Trials@uspto.gov
`571-272-7822
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` Paper No. 8
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` Entered: July 24, 2019
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MODERNA THERAPEUTICS, INC.,
`Petitioner,
`
`v.
`
`ARBUTUS BIOPHARMA CORPORATION,
`Patent Owner.
`____________
`
`Case IPR2019-00554
`Patent 8,058,069 B2
`____________
`
`
`
`Before CHRISTOPHER G. PAULRAJ, JACQUELINE T. HARLOW and
`TIMOTHY G. MAJORS, Administrative Patent Judges.
`
`HARLOW, Administrative Patent Judge.
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`35 U.S.C. § 314
`
`
`
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`
`571-272-7822
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` Paper No. 8
`
` Entered: July 24, 2019
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MODERNA THERAPEUTICS, INC.,
`Petitioner,
`
`v.
`
`ARBUTUS BIOPHARMA CORPORATION,
`Patent Owner.
`____________
`
`Case IPR2019-00554
`Patent 8,058,069 B2
`____________
`
`
`
`Before CHRISTOPHER G. PAULRAJ, JACQUELINE T. HARLOW and
`TIMOTHY G. MAJORS, Administrative Patent Judges.
`
`HARLOW, Administrative Patent Judge.
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`35 U.S.C. § 314
`
`
`
`
`
`
`
`IPR2019-00554
`Patent 8,058,069 B2
`
`
`I. INTRODUCTION
`
`Petitioner, Moderna Therapeutics, Inc., filed a Petition (Paper 1,
`
`“Pet.”), requesting inter partes review of claims 1–22 of U.S. Patent
`
`No. 8,058,069 B2 (Ex. 1001, “the ’069 patent”). Patent Owner, Arbutus
`
`Biopharma Corporation, timely filed a Preliminary Response (Paper 7,
`
`“Prelim. Resp.”).
`
`Under 35 U.S.C. § 314(a), an inter partes review may not be instituted
`
`unless the information presented in the petition “shows that there is a
`
`reasonable likelihood that the petitioner would prevail with respect to at
`
`least 1 of the claims challenged in the petition.” For the reasons stated
`
`below, we determine that there is a reasonable likelihood that Petitioner
`
`would prevail with respect to at least one challenged claim. We hereby
`
`institute inter partes review of the challenged claims on all the grounds of
`
`unpatentability asserted in the Petition.
`
`A. Related Matters
`
`Petitioner filed petitions seeking inter partes review of two additional
`
`patents 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 review in each proceeding on September 11, 2018.
`
`
`
`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.
`
`2
`
`
`
`IPR2019-00554
`Patent 8,058,069 B2
`
`See IPR2018-00680 (Paper 13); IPR2018-00739 (Paper 15). The
`
`’435 patent at issue in the ’739 IPR is a continuation of the ’069 patent
`
`challenged here. Ex. 1002, (63).
`
`B. The ’069 Patent
`
`The ’069 patent relates to “stable nucleic acid-lipid particles (SNALP)
`
`comprising a nucleic acid (such as one or more interfering RNA), methods
`
`of making the SNALP, and methods of delivering and/or administering the
`
`SNALP.” Ex. 1001, Abstract. The ’069 patent 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 delivery 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 stable nucleic acid-lipid particles
`(SNALP) that advantageously impart increased activity of the
`encapsulated nucleic acid (e.g., an interfering RNA such as
`siRNA) and improved tolerability of the formulations in vivo,
`resulting in a significant increase in the therapeutic index as
`compared 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 formulations of the invention are highly effective in
`
`3
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`IPR2019-00554
`Patent 8,058,069 B2
`
`downregulating the mRNA and/or protein levels of target genes.” Ex. 1001,
`
`5:61–6:3. In characterizing the 1:57 SNALP and 1:62 SNALP formulations,
`
`the ’069 patent explains that these are “target formulations, and [] the
`
`amount of lipid (both cationic and non-cationic) present 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 formulation
`
`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
`
`formulation. Id. at 68:39–44. 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 reports 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, in a test of SNALP
`
`formulations targeting apolipoprotein B (“ApoB”), a protein associated 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
`
`indicating that the ApoB 1:57 SNALP formulation “was more than 10 times
`
`as efficacious as the 2:30 SNALP [a prior art SNALP composition] in
`
`4
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`IPR2019-00554
`Patent 8,058,069 B2
`
`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).
