Trials@uspto.gov
`Tel: 571-272-7822
`
`
`
`
`Paper 8
`Entered: March 31, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`BENITEC BIOPHARMA LIMITED,
`Petitioner,
`
`v.
`
`COLD SPRING HARBOR LABORATORY
`Patent Owner.
`_______________
`
`Case IPR2016-00016
`Patent 8,153,776 B2
`_______________
`
`
`
`Before TONI R. SCHEINER, SHERIDAN K. SNEDDEN, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`SNEDDEN, Administrative Patent Judge.
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`

`
`Case IPR2016-00016
`Patent 8,153,776 B2
`
`
`INTRODUCTION
`Benitec Biopharma Limited (“Petitioner”) filed a Petition (Paper 1;
`“Pet.”) to institute an inter partes review of claims 1–10 of US 8,153,776 B2
`(Ex. 1001; “the ’776 patent”). Cold Spring Harbor Laboratory (“Patent
`Owner”) filed a Patent Owner Preliminary Response. Paper 7 (“Prelim.
`Resp.”). We have jurisdiction under 35 U.S.C. § 314.
`For the reasons provided below, we determine Petitioner has not
`established a reasonable likelihood that it would prevail in showing the
`unpatentability of at least one challenged claim of the ’776 patent. See
`35 U.S.C. § 314(a). We, therefore, deny the Petition for an inter partes
`review.
`
`a. Related Proceedings
`In addition to the case before us, Petitioner has requested inter partes
`review of claims 1–10 of US 8,202,846 B2 (“the ’846 patent”) in IPR2016-
`00014; claims 1–20 of US 8,383,599 B2 (“the ’599 patent”) in IPR2016-
`00015; and claims 1–10 of US 8,829,264 B2 (“the ’264 patent”) in
`IPR2016–00017.
`The ʼ599 patent issued from a continuation of application
`No. 10/055,797, filed Jan. 22, 2002. The ’846, ’776, and ’264 patents derive
`from a continuation-in-part of Application No. 10/055,797 (Application
`No. 10/997,086, filed Nov. 23, 2004) and share substantially the same
`specification.
`
`b. Technical Background
`The ’776 patent relates to methods for silencing the expression of
`target genes by RNA interference (“RNAi”). RNAi is part of an endogenous
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`cellular system in plants and animals that recognizes double stranded RNA
`(“dsRNA”) associated with viral infection, and subsequently targets viral
`mRNA for degradation or translational silencing. See, e.g., Ex. 1001, 1:20–
`2:18; Ex. 2001, 363;1 Ex. 2007, 188.2 At a high level of generality, a
`nuclease known as “Dicer” processes long dsRNAs into double-stranded
`fragments of approximately 21–25 nucleotides in length. See generally, Ex.
`1002,3 722–727; Ex. 1001, 19:51–65, 20:17–30. The resulting fragments,
`known as short interfering RNAs (“siRNAs”), are themselves incorporated
`into an RNA-induced silencing complex (“RISC”). See Ex. 1002, 722–724.
`One strand of an siRNA incorporated into RISC acts as a guide to direct the
`RISC/siRNA nuclease complex to a complementary sequence in a target
`mRNA, where it mediates sequence-specific gene silencing. Id.
`In addition to the Dicer/RISC pathway, mammalian cells have an
`additional innate anti-viral response, involving a double-stranded RNA
`activated protein kinase (“PK”). See generally, id. at 722–727; Ex. 1001,
`20:37–46. As Petitioner points out, however, “PK binds dsRNA and
`initiates a type of post-transcriptional gene silencing different from RNAi.”
`Pet. 6. “PK triggers interferon synthesis, initiates interferon-related cellular
`immune responses and causes cellular death through apoptotic pathways.”
`Id. at 6–7.
`
`
`1 Emily Bernstein et al., Role for a Bidentate Ribonuclease in the Initiation
`Step of RNA Interference, 409 NATURE 363 (2001).
`2 Sayda M. Elbashir et al., RNA Interference Is Mediated by 21- and 22-
`Nucleotide RNAs, 15 GENES & DEV. 188 (2001).
