UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner
`
`v.
`
`REGENERON PHARMACEUTICALS, INC.,
`Patent Owner
`
`Inter Partes Review No.: IPR2021-00880
`
`U.S. Patent No. 9,669,069 B2
`Filed: December 17, 2015
`Issued: June 6, 2017
`Inventor: George D. Yancopoulos
`
`Title: USE OF A VEGF ANTAGONIST TO TREAT
`ANGIOGENIC EYE DISORDERS
`
`EXPERT DECLARATION OF DR. THOMAS A. ALBINI
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 9,669,069 B2
`
`CELLTRION - EXHIBIT 1002
`
`

`

`TABLE OF CONTENTS
`
`Page
`
`I.
`
`QUALIFICATIONS AND BACKGROUND. ................................................ 1
`
`A.
`
`Education and Experience. .................................................................... 1
`
`B.
`
`Bases for Opinions and Materials Considered. ..................................... 4
`
`C.
`
`Scope of Work. ...................................................................................... 4
`
`II.
`
`LEGAL STANDARDS. .................................................................................. 4
`
`III.
`
`PERSON OF ORDINARY SKILL IN THE ART. ......................................... 9
`
`IV. SUMMARY OF OPINIONS. ........................................................................ 11
`
`V.
`
`THE ’069 PATENT (Ex.1001). ..................................................................... 13
`
`A.
`
`Claim Construction. ............................................................................ 15
`
`VI. BACKGROUND. .......................................................................................... 20
`
`A. Vitreoretinal Disorders. ....................................................................... 20
`
`1.
`
`2.
`
`3.
`
`4.
`
`Age-related macular degeneration (AMD). .............................. 22
`
`Diabetic retinopathy (DR). ........................................................ 24
`
`Diabetic macular edema (DME). .............................................. 24
`
`Retinal vein occlusion (RVO). .................................................. 24
`
`B.
`
`Angiogenesis and Vascular Endothelial Growth Factor (VEGF). ...... 25
`
`C.
`
`VEGF Antagonists. ............................................................................. 25
`
`D. VEGF Trap-Eye/Aflibercept. .............................................................. 30
`
`E.
`
`Regeneron’s Press Releases and Clinical Trials. ................................ 33
`
`VII. SCOPE AND CONTENT OF THE PRIOR ART REFERENCES. ............. 42
`
`i
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`
`
`A. Dixon (Ex.1006). ................................................................................. 42
`
`Page
`
`B.
`
`Adis (Ex.1007). ................................................................................... 47
`
`C.
`
`Regeneron (28-April-2008) (Ex.1012). ............................................... 50
`
`D. Heier-2009 (Ex.1020). ......................................................................... 51
`
`E.
`
`Regeneron (30-April-2009) (Ex.1028). ............................................... 54
`
`F. Mitchell (Ex.1030). ............................................................................. 55
`
`G.
`
`Lalwani (Ex.1035). .............................................................................. 57
`
`H.
`
`’758 Patent (Ex.1010). ....................................................................... 59
`
`I.
`
`Dix (Ex.1033). ..................................................................................... 60
`
`VIII. UNPATENTABILITY OF THE ’069 PATENT. ......................................... 61
`
`A.
`
`Claims 1 and 9-12 of the ’069 Patent Are Anticipated by the
`CLEAR-IT-2 Disclosures in Either Heier-2009 (Ex.1020) or
`Dixon (Ex.1006). ................................................................................. 61
`
`1.
`
`2.
`
`3.
`
`4.
`
`Claim 1 is anticipated by Heier-2009 and Dixon. .................... 61
`
`Dependent claims 9 and 10 are anticipated by Heier-2009
`and Dixon. ................................................................................. 67
`
`Dependent claim 11 is anticipated by Heier-2009 and
`Dixon. ........................................................................................ 68
`
`Dependent claim 12 is anticipated by Heier-2009 and
`Dixon. ........................................................................................ 70
`
`B.
`
`Claims 1 and 9-12 of the ’069 Patent Are Anticipated by
`Regeneron (30-April-2009) (Ex.1028). ............................................... 71
`
`1.
`
`Claim 1 of the ’069 patent is anticipated by Regeneron
`(30-April-2009). ........................................................................ 71
`
`ii
`
`

