`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`SAMSUNG BIOEPIS CO., LTD.,
`Petitioner,
`v.
`REGENERON PHARMACEUTICALS, INC.,
`Patent Owner.
`
`Patent No. 10,888,601
`
`_______________
`Inter Partes Review No. IPR2023-00739
`____________________________________________________________
`
`DECLARATION OF MICHAEL W. STEWART, M.D.
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`Regeneron Pharmaceuticals, Inc. Exhibit 2027 Page 1
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`Samsung Bioepis Exhibit 1089
`Page 1
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`IPR2023-00739
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`CONTENTS
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`
`
`INTRODUCTION ........................................................................................... 3
`I.
`SUMMARY OF OPINIONS ........................................................................... 3
`II.
`III. QUALIFICATIONS ........................................................................................ 4
`IV. MATERIALS CONSIDERED ........................................................................ 6
`V.
`LEGAL STANDARDS ................................................................................... 7
`VI. TECHNICAL BACKGROUND ................................................................... 10
`A. Diabetic retinopathy and diabetic macular edema.........................................10
`B. Prior art therapies for angiogenic eye disorders ............................................14
`C. Eylea ..............................................................................................................21
`VII. THE ’601 PATENT ....................................................................................... 25
`VIII. PETITIONER’S PRIOR ART REFERENCES............................................. 26
`A. 2009 Press Release (Ex.1009) .......................................................................26
`B. Shams (Ex.1010) ............................................................................................27
`C. Elman 2010 (Ex.1006) ...................................................................................28
`IX. PERSON OF ORDINARY SKILL IN THE ART ........................................ 29
`X.
`CLAIM CONSTRUCTION .......................................................................... 30
`A. “[E]very 4 weeks for the first 5 injections followed by . . . every 8
`weeks” refers to a predetermined dosing regimen. .............................................30
`B. “[M]ethod for treating” / “effective amount” ................................................37
`1. The claims require efficacy comparable to monthly ranibizumab or
`bevacizumab ..................................................................................................37
`2. The claims require intent to treat a specific angiogenic eye disorder ......41
`XI. THE FIVE LOADING-DOSE REGIMEN RECITED IN THE
`CHALLENGED CLAIMS IS NOT OBVIOUS............................................ 42
`A. The dosing regimen recited in the ’601 claims is not obvious over the
`2009 Press Release alone or in view of Shams ..................................................44
`1. The 2009 Press Release and Shams do not teach towardfive loading
`doses. ..............................................................................................................45
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`2. A POSA would not arrive at the claimed regimen with “routine
`optimization” or “routine adjustments.” ........................................................52
`3. A POSA would not have a reasonable expectation of success in using a
`fixed extended dosing regimens in order to treat effectively while
`minimizing the number of loading doses. .....................................................56
`B. The recited dosing regimen is not obvious over the 2009 Press
`Release in view of Elman 2010. .........................................................................58
`1. Elman 2010 does not teach toward five loading doses ............................59
`2. There is no motivation to combine Elman 2010 with the 2009 Press
`Release ...........................................................................................................68
`XII. The prior art does not disclose the required efficacy. ................................... 79
`A. 2009 Press Release ........................................................................................80
`B. Shams .............................................................................................................81
`C. Elman 2010 ....................................................................................................82
`D. PIER ...............................................................................................................83
`E. CATT .............................................................................................................83
`XIII. The prior art does not disclose intent to treat diabetic retinopathy. .............. 83
`A. DR and DME are defined and measured differently. ....................................84
`B. The 2009 Press Release does not disclose any indication of intent to
`treat DR. ..............................................................................................................87
`C. Treating DME is not tantamount to treating DR. ..........................................90
`XIV. Commercial success....................................................................................... 92
`A. Nexus to Eylea ...............................................................................................93
`B. Commercial success of Eylea ........................................................................96
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`2
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`I, Michael W. Stewart, M.D., declare as follows:
`
`I.
`
`INTRODUCTION
`
`
`
`1.
`
`I have been retained by counsel for Patent Owner, Regeneron
`
`Pharmaceuticals, Inc. (“Regeneron”), as a technical expert in connection with the
`
`proceeding identified above. I submit this declaration in support of Patent Owner
`
`Regeneron’s Responses in connection with the Inter Partes Review of United States
`
`Patent No. 10,888,601 (“the ’601 Patent”).
`
`2.
