`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`REGENERON PHARMACEUTICALS, INC.
`
`Petitioner,
`
`V.
`
`NOV ARTIS PHARMA AG,
`NOV ARTIS TECHNOLOGY LLC,
`NOV ARTIS PHARMACEUTICALS CORPORATION,
`
`Patent Owners.
`
`Patent Number: 9,220,631
`
`DECLARATION OF DR. SZILARD KISS
`
`Regeneron Exhibit 1031.001
`
`
`
`TABLE OF CONTENTS
`
`Page
`
`I.
`
`II.
`
`Introduction ...................................................................................................... I
`
`Qualifications and Compensation .................................................................... I
`
`III. Relevant Legal Standards ................................................................................ 4
`
`A.
`
`B.
`
`Claim Construction ............................................................................... 4
`
`Invalidity ............................................................................................... 5
`
`IV. Person of Ordinary Skill in the Art. ................................................................. 7
`
`V.
`
`Relevant Technical Background ...................................................................... 9
`
`VI. Obviousness of Claim 24 ............................................................................... 14
`
`VII. Obviousness of Claim 25 ............................................................................... 16
`
`VIII. Obviousness of Claim 26 ............................................................................... 17
`
`IX. Declaration ..................................................................................................... 20
`
`1
`
`Regeneron Exhibit 1031.002
`
`
`
`I.
`
`Introduction
`
`1.
`
`I have been retained by Petitioner Regeneron Pharmaceuticals, Inc.
`
`("Petitioner" or "Regeneron"), as an independent expert witness in the above(cid:173)
`
`captioned inter partes review ("IPR"), in which Regeneron has requested that the
`
`U.S. Patent and Trademark Office cancel as unpatentable all claims of U.S. Patent
`
`No. 9,220,631 ("the '631 patent"). This declaration sets forth my analyses and
`
`opinions based on my knowledge, experience, and the materials I have considered.
`
`2.
`
`I provide this declaration to explain that certain ophthalmology-related
`
`subject matter disclosed and claimed in the '631 patent was well-known prior to
`
`2012, and also to specifically opine on the obviousness of claims 24-26.
`
`3.
`
`For purposes of this declaration, I have assumed that claim 1 of the '631
`
`patent has separately been shown to be obvious based on the prior art and the
`
`Declarations of Horst Koller (Ex. 1003) and James Agalloco (Ex. 1005).
`
`II. Qualifications and Compensation
`
`4.
`
`I received my B.A. in Biology from Columbia College in 1997 and my
`
`M.D. from Columbia University College of Physicians & Surgeons in 2002.
`
`Following graduation from medical school, I was an Intern in the Department of
`
`Internal Medicine at St. Luke's Roosevelt Hospital, Columbia University College of
`
`Physicians & Surgeons, from 2002 to 2003.
`
`I then became a Resident in the
`
`1
`
`Regeneron Exhibit 1031.003
`
`
`
`Ophthalmology Department of the Massachusetts Eye and Ear Infirmary of Harvard
`
`Medical School from 2003 to 2006.
`
`5.
`
`Including my residency at Harvard, I have over sixteen years of
`
`experience in treating patients with ophthalmological diseases. I was certified by
`
`the American Board of Ophthalmology in 2007. Following my Residency, I was
`
`appointed as a Fellow of the Vitreo-Retinal Service in the Ophthalmology
`
`Department of the Massachusetts Eye & Ear Infirmary at Harvard Medical School
`
`in 2006 and promoted to Chief Fellow in 2007. In 2008, I became an Assistant
`
`Professor of Ophthalmology at Weill Cornell Medical College, and I was promoted
`
`to Associate Professor in 2013. I was given the title of Associate Dean of Clinical
`
`Compliance in 2019. During this time, I also held a number of other clinical
`
`positions. I also hold the title of Vice Chair of Research, Vice Chair of Compliance,
`
`Director of Retina Service and Director of Tele-Ophthalmology at Weill Cornell
`
`Medical College. I also hold the positions of Associate Attending Physician and
`
`Associate Attending Surgeon. My clinical duties involve outpatient evaluation and
`
`management for complex vitreo-retinal pathologies such as age-related macular
`
`degeneration, diabetic retinopathy, retinal vascular disorders, inherited retinal
`
`degenerations, infectious and non-infectious uveitis, and inherited and acquired
`
`maculopathies. I also perform surgical management for patients with the above
`
`complex vitreo-retinal pathologies.
