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`Paper No. ___
`Filed: March 31, 2020
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`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 SUR-REPLY
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`TABLE OF CONTENTS
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`Page
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`INTRODUCTION .......................................................................................... 1
`I.
`CLAIM CONSTRUCTION ........................................................................... 4
`II.
`III. DR. ANCHORDOQUY IS NOT A QUALIFIED EXPERT ......................... 6
`IV. PETITIONER ABANDONS ANTICIPATION ............................................ 8
`V.
`THE PETITION FAILS TO DEMONSTRATE THE
`OBVIOUSNESSS OF THE CLAIMS ........................................................... 9
`VI. PETITIONER’S NEWLY ADVANCED OBVIOUSNESS
`THEORIES ALSO FAIL ................................................................................ 9
`A. An Overlapping Phospholipid Range is NOT Disclosed ................... 10
`B.
`Petitioner’s Belated Assertions of Routine Optimization .................. 12
`1.
`Petitioner Invalid Assumption of Four Lipid
`Component Systems ................................................................. 13
`Petitioner’s Spurious Assertion of a “Trend”
`Toward Increased Cationic Lipid ............................................ 15
`Petitioner’s New N/P Ratio Argument is an
`Irrelevant Distraction ............................................................... 16
`The Conjugated Lipid Range was Not Obvious ...................... 19
`The Claimed Cholesterol Range Was Not Obvious ................ 20
`Petitioner fails to establish the claimed
`phospholipid concentration was obvious ................................. 20
`VII. EXPERIMENTAL TESTING FURTHER CONFIRMS THE
`PATENTABILITY OF THE CLAIMS ........................................................ 21
`VIII. BELATED ATTACKS ON OBJECTIVE INDICIA ARE
`UNFOUNDED AND UNAVAILING ......................................................... 24
`IX. CONCLUSION ............................................................................................. 26
`X. APPENDIX – LIST OF EXHIBITS ............................................................. 28
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`2.
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`3.
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`4.
`5.
`6.
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`I.
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`INTRODUCTION
`The Reply is largely an untimely attempt to cure deficiencies identified in
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`the Patent Owner Response (POR). Consolidated Trial Practice Guide, 73
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`(“Petitioner may not submit new evidence in reply that it could have presented
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`earlier, e.g. to make out a prima facie case of unpatentability.”s); Intelligent Bio-
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`Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1369 (Fed. Cir. 2016)
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`(“Unlike district court litigation… the expedited nature of IPRs bring with it an
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`obligation for petitioners to make their case in their petition to institute.”).
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`Much of the Reply relies on attacking arguments Patent Owner (“PO”) never
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`made, mischaracterizing the deposition testimony of PO’s expert, and blatantly
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`ignoring detrimental testimony from Petitioner’s first expert. Beyond that, the
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`Reply newly attempts to overstate the importance of irrelevant parameters (e.g.,
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`N/P ratio), fabricate “trends,” and falsely argue non-toxic cationic lipids. These
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`arguments not only lack any supporting evidence, but are contradicted by the
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`references of record, including Petitioner’s own publications.
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`First, Petitioner’s anticipation charge is unaddressed in the Reply, and now
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`appears abandoned.
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`As to Petitioner’s obviousness assertions, PO’s Response (“POR”) (e.g., 2-4,
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`11-31) laid out in detail how Petitioner failed to substantiate the “routine
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`optimization” rationale at the heart of the cited Peterson and du Pont cases—i.e.,
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`the only obviousness theory identified in the petition and instituted by the Board
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`under SAS. E.g., Pet. 31-33, 38-40, 54, 56-59; Decision on Institution (“DI”), 24-
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`27, 35-37. In fact, up until the Reply, Petitioner and its expert, Dr. Janoff, agreed
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`on the inapplicability of routine optimization. The petition materials, presumably
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`concerned by extensive experimental testing reported in the ’069 patent, embraced
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`the complexity of the technology and argued wild unpredictability. During cross-
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`examination, Petitioner’s expert witness repeatedly testified the prior art lipid
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`ranges are “immense” and “would require undue experimentation, not simple
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`optimization.” EX2033, 60:5-16; 42:7-10; 19:25-20:15; POR 4, 19-27. As
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`explained in the POR, Dr. Janoff was correct in this regard, undermining the ill-
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`conceived obviousness case in the petition.
