Trials@uspto.gov
`571.272.7822
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`Paper No. 15
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` Entered: September 12, 2018
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MODERNA THERAPEUTICS, INC.,
`Petitioner,
`
`v.
`
`PROTIVA BIOTHERAPEUTICS, INC.,
`Patent Owner.
`____________
`
`Case IPR2018-00739
`Patent 9,364,435 B2
`____________
`
`
`Before SHERIDAN K. SNEDDEN, SUSAN L.C. MITCHELL, and
`RICHARD J. SMITH, Administrative Patent Judges.
`
`MITCHELL, Administrative Patent Judge.
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`35 U.S.C. § 314(a)
`
`
`
`
`
`
`
`

`

`IPR2018-00739
`Patent 9,364,435 B2
`
` INTRODUCTION
`Moderna Therapeutics, Inc. (“Petitioner”) filed a Petition to institute
`an inter partes review of claims 1–20 of U.S. Patent 9,364,435 B2 (the “’435
`patent”). Paper 2 (“Pet.”). Protiva Biotherapeutics, Inc. (“Patent Owner”)1
`filed a Preliminary Response to the Petition. Paper 12 (“Prelim. Resp.”).
`We have authority under 35 U.S.C. § 314(a) to determine whether to
`institute an inter partes review. To institute an inter partes review, we must
`determine that the information presented in the Petition shows “a reasonable
`likelihood that the petitioner would prevail with respect to at least 1 of the
`claims challenged in the petition.” 35 U.S.C. § 314(a). On April 24, 2018,
`the Supreme Court held that a decision to institute under 35 U.S.C. § 314(b)
`may not institute review on less than all claims challenged in the petition.
`SAS Inst., Inc. v. Iancu, 138 S. Ct. 1348, 1355–56 (2018). Also, in
`accordance with USPTO Guidance, “if the PTAB institutes a trial, the PTAB
`will institute on all challenges raised in the petition.” See Guidance on the
`Impact of SAS on AIA Trial Proceedings (April 26, 2018) (available at
`https://www.uspto.gov/patents-application-process/patent-trial-and-appeal-
`board/trials/guidance-impact-sas-aia-trial).
`
`
`
`1 According to Patent Owner, Protiva Biotherapeutics, Inc. (“Protiva”)
`existed as a wholly-owned subsidiary of Arbutus Biopharma Corporation
`and was amalgamated into Arbutus Biopharma Corporation in January 2018.
`Paper 14, 2. Patent Owner identifies Arbutus Biopharma Corporation (fka
`“Tekmira”), Genevant Sciences, Ltd., and its fully owned subsidiaries:
`Genevant Sciences Holding, Ltd., Genevant Sciences Corporation, Genevant
`Sciences, Inc., and Genevant Sciences, GmbH, as the real parties in interest.
`Id.
`
`2
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`IPR2018-00739
`Patent 9,364,435 B2
`Applying those standards, and upon consideration of the information
`presented in the Petition and the Preliminary Response, we conclude that
`Petitioner has established a reasonable likelihood that it would prevail in
`showing the unpatentability of at least one challenged claim of the ’435
`patent. Therefore, we institute an inter partes review for claims 1–20 of the
`’435 patent.
`
`
`Related Proceedings
`A.
`Patent Owner identifies the following related matters:
`Moderna Therapeutics, Inc. v. Protiva Biotherapeutics, Inc.,
`IPR2018-00680 regarding U.S. Patent No. 9,404,127 B2; and European
`Patent Office Opposition proceedings regarding EP 2 279 254. Paper 14, 2.
`
`The ’435 Patent (Ex. 1001)
`B.
`The ’435 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 ’435 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 5:55-62. The
`’435 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
`
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`IPR2018-00739
`Patent 9,364,435 B2
`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 5:62–6:5.
`
` The ’435 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
`downregulating the mRNA and/or protein levels of target genes.” Id. at 6:5–
`30.
`
`Illustrative Claim
`C.
`Petitioner challenges claims 1–20 of the ’435 patent. Claim 1 is
`illustrative and reproduced below:
`1. A nucleic acid-lipid particle comprising:
`(a) a nucleic acid;
`(b) a cationic lipid comprising from 50 mol % to 85 mol % of the
`total lipid present in the particle;
`(c) a non-cationic lipid comprising from 13 mol % to 49.5 mol %
`of the total lipid present in the particle; and
`(d) a conjugated lipid that inhibits aggregation of particles
`comprising from 0.5 mol % to 2 mol % of the total lipid present
`in the particle.
