Trials@uspto.gov
`571-272-7822
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` Paper 40
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`Entered: July 23, 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.
`____________
`
`IPR2019-00554
`Patent 8,058,069 B2
`____________
`
`
`Before TINA E. HULSE, CHRISTOPHER G. PAULRAJ, and TIMOTHY G. MA-
`JORS, Administrative Patent Judges.
`
`PAULRAJ, Administrative Patent Judge.
`
`
`
`
`JUDGMENT
`Final Written Decision - 35 U.S.C. § 318(a)
`Determining No Challenged Claims Unpatentable
`Denying Patent Owner’s Motion to Strike
`Denying Patent Owner’s Motion to Exclude
`
`
`
`
`

`

`IPR2019-00554
`Patent 8,058,069 B2
`
`
`
`I.
`
`INTRODUCTION
`
`A. Background and Summary
`
`This is a Final Written Decision entered pursuant to 35 U.S.C. § 318(a) and
`
`37 C.F.R. § 42.73.
`
`On January 9, 2019, Moderna Therapeutics, Inc., (“Petitioner”) filed a Peti-
`
`tion requesting institution of an inter partes review of claims 1–22 of U.S. Patent
`
`No. 8,058,069 B2 (“the ’069 patent,” Ex. 1001). Paper 1 (“Pet.”). Arbutus Bio-
`
`pharma Co. (“Patent Owner”) timely filed a Preliminary Response (Paper 7, “Pre-
`
`lim. Resp.”). In our Institution Decision, we determined that there was a reasona-
`
`ble likelihood that Petitioner would prevail with respect to at least one challenged
`
`claim and, accordingly, instituted an inter partes review pursuant to 35 U.S.C.
`
`§ 314 based on all grounds presented in the Petition. Paper 8 (“Inst. Dec.”). Fol-
`
`lowing institution, Patent Owner filed its post-institution Patent Owner Response
`
`(Paper 15, “PO Resp.”), Petitioner filed its Reply to Patent Owner’s Response (Pa-
`
`per 21, “Pet. Reply”), and Patent Owner filed its Sur-Reply (Paper 30, “Sur-Re-
`
`ply”). No motion to amend was filed in this proceeding. An oral hearing was held
`
`on April 22, 2020, and a transcript of that hearing has been entered into the record.
`
`Paper 39 (“Tr.”).
`
`For the reasons set forth below, having considered all the evidence and argu-
`
`ments set forth by the parties, we determine that Petitioner has not shown by a pre-
`
`ponderance of the evidence that claims 1–22 of the ’069 patent are unpatentable
`
`under 35 U.S.C. § 103. We also deny Patent Owner’s Motion to Strike Petitioner’s
`
`Reply (Paper 28) and Patent Owner’s Motion to Exclude certain evidence (Paper
`
`31).
`
`
`
`
`
`2
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`IPR2019-00554
`Patent 8,058,069 B2
`
`B. Related Proceedings
`
`Petitioner filed petitions seeking inter partes review of two additional pa-
`
`tents held by Patent Owner in IPR2018-00680, challenging U.S. Patent No.
`
`9,404,127 B2, and IPR2018-00739 (“the ’739 IPR”), challenging U.S. Patent No.
`
`9,364,435 B2 (“the ’435 patent).1 Pet. 4; Paper 4, 2–3. The Board instituted re-
`
`view in each proceeding on September 11, 2018. See IPR2018-00680 (Paper 13);
`
`IPR2018-00739 (Paper 15). The ’435 patent at issue in the ’739 IPR is a continua-
`
`tion of the ’069 patent challenged here. Ex. 1002, code (63).
`
`C. The ’069 Patent (Ex. 1001)
`
`The ’069 patent relates to lipid formulations for nucleic acid delivery and, in
`
`particular, “stable nucleic acid-lipid particles (SNALP) comprising a nucleic acid
`
`(such as one or more interfering RNA), methods of making the SNALP, and meth-
`
`ods of delivering and/or administering the SNALP.” Ex. 1001, Abstract. These
`
`nucleic-acid lipid particles may be used to deliver nucleic acids to cells for thera-
`
`peutic techniques such as RNA interference (RNAi). Id. at 1:28–40. The ’069 pa-
`
`tent states that
`
`[t]he present invention is based, in part, upon the surprising discovery
`that lipid particles comprising from about 50 mol % to about 85 mol %
`of a cationic lipid, from about 13 mol % to about 49.5 mol % of a non-
`cationic lipid, and from about 0.5 mol % to about 2 mol % of a lipid
`conjugate provide advantages when used for the in vitro or in vivo de-
`livery of an active agent, such as a therapeutic nucleic acid (e.g., an
`interfering RNA).
