`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`———————————
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`———————————
`
`REGENERON PHARMACEUTICALS, INC.
`
`Petitioner,
`
`v.
`
`NOVARTIS PHARMA AG,
`NOVARTIS TECHNOLOGY LLC,
`NOVARTIS PHARMACEUTICALS CORPORATION,
`
`Patent Owners.
`
`
`———————————
`
`
`Patent Number: 9,220,631
`
`
`———————————
`
`REPLY DECLARATION OF DR. SZILÁRD KISS
`
`Regeneron Exhibit 1106.001
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`TABLE OF CONTENTS
`
`
`
`
`V.
`
`Page
`I.
`Introduction ...................................................................................................... 1
`II. Qualifications and Compensation .................................................................... 1
`III. Person of Ordinary Skill in the Art .................................................................. 2
`IV. Response to Dr. Calman’s Assertions Concerning Clinical
`Requirements for Intravitreal Injection ........................................................... 4
`Response to Dr. Calman’s and Dr. Wolfe’s Assertions Concerning the
`Operational Forces for Using a PFS ................................................................ 8
`VI. Response to Dr. Calman’s Assertion Concerning Long-Felt Need .............. 10
`VII. Response to Dr. Calman’s Assertions that Lucentis PFS Satisfied a
`Long-Felt Need .............................................................................................. 12
`VIII. Response to Dr. Malackowski’s, Dr. Calman’s, and Dr. Wolfe’s
`Assertions Concerning the Benefits and Commercial Success of
`Lucentis PFS .................................................................................................. 14
`IX. NOVARTIS’S PROPOSED SUBSTITUTE CLAIMS ................................. 22
`A. Obviousness of Proposed Substitute Claim 50 ................................... 23
`B.
`Obviousness of Proposed Substitute Claim 51 ................................... 29
`C. Obviousness of Proposed Substitute Claims 52 .................................. 30
`X. Declaration ..................................................................................................... 33
`
`
`
`
`
`i
`
`Regeneron Exhibit 1106.002
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`
`I.
`
`
`
`
`
`Introduction
`I have been retained by Petitioner Regeneron Pharmaceuticals, Inc.
`1.
`
`(“Petitioner” or “Regeneron”), as an independent expert witness in the above-
`
`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”). I previously submitted a declaration in this
`
`matter, which I understand was submitted as Ex. 1031.
`
`2.
`
`I provide this declaration to respond to certain issues raised in the
`
`declarations of Dr. Andrew Calman (Ex. 2204) and Dr. Jeremey Wolfe (Ex. 2206).
`
`I also 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 proposed substitute claims 50-52.
`
`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
`
`Declaration of Horst Koller (Ex. 1003). I have also assumed that proposed
`
`substitute claim 27 of the ’631 patent has separately been shown to be obvious
`
`based on the prior art and the Second Declaration of Horst Koller (Ex. 1105).
`
`II. Qualifications and Compensation
`The declaration I previously submitted in this matter sets forth my
`4.
`
`qualifications and compensation. See Ex. 1031.
`
`
`
`
`1
`
`Regeneron Exhibit 1106.003
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`
`III. Person of Ordinary Skill in the Art
`As noted in my initial declaration, I reviewed and adopted the
`5.
`
`
`
`
`
`
`
`definition of a person of ordinary skill in the art (“POSITA”) as of July 2012 set
`
`forth in the Koller Decl. (Ex. 1003). Specific to claims 24-26, Mr. Koller opined
`
`that a POSITA 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.
`
`6.
`
`I understand that Novartis and its expert Mr. Leinsing have set forth
`
`the following definition for a POSITA:
`
`A POSA would have had an advanced degree (i.e., an M.S., a Ph.D.,
`or equivalent) in mechanical engineering, biomedical engineering,
`materials science, chemistry, chemical engineering, or a related field,
`and at least 2–3 years of professional experience, including in the
`design of a PFS and/or the development of ophthalmologic drug
`products or drug delivery devices. Such a person would have been a
`member of a product development team and would have drawn upon
`not only his or her own skills, but also the specialized skills of team
`members in complementary fields including ophthalmology,
`microbiology and toxicology.