`
`C. Challenged Claims
`
`Petitioner challenges claims 1–22 of the ’069 patent. Claim 1, the
`
`sole independent 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 comprises from 4 mol % to 10 mol % of the
`total lipid present in the particle 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 comprising from 0.5 mol % to 2 mol % of the total
`lipid present in the particle.
`
`Ex. 1001, 91:23–35.
`
`5
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`IPR2019-00554
`Patent 8,058,069 B2
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`D. Asserted Grounds of Unpatentability
`
`Petitioner asserts the following grounds of unpatentability (Pet. 5):
`
`Claims
`
`Basis
`
`References
`
`1–22
`
`§§ 102 and 103
`
`1–22
`
`§ 103
`
`1–22
`
`§§ 102 and 103
`
`’196 PCT 2 and ’189 Publication3
`’196 PCT, ’189 Publication, Lin,4 and
`Ahmad5
`’554 Publication6
`
`Petitioner also relies on the Declaration of Dr. Andrew S. Janoff,
`
`Ph.D. (Ex. 1008) to support its challenge.
`
`
`
`
`
`
`
`2 MacLachlan et al., WO 2005/007196 A2, published Jan. 27, 2005
`(“’196 PCT”). Ex. 1003.
`
`3 MacLachlan et al., US 2006/0134189 A1, published Jun. 22, 2006
`(“’189 Publication”). Ex. 1004.
`
`4 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.
`
`5 Ahmad et al., New Multivalent Cationic Lipids Reveal Bell Curve for
`Transfection Efficiency Versus Membrane Charge Density: Lipid-DNA
`Complexes for Gene Delivery, 7 J. GENE MED. 739–48 (2005) (“Ahmad”).
`Ex. 1007.
`
`6 Chen et al., US 2006/0240554 A1, published Oct. 26, 2006
`(“’554 Publication”). Ex. 1005.
`
`6
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`IPR2019-00554
`Patent 8,058,069 B2
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`
`II. ANALYSIS
`
`A. Patent Owner’s Request for Denial under 35 U.S.C. § 314(a)
`
`Patent Owner argues that the Petition should be denied under
`
`35 U.S.C. § 314(a). Prelim. Resp. 3–4. Section 314(a) states that
`
`[t]he Director may not authorize an inter partes review to be
`instituted unless the Director determines that the information
`presented in the petition filed under section 311 and any response
`filed under section 313 shows that there is a reasonable
`likelihood that the petitioner would prevail with respect to at least
`1 of the claims challenged in the petition.
`
`Under § 314(a), the Director has discretion to deny institution of an inter
`
`partes review. Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2140
`
`(2016) (“[T]he agency’s decision to deny a petition is a matter committed to
`
`the Patent Office’s discretion.”). We consider several non-exclusive factors
`
`when determining whether to deny institution under § 314(a), including
`
`1. whether the same petitioner previously filed a petition
`directed to the same claims of the same patent;
`
`2. whether at the time of filing of the first petition the
`petitioner knew of the prior art asserted in the second petition or
`should have known of it;
`
`3. whether at the time of filing of the second petition the
`petitioner already received the patent owner’s preliminary
`response to the first petition or received the Board’s decision on
`whether to institute review in the first petition;
`
`4. the length of time that elapsed between the time the
`petitioner learned of the prior art asserted in the second petition
`and the filing of the second petition;
`
`5. whether the petitioner provides adequate explanation
`for the time elapsed between the filings of multiple petitions
`directed to the same claims of the same patent;
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`IPR2019-00554
`Patent 8,058,069 B2
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`6. the finite resources of the Board; and
`
`7. the requirement under 35 U.S.C. § 316(a)(11) to issue
`a final determination not later than 1 year after the date on which
`the Director notices institution of review.
`
`General Plastic Indus. Co., Ltd. v. Canon Kabushiki Kaisha, Case IPR2016-
`
`01357, slip op. at 15–16 (PTAB Sept. 6, 2017) (Paper 19) (precedential).
`
`Our discretionary determination of whether to institute review also takes into
`
`account guidance in the Office Patent Trial Practice Guide, August 2018
`
`Update, 83 Fed. Reg. 39,989 (August 13, 2018) (“Trial Practice Guide
`
`Update”), https://go.usa.gov/xU7GP. In particular, the Trial Practice Guide
`
`Update states
`
`[t]here may be other reasons besides the “follow-on” petition
`context where the “effect . . . on the economy, the integrity of the
`patent system, the efficient administration of the Office, and the
`ability of the Office to timely complete proceedings,” 35 U.S.C.
