`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________
`
`
`Moderna Therapeutics, Inc.
`
`Petitioner
`
`v.
`
`Protiva Biotherapeutics, Inc.
`
`Patent Owner
`___________
`
`
`Case No. IPR2019-00554
`U.S. Patent No. 8,058,069
`
`___________
`
`
`DECLARATION OF THOMAS J. ANCHORDOQUY, PH.D.
`IN SUPPORT OF PETITIONER’S REPLY TO PATENT OWNER’S
`RESPONSE
`
`
`
`
`Mail Stop: PATENT BOARD
`Patent Trial and Appeal Board
`U.S. Patent & Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`10809138
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`
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`TABLE OF CONTENTS
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`I.
`
`II.
`
`III.
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`IV.
`
`V.
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`VI.
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`Page
`INTRODUCTION ..................................................................................................... 1
`
`SUMMARY OF OPINIONS ..................................................................................... 2
`
`QUALIFICATION AND EXPERIENCE ................................................................. 3
`
`LEVEL OF SKILL IN THE ART ............................................................................. 8
`
`CLAIM CONSTRUCTION ....................................................................................... 9
`
`THE INSTITUTED GROUNDS ............................................................................. 14
`
`A.
`
`B.
`
`C.
`
`D.
`
`An Overlapping Phospholipid Range Is Disclosed ..................................... 15
`
`The Same Four Lipid-Component Carrier Particles Are Disclosed ............ 18
`
`Lipid-Carrier Particles Are Amenable To Routine Optimization ................ 20
`
`Dependent claims ......................................................................................... 48
`
`VII.
`
`SECONDARY CONSIDERATIONS CANNOT OVERCOME
`PETITIONER’S OBVIOUSNESS SHOWING ...................................................... 53
`
`A.
`
`B.
`
`The Test Data Is Not Commensurate With The Scope Of The
`Claims .......................................................................................................... 53
`
`Test Data Does Not Show Unexpected Results ........................................... 54
`
`C.
`
`Other Secondary Considerations Lack The Required Nexus Or Are
`Attributable To The Prior Art ...................................................................... 58
`VIII. CONCLUSION ................................................................................................... 62
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`I, Dr. Thomas J. Anchordoquy, PhD, declare as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I am a tenured Professor in the Department of Pharmaceutical
`
`Sciences at the University of Colorado Anschutz Medical Campus in Aurora,
`
`Colorado. I have been retained by counsel for ModernaTX, Inc. (“Moderna”)
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`as an expert in the relevant art.
`
`2.
`
`I understand that Moderna formerly engaged Dr. Andrew Janoff
`
`as an expert in this matter and that he submitted a declaration dated January 2,
`
`2019 (“Janoff Declaration”) in support of Moderna’s Petition for Inter Partes
`
`Review (“IPR”) of U.S. Patent No. 8,058,069 (the “’069 patent”) (“Petition”).
`
`EX1008. I understand that Dr. Janoff passed away in December 2019 and that I
`
`have been engaged to replace him as Moderna’s expert in this proceeding.
`
`3.
`
`I have reviewed Dr. Janoff’s declaration and, while I may have
`
`emphasized different points or stated things differently, I agree with the general
`
`premises set-forth regarding the invalidity of the ’069 patent as stated therein.
`
`4.
`
`On November 13, 2019, Patent Owner Protiva Biotherapeutics,
`
`Inc. (“Patent Owner”) filed its response to Moderna’s Petition (“Response”). I
`
`have been asked to provide additional explanation regarding the prior art and
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`the state of the art in response to Patent Owner’s arguments in its Response.
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`While counsel for Moderna has assisted in the preparation of this declaration
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`(e.g., aiding in formatting and providing introductory language and legal
`
`standards), the substantive opinions discussed herein are my own.
`
`5.
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`This declaration is based on the information currently available to
`
`me. To the extent that additional information becomes available, I reserve the
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`right to continue my investigation and study, which may include a review of
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`documents and information that may be produced, as well as testimony from
`
`depositions.
`
`II.
`
`SUMMARY OF OPINIONS
`
`6.
`
`I understand that the Board ordered an IPR over the’069 patent
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`with respect to the following grounds of unpatentability for claims 1-22:
`
`A.
`
`B.
`
`C.
`
`7.