`3 Prosecution History of U.S. Patent No. 8,153,776.
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`
`c. The ’776 patent and Representative Claim
`The ’776 patent discloses methods for attenuating gene expression in
`a mammalian cell using short hairpin RNA (“shRNA”) molecules that are
`processed by Dicer, but do not trigger the PK response (“PKR”). See Ex.
`1001, 19:9–50. Claim 1, the sole independent claim of the patent, recites:
`1. A method for attenuating expression of a target gene in a
`mammalian cell, the method comprising
`introducing into mammalian cells a library of RNA
`expression constructs, each expression construct comprising:
`(i) an RNA polymerase promoter, and
`(ii) a sequence encoding a short hairpin RNA molecule
`comprising a double-stranded region wherein the double-
`stranded region consists of at least 20 nucleotides but not more
`than 29 nucleotides,
`wherein the short hairpin RNA molecule is a substrate for
`Dicer-dependent cleavage and does not trigger a protein kinase
`RNA-activated (PKR) response in the mammalian cell,
`wherein the double-stranded region of the short hairpin
`RNA molecule comprises a sequence that is complementary to a
`portion of the target gene, and
`wherein the short hairpin RNA molecule is stably
`expressed in the mammalian cell in an amount sufficient to
`attenuate expression of the target gene in a sequence specific
`manner, and is expressed in the cell without use of a PK inhibitor,
`whereby expression of the target gene is inhibited.
`
`d. Asserted Grounds of Unpatentability
`Petitioner asserts the following grounds of unpatentability.
`Claims challenged
`Basis
`Reference(s)
`1–10
`§ 102(e)
`
`Zamore4
`
`
`4 Zamore et al., US 7,691,995 B2, issued Apr. 6, 2010. Ex. 1003.
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`
`Claims challenged
`1–10
`
`Basis
`§ 102(b)
`
`1–10
`
`§ 103
`
`Reference(s)
`
`Graham5
`Graham and/or Zamore, Tuschl,6
`Fire,7 Harborth,8 Parrish,9 Sijen,10
`Green,11 Tian,12 Waterhouse,13
`and/or Symonds,14 in view of the
`knowledge of one skilled in the art
`
`ANALYSIS
`
`a. Claim Construction
`In an inter partes review, the Board interprets a claim term in an
`unexpired patent according to its broadest reasonable construction in light of
`the specification of the patent in which it appears. 37 C.F.R. § 42.100(b); In
`
`
`5 Graham, US 6,573,099 B2, issued June 3, 2003. Ex. 1005.
`6 Tuschl et al., US 2002/0086356 A1, published Jul. 4, 2002. Ex. 1007.
`7 Fire et al., US 6,506,559 B1, issued Jan. 14, 2003. Ex. 1006.
`8 Jens Harborth et al., Identification of Essential Genes in Cultured
`Mammalian Cells Using Small Interfering RNAs, 114 J. CELL SCI. 4557
`(2001). Ex. 1012.
`9 Susan Parrish et al., Functional Anatomy of a dsRNA Trigger: Differential
`Requirement for the Two Trigger Strands in RNA Interference, 6
`MOLECULAR CELL 1077 (2000). Ex. 1010.
`10 Titia Sijen et al., On the Role of RNA Amplification in dsRNA-Triggered
`Gene Silencing, 107 CELL 465 (2001). Ex. 1011.
`11 Simon R. Green & Michael B. Mathews, Two RNA-Binding Motifs in the
`Double-Stranded RNA-Activated Protein Kinase, DAI, 6 GENES & DEV.
`2478 (1992). Ex. 1008.
`12 Bin Tian et al., Expanded CUG Repeat RNAs Form Hairpins that Activate
`the Double-Stranded RNA-Dependent Protein Kinase PKR, 6 RNA 79
`(2000). Ex. 1009.
`13 Peter M. Waterhouse et al., Gene Silencing As an Adaptive Defense
`Against Viruses, 411 NATURE 834 (2001). Ex. 1013.
