Paper No. ___
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________
`
`BENITEC BIOPHARMA LIMITED,
`Petitioner,
`v.
`
`COLD SPRING HARBOR LABORATORY,
`Patent Owner.
`____________
`
`Case IPR2016-00016
`Patent No. 8,153,776
`____________
`
`PATENT OWNER PRELIMINARY RESPONSE TO PETITION FOR
`INTER PARTES REVIEW OF U.S. PATENT NO. 8,153,776 UNDER 35
`U.S.C. §§ 311-319 AND 37 C.F.R. § 42.1 et seq.
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`TABLE OF CONTENTS
`
`INTRODUCTION ........................................................................................... 1
`
`OVERVIEW OF DR. HANNON’S PIONEERING SHORT HAIRPIN
`RNA INVENTION .......................................................................................... 2
`
`I.
`
`II.
`
`III. THE PETITION SHOULD BE DENIED BECAUSE THE GROUNDS
`RECYCLE ARGUMENTS THE PTO CONSIDERED IN DETAIL
`AND REJECTED ............................................................................................ 5
`
`A. The Hannon shRNA Patents Were Extensively Examined by the
`PTO .......................................................................................................... 5
`
`B. Grounds 1 to 3 Were Previously Considered by the Office .................... 7
`
`IV. THE PETITION SHOULD BE DENIED BECAUSE IT FAILS TO
`DEMONSTRATE A REASONABLE LIKELIHOOD OF
`PREVAILING AS TO ANY CHALLENGED CLAIM ................................. 8
`
`A. Level of Ordinary Skill in the Art ............................................................ 8
`
`B. Claim Construction .................................................................................. 9
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`C. Petitioner Offers No Testimony Regarding the Knowledge of a
`Person of Ordinary Skill in the Art .......................................................... 9
`
`D. Ground 1: Claims 1-10 Are Not Anticipated by Graham ..................... 14
`
`
`
` Overview of Graham ...................................................................... 14 1.
`
`
`
` Graham Does Not Disclose All the Features of Claims 1-10 ........ 15 2.
`
`
` Graham Does Not Disclose Any Activity in a Mammalian a.
`Cell.......................................................................................... 16
`
`
` Graham Also Does Not Disclose a Sequence Encoding a b.
`Short Hairpin RNA Molecule for Attenuating Expression
`of a Target Gene in a Mammalian Cell .................................. 18
`
`
` Graham Does Not Disclose “a Sequence Encoding c.
`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” ................................................... 21
`
`E. Ground 2: Claims 1-10 Are Not Anticipated by the Zamore Patent .... 23
`
` The Zamore Patent Is Not Available as a Prior Art Reference 1.
`
`
`under 35 U.S.C. § 102(e) Because Its Issued Claims Are Not
`Supported by The Zamore ‘185 Provisional .................................. 24
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`a.
`
`
`Independent Claim 1 and Independent Claim 41 of the
`Zamore Patent Are Not Supported by the Zamore ‘185
`Provisional .............................................................................. 25
`
`
` The Dependent Claims of the Zamore Patent Are Also b.
`Not Supported by the Zamore ‘185 Provisional
`Application ............................................................................. 26
`
` On the Merits, the Zamore ‘185 Provisional Does Not 2.
`
`
`Anticipate the Challenged Claims of the ‘776 Patent .................... 28
`
`
` The ‘185 Provisional Does Not Disclose Use of a Short a.
`Hairpin RNA Molecule Comprising a Double-Stranded
`Region of 20-29 Nucleotides for Avoiding PK Response
`and Attenuating Expression of a Target Gene in a
`Mammalian Cell. .................................................................... 29
`
`
` The Critical Disclosure in the Zamore Patent Was Added b.
`after Patent Owner’s Intervening Paddison Publication ........ 31
`
`F. Ground 3: Claims 1-10 Would Not Have Been Obvious Over
`Graham and/or the Zamore Patent, in View of a Combination of
`Tuschl, Fire, Harborth, Parrish, Sijen, Green, Tian, Waterhouse
`and/or Symonds ..................................................................................... 34
`
`1.