`Ex. 1001, 89:55–63.
`
`Claim 1 is the only independent claim, and claims 2–20 are directly or
`indirectly dependent on claim 1. Id. at 89:55–92:22.
`
`The Asserted Grounds of Unpatentability
`D.
`Petitioner contends that the challenged claims are unpatentable under
`35 U.S.C. §§ 102 and 103 based on the following grounds. Pet. 5.
`
`4
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`IPR2018-00739
`Patent 9,364,435 B2
`Reference[s]
`WO 2005/007196 A22 and
`US 2006/0134189 A13
`’196 PCT, ’189 Publication,
`Lin,4 and Ahmad5
`US 2006/0240554 A16
`
`Basis
`§ 103
`
` § 103
`
`Claims challenged
`1–20
`
`1–20
`
`§§ 102 and 103 1–20
`
`Petitioner also relies on the Declaration of Dr. Andrew S. Janoff,
`Ph.D. (“Janoff Declaration” or “Decl.”). Ex. 1007; see generally Pet.
` ANALYSIS
`Person of Ordinary Skill in the Art
`A.
`Petitioner asserts that a person having ordinary skill in the art
`(“POSITA”) “would have specific experience with lipid particle formation
`and use in the context of delivering therapeutic 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. 5 (citing Ex. 1007 ¶¶ 31–32). Petitioner
`
`
`2 Ian MacLachlan et al., WO 2005/007196 A2, published Jan. 27, 2005
`(“’196 PCT”). Ex. 1002.
`3 Ian MacLachlan et al., US 2006/0134189 A1, published Jun. 22, 2006
`(“’189 Publication”). Ex. 1003.
`4 Alison J. 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. 1005.
`5 Ayesha Ahmad et al., New Multivalent Cationic Lipids Reveal Bell Curve
`for Transfection Efficiency Versus Membrane Charge Density: Lipid-DNA
`Compleses for Gene Delivery, 7 J. GENE MED. 739–48 (2005) (“Ahmad”).
`Ex. 1006.
`6 Tongqian Chen et al., US 2006/0240554 A1, published Oct. 26, 2006
`(“’554 Publication”). Ex. 1004.
`
`5
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`IPR2018-00739
`Patent 9,364,435 B2
`further states that “[t]his level of skill is representative of the inventors on
`the ’435 patent and authors/inventors of prior art cited herein.” Id. at 6.
`Patent Owner contends that Petitioner’s proposed level of ordinary
`skill should be rejected because it “equates the level of ordinary skill with
`knowledge possessed by the inventors themselves” who may possess
`exceptional skill beyond the ordinary skill requirements. Prelim. Resp. 18.
`Patent Owner also takes issue with a person of ordinary skill having a
`medical degree when the Petitioner does not address any therapeutic
`considerations, such as toxicity, in vivo aggregation, and overall systemic
`tolerance in the Petition. Id.
`On this record and at this stage of the proceeding, we agree with the
`Petitioner’s definition of a person of ordinary skill in the art as supported by
`the testimony of Dr. Janoff. See Pet. 5–6; Ex. 1007 ¶¶ 29–32. 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 ’435 patent, and provides the definition
`of one of skill in the art as set forth above by the quoted text of Petitioner in
`light of his “review of the ’435 patent, its file history, and [his] knowledge
`of the field of the ’435 patent.” Ex. 1007 ¶¶ 30–31. Although Dr. Janoff
`notes that the level of skill he defines is “representative of the inventors on
`the ’435 patent and authors/inventors of prior art cited herein,” Dr. Janoff
`expressly indicates that the defined level of skill is that of an ordinary
`artisan, not one with extraordinary skill. Id. ¶ 31.
`We also do not agree based on the record evidence that Patent
`Owner’s assertion that a person with a medical degree may be one of skill
`who is “detached from the actual concerns of those of ordinary skill in the
`art at the time of the invention.” See Prelim. Resp. 18. Petitioner does not
`posit that someone with a medical degree alone is one of ordinary skill, but
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`IPR2018-00739
`Patent 9,364,435 B2
`someone that also has “specific experience with lipid particle formation and
`use in the context of delivering therapeutic payloads.” Pet. 5; Ex. 1007 ¶ 31.