`
`I am being paid at my usual hourly rate for my work on this matter. I
`
`have no personal or financial stake or interest in the outcome of the present
`
`proceeding.
`
`II.
`
`SUMMARY OF OPINIONS
`
`3.
`
`It is my opinion that the challenged claims of the ’601 Patent are
`
`patentable and nonobvious. The following is a summary of my opinions:
`
`• The plain and ordinary meaning of the challenged claims requires a
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`predetermined dosing regimen.
`
`• The plain and ordinary meaning of the challenged claims requires both
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`(1) an intent to treat a specific angiogenic disorder and (2) treating the
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`angiogenic eye disorder with a level of efficacy comparable to monthly
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`Lucentis or Avastin.
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`
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`3
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`• The dosing regimen recited in the challenged claims of the ’601 Patent
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`is not obvious over the 2009 Press Release either alone or in
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`combination with Shams.
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`• The recited dosing regimen is not obvious over the 2009 Press Release
`
`in view of Elman 2010.
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`• The prior art does not disclose the level of efficacy required by the
`
`challenged claims.
`
`• The prior art does not disclose intent to treat diabetic retinopathy.
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`• Eylea embodies the claims of the ’601 Patent such that there is a nexus
`
`between the ’601 Patent and the commercial success of Eylea.
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`III. QUALIFICATIONS
`
`4.
`
`I am the Chair of the Department of Ophthalmology at Mayo Clinic in
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`Jacksonville, Florida, where I have been Chair since 2005 and Consultant since
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`2002. I have been a Professor of Ophthalmology at the Mayo Clinic College of
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`Medicine and Science since 2014 and am currently the Knights Templar Eye
`
`Foundation, Inc. Professor of Ophthalmology Research.
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`5.
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`I graduated from Harvard University with a degree in Chemistry
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`cum laude in 1979. I received my M.D. at McGill University School of Medicine in
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`
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`4
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`1983. I completed fellowships at the Retina Research Foundation and University of
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`
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`California, Davis, in Vitreoretinal Diseases from 1987 to 1989.
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`6.
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`I have been a Councilor of the American Academy of Ophthalmology;
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`Chief of Ophthalmology at St. Luke’s Hospital at Mayo Clinic during 2002–2008;
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`Executive or Associate Editor at the American Journal of Ophthalmology since
`
`2013; President or Vice President of the Florida Society of Ophthalmology during
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`2004–2005; and President of Duval County Ophthalmology Society during 1992–
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`1994. I am the current President of the International Joint Commission of Allied
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`Health Personnel in Ophthalmology, and I have served in numerous additional
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`leadership roles in professional organizations and societies in the ophthalmology
`
`field over the past three decades. I have also been a peer reviewer for journals in the
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`field, including Retina, Ophthalmology, and the British Journal of Ophthalmology.
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`7.
`
`I maintain an active medical and surgical practice and have been
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`continuously elected as one of “America’s Best Physicians” since 2016. My honors
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`include the American Academy of Ophthalmology Honor Award (2010); Hiram
`
`Hunn Award from Harvard University (2012); American Society of Retina
`
`Specialists Honor Award (2016); Marquis Who’s Who in America (2018); and
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`President’s Award from the Florida Society of Ophthalmology (2020–2021).
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`
`
`
`
`
`
`5
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`8.
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`I have written and published over 600 national and international
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`meeting presentation, abstracts, book chapters, and scientific papers including many
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`of the primary papers on treatment of diabetic retinopathy and diabetic macular
`
`edema, using anti-vascular endothelial growth factor (“anti-VEGF”) therapies,
`
`especially intravitreal aflibercept.
`
`9.
`
`I have extensive experience as a Principal Investigator on a number of
`
`clinical trials, including clinical trials of anti-VEGF agents, such as aflibercept
`
`(Regeneron’s Eylea), in age-related macular degeneration and diabetic macular
`
`edema. For example, I was a lead investigator on Regeneron’s Phase III studies of
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`the efficacy, safety, and tolerability of repeated doses of intravitreal VEGF Trap in
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`subjects with neovascular age-related degeneration (VIEW1 and VIEW 2), as well
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`as Regeneron’s Investigation of Efficacy and Safety in Central Retinal Vein
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`Occlusion (CRVO) (GALILEO).
`
`10. A current copy of my curriculum vitae is filed with this declaration as
`
`Ex.2028.
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`IV. MATERIALS CONSIDERED
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`11.
