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`Paper No. ___
`Filed: December 21, 2018
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
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`MODERNA THERAPEUTICS, INC.,
`Petitioner,
`
`v.
`
`PROTIVA BIOTHERAPEUTICS, INC.,
`Patent Owner.
`_____________________________
`
`Case IPR2018-00739
`Patent No. 9,364,435
`_____________________________
`
`
`
`PATENT OWNER’S CONTINGENT MOTION TO AMEND
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`

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`TABLE OF CONTENTS
`I.Preliminary Statement ............................................................................................. 1 
`II.Facts ........................................................................................................................ 1 
`A. 
`Claims of the ’435 Patent ...................................................................... 1 
`B. 
`The Instituted Grounds .......................................................................... 1 
`C. 
`Burden of Persuasion ............................................................................ 2 
`III.Argument .............................................................................................................. 2 
`A. 
`Contingent Nature of the Motion .......................................................... 2 
`B. 
`Proposed Amendments .......................................................................... 3 
`C. 
`Claim Construction ............................................................................... 4 
`D. 
`Proposed Amendments are Supported by the Original
`Disclosure and Earlier-Filed Disclosures .............................................. 4 
`(i) 
`Independent Claim 21 .................................................................... 5 
`(ii)  Dependent Claims 22-40 ................................................................ 8 
`Proposed Amendments Do Not Enlarge the Scope of the Claims ...... 12 
`Proposed Amendments are Responsive to Petitioner’s Grounds ........ 13 
`(i) 
`“Serum-Stable” ............................................................................. 13 
`(ii) 
`“a cationic lipid comprising from 50 mol % to 75 mol % of the
`total lipid present in the particle” ...................................................................... 16 
`(iii) 
`“wherein the particle is formulated such that that the nucleic acid
`is not substantially degraded after exposure of the particle to a nuclease at
`37ºC for 20 minutes” ......................................................................................... 17 
`IV.Conclusion .......................................................................................................... 19 
`Appendix A ................................................................................................................. i 
`
`
`
`E. 
`F. 
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`-i-
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`I.
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`PRELIMINARY STATEMENT
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`This Contingent Motion to Amend is submitted in IPR2018-00739 involving
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`U.S. Patent No. 9,364,435 (“the ’435 patent”), pursuant to 37 C.F.R. §42.121 and
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`the Board’s authorization via email on December 11, 2018. In the event that the
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`Board finds any of claims 1-20 of the ’435 patent unpatentable, Patent Owner
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`Protiva Biotherapeutics, Inc. requests that the unpatentable claim(s) be replaced
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`with the corresponding substitute claim(s) 21-40.
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`II.
`
`FACTS
`
`A. Claims of the ’435 Patent
`
`Claims 1-20 of the ’435 patent were issued on June 14, 2016. Of the 20
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`claims, claim 1 is the only independent claim. The issued claims of the ’435 patent
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`are directed to a nucleic acid-lipid particle comprising a nucleic acid and specific
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`concentrations of a cationic lipid (50-85 mol %), a non-cationic lipid (13-49.5 mol
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`%), and a conjugated lipid (0.5-2 mol %).
`
`B.
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`The Instituted Grounds
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`The Board instituted “all grounds as set forth in the Petition.” Paper 15, at
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`33. The petition set forth three grounds of alleged unpatentability. As presented by
`
`the petition, Ground 1 alleges obviousness based on the combination of the ’196
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`PCT (EX1002) and ’189 Publication (EX1003); Ground 2 alleges obviousness
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`based on the combination of patent owner’s prior disclosure, Lin (EX1005), and
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`-1-