`

`
`
`TABLE OF CONTENTS
`(continued)
`
`Page
`
`2.
`
`3.
`
`4.
`
`Dependent claims 9 and 10 are anticipated by Regeneron
`(30-April-2009). ........................................................................ 75
`
`Dependent claim 11 is anticipated by Regeneron (30-
`April-2009). ............................................................................... 77
`
`Dependent claim 12 is anticipated by Regeneron (30-
`April-2009). ............................................................................... 78
`
`C.
`
`Claims 1 and 8-12 of the ’069 Patent Are Anticipated and Made
`Obvious by the VIEW1/VIEW2 Disclosures in Dixon. ..................... 78
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`Claim 1 of the ’069 patent is anticipated by the
`VIEW1/VIEW2 disclosures. ..................................................... 78
`
`Claim 1 of the ’069 patent is made obvious by the
`VIEW1/VIEW2 disclosures in Dixon. ...................................... 87
`
`Dependent claim 8 is anticipated and made obvious by
`the VIEW1/VIEW2 disclosures. ............................................... 90
`
`Dependent claims 9 and 10 of the ’069 patent are
`anticipated and made obvious by the VIEW1/VIEW2
`disclosures. ................................................................................ 91
`
`Dependent claim 11 is anticipated and made obvious by
`the VIEW1/VIEW2 disclosures. ............................................... 92
`
`Dependent claim 12 is anticipated and made obvious by
`the VIEW1/VIEW2 disclosures. ............................................... 93
`
`D.
`
`Claims 1 and 8-12 of the ’069 Patent Are Made Obvious by
`Heier-2009 (Ex.1020) in View of Mitchell (Ex.1030), or
`Alternatively in View of Dixon (Ex.1006), and if Necessary, in
`View of the ’758 Patent (Ex.1010) or Dix (Ex.1033). ........................ 94
`
`1.
`
`2.
`
`Claim 1 of the ’069 patent is obvious. ...................................... 94
`
`Dependent claim 8 is obvious. ................................................103
`
`iii
`
`

`

`
`
`TABLE OF CONTENTS
`(continued)
`
`Page
`
`3.
`
`4.
`
`5.
`
`Dependent claims 9 and 10 are obvious. ................................105
`
`Dependent claim 11 is obvious. ..............................................105
`
`Dependent claim 12 is obvious. ..............................................106
`
`IX. SECONDARY CONSIDERATIONS. ........................................................107
`
`
`
`iv
`
`

`

`
`1. My name is Dr. Thomas A. Albini. I have been retained by counsel for
`
`Mylan Pharmaceuticals, Inc. (“Mylan” or “Petitioner”), to provide my opinion
`
`regarding U.S. Patent No. 9,669,069 (Ex.1001, “the ’069 patent”), which I
`
`understand is assigned to Regeneron Pharmaceuticals, Inc. I understand that
`
`Petitioner intends to petition for inter partes review of the ’069 patent, and will
`
`request that the United States Patent and Trademark Office (“USPTO”) cancel
`
`claims 1 and 8-12 of the ’069 patent (“challenged claims”) as unpatentable. My
`
`opinions in this expert declaration support Petitioner’s request for inter partes
`
`review of the ’069 patent, and the cancellation of the challenged claims.
`
`I.
`
`QUALIFICATIONS AND BACKGROUND.
`
`A. Education and Experience.
`
`2.
`
` I received a Bachelor of Arts degree, Magna Cum Laude, from
`
`Princeton University in 1994. I obtained my M.D. from Johns Hopkins University
`
`School of Medicine in 1999. I completed an internal medicine internship at Jackson
`
`Memorial Hospital in Miami, Florida, and an ophthalmology residency at the
`
`Doheny Eye Institute of the University of Southern California.
`
`3.
`
`After my residency, I completed a uveitis and ocular pathology clinical
`
`and research fellowship at the Doheny Eye Institute followed by a vitreoretinal
`
`surgery fellowship at the Cullen Eye Institute of the Baylor College of Medicine.
`
`1
`
`