`
`Ex. 2201, ¶ 16. I understand that Dr. Calman has further opined that the product
`
`development team would have included someone “who would have had an M.D.
`
`
`
`
`2
`
`Regeneron Exhibit 1106.004
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`
`with a specialty in clinical ophthalmology and some experience administering
`
`
`
`
`
`
`
`VEGF-antagonist intravitreal injections.” Ex. 2204, ¶ 25. As I explained in my
`
`initial declaration, I have served as a principal investigator in over three-dozen
`
`prospective clinical trials and laboratory investigations related to ophthalmologic
`
`drug products or drug delivery devices. I am therefore qualified to provide
`
`testimony from the perspective of an individual having specialized skills in
`
`ophthalmology that has been involved in the development of ophthalmologic drug
`
`products or drug delivery devices. I also have the requisite experience identified
`
`by Dr. Calman—namely that I am an M.D. with a specialty in clinical
`
`ophthalmology who has experience administering VEGF-antagonist intravitreal
`
`injections. Ex. 2204, ¶¶ 25, 40.
`
`7. My opinions regarding the obviousness of claims 24-26 are the same
`
`under either definition of a POSITA. In particular, it is my opinion that it would
`
`have been obvious to use the syringe of Claim 1 of the ’631 Patent according to the
`
`method steps recited in claims 24-26 under the definition of a POSITA offered by
`
`either Mr. Leinsing and Dr. Calman, or Mr. Koller. Similarly, it is my opinion that
`
`it would have been obvious to use the syringe of proposed substitute Claim 27 of
`
`the ’631 Patent according to the method steps recited in claims 50-52 under the
`
`definition of a POSITA offered by either Mr. Leinsing and Dr. Calman, or Mr.
`
`Koller.
`
`
`
`
`3
`
`Regeneron Exhibit 1106.005
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`
`
`
`
`
`
`
`IV. Response to Dr. Calman’s Assertions Concerning Clinical
`Requirements for Intravitreal Injection
`Dr. Calman’s declaration describes that ophthalmologists were aware
`8.
`
`that certain drug products and substances were known to present a risk of toxicity
`
`in patients. Ex. 2204, ¶¶ 61-66. Although I agree with Dr. Calman that there were
`
`known risks associated with certain drug products and materials with respect to
`
`intravitreal administration, ophthalmologists as of 2012 administered drugs that
`
`provided benefits to patients even though the drug and/or drug delivery mechanism
`
`were known to present a risk of side effects and/or adverse reactions to the patient.
`
`Ex. 2296.017 (“Any drug in any form may cause an adverse ocular reaction if it
`
`reaches the eye. Fortunately, most ocular changes induced by drugs are reversible
`
`if detected in the early stages of toxicity….”); see also Ex. 1027.001 (Lucentis vial
`
`label describing that adverse reactions can include “conjunctival hemorrhage, eye
`
`pain, vitreous floaters, increased intraocular pressure, and intraocular
`
`inflammation”). This is evident from the use of Avastin amongst
`
`ophthalmologists. In particular, it was well-known that administering Avastin
`
`carries with it the risk of injecting silicone oil into a patient’s eye due to the
`
`syringes that are used for administration. Ex.1067 (describing silicone oil
`
`contamination in patients due to injection of bevacizumab (Avastin)); Ex. 1025
`
`(describing silicone oil contamination and protein aggregates associated with
`
`
`
`
`4
`
`Regeneron Exhibit 1106.006
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`
`intravitreal injection of Avastin). Nonetheless, ophthalmologists, including Dr.
`
`
`
`
`
`
`
`Calman, have continued to administer Avastin despite this risk (largely due to its
`
`low cost or because it is required to be used by insurers), while monitoring patients
`
`for any potential side effects associated with intravitreal injection of Avastin that
`
`could also introduce silicone oil into the eye. See Ex. 1208 at 32:15-33:9 (Dr.