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`With the deficiencies in the petition case laid bare, Petitioner belatedly
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`attempts to cure them—ignoring the evidence and testimony of its own witness
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`entirely and now asserting “routine optimization.”1 Even if this untimely argument
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`is entertained, it can be rejected on the merits for at least the reasons set forth
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`1 Even in Reply, Petitioner continues its erratic oscillation on this point. While
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`now arguing routine optimization, Petitioner returns to embracing complexity and
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`unpredictability when attacking the extensive experimental testing. E.g., Reply 24-
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`25; compare EX2006, 405:5-12.
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`below. The evidence is overwhelming — achieving the nucleic acid-lipid particles
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`of the ’069 patent was not a matter of routine optimization.
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`To the extent any prima facie case of obviousness was established by
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`identification of overlapping lipid ranges in the art, that case is rebutted by the
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`extensive experimental data in the ’069 patent and numerous post-filing
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`publications showing unexpected results, including Petitioner’s own publications.
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`As corroborated in the literature (and unrebutted by Petitioner), high-level cationic
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`lipid formulations (e.g., 50-65% cationic lipid) would have been expected to have
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`relatively poor in vivo activity and elicit increased toxicity and immunogenicity
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`compared to lower-level cationic lipid formulations. EX1006, 3315; EX1007, 745;
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`EX1009, E96; EX2009, 30:34-41.
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`PO, however, found that the claimed formulations surprisingly impart
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`increased activity of the nucleic acid payload and improved tolerability of the
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`formulations in vivo, resulting in a significant increase in the therapeutic index.
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`POR, 31-42. Moreover, the claimed formulations are stable in circulation and are
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`substantially non-toxic when administered to mammals. These surprising results
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`are different in kind, and the Reply fails to demonstrate otherwise.
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`As such, when all the evidence of record is weighed and considered,
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`Petitioner fails to meet its burden of demonstrating the unpatentability of the
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`claims by a preponderance of the evidence, and the patentability of the claims
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`should be affirmed.
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`II. CLAIM CONSTRUCTION
`No claim construction is necessary in order to determine that the Petition
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`fails. The petition (23) offered no claim construction analysis, just the conclusory
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`assertion that the claims should be construed as in the DI in IPR2018-00739 under
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`a different claim construction standard—that is, “a particle that comprises a nucleic
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`acid and lipids, in which the nucleic acid may be encapsulated in the lipid portion
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`of the particle.” See also EX1008, ¶88 (same). It ignored the specification and the
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`prosecution history (including in IPR2018-00739) entirely, which is particularly
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`pertinent under the different Phillips standard. The petition materials failed to
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`satisfy the basic requirements of petition content. See 37 C.F.R. §42.104 (requiring
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`analysis of how the claims are to be construed); 35 U.S.C. §312(a)(3).
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`To the extent that the Board is inclined to reach claim construction,
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`Petitioner’s proffered construction of “nucleic acid lipid particle” is not only
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`inconsistent with the specification, but it is unreasonably broad at least in that it
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`encompasses empty particles. POR, 10. Dr. Anchordoquy concedes as much,
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`testifying the term “nucleic acid lipid particle” could not encompass an empty
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`particle because such a reading is excluded by the language of the claim itself.
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`EX1020, ¶30. Indeed, the claimed term is not “lipid particle” but “nucleic acid
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`lipid particle.” POR, 10; EX2031, ¶¶32-33.
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`Moreover, Petitioner’s construction is inconsistent with the prosecution
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`history, which includes the record in IPR2018-00739. See Patent Owner
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`Preliminary Response (“POPR”), 15-17; POR, 9-10; see also IPR2018-00739,
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`Paper 12, 16-17 (same); IPR2018-00739, Paper 24, 11-13 (same). Kakun Pharm.
