Trials@uspto.gov
`571.272.7822
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`
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` Paper No. 8
`
` Entered: March 19, 2018
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`AMBRY GENETICS CORPORATION,
`Petitioner,
`
`v.
`
`THE JOHNS HOPKINS UNIVERSITY,
`Patent Owner.
`____________
`
`Case IPR2017-02093
`Patent 7,824,889 B2
`____________
`
`
`Before LORA M. GREEN, TINA E. HULSE, and RICHARD J. SMITH,
`Administrative Patent Judges.
`
`SMITH, Administrative Patent Judge.
`
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`571.272.7822
`
`
`
`
`
` Paper No. 8
`
` Entered: March 19, 2018
`
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`AMBRY GENETICS CORPORATION,
`Petitioner,
`
`v.
`
`THE JOHNS HOPKINS UNIVERSITY,
`Patent Owner.
`____________
`
`Case IPR2017-02093
`Patent 7,824,889 B2
`____________
`
`
`Before LORA M. GREEN, TINA E. HULSE, and RICHARD J. SMITH,
`Administrative Patent Judges.
`
`SMITH, Administrative Patent Judge.
`
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`
`IPR2017-02093
`Patent 7,824,889 B2
`
`
` INTRODUCTION
`Ambry Genetics Corporation (“Petitioner”) filed a Petition to institute
`an inter partes review of claims 1 and 8 of U.S. Patent 7,824,889 B2 (the
`“’889 patent”). Paper 2 (“Pet.”) The Johns Hopkins University (“Patent
`Owner”) filed a Preliminary Response to the Petition. Paper 6 (“Prelim.
`Resp.”).
`We have authority to determine whether to institute an inter partes
`review under 35 U.S.C. § 314. To institute an inter partes review, we must
`determine that the information presented in the Petition shows “a reasonable
`likelihood that the petitioner would prevail with respect to at least 1 of the
`claims challenged in the petition.” 35 U.S.C. § 314(a). For the reasons set
`forth below, we conclude that Petitioner has established a reasonable
`likelihood that it would prevail in showing the unpatentability of at least one
`challenged claim of the ’889 patent. Therefore, we institute an inter partes
`review for claims 1 and 8 of the ’889 patent.
`Related Proceedings
`A.
`The ’889 patent has been asserted in pending district court
`proceedings: Esoterix Genetic Laboratories, LLC and The Johns Hopkins
`University v. Ambry Genetics Corporation, United States District Court for
`the Middle District of North Carolina, Case No. 1:16-cv-1111-WO-JEP (the
`“Ambry Litigation”). Pet. 1–2; Paper 4, 2. The ’889 patent was also
`asserted in litigation styled Esoterix Genetic Laboratories, LLC and The
`Johns Hopkins University v. Myriad Genetics, Inc. and Myriad Genetics
`Laboratories, Inc., United States District Court for the Middle District of
`North Carolina, Case No. 1:16-cv-1112-WE-JEP, but that case has been
`dismissed. Pet. 2; Paper 4, 2. The ’889 patent was also asserted in litigation
`
`2
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`IPR2017-02093
`Patent 7,824,889 B2
`styled Esoterix Genetic Laboratories, LLC and The Johns Hopkins
`University v. Life Technologies Corp, et al., Civil Action No. 1:12-cv-
`01173-CCE-JEP (MDNC). Paper 4, 2–3.
`Petitioner also filed petitions for inter partes review of certain claims
`of related U.S. Patent No. 6,440,706 (IPR2017-02086); U.S. Patent No.
`7,915,015 (IPR2017-02095); and U.S. Patent No. 8,859,206 (IPR2017-
`02096). Pet. 2; Paper 4, 2.
`
`The ’889 Patent
`B.
`The ’889 patent relates to diagnostic genetic analyses. Ex. 1001, 1:19.
`With the understanding that somatic mutations are the primary cause of
`cancer, new opportunities for basic research into the pathogenesis of cancer
`have arisen. Id. at 1:26–31. For example, in some cases, detecting
`neoplastic cells in urine, stool, and sputum is possible at a stage when the
`primary tumors are still curable and the patients are asymptomatic. Id. at
`1:34–39. Thus, it is important to be able to detect small populations of
`mutant cells among a large excess of normal cells. Id. at 1:32–34, 43–45.
