Arbutus Biopharma Corporation

Patent Trials and Appeals Board

Jul 23, 2020

IPR2019-00554 (P.T.A.B. Jul. 23, 2020)

Trials@uspto.gov Paper 40
571-272-7822 Entered: July 23, 2020

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

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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).

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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.
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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,
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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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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 §§ 102, 103 ’196 PCT,3 ’189 Publication4
1–22 § 103
’196 PCT, ’189 Publication, Lin,5
Ahmad6
1–22 §§ 102, 103 ’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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II. ANALYSIS
A. Level of Skill in the Art
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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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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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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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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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
LCα and inverted hexagonal H
C
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 L
C
α complexes, H
C
I I com-
plexes exhibit no dependence on σM (Fig. 4 D). This demonstrates a
structural basis (LCα versus H
C
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 HCI I and
LCα complexes and also for L
C
α 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 LCα complexes reveals a critical mem-
brane charge density (σ*M ) where LCα complexes with σM > σ*M achieve
high TE competitive with HCI I complexes. Thus, for example, to pro-
duce a high TE of LCα complexes with large mole fractions of the neutral
lipid requires that use of multivalent cationic lipid such as DOSPA to
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ensure that σM > σ*M . Previous to what we report here, it was thought
that one could not make a high TE LCα complex with such large mole
fractions of DOPC. In principle, extremely large mole fractions of neu-
tral helper lipid may be incorporated within an LCα 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 LCα 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 HCI I complexes always transfect much more efficiently
than lamellar LCα complexes. Our work has led us to redesigned L
C
α com-
plexes, which easily compete with the high TE of HCI 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)
Ahmad also studied transfection efficiencies with differing membrane
charge densities of CL-DNA complexes finding a universal, bell-shaped curve.
Ex. 1007, 739. Ahmad found that “[t]his [bell-shaped] curve leads to the identifi-
cation of three distinct regimes, related to interactions between complexes and
cells: at low σM, TE increases with increasing in σM; at intermediate in σM , TE ex-
hibits saturated behavior; and unexpectedly, at high in σM, TE decreases with in-
creasing in σM.” Id. Ahmad found that the intermediate, optimal regime “reflects a
compromise between the opposing demands on σM for endosomal escape and dis-
sociation in the cytosol.” Id.
In studying TE as a function of lipid composition, Ahmad transfected mouse
fibroblast cells at various MVL/DOPC ratios and included data for the monovalent
lipid DOTAP mixed with DOPC, a reference system. Id. at 743. As in Lin, dis-
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-
plexes. Id.
Figure 3A of Ahmad is depicted below.