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`Under §102 and §103 in view of either the ’196 PCT and ’189
`publication;
`
`Under §103 in view of each of the ’196 PCT and ’189 publication
`in view of Lin and/or Ahmad; and,
`
`Under §102 or §103 in view of the ’554 publication.
`
`The ’069 patent is directed to a nucleic acid-lipid particle
`
`comprising four lipid components (i.e., a cationic lipid, cholesterol, a
`
`phospholipid and a conjugated lipid), each of which fall within a claimed
`
`proportion with regard to the total lipid in the particles. See, e.g., EX1001, cl.
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`1. In my opinion, Moderna has shown that the cited prior art in Grounds 1-3
`
`renders each of the claims in the ’069 patent invalid by a preponderance of the
`
`evidence.
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`III. QUALIFICATION AND EXPERIENCE
`
`8.
`
`I possess the knowledge, skills, experience, training and the
`
`education to form an expert opinion and testimony in this case.
`
`9.
`
`I received a bachelor of science in biology from Oregon State
`
`University in 1982. I received my master’s and doctoral degrees from the
`
`University of California Davis in Zoology in 1988 and 1989, respectively. I did
`
`my doctoral thesis work under the direction of Dr. John Crowe at the
`
`University of California Davis. Dr. Crowe is an expert in the stability of
`
`liposomes during freezing and drying, and this was the main topic of my thesis
`
`work.
`
`10.
`
`I continued my studies at the University of Colorado as a post-
`
`doctoral researcher with Dr. John Carpenter in the University of Colorado
`
`School of Pharmacy, where I joined the faculty as an Assistant Professor in
`
`Pharmaceutical Sciences in 1998. I was promoted to Associate Professor in
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`Pharmaceutical Sciences with Tenure in 2005, and then to Full Professor in
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`2011.
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`11. While my doctoral degree is in Zoology, my laboratory focused
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`almost exclusively on liposomes as a model membrane system while I
`
`conducted my dissertation research. Accordingly, I have been working with
`
`liposomes since 1985. My initial work focused primarily on the physical
`
`stability of liposomes during freezing and drying. At that time, liposomes were
`
`being investigated as drug delivery vehicles, and our work on stabilization was
`
`of interest to the pharmaceutical industry.
`
`12. One of the main measures of stability for a liposome at the time
`
`was the extent to which it retained encapsulated drugs, and I frequently
`
`conducted assays to determine the extent to which liposomes leaked contents
`
`during various stresses.
`
`13.
`
`I began working on the ability of liposomes and lipid particles to
`
`facilitate the delivery of nucleic acids during my post-doctoral research. At that
`
`time, 1996, the interest in gene therapy was intense and many of the people
`
`who studied liposomes were now focusing on DNA delivery. This became my
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`predominant focus after I took my faculty position in 1998. During this time, I
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`was in regular communication with scientists at Ribozyme Pharmaceuticals,
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`which ultimately transitioned into Sirna Therapeutics, Inc. (the assignee of the
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`’554 publication (EX1005)) once the potential of siRNA technology became
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`evident.
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`14. My first issued patent (filed in 2004, issued in 2011) described
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`lipid encapsulation technology for use in delivering DNA and siRNA. In
`
`contrast to SNALP technology, my patent described a process by which lipid
`
`bilayers could be formed around a solution of nucleic acids, effectively
`
`surrounding the nucleic acids to achieve complete encapsulation within a lipid
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`vesicle.
`
`15.
`
`In addition, my laboratory focused on understanding the
`
`parameters that contributed to serum stability of lipid-nucleic acid particles as
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`well as the mechanisms responsible for effective intracellular delivery. After
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`two decades, my laboratory still focuses on understanding and optimizing
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`lipid-mediated nucleic acid delivery.
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`16. As part of my faculty position in the Department of
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`Pharmaceutical Sciences at the University of Colorado, I teach both pharmacy
`
`students and PhD students about the basics of pharmacy and drug development.
`
`Particularly relevant to the current proceeding, I train my PhD students and
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`postdoctoral researchers in liposomes and lipid-mediated nucleic acid delivery.
`
`One of my main teachings in the PhD curriculum is a course I developed
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`entitled “Liposome-based Drug Delivery” which reviews the genesis of many
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`fundamental ideas in the field from their initial applications in liposomes
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`through their adaptation to gene delivery and up to their current use for siRNA
`
`delivery.
`
`17.
