IN THE UNITED STATES PATENT AND TRADEMARKOFFICE
`
`In re U.S. Patent Number: 7,374,758
`
`(Application No. 11/016,503)
`
`For: Modified Chimeric Polypeptides with
`Improved Pharmacokinetic Properties
`and Methodsof Using Thereof
`
`Inventors: Papadopoulos, Davis and Yancopoulos
`
`Issued: May20, 2008
`Assignee: Regeneron Pharmaceuticals,Inc.
`
`RECEIVED
`
`DEC 2.2.rNSION
`EXT
`PATOPLA
`
`Office of Patent Legal Administration (via hand delivery)
`Room MDW 7D55
`600 DulanyStreet (Madison Building)
`Alexandria, VA 22314
`
`APPLICATION FOR EXTENSION OF PATENT TERM UNDER35 U.S.C. §156
`
`Dear Sir,
`
`Applicant, Regeneron Pharmaceuticals, Inc., hereby submits this application
`for extension of the term of United States Letters Patent No. 7,374,758 (the “’758
`patent”) under35 U.S.C. §156 and 37 C.F.R §1.740.
`
`Applicant representsthatit is the assigneeofthe entire interest in and to the
`‘758 patentby virtue of assignmentofall rights of inventors Nicholas J. Papadopoulos,
`Samuel Davis and George D. Yancopoulos (Papadopoulosetai.) to Regeneron
`Pharmaceuticals, Inc., as recordedin the U.S. Patent and TrademarkOffice on
`December17, 2004, Reel 016103, Frame 0015 (a copyof whichis attached in
`AttachmentA).
`
`85/69/2612 CKHLOK
`@1 FC:1457
`
`@8G@8089 188658
`1128.88 DA
`
`11016583
`
`CELLTRION - EXHIBIT 1024
`CELLTRION- EXHIBIT 1024
`0001
`0001
`
`

`

`U.S. Patent No. 7,374,758
`Papadopoulos,et al.
`Application Under35 U.S.C. § 156
`
`Page 2
`
`This application is based on the approval by the United States Food and Drug
`Administration (“FDA”) of a Biologics License Application (BLA No. BL 125387/0) on
`November18, 2011, for EYLEA ™ (afliberceptintravitreal injection, also known as
`aflibercept IVT, aflibercept ophthalmicinjection and aflibercept ophthalmic solution).
`
`1.
`
`Identification of the Approved Product under 37 C.F.R . §1.740 (a)(1)
`
`The nameof the approved product is EYLEA™. The nameofthe active
`ingredient of EYLEA™ is aflibercept, also knownas VEGF trap, VEGF-trap, VEGF Trap-
`Eye and VEGF-TRAPrirz. Afliberceptis a fusion protein consisting of (a) a vascular
`endothelial growth factor (VEGF) receptor componenthaving immunoglobulin-like
`(Ig) domainsconsisting of an Ig domain2 of a first VEGF receptor that is human Flt1
`and an Ig domain 3 of a second VEGF receptorthat is human Fik1; and (b) an Fc
`portion of human IgG1.
`
`2.
`
`Federal Statute Governing Regulatory Approvalof the Approved Product
`under37 C.F.R. §1.740(a)(2)
`
`The approved product was subject to regulatory review under,inter alia, the
`Public Health Service Act (42 U.S.C. § 201 et seq. , including 42 U.S.C. §262(a)) and the
`Federal Food, Drug and Cosmetic Act (21 U.S.C. § 355 et seq.).
`
`3.
`
`Date of Approval for Commercial Marketing under37 C.F.R . §1.740 (a)(3)
`
`.
`
`EYLEA™ wasapproved for commercial marketing or use under §351 of the
`Public Health Service Act on November18, 2011.
`
`4.
`
`(a)
`
`(b)
`
`Identification of Active Ingredient and Certifications Related to
`Commercial Marketing of Approved Product under37 C.F.R. §1.740(a)(4)
`
`Theactive ingredient of EYLEA™is aflibercept, which is a recombinant
`fusion protein consisting of a VEGF receptor componenthaving Ig domains
`consisting of an Ig domain 2 of human Fit1 and an Ig domain 3 of human
`FIk1, fused to the Fc domain of human |gG1.
`
`Applicantcertifies that aflibercept has not been approved for commercial
`marketingor use underthe Federal Food, Drug and Cosmetic Act, the
`Public Health Service Act or the Virus-Serum-Toxin Actprior to the
`approval granted on November18, 2011 to the present Applicant.
`
`0002
`0002
`
`

