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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`MODERNATX, INC.
`Petitioner
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`v.
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`CUREVAC AG
`Patent Owner
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`Patent No. 8,383,340
`Issued: February 26, 2013
`Filed: December 20, 2007
`Inventors: Ketterer et al.
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`Title: METHOD FOR PURIFYING RNA ON A PREPARATIVE SCALE BY
`MEANS OF HPLC
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`Inter Partes Review No. - not yet assigned
`_______________
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`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,383,340
`UNDER 35 U.S.C. §§311-319 AND 37 C.F.R. §§42.1-.80, 42.100-.123
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` I.
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`IPR of USPN 8,383,340
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`TABLE OF CONTENTS
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`Statement of the Precise Relief Requested and the Reasons Therefor (37
`C.F.R. §42.22(A)) ............................................................................................ 1
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`
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` II.
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`Summary .......................................................................................................... 1
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` Prior Art Overview .......................................................................................... 4 III.
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`A.
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`By 2006, large quantities of pure RNA were used in RNA-based
`strategies ................................................................................................ 4
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`B. High performance liquid chromatography (HPLC) was a commonly-
`used technique for purifying nucleic acids, including RNA ................. 5
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`C.
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`D.
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`E.
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`F.
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`The prior art taught IP RP HPLC for large scale RNA purification ..... 8
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`The prior art taught olystyrenedivinylbenzene (PSDVB) for purifying
`RNA .....................................................................................................10
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`The prior art taught using non-alkylated PSDVB to purify RNA ......11
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`The prior art taught using porous PSDVB to purify RNA .................12
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` The '340 Patent Disclosure and Claims .........................................................13 IV.
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` V.
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`Person of ordinary skill in the art (POSA) ....................................................14
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` Claim construction .........................................................................................15 VI.
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` VII.
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`Identification of the challenge (37 C.F.R. §42.104(b)) .................................18
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`A. Ground 1: Gjerde I anticipates Claims 1-5, 8, 10-22, and 26 .............18
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` 1.
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` 2.
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` 3.
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`Gjerde I anticipates claim 1 ......................................................19
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`Gjerde I anticipates dependent claims 2-4, relating to RNA type
`and size ......................................................................................24
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`Gjerde I anticipates dependent claim 5, relating to the reversed
`phase particle size .....................................................................26
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`IPR of USPN 8,383,340
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` 4.
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` 5.
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` 6.
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` 7.
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` 8.
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`Gjerde I anticipates dependent claim 8, relating to the reverse
`phase structure ...........................................................................27
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`Gjerde I anticipates dependent claim 10, relating to HPLC type
` ...................................................................................................28
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`Gjerde I anticipates dependent claims 11-19, relating to mobile
`phase contents ...........................................................................29
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`Gjerde I anticipates dependent claims 20-22, relating to
`methods of applying the mobile phase .....................................34
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`Gjerde I anticipates dependent claim 10, relating to
`chromatography type ................................................................36
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`B. Ground 2: Claims 1, 3-4, 6-19 and 21-26 would have been obvious
`over Zhang in view of Lloyd ...............................................................37
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` 1.
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` 2.
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`Claim 1 would have been obvious over Zhang in view of Lloyd
` ...................................................................................................38
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`Claims 3-4, 6-19, and 21-26 would have been obvious over
`Zhang in view of Lloyd .............................................................45
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`C. Ground 3: Claim 2 would have been obvious over Sullenger in view
`of Lloyd ...............................................................................................52
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`D. Ground 4: Claim 5 would have been obvious over Zhang in view of
`Lloyd and the Polymer Labs Catalog ..................................................56
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`E.
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`Ground 5: Claim 20 would have been obvious over Zhang in view of
`Lloyd and Gjerde II .............................................................................59
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`F.
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`Objective indicia do not support patentability ....................................61
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` Certification that the Patent May Be Contested via Inter Partes Review by VIII.
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`the Petitioner and Standing (37 C.F.R. §42.104(a)) ......................................63
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` Mandatory Notices (37 C.F.R. §42.8(a)(1)) ..................................................64 IX.
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` X.
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`Conclusion .....................................................................................................65
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`IPR of USPN 8,383,340
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` Statement of the Precise Relief Requested and the Reasons Therefor (37 I.