Figure 3A, above, plots the TE data as a function of the molar fraction of cationic
lipid. In interpreting Figure 3A shown above, Ahmad finds that
[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.
Id.
In comparing the membrane charge density to a varying lipid/DNA charge
ratio, as the lipid/DNA charge ratio is increased above 1, a maximum in transfec-
tion efficiency defining the optimal membrane charge density emerges, and a bell
curve of efficiency is observed with the optimal membrane charge density shifting
to higher values with increasing lipid/DNA charge ratio. Id. Referring to Figure
5C, Ahmad found that the maximum TE does not change appreciably with the li-
pid/DNA charge ratio. Id. Therefore, Ahmad concludes that
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.
Id. at 745–46.
5. The ’554 Publication (Ex. 1005)
The ’554 Publication discloses “novel cationic lipids, microparticles and
transfection agents that effectively transfect or deliver biologically active mole-
cules,” including “short interfering nucleic acid” and “siRNA,” to “relevant cells
and/or tissues, such as in a subject or organism.” Ex. 1005 ¶ 2. The ’554 Publica-
tion identifies two structurally different complexes comprising nucleic acid and
cationic lipid: a lamellar structure in which the nucleic acid monolayers sand-
wiched between cationic lipid bilayers, and an inverted hexagonal structure “in
which nucleic acid molecules are encircled by cationic lipid in the formation of a
hexagonal structure.” Id. ¶ 13. The ’554 Publication concludes that converting the
complexes to an inverted hexagonal structure using a suitable helper lipid or a co-
surfactant, however, is not suitable for delivery in biological systems. Id. ¶ 14.
Therefore, the ’554 Publication identifies a “need to design delivery agents that are
serum stable, i.e. stable in circulation, that can undergo structural transformation,
for example from lamellar phase to inverse hexagonal phase under biological con-
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.
Id. ¶ 15.
The ’554 Publication describes examples of serum-stable formula-
tions, e.g., the “L053” and “L054” formulations, as follows:
In one embodiment, the invention features a serum-stable formu-
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.
The L054 formulation was utilized in two evaluations, one of a formulated
siNA composition in models of chronic HBV infection, and a second of a formu-
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
vitro HCV replicon model of HCV infection showed an “example of formulated
siNA L053 and L054 (Table IV) nanoparticle constructs targeting viral replication
in a Huh7 HCV replicon system in a dose dependent manner.” Id. ¶ 400. Table
IV, a portion of which is reproduced below, identifies various lipid nanoparticle
formulations, including the applicable compositions and molar ratios for such for-
mulations.
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Id. at Table IV (partial). The partially reproduced table above identifies the appli-
cable compositions and molar ratios for the L051, L053, and L053 formulations,
which are four-component particles containing a cationic lipid, a phospholipid,
cholesterol, and a conjugated lipid. The L051 formulation has a composition of
CLinDMA/DSPC/Chol/PEG-n-DMG at a molar ratio of 48/40/10/2. The L053 and
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
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 claims their meaning.” Lindemann Maschinenfabrik GMBH v. Am. Hoist
& Derrick Co., 730 F.2d 1452, 1459 (Fed. Cir. 1984). “[U]nless a reference dis-
closes within the four corners of the document not only all of the limitations
claimed but also all of the limitations arranged or combined in the same way as re-
cited in the claim, it cannot be said to prove prior invention of the thing claimed
and, thus, cannot anticipate under 35 U.S.C. § 102.” Net MoneyIN, Inc. v. Ver-
iSign, Inc., 545 F.3d 1359, 1371 (Fed. Cir. 2008).
“[A]nticipation by inherent disclosure is appropriate only when the reference
discloses prior art that must necessarily include the unstated limitation.”
Transclean Corp. v. Bridgewood Servs., Inc., 290 F.3d 1364, 1373 (Fed. Cir.
2002). “Inherency, however, may not be established by probabilities or possibili-
ties. The mere fact that a certain thing may result from a given set of circumstances
is not sufficient.” Cont’l Can Co. USA, Inc. v. Monsanto Co., 948 F.2d 1264, 1269
(Fed. Cir. 1991). “The concept of ‘inherent disclosure’ does not alter the require-
ment that all elements must be disclosed in an anticipatory reference in the same
way as they are arranged or combined in the claim.” Therasense, 593 F.3d at
1332.
The disclosure of a broader range for a genus in the prior art does not neces-
sarily anticipate a narrower claimed range for a particular species. “If the prior art
discloses its own range, rather than a specific point, then the prior art is only antici-
patory if it describes the claimed range with sufficient specificity such that a rea-
sonable fact finder could conclude that there is no reasonable difference in how the
invention operates over the ranges.” Ineos USA LLC v. Berry Plastics Corp., 783
F.3d 865, 869 (Fed. Cir. 2015); see Atofina v. Great Lakes Chem. Corp., 441 F.3d
991, 998–1000 (Fed. Cir. 2006) (determining that prior art’s disclosure of a 100 to
500 °C temperature range and a 0.001 to 1.0 percent molar ratio range did not con-
stitute a “specific disclosure” of claims requiring a temperature range of 330 to 450
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°C and a molar ratio range of 0.1 to 5.0 percent). In some instances, an overlap-
ping range disclosed in the prior art may be sufficient to anticipate a claim when
the narrower claimed range is not shown to be “critical” to the invention, i.e., that
the invention would not operate differently across the broader range disclosed in
the prior art. Ineos, 783 F.3d at 869–871; see also ClearValue, Inc. v. Pearl River
Polymers, Inc., 668 F.3d 1340, 1345 (Fed. Cir. 2012).
b. Obviousness
A patent claim is unpatentable under 35 U.S.C. § 103 if the differences be-
tween the claimed subject matter and the prior art are such that the subject matter,
as a whole, would have been obvious at the time the invention was made to a per-
son having ordinary skill in the art to which said subject matter pertains. KSR Int’l
Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007). In Graham v. John Deere Co. of
Kansas City, 383 U.S. 1 (1966), the Supreme Court set out a framework for as-
sessing obviousness under § 103 that requires consideration of four factors: (1) the
“level of ordinary skill in the pertinent art,” (2) the “scope and content of the prior
art,” (3) the “differences between the prior art and the claims at issue,” and (4)
“secondary considerations” of nonobviousness such as “commercial success, long
felt but unsolved needs, failure of others, etc.” Id. at 17–18; KSR, 550 U.S. at 407.
“A prima facie case of obviousness typically exists when the ranges of a
claimed composition overlap the ranges disclosed in the prior art,” and “such over-
lap creates a presumption of obviousness.” E.I. Dupont De Nemours & Co. v.
Synvina C.V., 904 F.3d 996, 1006 (Fed. Cir. 2018) (“Dupont”) (citing In re Peter-
son, 315 F.3d 1325, 1329 (Fed. Cir. 2003)). The Dupont court recognized four dif-
ferent ways by which this presumption may be rebutted. “First, a modification of a
process parameter may be patentable if it ‘produce[s] a new and unexpected result
which is different in kind and not merely in degree from the results of the prior
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art.’” Id. (citing In re Aller, 220 F.2d 454, 456 (CCPA 1955)). “Second, and relat-
edly, a patentee may rebut the presumption of obviousness by showing that the
prior art taught away from the claimed range.” Id. (citing Ormco Corp. v. Align
Tech., Inc., 463 F.3d 1299, 1311 (Fed. Cir. 2006)). “Third, a change to a parame-
ter may be patentable if the parameter was not recognized as ‘result-effective.’”
Id. (citing In re Applied Materials, Inc., 692 F.3d 1289, 1295 (Fed. Cir. 2012)).
“Fourth, [the] disclosure of very broad ranges may not invite routine optimization.”
Id. (citing Genetics Inst., LLC v. Novartis Vaccines & Diagnostics, Inc., 655 F.3d
1291, 1306 (Fed. Cir. 2011)).
“The normal desire of scientists or artisans to improve upon what is already
generally known provides the motivation to determine where in a disclosed set of .
. . ranges is the optimum combination.” Peterson, 315 F.3d at 1330. “[W]here the
general conditions of a claim are disclosed in the prior art, it is not inventive to dis-
cover the optimum or workable ranges by routine experimentation.” Aller, 220
F.2d at 456. However, the parameter to be optimized must have been recognized
by those skilled in the art to be a “result-effective variable.” In re Antonie, 559
F.2d 618, 620 (CCPA 1977). “While the absence of any disclosure regarding the
relationship between the variable and the affected property may preclude a finding
that the variable is result-effective, the prior art need not provide the exact method
of optimization for the variable to be result-effective.” Applied Materials, Inc.,
692 F.3d at 1297. Rather, “[a] recognition in the prior art that a property is af-
fected by the variable is sufficient to find the variable result-effective.” Id. More-
over, where multiple result-effective variables are combined, “[e]vidence that the
variables interacted in an unpredictable or unexpected way could render the combi-
nation nonobvious.” Id. at 1298 (citing KSR, 550 U.S. at 421).