`Accordingly, the specification states that “[i]t is an object of the present
`invention to provide methods for determining the presence of a selected
`genetic sequence in a population of genetic sequences.” Id. at 2:3–5.
`The disclosed method involves diluting a biological sample to a point
`where a practically usable number of the diluted samples contain a
`proportion of the selected genetic sequence (analyte) relative to total
`template molecules. Id. at 4:20–23. The diluted samples are separately
`amplified so that the amplified products have a proportion of the analyte
`sequence that is detectable by the detection means chosen. Id. at 4:7–10.
`With this method, single template molecules can be amplified so that the
`products are completely mutant or completely wild-type. Id. at 4:11–13.
`
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`IPR2017-02093
`Patent 7,824,889 B2
`The specification refers to this method as “digital amplification.” Id.
`at 4:42–43. According to the specification, “[t]he ultimate utility of Digital
`Amplification lies in its ability to convert the intrinsically exponential nature
`of PCR to a linear one.” Id. at 6:1–3. The specification further states that
`“[i]t should thereby prove useful for experiments requiring the investigation
`of individual alleles, rare variants/mutations, or quantitative analysis of PCR
`products.” Id. at 6:3–5. For example, the specification identifies detecting
`“allelic imbalance” as a potential application of digital amplification. Id. at
`5:29–30; 40–65 (Table 1). According to the specification, “[a]llelic
`imbalances often result from a disease state.” Id. at 6:56–57.
`Illustrative Claims
`C.
`Petitioner challenges claims 1 and 8 of the ’889 patent. Claims 1 and
`8, as amended during ex parte reexamination, are reproduced below:
`1. A method for determining an allelic imbalance in a
`biological sample, comprising the steps of:
`
`
`distributing isolated nucleic acid template molecules to
`form a set comprising a plurality of assay samples, wherein the
`nucleic acid template molecules are isolated from the biological
`sample;
`
`
`amplifying the template molecules within the set to form
`a population of amplified molecules in individual assay samples
`of the set;
`
`
`analyzing the amplified molecules in the assay samples
`of the set to determine a first number of assay samples which
`contain a selected genetic sequence on a first chromosome and
`a second number of assay samples which contain a reference
`genetic sequence on a second chromosome, wherein between
`0.1 and 0.9 of the assay samples yield an amplification product
`of at least one of the selected and the reference genetic
`sequences;
`
`4
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`IPR2017-02093
`Patent 7,824,889 B2
`
`
`comparing the first number of assay samples to the
`second number of assay samples to ascertain an allelic
`imbalance in the biological sample.
`
`The method of claim 1 wherein between 0.1 and 0.6 of the
`8.
`assay samples yield an amplification product of at least one of
`the selected and the reference genetic sequences.
`Ex. 1001, 21.
`
`The Asserted Grounds of Unpatentability
`D.
`Petitioner contends that the challenged claims are unpatentable under
`35 U.S.C. §§ 102(b) and/or 103 based on the following specific grounds.
`Pet. 4.
`Reference[s]
`Chiang1
`
`Sykes2
`
`Claims challenged
`1
`
`1, 8
`
`Basis
`§ 102(b)
`
`§ 102(b)
`
`Chiang and/or Sykes
`
`§ 102(b)/§103
`
`1, 8
`
`
`
`Petitioner also relies on the Declaration of Gregory A. Buck, Ph.D.
`Ex. 1007.
`
` ANALYSIS
`Person of Ordinary Skill in the Art
`A.
`Petitioner asserts that as of August 2, 1999, a person of ordinary skill
`in the art “would typically have earned a Master’s degree in the biological
`
`
`1 Pie-Wen Chiang et al., Use of a Fluorescent-PCR Reaction to Detect
`Genomic Sequence Copy Number and Transcriptional Abundance, 6
`GENOME RESEARCH 1013–26 (1996) (“Chiang”). Ex. 1031.