`14 Symonds et al., US 7,345,025 B2, issued Mar. 18, 2008. Ex. 1015.
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`re Cuozzo Speed Techs., LLC, 793 F.3d 1268, 1275–79 (Fed. Cir. 2015),
`cert. granted sub nom. Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 890
`(mem.) (2016). Under that standard, and absent any special definitions, we
`assign claim terms their ordinary and customary meaning, as would be
`understood by one of ordinary skill in the art at the time of the invention,15
`in the context of the entire patent disclosure. In re Translogic Tech., Inc.,
`504 F.3d 1249, 1257 (Fed. Cir. 2007). Only terms that are in controversy
`need to be construed, however, and then 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).
`In the present matter, the parties do not dispute the meaning of any
`claim term nor, for the purposes of our decision, do we find that any term
`requires express construction. See Pet. 5; Prelim. Resp. 9.
`
`b. Anticipation in view of Zamore
`Petitioner asserts that claims 1–10 of the ’776 patent are anticipated
`by the Zamore patent under 35 U.S.C. § 102(e). Pet. 23–41. Patent Owner
`contends that Zamore does not qualify as prior art under § 102(e) because
`none of the issued claims of the Zamore patent are supported by US
`Provisional Application No. 60/305,185 (“the ’185 provisional application”
`(Ex. 1004). Prelim. Resp. 23–34. On the record before us, we agree with
`Patent Owner.
`
`
`15 Patent Owner adopts, as do we, Petitioner’s definition of a person of
`ordinary skill in the art as “a graduate or post-graduate student in the life
`sciences field, or hav[ing] a Master’s degree or Ph.D. in molecular biology,
`microbiology, biochemistry, chemistry or a related discipline.” Prelim.
`Resp. 8 (quoting Pet. 4).
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`
`The effective filing date of the ʼ776 patent is January 22, 2002. See
`Ex. 1001, 1; Pet. 8; Prelim. Resp. 23. Zamore issued from a non-provisional
`application filed on July 12, 2002, and claiming benefit of priority under 35
`U.S.C. § 119(e) of the ’185 provisional application, filed on July 12, 2001.
`Ex. 1003, [21], [22], [60], 1:5–7. Accordingly, Zamore is only available as
`prior art under § 102(e) if Petitioner can show that Zamore is entitled to the
`earlier filing date of the ʼ185 provisional application. To make such a
`showing, Petitioner must demonstrate that the ʼ185 provisional application
`provides written descriptive support for at least one claim of the Zamore
`patent. See, e.g., Dynamic Drinkware, LLC v. Nat’l Graphics, Inc., 800 F.3d
`1375, 1381 (Fed. Cir. 2015) (“A reference patent is only entitled to claim the
`benefit of the filing date of its provisional application if the disclosure of the
`provisional application provides support for the claims in the reference
`patent in compliance with § 112, ¶ 1.”).
`The claims of the Zamore patent are generally directed to nucleic
`acids “capable of inducing RNA interference (RNAi) in a mammalian cell in
`vivo.” See Ex. 1003, claim 1. Independent claims 1 and 41 require first and
`second stem portions comprising complementary RNA sequences of “about
`18 to about 40 nucleotides” in length. Id. at claims 1, 41. Various
`dependent claims further recite stem portions of “18 to 40 nucleotides” (id.
`at claims 20, 58), “22 to 28 nucleotides,” (id. at claims 21, 59), “18 to 30
`nucleotides,” (id. at claim 22), and “18 to 40 nucleotides” (id. at claim 58).
`The Zamore ʼ185 provisional application, by contrast, describes stem
`portions of “19 to 22,” “21 or 22,” and “21 or 40” nucleotides in length. Ex.
`1004, 2, 7. For the reasons discussed on pages 24 through 27 of Patent
`Owner’s Preliminary Response, we agree that these disclosures do not
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`provide written descriptive support for the ranges claimed in the issued
`patent.