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`Ahmad (EX1006); Ground 3 alleges anticipation or obviousness based on the ’554
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`Publication (EX1004). Pet. 5.
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`C. Burden of Persuasion
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`In a motion to amend, the burden of persuasion rests on the petitioner to
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`demonstrate that the substitute claims are unpatentable. Aqua Products, Inc. v.
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`Matal, 872 F.3d 1290, 1327 (Fed. Cir. 2017). The Federal Circuit has held that:
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`“(1) the PTO has not adopted a rule placing the burden of persuasion with respect
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`to the patentability of amended claims on the patent owner that is entitled to
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`deference; and (2) in the absence of anything that might be entitled deference, the
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`PTO may not place that burden on the patentee.” Id. Accordingly, Patent Owner
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`respectfully submits that this paper and supporting evidence provided herewith
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`meets the requisite burden of production.
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`III. ARGUMENT
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`A. Contingent Nature of the Motion
`
`This motion is contingent upon a finding that any of original claims 1-20 are
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`unpatentable. Patent Owner is not surrendering the original claims, and if they are
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`all found to be patentable, then this motion need not be considered. See Corning
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`Optical Communications RF LLC v. PPC Broadband, Inc., IPR2014-00441, Paper
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`19 at 3 (“[T]he request to substitute claims is always contingent.”). Any claims
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`found not unpatentable should not be replaced.
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`-2-
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`B.
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`Proposed Amendments
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`Proposed substitute claims for each of claims 1-20 are submitted in the claim
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`listing attached as Appendix A. Claims 21-40 are claim-for-claim substitutions of
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`claims 1-20 and thus are presumptively reasonable under 37 C.F.R. § 42.121(a)(3).
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`In response to the grounds on which trial was instituted by the Board,
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`substitute claim 21 amends independent claim 1 by reciting a narrower range for
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`the concentration of the cationic lipid, and a narrower range for the concentration
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`of non-cationic lipid. Also in response to the instituted grounds, substitute claim
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`21 further recites the term “serum stable” in reference to the claimed nucleic acid-
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`lipid particle, as well as the language “wherein the particle is formulated such that
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`the nucleic acid is not substantially degraded after exposure of the particle to a
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`nuclease at 37ºC for 20 minutes.”
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`Specifically, substitute claim 21 is shown below in mark-up form relative to
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`independent claim 1:
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`21.
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`(Substitute for claim 1) A serum-stable nucleic acid-lipid particle
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`comprising:
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`
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`(a) a nucleic acid;
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`(b) a cationic lipid comprising from 50 mol % to [[85]] 75 mol % of
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`the total lipid present in the particle;
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`(c) a non-cationic lipid comprising from [[13]] 23 mol % to 49.5
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`mol% of the total lipid present in the particle; and
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`
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`(d) a conjugated lipid that inhibits aggregation of particles comprising
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`from 0.5 mol % to 2 mol % of the total lipid present in the particle;
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`
`
`wherein the particle is formulated such that that the nucleic acid is not
