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`Apotex Exhibit 1013
`Apotex Exhibit 1013
`Page 1 of 423
`Page 1 of 423
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`C] Powerof Attorney
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`Other:
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`PTO/AIA/15 (03-13)
`Approved for use through 01/31/2014, OMB 0651-0032
`U.S, Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
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`Attorney Dacket No.
`725A1
`UTILITY
`anaes|YANCOPOULOS
`PATENT APPLICATION
`TRANSMITTAL
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`37 CFR 3.73(c) Statement
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`19. CORRESPONDENCE ADDRESS
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`The address associated with Customer Number; 96387
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`fsignature |/ Frank R. Cottingham / July 12, 2013
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`Apotex Exhibit 1013
`Apotex Exhibit 1013
`Page 2 of 423
`Page 2 of 423
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`Apotex Exhibit 1013
`Apotex Exhibit 1013
`Page 3 of 423
`Page 3 of 423
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`Electronic Patent Application Fee Transmittal
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`Application Number:
`
`Filing Date:
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`Title of Invention:
`
`USE OF A VEGF ANTAGONIST TO TREAT ANGIOGENIC EYE DISORDERS
`
`Frank Robert Cottinaham
`
`
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`First Named Inventor/Applicant Name: George D. YANCOPOULOS
`
`Filer:
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`Attorney Docket Number: 725A1
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`Utility application filing
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`1
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`280
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`280
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`UtilitySearch Fee
`Utility Examination Fee
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`600
`720
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`|
`|
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`600
`720
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`|
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`1111
`1311
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`1
`1
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`Apotex Exhibit 1013
`Apotex Exhibit 1013
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`Apotex Exhibit 1013
`Apotex Exhibit 1013
`Page 5 of 423
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`Electronic AcknowledgementReceipt
`
`
`16298087
`EFS ID;
`
`
`Application Number:
`
`13940370
`
`International Application Number:
`
`Confitmation Number:
`
`1055
`
`Title of Invention:
`
`USE OF A VEGF ANTAGONIST TO TREAT ANGIOGENIC EYE DISORDERS
`
`
`
`
`
`First Named Inventor/Applicant Name:
`
`George D. YANCOPOULOS
`
`
`
`Customer Number:
`
`96387
`
`Filer:
`
`Frank Robert Cottingham
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`Attorney Docket Number:
`
`725A1
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`Receipt Date:
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`12-JUL-2013
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`Filing Date:
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`Time Stamp:
`11:18:49
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`Application Type: Utility under 35 USC 17 1la)
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`Apotex Exhibit 1013
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`Abstract
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`Apotex Exhibit 1013
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`Page 7 of 423
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`Transmittal of New Application
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`pdf
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`(Aaahseh peBT
`ani
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`Information:
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`32862
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`B
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`Fee Worksheet (SBO6)
`
`eee day Laldle detteb iteeueal pall,
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`fee-info.pdF
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`no
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`F
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`This Acknowledgement Receipt evidences receipt on the noted date by the USPTO of the indicated documents,
`characterized by the applicant, and including page counts, where applicable.It serves as evidence of receipt similar toa
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`Apotex Exhibit 1013
`Apotex Exhibit 1013
`Page 8 of 423
`Page 8 of 423
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`
`Electronic AcknowledgementReceipt
`
`
`16298087
`EFS ID;
`
`
`Application Number:
`
`13940370
`
`International Application Number:
`
`Confitmation Number:
`
`1055
`
`Title of Invention:
`
`USE OF A VEGF ANTAGONIST TO TREAT ANGIOGENIC EYE DISORDERS
`
`
`
`
`
`First Named Inventor/Applicant Name:
`
`George D. YANCOPOULOS
`
`
`
`Customer Number:
`
`96387
`
`Filer:
`
`Frank Robert Cottingham
`
`Attorney Docket Number:
`
`725A1
`
`
`
`Receipt Date:
`
`12-JUL-2013
`
`Filing Date:
`
`Time Stamp:
`11:18:49
`
`
`
`
`Application Type: Utility under 35 USC 17 1la)
`
`Paymentinformation:
`
`Submitted with Payment
`
`
`
`Authorized User
`
`The Director of the USPTO is hereby authorized to charge indicated fees and credit any overpaymentas follows:
`Charge any Additional Fees required under 37 CF.R. Section 1.16 (National application filing, search, and examinationfees)
`Charge any Additional Fees required under 37 CF.R. Section 1.17 (Patent application and reexamination processing fees)
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`Apotex Exhibit 1013
`Apotex Exhibit 1013
`Page 9 of 423
`Page 9 of 423
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`Charge any Additional Fees required under 37 CF.R. Section 1.19 (Document supply fees)
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`Number Message Digest|Part/.zip|Recimtet Desceean Cie Name (ifappl.)
