Paper No. ___
`Filed: April 20, 2020
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________________
`
`MODERNA THERAPEUTICS, INC.,
`Petitioner,
`
`v.
`
`ARBUTUS BIOPHARMA CORPORATION
`Patent Owner.
`
`—————————————————
`Case IPR2019-00554
`Patent No. 8,058,069
`_____________________________
`
`PATENT OWNER’S NOTICE OF OBJECTION TO
`DEMONSTRATIVE EXHIBITS
`
`
`
`
`Filed: April 20, 2020
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________________
`
`MODERNA THERAPEUTICS, INC.,
`Petitioner,
`
`v.
`
`ARBUTUS BIOPHARMA CORPORATION
`Patent Owner.
`
`—————————————————
`Case IPR2019-00554
`Patent No. 8,058,069
`_____________________________
`
`PATENT OWNER’S NOTICE OF OBJECTION TO
`DEMONSTRATIVE EXHIBITS
`
`
`
`
`
`
`
`I.
`
`INTRODUCTION
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`Pursuant to the Board’s trial hearing order (Paper 32, 4), Arbutus Biopharma
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`Corporation (“Patent Owner”) submits the following objections to Moderna
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`Therapeutics, Inc. (“Petitioner”)’s demonstrative slides, and any reference to or
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`reliance on the foregoing by Petitioner. The demonstrative slides are objected to
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`under FRE106, 401, 403, and 705. Further non-limiting discussion is provided
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`below and is meant to illustrate the objectionable content.
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`II. OBJECTIONS
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`1.
`Slides 5 and 29
`Slides 5 and 29 are improper as irrelevant to the obviousness inquiry – the
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`’910 publication is not a grounds reference. FRE106, 401, 403. Additionally, the
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`documents are incomplete and more prejudicial than probative. The slide 5
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`depiction of an Examiner’s Office Action rejection in view of the ’910 publication
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`reflects an incomplete record. FRE106. Slide 29 presents only a portion of Fig. 23.
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`Petitioner fails to mention that the Office Action challenges were overcome during
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`prosecution or that the ’910 publication specifically identifies the 30mol% cationic
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`lipid concentration as the best concentration and that all subsequent in vivo testing
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`was limited to formulations having 30% or less cationic lipid. EX1015 ¶¶335, 337-
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`354; see also Surreply, 15-16; EX2043, 12:18-20, 16:6-11, 17:24-19:24.
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`-1-
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`2.
`Slides 6, 7, 53, 55
`These slides are more prejudicial than probative as they falsely represent the
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`1:57 as one single formulation. FRE403. EX1001, 3:45-56 (defining the “1:57
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`formulation” as those including “a cationic lipid comprising from about 52 mol %
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`to about 62 mol % of the total lipid present in the particle”); see also POR, 33-37
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`(detailing the ’069 patent’s testing of multiple 1:57 formulations); EX2008.
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`3.
`Slides 10 and 11
`It was Petitioner’s witness, Dr. Janoff – not Patent Owner – that testified for
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`limiting the claimed invention to SNALPs. EX2001, 118:19-119:4, 119:9-17,
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`120:5-6, 121:14-25. In the ’739 IPR, the Board confused Dr. Janoff’s interpretation
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`with the more tempered construction advanced by Patent Owner. Slides 10 and 11
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`are thus irrelevant and more prejudicial than probative. FRE401, 403
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`4.
`Slide 14
`Slide 14 is an incomplete representation of the cited evidence, and is more
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`prejudicial than probative. FRE401, 403. Dr. Janoff’s initially proffered definition
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`in his ’739 IPR declaration (referenced in Slide 14) was rejected at institution in
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`the ’739 IPR and abandoned by Petitioner. During cross-examination, Dr. Janoff
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`repeatedly testified that the claimed particle of the ’739 IPR should be defined as a
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`SNALP. EX2001, 118:19-119:4, 119:9-17, 120:5-6, 121:14-25; see also POR, 10.
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`-2-
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`5.