` Petitioner Ignores Evidence Establishing a Lack of Reasonable
`Expectation of Success ................................................................... 35
`
`
`
` Claims 1-10 Are Not Rendered Obvious by Graham .................... 38 2.
`
` Claims 1-10 Are Not Rendered Obvious by the Zamore Patent, 3.
`
`
`Alone or in Combination with Graham ......................................... 39
`
` Claims 1-10 Are Not Rendered Obvious by Graham and/or the 4.
`
`
`Zamore Patent in view of Tuschl ................................................... 39
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`
`
` Overview of Tuschl ................................................................ 40 a.
`
`
`
` Tuschl Does Not Remedy the Deficiencies of Graham ......... 41 b.
`
`5.
` Claims 1-10 Are Not Rendered Obvious by Graham and/or the
`Zamore Patent Alone or in view of Tuschl and Further in view
`of Fire ............................................................................................. 42
`
`
`
` Overview of Fire .................................................................... 43 a.
`
`
` Fire Does Not Remedy the Deficiencies of Graham and/or b.
`the Zamore Patent Alone or in view of Tuschl ...................... 43
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` Petitioner Conceded that Fire Is Not Enabling for
`c.
`Decreasing Gene Expression in Mammalian Cells ................ 45
`
`6.
`
`
`“Gene Silencing References”: Parrish, Sijen and Harborth Do
`Not Remedy the Deficiencies of Graham and/or the Zamore
`Patent Alone or in view of Tuschl and/or Fire ............................... 46
`
`7.
`
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`8.
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`
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` Parrish ..................................................................................... 47 a.
`
`
`
` Sijen ........................................................................................ 48 b.
`
`
`
` Harborth .................................................................................. 48 c.
`
`“PKR Trigger References”: Tian and Green Do Not Remedy
`the Deficiencies of Graham and/or the Zamore Patent Alone or
`in view of Tuschl and/or Fire and or Parrish and/or Sijen
`and/or Harborth .............................................................................. 49
`
`
`
` Tian ......................................................................................... 49 a.
`
`
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` Green ...................................................................................... 51 b.
`
`“Expression of Transgene References”: Waterhouse and
`Symonds Do Not Remedy the Deficiencies of Graham and/or
`the Zamore Patent Alone or in view of Tuschl and/or Fire and
`or Parrish and/or Sijen and/or Harborth and/or Green and/or
`Tian ................................................................................................. 52
`
`V. OBJECTIVE INDICIA DEMONSTRATE THAT THE CHALLENGED
`CLAIMS ARE PATENTABLE .................................................................... 54
`
`A. Using Short Hairpin RNA To Attenuate Gene Expression in
`Mammalian Cells Satisfied a Long-Felt and Unmet Need .................... 55
`
`B. Patent Owner’s Invention Has Been Widely Praised ............................ 56
`
`C. Commercial Success of shRNA ............................................................. 58
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`VI. CONCLUSION .............................................................................................. 60
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`TABLE OF AUTHORITIES
`
`
`Cases
`
`Alexsam, Inc. v. IDT Corp.,
`715 F.3d 1336 (Fed. Cir. 2013) ............................................................................13
`
`Atlas Powder Co. v. Ireco, Inc.,
`190 F.3d 1342 (Fed. Cir. 1999) ..................................................................... 12, 22
`
`Atofina v. Great Lakes Chemical Corp.,
`441 F.3d 991 (Fed. Cir. 2006) ..............................................................................21
`
`Belden Inc. v. Berk-Tek LLC,
`805 F.3d 1064 (Fed. Cir. 2015) ............................................................................11
`
`Bilstad v. Wakalopulos,
`386 F.3d 1116 (Fed. Cir. 2004) ............................................................................26
`
`Creative Compounds, LLC v. Starmark Labs.,
`651 F.3d 1303 (Fed. Cir. 2011) ............................................................................12