`
`substantially degraded after exposure of the particle to a nuclease at 37ºC for
`
`20 minutes.
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`C. Claim Construction
`
`The amended terms should be given their plain and ordinary meaning as
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`understood by a person of ordinary skill in the art in view of the specification. The
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`term “serum-stable” is defined in the specification of the ’435 patent. EX1001,
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`13:32-35 (“‘Serum-stable’ in relation to nucleic acid-lipid particles such as SNALP
`
`means that the particle is not significantly degraded after exposure to a serum or
`
`nuclease assay that would significantly degrade free DNA or RNA.”).
`
`D.
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`Proposed Amendments are Supported by the Original Disclosure
`and Earlier-Filed Disclosures
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`The ’435 patent was filed Aug. 18, 2014, as U.S. Application No.
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`14/462,441 (“the ’441 application,” EX2045). The ’435 patent also claims priority
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`through a series of three continuation applications: U.S. Application No.
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`13/928,309 filed June 26, 2013, (“the ’309 application,” EX2044); U.S.
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`Application No. 13/253,917 filed October 5, 2011, (“the ’917 application,”
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`EX2043); and U.S. Application No. 12/424,367 filed April 15, 2009 (“the ’367
`
`application,” EX2042). The ’441 application, as well as each continuation, further
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`claims priority to Provisional Application No. 61/045,228 filed April 15, 2008
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`(“the ’228 provisional,” EX2041).
`
`Pursuant to 37 C.F.R. § 42.121(b), the analysis below indicates how each
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`substitute claim is supported by the original disclosure and the earlier-filed
`
`disclosures for the ’435 patent. Patent Owner notes that the ’441 application,
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`the ’309 application, the ’917 application, and the ’367 application share the same
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`specification. Compare EX2045 with EX2044 with EX2043, and with EX2042.
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`Thus, where citations are provided for any of these four applications, support can
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`also be found in the other three applications at the same cited paragraphs.
`
`(i)
`Independent Claim 21
`The ʼ441 application and the earlier-filed specifications, including the ’228
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`provisional, provide support for the preamble of claim 21, “a serum-stable nucleic
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`acid-lipid particle.” EX2041, ¶¶90, 176, 183, 187, 196; EX2045, ¶¶14, 17, 49, 89,
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`94, 141, 240; EX2040, ¶27. The disclosures make clear that the invention is
`
`directed to serum-stable nucleic acid-lipid particles. For example, in discussing
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`preparation of the particles, the ’228 provisional explains that “[t]he serum-stable
`
`nucleic acid-lipid particles of the present invention can be formed using a number
`
`of methods known in the art.” EX2041, ¶176 (emphasis added); see also id., ¶90
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`-5-
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`(“‘Serum-stable’ in relation to nucleic acid-lipid particles means that the particle is
`
`not significantly degraded after exposure to a serum or nuclease assay that would
`
`significantly degrade free DNA or RNA”); EX2045, ¶17 (“[T]he present invention
`
`provides serum-stable nucleic acid-lipid particles (SNALP) comprising a nucleic
`
`acid…”). In discussing the administration of the particles, the ’228 provisional
`
`explains that “[o]nce formed, the serum-stable nucleic acid-lipid particles of the
`
`present invention are useful for the introduction of nucleic acids (e.g., siRNA) into
`
`cells.” EX2041, ¶196 (emphasis added); see also EX2045, ¶¶22, 149, 194, 287,
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`307; EX2040, ¶27.
`
`In fact, the original and earlier-filed disclosures specifically explain that
`
`“‘[s]erum-stable’ in relation to nucleic acid-lipid particles means that the particle is
`
`not significantly degraded after exposure to a serum or nuclease assay that would
`
`significantly degrade free DNA or RNA. Suitable assays include, for example, a
`
`standard serum assay, a DNAse assay, or an RNAse assay.” EX2041, ¶90; see
`
`also EX2045, ¶89; EX2040, ¶27.
`
`The ʼ441 application and the earlier-filed specifications, including the ’228
`
`provisional, also provide support for “a nucleic acid.” E.g. EX2041, ¶¶10, 19, 25-
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`29; EX2045, ¶¶17-18, 61, 76, 140, 307; EX2040, ¶28. The disclosure is directed