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`In preparing this declaration, I have reviewed, among other things, the
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`following materials:
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`
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`6
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`a.
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`the Petition for Inter Partes Review of the ’601 Patent, Paper 1
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`
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`(“Petition”);
`
`b.
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`the Declaration of Dr. Edward Chaum, Ex.1002 (“Chaum
`
`Declaration”);
`
`c.
`
`the Board’s Decision Granting Institution of Inter Partes
`
`Review, Paper 9; and
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`d.
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`all exhibits cited in this declaration.
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`V. LEGAL STANDARDS
`
`12.
`
`I have been informed that claim terms are given their plain and ordinary
`
`meaning as understood by a so-called “Person of Ordinary Skill in the Art” or
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`“POSA” at the time of the invention. I understand that the most relevant information
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`for construing claims is the intrinsic record of the patent. The intrinsic record
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`includes the specification, prosecution history, claims, and related patents. If this
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`record is inconclusive, I understand that extrinsic evidence, such as dictionary
`
`definitions and trade usage, may be used to inform the meaning of a term.
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`13.
`
`I have been informed that the obviousness of an invention is considered
`
`from the perspective of a POSA as of the priority date of the patent. The POSA is a
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`hypothetical person who is presumed to have understood the state of the art in the
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`field of the claimed invention and who can apply that understanding with ordinary
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`
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`7
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`creativity. I have been asked to assume that the priority date of the ’601 Patent is
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`
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`January 13, 2011. I have therefore considered the art from the perspective of a POSA
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`as of January 13, 2011. I understand that Petitioner has applied a priority date of July
`
`12, 2013. My conclusions would be the same if I were to consider the art from the
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`perspective of a POSA as of July 12, 2013.
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`14.
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`I have also been informed and understand that the subject matter of a
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`patent claim is obvious if the differences between the subject matter of the claim and
`
`the prior art are such that the subject matter as a whole would have been obvious at
`
`the time the invention was made to a POSA to which the subject matter pertains. I
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`have also been informed that the framework for determining obviousness involves
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`considering the following factors: (i) the scope and content of the prior art; (ii) the
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`differences between the prior art and the claimed subject matter; (iii) the level of
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`ordinary skill in the art; and (iv) any objective evidence of non-obviousness. I also
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`understand that for a POSA to rely on the disclosures of multiple references, there
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`must be some motivation to combine their respective disclosures. I understand that
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`the claimed subject matter would have been obvious to a POSA if, for example, it
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`results from the combination of known elements according to known methods to
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`yield predictable results, the simple substitution of one known element for another
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`to obtain predictable results, or use of a known technique to improve similar devices
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`
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`8
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`in the same way or applying a known technique to a known device ready for
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`
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`improvement to yield predictable results. I have also been informed that the analysis
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`of obviousness may include recourse to logic, judgment, and common sense
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`available to the POSA, and is not limited to statements made in the prior art
`
`references.
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`15.
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`I have been informed and understand that a result or solution may be
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`“obvious to try” when a POSA is choosing from a finite number of identified,
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`predictable solutions with a reasonable expectation of success. I have also been
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`informed that, where prior art only gives general guidance and gives no direction as
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`to which of many possible choices is likely to be successful, relying on an obvious-
`
`to-try theory is not appropriate. Similarly, I have been informed that a POSA may
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`arrive at the claimed invention using “routine optimization” within a limited range
`
`disclosed in the prior art.
`
`16.
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`I have also been informed and understand that whether a prior art
`
`document “teaches away” from a particular path or combination of elements may
`
`inform whether or not the claimed element is obvious. I understand teaching away
`
`to mean that a POSA would be discouraged from following a path set out in a
`
`reference or would be led in a direction divergent from the path taken by the Patent
`
`Owner.
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`
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`9
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`17.
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`I have also been informed and understand that when considering
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`obviousness, the commercial success of a patented product may indicate that the
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`claims are less obvious. I understand that in order for commercial success to be
`
`considered, there must be a nexus between the claims and the product, meaning the
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`value of the product is derived from the patented features. I understand that a nexus
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`can be shown by demonstrating that the commercially successful product or method
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`embodies or practices the claimed invention.
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`VI. TECHNICAL BACKGROUND
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`A. Diabetic retinopathy and diabetic macular edema
`18. Diabetic retinopathy (DR) and diabetic macular edema (DME) are
`
`angiogenic eye disorders. Angiogenesis is the process of forming new blood vessels
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`from preexisting vasculature. It is a complex process comprising multiple steps,
`
`illustrated in Figure 1:
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`10
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`Figure 1: Steps of angiogenesis. Ex.2044, 3.
