Claim i:
`
`Dixon
`same molecular structure . .
`1575).18
`
`” (M -
`
`As a result, Dixon anticipates claim 1 of the '338 patent.
`
`2. Dependent claims 3 and 4 are anticipated by Dixon.
`129. I have been informed that claims 3 and 4 can be described as
`
`“dependent” on claim 1. It is my understanding that a dependent claim incorporates
`
`the elements of the claims from which it depends.
`
`130. Claim 3 limits the method of claim 1 to “wherein only two secondary
`
`doses are administered to the patient, and wherein each secondary dose is
`
`administered 4 weeks after the immediately preceding close.” And, claim 4 further
`
`limits the method of claim 3 to “wherein each tertiary dose is administered 8 weeks
`
`after the immediately preceding dose.”
`
`131. As illustrated in my modified Figure 1 of the 338 patent as provided
`
`below, which exemplifies a regimen falling within the scope of all the challenged
`
`claims, Dixon discloses the elements of claim 3 (each secondary-' dose is iS *
`
`iS As discussed above, the structure and sequence of VEGF Trap-Eye/aflibercept
`
`was well known to those of ordinary skill in the art. (See., e.g., supra Sec. VIII(A))
`
`64
`
`Mylan Exhibit 1002
`Mylan v. Regeneron, IPR2021 -00881
`Page 71
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2013 PAGE 718
`
`

`

`administered 4 weeks alter the immediately preceding dose) and claim 4 (each
`
`tertiary dose is administered 8 weeks after the immediately preceding dose):
`
`wits svsMsg Z.% at mn 8 YSftsaS
`
`Satssmsi
`
`Ovm switify <tosssy:)
`
`;
`
`O<$>
`
`gytefif-
`
`S |l» f
`
`i
`
`ill Hi I
`
`SI
`
`A
`1
`
`S5»
`.... ; "
`IXstsfy |
`Dews
`
`g wgffer
`
`////A-
`
`////.
`
`I1
`
`Dixon at 1576
`I
`
`I #
`♦ 1-:0
`i I III Ml!] It
`■ If I f
`J.J
`I inifes
`l: Q<m
`*■
`' pss&sti
`s
`
`g wmkm*
`
`(Ex. 1001!338 patent. Fig. 1 t. modilications added))
`
`132. Accordingly, for these reasons, as well as the reasons set forth for claim
`
`1 above, it is my opinion that claims 3 and 4 of the 5338 patent are anticipated by
`
`Dixon.
`
`3.
`
`Dependent claim 5 is anticipated by Dixon.
`
`133. Claim 5 claims the method of claim 1, “wherein at least 5 tertiary
`
`doses” are administered, and “wherein the first four tertiary does are administered 8
`
`weeks after the immediately preceding dose, and wherein each subsequent tertiary
`
`dose is administered 8 or 12 weeks after the immediately preceding dose.”
`
`134. Dixon discloses that the every-8-week aspect of the VIEW1 and
`
`VIEW2 clinical trials will last at least a year. (Ex. 1006, Dixon, 1576 (“After the first
`
`year of the study, patients will enter a second year of p.r.n. dosing [Tjlie primary
`
`65
`
`Mylan Exhibit 1002
`Mylan v. Regeneron, IPR2021 -00881
`Page 72
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2013 PAGE 719
`
`

`

`outcome will be the proportion of patients who maintain vision at week 52.”
`
`(emphasis added)}. As illustrated in my modified Figure i below, the “8 week
`
`dosing interval” disclosed in Dixon would result in “at least 5 tertiary doses,” e.g..
`
`administered at weeks 16, 24. 32, 40, and 48 (red arrows), each administered 8
`
`weeks after the immediately preceding dose:
`
`# 50
`1
`!
`
`t
`
`t
`
`I
`
`80 I
`
`k
`
`Dixon at 1576
`
`will wsto&t S.S sns si «« § skss* <5s*i;;ci isStrasi (kfcsSii? te®*
`
`Weeks
`30
`
`!
`
`j k
`
`I
`
`i i
`
`mmm*
`
`Tfefticiry
`Doses
`
`10
`
`f 20
`
`t t t
`
`t
`Dose Secondary
`Doses
`
`(Ex. 1001, ”338 patent, Fig.l (modifications added)).
`
`135. Thus, for these reasons, as well as for the reasons discussed above for
`
`claim 1, it is my opinion that claim 5 of the "338 patent is anticipated by Dixon.
`
`4.
`
`Dependent claims 6 and 7 are anticipated by Dixon.
`
`136. Claim 6 is dependent on claim 1 and recites the method of claim 1,
`
`“wherein the angiogenic eye disorder is selected from the group consisting of
`
`several well-known eye disorders, including AMD. Claim 7, which depends from
`
`claim 6, recites “wherein the angiogenic eye disorder is age related macular
`
`degeneration.”
`
`66
`
`Mylan Exhibit 1002
`Mylan v. Regeneron, IPR2021 -00881
`Page 73
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2013 PAGE 720
`
`