`
`In addition to training half a dozen postdoctoral researchers, I
`
`have graduated seven PhD students in my career, all of whom work in the
`
`pharmaceutical industry. Of particular relevance to the current proceeding, my
`
`first PhD student, Dr. Ye Zhang, graduated from my lab the day before being
`
`hired at Sirna Therapeutics in nearby Boulder, CO. Dr. Zhang is an inventor
`
`listed on the ’554 publication. EX1005.
`
`18. Throughout my career, I have published over 100 manuscripts in
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`peer-reviewed journals and books. The vast majority of these publications
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`involve lipids and/or nucleic acids and focus on stability, formulation, and
`
`delivery. In addition, I have filed over a dozen patent applications mostly
`
`focused on the formulation of small molecule pharmaceuticals.
`
`19. As mentioned previously, I am a recognized expert in the field of
`
`liposomes and lipid-mediated delivery, and I serve on the editorial/advisory
`
`board of several scientific journals including Pharmaceutics, Journal of
`
`Pharmaceutical Sciences, and Therapeutic Delivery. In addition to organizing
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`symposia on gene and drug delivery for national meetings, I also frequently
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`serve as a reviewer for the National Institutes of Health on study sections to
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`evaluate grant applications associated with nucleic acid delivery, e.g., Gene
`
`and Drug Delivery, Nanotechnology, Biomaterials and Biointerfaces. My
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`curriculum vitae is attached as EX1021.
`
`20.
`
`I am being compensated by Moderna for my time spent in
`
`developing this declaration and for any time spent testifying in connection with
`
`this declaration at a rate of $750 per hour. My compensation is not contingent
`
`upon the substance of my opinion, the content of this declaration or any
`
`testimony I may provide, or the outcome of the inter partes review or any other
`
`proceeding. I have no financial interest in Moderna.
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`21. My opinions expressed in this declaration are in response to the
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`Patent Owner’s Response and the associated Declaration of Dr. Thompson
`
`(EX2031). I have specifically reviewed the Petition and exhibits cited in the
`
`Petition, the Patent Owner’s Response and exhibits cited in the Response, and
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`other documents and materials identified in this declaration, including the ’069
`
`patent (EX1001), the prior art references and materials discussed in this
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`declaration, and any other references specifically identified in this declaration.
`
`22.
`
`I am aware of information generally available to, and relied upon
`
`by, persons of ordinary skill in the art at the relevant times, including technical
`
`dictionaries and technical reference materials (including, for example,
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`textbooks, manuals, technical papers, articles, and relevant technical
`
`standards).
`
`23.
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`I am not a patent attorney or an expert in patent law. I have
`
`reviewed the legal section of the Janoff Declaration (¶¶33-59) and have used
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`those legal standards to guide my analysis.
`
`24.
`
`I reserve the right to supplement my opinions to address any
`
`information obtained, or positions taken, based on any new information that
`
`comes to light throughout this proceeding.
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`IV. Level Of Skill In The Art
`
`25.
`
`I have reviewed Dr. Janoff’s opinions regarding the level of skill
`
`in the art and the Board’s determinations related thereto in the Institution
`
`Decision, Paper 8 (“ID”), in this case, and agree that a person of ordinary skill
`
`in the art (“POSITA”) “would have specific experience with lipid particle
`
`formation and use in the context of delivering therapeutic nucleic acid
`
`payloads, and would have a Ph.D., an M.D., or a similar advanced degree in an
`
`allied field (e.g., biophysics, microbiology, biochemistry) or an equivalent
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`combination of education and experience.”
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`26. Based upon my education and experience, I am at least a POSITA.
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`I also agree with the Board that the level of ordinary skill in that art in this field
`
`is “high.” ID, 25.
`
`V. Claim construction
`
`27.
`
`In the related ’435 patent IPR, the Board construed “Nucleic Acid
`
`Lipid Particle” as “a particle that comprises a nucleic acid and lipids, in which
`
`the nucleic acid may be encapsulated in the lipid portion of the particle.”
`
`EX1022, 10-13. While I understand that the Board applied the “broadest
`
`reasonable interpretation” standard in the ’435 patent IPR, it noted that it was
`
`“construing this claim term when read in light of the Specification of the ’435
`
`patent ….” Id. I agree with the Board’s reasoning therein and agree that this is
`
`also the appropriate construction given the disclosures in the ’435 patent and
`
`file history as understood by a POSITA at the time.