`
`2
`
`Regeneron Exhibit 1031.004
`
`
`
`6.
`
`A recent copy of my curriculum vitae ("CV") is attached as Exhibit
`
`1032 hereto, and provides information about my experience, expertise, and
`
`presentations.
`
`7.
`
`In addition to my work experience, I have many years of experience
`
`participating in professional organizations relating to ophthalmology. Specifically,
`
`I am a member of the American Academy of Ophthalmology, the Association for
`
`Research in Vision and Ophthalmology, the American Society of Retina Specialists,
`
`the Pan-American Association of Ophthalmology, and a number of other
`
`professional societies and organizations.
`
`8.
`
`In addition to the above, I have given numerous presentations at
`
`industry meetings and medical conferences relating to ocular diseases, including wet
`
`macular degeneration. These include, for example, a presentation specifically
`
`regarding anti-VEGF agents in wet age-related macular degeneration (wet AMD),
`
`sustained delivery systems, keratoprosthesis, retinal vein occlusion, uveitis, macular
`
`edema secondary to diabetic retinopathy, retinal vein occlusion, and diseases of the
`
`vitreomacular interface. I have also performed research on novel drug delivery
`
`approaches such as gene therapy, and developed a number of imaging methods. I
`
`have authored or co-authored a number of papers, a substantial number of which are
`
`listed on the attached CV. I am also on the editorial board of several journals, and I
`
`am an ad hoc reviewer for other journals and grants.
`
`3
`
`Regeneron Exhibit 1031.005
`
`
`
`9.
`
`Through my professional experience, I have gained extensive expertise
`
`in a wide variety of complex vitreo-retinal pathologies. I have experience with
`
`treatment of all of the following conditions by using intravitreal administration of
`
`VEGF antagonists: choroidal neovascularisation, wet age-related macular
`
`degeneration, macular edema secondary to retinal vein occlusion (RVO) including
`
`both branch RVO (bRVO) and central RVO (cRVO), choroidal neovascularisation
`
`secondary to pathologic myopia (PM), diabetic macular edema (DME), diabetic
`
`retinopathy, and proliferative retinopathy.
`
`In many instances prior to the 2012
`
`priority date, I administered VEGF antagonist pegaptanib (Macugen®) via a pre(cid:173)
`
`filled syringe intravitreally.
`
`10.
`
`I am being compensated at my standard rate of $850/hour. My
`
`compensation is in no way contingent upon my opinions or the outcome of the
`
`proceeding. I may testify on any or all of the opinions expressed in this declaration.
`
`III. Relevant Legal Standards
`
`11.
`
`I am not an attorney, and therefore my understanding of patent law and
`
`the legal standards set forth in this report is based on explanations provided to me
`
`by counsel.
`
`A.
`
`Claim Construction
`
`12.
`
`It is my understanding that the numbered paragraphs at the end of the
`
`disclosure of a U.S. Patent are the patent "claims" that define the metes and bounds
`
`4
`
`Regeneron Exhibit 1031.006
`
`
`
`of the alleged invention. I understand that these claims of the '631 patent are what
`
`is being challenged in the present IPR proceeding.
`
`13.
`
`I have been informed that, in this proceeding, the Board must determine
`
`the scope of the claims by giving the claims their ordinary and customary meaning
`
`in light of the specification, as the claims would be interpreted by one of ordinary
`
`skill in the art.
`
`14.
`
`I understand that patent claims generally include a "transitional" term
`
`or phrase, such as "consisting" or "comprising," which may connect the preamble
`
`of the claim to the body of the claim. I have been informed that if a claim uses the
`
`term "consisting" as a transition term, that means that the claim is a "closed" claim,
`
`which means that the claim is limited to the claim features that follow the transition
`
`term and nothing else. On the other hand, I understand that the transition term
`
`"comprising" denotes an "open" claim, which means that the claim is not limited to
`
`only the features recited in the claim, and could encompass the listed elements as
`
`well as other unrecited elements.
`
`B.
`
`Invalidity
`
`15.
`
`I understand that Regeneron bears the burden of proving that the
`
`challenged claims of the '631 patent are invalid, and must prove this by a
`
`preponderance of the evidence, which means that invalidity must be shown to be
`
`more likely than not.
