DocCode - SEQ.TXT
`
`SCORE Placeholder Sheet for IFW Content
`
`Application Number: 13940370
`
`Document Date: 07/12/2013
`
`The presence of this form in the IFW record indicates that the following document type was
`received in electronic format on the date identified above. This content is stored in the SCORE
`database.
`
`Sequence Listing
`
`Since this was an electronic submission, there is no physical artifact folder, no artifact folder is
`recorded in PALM, and no paper documents or physical media exist. The TIFF images in the
`IFW record were created from the original documents that are stored in SCORE.
`
`To access the documents in the SCORE database, refer to instructions developed by SIRA.
`
`At the time of document entry (noted above):
`• Examiners may access SCORE content via the eDAN interface.
`•Other USPTO employees can bookmark the current SCORE URL
`(http://es/ScoreAccessWeb/).
`•External customers may access SCORE content via the Public and Private PAIR
`interfaces.
`
`Form Revision Date: February 8, 2006
`
`Mylan Exhibit 1017
`Mylan v. Regeneron, IPR2021-00881
`Page 1
`
`Joining Petitioner: Apotex
`
`

`

`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
`Under the Panerwork Reduction Act of 1995 no nersons are renuired to resnond to a collection of information unless it disnlavs a valid OMB control number
`""'\
`725A1
`First Named Inventor YANCOPOULOS
`
`Attorney Docket No.
`
`UTILITY
`PATENT APPLICATION
`TRANSMITTAL
`
`r
`
`\...
`
`(Only for new non provisional applications under 37 CFR 1.53{b))
`
`APPLICATION ELEMENTS
`See MPEP chapter 600 concerning utility patent application contents.
`
`i .D Fee Transmittal Form
`(PTO/SB/17 or equivalent)
`
`2.0 Applicant asserts small entity status.
`See 37 CFR 1.27
`3.o Applicant certifies micro entity status. See 37 CFR 1.29.
`Applicant must attach form PTO/SB/15A or B or equivalent.
`
`Title
`
`Use of a VEGF Antagonist to Treat Angiogenic.
`
`Express Moil Lobel No. N/A
`
`ADDRESS TO:
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`ACCOMPANYING APPLICATION PAPERS
`10. D Assignment Papers
`(cover sheet & document(s))
`Name of Assignee
`
`[Toto/ Pages 24
`4.0 Specification
`Both the claims and abstract must start on a new page.
`(See MPEP § 608.0l{a) for information on the preferred arrangement)
`12.D English Translation Document
`l
`(if applicable)
`l 13.o Information Disclosure Statement
`(PTO/SB/08 or PT0-1449)
`
`l 1i.D 37 CFR 3.73(c) Statement
`(when there is an assignee)
`
`D
`
`Power of Attorney
`
`5. 0
`
`Drawing(s) (35 U.S.C. 113)
`
`[Toto/ Sheets 1
`
`6. Inventor's Oath or Declaration
`[Toto/ Pages
`(including substitute statements under 37 CFR 1. 64 and assignments
`serving as an oath or declaration under 37 CFR 1. 63(e))
`
`a. D
`
`Newly executed (original or copy)
`
`b. D
`
`A copy from a prior application (37 CFR 1.63(d))
`
`7.0 Application Data Sheet
`*See note below.
`See 37 CFR 1.76 (PTO/AIA/14 or equivalent)
`
`8.
`
`CD-ROM or CD-R
`in duplicate, large table, or Computer Program (Appendix)
`
`Landscape Table on CD
`
`D
`9. Nucleotide and/or Amino Acid Sequence Submission
`(if opplicob/e, items o. - c. ore required)
`
`a. 0
`
`b. 0
`
`Computer Readable Form (CRF)
`
`Specification Sequence Listing on:
`
`i. D CD-ROM or CD-R (2 copies); or
`
`ii.0 Paper
`
`c. 0
`
`Statements verifying identity of above copies
`
`D
`
`Copies of citations attached
`
`14.o Preliminary Amendment
`Return Receipt Postcard
`15. 0
`(MPEP § 503) (Should be specifically itemized)
`
`16.o Certified Copy of Priority Document(s)
`(if foreign priority is claimed)
`
`17. 0
`
`Nonpublication Request
`Under 35 U.S.C. 122(b)(2)(B)(i). Applicant must attach form PTO/SB/35
`or equivalent.
`
`18. 0
`
`Other:
`
`*Note: (1) Benefit claims under 37 CFR 1. 78 and foreign priority claims under 1.55 must be included in an Application Data Sheet (ADS).
`(2) For applications filed under 35 U.S.C. 111, the application must contain an ADS specifying the applicant if the applicant is an
`assignee, person to whom the inventor is under an obligation to assign, or person who otherwise shows sufficient proprietary
`interest in the matter. See 37 CFR 1.46(b).
`19. CORRESPONDENCE ADDRESS
`
`The address associated with Customer Number: 96387
`
`0
`
`ORD Correspondence address below
`
`Name
`
`I Zip Code
`I
`
`Email
`
`Address
`
`City
`
`Country
`
`Signature
`
`Name
`(Print/Type)
`
`State I
`I
`I Telephone I
`I Frank R. Cottingham I
`Frank R. Cottingham
`This collection of information is required by 37 CFR 1.53(b). The information is required to obtain or retain a benefit by the public which is to file (and by the USPTO
`to process) an application. Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.11and1.14. This collection is estimated to take 12 minutes to complete,
`including gathering, preparing, and submitting the completed application form to the USPTO. Time will vary depending upon the individual case. Any comments on
`the amount of time you require to complete this form and/or suggestions for reducing this burden, should be sent to the Chief Information Officer, U.S. Patent and
`Trademark Office, U.S. Department of Commerce, P.O. Box 1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED FORMS TO THIS ADDRESS. SEND
`TO: Commissioner for Patents, P.O. Box 1450, Alexandria, VA 22313-1450.
`If you need assistance in completing the form, call 1-800-PT0-9199 and select option 2.
`
`Date
`
`July 12, 2013
`Registration No. 50,437
`
`(Attorney/Agent)
`
`Mylan Exhibit 1017
`Mylan v. Regeneron, IPR2021-00881
`Page 2
`
`Joining Petitioner: Apotex
`
`