`

`
`I was an instructor in ocular inflammation, uveitis, and ophthalmic
`
`4.
`
`pathology at the Doheny Eye institute from 2003-2004. I joined the faculty at the
`
`Bascom Palmer Eye Institute of the University of Miami Miller School of Medicine
`
`as an Assistant Professor of Clinical Ophthalmology in 2006. I held the position of
`
`Associate Professor of Clinical Ophthalmology at the Bascom Palmer Eye Institute
`
`from 2012 to June 2018. Since July 2016, I have served as co-director of the
`
`vitreoretinal surgery fellowship. Since June 2018, I have been a Professor of Clinical
`
`Ophthalmology. In my current and prior positions, I have been involved in the
`
`teaching and training of medical students, fellows, and residents in the area of
`
`ophthalmological surgical techniques, specifically, injection protocols for the
`
`administration of therapeutics for the treatment of age-related macular degeneration
`
`(AMD) and other vitreoretinal eye disorders. Further, in 2006, I began my current
`
`roles as a staff ophthalmologist at both the Anne Bates Leach Eye Hospital of the
`
`Bascom Palmer Eye Institute as well as the Jackson Memorial Hospital.
`
`5.
`
`I was awarded the American Academy of Ophthalmology Achievement
`
`Award in 2011 and Senior Achievement Award in 2019. In 2012, I received the
`
`Service Award from the American Society of Retina Specialists for outstanding
`
`service to the Society’s scientific and educational programs. I also received the
`
`Senior Honor Award from the American Society of Retina Specialists in 2012.
`
`2
`
`

`

`
`I have served as an editor, co-editor, or on the editorial board of several
`
`6.
`
`publications, including Retina Today, the website for the American Society of
`
`Retina Specialists, New Retina MD, and the Journal of VitreoRetinal Diseases.
`
`7. My clinical practice is focused on the diagnosis and treatment of
`
`patients suffering from various macular diseases, such as AMD, diabetic retinopathy
`
`and related disorders, as well as uveitis. I have experience with surgical
`
`interventions as well as the prescription and administration of various intravitreally-
`
`administered anti-angiogenesis agents.
`
`8.
`
`I was and currently am a member in several Professional and Academic
`
`Societies, including American Academy of Ophthalmology, Association for
`
`Research in Vision and Ophthalmology, American Society of Retina Specialists,
`
`Miami Ophthalmological Society, Vitrectomy Buckle Society, American Uveitis
`
`Society, The Macula Society, Pan American Association of Ophthalmology, and
`
`The Retina Society, among others.
`
`9.
`
`I have authored or co-authored over two hundred and fifty (250)
`
`publications, including book chapters, peer-reviewed scientific papers, abstracts,
`
`and other published works. Several of these publications pertain to AMD, retinal
`
`detachment, retinal and choroidal diseases, or diabetic macular edema (DME),
`
`among other disorders of the eye.
`
`3
`
`

`

`
`In all, I have over fifteen (15) years of hands-on clinical and research
`
`10.
`
`experience specializing in treating vitreoretinal disorders and the prescription, and
`
`intravitreal administration, of VEGF antagonists. I have included a copy of my
`
`curriculum vitae in support of my opinions. (Ex.1038, Albini CV).
`
`B.
`
`Bases for Opinions and Materials Considered.
`
`11.
`
`In addition to my education, knowledge of the relevant published art,
`
`training, and experience, in forming the opinions I provide in this declaration, I have
`
`also considered the exhibits cited herein.
`
`C.
`
`Scope of Work.
`
`12.
`
`I have been retained by Petitioner as an expert in this matter to provide
`
`various opinions regarding the ’069 patent. I receive $500 per hour for my services.
`
`No part of my compensation is dependent upon my opinions given or the outcome
`
`of this case. I do not have any current or past affiliation with Regeneron, or any of
`
`the named inventors on the ’069 patent.
`
`II. LEGAL STANDARDS.
`
`13. For my opinions in this declaration, I understand that it requires
`
`applying various legal principles. As I am not an attorney, I have been informed
`
`about various legal principles that govern my analysis. I have used my
`
`4
`
`

