`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
`
`
`Inter Partes Review No.: IPR2021-008801
`U.S. Patent No. 9,669,069 B2
`
`
`
`
`
`EXPERT DECLARATION OF DR. THOMAS A. ALBINI
`IN SUPPORT OF PETITIONER’S REPLY
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`
`
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`1 IPR2022-00257 and IPR2022-00301 have been joined with this proceeding.
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`Mylan Exhibit 1114
`Mylan v. Regeneron, IPR2021-00880
`Page 1
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`TABLE OF CONTENTS
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`Page
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`I.
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`QUALIFICATIONS AND BACKGROUND. ................................................ 1
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`A.
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`B.
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`C.
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`Education and Experience. .................................................................... 1
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`Bases for Opinions and Materials Considered. ..................................... 1
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`Scope of Work. ...................................................................................... 1
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`II.
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`LEGAL STANDARDS. .................................................................................. 2
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`III.
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`PERSON OF ORDINARY SKILL IN THE ART. ......................................... 2
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`IV. CLAIM CONSTRUCTION. ........................................................................... 3
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`V.
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`VI.
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`’069 PATENT, GROUNDS 1-3: THE PRIOR ART DISCLOSED
`THE SEQUENCE FOR VEGF TRAP-EYE/AFLIBERCEPT. ...................... 4
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`’069 PATENT, GROUND 4: THE CHALLENGED CLAIMS ARE
`ANTICIPATED OR OBVIOUS BASED ON VIEW 1/VIEW 2 AS
`DISCLOSED IN DIXON. ............................................................................... 9
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`A.
`
`B.
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`Regeneron Described the VIEW 8-Week Dosing Regimen as
`“Of the Type Claimed” in the ’069 Patent. ........................................... 9
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`The POSA Would Have Been Motivated to Adopt VIEW’s
`PRN Dosing Regimen and VIEW’s Three Monthly Loading
`Doses. ..................................................................................................10
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`VII.
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`’069 PATENT, GROUND 5: THE CHALLENGED CLAIMS ARE
`OBVIOUS BASED ON HEIER-2009 IN VIEW OF MITCHELL OR
`DIXON...........................................................................................................17
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`
`
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`i
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`Mylan Exhibit 1114
`Mylan v. Regeneron, IPR2021-00880
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`1. My name is Dr. Thomas A. Albini and I have been retained by counsel
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`for Mylan Pharmaceuticals, Inc. (“Mylan” or “Petitioner”), to provide my opinions
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`in support of Mylan’s Petitioner Reply. I am the same Dr. Albini who provided
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`declarations in support of Mylan’s Petition for Inter Partes Review of U.S. Patent
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`Nos. 9,669,069 B2 (“the ’069 patent”) and 9,254,338 B2, instituted as IPR2021-
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`00880 and IPR2021-00881, respectively. I also have been asked to reply to the
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`opinions and views of Patent Owner’s declarants, Diana V. Do, M.D., David M.
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`Brown, M.D., Lucian V. Del Priore, M.D., Ph.D., and Alexander M. Klibanov, Ph.D.
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`I.
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`QUALIFICATIONS AND BACKGROUND.
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`A. Education and Experience.
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`2. My qualifications, education, and experience are set forth in my
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`previous report, Exhibit 1002, and my curriculum vitae is attached as Exhibit 1038.
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`I incorporate both as if set forth herein.
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`B.
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`3.
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`Bases for Opinions and Materials Considered.
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`In addition to my education, knowledge of the relevant published art,
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`training, and experience, in forming the opinions I provide in this declaration, I have
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`also considered the exhibits cited herein and in Exhibits 2048, 2049, 2050, and 2051.
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`C.
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`4.
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`Scope of Work.
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`I have been retained by Petitioner as an expert in this matter to provide
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`various opinions regarding the ’069 patent. I receive $500 per hour for my services.
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`No part of my compensation is dependent upon my opinions given or the outcome
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`of this case. I do not have any current or past affiliation with Regeneron, or any of
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`the named inventors on the ’069 patent.
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`II. LEGAL STANDARDS.
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`5.