`
`Id. at 5:44–51. The ’069 patent further states that
`
`the present invention provides [SNALPs] that advantageously impart
`increased activity of the encapsulated nucleic acid (e.g., an interfering
`
`1 Patent Owner explains that Protiva Biotherapeutics, Inc., identified as the patent
`owner in IPR2018-00680 and IPR2018-00739, previously “existed as a wholly-
`owned subsidiary of Arbutus Biopharma Corporation,” and was “amalgamated into
`Arbutus Biopharma Corporation in January 2018.” Paper 4, 2.
`
`
`
`3
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`

`

`IPR2019-00554
`Patent 8,058,069 B2
`
`RNA such as siRNA) and improved tolerability of the formulations in
`vivo, resulting in a significant increase in the therapeutic index as com-
`pared to nucleic acid-lipid particle compositions previously described.
`Additionally, the SNALP of the invention are stable in circulation, e.g.,
`resistant to degradation by nucleases in serum and are substantially
`non-toxic to mammals such as humans.
`
`Id. at 5:51–61.
`
`The ’069 patent identifies specific SNALP formulations that encapsulate
`
`siRNA as the nucleic acid, such as the “1:57 SNALP” and the “1:62 SNALP,” and
`
`states that “the Examples herein illustrate that the improved lipid particle formula-
`
`tions of the invention are highly effective in downregulating the mRNA and/or
`
`protein levels of target genes.” Ex. 1001, 6:6–15. In characterizing the 1:57
`
`SNALP and 1:62 SNALP formulations, the ’069 patent explains that these are “tar-
`
`get formulations, and [] the amount of lipid (both cationic and non-cationic) pre-
`
`sent and the amount of lipid conjugate present in the formulation may vary.” Id. at
`
`68:35–39. In this regard, the ’069 patent explains that the 1:57 SNALP formula-
`
`tion usually includes 57 mol % ± 5 mol % cationic lipid and 1.5 mol % ± 0.5 mol
`
`% lipid conjugate, with non-cationic lipid making up the balance of the formula-
`
`tion. Id. at 68:39–43. Similarly, the 1:62 SNALP formulation typically includes
`
`62 mol % ± 5 mol % cationic lipid and 1.5 mol % ± 0.5 mol % lipid conjugate,
`
`with non-cationic lipid making up the remainder. Id. at 68:44–48.
`
`The ’069 patent describes several studies comparing the efficacy of siRNA
`
`encapsulated in different SNALP formulations. For example, in a study examining
`
`siRNA SNALP formulations directed at silencing Eg5, a kinesin-related protein
`
`critical for mitosis in mammalian cells (Ex. 1001, 68:55–62), the ’069 patent re-
`
`ports that the 1:57 SNALP formulation “was among the most potent inhibitors of
`
`tumor cell growth at all siRNA concentrations tested” (id. at 70:19–22). Similarly,
`
`
`
`4
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`

`IPR2019-00554
`Patent 8,058,069 B2
`
`in a test of SNALP formulations targeting apolipoprotein B (“ApoB”), a protein as-
`
`sociated with hypercholesterolemia (id. at 70:55–59), the ’069 patent explains that
`
`the 1:57 SNALP formulation “was the most potent at reducing ApoB expression in
`
`vivo” (id. at 72:21–23). The ’069 patent also reports experimental results indicat-
`
`ing that the ApoB 1:57 SNALP formulation “was more than 10 times as effica-
`
`cious as the 2:30 SNALP [a prior art SNALP composition] in mediating ApoB
`
`gene silencing in mouse liver at a 10-fold lower dose” (id. at 73:64–67), and that
`
`the “1:57 and 1:62 SNALP formulations had comparable ApoB silencing activity
`
`in vivo” (id. at 74:51–53).
`
`D. Challenged Claims
`
`Petitioner challenges claims 1–22 of the ’069 patent. Claim 1, the sole inde-
`
`pendent claim of the ’069 patent, is illustrative, and is reproduced below:
`
`1.