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`to “stable nucleic acid-lipid particles encapsulating a nucleic acid.” EX2041, ¶10;
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`EX2045, ¶¶289, 329, 331; EX2040, ¶28.
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`-6-
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`The original and earlier-filed disclosures also provide support for “a cationic
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`lipid comprising from 50 mol % to 75 mol % of the total lipid present in the
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`particle.” EX2045, ¶¶14, 139. Specifically, the ’441 explains that “[t]he cationic
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`lipid typically comprises from … about 50 mol % to about 75 mol % … of the total
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`lipid present in the particle.” Id., ¶14. The ’228 provisional also provides support
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`for “a cationic lipid comprising from 50 mol % to 75 mol % of the total lipid
`
`present in the particle.” EX2041, ¶¶14, 139. Specifically, the ’228 provisional
`
`explains that “[t]he cationic lipid typically comprises from … about 50 mol % to
`
`about 75 mol % … of the total lipid present in the particle.” Id., ¶14; see also
`
`EX2040, ¶29.
`
`The original and earlier-filed disclosures also provide support for “a non-
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`cationic lipid comprising from 23 mol % to 49.5 mol% of the total lipid present in
`
`the particle.” EX2041, ¶¶21, 22, 146, Tables 2, 4, 6; see also EX2045 ¶¶126, 129,
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`131, Tables 2, 4, 6; EX2040, ¶30; EX2040, ¶29.
`
`The original and earlier-filed disclosures also provide support for “a
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`conjugated lipid that inhibits aggregation of particles comprising from 0.5 mol %
`
`to 2 mol % of the total lipid present in the particle.” For example, the ’228
`
`provisional discloses “a conjugated lipid that inhibits aggregation of particles
`
`comprising from about 0.5 mol % to about 2 mol % of the total lipid present in the
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`-7-
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`particle.” EX2041, ¶10; see also EX2041 ¶¶18, 173; EX2045, ¶¶18, 139; EX2040,
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`¶31.
`
`The original and earlier-filed disclosures also provide support for “wherein
`
`the particle is formulated such that that the nucleic acid is not substantially
`
`degraded after exposure of the particle to a nuclease at 37ºC for 20 minutes.” For
`
`example the ’228 provisional expressly states that “the nucleic acid in the nucleic
`
`acid-lipid particle is not substantially degraded after exposure of the particle to a
`
`nuclease at 37°C for 20 minutes.” EX2041, ¶19; EX2045, ¶140; see also EX2041,
`
`¶¶19, 22, claim 25. Moreover, the earlier-filed disclosures expressly state that
`
`“‘[s]erum-stable’ in relation to nucleic acid-lipid particles means that the particle is
`
`not significantly degraded after exposure to a serum or nuclease assay that would
`
`significantly degrade free DNA or RNA. Suitable assays include, for example, a
`
`standard serum assay, a DNAse assay, or an RNAse assay.” EX2041, ¶90; EX2045,
`
`¶89; see also EX2040, ¶¶32-33.
`
`(ii) Dependent Claims 22-40
`Substitute claims 22-40 amend references to claim dependencies relative to
`
`original claims 2-20. No further substantive amendments are proposed for these
`
`claims. Pursuant to 37 C.F.R. §42.121(b), Patent Owner identifies support in the
`
`original and earlier-filed disclosures in the table below. See also EX2040, ¶¶34-35.
`
`As mentioned, the ’441 application, the ’309 application, the ’917 application, and
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`-8-
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`the ’367 application share the same specification. Thus, where citations are
`
`provided for the ’441 application, support can also be found in the other three
`
`applications at the same cited paragraphs
`
`Claims
`22. The nucleic acid-lipid particle of claim 21,
`wherein the nucleic acid comprises an interfering
`RNA, mRNA, an antisense oligonucleotide, a
`ribozyme, a plasmid, an immunostimulatory
`oligonucleotide, or mixtures thereof.
`23. The nucleic acid-lipid particle of claim 22,
`wherein the interfering RNA comprises a small
`interfering RNA (siRNA), an asymmetrical
`interfering RNA (aiRNA), a microRNA (miRNA), or
`mixtures thereof.
`24. The nucleic acid-lipid particle of claim 21,
`wherein the cationic lipid comprises from 50 mol %
`to 65 mol % of the total lipid present in the particle.
`25. The nucleic acid-lipid particle of claim 21,
`wherein the non-cationic lipid comprises a mixture of
`a phospholipid and cholesterol or a derivative
`thereof.
`26. The nucleic acid-lipid particle of claim 25,
`wherein the phospholipid comprises
`dipalmitoylphosphatidylcholine (DPPC),
`distearoylphosphatidylcholine (DSPC), or a mixture
`
`Specification Support
`
`EX2041, ¶¶11, 70, 113-
`120; EX2045, ¶¶5, 53, 69,
`74, 97, 161, 228-230
`
`EX2041, ¶¶74, 55, 95, 109,
`Table 1; EX2045, ¶¶5, 69,
`151-152, 209-219
`
`EX2041, ¶¶10, 14, 139;
