Paper 12
`
`Trials@uspto.gov
`571-272-7822 Entered: July 30, 2018
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`ENVIROLOGIX INC.,
`Petitioner
`v.
`IONIAN TECHNOLOGIES, INC.,
`Patent Owner
`____________
`
`Case IPR2018-00405
`Patent 9,562,263 B2
`____________
`
`
`
`Before ULRIKE W. JENKS, CHRISTOPHER G. PAULRAJ, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`PAULRAJ, Administrative Patent Judge.
`
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`Trials@uspto.gov
`571-272-7822 Entered: July 30, 2018
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`ENVIROLOGIX INC.,
`Petitioner
`v.
`IONIAN TECHNOLOGIES, INC.,
`Patent Owner
`____________
`
`Case IPR2018-00405
`Patent 9,562,263 B2
`____________
`
`
`
`Before ULRIKE W. JENKS, CHRISTOPHER G. PAULRAJ, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`PAULRAJ, Administrative Patent Judge.
`
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`Case IPR2018-00405
`Patent 9,562,263 B2
`
`
`INTRODUCTION
`I.
`EnviroLogix Inc. (“Petitioner”) filed a Petition requesting an inter
`partes review of claims 1–8 and 10–35 of U.S. Patent No. 9,562,263 B2
`(Ex. 1001, “the ’263 patent”). Paper 1 (“Pet.”). Ionian Technologies, Inc
`(“Patent Owner”) filed a Preliminary Response to the Petition. Paper 10
`(“Prelim. Resp.”).
`We have authority under 35 U.S.C. § 314, which provides that an
`inter partes review may not be instituted “unless . . . there is a reasonable
`likelihood that the Petitioner would prevail with respect to at least 1 of the
`claims challenged in the petition.” 35 U.S.C. § 314(a). Upon consideration
`of the arguments and evidence presented in the Petition and the Preliminary
`Response, we are not persuaded that Petitioner has established a reasonable
`likelihood that it would prevail in its challenges to claims 1–8 and 10–35 of
`the ’263 patent. Accordingly, we do not institute an inter partes review of
`claims 1–8 and 10–35.
`
`BACKGROUND
`II.
`Related Proceedings
`A.
`Petitioner identifies three related patents: U.S. Patent No. 9,562,264
`B2 (“the ’264 patent”), U.S. Patent No. 9,617,586 B2 (“the ’586 patent”),
`U.S. Patent No. 9,689,031 B2 (“the ’031 patent”). Pet. 2 (“Petitioner
`reserves the right to petition for inter partes review of 9,562,263, 9,617,586
`and 9,689,031”). The claims in the ’264 patent are directed to a method of
`amplifying a target polynucleotide. We note that Petitioner has filed a
`request for inter partes review of the ’264 patent. See IPR2018-00406.
`Concurrently herewith, we issue also a decision in that related proceeding.
`
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`
`The ’263 Patent (Ex. 1001)
`B.
`The ’263 patent issued from Application No. 14/067,620, filed
`October 30, 2013, which is a continuation of Application No. 11/778,018,
`filed July 14, 2007.
`The ’263 patent relates to amplification of nucleic acid targets using a
`nicking enzyme. A nicking enzyme amplification reaction (NEAR) requires
`the presence of (1) a nucleic acid target, (2) at least two template
`oligonucleotides, (3) a thermophilic nicking enzyme, (4) a thermophilic
`polymerase, and (5) buffer components all held at the reaction temperature.
`Ex. 1001, 18:32–36.