`

`U.S. Patent No. 7,374,758
`Papadopoulos,etal.
`Application Under 35 U.S.C. § 156
`
`Page 3
`
`(c)
`
`(d)
`
`Aflibercept has been approvedfor the treatmentof patients with
`neovascular (wet) age-related macular degeneration. See EYLEA™ product
`label, provided as AttachmentB.
`
`EYLEA™, whoseactive ingredientis aflibercept, was approvedfor
`commercial marketing pursuant to § 351 of the Public Health Service Act
`(42 U.S.C. §262) under Regeneron’s existing Departmentof Health and
`HumanServices (DHHS) U.S. License No. 1760. See EYLEA™ approvalletter,
`provided as AttachmentC.
`
`Statement Regarding Timeliness of Submission of Patent Term Extension
`Request[§ 1.740(a)(5)]
`
`Applicant certifies that this application for patent term extension is being
`submitted within the sixty (60) day period permitted for submission specified
`in 35 U.S.C. § 156(d)(1), (as amended on September16, 2011), and 37 C.F.R. §
`1.720(f). The amended provisions of the America Invents Actstate that the
`date on which a productreceives permissionis the next business dayif
`permissionis “transmitted after 4:30 P.M., Eastern Time, on a business day
`....” Permission was transmitted at 5:47 P.M., Eastern Time,on Friday,
`November18, 2011, a business day. The next business day is Monday,
`November21, 2011. Accordingly, the last date on whichthis application may
`be submitted is January 19, 2012.
`
`Complete Identification of the Patent for Which Extension Is Being Sought
`[§ 1.740(a)(6)]
`
`The complete identification of the patent for which an extensionis being
`soughtis as follows:
`
`(a) Namesofthe inventors:
`
`Nicholas J. Papadopoulos, Samuel Davis and
`George D. Yancopoulos
`
`(b) Patent Number:
`
`U.S. Patent No. 7,374,758 (the “758
`patent”)
`
`(c) Date of Issue:
`
`May20, 2008
`
`(d) Date of Expiration:
`
`January 17, 2021
`
`0003
`0003
`
`

`

`U.S. Patent No. 7,374,758
`Papadopoulos,etal.
`Application Under 35 U.S.C. § 156
`
`Page 4
`
`7.
`
`Copy of the Patent for Which an Extension is Being Sought[§ 1.740(a)(7)]
`
`A copy of the 758 patentis provided as AttachmentD to the present
`application.
`
`8.
`
`Copiesof Disclaimers, Certificates of Correction, Receipt of Maintenance
`Fee Payment, or ReexaminationCertificate [§ 1.740(a)(8)]
`
`The’758 patent is subject to a terminal disclaimer, a copy of whichis
`(a)
`attached in AttachmentE.
`
`(b)
`
`(c)
`
`(d)
`
` Nocertificate of correction has been issued for the ’758 patent.
`
`The first maintenancefee for the ’758 patent was paid on November14,
`2011 (See AttachmentF).
`
`The’758 patent has not been the subject of a reexamination
`proceeding.
`
`9.
`
`Statement Regarding Patent Claims Relative to Approved Product
`[§ 1.740(a)(9)]
`
`The statements below are madesolely to comply with the requirements of37
`CF R. § 1.740 (a)(9). Applicant notes that, as the M.P.E.P. acknowledges, § 1.740 (a)(9)
`does not require an applicant to show whetheror howthelisted claims would be
`infringed, and that this question cannot be answered withoutspecific knowledge
`concerning acts performed by third parties. As such, these comments are not an
`assertion or an admission ofApplicant as to the scope ofthe listed claims, or whether or
`how anyofthe listed claims would be infringed, literally or under the doctrine of
`equivalents, by the manufacture,use, sale, offerfor sale or the importation ofany
`product.
`
`Atleast the following claims of the ’758 patent claim a methodof using
`(a)
`the approved product: claims 1 and 2.
`
`(b)
`
`Pursuant to M.P.E.P. § 2753 and 37 C.F.R. § 1.740(a)(9), the following
`explanation is provided which showshowtheabove-listed claimsof the
`‘758 patent claim a methodofusing the approved product.
`
`(1)_Description ofthe approved product
`
`0004
`0004
`
`