`

`137. The Dixon reference indicates in the title that VEGF Trap-Eye was
`
`being studied for the treatment of AMD, which is an angiogenic eye disorder.
`
`Likewise, the bulk of the reference discusses VEGF Trap-Eye as it relates to the
`
`treatment of AMD, including the discussion of the Phase 1 CLEAR-IT-.1 clinical
`
`trial in patients with neovascular AMD; the Phase 2 CLEAR-Ff-2 clinical trials in
`
`wet: AMD; and the Phase 3 VIEW! and VIEW2 clinical trials. It is in the discussion
`
`of the VIEW1 and VIEW2 trials for wet AMD that the dosing regim en of 3 monthly
`
`doses followed by ever}/ 8 week dosing was disclosed, after reporting that the Phase
`
`2 trial results had shown mean improvements in visual acuity and retinal thickness,
`
`which are key indicators of success when treating AMD. Thus, Dixon discloses the
`
`treatment of AMD, which was known to be an angiogenic eye disorder.
`
`138. Thus, for these reasons, as well as for the reasons discussed above for
`
`claim 1, it is my opinion that claims 6 and 7 of the ’338 patent are anticipated by
`
`Dixon.
`
`139. Dependent claim 8 depends from claim 1 and recites “wherein all doses
`
`of the VEGF antagonist are administered to the patient by topical adm inistration or
`
`by intraocular administration.
`
`140. Claim 9 depends from claim 8 and specifies intraocular' administration.
`
`67
`
`Mylan Exhibit 1002
`Mylan v. Regeneron, IPR2021 -00881
`Page 74
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2013 PAGE 721
`
`

`

`141. Claim 10 depends from claim 9 and specifies that “the intraocular
`
`administration is intravitreal administration.
`
`142. Dixon discloses that the VIEW1 and V1EW2 studies “will evaluate the
`
`safety and efficacy of intravitreal VEGF Trap-Eye.
`
`(Ex. 1006, Dixon, 1576
`
`(emphasis added)). Intravitreal injection is a type of intraocular administration
`
`more specifically, administration directly into the vitreous of the eye. This element
`
`is therefore expressly disclosed and taught by Dixon.
`
`143. Therefore, for these reasons, as well as the reasons set forth for claim 1
`
`above, it is my opinion that claims 8-10 are anticipated by Dixon.
`
`144. Dependent claim 11 depends from claim 10 and recites “wherein all
`
`doses of the VEGF antagonist comprise from about 0.5 mg to about 2 mg of the
`
`VEGF antagonist. Dependent claim 13 depends from claim 11 and specifies
`
`“wherein all doses of the VEGF antagonist comprise 2 mg of the VEGF antagonist:.
`
`145. Dixon discloses the treatment arms in the VIEW! and VIEW2 studies
`
`which included “intravitreal VEGF Trap-Flye at...2.0 mg at an 8 week dosing
`
`interval (following three monthly doses).” (Ex. 1006, Dixon, 1576). Dixon therefore
`
`expressly discloses the doses of claims 11 and 13.
`
`146. Therefore, for these reasons, as well as the reasons set forth above for
`
`claim 10 and claim 1, it is my opinion that claims 11 and 13 are anticipated by Dixon.
`
`68
`
`Mylan Exhibit 1002
`Mylan v. Regeneron, IPR2021 -00881
`Page 75
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2013 PAGE 722
`
`