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`Co. v. Iancu, No. 18-2232, slip. op. at (Fed. Cir. March 23, 2020) (noting that
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`statements by applicant to induce patent grant are particularly helpful); Aylus
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`Networks, Inc. v. Apple Inc., 856 F.3d 1353, 1358 (Fed. Cir. 2017) (holding that
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`statements made during an IPR can be relied on to support prosecution disclaimer).
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`During prosecution, applicants specifically discussed encapsulation as a feature of
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`the claimed particles. EX1016, 38; EX2031, ¶34; POR, 9-10. And as discussed
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`above, encapsulation was extensively argued during IPR2018-00739, with PO
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`expressly arguing that the claims require encapsulation. POR, 9-10. That history
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`clearly reflects the inventors understanding the claims to require encapsulation of
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`the nucleic acid and cannot be ignored.
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`Even if the Board were to consider Petitioner’s argument in Reply after
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`review of the intrinsic record, it would not find in Petitioner’s favor. Petitioner’s
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`new argument in reply is inconsistent with Dr. Janoff’s testimony, which also
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`contradicts testimony from Petitioner’s second witness, Dr. Anchordoquy. Dr.
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`Janoff repeatedly testified that the same term “nucleic acid lipid particle”, in view
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`of the same specification as the ’069 patent, should be limited to SNALP, a
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`definition narrower than any construction previously or currently proffered.
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`EX2001, 118:19-119:4, 119:9-17, 120:5-6, 121:14-25. Dr. Janoff additionally
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`testified that lipoplex particles were fundamentally different than those described
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`in the current specification, and outside the scope of the patent. EX2001, 122:1-24.
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`In this regard, his testimony is consistent with the evidence of record. EX1001,
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`2:8-18, 2:50-54 (contrasting lipoplexes); EX2031, ¶¶152-58; EX1025, 13:15-22;
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`EX2009, 2:54-67 (contrasting liposomes and lipoplexes); see also POR, 5, 44.
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`Instead of addressing Dr. Janoff’s testimony and the evidence he cited, Petitioner
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`ignores the evidence and advances, through Dr. Anchordoquy, arguments that rely
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`heavily on lipoplexes. To the extent the new argument in Reply is considered, it
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`can be rejected as contradicted by the evidence of record.
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`III. DR. ANCHORDOQUY IS NOT A QUALIFIED EXPERT
`Dr. Anchordoquy is not a qualified expert in the relevant field and his
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`testimony should be given little, if any, weight. Dr. Anchordoquy is a zoologist,
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`not a lipid chemist with formal training in the subject matter at hand. EX1020, ¶9.
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`Clearly concerned by this new witness’ thin resume, Petitioner staged
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`unprompted and rehearsed questioning during redirect during Dr. Anchordoquy’s
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`recent deposition. EX2043, 77:4-79:25. But that testimony is hardly reassuring.
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`See e.g., EX2043, 77:22-23 (describing his zoology training as broadly
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`encompassing “everything related to animals”); 78:6-14 (testifying he was not in
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`the offered biophysics program);78:13-21; 79:10-11 (identifying other individuals
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`and lab equipment unrelated to the technology at hand in this proceeding). His
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`prepared remarks during redirect may shed further light on his lack of
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`qualifications but offer no reassurance his declaration testimony should be afforded
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`any meaningful weight.
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`Moreover, Dr. Anchordoquy fails to meet Petitioner’s own definition of the
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`ordinary artisan. EX1020, ¶25; DI, 11-12 (discussing the level of ordinary skill in
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`the art). Dr. Anchordoquy cites, as support for his expertise in the field, U.S. Patent
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`No. 7,914,714. EX1020, ¶14. That patent, however, is neither the same nor similar
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`to the technology at issue. Dr. Anchordoquy himself admitted that he has no
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`experience with SNALPs. EX2043, 70:13-14; see also id., 9:24-25 (noting he is an
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`expert in lyophilization). Indeed, it does not seem that Dr. Anchordoquy has any
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`relevant patents or publications at all.
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`In attempt to distract from the short-comings of its own expert, Petitioner
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`spuriously attacks Dr. Thompson as lacking experience with cationic lipids
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`because his current research involves developing polymer lipid carrier particles.