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`19.
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`In the first step, an angiogenic “switch” is turned on by a proangiogenic
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`growth factor, such as vascular endothelial growth factor (VEGF). From there,
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`endothelial cells are stimulated to proliferate. While angiogenesis is a normal part of
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`development and healing, as with most processes in the body, a balance must be
`
`achieved between production, degradation, and reformation. When there is
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`imbalance between proangiogenic factors (e.g., VEGF) and antiangiogenic factors,
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`pathology ensues. Ex.2045, 1. Since newly formed vessels do not yet have fully
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`formed and functional endothelial and pericyte layers, blood vessel leakage is often
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`associated with angiogenesis. Vascular leakage and angiogenesis are pathogenetic
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`findings in many diseases such as cancer metastasis, wet age-related macular
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`
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`degeneration (AMD), and DR. Ex.2045, 3, Figs.2–3.
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`20. DR and DME are related in that both occur in individuals with diabetes
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`as a result of damage to small blood vessels in the retina. The retina is the
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`multi-layered structure of light-sensitive and processing cells in the back of the eye
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`that converts light into electrical signals. Retinopathy is the most common
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`microvascular complication of diabetes. In people with diabetes, high blood sugar
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`levels over extended periods of time can damage the tiny blood vessels within the
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`retina or cause them to block completely. As a result, tiny bulges called
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`microaneurysms form in the blood vessels (microaneurysms). Fluid may also leak
`
`from incompetent blood vessels. This leakage can cause swelling in the center part
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`of the retina, which is called the macula, resulting in DME.
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`21. Several pathologic findings characterize DR. In the earliest stage,
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`microaneurysms can form as a result of weakened and/or blocked blood vessels.
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`Moderate nonproliferative DR (NPDR), more than just microaneurysms, also has
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`venous beading (a sausage-like dilatation), and intraretinal hemorrhages. Severe
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`NPDR is characterized by many intraretinal hemorrhages in each of the 4 quadrants
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`of the eye, definite venous beading in 2+ quadrants, and prominent intraretinal
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`microvascular abnormalities in 1+ quadrant. The most advanced stage of DR is
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`12
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`proliferative diabetic retinopathy (PDR), wherein new blood vessels grow on the
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`
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`surface of the retina (neoangiogenesis), which causes scar tissue to also form. This
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`scar tissue can contact and cause the retina to pull away from the back of the eye
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`(detach), resulting in blurriness, reduced field of vision, or even permanent and
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`complete blindness. Ex.2089, 6 Table 2; Ex.2091, 8.
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`22. Physicians commonly use ophthalmoscopy or multiple-field
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`photography on the retina to observe these characteristics of DR. Ex.2089, 4. In
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`clinical trials, it is desirable to reliably quantify progression or regression of disease.
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`Therefore, a common measure of DR in clinical trials is the Diabetic Retinopathy
`
`Severity Score (DRSS). Ex.2091, 8. DRSS is a composite score graded on a 10-point
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`scale by a central reading center by comparing patient fundus photographs with a set
`
`of standard images. A lower score indicates less severe diabetic retinopathy.
`
`Ex.2032. For example, the proportion of eyes with a 2-step or greater improvement
`
`in DRSS was used as the primary endpoint in the PANORAMA study evaluating
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`intravitreal aflibercept for treatment of severe NPDR. Ex.2092, 2.
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`23. Leakage from the microvasculature can occur at any stage of DR and
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`can cause swelling of the macula, a characteristic finding of DME. Ex.2090, 1. The
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`macula is the part of the retina at the back of the eye responsible for central vision
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`and fine detail. DME is the most common cause of vision loss among diabetic
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`13
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`patients. Ex.2097, 1; Ex.1001, 1:44–45. According to the guidelines of the Early
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`
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`Treatment of Diabetic Retinopathy Study (ETDRS), criteria for Clinically
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`Significant Macular Edema (CSME) include:
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`• Retinal thickening at the center of the macula,
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`• Retinal thickening and/or adjacent hard exudates at or within 500 microns
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`of the center of the macula,
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`• An area of retinal thickening greater than or equal to one disc area, any
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`part of which is within 1 disc diameter of the center of the macula.