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`§29155
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`725A1_Specification.pdf
`FebE16 Tal? 15UeeS
`al
`
`eee peeeeuonsetfend
`
`Multipart Description/PDF files in .zip description
`
`
`
`
`
`Specification
`
`Abstract
`
`1
`
`22
`
`24
`
`21
`
`23
`
`24
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`Warnings:
`Information:
`
`:
`caine
`‘3
`725A1_Figureipdf
`Drawings ae on white line
`3
`9
`ASRGSS TT eSRSIS0S |
`Wibdke
`
`Warnings:
`
`105393
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`The page size in the PDF is too large. The pages should be 8.5 x 11 of A4 If this PDF is submitted, the pages will be resized upon entry inta the
`Image File Wrapper and may affect subsequent processing
`Information:
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`725A1_SeqList-paper,pdf
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`S11 (Uneiadhe| (onSame sy I
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`Warnings:
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`4
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`SequenceListing (Text File)
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`725A1_SeqList.txt
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`6076
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`1255991
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`Application Data Sheet
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`725A1_AppDataSheet.pdf
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`Apotex Exhibit 1013
`Apotex Exhibit 1013
`Page 10 of 423
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`Transmittal of New Application
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`725A1_ApplicationTransmittal.
`pdf
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`(Aaahseh peBT
`ani
`
`Information:
`
`32862
`
`B
`
`Fee Worksheet (SBO6)
`
`eee day Laldle detteb iteeueal pall,
`
`
`fee-info.pdF
`
`no
`
`F
`
`Warnings:
`Information:
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`Tatal Files Size (in bytes)
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`2528997
`
`This Acknowledgement Receipt evidences receipt on the noted date by the USPTO of the indicated documents,
`characterized by the applicant, and including page counts, where applicable.It serves as evidence of receipt similar toa
`Post Card, as described in MPEP 503.
`
`New Applications Under 35 U.S.C. 111
`If a new applicationis being filed and the application includes the necessary componentsfor a filing date (see 37 CFR
`1.53(b)-(d) and MPEP 506), a Filing Receipt (37 CFR 1.54) will be issued in due course and the date shown onthis
`AcknowledgementReceiptwill establish the filing date of the application,
`
`National Stage of an International Application under 35 U.S.C, 371
`Ifa timely submission to enter the national stage of an international application is compliant with the conditions of 35
`U.S.C. 371 and other applicable requirements a Form PCT/DO/EO/903 indicating acceptance of the application asa
`national stage submission under 35 U.S.C. 371 will be issued in addition to the Filing Receipt, in due course.
`
`New International Application Filed with the USPTO as a Receiving Office
`If a new international application is being filed and the international application includes the necessary components for
`an international filing date (see PCT Article 11 and MPEP 1810), a Notification of the International Application Number
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`Apotex Exhibit 1013
`Apotex Exhibit 1013
`Page 11 of 423
`Page 11 of 423
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`USE OF A VEGF ANTAGONIST TO TREAT ANGIOGENIC EYE DISORDERS
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`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
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`caused by or associated with angiogenesis.
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`BACKGROUND
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`[0003]
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`Several eye disorders are associated with pathological angiogenesis. For example, the
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`developmentof age-related macular degeneration (AMD)is associated with a process called
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`choroidal neovascularization (CNV). Leakage from the CNV causes macular edema and collection
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`of fluid beneath the macula resulting in vision loss. Diabetic macular edema (DME) is another eye
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`disorder with an angiogenic component. DMEis the most prevalent cause of moderate vision loss
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`in patients with diabetes and is a common complication of diabetic retinopathy, a disease affecting
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`the blood vessels of the retina. Clinically significant DME occurs whenfluid leaks into the center of
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`the macula, the light-sensitive part of the retina responsible for sharp, direct vision. Fluid in the
`
`macula can cause severevision loss or blindness. Yet another eye disorder associated with
`
`abnormal angiogenesis is central retinal vein occlusion (CRVO). CRVOis caused by obstruction of
`
`the central retinal vein that leads to a back-up of blood andfluid in the retina. The retina can also
`
`becomeischemic, 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 CRVOinclude
`[0004]
`the administration of an anti-VEGF antibody called ranibizumab (Lucentis®, Genentech, Inc.) on a
`
`monthly basis byintravitreal injection.