`
`A nucleic acid-lipid particle comprising:
`
`(a) a nucleic acid;
`
`(b) a cationic lipid comprising from 50 mol % to 65 mol % of
`the total lipid present in the particle;
`
`(c) a non-cationic lipid comprising a mixture of a phospholipid
`and cholesterol or a derivative thereof, wherein the phospholipid com-
`prises from 4 mol % to 10 mol % of the total lipid present in the parti-
`cle and the cholesterol or derivative thereof comprises from 30 mol %
`to 40 mol % of the total lipid present in the particle; and
`
`(d) a conjugated lipid that inhibits aggregation of particles com-
`prising from 0.5 mol % to 2 mol % of the total lipid present in the par-
`ticle.
`
`Ex. 1001, 91:23–35.
`
`
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`IPR2019-00554
`Patent 8,058,069 B2
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`E. Asserted Grounds of Unpatentability
`
`Petitioner asserts the following grounds of unpatentability (Pet. 5):
`
`Claims Challenged
`
`35 U.S.C.2
`
`Reference(s)/Basis
`
`1–22
`
`1–22
`
`1–22
`
`§§ 102, 103
`
`§ 103
`
`§§ 102, 103
`
`’196 PCT,3 ’189 Publication4
`’196 PCT, ’189 Publication, Lin,5
`Ahmad6
`’554 Publication7
`
`Petitioner relies upon the Declaration of Dr. Andrew S. Janoff, Ph.D.,
`
`(Ex. 1008) in support of its Petition and the Declaration of Thomas J. Anchordo-
`
`quy, Ph.D., (Ex. 1020) in support of its Reply.8 Patent Owner relies upon the Dec-
`
`laration of David H. Thompson, Ph.D., (Ex. 2031) in support of its Patent Owner
`
`Response.
`
`
`2 The Leahy-Smith America Invents Act (“AIA”) included revisions to 35 U.S.C.
`§§ 102 and 103 that became effective on March 16, 2013. Because the ’069 patent
`issued from an application filed before March 16, 2013, we apply the pre-AIA ver-
`sion of the statutory bases for unpatentability.
`
` 3
`
` MacLachlan et al., WO 2005/007196 A2, published Jan. 27, 2005 (“’196 PCT”).
`Ex. 1003.
`
`4 MacLachlan et al., US 2006/0134189 A1, published Jun. 22, 2006 (“’189 Publi-
`cation”). Ex. 1004.
`
`5 Lin et al., Three-Dimensional Imaging of Lipid Gene-Carriers: Membrane
`Charge Density Controls Universal Transfection Behavior in Lamellar Cationic
`Liposome-DNA Complexes, 84 BIOPHYSICAL J. 3307–16 (2003) (“Lin”). Ex. 1006.
`
`6 Ahmad et al., New Multivalent Cationic Lipids Reveal Bell Curve for Transfec-
`tion Efficiency Versus Membrane Charge Density: Lipid-DNA Complexes for
`Gene Delivery, 7 J. GENE MED. 739–48 (2005) (“Ahmad”). Ex. 1007.
`
`7 Chen et al., US 2006/0240554 A1, published Oct. 26, 2006 (“’554 Publication”).
`Ex. 1005.
`8 Dr. Janoff unfortunately passed away on December 19, 2019 and Dr. Anchordo-
`quy stepped in as Petitioner’s declarant. Paper 25, 2.
`
`
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`IPR2019-00554
`Patent 8,058,069 B2
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`
`
`A. Level of Skill in the Art
`
`II. ANALYSIS
`
`Petitioner, relying upon the testimony of Dr. Janoff, contends that a person
`
`of ordinary skill in the art (“skilled artisan” or “POSA”) for the ’069 patent “would
`
`have specific experience with lipid particle formation and use in the context of de-
`
`livering therapeutic nucleic acid payloads, and would have a Ph.D., an M.D., or a
`
`similar advanced degree in an allied field (e.g., biophysics, microbiology, bio-
`
`chemistry) or an equivalent combination of education and experience.” Pet. 6 (cit-
`
`ing Ex. 1008 ¶¶ 29–32). Petitioner further asserts that “[t]his level of skill is repre-
`
`sentative of the authors/inventors of prior art cited herein.” Id. (citing Ex. 1008
`
`¶¶ 29–32). In his Reply Declaration, Dr. Anchordoquy agrees with the level of
`
`skill in the art that was previously set forth by Dr. Janoff. Ex. 1020 ¶ 25.