`2 P.J. Sykes et al., Quantitation of Targets for PCR by Use of Limiting
`Dilution, 13 BIOTECHNIQUES 444–49 (1992) (“Sykes”). Ex. 1011.
`5
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`Patent 7,824,889 B2
`sciences or a related field, and have at least four years of molecular biology
`laboratory experience, or alternatively, have a Ph.D. degree in the biological
`sciences or a related field, and have at least two years of molecular biology
`laboratory experience.” Pet. 8–9.
`Patent Owner disagrees with Petitioner, and contends that one of
`ordinary skill in the art “would have been a person with training and
`education in molecular biology techniques, such as PCR and related
`laboratory procedures, having either a Bachelor’s degree in biological or
`chemical sciences and at least three years of experience in a laboratory, or a
`Master’s degree in biochemical sciences and at least one year of laboratory
`experience.” Prelim. Resp. 2–3.
`On this record and at this stage of the proceeding, we do not discern
`an appreciable difference in the parties’ respective definitions of a person of
`ordinary skill in the art. Accordingly, we find that a person of ordinary skill
`in the art (1) would have had a Master’s degree in the biological or
`biochemical sciences, and (2) at least two years of molecular biology
`laboratory experience.
`We further note that the prior art itself demonstrates the level of skill
`in the art at the time of the invention. See Okajima v. Bourdeau, 261 F.3d
`1350, 1355 (Fed. Cir. 2001) (explaining that specific findings regarding
`ordinary skill level are not required “where the prior art itself reflects an
`appropriate level and a need for testimony is not shown”) (quoting Litton
`Indus. Prods., Inc. v. Solid State Sys. Corp., 755 F.2d 158, 163 (Fed. Cir.
`1985)).
`
`Claim Construction
`B.
`In an inter partes review, the Board interprets claim terms in an
`unexpired patent according to the broadest reasonable construction in light
`
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`Patent 7,824,889 B2
`of the specification of the patent in which they appear. 37 C.F.R. § 100(b);
`Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2142 (2016) (affirming
`applicability of broadest reasonable construction standard to inter partes
`review proceedings). Under that standard, and absent any special
`definitions, we generally give claim terms their ordinary and customary
`meaning, as would be understood by one of ordinary skill in the art at the
`time of the invention. See In re Translogic Tech., Inc., 504 F.3d 1249, 1257
`(Fed. Cir. 2007). Any special definitions for claim terms must be set forth
`with reasonable clarity, deliberateness, and precision. See In re Paulsen, 30
`F.3d 1475, 1480 (Fed. Cir. 1994).
`Disputed Terms
`Petitioner raises issues with respect to the following phrases in claim
`
`1:
`
`“to form a set comprising a plurality of assay samples;”
`(1)
`“assay samples of the set;” and
`(2)
`“comparing the first number of assay samples to the second
`(3)
`number of assay samples to ascertain an allelic imbalance in the biological
`sample.”3 Pet. 9–11.
`As to these phrases, Petitioner asserts what it believes to be Patent
`Owner’s proposed construction based on positions taken in the Ambry
`Litigation. Id. Patent Owner contends that “Petitioner’s proposed
`constructions are unreasonable” (too broad), and “mischaracterize[] Patent
`Owner’s position in related litigation.” Prelim. Resp. 8–9.
`
`
`3 Petitioner also argues that “the preamble of claim 1 should not be
`limiting.” Pet. 9. Patent Owner does not contest that argument. However,
`we need not reach that issue at this stage of the proceeding.
`7
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`IPR2017-02093
`Patent 7,824,889 B2
`We determine that at this stage of the proceeding, and solely for
`purposes of this Decision, we need not resolve the disputed construction of
`these phrases. Our decision not to institute inter partes review as to Chiang
`is not based on a construction of any of these phrases as proposed by Patent
`Owner, and our decision to institute inter partes review as to Sykes is not
`based on a construction of any of these phrases as proposed by Petitioner.
`Rather, we find that the ordinary and customary meaning of these phrases is
`sufficient for evaluating the applicability of the Chiang and Sykes references
`to the claims at issue in the Petition.