`The ’263 patent provides that when using “a double-stranded target,
`both templates can interact with the corresponding target strands
`simultaneously.” Id. 18:47–48. “The double-strand formed from the
`extension of both templates creates a nicking enzyme binding site on either
`end of the duplex. This double-strand is termed the NEAR amplification
`duplex.” Id. 19:16–19. The NEAR amplification method “do[es] not
`require the use of temperature cycling, as often is required in methods of
`amplification to dissociate the target sequence from the amplified nucleic
`acid.” Id. 19:51–54. The ’263 patent provides that even though temperature
`cycling is not required, the temperature should be high enough to minimize
`nonspecific binding. Id. 20:2–3. “The polymerase may be mixed with the
`target nucleic acid molecule before, after, or at the same time as, the nicking
`enzyme.” Id. 19:54–58. “The reaction is run at a constant temperature,
`usually between 54° C. and 60° C. for the enzyme combination of Bst
`polymerase (large fragment) and Nt.Bst.NBl nicking enzyme.” Id. 21:17–
`20. The product of the NEAR amplification can be visualized by gel
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`electrophoresis or mass spectroscopy. Id. 10–67. Alternatively, the product
`can be detected in real-time using SYBR II fluorescence (id. 27: 6–15),
`Fluorescence Resonance Energy Transfer (FRET) (id. at 27:18–32), or using
`molecular beacons. Id. at 27:36–47.
`C.
`Illustrative Claim
`Claim 1, the sole independent claim of the ’263 patent is illustrative
`and reproduced below:
`1.
`A method of amplifying a target polynucleotide sequence, the
`method comprising:
`(a) obtaining, from an animal, plant or food, a sample
`comprising a target nucleic acid, the target nucleic acid
`comprising the target polynucleotide sequence,
`(b) without first subjecting the target nucleic acid to a thermal
`denaturation step associated with amplification of the target
`polynucleotide sequence, combining, in a single step, the
`obtained sample directly with an amplification reagent
`mixture or diluting the obtained sample and combining, in a
`single step, the diluted sample with an amplification reagent
`mixture, in either case, the amplification reagent mixture
`being free of bumper primers and comprising:
`(i) a polymerase,
`(ii) a nicking enzyme,
`(iii) a first oligonucleotide comprising a 5' portion that
`comprises a nicking enzyme binding site that is non-
`complementary to the target polynucleotide sequence
`and a 3' portion that hybridizes to the target
`polynucleotide sequence, and
`(iv) a second oligonucleotide comprising a 5' portion that
`comprises a nicking enzyme binding site that is non-
`complementary to the target polynucleotide sequence
`and a 3' portion that hybridizes to the target
`polynucleotide sequence,
`(c) subjecting the reaction mixture formed by the step of
`combining to essentially isothermal conditions to amplify
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`the target polynucleotide sequence without the assistance of
`bumper primers, and
`(d) detecting the amplified target polynucleotide sequence in
`real time within 10 minutes of subjecting the reaction
`mixture to essentially isothermal conditions.
`
`
`Ex. 1001, 32:14–47 (formatting added).
`D.
`Prior Art
`Petitioner relies upon the following prior art references:
`Ehses et al.
`Optimization and design of oligonucleotide
`(“Ehses”)
`setup for strand displacement
`amplification, 63 J. BIOCHEM. BIOPHYS.
`METHODS 170–186 (2005).
`
`Isothermale in vitro Selektion und
`Amplifikation zur Untersuchung von
`Evolutionsvorgängen, Dissertation (2005).
`
`Isothermal In Vitro Selection and
`Amplification to Investigate Evolutionary
`Processes.
`
`US 2005/0112631 Al, publ. May 26, 2005. Ex. 1005
`
`Ehses
`(“Ehses
`Dissertation”)
`
`Ex. 1002
`
`Ex. 1003
`
`Ex. 1004
`
`Ehses
`(Dissertation
`Translation”)
`
`Piepenburg et al.
`(“Piepenburg”)
`
`Kong et al.
`(“Kong”)
`Kato and
`Kuramitsu
`(“Kato”)
`
`WO 01/94544 A2, publ. Dec. 13, 2001.
`
`Ex. 1006
`
`Characterization of thermostable RecA
`protein and analysis of its interaction with
`single-stranded DNA, 259 FEBS Journal
`592–601 (1999).
`
`Ex. 1007
`
`
`Petitioner also relies upon the Declaration of Dr. Jeremy Edwards.
`(Ex. 1008).
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`
`§ 102(b)
`
`Ehses Dissertation
`
`§ 103(a)
`
`Ehses and Ehses Dissertation
`
`Asserted Grounds of Unpatentability
`E.
