UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________________________
`
`FORESIGHT DIAGNOSTICS INC.,
`Petitioner,
`
`v.
`
`PERSONALIS, INC.,
`Patent Owner.
`
`Case Nos. IPR2023-00224 and IPR2023-00317
`U.S. Patent Nos. 11,384,394 and 11,408,033
`
`DECLARATION OF HENRY MORRICE FURNEAUX, PH.D.
`
`Personalis EX2031
`
`
`__________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________________________
`
`FORESIGHT DIAGNOSTICS INC.,
`Petitioner,
`
`v.
`
`PERSONALIS, INC.,
`Patent Owner.
`
`Case Nos. IPR2023-00224 and IPR2023-00317
`U.S. Patent Nos. 11,384,394 and 11,408,033
`
`DECLARATION OF HENRY MORRICE FURNEAUX, PH.D.
`
`Personalis EX2031
`
`
`
`TABLE OF CONTENTS
`
`
`Page No.
`
`
`
`
`
`I. INTRODUCTION .................................................................................................. 1
`II. ENGAGEMENT ................................................................................................. 11
`III. BACKGROUND AND QUALIFICATIONS ................................................... 12
`A.
`Patents Awarded .................................................................................. 17
`B.
`Research And Teaching Experience ................................................... 18
`C.
`Industry Experience ............................................................................. 22
`D.
`Professional Society Involvement ....................................................... 23
`IV. MATERIALS CONSIDERED .......................................................................... 23
`V. LEGAL STANDARDS ....................................................................................... 23
`A. Anticipation ......................................................................................... 24
`B.
`Nonobviousness ................................................................................... 24
`VI. THE PERSON OF ORDINARY SKILL IN THE ART ................................... 25
`VII. CLAIM CONSTRUCTION ............................................................................. 26
`A.
`Construction of “whole genome sequencing” ..................................... 26
`B.
`Construction of “capture probes” ........................................................ 28
`1.
`The plain meaning of “capture probes” .................................... 28
`2.
`The preliminary construction does not comply with the plain
`meaning of “capture probes” .................................................... 30
`The specification does not contradict the plain meaning of
`“capture probe” ......................................................................... 38
`
`3.
`
`Table of Contents, Page 1
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`Personalis EX2031
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`
`
`TABLE OF CONTENTS
`(cont’d.)
`
`4.
`
`Page No.
`
`
`PCR primers and capture probes were two different techniques
` ................................................................................................... 45
`VIII. THE GROUNDS CHALLENGING PATENTABILITY OF THE ′394 AND
`′033 PATENTS .............................................................................................. 50
`IX. FORESIGHT HAS NOT PROVEN UNPATENTABILITY OF ANY CLAIM
`FROM THE ′394 PATENT ........................................................................... 53
`A. Overview of the ′394 Patent ................................................................ 53
`B.
`Ground 1: The claims are nonobvious over Leary (EX1002) ............ 56
`1.
`Claim 1 is nonobvious over Leary (EX1002) ........................... 57
`a.
`Leary (EX1002) does not teach or suggest limitation
`1(b) .................................................................................. 57
`i.
`Leary does not teach whole genome sequencing .... 58
`
`ii. Leary does not suggest WGS .................................. 74
`
`(a) The data burden of WGS .................................. 74
`
`(b) At this time WGS was at least an order of
`
`magnitude more expensive than targeted approaches
`
` 83
`
`iii. Simply increasing Leary’s coverage depth would not
`
`convert Leary’s PARE to WGS ...................................... 89
`
`b.
`
`Leary does not teach or suggest the “second nucleic
`acid sample” of limitation 1(c)(i) ................................... 92
`
`Table of Contents, Page 2
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`Personalis EX2031
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`
`
`TABLE OF CONTENTS
`(cont’d.)
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`Page No.
`
`
`
`Leary does not teach or suggest the “capture probes”
`of limitation 1(c)(i)-(ii) ................................................... 94
`i.
`Leary does not teach or suggest “capture probes” .. 94
`
`c.
`
`d.
`
`e.
`
`Leary does not teach or suggest the “plurality of
`capture probes of limitation 1(e) .................................... 99
`Leary does not teach or suggest the “third
`sequencing assay” of limitation 1(f) ............................. 104
`Lack of motivation to modify Leary ............................ 106
`f.
`Claims 17 and 18 are nonobvious over Leary ........................107
`2.
`Claim 19 is nonobvious over Leary ........................................108
`3.
`Ground 2: The claims are nonobvious over Leary and Ley .............109
`C.
`D. Ground 3: The claims are nonobvious over Leary, Chan, and Liao 113
`1.