`Additional Terms
`Although we need not expressly construe any undisputed terms, we
`find that it would be helpful to explain our understanding of the meaning of
`“allelic imbalance” for purposes of our Decision. See Nidec Motor Corp. v.
`Zhongshan Broad Ocean Motor Co. Ltd., 868 F.3d 1013, 1017 (Fed. Cir.
`2017) (“[W]e need only construe terms ‘that are in controversy, and only to
`the extent necessary to resolve the controversy’” (quoting Vivid Techs., Inc.
`v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999))).
` “allelic imbalance”
`Patent Owner took the position in the reexamination proceeding of
`U.S. Patent No. 7,915,015 B2 (a divisional of the ’889 patent), that the term
`“allelic imbalance” means “the difference between the number of a first
`allelic form of a marker and the number of a second allelic form of a
`marker.” Ex. 1004, IPR2017-02095 (Reexamination Control No.
`90/012,896, Response to Office Action, dated Jan. 27, 2014, at 9). Our
`understanding of the meaning of “allelic imbalance,” at this stage of the
`proceeding and solely for purposes of this institution decision, is the same
`meaning as set forth by Patent Owner in the reexamination proceeding.
`
`8
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`Patent 7,824,889 B2
`
`C. Principles of Law
`Anticipation requires that “each and every element as set forth in the
`claim is found, either expressly or inherently described, in a single prior art
`reference.” In re Robertson, 169 F.3d 743, 745 (Fed. Cir. 1999) (citation
`omitted). “To establish inherency, the extrinsic evidence ‘must make clear
`that the missing descriptive matter is necessarily present in the thing
`described in the reference.’” Id. In considering the disclosure of a reference
`for anticipation, “it is proper to take into account not only specific teachings
`of the reference but also the inferences which one skilled in the art would
`reasonably be expected to draw therefrom.” In re Preda, 401 F.2d 825, 826
`(CCPA 1968).
`A conclusion of obviousness “cannot be sustained by mere conclusory
`statements; instead, there must be some articulated reasoning with some
`rational underpinning to support the legal conclusion of obviousness.” KSR
`Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007) (quoting In re Kahn, 441
`F.3d 977, 988 (Fed. Cir. 2006)).
`We analyze the asserted grounds of unpatentability in accordance with
`the above-stated principles.
`D. Anticipation by Chiang
`Petitioner asserts that claim 1 of the ’889 patent is anticipated by
`Chiang. Pet. 12–17. On this record, we determine that Petitioner has not
`established a reasonable likelihood that it would prevail in showing that
`claim 1 is anticipated by Chiang.
`Chiang (Ex. 1031)
`1.
`Chiang describes the use of a fluorescent-PCR reaction to detect
`genomic sequence copy number and transcriptional abundance. Ex. 1031,
`1013 (Abstract). Chiang describes an assay in which “[t]wo PCR reactions
`
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`IPR2017-02093
`Patent 7,824,889 B2
`were performed in parallel on both the unknown and the reference samples.”
`Id. at 1014. Chiang used “primers from the experimental S100β marker on
`chromosome 21” for one of the PCR reactions and “primers from the
`reference (eusomic) IGF-1 marker on chromosome 12” for the other PCR
`reaction. Id. Chiang states that “[b]ecause both reactions were monitored in
`exponential phase, the PCR signal depended directly on the initial target
`concentration.” Id. According to Chiang, “the ratio of PCR signal from the
`two reactions (S100β /IGF-1) in the unknown DNA, divided by the ratio of
`PCR signal from the two reactions (S100β /IGF-1) in the control (normal
`placental) DNA, accurately reflected the relative dosage of S100β to IGF-1
`in the unknown DNA.” Id. Chiang states that this enabled the calculations
`that one sample had one copy of S100β, two samples had two copies of
`S100β, and two other samples had three copies of S100β. Id. at Table 1.
`Analysis
`2.
