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. IPR2018-00739
`U.S. Patent No. 9,364,435
`
`___________
`
`DECLARATION OF ANDREW S. JANOFF, PH.D.
`IN SUPPORT OF MODERNA THERAPEUTICS, INC.’S
`PETITIONER’S REPLY TO PATENT OWNER RESPONSE
`
`
`
`
`Mail Stop: PATENT BOARD
`Patent Trial and Appeal Board
`U.S. Patent & Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`
`
`
`
`
`ARBUTUS - EXHIBIT 2003
`Moderna Therapeutics, Inc. v. Arbutus Biopharma Corporation
`IPR2019-00554
`
`
`__________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________
`
`
`Moderna Therapeutics, Inc.
`
`Petitioner
`
`v.
`
`Protiva Biotherapeutics, Inc.
`
`Patent Owner
`___________
`
`
`Case No. IPR2018-00739
`U.S. Patent No. 9,364,435
`
`___________
`
`DECLARATION OF ANDREW S. JANOFF, PH.D.
`IN SUPPORT OF MODERNA THERAPEUTICS, INC.’S
`PETITIONER’S REPLY TO PATENT OWNER RESPONSE
`
`
`
`
`Mail Stop: PATENT BOARD
`Patent Trial and Appeal Board
`U.S. Patent & Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`
`
`
`
`
`ARBUTUS - EXHIBIT 2003
`Moderna Therapeutics, Inc. v. Arbutus Biopharma Corporation
`IPR2019-00554
`
`
`
`Case No. IPR2018-00739
`U.S. Patent No. 9,364,435
`
`TABLE OF CONTENTS
`
`Page
`INTRODUCTION .................................................................................. 1
`I.
`SUMMARY OF OPINIONS .................................................................. 2
`II.
`III. QUALIFICATION AND EXPERIENCE .............................................. 2
`IV. CLAIM CONSTRUCTION ................................................................... 4
`V.
`THE INSTITUTED GROUNDS ............................................................ 4
`VI. CONCLUSION .................................................................................... 12
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`Case No. IPR2018-00739
`U.S. Patent No. 9,364,435
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`
`I.
`
`I, Dr. Andrew S. Janoff, PhD, declare as follows:
`INTRODUCTION
`1. My name is Andrew S. Janoff. I am a consultant in biotechnology
`
`and drug delivery, primarily focusing on lipid and liposome technology. I have
`
`been retained by counsel for Moderna Therapeutics, Inc. (“Moderna”) as an
`
`expert in the relevant art.
`
`2.
`
`I submitted a declaration dated March 5, 2018 in support of
`
`Moderna’s Initial Petition for Inter Partes Review of U.S. Patent No. 9,364,435
`
`(the “’435 patent”) (“Petition”). See EX1007.
`
`3.
`
`On December 21, 2018, Patent Owner Protiva Biotherapeutics,
`
`Inc. (“Patent Owner”) filed its response to Moderna’s Petition (“Response”). I
`
`have been asked to provide additional opinions in response to Patent Owner’s
`
`Response that are relevant to Moderna’s reply. The opinions discussed herein
`
`are my own.
`
`4.
`
`This declaration is based on the information currently available to
`
`me. To the extent that additional information becomes available, I reserve the
`
`right to continue my investigation and study, which may include a review of
`
`documents and information that may be produced, as well as testimony from
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`depositions.
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`U.S. Patent No. 9,364,435
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`II.
`
`SUMMARY OF OPINIONS
`5.
`The Board ordered an IPR over the’435 patent with respect to the
`
`following grounds of unpatentability for claims 1-20:
`
`a)
`
`Under § 103 in view of 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 ’435 patent is directed to a composition of nucleic acid-lipid
`
`b)
`
`c)
`
`6.
`
`particles comprising three lipid components (i.e., cationic lipid, non-cationic
`
`lipid and conjugated lipid), each of which fall within a claimed proportion with
`
`regard to the total lipid in the particles. See, e.g., id., cl. 1. The cited prior art
`
`in Grounds 1-3 renders the claims invalid by a preponderance of the evidence.
`
`III. QUALIFICATION AND EXPERIENCE
`7.
`I possess the knowledge, skills, experience, training and the
`
`education to form an expert opinion and testimony in this case. A detailed
`
`record of my professional qualifications and relevant experience, including a
`
`list of patents and academic and professional publications, is set forth in my
`
`declaration dated March 5, 2018 (EX1007), and my curriculum vitae submitted
`
`therewith (EX1018).
