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`Exhibit 1
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`Case 1:22-cv-00061-TSK-JPM Document 505-2 Filed 05/26/23 Page 2 of 75 PageID #:
`40061
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`Paper No. 93
`Entered: October 26, 2022
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`Trials@uspto.gov
`571-272-7822
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________
`
`MYLAN PHARMACEUTICALS INC., CELLTRION, INC., and
`APOTEX, INC.,
`Petitioners,
`
`v.
`
`REGENERON PHARMACEUTICALS INC.,
`Patent Owner.
`______________
`
`IPR2021-00880 (Patent 9,669,069 B2)1
`IPR2021-00881 (Patent 9,254,338 B2)2
`______________
`
`Record of Oral Hearing
`Held: August 10, 20223
`______________
`
`
`
`
`Before ERICA A. FRANKLIN, JOHN G. NEW, and
`SUSAN L. C. MITCHELL, Administrative Patent Judges.
`
`
`
`1 IPR2022-00257 and IPR2022-00301 have been joined with this
`proceeding.
`2 IPR2022-00258 and IPR2022-00298 have been joined with this
`proceeding.
`3 The consolidated hearing for these cases does not indicate that IPR2021-
`00880 and IPR2021-00881 have been joined.
`
`
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`Case 1:22-cv-00061-TSK-JPM Document 505-2 Filed 05/26/23 Page 3 of 75 PageID #:
`40062
`IPR2021-00880 (Patent 9,669,069 B2)
`IPR2021-00881 (Patent 9,254,338 B2)
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`
`
`APPEARANCES:
`
`ON BEHALF OF THE PETITIONER:
`
`
`NEIL B. MCGLAUGHLIN, PH.D.
`RMMS Legal
`6 West Hubbard Street
`Chicago, Illinois 60654
`(703)-943-6084
`nmcglaughlin@rmmslegal.com
`
`
`
`ON BEHALF OF THE PATENT OWNER:
`
`
`DEBORAH FISHMAN, ESQ.
`Arnold & Porter Kaye Scholer LLP
`601 Massachusetts Avenue NW
`Washington, DC 20001
`202-942-6828
`deborah.fishman@arnoldporter.com
`
`
`
`
`
`The above-entitled matter came on for hearing on Wednesday,
`August 10, 2022, commencing at 2:00 p.m. EST, in Hearing Room D.
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`Case 1:22-cv-00061-TSK-JPM Document 505-2 Filed 05/26/23 Page 4 of 75 PageID #:
`40063
`IPR2021-00880 (Patent 9,669,069 B2)
`IPR2021-00881 (Patent 9,254,338 B2)
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`
`P R O C E E D I N G S
`- - - - -
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`
`
`2:00 p.m.
`JUDGE NEW: Good afternoon. Welcome to the Board. My name
`is Judge New. I am joined today by Judge Mitchell and remotely by Judge
`Franklin.
`We are convened to hear oral arguments in the matter of IPR2021-
`00880 and 00881. This hearing relates to claims 1 to 12 of US Patent
`9,669,069 B2 in the 00880 IPR; and claims 1, 3 to 11, 13, 14, 16 to 24, and
`26 of US Patent 9,254,338 B2 in the 00881 IPR.
`Consistent with the hearing order, each party has a total of 60
`minutes for its presentation. Petitioner may reserve a portion of their time to
`respond to arguments presented by Patent Owner. Patent Owner has also
`been authorized to reserve a portion of time for rebuttal.
`Please be mindful that a court reporter is transcribing this hearing
`and there is no shared display for demonstrative exhibits for Judge Franklin,
`who is with us remotely. So please, when referring to a particular
`demonstrative exhibit, identify it clearly by number so that she can follow
`along with all of us here.
`We're in receipt of the parties' objections to various evidence and
`Petitioner's motion to exclude. However, we will reserve ruling upon the
`objections and motions at this time.