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`Id.; Ex.2098.
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`24. As a result, quantitative assessment of macular edema can be performed
`
`with optical coherence tomography, which allows a physician to measure the
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`thickness of the retina. Ex.2093, 2.
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`Prior art therapies for angiogenic eye disorders
`B.
`25. Retinal laser therapy has been used to treat angiogenic eye disorders for
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`over 50 years. One type of laser treatment is focal laser treatment, wherein the laser
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`is placed within the macula. Another type of laser treatment is scatter laser, or
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`panretinal photocoagulation, which comprises more extensive laser treatment that
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`treats multiple spots throughout the retina, the majority of which is placed outside
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`the macula.
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`14
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`26. From the 1970s through the 1990s, the Diabetic Retinopathy Study
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`
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`(DRS) and ETDRS evaluated laser photocoagulation treatment for DR, PDR, and
`
`DME. Ex.2095; Ex.2098; Ex.2094. It had been recognized early on that “[h]armful
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`effects of treatment” existed, namely, that laser photocoagulation caused injury to
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`photoreceptor cells, and this could also lead to vision loss. For PDR, however, it was
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`recommended that “[t]he risk of severe visual loss without treatment substantially
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`outweighs the risks of photocoagulation… and prompt treatment is usually
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`advisable.” Ex.2095, 7. On the other hand, “[f]or eyes without macular edema,
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`neither of the strategies for early photocoagulation… was better than deferral of
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`photocoagulation for preventing either moderate or severe visual loss…. Eyes
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`assigned to early full scatter were more likely to have moderate visual loss during
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`the first 2 years of follow-up than eyes assigned to deferral” Ex.2094, 17 (emphasis
`
`added). In other words, while the risk of visual loss due to laser may have been
`
`balanced for patients at high risk of vision loss due to the underlying disease (i.e.,
`
`patients with severe DR, PDR, and DME), there was “small benefit of early
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`photocoagulation in reducing risk of severe visual loss” for patients who had not yet
`
`reached such a stage. Ex.2094, 19. Focal laser became the gold standard for treating
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`DME, while scatter laser was used when treating DR or PDR with laser. Ex.2099,
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`1–2; Ex.2100, 1–2.
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`15
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`27. Around the same time, researchers were characterizing a family of
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`
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`potent growth factors called VEGFs. As described above in VI.A and Figure 1,
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`VEGF is a secreted endothelial cell mitogen and angiogenesis factor regulated by
`
`hypoxia
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`(or
`
`low oxygen) conditions, which are known
`
`to stimulate
`
`neovascularization. Ex.1045, 1; Ex.2046, 3; Ex.2089, 3. VEGF levels are
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`significantly increased in eyes with DR and other angiogenic eye disorders, and
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`blocking VEGF leads to a pronounced reduction in retinal neovascularization.
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`Ex.2046, 7, 11; Ex.2089, 3. VEGF soon became known as the principal mediator of
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`angiogenic eye disorders.
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`28. Beginning in 2004, the U.S. FDA approved a series of anti-VEGF
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`agents. Macugen (pegaptanib) was the first such agent for use in neovascular (wet)
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`age-related macular degeneration (wAMD), an angiogenic eye disorder. Ex.2047. In
`
`the same year, the anti-VEGF monoclonal antibody Avastin (bevacizumab) was
`
`approved for use in advanced solid cancers and was soon adopted for off-label
`
`treatment of angiogenic eye disorders. Ex.2030, 2, 7; Ex.2031. Shortly after, in 2006,
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`the antibody fragment Lucentis (ranibizumab) was approved for treatment of
`
`neovascular wAMD. Ex.1015, 2, 5.
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`29. ANCHOR and MARINA were Genentech’s pivotal trials evaluating
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`Lucentis. Running from March 2003 to December 2005, the MARINA trial recruited
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`
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`16
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`716 wAMD patients with either minimally classic or occult choroidal
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`
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`neovascularization. MARINA subjects were randomly assigned to receive 1) 24
`
`monthly intravitreal injections of ranibizumab at a dose of 0.3 mg or 0.5 mg, or 2)
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`sham injections. The one-year interim results, presented July 2005, showed that
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`nearly 95% of study subjects reached the primary endpoint of losing fewer than 15
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`letters from baseline visual acuity at 12 months. Ex.2055, 4. Furthermore, the two-
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`year results, which were published in October 2006, showed that subjects were not
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`merely losing less visual acuity, but in fact they were gaining a mean of +6.5 letters
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`in the 0.3 mg group and +7.2 letters in the 0.5 mg treatment groups, while the sham
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`treated subjects were losing a mean of -10.3 letters. Ex.1038, 1.