`Petitioner challenges the patentability of claims 1–8 and 10–35 of the
`’263 patent on the following grounds (Pet. 3):
`Claims Challenged Basis
`References
`1-6, 8, 10-13, 15, 16,
`§ 102(b)
`Ehses
`and 18–35
`1-6, 8, 10-13, 15, 16,
`and 18–35
`1-6, 8, 10-13, 15, 16,
`and 18–35
`1–8, 10–17, 19, and
`22–35
`18
`
`§ 102(b)
`
`Piepenburg
`
`§ 103(a)
`
`Piepenburg in view of Kong
`
`20
`
`1–8 and 10–35
`
`1–8 and 8–35
`
`
`
`§ 103(a)
`
`§ 103(a)
`
`§ 103(a)
`
`Piepenburg in view of Kato
`
`Piepenburg in view of Ehses and
`Ehses Dissertation
`Ehses and Ehses Dissertation in view
`of Piepenburg
`
`III. ANALYSIS
`Claim Construction
`A.
`Petitioner includes a claim construction section for numerous claim
`terms or phrases that appear in the claims. Pet. 8–13. Patent Owner’s
`position is that no claim terms require construction at this stage of the
`proceeding. Prelim. Resp. 2. On this record, we determine that no claim
`term requires express construction for the purpose of rendering this decision.
`See Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir.
`1999) (“[O]nly those terms need be construed that are in controversy, and
`only to the extent necessary to resolve the controversy.”).
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`Level of Skill in the Art
`B.
`Petitioner contends that person of ordinary skill in the art (“POSITA”)
`would have “knowledge of molecular biology, a Ph.D. in molecular biology,
`and experience in nucleic acid amplification techniques, detection, and
`analysis.” Pet. 5. Patent Owner does not address the level of skill in the art
`in its preliminary response. For purposes of this decision, we find
`Petitioner’s requirements for the POSITA to be reasonable and apply that
`skill level for our analysis.
`C.
`Anticipation by Ehses (Ex. 1002)
`1.
`Overview of Ehses
`Ehses is a journal article, published in May 2005, which is directed to
`optimizing strand displacement amplification (SDA). Ex. 1002, Abstract.
`SDA is an all-purpose DNA amplification reaction that works in isothermal
`conditions. Ex. 1002, Abstract; see id. at 171 (SDA method is “a sensitive
`and universal tool for amplification of nucleic acids”). According to Ehses,
`the problem with isothermal amplification mechanisms is the accumulation
`of unpredictable byproduct. Id., Abstract.
`Ehses teaches optimizing oligonucleotides for SDA. Ex. 1002, Title.
`Ehses’s test system contains only the essential components for the SDA
`reaction: DNA, primer, enzymes, buffer. Id. at 175. “[T]he primer consists
`of a 5’ overlapping end following the recognition site of the restriction
`enzyme and a template-binding region on its 3’ end.” Id. at 173. The
`standard SDA protocol and nicking-SDA protocol described in Ehses both
`dilute primers in buffer and add template DNA, before incubating this
`mixture for
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`3 min at 95°C followed by 1 min at 55°C. Upon addition of the
`enzymes, the amplification mixture was incubated 15–60 min in
`an ICycler (BioRAD) and the increase in fluorescence intensity
`was monitored. The reaction was stopped by addition of
`denaturing Stop/Loading dye and products were denatured at
`95°C for 10 min. Aliquots of 10 μl from each sample were
`added to 5 μl of the loading dye and analyzed by 12%
`denaturing polyacrylamide gel electrophoresis, with subsequent
`staining via SYBR Gold or SYBR Green II and visualization
`under UV illumination.
`Id. at 175. “When performing the standard reaction . . . the expected
`products were achieved with amplification starting with template
`concentrations of 10 and 100 pM in 20 min for SDA and nicking SDA
`respectively.” Id. at 177. “When starting with less template, omitting the
`initial denaturation step or increasing the reaction time, the standard SDA
`system as well as the nicking system shows the tendency to [develop] side-
`reactions.” Id. at 177. “When using an intercalating fluorescence dye
`TOPRO-1 in real-time detection, after about 20 min the fluorescence
`intensity signal shows a steep increase (results not shown).” Id. at 178.