`EX2045, ¶¶16, 18, 48, 116,
`247
`
`EX2041, ¶¶15, 16, 21-22,
`141-149; EX2045, ¶¶20,
`122, 133-134, 146, 256-258
`
`EX2041, ¶¶16, 22, 142,
`149, 243, Tables 2, 4, 6,
`claim 18; EX2045, ¶¶79,
`124, 250, 258
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`-9-
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`thereof.
`27. The nucleic acid-lipid particle of claim 25,
`wherein the phospholipid comprises from 3 mol % to
`15 mol % of the total lipid present in the particle.
`28. The nucleic acid-lipid particle of claim 25,
`wherein the cholesterol or derivative thereof
`comprises from 30 mol % to 40 mol % of the total
`lipid present in the particle.
`29. The nucleic acid-lipid particle of claim 21,
`wherein the conjugated lipid that inhibits aggregation
`of particles comprises a polyethyleneglycol (PEG)-
`lipid conjugate.
`30. The nucleic acid-lipid particle of claim 29,
`wherein the PEG-lipid conjugate comprises a PEG-
`diacylglycerol (PEG-DAG) conjugate, a PEG-
`dialkyloxypropyl (PEG-DAA) conjugate, or a
`mixture thereof.
`31. The nucleic acid-lipid particle of claim 30,
`wherein the PEG-DAA conjugate comprises a PEG-
`dimyristyloxypropyl (PEG-DMA) conjugate, a PEG-
`distearyloxypropyl (PEG-DSA) conjugate, or a
`mixture thereof.
`32. The nucleic acid-lipid particle of claim 21,
`wherein the conjugated lipid that inhibits aggregation
`of particles comprises from 1 mol % to 2 mol % of
`the total lipid present in the particle.
`
`EX2041, ¶¶16, 149, 231,
`Tables 2, 4, 6, claim 16;
`EX2045, ¶133
`
`EX2041, ¶¶15, 16, 147-
`148; EX2045, ¶¶125, 132-
`133, 258
`
`EX2041, ¶¶17-18, 74, 78,
`150-53; EX2045, ¶¶135,
`138-139
`
`EX2041, ¶¶18, 21-22, 151,
`161, 163, 192; EX2045,
`¶¶135, 145-146, 260-261,
`273-274, 303
`
`EX2041, ¶¶18, 163, 195,
`231, 287, 301-9; EX2045,
`¶¶135, 274, 412
`
`EX2041, ¶¶10, 21-22, 173;
`EX2045, ¶¶18, 139, 145-
`146
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`33. The nucleic acid-lipid particle of claim 21,
`wherein the nucleic acid is fully encapsulated in the
`nucleic acid-lipid particle.
`34. A pharmaceutical composition comprising a
`nucleic acid-lipid particle of claim 21 and a
`pharmaceutically acceptable carrier.
`35. A method for introducing a nucleic acid into a
`cell, the method comprising: contacting the cell with
`a nucleic acid-lipid particle of claim 21.
`36. A method for the in vivo delivery of a nucleic
`acid, the method comprising: administering to a
`mammalian subject a nucleic acid-lipid particle
`of claim 21.
`37. A method for treating a disease or disorder in a
`mammalian subject in need thereof, the method
`comprising: administering to the mammalian subject
`a therapeutically effective amount of a nucleic acid-
`lipid particle of claim 21.
`
`38. The method of claim 37, wherein the disease or
`disorder is a viral infection.
`
`39. The method of claim 37, wherein the disease or
`disorder is a liver disease or disorder.
`
`40. The method of claim 37, wherein the disease or
`disorder is cancer.
`
`EX2041, ¶¶10, 19, 74, 77,
`202; EX2045, ¶¶15, 74, 76,
`96, 140-142, 163, 239, 313
`EX2041, ¶¶23, 27, 198-
`199, 207; EX2045, ¶¶21,
`148, 318
`
`EX2041, ¶¶24-25, 196;
`EX2045, ¶¶22, 149, 307
`
`EX2041, ¶¶24, 28-29, 203,
`claims 46, 48; EX2045,
`¶¶23-24, 149
`
`EX2041, ¶¶29, 58;
`EX2045, ¶¶24, 57, 151
`
`EX2041, ¶¶121-22, 125;
`EX2045, ¶¶195-196, 199,
`212, 218
`EX2041, ¶¶2, 121, 126;
`EX2045, ¶¶6, 195, 200
`EX2041, ¶¶2, 9, 94, 129,
`219, 234, 287; EX2045,
`¶¶6, 13, 93, 195, 330
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`E.
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`Proposed Amendments Do Not Enlarge the Scope of the Claims
`
`The proposed amendments do not enlarge the scope of the original claims.
`
`The amendments further add the term serum-stable nucleic acid-lipid particle. It is
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`Patent Owner’s position that it is superfluous to modify the term “nucleic acid-
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`lipid particle” with “serum-stable.” However, while serum-stable may be
`
`redundant and superfluous, it is certainly not broadening. Further, the amendments
`
`recite that “the particle is formulated such that that the nucleic acid is not
`
`substantially degraded after exposure of the particle to a nuclease at 37ºC for 20
`
`minutes.” As set forth in the specification, a nucleic acid-lipid particle is defined
`
`as “serum-stable” when it “is not significantly degraded after exposure to a serum
`
`or nuclease assay that would significantly degrade free DNA or RNA.” EX1001,
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`13:33-35. The added language specifies aspects of a nuclease assay for assessing
`
`serum stability.
`
`These amendments add language to the independent claim and do not
`
`enlarge the claim scope. Lastly, substitute claim 21 recites narrower ranges for the
`
`concentrations of cationic lipids and non-cationic lipid. Because no conceivable
`
`composition would infringe the substitute claims without infringing the original
`
`claims, the substitute claims have not been broadened. See In re Cuozzo Speed
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`Techs., LLC, 793 F.3d 1268, 1283 (Fed. Cir. 2015) (“[A] claim is broader in scope
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`-12-