`

`
`understanding of those principles in forming my opinions. I summarize my
`
`understanding of those legal principles as follows:
`
`14. Burden of Proof. I understand that Petitioner bears the burden of
`
`proving unpatentability in this proceeding by a preponderance of the evidence. I am
`
`informed that this preponderance of the evidence standard means that Petitioner
`
`must show that unpatentability is more probable than not.
`
`15. Claim Construction. I have also been told that when I review and
`
`consider the claims, the claim term(s) should be analyzed under their ordinary and
`
`customary meaning as understood from the perspective of one of ordinary skill in
`
`the art, taking into account the claim language itself, specification, and prosecution
`
`history pertaining to the patent, as well as relevant extrinsic evidence. I have applied
`
`this standard in formulating my opinions, and set forth my understanding of the
`
`scope of particular claim terms discussed below.
`
`16. Anticipation. I have been asked to consider the question of
`
`anticipation, namely, whether the claims cover something that is new, or novel. I
`
`am told that the concept of anticipation requires that each and every element of a
`
`challenged claim is present in or otherwise taught by a single reference. I also
`
`understand that an anticipatory reference does not need to explicitly describe each
`
`5
`
`

`

`
`element because anticipation can occur when a claimed limitation is necessarily
`
`inherent or otherwise implicit in the relevant reference.
`
`17. Obviousness. I have been asked to consider the question of
`
`obviousness/non-obviousness. Again, I am told that this analysis must be from the
`
`perspective of the person of ordinary skill in the art, and whether such person would
`
`consider any differences between the prior art and what is claimed to have been
`
`obvious. To make this assessment, I have been informed that the concept of patent
`
`obviousness involves four factual inquiries:
`
`•
`
`the scope and content of the prior art;
`
`•
`
`the differences between the claimed invention and the prior art;
`
`•
`
`the level of ordinary skill in the art; and
`
`• so-called secondary considerations of non-obviousness.
`
`18.
`
`I have further been instructed that one cannot use the challenged patent
`
`itself (here, the ’069 patent) as a guide from which to select prior art elements, or
`
`otherwise engage in hindsight. Rather, the better approach is to consider what the
`
`person of ordinary skill in the art knew, and what the art taught; suggested; or
`
`motivated the person of ordinary skill in the art to further pursue; and to differentiate
`
`between steps that were routinely done (such as in response to known problems,
`
`6
`
`

`

`
`steps or obstacles), and those which, for example, may have represented a different
`
`way of solving existing or known problems.
`
`19.
`
`I am also informed that when there is some recognized reason to solve
`
`a problem, and there are a finite number of identified, predictable and known
`
`solutions, a person of ordinary skill in the art has good reason to pursue the known
`
`options within his or her technical grasp. If such an approach leads to the expected
`
`success, it is likely not the product of innovation but of ordinary skill and common
`
`sense. In addition, when a patent simply arranges old elements with each performing
`
`its known function and yields no more than what one would expect from such an
`
`arrangement, the combination is obvious.
`
`20.
`
`I understand that before reaching any final conclusion on obviousness,
`
`the obviousness analysis requires consideration of objective indicia of non-
`
`obviousness, if offered. These must be considered to ensure that, for example, there
`
`were not some unanticipated problems, obstacles, or hurdles that may seem easy to
`
`overcome in hindsight, but which were not readily overcome prior to the relevant
`
`invention date of the patents/claims at issue here. I understand that these objective
`
`indicia are also known as “secondary considerations of non-obviousness,” and may
`
`include long-felt but unmet need and unexpected results, among others. I also
`
`understand, however, that any offered evidence of secondary considerations of non-
`
`7
`
`

