I 1111111111111111 11111 1111111111 111111111111111 1111111111111111 IIII IIII IIII
`US009669069B2
`
`c12) United States Patent
`Yancopoulos
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 9,669,069 B2
`*Jun. 6, 2017
`
`(54) USE OF A VEGF ANTAGONIST TO TREAT
`ANGIOGENIC EYE DISORDERS
`
`2006/0058234 Al
`2006/0172944 Al
`2007/0190058 Al
`
`3/2006 Daly et al.
`8/2006 Wiegand et al.
`8/2007 Shams
`
`(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 ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by O days.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21) Appl. No.: 14/972,560
`
`(22) Filed:
`
`Dec. 17, 2015
`
`(65)
`
`Prior Publication Data
`
`US 2016/0101152 Al
`
`Apr. 14, 2016
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 13/940,370, filed on
`Jul. 12, 2013, now Pat. No. 9,254,338, which is a
`continuation-in-part
`of
`application
`No.
`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.
`
`(51)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 38/18
`C07K 14171
`A61K 38/17
`C07K 16122
`A61K 47148
`A61K 9/00
`A61K 39/00
`(52) U.S. Cl.
`CPC .......... A61K 38/179 (2013.01); A61K 9/0048
`(2013.01); A61K 47/48415 (2013.01); C07K
`14171 (2013.01); C07K 16122 (2013.01); A61K
`2039/505 (2013.01); C07K 2319/30 (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 Al
`2005/0163798 Al
`2005/0260203 Al
`
`7 /2008 Daly et al.
`9/2003 Guyer
`7/2005 Papadopoulos et al.
`11/2005 Wiegand et al.
`
`FOREIGN PATENT DOCUMENTS
`
`JP
`WO
`WO
`WO
`
`2010-509369
`00/75319
`2007/022101 A2
`2008/063932
`
`3/2010
`12/2000
`2/2007
`5/2008
`
`OTHER PUBLICATIONS
`
`Anonymous "Lucentis (rangibizymab injection) Intravitreal Injec(cid:173)
`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 in patients with diabetic macular oedema"
`Br J Opthamol. 93(2)144-1449 (Feb. 2009).
`Do et al., "The Da Vinci Study: phase 2 primary results ofVEGF
`Trap-Eye in patients with diabetic macular edema" Opthamology
`118(9): 1819-1826 (Sep. 2011).
`The Eyetech Study Group, "Anti-Vascular Endothelial Growth
`Factor Therapy for Subfoveal Choroidal Neovascularization Sec(cid:173)
`ondary to Age-related Macular Degeneration" American Academy
`of Ophthamology, 110(5):979-986 (May 2003).
`Heier et al., "rhuFab V2 (anti-VEGF Antibody) for Treatment of
`Exudative AMD" Symposium 8:Experimental and Emerging Treat(cid:173)
`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., Phila(cid:173)
`delphia, PA, US, 116(11):2141-2148 (Nov. 1, 2009).
`Nichols, Earl R., "AAO: Ranibizumab (rhuRab) May Improve
`Vision in Age-Related Macular Degeneration" Doctors Guide
`Global Edition, www.pslgroup.com/dg/23f2aa.htrn, pp. 1-2 (Nov.
`24, 20013).
`Pai et al., "Current concepts in intravitreal drug therapy for diabetic
`retinopathy" Saudi Journal ofOpthamology 24(4)143-149 (Jun. 30,
`2010).
`Stewart, "THe expanding role of vascular endothelial growth factor
`inhibitors m opthamology" Mayo Clin Proc. 87(1):77-88 (Jan.
`2012).
`
`(Continued)
`Primary Examiner - Christine J Saoud
`Jon M Lockard
`Assistant Examiner -
`(74) Attorney, Agent, or Firm - Frank Cottingham; Karl
`Bozicevic
`ABSTRACT
`(57)
`The present invention provides methods for treating angio(cid:173)
`genic 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, branch retinal vein occlusion, and corneal neo(cid:173)
`vascularization.
`12 Claims, 1 Drawing Sheet
`
`Mylan Exhibit 1001
`Mylan v. Regeneron, IPR2021-00880
`Page 1
`
`Joining Petitioner: Apotex
`
`