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`C.F.R. §42.22(A))
`ModernaTX, Inc. petitions for Inter Partes Review, seeking cancellation of
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`claims 1-26 of U.S. Patent No 8,383,340 to Ketterer et al. ("the '340 patent")
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`(EX1001), assigned to CureVac AG. As set forth in detail below, '340 patent
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`claims 1-26 are unpatentable under 35 U.S.C. §§102 and 103 in view of the prior
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`art. This Petition is supported by a Declaration of Dr. David Hornby (EX1002),
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`Moderna's techinical expert.
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` Summary II.
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`The '340 patent claims methods of purifying RNA using high performance
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`liquid chromatography
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`("HPLC") or
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`low or normal pressure
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`liquid
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`chromatography, using a porous reversed phase as a stationary phase and a mobile
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`phase, wherein
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`the porous
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`reversed phase
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`is a porous non-alkylated
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`polystyrenedivinylbenzene ("PSDVB"). The dependent claims further limit the
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`RNA type, the PSDVB characteristics, or chromatography method's reagents and
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`steps. The '340 patent alleges a foreign priority date of December 22, 2006, and
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`PCT filing date of December 20, 2007.1
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`The reversed phase chromatography methods described and claimed in the
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`1 Petitioner does not concede that the '340 patent is entitled to its asserted
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`priority date.
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`IPR of USPN 8,383,340
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`'340 patent were already known well before the alleged priority date. EX1002,
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`¶¶37-50. For example, Huck et al. (EX1009; "Huck") disclosed in 2005 that
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`reversed phase HPLC was applied in the "[s]eparation of nucleic acid mixtures"
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`because of its "high resolution capability and flexibility to separate both single-
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`and double-stranded nucleic acids in a size range from a few nucleotides to several
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`thousand base pairs." EX1009, 431:1:1. The known nucleic acid applications
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`included the reversed phase HPLC methods for "segregation of RNA molecules"
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`described in Gjerde et al., U.S. Patent No. 6,576,133 ("Gjerde I"). EX1004,
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`Abstract, 7:24-64; EX1044, 673, 677; EX1008, 8-9.
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`Using porous nonalkylated PSDVB as the reversed phase in HPLC RNA
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`purification was likewise well-known before 2006. EX1002, ¶¶51-64. Literature
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`reviews of PSDVB's application as a "[m]edia for [l]iquid [c]hromatography"
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`taught that PSDVB had "been used in a wide range of applications" such as the
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`separating "[r]ibonucleic acids," using PSDVB was considered "the standard in
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`HPLC of nucleic acids," and purification with porous nonalkylated PSDVB
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`polymers was considered "the future of oligonucleotide analysis and purification."
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`EX1010, Table 2, 1470:1:2; EX1012, 28:2:1; EX1002, ¶¶51-56; EX1044,
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`673:Abstract, 674; EX1005, 223:Title.
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`As
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`discussed
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`above, Gjerde
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`I
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`disclosed
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`a
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`"[p]olynucleotide
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`[c]hromatography method and system for size-based segregation of a mixture of
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`IPR of USPN 8,383,340
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`RNA molecules." EX1004, Abstract. Gjerde I's methods include preparing a
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`"monolith chromatography column" with a nonalkylated polymer of "styrene and
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`divinylbenzene" with "through-pores" for use in reversed phase HPLC of RNA.
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`See, e.g., EX1004, 31:27-60. Based these and other teachings, Gjerde I discloses
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`all elements of claims 1-5, 10-22, and 26 of the '340 patent, arranged as claimed,
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`and would have enabled a person of ordinary skill in the art to perform these
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`claimed methods. Accordingly, Gjerde I anticipates claims 1-5, 8, 10-22, and 26 of
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`the '340 patent. See §VII.A below.
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`Additionally, claims 1, 3-4, 6-19 and 21-26 would have been obvious in
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`view of Zhang et al. (EX1038) and Lloyd et al. (EX1005). See §VII.B below.
