UNITED STATES PATENT AND TRADEMARK OFFICE
`
`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
`
`
`
`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
`
`
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