`

`
`obviousness must be comparable with the scope of the challenged claims. This
`
`means that for any offered evidence of secondary considerations of non-obviousness
`
`to be given substantial weight, I understand the proponent of that evidence must
`
`establish a “nexus” or a sufficient connection or tie between that evidence and the
`
`merits of the claimed invention, which I understand specifically incorporates any
`
`novel element(s) of the claimed invention. If the secondary considerations evidence
`
`offered actually results from something other than the merits of the claim, then I
`
`understand that there is no nexus or tie to the claimed invention. I also understand
`
`it is the patentee that has the burden of proving that a nexus exists.
`
`21. With respect to long-felt need, I understand that the evidence must
`
`show that a particular problem existed for a long period of time. More specifically,
`
`I understand that for a “need” to be long-felt and unmet, (1) the need must be
`
`persistent and recognized by those of ordinary skill in the art; (2) the need must not
`
`be satisfied by another before the alleged invention; and (3) the claimed invention
`
`itself must satisfy the alleged need. I also understand that long-felt need is analyzed
`
`as of the date that the problem is identified. Furthermore, I understand that long-felt
`
`need should be based upon alleged inadequacies in the technical knowledge of those
`
`skilled in the art, not due to business-driven market forces.
`
`8
`
`

`

`
`I further understand that, absent a showing of a long-felt, unmet need,
`
`22.
`
`the mere passage of time without the claimed invention is not evidence of non-
`
`obviousness.
`
`23. With respect to unexpected results, I understand that any results upon
`
`which a patentee wishes to rely as an indicator of non-obviousness must be based on
`
`a comparison of the purported inventions with the closest prior art.
`
`24. However, I understand that secondary considerations will not overcome
`
`a strong showing of obviousness.
`
`25. Public Availability. I have also been asked to consider whether there
`
`is a reasonable likelihood that some of the references discussed herein would have
`
`been publicly accessible before the priority date of the ’069 patent. I have been
`
`informed that a reference is “publicly accessible” if the document has been
`
`disseminated or otherwise made available to the extent that persons interested and
`
`ordinarily skilled in the subject matter or art exercising reasonable diligence, can
`
`locate it.
`
`III. PERSON OF ORDINARY SKILL IN THE ART.
`
`26. As I mentioned above, I have been informed by counsel that my
`
`analysis is to be conducted from the perspective of a person of ordinary skill in the
`
`art at the time of the invention. I also understand that the person of ordinary skill
`
`9
`
`

`

`
`in the art is assumed to know, understand and be familiar with all of the relevant
`
`prior art, and that such person is not an automaton, but rather a person of ordinary
`
`creativity.
`
`27.
`
`I have also been informed by counsel that in defining a person of
`
`ordinary skill in the art the following factors may be considered: (1) the educational
`
`level of the inventor; (2) the type of problems encountered in the art; (3) prior art
`
`solutions to those problems; (4) rapidity with which innovations are made; and (5)
`
`sophistication of the technology and educational level of active workers in the field.
`
`28. After considering the above-mentioned factors, it is my opinion that a
`
`person of ordinary skill in the art would have: (1) knowledge regarding the diagnosis
`
`and treatment of angiogenic eye disorders, including the administration of therapies
`
`to treat said disorders; and (2) the ability to understand results and findings presented
`
`or published by others in the field, including the publications discussed herein.
`
`Typically, such a person would have an advanced degree, such as an M.D. or Ph.D.
`
`(or equivalent, or less education but considerable professional experience in the
`
`medical, biotechnological, or pharmaceutical field), with practical academic or
`
`medical experience in: (i) developing treatments for angiogenic eye disorders, such
`
`as AMD, including through the use of VEGF antagonists, or (ii) treating of same,
`
`including through the use of VEGF antagonists.
`
`10
`
`