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2. Ground 1: Anticipation or Obviousness in View of the ’196 PCT or
the ’189 Publication
Under Ground 1, Petitioner contends that claims 1–22 are anticipated or ren-
dered obvious by each of the ’196 PCT and the ’189 Publication. Pet. 31–49. As
it is dispositive to our conclusions here, we focus our analysis on independent
claim 1. We address both the anticipation and obviousness challenges together be-
low.
As discussed above, the ’196 PCT and ’189 Publication each generally dis-
close nucleic acid-lipid particles containing a cationic lipid component within a
broad range of 2–60% of the total lipid present in the particle. Ex. 1003 ¶ 88;
Ex. 1004 ¶ 9. The references disclose that a non-cationic lipid component is pre-
sent within a broad range of 5–90% of the total lipid present. Ex. 1003 ¶ 91; Ex.
1004 ¶¶ 10, 152. The ’196 PCT also discloses a bilayer stabilizing component,
which may be a conjugated lipid, with the broadest range of 0.5–50%, and the
’189 Publication more particularly discloses a PEG-lipid conjugate within a range
of 0.5–20%. Ex. 1003 ¶ 22; Ex. 1004 ¶¶ 11, 152. Each of these references also
discloses examples of non-cationic lipids that include phospholipids and choles-
terol. Ex. 1003 ¶ 89; Ex. 1004 ¶ 159. And the references disclose that, if choles-
terol is included as a non-cationic lipid, it may be present within a broad range of
about 10–60% of the total lipid present. Ex. 1003 ¶ 91; Ex. 1004 ¶¶ 12, 152.
Petitioner does not point to any express disclosure of a phospholipid range in
either the ’196 PCT or the ’189 Publication. Petitioner, however, contends that
“when combined with a cationic lipid proportion at the high end of the disclosed
range (i.e., 60%), the available range for cholesterol is decreased to 20-40%,” and
“[t]he range for the other non-cationic lipid (e.g., a phospholipid) is also decreased
to the portion not filled with cholesterol (or PEG conjugate as described below in
Claim 1(e)), namely 0%-19.5%.” Pet. 39. Petitioner contends that “[g]iven the
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breadth of the claimed ranges for the phospholipid and cholesterol, these disclo-
sures are sufficiently specific to anticipate the claimed ranges.” Id. Petitioner also
contends that “[g]iven the explicit disclosure of encompassing ranges, this limita-
tion is prima facie obvious.” Id. Petitioner contends that the overlapping ranges
creates a presumption of obviousness under Dupont. Id. at 32. Petitioner summa-
rizes a scenario in which the claimed ranges overlap the prior art ranges in the fol-
lowing table:

Id. at 39. Petitioner’s table above identifies the claimed ranges for each lipid com-
ponent and the amounts or ranges in the prior art disclosures that Petitioner con-
tends overlaps the claimed ranges.
We have considered the arguments and evidence presented and determine
that Petitioner has not met its burden with respect to its Ground 1 challenges. In
particular, we determine that the teachings of the ’196 PCT and ’189 Publication
do not anticipate or otherwise render obvious a nucleic acid-lipid particle contain-
ing each of the recited lipid components within the claimed ranges, including spe-
cifically a phospholipid range of 4–10%.9

9 The Board reached a similar conclusion with respect to a dependent claim requir-
ing a phospholipid range of 3–15% for the related ’435 patent that was challenged
in the ’739 IPR. See IPR2018-00739, Paper 51 at 30–32, 35–37. Although the
challenged claims of the ’069 patent are different from those considered by the
Board in the ’739 IPR—insofar as the claims here require both phospholipid and
cholesterol and recite a slightly narrower phospholipid range—Petitioner’s basic
argument as to why the prior art satisfies the phospholipid range requirement is the
same. We reach our conclusions here based on the evidence and arguments pre-
sented in this proceeding.
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As to the anticipation challenge under this Ground, there is no dispute that
neither the ’196 PCT nor the ’189 Publication recites any range specifically for a
phospholipid component that falls within or overlaps the claimed 4–10% range.
Petitioner also does not rely upon an inherent anticipation theory to argue that the
phospholipid range is necessarily satisfied by the prior art disclosures. Nonethe-
less, Petitioner contends that a POSA would have understood that the claimed
phospholipid range is satisfied because the references disclose a broader range of
5–90% for non-cationic/neutral lipids and identify phospholipids as one of the dis-
closed species of non-cationic/neutral lipids. Pet. Reply 5. We are unpersuaded by
this contention.
Here, the 5–90% range for non-cationic lipids generally disclosed in the
’196 PCT and ’189 Publication is considerably broader than the 4–10% range
claimed specifically for phospholipids. Moreover, the references each disclose
more preferred ranges for the non-cationic lipids that do not overlap with the
claimed phospholipid range. Ex. 1003 ¶ 91 (disclosing a preferred range of 20–
85% for the non-cationic lipid); Ex. 1004 ¶ 152 (disclosing more preferred
amounts of 10–85%, 20–80%, 30–70%, 40–60%, and 48% for the non-cationic li-
pid). Petitioner does not contend that the amount of phospholipid would not be
considered “critical” to the claimed invention such that the broader prior art range
may nonetheless anticipate the narrower claimed range. See Ineos, 783 F.3d at
869. To the contrary, Petitioner acknowledges that having too much phospholipid
“will inhibit release of the payload upon contact with the endosome.” Pet. Reply
21–22. As discussed further below in addressing Petitioner’s optimization argu-
ments, the evidence of record does not suggest the claimed nucleic acid-lipid parti-
cle would operate in the same manner if the phospholipid amount was adjusted
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across the entirety of the 5–90% range disclosed in the ’196 PCT and ’189 Publica-
tion.10
As to the obviousness challenge under this Ground, we are not persuaded by
Petitioner’s contention that the claims are presumed prima facie obvious in light of
the overlapping ranges disclosed in the prior art such that the burden of production
shifts to Patent Owner. As stated above, neither the ’196 PCT nor the ’189 Publi-
cation explicitly discloses a phospholipid range. And while Petitioner derives an
overlapping phospholipid range by making certain assumptions about the other li-
pid components of the particle, nothing in Dupont or any other Federal Circuit de-
cision we are aware of suggests that a presumption of obviousness applies under
the circumstances presented here, i.e., when one of the claimed ranges for one of
the expressly claimed sub-components of the claimed composition is not neces-
sarily disclosed based on broader ranges for other components disclosed in the
prior art.11 To the contrary, the Federal Circuit has only applied the presumption
where the overlapping range is expressly disclosed, not where an overlap might be
assumed based on other motivating factors. See Galderma Labs., L.P. v. Tolmar,
Inc., 737 F.3d 731, 738 (Fed. Cir. 2013) (noting that burden of production shifts to