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`Zhang teaches that antisense RNA molecules, such as ribozymes, are "very
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`attractive as therapeutics." EX1038, 22:4. Lloyd discloses preparative scale
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`purification of DNA oligonucleotides with ion-pair reversed-phase HPLC using
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`porous nonalkylated PSDVB media. EX1005, 223, 225. A person of ordinary skill
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`in the art ("POSA") would have had reason to purify RNA needed for Zhang's
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`RNA-based therapy using Lloyd's oligonucleotide purification methods because
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`Lloyd teaches that its method is "an obvious choice" to "produce large quantities of
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`well-defined oligonucleotides…[because it has] excellent selectivity and high
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`capacity." EX1005, 227. And a POSA would have had a reasonable expectation of
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`success in doing so because it was generally known in the art that "IP RP HPLC
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`IPR of USPN 8,383,340
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`technology methods [developed for DNA]…extended to RNA analysis." EX1008,
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`1:2:1-2.
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`Finally, dependent claims 2, 5, and 20 would have been obvious in view of
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`Lloyd combined with teachings in the art relating to RNA types to be purified,
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`using particular bead
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`sizes, and performing
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`isocratic elutions during
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`chromatography. See §§VII.C-E below.
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` Prior Art Overview III.
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`A. By 2006, large quantities of pure RNA were used in RNA-based
`strategies
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`By 2006, the field recognized that "large quantities" of pure RNA were
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`needed as part of methods "to therapeutically exploit [] RNA." EX1041, 988:1:1;
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`EX1002, ¶¶31-36. RNA-based therapies included "antisense" therapies, repair of
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`genetic instructions, and immunotherapy. EX1039; EX1002, ¶32. And researchers
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`predicted that "the breadth of clinical indications that one can foresee treating with
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`[RNA-based therapeutics] is remarkable." EX1039, 257:1:5. As early as the 2000's,
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`RNA-based therapies were "being evaluated in clinical trials for the treatment of
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`disorders ranging from cancer to infectious disease." EX1039, 252:1:2. And "more
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`preclinical and clinical investigations [were] anticipated to take place in the near
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`future to finally fulfill the promise of antisense therapeutics in humans." EX1038,
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`11; EX1002, ¶¶32-35. With RNA-based therapies, RNA purity was "essential."
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`EX1005, 223:2:1; EX1039; EX1038.
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`B. High performance liquid chromatography (HPLC) was a commonly-
`used technique for purifying nucleic acids, including RNA
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`Briefly, chromatography refers to separating mixtures of substances in
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`which the mixture, contained in a mobile phase (i.e., a liquid), is allowed to run
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`over or through a stationary phase held within a container referred to as a column.
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`EX1002, ¶¶38-39; EX1004, 2:56-65, 3:22-35. "[S]eparation of a mixture of
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`components occurs because the mixture components have slightly different
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`affinities for the stationary phase and/or solubilities in the mobile phase…."
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`EX1004, 3:16-18; EX1002, ¶39; EX1011, ¶[0002]. By collecting fractions as
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`mobile phase exits the column, chromatography permits "quantification and
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`purification" of mixture components. EX1008, 1; EX1002, ¶39; EX1004, 4:27-30;
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`EX1005, 225. A representative depiction of components "A" and "B" being
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`separated over time via column chromatography is shown below. EX1002, ¶39.
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`HPLC is a chromatography technique in which high pressure is applied to
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`"cause the mobile phase to flow through the column." EX1002, ¶41; EX1004,
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`3:22-35; EX1011, ¶[0002]; EX1027, 15; EX1001, 1:26-32. Before December
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`2006, HPLC was "one of the most widely used separation techniques…and its
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`applications range[d] from industrial preparation to trace level detection." EX1011,
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`¶[0001]; EX1002, ¶38.