`2.
`Analysis
`Petitioner contends that claims 1–-6, 8, 10–13, 15, 16, and 18–35 are
`anticipated by Ehses. Pet. 14–30. We focus our analysis on certain
`limitations of independent claim 1 as they are dispositive to our conclusion
`for all the challenged claims.
`Petitioner asserts that Ehses’s disclosed AmpRxn protocol (a variation
`of SDA) is a method of amplifying a target polynucleotide. Id. at 16 (citing
`Ex. 1008 ¶ 68). According to Petitioner, because Ehses discloses that SDA
`amplification is valuable for DNA diagnostics, a POSITA would understand
`that the diagnostic applications include the analysis of polynucleotide
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`samples derived from animals. Id. at 17 (citing Ex. 1008 ¶ 69; Ex. 1002,
`171). With respect to the claim limitation “without first subjecting the target
`nucleic acid to a thermal denaturation step associated with amplification of
`the target polynucleotide sequence,” Petitioner asserts that Ehses’s
`disclosure of “omitting the initial denaturation step” demonstrates that
`“thermal denaturation is not required for amplification of a Target.” Id. at
`17–18 (citing Ex. 1008 ¶ 71; Ex. 1002, 177). Additionally, with respect to
`the requirement of “combining in a single step” the sample with an
`amplification reagent mixture that is “free of bumper primers,” Petitioner
`contends that “[b]ecause thermal denaturation is not required, the sample
`and AmpRxn components are combined and incubated in a single step.” Id.
`at 18 (citing Ex. 1008 ¶ 72). Petitioner also contends that the SDA protocol
`“includes a pair of primers for amplifying a sample, but does not include or
`require bumper primers for amplification.” Id. (citing Ex. 1008 ¶ 73).
`Petitioner notes that the Ehses amplification reagent comprises a
`polymerase, a nicking enzyme, and a first and second oligonucleotide. Id. at
`19–20. According to Petitioner, Ehses’s SDA reaction protocol “does not
`require an initial denaturation step, but is performed under isothermal
`conditions, i.e., at 55ºC.” Id. at 20–21 (citing Ex. 1002, 175, 177).
`Petitioner contends that Ehses discloses detecting amplification of the
`Target in real time (RT), and further asserts that “[g]iven that the reaction [in
`Ehses] is monitored throughout the incubation, the presence of amplification
`product is detected as it accumulates.” Id. at 21–22. Specifically, Petitioner
`directs our attention to the incubation times of assays that indicates an
`incubation time varying from 15 to 60 minutes. Id. at 22 (citing Ex. 1002,
`175; Ex. 1008 ¶ 84 (“Given that nSDA is performed using the same
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`components and under the same conditions as the claimed method, a POSA
`understands that the time to detection would necessarily be the same”)).
`Petitioner also relies upon its declarant Dr. Edwards’ assertion that “[d]yes
`that bind DNA, like TO-PRO-1, generate a fluorescent signal upon binding
`that is detected in RT.” Id. at 21 (citing Ex. 1008 ¶ 82).
`Patent Owner responds that Ehses does not expressly teach the
`following claim requirements: (1) a DNA sample derived from an animal,
`(2) a reaction that omits a denaturation step and still detects target DNA, (3)
`a single step reaction, and (4) and detection of the product within 10
`minutes. See Prelim. Resp. 4–11. For the reasons set out below, we agree
`with Patent Owner that Petitioner has not shown, on this record, a reasonable
`likelihood of establishing that any of the challenged claims are anticipated
`by Ehses. In particular, we determine that Petitioner has not shown a
`reasonable likelihood of establishing that Ehses teaches at least the claim
`requirements of omitting a thermal denaturation step and detecting the
`amplified product within 10 minutes after subjecting the reaction mixture to
`essentially isothermal conditions.