10 Although Petitioner has also pointed to the ’189 Publication’s disclosure of the
2:40 formulation that included 10% phospholipid, the amounts of cholesterol
(48%) and cationic lipid (40%) in that formulation do not satisfy the claim require-
ments, and thus the 2:40 formulation cannot anticipate the claims. Ex. 1004 ¶ 351.
11 We recognize that a prior art range that is not expressly disclosed may nonethe-
less be satisfied by necessary implication in some circumstances. For example, a
reference that expressly discloses a four-component nucleic acid-lipid particle con-
taining 60% cationic lipid, 20–30% cholesterol, 0.5–6% conjugated lipid, with the
balance of the lipid content being phospholipid, necessarily implies an overlapping
phospholipid range of 4–19.5%. But that is not the situation presented by Peti-
tioner in this case.

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patentee “where there is a range disclosed in the prior art, and the claimed inven-
tion falls within that range”) (emphasis added); Ormco Corp. v. Align Tech., Inc.,
463 F.3d 1299, 1311 (Fed. Cir. 2006) (“Where a claimed range overlaps with a
range disclosed in the prior art, there is a presumption of obviousness.”) (emphasis
added). We, therefore, do not find a presumption of obviousness to be appropriate
in this case. As explained below, Petitioner’s motivations and assumptions for
choosing amounts of the various lipid components from the broadly disclosed
ranges in the prior art to arrive at an overlapping phospholipid range are not neces-
sarily well-founded. Furthermore, as also explained below, even if a presumption
could apply here, it is rebutted because we find nothing in the cited evidence indi-
cating that the amount of phospholipid in a nucleic acid-lipid particle was recog-
nized in the prior art as a result-effective variable.
Petitioner arrives at a phospholipid range of 0–19.5% by first assuming that
the skilled artisan would have selected a cationic lipid amount of 60%, cholesterol
in the amount 20–40%, and PEG in the amount of 0.5–25%. Pet. 39. Petitioner,
however, does not explain sufficiently why a POSA would have chosen those par-
ticular amounts of the other non-phospholipid components from the broader ranges
disclosed in the references. Indeed, Petitioner’s assumption of PEG in an amount
up to 25% is contradictory to the maximum amount of 20% for the PEG-lipid con-
jugate disclosed in the ’189 Publication. Ex. 1004 ¶ 152. Although Petitioner indi-
cates that a POSA would have been motivated to maximize the cationic lipid
amount in order to increase transfection efficiency, there is no persuasive reason
provided as to why the amounts of the remaining lipid components (and in particu-
lar the phospholipid) would have necessarily overlapped with the claimed ranges.
The ’196 PCT and ’189 Publication only identify phospholipid as an optional ex-
ample of a non-cationic lipid, and we find nothing in the references that suggests
that a particle with all four claimed lipid components was necessary or desirable.
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Other prior art of record shows that two and three component lipid particles were
known in the art. See, e.g., Ex. 1006, 3308 (Lin describing two component parti-
cles comprising cationic lipid and phospholipid, but lacking cholesterol or a conju-
gated lipid); Ex. 1010, 51, Figs. 1 and 2 (Bennet describing three component lipid
particles comprising cationic lipid, phospholipid, and cholesterol, but lacking a
conjugated lipid); Ex. 1005, 90, Table IV (’554 Publication describing three com-
ponent lipid particles comprising cationic lipid, cholesterol, and a conjugated lipid,
but lacking phospholipid). Nor does Petitioner point to any suggestion in the ’196
PCT or the ’189 Publication that the entirety of the broadly disclosed ranges could
apply if all four claimed lipid components were to be included as part of the nu-
cleic-acid lipid particle.
In addition to the overlapping ranges argument, Petitioner argues that adjust-
ing the amount of the various lipid components in the particle would have been a
matter of “routine optimization,” and identifies reasons to optimize the amounts of
cationic lipid, conjugated lipid, cholesterol, and phospholipid to arrive at the
claimed amounts. Pet. Reply 7–22. With respect to the phospholipid component,
Petitioner contends that a POSA would have been motivated to include a phospho-
lipid as a bilayer stabilizing component, but would have been aware that having
too much phospholipid will inhibit the release of the “payload” (i.e., the nucleic
acid) upon contact with the endosome of the target cell. Id. at 21. Because the
concentrations of the different lipid components are highly interdependent, Peti-
tioner contends that the range of phospholipid must necessarily be decreased when
a higher amount of cationic lipid is used and cholesterol is added to the mix. Id. at
21–22. Petitioner also points to the 2:40 formulation disclosed in the ’189 Publica-
tion as the starting point for optimization. Id. at 7–8.
We are not persuaded by Petitioner’s routine optimization argument at least
as applied to the claimed phospholipid range. We have considered the testimony
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of Petitioner’s experts and find it unpersuasive in supporting Petitioner’s routine
optimization argument. Dr. Janoff did not present any arguments for why the
skilled artisan would have been motivated to optimize the phospholipid component
in his declaration submitted with the Petition. See generally Ex. 1008. At his dep-
osition, Dr. Janoff testified that the non-cationic lipid range of 13–49.5% recited in
the related ’435 patent represented an “immense universe”—“some phospholipids,
some not”—and “in order for a person of ordinary skill in the art to find utility be-
cause of the immense range, this would require undue experimentation, not simple
optimization.” Ex. 2033, 59:11–60:16.
In the expert declaration submitted with Petitioner’s Reply, Dr. Anchordo-
quy attests that “[a]s with the conjugated lipid, a [POSA] would have been aware
that having some amount of phospholipid can provide structural stability to the re-
sulting particles, but having too much will inhibit release of the payload upon con-
tact with the endosome.” Ex. 1020 ¶ 109. Dr. Anchordoquy, however, does not
support this assertion with any prior art teaching (or other persuasive evidence
showing) that the amount of phospholipid was known to affect structural stability
or the payload release of the nucleic acid-particle. See Ashland Oil, Inc. v. Delta
Resins & Refractories, Inc., 776 F.2d 281, 294 (Fed. Cir. 1985) (“Lack of factual
support for expert opinion going to factual determinations” at hand “may render
the testimony of little probative value in a validity determination.”). Rather, Dr.
Anchordoquy only cites to prior art showing that stability and delivery efficiency
were general considerations to be taken into account when designing a nucleic
acid-lipid particle. Id. ¶ 107 (citing Ex. 1005 ¶ 137; Ex. 1024, 239–40). The por-
tions of the prior art references cited by Dr. Anchordoquy above do not mention
phospholipids. Dr. Anchordoquy also notes that “[e]ach prior art reference dis-
closes four lipid component particles that are effective in vivo which contain a
phospholipid” and “[t]he disclosed phospholipid range is thus not theoretical.” Id.
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¶ 108 (citing Ex. 1003 ¶ 223; Ex. 1004 ¶¶ 289, 369; Ex. 1005, Table IV). While