`
`Calman acknowledging that he administered Avastin even though he was aware
`
`injections could introduce silicone oil into patients’ eyes).
`
`9.
`
`Dr. Calman also states in his declaration that an ophthalmologist
`
`would have been “skeptical of any new or untested excipients in any drug or
`
`device designed for intraocular injection (especially repeated injections), without
`
`such drug or device first receiving FDA approval for this use or the publication in
`
`peer-reviewed scientific literature demonstrating the safety of the excipient for the
`
`intended intraocular use.” Ex. 2204, ¶65. Although drug products and devices
`
`may not be widely used by ophthalmologists before FDA approval and/or peer
`
`review, an ophthalmologist as of 2012 would have understood that drug products
`
`and/or devices can be used in clinical studies before gaining FDA approval and/or
`
`peer approval, the very purpose of which is to demonstrate their safety and
`
`efficacy. During such studies, ophthalmologists would administer drugs to patients
`
`in view of the expected benefits of the drug product and/or delivery mechanism,
`
`while monitoring the patients for potential adverse reactions and side effects.
`
`
`
`
`5
`
`Regeneron Exhibit 1106.007
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`
`10. For example, Avastin (bevacizumab) was used in studies by
`
`
`
`
`
`
`
`ophthalmologists even though it was not FDA-approved for intravitreal injection
`
`(and still is not approved for that purpose).1 Ex. 2284.003 (2006 article noting that
`
`even “though there were limited data available, we offered intravitreal
`
`bevacizumab….”). And even though Avastin has been injected by
`
`ophthalmologists intravitreally, the syringes used for administering Avastin are not
`
`necessarily approved by the FDA specifically for intravitreal injection. In
`
`particular, compounding pharmacies that process Avastin2 for intravitreal use
`
`
`1 After over fifteen years of off-label use, a company recently submitted a
`
`Biologics License Application for FDA approval of a version of bevacizumab
`
`(Avastin). https://www.ophthalmologytimes.com/view/outlook-therapeutics-
`
`submits-biologics-license-application-to-fda-for-ons-5010-as-a-treatment-for-wet-
`
`amd.
`
`2 Avastin is only approved by the FDA as a cancer treatment. It is administered by
`
`ophthalmologists off-label to treat certain eye diseases, but must first be processed
`
`by compounding pharmacies into a solution that is suitable for intravitreal
`
`injection. Because of this process, the relatively higher risk of contamination and
`
`endophthalmitis relative to an FDA-approved and manufactured treatment is well-
`
`known by ophthalmologists.
`
`
`
`
`6
`
`Regeneron Exhibit 1106.008
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`
`typically select the syringes in which Avastin is filled. In my experience,
`
`
`
`
`
`
`
`compounding pharmacies use a wide variety of small volume syringes (e.g., 0.5 –
`
`1.5 mL), many of which are not specifically designed or intended for intravitreal
`
`use. See also Ex. 1208 at 47:3-7. Thus, a clinical ophthalmologist as of 2012
`
`would have been receptive to using new treatments and/or delivery mechanisms for
`
`intravitreal use that were expected to provide benefits to the patient at least for the
`
`purpose of obtaining data to determine their efficacy and safety.