`

`U.S. Patent No. 7,374,758
`Papadopoulos,etal.
`Application Under 35 U.S.C. § 156
`
`Page 5
`
`The approved productis described as follows in the approved
`label for EYLEA™, a copy of which is provided as AttachmentB.
`
`EYLEA™(aflibercept ophthalmic solution) is a recombinant
`fusion protein consisting of portions of human VEGF receptors 1 and 2
`extracellular domains fused to the Fc portion of human IgG1 and
`specially purified and formulated as an iso-osmotic solution for
`intravitreal administration. Aflibercept is a dimeric glycoprotein with a
`protein molecular weight of 97 kilodaltons (kDa) andis glycosylated,
`with the glycosylation constituting an additional 15% ofthetotal
`molecular mass, resulting in a total molecular weight of 115 kDa.
`Aflibercept is produced in Chinese hamster ovary (CHO) K1 cells by
`recombinant DNAtechnology.
`
`EYLEA™is a sterile, clear, and colorless to pale yellow,iso-
`osmotic solution.It is supplied as a preservative-free, sterile, aqueous
`solution in a single-use,sterile, pre-filled, glass syringe or single-use,
`glass vial designed to deliver 0.05 mL (50 microliters) of EYLEA™ (40
`mg/mL) with 10 mM sodium phosphate, 40 mM sodium chloride,
`0.03% polysorbate 20, and 5% sucrose, pH 6.2.
`
`Afliberceptis also described in Holashetal. Proc. Natl. Acad.Sci.
`USA, August 20, 2002, Vol. 99, No. 17, pp. 11393-11398 (“Holash,”
`Attachment G) as VEGF-Traprirz, which has the Ig domain 2 of VEGF
`receptor 1 (VEGFR1; also knownasFit-1) fused to the Ig domain 3 of
`VEGF receptor 2 (VEGFR2; also knownas FIk-1), whichin turn is fused
`to the constant region (Fc) of human IgG1. See paragraph bridging
`pages 11393 and 11394 and Figure 1A. Moreover,Holashetal.
`demonstratethataflibercept is a VEGF antagonistthat binds to and
`inhibits the biologic activity of human vascular endothelial growth
`factor (VEGF)in variousin vitro and in vivo assay systems.
`
`(2)
`
`Explanation Regarding Claims 1 and 2 Relative to Aflibercept
`
`As explained below,a methodfor using aflibercept, the active
`ingredient of the approved product, is covered by claims 1 and2.
`
`Claims 1 and 2 read as follows:
`
`A methodofinhibiting vascular endothelial growth factor
`1.
`(VEGF)activity ina mammal, comprising:
`administering a pharmaceutical composition to the
`mammal, wherein the pharmaceutical composition comprises
`(a) a VEGF antagonist, and
`
`0005
`0005
`
`

`

`U.S. Patent No. 7,374,758
`Papadopoulos,etal.
`Application Under 35 U.S.C. § 156
`
`Page 6
`
`(b) a pharmaceutically acceptable carrier
`wherein the VEGF antagonist comprises a dimeric fusion
`polypeptide comprising twofusion polypeptides, each fusion
`polypeptide comprising:
`(i) a VEGF receptor componentconsisting of an
`immunoglobulin-like (Ig) domain 2 of a first VEGF receptor
`human FIt1 and Ig domain 3 of a second VEGF receptor human
`Flk1 or humanFlt4; and
`(ii) a multimerizing component, wherein VEGF activity is
`inhibited.
`
`2.
`
`The methodof claim 1, wherein the mammalis a human.
`
`Comparison of aflibercept to Claim 1
`
`Aflibercept inhibits the activation of VEGF receptors by binding
`to VEGF andthus, is a VEGF antagonistas defined by claim 1. See
`section 12.1 of EYLEA™ label, provided as AttachmentB, and as shown
`further, below. As noted above,alfibercept is a dimeric glycoprotein
`comprising recombinantfusion polypeptides, each of which consists of
`humanVEGF receptors1 and 2 extracellular domainsfused to the Fc
`portion of human [gG1. See section 11 of EYLEA™label. Aflibercept
`includes an Ig domain 2 from VEGFR1 fused to an Ig domain 3 from
`VEGFR2 as described in Holash (See AttachmentG, paragraphbridging
`pages 11393 and 11394 and Figure 1A). The 758 patentrefers to
`VEGFR-1 as FIt1 in column 25, line 57 and refers to VEGFR-2 as FIk1 in
`column 26, line 12. In addition, Holash discloses that VEGFR-1 is also
`knownasFlt-1 and VEGFR-2 is also knownasFIk-1. See Figure 1A of
`Holash. Thus,aflibercept has a VEGF receptor componentconsisting of
`an Ig domain 2 of a first VEGF receptor human Fit-1 and an Ig domain 3
`of a second VEGF receptor humanFlk-1 as defined in claim 1.
`
`Holash further describes VEGFR1 and VEGFR2 on page 11393,in
`the second paragraph,as being “highly related transmembranetyrosine
`kinases that use their ectodomains to bind VEGF.” The disclosureof the
`Flt1 and Flk1 componentsin the approved product and the construction
`of the expression vector used in makingthe active ingredientin the
`approved productis discussed in the ’758 patent in Example 20, column
`29, lines 41-56. The aminoacid sequenceofboth the Flt1 and Flk1
`components of the approved productare disclosed in Figures 24A-24C.
`Flt1 Ig domain 2 spans aminoacid residues 27 through 129 and Flk1 Ig
`domain 3 spans aminoacid residues 130 through 231 of the fusion
`protein.
`
`0006
`0006
`
`