`
`28. Given the same specification and claim language in the instant
`
`proceeding, it is my opinion that the term should receive the same construction
`
`here. See EX1001, 11:4-12.
`
`29. Patent Owner and Dr. Thompson argue for the same construction
`
`that the Board rejected in the ’435 patent IPR. See Resp., 9 (“… necessarily
`
`including a nucleic acid encapsulated in the lipid portion of the particle,
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`thereby protecting it from enzymatic degradation.”). The Board soundly
`
`rejected this argument (see EX1022, 11-13). I agree with the Board’s rejection
`
`and the reasoning stated therein.
`
`30. Patent Owner and Dr. Thompson argue that the Board’s ’435
`
`patent construction of this term “would encompass an empty lipid particle.”
`
`Resp., 10; EX2031, ¶¶32-33. This is not accurate as the claims also require a
`
`nucleic acid payload to be included as part of the particle. See EX1001, cl. 1.
`
`31.
`
`In addition, the specification states “[t]he lipid particles and
`
`compositions of the present invention may be used for a variety of purposes,
`
`including the delivery of associated or encapsulated therapeutic agents to
`
`cells, both in vitro and in vivo.” EX1001, 6:20-23 (emphasis added). A
`
`POSITA would understand that “associated” as quoted is different from
`
`“encapsulated” and encompasses particles in which the nucleic acid is not
`
`within the interior of the particle and/or surrounded by lipids.
`
`32. For example, it was known in the art at the time of the ’069 patent
`
`that the extent to which a nucleic acid is surrounded by lipids depends on the
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`amount of nucleic acid and lipid used in the preparation, and the ratio of
`
`positive charges from the cationic lipids relative to anionic charges from the
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`nucleic acid (the “N/P ratio”). For example, in many systems at low N/P ratios
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`containing comparatively less lipid, it was known that the probability of
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`encasement of nucleic acids within a lipid barrier was reduced as compared to
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`the situation at higher N/P ratios.
`
`33. Furthermore, the term “encapsulation” is defined in the ’069
`
`patent as protection from degradation by nucleases (EX1001, 22:63-23:13), but
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`it was well known that binding to many cations, e.g., polylysine, resulted in
`
`nuclease resistance and reduced dye staining even though such polymers do not
`
`contain an internal volume and structure that would be capable of physically
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`surrounding the nucleic acid.
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`34. Patent Owner relies on a passage of the ’069 patent stating
`
`“nucleic acids, when present in the lipid particles of the present invention, are
`
`resistant in aqueous solution to degradation with a nuclease.” See EX1001,
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`11:42-55. There are several methods of protecting different types of nucleic
`
`acids from degradation that were known in the art and do not involve
`
`encapsulation, including chemical synthesis with modifications to prevent
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`degradation as described for ribozymes in the ’069 patent. Id., 44:33-35; see
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`also EX1005, ¶20 (“The use of chemically-modified siNA improves various
`
`properties of native siRNA molecules through increased resistance to nuclease
`
`degradation in vivo, improved cellular uptake, and improved pharmacokinetic
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`properties in vivo.”). Patent Owner’s arguments ignore these disclosures.
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`35. As the Board determined in the ’435 patent Final Decision, the
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`portions of the prosecution history cited by Dr. Thompson address a SNALP,
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`which is but one example of a nucleic-acid lipid particle. See EX1022, 12
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`(“For instance, the ’435 patent identifies a ‘stable nucleic acid-lipid particle’ or
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`SNALP as an example of a ‘nucleic acid-lipid particle,’ see, e.g., Ex. 1001,
`
`3:38–39 (stating ‘nucleic acid-lipid particle (e.g., SNALP)’), 3:47–48, 3:57–58,
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`4:4–8, 4:12–13, 4:17–19, 27:43–45, and the term ‘nucleic acid-lipid particle’ is
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`broader than a SNALP.’”).
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`36. Patent Owner and Dr. Thompson’s argument that the scope of the
`
`relevant art excludes references addressing lipoplexes (see, e.g., Resp. at 5, 44,
`
`56-57; EX2031, ¶¶153-157) is misplaced and ignores express disclosures in the
`
`’069 patent and prior art.