`
`11. Dr. Calman also states that “ophthalmologists would not have
`
`considered it acceptable to use a syringe containing a stopper coating that had
`
`never been validated for injection into the eye and had not been used in a product
`
`approved by the FDA for this purpose (or widely used off-label by
`
`ophthalmologists without attributable adverse events), as a component of a PFS for
`
`intravitreal injection.” Ex. 2204, ¶66. In my opinion, ophthalmologists are
`
`generally not aware of what coatings are used on stoppers in syringes, or whether
`
`all stopper coatings have been specifically approved for use in intravitreal
`
`injection. Although an ophthalmologist would expect that the stopper coatings
`
`used for Eylea PFS and Lucentis PFS had been specifically approved for
`
`intravitreal injection, ophthalmologists frequently administer Avastin in a variety
`
`of syringes without knowing whether those syringes and the coatings used therein
`
`have been specifically approved for intravitreal injection. For example,
`
`
`
`
`7
`
`Regeneron Exhibit 1106.009
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`
`ophthalmologists frequently administer Avastin using insulin or tuberculin
`
`
`
`
`
`
`
`syringes, which are syringes designed for subcutaneous injection (i.e., through the
`
`skin). See e.g., 1025.002 (describing use of insulin syringes to administer Avastin
`
`intravitreally); 1025.003 (describing use of tuberculin syringes to administer
`
`Avastin intravitreally).
`
`12. According to Dr. Calman, the purported risks “associated with the use
`
`of the Parylene-C coating of Boulange in a VEGF-antagonist PFS would have been
`
`of concern to an ophthalmologist.” Ex. 2204, ¶ 134. As noted above, an
`
`ophthalmologist generally would not be aware of what coating is used on the
`
`stopper of a pre-filled syringe. Moreover, I understand from Dr. Cohen that a
`
`toxicologist would not have considered Parylene C to be unsafe, toxic, or
`
`unacceptable to be used as a stopper coating in a prefilled syringe for intravitreal
`
`injection of a VEGF antagonist. Ex. 1108, ¶ 2. Based on that understanding, an
`
`ophthalmologist would not be deterred from using a PFS comprising a stopper
`
`coated with Parylene C to inject ranibizumab, which provided known benefits for
`
`treating patients with certain eye diseases.
`
`V. Response to Dr. Calman’s and Dr. Wolfe’s Assertions Concerning the
`Operational Forces for Using a PFS
`13. Dr. Calman’s declaration identifies a number of potential
`
`complications associated with intravitreal injection. Ex. 2204, ¶¶ 67-73. Dr.
`
`
`
`
`8
`
`Regeneron Exhibit 1106.010
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`
`Calman attributes these complications to “high” break loose and slide forces
`
`
`
`
`
`
`
`required to dispense the drug product from the syringe, as well as “unpredictable”
`
`forces. Ex. 2204, ¶¶ 67-73. Dr. Calman, however, does not identify what
`
`constitutes a “high” force, or what amount of variation would make the forces
`
`“unpredictable.” Similarly, Dr. Wolfe states that “less break-loose and glide forces
`
`increases the physician’s control in administering a drug thereby reducing the risk
`
`of injury due to drug administration, and increasing patient comfort,” and that a
`
`“syringe for intravitreal injection that requires a consistent level of glide force over
`
`the course of the injection allows for a smoother injection and is superior to a
`
`syringe that requires inconsistent levels of glide force during injection.” Ex. 2209,
`
`¶ 38. As with Dr. Calman, however, Dr. Wolfe does not quantify what magnitude
`
`of forces and variations thereof would have been acceptable or unacceptable for
`
`intravitreal injection.
`
`14. Although I agree with Dr. Calman and Dr. Wolfe that a PFS for
`
`intravitreal injection should have suitable forces to enable the physician to
`
`administer the injection, each of the PFS products I have used in my career have
`
`had acceptable forces for administration. For example, when I administered
`
`Macugen PFS from 2006-2008, I found the forces to be sufficiently low to allow
`
`me to safely administer the injection. Similarly, when I presently administer
`
`EYLEA PFS, I have found the forces to be sufficiently low to allow me to safely
`
`
`
`
`9
`
`Regeneron Exhibit 1106.011
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`
`administer the injection. Moreover, I have found the forces required to administer
`
`
`
`
`
`
`
`EYLEA PFS to be consistent for each injection that I perform.