`
`5
`
`Regeneron Exhibit 1031.007
`
`
`
`16.
`
`I have been asked to consider the question of whether certain claims of
`
`the '631 patent would have been obvious. I understand that this analysis must be
`
`conducted from the perspective of the person of ordinary skill in the art, and whether
`
`the skilled artisan 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: (1) the scope and
`
`content of the prior art; (2) the differences between the claimed invention and the
`
`prior art; (3) the level of ordinary skill in the art; and ( 4) secondary considerations
`
`of non-obviousness. I have been instructed that one must not engage in hindsight.
`
`Rather, the better approach is to consider what the person of ordinary skill in the art
`
`would have reason to pursue further, and steps that were routinely done, such as in
`
`response to known problems, steps or obstacles.
`
`17.
`
`It is my understanding that some teaching, suggestion, or motivation in
`
`the prior art that would have led one of ordinary skill to modify the prior art reference
`
`or to combine prior art reference teachings to arrive at the claimed invention may
`
`support the obviousness of an invention. Other rationales that may support the
`
`obviousness of the invention include a simple substitution of one known element for
`
`another to obtain predictable results, and applying a known technique to a known
`
`device ready for improvement to yield predictable results.
`
`6
`
`Regeneron Exhibit 1031.008
`
`
`
`18.
`
`It is my understanding that the motivation to combine pnor art
`
`references may be implicit and may be found in the knowledge of one of ordinary
`
`skill in the art, or in the nature of the problem to be solved. Specifically, it is my
`
`understanding that an implicit motivation to combine exists not only when a
`
`suggestion may be gleaned from the prior art as a whole, but when the
`
`"improvement" is technology-independent and the combination of references results
`
`in a product or process that is more desirable, for example because it is stronger,
`
`cheaper, cleaner, faster, lighter, smaller, more durable or more efficient. It is my
`
`further understanding that the motivation to combine references may be found in the
`
`nature of the problem to be solved where prior art references are directed to precisely
`
`the same problem.
`
`19.
`
`I also understand that pnor art may be relied on for its express
`
`disclosure and teachings. I also understand that the prior art may be relied upon for
`
`a teaching of features that are necessarily present in the prior art reference even if
`
`that specific feature is not expressly or explicitly disclosed.
`
`IV. Person of Ordinary Skill in the Art
`
`20.
`
`I have been asked to review the '631 patent from the perspective of a
`
`person of ordinary skill in the art ("POSIT A"). I understand that the '631 patent
`
`7
`
`Regeneron Exhibit 1031.009
`
`
`
`claims an earliest priority date of July 3, 2012. 1 Therefore, I have considered the
`
`state of the art as of July 3, 2012 and shortly before that date, and the level of
`
`knowledge that a POSITA would have possessed at that time. Unless I state
`
`otherwise, whenever I refer to any principle or technical subject matter as having
`
`been known or understood, this is meant to denote the knowledge and understanding
`
`of a POSITA at or prior to July 3, 2012. 2
`
`21.
`
`I have reviewed and adopted the definition of POSIT A as of July 2012
`
`set forth in the Koller Deel. Specific to claims 24-26, I agree that a POSITA with
`
`respect to these claims would be an ophthalmologist with some experience
`
`administering VEGF -antagonist drugs to patients via the intravitreal route, because
`
`claims 24-26 relate to methods of treating a patient suffering from eye disease by
`
`administering an ophthalmic solution using a pre-filled syringe. See Ex. 1015.036
`
`("Since an excellent knowledge of the anatomy and function of the eye is required,
`
`only an ophthalmologist should attempt these procedures."). My use of the term
`
`1 I have been informed that the date of "July 30, 2012" for EP 12174860 listed on
`the face of the '631 patent is typographical error and should be July 3, 2012.
`
`2 I understand that the '631 patent may not be entitled to the July 3, 2012 priority
`date, and that the next earliest priority date claimed by the patent would be October
`23, 2012. For purposes of my opinions, there is no appreciable difference in the
`state of the art between July 3 and October 23, 2012, because the subject matter I
`describe herein as it relates to the '631 patent was well-known and conventional well
`before July 3, 2012.