`Lastly, I'd like to remind you all that there are a number of
`documents and exhibits under seal in these proceedings, and that this hearing
`and trial transcript will be available to the public. I therefore caution
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`Case 1:22-cv-00061-TSK-JPM Document 505-2 Filed 05/26/23 Page 5 of 75 PageID #:
`40064
`IPR2021-00880 (Patent 9,669,069 B2)
`IPR2021-00881 (Patent 9,254,338 B2)
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`counsel against discussing or raising any matter that may be under seal and
`considered confidential.
`And with that, Counsel for Petitioner, you may proceed after
`introducing yourself and indicating any time you would like to reserve for
`rebuttal.
`MR. McGLAUGHLIN: Thank you, Your Honors. Neil
`McGlaughlin on behalf of Petitioners, Mylan Pharmaceuticals and the joint
`parties.
`We would like to reserve 15 minutes of our time for rebuttal.
`We also want to bring the Board's attention to, in case you didn't
`receive it, the corrected exhibits that Petitioner filed. Do you have copies of
`those?
`
`JUDGE NEW: We do, yes. Thank you very much.
`MR. McGLAUGHLIN: The '069 patent claims are directed to a
`prior art PRN dosing regimen that was in use by ophthalmologists when
`administering anti-VEGF agents long before the filing date of the '069
`patent.
`
`The '069 claims set forth the same regimen using a prior art
`molecule, aflibercept, also known as VEGF Trap-Eye, a molecule of known
`structure and sequence. Petitioner has set forth in this proceeding clear,
`straightforward grounds of anticipation based on disclosures of use of VEGF
`Trap-Eye in PRN dosing clinical trials, one example of which is shown here
`on slide 2.
`This is from Exhibit 1006, the Dixon reference, from page 1576, the
`disclosure of the CLEAR-IT-2 Phase II trial in which VEGF Trap-Eye, also
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`Case 1:22-cv-00061-TSK-JPM Document 505-2 Filed 05/26/23 Page 6 of 75 PageID #:
`40065
`IPR2021-00880 (Patent 9,669,069 B2)
`IPR2021-00881 (Patent 9,254,338 B2)
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`known as aflibercept, was used to treat patients, both A and B, using a series
`of monthly loading doses followed by PRN dosing.
`Similar disclosures are found in the Heier 2009 reference, which
`serves as our Ground 1 reference. That's Exhibit 1020.
`On slide 3 is set forth our Ground 3 reference, the April 2009 press
`release from Regeneron, which disclosed the VEGF Trap-Eye Phase III
`CRVO trial using PRN dosing after a series of six monthly loading doses.
`In other words, an initial dose followed by one or more secondary doses.
`Slide 4, Petitioner's asserted art references cover each and every
`limitation of the claims. It's undisputed in these proceedings that the
`references disclosed the dosing regimen steps and the molecule VEGF Trap-
`Eye, also known as aflibercept. The dosing steps are indicated here on this
`slide in the green highlighting.
`The sole dispute at issue in these proceedings centers around the
`sequence. However, as we'll show, Patent Owner's arguments in this regard
`should be given no weight.
`At this point, I would like to jump ahead real quick to slide 10 just to
`show you the sequence that we're talking about. This is actually an
`alignment that we put into the record as Exhibit 1122. This shows an
`alignment of the '069 and '338 claimed sequences. This is the sequence from
`that last wherein of claim 1 of each of the patents.
`The top line in this alignment is that of the '069 and '338 claimed
`sequence. The next line down is the sequence of the prior art, 2006 WHO
`Drug Information aflibercept sequence. And then the lines below that are
`the prior art '758 and '959 patent sequences, showing that these sequences
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`Case 1:22-cv-00061-TSK-JPM Document 505-2 Filed 05/26/23 Page 7 of 75 PageID #:
`40066
`IPR2021-00880 (Patent 9,669,069 B2)
`IPR2021-00881 (Patent 9,254,338 B2)
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`are identical, and that there's no dispute that this sequence was in the prior
`art.