`
`In its Preliminary Response, Patent Owner noted in a footnote that “[e]ach of
`
`the petition challenges are additionally flawed for being based on an improper if
`
`not indeterminable, proffered level of skill. Indicative of impermissible hindsight,
`
`the petition equates the level of skill of the artisan with the level of skill of the arti-
`
`sans of the ’069 patent.” Prelim. Resp. 15, n.2. Patent Owner does not address the
`
`level of skill in the art in its post-institution Response. But Patent Owner’s expert,
`
`Dr. Thompson, applies the definition of a person of ordinary skill in the art adopted
`
`by the Board in IPR2018-00739 as to the related ’435 patent. Ex. 2031 ¶¶ 28–29.
`
`That definition is consistent with the level of skill proposed by Petitioner and its
`
`experts.
`
`In our Institution Decision, we adopted Dr. Janoff’s definition of the POSA
`
`because Dr. Janoff testified that he is familiar with the technology at issue and the
`
`state of the art at the earliest priority date for the ’069 patent, and because he ex-
`
`plained that he arrived at his definition of the level of ordinary skill in the art in
`
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`IPR2019-00554
`Patent 8,058,069 B2
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`light of his “review of the ’069 patent, its file history, and [his] knowledge of the
`
`field of the art.” Ex. 1008 ¶¶ 30–31; Inst. Dec. 11–13. We determine that this
`
`level of ordinary skill in the art is consistent with the evidence of the record, in-
`
`cluding the level of skill reflected in the prior art of record. See Okajima v.
`
`Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001). We continue to apply that same
`
`skill level in our analysis for this Final Written Decision. We further find that the
`
`parties’ experts are qualified to provide opinions about the ’069 patent from the
`
`perspective of the POSA.
`
`B. Claim Construction
`
`Based on the filing date of the Petition, we apply the same claim construc-
`
`tion standard used in federal district court, which includes construing the claim in
`
`accordance with the ordinary and customary meaning of the claim as understood
`
`by one of ordinary skill in the art and the prosecution history pertaining to the pa-
`
`tent. See Changes to the Claim Construction Standard for Interpreting Claims in
`
`Trial Proceedings Before the Patent Trial and Appeal Board, 83 Fed. Reg. 51,340,
`
`51,340, 51,358 (Oct. 11, 2018) (amending 37 C.F.R. § 42.100(b) effective Novem-
`
`ber 13, 2018) (now codified at 37 C.F.R. § 42.100(b) (2019)).
`
`Petitioner proposed a construction for “nucleic acid-lipid particle.” Pet. 23.
`
`Patent Owner contends that no claim construction is necessary, but also disputes
`
`Petitioner’s proffered construction of “nucleic acid-lipid particle.” PO Resp. 9–10.
`
`We determine that it is not necessary to construe any claim terms to resolve the is-
`
`sues before us. See Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co.
`
`Ltd., 868 F.3d 1013, 1017 (Fed. Cir. 2017) (noting that “we need only construe
`
`terms ‘that are in controversy, and only to the extent necessary to resolve the con-
`
`troversy’”) (citing Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803
`
`(Fed. Cir. 1999)).
`
`
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`IPR2019-00554
`Patent 8,058,069 B2
`
`
`
`C. Overview of the Prior Art
`
`Petitioner relies primarily upon the following prior art teachings in its chal-
`
`lenge.
`
`1. The ’196 PCT (Ex. 1003)
`
`The ’196 PCT describes “compositions and methods for the therapeutic de-
`
`livery of a nucleic acid by delivering a serum-stable lipid delivery vehicle encapsu-
`
`lating the nucleic acid to provide efficient RNA interference (RNAi) in a cell or
`
`mammal.” Ex. 1003 ¶ 2. More particularly, the ’196 PCT discloses “using a small
`
`interfering RNA (siRNA) encapsulated in a serum-stable lipid particle having a
`
`small diameter suitable for systemic delivery.” Id. ¶¶ 2, 10.
`
`In describing one embodiment, the ’196 PCT states that the nucleic acid-li-
`
`pid comprises a cationic lipid, a non-cationic lipid, a conjugated lipid, a bilayer sta-
`
`bilizing component for inhibiting aggregation of particles, and a siRNA. Id. ¶¶ 11,
`
`85 (describing SNALP with the same components). In describing how embodi-
`
`ments are made, the ’196 PCT also states that preferred embodiments are charge
`
`neutralized. Id. ¶ 14.