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`Reversed-phase HPLC ("RP HPLC") was known before 2006 to be effective
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`for segregating RNA and other nucleic acids. EX1004, Abstract, 7:24-64; EX1005,
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`Abstract; EX1006, 1:36-42, 9:55-56; EX1008, Abstract; EX1015, 1067; EX1016,
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`85; EX1019, 5:11-13; EX1023, Abstract, 110:1:3; EX1024, 83, 100-106; EX1002,
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`¶¶42-47. "In reversed-phase chromatography, the stationary phase is nonpolar,
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`often a hydrocarbon, and the mobile phase is relatively polar." EX1033, 739-740
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`(emphasis original); EX1002, ¶42. Ion-pair reversed-phase HPLC ("IP RP HPLC")
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`is used to separate nucleic acids and other charged molecules, where "a counter ion
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`of opposite charge" is included in the mobile phase to bind and neutralize charged
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`molecules. EX1033, 747-748; EX1011, ¶[0072]; EX1002, ¶42. IP RP HPLC had
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`"long been a method of choice" because including the ion pairing agent
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`"improve[s] the resolution of a chromatographic separation." EX1011, ¶[0072];
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`EX1002, ¶44. For nucleic acids, IP RP HPLC had "gained widespread acceptance"
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`because it "provides a means for sequence-independent sizing." EX1008, 1:2:1;
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`EX1004, 3:41-52; EX1007, 1:16-22; EX1006, 1:36-42; 8:50-61; EX1009, 431:1:1;
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`EX1002, ¶44. Before 2006, "ion pairing/reverse phase chromatography [was]
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`among the most frequently used methodologies for the separation of nucleic acid
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`species." EX1007, 1:20-22; EX1008, 1:2:1-2; EX1002, ¶44.
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`A POSA would have known, based on general knowledge of the art, that IP
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`RP HPLC nucleic acid purification techniques developed for DNA would also
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`work for RNA. EX1002, ¶¶45-46. Azarani and Hecker (EX1008; "Azarani") stated
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`that "[s]eparation characteristics of RNA [in IP RP HPLC] are expected to
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`IPR of USPN 8,383,340
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`resemble those of ssDNA under fully denaturing conditions," and demonstrated
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`that PSDVB-based "IP RP HPLC
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`technology methods
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`[developed
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`for
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`DNA]…extended to RNA analysis." EX1008, 1:2:1-2. And multiple patents by
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`Gjerde et al., e.g., U.S. 6,066,258 (EX1006; "Gjerde II") and U.S. 6,156,206
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`(EX1022), also noted that their PSDVB-based IP RP HPLC techniques are
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`"generally applicable to the chromatographic separation of single stranded and
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`double stranded polynucleotides of DNA and RNA." EX1006, 14:27-30; EX1022,
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`1:20-21, 5:16-18.
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`C. The prior art taught IP RP HPLC for large scale RNA purification
`Before 2006, a POSA would have known IP RP HPLC can be used for
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`preparative scale nucleic acid purifications, including RNA purifications. EX1002,
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`¶¶48-50. For example, Polymer Laboratories' 2004-2005 catalog discloses
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`"preparative scale column[s]" had been used successfully in IP RP HPLC
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`purifications of DNA, and were intended for use with RNA as well. EX1024, 78,
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`101; EX1005, 225:1:1; EX1017, 129; EX1002, ¶49. Multiple publications taught
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`performing such large-scale IP RP HPLC purification of DNA and RNA. EX1005,
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`227:1:2-2:1, Table 1; EX1015, Abstract; EX1023, 110:1:3; EX1011, ¶¶[0102],
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`[0119]; EX1016, 88:4; EX1044, 677:2:1. Lloyd discloses that when "[t]here is a
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`requirement to produce large quantities of well-defined oligonucleotides in an
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`economic and timely fashion for clinical trials, etc.[,] [r]eversed-phase ion-pair
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`chromatography is an obvious choice, as excellent selectivity and high capacity, as
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`has been demonstrated above [with PSDVB], is achieved." EX1005, 227:1:2-2:1.