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`For my opinions in this declaration, I understand that it requires
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`applying various legal principles. As I am not an attorney, I have been informed
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`about various legal principles that govern my analysis. I have used my
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`understanding of those principles in forming my opinions. I summarized my
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`understanding of those legal principles in my previous report, Exhibit 1002, and I
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`incorporate that understanding as if set forth herein
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`III. PERSON OF ORDINARY SKILL IN THE ART.
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`6.
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`It is my opinion that a person of ordinary skill in the art would
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`have: (1) knowledge regarding the diagnosis and treatment of angiogenic eye
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`disorders, including the administration of therapies to treat said disorders; and (2) the
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`ability to understand results and findings presented or published by others in the
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`field, including the publications discussed herein. Typically, such a person would
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`have an advanced degree, such as an M.D. or Ph.D. (or equivalent, or less education
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`but considerable professional experience in the medical, biotechnological, or
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`pharmaceutical field), with practical academic or medical experience in: (i)
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`developing treatments for angiogenic eye disorders, such as AMD, including
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`2
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`through the use of VEGF antagonists, or (ii) treating of same, including through the
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`use of VEGF antagonists. (See Ex.1002, Albini, ¶¶26-28).
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`7.
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`Although I disagree with Patent Owner’s definition of the POSA, my
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`opinions set forth in this declaration remain the same under either Patent Owner’s or
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`Petitioner’s definition.
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`IV. CLAIM CONSTRUCTION.
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`8.
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`I understand that the Board has found “that no construction of [the
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`claim terms “initial dose,” “secondary dose,” “tertiary dose,” “4 weeks,” “pro re
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`nata
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`(PRN),”
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`“VEGFR1 Component,”
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`“VEGFR2 Component,”
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`and
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`“Multimerization Component”] is necessary for the purposes of this Decision to
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`Institute a trial.” (Paper 21, Institution Decision, 7). I further understand that “Patent
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`Owner does not advance claim construction positions for these terms at this time
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`because construction of these terms is not necessary to resolve the arguments
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`presented in its Preliminary Response.” (Id.). However, if the Board decides that it
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`is necessary to construe these terms in this IPR, it should do so consistently with the
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`constructions that I have proposed in my opening declaration, IPR2021-00880,
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`Ex.1002.
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`9.
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`I understand that Patent Owner has taken the position that the phrase
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`“assessed by a physician or other qualified medical professional” is a positive claim
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`limitation. (See Paper 21, Institution Decision, 31 n.12). I have been asked whether
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`3
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`that language is a necessary aspect of as-needed/PRN dosing. Based on my
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`experience, it is. Ophthalmologists engaged in as-needed administration of anti-
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`VEGF agents, necessarily review various criteria, usually including, but not limited
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`to, visual acuity and/or OCT imaging data, in assessing whether a patient requires
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`an injection of the anti-VEGF agent. (See, e.g., Ex.1006, Dixon, 1576 (PRN
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`redosing criteria included OCT and ETDRS letter evaluation); see also, e.g.,
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`Ex.2103, Retinal Physician – Ongoing Treatment, 1 (“I treat with ranibizumab
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`monthly until optical coherence tomography (OCT) shows the macula to be
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`completely free of fluid”); 2 (Dr. Brown: “I treat and extend from the start. I give 3
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`monthly injections and see them in 8 weeks. If fluid is absent at that visit, I give
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`another injection and see them in 10 weeks.”) (emphasis added)). The criteria relied
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`upon may vary from doctor to doctor, and from patient to patient, but in a PRN
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`dosing scheme, some criteria are assessed prior to each injection being given, and
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`that assessment is done by a physician or other qualified medical professional under
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`that physician’s supervision.
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`V.
`
`’069 PATENT, GROUNDS 1-3: THE PRIOR ART DISCLOSED THE
`SEQUENCE FOR VEGF TRAP-EYE/AFLIBERCEPT.
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`10. As I discussed in my opening declaration, Regeneron started to report
`
`its VEGF Trap-Eye clinical trials in the mid-2000s. (Ex.1002, Albini, ¶70).