`

`7.
`Independent claim 14 is anticipated by Dixon.
`147. Claim 14 of the ’338 patent is identical to claim 1 with the only
`
`14 A roeffcttfJ ihr irrafkig
`
`pniteuh sitkl iTjcthtkl- Odmpksirig
`
`exception being in the third “wherein” clause:
`
`1: A rrjotkod for uvdthig on ettgiogenk «y* disoivlcr u» a
`ptitiiM, snid method ccunprising sequeiitftdly ndmirdskMing.
`to the ptjlkxp. a single nftual dose of & VkGF unhtgouisi.
`followed by one or «K>tv secondary dobc-s of ?iie V'lfOf: *
`antagonist followed fey one or more tertiary doses of die
`VViCri:’ antagon i 4i:
`cvteein oavh wzQtvmy dose is aekukastcml 2 to 4 weeks
`after the ireii.vei.ttaiely ■‘•srecMuig tto&i: mid
`wherdtj each tertiary dose is admiais^fed at teayfc 8 <vet4cs s:;;
`idler thv? immediitidy pr^eding dose:
`wherein the V r'GF aoi-agothst' is a V'FGF reeepurrdkwed
`ehitvieric nedecoJe eoiTipnsink:ffyhi:^ffifth^:|kddjhpdf
`:: ifkt ift
`flk i Si?:; fft
`i isc fki : il S ^jf i
`iff
`i2: i iif
`k(i2: ^ ky
`: ik y riiii
`tpftdiikdiMp^ni^hdftfjftdkkbidkkSdSile^hFtSliitlhliS
`;j!g!||,,:,:,:^
`
`>5
`
`it'
`
`IS
`
`oyo disorder i ft a
`
`tiLfykftkkYkih
`
`to ilk' patfortf & suigki initial &>$«:■ of a VEGF antagonise
`ioikovod by syaa of .UF-ve seoouoaiy dosos of the V.BGF
`aniogonisi., fcjknved by one or raoro tori''ary
`of iho
`Vk( vF ontny.onis{ ■
`wherein each *rtt>fG.-p;y dose k tidmhmfcinid 2 to 4 week's
`;tikv the imtoetljeteiv preceding dosa; and
`wherein each toG.kfv do^e is ndetirhstoted at
`k wwks
`oiks the immediately preceding dose;
`w:heiein the VFC.F ontepon’A h o VFkVF irouoptoebafttki
`s'ii kik Si ik* L x<=; toos.nk ^ f t il F V2'KA* JkG
`
`148. First, claim 14 recites the same dosing regimen as that recited in claim
`
`1: “wherein each secondary dose is administered 2 to 4 weeks after the immediately
`
`preceding dose; and wherein each tertiary dose is administered at least 8 weeks after
`
`the immediately preceding dose.” Thus, for the same reasons discussed above with
`
`respect to claim L (see f 128), it is also my opinion that Dixon discloses these
`
`identical elements in claim 14.
`
`149. Second, in my opinion, Dixon also discloses the VEGF antagonist
`
`element of claim 14. Just as for claim 1, Dixon expressly discloses VEGF Trap-
`
`Eye/ailibereept, and the sequence aspect of claim 14 was widely published in the
`
`prior art. (See, e.g.. Ex. 1006, Dixon, 1575-76, Fig.l: Ex. 1010, ’758 patent, Fig.24A-
`
`69
`
`Mylan Exhibit 1002
`Mylan v. Regeneron, IPR2021 -00881
`Page 76
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2013 PAGE 723
`
`

`

`C (disclosing the nucleotide sequence and deduced amino acid sequence, as well as
`
`a description of each molecular component therein (i.e., the signal sequence, the
`
`FLT1 Ig domain 2, the FLK1 Ig domain 3, and the FcACl domain); id., 10:15-17
`
`(specifying that this molecule is termed “VEGFR.lR2-FcACl(a).”)); Ex. 1033, Dix,
`
`[Q013]~[0014], [0030]; Ex,1039, ’095 patent, 1:45-54; Ex.1021, 2009 10-Q, 20
`
`(using VEGF Trap and aflibercept interchangeably and explaining that “VEGF Trap
`
`Eye is a specially purified and formulated form of VEGF Trap for use in intraocular
`
`applications”); Ex. 1007, Adis, 261 (indicating in the title that aflibercept, VEGF
`
`Trap (R1R2) and VEGF Trap-Eye, among other terms, are understood by a person
`
`of ordinary skill in the art: to refer, interchangeably, to the same drag); Fix. 1094).
`
`150. Therefore, for these reasons, as well as the reasons set forth above for
`
`claim 1, it is my opinion that claim 14 is anticipated by Dixon.
`
`are
`
`151. Claim 16 limits the method of claim 14 to “wherein only two secondary
`
`doses are administered to the patient, and wherein each secondary dose is
`
`administered 4 weeks aider the immediately preceding dose.” Claim 17 further limits
`
`the method of claim 16 to “wherein each tertiary dose is administered 8 weeks after
`
`the immediately preceding dose.
`
`152. As I explained with respect to claims 3 and 4 above, Dixon discloses
`
`the elements of claim 16 (each secondary dose administered 4 weeks after the
`
`70
`
`Mylan Exhibit 1002
`Mylan v. Regeneron, IPR2021 -00881
`Page 77
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2013 PAGE 724
`
`