`§ 316(b), favors denying a petition even though some claims
`meet the threshold standards for institution under 35 U.S.C.
`§§ 314(a), 324(a).
`
`Trial Practice Guide Update 10–11. We additionally construe our rules to
`
`“secure the just, speedy, and inexpensive resolution of every proceeding.”
`
`37 C.F.R. § 42.1(b); Deeper, UAB v. Vexilar, Inc., Case IPR2018-01310,
`
`slip op. at 42 (PTAB Jan. 24, 2019) (Paper 7) (informative).
`
`Patent Owner acknowledges that the ’739 IPR is directed to a
`
`different patent than is challenged in this proceeding. Prelim. Resp. 4.
`
`Nevertheless, Patent Owner contends that exercise of our discretion to deny
`
`institution is warranted here because the’069 patent and the previously
`
`challenged ’435 patent are related, “have similar, although not identical
`
`claims,” and face challenges based on the same prior art. Id. Patent Owner
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`8
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`IPR2019-00554
`Patent 8,058,069 B2
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`further contends that Petitioner knew of the prior art asserted in the
`
`’739 IPR, benefited from Patent Owner’s filings and the Board’s rulings in
`
`that case, and cannot justify the ten month delay between the filing of the
`
`petition in the ’739 IPR and its filing of this Petition. Id. at 6–7. Patent
`
`Owner additionally asserts that “re-litigating the issues of the ’739 IPR” is
`
`an inefficient use of the Board’s resources, and the potential overlap
`
`between this Decision and the forthcoming final decision in the ’739 IPR
`
`militate in favor of denial. Id. at 8–9 (emphasis omitted). Patent Owner
`
`concludes by arguing that the Petition is deficient because it does not
`
`address various arguments and evidence presented in the ’739 IPR, and that
`
`it was filed in an attempt to harass Patent Owner. Id. at 9–12.
`
`Certain of Patent Owner’s concerns regarding the overlap between
`
`this proceeding and the ’739 IPR resonate. For example, we recognize that
`
`it would have been more efficient for the parties and the Board had the two
`
`petitions been concurrently filed. But such efficiencies, as well as Patent
`
`Owner’s additional concerns, are outweighed in this case by the fact that the
`
`instant proceeding challenges a different patent, reciting claims of different
`
`scope, than are addressed in the ’739 IPR. For example, the sole
`
`independent claim of the ’069 patent includes specific requirements for
`
`cationic lipid, phospholipid, and cholesterol content not present in the sole
`
`independent claim of the ’435 patent. Compare Ex. 1001, 91:23–35 with
`
`Ex. 1002, 89:55–63. We are unaware of, and Patent Owner does not
`
`identify, any decision by the Board relying on a previously filed petition
`
`concerning one patent as a basis for denying institution under § 314(a) of a
`
`subsequent petition challenging a second (albeit, related) patent. In addition,
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`IPR2019-00554
`Patent 8,058,069 B2
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`the fact that the sole independent claim of the ’069 patent is narrower than
`
`that of the previously challenged ’435 patent defuses Patent Owner’s
`
`arguments that the Petition should have more thoroughly addressed the
`
`evidence of record in the ’739 IPR, and that the instant Petition was filed
`
`only to harass Patent Owner (Prelim. Resp. 8–12).
`
`Not only is this Petitioner’s first challenge to the ’069 patent, but
`
`neither Patent Owner nor Petitioner identifies any other challenge to the
`
`’069 patent before the Board. Cf. Valve Corp. v. Elec. Scripting Prods., Inc.,
`
`Case IPR2019-00062, -00063, -00084, Paper 11 (Apr. 2, 2019)
`
`(precedential) (exercising discretion to deny institution of follow-on petition
`
`filed by a party having a “significant relationship” with the party that filed
`
`the first petition against the challenged patent, and where there was
`
`complete overlap in the challenged claims between the petitions). Nor do
`
`the parties apprise us of litigation concerning the ’069 patent in another
`
`forum. To the contrary, Patent Owner represents that “there is no underlying
`
`district court dispute over the ’069 patent.” Prelim. Resp. 11; cf. NHK
`
`Spring Co., Ltd. v. Intri-Plex Techs., Inc., Case IPR2018-00752, Paper 8
`
`(Sept. 12, 2018) (precedential) (recognizing the advanced state of a
`
`co-pending district court proceeding involving the same petitioner asserting
`
`the same prior art relied on in its petition for inter partes review as an
`
`additional factor weighing in favor of discretionary denial under § 314(a)).