`

`Privacy Act Statement
`
`The Privacy Act of 1974 (P.L. 93-579) requires that you be given certain information in connection with your
`submission of the attached form related to a patent application or patent. Accordingly, pursuant to the
`requirements of the Act, please be advised that: (1) the general authority for the collection of this information is
`35 U.S.C. 2(b)(2); (2) furnishing of the information solicited is voluntary; and (3) the principal purpose for which
`the information is used by the U.S. Patent and Trademark Office is to process and/or examine your submission
`If you do not furnish the requested information, the U.S. Patent and
`related to a patent application or patent.
`Trademark Office may not be able to process and/or examine your submission, which may result in termination
`of proceedings or abandonment of the application or expiration of the patent.
`
`The information provided by you in this form will be subject to the following routine uses:
`
`1. The information on this form will be treated confidentially to the extent allowed under the Freedom of
`Information Act (5 U.S.C. 552) and the Privacy Act (5 U.S.C 552a). Records from this system of
`records may be disclosed to the Department of Justice to determine whether disclosure of these
`records is required by the Freedom of Information Act.
`2. A record from this system of records may be disclosed, as a routine use, in the course of presenting
`evidence to a court, magistrate, or administrative tribunal, including disclosures to opposing counsel in
`the course of settlement negotiations.
`3. A record in this system of records may be disclosed, as a routine use, to a Member of Congress
`submitting a request involving an individual, to whom the record pertains, when the individual has
`requested assistance from the Member with respect to the subject matter of the record.
`4. A record in this system of records may be disclosed, as a routine use, to a contractor of the Agency
`having need for the information in order to perform a contract. Recipients of information shall be
`required to comply with the requirements of the Privacy Act of 1974, as amended, pursuant to 5 U.S.C.
`552a(m).
`5. A record related to an International Application filed under the Patent Cooperation Treaty in this
`system of records may be disclosed, as a routine use, to the International Bureau of the World
`Intellectual Property Organization, pursuant to the Patent Cooperation Treaty.
`6. A record in this system of records may be disclosed, as a routine use, to another federal agency for
`purposes of National Security review (35 U.S.C. 181) and for review pursuant to the Atomic Energy Act
`(42 U.S.C. 218(c)).
`7. A record from this system of records may be disclosed, as a routine use, to the Administrator, General
`Services, or his/her designee, during an inspection of records conducted by GSA as part of that
`agency's responsibility to recommend improvements in records management practices and programs,
`under authority of 44 U.S.C. 2904 and 2906. Such disclosure shall be made in accordance with the
`GSA regulations governing inspection of records for this purpose, and any other relevant (i.e., GSA or
`Commerce) directive. Such disclosure shall not be used to make determinations about individuals.
`8. A record from this system of records may be disclosed, as a routine use, to the public after either
`publication of the application pursuant to 35 U.S.C. 122(b) or issuance of a patent pursuant to 35
`U .S.C. 151. Further, a record may be disclosed, subject to the limitations of 37 CFR 1.14, as a routine
`use, to the public if the record was filed in an application which became abandoned or in which the
`proceedings were terminated and which application is referenced by either a published application, an
`application open to public inspection or an issued patent.
`9. A record from this system of records may be disclosed, as a routine use, to a Federal, State, or local
`law enforcement agency, if the USPTO becomes aware of a violation or potential violation of law or
`regulation.
`
`Mylan Exhibit 1017
`Mylan v. Regeneron, IPR2021-00881
`Page 3
`
`Joining Petitioner: Apotex
`
`