`
`Going back to slide 5. Now that I'm discussing the sequences, I
`should mention that now is the -- first of all, I'll begin by saying that I'm
`going to be covering the '069 patent grounds. And then because of the
`overlap in the subject matter, I'm going to be covering the sequences as well,
`and that portion of my presentation will be directed to both IPRs.
`JUDGE FRANKLIN: Counsel?
`MR. McGLAUGHLIN: Yes.
`JUDGE FRANKLIN: This is Judge Franklin. Quick question on the
`demonstratives that were corrected. Those were filed yesterday; is that
`correct?
`MR. McGLAUGHLIN: Correct. Correct, Your Honor.
`JUDGE FRANKLIN: Were those filed with authorization from the
`Board?
`MR. McGLAUGHLIN: We didn't seek the Board's authorization,
`but this came as a result of the parties conferring. Objections were raised to
`our slides. We conferred. And rather than bring the dispute to the Board
`and waste the resources of the Board and the parties, we decided to just
`amend the slides and submit corrected copies, Your Honor.
`JUDGE FRANKLIN: Okay. But you understand that filing
`corrected exhibits, including demonstratives, would normally require a
`Board authorization?
`MR. McGLAUGHLIN: Apologies for that, Your Honor.
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`Case 1:22-cv-00061-TSK-JPM Document 505-2 Filed 05/26/23 Page 8 of 75 PageID #:
`40067
`IPR2021-00880 (Patent 9,669,069 B2)
`IPR2021-00881 (Patent 9,254,338 B2)
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`JUDGE FRANKLIN: I just want to confirm at this point that Patent
`Owner does not have any challenge or dispute regarding your slides or our
`referring to them today.
`MS. FISHMAN: That's correct, Your Honor. We consented to it
`and agreed that it would resolve the objections that we raised during the
`confer.
`
`JUDGE FRANKLIN: Thank you.
`Thank you for that clarification. You may continue.
`MR. McGLAUGHLIN: Thank you, Your Honor.
`So it's undisputed that the sequence set forth here in the yellow
`highlighting from claim 1 of the '338/'069 patents, it's undisputed that that
`sequence was in the prior art. It's also undisputed that that's the sequence of
`aflibercept, and that VEGF Trap-Eye has always been aflibercept and still is
`aflibercept.
`Patent Owner's only approach in these proceedings has been to
`present unsupported speculation that a person of ordinary skill in the art
`would not necessarily have known that VEGF Trap-Eye was aflibercept or
`to have the claimed sequences. As we'll show, this is unsupported and, in
`fact, contradicted by the record, and Patent Owner arguments should be
`rejected.
`Slide 6. For example, there is no confusion among persons of
`ordinary skill in the art. This is a callout from Exhibit 1006, page 1573,
`from the opening abstract in which the authors state in connection with
`AMD treatments that "one promising new drug is aflibercept/VEGF Trap-
`Eye, a fusion protein," making it clear that VEGF Trap-Eye is in fact
`aflibercept.
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`Case 1:22-cv-00061-TSK-JPM Document 505-2 Filed 05/26/23 Page 9 of 75 PageID #:
`40068
`IPR2021-00880 (Patent 9,669,069 B2)
`IPR2021-00881 (Patent 9,254,338 B2)
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`
`In addition, on slide 7 we have a callout from Exhibit 1007, the Adis
`reference, at page 261, again in the opening abstract. The authors state
`"Regeneron and Bayer are developing the agent for eye disorders", where
`the agent refers back to the aflibercept at the beginning of the sentence.
`Also included in the title are synonyms for the term aflibercept, one
`of those being VEGF Trap-Eye, making it clear to persons of ordinary skill
`in the art that aflibercept was VEGF Trap-Eye and VEGF Trap-Eye was
`aflibercept. Furthermore, on page 264 of the Adis reference is set forth a
`unique CAS identifier number.