`

`U.S. Patent No. 7,374,758
`Papadopoulos,etal.
`Application Under35 U.S.C. § 156
`
`Page 7
`
`Aflibercept comprises the Fc domain of human IgG1 fused to the
`extracellular domains from the VEGF receptors. See section 11 of
`EYLEA™label, provided as Attachment B. A “multimerizing
`component’ofthe fusion protein of claim 1 can comprise an
`immunoglobulin domain, such as the Fc domain ofIgG. See col. 5, lines
`42-46 andcol. 7, lines 25-30 of the ‘758 patent. Thus,aflibercept also
`includes a multimerizing componentas definedin claim 1. The
`multimerizing componentofthe fusion protein, the Fc region of human
`IgG, is referenced throughout the ’758 patent. The disclosure of the Fc
`multimerizing componentin the actual product is discussed in Example
`20, column 29,lines 41-56, and its amino acid sequenceis disclosed in
`Figures 24A-24C, from aminoacid residue 232 through 458.
`
`As described in Section 11 of the EYLEA™ label (AttachmentB),
`EYLEA™, the approved product, is a pharmaceutical composition
`comprising aflibercept(i.e. VEGF antagonist) and an iso-osmotic
`aqueoussolution(i.e. pharmaceutically acceptable carrier). As
`explained above,aflibercept is a dimeric protein comprising two fusion
`polypeptides, each of which comprises a VEGF receptor component
`consisting of an Ig domain 2 of a first VEGF receptor human Fit1 and Ig
`domain 3 of a second VEGF receptor human FIk1 and a multimerizing
`component. Thus, the approved productis a pharmaceutical
`composition administered to a mammal according to the method of
`claim 1.
`
`Aflibercept thus meetsall of the limitations of claim 1.
`
`Aflibercept inhibits VEGFactivity, as shownin various Examples
`throughoutthe ’758 patent.
`For example, aflibercept was able to block the ability of VEGF to
`activate its receptorin vitro. This was shownbythe ability of
`aflibercept to block VEGF-induced VEGFR2 phosphorylation when
`added at a 1.5 fold molar excess when compared with added VEGF (See
`the ’758 patent, Example 23, column 31,lines 21-67 and column 32,
`lines 1-10. See also Figure 25A-C and Figure 26A-B).
`Aflibercept wasalso effective in blocking VEGF-inducedcell
`proliferation in cells engineered to express a chimeric VEGFR2receptor,
`which mediatesa strongcell proliferation response to VEGFin vitro
`(See the ’758 patent, Example 24, column 32, lines 12-51 and also
`Figure 27).
`Furthermore,aflibercept wasalso effective in inhibition of tumor
`growthin mice (See the '758 patent, Example 30, column 36,lines 48-
`67 and column 37,lines 1-8 and also Figure 40).
`Theeffect of aflibercept was also studied in the female
`
`0007
`0007
`
`

`

`U.S. Patent No. 7,374,758
`Papadopoulos,et al.
`Application Under 35 U.S.C. § 156
`
`Page 8
`
`reproductive system using twodifferent readoutsto assess the effect of
`aflibercept on VEGF activity in rats. These are described in Example 31
`of the ’758 patent, column 38,lines 24-67.
`In this study, pregnant mare’s serum gonadotropin (PMSG) was
`injected subcutaneously to induce ovulation in pre-pubertal female rats.
`This results in a surge of estradiol after two days, which in turn causes
`an induction of VEGF in the uterus. This induction results in
`hyperpermeability of the uterus and anincreasein uterine wet weight 6
`hours later. The study was doneto determineif aflibercept could block
`the effect of VEGF on uterine wet weight. The results demonstrated that
`injection of aflibercept resulted in about a 50% reductionin uterine wet
`weight. These results are shownin Figure 41.
`The other assay measuredtheeffect of aflibercept on VEGF-
`induced bloodvessel] formation in the corpus luteum. This allowsfor
`secretion of progesteroneinto the blood stream in order to prepare the
`uterus for implantation. If aflibercept was effective at blocking VEGF
`activity in this model, then the animals receiving aflibercept should
`show a reductionin progesteronein the blood stream.Injection of
`aflibercept at 25 mg/kg or 5 mg/kg at one hourafter injection of PMSG
`resulted in complete inhibition of progesterone induction at day 4 (See
`Figure 42A-42B).
`
`Comparison of aflibercept to Claim 2
`
`According to the EYLEA™label, provided as AttachmentB, the
`approved productis intended for the treatment of human patients. In
`addition, the ’758 patent, at column6,lines 43-48,lines 52-54 andlines
`60-61, discloses several embodiments in whichaflibercept can be used
`in humans. For example, lines 43-48 described a methodof decreasing
`or inhibiting plasma leakage in a mammal comprising administering the
`fusion polypeptide described, including embodiments wherein the
`mammalis a human. Lines 52-54 describe a preferred embodiment
`being a method of blocking blood vessel growth in a human comprising
`administering the fusion polypeptide of the invention. Lines 60-61 note
`that preferred embodimentsof the methodsare wherein the mammalis
`a human.
`
`Aflibercept thus meetsall of the limitations of claim 2.
`
`Conclusion
`
`Because aflibercept meetsall of the limitations of claims 1 and 2
`of the '758 patent, and becauseafliberceptis the active ingredient of
`EYLEA™, claims 1 and 2 of U.S. Patent No. 7,374,758 cover a method of
`
`0008
`0008
`
`