`[0005] Methodsfortreating 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,
`
`ete
`
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`
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`there remains a need in the art for new administration regimens for angiogenic eye disorders,
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`especially those which allow for less frequent dosing while maintaining a high level of efficacy,
`
`BRIEF SUMMARY OF THE INVENTION
`
`[0006] The present invention provides methodsfortreating angiogenic eye disorders. The
`
`methodsof 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 more tertiary 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 presentinvention, each secondary dose of VEGF
`
`antagonist is administered 2 to 4 weeksafter the immediately preceding dose, and eachtertiary
`
`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
`
`regimenis 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) comparedto prior administration regimensfor
`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, é.g., age related macular degeneration, diabetic retinopathy, diabetic macular edema,
`
`central retinal vein occlusion, corneal neovascularization, etc.
`
`[0008] The methodsof 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 usedin 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 methodsof 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 administered byintravitreal injection every 4
`
`-2-
`
`
`
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`weeksfor the first three months, followed by 2 mg administered byintravitreal injection once every
`8 weeks.
`
`[0011] Other embodiments of 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,
`
`andat least 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 understood that the terminology Usedherein is for the purpose
`
`of describing particular embodiments only. and is not intended to belimiting. since the scope of the
`
`presentinvention will be limited only by the appendedclaims.
`
`[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 used in reference to a particular recited numerical value,
`meansthat 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 107 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
`
`usedin the practice or testing of the present invention, the preferred methods and materials are
`now described.
`
`DOSING REGIMENS
`
`[0016] The present invention provides methodsfor 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 thal each dose of VEGF antagonist
`
`is administered to the patient al 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 patienta single initial dose of a VEGF
`
`-3-
`
`
`
`
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`antagonist, followed by one or more secondary doses of the VEGF antagonist, followed by one or
`
`more tertiary 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. Theinitial, 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 contained in theinitial, secondary and/ortertiary doses will vary from
`
`one another(e.g., adjusted up or down as appropriate) during the course of treatment.
`
`[0018]
`
`In one exemplary embodimentof the present invention, each secondary doseis
`
`administered 2 to 4 (@.g., 2, 244, 3, 34, or 4) weeksafter the immediately preceding dose, and each
`
`tertiary dose is administered at least 8 (e.g., 8, 844, 9, 914, 10, 10%, 11, 1114, 12, 1214, 13, 13%, 14,
`
`14%, 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
`
`VEGFantagonist 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 embodimentof the present invention, a singleinitial 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(i.e,, at week 4 and at week8). followed by at least 5 tertiary doses, each administered eight
`
`weeksafter the immediately preceding dose (/.e., at weeks 16, 24, 32,40 and 48). Thetertiary
`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.
`
`[0020]
`
`The methodsof the invention may comprise administering to a patient any number of
`
`secondary and/ortertiary 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(eé.g.. 2,
`
`3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient. Likewise, in certain
`
`In other embodiments, two
`embodiments, only a single tertiary dose is administered to the patient.
`or more (@.g., 2. 3, 4, 5, 6, 7, 8, or more)tertiary doses are administered to the patient.
`
`[0021]
`
`|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 weeksafter the immediately preceding dose. Similarly,
`in embodiments 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
`
`-4-
`
`
`
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`to the patient 8 weeksafter the immediately preceding dose. Alternatively, the frequency at which
`
`the secondary and/ortertiary 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 antagonisl, followed by at least 5 tertiary doses of the VEGF
`
`antagonist, wherein thefirst four tertiary doses are administered 8 weeksafter the immediately
`
`preceding dose, and wherein each subsequenttertiary dose is administered from 8 to 12 (e.g., 8,
`
`8%, 9, 9%, 10, 10%, 11, 11%, 12) weeks after the immediately preceding dose. The frequencyof
`
`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
`
`[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
`
`antagonisl" means any molecule that blocks, reducesorinterferes with the normalbiological activity
`of VEGF.
`
`[0023] VEGF antagonists include molecules which interfere with the interaction between VEGF
`
`and a natural VEGFreceptor, e.g., molecules which bind to VEGF or a VEGF receptor and prevent
`
`or otherwise hinderthe interaction between VEGF and a VEGF receptor, Specific exemplary VEGF
`
`antagonists include anti-VEGF antibodies. a