`And then if we go to slide 8, this shows the WHO 2006 Drug
`Information Index, Exhibit 1107. And the aflibercept entry from that index,
`found on pages 118 to 119, which includes information describing the
`structure of the molecule aflibercept, as well as the precise amino acid
`sequence of the aflibercept molecule. And this is from 2006. This would
`have been available to any person of ordinary skill in the art reading the
`disclosures of Dixon and Adis, and those references' disclosure of the use of
`aflibercept in the treatment of AMD.
`Further, on slide 9, even without the 2006 WHO Index, it would
`have been clear to persons of ordinary skill in the art what the sequence of
`VEGF Trap-Eye was. For example, Petitioner's expert, Dr. Gerritsen,
`recounts in her reply declaration, Exhibit 1115, in paragraphs 36 to 56, the
`construction of the molecule that would eventually become known as VEGF
`Trap-Eye and aflibercept.
`For example, in the upper left-hand corner of this slide is shown a
`callout from Exhibit 1004, the Holash reference, at page 11397. This is a
`reference from 2002. This is the reference that described the initial
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`Case 1:22-cv-00061-TSK-JPM Document 505-2 Filed 05/26/23 Page 10 of 75 PageID #:
`40069
`IPR2021-00880 (Patent 9,669,069 B2)
`IPR2021-00881 (Patent 9,254,338 B2)
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`construction of the molecule that would eventually become known as
`aflibercept and VEGF Trap-Eye. In this reference they called it
`VEGFTrapR1R2.
`And then if you go to Regeneron's prior art '173 patent -- that's
`Exhibit 1008, the callout of which is shown in the center of slide 9 -- in that
`reference they provide for a specific and preferred embodiment, and set forth
`a precise, unique sequence, both nucleotide and amino acid. And then
`associate that sequence with the terms VEGFTrapR1R2, as well as the term
`
`So you recognize that VEGFTrapR1R2 nomenclature is the same used
`in the 2002 Holash paper. And you also recognize that VEGFR1R2-
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`VEGFR1R2-Fc∆C1(a).
`Fc∆C1(a) terminology is the same used in the other prior art Regeneron
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`patent, the '758 patent, Exhibit 1010, the callout for which is shown in the
`upper right of this slide. All of these sequences are identical.
`And another thing I should note, after Holash was published in 2002,
`numerous prior art references disclose the use of VEGF Trap-Eye and
`aflibercept and referred back to Holash, citing back to Holash in its
`construction of that VEGFTrapR1R2 molecule.
`For example, Exhibit 2080, the Heier reference shown here at the
`bottom of slide 9. It discloses VEGF Trap-Eye and it cites back to Holash in
`its use of that terminology. VEGFTrapR1R2, as we see in the callout in the
`center of the slide, that terminology was associated with a specific and
`unique sequence in the prior art. And that sequence is identical to that that
`they now claim in the '069 and '338 patents.
`Again, this is from Exhibit 1122 where we've aligned the sequences
`from the '069 and '338 patent and shown that they're the same as the prior art
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`Case 1:22-cv-00061-TSK-JPM Document 505-2 Filed 05/26/23 Page 11 of 75 PageID #:
`40070
`IPR2021-00880 (Patent 9,669,069 B2)
`IPR2021-00881 (Patent 9,254,338 B2)
`
`2006 WHO Drug Information's aflibercept sequence, and also the same as
`the '758 and '959 patents' figure 24 sequence, thus confirming that VEGF
`Trap-Eye, which was also known as aflibercept, was known in the prior art
`to have one specific structure and sequence.
`There is no evidence of any differences in structure or sequence that
`has been presented in these proceedings. And thus, disclosure of the
`molecule using the terms VEGF Trap-Eye and aflibercept in Petitioner's
`asserted art is an expressed disclosure of the sequence or, at the very least,
`evidence that the sequence was a necessary feature of the prior art molecule.
`Patent Owner arguments to the contrary lack merit.
`I'll skip slide 11 in the interest of time. I'll come back to that on
`rebuttal.