`
`8
`
`Regeneron Exhibit 1031.010
`
`
`
`"ophthalmologist" in this declaration will be in reference to the aforementioned
`
`POSITA ophthalmologist, unless specified otherwise.
`
`V.
`
`Relevant Technical Background
`
`22.
`
`"VEGF" is short for "vascular endothelial growth factor," which is a
`
`protein within the human body.
`
`It was well-known prior to 2012 that the
`
`overexpression of VEGF contributes to diseases including cancer and vascular
`
`diseases of the eye, and therefore that compounds that inhibit the expression of
`
`VEGF are useful in the treatment of such diseases. Diseases that were known to be
`
`related to the expression or over-expression of VEGF, and therefore treatable by
`
`administration of VEGF-antagonist drug
`
`formulations,
`
`include choroidal
`
`neovascularisation, wet age-related macular degeneration, macular edema secondary
`
`to retinal vein occlusion (RVO) including both branch RVO (bRVO) and central
`
`RVO ( cRVO), choroidal neovascularisation secondary to pathologic myopia (PM),
`
`diabetic macular edema (DME), diabetic retinopathy, and proliferative retinopathy.
`
`See, e.g., Ex. 1054.002-003; Ex. 1055.018, 029.
`
`23.
`
`Several VEGF-antagonists were known and commercially available
`
`prior to 2012 that an ophthalmologist would have known could be used for the
`
`treatment of some or all of the eye diseases mentioned above. These include
`
`ranibizumab (Lucentis®), aflibercept (Eylea®), pegaptanib (Macugen®). See Ex.
`
`1027, Ex. 1040, Ex. 1009. All three of these VEGF-antagonist drug formulations
`
`9
`
`Regeneron Exhibit 1031.011
`
`
`
`are intended for administration via the intravitreal route. As used herein,
`
`"intravitreal" administration refers to "injection directly into the vitreous cavity of
`
`the eye." Ex. 1015.035. An intravitreal injection is a type of "intraocular
`
`injection"-a more general term for injection into the eye. Id..
`
`24. Because of the delicate structures in the eye, an ophthalmologist would
`
`have been well aware that "[ e ]xtreme care and precise technique are required to
`
`minimize or prevent damage to the eye, especially to the corneal endothelium." Ex.
`
`1015.036. It was known that numerous medical complications could occur from
`
`incorrect intravitreal administration, such as retinal detachment and ocular
`
`hemorrhage, including massive subretinal hemorrhage, and infection is always a
`
`threat, which can lead to further complications. As such, intravitreal injections are
`
`typically administered only by ophthalmologists. Id.
`
`25.
`
`It was also known that only small volumes of around 0 .1 mL
`
`(sometimes 0.15 mL) or typically even less than that should be injected
`
`intravitreally, unless fluid from the vitreous humour is first removed from the eye of
`
`the patient via paracentesis. Id.; see Ex. 1059 .004. This prevents elevation of ocular
`
`pressure. Ex. 1059 .004. The Macugen® label, for example, states that the deliverable
`
`volume is 90 µL, or 0.090 mL. Ex. 1009.009. Because VEGF-antagonist
`
`formulations are administered by injection into the eye, they are typically dispensed
`
`either in vials to be used with empty disposable syringes (see Ex. 1040.014), or in a
`
`10
`
`Regeneron Exhibit 1031.012
`
`
`
`pre-filled syringe (see Ex. 1009.001). Because of the low injection volume needed
`
`for intravitreal administration, pre-filled syringes for injection of such small doses
`
`are likewise small. For example, the original 2004 prescribing information for
`
`Macugen® specified that the supplied syringe was a "l mL glass syringe." Ex.
`
`1062.009; see also Ex. 1063.016 (describing Macugen clinical trial intravitreal
`
`injection performed with pegaptanib packaged in a "single-use, USP type 1
`
`graduated glass 1 mL syringe"). International Patent Application Publication No.
`
`WO 2007/149334 also discloses a VEGF-antagonist in a 1 mL pre-filled glass
`
`syringe. Ex. 1021 at [0059], [0061].