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`Reply, 2-3. This illogical argument is akin to attacking a climate scientist as
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`ignorant of greenhouse gases on the basis she is developing technology to reduce
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`them. Dr. Thompson is currently developing lipid carriers using polymers as a
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`replacement of the more toxic cationic lipids, which he routinely uses as
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`benchmarks in his research. EX1025, 8:19-9:10. Unlike Petitioner's expert, Dr.
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`Thompson has published extensively and has decades of experience with lipid
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`particles (including cationic lipids) and their in vivo delivery. EX1025, 7:19-25:6.
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`The Reply (2-3) attacks Dr. Thompson for citing a 2014 patent (EX2012) in
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`discussing the formulation patisiran (trade name, Onpattro), widely reported in the
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`literature and by the manufacturer (and described by Dr. Janoff) as having “50%
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`cationic lipid, 38.5% cholesterol, 10% DSPC and 1.5% PEG.” EX2003, ¶33. But,
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`the evidence of record is clear, and each of Dr. Thompson (EX2031, ¶¶117-118,
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`134-136), Dr. Janoff (EX2003, ¶33), and Dr. Anchordoquy (EX2043, 71:19-24,
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`72:24-73:3) each agree that the challenged claims encompass patisiran.
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`IV. PETITIONER ABANDONS ANTICIPATION
`The petition (5) asserted that claims 1-22 were anticipated by or obvious
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`over the ’196 PCT, the ’189 publication, or the ’554 publication. The POR (50-55)
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`provided extensive argument as to why the petition failed to demonstrate
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`anticipation of the claimed ranges. The Reply offers no rebuttal evidence or
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`argument, thus PO maintains Petitioner has not shown anticipation of claims 1-22.
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`V. THE PETITION FAILS TO DEMONSTRATE THE OBVIOUSNESSS
`OF THE CLAIMS
`As discussed in the POR, the Petition did not address whether the POSITA
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`would consider formulating nucleic acid-lipid particles a matter of routine
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`optimization, and the unrefuted evidence of record demonstrated that it was not.
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`POR, 19-24. In addition, the Petition never explained how the broad ranges for
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`lipid components disclosed by the prior art were sufficient under the caselaw as
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`being the conditions required by the claims. POR, 25-27. Accordingly, the petition
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`failed to meet its burden of demonstrating the obviousness of the claims under
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`Peterson and du Pont by a preponderance of the evidence.
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`VI. PETITIONER’S NEWLY ADVANCED OBVIOUSNESS THEORIES
`ALSO FAIL
`The Reply now attempts to back-fill the identified holes in its petition case,2
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`belatedly arguing motivation and a reasonable expectation of success of achieving
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`the claimed particles through routine experimentation. Such arguments should not
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`be presented for the first time on reply and should be disregarded. However, as
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`explained below, even if considered, they fall far short of establishing obviousness
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`by a preponderance of the evidence.
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`2 Petitioner also improperly attempted such gap-filling in contravention of
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`proper scope for re-direct during Dr. Janoff’s deposition. EX2033, 147:18-166:9.
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`In addition, Petitioner argues mere possibilities in asserting what “could” or
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`can” be done. E.g., Reply, 4 (“structures existed at the time of the ’069 patent that
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`can meet the claim limitations”), 13 (“POSITA would have understood …
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`potential cationic lipid concentration ranges”), 22 (“could embrace”), 28 (“could
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`be attributable”). Such assertions have never been sufficient to support
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`obviousness. PersonalWeb Techs., LLC v. Apple, Inc., 848 F.3d 987, 944-95 (Fed.
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`Cir. 2017) (“reasoning...that [references] could be combined...is not enough: it
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`does not imply a motivation”).
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`At best, the allegations of unpatentability in the petition amount to little
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`more than notice pleading. Such challenges, therefore, are insufficient and do not
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`meet the statutory requirement of “particularity,” and cannot be remedied on reply.