`Slide 21
`To the extent Petitioner relies on slide 21 as supporting a phospholipid range
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`of 5 mol % to about 90 mol %, it is irrelevant to the challenge advanced in the
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`petition materials. FRE401. Petitioner never presented such an invalidity theory in
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`the petition. Rather, the petition alleged that one might arrive at phospholipid
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`ranges of 0-19.5% and 0-19% after making a series of assumptions. Pet. 39, 54.
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`Indeed, paragraph [0152] of the ’189 publication as shown on slide 21 was never
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`relied upon in the petition.
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`6.
`Slides 22, 24, 26
`These slides are irrelevant to the instituted grounds and are more prejudicial
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`than probative. FRE401, FRE 403. The petition never argued that the 2:40
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`formulation was a starting point for optimization. Tellingly, slides 22, 24, and 26
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`do not offer any citations to the petition and instead only point to the reply, where
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`such arguments were first introduced.
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`7.
`Slide 27
`The content of this slide is irrelevant to establishing prima facie obviousness
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`– the ’069 patent is not prior art against itself. FRE401. Thus, to the extent that
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`any relevance is attributed to slide 27, it supports the criticality of the claimed
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`range and the validity of the ’069 patent.
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`-3-
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`8.
`Slide 28
`Slide 28 is irrelevant to the obvious inquiry in the manner submitted.
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`FRE401. WO2010088537 is not a reference for any of the instituted grounds.
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`Indeed, it is not prior art to the ’069 patent at all. To the extent that the reference is
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`relied upon, it demonstrates post-filing data reflecting criticality of the claimed
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`range. See also POR, 37-43; Surreply, 3.
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`9.
`Slide 30
`Slide 30 is a yet another new, attorney-generated graphical representation of
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`unsubstantiated argument of a fabricated “trend.” Petitioner’s own witness, Dr.
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`Anchordoquy, conceded that there were “hundreds, if not thousands” publications
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`existing before the time of invention – none of which are identified on slide 30.
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`EX2043, 29:25-30:4, 30:25-31:7; Surreply, 15. Further, Petitioner plots for the
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`time on slide 30 an additional datapoint for the year 2008, presumably based on the
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`’069 patent itself. Slide 30 is thus an incomplete and prejudicial depiction of the
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`state of the art and, as a further extension of new arguments asserted in reply, has
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`no relevance to the invalidity theories presented in the petition. FRE106, 401, 403.
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`10.
` Slide 31
`The new assertion of a “trend” to “keep PEG low” was never presented in
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`the petition or in any of Petitioner’s briefings. Slide 31 is thus irrelevant to the
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`obviousness theories advanced in the petition materials. FRE401. Slide 31
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`mischaracterizes the very evidence it cites, rendering slide 31 more prejudicial than
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`probative. FRE403. Paragraph 98 as depicted in slide 31 cites to EX1024, which
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`describes conjugated lipids at 10% concentrations – far higher than the ranges
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`claimed in the ’069 patent. EX1024, 22 (citing Judge, EX2042, 335).
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`11. Slide 32
`Slide 32 is an incomplete document as it omits Dr. Thompson’s extensive
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`testimony and corroborating evidence that higher PEG concentrations (e.g., 5-
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`10%) were typical. EX2031, ¶¶48-49; EX1025, 57:1-7, 62:3-6, 132:9-133:23,
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`175:3-13; FRE106.
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`12. Slide 33
`Slide 33 is irrelevant to the instituted grounds, as Petitioner has never argued
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`that there is a trend for including non-cationic lipids. FRE401. To the contrary,
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`Petitioner cited submitted numerous references, each at most describing non-
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`cationic lipids (e.g. phospholipids or cholesterol) as non-required, optional
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`components. EX1005, ¶¶12, 120 (conjugated lipid optional), ¶¶97-115 (cholesterol
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`optional), ¶92 (neutral lipid is optionally a phospholipid); EX1004, ¶150
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`(conjugated lipid optional), ¶152 (cholesterol optional), ¶79 (non-cationic lipid is
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`optionally a phospholipid); see also Surreply, 14.