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`A POSA also would have known that methods tested on a small scale can be
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`adapted to large-scale nucleic acid purification. EX1002, ¶¶49-50. For example,
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`the Polymer Labs Catalog taught that IP RP HPLC "[s]eparations developed on an
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`analytical scale column can be transferred to a preparative scale column with
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`minimal method re-development." EX1024, 101; EX1011, ¶¶[0092], [0100]-
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`[0102]; EX1005, 227:1:2-2:1. And a book titled "Scale-Up and Optimization in
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`Preparative Chromatography" by Rathore et al. ("Rathore") discloses how "to
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`handle the increased volume of load" when converting between "Lab scale," "Pilot
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`plant scale," and "Commercial scale" purifications. EX1036, 13. For example,
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`Rathore teaches that "the most common procedure used to increase column volume
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`is to increase column diameter." EX1036, 13; EX1024, 101. Rathore also teaches
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`that "[i]n order to have a successful scale-up it is desirable to maintain kinetic
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`(particle size, pore size, ligand chemistry, temperature, mobile phase) and dynamic
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`(bed height,
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`flow velocity, packing density) equivalence between
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`the
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`chromatography columns used in the laboratory and the pilot plant." EX1036, 12-
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`13. Accordingly, a POSA would have understood that small scale purification
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`methods would have provided information necessary to perform larger-scale
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`purifications. EX1002, ¶¶49-50.
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`D. The prior art
`purifying RNA
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`taught olystyrenedivinylbenzene
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`(PSDVB)
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`for
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`Since PSDVB particles were created in 1967, PSDVB media had "been
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`widely applied." EX1010, 1470:1:2; EX1002, ¶¶51-56. Oefner and Huber's 2002
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`review noted that PSDVB media "[had] remained until this very day the standard
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`in HPLC of nucleic acids." EX1012, 28:2:1, 39:1:2; EX1046, 6 (describing
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`PSDVB beads as "the premier column packing material"); EX1002, ¶51. As
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`Gjerde II states, PSDVB media "can be used in the separation of RNA." EX1006,
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`9:52-55, 7:19-8:9; EX1024, 101; EX1004, 23:6-17, 23:41-57; EX1005, 224:2:2-
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`225:1:1; EX1007, 4:40-67; EX1008, 1; EX1009, Abstract; EX1013, Abstract,
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`13:26-35, 17:28-18:4; EX1016, 88:4; EX1023, 110:1:2-3. For example, a POSA
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`would have been aware of successful IP RP HPLC RNA purifications with
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`PSDVB to isolate mRNA, single stranded ribozymes, total RNA extracts,
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`ribosomal RNA, and RNA oligonucleotides. EX1002, ¶¶57-64; EX1004, 18:7-59,
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`Examples 1-5; EX1008, 7-8; EX1023, Abstract; EX1044, 673.
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`PSDVB chromatography media was commercially available before 2006.
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`For example, Polymer Laboratories sold PLRP-S media, "a styrene/divinylbenzene
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`copolymer with an inherently hydrophobic surface." EX1002, ¶¶52-54; EX1024,
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`78, 101; EX1005, 225:1:1; EX1017, 129. The 2004-2005 Polymer Laboratories'
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`product catalog includes "pre-packed [PLRP-S] columns from capillary through
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`process scale," including "preparative HPLC columns." EX1024, 84, 101. The
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`PLRP-S media were appropriate for purifying "large DNA [and] RNA oligomers,"
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`and were known to be "ideal for oligonucleotide analysis due to their chemical and
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`thermal stability and excellent selectivity." EX1024, 101, 105; EX1005, Abstract,
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`225:1:1; EX1017, Abstract, 129:1:4; EX1046, 6; EX1002, ¶52.
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`Before 2006, PSDVB was commonly used as small PSDVB beads packed
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`into a column. EX1002, ¶¶55-56; EX1004, 7:49-64; EX1008; EX1007. Another
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`common form for PSDVB was a molded polymer block, i.e. a monolith, that fills a
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`column and "consists of a single piece of a rigid polymer which has no interstitial
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`volume but only internal porosity." EX1010, 1463:1:3 EX1004, 7:49-64; EX1002,
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`¶¶55-56.
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`E. The prior art taught using non-alkylated PSDVB to purify RNA
`While alkylation was a known method of increasing hydrophobicity of
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`media for reversed phase chromatography, a POSA would have known that
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`"PLRP-S HPLC media is inherently hydrophobic and reproducible, and does not
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`require a bonded alkyl chain, e.g. C8, C18, to confer hydrophobicity.” EX1024, 84;
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`EX1025, Abstract; EX1026, 202; EX1002, ¶¶57-59. Huber et al.'s "observations
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`with monolithic PS-DVB supports" had indicated that, relative to alkylated
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`PSDVB, "similar to even better separation of nucleic acids could be accomplished
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`without alkylation." EX1012, 29:2:1-30:1:1 (citing EX1046); EX1013, 17:28-30.