`

`US 9,669,069 B2
`Page 2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`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 degenera(cid:173)
`tion" Ophthalmology (Sep. 2006) 113(9):1522el-1522el4 (epub
`Jul. 28, 2006).
`Charles, Steve (Guest Lecturer) "VEGF Trap Has Positive DME
`Data" Tenth Annual Retina Fellows Forum Jan. 29 and 30, Chicago,
`Article Date Mar. 1, 2010.
`Dixon et al., "VEGF Trap-Eye for the treatment of neobascular
`age-related macular degeneration" Expert Opin. Investig. Drugs
`(2009) 18 (10): 1-8.
`Information from Clinica!Trials.gov archive on the View 2 study
`(NCT00637377) "VEGF Trap-Eye: Investigation of Efficacy and
`Safety in Wet AMD (View 2)" version available and updated on
`Mar. 17, 2008.
`Information from ClinicalTrials.gov archive on the view of
`NCT00509795 "Vascular Endothelial Growth Factor (VEGF) Trap(cid:173)
`Eye: Investigation of Efficacy and Safety in Wet Age-Related
`Macular Degeneration (AMD)" (Dec. 1, 2009).
`
`Information from Clinica!Trials.gov archive on the view of
`NCT00789477 "DME and VEGF Trap-Eye: Investigation of Clini(cid:173)
`cal Impact" (Nov. 18, 2010).
`Information from Clinica!Trials.gov archive on the view of
`NCT00509795 "Vascular Endothelial Growth Factor (VEGF) Trap(cid:173)
`Eye: Investigation of Efficacy and Safety in Wet Age-Related
`Macular Degeneration (AMD)" (Jan. 7, 2011).
`Mousa and Mousa, "Current Status of Vascular Endothelial Growth
`Factor Inhibition in Age-Related Macular Degeneration" Biodrugs
`2010; 24(3); 183-194.
`Regeneron Pharmaceuticals, Inc. Form 10-Q, published on Nov. 7,
`2007 for the period ending Sep. 30, 2007.
`Regeneron, Press release "Regeneron Reports First Quarter 2008
`Financial and Operating Results", May 1, 2008.
`Regeneron Press Release "Bayer and Regeneron Report Positive
`Top-Line Results of Two Phase 3 Studies with VEGF Trap-Eye in
`Wet Age-related Macular Degeneration" Nov. 22, 2010.
`Regeneron Press Release "Regeneron and Bayer Report Positive
`Results for VEGF Trap-Eye in Phase 3 Study in Central Retinal Vein
`Occlusion (CRVO) and in Phase 2 Study in Diabetic Macular
`Edema (DME)" Dec. 20, 2010.
`Simo and Hernandez, "Advances in Medical Treatment of Diabetic
`Retinopathy" Diabetes Care, vol. 32, No. 8, Aug. 2009.
`Slides for the 2008 Retina Society Meeting "VEGF Trap-Eye in Wet
`AMD Clear-It 2: Summary of One-Year Key Results", Sep. 28,
`2008.
`WHO Drug Information, "International Nonproprietary Names for
`Pharmaceutical Substances (INN)" vol. 20, No. 2, 2006, pp. 115-
`119.
`
`Mylan Exhibit 1001
`Mylan v. Regeneron, IPR2021-00880
`Page 2
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`Jun.6,2017
`
`US 9,669,069 B2
`
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`Mylan Exhibit 1001
`Mylan v. Regeneron, IPR2021-00880
`Page 3
`
`Joining Petitioner: Apotex
`
`