this may be true, there is nothing in the cited portions of those references that dis-
closes how the phospholipid amount affects the properties of the nucleic acid-lipid
particle.
Petitioner also cites to the deposition testimony of Patent Owner’s expert
Dr. Thompson as an admission that it was “known to add [phospholipid] to ‘stabi-
lize [the] complex.’” Pet. Reply 21 (citing Ex. 1025, 28:8–22). Dr. Thompson’s
testimony, however, is more nuanced than what is suggested by Petitioner. When
asked whether DSPC and DPPC (two particular types of phospholipids) were “con-
sidered potential helper lipids for delivery particles,” Dr. Thompson responded as
follows:
Those two lipids were often referred to or were thought of, at the
time of the ’069, were viewed as a way to stabilize the complex. So
helper not in the sense that that language was typically used in the lit-
erature where helper, meaning helping the cargo to escape the endo-
some. That’s not the property that those lipids were designed to impart
in the complex. DPPC and DSPC are helping in the sense that they are
helping the stability of the complex during circulation. They are
providing -- by our understanding, providing the kind of serum stability
that allows your, the particle to reach its target.
Ex. 1025, 28:8–22. Thus, while Dr. Thompson stated that two particular phospho-
lipids, DPPC and DSPC, “were viewed as a way to stabilize the complex,” he did
not state that the prior art recognized that the amount of phospholipid could be ad-
justed in order to impart serum stability. When pressed for other reasons people in
the industry would include a phospholipid in the carrier particles, Dr. Thompson
emphasized that one would need “an understanding of how all the components
work together” rather than “just as a sum of a set of components.” Id. at 29:11–
30:3. And when asked to confirm that those in the industry had a “hypothesis” that
phospholipids increased serum stability, Dr. Thompson noted “there were different
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hypotheses of what role the components were playing,” “[a]nd the measurable out-
come is the result of viewing it as more than one component of the . . . formula-
tion.” Id. at 30:4–15. Dr. Thompson also indicated that the motivation to include a
phospholipid could have been based on commercial considerations or what was
readily available in the laboratory rather than any recognition in the art that it af-
fected the stability of the particle during circulation. Id. at 30:16–31:5.
We thus find the testimony of the parties’ experts insufficient to establish
that the claimed phospholipid range in particular was a recognized result-effective
variable subject to routine optimization. See Dupont, 904 F.3d at 1008 (“The idea
behind the ‘result-effective variable’ analysis is . . . that a person of ordinary skill
would not always be motivated to optimize a parameter ‘if there is no evidence in
the record that the prior art recognized that [that] particular parameter affected the
result.’”) (quoting Antonie, 559 F.2d at 620).
We have also considered, but are not persuaded by, Petitioner’s argument re-
lying upon the “2:40” formulation disclosed in the working examples as the start-
ing point for optimization. Pet. 26; Pet. Reply 6–7. The 2:40 formulation includes
40% cationic lipid, 2% conjugated lipid, 48% cholesterol, and 10% phospholipid.
Ex. 1004 ¶ 351. Petitioner does not sufficiently explain in its Petition or Reply
how or why a POSA would have modified the 2:40 formulation to arrive at the
claimed amounts. However, during oral argument, Petitioner’s counsel argued that
a POSA would have been motivated to upwardly adjust the amount of cationic li-
pid in order to increase transfection efficiency, maintain the amount of conjugated
lipid at 2% and the amount of phospholipid at 10%, and downwardly adjust the
amount of cholesterol in order to balance out the remaining lipid content. Tr.
14:9–15:25. We are not persuaded by this contention even assuming it was
properly and timely presented. Although Petitioner identifies reasons to adjust
each of the lipid components individually, Petitioner’s optimization argument does
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not take into account the interdependence of the claimed lipid components or how
the adjustments would affect the nucleic acid-lipid particle as a whole. The parties
are in agreement that “the concentrations of different lipid components are highly
interdependent.” PO Resp. 28; Pet. Reply 21.
Even if a POSA would have been primarily motivated by a desire to improve
transfection efficiency by increasing the amount of cationic lipid, Petitioner does
not explain why that would have prompted the POSA to maintain the same amount
of conjugated lipid and phospholipid as the 2:40 formulation, while decreasing the
amount of cholesterol. Indeed, if a POSA had chosen to maximize the amount of
cationic lipid at 60% (the highest amount within the prior art range), maintain the
amount of conjugated lipid at 2% and the phospholipid at 10%, the remaining
available balance of 28% for the cholesterol component would not fall within the
claimed range of 30–40%. The cited references also suggest that lower amounts of
cationic lipid and higher amounts of phospholipid were acceptable. In this regard,
we note that the ’189 Publication also discusses a “2:30” formulation, which con-
tained a higher amount of phospholipid (20%) and a lower amount of cationic lipid
(30%) than what is required by the challenged claims. Ex. 1004 ¶ 327. The work-
ing examples demonstrated significant downregulation of the Apo-B protein using
the 2:30 formulation. See, e.g., id. ¶ 301 (noting that treatment with a 5 mg/kg
dosage using a 2:30 SNALP led to a decrease in ApoB expression as much as
88%). Petitioner does not direct us to anything in the references suggesting that
the 2:40 formulation would have been considered a more appropriate starting point
for optimization than the 2:30 formulation. Thus, any further adjustments to the
amounts of the various lipid components in the 2:40 formulation in order to meet
the claim requirements appears, on this record, to be hindsight driven.
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In sum, Petitioner has not demonstrated by a preponderance of the evidence
that claim 1 is anticipated by either the ’196 PCT or the ‘189 Publication. Peti-
tioner has also not demonstrated by a preponderance of the evidence that claim 1 is
obvious based on the overlapping ranges disclosed in the ’196 PCT and the ’189
Publication or the 2:40 formulation disclosed in the ’189 Publication.12 Because
each of dependent claims 2–22 further narrows the scope of claim 1, Petitioner has
also not proven anticipation or obviousness of these dependent claims for the same
reasons.
3. Ground 2: Obviousness in View of Patent Owner’s Prior Dis-
closures and in Light of Lin and Ahmad
Under Ground 2, Petitioner asserts that claims 1–22 are obvious in view of
Patent Owner’s “prior disclosures” in light of Lin and Ahmad. Pet. 49–53. Peti-
tioner relies upon the teachings of the ’196 PCT and the ’189 Publication, as dis-
cussed above for Ground 1, as Patent Owner’s prior disclosures under this ground.
Petitioner contends that:
[t]o the extent that those disclosures alone are determined not to dis-
close a proportion of cationic lipid in the 50%–65% range, a [POSA]
would have understood from Lin and Ahmad that such proportions of
cationic lipid may increase transfection efficacy and would have been
motivated to combine those disclosures with the system disclosed in the