`
`Dynamic Drinkware, LLC v. National Graphics, Inc.,
`800 F.3d 1375 (Fed. Cir. 2015) ............................................................... 23, 24, 53
`
`Eiselstein v. Frank,
`52 F.3d 1035 (Fed. Cir. 1995) ....................................................................... 25, 27
`
`Ex Parte Takako Yamaguchi,
`Appeal 2007-4412, 2008 WL 4233306, at *5 (BPAI Aug. 29, 2008) .......... 13, 24
`
`Excelsior Medical Corp. v. Lake,
`IPR2013-00494, Slip op. (Feb. 6, 2014) (Paper 10) .............................................. 7
`
`In re Giacomini,
`612 F.3d 1380 (Fed. Cir. 2010) ............................................................................24
`
`In re Napier,
`55 F.3d 610 (Fed. Cir. 1995) ................................................................................22
`
`In re Piasecki,
`745 F.2d 1468 (Fed. Cir. 1984) ............................................................................55
`
`Institut Pasteur & Universite Pierre Et Marie Curie v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) ............................................................................57
`
`Johns Manville Corp. v. Knauf Insulation, Inc.,
`IPR2015-01402, Slip op. (Oct. 21, 2015) (Paper 18) ...........................................17
`
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`Monsanto Company v. Pioneer Hi-Bred International, Inc.,
`IPR2013-00022, Slip op. (Apr. 11, 2013) (Paper 43) ..........................................12
`
`Moses Lake Indus., Inc. v. Enthone, Inc.,
`IPR2014-00243, Slip op. (June 18, 2014) (Paper 6) ............................................11
`
`Net MoneyIN, Inc. v. Verisign, Inc.,
`545 F.3d 1359 (Fed. Cir. 2008) ............................................................................20
`
`Nora Lighting, Inc. v. Juno Mfg., LLC,
`IPR2015-00601, Slip op. (Aug. 12, 2015) (Paper 13)............................................ 7
`
`Omron Oilfield & Marine Inc. v. MD/TOTCO, L.P.,
`IPR2013-00265, Slip op. (Oct. 31, 2013) (Paper No. 11) ....................................58
`
`Par Pharm,. Inc. v. Jazz Pharm., Inc.,
`IPR2015-00548, Slip op. (July 28, 2015) (Paper 19) ............................................. 9
`
`Prism Pharma Co. v. Choongwae Pharma Corp.,
`IPR2014-00315, Slip op. (Jul. 8, 2014) (Paper 14) ................................................ 7
`
`Proveris Scientific Corp. v. Innovasystems, Inc.,
`536 F.3d 1256 (Fed. Cir. 2008) ............................................................................13
`
`Scripps Clinic & Research Found. v. Genentech, Inc.,
`927 F.2d 1565 (Fed. Cir. 1991) ............................................................................15
`
`Securus Techs., Inc., v. Global Tel*Link Corp.,
`IPR2015-00153, Slip op. (May 1, 2015) (Paper 12) ..................................... 33, 34
`
`Shopkick Inc. v. Novitaz, Inc.,
`IPR2015-00277-278, Slip op. (May 29, 2015) (Paper 7) .....................................20
`
`Shopkick Inc., v. Novitaz, Inc.,
`IPR2015-00279, Slip op. (May 29, 2015) (Paper 7) ............................................15
`
`Tec Air, Inc. v. Denso Mfg. Michigan Inc.,
`192 F.3d 1353 (Fed. Cir. 1999) ............................................................................54
`
`Veeam Software Corp. v. Symantec Corp.,
`IPR2013-00145, Slip op. (Aug. 7, 2013) (Paper 12)............................................12
`
`Wowza Media Systems, LLC v. Adobe Systems Inc.,
`IPR2013-00054, Slip op. (April 8, 2013) (Paper 12) ...........................................35
`
`Statutes
`
`35 U.S.C. § 102 ................................................................................................ passim
`
`35 U.S.C. § 103 ............................................................................................. 7, 10, 28
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`35 U.S.C. § 112 ........................................................................................................45
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`35 U.S.C. § 312 ................................................................................................. 22, 35
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`35 U.S.C. § 314 .......................................................................................................... 6
`
`35 U.S.C. § 325 ................................................................................................ passim
`
`Rules
`
`Rule of Practice for Trials Before the Patent Trial and Appeal Board,