`
`37. As discussed above, the ’069 patent claims are not limited to
`
`SNALPs, which are identified as but one example of the claimed nucleic acid-
`
`lipid particles. See, e.g., EX1001, 3:27-28 (“In certain embodiments, the
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`nucleic acid-lipid particle (e.g., SNALP) comprises ….”). A POSITA would
`
`understand that lipoplex and liposomal structures existed at the time of the ’069
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`patent that meet the additional claim limitations.
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`38. A POSITA at the time of the ’069 patent working with SNALPs,
`
`liposomes, or lipoplexes, would also regularly look at research and publications
`
`regarding other types of lipid carrier particles to inform their work. Indeed, the
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`’069 patent specifically references prior work done with types of carrier
`
`particles other than SNALPs. See, e.g., EX1001, 59:28-32 (“One sizing
`
`method, used for liposomes and equally applicable to the present particles
`
`….”), 63:31-33 (referencing liposome sterilization techniques). The ’069 patent
`
`also incorporates the ’618 patent by reference. EX1001, 12:51-64. The ’618
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`patent is directed at polynucleotide lipid complexes (i.e., lipoplexes). See
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`EX1017, 30:22-41.
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`39. Further, a 2005 article published by the inventors on their work
`
`with SNALPs specifically cites to prior work done with other types of carrier
`
`particles, including liposomes and lipoplexes. See, EX1011, 277 (citing to prior
`
`work with fusogenic phospholipids in lipoplexes to inform research on
`
`SNALPs), 286-287 (multiple lipoplex and liposome research papers cited in
`
`the references as supporting various informative propositions). This confirms
`
`my opinion.
`
`40. My own work in the field also supports looking at research for
`
`different types of lipid carrier particles to help inform further particle
`
`development. My graduate course in liposome-mediated drug delivery traces
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`the origins of many of the lipid-carrier particle concepts described in the ’069
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`patent (i.e., three-dimensional structure, PEGylation, and endosomal escape)
`
`from their initial use in liposomes up to their use in cationic lipid nanoparticles
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`for use in siRNA delivery. In my opinion, it is irrefutable that these
`
`fundamental phenomena were established in the 1980s (when I was in graduate
`
`school), later applied to gene delivery using liposomes and lipoplexes, and
`
`ultimately co-opted for the development of siRNA delivery vehicles.
`
`41.
`
`I thus agree with Dr. Janoff that a POSITA would have been
`
`motivated to combine earlier teachings regarding liposomes and lipoplexes
`
`(e.g., Lin (EX1006) and Ahmad (EX1007)) with the teachings of either the
`
`’189 publication (EX1004) or the ’196 PCT (EX1003).
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`VI. THE INSTITUTED GROUNDS
`
`42. Based upon the evidence presented, it is my opinion that
`
`Petitioner has demonstrated that claims 1-22 of the ’069 patent are invalid by a
`
`preponderance of the evidence. Each of the cited prior art references discloses
`
`nucleic acid-lipid particles with the four claimed lipid components and
`
`formulated with overlapping ranges for each of the lipid components. See
`
`EXS1003-1005. Patent Owner and Dr. Thompson’s arguments to the contrary
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`do not change my opinion.
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`43. Patent Owner relies on arguments directed at the claimed range
`
`for the phospholipid and cholesterol components. Response, 14, 17. There does
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`not appear to be anything special or critical about the claimed ranges for these
`
`components (i.e., phospholipid 4-10 mol%, cholesterol 30-40 mol%). EX1001,
`
`cl. 1. The lipid components are generally added as a bilayer stabilizing
`
`component or to provide rigidity to the lipid carrier particle. Generally, the
`
`concentrations of these lipids can be varied within reason with less impact on
`
`particle performance. For example, a POSITA would not expect a particle with
`
`11 mol% phospholipid versus 10 mol% in the claims or 41 mol% cholesterol
`
`versus 40 mol% as in the claims to behave differently in any impactful way.
`
`A.
`
`An Overlapping Phospholipid Range Is Disclosed
`
`44. Both prior art reference discloses a non-cationic lipid range of 5-
`
`90%. EX1003, [0091]; EX1004, [0152]; EX1005, [0313]. In addition, each
`
`reference discloses a narrower range for the non-cationic lipid that also
`
`overlaps with the claimed range. EX1003, [0091] (20-85%); EX1004, [0152]
`
`(30-70%); EX1005, [0313] (20-85%).