`
`26. An ophthalmologist would have been well aware of pre-filled syringes
`
`that had been FDA approved and commercially available for
`
`intravitreal
`
`administration prior to 2012. One example is Allergan's Trivaris®, which was
`
`available as a pre-filled syringe containing a corticosteroid for intravitreal
`
`administration to treat sympathetic ophthalmia, temporal arteritis, uveitis, and ocular
`
`inflammatory conditions unresponsive to topical corticosteroids. See Ex. 1056.003-
`
`005. Similarly, Macugen® (pegaptanib sodium injection), was a well-known VEGF
`
`antagonist formulation indicated for the treatment of neovascular (wet) age-related
`
`11
`
`Regeneron Exhibit 1031.013
`
`
`
`macular degeneration (AMD) and available m a pre-filled syringe. 3 See Ex.
`
`1009.001.
`
`27.
`
`The Macugen® Label (Ex. 1009) provides the prescribing information
`
`for Macugen® as presented on the Drugs.com website as of March 7, 2011. Prior to
`
`July 3, 2012, and prior to the March 7, 2011 public availability of the Macugen®
`
`Label, I was aware of the Drugs.com website, and I used the Drugs.com website in
`
`my professional capacity to find prescribing information and data about drugs.
`
`Physicians in general would have known that Drugs.com was a source for drug
`
`prescribing information as of 2011, and physicians could and did access drug
`
`prescribing information on Drugs.com, as I did. Likewise, a person interested in the
`
`art in 2011 would have accessed Drugs.com and been able to use its searching and
`
`indexing capabilities to find prescribing information for specific drugs.
`
`28. An ophthalmologist would have been well aware in 2012 and before
`
`that thin needle sizes and short needle lengths are preferred for intravitreal
`
`administration. A 30 gauge needle size was preferred by surgeons performing
`
`intravitreal injections, although 27 gauge needles were also used as of 2012. Ex.
`
`1058.002. Thin needle sizes are desirable in order to reduce patient discomfort that
`
`3 Macugen was the first anti-VEGF approved by FDA in 2004 to treat wet AMD.
`While still technically available in 2020, newer anti-VEGFs have shown to be more
`effective than Macugen. As a result, Macugen is now rarely prescribed anymore, if
`at all, or used to treat wet AMD patients.
`
`12
`
`Regeneron Exhibit 1031.014
`
`
`
`may be caused by thicker needles, as well as to reduce the risk of retinal detachment
`
`and endophthalmitis. See Ex. 1059.004. Shorter needle lengths are preferred
`
`because of the limited depth of injection into the eye, as illustrated in Nema. Ex.
`
`1015.036; see also Ex. 1059.003 (recommending an injection depth of 5 to 7 mm,
`
`which is about half of the 0.5 inch needle (12.7 mm)). The Macugen® label states
`
`that the pre-filled syringe was supplied with a 30 G x 0.5 inch needle. Ex. 1009.009.
`
`Thus, it was generally known that syringes for intravitreal administration had a 27
`
`gauge needle or higher (such as 30 gauge), and generally had a 0.5 inch length. See,
`
`e.g., Ex. 1056.004; Ex. 1009.009; Ex. 1027.002.
`
`29.
`
`The '631 patent describes priming as "allow[ing] the physician to align
`
`a pre-determined part of the stopper ( such as the tip of the front surface or one of the
`
`circumferential ribs, discussed later) or plunger with the mark, thus expelling excess
`
`ophthalmic solution and any air bubbles from the syringe. The priming process
`
`ensures that an exact, pre-determined dosage is administered to the patient." Ex.
`
`1001 at 2:25-32. It is known that prior to administering a drug using a pre-filled
`
`syringe or any syringe for that matter, ophthalmologists routinely perform the step
`
`of aligning the syringe stopper with a mark provided on the syringe to expel excess
`
`solution and ensure accurate dosing. Ex. 1009.001-002, 007. Having dosing marks
`
`on a syringe is a common feature of syringes that is not unique to any specific drug.
`
`13
`
`Regeneron Exhibit 1031.015
`
`
`
`Accordingly, "priming" has been a known and routine step in the intravitreal drug
`
`administration process well before 2012.
`
`VI. Obviousness of Claim 24
`
`30.