`
`The ’196 PCT further provides detailed descriptions of the components of
`
`SNALPs. See Ex. 1003 ¶¶ 86–107. Concerning the preferred makeup of the dis-
`
`closed SNALPs, the ’196 PCT states the following about the amount of cationic li-
`
`pid included as part of the particle:
`
`The cationic lipid typically comprises from about 2% to about
`60% of the total lipid present in said particle, preferably from about 5%
`to about 45% of the total lipid present in said particle. In certain pre-
`ferred embodiments, the cationic lipid comprises from about 5% to
`about 15% of the total lipid present in said particle. In other preferred
`embodiments, the cationic lipid comprises from about 40% to about
`50% of the total lipid present in said particle. Depending on the in-
`tended use of the nucleic acid-lipid particles, the proportions of the
`
`
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`IPR2019-00554
`Patent 8,058,069 B2
`
`components are varied and the delivery efficiency of a particular for-
`mulation can be measured using an endosomal release parameter (ERP)
`assay. For example, for systemic delivery, the cationic lipid may com-
`prise from about 5% to about 15% of the total lipid present in said par-
`ticle and for local or regional delivery, the cationic lipid comprises from
`about 40% to about 50% of the total lipid present in said particle.
`
`Id. ¶ 88.
`
`For the amount of non-cationic lipid content of the SNALP, the ’196 PCT
`
`states that “[t]he non-cationic lipid typically comprises from about 5% to about
`
`90% of the total lipid present in said particle, preferably from about 20% to about
`
`85% of the total lipid present in said particle.” Id. ¶ 91.
`
`With regard to the bilayer stabilizing component, such as a conjugated lipid,
`
`the ’196 PCT states the following:
`
`Typically, the bilayer stabilizing component is present ranging
`from about 0.5% to about 50% of the total lipid present in the particle.
`In a preferred embodiment, the bilayer stabilizing component is present
`from about 0.5% to about 25% of the total lipid in the particle. In other
`preferred embodiments, the bilayer stabilizing component is present
`from about 1% to about 20%, or about 3% to about 15% or about 4%
`to about 10% of the total lipid in the particle. One of the ordinary skill
`in the art will appreciate that the concentration of the bilayer stabilizing
`component can be varied depending on the bilayer stabilizing compo-
`nent employed and the rate at which the liposome is to become fuso-
`genic [i.e., has the ability to fuse with membranes of a cell].
`
`Id. ¶ 93. The ’196 PCT also states that “[b]y controlling the composition and the
`
`concentration of the bilayer stabilizing component, one can control the rate at
`
`which the bilayer stabilizing component exchanges out of the liposome and, in
`
`turn, the rate at which the liposome becomes fusogenic.” Id. ¶ 94.
`
`2. The ’189 Publication (Ex. 1004)
`
`The ’189 Publication describes “nucleic acid-lipid particles comprising
`
`siRNA molecules that silence ApoB expression and methods of using such nucleic
`
`acid-lipid particles to silence ApoB expression.” Ex. 1004, Abstract. In describing
`
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`IPR2019-00554
`Patent 8,058,069 B2
`
`these nucleic acid-lipid particles, the ’189 Publication states that they may com-
`
`prise an siRNA molecule that silences ApoB expression, a cationic lipid, a non-cat-
`
`ionic lipid, and a conjugated lipid that inhibits aggregation of particles. Id. ¶ 8. In
`
`describing the relative weight percentages of the content of the nucleic acid-lipid
`
`particles, the ’189 Publication states:
`
`The cationic lipid may comprise from about 2 mol % to about 60 mol
`%, about 5 % mol % to about 45 mol %, about 5 mol % to about 15
`mol%, about 30 mol % to about 50 mol % or about 40 mol % to about
`50 mol % of the total lipid present in the particle.
`
`. . . The non-cationic lipid comprises from about 5 mol % to about
`90 mol % or about 20 mol % to about 85 mol % of the total lipid present
`in the particle.
`
`. . . The conjugated lipid that prevents aggregation of particles
`may comprise from about 0 mol % to about 20 mol %, about 0.5 mol
`% to about 20 mol %, about 1 mol % to about 15 mol %, about 4 mol
`% to about 10 mol %, or about . . . 2 mol % of the total lipid present in
`said particle.