`

`US 9,669,069 B2
`
`1
`USE OF A VEGF ANTAGONIST TO TREAT
`ANGIOGENIC EYE DISORDERS
`
`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 US Provisional Appli(cid:173)
`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 VEGF antagonists to treat
`eye disorders caused by or associated with angiogenesis.
`
`BACKGROUND
`
`10
`
`2
`VEGF antagonist to a patient over time. In particular, the
`methods of the invention comprise sequentially administer(cid:173)
`ing to the patient a single initial dose of a VEGF antagonist,
`followed by one or more secondary doses of the VEGF
`5 antagonist, followed by one or more tertiary doses of the
`VEGF antagonists. The present inventors have surprisingly
`discovered
`that beneficial
`therapeutic effects can be
`achieved in patients suffering from angiogenic eye disorders
`by administering a VEGF antagonist to a patient at a
`frequency of once every 8 or more weeks, especially when
`such doses are preceded by about three doses administered
`to the patient at a frequency of about 2 to 4 weeks. Thus,
`according to the methods of the present invention, each
`secondary dose of VEGF antagonist is administered 2 to 4
`weeks after the immediately preceding dose, and each
`15 tertiary dose is administered at least 8 weeks after the
`immediately preceding dose. An example of a dosing regi(cid:173)
`men of the present invention is shown in the FIGURE. 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
`20 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.).
`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(cid:173)
`ization, etc.
`The methods of the present invention comprise adminis-
`tering any VEGF antagonist to the patient. In one embodi(cid:173)
`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
`35 invention is a multimeric VEGF-binding protein comprising
`two or more VEGF receptor-based chimeric molecules
`referred to herein as "VEGFR1R2-FcllCl(a)" or "afliber(cid:173)
`cept."
`Various administration routes are contemplated for use in
`40 the methods of the present invention, including, e.g., topical
`administration or intraocular administration ( e.g., intravit(cid:173)
`real administration).
`Aflibercept (EYLEA™, Regeneron Pharmaceuticals, Inc)
`was approved by the FDA in November 2011, for the
`45 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
`intravitreal injection once every 8 weeks.
`Other embodiments of the present invention will become
`apparent from a review of the ensuing detailed description.
`
`30
`
`Several eye disorders are associated with pathological
`angiogenesis. For example, the development of age-related 25
`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
`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 abnor(cid:173)
`mal 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-promot(cid:173)
`ing properties of VEGF appears to be an effective strategy
`for treating angiogenic eye disorders.
`FDA-approved treatments of angiogenic eye disorders 50
`such as AMD and CRVO include the administration of an
`anti-VEGF antibody called
`ranibizumab
`(Lucentis®,
`Genentech, Inc.) on a monthly basis by intravitreal injection.
`Methods for treating eye disorders using VEGF antago(cid:173)
`nists are mentioned in, e.g., U.S. Pat. No. 7,303,746; U.S. 55
`Pat. No. 7,306,799; U.S. Pat. No. 7,300,563; U.S. Pat. No.
`7,303,748; and US 2007/0190058. Nonetheless,
`there
`remains a need in the art for new administration regimens for
`angiogenic eye disorders, especially those which allow for
`less frequent dosing while maintaining a high level of 60
`efficacy.
`
`BRIEF SUMMARY OF THE INVENTION
`
`BRIEF DESCRIPTION OF THE FIGURE
`
`The FIGURE shows an exemplary dosing regimen of the
`present invention. In this regimen, a single "initial dose" of
`VEGF antagonist ("VEGFT') is administered at the begin(cid:173)
`ning of the treatment regimen (i.e. at "week O"), two
`"secondary doses" are administered at weeks 4 and 8,
`respectively, and at least six "tertiary doses" are adminis(cid:173)
`tered once every 8 weeks thereafter, i.e., at weeks 16, 24, 32,
`40, 48, 56, etc.).
`
`DETAILED DESCRIPTION
`
`The present invention provides methods for treating 65
`angiogenic eye disorders. The methods of the invention
`comprise sequentially administering multiple doses of a
`
`Before the present invention is described, it is to be
`understood that this invention is not limited to particular
`
`Mylan Exhibit 1001
`Mylan v. Regeneron, IPR2021-00880
`Page 4
`
`Joining Petitioner: Apotex
`
`