`Petitioner has not established a reasonable likelihood that it would
`prevail in showing that Chiang discloses each step of claim 1. For example,
`claim 1 requires the step of “comparing the first number of assay samples to
`the second number of assay samples to ascertain an allelic imbalance in the
`biological sample.”4 Ex. 1001, 21. Petitioner, however, has not shown
`sufficiently that Chiang discloses that step. Instead, Petitioner makes the
`conclusory statement that “Chiang discloses ascertaining allelic imbalance in
`a biological sample and thereby meets step (d).” Pet. 14. Petitioner supports
`that statement by citing a sentence in Chiang that refers to the respective
`
`
`4 Petitioner refers to this step as “(d)” and the previous “analyzing” step as
`step “(c).” Pet. 13–16.
`
`10
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`IPR2017-02093
`Patent 7,824,889 B2
`copy numbers of S100β in five different samples, and by citing the Buck
`Declaration. Id. (citing Ex. 1031 (Chiang), 1015; Ex. 1007 (Buck Decl.)
`¶ 44.) That cited paragraph in the Buck Declaration, however, is merely a
`duplicate of the paragraph in the Petition. Compare Ex. 1007 ¶ 44 with Pet.
`14. Moreover, in Petitioner’s claim chart for claim 1, step (d), Petitioner
`simply states “See Claim 1, step (c).” Pet. 16.
`Petitioner, however, fails to explain how Chiang discloses the
`“comparing” step of claim 1. For example, Petitioner does not explain how
`Chiang’s disclosure of detecting the S100β copy numbers from five different
`samples necessarily discloses “comparing the first number of assay samples
`to the second number of assay samples,” as required by the claim.
`Conclusory statements by Petitioner and its declarant are insufficient to
`show Chiang discloses the limitation. Accordingly, we determine that
`Petitioner has not shown a reasonable likelihood that it would prevail on its
`assertion that claim 1 is anticipated by Chiang.
`Anticipation by Sykes
`E.
`Petitioner asserts that claims 1 and 8 of the ’889 patent are anticipated
`by Sykes. Pet. 17–24. Patent Owner advances arguments in response to
`Petitioner’s reliance on Sykes (Prelim. Resp. 15–18, 24–30), and submits the
`supporting Declaration of Fred Russell Kramer, Ph.D. (Ex. 2001).
` Sykes (Ex. 1011)
`1.
`Sykes “describe[s] a general method to quantitate the total number of
`initial targets present in a sample using limiting dilution, PCR and Poisson
`statistics.” Ex. 1011, 444. Sykes uses the rearranged immunoglobulin
`heavy chain (IgH) gene from a leukemic clone as an example target. Id. In
`a particular patient with acute lymphoblastic leukemia (ALL), all leukemic
`cells will have the same rearranged IgH gene that can act as a genetic marker
`
`11
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`IPR2017-02093
`Patent 7,824,889 B2
`to distinguish leukemic cells from normal cells. Id. Sykes also used the N-
`ras gene as an internal control. Id.
`Sykes identifies two problems with quantitating the unique
`rearrangement of the leukemic clones: (1) “only a few copies may be
`present in a tissue sample taken from a patient in remission following
`treatment” and (2) “germ-line IgH genes from cells, other than B
`lymphocytes, and rearranged IgH genes from normal B lymphocytes will be
`present” and may compete with the target gene in the PCR. Id. To address
`these problems, Sykes uses the principle of limiting dilution, which uses a
`qualitative all-or-none end point. Id. By having some end points that are
`positive and some that are negative, “the number of targets present can be
`calculated from the proportion of negative end points by using Poisson
`statistics.” Id.
`Sykes states that the “problem in our study was the detection of rare
`leukemic cells in a large population of normal cells, which in molecular
`terms became the problem of detection of a rare unique IgH sequence
`against a background of numerous other IgH sequences.” Id. at 448. The
`described study determined ratios of the number of N-ras targets detected to
`the number of IgH targets detected. Id. at 446–447, Table 2. Those ratios
`were determined based on samples in which DNA from patients with ALL
`(a source of leukemic IgH targets and normal N-ras targets) included PBL1
`DNA (a source of normal IgH and N-ras targets) or excluded PBL1 DNA.
`Id. at Table 2; 445. Based on those ratios, Sykes states that “in the presence
`of competing targets, it proved possible to amplify a mean of 52%, i.e., to
`detect approximately two (1/0.52) potentially amplifiable leukemic targets.”