`
`Id. ¶¶ 9–11; see id. ¶¶ 150–181 (describing the content of the SNALP).
`
`The ’189 Publication describes embodiments wherein the siRNA is fully en-
`
`capsulated in the nucleic acid-lipid particle. Id. ¶ 14. In particular, the ’189 Publi-
`
`cation discloses, as an example, the “2:40 formulation” that “was prepared using a
`
`Direct Dilution process” and discusses the formulations efficacy during tests. Id.
`
`¶¶ 351–391. The formulation comprises 10% molar distearoylphosphatidylcholine
`
`(DSPC) (a non-cationic phospholipid), 48% molar cholesterol, 2% PEG-CDMA (a
`
`conjugated lipid), and 40% 1,2-DiLinoleyloxy-N, N-dimethylaminopropane
`
`(DLinDMA) (a cationic lipid). Id. ¶ 351.
`
`3. Lin (Ex. 1006)
`
`Lin describes three-dimensional laser scanning confocal microscopy studies
`
`of cationic liposome-DNA (“CL-DNA”) complexes to study how to enhance trans-
`
`fection efficiencies (“TE”). Ex. 1006, Abstract. From these studies, Lin draws the
`
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`following conclusions concerning the TE of CL-DNA complexes for both lamellar
`
`α and inverted hexagonal HC
`LC
`I I nanostructures.
`
`We have identified the membrane charge density of the CL-vec-
`tor (i.e., the average charge per unit area of the membrane, σM) as a key
`universal parameter that governs the transfection efficiency (TE) be-
`
`havior of LCα complexes in cells. In contrast of LCα complexes, HC
`
`I I com-
`plexes exhibit no dependence on σM (Fig. 4 D). This demonstrates a
`α versus HC
`structural basis (LC
`I I) for the dependence of transfection effi-
`ciency on a physical-chemical parameter (σM) of CL-DNA complexes.
`The importance of the nanostructure of CL-DNA complexes to trans-
`fection mechanisms is further underscored in confocal microscopy im-
`ages showing distinct pathways and interactions with cells for HC
`I I and
`
`
`LCα complexes and also for LCα complexes with low and high σM.
`
`The claim that σM is a universal parameter for TE results from
`the observation that while TE magnitudes for univalent versus multiva-
`lent cationic lipids are different at the same values of the mole fraction
`of the neutral lipid (Fig. 4 A), the magnitudes are equal (within the ex-
`perimental error bars), when the comparison is made at the same value
`of σM (Fig. 4 B). Previous work by others has typically focused on
`optimizing transfection efficiency as a function of increasing cationic
`lipid-to-DNA charge ratio . . . . What is remarkable about what we
`report in this article is that all transfection efficiency measurements
`were done with 2 μg of plasmid DNA at a constant cationic-to-anionic
`charge ratio of 2.8 (chosen as it corresponded to the middle of a typical
`plateau region observed for optimal transfection conditions as a func-
`tion of increasing cationic-to-anionic charge ratio above the isoelectric
`point of the complex). Thus, the nearly four orders-of-magnitude in-
`crease observed in the universal transfection curve (Fig. 4 B) occurs
`under the condition where each data point contains the same amount of
`cationic charge form cationic lipid and anionic charge from DNA, and
`the variation in σM is achieved simply by varying the amount of neutral
`lipid.
`
`The universal TE curve for LC
`α complexes reveals a critical mem-
`brane charge density (σ*M ) where LC
`α complexes with σM > σ*M achieve
`high TE competitive with HC
`I I complexes. Thus, for example, to pro-
`duce a high TE of LC
`α complexes with large mole fractions of the neutral
`lipid requires that use of multivalent cationic lipid such as DOSPA to
`
`
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`

`IPR2019-00554
`Patent 8,058,069 B2
`ensure that σM > σ*M . Previous to what we report here, it was thought
`that one could not make a high TE LC
`α complex with such large mole
`fractions of DOPC. In principle, extremely large mole fractions of neu-
`tral helper lipid may be incorporated within an LC
`α complex with the
`retention of high TE if the condition of σM > σ*M is satisfied with the use
`of the appropriate multivalent cationic lipid. Recent work has shown
`such behavior with high TE LC
`α complexes with .80 mol fraction of
`DOPC and 0.20 mol fraction of a new multivalent cationic lipid, MVL5
`. . . .