`

`US 9,669,069 B2
`
`15
`
`3
`methods and experimental conditions described, as such
`methods and conditions may vary. It is also to be understood
`that the terminology used herein is for the purpose of
`describing particular embodiments only, and is not intended
`to be limiting, since the scope of the present invention will 5
`be limited only by the appended claims.
`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 10
`used in reference to a particular recited numerical value,
`means that the value may vary from the recited value by no
`more than 1 %. For example, as used herein, the expression
`"about 100" includes 99 and 101 and all values in between
`(e.g., 99.1, 99.2, 99.3, 99.4, etc.).
`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
`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 ofVEGF antagonist is 25
`administered to the patient at a different point in time, e.g.,
`on different days separated by a predetermined interval ( e.g.,
`hours, days, weeks or months). The present invention
`includes methods which comprise sequentially administer(cid:173)
`ing to the patient a single initial dose of a VEGF antagonist, 30
`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 35
`the VEGF antagonist. Thus, the "initial dose" is the dose
`which is administered at the beginning of the treatment
`regimen (also referred to as the "baseline dose"); the "sec(cid:173)
`ondary doses" are the doses which are administered after the
`initial dose; and the "tertiary doses" are the doses which are 40
`administered after the secondary doses. The initial, second(cid:173)
`ary, and tertiary doses may all contain the same amount of
`VEGF antagonist, but will generally differ from one another
`in terms of frequency of administration. In certain embodi(cid:173)
`ments, however, the amount of VEGF antagonist contained 45
`in the initial, secondary and/or tertiary doses will vary from
`one another ( e.g., adjusted up or down as appropriate) during
`the course of treatment.
`In one exemplary embodiment of the present invention,
`each secondary dose is administered 2 to 4 (e.g., 2, 2½, 3,
`3½, or 4) weeks after the immediately preceding dose, and
`each tertiary dose is administered at least 8 (e.g., 8, 8½, 9,
`9½, 10, 10½, 11, 11 ½, 12, 12½, 13, 13½, 14, 14½, or more)
`weeks after the immediately preceding dose. The phrase "the
`immediately preceding dose," as used herein, means, in a
`sequence of multiple administrations, the dose of VEGF
`antagonist which is administered to a patient prior to the
`administration of the very next dose in the sequence with no
`intervening doses.
`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 adminis(cid:173)
`tered 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
`
`4
`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
`the FIGURE.
`The methods of the invention may comprise administer(cid:173)
`ing to a patient any number of secondary and/or tertiary
`doses of a VEGF antagonist. For example, in certain
`embodiments, only a single secondary dose is administered
`to the patient. In other embodiments, two or more ( e.g., 2, 3,
`4, 5, 6, 7, 8, or more) secondary doses are administered to
`the patient. Likewise, in certain embodiments, only a single
`tertiary dose is administered to the patient. In other embodi(cid:173)
`ments, 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
`immediately preceding dose. Similarly, in embodiments
`20 involving multiple tertiary doses, each tertiary dose may be
`administered at the same frequency as the other tertiary
`doses. For example, each tertiary dose may be administered
`to the patient 8 weeks after the immediately preceding dose.
`Alternatively, the frequency at which the secondary and/or
`tertiary doses are administered to a patient can vary over the
`course of the treatment regimen. For example, the present
`invention includes methods which comprise administering
`to the patient a single initial dose of a VEGF antagonist,
`followed by one or more secondary doses of the VEGF
`antagonist, followed by at least 5 tertiary doses of the VEGF
`antagonist, wherein the first four tertiary doses are admin-
`istered 8 weeks after the immediately preceding dose, and
`wherein each subsequent tertiary dose is administered from
`8 to 12 (e.g., 8, 8½, 9, 9½, 10, 10½, 11, 11 ½, 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(cid:173)
`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
`interferes with the normal biological activity of VEGF.
`VEGF antagonists include molecules which interfere with
`the interaction between VEGF and a natural VEGF receptor,
`e.g., molecules which bind to VEGF or a VEGF receptor and
`prevent or otherwise hinder the interaction between VEGF
`and a VEGF receptor. Specific exemplary VEGF antagonists
`50 include anti-VEGF antibodies, anti-VEGF receptor antibod(cid:173)
`ies, and VEGF receptor-based chimeric molecules (also
`referred to herein as "VEGF-Traps").
`VEGF receptor-based chimeric molecules include chime(cid:173)
`ric polypeptides which comprise two or more immunoglobu-
`55 !in (Ig)-like domains of a VEGF receptor such as VEGFRl
`(also referred to as Fltl) and/or VEGFR2 (also referred to as
`Flkl or KDR), 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).
`60 An exemplary VEGF receptor-based chimeric molecule is a
`molecule referred to as VEGFR1R2-FcllCl(a) which is
`encoded by the nucleic acid sequence of SEQ ID NO: 1.
`VEGFR1R2-FcllCl(a) comprises three components: (1) a
`VEGFRl component comprising amino acids 27 to 129 of
`65 SEQ ID NO:2; (2) a VEGFR2 component comprising amino
`acids 130 to 231 of SEQ ID NO:2; and (3) a multimerization
`component ("FcllCl(a)") comprising amino acids 232 to
`
`Mylan Exhibit 1001
`Mylan v. Regeneron, IPR2021-00880
`Page 5
`
`Joining Petitioner: Apotex
`
`