`
`8.
`
`I am being compensated by Moderna for my time spent in
`
`developing this declaration at a rate of $750 per hour, and for any time spent
`
`
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`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.
`
`9.
`
`I have no financial interest in Moderna.
`
`10. My opinion expressed in this declaration are based on the Petition
`
`and exhibits cited in the Petition, Patent Owner’s Response and exhibits cited
`
`in the Response, the exhibits attached to Moderna’s reply to Patent Owner’s
`
`Response, and other documents and materials identified in this declaration,
`
`including the ’435 patent (EX1001) and its prosecution history (EX1016), the
`
`prior art references and materials discussed in this declaration, and any other
`
`references specifically identified in this declaration.
`
`11.
`
`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,
`
`textbooks, manuals, technical papers, articles, and relevant technical
`
`standards).
`
`12.
`
`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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`U.S. Patent No. 9,364,435
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`
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`IV. CLAIM CONSTRUCTION
`13.
`I have reviewed the Board’s preliminary construction of “nucleic
`
`acid-lipid particle” in the Initial Determination 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.” See EX1001, 11:14–22. I agree with this
`
`construction and that it is appropriate.
`
`V. THE INSTITUTED GROUNDS
`14. Based upon the evidence presented, I continue to believe that
`
`Petitioner has demonstrated that claims 1-20 of the ’435 patent are invalid by a
`
`preponderance of the evidence. Each of the cited prior art references disclose
`
`particles formulated with overlapping ranges for each of the lipid components
`
`identified in the ’435 patent. EX1002-1004. In addition, the ’554 publication
`
`created an anticipatory particle with lipid components meeting each of the
`
`claim limitations in claim 1. EX1004, Table IV (L054 formulation).
`
`15.
`
`It was well-known in the prior art that toxicity in nucleic acid-lipid
`
`particles is largely a function of such particles having a net positive charge.
`
`The impact of the amount of cationic lipid on the net charge of the resulting
`
`particles depends, among other things, on whether the cationic lipid carries a
`
`positive charge at physiological pH. To address potential toxicity issues, years
`
`before the ’435 patent priority date, ionizable cationic lipids had been
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`developed whose charge was low or virtually neutral at physiological pH.
`
`EX1003 [0223] (using DLinDMA); EX1010, 280 (same), Fig. 1 (showing
`
`substantially neutral charge at pH 7.4).
`
`16. Because of the low charge of such cationic lipids at physiological
`
`pH, higher concentrations of cationic lipid could be used while maintaining a
`
`substantially neutral (non-toxic) charge in resulting particles. In fact, the prior
`
`art relied on in the Petition evinces such use at high cationic lipid
`
`concentrations. See, e.g., EX1003 [0351-0391] (in vivo testing of 2:40
`
`formulation using DLinDMA), [0076, 0151] (resulting particles “substantially
`
`non-toxic.”).
`
`17. The following language from ’196 PCT is permissive not
`
`required: “for systemic delivery, the cationic lipid may comprise from about 5
`
`mol% to about 15 mol% ....” Resp. 17; EX1002 [0088] (emphasis added). This
`
`range limitation is permissive for good reason. As I explained, it may be
`
`appropriate for certain cationic lipids (e.g., non-ionizable), but unnecessary for
`
`others (e.g., ionizable lipids like DLinDMA).
`
`18. This point is also illustrated in the cited prior art ’189 publication,
`
`which includes the same permissive language regarding the 5-15 mol%
`
`cationic lipid for systemic use. EX1003, [0152]. The ’189 publication also
`
`describes systemic in vivo testing of the 2:40 formulation well above the
`
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`disclosed 5-15 mol% range by using DLinDMA. Id., [0351-0391]. Thus, even
`
`if Patent Owner’s in vivo limitations are imported into the claims, the prior art
`
`still discloses overlapping ranges for cationic lipids when such substantially
`
`non-toxic cationic lipids are used.
`
`19. The following “PEG dilemma” was known in the art: including
`
`enough PEG to stabilize the particle, but not so much that the particle is unable
`
`to engage the target in vivo. In other words, it was known that the amount of
`
`conjugated lipid (e.g., PEG) could be minimized to allow the nucleic acid
`
`payload to interact with the target. Indeed, the formulations tested in the cited
`
`prior art have low amounts of PEG, such as in the 2-3% range, coupled with
`
`high cationic lipid concentrations. Id., [0351-0391] (2:40 formulation in the
`
`’189 patent showing in vivo efficacy with 2% PEG); EX1004, Table IV (L077,
`
`L069, L080, L082, L083, L060, L061, and L051 showed efficacy in vivo with
`
`2-3% PEG).