`

`immediately preceding dose) and claim 17 (each tertiary dose is administered 8
`
`weeks after the immediately preceding dose), as is illustrated in modified Figure I
`
`below:
`
`Dixon at 1576 pfSSxSSS ssS svaissip S O ;s sss § msfc.
`
`ffoSowis'kg Hsis* *»ealhSy stoss}5’)
`
`Oo
`>
`
`*
`
`'/////.
`
`i
`
`8 «ls-
`■ ip i g |
`
`W//V//VA
`
`\
`
`i
`
`W<sM
`3Q ^
`
`P
`
`t
`
`llilillllll&
`
`1
`
`f ®
`p 1
`1
`«sS
`■;SftS®:p
`Dosos
`
`O
`
`////,
`
`-'
`
`| i
`...
`
`i
`
`i.
`
`;C>:
`
`8 wPtfey
`
`♦n
`
`U |
`i
`
`A *«ll
`
`I
`*
`u. i :
`J
`:
`Dos® ®'iV® SCp ';■
`pOSSiS
`i
`
`i
`
`(Ex.1001, ’338 patent. Fig. 1 (modifications added))
`
`153. Accordingly, for these reasons, as well as for the reasons discussed
`
`above for claim 14, it is my opinion that claims 16 and 17 of the ’338 patent are
`
`anticipated by Dixon.
`
`9.
`
`Dependent claims 18 and 20 are anticipated by Dixon.
`
`154. Claim 18 is dependent on claim 17, which ultimately depends from
`
`claim 14, and recites “wherein the angiogenic eye disorder is age related macular
`
`degeneration.” Claim 20 is dependent on claim 14 and recites ‘'wherein the
`
`angiogenic eye disorder is selected from the group consisting of’ several well-
`
`known eye disorders, including AMD.
`
`71
`
`Mylan Exhibit 1002
`Mylan v. Regeneron, IPR2021 -00881
`Page 78
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2013 PAGE 725
`
`

`

`155. The Dixon reference indicates in the title that VEGF Trap-Eye was
`
`being studied for the treatment of AMD. Likewise, the hulk of the reference
`
`discusses VEGF Trap-Eye as it relates to the treatment of AMD, including the
`
`discussion of the Phase 1 CLEAR-IT-1 clinical trial in patients with neovascular
`
`AMD; the Phase 2 CLEAR-IT-2 clinical trials in wet AMD; and the Phase 3 VIEW!
`
`and VEEW2 clinical trials. It is in the discussion of the VIEW! and VIEW2 trials
`
`for wet AMD that the dosing regimen of 3 monthly doses followed by every 8 week
`
`dosing was disclosed, after reporting that the Phase 2 trial results had shown mean
`
`improvements in visual acuity and retinal thickness, which are key indicators of
`
`success when treating AMD. Dixon therefore expressly discloses treating an
`
`angiogenic eye disorder, including AMD, as required by claims 18 and 20.
`
`156. Thus, for these reasons, as well as for the reasons discussed above for
`
`claims 14, 16, and 17, it is my opinion that claims 18 and 20 of the ’338 patent are
`
`anticipated by Dixon.
`
`157. Claim 19 claims the method of claim 14, “wherein at least 5 tertiary
`
`doses” are administered, and “wherein the first four tertiary does are administered 8
`
`weeks after the immediately preceding dose, and wherein each subsequent tertiary
`
`dose is administered 8 or 12 weeks after the immediately preceding dose.
`
`72
`
`Mylan Exhibit 1002
`Mylan v. Regeneron. IPR2021 -00881
`Page 79
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2013 PAGE 726
`
`

`

`158. Dixon discloses that the VIEVV1 and VIEW2 clinical trials will last at
`
`least a year. (Ex.1006, Dixon, 1576 (“After the first year of the study, patients will
`
`enter a second year of p.r.n. dosing .... [T]he primary outcome will be the
`
`proportion of patients who maintain vision at week 52.” (emphasis added)).
`
`159. As explained above with respect to claim 5, moreover, one year of
`
`dosing on an every-8-week dosing schedule after three monthly doses would result
`
`in at least 5 “tertiary” doses (reel arrows in above figure). For example, after three
`
`monthly doses at weeks 0, 4, and 8, the every-8-week dosing regimen disclosed in
`
`Dixon for the VIEW! and VIEW2 studies would result in doses being administered
`
`at weeks 16. 24, 32, 40, and 48, meaning that “at least 5 tertiary' doses” would be
`
`administered at least 8 weeks after the immediately preceding dose, before the end
`
`of the one year trial.
`
`160. Thus, for these reasons, as well as for the reasons discussed above for
`
`claim 14, it is my opinion that claim 19 of the "338 patent is anticipated by Dixon.
`
`161. Dependent claim 21 depends from claim 14 and recites “wherein all
`
`doses of the VEGF antagonist are administered to the patient by topical
`
`administration or by intraocular administration.
`
`162. Claim 22 depends from claim 21 and specifies intraocular
`
`administration.
`
`73
`
`Mylan Exhibit 1002
`Mylan v. Regeneron, IPR2021 -00881
`Page 80
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2013 PAGE 727
`
`