`Final Rule 77 FR 48612 ................................................................................ 17, 33
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`Regulations
`
`37 C.F.R. § 42.100 .................................................................................................2, 9
`
`37 C.F.R. § 42.104 ............................................................................................ 17, 33
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`37 C.F.R. § 42.22 ........................................................................................ 17, 33, 35
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`APPENDIX LISTING OF EXHIBITS
`
`Description
`Exhibit
`2001 Bernstein et al., “Role for a bidentate ribonuclease in the initiation step
`of RNA interference” Nature, 409:363-366 (18 January 2001)
`2002 Barrangou et al., “Advances in CRISPR-Cas9 genome engineering:
`lessons learned from RNA interference” Nucleic Acids Research,
`43(7):3407-3419 (23 March 2015)
`2003 Benitec Biopharma “Licensed Patents” Webpage
`(http://www.benitec.com/intellectual-property/licensed-patents)
`accessed January 4, 2016
`2004 Hammond, “Breeding strategies for the development of the Australian
`beef industry: an overview” Australian Journal of Experimental
`Agriculture, 46:183-198 (2006)
`2005 RESERVED
`2006 RESERVED
`2007
`Elbashir et al., “RNA interference is mediated by 21- and 22-nucleotide
`RNAs”, Genes and Development, 15:188-200 (2001)
`2008 April 12, 2006 Non-Final Office Action and June 12, 2006 Amendment
`in Response to Non-Final Office Action by Patent Owner in an Ex Parte
`Reexamination, Serial No. 90/007,247
`2009 U.S. Provisional Patent Application No. 60/304,127
`2010 U.S. Provisional Patent Application No. 60/304,283
`2011 U.S. Provisional Patent Application No. 60/343,484
`2012 U.S. Provisional Patent Application No. 60/386,063
`2013 U.S. Patent No. 7,345,025 (Ex. 1015 with highlighting)
`2014 Google Scholar Screenshot
`(https://scholar.google.com/scholar?as_sdt=1,22&q=short+hairpin+RN
`As+%28shRNAs%29+induce+sequence-
`specific+silencing+in+mammalian+cells&hl=en)
` accessed January 7, 2016
`2015 Hairpin Technologies “Who We Are” Webpage
`(http://www.hairpintechnologies.com/company.html) accessed January
`4, 2016
`2016 Hairpin Technologies “Licensed Partners” Webpage
`(http://www.hairpintechnologies.com/licensed-partners.html) accessed
`January 4, 2016
`2017 Benitec Biopharma “Licensing Options” Webpage
`(http://www.benitec.com/pipeline/licensing-options) accessed January 4,
`
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`2016
`2016
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`451o479_1
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`I.
`
`INTRODUCTION
`
`Patent Owner Cold Spring Harbor Laboratory submits this Preliminary
`
`Response to the Petition filed by Benitec Biopharma Limited seeking inter partes
`
`review of claims 1-10 of U.S. Patent No. 8,153,776. The Petition should be denied
`
`because it fails to demonstrate a reasonable likelihood of prevailing with respect to
`
`any of the challenged claims. Ground 1 relies on a reference that was considered
`
`during prosecution and does not disclose key limitations recited in the claims.
`
`Ground 2 relies on a reference that is not available as prior art to the ‘776 patent
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`and repeats the same arguments that were overcome during prosecution. Ground 3
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`combines 11 references in over 1,500 different possible combinations, without any
`
`evidence for how such a multitude of possibilities would have led one of ordinary
`
`skill in the art to the claimed invention. Moreover, the Petition requires the Board
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`to ignore the extensive consideration by the PTO of the same arguments and
`
`references presented by Petitioner, to ignore two expert declarations that were
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`central to the prosecution of the ‘776 patent, and to ignore extensive evidence of
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`secondary considerations in the record.
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`Accordingly, Petitioner failed to establish a reasonable likelihood of
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`prevailing, and Patent Owner requests that the Patent Trial and Appeal Board
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`(“Board”) deny institution of inter partes review.