`On slide 12, one argument that the Patent Owner makes is that
`VEGF Trap-Eye might have been thought to be a genus. This is not the
`case. This is directly contradicted by the record, including the Dixon and
`Adis references, which consistently refer to the agent in the singular and
`disclose it in Phase II and Phase III clinical trials.
`It's also the case that Regeneron's public disclosures make clear that
`the ophthalmology and oncology products contain the same active
`ingredient, aflibercept. For example, if we take a look at Exhibit 1021, the
`2009 10-Q form submitted to the SEC by Regeneron -- this is a prior art
`submission.
`In the submission they describe their oncology product as
`"aflibercept/VEGF Trap." That's on page 18. On the very next page, page
`19, they refer to VEGF Trap-Eye and state, "VEGF Trap-Eye is a specially
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`Case 1:22-cv-00061-TSK-JPM Document 505-2 Filed 05/26/23 Page 12 of 75 PageID #:
`40071
`IPR2021-00880 (Patent 9,669,069 B2)
`IPR2021-00881 (Patent 9,254,338 B2)
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`purified and formulated form of VEGF Trap for use in intraocular
`applications."
`Thus, they're taking that term VEGF Trap and they're associating it
`with both aflibercept and VEGF Trap-Eye, making it clear to persons of
`ordinary skill in the art that this is the same protein, the same active.
`This is also consistent with -- sorry, this is a little trigger happy.
`This is also consistent with Exhibit 1113, shown here on slide 13. This is
`the Rudge 2008 reference authored by a group of Regeneron researchers in
`which they describe VEGF Trap-Eye as one such protein-based agent, and
`state that that one agent "is now being evaluated in clinical trials in several
`types of cancer, as well as the 'wet' or neovascular form of age-related
`macular degeneration (AMD)", thus again making it clear based on public
`prior art statements that VEGF Trap-Eye is aflibercept.
`Persons of ordinary skill in the art reading Petitioner's asserted
`references would have known the sequence, which was also in the prior art,
`because we submit there's no serious argument that the sequences were not
`in the prior art and known to be VEGF Trap-Eye.
`We submit that we've shown by preponderance of the evidence that
`claims 1 and 9 through 12 of the '069 patent are anticipated by each of
`Petitioner's asserted references, and thus respectfully request cancellation of
`those claims under Grounds 1 through 3.
`JUDGE FRANKLIN: Counselor, this is Judge Franklin. In terms of
`what you've gone through in these slides to show that a person of skill in the
`art would not have been confused that VEGF Trap-Eye and aflibercept share
`the same sequence, do we have a declaration or deposition testimony from
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`Case 1:22-cv-00061-TSK-JPM Document 505-2 Filed 05/26/23 Page 13 of 75 PageID #:
`40072
`IPR2021-00880 (Patent 9,669,069 B2)
`IPR2021-00881 (Patent 9,254,338 B2)
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`Petitioner's expert on that? I see you're pointing to a transcript -- excuse me
`-- deposition.
`MR. McGLAUGHLIN: We do, Your Honor. We have declaration
`testimony from our expert, Dr. Gerritsen. That's Exhibit 1115. She spends
`quite a bit of space in her declaration devoted to discussion of the molecule,
`the sequence, and its identity in the -- its disclosure in the prior art.
`I would direct Your Honor's attention, for example, to paragraphs 36
`to 56 of Dr. Gerritsen's reply declaration.
`JUDGE FRANKLIN: Thank you.
`MR. McGLAUGHLIN: You're welcome.
`JUDGE NEW: Do you mean Dr. Gerritsen's reply declaration or Dr.
`Albini's reply declaration?
`MR. McGLAUGHLIN: Dr. Gerritsen.
`JUDGE NEW: Okay. Thank you.
`MR. McGLAUGHLIN: Now turning to Ground 4, Ground 4
`obviousness. The essence of Ground 4 as a Patent Owner should be held to
`the representations that were made during the prosecution of the '069 PRN
`dosing patent claims.