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`Gjerde I also teaches that PSDVB media used in RNA purification "can be
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`unsubstituted." EX1004, 23:51-57, 22:35-23:5, 5:9-16. And Lloyd "demonstrate[d]
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`the feasibility" of using a nonalkylated PSDVB media to purify oligonucleotides.
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`EX1005, 224.
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`F. The prior art taught using porous PSDVB to purify RNA
`Before 2006, using porous PSDVB "for the separation of polynucleotide
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`mixtures [was] well known in the art and [wide pore media were] commercially
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`available." EX1022, 6:44-46, 6:1-7; EX1005, Abstract, 225; EX1024, 84; EX1002,
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`¶¶52, 60-64. Multiple prior art references taught purifying RNA using porous
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`PSDVB both in bead form and as a monolith. EX1002, ¶¶60-64; EX1004, 7:46-48;
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`EX1019, 1:17-21, 7:23-24, 9:7-10; EX1013, 1:31-34, 13:26-35, 17:28-30;
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`EX1022, 1:19-20, 2:30-35, 5:16-18, 6:21-24; EX1024, 101. For example, Hölzl et
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`al. (EX1044; "Hölzl ") disclosed that "[m]onolithic, poly(styrene-divinylbenzene)-
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`based capillary columns allowed the rapid and highly efficient fractionation of both
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`synthetic and biological ribonucleic acids." EX1044, 673.
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`Porous nonalkylated PSDVB beads (i.e., PLRP-S beads) were a
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`"conventional commercial product" with pore sizes ranging from 100 to 4000 Å.
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`EX1001, 14:20-25, 15:11-15, 15:48-52, 16:18-21, 16:59-62, 17:35-38; EX1024,
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`78, 82, 101, 108, 123; EX1002, ¶63; EX1005, 225:1:1, EX1017, 129:2:3. Lloyd
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`tested PLRP-S media with each of these pore sizes in oligonucleotide separation,
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`and disclosed that "[a]s the pore size of the [PLRP-S] HPLC media increases so the
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`resolving range increases." EX1005, 225:2:1. Accordingly, "[t]he choice of media
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`pore size will depend on the size of the oligonucleotide to be separated/purified."
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`EX1005, 225:1:3.
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`Using porous beads offers the advantages of having greater surface area and
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`allowing liquid to pass through the beads. EX1005, 224:1:2; EX1029, 29:2, 23-24;
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`EX1002, ¶60. Porous beads having higher capacity means more nucleic acid can
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`be purified, and lower operating pressure means that pressures can be safely
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`increased to facilitate quicker separations. EX1002, ¶61; EX1029, 29:2, 23-24.
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` The '340 Patent Disclosure and Claims IV.
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`The '340 patent, titled "Method for Purifying RNA on a Preparative Scale by
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`Means of HPLC," issued on February 26, 2013. The '340 patent alleges a
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`December 22, 2006 priority date. The sole independent claim is reproduced below:
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`1. A method for purifying RNA on a preparative
`scale, wherein the RNA is purified by HPLC or low or
`normal pressure liquid chromatography using a porous
`reversed phase as stationary phase and a mobile phase,
`wherein the porous reversed phase is a porous non-
`alkylated polystyrenedivinylbenzene.
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`Dependent claims 2 to 26 add limitations relating to RNA type and size
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`(claims 2-4), reversed phase particle size (claim 5), reversed phase pore size
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`(claims 6-7), reversed phase structure (claim 8), chromatography column
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`characteristics (claim 9), chromatography type (claims 10 and 26), mobile phase
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`contents (claims 11-19), and methods of applying the mobile phase (claims 20-25).
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` Person of ordinary skill in the art (POSA) V.
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`A POSA is a hypothetical person who is presumed to be aware of all
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`pertinent art, thinks along conventional wisdom in the art, and is a person of
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`ordinary creativity. A POSA in the field of nucleic acid biochemistry would have
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`had knowledge of the scientific literature and have skills relating to nucleic acid
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`manipulations, including nucleic acid purification chromatography methods,
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`nucleic acids identification and characterization, nucleic acid synthesis, and
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`application of nucleic acids in research before December 22, 2006. EX1002, ¶27.