`

`IV. SUMMARY OF OPINIONS.
`
`
`
`29.
`
`It is my opinion that at least claims 1 and 9-12 of the ’069 patent are
`
`anticipated through the disclosure, in references such as Heier-2009 and Dixon, of
`
`the dosage regimen used by Regeneron in their Phase 2 CLEAR-IT-2 AMD trial
`
`(monthly doses until week 12, followed by pro re nata, i.e., as-needed, dosing
`
`(“PRN”)), and the results reported therein.
`
`30.
`
`It is my opinion that Regeneron’s April 2009 Press Release
`
`(“Regeneron (30-April-2009)”) anticipates at least claims 1 and 9-12 of the ’069
`
`patent through its disclosure of the dosage regimen used by Regeneron in their Phase
`
`3 COPERNICUS and GALILEO RVO trials (6 monthly doses of 2 mg, followed by
`
`PRN dosing).
`
`31.
`
`It is my opinion that, under Regeneron’s interpretation of the ’069
`
`patent claims, the VIEW1/VIEW2 dosing regimens disclosed in references such as
`
`Dixon and others, anticipate claims 1 and 8-12 of the ’069 patent. During
`
`prosecution of the claims of the ’069 patent, Regeneron argued that the
`
`VIEW1/VIEW2 dosing regimens exhibited surprising results and that the
`
`VIEW1/VIEW2 regimens were of the type claimed in the ’069 patent PRN dosing
`
`regimen claims. If that interpretation is applied, then, in my opinion the pre-filing
`
`11
`
`

`

`
`date disclosures of the VIEW1/VIEW2 regimens anticipate claims 1 and 8-12 of the
`
`’069 patent and/or render those claims obvious.
`
`32.
`
`It is my opinion that claims 1 and 8-12 are obvious in view of the
`
`positive results reported for Regeneron’s Phase 2 AMD trial, as reported in Heier-
`
`2009, in combination with either Mitchell, which disclosed, among other things, the
`
`ranibizumab AMD PrONTO trial of 3 initial monthly doses followed by PRN
`
`dosing, or in the alternative, in view of Dixon, which disclosed the Phase 3 VIEW
`
`regimen of three monthly loading doses followed by extended dosing, and if
`
`necessary, the ’758 patent or Dix, which reported the sequences and molecular
`
`structure of VEGF Trap-Eye/aflibercept.
`
`33.
`
`It is also my opinion that there are no “secondary considerations” that
`
`would support the patentability of the claims of the ’069 patent. First, it is my
`
`understanding that secondary considerations are not relevant in the context of
`
`anticipation and so should not be considered in connection with the anticipation
`
`grounds above. Second, in the context of obviousness, it is my opinion that the
`
`arguments presented by Regeneron to the USPTO do not support a finding of
`
`unexpected results or any other secondary consideration, especially given the
`
`positive and promising results reported for Regeneron’s Phase 2 trials, among others.
`
`
`
`12
`
`

`

`V. THE ’069 PATENT (Ex.1001).
`
`
`
`34.
`
`I have read the ’069 patent, which is titled “Use of a VEGF Antagonist
`
`to Treat Angiogenic Eye Disorders,” as well as the issued claims. I am very familiar
`
`with the state of the art at the time this patent was first filed, which I have been asked
`
`to assume is January 13, 2011.1 The ’069 patent lists George D. Yancopoulos as the
`
`sole inventor.
`
`
`1 I understand the following from the cover page of the ’069 patent: (i) Application
`
`No. 14/972,560 (“the ’560 application”) issued as the ’069 patent on or about June
`
`6, 2017; (ii) the ’560 application was filed December 17, 2015; (iii) as a
`
`“continuation” of application No. 13/940,370, filed July 12, 2013; (iv) as a
`
`“continuation-in-part” of application No. PCT/US2012/020855, which was filed on
`
`January 11, 2012; and (v) the ’069 patent lists three “provisional” applications filed,
`
`respectively, on (a) January 13, 2011; (b) January 21, 2011; and (c) November 21,
`
`2011, as “Related U.S. Application Data.” (See Ex.1001, ’069 patent at cover). I
`
`have been asked to assume that the priority date of the ’069 patent is January 13,
`
`2011. I have not been asked to form an opinion regarding the merit of the ’069
`
`patent’s claim to that date.
`
`13
`
`