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`Through their press releases, Regeneron made clear that the compound being
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`4
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`assessed was VEGF Trap-Eye. (Ex.1002, Albini, ¶¶72-73). The press releases, and
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`other publications and materials, revealed that VEGF Trap-Eye had completed phase
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`1 and 2 clinical trials, and was in phase 3 clinical trials by 2009. (See id.).
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`11.
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`It was common knowledge among ophthalmologists as of 2010 that
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`Regeneron’s anti-VEGF agent was aflibercept, and that VEGF Trap-Eye was
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`another term for this agent. This was clear from a review of the literature directed
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`to ophthalmologists at the time, including Dixon, the authors of which noted that for
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`the treatment of AMD “one promising new drug is aflibercept (VEGF Trap-Eye).”
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`(Ex.1006, Dixon, Abstract).
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`12.
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`I provided opinions in my opening expert report relating to the identity
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`of VEGF Trap-Eye, and how an ophthalmologist such as myself would have
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`understood the term. (Ex.1002, Albini, ¶¶39, 63-69, 125).
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`13.
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`I have reviewed the declarations of Dr. Klibanov, Ex.2049, and Dr. Del
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`Priore, Ex.2048, and the discussions therein that relate to the sequences of VEGF
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`Trap-Eye.
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`14. Nothing therein changes the opinions that I provided in my opening
`
`declaration. I find that most of their discussion amounts to speculation about what
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`a person of ordinary skill in the art could have thought about the sequence of the
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`molecule known as VEGF Trap-Eye and aflibercept. However, I did not see any
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`evidence presented in their declarations that any person of ordinary skill in the art
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`actually believed VEGF Trap-Eye and aflibercept to have different sequences and
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`thus be different molecules.
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`15.
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`In my opinion, and as I discuss in my first declaration, Regeneron’s
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`public statements indicated that the only differences between Regeneron’s oncology
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`product and ophthalmology product were the purification and formulation steps.
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`(Ex.1002, Albini, ¶39; Ex.1021, 2009 10-Q, 19 (“VEGF Trap-Eye is a specially
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`purified and formulated form of VEGF Trap for use in intraocular applications.”);
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`Ex.1041, Regeneron (26-February-2009), 1). No mention is made of any changes
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`or alterations to the active pharmaceutical ingredient. Dr. Klibanov’s and Dr. Del
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`Priore’s discussion of the drug products does not include any evidence that the
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`products had different active pharmaceutical ingredients, and I am aware of no such
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`evidence.
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`16.
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`I disagree with Dr. Del Priore with respect to his discussion of
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`Avastin® and Lucentis®. It was widely known that bevacizumab and ranibizumab
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`were very different active pharmaceutical ingredients. While they both were known
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`to bind to VEGF, it also was well-known that they possessed very different
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`molecular structures. (See, e.g., Ex.2055, Ferrara 2006, 862-66). However, I
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`disagree with Dr. Del Priore’s suggestion that a person of ordinary skill in the art
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`would have believed that VEGF Trap-Eye was a truncated form of aflibercept. First,
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`Dr. Del Priore provides no evidence that any ophthalmologist at the time actually
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`believed that to be the case, making Dr. Del Priore’s suggestion, in my opinion,
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`merely unsupported speculation. Second, this runs contrary to the public disclosures
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`from Regeneron itself, in which they describe purification and formulation as being
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`the only differences between the ophthalmology and oncology products. (Ex.1021,
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`2009 10-Q, 19; Ex.1041, Regeneron (26-February-2009), 1). Dr. Del Priore’s
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`suggestion also is inconsistent with the disclosures from other ophthalmologists at
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`the time. (Ex.1006, Dixon, 1575 (“VEGF Trap-Eye and aflibercept (the oncology
`
`product) have the same molecular structure, but there are substantial differences
`
`between the preparation of the purified drug product and their formulations.”)).
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`Third, Dr. Del Priore provides no evidence that bevacizumab and ranibizumab were
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`described as having the same molecular structure, like Dixon characterizes VEGF
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`Trap-Eye and aflibercept. Dr. Del Priore’s deposition testimony also contradicts the
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`opinions he set forth in his declaration:
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`(Ex.1111, Del Priore Dep. Tr., 106:8-15).
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`(Ex.1111, Del Priore Dep. Tr., 107:8-17).