`

`Electronic Patent Application Fee Transmittal
`
`Application Number:
`
`Filing Date:
`
`Title of Invention:
`
`USE OF A VEGF ANTAGONIST TO TREAT ANGIOGENIC EYE DISORDERS
`
`First Named Inventor/Applicant Name:
`
`George D. YANCOPOULOS
`
`Filer:
`
`Frank Robert Cottingham
`
`Attorney Docket Number:
`
`725Al
`
`Filed as Large Entity
`
`Utility under 35 USC 111 (a) Filing Fees
`
`Description
`
`Fee Code
`
`Quantity
`
`Amount
`
`Sub-Total in
`USO($)
`
`Basic Filing:
`
`Utility application filing
`
`Utility Search Fee
`
`Utility Examination Fee
`
`1011
`
`1111
`
`1311
`
`1
`
`1
`
`1
`
`280
`
`600
`
`720
`
`280
`
`600
`
`720
`
`Pages:
`
`Claims:
`
`Miscellaneous-Filing:
`
`Petition:
`
`Patent-Appeals-and-Interference:
`
`Mylan Exhibit 1017
`Mylan v. Regeneron, IPR2021-00881
`Page 4
`
`Joining Petitioner: Apotex
`
`

`

`Description
`
`Fee Code
`
`Quantity
`
`Amount
`
`Sub-Total in
`USO($)
`
`Post-Allowance-and-Post-Issuance:
`
`Extension-of-Time:
`
`Miscellaneous:
`
`Total in USO($)
`
`1600
`
`Mylan Exhibit 1017
`Mylan v. Regeneron, IPR2021-00881
`Page 5
`
`Joining Petitioner: Apotex
`
`

`

`Electronic Acknowledgement Receipt
`
`EFSID:
`
`Application Number:
`
`16298087
`
`13940370
`
`International Application Number:
`
`Confirmation 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
`
`Filer Authorized By:
`
`Attorney Docket Number:
`
`725Al
`
`Receipt Date:
`
`12-JUL-2013
`
`Filing Date:
`
`Time Stamp:
`
`11:18:49
`
`Application Type:
`
`Utility under 35 USC 111 (a)
`
`Payment information:
`
`Submitted with Payment
`
`Payment Type
`
`Payment was successfully received in RAM
`
`RAM confirmation Number
`
`Deposit Account
`
`Authorized User
`
`yes
`
`Deposit Account
`
`$1600
`
`9349
`
`180650
`
`The Director of the USPTO is hereby authorized to charge indicated fees and credit any overpayment as follows:
`
`Charge any Additional Fees required under 37 C.F.R. Section 1.16 (National application filing, search, and examination fees)
`
`Charge any Additional Fees required under 37 C.F.R. Section 1.17 (Patent application and reexamination processing fees)
`
`Mylan Exhibit 1017
`Mylan v. Regeneron, IPR2021-00881
`Page 6
`
`Joining Petitioner: Apotex
`
`