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`than the original claims if it contains within its scope any conceivable apparatus or
`
`process which would not have infringed the original patent.”).
`
`Accordingly, substitute claim 21 is not broader than original claim 1. Thus,
`
`the proposed substitute claims comply with 37 C.F.R. §42.121(2)(ii).
`
`F.
`
`Proposed Amendments are Responsive to Petitioner’s Grounds
`
`Pursuant to 37 C.F.R. §42.121(2)(i), each of the proposed amendments in
`
`substitute claim 21 responds to the instituted grounds to further distinguish over
`
`the prior art cited against the patentability of original claims 1-20 of the ’435
`
`patent. Specifically, the prior art fails to teach a serum-stable nucleic acid-lipid
`
`particle having cationic lipid levels in the range of 50 mol % to 75 mol %, wherein
`
`the particle is formulated such that that the nucleic acid is not substantially
`
`degraded after exposure of the particle to a nuclease at 37ºC for 20 minutes.
`
`EX2040, ¶36.
`
`(i)
`“Serum-Stable”
`Reciting the term “serum-stable” nucleic acid-lipid particle is responsive to
`
`each of instituted Grounds 1, 2, and 3 and the institution decision. A person of
`
`skill in the art would understand that serum stability of nucleic acid-lipid particles
`
`is a concern if the particles will interact with serum, such as when such particles
`
`are administered systemically (e.g., intravenously). The ’435 patent describes
`
`serum stability as a property of nucleic acid-lipid particles formulated for systemic
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`use. EX1001, 13:38-49. By contrast, serum stability is not a property of other
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`types of compositions, such as lipoplexes, and is not necessary for nucleic acid-
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`lipid particles formulated only for in vitro or local delivery of nucleic acids to cells.
`
`See, e.g., EX1008 at 4; see also EX2040, ¶¶37-38.
`
`The prior art cited in the petition does not disclose serum-stable nucleic
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`acid-lipid particles with cationic lipid levels greater than 50 mol %. That is, to the
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`extent that the prior art discloses lipid particles formulated for systemic
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`administration, none of these formulations are within the scope of claim 21.
`
`EX2040, ¶39.
`
`With respect to Ground 1, the petition relies on ranges of cationic lipid that
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`would not have been expected to be suitable for systemic administration, i.e.,
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`cationic lipid ranges of about 2% to about 60% and about 40% to about 50%.
`
`EX1007, ¶110 (citing EX1002, ¶88). The former range is not indicated for any
`
`particular use and the latter is indicated only for local delivery. See EX1002, ¶88.
`
`The ’196 PCT teaches that the use determines the optimal proportion of lipid
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`components and, for systemic use, nucleic acid-lipid particles should contain
`
`between 5% and 15% cationic lipid. That is, the nucleic acid-lipid particles of
`
`the ’196 PCT that are formulated for systemic use have cationic lipid levels outside
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`the scope of claim 1. EX2040, ¶40.
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`With respect to Ground 2, the petition argued that a person of skill in the art
`
`would have increased the cationic lipid level in nucleic acid-lipid particles of
`
`the ’196 PCT according to the levels present in the lipoplex formulations of Lin
`
`and Ahmad. See, e.g., EX1007 ¶139. However, lipoplexes were not suitable for
`
`systemic use. The lipoplex formulations of Lin and Ahmad are described as not
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`suitable for transfection of cells in the presence of serum. EX1005 at 9 (“However,
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`the current work is not expected to be predictive of transfection behavior in blood
`
`for systemic in vivo applications in the presence of serum.”); EX1006 at 747
`
`(describing results as relevant for ex vivo applications only). A person of ordinary
`
`skill in the art would not have had reason to modify prior art nucleic acid-lipid
`
`particles according to formulations known as unsuitable for systemic delivery, or
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`any reasonable expectation of success. EX2040, ¶41.
`
`With respect to Ground 3, the petition does not address whether L054-
`
`derived nanoparticles were formulated for systemic administration. The ’554
`
`publication distinguishes between embodiments formulated for in vitro use and
`
`those formulated for in vivo use. See, e.g., EX1004 ¶¶136, 462. Furthermore,
`
`the ’554 publication stresses that serum-stability is a critical property of in vivo
`
`formulations. See, e.g., EX1004 ¶¶14, 15, 158. However, L054 was only tested in
`
`vitro. See EX1004 ¶395. While another formulation (outside the scope of the ’435
`
`claims) was tested in vivo, the L054 formulation was not. EX1004 ¶596; EX2040,
`
`-15-
`
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`