`
`45. Each reference identifies a phospholipid as one of the species that
`
`can be used in the disclosed lipid-carrier particles. EX1003, [0089]; EX1004,
`
`[0159]; EX1005, [0455]. I agree with the Board’s reasoning that an
`
`overlapping range of phospholipids is thus disclosed to a POSITA in the prior
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`Case No. IPR2019-00554
`U.S. Patent No. 8,058,069
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`art references. See ID, 22-24 (Phospholipid disclosed (’196 PCT/’189
`
`publication)), 36-37 (same for ’554 publication).
`
`46. Patent Owner and Dr. Thompson argue that no range for a
`
`phospholipid is disclosed, because a phospholipid is just one type of potential
`
`non-cationic lipid. Response, 13-17; EX2031, ¶¶40-41. First, the prior art
`
`disclosures would have put a POSITA on notice that a phospholipid could be
`
`used in the disclosed carrier particles in the ranges cited above, even if it is
`
`only one potential non-cationic lipid species. Second, these arguments ignore
`
`the further disclosures in the working examples of each prior art reference
`
`discussed below.
`
`47.
`
`In its Final Decision, the Board in the ’435 patent IPR found that
`
`there was no “particular range for the phospholipid [in the prior art] that
`
`overlaps the range required” in the ’435 patent claims. EX1022, 35. Patent
`
`Owner and Dr. Thompson offer similar arguments here. See, e.g., Resp. 2;
`
`EX2031, ¶¶38-58. I understand that the question is what a POSITA reading the
`
`reference would understand. Any argument that a POSITA would not be put on
`
`notice that a phospholipid could be used in the disclosed carrier particles in the
`
`ranges is contrary to the patentee’s statements in the ’069 patent file history
`
`(EX1016) and is not consistent with what a POSITA would understand having
`
`read the prior art and intrinsic record.
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`U.S. Patent No. 8,058,069
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`48. The prosecution history confirms the disclosure of overlapping
`
`ranges for each lipid component. During the prosecution of the ’069 patent, the
`
`Examiner cited Protiva’s earlier ’910 publication as prior art. EX1016, 5-6. The
`
`Examiner pointed to ¶85 of the ’910 publication to support disclosure of
`
`overlapping range for each of the four lipid components: “MacLachlan teaches
`
`particles formulated with ranges of amounts that overlap with the instantly
`
`claimed ranges….” Id.
`
`49. Patentee did not dispute the Examiner’s understanding and,
`
`indeed, put for the chart below identifying the prior art disclosed ranges for
`
`each lipid component (including the phospholipid):1
`
`
`
`As can be seen, a phospholipid range of 5-90 mol% is indicated.
`
`50. The disclosures in the ’910 publication at ¶85 are substantively
`
`identical to the disclosures in Protiva’s later disclosures cited as prior art in this
`
`proceeding. See, e.g., EX1004, ¶152. Reading the file history, a POSITA
`
`
`1 I note that the patentee did not decrease to the range of the phospholipid to
`accommodate the presence of cholesterol in the chart including in the file history.
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`U.S. Patent No. 8,058,069
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`would thus understand the cited prior art to disclose an overlapping range for
`
`the phospholipid (and the other lipid components as well).
`
`B.
`
`The Same Four Lipid-Component Carrier Particles Are
`Disclosed
`
`51. Patent Owner and Dr. Thompson’s argument that “[t]he petition
`
`separately parses the claimed amounts of cationic lipids, conjugated lipids, and
`
`non-cationic lipids from the references, without regard to one another”
`
`(Response, 27) is misplaced.
`
`52. Each prior art reference describes lipid carrier particles with the
`
`four lipid components claimed in the ’069 patent (i.e., a cationic lipid,
`
`phospholipid, cholesterol and conjugated lipid). EX1003 [0088]-[0093];
`
`EX1004, [0152]; EX1005 [0313]. I agree with Dr. Janoff and the Board in its
`
`initial determination that EXS1003-1005 disclose overlapping ranges for each
`
`of these lipid components. ID, 16-18 (’196 PCT), 18 (’189 publication), 34-36
`
`(’554 publication); Janoff Decl. ¶¶92-99. A chart is included below
`
`summarizing the disclosed ranges:
`
`
`
`’196
`’189
`
`’554
`
`Cationic Lipid
`
`2-60% [0088]
`2-60% [0152]
`
`2-60% [0313]
`
`Non-Cationic
`Lipid
`5-90% [0091]
`5-90% [0152]
`
`Conjugated Lipid
`
`0.5-25% [0093]
`0.5-20% [0152]
`
`5-90% [0313]
`
`1-20% [0313]
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`53. Each reference also specifically discloses that the non-
`
`cationic/neutral lipid can be a mixture of a phospholipid and cholesterol.
