. Like
`wise, 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.
`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 imme
`diately preceding dose. Similarly, in embodiments involving
`multiple tertiary doses, each tertiary dose may be adminis
`tered 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. Alter
`natively, the frequency at which the secondary and/or tertiary
`doses are administered to a patient can vary over the course of
`the treatment regimen. For example, the present invention
`includes methods which comprise administering to the
`patient a single initial dose of a VEGFantagonist, followed by
`one or more secondary doses of the VEGF antagonist, fol
`lowed 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 Sub
`sequent tertiary dose is administered from 8 to 12 (e.g., 8,8/2.
`9, 9/2, 10, 10%, 11, 11/2, 12) weeks after the immediately
`preceding dose. The frequency of administration may also be
`adjusted during the course of treatment by a physician
`depending on the needs of the individual patient following
`clinical examination.
`VEGF Antagonists
`The methods of the present invention comprise adminis
`tering to a patient a VEGF antagonist according to specified
`dosing regimens. As used herein, the expression “VEGF
`antagonist’ means any molecule that blocks, reduces or inter
`feres with the normal biological activity of VEGF.
`VEGFantagonists include molecules which interfere with
`the interaction between VEGF and a natural VEGF receptor,
`e.g., molecules which bind to VEGF or a VEGF receptor and
`prevent or otherwise hinder the interaction between VEGF
`and a VEGF receptor. Specific exemplary VEGFantagonists
`include anti-VEGF antibodies, anti-VEGF receptor antibod
`ies, and VEGF receptor-based chimeric molecules (also
`referred to herein as “VEGF-Traps').
`VEGF receptor-based chimeric molecules include chi
`meric polypeptides which comprise two or more immunoglo
`bulin (Ig)-like domains of a VEGF receptor such as VEGFR1
`(also referred to as Flt1) and/or VEGFR2 (also referred to as
`Flk1 or KDR), and may also contain a multimerizing domain
`(e.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
`encoded by 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
`SEQID NO:2; (2) a VEGFR2 component comprising amino
`acids 130 to 231 of SEQID NO:2; and (3) a multimerization
`component (“FcAC1(a)”) comprising amino acids 232 to 457
`of SEQID NO:2 (the C-terminal amino acid of SEQID NO:2
`i.e., K458 may or may not be included in the VEGFantago
`
`Mylan Exhibit 1019
`Mylan v. Regeneron, IPR2021-00880
`Page 4
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`Joining Petitioner: Apotex
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`5
`nist used in the methods of the invention; see e.g., U.S. Pat.
`No. 7,396,664). Amino acids 1-26 of SEQ ID NO:2 are the
`signal sequence.
`The VEGFantagonist 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 VEGF receptor-based chimeric molecules which
`can be used in the context of the present invention are dis
`closed in U.S. Pat. Nos. 7,396,664, 7,303,746 and WO
`OOf753.19.
`10
`Angiogenic Eye Disorders
`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 reti
`nal 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, pan
`nus, pterygium, Vascular retinopathy, and diabetic retinopa
`thies.
`Pharmaceutical Formulations
`The present invention includes methods in which the
`VEGF antagonist that is administered to the patient is con
`tained within a pharmaceutical formulation. The pharmaceu
`tical formulation may comprise the VEGFantagonist along
`with at least one inactive ingredient Such as, e.g., a pharma
`ceutically acceptable carrier. Other agents may be incorpo
`rated into the pharmaceutical composition to provide
`improved transfer, delivery, tolerance, and the like. The term
`“pharmaceutically acceptable” means approved by a regula
`tory agency of the Federal or a state government or listed in
`the U.S. Pharmacopeia or other generally recognized phar
`macopeia for use in animals, and more particularly, in
`humans. The term “carrier refers to a diluent, adjuvant,
`excipient, or vehicle with which the antibody is administered.
`A multitude of appropriate formulations can be found in the
`formulary known to all pharmaceutical chemists: Reming
`ton'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, lip
`ids, lipid (cationic or anionic) containing vesicles (such as
`LIPOFECTINTM), DNA conjugates, anhydrous absorption
`pastes, oil-in-water and water-in-oil emulsions, emulsions
`carbowax (polyethylene glycols of various molecular
`weights), semi-solidgels, and semi-solid mixtures containing
`carbowax. Any of the foregoing mixtures may be appropriate
`in the context of the methods of the present invention, pro
`vided that the VEGF antagonist is not inactivated by the
`formulation and the formulation is physiologically compat
`ible and tolerable with the route of administration. See also
`Powell et al. PDA (1998) J Pharm SciTechnol. 52:238-311
`and the citations therein for additional information related to
`excipients and carriers well known to pharmaceutical chem
`ists.
`Pharmaceutical formulations useful for administration by
`injection in the context of the present invention may be pre
`pared by dissolving, Suspending or emulsifying a VEGF
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`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., etha
`nol), a polyalcohol (e.g., propylene glycol, polyethylene gly
`col), a nonionic surfactant e.g., polysorbate 80, HCO-50
`(polyoxyethylene (50 mol) adduct of hydrogenated castor
`oil), etc. As the oily medium, there may be employed, e.g.,
`sesame oil, soybean oil, etc., which may be used in combina
`tion with a solubilizing agent such as benzylbenzoate, benzyl
`alcohol, etc. The injection thus prepared can be filled in an
`appropriate ampoule if desired.