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`30. The ANCHOR trial, which ran from May 2003 to September 2006, had
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`the same primary endpoint of measuring the proportion of patients losing fewer than
`
`15 letters from baseline visual acuity at 12 months. In this study, 423 patients with
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`predominantly classic choroidal neovascularization in wAMD were enrolled.
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`Ex.1035, 1. ANCHOR subjects were randomly assigned to receive 1) monthly 0.3
`
`mg or 0.5 mg ranibizumab or 2) photodynamic therapy every 3 months. Similar to
`
`the MARINA trial, interim one-year results showed that between 94% and 96% of
`
`the patients receiving ranibizumab maintained or improved vision. Ex.2055, 2–3. By
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`two years, the ANCHOR study concluded that subjects treated with ranibizumab had
`
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`17
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`gained a mean of +8.1 to +10.7 letters, while the comparator arm saw a mean loss
`
`
`
`of -9.8 letters. Ex.1035, 1.
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`31.
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`In both ANCHOR and MARINA, the exceedingly positive outcomes
`
`for patients treated with ranibizumab resulted in a protocol amendment that allowed
`
`patients in the comparator arm to be offered monthly ranibizumab injections.
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`Ex.2055, 3–4.
`
`32. Anti-VEGF drugs were believed to hold potential for the treatment of
`
`other angiogenic disorders, so several clinical trials were conducted to evaluate the
`
`efficacy of Lucentis for treatment of other disorders like DR and DME. The safety
`
`and efficacy of Lucentis was subsequently studied in more than 9,000 patients,
`
`across eight pivotal and 23 clinical trials. [Genentech-PR-Oct2016], 3. In 2007, the
`
`RISE and RIDE trials began enrollment to evaluate monthly Lucentis for the
`
`treatment of DME. Ex.2032, 4. The protocol comprised 0.3 mg or 0.5 mg monthly
`
`intravitreal injections of the study drug, with sham injections and deferred laser
`
`given to the control group. The primary endpoint was the percentage of patients who
`
`gained ≥ 15 letters in their Best Corrected Visual Acuity (BCVA) Score from
`
`baseline at month 24. Ex.2032, 8. A secondary endpoint was percentage of patients
`
`with a ≥ 3-step worsening from baseline in the ETDRS Diabetic Retinopathy
`
`Severity Scale Score (DRSS) for eyes at months 24 and 36. Ex.2032, 8. Based on
`
`
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`18
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`the results from the pivotal RIDE and RISE Phase III clinical trials, Lucentis was
`
`
`
`approved for the treatment of DME in 2012 and DR in patients with DME in 2015.
`
`Ex.2033, 1–2.
`
`33.
`
`In 2017, Lucentis was further approved for treatment of DR either with
`
`or without DME. This indication was approved based on based on the Diabetic
`
`Retinopathy Clinical Research Network’s (DRCR.net) Protocol S study, a
`
`randomized, active-controlled study comparing Lucentis to panretinal or scatter
`
`photocoagulation (PRP) in 305 patients with PDR, including those with and without
`
`DME. Ex.2033, 1–2; Ex.2034; Ex.2101.
`
`34. The Lucentis label instructs monthly injections for the treatment of
`
`AMD and DME. Ex.2034. There are many reasons that monthly intravitreal
`
`injections are a less-than-ideal dosing regimen, including patient discomfort,
`
`inconvenience, cost, compliance, and risks associated with injections. It was not for
`
`lack of effort that Genentech has not been able to get a less-frequent fixed dosing
`
`schedule approved on its Lucentis label. In fact, Genentech conducted several
`
`large-scale, expensive clinical trials in an attempt to demonstrate the efficacy of
`
`less-frequent dosing. These studies include SUSTAIN, EXCITE, SAILOR, and
`
`PIER. Ex.2088, 6–7. However, each of these studies failed to demonstrate efficacy
`
`on par with that of monthly dosing with Lucentis.
`
`
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`19
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`35. For example, in the PIER study (2004–2007), AMD patients in the
`
`
`
`treatment groups received ranibizumab every month for three doses, followed by
`
`quarterly doses. Ex.1004, 1. BCVA was measured per ETDRS s