`

`U.S. Patent No. 7,374,758
`Papadopoulos,etal.
`Application Under 35 U.S.C. § 156
`
`using the approved product.
`
`Page 9
`
`0009
`0009
`
`

`

`U.S. Patent No. 7,374,758
`Papadopoulos,etal.
`Application Under 35 U.S.C. § 156
`
`Page 10
`
`Relevant Dates Under35 U.S.C. § 156 for Determination of Applicable
`10.
`Regulatory Review Period [§ 1.740(a)(10)]
`
`(a)
`
`Patent Issue Date
`
`The ’758 patent issued on May 20, 2008.
`
`(b)
`
`IND Effective Date [35 U.S.C. § 156(g)(1)(B)(i); 37 CF.R. § 1. 740(a)(10)(V)(A)]
`
`The date that an exemption under§ 505(i) of the Federal Food, Drug and
`Cosmetic Act becameeffective(i.e., the date that an investigational new drug
`application ("IND") becameeffective) for EYLEA™ (referred to in the IND-
`receipt letter as “Vascular Endothelial Growth Factor Fc Protein (human,
`recombinant, CHO cells, Regeneron)”) was June 15, 2005. The application date
`for this IND was May 13, 2005. The IND was assigned number BB-IND #
`12462. A copyofthe letter from the FDAreflecting the IND’s number,date of
`submission and date of receipt is provided in Attachment H.
`
`(¢)
`
`BLA Submission Date [35 U.S.C § 156(g)(1)(B)()); 37 CFR.
`§ 1.740(a)(10)(i)(B)]
`
`The BLA was submitted on February 17, 2011 and received by the FDA on
`February 18, 2011, as shownin Attachment J. The BLA was assigned number
`BL 125387/0.
`
`(d)
`
`BLA Issue Date [35 US.C § 156(g)(I)(B)(ii); 37 CER. § 1. 740(a)(10)(i)(C)]
`
`The FDA approved biologic license application 125387/0 authorizing the
`marketing of EYLEA™ on November18, 2011. EYLEA™ was approved under
`Departmentof Health and HumanServices (DHHS) U.S. License No. 1760. A
`copy of the approvalletter from the FDAis provided as AttachmentC.
`
`0010
`0010
`
`

`

`U.S. Patent No. 7,374,758
`Papadopoulos,et al.
`Application Under35 U.S.C. § 156
`
`Page 11
`
`11. Summary ofSignificant Events During Regulatory Review Period
`[§1.740(a)(11)]
`
`Pursuantto 37 C.F.R. § 1.740(a)(11), the following providesa brief description
`of the activities of Regeneron Pharmaceuticals, Inc., before the FDAin relation to the
`regulatory review of EYLEA™. The brief description lists the significant events that
`occurred during the regulatory review period for the approved product. In several
`instances, communicationsto or from the FDA are referenced. Pursuantto 37 C.F.R. §
`I. 740(a)(11), 21 C.F.R. § 60.20(a), and M.P.E.P. § 2753, copies of such communications
`are not providedin this application, but can be obtained from records maintained by
`the FDA.
`
`On May 13, 2005 Regeneron submitted to FDA aninvestigational new drug
`application for a recombinantfusion protein (originally vascular endothelial growth
`factor Fc protein, now aflibercept) consisting of (a) a vascular endothelial growth
`factor (VEGF) receptor componenthaving immunoglobulin-like (Ig) domains
`consisting of an lg domain 2 of a first VEGF receptorthat is human FIlt1 and an Ig
`domain 3 of a second VEGFreceptorthat is human FIk1; and (b) an Fc portion of
`human IgG1. The fusion protein was developed as a potential new therapeutic for
`intravitreal administration for treating (wet) age-related macular degeneration.
`
`On June 15, 2005, BB-IND #12462 becameeffective via a communication
`mailed to Regeneron on May24, 2005, (see Attachment H). According to the
`FDA,initiation of trials could begin 30 days after May 16, 2005.
`
`From approximately July 2005 until approximately June 2008,a series ofU.S.
`Phase | and II clinical trials were conducted. In addition, an extensiontrial is ongoing
`as of the date ofthis application.
`
`Between approximately July 2007 and July 2011, PhaseIII clinical trials
`were conducted. In addition, an extensiontrial is ongoing as of the dateof this
`application.
`
`On June 1, 2009, representatives of Regeneron and CBERparticipated ina
`Type C meeting to seek agency agreementon the pharmacology/toxicology program
`for aflibercept.
`
`On September15, 2009, representatives of Regeneron and CBERparticipated
`in a Type C meeting to review the status and developmentof pre-filled syringes as the
`intended container-closure device to support commercialization of aflibercept.
`
`On September8, 2010, representatives of Regeneron and CBER participated in
`a Type B pre-BLA submission meeting to discuss and reviewclinical results of trials
`conductedpriorto thatdate.
`
`0011
`0011
`
`