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`1
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`
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`II. OVERVIEW OF DR. HANNON’S PIONEERING SHORT HAIRPIN
`RNA INVENTION
`
`
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`The ‘776 patent—and the related ‘846, ‘599 and ‘264 patents1—are directed
`
`to a pioneering method for reducing gene expression in mammalian cells using a
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`novel class of RNA molecules invented by Dr. Gregory Hannon and his team of
`
`scientists at Cold Spring Harbor Laboratory. Dr. Hannon called the novel
`
`molecules “short hairpin RNA” or simply “shRNA,” and these molecules allowed
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`researchers for the first time to stably attenuate the expression of any gene in any
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`mammalian cell. Ex. 1001, 15:62-16:3.
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`
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`It was known in the art that one could use RNA interference (“RNAi”) to
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`reduce gene expression in certain cells using double-stranded RNA (“dsRNA”)
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`molecules complementary to a target gene. Ex. 1002 at 530-538, ¶ 8. In fact, it
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`was Dr. Hannon and his team who discovered that such dsRNA molecules were
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`processed by an enzyme called Dicer into small interfering RNAs (“siRNAs”),
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`which were active in mediating gene expression. Id.; Ex. 2001 at 363. Yet the art
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`also recognized significant problems with using dsRNA in mammalian cells. Ex.
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`1001, 2:3-8; Ex. 1017 at 1-2, 4; Ex. 1002 at 530-538, ¶¶ 16, 18. In particular,
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`mammalian cells were known to contain an anti-viral response, referred to as a
`
`
`1 IPR2016-0016 Petition for Inter Partes Review of U.S. Patent No. 8,153,776
`
`Under 37 C.F.R. § 42.100 (“Pet.”) at 1.
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`2
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`“PK response,” “PKR response,” or simply “PKR,” which would kill the cell in
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`response to the presence of dsRNA. Ex. 1001, 54:35-40; Ex. 1017 at 1-2, 4; Ex.
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`1002 at 530-538, ¶ 18. Moreover, although synthetic siRNA molecules could be
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`introduced into mammalian cells to briefly reduce gene expression, they would not
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`stably attenuate gene expression over time. Ex. 1001, 56:19-28; Ex. 1017 at 7-8.
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`Dr. Hannon solved those problems by engineering short hairpin RNA
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`molecules that could be stably expressed in mammalian cells without triggering a
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`PK response while at the same time could be processed by Dicer (serve “as a
`
`substrate for Dicer-dependent cleavage”) and attenuate gene expression. Ex. 1001,
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`Example 7, FIG. 46. Although the prior art taught away from such an approach
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`(Ex. 1002 at 530-538, ¶¶ 7-19), Dr. Hannon recognized that “shRNAs specifically
`
`designed as Dicer substrates can be used as more potent inducers of RNAi than
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`siRNAs.” Ex. 1001, 19:35-37.
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`The priority application to the ‘776 patent (and the related ‘599, 846 and
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`‘264 patents) was filed in January 2002. Two weeks later, Dr. Hannon’s team
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`submitted their results to Genes & Development, which became a landmark
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`publication entitled “Short hairpin RNAs (shRNAs) induce sequence-specific
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`silencing in mammalian cells.” Ex. 1017 (the “Paddison article”) at 1. The
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`Paddison article, submitted during prosecution as evidence of the pioneering nature
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`of the claimed shRNA invention, was cited in over 500 subsequent articles from
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`3
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`2002 to 2006, making it one of the most cited articles in the field of molecular
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`biology. Ex. 1002 at 1050-1073 (at 1073). As a result, Dr. Hannon received the
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`Award for Outstanding Achievement in Cancer Research from the American
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`Association for Cancer Research for his shRNA work in mammalian cells. Ex.
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`1002 at 803-819, ¶ 37; 1050-1073 (at 1072). Today, Dr. Hannon’s shRNA
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`invention is recognized as a “milestone” in the field of RNAi. Ex. 2002 at FIG. 2.
`
`Indeed, the Commonwealth Scientific Industrial Research Organization
`
`(“CSIRO”)—the owner of the Graham patent exclusively licensed to Petitioner and
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`the subject of Grounds 1 and 3—described the invention as “the major
`
`breakthrough confirming the presence of ribonucleic acid interference (RNAi)
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`post-transcriptional gene silencing activity in mammalian (human) cells (Paddison
`
`et al. 2002).” Ex. 2003; Ex. 2004 at p. 188, left col.