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`A. An Overlapping Phospholipid Range is NOT Disclosed
`Petitioner’s obviousness case asserted a presumption of obviousness based
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`on alleged disclosure of overlapping ranges in the cited prior art where no such
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`phospholipid range is disclosed. E.g., POR, 12-19. Petitioner (Pet., 39, 58)
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`contrived a phospholipid range of 0-19% or 0-19.5% through a series of
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`assumptions. That was acknowledged by the Board in the DI, crediting a
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`phospholipid range on the basis one could be manufactured through “reasonable
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`inferences.” DI, 23, 36.
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`The POR (12-19), however, explains the disconnect between the proffered
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`legal theory (i.e., presumption of obviousness under Peterson and du Pont) and the
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`facts (i.e., content of the prior art). Neither of those cases, or any other identified
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`overlapping range case, supports an overlapping range presumption where there is
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`no overlapping range. Petitioner disputes none of this in reply.
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`The Reply (5) does not dispute the cited art fails to expressly disclose a
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`phospholipid range, it simply asserts that fact “is irrelevant.” Not so. Petitioner
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`cites to IXI IP, LLC v. Samsung Elecs. Co., LTD., 903 F.3d 1257, 1264-1265 (Fed.
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`Cir. 2018); it is inapposite. IXI is not an overlapping range case at all, and certainly
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`does not support a presumption of obviousness under Peterson and du Pont by
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`making a series of inferences to arrive at a range not affirmatively disclosed.
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`Petitioner’s attempt to shoehorn the present facts into an inapplicable legal
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`framework must be rejected.
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`The Reply (5-6) also does not contest that its contrived phospholipid range
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`of 0-19% or 0-19.5% is not at all reasonable. POR (14-19). Instead, Petitioner
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`(Reply 5-6) abandons its original argument in favor of arguing a much broader
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`phospholipid range of 5-90mol%. This too must be inferred from a more generic
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`discussion of “non-cationic/neutral lipid”., The Reply falsely claiming Dr.
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`Thompson agreed during deposition. Dr. Thompson expressly rejected it. E.g.,
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`EX1025, 169:9-13 (“That’s not the way I read this….”).
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`Furthermore, Reply (5) also attempts to pivot to a new reference—Protiva’s
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`’910 publication (EX1015) that was cited by the Examiner during ex parte
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`prosecution. Prosecution counsel’s representation of the Examiner’s Office Action
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`rejection (which was overcome) is hardly an admission or evidence probative of
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`the perspective of a POSITA. If Petitioner wanted to rely on the ’910 publication
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`as a ground reference it should have done so in its petition. See also 35 U.S.C.
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`§325(d).
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`Accordingly, Petitioner’s challenge based on a presumption of obviousness
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`in view of overlapping ranges at least fails due to the lack of identified overlapping
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`ranges.
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`B.
`Petitioner’s Belated Assertions of Routine Optimization
`As discussed in the POR (19-24), obviousness based on routine optimization
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`was never substantiated in the petition materials. In fact, until the Reply, it was
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`undisputed that developing nucleic acid-lipid particles was not a simple matter of
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`routine optimization. That is supported by the scientific literature, testimony of Dr.
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`Thompson, and testimony of Petitioner’s first expert, Dr. Janoff. E.g., EX2006,
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`403:22-25 (“Q. In the 2008 timeframe, was developing nucleic acid-lipid particles
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`considered a routine matter of optimizing variables? A. No.”); EX2001, 144:18-
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`145:1; see also EX2014, Fig. 12 (demonstrating that even small changes in the
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`amount of conjugated lipid concentration can impact the efficacy of the particles).
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`Moreover, Dr. Janoff repeatedly testified that he considered lipid ranges even
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`narrower than those in the prior art to be immense. E.g., EX1008, ¶74; EX2028,
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`¶¶73, 112; EX2033, 42:7-10 (“[i]f the range is immense, there would be undue
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`experimentation I believe to find a combination or a range that behaved in a
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`desirable light.”). The petition (e.g., 36) is littered with arguments of complexity
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`and unpredictability, acknowledging that “even minor variations in lipid
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`percentages appeared to impact efficacy.”
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`The Reply ignores the extensive evidence to the contrary, its own prior
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`arguments, and testimony of its previous expert, and attempts a 180º turn. To the
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`extent the new routine optimization argument is considered, it fails on the merits
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`for at least the reasons set forth below.