12 For the grounds based on obviousness, Patent Owner also contends that objec-
tive indicia, including evidence of unexpected results, long-felt need, failure of
others, skepticism, and commercial success, further rebut any prima facie obvious-
ness. PO Resp. 31–50. Because we have determined that Petitioner has not met its
burden of showing obviousness based on the first three Graham factors, we need
not address Patent Owner’s objective indicia arguments and evidence. See Otsuka
Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1296 (Fed. Cir. 2012) (“Because we
agree with the district court that the Defendants failed to prove that claim 12 of the
’528 patent would have been prima facie obvious over the asserted prior art com-
pounds, we need not address the court’s findings regarding objective evidence of
nonobviousness.”).
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’196 PCT and ’189 publication with a reasonable expectation of suc-
cess.
Id. at 49.
As set forth above, we determine neither the ’196 PCT nor the ’189 Publica-
tion teach or otherwise suggest a phospholipid range of 4–10%. Petitioner does
not rely upon the teachings of Lin or Ahmad to make up this for deficiency with
respect to the claimed phospholipid range. We thus determine that claims 1–22 are
not rendered obvious based on the additional teachings of Lin and Ahmad.
4. Ground 3: Anticipation or Obviousness in View of the ’554
Publication
Under Ground 3, Petitioner contends that claims 1–22 are anticipated or ren-
dered obvious by the ’554 Publication. Pet. 54–67. We again focus our analysis
on claim 1 as it is dispositive to our conclusions here.
As discussed above, the ’554 Publication generally discloses nucleic acid-
lipid particles wherein the cationic lipid component can comprise from about 2–
60% of the total lipid, the neutral (non-cationic) lipid can comprise from about 5–
90% of the total lipid, the PEG conjugate can comprise from about 1–20% of the
total lipid, and cholesterol can comprise from about 10–60% of the total lipid.
Ex. 1005 ¶¶ 116–119, 313. Although the reference also identifies phospholipids
among the examples of useful non-cationic lipids (id. ¶ 455), it does not teach any
range specifically for the amount of phospholipid that may be included in the parti-
cle.
Petitioner’s arguments for how the phospholipid range is satisfied by the
’554 Publication are similar to those presented under Ground 1 with respect to the
’196 PCT and ’189 Publication. Pet. 57–58. Petitioner points to the more pre-
ferred range of 20–85% for the neutral lipid component and the more preferred
range of 20–45% for the cholesterol component disclosed in the ’554 Publication.
Id. at 57 (citing Ex. 1005 ¶ 313). Petitioner also points to specific formulations
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discussed in the ’554 Publication that include cholesterol at a 30% proportion. Id.
(citing Ex. 1005, Table 4 (e.g., L106)). Petitioner contends that “when the cationic
lipid is set at the maximum disclosed (i.e., 60%), the ’554 publication discloses the
remaining 40% can be made up of cholesterol at 20–40%.” Id. And “[w]hen the
cholesterol is less than the full remaining 40%, another non-cationic lipid (e.g., a
phospholipid) may be added at up to 20% (unless a PEG conjugate is also added . .
. , in which case this percentage is adjusted accordingly.)” Id. Petitioner summa-
rizes a scenario in which the claimed ranges overlap with the ranges disclosed in
the ’554 Publication in the following table:

Id. at 58. Petitioner’s table above identifies the claimed ranges for each lipid com-
ponent and the amounts or ranges disclosed in the ’554 Publication that Petitioner
contends overlaps the claimed ranges.
We have considered the arguments and evidence presented and determine
that Petitioner has not demonstrated that the ’554 Publication anticipates or renders
obvious the challenged claims. Our reasons are similar to those discussed above
with respect to Ground 1.
In particular, the ’554 Publication fails to recite any range for a phospholipid
component. We are also not persuaded the broader range of 5–90% (or even the
more preferred range of 20–85%) for non-cationic lipids generally disclosed is suf-
ficient to anticipate the claimed phospholipid range. As noted above, Petitioner
does not allege or otherwise point to any evidence suggesting that the phospholipid
range would not be critical such that a broader prior art range may nonetheless an-
ticipate the narrower claimed range.
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Furthermore, as with Ground 1, we are not persuaded that the ’554 Publica-
tion teaches an overlapping phospholipid range such that the claims are prima facie
obvious or that the adjustment of the phospholipid amount to within the claimed
range would have been a matter of routine optimization. In order to arrive at an
overlapping phospholipid range, Petitioner relies upon certain assumptions that are
not expressly supported in the ’554 Publication, e.g., by assuming that a skilled ar-
tisan would maximize the cationic lipid at 60% and balance the remaining amount
with cholesterol, a conjugated lipid, and phospholipid in amounts that overlap the
claimed range. But even assuming that a POSA would have been motivated to
maximize the cationic lipid amount in order to increase transfection efficiency,
there is no reason provided as to why the amounts of the remaining lipid compo-
nents (an in particular the phospholipid) would have overlapped with the claimed
ranges. In this regard, we note that most of the formulations disclosed in Table IV
of the ’554 Publication, including L106 identified by Petitioner, are three-compo-
nent systems lacking any phospholipid. Ex. 1005, 90, Table IV. And for the four-
component formulations that do include phospholipid, none of them include phos-
pholipid within the claimed range. Id. (e.g., L051 including 48% cationic lipid,
40% phospholipid, 10% cholesterol, and 2% conjugated lipid; L053 including 30%
cationic lipid, 20% phospholipid, 48% cholesterol, and 2% conjugated lipid). As
discussed above, Petitioner has not demonstrated that the amount of phospholipid
was recognized as a result-effective variable that could have been optimized.
In sum, Petitioner has not demonstrated by a preponderance of the evidence
that claim 1 is anticipated or rendered obvious by the ’554 Publication. Because
each of dependent claims 2–22 further narrows the scope of claim 1, Petitioner has
also not proven anticipation or obviousness of these dependent claims for the same
reasons.