`
`VI. Response to Dr. Calman’s Assertion Concerning Long-Felt Need
`15. Dr. Calman contends that there were “recognized, unsolved problems
`
`with respect to the lack of a PFS with low levels of silicone oil while maintaining
`
`low, predictable operation forces for sterile intravitreal injection of VEGF
`
`antagonists.” Ex. 2204.039. I respond to Dr. Calman’s assertions below.
`
`16. First, Dr. Calman asserts that there was an unsolved problem in the art
`
`concerning sterile intravitreal injection of VEGF antagonists. Ex. 2204, ¶¶ 80-88.
`
`I disagree that this problem had not been solved by 2012. In particular, an
`
`ophthalmologist by 2012 would have understood that VEGF-antagonists were
`
`offered in two presentations—vial or a pre-filled syringe. It was also known that a
`
`PFS reduced the risk of contamination and endophthalmitis relative to a vial
`
`presentation because a PFS requires fewer administration steps. Ex. 2204, ¶ 88;
`
`Ex. 2215.007 (“By eliminating several steps required to transfer medication from
`
`vial to syringe with conventional preparation of anti-VEGF medications, there may
`
`be a lower risk of introducing bacteria during the process.”). As of 2012, Lucentis
`
`and Eylea were offered only in a vial presentation, while Macugen was approved
`
`by the FDA and available in a PFS (and had been since 2004). Ex. 1009 (2008
`
`Macugen Label); Ex. 1062 (2004 Macugen Label). Moreover, I understand from
`
`
`
`
`10
`
`Regeneron Exhibit 1106.012
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`
`Mr. Koller that Macugen was offered in a sterile PFS by 2008. Ex. 1003, ¶ 303.
`
`
`
`
`
`
`
`Thus, the problem of reducing infections by offering a sterile PFS for intravitreal
`
`injection had been solved by the makers of Macugen before Lucentis PFS.
`
`17. Second, Dr. Calman also states that “ophthalmologists wanted a PFS
`
`with low and predictable break loose and slide forces.” Ex. 2204, ¶ 98. In my
`
`experience, however, the Macugen PFS had sufficiently low and predictable break
`
`loose and slide forces, such that it was suitable for intravitreal injection without
`
`creating additional risk to patients.
`
`18. Third, Dr. Calman asserts there was an unsolved problem in the art
`
`concerning silicone oil content in syringes for use in intravitreal injection.3 Ex.
`
`2204, ¶¶ 89-100. Dr. Wolfe likewise asserts that in “the past, certain ophthalmic
`
`syringes were known to inadvertently inject small amounts of this silicone oil
`
`along with the medication into the patient’s eye.” Ex. 2209, ¶ 36. While I agree
`
`with Dr. Calman and Dr. Wolfe that an ophthalmologist would have been
`
`concerned about the amount of silicone oil being injected into a patient’s eye, an
`
`
`3 Prior to 2012, there were reports of silicone oil contamination in patients caused
`
`by intravitreal injection of Macugen PFS. See e.g., Ex. 1080. I understand that the
`
`Macugen PFS had silicone oil applied to the syringe barrel in quantities greater than
`
`those claimed in the’631 Patent. See Patent Owner Response (Paper 35) at 2.
`
`
`
`
`11
`
`Regeneron Exhibit 1106.013
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`
`ophthalmologist would not be particularly concerned or aware of how much
`
`
`
`
`
`
`
`silicone oil is applied to the syringe barrel.4 Instead, an ophthalmologist would
`
`only be concerned about how much silicone oil from the entire syringe ultimately
`
`migrates into the drug product, which can interact negatively with the drug product
`
`and ultimately end up in the patient’s eyes. I understand that Mr. Koller has
`
`addressed whether the amount of silicone oil applied to the syringe barrel is
`
`indicative of how much silicone oil is in the drug product, and therefore I have
`
`offered no opinion on that.