`Id. at 447, Table 2.
`
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`Patent 7,824,889 B2
`
`2.
`
`Analysis
`
`Claim 1
`Petitioner provides evidence and arguments that each and every step
`in claim 1 is disclosed by Sykes. Pet. 17–23; Ex. 1007 ¶¶ 46–56. For the
`purpose of this institution decision, we focus on the claimed steps of
`“analyzing the amplified molecules in the assay samples of the set” and
`“comparing the first number of assay samples to the second number of assay
`samples to ascertain an allelic imbalance.” Ex. 1001, 21.
`Analyzing Step
`In addressing the disclosure by Sykes of the “analyzing” step,
`
`Petitioner states that:
`The amplified IgH and N-ras products in the assay samples of
`the set were analyzed by counting the number of assay samples
`with IgH and the number of assay samples with N-ras. . . . For
`example, at a certain dilution, 6/10 tubes scored positive for N-
`ras, while 3/10 tubes scored positive for IgH (Table 1).
`Pet. 18.
`
`Petitioner also states that Sykes “discloses using Poisson statistics to
`quantitate the initial numbers of leukemic and non-leukemic templates
`present.” Id. at 18–19 (citing Ex. 1011, Abstract, 444, 446–447; Ex. 1007
`¶ 53.); see also Pet. 22–23.
`
`Comparing Step
`In addressing the disclosure by Sykes of the “comparing” step,
`Petitioner points to the ratios of N-ras to IgH and the statement in Sykes
`that:
`
`Because the number of N-ras copies detected depends on
`both the total number of copies which are present and the
`proportion which are amplifiable, the ratios of the number of
`N-ras targets detected to the number of IgH targets detected
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`give the proportion of potentially amplifiable IgH targets that
`were actually amplified.
`Pet. 23 (citing Ex. 1011, 447).
`Thus, according to Petitioner, “[t]he number of assay samples
`containing the leukemic templates (IgH) were compared with the number of
`assay samples containing the total templates, to ascertain a ratio (‘Ratio N-
`ras/IgH,’ Table 2) which reflects an allelic imbalance of the biological
`sample (i.e., Ho DNA).” Pet. 19. That is, according to Petitioner, Sykes
`discloses a comparison of the first number of assay samples to the second
`number of assay samples to ascertain “the difference between the number of
`a first allelic form of a marker and the number of a second allelic form of a
`marker,” i.e., an “allelic imbalance” in the biological sample.
`
`Claim 8
`
`Petitioner provides further evidence and arguments regarding
`dependent claim 8. Pet. 23–24; Ex. 1007 ¶¶ 57, 58. For example, Petitioner
`points to Table 1 of Sykes as showing that “6 of the 10 samples (0.6) were
`positive for N-ras and 3 of the 10 samples were positive for IgH (0.3).” Pet.
`23 (citing Ex. 1011, 446, Table 1). According to Petitioner, “Sykes
`discloses diluting and distributing a mixture of leukemic and nonleukemic
`templates into 10 replicates, i.e., assay samples, and determining that 3/10
`(0.3) contained the leukemic template IgH and 6/10 (0.6) contained the
`nonleukemic template N-ras. (Ex. 1011; Table 1.),” thereby establishing that
`between 0.1 and 0.6 of the assay samples yielded an amplification product of
`at least one of the selected and the reference genetic sequences, as recited in
`claim 8. Pet. 24; Ex. 1007 ¶ 58.
`
`14
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`Patent Owner’s Arguments and Evidence
`Patent Owner advances arguments and evidence that claim 1 is not
`
`anticipated because “Sykes fails to disclose the ‘analyzing’ and ‘comparing’
`steps.” See Prelim. Resp. 24–30; Ex. 2001 ¶¶ 53–58, 92–94. Patent Owner
`relies on the same arguments and evidence in addressing dependent claim 8.
`Prelim. Resp. 29–30.