`With respect to the requirement that thermal denaturation is omitted,
`Patent Owner argues that “[t]he sentence of Ehses upon which Petitioner
`relies for disclosure of omitting an initial denaturation step expressly teaches
`the reader not to omit an initial denaturation step—because doing so ‘shows
`the tendency to side-reactions.’” Prelim. Resp. 6 (citing Ex. 1002, 177).
`Ehses discloses that undesirable side-reactions result in DNA product that is
`not detectable, for example with staining. See Ex. 1002, Fig. 3 C
`(“Comparative product analysis after 90 min reaction time at 55°C. . . .
`Because of the increased side-reactions, the desired product cannot be
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`detected by subsequent staining with SYBR Gold”). Ehses teaches other
`sample handling conditions also result in undesirable side reactions, such as
`for example omitting the denaturation step. Id. at 177 (“When starting with
`less template, omitting the initial denaturation step or increasing the reaction
`time, the standard SDA system as well as the nicking system shows the
`tendency to side-reactions”). Thus, although Ehses might disclose a
`methodology that omits the initial thermal denaturation step, Petitioner has
`not shown that this method results in a detectable product. See id. The
`claims, however, require amplifying the target sequence such that the
`amplified target polynucleotide sequence is detectable. Therefore, we agree
`with the Patent Owner that there is insufficient evidence, on this record, to
`show that a target product would be detectable when the thermal
`denaturation step is omitted as taught by Ehses, despite that Ehses teaches
`such a step may be omitted.
`With respect to the requirement of detecting in real time the amplified
`product within 10 minutes, Patent Owner argues:
`Ehses does not disclose any results of amplification reactions in
`which target DNA was detected within ten minutes—nor does
`Ehses state that its amplification reactions are capable of
`producing detectable target within ten minutes. In fact, both of
`the SDA protocols that Ehses discloses require incubation with
`DNA polymerase for a minimum of 15 minutes.
`Prelim. Resp. 9. We agree with the Patent Owner that Petitioner presents
`insufficient evidence showing that Ehses discloses that the desirable product
`can be detected before a minimum 15 minute time interval. In both the SDA
`and nicking SDA reactions described in Ehses, the amplification mixture
`was “incubated 15–60 [minutes] . . . and the increase in fluorescence
`intensity was monitored. The reaction was stopped by addition of
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`denaturing Stop/Loading dye and products were denatured at 95°C for 10
`[minutes].” Ex. 1002, 175. Following the standard procedure outlined in
`Ehses, the detection of product took minimally a 15 minute incubation in
`addition to a 10 minute denaturation step before the product is finally
`detected on the gel. See id. The reaction can proceed as long as 60 minutes.
`See id. Ehses also discloses the use of real-time detection, but indicates that
`fluorescence intensity increases after 20 minutes. See id. at 178 (“An
`indication of the amplification of non-specific products is also given by a
`two step kinetic profile. When using an intercalating fluorescence dye
`TOPRO-1 in real-time detection, after about 20 min the fluorescence
`intensity signal shows a steep increase”). Thus, the Ehses reference itself
`indicates that using real-time detection based on fluorescence intensity will
`take longer than 10 minutes.
`In sum, we agree with Patent Owner that the record does not show
`that Ehses discloses a procedure that omits the denaturation step for the
`amplification of target DNA, and achieving target detection within 10
`minutes as claimed. Nor does the record establish that there is a reasonable
`likelihood that Petitioner would prevail at trial in establishing Ehses does
`provide such disclosure. Accordingly, we decline to institute inter partes
`review on this ground.
`D.
`Anticipation by Ehses Dissertation (Ex. 1003/Ex. 1004)
`Petitioner also asserts that claims 1–6, 8, 10–13, 15, 16, and 18–35 are
`anticipated by the Ehses Dissertation. Pet. 30–42. Petitioner asserts that
`“Ehses-Dissertation1 is prior art to the ’263 patent under 35 U.S.C. §102(b)
`
`
`1 Petitioner provides a copy of Ehses Dissertation written in German (Ex.
`1003); all references to the Ehses Dissertation in this decision are made in
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`(pre-AIA) because it was published on August 7, 2005.” Id. at 30.