`We find on this record that such definition of a person with ordinary skill is
`appropriate in light of the concerns of those of ordinary skill at the time of
`the invention.
`At this stage of the proceeding based on the record before us, we find
`that one of skill in the art “would have specific experience with lipid particle
`formation and use in the context of delivering therapeutic 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,” and also find on this record that Dr. Janoff is
`one of at least ordinary skill under this standard. See Ex. 1007 ¶¶ 8–22;
`Ex. 1018 (curriculum vitae of Dr. Janoff).
`We further note that the prior art itself demonstrates the level of skill
`in the art at the time of the invention. 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
`Indus. Prods., Inc. v. Solid State Sys. Corp., 755 F.2d 158, 163 (Fed. Cir.
`1985)).
`
`Claim Construction
`B.
`In an inter partes review, the Board interprets claim terms in an
`unexpired patent according to the broadest reasonable construction in light
`of the specification of the patent in which they appear. 37 C.F.R.
`§ 42.100(b); Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2142
`(2016) (affirming applicability of broadest reasonable construction
`standard to inter partes review proceedings). “Under a broadest
`
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`IPR2018-00739
`Patent 9,364,435 B2
`reasonable interpretation, words of the claim must be given their plain
`meaning, unless such meaning is inconsistent with the specification and
`prosecution history.” Trivascular, Inc. v. Samuels, 812 F.3d 1056, 1062
`(Fed. Cir. 2016). Any special definitions for claim terms must be set forth
`with reasonable clarity, deliberateness, and precision. See In re Paulsen,
`30 F.3d 1475, 1480 (Fed. Cir. 1994). Only terms in controversy must be
`construed and only to the extent necessary to resolve the controversy.
`Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir.
`1999).
`Petitioner provides a proposed construction of the claim terms
`“nucleic acid-lipid particle” and “cationic lipid.” Pet. 23–24. According to
`Patent Owner, “[t]he terms identified in the petition do not require
`construction in order to reach a decision denying institution,” and “[t]he
`constructions proposed in the petition . . . should be rejected as being
`unreasonably broad and largely detached from the ’435 patent
`specification.” Prelim. Resp. 15. Because Patent Owner substantively
`challenges the proposed construction of the term “nucleic acid-lipid particle”
`and relies on its narrower definition of the term in its arguments addressing
`the grounds asserted, we address the construction of that term, but find that
`we need not construe any other terms addressed by Petitioner for the purpose
`of reaching our institution decision. We do note, however, that Petitioner
`provides the same definition for “cationic lipid” as the express definition set
`forth in the specification of the ’435 patent, namely, “any of a number of
`lipid species that carry a net positive charge at a selected pH, such as
`physiological pH (e.g., pH of about 7.0).” Compare Pet. 24, with Ex. 1001,
`12:59–61.
`
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`IPR2018-00739
`Patent 9,364,435 B2
`nucleic acid-lipid particle
`Petitioner proposes that “nucleic acid-lipid particle” means “a
`composition of lipids and a nucleic acid for delivering a nucleic acid to a
`target site of interest.” Pet. 24 (citing Ex. 1001, 11:14–17; Ex. 1007 ¶ 87).
`Patent Owner contends that Petitioner’s proposed construction is
`unreasonably broad, and that the specification’s use of “nucleic acid-lipid
`particle” refers to “particles specifically formulated for systemic (in vivo)
`administration and having the nucleic acid component encapsulated within
`the lipid.” Prelim. Resp. 16.7
`On this record and at this stage of the proceeding, we find that neither
`Petitioner’s nor Patent Owner’s proposed constructions of “nucleic acid-
`lipid particle” are appropriate. Petitioner’s proposed construction is a
`general restatement of the composition recited in claim 1 and a use thereof
`as described in the ’435 patent. See Ex. 1001, 11:14–17, 89:55–63. Also,
`Patent Owner’s proposed construction is inconsistent with claim 1 because it
`limits the term “nucleic acid-lipid particle” as used in claim 1 to the
`definition of a stable nucleic acid-lipid particle or SNALP. Prelim. Resp.
`16–17 (citing Ex. 1001, 11:31–42 (defining SNALP), 5:62–6:2, 6:25–30,
`2:38–47, 13:38–49). Because claim 1 is drawn to the broader term “nucleic
`acid-lipid particle,” it should not be limited to the definition of SNALP.