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`(Ex.1111, Del Priore Tr., 107:24-108:5).
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`17. Lastly, I have reviewed the declaration being provided by Dr. Mary
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`Gerritsen, which I understand Mylan will be submitting concurrently with my
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`declaration. While I am not a molecular biologist, I am familiar with many of the
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`concepts discussed in Dr. Gerritsen’s declaration. From the perspective of a
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`practicing retinal specialist, I agree with Dr. Gerritsen’s opinions and I see nothing
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`in Dr. Gerritsen’s declaration that change the opinions I set forth herein or that are
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`set forth in my first declaration.
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`18.
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`In conclusion, I stand by the opinions provided in my opening
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`declaration, and I have seen no evidence or testimony from Dr. Brown, Dr. Do, Dr.
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`Klibanov, or Dr. Del Priore that would change my opinions.
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`VI.
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`’069 PATENT, GROUND 4: THE CHALLENGED CLAIMS ARE
`ANTICIPATED OR OBVIOUS BASED ON VIEW 1/VIEW 2 AS
`DISCLOSED IN DIXON.
`
`A. Regeneron Described the VIEW 8-Week Dosing Regimen as “Of
`the Type Claimed” in the ’069 Patent.
`
`19. As described in my opening declaration, when submitting Heier 2012
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`to the Examiner during the prosecution of the ’069 patent, Regeneron represented
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`that the results of the VIEW1/VIEW2 extended dosing arm (every 8 weeks following
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`3 monthly doses) “shows results of a treatment protocol of the type claimed.”
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`(Ex.1002, Albini, ¶160). After applying Regeneron’s statements in the ’069 patent
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`prosecution history, it is my opinion that Dixon’s VIEW1/VIEW2 disclosures
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`disclose every element of the claimed method(s) under Regeneron’s interpretation
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`and thus anticipate each of the challenged claims. (Id., ¶¶ 162-65). In other words,
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`the VIEW 2Q8 arm was disclosed in the prior art, as I set forth in my first declaration,
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`and this is the same 2Q8 dosing arm that Regeneron relied upon from the Heier 2012
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`article during prosecution.
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`20. Dr. Brown in his sworn declaration, states that a POSA would not
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`equate the VIEW 8-week dosing regimen with a PRN dosing regimen. (Ex.2050,
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`Brown Decl., ¶¶131-38). However, as I stated in my opening declaration, this is
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`exactly what Regeneron did when it presented the Patent Office with the Heier-2012
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`paper that reported results from the VIEW1/VIEW2 trials, and stated that the “Heier
`
`et al. paper shows results of a treatment protocol of the type claimed” and that the
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`“results clearly show that by administering the VEGF antagonist in accordance with
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`a dosage regimen as claimed in independent claim 1, it is possible to treat angiogenic
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`eye disorders such as AMD while administering doses on a less frequent basis.”
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`(Ex.1017, ’069 FH, 1/30/17 Remarks, 6 (emphasis added)).
`
`B.
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`The POSA Would Have Been Motivated to Adopt VIEW’s PRN
`Dosing Regimen and VIEW’s Three Monthly Loading Doses.
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`21. As I stated in my opening declarations, if a decision is made by the
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`Board in this case that Dixon or the other VIEW references do not anticipate the
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`dosing regimen in claims 1 and 8-12, based upon Regeneron representations to the
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`Patent Office, these claims nevertheless are drawn to an obvious variation of well-
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`known as-needed dosing schemes being used by practicing ophthalmologists for
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`years prior to the filing of the ’069 patent application, including those dosing
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`regimens disclosed for the VIEW studies. I understand that Dr. Brown has expressed
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`an opinion that a person of ordinary skill in the art would not have been motivated
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`to replace the 8-week dosing regimen of the VIEW trial with a PRN dosing regimen.
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`I disagree with the framing of his opinion and his overall opinion.
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`22.
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`In my opinion, it is not a matter of “replacing” the 8-week dosing with
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`PRN dosing. I view the disclosures of the phase 3 VIEW trials as presenting two
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`viable and reasonable dosing regimens for aflibercept, both the 8-week (year 1) and
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`PRN (year 2) regimens.