`For example, during prosecution Patent Owner stated that the
`currently pending PRN dosing claims -- in terms of those PRN claims, when
`arguing purported unexpected results of those claims, the Heier et al. paper,
`which disclosed a VIEW 8 regimen, was "a treatment protocol of the type
`claimed" and "a dosage regimen as claimed in independent claim 1".
`Patent Owner was thus equating that every eight-week dosing used
`in the VIEW trials disclosed in Heier 2012 with the currently pending PRN
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`Case 1:22-cv-00061-TSK-JPM Document 505-2 Filed 05/26/23 Page 14 of 75 PageID #:
`40073
`IPR2021-00880 (Patent 9,669,069 B2)
`IPR2021-00881 (Patent 9,254,338 B2)
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`dosing claims. This comes from Exhibit 1017, the '069 patent file history, at
`page 136.
`On page 137 of that file history, they go on to state that the purported
`unexpected results are also shown by the results summarized in Table 1 of
`the present application. That Table 1 is strictly limited to the disclosure and
`the discussion of the every-eight-week results of the VIEW trial, not the
`PRN results.
`The bottom line is that there's nothing in the Heier 2012 reference,
`which Patent Owner relied upon for unexpected results, that's not also in the
`prior art.
`Patent Owner now in their Patent Owner response claims that what
`they were discussing during prosecution was the PRN phase of the VIEW
`trial and not the every-eight-week phase, that those were the rules they were
`relying on.
`First, that's contradicted by the record, as we just showed on the
`previous slide. Secondly, that doesn't help them because our prior art also
`discloses the second-year PRN dosing phase of the VIEW trial, and thus
`anticipates.
`Further, Dixon also renders obvious the PRN dosing claim of the
`'069 patent, including claim 8, which is drawn to three monthly loading
`doses, followed by PRN dosing. That's based on the same disclosures in
`Dixon as from slide 16. Shown here is Exhibit 1006, the Dixon reference, at
`page 1576, which disclosed the use of three monthly loading doses with
`VEGF Trap-Eye and then a maintenance dosing scheme of PRN dosing.
`Slide 17. Dixon also sets forth the motivation to reduce the number
`of injections that patients were receiving. This comes in the form of Dixon's
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`Case 1:22-cv-00061-TSK-JPM Document 505-2 Filed 05/26/23 Page 15 of 75 PageID #:
`40074
`IPR2021-00880 (Patent 9,669,069 B2)
`IPR2021-00881 (Patent 9,254,338 B2)
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`disclosure of the time and financial burdens of monthly injections, as well as
`the serious risks of inflammation and infection that comes with each
`individual injection. These disclosures are found in Exhibit 1006 at pages
`1574 and 1577.
`Slide 18 --
`JUDGE NEW: Mr. McGlaughlin?
`MR. McGLAUGHLIN: Yes.
`JUDGE NEW: Isn't there a countervailing argument here that in
`order to acquire a proper baseline of visual acuity, you need at least three or
`possibly four secondary injections before you go to the PRN doses?
`MR. McGLAUGHLIN: There is a counter-argument being
`presented in these proceedings, Your Honor.
`JUDGE NEW: I would like you to address that if you could, please.
`MR. McGLAUGHLIN: I can address that now.
`So actually, we'll jump to slide 30. What Patent Owner has argued is
`that the fourth monthly loading dose of the CLEAR-IT-2 Phase II trials
`would have discouraged the use of three monthly loading doses.
`First, we want to point out that the claims don't require any particular
`level of efficacy, undermining those arguments. And any claim construction
`arguments to the contrary have been waived and forfeited. That's our
`position.
`Second, what's clear is that in the Dixon reference, which discloses
`both the Phase II and Phase III trial, what they disclose is that the decision
`had already been made to implement three monthly loading doses. That
`comes on the heels of the Phase II trial and having this data in hand. So with
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`Case 1:22-cv-00061-TSK-JPM Document 505-2 Filed 05/26/23 Page 16 of 75 PageID #:
`40075
`IPR2021-00880 (Patent 9,669,069 B2)
`IPR2021-00881 (Patent 9,254,338 B2)
`
`this data in hand, they nevertheless implemented three monthly loading
`doses in their next trial.