`Petitioner relies upon the date of oral examination identified in the Ehses
`Dissertation as the date of publication. Ex. 1004, 3.
`Patent Owner opposes Petitioner’s assertions because, inter alia, the
`Petition fails to show that the Ehses Dissertation qualifies as a “printed
`publication.” Prelim. Resp. 12. We agree with Patent Owner that Petitioner
`has not met its burden of establishing that the Ehses Dissertation qualifies as
`prior art. As such, we do not address the technical merits of Petitioner’s
`anticipation challenge based on the Ehses Dissertation.
`A party seeking to introduce a reference “should produce sufficient
`proof of its dissemination or that it has otherwise been available and
`accessible to persons concerned with the art to which the document relates
`and thus most likely to avail themselves of its contents.” In re Wyer, 655
`F.2d 221, 227 (CCPA 1981) (quoting Philips Elec. & Pharm. Indus. Corp. v.
`Thermal & Elecs. Indus., Inc., 450 F.2d 1164, 1171 (3d Cir. 1971)). The
`determination of whether a given reference qualifies as a prior art “printed
`publication” involves a case-by-case inquiry into the facts and circumstances
`surrounding the reference’s disclosure to members of the public. In re
`Klopfenstein, 380 F.3d 1345, 1350 (Fed. Cir. 2004). “Because there are
`many ways in which a reference may be disseminated to the interested
`public, ‘public accessibility’ has been called the touchstone in determining
`whether a reference constitutes a ‘printed publication’ bar under 35 U.S.C.
`§ 102(b).” In re Hall, 781 F.2d 897, 898–99 (Fed. Cir. 1986). A reference
`is publicly accessible if there is sufficient evidence establishing it has been
`
`
`reference to the English translation submitted as Exhibit 1004.
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`disseminated or otherwise made accessible to persons interested and
`ordinarily skilled in the subject matter to which the document relates prior to
`the critical date. Kyocera Wireless Corp. v. Int’l Trade Comm’n, 545 F.3d
`1340, 1350 (Fed. Cir. 2008).
`Upon consideration of the facts in the present record, we agree with
`Patent Owner’s contention that Petitioner’s reliance on the disclosure of the
`date of an oral dissertation defense is not sufficient to establish that the
`dissertation was made publicly available at that time. See generally Prelim.
`Resp. 12–16; see also id. at 13–14 (“the date of the author’s oral
`examination does not establish when the dissertation became accessible to
`the public”). Absent in the Petition is evidence related to whether the Ehses
`Dissertation was publicly accessible in the relevant time frame, how one
`might have obtained a copy of the dissertation, or whether the dissertation
`was reasonably accessible through generally available means, or by a
`showing of a general library procedure as to indexing, cataloging, and
`shelving of doctoral thesis. We acknowledge that Petitioner may rely on
`evidence of routine business practices, such as by a showing of general
`library procedures as to indexing, cataloging, and shelving of doctoral thesis,
`and that Petitioner does not have to show a specific date on which Ehses
`Dissertation was publicly accessible. See Hall, 781 F.2d at 899. Here,
`though, Petitioner does not submit evidence from which we can even
`approximate when Ehses Dissertation became publicly accessible. We agree
`with Patent Owner that “[w]ithout more here, [the] contentions and evidence
`cited by Petitioner do not rise to the level of ‘threshold evidence’ that
`justifies going forward with a trial on any ground that relies on the [Eshes
`Dissertation] as ‘printed publication’ prior art.” See Prelim. Resp. 16 (citing
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`Seabery North America, Inc. v. Lincoln Global, Inc., IPR2016-00904, Paper
`12 at 7-8 (PTAB Nov. 3, 2016)).
`Because we are not persuaded that Petitioner has made a threshold
`showing that the Ehses Dissertation was sufficiently publicly accessible to
`qualify as a “printed publication” under § 102(b), we also decline to institute
`inter partes review based on this ground.
`E.
`Anticipation by Piepenburg (Ex. 1005)
`1.
`Overview of Piepenburg
`Piepenburg is a U.S. Patent Application published May 26, 2005.