`The relevance of Zamore was squarely before the Examiner during the
`prosecution leading to the issuance of the ’776 patent. See Ex. 1002, 1157–
`63. Petitioner appears to argue that the Examiner erred in allowing the ’776
`patent over Zamore because she “was seemingly unaware” that the ’185
`provisional application inherently disclosed the minimum length of dsRNA
`known in the art to trigger the PK response. See Pet. 23–28. In particular,
`Petitioner points to the statement in the ’185 provisional application that,
`[a]nother defining feature of these engineered RNA precursors is
`that as a consequence of their length, sequence, and/or structure,
`they do not induce sequence non-specific responses such as
`induction of the interferon response or apoptosis, or that they
`induce a lower level of such sequence non-specific responses
`than long, double stranded RNA (>150 bp) currently used to
`induce RNAi.
`Id. at 27 (quoting Ex. 1004, 8:11–15). In light of this statement, Petitioner
`argues that because “[t]he lengths, sequences and structures known to trigger
`PKR were widely known prior to the filing of Zamore’s ’185 provisional”
`“one of ordinary skill in view of the cited teachings and knowledge in the art
`would understand that Zamore had possession of the means to avoid PKR
`when utilizing the gene silencing technology.” Id. at 28–29.
`“[T]he hallmark of written description is disclosure.” Ariad Pharm.,
`Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc). The
`test for written description “requires an objective inquiry into the four
`corners of the specification from the perspective of a person of ordinary skill
`in the art. Based on that inquiry, the specification must describe an
`invention understandable to that skilled artisan and show that the inventor
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`actually invented the invention claimed.” Id. No particular form of
`disclosure is required, but “a description that merely renders the invention
`obvious does not satisfy the requirement.” Id. at 1352. To find an element
`inherently disclosed demands that “the allegedly inherent characteristic
`necessarily flows from the teachings of the applied prior art.” Ex parte Levy,
`17 USPQ2d 1461, 1464 (BPAI 1990). “The mere fact that a certain thing
`may result from a given set of circumstances is not sufficient.” In re
`Robertson, 169 F.3d 743, 745 (Fed. Cir. 1999) (emphasis added) (quoting
`Continental Can Co. USA v. Monsanto Co., 948 F.2d 1264, 1269 (Fed. Cir.
`1991)).
`In the present case, Petitioner presents no expert opinion with respect
`to the understanding of one of ordinary skill in the art, including with respect
`to the disclosure of the Zamore ’185 provisional application. Petitioner’s
`limited evidence and assertion that “[t]he lengths, sequences and structures
`known to trigger PKR were widely known prior to the filing of Zamore’s
`’185 provisional,” fails to convince us that one of ordinary skill in the art
`would understand that the ’185 provisional application inherently discloses
`the ranges claimed in the Zamore patent. See Pet. 28. Accordingly, we are
`not persuaded that Zamore qualifies as prior art under 35 U.S.C. § 102(e).
`Absent such a showing, Petitioner has not established a reasonable
`likelihood that it would prevail in showing the unpatentability of at least one
`challenged claim of the ’776 patent based on this reference.
`
`c. Anticipation by Graham
`Petitioner further contends that Graham anticipates claims 1–10 of the
`’776 patent under 35 U.S.C. § 102(b). Pet. 9–23; see also id. at 18
`(“Petitioner asserts that all elements of claim 1 are described and inherently
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`present in Graham.”). As an initial matter, we take issue with Petitioner’s
`assertion that “Graham was not considered during prosecution” and is thus,
`(in combination with Zamore), “non-cumulative to the prior art of record
`cited against the application that led to the ’776 patent.” See id. at 44. To
`the contrary, Graham is listed on the face of the ’776 patent among the
`“References Cited,” and was considered by the Examiner during
`prosecution. See Ex. 1002, 1231; MPEP 609.04(a) (An Examiner’s initials
`on an IDS form “provides . . . a clear record in the application to indicate
`which documents have been considered by the examiner in the
`application.”).
`Graham discloses “synthetic genes and genetic constructs which are
`capable of repressing[,] delaying[,] or otherwise reducing the expression of
`. . . a target gene in an organism.” Ex. 1005, Abstract; see id. at 2:8–22.