`
`VII. Response to Dr. Calman’s Assertions that Lucentis PFS Satisfied a
`Long-Felt Need
`19. Dr. Calman asserts that Lucentis PFS satisfied the long felt-need he
`
`identified. First, Dr. Calman contends that Lucentis PFS satisfied the long-felt
`
`need for “low, predictable operation forces to allow for smooth and controlled
`
`delivery.” Ex. 2204, ¶ 106. As I noted above, however, in my experience the
`
`Macugen PFS provided low, predictable operation forces to allow for smooth and
`
`controlled delivery years before Lucentis PFS was brought to market.
`
`
`4 I understand that the claims of the ’631 Patent recite a certain amount of silicone
`
`oil that is applied to the syringe barrel. See Ex. 1001 at Claim 1.
`
`
`
`
`12
`
`Regeneron Exhibit 1106.014
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`
`20. Second, Dr. Calman contends that Lucentis PFS satisfied a need for
`
`
`
`
`
`
`
`sterile intravitreal injection. Ex. 2204, ¶ 107. While Dr. Calman attributes this to
`
`the fact that Lucentis PFS is “terminally sterilized,” one of the articles cited by Dr.
`
`Calman describes that reduced infections and endophthalmitis incidences
`
`associated with using a PFS are largely due to the reduced preparation steps needed
`
`to administer a PFS (and not due to terminal sterilization). Ex. 2215.007 (“By
`
`eliminating several steps required to transfer medication from vial to syringe with
`
`conventional preparation of anti-VEGF medications, there may be a lower risk of
`
`introducing bacteria during the process.”). Moreover, as I noted above, Macugen
`
`was already presented in a PFS with fewer administration steps by 2004, and in a
`
`sterile PFS by 2008, so the Lucentis PFS was not the first to address that problem.
`
`See ¶ 16 above.
`
`21. Third, Dr. Calman asserts that Lucentis PFS satisfied a long-felt need
`
`for low silicone oil. Ex. 2204, ¶ 108. As I noted above, an ophthalmologist would
`
`not be concerned about how much silicone oil is applied to the syringe barrel
`
`alone, but would be concerned about how much silicone oil can migrate from the
`
`entire syringe into the drug product. I understand that Mr. Koller has responded to
`
`Dr. Calman’s assertion that Lucentis PFS and the claims of the ’631 Patent
`
`addressed this need, and therefore I have offered no opinion on it.
`
`
`
`
`13
`
`Regeneron Exhibit 1106.015
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`
`
`
`
`
`
`
`VIII. Response to Dr. Malackowski’s, Dr. Calman’s, and Dr. Wolfe’s
`Assertions Concerning the Benefits and Commercial Success of Lucentis
`PFS
`22.
`
`I understand that Mr. Malackowski has opined that “a nexus exists
`
`between the technology of the claimed invention and the commercial success of
`
`the Lucentis PFS.” Ex. 2205, ¶ 11. I further understand that Mr. Malackowski has
`
`opined that “the ʼ631 Patent is critical to the Lucentis PFS and that, along with any
`
`patents protecting the active pharmacological ingredients for each product, would
`
`be among the most important contributions to the success of the products.” Ex.
`
`2205, ¶ 44. Mr. Malackowski attributes this opinion to Dr. Calman, who opined
`
`that “ophthalmologists were willing to administer the Lucentis PFS as an
`
`alternative to the Lucentis vial because of the sterility, safety, and ease of use of
`
`the PFS.” Ex. 2204, ¶ 112. Dr. Calman has also opined that “Ophthalmologists
`
`Have Used the Lucentis PFS…as a Result of the Features Claimed as the Invention
`
`of the ‘631 Patent.” Ex.2204.0058; see also Ex. 2204, ¶¶ 110-111 (Dr. Calman
`
`attributing use of Lucentis PFS to the claimed features of the ’631 Patent,
`
`including “that it is terminally sterilized; has low silicone oil; and has low,
`
`predictable operation forces.”).
`
`23.