`Modes of Administration
`The VEGF antagonist (or pharmaceutical formulation
`comprising the VEGFantagonist) may be administered to the
`patient by any known delivery system and/or administration
`method. In certain embodiments, the VEGF antagonist is
`administered to the patient by ocular, intraocular, intravitreal
`or Subconjunctival injection. In other embodiments, the
`VEGFantagonist can be administered to the patient by topi
`cal 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, epidu
`ral, and oral.
`Amount of VEGF Antagonist Administered
`Each dose of VEGFantagonist administered to the patient
`over the course of the treatment regimen may contain the
`same, or substantially the same, amount of VEGFantagonist.
`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 VEGFantagonist is administered in the initial
`dose, a second quantity of VEGFantagonist is administered
`in the secondary doses, and a third quantity of VEGFantago
`nist is administered in the tertiary doses. The present inven
`tion contemplates dosing schemes in which the quantity of
`VEGF antagonist contained within the individual doses
`increases over time (e.g., each Subsequent dose contains more
`VEGF antagonist than the last), decreases over time (e.g.,
`each Subsequent dose contains less VEGFantagonist than the
`last), initially increases then decreases, initially decreases
`then increases, or remains the same throughout the course of
`the administration regimen.
`The amount of VEGF antagonist administered to the
`patient in each dose is, in most cases, a therapeutically effec
`tive 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 pro
`gression 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 about 0.05 mg to about 5 mg.
`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 0.4
`mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6
`mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8
`mg, about 0.85 mg, about 0.9 mg, about 1.0 mg, about 1.05
`mg, about 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 1.8 mg, about 1.85
`
`Mylan Exhibit 1019
`Mylan v. Regeneron, IPR2021-00880
`Page 5
`
`Joining Petitioner: Apotex
`
`

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`7
`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 receptor-based chimeric
`molecule.
`The amount of VEGFantagonist contained within the indi
`vidual doses may be expressed in terms of milligrams of
`antibody per kilogram of patient body weight (i.e., mg/kg).
`For example, the VEGFantagonist may be administered to a
`patient at a dose of about 0.0001 to about 10 mg/kg of patient
`body weight.
`Treatment Population and Efficacy
`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 0), 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 AMD, CRVO,
`and DME, “efficacy’ means that, from the initiation of treat
`ment, the patient exhibits a loss of 15 or fewer letters on the
`Early Treatment Diabetic Retinopathy Study (ETDRS) visual
`acuity chart. In certain embodiments, “efficacy’ means again
`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.
`
`10
`
`15
`
`25
`
`30
`
`EXAMPLES
`
`The following examples are put forth so as to provide those
`of ordinary skill in the art with a complete disclosure and
`description of how to make and use the methods and compo
`sitions 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 indi
`cated otherwise, parts are parts by weight, molecular weight
`is average molecular weight, temperature is in degrees Cen
`45
`tigrade, and pressure is at or near atmospheric. The exemplary
`VEGF antagonist used in all Examples set forth below is a
`dimeric molecule having two functional VEGF binding units.
`Each functional binding unit is comprised of Ig domain 2
`from VEGFR1 fused to Ig domain 3 from VEGFR2, which in
`turn is fused to the hinge region of a human IgG1 Fc domain
`(VEGFR1R2-FcAC1(a): encoded by SEQ ID NO:1). This
`VEGF antagonist is referred to in the examples below as
`“VEGFT. For purposes of the following Examples,
`“monthly dosing is equivalent to dosing once every four
`weeks.
`
`35
`
`40
`
`50
`
`55
`
`Example 1
`
`Phase I Clinical Trial of Intravitreally Administered
`VEGF Receptor-Based Chimeric Molecule
`(VEGFT) in Subjects with Neovascular AMD
`
`60
`
`In this Phase I study, 21 subjects with neovascular AMD
`received a single intravitreal (IVT) dose of VEGFT. Five
`65
`groups of three subjects each received either 0.05, 0.15, 0.5, 2
`or 4 mg of VEGFT, and a sixth group of six subjects received
`
`US 9,254,338 B2
`
`8
`1 mg. No serious adverse events related to the study drug, and
`no identifiable intraocular inflammation was reported. Pre
`liminary results showed that, following injection of VEGFT.
`a rapid decrease in foveal thickness and macular volume was
`observed that was maintained through 6 weeks. At Day 43
`across all dose groups, mean excess retinal thickness excess
`retinal thickness=(retinal thickness-1791) on optical coher
`ence tomography (OCT) was reduced from 119L to 27L as
`assessed by Fast Macular Scan and from 1941 to 60LL as
`assessed using a single Posterior Pole Scan. The mean
`increase in best corrected visual acuity (BCVA) was 4.75
`letters, and BCVA was stable or improved in 95% of subjects.
`In 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
`Intravitreally Administered VEGF Receptor-Based
`Chimeric Molecule (VEGFT) in Subjects with
`Neovascular AMD
`
`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 mg every 12 weeks and 5)
`4 mg every 12 weeks. Subjects were dosed at a fixed interval
`for the first 12 weeks, after which they were evaluated every
`