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`1.
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`Petitioner Invalid Assumption of Four Lipid Component
`Systems
`The Reply (6-7), without explanation or analysis, erroneously presumes a
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`four-lipid component starting point. This assumption acts as a lynchpin for its new
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`optimization argument. This reasoning is wholly circular (assuming a four-
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`component system to arrive at the conclusion of a four-component system) is
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`driven by nothing but impermissible hindsight, not any logical underpinnings to an
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`obviousness assertion. In re Kahn, 441 F.3d 977, 988 (2006). Moreover, this
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`hindsight is contradicted by the very references cited by Petitioner, none of which
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`identify the four lipid components claimed as being required in a formulation.
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`Lin, Ahmad, and the ’618 and ’613 patents disclose two-component lipid
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`particles, lacking both cholesterol and conjugated lipid. EX1006, 3308 (describing
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`particles comprising cationic and phospholipid); EX007, 740-41 (same); EX1017,
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`Fig. 2 (same); EX1012, 1:54-57, 1:66-67 (same). Bennett and the ’618 and ’505
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`patents disclose three-component lipid particles which lack conjugated lipid.
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`EX1010, 51 (Figures 1 & 2) (describing particles comprising cationic,
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`phospholipid, and cholesterol); EX1017, 34:65-35:25 (same); EX1013, 5:21-24
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`(same).
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`The ’554, ’196, and ’189 publications describe phospholipid, cholesterol,
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`and conjugated lipid as optional components. EX1005, ¶¶12, 120 (conjugated lipid
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`optional), ¶¶97-115 (cholesterol optional), ¶92 (neutral lipid is optionally a
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`phospholipid); EX1004, ¶150 (conjugated lipid optional), ¶152 (cholesterol
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`optional), ¶79 (non-cationic lipid is optionally a phospholipid); see also EX1025,
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`205:7-16 (possible to have particles without phospholipid, cholesterol, or
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`conjugated lipid). The ’196 publication describes phospholipid and cholesterol are
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`optional components. EX1003, ¶89 (describing that cholesterol and phospholipids
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`are optional), ¶216 (exemplifying three-component particle). Furthermore, most of
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`the formulations disclosed in the ’554 publication are not four-component lipid
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`particles — most lack a phospholipid entirely. EX1005, Table IV. Other
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`formulations of the ’554 publication lack both phospholipid and cholesterol (e.g.,
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`L100) and yet others are five-component systems (e.g., L086, L104). Id.
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`Moreover, some lipid particle delivery platforms lack cationic lipid entirely.
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`For example, Dr. Thompson explains that his research developing polymer-based
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`particles as one of the efforts to “advance the field [] beyond cationic lipid
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`particles.” EX1025, 7:12-18.
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`Petitioner’s optimization argument can be rejected at least for being based
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`on this faulty premise.
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`2.
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`Petitioner’s Spurious Assertion of a “Trend” Toward Increased
`Cationic Lipid
`Another cornerstone of the belated Reply (13-14) optimization argument is
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`the false assertion of a “trend” in the prior art towards higher cationic lipid
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`concentrations. There was no such trend in the art.
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`As Dr. Anchordoquy confirmed, there was no scientific analysis here—
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`rather, Petitioner’s counsel conjured this “trend” by cherry-picking only three data
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`points from a very limited time frame—2003 to late 2004. EX2043, 52:9-16
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`(confirming he did not construct the “trend”), 61:20-22 (confirming only 3
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`datapoints), 61:13-25 (confirming no statistical fit or regression analysis). As Dr.
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`Anchordoquy conceded, there were “hundreds, if not thousands” publications
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`existing before the time of invention (filed in 2008). EX2043, 29:25-30:4, 30:25-
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`31:7 (more than 30 patent publications by PO by 2008).