`

`163. Claim 23 depends from claim 22 and specifies that “the intraocular
`
`administration is intravitreal administration.
`
`164. To a person of ordinary skill in the art, it is well understood that
`
`intravitreal administration is a form of intraocular administration. Intraocular
`
`administration refers to administration to the eye generally, while intravitreal
`
`administration, a subset of intraocular administration, refers to administration
`
`directly into the vitreous of the eye.
`
`165.
`
`In Dixon's disclosure of the VIEW1 and VIEW2 studies, Dixon stated
`
`that the study “will evaluate the safety and efficacy of intravitreal VEGF Trap-Eye.
`
`(Ex. 1006, Dixon, 1576),
`
`Dixon therefore expressly discloses intravitreal
`
`administration.
`
`166. Therefore, for these reasons, as well as for the reasons discussed above
`
`for claim 14, it is my opinion that claims 21-23 are anticipated by Dixon.
`
`167. Dependent claim 24 depends from claim 23 and recites “wherein all
`
`doses of the VEGF antagonist comprise from about 0.5 mg to about 2 mg of the
`
`VEGF antagonist. Dependent claim 26 depends from claim 24 and specifies
`
`“wherein all doses of the VEGF antagonist comprise 2 mg of the VEGF antagonist .
`
`168. Dixon discloses the VIEW! and VIEW2 studies in which the treatment
`
`arms included, “intravitreal VEGF Trap-Eye at ... 2.0 mg at an 8 week dosing
`
`74
`
`Mylan Exhibit 1002
`Mylan v. Regeneron. IPR2021 -00881
`Page 81
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2013 PAGE 728
`
`

`

`interval (following three monthly doses).” (Ex. 1006, Dixon, 1576). Dixon therefore
`
`expressly discloses the doses of claims 24 and 26.
`
`169. Therefore, for these reasons, as well as the reasons set forth above for
`
`the claims from which claims 24 and 26 depend, it is my opinion that claims 24 and
`
`yuft
`
`Xxxxk
`
`26 are anticipated by Dixon.
`
`170. Claim 1 of the ’338 patent has been set forth above.
`
`171. I was asked to review the challenged claims of the ’338 patent and
`
`compare them to the disclosures of Adis. It is my opinion that Adis discloses every
`
`element of the claimed method(s ) and thus anticipates each of the challenged claims
`
`of the ’338 patent.
`
`172. For example, like Dixon above, Adis discloses Regeneron A planned
`
`Phase 3 trials being conducted with VEGF Trap-Eye, VIEW1 and VIEW2. Adis
`
`discloses the VIEW regimen, i.e., “2.0 mg at an 8-week dosing interval, including
`
`one additional 2,0 mg dose at week 4.” (Ex.1007, Adis, 263). In other words, one
`
`of the dosing regimens being tested in the VIEW trials was every-8-week dosing
`
`following three monthly doses. This has been shown using the same overlay
`
`presented above, in which I have used Figure 1 of the ’338 patent, which show's a
`
`75
`
`Mylan Exhibit 1002
`Mylan v. Regeneron, IPR2021 -00881
`Page 82
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2013 PAGE 729
`
`

`

`regimen that exemplifies each cliallenged claim, to illustrate how Adis discloses the
`
`exact dosing regimen set forth in Figure I of the ’338 patent, as well as that which
`
`is claimed in the challenged claims of the ’338 patent, as depicted here:
`
`rtrfe S63 fjVlS'rVS vsiiS
`
`aosmg imsrv's:. l»Kta«te§ sms sdsistio^id 2,0 mg com atwsssfc 4"}
`
`Of
`
`-D
`
`# 50
`
`Weeks
`30#
`
`OC
`
`M
`
`I
`
`t t t
`
`[
`Initial
`T
`Dose Secondary'
`Doses
`
`Tertiary
`Doses
`
`(Ex. 1001, ’338 patent Ftg.l (modifications added)).
`
`173. While Adis does not use the exact terms “initial,” “secondary,” and
`
`“tertiary,” one of ordinary skill in the art readily would have recognized that the
`
`“initial dose” would have been the first dose given-
`
`in this case the dose given at
`
`time zero—and that the “secondary doses . . . wherein each secondary dose is
`
`administered 2 to 4 weeks after the immediately preceding dose,” could be found in
`
`Adis’ disclosure of “an 8-week dosing interval, including one additional 2.0 mg dose
`
`at week 4” (bine arrows). (See, e.gEx. 1007, Adis, 263 (emphasis added)).
`
`174. Similarly, one of ordinary skill in the art would have recognized that
`
`the “tertiary doses . . . wherein each tertiary dose is administered at least 8 weeks
`
`76
`
`Mylan Exhibit 1002
`Mylan v. Regeneron. IPR2021 -00881
`Page 83
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2013 PAGE 730
`
`