`

`35.
`
`Ihave reviewed the ’069 patent claims from the perspective of a person
`
`of ordinary skill in the art and applied each claim’s ordinary and customary meaning
`
`in light of the claims, the specification, and the prosecution history, as well as any
`
`relevant extrinsic evidence. I understand that Petitioner is challenging all claims of
`
`the °069 patent.
`
`36.
`
`Claim | recites:
`
`
`
`1. A method for treating an angiogenic eye disorder in a
`patient, said method comprising sequentially administering
`to the patient a single initial dose of a VEGF antagonist,
`followed by one or more secondary doses of the VEGF
`antagonist, followed by one or moretertiary doses of the
`VEGFantagonist;
`wherein each secondary dose is administered 2 to 4 weeks
`afier the immediately preceding dose; and
`wherein each tertiary dose is administered on an as-
`needed/pro re nata (PRN)basis, based on visual and/or
`anatomical outcomes as assessed by a physician or
`other qualified medical professional;
`wherein the VEGF antagonist is a receptor-based chime-
`ric molecule comprising (1) a VEGFRI1 component
`comprising amino acids 27 to 129 of SEQ ID NO:2: (2)
`a VEGFR2 component comprising amino acids 130-
`231 of SEQ ID NO:2; and (3) a multimerization
`component comprising amino acids 232-457 of SEQ
`ID NO:2.
`
`(Ex.1001, ’069 patent, 21:42-60).
`
`37.
`
`Claims 2-12 further restrict the claimsto, inter alia, specific numbers
`
`of secondary doses, dosage amounts, eye disorders and routes of administration.
`
`14
`
`

`

`A. Claim Construction.
`
`
`
`38.
`
`In my opinion, a person of ordinary skill in the art would reach at least
`
`the following conclusions regarding the claim language:
`
`39. First, with respect to claims 1 and 12 (and the claims that depend
`
`therefrom), a person of ordinary skill in the art would understand that the “VEGFR1
`
`component,” “VEGFR2 component,” and the “multimerization component”—all of
`
`which refer to separate amino acid domains of “SEQ ID NO:2”—and VEGFR1R2-
`
`FcΔC1(a) encoded by SEQ ID NO:1, as collectively referring to aflibercept (a/k/a/
`
`VEGF Trap or VEGF Trap-Eye), for at least the following reasons:
`
`• The amino acid sequence provided in the ’069 patent specification for
`
`“SEQ ID NO:2” is the identical amino acid sequence Regeneron
`
`previously submitted to the USPTO as referring to aflibercept (a/k/a VEGF
`
`Trap or VEGF Trap-Eye). (Compare Ex.1001, ’069 patent, cols. 19-22,
`
`with Ex.1010, ’758 patent, Fig.24A-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 FcΔC1 domain), 10:15-17
`
`(specifying that this molecule is termed “VEGFR1R2-FcΔC1(a).”); see
`
`also, e.g., Ex.1024, ’758 FH, 12/22/2011 PTE, 2, 6-7 (“The name of the
`
`15
`
`

`

`
`active ingredient of EYLEATM is aflibercept, also known as VEGF trap,
`
`VEGF-trap, VEGF Trap-Eye and VEGF-TRAPR1R2 . . . [,] a fusion protein
`
`consisting of (a) a vascular endothelial growth factor (VEGF) receptor
`
`component having immunoglobulin-like (Ig) domains consisting of an lg
`
`domain 2 of a first VEGF receptor that is human Fltl and an Ig domain 3
`
`of a second VEGF receptor that is human Flkl; and (b) an Fc portion of
`
`human IgG1,” and further explaining to the USPTO that the amino acid
`
`sequence of aflibercept is set forth in Figures 24A-24C of the ’758
`
`patent));2
`
`• The ’069 patent specification states that “[a]n exemplary VEGF antagonist
`
`that can be used in the context of the present invention is a multimeric
`
`VEGF-binding protein comprising two or more VEGF receptor-based
`
`
`
`2 In the course of my analysis, I requested that exhibits be created that compare the
`
`SEQ ID NO:1 and SEQ ID NO:2 of the ’069 patent with sequences disclosed in the
`
`prior art references. I have reviewed these exhibits and confirmed that these
`
`sequences are the same. (Ex.1082 (amino acid sequences); Ex.1083 (nucleic acid
`
`sequences)).
`
`16
`
`