`JUDGE NEW: Is the fact that the claims don't require efficacy
`relevant here? I mean, what we're talking about is motivation to reduce it to
`two with respect to claim 8.
`Just because the claims don't recite that, if you're going to meet that
`requirement in claim 8 of only two secondary notices, then we look to
`motivation. And that doesn't necessarily have to be recited and expressed in
`the claims.
`MR. McGLAUGHLIN: That's true, Your Honor. But when it
`comes to motivation, in our papers we've set forth quite a bit of motivation.
`That comes from the desire to minimize objections, to reduce the risks and
`the discomfort and anxiety the patients were going through.
`So back in that time frame, the key thing that practitioners were
`looking at was how to reduce the dosing frequency. And they would have
`seen the disclosure of three monthly loading doses in Dixon and its use of
`those three monthly loading doses in Phase III, and would have been
`motivated to adopt that in order to reduce, again, the number of loading
`doses the patients were receiving.
`The third thing I want to point out is that the data doesn't actually
`support what Patent Owners are arguing here. So there's an abundance of
`evidence in the record that what practitioners were doing -- what
`ophthalmologists were interested in doing was treating with monthly loading
`doses until the macula was dry, so treat until retinal dryness was achieved.
`This is clear from looking at Dr. Brown's declaration, Exhibit 2050.
`For example, paragraph 149, in which she states physicians will typically
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`Case 1:22-cv-00061-TSK-JPM Document 505-2 Filed 05/26/23 Page 17 of 75 PageID #:
`40076
`IPR2021-00880 (Patent 9,669,069 B2)
`IPR2021-00881 (Patent 9,254,338 B2)
`
`give monthly loading until the retina appears dry on OCT. The same is true
`of Exhibit 2103, of which there are multiple practitioners describing their
`practice, including on pages 2 and 3, of treating until the macula was dry.
`Now, if you look at the actual data from CLEAR-IT-2 -- and what
`we're looking at here on slide 30 is the aqua with the squares. So the data
`indicated by the aqua line here with squares, that's the arm in which patients
`were treated with monthly loading doses followed by PRN dosing.
`What you see under Week 4 is the results of the first loading dose.
`Under Week 8 is where you would see the results of the second loading
`dose. After that second loading dose, there doesn't appear to be any further
`significant drying of the retina, further undermining Patent Owner's
`arguments here.
`The last thing I'll say about this is that this is all irrelevant, as we set
`forth in our reply. Controlling Federal Circuit Precedents states that our case
`law does not require the particular combination must be the preferred or the
`most desirable combination described in the prior art in order to provide
`motivation. And that's from In re Fulton, 391 F.3d 1195, at page 1200.
`I'd like to go back to slide 18. Dixon does in fact provide a
`motivation and a reasonable expectation of success -- this is based on the
`CLEAR-IT-2 Phase II trials -- showing that with monthly loading doses
`followed by PRN dosing, visual acuity gains could be achieved and using far
`fewer doses than what would have been expected under a monthly dosing
`scheme.
`Patent Owner's counter-arguments here lack merit. First, they argue
`that there was no motivation set forth in our papers. There is abundant
`evidence and motivation set forth here. Some examples are on slide 19.
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`Case 1:22-cv-00061-TSK-JPM Document 505-2 Filed 05/26/23 Page 18 of 75 PageID #:
`40077
`IPR2021-00880 (Patent 9,669,069 B2)
`IPR2021-00881 (Patent 9,254,338 B2)
`
`
`For example, in Exhibit 1002, Dr. Albini's opening declaration, at
`paragraphs 59 to 60, where he discusses the complications, the discomfort,
`and anxiety associated with monthly injections and the desire to reduce those
`injections with new treatment regimens.