`

`Charge any Additional Fees required under 37 C.F.R. Section 1.19 (Document supply fees)
`
`Charge any Additional Fees required under 37 C.F.R. Section 1.20 (Post Issuance fees)
`
`Charge any Additional Fees required under 37 C.F.R. Section 1.21 (Miscellaneous fees and charges)
`
`File Listing:
`
`Document
`Number
`
`Document Description
`
`File Name
`
`File Size( Bytes)/
`Message Digest
`
`Multi
`Part /.zip
`
`Pages
`(if appl.)
`
`529155
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`
`yes
`
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`Multipart Description/PDF files in .zip description
`
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`Claims
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`Abstract
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`Warnings:
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`2
`
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`The page size in the PDF is too large. The pages should be 8.5 x 11 or A4. If this PDF is submitted, the pages will be resized upon entry into the
`Image File Wrapper and may affect subsequent processing
`
`Information:
`
`3
`
`Sequence Listing
`
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`CRF Statement Paper and CRF are the
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`no
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`3dbd8e1d133322201 e20b1 e6b08ca481 c8
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`Mylan Exhibit 1017
`Mylan v. Regeneron, IPR2021-00881
`Page 7
`
`Joining Petitioner: Apotex
`
`

`

`Warnings:
`
`Information:
`
`7
`
`Transmittal of New Application
`
`725A 1 _ApplicationTransmittal.
`pdf
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`276559
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`fee-info.pdf
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`no
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`Total Files Size (in bytes)
`
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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 to a
`Post Card, as described in MPEP 503.
`
`New A~~lications Under 35 U.S.C. 111
`If a new application is being filed and the application includes the necessary components for 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 on this
`Acknowledgement Receipt will establish the filing date of the application.
`
`National Stage of an International A~~lication under 35 U.S.C. 371
`If a 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/E0/903 indicating acceptance of the application as a
`national stage submission under 35 U.S.C. 371 will be issued in addition to the Filing Receipt, in due course.
`
`New International A~~lication 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 181 O), a Notification of the International Application Number
`and of the International Filing Date (Form PCT/R0/1 OS) will be issued in due course, subject to prescriptions concerning
`national security, and the date shown on this Acknowledgement Receipt will establish the international filing date of
`the application.
`
`Mylan Exhibit 1017
`Mylan v. Regeneron, IPR2021-00881
`Page 8
`
`Joining Petitioner: Apotex
`
`

`

`Electronic Acknowledgement Receipt
`
`EFSID:
`
`Application Number:
`
`16298087
`
`13940370
`
`International Application Number:
`
`Confirmation 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
`
`Filer Authorized By:
`
`Attorney Docket Number:
`
`725Al
`
`Receipt Date:
`
`12-JUL-2013
`
`Filing Date:
`
`Time Stamp:
`
`11:18:49
`
`Application Type:
`
`Utility under 35 USC 111 (a)
`
`Payment information:
`
`Submitted with Payment
`
`Payment Type
`
`Payment was successfully received in RAM
`
`RAM confirmation Number
`
`Deposit Account
`
`Authorized User
`
`yes
`
`Deposit Account
`
`$1600
`
`9349
`
`180650
`
`The Director of the USPTO is hereby authorized to charge indicated fees and credit any overpayment as follows:
`
`Charge any Additional Fees required under 37 C.F.R. Section 1.16 (National application filing, search, and examination fees)
`
`Charge any Additional Fees required under 37 C.F.R. Section 1.17 (Patent application and reexamination processing fees)
`
`Mylan Exhibit 1017
`Mylan v. Regeneron, IPR2021-00881
`Page 9
`
`Joining Petitioner: Apotex
`
`