`
`Accordingly, because this inter partes review represents the first
`
`challenge to the ’069 patent before the Board or elsewhere, based on a
`
`balanced assessment of the circumstances of this case, we decline to exercise
`
`our discretion to deny institution under § 314(a).
`
`10
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`IPR2019-00554
`Patent 8,058,069 B2
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`
`B. Level of Ordinary Skill in the Art
`
`Petitioner contends that a person of ordinary skill in the art (“skilled
`
`artisan” or “POSITA”) “would have specific experience with lipid particle
`
`formation and use in the context of delivering 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, biochemistry) or an
`
`equivalent combination of education and experience.” Pet. 6 (citing
`
`Ex. 1008 ¶¶ 29–32). Petitioner further asserts that “[t]his level of skill is
`
`representative of the authors/inventors of prior art cited herein.” Id. (citing
`
`Ex. 1008 ¶¶ 29–32).
`
`Patent Owner limits its response to a footnote, stating, “[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 artisans of the ʼ069 patent.” Prelim. Resp. 15, n.2.
`
`As an initial matter, we note that the level of ordinary skill proposed
`
`in the Petition differs somewhat from the level of skill identified by
`
`Dr. Janoff, as well as from that advanced by Petitioner in the ’739 IPR.
`
`Compare Pet. 6 with Ex. 1008 ¶ 31 and ’739 IPR, Paper 2, 5. In particular,
`
`the Petition asserts that a skilled artisan would have “specific experience
`
`with lipid particle formation and use in the context of delivering therapeutic
`
`nucleic acid payloads” (Pet. 6 (emphasis added)), while Dr. Janoff and the
`
`petition in the ’739 IPR state that such an artisan “would have specific
`
`experience with lipid particle formation and use in the context of delivering
`
`11
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`IPR2019-00554
`Patent 8,058,069 B2
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`therapeutic payloads” (Ex. 1008 ¶ 31 (emphasis added); ’739 IPR, Paper 2,
`
`5). Petitioner does not explain the discrepancy.
`
`For purposes of this decision, we adopt Dr. Janoff’s formulation of the
`
`level of ordinary skill as set forth above. Dr. Janoff testifies 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 explains that he arrived at his definition
`
`of the level of ordinary skill in the art in light of his “review of the
`
`’069 patent, its file history, and [his] knowledge of the field of the art.”
`
`Ex. 1008 ¶¶ 30–31. We note, however, that our institution decision is
`
`unaffected by whether we include a requirement that the skilled artisan’s
`
`experience with lipid particle formation and use in the context of delivering
`
`therapeutic payloads must further include experience particular to
`
`therapeutic nucleic acid payloads.
`
`Concerning Patent Owner’s assertion that “the petition equates the
`
`level of skill of the artisan with the level of skill of the artisans of the
`
`ʼ069 patent” (Prelim. Resp. 15, n.2), we observe that the Petition and
`
`Dr. Janoff state only that “[t]his level of skill is representative of the
`
`authors/inventors of prior art cited herein” (Pet. 6 (quoting Ex. 1008 ¶ 31)),
`
`and do not characterize the level of skill exhibited by the inventors of the
`
`’069 patent itself. Furthermore, based on the record before us, we find that
`
`the level of ordinary skill in the art articulated by Dr. Janoff is consistent
`
`with that reflected in the prior art of record. See Okajima v. Bourdeau, 261
`
`F.3d 1350, 1355 (Fed. Cir. 2001) (explaining that specific findings regarding
`
`ordinary skill level are not required “where the prior art itself reflects an
`
`appropriate level and a need for testimony is not shown”) (quoting Litton
`
`12
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`IPR2019-00554
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`Indus. Prods., Inc. v. Solid State Sys. Corp., 755 F.2d 158, 163 (Fed. Cir.
`
`1985)).
`
`C. Claim Construction
`
`Based on the filing date of the Petition, we apply the same claim
`
`construction 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 patent. 37 C.F.R. § 42.100(b); 83 Fed.
`
`Reg. 51358 (Oct. 11, 2018) (amending the claim construction standard for
`
`trial proceedings before the Board).