`Disclosure of the “Analyzing” Step
`Patent Owner argues that claim 1 is not anticipated because Sykes
`fails to disclose the “analyzing” step. Prelim. Resp. 25–26. According to
`Patent Owner, Sykes discloses performing separate assays for detection of
`rearranged IgH sequences and the internal control, N-ras. Id. at 26. In
`particular, Patent Owner contends that “Sykes describes using one set of ten
`assay samples for detecting mutant IgH and another set of ten assay samples
`for detecting N-ras,” and that Sykes thus “fails to anticipate independent
`claim 1 because Sykes fails to disclose the third step of the claim[], which
`requires analysis of the assay samples of the same set, not multiple sets.”5
`Id.
`
`Claim 1 recites “a set comprising a plurality of assay samples,” and
`the use of a plurality of (multiple) samples does not equate to multiple sets.
`Moreover, notwithstanding that Sykes may describe using ten assay samples
`for detecting mutant IgH and ten assay samples for detecting N-ras, Sykes
`still discloses “an analysis of the assay samples of the same set, not multiple
`
`
`5 To the extent that Patent Owner may be arguing that the analyzing step of
`claim 1 requires that the selected and reference sequences be analyzed
`within the same well or vial, we are not persuaded on this record that claim 1
`is so limited.
`
`
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`sets.” That is, Sykes discloses analyzing the amplified molecules in the
`assay samples of the set to determine a first number of assay samples that
`contain a selected genetic sequence (IgH) on a first chromosome and a
`second number of assay samples that contain a reference genetic sequence
`(N-ras) on a second chromosome. Even under Patent Owner’s interpretation
`of Sykes, all of the nucleic acid template molecules in the plurality of the
`samples in the “first experiment” are from the same biological sample, i.e.,
`Ho DNA isolated from a bone marrow sample of a patient with acute
`lymphoblastic leukemia. Prelim. Resp. 25. Furthermore, Patent Owner’s
`contention that Sykes divides twenty assay samples, from the same
`biological sample, into two sets of ten samples each appears to be
`inconsistent with Patent Owner’s contention that, in claim 1, the assay
`samples of the set “remain part of the set, regardless of the physical location
`or characteristics of the assay samples.” Prelim. Resp. 12.
`Disclosure of the “Comparing” Step
`Patent Owner contends that Sykes cannot disclose the “comparing”
`step because Sykes fails to disclose or suggest the “analyzing” step. Prelim.
`Resp. 27. In advancing that argument, Patent Owner repeats arguments
`advanced and addressed in connection with the “analyzing” step above,
`particularly in conflating a plurality of samples with multiple sets. Id. at 27–
`30. Our response is the same as set forth above. Patent Owner further
`argues that, with respect to the “first experiment,” Sykes does not compare
`assay samples from a single set of assay samples to ascertain an allelic
`imbalance because that is not the purpose of the experiment and is not
`possible, and because the numbers of wild-type N-ras and mutant IgH are
`already known based on the concentration of the initial sample. Id. at 27–
`28.
`
`16
`
`
`
`IPR2017-02093
`Patent 7,824,889 B2
`Patent Owner’s contention regarding the “purpose of the [first]
`experiment” does not persuasively address the disclosure by Sykes of the
`claimed “comparing” step as set forth by Petitioner. See Pet. 23. Moreover,
`Patent Owner does not persuasively explain why it is not possible to
`ascertain the difference between the number of IgH sequences and N-ras
`sequences from the disclosure in Sykes. Furthermore, even if the numbers
`of wild-type N-ras and mutant IgH are already known, that does not
`persuasively explain why Sykes does not disclose the claimed comparing
`step, particularly in light of the possibility that Sykes is confirming the
`viability of a method based on known numbers.