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`Curiously, the Reply (14) points to PO’s ’910 publication (citing Example
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`12, Figure 23) as somehow confirming this fabricated trend when it does just the
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`opposite. Dr. Anchordoquy conceded during cross-examination the ’910
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`publication expressly identifies the 30mol% cationic lipid concentration (not the
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`40mol% that serves as the basis of Petitioner’s optimization argument) as best
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`performing in this in vitro screen. EX2043, 12:18-20, 16:6-11, EX1015 ¶335
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`(“SNALP comprising 30% DLinDMA was more effective in reducing luciferase
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`expression in the Neuro2A cells than SNALP comprising DODAC or DODMA
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`were.”). Dr. Anchordoquy further acknowledged that all subsequent in vivo testing
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`(EX1015 ¶¶337-354) was limited to formulations having 30% or less cationic lipid,
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`which admittedly illustrates the lack of interest in higher cationic lipid
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`concentrations. EX2043, 16:6-11; 17:24-19:24; EX1025, 184:4-186:14. Finally,
`
`Dr. Anchordoquy conceded that plotting even one of the datapoints from the ’910
`
`publication (none were plotted in the reply materials) would destroy the fabricated
`
`“trend.” EX2043, 59:7-61:7.
`
`3.
`
`Petitioner’s New N/P Ratio Argument is an Irrelevant
`Distraction
`The Reply (11-13, 16-17) argues that a newly introduced parameter, N/P
`
`ratio, would somehow drive a POSITA’s optimization efforts to arrive at the
`
`claimed composition. E.g., EX1020, ¶¶72-75, EX2043, 33:17-35:15. Even if
`
`- 16 -
`
`
`
`
`
`considered, there is no explanation how this admittedly irrelevant parameter would
`
`render challenged claims obvious.
`
`As an initial matter, argument based on N/P ratio should be given little
`
`weight due to the fact that neither Petitioner nor Dr. Anchordoquy provide any of
`
`their underlying calculations. 37 C.F.R. §42.65. This is especially important given
`
`Dr. Anchordoquy conceded during cross-examination, that there are a number of
`
`variables involved, some of which he did not know, requiring him to make certain
`
`(unexplained) assumptions. EX2043, 36:8-40:17, 44:20-45:16. He further
`
`conceded he actually made “approximations” rather than any precise calculation.
`
`Id., 44:24-45:13. As a result, both PO and the Board are denied to ability to
`
`critically evaluate the accuracy of Dr. Anchordoquy’s assumptions.
`
`Beyond that, Petitioner’s assertion that an N/P ratio of 6 was recognized as
`
`“optimized,” while a lower ratio (e.g., “approximately 3”) is suboptimal, lacks a
`
`shred of supporting evidence. Reply, 11-12. The evidence of record states the
`
`contrary. For example, the Reply ignores the fact that the N/P ratio for the
`
`optimized commercial product, patisiran, is 3.4 (EX2041). When probed during
`
`deposition, Dr. Anchordoquy conceded that he had calculated the N/P ratio but
`
`chose to exclude it from his declaration. EX2043, 65:13-66:2; 66:19-67:13. Such
`
`information is clearly probative as to the lack of credibility to this argument and
`
`should not have been withheld.
`
`- 17 -
`
`
`
`
`
`The Reply (17) points to Lin and Ahmad but similarly fails to inform the
`
`Board that these references describe maintaining a constant N/P ratio of 2.8—i.e.,
`
`contrary to the new optimization argument. See, e.g., (Lin) EX1006, 3314;
`
`(Ahmad) EX1007, 743. The ’196 and ’189 publications identify its most narrow
`
`preferred charge ratio expansively—anywhere from 2:1 to 6:1. EX1003, ¶126;
`
`EX1004, ¶197 (same).
`
`Finally, as Dr. Anchordoquy admitted during deposition, the N/P ratio is
`
`ultimately irrelevant to the claimed composition, as N/P ratio is neither recited nor
`
`dependent on any of the concentrations of the lipid component concentrations that
`
`are recited. That is, Dr. Anchordoquy conceded that the amount of conjugated
`
`lipid, cholesterol, and conjugated lipid all have no impact on the N/P ratio.
`
`EX2043, 35:16-36:2. In fact, Dr. Anchordoquy conceded that the N/P ratio is
`
`ultimately irrelevant to the concentration of the cationic lipid.