`
`I understand that claim 24 depends from claim 1 and therefore
`
`incorporates all of the features of claim 1. Claim 24 is reproduced below:
`
`24. A method of treating a patient suffering from of [sic]- an ocular
`
`disease selected from choroidal neovascularisation, wet age-related
`
`macular degeneration, macular edema secondary to retinal vein
`
`occlusion (RVO) including both branch RVO (bRVO) and central RVO
`
`( cRVO), choroidal neovascularisation secondary to pathologic myopia
`
`(PM), diabetic macular edema (DME), diabetic retinopathy, and
`
`proliferative retinopathy, comprising the step of administering an
`
`ophthalmic solution to the patient using a pre-filled syringe according
`
`to claim 1.
`
`31. The '631 patent contains no disclosure showing that any of these
`
`diseases could have been treated by any substance or method described in the '631
`
`patent. Nevertheless, an ophthalmologist would have been well aware that the listed
`
`diseases were caused by or related to VEGF expression and therefore can be treated
`
`by a VEGF-antagonist. See generally, Ex. 1054; Ex. 1055.
`
`32.
`
`For example, an ophthalmologist prior to 2012 would have been well
`
`aware that ranibizumab (Lucentis®) was FDA approved in 2006 for the treatment of
`
`wet age-related macular degeneration, and for macular edema secondary to retinal
`
`14
`
`Regeneron Exhibit 1031.016
`
`
`
`vein occlusion (RVO). Ex. 1027.001, 006. Macugen® (pegaptanib sodium injection)
`
`was FDA approved in a pre-filled syringe in 2004 for the treatment of wet age(cid:173)
`
`related macular degeneration. Ex. 1009.005, 011. Eylea® (aflibercept) was FDA
`
`approved in 2011 for the treatment of wet age-related macular degeneration. Ex.
`
`1040.001. A POSIT A would further have known that Lucentis, Macugen and Eylea
`
`are all VEGF-antagonist solutions. 4
`
`33.
`
`It is my understanding that the Sigg (Ex. 1007) and Lam (Ex. 1029)
`
`references disclose a sterilized, pre-filled syringe including Lucentis®. Ex. 1007 at
`
`9:11-14; 20:17-21; Ex. 1029 at 13:14-15. An ophthalmologist would understand
`
`that the very purpose of a pre-filled syringe including Lucentis® is to treat a patient
`
`suffering from ocular diseases listed in claim 24. Indeed, the Lucentis® label (June
`
`2010 revision) specifically states that Lucentis is indicated for the treatment of
`
`patients with Neovascular (Wet) Age-Related Macular Degeneration (AMD) and
`
`Macular Edema Following Retinal Vein Occlusion (RVO). Ex. 1027.001.
`
`34. Assuming, as I have for purposes of this declaration, that the pre-filled
`
`syringe of claim 1 is obvious, then the step of using an ophthalmic solution in a pre(cid:173)
`
`filled syringe to treat the recited list of diseases would also have been obvious and
`
`4 Eylea is a non-antibody VEGF antagonist and Lucentis is an anti-VEGF antibody
`fragment, which is characterized in the '631 Patent as an antibody VEGF antagonist.
`Ex. 1001 at 6:34-36 ("Two antibody VEGF antagonists have been approved for
`human use, namely ranibizumab (Lucentis®) and bevacizumab (Avastin®).").
`
`15
`
`Regeneron Exhibit 1031.017
`
`
`
`well within the ordinary skill and routine practice of an ophthalmologist. The
`
`"ophthalmic solution" is merely
`
`the VEGF-antagonist solution (i.e., drug
`
`formulation) recited in claim 1, and administering such an ophthalmic solution to a
`
`patient to treat the recited list of diseases would be a routine and expected step for
`
`an ophthalmologist. As such, assuming that claim 1 has been rendered obvious, it is
`
`my opinion that claim 24 is also rendered obvious.
`
`VII. Obviousness of Claim 25
`
`35.
`
`I understand that claim 25 depends from and incorporates all of the
`
`features of claims 1 and 24. Claim 24 is obvious as discussed in Section V above.
`
`Claim 25 recites the method of claim 24 and adds the additional routine and well(cid:173)
`
`known step of "priming" the pre-filled syringe. This is a common step performed
`
`by an ophthalmologist prior to administration to expel excess solution and ensure
`
`accurate dosing.
`
`36.
`
`For example, the Macugen® Label describes and illustrates the priming
`
`step in which the physician depresses the plunger "to eliminate all the bubbles and
`
`to expel the excess drug so that the top edge of the 3rd rib on the plunger stopper
`
`aligns with the pre-printed black dosing line" of the pre-filled syringe. Ex. 1009 .007.