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`Petitioner ignores that overwhelming evidence of patentability to
`
`mischaracterize the ‘776 patent as merely claiming the inherent PK response in
`
`mammalian cells. See, e.g., Pet. at 7 (“Accordingly, Patentee’s alleged ‘invention’
`
`amounts to nothing more than incorporation of well-known features relative to
`
`RNA length and PKR, already disclosed before January 22, 2002.”). That is not
`
`true. The claimed invention is directed to a specific and pioneering method for
`
`attenuating gene expression in a mammalian cell by: 1) stably expressing a
`
`sequence encoding a short hairpin RNA molecule; 2) comprising a double-stranded
`
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`4
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`region complementary to a portion of the target gene, wherein the double-stranded
`
`region consists of at least 20 nucleotides but not more than 29 nucleotides; and 3)
`
`wherein the short hairpin RNA molecule is both a substrate for Dicer-dependent
`
`cleavage and does not trigger a PK response in the mammalian cell.
`
`III. THE PETITION SHOULD BE DENIED BECAUSE THE GROUNDS
`RECYCLE ARGUMENTS THE PTO CONSIDERED IN DETAIL
`AND REJECTED
`
`The prosecution of the ‘776 patent was extensive and resulted in claims that
`
`the PTO determined were patentable over the prior art, including the primary
`
`references that Petitioner relies upon. Because Petitioner recycles art and
`
`arguments the PTO previously considered and rejected, the Board should exercise
`
`its discretion to deny the Petition under 35 U.S.C. § 325(d).
`
`A. The Hannon shRNA Patents Were Extensively Examined
`by the PTO
`
`The ‘776 patent (Application No. 11/894,676) underwent nearly five years
`
`of examination by the PTO. There were five substantive rejections, eight rounds of
`
`substantive claim amendments, eight interviews with multiple Examiners, and two
`
`supporting expert declarations from a leading researcher in the field of RNAi—
`
`Professor Nouria Hernandez, Ph.D. Ex. 1002 at 149, 453-454, 480-493, 515-528,
`
`530-538, 546-549, 550-563, 567-581, 590-592, 593-596, 599-601, 659-661, 666-
`
`685, 696-698, 699-715, 718-1013, 803-819, 837-855, 1050-1073, 1076-1078,
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`5
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`1079-1084, 1094-1098, 1130-1132, 1136-1142, 1154-1164, 1168-1171, 1172-
`
`1192, 1201-1205.
`
`Patent Owner invited that exhaustive examination of its shRNA patent
`
`applications when it discovered that specific portions of the original specification
`
`were copied, without its knowledge, from an unrelated application filed on behalf
`
`of Fire. Patent Owner retained new patent counsel, disclosed the copying to the
`
`PTO, and disclaimed those portions of the specification. Ex. 1002 at 439-445,
`
`453-454. Accordingly, in addition to the Primary Examiner, three Supervisory
`
`Patent Examiners (SPEs) considered the applications as well. The examination
`
`included a detailed interview during which Patent Owner and Dr. Hernandez
`
`presented a review of the cited prior art and the invention to all four Examiners.
`
`Ex. 1002 at 1050-1073. After that interview and several additional interviews and
`
`responses, the prior art rejections were withdrawn and the application was allowed
`
`to issue as the ‘776 patent. Ex. 1002 at 1076-1078, 1079-1084, 1094-1098, 1130-
`
`1132, 1136-1142, 1154-1164, 1168-1171, 1172-1192, 1201-1205.
`
`The present Petition does not include any new evidence, let alone expert
`
`testimony, to contradict the substantial evidence of patentability submitted during
`
`prosecution. Instead, Petitioner simply argues that the Examiners who granted the
`
`‘776 patent got it wrong.