`Graham teaches that synthetic genes comprise at least one “structural gene
`component” that is substantially identical to at least about 30 contiguous
`nucleotides of an endogenous or other target gene. Id. at 5:7–20, 6:18–24.
`Graham further states that “[p]referred structural gene components . . .
`comprise at least about 20–30 nucleotides in length derived from [a target
`gene].” Id. at 6:25–40.
`Graham teaches that a synthetic gene may comprise multiple
`structural gene sequences that are “substantially identical to the nucleotide
`sequence of the target gene . . . or a complementary sequence thereto.” Id.
`at 9:53–63.
`Accordingly, a multiple structural gene sequence may comprise
`a tandem repeat or concatemer of two or more identical
`nucleotide sequences or alternatively, a tandem array or
`concatamer of non-identical nucleotide sequences, the only
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`requirement being that each of the structural gene sequences
`contained therein is substantially identical to the target gene
`sequence or a complementary sequence thereto.
`Id. at 9:67–10:7.
`Patent Owner argues that Graham contains “no data regarding
`attenuating expression of a target gene in a mammalian cell” and, thus, fails
`to disclose a molecule “stably expressed in the mammalian cell in an amount
`sufficient to attenuate expression of the target gene in a sequence specific
`manner . . . whereby expression of the target gene is inhibited,” as required
`by the challenged claims. See Prelim. Resp. 14–17.
`Graham discloses specific constructs designed to express synthetic
`genes using genetic elements known to be active in eukaryotic cells. See,
`e.g., Ex. 1005, 17:39–51 (“Plasmid pEGFP.BEV.1 (FIG. 9) is capable of
`expressing the BEV polymerase structural gene as a GFP fusion polypeptide
`under the control of the CMV-IE promoter sequence.”); see id. at 8:4–34.
`Petitioner, however, points to no evidence indicating that such constructs
`were ever introduced into mammalian cells; nor do we discern in Graham
`any evidence that the disclosed constructs were successfully expressed in
`mammalian cells, or that they subsequently produced a measurable effect on
`a target gene in accord with the claim language.
`Based on our review of the record to date, we acknowledge the
`substantial complexity of the subject matter16 and unpredictability of the art.
`See Mycogen Plant Sci. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir.
`2001) (recognizing the unpredictability of the biological arts); In re Fisher,
`
`16 See e.g., Ex. 1002, 854 ¶ 43 (cited in full, infra) (“Further evidence of the
`non-obviousness of the Hannon et al. invention is evidenced in the
`complicated nature of the methods provided in the cited references.”).
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`427 F.2d 833, 839 (CCPA 1970) (2008) (contrasting predictable factors
`involving mechanical or electrical elements with “cases involving
`unpredictable factors, such as most chemical reactions and physiological
`activity”). Given this background, and Petitioner’s lack of testimonial
`evidence, we do not find that Petitioner has established that Graham
`expressly or inherently discloses a molecule “stably expressed in the
`mammalian cell in an amount sufficient to attenuate expression of the target
`gene in a sequence specific manner . . . whereby expression of the target
`gene is inhibited,” as required by claim 1. For at least this reason, Petitioner
`has not shown that Graham anticipates the challenged claims.