`Compare Ex. 1001, 11:14–22 (describing “lipid particle” used to deliver an
`active or therapeutic agent such as a nucleic acid), with Ex. 1001, 11:23–46
`
`
`7 We note in the companion request for inter partes review, Patent Owner
`defined the same term “nucleic acid-lipid particle” somewhat differently as
`“non-lamellar particles formulated to fully encapsulate the nucleic acid
`component and to be stable in serum following systemic (in vivo)
`administration.” See IPR2018-00739, Prelim Resp. 4.
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`IPR2018-00739
`Patent 9,364,435 B2
`(describing SNALP” as a lipid particle that fully encapsulates the nucleic
`acid with the lipid).
`We also find on this record that “nucleic acid-lipid particle” is not
`limited to in vivo use. The specification of the ’435 patent states that
`The 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).
`. . . The lipid particles and compositions of the present
`invention may be used for a variety of purposes, including the
`delivery of associated or encapsulated therapeutic agents to
`cells, both in vitro and in vivo.
`Ex. 1001, 6:31–34. Example 2 in the ’435 patent also describes in vitro use
`of nucleic acid-lipid particles. See id. at 69:6–70:52 (stating 1:57 SNALP
`are Potent Inhibitors of Cell Growth In Vitro). Because the specification of
`the ’435 patent describes both in vitro and in vivo use of nucleic acid-lipid
`particles, we also find nucleic acid-lipid particle is not limited to in vivo use
`as Patent Owner contends.
` Our preliminary construction of “nucleic acid-lipid particle” at this
`stage of the proceeding and for purposes of this decision is derived from the
`express definition of “lipid particle” as set forth in the ’435 patent that
`generally describes use of such a lipid particle to deliver nucleic acid as an
`active or therapeutic agent where the nucleic acid may be encapsulated in
`the lipid to protect it from enzymatic degradation. At this stage of the
`proceeding, we define “nucleic acid-lipid particle” as “a particle that
`
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`IPR2018-00739
`Patent 9,364,435 B2
`comprises a nucleic acid and lipids, in which the nucleic acid may be
`encapsulated in the lipid portion of the particle.” See Ex. 1001, 11:14–22.
`We determine that we need not expressly construe any other terms for
`purposes of determining whether to institute an inter partes review in this
`case. See Vivid Techs., 200 F.3d at 803
`
`Principles of Law
`C.
` To show anticipation, each and every claim element, arranged as in
`the claim, must be found in a single prior art reference either explicitly or
`inherently. Net MoneyIN, Inc. v. Verisign, Inc., 545 F.3d 1359 (Fed. Cir.
`2008); see Atlas Powder Co. v. Ireco, Inc., 190 F.3d 1342, 1346 (Fed. Cir.
`1999) (quoting In re Schreiber, 128 F.3d 1473, 1477 (Fed. Cir. 1997)). The
`prior art need not, however, use the same words as recited in the claims in
`order to find anticipation. In re Gleave, 560 F.3d 1331, 1334 (Fed. Cir.
`2009). To the contrary, it is permissible to take into account not only the
`literal teachings of the prior art reference, but also the inferences the skilled
`artisan would be reasonably expected to draw from the reference. Eli Lilly v.
`Los Angeles Biomedical Res. Inst., 849 F.3d 1073, 1074–75 (Fed. Cir.
`2017); In re Preda, 401 F.2d 825, 826 (CCPA 1968).
`“Inherency is not necessarily coterminous with the knowledge of
`those of ordinary skill in the art. . . . Artisans of ordinary skill may not
`recognize the inherent characteristics or functioning of the prior art.” Atlas
`Powder, 190 F.3d at 1347 (citing Titanium Metals Corp. v. Banner, 778 F.2d
`775, 780, 782 (Fed. Cir. 1985).
`“[T]he discovery of a previously unappreciated property of a prior art
`composition, or of a scientific explanation for the prior art’s functioning,
`does not render the old composition patentably new to the discoverer.” Id.
`
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`Patent 9,364,435 B2
`(citing Titanium Metals, 778 F.2d at 782). “It is also an elementary principle
`of patent law that when, as by a recitation of ranges or otherwise, a claim
`covers several compositions, the claim is ‘anticipated’ if one of them is in
`the prior art.” Titanium Metals, 778 F.2d at 782.