`

`after the immediately preceding dose,’5 correspond to the “8-week dosing interval
`doses disclosed in Adis (red arrows). (See, e.g., id).
`
`175.
`
`In my opinion, the VIEW dosing regimen described in Adis is the
`
`precise dosing regimen that was described in Figure 1 in the ’338 patent and which
`
`falls squarely within the scope of claim 1.
`
`176. With respect to the VEGF antagonist element: of claim 1,1 note that: this
`
`description is merely a recitation of the molecular architecture of the “aflibercept
`
`and “VEGF Trap-Eye” disclosed in Adis, a fact that was disclosed well before
`
`January 2011. (See, e.g., Ex.1006, Dixon, 1575-76, Fig. 1; Ex.1010, ’758 patent,
`
`Fig.24A-C (disclosing the nucleotide sequence and deduced amino acid sequence,
`
`as w?ell as a description of each molecular component therein (i.e., the signal
`
`sequence, the FLIT Ig domain 2, the FLK1 Ig domain 3, and the FcACl domain);
`
`id., 10:15-17 (specifying that this molecule is termed “VEGFRlR2-FcACl(a).”));
`
`Ex.1033, Dix, [0013]-[0014], [0030]; Ex.1039, ’095 patent, 1:45-54; Ex.1021, 2009
`
`10-Q, 20 (using VEGF Trap and aflibercept interchangeably and explaining that
`
`'VEGF Trap-Eye is a specially purified and formulated form of VEGF Trap for use
`
`in intraocular applications”); Ex. 1007, Adis, 261 (indicating in the title that
`
`aflibercept, VEGF Trap (R1R2) and VEGF Trap-Eye, among other terms, are
`
`understood by a person of ordinary skill in the art to refer, interchangeably, to the
`
`77
`
`Mylan Exhibit 1002
`Mylan v. Regeneron, IPR2021 -00881
`Page 84
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2013 PAGE 731
`
`

`

`same drug); Ex. 1093). As a result, through Adis’ disclosure of VEGF Trap
`
`Eye/aflibercept, Adis discloses this aspect of claim 1.
`
`19
`
`177. Accordingly, for these reasons, it is my opinion that claim 1 of the ’338
`
`patent is anticipated by Adis.
`
`178. Dependent claim 3 claims the method of claim 1, “wherein only two
`
`secondary doses are administered to the patient, and wherein each secondary dose is
`
`administered 4 weeks after the immediately preceding dose.
`
`179.
`
`Claim 4 claims the method of claim 3, “wherein each tertiary dose is
`
`administered 8 weeks after the immediately preceding dose.
`
`180. As discussed above and illustrated in my modified Figure 1 of the ’338
`
`patent, Adis discloses the elements of claim 3 (each secondary dose administered 4
`
`weeks after the immediately preceding dose) and claim 4 (each tertiary dose is
`
`administered 8 weeks after the immediately preceding dose):
`
`19 Regarding the preamble, see, e.g., supra note 18; Ex.1007, Adis, 268 (“After the
`
`last fixed-dose administration at week 12, patients from all dose groups required on
`
`average only one additional injection over the following 20 weeks to maintain visual
`
`acuity gain achieved.”).
`
`78
`
`Mylan Exhibit 1002
`Mylan v. Regeneron. IPR2021 -00881
`Page 85
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2013 PAGE 732
`
`

`

`1I1I11111I1I11111II
`
`A:«:s at Sas :5;fv'S£WS 55,5:5 ssvas;.s;a| sa Saaaaa siossas feW'VAS, ia«Si.a'iffS§ ««« 5S5S«SsSl»«,s5 2.S aag siassss at
`
`4-"i
`
`yv
`
`.
`
`a
`
`L.sssssty>/'-
`
`-yyyyyyyyy.
`
`V/////,
`
`i
`
`vwyks
`
`B
`
`WsskS
`
`1
`
`t
`
`i4
`
`'///A
`
`S f
`
`ff
`
`ISS'iijsry
`
`20:
`
`I
`Y
`m \ * >
`58
`t
`&
`f*
`
`i
`
`Mi0m
`m
`
`Mm
`
`i
`
`\
`
`11 m
`.4 8i
`
`#I
`f?
`
`'///Mfr-
`
`; t
`
`M1
`
`L
`
`j ;
`
` l!)oss4
`\
`
`(Ex. 1001, "338 patent, Fig.l (modifications added)).
`
`181. According!)’, for these reasons, as well as the reasons presented for
`
`claim L it is my opinion that claims 3 and 4 of the 5 338 patent are anticipated by
`
`Adis.
`
`3.
`Dependent claim 5 is anticipated by Adis.
`182. Claim 5 claims the method of claim 1, “wherein at least 5 tertiary
`
`doses” are administered, and “wherein the first four tertiary does are administered 8
`
`weeks after the immediately preceding dose, and wherein each subsequent tertiary
`
`dose is administered 8 or 12 weeks after the immediately preceding dose.”
`
`183. Adis discloses that die VIEW! and V1EW2 clinical trials will last at
`
`least a year. (Ex. 1007, Adis, 263 (“Patients will continue to be treated and followed
`
`for an additional year, after the first year of treatment' and “[f]he primary endpoint
`
`79
`
`Mylan Exhibit 1002
`Mylan v. Regeneron, IPR2021 -00881
`Page 86
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2013 PAGE 733
`
`