`
`The parties here disagree regarding the proper construction of the
`
`claim term “nucleic acid-lipid particle.” While acknowledging that it was
`
`reached applying a different standard (i.e., broadest reasonable
`
`interpretation), Petitioner contends that, as in the ’739 IPR institution
`
`decision, “nucleic acid-lipid particle” should be construed here to mean “a
`
`particle that comprises a nucleic acid and lipids, in which the nucleic acid
`
`may be encapsulated in the lipid portion of the particle.” Pet. 23 (emphasis
`
`added). Patent Owner responds that Petitioner’s proffered construction is
`
`too broad, and asserts instead that “the claimed nucleic acid-lipid particle
`
`necessarily includes a nucleic acid encapsulated in the lipid portion of the
`
`particle.” Prelim. Resp. 17 (emphasis added). Patent Owner acknowledges,
`
`however, that construing “nucleic acid-lipid particle” is not required for this
`
`Decision because its arguments against institution do not rely on a
`
`construction of that term requiring encapsulation of the recited nucleic acid.
`
`Prelim. Resp. 17 (“Regardless of whether the Board construes ‘nucleic
`
`13
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`IPR2019-00554
`Patent 8,058,069 B2
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`acid-lipid particle’ as a SNALP as indicated by Petitioner’s expert; as a lipid
`
`particle with an encapsulated nucleic acid; or under the broad construction
`
`advanced by the Petitioner, the petition fails to show that there is a
`
`reasonable likelihood that the Petitioner would prevail on any of the grounds
`
`of challenge.”).
`
`At this stage in the proceeding, we determine that the term “nucleic
`
`acid-lipid particle” does not require express construction to resolve the
`
`issues 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 controversy’”) (citing Vivid Techs., Inc. v. Am. Sci. & Eng’g,
`
`Inc., 200 F.3d 795, 803 (Fed. Cir. 1999)). As highlighted above, Patent
`
`Owner does not, at this stage, join the question of whether Petitioner’s
`
`asserted grounds of unpatentability teach or suggest a nucleic acid
`
`encapsulated in the lipid portion of the nucleic acid-lipid particle. See
`
`generally, Prelim. Resp. In addition, the Petition identifies disclosure of “a
`
`small interfering RNA (siRNA) encapsulated in a serum-stable lipid particle
`
`having a small diameter suitable for systemic delivery” by each of the
`
`’196 PCT and the ’189 Publication (Ex. 1003 ¶ 2; Ex. 1004 ¶ 182) as
`
`supporting certain of its unpatentability arguments. Pet. 32. Thus, were we
`
`to agree with Patent Owner and construe “nucleic acid-lipid particle” to
`
`require encapsulation of the nucleic acid within the lipid, our determination,
`
`set forth in Part II.D.3., below, that Petitioner has established a reasonable
`
`likelihood of prevailing on its assertion that each of the ’196 PCT and the
`
`’189 Publication render claim 1 unpatentable would not change. To the
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`14
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`IPR2019-00554
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`extent the parties raise patentability arguments turning on whether the
`
`’069 patent requires encapsulation of the nucleic acid within the lipid
`
`particle during trial, we urge them to further brief the issue in their
`
`post-institution briefs, and we will revisit whether the term needs to be
`
`construed after consideration of the full record. But for purposes of this
`
`Decision, it is unnecessary to construe “nucleic acid-lipid particle,” as our
`
`determination to institute inter partes review remains unchanged regardless
`
`of whether we apply Petitioner’s or Patent Owner’s proposed construction.
`
`D. Anticipation or Obviousness Based on
`’196 PCT or ’189 Publication
`
`Petitioner contends that claims 1–22 are anticipated or rendered
`
`obvious by each of the ’196 PCT and the ’189 Publication. Pet. 31–49.
`
`Petitioner explains that it presents its arguments based on the ’196 PCT and
`
`’189 Publication together “because the ’189 publication is substantively
`
`similar to the ’196 PCT, the primary difference being that it also discloses
`
`testing relating to the admitted prior art 2:40 formulation.” Id. at 31 (citing
`
`Ex. 1004 ¶¶ 350–391; Ex. 1008 ¶ 108). To support its contentions,
`
`Petitioner cites to Dr. Janoff’s declaration testimony (Ex. 1008).
`
`Patent Owner responds that neither the ’196 PCT nor the
`
`’189 Publication discloses the recited concentration ranges for
`
`phospholipids, and contends that Petitioner relies improperly on hindsight to
`
`arrive at the claimed phospholipid range. Prelim. Resp. 18–23. Patent
`
`Owner also argues that Petitioner fails to articulate a rationale for arriving at
`
`the claimed proportions of the various components recited in the challenged
`
`claims. Id. at 23–29. Finally, Patent Owner asserts that evidence of
`
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`unexpected results and objective indicia of nonobviousness developed
`
`during trial in the ’739 IPR support denial of institution here. Id. at 32–48.