`Patent Owner also argues that “[a]lthough Sykes discloses
`determining a ratio of N-ras to mutant IgH, as shown in Table 2, this ratio
`does not reflect an allelic imbalance.” Prelim. Resp. 29. Rather, according
`to Patent Owner, the ratio is used “to determine if template degradation
`affects the interpretation of their results.” Id. Patent Owner states that
`“Sykes describes using this ratio to account for a factor that could result in
`under-quantitation of the mutant IgH sequence (e.g., DNA degradation in the
`sample),” citing paragraph 58 of the Kramer Declaration. Id. Paragraph 58
`of the Kramer Declaration similarly states that “Sykes indicated that this
`ratio was used to account for under-quantitation of the mutant IgH sequence
`(e.g., DNA degradation in the sample),” citing page 447 of Sykes. Ex. 2001
`¶ 58. However, a statement that merely points to a page in Sykes without a
`discussion of specific text does not persuasively explain why the ratio
`disclosed in Table 2 of Sykes, or other portions of Sykes relied on by
`Petitioner, do not disclose the claimed comparing step.
`
`
`
`17
`
`
`
`IPR2017-02093
`Patent 7,824,889 B2
`
`Additional Arguments by Patent Owner
`Patent Owner argues that Sykes is redundant “because it was already
`considered by the Patent Office and also in light of the Patent Office’s
`treatment of other limiting dilution PCR art considered.” Prelim. Resp. 16.
`Petitioner thus requests that we exercise our discretion under 35 U.S.C.
`§ 325(d) and not institute inter partes review as to Sykes. Id. at 17.
`We decline to exercise such discretion as requested by Patent Owner.
`While Sykes was cited during original prosecution and reexamination of the
`’889 patent, Patent Owner does not point to any discussion of Sykes in either
`of those ex parte proceedings. Furthermore, we are not persuaded that
`Sykes is “redundant” based on Patent Owner’s cursory argument that “Sykes
`describes limiting dilution PCR methods” and “other limiting dilution
`references” were also before the Patent Office. See Prelim. Resp. 15–17.
`Patent Owner also contends that the Buck Declaration is merely
`attorney argument in the guise of expert testimony. Prelim. Resp. 12–14.
`However, the focus of Patent Owner’s argument is directed to Dr. Buck’s
`position on Chiang and Petitioner’s claim construction arguments. See id.
`In light of our decision not to institute inter partes review as to Chiang and
`not to construe the claim phrases as requested by Petitioner, Patent Owner’s
`argument is not persuasive on the issue of whether to institute inter partes
`review as to Sykes. Patent Owner also argues that ground 1 (Chiang) and
`ground 2 (Sykes) are redundant (Prelim. Resp. 17–18), but that issue is moot
`given our decision not to institute inter partes review as to Chiang.
`Summary
`3.
`On this record and at this stage of the proceeding, we determine that
`Petitioner has established a reasonable likelihood that it would prevail in
`showing that claims 1 and 8 are anticipated by Sykes. Furthermore, for the
`
`18
`
`
`
`IPR2017-02093
`Patent 7,824,889 B2
`reasons set forth above, we are not persuaded by Patent Owner’s arguments
`at this time. Moreover, while we take account of the testimonial evidence of
`Patent Owner’s declarant, Dr. Kramer, any genuine issue of material fact
`created by such evidence is viewed in the light most favorable to Petitioner
`solely for the purpose of deciding whether to institute an inter partes review.
`37 C.F.R. § 42.108 (c).
`Accordingly, having considered the arguments and evidence of
`Petitioner and Patent Owner at this stage of the proceeding, we are
`persuaded that Petitioner has shown a reasonable likelihood that it would
`prevail in showing claims 1 and 8 are anticipated by Sykes.
`F. Obviousness over Chiang and/or Sykes
`In a single paragraph, Petitioner asserts that claims 1 and 8 of the
`’889 patent are unpatentable as obvious in view of Chiang and/or Sykes.
`Pet. 24. Petitioner supports that argument with three conclusory sentences
`and a citation to the same three sentences in the Buck Declaration. Id.
`(citing Ex. 1007 ¶ 63). Such conclusory statements with no analysis by
`Petitioner are insufficient to establish obviousness. See KSR, 550 U.S. at
`418.
`
`Accordingly, we determine that Petitioner has not shown a reasonable
`likelihood that it would prevail on its assertion that claims 1 and 8 are
`unpatentable as obvious in view of Chiang and/or Sykes.
`
`
` CONCLUSION
`For the foregoing reasons, we conclude that Petitioner has established
`a reasonable li
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