`

`will be the proportion of patients treated with aflibercept who maintain vision at the
`
`end of 1 year compared with ranibizumab patients.” (emphases added}}.
`
`184. One year of dosing on an every-8-week dosing schedule after three
`
`monthly doses would result in at least 5 “tertiary” doses administered at least 8
`
`weeks after the immediately preceding dose. Again, a graphic is useful in illustrating
`
`this;
`
`Aefe* si K4S rWsCW? will svfMiisisl
`
`iJfisrwi; ms.lsjdmg ms 'SridslisssW Z.® mg si wssSs 4 ’■
`
`1
`
`# 50
`
`60 |
`
`Weeks1
`
`30#
`
`/$?////,
`
`QC
`
`M
`
`O
`
`YSSSj
`
`¥4
`
`Dose Secondary
`Doses
`
`Tertiary
`Doses
`
`1
`1
`
`(Ex. 1001, ’338 patent, Fig.l (modifications added)). Using the modified graphic
`
`from the ’338 patent, it is apparent that the every-8-week dosing regimen disclosed
`
`in Adis for the VIEW1 and VIEW2 studies would result in “tertiary” doses being
`
`administered at least at weeks 16, 24, 32, 40, and 48, meaning that “at least 5 tertiary
`
`doses” would be administered before the end of the one-year trial.
`
`185.
`
`Thus, for these reasons, as well as for the reasons discussed above for
`
`claim i, it is my opinion that claim 5 of the ’338 patent is anticipated by Adis.
`
`80
`
`Mylan Exhibit 1002
`Mylan v. Regeneron. IPR2021 -00881
`Page 87
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2013 PAGE 734
`
`

`

`are
`
`186. Claim 6 is dependent on claim 1 and recites the method of claim 1,
`
`“wherein the angiogenic eye disorder is selected from the group consisting of
`
`several well-known eye disorders, including AMD. Claim 7, which depends from
`
`claim 6, recites “wherein the angiogenic eye disorder is age related macular
`
`degeneration.
`
`187. The Adis reference indicates in the abstract that aflibercept was being
`
`developed for eye disorders and that “[h]loekade of VEGF can also prevent blood
`
`vessel formation and vasuclar [sic] leakage associated with wret age-related macular
`
`degeneration (AMD).
`
`(Ex. 1007, Adis, 261).
`
`Likewise, Adis discusses
`
`Regeneron’s disclosures of the V1EW1 and VIEW2 trials, which were intended to
`
`study VEGF Trap-Eye/aflibercept in wet AMD. (Id, 263). It is in the discussion of
`
`the VIEW! and VIEW2 trials for wet AVID, which is an angiogenic eye disorder,
`
`that the dosing regimen of doses at weeks 0, 4, and 8, followed by every-8-week
`
`dosing, was disclosed. Thus, Adis discloses the treatment of AMD, a well-known
`
`angiogenic eye disorder.
`
`188. Thus, for these reasons, as well as for the reasons discussed above for
`
`claim 1, it is my opinion that claims 6 and 7 of the ’338 patent are anticipated by
`
`Adis.
`
`Mylan Exhibit 1002
`Mylan v. Regeneron, IPR2021 -00881
`Page 88
`
`GO
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2013 PAGE 735
`
`

`

`are
`
`189. Dependent claim 8 depends from claim 1 and recites “wherein all doses
`
`of the VEGF antagonist are administered to the patient by topical administration or
`
`by intraocular administration.
`
`190.
`
`Claim 9 depends from claim 8 and specifies intraocular administration.
`
`191. Claim 10 depends from claim 9 and specifies that “the intraocular
`
`administration is intravitreal administration.
`
`192. In Adis’ disclosure of the VIEW studies, Adis states that the study “will
`
`evaluate the safety and efficacy of intravitreal aflibercept.” (Ex. 1007, Adis, 263).
`
`Adis also notes that Regeneron’s Phase 2 trial was designed to “evaluate the safety
`
`and efficacy of intravitreal aflibercept using different doses and dose regimens.”
`
`(M),
`
`Intravitreal injection is a type of intraocular administration—more
`
`specifically, administration directly into the vitreous of the eye. This element is
`
`therefore expressly disclosed and taught by Adis.
`
`193. Thus, for these reasons, as well as for the reasons discussed above for
`
`claim 1, it is my opinion that claims 8-10 of the ’338 patent are anticipated by Adis.
`
`194. Dependent claim 11 depends from claim 10 and recites “wherein ail
`
`doses of the VEGF antagonist comprise from about 0.5 mg to about 2 mg of the
`
`82
`
`Mylan Exhibit 1002
`Mylan v. Regeneron, IPR2021 -00881
`Page 89
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2013 PAGE 736
`
`