`A claim is unpatentable under 35 U.S.C. § 103(a) if the differences
`between the claimed subject matter and the prior art are such that the subject
`matter, as a whole, would have been obvious to the person of ordinary skill
`in the art at the time of the invention. KSR Int’l Co. v. Teleflex Inc., 550
`U.S. 398, 406 (2007). “If a person of ordinary skill in the art can implement
`a predictable variation [of the claimed subject matter from what is taught
`and suggested in the prior art], § 103 likely bars its patentability.” Id. at 417.
`The question of obviousness is resolved on the basis of underlying factual
`determinations including: (1) the scope and content of the prior art; (2) any
`differences between the claimed subject matter and the prior art; (3) the level
`of ordinary skill in the art; and (4) objective evidence of obviousness.
`Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966). “[A] patent
`composed of several elements is not proved obvious merely by
`demonstrating that each of its elements was, independently, known in the
`prior art.” KSR, 550 U.S. at 418. “[I]t can be important to identify a reason
`that would have prompted a person of ordinary skill in the relevant field to
`combine elements in the way the claimed new invention does.” Id.
` We analyze the asserted grounds of unpatentability in accordance with
`the above-stated principles.
`D. Obviousness over ’196 PCT and ’189 Publication
`Petitioner asserts that claims 1–20 of the ’435 patent are unpatentable
`as obvious over the ’196 PCT and the ’189 Publication. Pet. 32–48. Patent
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`IPR2018-00739
`Patent 9,364,435 B2
`Owner advances several arguments in response to Petitioner’s assertions.
`Prelim. Resp. 22–33.
`
`1. ’196 PCT (Ex. 1002)
`The invention of the ’196 PCT is described as “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. 1002 ¶ 2.
`More particularly, the invention of the ’196 PCT is described as “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 SNALPs 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 id. ¶¶ 86–107.
`Concerning the preferred makeup of the 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
`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
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`IPR2018-00739
`Patent 9,364,435 B2
`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. 1002 ¶ 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. For
`the bilayer stabilizing component such as a conjugated lipid, the ’196 patent
`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
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`IPR2018-00739
`Patent 9,364,435 B2
`liposome and, in turn, the rate at which the liposome becomes fusogenic.”
`Id. ¶ 94.
`
`2. ’189 Publication (Ex. 1003)
`The ’189 Publication describes “nucleic acid-lipid particles
`comprising siRNA molecules that silence [Apolipoprotein B “ApoB”]
`expression and methods of using such nucleic acid-lipid particles to silence
`ApoB expression.” Ex. 1003, Abst., ¶ 0007. In describing these nucleic
`acid-lipid particles, the ’189 Publication states that they may comprise a
`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
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`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 SNALPs). The ’189
`Publication describes embodiments wherein the siRNA is fully encapsulated
`in the nucleic acid-lipid particle. Id. ¶ 14.
`
`3. Analysis
`a. Obviousness – claim 1
`Petitioner provides a detailed analysis of how each claim limitation of
`claim 1 is met by the disclosure of the ’196 PCT. See Pet. 32–40.8
`Petitioner concludes that:
`While the ’196 PCT does not disclose the exact same
`range of lipid components from claim 1 of the ’435 patent
`explicitly, it discloses encompassing and overlapping ranges
`that establish a prima facie case of obviousness and the testing
`in the ’435 patent does not support alleged unexpected results
`for the claimed ranges. Janoff Decl. ¶ 106.
`The ’189 publication is substantively similar to the ’196
`PCT and also discloses SNALPs comprising overlapping ranges
`of the lipid components similar to those discussed below for the
`’196 PCT. In addition, the ’189 publication discloses testing
`relating to the admitted prior art 2:40 formulation.
`Pet. 32–33.
`
`Petitioner also argues that Patent Owner cannot rely on any
`unexpected results for the claimed ranges for the components of the nucleic
`acid-lipid particle because the testing as described in the ’435 patent “dealt
`
`
`8 Petitioner also details how each additional limitation of claims 2–20 that
`depend either directly or indirectly on claim 1 is met by the disclosure of the
`’196 PCT. See Pet. 40–48. At this stage of the proceeding, Patent Owner
`has not addressed the dependent claims individually for any of the asserted
`grounds. See Prelim. Resp. 23–45.
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`with only a few lipid species and proportions [that are] not co-extensive with
`the claim scope.” Pet. 34–38. Specifically, Petitioner asserts the following.