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III. MOTIONS
A. Patent Owner’s Motion to Strike
Patent Owner moves to strike Petitioner’s Reply, in its entirety or at least
certain portions, for presenting untimely arguments. Paper 28. In particular Patent
Owner contends that the Reply presents a new theory that overlapping phospho-
lipid ranges could be derived by assuming levels for cationic lipid, cholesterol, and
conjugated lipid. Id. at 1–2. Patent Owner further contends that Petitioner’s asser-
tions of routine optimization and motivation to include optional lipids are un-
timely. Id. at 3–4. Patent Owner also contends that Petitioner’s belated arguments
regarding objective indicia and attempts to abandon Dr. Janoff’s testimony are im-
proper. Id. at 4–5. Petitioner filed an opposition to Patent Owner’s Motion to
Strike and Patent Owner filed a reply in support of its Motion to Strike. Paper 34;
Paper 36.
“A reply may only respond to arguments raised in the corresponding . . . pa-
tent owner response.” 37 C.F.R. § 42.23(b). It may be appropriate to strike argu-
ments in a reply where the petitioner identifies new portions of a prior art reference
to make a “meaningfully distinct contention” or presents an “entirely new ra-
tionale” not previously set forth in the petition. Ariosa Diagnostics v. Verinata
Health, Inc., 805 F.3d 1359, 1367 (Fed. Cir. 2015); Intelligent Bio-Systems, Inc. v.
Illumina Cambridge Ltd., 821 F.3d 1359, 1370 (Fed. Cir. 2016). The Federal Cir-
cuit, however, has also cautioned that the Board should not parse the arguments on
reply with “too fine a filter” and that the petitioner may appropriately use the reply
to “expand” or “elaborate” on a previously argued rationale,” or to otherwise re-
spond to arguments made in patent owner’s response. Apple Inc. v. Andrea Elecs.
Corp., 949 F.3d 697, 706 (Fed. Cir. 2020); Chamberlain Grp., Inc. v. One World
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Techs., Inc., 944 F.3d 919, 925 (Fed. Cir. 2019); Ericsson Inc. v. Intellectual Ven-
tures I LLC, 901 F.3d 1374, 1381 (Fed. Cir. 2018).
We are not persuaded that we should strike any portion of Petitioner’s Re-
ply. We agree with Patent Owner that Petitioner has appeared to shift its obvious-
ness theory in its Reply rather than merely expand or elaborate upon the arguments
presented in the Petition. For instance, with respect to the claimed phospholipid
range, Petitioner originally argued that the prior art explicitly disclosed an encom-
passing range. Pet. 38–39, 57–58. In its Reply, Petitioner argues that adjustment
of the phospholipid range would have been a matter of routine optimization since
“a [POSA] would have been aware that having some amount of phospholipid can
provide structural stability to the resulting particles, but having too much will in-
hibit release of the payload upon contact with the endosome.” Pet. Reply 21–22.
The Petition does not mention structural stability as a reason to optimize the phos-
pholipid amount. Petitioner in the Reply also points to the 2:40 formulation dis-
closed in the ’189 Publication. Pet. Reply 14–15. Although Petitioner generally
discussed the 2:40 formulation in the Petition (Pet. 26), Petitioner did not previ-
ously contend that the 2:40 formulation would have been the “starting point” for
optimization as argued in the Reply. Nonetheless, we also note that Patent Owner
in its Patent Owner’s Response specifically argued against routine optimization as
a basis for obviousness and also discussed the 2:40 formulation. PO Resp. 11–12,
19–27, 36. As such, Petitioner’s arguments on Reply may be considered properly
responsive to Patent Owner’s arguments. Furthermore, any surprise or prejudice to
Patent Owner based on the allegedly new arguments is mitigated in this case be-
cause Patent Owner substantively responded to those arguments in its Sur-Reply.
See Sur-Reply 12–21.
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Even upon considering the arguments in Petitioner’s Reply, we have deter-
mined that Petitioner has not met its burden of proving obviousness for the reasons
set forth above. We, therefore, deny Patent Owner’s Motion to Strike.
B. Patent Owner’s Motion to Exclude
Patent Owner also moves to exclude Exhibit 1020 (the declaration of
Dr. Anchordoquy) and portions of Exhibit 2033 (the deposition testimony of
Dr. Janoff). With respect to Dr. Anchordoquy’s declaration, Patent Owner argues
that Dr. Anchordoquy is a zoologist, not a lipid chemist with formal training in the
subject matter at hand, and thus is not qualified to provide opinion testimony in
this proceeding. Paper 31, 1–7. With respect to the portions of Dr. Janoff’s depo-
sition testimony, Patent Owner argues that counsel for Petitioner improperly used
an opportunity for redirect to fill in holes in Petitioner’s obviousness challenge. Id.
at 8–10. Petitioner filed an opposition to Patent Owner’s Motion to Exclude. Pa-
per 35.
We determine that Patent Owner’s arguments go to the weight that should be
afforded to Petitioner’s expert testimony rather than the admissibility of that testi-
mony. Accordingly, we deny Patent Owner’s Motion to Exclude.
IV. CONCLUSION
Petitioner has not demonstrated by a preponderance of the evidence that
claims 1–22 of the ’069 patent would have been anticipated or obvious based on
the challenges presented in the Petition. In summary:
Claims 35
U.S.C.
Reference(s)/Basis

Claims
Shown
Unpatentable
Claims
Not Shown
Unpatentable
1–22 §§ 102,
103
’196 PCT, ’189
Publication

1–22
1–22 § 103 ’196 PCT, ’189 1–22
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V. ORDER
Accordingly, it is hereby:
ORDERED that Petitioner has not demonstrated by a preponderance of the
evidence that claims 1–22 of the ’069 patent are unpatentable;
ORDERED that Patent Owner’s Motion to Strike is denied;
ORDERED that Patent Owner’s Motion to Exclude is denied; and
FURTHER ORDERED that, because this is a Final Written Decision, any
party to the proceeding seeking judicial review of the decision must comply with
the notice and service requirements of 37 C.F.R. § 90.2.

Publication, Lin,
Ahmad

1–22 §§ 102,
103
’554 Publication 1–22
Overall
Outcome
1–22
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PETITIONER:

Michael Fleming
C. Maclain Wells
IRELL & MANELLA LLP
mfleming@irell.com
mwells@irell.com

PATENT OWNER:

Michael T. Rosato
Steven W. Parmelee
Sonja R. Gerrard
Lora M. Green
WILSON SONSINI GOODRICH & ROSATI
mrosato@wsgr.com
sparmelee@wsgr.com
sgerrard@wsgr.com
lgreen@wsgr.com