`
`Before what we describe in our article, it was assumed that in-
`verted hexagonal HC
`I I complexes always transfect much more efficiently
`
`
`than lamellar LCα complexes. Our work has led us to redesigned LCα com-
`plexes, which easily compete with the high TE of HC
`I I complexes, even
`in the presence of large mole fractions of order 0.70 DOPC (Fig. 4 A,
`DOSPA/DOPC complexes).
`Id. at 3314–15.
`
`4. Ahmad (Ex. 1007)
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`Ahmad also studied transfection efficiencies with differing membrane
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`charge densities of CL-DNA complexes finding a universal, bell-shaped curve.
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`Ex. 1007, 739. Ahmad found that “[t]his [bell-shaped] curve leads to the identifi-
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`cation of three distinct regimes, related to interactions between complexes and
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`cells: at low σM, TE increases with increasing in σM; at intermediate in σM , TE ex-
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`hibits saturated behavior; and unexpectedly, at high in σM, TE decreases with in-
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`creasing in σM.” Id. Ahmad found that the intermediate, optimal regime “reflects a
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`compromise between the opposing demands on σM for endosomal escape and dis-
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`sociation in the cytosol.” Id.
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`In studying TE as a function of lipid composition, Ahmad transfected mouse
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`fibroblast cells at various MVL/DOPC ratios and included data for the monovalent
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`lipid DOTAP mixed with DOPC, a reference system. Id. at 743. As in Lin, dis-
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`cussed above, Ahmad prepared the complexes at a fixed lipid/DNA charge ratio of
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`2.8, which Lin found to be the optimum charge ratio for DOTAP/DOPC com-
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`plexes. Id.
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`Figure 3A of Ahmad is depicted below.
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`Figure 3A, above, plots the TE data as a function of the molar fraction of cationic
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`lipid. In interpreting Figure 3A shown above, Ahmad finds that
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`
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`[f]or all cationic lipids, a maximum in TE as a function of lipid compo-
`sition is observed: at 65 mol% for MVL2, 70 mol% for MVL3, 50
`mol% for MVL5, 55 mol% for TMVL5, and 90 mol% for DOTAP.
`The optimal molar ratio results in a TE that is over two decades higher
`than that of the lowest transfecting complexes in these systems, and
`each data set fits a skewed bell-shaped curve.
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`Id.
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`In comparing the membrane charge density to a varying lipid/DNA charge
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`ratio, as the lipid/DNA charge ratio is increased above 1, a maximum in transfec-
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`tion efficiency defining the optimal membrane charge density emerges, and a bell
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`curve of efficiency is observed with the optimal membrane charge density shifting
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`to higher values with increasing lipid/DNA charge ratio. Id. Referring to Figure
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`5C, Ahmad found that the maximum TE does not change appreciably with the li-
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`pid/DNA charge ratio. Id. Therefore, Ahmad concludes that
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`A relatively low lipid/DNA charge ratio, therefore, can be considered
`optimal since it allows for achievement of maximum TE with the least
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`amount of cationic lipid. This is due to the unexpected increase of
`σM* with ρchg. Minimizing the amount of cationic lipid is desirable to
`reduce cost as well as potential toxic effects of the cationic lipid. In
`addition, achieving a given σM with fewer, more highly charged mole-
`cules should mean a smaller metabolic effort for the elimination of the
`lipids from the cell. This reasoning would favor multivalent over mon-
`ovalent lipids. In this context, it is important to note that with the
`amounts of cationic lipid employed in our in vitro experiments, we find
`no toxic effects on the cells as judged by cell morphology and the
`amount of total cellular protein.
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`Id. at 745–46.
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`5. The ’554 Publication (Ex. 1005)
`
`The ’554 Publication discloses “novel cationic lipids, microparticles and
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`transfection agents that effectively transfect or deliver biologically active mole-
`
`cules,” including “short interfering nucleic acid” and “siRNA,” to “relevant cells
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`and/or tissues, such as in a subject or organism.” Ex. 1005 ¶ 2. The ’554 Publica-
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`tion identifies two structurally different complexes comprising nucleic acid and
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`cationic lipid: a lamellar structure in which the nucleic acid monolayers sand-
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`wiched between cationic lipid bilayers, and an inverted hexagonal structure “in
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`which nucleic acid molecules are encircled by cationic lipid in the formation of a
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`hexagonal structure.” Id. ¶ 13. The ’554 Publication concludes that converting the
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`complexes to an inverted hexagonal structure using a suitable helper lipid or a co-
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`surfactant, however, is not suitable for delivery in biological systems. Id. ¶ 14.