`

`
`
`¶42. A person of ordinary skill in the art would have expected particles derived
`
`from L054 to be too toxic for systemic use, because DMOBA, the cationic lipid
`
`used in the L054 lipid mixture (see Table IV), was regarded to be particularly toxic.
`
`EX2040, ¶43.
`
`(ii)
`
`“a cationic lipid comprising from 50 mol % to 75 mol
`% of the total lipid present in the particle”
`Narrowing the range of cationic lipid to 50 mol % to 75 mol % (and non-
`
`cationic lipid to 23 mol % to 49.5 mol %) is responsive to Ground 1. The ’435
`
`patent discloses efficacy and tolerance data for nucleic acid-lipid particles
`
`spanning the amended range (i.e., 54 mol % to 70 mol %). See, e.g., EX1001,
`
`Table 2, 4, and 6. Furthermore, post-filing date data includes nucleic acid-lipid
`
`particle formulations with 50 mol % and 57 mol % cationic lipid. See e.g. EX2017,
`
`Figure 7 (testing several 1:57 formulations); EX2018, Figure 5 (same); EX2019,
`
`¶46, Table 1, (testing the 1:50 formulation directed at the commercial product,
`
`Onpattro™ (i.e., patisiran)); Semple et al., Rational Design of Cationic Lipids for
`
`siRNA Delivery, 28 Nature Biotechnology 172-178, 177 (2010) (“Semple,”
`
`EX2021)(testing 1:57 formulations). That is, the data demonstrating the
`
`unexpected efficacy and tolerance of the claimed nucleic acid-lipid particle
`
`formulations is nearly co-extensive with the claimed range. The narrowed range
`
`further supports a conclusion of nexus with the unexpected results. EX2040, ¶44.
`
`-16-
`
`
`

`

`
`
`(iii)
`
`“wherein the particle is formulated such that that the
`nucleic acid is not substantially degraded after
`exposure of the particle to a nuclease at 37ºC for 20
`minutes”
`The contingent amendment further recites that the serum-stable nucleic acid-
`
`lipid particles to those particles that are “formulated such that that the nucleic acid
`
`is not substantially degraded after exposure of the particle to a nuclease at 37ºC for
`
`20 minutes,” and is responsive to arguments presented in the petition and the
`
`institution decision. EX2040, ¶45.
`
`As explained in the ’435 patent, nucleic acids are protected from degradation
`
`by a nuclease when encapsulated in serum-stable nucleic acid-lipid particles.
`
`In preferred embodiments, a SNALP comprising a nucleic acid such as
`an interfering RNA (e.g., siRNA) is encapsulated within the lipid portion
`of the particle, such that the nucleic acid in the SNALP is not
`substantially degraded after exposure of the particle to a nuclease at
`37°C. for at least about 20, 30, 45, or 60 minutes.
`
`EX1001, 22:55-62, see also id. at 47:12-16. A person of ordinary skill in the art
`
`would thus understand that the claimed serum-stable nucleic acid-lipid particles are
`
`limited to such particles that can withstand nuclease exposure for 20 min at 37°C.
`
`EX2040, ¶46.
`
`The prior art cited in the petition and relied on in the institution decision
`
`does not disclose nucleic acid-lipid particles formulated for systemic use that can
`
`withstand nuclease exposure for 20 min at 37°C. See id., ¶47.
`-17-
`
`
`

`

`
`
`With respect to Ground 1, the ’196 PCT reports exposure of exemplary
`
`nucleic acid-lipid particles to a nuclease degradation assay, however none of the
`
`exemplary formulations have cationic lipid and conjugated lipid levels within the
`
`scope of claim 1. See e.g. EX1008, ¶48 (teaching that a much lower concentration
`
`of cationic lipids than claimed is appropriate for systemic delivery); see also
`
`EX2040, ¶48.
`
`With respect to Ground 2, neither Lin nor Ahmad discloses a nuclease
`
`degradation assay nor do they disclose whether the lipoplex formulations protected
`
`nucleic acid from degradation. Moreover, Lin and Ahmad disclose in vitro testing
`
`of formulations — that is, in an environment where protection of nucleic acids
`
`from nuclease degradation is unnecessary. EX1005 at 9; EX1006 at 747; EX2007,
`
`2:27-40, 2:57; see also EX2040, ¶49.
`
`Finally, with respect to Ground 3, the ’554 publication does not disclose a
`
`nuclease degradation assay nor does it disclose whether any lipid particle
`
`formulation protects nucleic acid from degradation. See, e.g., EX1004 ¶¶136, 158,
`
`395, 462 (only performing in vitro tests for lipid mixtures cited by the Petitioner).
`
`The foregoing explains how the contingent amendment limitations of claim
`
`21 are responsive to the grounds of challenge and to the institution decision. A
`
`person of ordinary skill in the art would understand the additional limitations of
`
`-18-
`
`
`