`
`Q. (By Mr. Rosato) Okay. It is possible for two different lipid particle
`formulations to have different cationic lipid concentrations but have
`the same N-to-P ratio?
`A. Yeah.
`EX2043, 40:18-22.
`
`Accordingly, N/P ratio argument is an irrelevant distraction, unsupported by
`
`any credible evidence.
`
`- 18 -
`
`
`
`
`
`4.
`The Conjugated Lipid Range was Not Obvious
`The Reply (18-19) newly offers a motivation for adding a conjugated lipid,
`
`but as pointed out in the POR (3, 27) such arguments were never made in the
`
`petition, neither was necessary corresponding argument demonstration a
`
`reasonable expectation of success of arriving at the claimed range.
`
`Even if considered, Petitioner’s reply arguments are still unavailing. The
`
`Reply ignores the fact that, even if this optional component were included, much
`
`higher amounts of conjugated lipid were considered optimal at the time of
`
`invention. That was especially pertinent if the amount of cationic lipid was
`
`hypothetically increased. As Dr. Thompson has testified, both in his declaration
`
`(EX2031, ¶¶48-49) and his deposition (EX1025, 57:1-7, 62:3-6, 132:9-133:23,
`
`175:3-13), amounts such as 5-10% were more typically used. See also, the newly
`
`cited MacLachlan chapter (EX1024, 258), citing Judge (EX2042) as providing
`
`evaluation of preferred conjugated lipid concentration. EX2042, 335 (describing
`
`10% conjugated lipid); EX2043, 31:15-32:16.
`
`Neither the petition nor the Reply provide any meaningful rebuttal to PO’s
`
`evidence and argument that higher cationic lipid together with lowering conjugated
`
`lipid would have been counterintuitive at the time. Petitioner’s entire analysis
`
`reduces to the legally deficient argument that one “could” have included
`
`conjugated lipid.
`
`- 19 -
`
`
`
`
`
`5.
`The Claimed Cholesterol Range Was Not Obvious
`The Reply (20) newly argues motivation to include cholesterol on the basis
`
`of adding rigidity to the particle, but never explains why this necessitates
`
`cholesterol in a formation at all, let alone the specific concentrations claimed.
`
`
`
`The cited art all describe cholesterol as an optional component. EX1003, ¶91
`
`(“If present, the cholesterol…..”); EX1004, ¶152 (same); EX1005, ¶98. The
`
`particles of Lin (EX1006) and Ahmad (EX1007) contain no cholesterol at all. See
`
`also EX1025, 205:12-14. The petition and Reply never provide any evidence based
`
`analysis of why a POSITA would have included cholesterol at the claimed
`
`concentration. E.g., EX1020, ¶106 (Dr. Anchordoquy failing to cite evidence for
`
`the proposition that the “claimed range of 30-48mol% is squarely within the
`
`generally acceptable ranges in the field.”). At best, Petitioner’s argument amount
`
`to no more than a POSTA “could” have included cholesterol.
`
`6.
`
`Petitioner fails to establish the claimed phospholipid
`concentration was obvious
`The Reply (21) argument of including a phospholipid as a “bilayer
`
`stabilizing component” is untimely and insufficient.
`
`The cited art provides a broad list of optional bilayer stabilizing components
`
`far more expansive than just a phospholipid. EX1004, ¶88. Petitioner does not
`
`explain why one would specifically select a phospholipid as opposed to any other
`
`compound. Moreover, Petitioner advances the same argument presented for
`
`- 20 -
`
`
`
`
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`cholesterol with only slightly different verbiage, but does not explain why both
`
`phospholipid and cholesterol would be added for particle rigidity/stability. The
`
`prior art cited by Petitioner discusses phospholipid as optional. EX1003, ¶89;
`
`EX1004, ¶79; EX1005, ¶455; see also EX1025, 205:7-9 (phospholipid not
`
`necessary). Again, Petitioner’s arguments distill down to little more than a
`
`phospholipid “could” be present.
`
`
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`Finally, the independent claim at issue here has a similar limitation to a
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`range of phospholipids as claim 7 of the ’435 patent. The Board issued a F
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