`

`US 9,669,069 B2
`
`5
`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.,
`U.S. Pat. No. 7,396,664).Amino acids 1-26 of SEQ ID NO:2
`are the signal sequence.
`The VEGF antagonist used in the Examples set forth
`herein below is a dimeric molecule comprising two
`VEGFR1R2-FcllCl(a) molecules and is referred to herein as
`"VEGFT." Additional VEGF receptor-based chimeric mol(cid:173)
`ecules which can be used in the context of the present
`invention are disclosed in U.S. Pat. Nos. 7,396,664, 7,303,
`746 and WO 00/75319.
`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 prolif(cid:173)
`eration of blood vessels or by blood vessel leakage. Non(cid:173)
`limiting examples of angiogenic eye disorders that are
`treatable using the methods of the present invention include
`age-relatedmacular degeneration (e.g., wetAMD, 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, cor(cid:173)
`neal neovascularization, retinal neovascularization, vitreal
`neovascularization, pannus, pterygium, vascular retinopa(cid:173)
`thy, and diabetic retinopathies.
`Pharmaceutical Formulations
`The present invention includes methods in which the
`VEGF antagonist that is administered to the patient is
`contained within a pharmaceutical formulation. The phar(cid:173)
`maceutical formulation may comprise the VEGF antagonist
`along with at least one inactive ingredient such as, e.g., a
`pharmaceutically acceptable carrier. Other agents may be
`incorporated into the pharmaceutical composition to provide
`improved transfer, delivery, tolerance, and the like. The term
`"pharmaceutically acceptable" means approved by a regu(cid:173)
`latory 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 adminis(cid:173)
`tered. A multitude of appropriate formulations can be found
`in the formulary known to all pharmaceutical chemists:
`Remington's Pharmaceutical Sciences (15th ed, Mack Pub(cid:173)
`lishing 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
`LIPOFECTIWM), 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 contain(cid:173)
`ing carbowax. Any of the foregoing mixtures may be appro(cid:173)
`priate 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 compat(cid:173)
`ible and tolerable with the route of administration. See also
`Powell et al. PDA (1998) J Pharm Sci Technol. 52:238-311
`and the citations therein for additional information related to
`excipients and carriers well known to pharmaceutical chem(cid:173)
`ists.
`
`6
`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
`5 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.,
`10 ethanol), a polyalcohol (e.g., propylene glycol, polyethylene
`glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50
`(polyoxyethylene (50 mo!) 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 combi-
`15 nation with a solubilizing agent such as benzyl benzoate,
`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
`20 comprising the VEGF antagonist) may be administered to
`the patient by any known delivery system and/or adminis(cid:173)
`tration method. In certain embodiments, the VEGF antago(cid:173)
`nist is administered to the patient by ocular, intraocular,
`intravitreal or subconjunctival injection. In other embodi-
`25 ments, 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,
`30 intramuscular, intraperitoneal, intravenous, subcutaneous,
`intranasal, epidural, and oral.
`Amount of VEGF Antagonist Administered
`Each dose ofVEGF antagonist administered to the patient
`over the course of the treatment regimen may contain the
`35 same, or substantially the same, amount of VEGF antago(cid:173)
`nist. Alternatively, the quantity of VEGF antagonist con(cid:173)
`tained within the individual doses may vary over the course
`of the treatment regimen. For example, in certain embodi(cid:173)
`ments, a first quantity ofVEGF antagonist is administered in
`40 the initial dose, a second quantity of VEGF antagonist is
`administered in the secondary doses, and a third quantity of
`VEGF antagonist is administered in the tertiary doses. The
`present invention contemplates dosing schemes in which the
`quantity ofVEGF antagonist contained within the individual
`45 doses increases over time (e.g., each subsequent dose con(cid:173)
`tains more VEGF antagonist than the last), decreases over
`time ( e.g., each subsequent dose contains less VEGF antago(cid:173)
`nist than the last), initially increases then decreases, initially
`decreases then increases, or remains the same throughout the
`50 course of the administration regimen.
`The amount of VEGF antagonist administered to the
`patient in each dose is, in most cases, a therapeutically
`effective amount. As used herein, the phrase "therapeutically
`effective amount" means a dose of VEGF antagonist that
`55 results in a detectable improvement in one or more symp(cid:173)
`toms 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
`60 molecule such as VEGFR1R2-FcllCl(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
`65 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
`
`Mylan Exhibit 1001
`Mylan v. Regeneron, IPR2021-00880
`Page 6
`
`Joining Petitioner: Apotex
`
`

`

`US 9,669,069 B2
`
`5
`
`8
`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 1 mg. No serious adverse events related to the study
`drug, and no identifiable intraocular inflammation was
`reported. Preliminary results showed that, following injec(cid:173)
`tion 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 thick-
`10 ness-179µ)] on optical coherence tomography (OCT) was
`reduced from 119µ to 27µ as assessed by Fast Macular Scan
`and from 194µ to 60µ 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
`15 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 2:3 lines.
`
`Example 2: Phase II Clinical Trial of Repeated
`Doses of Intravitreally Administered VEGF
`Receptor-Based Chimeric Molecule (VEGFT) in
`Subjects with Neovascular AMD
`
`7
`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
`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 VEGF anta