`
`16
`
`Regeneron Exhibit 1031.018
`
`
`
`fo
`ala·
`3yvary)
`Macugen® Label (Ex. 1009.001)
`
`As explained in if29 above, it would have been readily understood that the "black
`
`dosing line" described in the Macugen ® Label is a "priming mark" as recited in
`
`claim 25. Moreover, the step of priming a pre-filled syringe before administration
`
`was completely routine and conventional prior to 2012, and was not specific to any
`
`drug or syringe but rather a typical step that would have been performed to ensure
`
`accurate dosing of the drug. Thus, assuming that claim 1 is obvious, it is my opinion
`
`that claim 25 is also obvious.
`
`VIII. Obviousness of Claim 26
`
`3 7.
`
`I understand that claim 26 depends from and incorporates all of the
`
`features of claims 1 and 24. Claim 24 is obvious as discussed in Section V above.
`
`Claim 26 recites the method of claim 24 and adds the additional limitation that "the
`
`VEGF antagonist administered is a non-antibody VEGF antagonist and wherein the
`
`patient has previously received treatment with an antibody VEGF antagonist."
`
`17
`
`Regeneron Exhibit 1031.019
`
`
`
`38. Dixon, published in 2009, reviewed the then-current literature for
`
`VEGF-Trap, an earlier name for aflibercept (Eylea). Dixon discloses that "[ i ]f
`
`effective at 8 week intervals, [aflibercept] offers the opportunity to significantly
`
`reduce treatment burden on patients and physicians, and would probably find wide
`
`acceptance." Ex. 1030.008. Dixon supports this statement with results from studies
`
`indicating that aflibercept had an advantage over ranibizumab or bevacizumab, thus
`
`motivating one of ordinary skill in the art to switch from an antibody VEGF(cid:173)
`
`antagonist (ranibizumab or bevacizumab) to non-antibody VEGF-antagonist
`
`(aflibercept). Id. Notably "[i]n contrast to current anti-VEGF antibodies, which are
`
`rapidly cleared, [ aflibercept] is relatively inert, and is degraded more slowly" (Ex.
`
`1030.008), thus making it a desirable option for clinicians to switch to. Before
`
`aflibercept was approved, "[b ]y far the most commonly used anti-VEGF drugs
`
`currently in use for neovascular AMD are ranibizumab and bevacizumab," (Lucentis
`
`and Avastin 5
`
`) which are both antibody VEGF-antagonists.
`
`Ex. 1030.005.
`
`Aflibercept was approved by the FDA prior to 2012, and was viewed in some
`
`respects as a superior option for the treatment of neovascular AMD. See generally
`
`Ex. 1022 (Explaining that "[ aflibercept' s] less frequent dosing compared with
`
`5 An ophthalmologist would have been aware that Avastin® (bevacizumab) was
`available and widely used off-label for treatment of wet age-related macular
`degeneration and other ocular diseases prior to 2012.
`
`18
`
`Regeneron Exhibit 1031.020
`
`
`
`Lucentis [ranibizumab] (see main text) appears to be perceived by physicians as a
`
`moderate advantage, and analysts predict that its uptake will be robust").
`
`39.
`
`For the above reasons, it would have been obvious to administer a non(cid:173)
`
`antibody VEGF antagonist such as Eylea to a patient who has previously received
`
`treatment with an antibody VEGF antagonist such as Lucentis or Avastin. As such,
`
`assuming claim I is obvious, and because claim 24 is obvious as demonstrated
`
`above, it is my opinion that claim 26 is also obvious.
`
`19
`
`Regeneron Exhibit 1031.021
`
`
`
`IX. Declaration
`
`40.
`
`I declare that all statements made herein of my own knowledge are true
`
`and that all statements made on information and belief are believed to be true; and
`
`further that these statements were made with the knowledge that willful false
`
`statements and the like so made are punishable by fine or imprisonment, or both,
`
`under Section I 00 I of Title 18 of the United States Code.
`
`Dated: 15-July-2020
`
`By: a::_
`
`\;? S ·1, dK.
`ur. Zl ar
`
`lSS
`
`20
`
`Regeneron Exhibit 1031.022
`
`