`
`20. That other systems using higher PEG percentages may have
`
`existed does not negate that a POSITA would have been well aware of the
`
`examples above, in which lower levels of PEG were used.
`
`21. The bilayer stabilizing component actually used in testing in the
`
`’196 PCT and ’189 publications was PEG, the exact same conjugated lipid
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`disclosed and used in the testing in the ’435 patent. See, e.g., EX1003 [0351-
`
`0391] (2% PEG).
`
`22. As the Board noted in the Institution Decision, “[c]laim 1 is a
`
`composition claim with various ranges for the lipid components of the claimed
`
`nucleic acid-lipid particle.” Paper 15, 21; see also EX1001, cl. 1. Each of the
`
`cited prior art references is also directed at nucleic acid-lipid particles made
`
`from common lipid components (e.g., cationic, non-cationic, conjugated) with
`
`a nucleic acid payload. EX1002-EX1004. The 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-just like
`
`the claimed invention. In other words, as with the ’435 patent, a POSITA
`
`would consider it appropriate to combine lipid components, using the disclosed
`
`range for each component, to create a carrier particle.
`
`23. Patent Owner’s argument also fails to acknowledge that the cited
`
`prior art also contains specific examples containing high cationic lipid
`
`concentrations coupled with low PEG percentages. EX1003 [0351-0391] (40
`
`mol% cationic lipid/2 mol% PEG); EX1004, [0408], Table IV (L077, L069,
`
`L080, L082, L083, L060, L061, and L051 with 48-52 mol% cationic lipid and
`
`2-3 mol% PEG). While these specific formulations vary slightly from the
`
`claimed ranges, they do establish the falsity of Patent Owner’s assertion that
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`use of high cationic lipid concentrations coupled with low PEG concentrations
`
`in vivo was not known.
`
`24.
`
`I believe a POSITA would have looked to these examples
`
`showing high cationic lipid concentrations coupled with low PEG percentages
`
`in choosing the upper end of the cationic lipid range and the lower end of the
`
`PEG range when formulating particles. Such selections would be a simple
`
`matter of varying the lipid proportions using prior art methodologies to achieve
`
`optimization. EX1007, ¶110. Given the stated efficacy of the prior art
`
`formulations, I conclude that a POSITA would have expected any such minor
`
`variations to also be effective.
`
`25. While Lin and Ahmad tested lipoplex formulations and the
`
`complicated nature of what affects transfection efficiencies of the CL-DNA
`
`complexes, the testing therein establishes that for certain cationic lipids,
`
`increasing cationic lipid concentrations above 50 mol% increased transfection
`
`efficiency. Id., ¶¶138–139. I believe that this provides further impetus for a
`
`POSITA to choose the upper end of the disclosed cationic lipid range (i.e., 50-
`
`60 mol%) in the ’189 publication and ’554 publication.
`
`26. Ahmad notes that the “toxic effects” are only a mere possibility:
`
`“minimizing the amount of cationic lipid is desirable to reduce cost as well as
`
`potential toxic effects of the cationic lipid.” EX1006, 745 (emphasis added).
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`Ahmad specifically noted that in vitro, the tested cationic lipid amounts
`
`showed “no toxic effects on the cells as judged by cell morphology and the
`
`amount of total cellular protein.” EX1006, 745-46. Because claim 1
`
`encompasses in vitro use, a POSITA would have considered the findings of
`
`Ahmad informative. EX1007, ¶¶138-139. Second, Ahmad was directed at
`
`multivalent cationic lipids, and one of the benefits of such lipids is that less can
`
`be used to attain a certain charge. A POSITA would understand the statement
`
`cited by Patent Owner to be promotional of multivalent cationic lipids, and not
`
`a characterization of all cationic lipids as toxic.
`
`27. The ’554 publication uses input percentages in describing its
`
`formulations as opposed to lipid percentages in the final particles, but that was
`
`accepted practice in the field.
`
`28. The ’554 publication discusses encapsulation. EX1004, [0011],
`
`[0136], [0317] (nanoparticles may include encapsulated nucleic acid), [0400]
`
`(nanoparticles produced using L054 formulation). I believe that a POSITA
`
`would appreciate from these disclosures that encapsulation with the L054
`
`formulation is disclosed.