`

`
`chimeric molecules referred to herein as ‘VEGFR1R2-FcΔC1(a)’ or
`
`‘aflibercept.’” (Ex.1001, ’069 patent, 2:33-38); and
`
`• It was well known in the art that this fusion VEGF antagonist was
`
`commonly referred to as “VEGF Trap,” and also known as “aflibercept,”
`
`as well as “VEGF Trap-Eye” when formulated for intraocular delivery.
`
`(See, e.g., Ex.1006, Dixon, 1575 (“VEGF Trap-Eye and aflibercept (the
`
`oncology product) have the same molecular structure.”); Ex.1039, ’095
`
`patent, 1:45-54; Ex.1040, WHO Drug Info, 118-19; Ex.1021, 2009 10-Q,
`
`20; Ex.1041, Regeneron (26-February-2009), 1-2 (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, were
`
`understood by a person of ordinary skill in the art to refer, interchangeably,
`
`to the same drug)).
`
`40. Second, although the terms “initial dose,” “secondary dose,” and
`
`“tertiary dose” are not typically used in practice, a person of ordinary skill in the art
`
`would understand those terms to have the meaning expressly given to them in
`
`the ’069 patent:
`
`17
`
`

`

`29 66
`
`“secondary doses,” and “tertiary
`The terms “initial dose,”
`doses,” refer to the temporal sequence ofadministration of
`the VEGFantagonist. Thus, the “initial dose” is the dose
`which is administered at the beginning of the treatment
`regimen (also referred to as the “baseline dose”); the “sec-
`ondary doses”are the doses which are administered after the
`initial dose; and the “tertiary doses” are the doses which are
`administered after the secondary doses.
`
`(See Ex.1001, ’069 patent, 3:34-41). The ’069 patentfurtherstates that “[t]heinitial,
`
`secondary, and tertiary doses .
`
`.
`
`. will generally differ from one anotherin terms of
`
`frequency of administration.” (/d., 3:41-44). For example, the ’069 patent states
`
`that “each secondary dose is administered 2 to 4 .
`
`.
`
`. weeks after the immediately
`
`preceding dose, and eachtertiary dose is administered at least 8 .
`
`.
`
`. weeks after the
`
`immediately preceding dose.” (/d., 3:50-54). The ’069 patent explains that “the
`
`immediately preceding dose” means “in a sequence of multiple administrations, the
`
`dose of VEGF antagonist which is administered to a patient prior to the
`
`administration ofthe very next dose in the sequence with nointervening doses.” (/d.,
`
`3:54-59). These are the meanings I have applied to these terms in formulating my
`
`opinions.
`
`41.
`
`Third,
`
`to a person of ordinary skill
`
`in the art,
`
`the reference to
`
`administering at “4 weeks” in the claims is synonymous in the art of treating
`
`angiogenic eye disorders with monthly administration. Likewise, the reference to
`
`18
`
`

`

`
`“administered at least 8 weeks” is synonymous in the art of treating angiogenic eye
`
`disorders with bimonthly (or every-other-month) administration. This is also
`
`consistent with my own experience treating angiogenic eye disorders—i.e., I
`
`consider “4 weeks” to be synonymous (or interchangeable) with “monthly,” and “8
`
`weeks” to be synonymous (or interchangeable) with “bimonthly” (or every-other-
`
`month). (See Ex.1001, ’069 patent, 7:57-59).
`
`42. Fourth, although I have been informed tha