`

`U.S. Patent No. 7,374,758
`Papadopoulos,etal.
`Application Under 35 U.S.C. § 156
`
`Page 12
`
`On September27, 2010, representatives of Regeneron and CBER participated
`in a Type B pre-BLA submission meeting to discuss information and requirementsfor
`the chemical, manufacturing and control (CMC) chapterof the BLA.
`
`On April 15, 2011, FDA grantedpriority reviewfor aflibercept for AMD.
`
`On November18, 2011, FDA approved BLA No.BL 125387/0, issuing
`marketing authorization for EYLEA™. (See AttachmentC.)
`
`0012
`0012
`
`

`

`U.S. Patent No. 7,374,758
`Papadopoulos,etal.
`Application Under35 U.S.C. § 156
`
`Page 13
`
`12. Statement ConcerningEligibility for and Duration of Extension Sought Under
`35 U.S.C. § 156 [37 C.F.R § 1.740(a)(12)]
`
`(a) In the opinion of the Applicant, U.S. Patent No. 7,374,758 is eligible for an
`extension under § 156 because:
`
`(i) one or moreclaimsof the ’758 patent claim a method of using the approved
`product;
`
`(ii) the term of the ’758 patent has not been previously extended on the basis
`of § 156;
`
`(iii) the 758 patent has not expired;
`
`(iv) no other patent has been extended pursuant to § 156 on the basis of the
`regulatory review process associated with the approved product, EYLEA™;
`
`(v) thereis an eligible period of regulatory review by which the patent may be
`extended pursuantto § 156;
`
`(vi) the applicant for marketing approval exercised due diligence within the
`meaning of § 156(d)(3) during the period of regulatory review;
`
`(vii) the present application has been submitted within the 60-day period
`following the approval date of the approved product, pursuantto § 156(c); and
`
`(viii) this application otherwise complies with all requirements of 35 U.S.C.
`§ 156 and applicable rules and procedures.
`
`(b) The period by which the term of the ’758 patent is requested by Applicant to be
`extended is 775 days.
`
`(c) The requested period of extension of term for the ’758 patent corresponds to the
`regulatory review periodthatis eligible for extension pursuant to §156, based on the
`facts and circumstancesof the regulatory review associated with the approved
`product EYLEA™, The period was determinedasfollows.
`
`(i) The relevant dates for calculating the regulatory review period, based on
`the events discussedin the section above,are the following.
`
`Exemption under FDCA § 505(i) becameeffective June 15, 2005 (30 daysafter
`FDAreceipt of the IND on May 16, 2005)
`
`Patent was granted May 20, 2008
`
`0013
`0013
`
`

`

`U.S. Patent No. 7,374,758
`Papadopoulos,etal.
`Application Under 35 U.S.C. § 156
`
`Page 14
`
`Biologics License Application (BLA) under PHSA § 351 wasfiled February 17,
`2011
`
`BLA wasapproved November18, 2011
`
`(ii) The ’758 patent was granted during the period specified in
`§156(g)(1)(B)(i) (i.e, the period from the date of the grant of the exemption under
`§ 505(i) of the FDCA until the date of submission of the BLA). Pursuant to § 156(b)
`and (c)(2 ), the calculated regulatory review period includes a componentequalto
`half of the numberof days within that period thatare after the grant of the patent
`(1/2 of 1002, or 501 days).
`
`(iii) Because the patent was granted beforethestart of the period specified in
`§ 156(g)(1)(B)(ii) (ie, the period from the date of submission of the BLA until the
`date of approval), the regulatory review period under§ 156(b) includes a component
`equalto the total numberof daysin that period (274 days).
`
`(iv) The ’758 patentwill expire on January 17, 2021 taking into accountthe
`Terminal Disclaimer (See AttachmentE).
`
`(v) Taking into account the 501 daysspecified in (ii) above, which accounts for
`the time period betweenthedateof grant of the exemption under § 505(i) of the
`FDCA until the date of submission of the BLA), and further pursuantto § 156(b) and
`(c)(2 ), whereby the calculated regulatory review period includes a componentequal
`to half of the numberofdays within that period thatare after the grant of the patent,
`plus the 274 daysspecified in the regulatory review period under§ I56(b) and noted
`in (iii) above, which includes the numberof days from the date of submission of the
`BLA until the date of approval, the total numberof daysto be included for
`consideration of patent term extensionis believed to be 775 days.
`
`(vi) The date of approval of the approved product is November18, 2011.
`
`(vii) The date that is fourteen years from the date of approval of the approved
`product is November18, 2025.
`
`(viii) The addition of 775 days to the time of patent expiry (which includes the
`period disclaimedvia the terminal disclaimer) brings the projected patent expiry date
`to March 3, 2023. The date until the end of the fourteen-year period specified in §156
`(c)(3) is November18, 2025. Accordingly, the projected date of expiration taking into
`accountthe 775 day patent term extension does not exceed the date projected to be
`14 years beyond the date of BLA approval. As such, the period by which the patent
`maybe extendedis not limited by the fourteen-year rule of § 156(c)(3).
`
`0014
`0014
`
`