`
`29. Patent Owner improperly relies on test data that covers only a
`
`small portion of the potential numeric ranges in the claims, and an even smaller
`
`portion of the potential lipid components and payloads used. Given that the test
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`data involves only a limited subset of payloads, lipid components, formulations
`
`and production techniques, the test data is not commensurate with the scope of
`
`the claims.
`
`30. Patent Owner cites to later testing in arguing that “nucleic acid-
`
`lipid particle formulations with cationic lipid in the range of 50 mol% to 70
`
`mol% … [and] eight different cationic lipids were tested and found to be
`
`efficacious and well tolerated.” Resp. 61; EX2009, ¶189. This data does not
`
`cover the portion of the claimed range from 70-85 mol% cationic lipid. Patent
`
`Owner also fails to inform the Board that the testing showed that the 1:57
`
`formulation with several cationic lipids did not perform any better than the
`
`PBS standard. EX2017, Fig. 2; EX1020, 393:21:394:24 (1:57 formulation with
`
`DLinMorph shows no efficacy); EX2018, Figs. 3; EX1021, 401:6-21 (other
`
`cationic lipids using 1:57 formulation “have similar knockdown levels as--as
`
`PBS.”).
`
`31. For long felt need, Patent Owner erroneously points to its “500
`
`person-years and $200M” investments in “SNALP technology.” Resp., 56. But
`
`a significant portion of the investment could be attributable to the work leading
`
`to the Patent Owner’s prior art SNALP disclosures (e.g., EX1002-1003,
`
`EX1010). As another example, Patent Owner points to Roche switching to
`
`“[Patent Owner’s] SNALP liposome.” EX2015, 10. But there is no indication
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`that Roche used the SNALPs of the ’435 patent as opposed to prior art SNALP
`
`systems.
`
`32. Regarding failure of others and skepticism, Patent Owner repeats
`
`its mistaken argument that toxicity favored teaching away. Resp. 56-57. Patent
`
`Owner ignores that prior art cationic lipids were developed that were
`
`substantially non-toxic, e.g., DLinDMA, and that these ionizable cationic lipid
`
`were used in vivo. EX1003, [0351]-[0391].
`
`33.
`
`For commercial success, Patent Owner points to the commercial
`
`product Patisan. Resp. 53. Partisan is not the 1:57 formulation detailed in the
`
`’435 patent; it contains 50% cationic lipid, 38.5% cholesterol, 10% DSPC and
`
`1.5% PEG. EX2009, ¶192. Patent Owner asserts that there is a presumed nexus
`
`because the product “is the invention disclosed and claimed in the patent.”
`
`Resp., 53. But each of the cited prior art references disclose particles with lipid
`
`ranges including these concentrations. EX1002, [0088] (cationic lipid), [0091]
`
`(non-cationic lipid), [0092-0093] (conjugated lipid); EX1003, [0152]; EX1004,
`
`[0116] (cationic lipid), [0313] (non-cationic lipid), [0118] (conjugated lipid).
`
`Moreover, much of the alleged evidence of secondary considerations relates to
`
`the siRNA payload, not the delivery vehicle. EX2023-2025 (first in class
`
`siRNA therapeutic). I believe Patent Owner also fails to detail any actual
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`success of the Partisan product, claiming only that it is subject to royalties. See
`
`Resp., 61.
`
`34. Given the lack of sufficient nexus to the claimed ranges and scope
`
`of the prior art, I conclude that a POSITA would consider Patent Owner’s
`
`evidence of non-obviousness to be insufficient to overcome the strong
`
`obviousness showing.
`
`35. Regarding the dependent claims, as with the ’435 patent, a
`
`POSITA would consider it appropriate to combine the disclosed ranges for
`
`each lipid component and various listed lipid components in determining the
`
`particle formulations.
`
`VI. CONCLUSION
`36.
`In sum, it is my opinion that Grounds 1-3 advanced in the Petition
`
`demonstrate that the challenged claims of the ’435 patent are disclosed or
`
`rendered obvious by the cited prior art by a preponderance of the evidence.
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`I hereby declare that all statements made herein of my own knowledge
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`are true and that all statements made on information and belief are believed to
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`that be true; and furt her that these statements were made with the knowledge
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`willful false statements and the like so made are punishable by fine or
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`
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`1001 of the Title 18 of the United States imprisonment, or both, under Section
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`
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`Code.
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`
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`Executed on March 22, 2019 in Princeton, NJ.
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