`

`Charge any Additional Fees required under 37 C.F.R. Section 1.19 (Document supply fees)
`
`Charge any Additional Fees required under 37 C.F.R. Section 1.20 (Post Issuance fees)
`
`Charge any Additional Fees required under 37 C.F.R. Section 1.21 (Miscellaneous fees and charges)
`
`File Listing:
`
`Document
`Number
`
`Document Description
`
`File Name
`
`File Size( Bytes)/
`Message Digest
`
`Multi
`Part /.zip
`
`Pages
`(if appl.)
`
`529155
`
`1
`
`725A 1 _Specification.pdf
`
`yes
`
`24
`
`Multipart Description/PDF files in .zip description
`
`66488c5 3 63 7f4b 7715 ffe 32f0b65 96663f6e(
`2cd
`
`Document Description
`
`Start
`
`End
`
`Specification
`
`Claims
`
`Abstract
`
`Warnings:
`
`Information:
`
`2
`
`Drawings-only black and white line
`drawings
`
`Warnings:
`
`21
`
`23
`
`24
`
`1
`
`22
`
`24
`
`105393
`
`725A 1 _Figure.pdf
`
`no
`
`1
`
`2d582f645d0c5d 17d717 e589b029a39331 ~
`91bdb
`
`The page size in the PDF is too large. The pages should be 8.5 x 11 or A4. If this PDF is submitted, the pages will be resized upon entry into the
`Image File Wrapper and may affect subsequent processing
`
`Information:
`
`3
`
`Sequence Listing
`
`725A l_Seqlist-paper.pdf
`
`no
`
`3
`
`151078
`
`Warnings:
`
`Information:
`
`Sbl c06a0fa4a3bbb8b721196755d8f10323
`8fb0e
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`6076
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`4
`
`Sequence Listing (Text File)
`
`725A 1 _Seqlist.txt
`
`no
`
`0
`
`Warnings:
`
`Information:
`
`5
`
`CRF Statement Paper and CRF are the
`same
`
`725A 1 _SeqlistStatement.pdf
`
`no
`
`1
`
`171883
`
`fl b5760b5b501 c526e4fd94266bc7452ce8
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`
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`
`Application Data Sheet
`
`725A 1 _AppDataSheet.pdf
`
`no
`
`6
`
`1255991
`
`3dbd8e1d133322201 e20b1 e6b08ca481 c8
`ddef80
`
`Mylan Exhibit 1017
`Mylan v. Regeneron, IPR2021-00881
`Page 10
`
`Joining Petitioner: Apotex
`
`