`

`
`
`claim 21 further distinguish over the prior art cited against the patentability of
`
`original claims 1-20 of the ’435 patent.
`
`IV. CONCLUSION
`
`For the foregoing reasons, if the contingency occurs the Board should permit
`
`amendment of the claims in the form of claims 21-40, and find these claims
`
`patentable and allow these claims to issue in the ’435 patent.
`
`
`
`Date: December 21, 2018
`
`Respectfully submitted,
`
`
`
`/ Michael T. Rosato /
`Michael T. Rosato, Lead Counsel
`Reg. No. 52,182
`
`
`
`-19-
`
`
`

`

`
`
`CERTIFICATE OF SERVICE
`
`I certify that the foregoing Patent Owner’s Contingent Motion to Amend
`
`was served on this 21st day of December, 2018, on the Petitioner at the following
`
`electronic service addresses:
`
`
`Michael Fleming
`C. Maclain Wells
`IRELL & MANELLA LLP
`mfleming@irell.com
`mwells@irell.com
`ModernaIPR@irell.com
`
`
`
`
`
`
`
`Date: December 21, 2018
`
`
`
`
`
`Respectfully submitted,
`
`
`/ Michael T. Rosato /
`Michael T. Rosato, Lead Counsel
`Reg. No. 52,182
`
`
`
`
`
`-20-
`
`
`

`

`
`
`APPENDIX A
`
`Proposed amended claims are shown in marked-up form in the listing of
`
`claims below. The substitute claims have: (1) underlining indicating inserted text,
`
`and (2) double brackets indicating deleted text:
`
`
`
`
`
`21.
`
`(Substitute for claim 1, if found unpatentable) A serum-stable nucleic
`
`acid-lipid particle comprising:
`
`
`
`
`
`(a) a nucleic acid;
`
`(b) a cationic lipid comprising from 50 mol % to [[85]] 75 mol % of the total
`
`lipid present in the particle;
`
`
`
`(c) a non-cationic lipid comprising from [[13]] 23 mol % to 49.5 mol% of
`
`the total lipid present in the particle; and
`
`
`
`(d) a conjugated lipid that inhibits aggregation of particles comprising from
`
`0.5 mol % to 2 mol % of the total lipid present in the particle;
`
`
`
`wherein the particle is formulated such that that the nucleic acid is not
`
`substantially degraded after exposure of the particle to a nuclease at 37ºC for 20
`
`minutes.
`
`
`
`
`
`22.
`
`(Substitute for claim 2, if found unpatentable) The nucleic acid-lipid
`
`particle of claim [[1]] 21, wherein the nucleic acid comprises an interfering RNA,
`
`-i-
`
`
`

`

`
`
`mRNA, an antisense oligonucleotide, a ribozyme, a plasmid, an
`
`immunostimulatory oligonucleotide, or mixtures thereof.
`
`
`
`
`
`23.
`
`(Substitute for claim 3, if found unpatentable) The nucleic acid-lipid
`
`particle of claim [[2]] 22, wherein the interfering RNA comprises a small
`
`interfering RNA (siRNA), an asymmetrical interfering RNA (aiRNA), a
`
`microRNA (miRNA), or mixtures thereof.
`
`
`
`
`
`24.
`
`(Substitute for claim 4, if found unpatentable) The nucleic acid-lipid
`
`particle of claim [[1]] 21, wherein the cationic lipid comprises from 50 mol % to
`
`65 mol % of the total lipid present in the particle.
`
`
`
`
`
`25.
`
`(Substitute for claim 5, if found unpatentable) The nucleic acid-lipid
`
`particle of claim [[1]] 21, wherein the non-cationic lipid comprises a mixture of a
`
`phospholipid and cholesterol or a derivative thereof.
`
`
`
`
`
`26.
`
`(Substitute for claim 6, if found unpatentable) The nucleic acid-lipid
`
`particle of claim [[5]] 25, wherein the phosph