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`13. Slide 34
`Slide 34 is irrelevant as an argument that was never advanced in the petition
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`materials and lacks supporting evidence. FRE401. Petitioner has failed to present
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`-5-
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`
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`any meaningful discussion or evidence regarding an “accepted cholesterol range”
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`or any motivation for using the range identified on slide 34.
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`14. Slide 35
`Presenting new arguments, slide 35 is irrelevant and more prejudicial than
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`probative. FRE106, FRE403. The petition materials never argued that there is an
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`“accepted phospholipid range.” Indeed, slide 35 reflects Petitioner’s ever evolving
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`position on the purported phosphide range taught by the prior art. Surreply, 9-20.
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`The petition argued making a series of assumptions to arrive at phospholipid
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`ranges of 0-19.5 mol% and 0-19 mol%. Pet. 39, 54. The reply changed tack,
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`conflated non-cationic lipids with phospholipids and advanced a range of 5-90
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`mol%. Reply, 5. Now, for the first time in this proceeding, slide 35 alleges a
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`phospholipid range of 0-70 mol%.
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`15. Slide 37
`The newly annotated figures from Lin and Ahmad are erroneous and
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`incomplete documents, and prejudicial as they mischaracterize the results reported
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`in those references. FRE106, FRE403. In contrast, both references describe
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`transfection efficiency plateauing below 50 mol%. EX1006, 3315; EX1007, 740.
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`Further, slide 37 omits the more probative evidence of Petitioner’s own witness,
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`Dr. Janoff, testifying that the overall goal of Lin and Ahmad was to reduce the
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`concentration of cationic lipid in formulations. EX2002, 31:7-39:9; see also
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`-6-
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`EX2006, 409:3-19 (“the bottom line message of Lin and Ahmad is how to reduce
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`cationic lipid concentration in a formulation...”), 251:3-22, 252:11-19.
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`16. Slide 38
`The quotations on slide 38 are incomplete writings and prejudicial. FRE106,
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`FRE403. Far more probative are the relevant passages from the ’069 patent
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`expressly distinguishing lipoplexes from lipid particles of the invention. EX1001,
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`2:8-9 (“Cationic liposome complexes are large, poorly defined systems that are not
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`suited for systemic applications”); see also EX2001, 122:1-24 (Dr. Janoff
`
`testifying that lipoplex particles were fundamentally different than those described
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`in the current specification, and outside the scope of the patent); Surreply, 6.
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`17. Slide 44
`Slide 44 advances yet another new argument seeking to locate a
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`phospholipid range, including a new argument that a phospholipid of 0-65 mol%
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`was taught by the ’554 publication, making the slide irrelevant and more
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`prejudicial than probative. FRE401, FRE403; see Objections to Slide 35.
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`18. Slides 47, 48 & 49
`Slides 47, 48, and 49 are irrelevant, lacking in underlying basis, and are an
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`incomplete writing. FRE106, FRE401, FRE403. These slides omit the ’069
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`patent’s disclosure that “the 1:57 SNALP formulation … was the most potent at
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`reducing ApoB expression in vivo” EX1001, 72:21-24. Further, with respect to the
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`error bars, the conclusions drawn on the slides are prejudicial. Dr. Janoff testified
`-7-
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`
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`that his conclusions were based solely on a visual inspect. EX2033, 113:2-8,
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`122:12-123:23 (“Q. That's based on a visual inspection of the figure? A. That's the
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`only thing available to me here.”). Yet, he made clear that he had problems with
`
`his vision. EX2001, 19-25 (“I have difficulty with my eyesight in general now”);
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`see also EX2033, 7:19-8:3. More probative is his testimony that “I have no reason
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`not to believe the data.” EX2033, 104:8-9.
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`Petitioner also mischaracterizes the reported data on these slides. For
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`instance, Petitioner fails to disclose on slide 47 that groups 2, 4, 5, and 7 are also
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`2:40 formulations that were clearly outperformed by the 1:57 formulation of group
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`11. See e.g., EX1001, Table 4, Fig. 2.
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`19. Slide 52
`Slide 52 depicts Dr. Thompson’s testimony regarding the data presented in
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`the ’069 patent itself. Thus, it is irrelevant to the obvious attack advanced in that it
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`is not reflective of a person of ordinary skill in the art’s understanding prior to the
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`invention. FRE401. Further, the quoted passage is incomplete. FRE106. Dr.