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`23.
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`I do not see any dispute from Dr. Brown that Dixon does in fact disclose
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`the VIEW phase 3 regimens, including the extended dosing arm. The extended
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`dosing arm of that trial (2Q8) was designed to test, in effect, two different
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`maintenance dosing schemes after three monthly loading doses: every-8-week
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`dosing in the first year, and PRN, or as-needed dosing, in the second year. (Ex.1006,
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`Dixon, 1576). I disagree with Dr. Brown’s opinions regarding the adoption of a
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`PRN regimen, for at least the following reasons. First, as I noted above and
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`discussed previously, PRN had already become
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`the default anti-VEGF
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`administration strategy for many ophthalmologists treating angiogenic eye
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`disorders, including AMD. (Ex.1002, Albini, ¶¶61, 220; IPR2021-00881 Ex.2259,
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`2009 PAT survey, slide 17). Based on statements made by Dr. Brown prior to 2010,
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`this appears to have been the case in his practice as well, and contradicts his position
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`regarding motivation. (Ex.2103, Retinal Physician – Ongoing Treatment, 2; see also
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`Ex.1110, Brown Tr., 149:15-17 (“But our clinical practice, as was stated in the 2007
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`paper, was to give three monthly doses, and then assess how the patient is doing.”)).
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`Second, Regeneron had already settled on and tested PRN dosing with aflibercept in
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`its CLEAR-IT-2 phase 2 clinical trial , and achieved success. (Ex.1006, Dixon, 1576
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`(“Two groups received monthly doses of either 0.5 or 2.0 mg for 12 weeks (at weeks
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`0, 4, 8 and 12) . . . . Following this fixed dosing period, patients were treated with
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`the same dose of VEGF Trap-Eye on a p.r.n. basis.”)). Third, as I noted above, after
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`the success of the phase 2 trial, Regeneron had also included PRN regimens in its
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`phase 3 VIEW studies, in the second year. (See, e.g., Ex.1014, NCT-795, 8;
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`Ex.1015, NCT-377, 6; Ex.1013, Regeneron (8-May-2008), 1; Ex.1056, Regeneron
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`(28-September-2008), 2; Ex.1006, Dixon, 1576; Ex.1007, Adis, 263). Fourth,
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`Regeneron had incorporated PRN dosing into several other studies as well.
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`(Ex.1028, Regeneron (30-April-2009), 1; Ex.1057, Regeneron (18-February-
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`2010), 1).
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`24. Dr. Brown’s opinion is contradicted by his own clinical practice, as well
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`as the prevailing trend among retina specialists in the 2009-2010 timeframe. At least
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`as early as 2007, clinical practitioners, including Dr. Brown, were having success
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`dosing anti-VEGF therapy according to regimens that involved “3 monthly
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`injections and see them in 8 weeks.” (Ex.2103, Retinal Physician – Ongoing
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`Treatment, 2; see also Ex.1110, Brown Dep. Tr., 149:15-17 (“But our clinical
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`practice, as was stated in the 2007 paper, was to give three monthly doses, and then
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`assess how the patient is doing.”)). As stated in my first declaration, this was my
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`typical practice as well, and the typical practice of many retina specialists. (Ex.1002,
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`Albini, ¶¶61, 220; IPR2021-00881 Ex.2259, 2009 PAT survey, slide 17).
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`25. Genentech’s popular PrONTO study also was designed to assess PRN
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`dosing after 3 monthly loading doses. (Ex.1002, Albini, ¶¶117, 169; Ex.1006,
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`Dixon, 1574 (“The PrONTO study looked at as needed (p.r.n.) dosing of
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`ranibizumab after three consecutive monthly doses”); Ex.1026, Engelbert-2009,
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`1429 (“The PrONTO study explored three monthly injections followed by dosing on
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`an as-needed or PRN basis”)). The PrONTO study was well-received and became a
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`popular dosing strategy for anti-VEGF agents. (Ex.1002, Albini, ¶169; Ex.1025,
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`Engelbert-2010, 1369 (“PrONTO-style dosing has become popular.”); Ex.1030,
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`Mitchell, 6; Ex.1094, Dadgostar 2009, 1741 (“This as-needed dosing scheme based
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`on OCT [PrONTO] has largely been adopted.”)).