`
`1. Overview of ’196 PCT
`
`The’196 PCT describes “compositions and methods for the
`
`therapeutic delivery of a nucleic acid by delivering a serum-stable lipid
`
`delivery vehicle encapsulating 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-lipid comprises a cationic lipid, a non-cationic lipid, a conjugated lipid,
`
`a bilayer stabilizing component for inhibiting aggregation of particles, and a
`
`siRNA. Id. ¶¶ 11, 85 (describing SNALP with same components). In
`
`describing how embodiments are made, the ’196 PCT also states that
`
`preferred embodiments are charge neutralized. Id. ¶ 15.
`
`The ’196 PCT further provides detailed descriptions of the
`
`components of stable nucleic acid-lipid particles. See Ex. 1003, ¶¶ 86–107.
`
`Concerning the preferred makeup of the disclosed SNALP, the ’196 PCT
`
`states the following about the amount of cationic lipid in the SNALP.
`
`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 preferred 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
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`16
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`IPR2019-00554
`Patent 8,058,069 B2
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`
`present in said particle. Depending on the intended use of the
`nucleic acid-lipid particles, the proportions of the components
`are varied and the delivery efficiency of a particular formulation
`can be measured using an endosomal release parameter (ERP)
`assay. For example, for systemic delivery, the cationic lipid may
`comprise from about 5% to about 15% of the total lipid present
`in said particle and for local or regional delivery, the cationic
`lipid comprises from about 40% to about 50% of the total lipid
`present in said particle.
`
`Ex. 1003 ¶ 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.” Ex. 1003
`
`¶ 91. For 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
`component employed and the rate at which the liposome is to
`become fusogenic [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
`17
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`IPR2019-00554
`Patent 8,058,069 B2
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`liposome and, in turn, the rate at which the liposome becomes fusogenic.”
`
`Id. ¶ 94.
`
`2. Overview of ’189 Publication
`
`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 these nucleic acid-lipid particles, the
`
`’189 Publication states that they may comprise an siRNA molecule that
`
`silences ApoB expression, a cationic lipid, a non-cationic 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 content of SNALP). The
`
`’189 Publication describes embodiments wherein the siRNA is fully
`
`encapsulated in the nucleic acid-lipid particle. Id. ¶ 14.
`
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`3. Analysis
`
`Given the substantial similarity between the references, and because
`
`the parties address Petitioner’s unpatentability challenges based on the
`
`’196 PCT and the ’189 Publication together, we do as well.
`
`Petitioner asserts that claim 1 is anticipated or rendered obvious by
`
`each of the ’196 PCT and the ’189 Publication.7 For example, Petitioner
`
`contends that the disclosure by each reference of “compositions and methods
`
`for silencing gene expression by delivering nucleic acid-lipid particles
`
`comprising a siRNA molecule to a cell” (Ex. 1003, Abstract; Ex. 1004,
`
`Abstract) teaches or suggests “[a] nucleic acid-lipid particle” (Ex. 1001,
`
`91:23) as recited in the preamble of claim 1. Pet. 32 (citing Ex. 1008 ¶ 110).
`
`Petitioner likewise asserts that the claim 1(a) requirement for “a
`
`nucleic acid” (Ex. 1001, 91:24) is satisfied by the disclosure in the ’196 PCT
`
`and the ’189 Publication that “the present invention is directed to using a
`
`small interfering RNA (siRNA) encapsulated in a serum-stable lipid particle
`
`having a small diameter suitable for systemic delivery” (Ex. 1003 ¶ 2;
`
`Ex. 1004 ¶ 182). Pet. 32 (citing Ex. 1008 ¶ 111).8
`
`
`
`7 Petitioner also details how each limitation of dependent claims 2–22 is met
`by the disclosures of the ’196 PCT and the ’189 Publication. See Pet. 41–49.
`At this stage of the proceeding, Patent Owner has not addressed the
`dependent claims individually for any of the asserted grounds. See
`generally, Prelim. Resp. Accordingly, we focus our analysis on claim 1.
`
`8 Although Petitioner adopts its own numbering scheme to identify the
`various elements of claim 1 (see, e.g., Pet. 32), we adhere to the numbering
`set forth in claim 1 itself (see Ex. 1001, 91:24–35).
`19
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`IPR2
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