`
`In my opinion, ophthalmologists do not use Lucentis PFS due to the
`
`claimed features of the ‘631 Patent, such as terminal sterilization, a glass body,
`
`syringe size, specified ranges of silicone oil on the syringe barrel, and certain
`
`
`
`
`14
`
`Regeneron Exhibit 1106.016
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`
`ranges of injection forces. Instead, any commercial success of the Lucentis PFS is
`
`
`
`
`
`
`
`due to the safety and efficacy of the Lucentis drug itself, as well as the
`
`convenience, efficiency, and reduced risk of infection due to fewer administration
`
`steps associated with a PFS, all of which are features that existed in the prior art,
`
`including Macugen® PFS.
`
`24. First, Mr. Malackowski opined that “[t]he ’631 Patent is critical to the
`
`Lucentis PFS” because it “enabled terminal sterilization of a PFS suitable for
`
`intravitreal injection.” Ex. 2205, ¶ 44. To the extent that Mr. Malackowski is
`
`asserting that ophthalmologists use Lucentis PFS because it is “terminally
`
`sterilized,” I disagree. In my experience, most ophthalmologists would not be
`
`aware of whether Lucentis PFS is terminally sterilized, and do not choose to
`
`prescribe Lucentis PFS based on that feature. Instead, most ophthalmologists
`
`would assume that because the Lucentis PFS has been approved by the FDA, it is
`
`safe and suitable for intravitreal injection regardless of whether it was terminally
`
`sterilized. For example, ophthalmologists administered Macugen PFS beginning in
`
`2004 after FDA approval, even though I understand from Mr. Koller that Macugen
`
`was not terminally sterilized until 2008. Ex. 1003, ¶¶ 149-150. Moreover,
`
`terminal sterilization of Macugen beginning in 2008 did not cause an increase in its
`
`usage amongst ophthalmologists, which further demonstrates that ophthalmologists
`
`do not select a treatment based on that feature.
`
`
`
`
`15
`
`Regeneron Exhibit 1106.017
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`
`25. Second, that the Lucentis PFS uses a syringe with a glass body and a
`
`
`
`
`
`
`
`maximum nominal fill volume of 0.5 mL5 does not show that the ’631 Patent
`
`contributes to the alleged success of the Lucentis PFS. An ophthalmologist would
`
`understand that almost all drugs intended for intravitreal injection can be
`
`administered in a 0.5 or 1 mL syringe, which can be made of glass, due to the
`
`small amount of drug product that can be safely administered into the eye. See Ex.
`
`1031, ¶ 27 (explaining that drugs for intravitreal injection are generally supplied in
`
`small syringes such as 1 mL syringes). For example, I used a 1 mL glass syringe
`
`to administer Macugen intravitreally from 2006-2008. See e.g., Ex. 1062.009
`
`(2004 Macugen Label indicating that the drug product is supplied in a 1 ml glass
`
`syringe).
`
`26. Moreover, as long as an ophthalmologist can administer the syringe
`
`without compromising his or her injection technique, an ophthalmologist is not
`
`concerned with nominal differences in size or the material of the syringe barrel.
`
`For example, I have used 1.5 mL syringes for intravitreal injection of Avastin
`
`without any issue, which I understand is outside the scope of the ’631 Patent
`
`
`5 I understand that the claims of the ’631 Patent require a nominal maximum fill
`
`volume from about 0.5 mL to 1.0 mL.
`
`
`
`
`16
`
`Regeneron Exhibit 1106.018
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`
`claims (0.5 mL – 1.0 mL). I have likewise used plastic syringes to administer
`
`
`
`
`
`
`
`Avastin intravitreally, and have found it just as easy to operate as a glass syringe.
`
`27. Third, ophthalmologists do not use Lucentis PFS because it has a
`
`certain amount of silicone oil applied to the syringe barrel. In my experience, an
`
`ophthalmologist would generally be unaware of how much silicone oil is applied to
`
`the syringe barrel in a PFS, and instead would only be concerned about how much
`
`silicone oil ultimately migrates from the entire syringe to the drug product and into
`
`the eye.6 I understand that Mr. Koller has addressed whether the ’631 Patent
`
`claims address the total amount of silicone oil that can migrate from the entire
`
`syringe to the drug product, and therefore I have offered no opinion on that.