`

`Warnings:
`
`Information:
`
`7
`
`Transmittal of New Application
`
`725A 1 _ApplicationTransmittal.
`pdf
`
`276559
`
`1 f3a69d8d 94bef563f27 d 244 3 e518e 782b 1
`8cb70
`
`no
`
`2
`
`Warnings:
`
`Information:
`
`8
`
`Fee Worksheet (SB06)
`
`fee-info.pdf
`
`no
`
`2
`
`32862
`
`1 e8c487df991 d67f0cd6fb4c4f879022d7ef~
`49,
`
`Warnings:
`
`Information:
`
`Total Files Size (in bytes)
`
`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 to a
`Post Card, as described in MPEP 503.
`
`New A~~lications Under 35 U.S.C. 111
`If a new application is being filed and the application includes the necessary components for 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 on this
`Acknowledgement Receipt will establish the filing date of the application.
`
`National Stage of an International A~~lication under 35 U.S.C. 371
`If a 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/E0/903 indicating acceptance of the application as a
`national stage submission under 35 U.S.C. 371 will be issued in addition to the Filing Receipt, in due course.
`
`New International A~~lication 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 181 O), a Notification of the International Application Number
`and of the International Filing Date (Form PCT/R0/1 OS) will be issued in due course, subject to prescriptions concerning
`national security, and the date shown on this Acknowledgement Receipt will establish the international filing date of
`the application.
`
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`USE OF AVEGF ANTAGONIST TO TREAT ANGIOGENIC EYE DISORDERS
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`CROSS-REFERENCE TO RELATED APPLICATIONS
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`[0001] This application is a continuation-in-part of International Patent Application No.
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`PCT/US2012/020855, filed on January 11, 2012, which claims the benefit of US Provisional
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`Application Nos. 61/432,245, filed on January 13, 2011, 61/434,836, filed on January 21, 2011, and
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`61/561,957, filed on November 21, 2011, the contents of which are hereby incorporated by
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`reference in their entireties.
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`FIELD OF THE INVENTION
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`[0002] The present invention relates to the field of therapeutic treatments of eye disorders. More
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`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] Several eye disorders are associated with pathological angiogenesis. For example, the
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`development of age-related macular degeneration (AMO) 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. DME is 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 when fluid 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
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`macula can cause severe vision loss or blindness. Yet another eye disorder associated with
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`abnormal angiogenesis is central retinal vein occlusion (CRVO). CRVO is caused by obstruction of
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`the central retinal vein that leads to a back-up of blood and fluid in the retina. The retina can also
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`become ischemic, resulting in the growth of new, inappropriate blood vessels that can cause further
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`vision loss and more serious complications. Release of vascular endothelial growth factor (VEGF)
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`contributes to increased vascular permeability in the eye and inappropriate new vessel growth.
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`Thus, inhibiting the angiogenic-promoting properties of VEGF appears to be an effective strategy
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`for treating angiogenic eye disorders.
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`[0004] FDA-approved treatments of angiogenic eye disorders such as AMO and CRVO include
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`the administration of an anti-VEGF antibody called ranibizumab (Lucentis®, Genentech, Inc.) on a
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`monthly basis by intravitreal injection.
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`[0005] Methods for treating eye disorders using VEGF antagonists are mentioned in, e.g., US
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`7,303,746; US 7,306,799; US 7,300,563; US 7,303,748; and US 2007/0190058. Nonetheless,
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`-1-
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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.
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`BRIEF SUMMARY OF THE INVENTION
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`[0006] The present invention provides methods for treating angiogenic eye disorders. The
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`methods of the invention comprise sequentially administering multiple doses of a VEGF antagonist
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`to a patient over time. In particular, the methods of the invention comprise sequentially
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`administering to the patient a single initial dose of a VEGF antagonist, followed by one or more
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`secondary doses of the VEGF antagonist, followed by one or more tertiary doses of the VEGF
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`antagonists. The present inventors have surprisingly discovered that beneficial therapeutic effects
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`can be achieved in patients suffering from angiogenic eye disorders by administering a VEGF
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`antagonist to a patient at a frequency of once every 8 or more weeks, especially when such doses
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`are preceded by about three doses administered to the patient at a frequency of about 2 to 4
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`weeks. Thus, according to the methods of the present invention, each secondary dose of VEGF
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`antagonist is administered 2 to 4 weeks after the immediately preceding dose, and each tertiary
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`dose is administered at least 8 weeks after the immediately preceding dose. An example of a
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`dosing regimen of the present invention is shown in Figure 1. One advantage of such a dosing
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`regimen is that, for most of the course of treatment (i.e., the tertiary doses), it allows for less
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`frequent dosing (e.g., once every 8 weeks) compared to prior administration regimens for
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`angiogenic eye disorders which require monthly administrations throughout the entire course of
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`treatment. (See, e.g., prescribing information for Lucentis® [ranibizumab], Genentech, Inc.).
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`[0007] The methods of the present invention can be used to treat any angiogenic eye disorder,
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`including, e.g., age related macular degeneration, diabetic retinopathy, diabetic macular edema,
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`central retinal vein occlusion, corneal neovascularization, etc.
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`[0008] The methods of the present invention comprise administering any VEGF antagonist to the
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`patient. In one embodiment, the VEGF antagonist comprises one or more VEGF receptor-based
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`chimeric molecule(s), (also referred to herein as a "VEGF-Trap" or "VEGFT"). An exemplary VEGF
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`antagonist that can be used in the context of the present invention is a multimeric VEGF-binding
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`protein comprising two or more VEGF receptor-based chimeric molecules referred to herein as
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`"VEGFR1 R2-Fc.6.C1 (a)" or "aflibercept."
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`[0009] Various administration routes are contemplated for use in the methods of the present
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`invention, including, e.g., topical administration or intraocular administration (e.g., intravitreal
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`administration).
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`[0010] Aflibercept (EYLEATM, Regeneron Pharmaceuticals, Inc) was approved by the FDA in