`Also is the demonstrated ability to do just that, to minimize
`injections using a PRN regimen with VEGF Trap-Eye, which was shown in
`the prior art. This is discussed in Dr. Albini's declaration, Exhibit 1002, in
`paragraph 171 where he discusses the results of the CLEAR-IT-2 trial,
`which were that PRN Phase II dosing would result in 5.6 injections on
`average being administered in that first year compared to 12 injections that
`would be required under a standard monthly dosing regimen.
`Slide 20. Patent Owner also argues that PRN dosing would
`reportedly be more burdensome because of monthly office visits. First,
`there's nothing in the claims or specification about PRN dosing requiring
`monthly visits. PRN is defined in the claims solely as needed.
`Secondly, Patent Owner disregards that PRN as-needed dosing
`regimens were in the prior art that did not involve monthly visits, examples
`of which are shown here. The callout is from Exhibit 2103 and Dr. Brown's
`transcript, Exhibit 1110.
`Further, on slide 21, it was also the case that the '069 claims were
`directed to nothing more than what was the prevailing trend at the time for
`treating AMD. For example, Exhibit 2259, page 17 reveals that the majority
`of ophthalmologists were treating on a PRN basis after three to four monthly
`loading doses.
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`Case 1:22-cv-00061-TSK-JPM Document 505-2 Filed 05/26/23 Page 19 of 75 PageID #:
`40078
`IPR2021-00880 (Patent 9,669,069 B2)
`IPR2021-00881 (Patent 9,254,338 B2)
`
`
`Further, Dr. Albini also testifies that minimizing injections was the
`primary focus back in this time frame. This is from his reply declaration at
`paragraph 28.
`The last thing I'll say about Ground 4 is that it's also the case that
`Regeneron had implemented PRN dosing with VEGF Trap-Eye in no fewer
`than six clinical trials prior to 2010, again undercutting any arguments about
`the purported burdens of PRN dosing.
`I just want to quickly go through our Ground 5. This is based on
`PRN dosing in Heier in combination with prior art disclosing three monthly
`loading doses. These are the disclosures from Heier showing the dosing
`regimen, as well as the positive results and the few injections that it required.
`Dixon, again, as we've discussed, disclosed the use of three monthly
`loading doses. This is on the heels of Phase II with the Phase II trial data in
`hand.
`
`Mitchell also discloses the popular PrONTO study. This is three
`monthly loading doses followed by PRN dosing, which was widely adopted
`by practitioners prior to filing the '069 patent. The motivation was the same,
`reducing injection frequency, and the reasonable expectation of success
`comes from the positive results from that Phase II trial.
`And then in the interest of time, I will reserve the rest of my time for
`rebuttal. I will hand it over to my colleague, Heinz Salmen, to discuss the
`'338 patent.
`MR. SALMEN: Thank you.
`Heinz Salmen, Your Honors, on behalf of Petitioner Mylan.
`Your Honors, in the '338 patent, the 881 proceeding, the challenged
`claims are directed towards administering VEGF Trap-Eye under a specific
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`Case 1:22-cv-00061-TSK-JPM Document 505-2 Filed 05/26/23 Page 20 of 75 PageID #:
`40079
`IPR2021-00880 (Patent 9,669,069 B2)
`IPR2021-00881 (Patent 9,254,338 B2)
`
`temporal sequence of doses, which we refer to as key wave dosing. The
`claims here are clear and have a plain and ordinary meaning that a person of
`ordinary skill in the art would have understood.
`Accordingly, Petitioner here has submitted claim constructions that
`are fully supported by and consistent with the entrants of record. All in all,
`claim construction here should be very straightforward, and the Board
`should construe the terms of the '338 patent consistent with its institution
`decision which follows that intrinsic evidence.
`Petitioner has also asserted clear grounds that render the claims
`unpatentable. The asserted prior art expressly discloses the exact Q8 dosing
`regimen that these claims purportedly cover.
`Here in the modified callouts on slide 31 we illustrate how the
`disclosures in Dixon, Exhibit 1006, as illustrated in the blue and red arrows,
`line up perfectly with the '338 patents' preferre
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