`Chan is not prior art ................................................................113
`2.
`Leary, Chan, and Liao do not render the claims obvious .......113
`a.
`The combination of references do not teach or
`suggest the whole genome sequencing of limitation
`1(b) ................................................................................ 114
`The combination of references do not teach or
`suggest limitation 1(c) .................................................. 116
`The combination of references do not teach or
`suggest limitation 1(f) ................................................... 118
`Objective Indicia of Nonobviousness ...............................................119
`1.
`Nexus.......................................................................................119
`
`E.
`
`b.
`
`c.
`
`Table of Contents, Page 3
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`Personalis EX2031
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`Page No.
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`
`Industry Praise .........................................................................128
`2.
`Skepticism of Experts .............................................................130
`3.
`X. FORESIGHT HAS NOT PROVEN UNPATENTABILITY OF ANY CLAIM
`FROM THE ′033 PATENT .........................................................................131
`A. Overview of the ′033 Patent ..............................................................131
`B.
`Ground 1: Forshew (EX1030) does not anticipate the claims .........133
`1.
`Forshew is not prior art ...........................................................133
`2.
`Forshew does not teach the “capture probes” recited by claim 1
` .................................................................................................134
`a.
`Forshew does not teach the “capture probes” of
`limitation 1(a) ............................................................... 134
`Forshew does not teach the “plurality of capture
`probes” of limitation 1(b) ............................................. 135
`Forshew does not teach limitation 1(c) ........................ 136
`c.
`Forshew does not teach limitation 1(d) ........................ 136
`d.
`Ground 2: The claims are nonobvious over Forshew and Wagle ....137
`1.
`Forshew is not prior art ...........................................................138
`2.
`No motivation due to Forshew’s miniscule amounts of DNA
` .................................................................................................138
`No motivation to change the core reaction principle of Forshew
` .................................................................................................145
`No motivation to add capture probes to Forshew ...................148
`4.
`D. Ground 3: The claims are nonobvious over Wagle and Chan .........151
`
`C.
`
`b.
`
`3.
`
`TABLE OF CONTENTS
`(cont’d.)
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`Table of Contents, Page 4
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`Personalis EX2031
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`
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`TABLE OF CONTENTS
`(cont’d.)
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`E.
`
`Page No.
`
`
`Chan is not prior art ................................................................151
`1.
`2. Wagle and Chan do not teach or suggest limitation 1(d) ........152
`Objective Indicia of Nonobviousness ...............................................155
`1.
`Nexus.......................................................................................156
`2.
`Industry Praise .........................................................................160
`3.
`Skepticism of Experts .............................................................162
`XI. CERTIFICATION ...........................................................................................163
`
`
`Table of Contents, Page 5
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`Personalis EX2031
`
`
`
`Foresight Diagnostics v. Personalis
`IPR2023-00224 and IPR2023-00317
`
`
`1.
`
`I, Henry Morrice Furneaux, Ph.D., make this Declaration in connection
`
`with inter partes review proceedings at the U.S. Patent & Trademark Office
`
`concerning U.S. Patent No. 11,384,394 (“the ′394 patent”) and U.S. Patent No.
`
`11,408,033 (“the ′033 patent”).
`
`2.
`
`I am over the age of twenty-one (21) and am competent to make this
`
`Declaration. I reside at 146 Kenyon Street, Hartford, CT 06105.
`
`3.
`
`As discussed herein, the claims of the ′394 patent are nonobvious over
`
`(1) Leary EX1002, (2) Leary EX1002 and Ley EX1012, and (3) Leary EX1002,
`
`Chan EX1008, and Liao EX1009. The claims of the ′033 patent are not anticipated
`
`by Forshew EX1030. The claims of the ′033 patent are nonobvious over (1) Forshew
`
`EX1030 and Wagle EX1033, and (2) Wagle EX1033 and Chan EX1008.
`
`I. INTRODUCTION
`4.
`U.S. Patent Nos. 11,384,394 (“the ′394 Patent”) and 11,408,033
`
`(“the ′033 patent”) represent novel and nonobvious personalized unbiased
`
`approaches to cancer detection and monitoring that were far ahead of their time when
`
`the inventions were made in 2012, and they continue to receive acclaim to this day.
`
`5.