`
`EX1003, [0090], EX1004, [0159].EX1005, [0443]. A POSITA would
`
`understand the following ranges to apply when a phospholipid/cholesterol are
`
`present using simple math to deduce the low point of the disclosed cholesterol
`
`range (in each case 20%) from the highpoint and low points of the non-cationic
`
`lipid range to determine the range for the phospholipid:
`
`
`
`
`
`’196
`
`’189
`
`’554
`
`Cationic
`Lipid
`2-60%
`[0088]
`
`2-60%
`[0152]
`2-60%
`[0313]
`
`Non-Cationic
`Lipid
`0-70% [0091]
`
`Cholesterol
`
`20-45% [0091]
`
`Conjugated
`Lipid
`0.5-25% [0093]
`
`0-70% [0152]
`
`20-55% [0152]
`
`0.5-20% [0152]
`
`0-70% [0313]
`
`20-45% [0313]
`
`1-20% [0313]
`
`54. A POSITA would understand that individual lipid components in
`
`the prior art references are meant to be combined in the ranges of
`
`concentrations disclosed for each lipid to create the carrier particles. In other
`
`words, as with the ’069 patent, a POSITA would consider it appropriate to
`
`combine lipid components, using a point in the disclosed range for each
`
`component, to create carrier particles. A POSITA would have understood that
`
`if you increase the percentage of one lipid component, the remaining
`
`components have to decrease accordingly. Thus, the mathematical analysis that
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`Case No. IPR2019-00554
`U.S. Patent No. 8,058,069
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`Dr. Janoff and the Board conducted in the ID to determine various lipid
`
`percentages was well within the understanding of a POSITA.
`
`55. The four lipid component particles in each prior art reference
`
`including a cationic lipid, phospholipid, cholesterol and conjugated lipid are
`
`not theoretical. Each reference includes actual example formulations tested
`
`with such four-lipid component systems. For the four lipid component particles
`
`tested in the ’196 PCT, the formulation were 15/55/20/10
`
`(cationic/phospholipid/cholesterol/conjugated). See, e.g., EX1003, [0223]. For
`
`the four lipid component particles tested in the ’189 Publication, the
`
`formulation were 30/20/48/2 (cationic/phospholipid/cholesterol/conjugated) or
`
`40/10/48/2. EX1004 (Examples 13-17). For the four lipid component particles
`
`tested in the ’554 Publication, the formulations were 48/40/10/2, 30/20/48/2, or
`
`50/20/28/2. See, e.g., EX1005, Table IV (L051, L053, L054, L069, L077,
`
`L080, L082, L083, L109). Each of these examples are consistent with the
`
`ranges that I outlined in the charts above for four lipid component particles.
`
`The prior art thus expressly spells out the lipid components combined as in the
`
`’069 patent claims to a POSITA.
`
`C.
`
`Lipid-Carrier Particles Are Amenable To Routine
`Optimization
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`Moderna Ex 1020-p. 22
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`IPR2019-00554
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`Case No. IPR2019-00554
`U.S. Patent No. 8,058,069
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`56. Patent Owner and Dr. Thompson argue that the field involves
`
`complex technology and significant unpredictability. See, e.g., Resp. 12, 19-24;
`
`EX2004, ¶¶57-59, 136. I do not disagree with this general statement. For
`
`example, the claims encompass all nucleic acid payloads, cationic lipids, non-
`
`cationic lipids, and conjugated lipids. A POSITA would expect significant
`
`changes to the particle formulations like varying the payload (e.g., from a small
`
`siRNA to a large plasmid), the cationic lipid (e.g., from an ionizable cationic
`
`lipid to a non-ionizable cationic lipid), or the phospholipid (e.g., from a
`
`fusogenic phospholipid like DOPE to a stabilizing phospholipid like DSPC)
`
`would impact the effectiveness of a specific lipid composition. This is my
`
`understanding of what Dr. Janoff referred to in his declaration. See Janoff Decl.
`
`¶¶65-66.
`
`57. Howe
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