`

`U.S. Patent No. 7,374,758
`Papadopoulos,etal.
`Application Under35 U.S.C. § 156
`
`Page 15
`
`(ix) The '758 patentissued afterthe effective date of Public Law No. 98-417.
`As such,the two-or three -yearlimit of 35 U.S.C. § 156(g)(6)(C) does not apply.
`
`13. Statement Pursuantto 37 C.F.R. § 1.740(a)(13)
`
`Pursuantto 37 C.F.R. § 1.740(a)(13), Applicant acknowledgesits duty to
`disclose to the Director of the PTO and to the Secretary of Health and Human Services
`any information which is material to the determination of entitlementto the
`extension sought, particularly as that duty is defined in 37 C.F.R. § 1.765. In
`furtherance of this duty, Applicant wishesto inform the Director and Secretary that
`concurrently with the present Application for Extension of Patent Term Under 35
`U.S.C. §156 Applicanthasfiled an Application for Extension of Patent Term Under 35
`U.S.C. §156 (plus two copies) in connection with U.S. Patent Nos. 7,374,757 and
`7,070,959.
`
`14. Applicable Fee [§ 1.740(a)(14)]
`
`Please deductall fees necessary pursuantto 37 C.F .R. §1.20(j) corresponding
`to the fee for a patent term extension application under 35 U.S.C. § 156 from deposit
`account no. 18-0650. Please deduct any additional fee or fees deemed necessary in
`excess of this amountfrom our deposit accountno. 18-0650.
`
`15. Nameand Addressfor Correspondence[§ 1.740(a)(15)]
`
`Please direct all inquiries, questions, and communications regardingthis
`application for term extensionto:
`
`Valeta Gregg, Ph.D., J.D.
`Vice President and Assistant General Counsel, Patents
`Regeneron Pharmaceuticals,Inc.
`777 Old Saw Mill River Rd.
`Tarrytown, NY 10591-6707
`Tel. 914-847-1077
`Fax 914-847-7705
`email: valeta.gregg@regeneron.com
`
`0015
`0015
`
`

`

`U.S. Patent No.7,374,758
`Papadopoulos,etal.
`Application Under35 U.S.C. § 156
`
`Page 16
`
`Twoadditional copies of this application are enclosed, in compliance with 37
`C.F.R.§ 1.740(b).
`
`Sincerely,
`
`ettQh,
`
`Attorney/Agentfor Applicant
`Registration No. 35,127
`_
`Dated: o2/ Dec cz ov
`
`0016
`0016
`
`

`

`U.S. Patent No. 7,374,758
`Papadopoulos,etal.
`Application Under35 U.S.C. § 156
`
`Page 17
`
`Index of Attachments
`
`AttachmentA - Copyof Assignmentof U.S. Patent No. 7,374,758
`
`Attachment B - Copy of EYLEA™Product Label
`
`Attachment C - Copy of EYLEA™ BLA Approvalletter from the FDA
`
`AttachmentD - CopyofU.S. Patent No. 7,374,758
`
`Attachment E - Copy of Terminal Disclaimerfor U.S. Patent No. 7,374,758
`
`AttachmentF - Copy of Maintenance Fee Statementfor U.S. Patent No. 7,374,758
`
`AttachmentG - Copy of Holash et al. PNAS 99(17):11393-11398 (2002)
`
`Attachment H - Copy of IND-receipt letter from FDA
`
`AttachmentI - Copy of BLA Submission acknowledgementletter from FDA
`
`0017
`0017
`
`