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`A POSA also would have had knowledge of laboratory techniques and strategies
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`used in purifying nucleic acids and assessing the purity of the same, and would
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`have been able to carry out such techniques. Id. And a POSA would have had
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`knowledge of, and experience with the media and methodologies used in
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`chromatographic purification of nucleic acids. Id. A POSA would have also had
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`knowledge of nucleic acid structure and function, would have been aware of
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`naturally-occurring and synthetic nucleic acids, and would have known about
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`practical applications of the same, such as pre-clinical and clinical application.
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`Typically, a POSA would have had a Ph.D. in biochemistry, molecular
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`biology, chemistry, or a related discipline, with at least two years of experience in
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`nucleic acid manipulation. Id., ¶28.
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`A POSA would have known how to research the scientific literature in fields
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`relating to nucleic acid biochemistry, which would have included nucleic acid
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`identification, nucleic acid synthesis, nucleic acid purification, and applications of
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`nucleic acids; and a POSA would have had knowledge of, and skills relating to,
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`useful techniques for accomplishing the same. Id., ¶29. Also, a POSA may have
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`worked as part of a multidisciplinary team and drawn upon not only his or her own
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`skills, but also taken advantage of certain specialized skills of others on the team,
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`e.g., to solve a given problem. Id. For example, a chemist and a molecular biologist
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`may have been part of a team. Id.
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` Claim construction VI.
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`Under 37 C.F.R. §42.100(b), the claims must be given their broadest
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`reasonable interpretations in light of the specification and prosecution history. Any
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`claim terms not explicitly discussed below are plain on their face and should be
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`construed to have their plain and ordinary meanings consistent with the
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`specification and prosecution history. EX1002, ¶¶71-76.
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`Claim 1 contains a preamble stating that the method is "for purifying RNA
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`on a preparative scale," but this preamble is not limiting. EX1001, 19:57-62.
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`"Generally, the preamble does not limit the claims. However, a preamble may be
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`limiting if: it recites essential structure or steps; claims depend on a particular
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`disputed preamble phrase for antecedent basis; the preamble is essential to
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`understand limitations or terms in the claim body; the preamble recites additional
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`structure or steps underscored as important by the specification; or there was clear
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`reliance on the preamble during prosecution to distinguish the claimed invention
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`from the prior art." Georgetown Rail Equip. v. Holland L.P., No. 16-2297, Slip
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`Opinion at 8 (Fed. Cir. 2017) (internal citations omitted). The preamble's reference
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`to the claimed method being for use on a preparative scale does not change the
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`type of chromatography, does not change the reversed phase media used, and does
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`not add any steps to the claimed method; referencing what the method is "for" only
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`indicates the chromatographic method described in the claim body "results in
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`preparative RNA purification." EX1001, 3:14-15; EX1002, ¶75. No claims rely
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`upon "preparative scale" for antecedent basis, and reference to "the RNA" later in
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`claim 1 "does not necessarily convert the entire preamble into a limitation,
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`particularly one that only states the intended use of the invention." TomTom, Inc. v.
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`Adolph, 790 F.3d 1315, 1323 (Fed. Cir. 2015). CureVac did not rely on preparative
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`scale to distinguish from the prior art during prosecution, but instead alleged the
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`claims were patentable because the prior art "does not disclose a method of
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`purifying RNA using a porous reversed phase wherein the porous reversed phase
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`is…[PSDVB]." EX1021, 676; EX1001, 1:59-62. Accordingly, a POSA would have
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`understood the method described in the body of claim 1 to be the complete method
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`of the invention, that "preparative scale" refers only to the intended use, and that
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`the claims do not require a preparative nature to distinguish the method from the
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`prior art. EX1002, ¶75. "A preamble is not a claim limitation if the claim body
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`defines a structurally complete invention and uses the preamble only to state a
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`purpose or intended use for the invention." Georgetown Rail Equip., Slip Opinion
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`at 8 (internal citations omitted). Thus, the preamble is not limiting.