`Ex. 1005. Piepenburg describes several methods for recombination
`polymerase amplification (RPA) of target DNA. Ex. 1005, Abstract, ¶ 371.
`As explained in Piepenburg, “an RPA reaction may be used to determine the
`presence or absences of a nucleic acid molecule,” where “[t]he nucleic acid
`molecule may be from any organism.” Id. ¶ 223. Piepenburg’s
`amplification methods “avoid any requirement for thermal melting of DNA
`thermostable components.” Id. ¶ 12.
`The method [of Piepenburg] comprises two steps. In the first
`step, the following reagents are combined in a reaction: (1) at
`least one recombinase; (2) at least one single stranded DNA
`binding protein; (3) at least one DNA polymerase; (4) dNTPs or
`a mixture of dNTPs and ddNTPs; (5) a crowding agent; (6) a
`buffer; (7) a reducing agent; (8) ATP or ATP analog; (9) at least
`one recombinase loading protein; (10) a first primer and
`optionally a second primer; and (11) a target nucleic acid
`molecule. In the second step, the reagents are incubated until a
`desired degree of amplification is achieved.
`Id. ¶ 69. “The reaction may be incubated between 5 minutes and 16 hours,
`such as between 15 minutes and 3 hours or between 30 minutes and 2 hours.
`The incubation may be performed until a desired degree of amplification is
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`achieved.” Id. ¶ 91, see also id. ¶ 499 (“Using optimally short target
`sequences and sensitive detection method, we expect that a diagnostic
`amplification/detection assay could be performed within an hour”).
`Piepenburg discloses “[d]etection may be performed using any method, such
`as, for example, using electrophoresis on an agarose or PAGE gel followed
`by ethidium bromide staining.” Id. ¶ 101; see also id. ¶ 157 (The use of
`“[l]abeled primers offer the advantage of a more rapid detection of amplified
`product”). “RPA is initiated by targeting sequences using synthetic
`oligonucleotides coated with RecA, or a functional homologue.” Id. ¶ 121.
`Figure 11 of Piepenburg, reproduced below, shows uses of backfire
`RPA priming reaction.
`
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`Case IPR2018-00405
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`As depicted in the figure above, examples of backfire priming include the
`“introduction of a nicking enzyme target site, introduction of an RNA
`polymerase promoter, and the linear generation of short dsDNA fragments
`through successive invasion/synthesis/cleavage events.” Id. ¶ 29; see id. ¶¶
`411–412. “Backfire synthesis occurs when a recombinase-coated targeting
`oligonucleotide possessing a 5’ overhang invades a duplex DNA end in the
`presence of a suitable polymerase and dNTPs.” Id. ¶ 408. “[T]he 5’
`overhang of a targeting oligonucleotide is designed such that should backfire
`synthesis occur, a target for a nicking endonuclease is generated.” Id. ¶ 412.
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`In the presence of a nicking endonuclease and suitable polymerase,
`extension of the nick and displacement of DNA strand occurs. See id.
`“Multiple strands may be run-off by successive nicking and elongation from
`a single template.” Id.
`2.
`Analysis
`Petitioner asserts that claims 1–8, 10–17, 19, and 22–35 of the ’263
`patent are anticipated by Piepenburg. Pet. 44–57. We again focus our
`analysis on certain limitations of independent claim 1 as they are dispositive
`to our conclusion for all the challenged claims.
`With respect to the claim requirements of a “first oligonucleotide” and
`“second oligonucleotide” having “a 5′ portion that comprises a nicking
`enzyme binding site that is noncomplementary to the target polynucleotide
`sequence and a 3′ portion that hybridizes to the target polynucleotide
`sequence,” Petitioner contends that Piepenburg discloses the requisite first
`and second oligonucleotides. Id. at 49–51 (citing Ex. 1005 ¶¶ 29, 412, Fig.