`

`ATTACHMENT A
`
`Copy of AssignmentofU.S. Patent No.
`
`7,374,758
`
`0018
`0018
`
`

`

`
`
`0
`
`
`
`
`oO
`
`
`
`City:Tarrytown___state:_XY_Zip:_10591___
`
`2/4/02
`
`eveceree-—----=
`
`40.00
`
`
`eneron
`
`Pha
`
`is,
`
`42-30-2004
`| a =]
`
`el * MUMMUABMNOR|rereJe
`
`
`=
`aumgoaev 402914790
`
`
` Commissioner of Patents and Trademarks: Please record the attached original documents or copy therect.
`
`To the Honorable
`
`2. Name and address of receiving party(ies)
`
`4. Name of conveying party(les):
`Name: Fegeneron Pharmaceuticals, Inc.
`
`
`Nicholas J. Papadopoulos
`Samue! Davis
`
`
` internal Address:
`George D. Yancopoulos
`
`
` Additional name(s) of conveying partyjes) attached?|_|Yes| ¥’ JNo——————_,Oo
`
`
`3. Nature of conveyance:
`
` Street Addrese: 777 Old Saw Mill River Road
`Assignment
`{_]merger
`[[] Security Agreement
`[Ichangeof Name
`
`
`eeSERENE
`
`
`[_] Other.
`
`
`
`Execution Date: February 4, 2002
`Additional name(s) & address(es) attached? ||Yes iv|No
`
`
`4. Application number(s) or patent number(s):
`if this documentis being filed together with a new application, the execution date of the application is:
`
`
` eeewesewereoesewesrereeeons
`cececaececceceeceee
`B. Patent No.(s) .
`A. Patent Application No.(s) _
`
`
` 5. Name and address of party to whom correspondence
`
`conceming documentshould be mailed:
`
`
`
`
`7. Total fee (37 CFR 3.41)........+004$
`Valeta Gregg
`
`Name:
`([] Enclosed
`
`
`
`Internal Address: Regeneron Pharmaceuticals, Inc
`[7] Authorized to be charged to deposit accounta
`
`
`
`
`EE
`
`
`8. Deposit account number:
`
`Street Address: 777 014 Saw Mill River Road
`
`18-0650
`
`eeNNEnERD
`
`
`
`
`City;Tatytownstate:NY_zip:_1059!
`
`
`
`
`
`
`Valeta Gre
`December 17 , 2004
`
`Nameof Person Signing
`
`Seaneccet ath requires cover sheettaformation10!
`Commissioner of Patents & Trademarks, Box Assignments
`11016503
`Washington, 0.C, 20231
`
`9. Signature.
`
`DO NOT USE THIS SPACE
`
`12/29/2004 GTOMI1
`
`00000175 180650
`
`01 FCs8021
`
`49.00 BA
`
`PATENT
`REEL: 016103 FRAME: 0015
`
`0019
`0019
`
`

`

`Att. Docket No. REG 710-A-US
`
`ASSIGNMENT
`
`WHEREAS, We,Nicholas J. Papadopoulos, residing at 59 Heritage Lane, Lagrangeville,
`New York 12540, a citizen of the United States of America,Samuel Davis, residing at 332 W. 88th
`Street #B2, New York, New York 10024, a citizen of the United States of America, and George D.
`Yancopoulos, residing at 1519 Baptist Church Road, Yorktown Heights, New York 10598, a
`citizen of the United States of America (HEREINAFTER CALLED “ASSIGNORS”) are
`inventor(s) of the invention(s) disclosed and/or claimed in the following patent application:
`
`USSN 10/009,852 filed December 6, 2001,
`whichis the national stage filing of PCT/US00/14142 filed June 8, 1999;
`
`WHEREAS, REGENERON PHARMACEUTICALSINC., a corporation organized and
`existing under the laws of the State of New York, with offices at 777 Old Saw Mill River Road,
`Tarrytown, New York 10591-6707, U.S.A. (HEREINAFTER called “ASSIGNEE”)is desirous of
`acquiring our entire right, title and interestin,to, and under the said applications,
`
`NOW, THEREFORE,in consideration of the sum of One Dollar ($1.00) to us in hand
`paid, and other good and valuable consideration, the receipt of which is hereby acknowledged, ,
`We,the said ASSIGNORS,have sold, assigned, transferred and set over, and by these presents do
`hereby sell, assign,
`transfer and set over unto the said ASSIGNEE,its successors,
`legal
`representatives, and assigns, our entire right, title and interest for all countries in and to any andall
`inventions which are disclosed and claimed, and any andall inventions which are disclosed but
`not claimed in the above-described United, States applications, and in and to said United States
`Applications and all divisions, renewals, continuations, and continuations-in-part thereof, and all
`Patents of the United States which may be granted thereon andall reissues and extensions thereof;
`and all applications for industrial