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`26. Dixon also disclosed that PRN dosing in the Phase 2 trial (CLEAR-IT-
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`2) had led to mean increases in visual acuity (9.0 letters) and mean decreases in
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`retinal thickness (143 µm). (Ex.1002, Albini, ¶¶80, 171; Ex.1006, Dixon, 1576).
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`27.
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`I also disagree with Dr. Brown’s opinion that a person of ordinary skill
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`in the art would have been discouraged from using a three monthly loading dose
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`regimen since the CLEAR-IT-2 success had been demonstrated with four monthly
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`loading doses. The CLEAR-IT-2 data Dr. Brown cites actually show that a regimen
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`of three monthly loading doses resulted in significant visual acuity gains and retinal
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`thickness improvement. (Ex.1055, Retina Society Meeting Presentation, 17
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`(showing a gain of approximately 6-7 letters after 3 monthly injections)). In
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`addition, Regeneron had already made the decision to go from four to three monthly
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`loading doses in the design of its phase 3 VIEW trial extended dosing arm (2Q8), so
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`the prior art already demonstrated that Regeneron was not discouraged from going
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`to three loading doses.
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`28.
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`I also disagree with Dr. Brown that PRN still required burdensome
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`office visits. There is nothing in the claims of the ’069 patent requiring monthly
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`office visits. (Ex.1001, ’069 patent, 21:41-67, 22:41-66). In addition, Dr. Brown
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`fails to address the fact that many ophthalmologists (including Dr. Brown) were
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`employing PRN dosing with anti-VEGF agents in the treatment of AMD and other
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`eye disorders. (Ex.1110, Brown Dep. Tr., 149:15-17 (“But our clinical practice, as
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`was stated in the 2007 paper, was to give three monthly doses, and then assess how
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`the patient is doing.”)). Dr. Brown also avoids discussion of treat-and-extend. As I
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`noted in my first declaration, treat-and-extend (“TREX”) was a species of PRN
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`dosing that sought to extend time between office visits while still maintaining visual
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`acuity. (Ex.1002, Albini, ¶¶61, 117, 190; Ex.1027, Spaide, 305; Ex.1049, Spielberg,
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`24 (“Our modified ‘evaluate-and-extend’ approach utilized the same evaluation
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`strategy [as treat-and-extend], allowing for frequent evaluation of the fundus, but
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`only treated as-needed, in case of recurrence.”)). TREX was already being adopted
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`into clinical practice prior to the filing of the ’069 patent in 2011. (Id.; Ex.1002,
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`Albini, ¶¶61, 190). In any event, in my experience, while office visits could be
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`burdensome, the much more serious burden, and risks, were related to the intravitreal
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`injections. Imaging office visits might be time-consuming, but the injections
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`themselves caused discomfort, anxiety, and brought with them potentially severe
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`side effects, and in rare cases, complications and/or infections that could result in
`
`blindness. (Ex.1002, Albini, ¶59; Ex.1006, Dixon, 1577 (“Each injection subjects
`
`patients to risks of cataract, intraocular inflammation, retinal detachment and
`
`endophthalmitis.”)). Minimizing office visits was a goal, but by far the primary goal
`
`was to minimize intravitreal injections.
`
`29.
`
`I also disagree with Dr. Brown that SAILOR or HORIZON results
`
`would have discouraged adoption of a PRN regimen. Those studies involved
`
`quarterly office visits. Most retina specialists at that time were not spacing their
`
`office visits and monitoring of patients out to 12 weeks (i.e., quarterly), because
`
`quarterly monitoring was viewed as less than optimal. Four, six, or eight weeks were
`
`much more common intervals when treating on a PRN/TREX regimen. (Ex.2103,
`
`Retinal Physician – Ongoing Treatment, 2 (Dr. Brown: “I give 3 monthly injections
`
`15
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`Mylan Exhibit 1114
`Mylan v. Regeneron, IPR2021-00880
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`and see them in 8 weeks”), 3 (Dr. Brown: “[i]f the macula is dry, I extend the visit
`
`interval. If the macula is wet, I bring the patient back much sooner. Treating and
`
`extending reduces the number of times the macula accumulates fluid.”); see also
`
`Ex.1110, Brown Dep. Tr., 149:15-17 (“But our clinical practice, as was stated in the
`
`2007 paper, was to give three monthly doses, and then assess how the patient is
`
`doing.”); Ex.2103, Retinal Physician – Ongoing Treatment, 3 (Dr. Reichel: “I am a
`
`big believer in prn dosing. I give patients 1 injection and see them 4 weeks later. If
`
`the macula is dry, I see them in another 4 weeks. If the macula is dry after 2 cycles,
`
`I may extend the visit interval to 6 weeks. In general, I am seeing each patient every
`
`4 to 6 weeks.”)).