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`Grounds 2-5 specifically address the possibility that the Board finds
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`"purifying RNA on a preparative scale" to be limiting, and accordingly a
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`construction of preparative scale is provided here. Based on the '340 patent's
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`specification, a POSA would have understood purifying RNA on a preparative
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`scale to mean purifying at least 100 μg RNA. EX1002, ¶¶73-76. The '340 patent
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`states that "a preparative HPLC method should be understood to mean an HPLC
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`method in which relatively large quantities of RNA are purified." EX1001, 3:14-
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`30. More quantitatively, the '340 patent's specification refers to preparative
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`purifications as including "quantities of 0.5 mg or more, in particular 1.0 mg to
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`1000 mg or more, very particularly approximately 1.5 mg or more, upscaling even
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`to the [kilogram] range being possible." Id., 3:14-30. The '340 patent's Examples
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`also explicitly refer to purifying RNA quantities ranging from 100 µg to 3 mg as
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`being "on a preparative scale." EX1001, 14:52-55, 15:33-39, 16:3-8, 16:41-46,
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`17:15-20, 18:3-13, 18:47-54.
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`VII.
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`Identification of the challenge (37 C.F.R. §42.104(b))
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`Moderna requests IPR of all claims of the '340 patent based on the grounds
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`summarized below.
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`Ground 35 U.S.C. Section
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`Claims
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`References
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`1
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`2
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`3
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`4
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`5
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`§102(b)
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`§103(a)
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`§103(a)
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`§103(a)
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`§103(a)
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`1-5, 8, 10-22,
`and 26
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`1, 3-4, 6-19, and
`21-26
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`2
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`5
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`20
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`Gjerde I
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`Zhang and Lloyd
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`Sullenger and Lloyd
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`Zhang, Lloyd, and
`Polymer Laboratories
`Catalog
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`Zhang, Lloyd, and
`Gjerde II
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`While Ground 1's anticipation arguments and Grounds 2-5's obviousness
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`arguments relate to many of the same claims, they are not redundant for at least
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`two reasons. Grounds 2-5 demonstrate obviousness, which requires different
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`questions of fact and law than does anticipation. And Ground 1's anticipation
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`argument is presented in view of Petitioner's position that the "preparative scale"
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`language in the claim 1's preamble is not limiting (discussed above), while
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`Grounds 2-5 apply regardless of whether the preamble is limiting.
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`A. Ground 1: Gjerde I anticipates Claims 1-5, 8, 10-22, and 26
`U.S. 6,576,133 (EX1004, "Gjerde I") issued on June 10, 2003, and therefore
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`is prior art to the '340 patent claims under 35 U.S.C. §102(b). Gjerde I discloses a
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`"method and system for size-based segregation of a mixture of RNA molecules."
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`EX1004, Abstract. As discussed below, and confirmed by Dr. Hornby, Gjerde I
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`discloses every element of claims 1-5, 8, 10-22, and 26, arranged as claimed and in
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`a manner enabling to a POSA. EX1002, ¶¶20, 79-142. Thus Gjerde I anticipates
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`claims 1-5, 8, 10-22, and 26. Id.
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` Gjerde I anticipates claim 1
`1.
`Gjerde I (EX1004)
`Non-limiting preamble
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`Claim 1
`A method for
`purifying RNA
`on a preparative
`scale,
`wherein the
`RNA is purified
`by HPLC or low
`or normal
`pressure liquid
`chromatography
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`using a porous
`reversed phase
`as stationary
`phase
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`"The present invention is directed to the analysis of RNA
`molecules by liquid chromatography. More specifically,
`the invention is directed to a liquid chromatography system
`and method, such as Matched Ion Polynucleotide
`Chromatography, which enhances the purification of
`RNA." EX1004, 1:28-32.
`"FIG. 9 is a front view of the process compartment of an
`HPLC RNA analyzer column oven, and FIG. 10 is a top
`view of the HPLC RNA analyzer column oven shown in
`FIG. 9." EX1004, 13:27-31.
`"Monoliths, such as rods, contain polymer separation media
`which have been formed inside a column as a unitary
`structure having through pores or interstitial spaces
`[i.e., a porous stationary phase] which allow eluting
`mobile phase and analyte to pass through and which p