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`Thompson’s testimony made clear that cationic lipids were understood to be toxic
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`when administered in vivo. EX2006, 244:6-9 (“It's because the cationic lipid is
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`toxic … It doesn't matter whether it's protonatable or not. It's still toxic.”). Even
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`Petitioner’s own publications provide extensive discussion about the toxicity
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`-8-
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`concerns of ionizable cationic lipids, including DLinDMA. EX2037, 21:10-12;
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`EX2031, ¶86; see also POR, 29-30.
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`20. Slide 56
`Slide 56 presents incomplete testimony and is more prejudicial than
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`probative. FRE106, FRE403. Petitioner omits Dr. Thompson’s testimony regarding
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`a difference in the perspective of a person of ordinary skill before and after the
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`invention’s disclosure. EX2006, 405:5-12 (“Q. Would the perspective of a person
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`of ordinary skill in the art prior to the `435 patent be the same as someone in the
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`field having studied the experimental data presented in the `435 patent? … [A.]
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`The individual or the experimentalist after the `435 patent would benefit from that
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`new knowledge.”). Petitioner’s arguments of unpredictability undermine any
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`belated assertions of routine optimization.
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`21. Slide 57
`Slide 57 is an incomplete document and mischaracterizes Dr. Thompson’s
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`testimony with respect to Figure 2. FRE106, FRE403. Dr. Thompson explained
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`that “Figure 2 is an experiment that is holding ratios of conjugate lipid and cationic
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`lipid constant across a family of cationic lipids for a direct comparison,
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`performance comparison, at keeping of though every -- all variables but cationic
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`lipid type constant.” EX2006, 412:11-15. Thus, the conclusion presented on slide
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`-9-
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`57 misrepresents witness testimony, is more prejudicial than probative, and lacks
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`underlying basis.
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`22. Slides 61
`The conclusory assertions on slide 61 lack underlying basis such as any
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`supporting calculations. FRE705. Slide 51 is also an incomplete representation of
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`the record and conflicts with the testimony of Petitioner’s own witness. E.g.
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`EX2003, ¶33 (Dr. Janoff explaining that “[Patisiran] … contains 50% cationic
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`lipid, 38.5% cholesterol, 10% DSPC and 1.5% PEG”). Further, Petitioner omits
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`Dr. Anchordoquy’s testimony that, even under his calculations, the formulations
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`would produce a population of particles infringing the claims of the ’069 patent.
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`EX2043, 72:24-73:3 (“Q. … with a 50 percent cationic lipid formulation, plus or
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`minus 5 percent variability would give you a range of 45 percent to 55 percent
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`cationic lipid; right? A. Sure”). The conclusions of slide 61 are thus irrelevant to
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`the invalidity arguments presented in the petition, and are more prejudicial than
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`probabtive. Indeed, Petitioner was well-aware of Patent Owner’s arguments with
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`respect to commercial success and chose not to address any of those arguments or
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`supporting evidence in the petition. POPR, 1-2, 10-11; POR, 31 n.4. Accordingly,
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`such arguments are untimely and overly prejudicial.
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`-10-
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`Dated: April 20, 2020
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`
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`Respectfully submitted,
`/ Michael T. Rosato /
`Michael T. Rosato, Lead Counsel
`Reg. No. 52,182
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`-11-
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`CERTIFICATE OF SERVICE
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`This is to certify that I caused to be served a true and correct copy of the
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`foregoing Patent Owner’s Notice of Objection to Demonstrative Exhibits was
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`served on April 20, 2020, on the Petitioner at the correspondence address of the
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`Petitioner as follows:
`
`Michael Fleming
`C. Maclain Wells
`IRELL & MANELLA LLP
`mfleming@irell.com
`mwells@irell.com
`ModernaIPR@irell.com
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`Dated: April 20, 2020
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`Respectfully submitted,
`
`/ Michael T. Rosato /
`Michael T. Rosato, Lead Counsel
`Reg. No. 52,182
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`
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`-12-
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