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`6
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`B. Grounds 1 to 3 Were Previously Considered by the Office
`
`The Board’s discretion to deny institution under § 314 “is guided, in part,”
`
`by § 325(d), which permits the Board to “reject the petition . . . because[] the same
`
`or substantially the same prior art or arguments previously were presented to the
`
`Office.” Nora Lighting, Inc. v. Juno Mfg., LLC, IPR2015-00601, Slip op. at 11
`
`(Aug. 12, 2015) (Paper 13); Prism Pharma Co. v. Choongwae Pharma Corp.,
`
`IPR2014-00315, Slip op. at 12-13 (Jul. 8, 2014) (Paper 14) (denying grounds under
`
`35 U.S.C. § 325(d) based on arguments rejected during prosecution of the
`
`challenged patent); Excelsior Medical Corp. v. Lake, IPR2013-00494, Slip op. at
`
`19-20 (Feb. 6, 2014) (Paper 10) (same).
`
`In the present petition, Grounds 1, 2, and 3 are based on references that the
`
`PTO previously considered in deciding to allow the ‘776 patent. Ground 1
`
`(completely) and Ground 3 (partially) rely on Graham as a primary reference.
`
`Graham was considered by the PTO during prosecution. Ex. 1001, 1. Ground 2
`
`(completely) and Ground 3 (partially) rely on the Zamore patent as a primary
`
`reference. As shown below, a rejection under § 103 over the Zamore patent was
`
`withdrawn because the Examiners determined that the key features cited in the
`
`Zamore patent were not disclosed in its earlier provisional application. Ex. 1002 at
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`1168-1171, 1172-1192, 1201-1205. Nevertheless, Petitioner recycles the same
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`arguments here. Finally, Ground 3 repeats arguments based on secondary
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`7
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`

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`
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`references, including Tuschl and Fire, that were thoroughly considered during
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`prosecution.
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`The ‘776 claims were allowed because the prior art does not disclose a
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`method for attenuating gene expression in a mammalian cell by: 1) stably
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`expressing a sequence encoding a short hairpin RNA molecule; 2) comprising a
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`double-stranded region complementary to a portion of the target gene, wherein the
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`double-stranded region consists of at least 20 nucleotides but not more than 29
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`nucleotides; and 3) wherein the short hairpin RNA molecule is both a substrate for
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`Dicer-dependent cleavage and does not trigger a PK response in the mammalian
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`cell.
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`
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`Because Grounds 1-3 present the same arguments considered and rejected
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`by multiple Examiners during prosecution, the Board should exercise its discretion
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`under § 325(d) and deny institution.
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`IV. THE PETITION SHOULD BE DENIED BECAUSE IT FAILS TO
`DEMONSTRATE A REASONABLE LIKELIHOOD OF
`PREVAILING AS TO ANY CHALLENGED CLAIM
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`A. Level of Ordinary Skill in the Art
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`Petitioner alleges that a person of ordinary skill in the art would be “a
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`graduate or post-graduate student in the life sciences field, or have a Master’s
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`degree or Ph.D. in molecular biology, microbiology, biochemistry, chemistry or a
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`related discipline.” Pet. at 4. Petitioner offers no testimony at all from such a
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`
`
`8
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`
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`person as of the effective filing date of the ‘776 patent or from one who would
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`have known what such a person would have understood as of that date.
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`For purposes of its Preliminary Response, however, Patent Owner accepts
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`Petitioner’s asserted level of ordinary skill in the art but reserves the right to offer
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`an alternative if this inter partes review is instituted.
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`B. Claim Construction
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`In this proceeding, claim terms should be given their broadest reasonable
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`interpretation absent a clear definition to the contrary in the patent. 37 C.F.R.
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`§ 42.100(b); Par Pharm,. Inc. v. Jazz Pharm., Inc., IPR2015-00548, Slip op. at 18-
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`19 (July 28, 2015) (Paper 19). Because the claim terms are not afforded such a
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`definition, they should be given their broadest reasonable construction as
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`understood by one of ordinary skill in the art and consistent with the disclosure.
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`C.