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`Therefore, the ’554 Publication identifies a “need to design delivery agents that are
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`serum stable, i.e. stable in circulation, that can undergo structural transformation,
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`for example from lamellar phase to inverse hexagonal phase under biological con-
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`ditions.” Id. In response to this, the ’554 Publication states that:
`
`The present application compounds, composition and method for
`significantly improving the efficiency of systemic and local delivery of
`biologically active molecules. Among other things, the present appli-
`cation provides compounds, compositions and methods for making and
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`using novel delivery agents that are stable in circulation and undergo
`structural changes under appropriate physiological conditions (e.g., pH)
`which increase the efficiency of delivery of biologically active mole-
`cules.
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`Id. ¶ 15.
`
`
`
`The ’554 Publication describes examples of serum-stable formula-
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`tions, e.g., the “L053” and “L054” formulations, as follows:
`
`In one embodiment, the invention features a serum-stable formu-
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`lated molecular composition comprising a biologically active molecule
`(e.g., a [short interfering nucleic acid (siNA)] molecule), a cationic li-
`pid, a neutral lipid, and a PEG-conjugate, in which the cationic lipid is
`DMOBA, the neutral lipid is distearoylphosphatidylcholine (DSPC),
`and the PEG conjugate is PEG-DMG. In another embodiment, the
`composition further comprises cholesterol or a cholesterol derivative.
`This is known as formulation L053 or L054 (see Table IV).
`
`Id. ¶ 140.
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`The L054 formulation was utilized in two evaluations, one of a formulated
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`siNA composition in models of chronic HBV infection, and a second of a formu-
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`lated siNA composition in an in vitro HCV replicon model of HCV infection. See
`
`id. ¶¶ 393, 400, 595, 603. The L054 formulation’s use in the chronic HBV infec-
`
`tion model showed an example of in vitro efficacy of siNA nanoparticles in reduc-
`
`ing HBsAg levels in HepG2 cells. Id. ¶ 395. The L054 formulation’s use in the in
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`vitro HCV replicon model of HCV infection showed an “example of formulated
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`siNA L053 and L054 (Table IV) nanoparticle constructs targeting viral replication
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`in a Huh7 HCV replicon system in a dose dependent manner.” Id. ¶ 400. Table
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`IV, a portion of which is reproduced below, identifies various lipid nanoparticle
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`formulations, including the applicable compositions and molar ratios for such for-
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`mulations.
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`Id. at Table IV (partial). The partially reproduced table above identifies the appli-
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`cable compositions and molar ratios for the L051, L053, and L053 formulations,
`
`which are four-component particles containing a cationic lipid, a phospholipid,
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`cholesterol, and a conjugated lipid. The L051 formulation has a composition of
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`CLinDMA/DSPC/Chol/PEG-n-DMG at a molar ratio of 48/40/10/2. The L053 and
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`L054 formulations both have a composition of DMOBA/DSPC/Chol/PEG-n-DMG
`
`at molar ratios of 30/20/48/2 and 50/20/28/2 respectively.
`
`D. Patentability Analysis
`
`1. Legal Standards
`
`a. Anticipation
`
`“For a claim to be anticipated, each claim element must be disclosed, either
`
`expressly or inherently, in a single prior art reference, and the claimed arrangement
`
`or combination of those elements must also be disclosed, either expressly or inher-
`
`ently, in that same prior art reference.” Therasense, Inc. v. Becton, Dickinson &
`
`Co., 593 F.3d 1325, 1332–33 (Fed. Cir. 2010). “Anticipation requires the presence
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`in a single prior art disclosure of all elements of a claimed invention arranged as in
`
`the claim.” Connell v. Sears, Roebuck & Co., 722 F.2d 1542, 1548 (Fed. Cir.
`
`1983). The requirement that the prior art elements themselves be “arranged as in
`
`the claim” means that claims cannot be “treated . . . as mere catalogs of separate
`
`parts, in disregard of the part-to-part relationships set forth in the claims and that
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`give the