`Patent Owner further argues that Graham fails to disclose expression
`of a construct that encodes a short hairpin RNA molecule, e.g., “a short
`hairpin RNA molecule comprising a double-stranded region, wherein the
`double-stranded region consists of at least 20 nucleotides but not more than
`29 nucleotides . . . wherein the double-stranded region of the short hairpin
`RNA molecule comprises a sequence that is complementary to a portion of
`the target gene,” as set forth in independent claim 1. See Prelim. Resp. 15,
`18–22. With respect to the limitations of the recited short hairpin RNA, we
`agree with Patent Owner’s reasoning as set forth on pages 18–22 of the
`Preliminary Response. For the sake of brevity, however, we focus on
`Petitioner’s assertion that “Graham discloses a silencing construct having
`short hairpin RNA, with duplex regions at least 20 [nucleotides] and not
`more than 29 in length.” See Pet. 13. To support this conclusion, Petitioner
`relies on statements in the following passage from Graham:
`The optimum number of structural gene sequences which
`may be involved in the synthetic gene of the present invention
`will vary considerably, depending upon the length of each of said
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`structural gene sequences, their orientation and degree of identity
`to each other. For example, those skilled in the art will be aware
`of the inherent instability of palindromic nucleotide sequences in
`vivo and the difficulties associated with constructing long
`synthetic genes comprising
`inverted repeated nucleotide
`sequences, because of the tendency for such sequences to form
`hairpin loops and to recombine in vivo. Notwithstanding such
`difficulties, the optimum number of structural gene sequences to
`be included in the synthetic genes of the present invention may
`be determined empirically by those skilled in the art, without any
`undue experimentation and by following standard procedures
`such as the construction of the synthetic gene of the invention
`using recombinase deficient cell lines, reducing the number of
`repeated sequences to a level which eliminates or minimises
`recombination events and by keeping the total length of the
`multiple structural gene sequence to an acceptable limit,
`preferably no more than 5–10 kb, more preferably no more than
`25 kb and even more preferably no more than 0.5–2.0 kb in
`length.
`Ex. 1005, 10:22–44; see Pet. 13–14, 16.
`The above passage contains Graham’s sole reference to a “hairpin.”
`Given the evidence of record, we agree with Patent Owner that Graham’s
`discussion of “hairpin loops” refers to a problem that may occur when using
`inverted repeat sequences. See Prelim. Resp. 18–20. Thus, rather than
`disclosing the use of such structures for attenuating expression of a target
`gene, Graham teaches that hairpin loops should be avoided. Petitioner
`presents no evidence suggesting that one of ordinary skill in the art would
`read Graham in any other way. Accordingly, Petitioner fails to show that
`Graham discloses the use of “a short hairpin RNA molecule comprising a
`double-stranded region, wherein the double-stranded region consists of at
`least 20 nucleotides but not more than 29 nucleotides . . . wherein the
`double-stranded region of the short hairpin RNA molecule comprises a
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`sequence that is complementary to a portion of the target gene,” as required
`by the challenged claims. This provides an independent reason why
`Petitioner has not established a reasonable likelihood that it would prevail in
`showing that at least one challenged claim of the ’776 patent is anticipated
`by Graham.
`
`d. Obviousness in view Graham and/or Zamore, Tuschl, Fire, Harborth,
`Parrish, Sijen, Green, Tian, Waterhouse, and/or Symonds
`
`Petitioner contends that claims 1–10 of the ’776 patent
`are rendered obvious by a combination of Graham (Ex. 1005)
`and/or Zamore (Ex. 1003), in view of a combination of Tuschl
`(Ex. 1007), Fire (Ex. 1006), Harborth (Ex. 1012), Parrish (Ex.
`1010), Sijen (Ex. 1011), Green (Ex. 1008), Tian (Ex. 1009),
`Waterhouse (Ex. 1013) and/or Symonds (Ex. 1015), in view of
`the knowledge of one skilled in the art pursuant to 35 U.S.C.
`§ 103.
`Pet. 3–4.
`Zamore is discussed above in the context of anticipation. Because
`Petitioner does not persuade us that Zamore qualifies as prior art, we do not
`consider it further. With respect to the remaining references, Petitioner
`argues the obviousness of claims 1–10 of the ’776 patent based on Graham
`(id. at 42); Graham and Tuschl (id. at 44); Graham and Fire (id. at 51);
`Graham, Tuschl and/or Fire, Parish, Sijen, and/or Harborth (id. at 52–53);
`Graham, Tian and/or Green (id. at 56); Graham, Tian and/or Green, Tuschl,
`Fire, Parrish, Sijen and/or Harborth (id.); and Graham, Tuschl, Fire, Parrish,
`Sijen, Harborth, Tian and/or Green, Waterhouse, and Symonds (id. at 58).17
`
`
`17 Waterhouse and Symonds, however, are discussed in detail only with
`respect to selected dependent claims. Id. at 41–44, 59–60.