`
`30.
`
`I also disagree with Dr. Brown that a person of ordinary skill in the art
`
`would have been discouraged from using PRN dosing based on risks of macular
`
`hemorrhage. Ophthalmologists were already using PRN dosing, and Dr. Brown was
`
`using PRN regimens in his own practice, which contradicts his opinions regarding
`
`any concerns with PRN dosing. (Ex.1110, Brown Dep. Tr., 149:15-17 (“But our
`
`clinical practice, as was stated in the 2007 paper, was to give three monthly doses,
`
`and then assess how the patient is doing.”)). In addition, risks of macular
`
`hemorrhaging come with any dosing regimen, and is typically isolated to a specific
`
`sub-population of high-risk patients. This is illustrated by the reference that Dr.
`
`Brown relies upon, Levine. In the Levine paper, the authors note that one of the
`
`16
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`Mylan v. Regeneron, IPR2021-00880
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`macular hemorrhage events occurred just one day after the patient had exhibited no
`
`fluid by OCT. (Ex.2042, Levine 2009, Abstract). Even a monthly regimen would
`
`not have prevented that macular hemorrhage event. In addition, the authors concede
`
`as to the limitations of the study, noting that only 6 eyes were observed, at least 4 of
`
`which were in patients that were currently taking anti-coagulants, medication known
`
`to increase the risk of hemorrhagic events. (Ex.2042, Levine 2009, 1078).
`
`31. Accordingly, my opinion has not changed. In my opinion, a person of
`
`ordinary skill in the art would have been motivated to combine the loading dose
`
`phase of three monthly injections with a PRN treatment strategy, both of which were
`
`disclosed in Dixon’s description of the VIEW trials, and like many retinal specialists
`
`already had incorporated into their clinical practice with other anti-VEGF agents.
`
`VII. ’069 PATENT, GROUND 5: THE CHALLENGED CLAIMS ARE
`OBVIOUS BASED ON HEIER-2009 IN VIEW OF MITCHELL OR
`DIXON.
`
`32. As outlined in my opening declaration, from articles such as Mitchell a
`
`POSA would have been informed about the three loading doses used in PrONTO
`
`and SUSTAIN, where those loading doses were followed by PRN dosing, and the
`
`comparable results to those found in ANCHOR and MARINA. (Ex.1030, Mitchell,
`
`6). Further, the POSA would have known through Heier-2009 and Dixon about the
`
`success of the PRN dosing used in CLEAR-IT-2 and also from Dixon about
`
`17
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`Mylan Exhibit 1114
`Mylan v. Regeneron, IPR2021-00880
`Page 19
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`
`
`Regeneron’s subsequent choice to use three loading doses in its phase 3 VIEW
`
`studies, along with a maintenance phase of PRN dosing in the second year.
`
`33.
`
`I disagree with Dr. Brown that “the POSA would not have been
`
`motivated to lower the number of loading doses used in the CLEAR-IT-2 dosing
`
`regimen, as described in Heier 2009 or Dixon.” (Ex.2050, Brown Decl., ¶139). As
`
`discussed above, Regeneron had already made the choice to go from four to three
`
`loading doses when designing its phase 3 VIEW trial extended dosing arm.