`11B; Ex. 1008 ¶ 184). Patent Owner responds that “neither paragraph of
`Piepenburg upon which Petitioner relies—nor Fig. 11B—discloses a second
`oligonucleotide of any kind.” Prelim. Resp. 27. We agree with Patent
`Owner. We do not glean any disclosure in the cited portions of Piepenburg
`of an amplification reaction involving two separate oligonucleotides having
`the structure recited in claim limitations 1(b)(iii) and 1(b)(iv).
`Separate from that, we find that Petitioner has also not shown that
`there is a reasonable likelihood that it will prevail in establishing that
`Piepenburg discloses detecting in real time the amplified product within 10
`minutes. Petitioner asserts that Piepenburg describes real-time detection of a
`target. Pet. 52 (citing Ex. 1005 ¶ 203). Based on Piepenburg’s disclosure
`
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`that the reaction can be carried out between 5 minutes and 16 hours,
`Petitioner contends “[t]he AmpRxns of Piepenburg include the same
`components under the same conditions as recited in the claims,” and “[t]hus,
`a POSA would expect that the AmpRxns of Piepenburg would achieve the
`same results as the claimed method, i.e., would amplify Target within 10
`minutes under isothermal conditions.” Id. (citing Ex. 1008 ¶ 191). As noted
`by Patent Owner, the disclosure relied upon by the Petitioner says nothing
`about detection and only refers to incubation. Prelim. Resp. 32 (citing Ex.
`1005 ¶ 91 (“The incubation may be performed until a desired degree of
`amplification is achieved”)). Although Piepenburg discloses incubation
`times that range from 5 minutes to 16 hours, we agree with Patent Owner
`that the evidence of record is insufficient to establish that an incubation time
`of 5 minutes would provide sufficient detectable product, especially when
`the working examples “exclusively refers to reaction incubation times on the
`order of an hour or more.” Id. at 33. We further agree with Patent Owner
`that teaching an incubation time of as little as 5 minutes in conjunction with
`the generic teaching “until a desired degree of amplification is achieved” is
`not sufficient to show that amplification for 5 minutes is sufficient to detect
`the product “in real time within 10 minutes” as claimed. Id. Anticipation by
`inherency requires that any material missing from the prior art must
`necessarily be present and would be recognized as such by POSITA. In re
`Robertson, 169 F.3d 743 (Fed. Cir. 1999).
`In sum, we agree with Patent Owner that the record does not show
`that Piepenburg discloses an amplification procedure that includes a “first
`oligonucleotide” and “second oligonucleotide,” and detecting the target in
`real time within 10 minutes as claimed. Nor does the record establish that
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`there is a reasonable likelihood that Petitioner would prevail at trial in
`establishing Piepenburg does provide such a disclosure. Accordingly, we
`decline to institute inter partes review based on this ground.
`F.
`Remaining Obviousness Grounds:
`1. Obviousness over Ehses and Ehses Dissertation
`2. Obviousness over Piepenburg and Kong (Ex. 1006)
`3. Obviousness over Piepenburg and Kato (Ex. 1007)
`4. Obviousness over Piepenburg in view of Ehses and Ehses
`Dissertation
`5. Obviousness over Ehses and Ehses Dissertation in view of
`Piepenburg
`
`
`
`Petitioner includes several obviousness challenges as part of its
`Petition. In particular, Petitioner asserts that claims 1–6, 8, 10–13, 15, 16,
`and 18–35 of the ’263 patent would have been obvious over the combination
`of Ehses and Ehses Dissertation. Pet. 42–44. Petitioner also asserts that
`claim 18 is rendered obvious by Piepenberg in view of Kong (id. at 57–58),
`that claim 20 is rendered obvious by Piepenburg in view of Kato (id. at 58–
`59), that claims 1-8 and 10–35 are rendered obvious by Piepenburg in view
`of Ehses and Ehses Dissertation (id. at 59–60), and that claims 1-8 and 10–
`35 are rendered obvious over Ehses and Ehses Dissertation in view of
`Piepenburg (id. at 60–61). Petitioner’s obviousness contentions do not
`remedy the deficiencies in Ehses, Ehses Dissertation, and Piepenburg noted
`above with respect to the anticipation grounds. Accordingly, we decline to
`institute inter pa
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