`
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`
`Patent Owner contends that Petitioner’s “kitchen sink” approach
`obscures the bases for the underlying obviousness challenge and, thus,
`requests that we deny the Petition as violating the particularity provisions of
`35 U.S.C. § 312(a)(3) and 37 C.F.R. § 42.22(a)(2); see also 37 C.F.R.
`§ 42.104(b)(4) and 42.104(b)(5). Prelim. Resp. 34–35. Patent Owner’s
`position is not without some merit. “Vague arguments and generic citations
`to the record are fundamentally unfair to an opponent and do not provide
`sufficient notice to an opponent and creates inefficiencies for the Board.”
`77 Fed. Reg. at 48620. We, nevertheless, address below Petitioner’s
`arguments to the extent we discern them.
`
`i. Graham
`Petitioner relies on Graham as teaching shRNAs, in particular, “short
`dsRNA constructs for gene silencing” (Pet. 45 (citing Ex. 1005, 6:25–40,
`10:22–32), and the “desirability of using short hairpin sequences to avoid
`cellular responses” (id. at 38–39 (citing Ex. 1005, 6:25–40)). As discussed
`above in the context of anticipation, however, Graham teaches that the
`potential of hairpin formation was a problem to be solved. Indeed, rather
`than teaching the “desirability” of using hairpin sequences, as Petitioner
`contends, Graham indicates that hairpins should be avoided and, thus,
`teaches away from the use of shRNAs for gene silencing in mammalian
`cells. Accordingly, Graham does not teach or suggest the use of “a sequence
`encoding a short hairpin RNA molecule comprising a double-stranded
`region wherein the double-stranded region consists of at least 20 nucleotides
`but not more than 29 nucleotides,” as required by claim 1.
`As we understand the Petition, Petitioner further relies on Tuschl,
`Fire, and Parrish for this limitation. Id. at 41–42.
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`ii. Parrish
`Petitioner does not explain how Parrish teaches or suggests the use of
`shRNA in any context. See e.g., Pet. 54 (“Parrish (Ex. 1010) itself renders
`obvious claims 1, 3, 4 and 5 relative to the sizes of the dsRNA, silencing of
`homologous target genes, processing through the Dicer pathway, and the
`lack of use of a PK inhibitor.”). Parrish teaches that double-stranded RNA
`molecules as short as 26 bp can trigger RNAi when injected into
`Caenorhabditis elegans, a non-mammalian organism that does not employ
`the PK response. See Ex. 1010, Abstract, id. at 1 (“In mammalian cells,
`dsRNA is associated with a sequence-nonspecific response that includes
`induction of interferon, phosphorylation of translation initiation factor eIF2
`(which leads to a general block in translation) an induction of a 2’-5’
`oligoadenylate synthetase (which can stimulate the RNA degrading enzyme
`RNase L) (Williams, 1999).”).18
`With respect to the claim limitation, “a sequence encoding a short
`hairpin RNA molecule comprising a double-stranded region, wherein the
`double-stranded region consists of at least 20 nucleotides but not more than
`29 nucleotides,” Petitioner relies on, for example, the Abstract and page 2,
`lines 17–18 of Parrish. Pet. 54. Although Petitioner’s selected passages
`refer to the length of duplex RNA fragments that may trigger RNAi, none
`refer to or suggest shRNA. At best, Figure 2 of the reference, which
`Petitioner does not rely on, indicates that injecting C. elegans with stem-
`
`
`18 Although we stop short of finding that Parrish teaches away from the use
`of dsRNA in mammalian cells, we disagree with Petitioner’s unsupported
`assertion that “Parrish provides motivation to employ short dsRNA to avoid
`PKR.” See Pet. 54.
`
`16
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`

`
`Case IPR2016-00016
`Patent 8,153,776 B2
`
`loop molecules having a very long double-stranded region (“corresponding
`to the entire 717 base gfp coding region”) triggered the RNAi response. See
`Ex. 1010, Fig. 2, 1079.