`In vitro testing (Example 2) showed that Sample 10 (claimed
`formulation) apparently performed worse than Sample 16
`(admitted prior art). Ex. 1001, Fig. 1; Janoff Decl. ¶¶ 81–82.
`In vivo testing (Example 3), Group 14 (claimed formulation)
`apparently performed worse than Group 7 (admitted 2:40 prior
`art). Ex. 1001, Figure 2; Janoff Decl. ¶¶ 83–84.
`
`. . . the in vivo testing in Example 3 shows that even
`minor variations in lipid percentages (and potentially changes
`to Lipid to drug ratios) appeared to impact efficacy. Janoff
`Decl. ¶ 106. Specifically, Sample 2 and Sample 12 from
`Table 4 contain the exact same lipid species in the respective
`ratios 2/40/10/48 and 1/40.4/10.1/48.5. Ex. 1001, Table 4.
`According to Figure 2, these slight variations in lipid
`proportions (and potentially changes to Lipid to drug ratios)
`lead to apparently different transfection efficiencies. Id., Fig. 2;
`Janoff Decl. ¶ 112. A POSITA would expect that similar minor
`variations in lipid proportions within the claimed range might
`lead to similar variations in transfection efficiency. Id.;
`Ex. 1006, 740 (parenthetical omitted).
`Pet. 35–36.
`
`By the same token, Petitioner asserts, the testing of only one cationic
`lipid, DLinDMA, in the ’435 patent when the claimed range of species of
`cationic lipids is much more extensive does not support the conclusion that
`other cationic lipids within the claim will behave in the same manner as the
`one tested. Id. at 37. Petitioner asserts that “[t]o the contrary, Example 5 in
`the ’435 patent shows variation of the cationic lipid impacts efficacy.” Id.
`(citing Ex. 1001, Table 6 (Samples 2 % 6 (DLin-DMA) vs. Sample 4
`(DODMA)); see also Pet. 38 (citing acknowledgement that alternative
`cationic lipids that work in essentially the same manner may have different
`efficiencies).
`
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`
`
`On this record and at this stage of the proceeding, we are persuaded
`that Petitioner has established a reasonable likelihood that it would prevail in
`showing that claim 1 of the ’435 patent would have been obvious over either
`the ’196 PCT or the ’189 Publication. Petitioner has shown that each of the
`’196 PCT and the ’189 Publication disclose nucleic acid-lipid particles that
`comprise a nucleic acid, and the lipid components—a cationic lipid, a non-
`cationic lipid, and a conjugated lipid—in mol percentage ranges that overlap
`with the claimed ranges. See Pet. 32–48; see Ex. 1007 ¶¶ 106–118; In re
`Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003) (“A prima facie case of
`obviousness typically exists when the ranges of the claimed composition
`overlap the ranges disclosed in the prior art”) (citations omitted).
`Specifically with regard to the claimed range for the cationic lipid
`component, which Patent Owner asserts was contrary to the conventional
`wisdom concerning “the community’s aversion to the toxicity and poor in
`vivo efficacy associated with formulations with a high level of cationic
`lipid,” see Prelim. Resp. 1, Dr. Janoff testifies as follows.
`The ’196 PCT teaches “[t]he cationic lipid typically comprises
`from about 2% to about 60% of the total lipid present in said
`particle … [i]n other preferred embodiments, the cationic lipid
`comprises from about 40% to about 50% of the total lipid
`present in said particle.” Id., [0088]. The ’196 PCT discloses
`that “[d]epending on the intended use of the nucleic acid-lipid
`particles, the proportions of the components are varied ….” Id.
`In addition, the ’196 PCT incorporates by reference the ’618
`patent, which discloses nucleic acid-lipoplex with 56% cationic
`lipid, 14% phospholipid and 30% cholesterol, as well as various
`other formulations containing over 50% cationic lipid. Ex.
`1017, 34:54-35:23. Given the explicit disclosure of overlapping
`ranges, this limitation is prima facie obvious. In addition,
`determining the optimal proportion of cationic lipid for a given
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`lipid combination would be a simple matter of varying the
`proportion using prior art methodologies.
`Ex. 1007 ¶ 110. On the record before us, we credit Dr. Janoff’s testimony
`and agree that given the disclosure of overlapping ranges for the
`compositions in each