`
`28. Fourth, ophthalmologists do not choose to use Lucentis PFS because it
`
`requires particular injection forces, such as less than about 11N of break loose
`
`force.7 Although an ophthalmologist would want to utilize a syringe that has
`
`sufficiently low operational forces to safely administer an injection, an
`
`
`6 I understand that the ’631 Patent claims a syringe comprising a barrel with about
`
`1-100 µg, about 3-100 µg, or about 1-50 µg of silicone oil.
`
`7 I understand that the ’631 Patent claims a syringe with a break loose force of less
`
`than about 11N (claim 1) or 5N (claim 14), and a stopper slide force of less than
`
`about 11N (claim 16) or 5N (claim 14).
`
`
`
`
`17
`
`Regeneron Exhibit 1106.019
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`
`ophthalmologist would be unaware of the numerical values associated with
`
`
`
`
`
`
`
`movement of the syringe stopper. Moreover, the ’631 Patent specification
`
`describes that forces less than 20N were known in the art for syringes for
`
`intravitreal injection:
`
`Smooth administration is particularly important in sensitive tissues
`such as the eye, where movement of the syringe during administration
`could cause local tissue damage. Break loose and slide forces for pre-
`filled syringes known in the art are typically in the region of less than
`20N, but where the pre-filled syringes contain about 100 μg-about 800
`μg silicone oil.
`
`Ex. 1001 at 5:31-38. In my opinion, an ophthalmologist would believe that a force
`
`less than 20N would be acceptable for intravitreal injection given that syringes
`
`used for intravitreal injection before the ’631 Patent had suitably low forces.
`
`29.
`
`In summary, the claimed features of the ’631 Patent do not contribute
`
`to commercial success in so far as they do not drive an ophthalmologist’s decision
`
`to choose a particular product for treatment. Instead, the primary drivers of
`
`ophthalmologist prescribing decisions are (1) the efficacy of the drug itself; (2) the
`
`cost; and (3) benefits of a PFS that were well-known to ophthalmologists before
`
`2012.
`
`30. While the PFS presentation does drive ophthalmologist administration
`
`decisions (i.e., for the same drug product, physicians overwhelmingly prefer a PFS
`
`
`
`
`18
`
`Regeneron Exhibit 1106.020
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`
`over vial), it does so for reasons that were already known in the prior art (e.g.,
`
`
`
`
`
`
`
`Macugen PFS). A PFS requires fewer steps and less time to administer. For
`
`example, using a vial requires two needles while using a PFS requires only one.
`
`See Ex. 2209, ¶ 32. Because administering a PFS requires fewer steps and less time
`
`than a vial and syringe, using a PFS allows an ophthalmologist to treat more
`
`patients. Moreover, fewer steps with PFS translates to a clinically meaningful
`
`reduction in the rate of endophthalmitis. See Ex. 2215.003; see also Ex. 2209, ¶ 35.
`
`Endophthalmitis is one of the most feared and devastating complications following
`
`an intravitreal injection, oftentimes leading to severe, irreversible blindness in the
`
`affected eye. By reducing the number of steps in which the potential for bacterial
`
`introduction can occur, PFS is currently the most preferred method for injection of
`
`anti-VEGF therapy into patients’ eyes. Therefore, ophthalmologists strongly
`
`prefer using the Lucentis PFS over the vial presentation of Lucentis because the
`
`PFS provides efficiency, convenience, and reduced risk of infection due to fewer
`
`administration steps.
`
`31. Dr. Wolfe, for example, has explained that PFS are “significantly more
`
`convenient, save physician time, minimize risk of physician error, and decrease the
`
`risk of infection.” Ex. 2209, ¶ 31. Moreover, Dr. Wolfe attributes the reduced risk
`
`of infection from using a PFS at least “in part to the elimination o
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