`In sum, Petitioner has not shown that Parrish teaches or suggests the
`use of shRNA in mammalian cells; or that one of ordinary skill in the art
`reading Parrish would have been motivated to use a stem-loop molecule of
`any dimensions in mammalian cells as set forth in the challenged claims
`with a reasonable expectation of success.
`
`iii. Tuschl
`Tuschl demonstrates that long double-stranded RNA molecules are
`processed to shorter sequences of 21 to 23 nucleotides in length, which can
`mediate RNAi in vitro. Ex. 1007, Abstract. Tuschl states that “[u]se of long
`dsRNAs in mammalian cells to elicit RNAi is usually not practical,
`presumably because of the deleterious effects of the interferon response,”
`but suggests, instead, that these 21 to 23 nucleotide fragments may be used
`to inactivate gene function. Id. ¶ 53.
`Tuschl demonstrates that the transfection of chemically synthesized
`21 nucleotide siRNA duplexes into mammalian cells specifically suppressed
`reporter gene expression without activating the interferon response (see id. ¶
`145), which, as Patent Owner notes, pertains to post-Dicer RNA-mediated
`interference (see Prelim. Resp. 40). Petitioner does not convince us that
`Tuschl provides any guidance for using siRNA as “a substrate for Dicer-
`dependent cleavage” as required by the challenged claims. And, as with
`Parrish, Tuschl does not teach or suggest use of “a sequence encoding a
`short hairpin RNA molecule comprising a double-stranded region, wherein
`the double-stranded region consists of at least 20 nucleotides but not more
`
`17
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`

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`Case IPR2016-00016
`Patent 8,153,776 B2
`
`than 29 nucleotides” for attenuating expression of a target gene in a
`mammalian cell.19
`
`iv. Fire
`Fire discloses sequence-specific inhibition of a target gene using
`double-stranded RNA “formed by a single self-complementary RNA strand
`or two complementary RNA strands.” See Ex. 1006, Abstract, 4:41–46,
`6:32–43; 7:42–52. Fire teaches that “RNA containing a [sic] nucleotide
`sequences identical to a portion of the target gene are preferred for
`inhibition” (id. at 7:53–54), and that “[t]he length of the identical nucleotide
`sequences may be at least 25, 50, 100, 200, 300 or 400 bases” (id. at 8:5–6).
`As we understand the argument, Petitioner relies on these teachings to assert
`that Fire teaches or suggests the use of “a sequence encoding a short hairpin
`RNA molecule comprising a double-stranded region, wherein the double-
`stranded region consists of at least 20 nucleotides but not more than 29
`nucleotides” for attenuating expression of a target gene in a mammalian cell.
`See Pet. 42, 48–52. In applying the reference, however, Petitioner appears to
`contend that the Examiner was wrong to withdraw a rejection over Fire
`during the prosecution leading to the issuance of the ’776 patent. Id. at 48–
`52. We do not find Petitioner’s argument persuasive.
`
`In distinguishing an obviousness rejection involving Fire, Applicants
`argued that
`
`
`19 We further agree with Patent Owner that Petitioner provides no support
`for the assertion that “the teachings of Tuschl with respect to reporter genes
`were adaptable by one of ordinary skill into silencing constructs, and one of
`skill in the art would have been motivated to use the siRNAs of Tuschl
`expressed from the transgenes of Graham and Zamore, to effect RNAi in
`mammalian cells.” See Prelim. Resp. 42 (quoting Pet. 48).
`
`18
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`

`
`Case IPR2016-00016
`Patent 8,153,776 B2
`
`
`Fire lacks any disclosure of a short hairpin RNA molecule as
`presently claimed, that is, a single-stranded RNA molecule
`comprising a double-stranded region having a length of at least
`20 nucleotides but not more than 29 nucleotides. The Examiner
`erroneously alleges that Fire discloses the length of the dsRNA
`region “to be at least 25 bases in length.” However, the language
`to which the Examiner expressly refers state