`

`VEGF antagonist. Dependent claim 13 depends from claim 11 and specifies
`
`“wherein all doses of the VEGF antagonist comprise 2 mg of the VEGF antagonist.
`
`195. Adis discloses the VIEVV1 and VIEW2 studies in which the treatment
`
`arms included VEGF Trap-Eye/aflibercept administered at a 2.0 mg dose. (Ex. 1007,
`
`Adis, 263). Adis therefore expressly discloses the doses of claims 11 and 13.
`
`196. Therefore, for these reasons, as well as the reasons set forth above for
`
`claim 10 and claim 1, it is my opinion that claims 11 and 13 are anticipated by Adis.
`
`7.
`
`is
`
`197. Claim 14 of the ’338 patent is identical to claim 1 with the only
`
`exception being in the third “wherein” clause.
`
`198. First, claim 14 recites the same dosing regimen as that recited in claim
`
`1: “wherein each secondary dose is administered 2 to 4 weeks aider the immediately
`
`preceding dose; and wherein each tertiary dose is administered at least 8 weeks after
`
`the immediately preceding dose.” Thus, for the same reasons discussed above with
`
`respect to claim 1, (see ff 170-77), it is also my opinion that Adis discloses these
`
`identical elements in claim 14.
`
`199. Second, in my opinion, Adis discloses the VEGF antagonist element of
`
`claim 14. Adis expressly discloses VEGF Trap-Eye/aflibercept, and the sequence
`
`aspect of claim 14 was widely published hi the prior art. (See, e.g., Ex. 1006, Dixon,
`
`1575-76, Fig.l; Ex. 1010, ’758 patent, Fig.24A-C (disclosing the nucleotide
`
`83
`
`Mylan Exhibit 1002
`Mylan v. Regeneron, IPR2021 -00881
`Page 90
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2013 PAGE 737
`
`

`

`sequence and deduced amino acid sequence, as well as a description of each
`
`molecular' component therein (i.e., the signal sequence, the FLT1 Ig domain 2, the
`
`FLK1 Ig domain 3, and the FcACl domain), 10:15-17 (specifying that this molecule
`
`is termed “VEGFRlR2-FcACl(a).”)); Ex.1033, Dix, [0013]-[0014], [0030];
`
`Ex.1039, ’095 patent, 1:45-54; Ex.1021, 2009 10-Q, 20 (using VEGF Trap and
`
`aflibercept interchangeably and explaining that “VEGF Trap-Five is a specially
`
`purified and formulated form of VEGF Trap for use in intraocular applications”);
`
`Fix.1007, Adis, 261 (indicating in the title that aflibercept, VEGF Trap (R1R2) and
`
`VEGF Trap-Eye, among other terms, are understood by a person of ordinary skill in
`
`the art to refer, interchangeably, to the same drug); Ex. 1094).
`
`200. Therefore, for these reasons, as well as the reasons set forth above for
`
`claim 1, it is my opinion that claim 14 is anticipated by Adis.
`
`are
`
`201. Claim 16 limits the method of claim 14 to “wherein only two secondary
`
`doses are administered to the patient, and wherein each secondary dose is
`
`administered 4 weeks after the immediately preceding dose.” Claim 17 further limits
`
`the method of claim 16 to “wherein each tertiary dose is administered 8 weeks after
`
`the immediately preceding dose.
`
`202. These elements are similar in scope to those discussed above with
`
`respect to claims 3 and 4, and as 1 explained with respect to those claims, Adis
`
`84
`
`Mylan Exhibit 1002
`Mylan v. Regeneron, IPR2021 -00881
`Page 91
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2013 PAGE 738
`
`

`

`discloses the elements of “each secondary dose is administered 4 weeks after the
`
`immediately preceding dose” and “each tertiary dose is administered 8 weeks after
`
`the immediately preceding dose ” (See, e.g., Ex, 1007, Adis, 263 (“2.0 nig at an 8
`
`week dosing interval, including one additional 2.0 mg dose at week 4.”)).
`
`203. Accordingly, for these reasons, as wrell as for the reasons discussed
`
`above for claims 3, 4, and 14, it is my opinion that claims 16 and 17 of the 7338
`
`patent are anticipated by Adis.
`
`204.
`
`Claim 18 depends from claim 17, which ultimately depends from claim
`
`14, and recites “wherein the angiogenic eye disorder is age related macular
`
`degeneration.” Claim 20 depends from claim 14 and recites “wherein the angiogenic
`
`eye disorder is selected from the group consisting of’ several well-known eye
`
`disorders, including AMD.
`
`205. These elements are similar in scope to those discussed above with
`
`respect to claims 6 and 7, and as I explained with respect to those claims, Adis
`
`discloses the VJEW1 and VIEW2 trials, and the treatment aims used therein, which
`
`were designed to assess wet AMD. (See, e.g., Ex. 1007, Adis, 263 (“Regeneron and
`
`Bayer initiated a phase III trial of aflibercept in approximately 1200 patients with
`
`the neovascular form of wet AMD . . . ,”)). Adis therefore expressly discloses
`
`treating AMD, an angiogenic eye disorder.
`
`85
`
`Mylars Exhibit 1002
`Mylars v. Regeneron, IPR2021 -00881
`Page 92
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2013 PAGE 739
`
`

`

`206. Thus, for these reaso