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`Petitioner Offers No Testimony Regarding the Knowledge
`of a Person of Ordinary Skill in the Art
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`The Petition is replete with allegations about what a person of ordinary skill
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`in the art would have been motivated to do and would have understood to be true
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`about the field of RNAi as of the January 2002 effective filing date of the ‘776
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`patent. For example:
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`A person of ordinary skill of the art, therefore, would have been
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`motivated to combine these references because these innate
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`biological systems were known, as discussed above, the references
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`evidence a strong motivation to utilize short hairpin dsRNA mediated
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`
`
`9
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`

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`
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`gene silencing in human therapies, with the desire and knowledge to
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`avoid triggering PKR, as will be discussed. Pet. at 9.2
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`
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`Expression of transgenes with promoter sequences is routine, and
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`obvious to one of ordinary skill in view of knowledge and the
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`teachings of Graham. Pet. at 22.
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`
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`It is clear from the above language that one of ordinary skill in view
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`of the cited teachings and knowledge in the art would understand
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`that Zamore had possession of the means to avoid PKR when utilizing
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`the gene silencing technology based on his reference to the “length,
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`sequence, and/or structure” of the constructs (Zamore ‘185 Prov., Ex.
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`1004, 8:12) and their effect on “induction of the interferon response”
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`(Zamore ‘185 Prov., Ex. 1004, 8:13) as well as the prior art teachings.
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`Pet. at 29.
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`
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`Likewise, the teachings of Graham and Zamore alone and in
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`combination, and in further view of the ordinary skill in the art and
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`the art cited also render claims 1-10 obvious under § 103(a), as set
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`forth. Pet. at 44.
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`
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`Graham and Zamore evidence that the teachings of Tuschl with respect
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`to reporter genes were adaptable by one of ordinary skill into
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`2 Unless otherwise indicated, all emphasis is added and internal citations are
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`omitted.
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`
`
`10
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`
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`silencing constructs, and one of skill in the art would have been
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`motivated to use the siRNAs of Tuschl expressed from the transgenes
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`of Graham and Zamore, to effect RNAi in mammalian cells. Pet. at 48.
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`Yet Petitioner submitted no testimony in support of its numerous factual
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`allegations. In doing so, Petitioner ignored the Board’s expectation that testimony
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`supporting a petition will be provided. See Trial Practice Guide, Section II.A.4.
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`(Aug. 14, 2012) (“The Board expects that most petitions and motions will rely
`
`upon affidavits of experts.”). The need for declaration evidence is particularly
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`acute for unpredictable inventions, like that at issue here. See Moses Lake Indus.,
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`Inc. v. Enthone, Inc., IPR2014-00243, Slip op. at 20 (June 18, 2014) (Paper 6)
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`(denying institution: “To the extent an art is unpredictable, as the chemical arts
`
`often are, KSR’s focus on these identified, predictable solutions may present a
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`difficult hurdle because potential solutions are less likely to be genuinely
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`predictable . . . we agree with [Patent Owner] that [Petitioner] must provide more
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`than conclusory expert testimony . . . and conclusory rationales to combine the
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`teachings, to present a prima facie case of obviousness.”); cf., Belden Inc. v. Berk-
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`Tek LLC, 805 F.3d 1064, 1079 (Fed. Cir. 2015) (“No rule requires a Petition to be
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`accompanied by any declaration” in a field where the prior art itself showed that
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`the claimed result “predictably would be achieved” by combining disclosures of
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`the asserted references). As a result, petitions for inter partes review lacking
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`supporting declarations are frequently denied institution. E.g., Monsanto Company
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`
`
`11
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`

`
`
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`v. Pioneer Hi-Bred International, Inc., IPR2013-00022, Slip op. at 7 (Apr. 11,
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`2013) (Paper 43) (denying institution after declining to consider expert testimony
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`as conclusory: “Absent [expert’s] declaration, Monsanto has failed to identify
`
`sufficient credible evidence to establish that the prior art meets the GDD limitation
`
`of the claims . . . . Therefore, absent [expert’s] declaration, Monsanto has not
`
`provided sufficient evidence to demonstrate that the prior art references anticipate
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`or render obvious the limitation.”); Veeam Software Corp. v. Symantec Corp.,
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`IPR2013-00145, Slip op. at 11-12 (Aug. 7, 2013) (Paper 12) (denying institution:
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`“Petitioner’s arguments . . . amount to little more than unsubstantiated assertions
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`about the combinability of [the prior art], the manner of their combination, and the
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`results thereby obtained.”).
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`The ex