`
`(Ex.1006, Dixon, 1576). In addition, the visual acuity gains demonstrated after three
`
`monthly loading doses in the CLEAR-IT-2 trial already were very good, and the
`
`absence of any error bars in the graphs that Dr. Brown relies upon makes it difficult
`
`to say whether the fourth loading dose actually resulted in any statistically significant
`
`gain in visual acuity. (Ex.2050, Brown Decl., ¶144). The retinal thickness
`
`measurements did not appear to improve at all with a fourth monthly loading dose
`
`at week 12. (Id.).
`
`34.
`
`I agree with Dr. Brown that “the POSA would have understood that
`
`ranibizumab and VEGF Trap-Eye were different proteins with different binding
`
`domains.” (Ex.2050, Brown Decl., ¶¶143, 146). In fact, it was known that
`
`aflibercept had been compared to and shown to have stronger binding and of a longer
`
`duration than ranibizumab. (Ex.2011, Stewart 2008, 668). However, I disagree with
`
`18
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`Mylan v. Regeneron, IPR2021-00880
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`Dr. Brown’s suggestion that PrONTO and ranibizumab regimens would not have
`
`informed a person of ordinary skill in the art when it came to aflibercept.
`
`35. First, while it is true that ranibizumab and aflibercept are different
`
`molecules, data from the clinical trials of the two molecules that had been completed
`
`and published before the ’069 patent filing date showed very similar efficacy. For
`
`example, data from the aflibercept CLEAR-IT-2 phase 2 clinical trial showed that
`
`patients exhibited an increase in visual acuity of 9.0 letters at 52 weeks. (Ex.1006,
`
`Dixon, 1576). The CLEAR-IT-2 trial involved a regimen of 4 monthly loading
`
`injections followed by PRN dosing for the remainder of the 52 weeks. (Id.). Further,
`
`patients required on average only 1.6 injections during the PRN phase, for a total of
`
`5.6 injections over the first year. (Id.). The data from the ranibizumab PrONTO
`
`clinical trial showed that patients exhibited an increase in visual acuity of 9.3 letters
`
`at 52 weeks. (Ex.1030, Mitchell, 9 (Table 3)). The PrONTO trial involved a
`
`regimen of 3 monthly loading injections, followed by PRN dosing for the remainder
`
`of the 52 weeks, with patients requiring on average 2.6 injections during the PRN
`
`phase, for a total of 5.6 injection over the first year. (Id.).
`
`36. Second, and as I discuss above, a person of ordinary skill in the art
`
`would have been aware that Regeneron already had chosen a loading dose regimen
`
`of three monthly loading doses for its phase 3 VIEW clinical trial extended dosing
`
`19
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`Mylan v. Regeneron, IPR2021-00880
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`arm. (Ex.1006, Dixon, 1576). Thus, there was motivation to adopt such a regimen
`
`in the art, separate and apart from the ranibizumab literature.
`
`37. Third, a person of ordinary skill in the art would have been aware of the
`
`popularity of PrONTO-style dosing, and would have been aware that ranibizumab
`
`and bevacizumab already were frequently being administered according to such a
`
`regimen. (IPR2021-00881 Ex.2259, 2009 PAT survey, slide 17; Ex.2103, Retinal
`
`Physician – Ongoing Treatment, 2 (Dr. Brown: “I give 3 monthly injections and see
`
`them in 8 weeks”); Ex.1110, Brown Dep. Tr., 149:15-17 (“But our clinical practice,
`
`as was stated in the 2007 paper, was to give three monthly doses, and then assess
`
`how the patient is doing.”)).
`
`38.
`
`I therefore disagree with Dr. Brown that adoption of three monthly
`
`loading doses followed by PRN injections would have been “indiscriminately
`
`cop[ying] ranibizumab prior art PRN dosing regimens.” An abundance of data about
`
`the similarity in results between ranibizumab and aflibercept, the fact that Regneron
`
`had, in fact, already adopted the claimed loading dose regimen for the extended
`
`dosing arm of the aflibercept phase 3 VIEW trials, and the routine practice of retinal
`
`specialists treating AMD with both ranibizumab and bevacizumab, make such a
`
`regimen very obvious, in my opinion. All of the above, along with the push in the
`
`industry to reduce the number of injections patients were receiving, including in the
`
`20
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`Mylan Exhibit 1114
`Mylan v. Regeneron, IPR2021-0
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