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`November 2011, for the treatment of patients with neovascular (wet) age-related macular
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`degeneration, with a recommended dose of 2 mg administered by intravitreal injection every 4
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`-2-
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`weeks for the first three months, followed by 2 mg administered by intravitreal injection once every
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`8 weeks.
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`[0011] Other embodiments of the present invention will become apparent from a review of the
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`ensuing detailed description.
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`BRIEF DESCRIPTION OF THE FIGURE
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`[0012] Figure 1 shows an exemplary dosing regimen of the present invention. In this regimen, a
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`single "initial dose" of VEGF antagonist ("VEGFT") is administered at the beginning of the treatment
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`regimen (i.e. at "week O"), two "secondary doses" are administered at weeks 4 and 8, respectively,
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`and at least six "tertiary doses" are administered once every 8 weeks thereafter, i.e., at weeks 16,
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`24, 32, 40, 48, 56, etc.).
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`DETAILED DESCRIPTION
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`[0013] Before the present invention is described, it is to be understood that this invention is not
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`limited to particular methods and experimental conditions described, as such methods and
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`conditions may vary. It is also to be understood that the terminology used herein is for the purpose
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`of describing particular embodiments only, and is not intended to be limiting, since the scope of the
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`present invention will be limited only by the appended claims.
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`[0014] Unless defined otherwise, all technical and scientific terms used herein have the same
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`meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
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`As used herein, the term "about," when used in reference to a particular recited numerical value,
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`means that the value may vary from the recited value by no more than 1 %. For example, as used
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`herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2,
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`99.3, 99.4, etc.).
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`[0015] Although any methods and materials similar or equivalent to those described herein can be
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`used in the practice or testing of the present invention, the preferred methods and materials are
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`now described.
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`DOSING REGIMENS
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`[0016] The present invention provides methods for treating angiogenic eye disorders. The
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`methods of the invention comprise sequentially administering to a patient multiple doses of a VEGF
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`antagonist. As used herein, "sequentially administering" means that each dose of VEGF antagonist
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`is administered to the patient at a different point in time, e.g., on different days separated by a
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`predetermined interval (e.g., hours, days, weeks or months). The present invention includes
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`methods which comprise sequentially administering to the patient a single initial dose of a VEGF
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`-3-
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`antagonist, followed by one or more secondary doses of the VEGF antagonist, followed by one or
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`more tertiary doses of the VEGF antagonist.
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`[0017] The terms "initial dose," "secondary doses," and "tertiary doses," refer to the temporal
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`sequence of administration of the VEGF antagonist. Thus, the "initial dose" is the dose which is
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`administered at the beginning of the treatment regimen (also referred to as the "baseline dose"); the
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`"secondary doses" are the doses which are administered after the initial dose; and the "tertiary
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`doses" are the doses which are administered after the secondary doses. The initial, secondary,
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`and tertiary doses may all contain the same amount of VEGF antagonist, but will generally differ
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`from one another in terms of frequency of administration. In certain embodiments, however, the
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`amount of VEGF antagonist contained in the initial, secondary and/or tertiary doses will vary from
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`one another (e.g., adjusted up or down as appropriate) during the course of treatment.
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`[0018]
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`In one exemplary embodiment of the present invention, each secondary dose is
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`administered 2 to 4 (e.g., 2, 2~, 3, 3~, or 4) weeks after the immediately preceding dose, and each
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`tertiary dose is administered at least 8 (e.g., 8, 8~, 9, 9~, 10, 10~, 11, 11~, 12, 12~, 13, 13~, 14,
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`14~, or more) weeks after the immediately preceding dose. The phrase "the immediately
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`preceding dose," as used herein, means, in a sequence of multiple administrations, the dose of
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`VEGF antagonist which is administered to a patient prior to the administration of the very next dose
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`in the sequence with no intervening doses.
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`[0019]
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`In one exemplary embodiment of the present invention, a single initial dose of a VEGF
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`antagonist is administered to a patient on the first day of the treatment regimen (i.e., at week 0),
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`followed by two secondary doses, each administered four weeks after the immediately preceding
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`dose (i.e., at week 4 and at week 8), followed by at least 5 tertiary doses, each administered eight
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`weeks after the immediately preceding dose (i.e., at weeks 16, 24, 32, 40 and 48). The tertiary
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`doses may continue (at intervals of 8 or more weeks) indefinitely during the course of the treatment
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`regimen. This exemplary administration regimen is depicted graphically in Figure 1.
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`[0020] The methods of the invention may comprise administering to a patient any number of
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`secondary and/or tertiary doses of a VEGF antagonist. For example, in certain embodiments, only
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`a single secondary dose is administered to the patient. In other embodiments, two or more (e.g., 2,
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`3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient. Likewise, in certain
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`embodiments, only a single tertiary dose is administered to the patient. In other embodiments, two
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`or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.
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`[0021]
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`In embodiments involving multiple secondary doses, each secondary dose may be
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`administered at the same frequency as the other secondary doses. For example, each secondary
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`dose may be administered to the patient