`
`Briefly, the claims of the ′394 Patent recite a specific process that
`
`describes the novel application of “bespoke” preparation and sequencing protocols
`
`that enable a much more comprehensive analysis of a whole human genome. This
`
`
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`comprehensive analysis coupled with a subsequent targeted sequencing assay based
`
`on using capture probes in accordance with the claimed method improves diagnosis
`
`and treatment of cancer patients. Cancer is essentially caused by alterations in the
`
`sequence of DNA. Thus, a more comprehensive analysis that both improves routine
`
`analysis of the “charted” regions of the human genome and increases the
`
`interrogation of hithertofore “uncharted regions”, is now appreciated to be much
`
`more likely to identify useful alterations that, serve to diagnose cancer, to monitor
`
`cancer trajectory and to predict effective therapies by using the claimed method.
`
`6.
`
`Claim 1 of the ′033 Patent recites a specific process that produces
`
`capture probes directed to polymorphisms that are associated with a disease or
`
`indication. By applying these probes to a nucleic acid sample, one can collect
`
`nucleic acid that is likely to encode disease-causing alterations in, for instance, the
`
`tumor genome of a cancer patient. DNA sequencing can then be used to identify the
`
`specific alterations at issue in the patient. The process of capturing DNA with
`
`capture probes and sequencing can be repeated over time, allowing one to monitor
`
`disease and response to therapy over time.
`
`7.
`
`As the ′394 and ′033 Patents explain, prior art methods using orthodox
`
`“one size fits all” sequence protocols were biased in fragment selection and analysis
`
`and could “fail to capture many biomedically important variants,” not to mention
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`perform poorly in certain critical regions of the genome. EX1001 (′394 Patent) at
`
`1:23-34.1 In addition, it was well acknowledged at that time that the cost of
`
`sequencing 16 million DNA fragments (3.2 billion /200 bp fragment size) enough
`
`times (estimates varied from 30-500X coverage) to determine a reliable sequence
`
`would be extremely cost prohibitive. The cost problem would also be compounded
`
`by the accepted belief that the sequence of many of these DNA fragments may be
`
`uninformative.
`
`8.
`
` Some very preliminary and partial solutions to these problems had
`
`been provided by only sequencing genomic segments that were hypothesized to be
`
`informative. However, each cancer patient has a unique alteration spectrum arising
`
`from the combination of distinct tumor subclones and a unique trajectory in terms of
`
`the appearance and disappearance of alterations in particular tumor subclones. Thus,
`
`there would be no guarantee that such hypothesis-driven approaches would identify
`
`useful alterations in a particular patient. Indeed, the inventors of the ′394 and ′033
`
`patent sought to overcome this problem by developing new personalized approaches.
`
`
`1 The ′394 and ′033 patents contain identical disclosures at the same column and line
`
`numbers as each other.
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`
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`9.
`
`Specifically, the inventors of the ′394 Patent recognized that such
`
`problems could be overcome by first performing an initial comprehensive sequence
`
`analysis of tumor DNA fragments from an individual, using novel and nonobvious
`
`methods that significantly decreased fragment bias and enabled increased sequence
`
`accuracy. This comprehensive personalized sequence information could then be
`
`used to identify informative fragments and to generate capture probes that could
`
`isolate such DNA fragments and thus enable an informative yet economic analysis.
`
`In particular such capture probes would be of significant utility in the analysis of
`
`subsequent patient samples in determining tumor trajectory, response to treatment
`
`and to the administration of novel and nonobvious therapies.
`
`10.
`
`It was also envisaged by the ′394 patent inventors that the extensive
`
`collection of these individual (personal) capture probe sequence databases could
`
`help illuminate novel pervasive alteration signatures and enable the prospective
`
`(without the first comprehensive DNA sequence analysis) use of such capture probe
`
`generated data.
`
`11. The inventors of the ′033 Patent recognized that problems with the prior
`
`art could be overcome by using novel and nonobvious methods to generate capture
`
`probes that could isolate DNA fragments associated with a plurality of
`
`polymorphisms. This would provide an informative yet economic analysis. Such
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`capture probes and sequencing assays would be of significant utility in the analysis
`
`of subsequent patient samples in determining tumor trajectory, response to
`
`treatment, and to the administration of novel and nonobvious therapies.
`
`12. By using the approaches claimed by the ′394 and ′033 patents,
`
`Personalis was able to pioneer new frontiers in techniques for detecting and
`
`monitoring disease in cancer patients with utmost sensitivity. The Personalis assay
`
`that practices the ′394 and ′033 Patents, for instance, can detect tumor DNA in blood
`
`plasma at levels of about one part per million (or 0.0001%). Recently, The Scientist
`
`magazine hailed the Personalis assay as the #1 scientific innovation of 2022:
`
`See EX2001 (The Scientist Magazine) at pages 1-2.
`
`13. Now, years after the Personalis inventors conceived of their approach,
`
`Petitioner contends that the ′394 and ′033 Patents are invalid in view of certain
`
`
`
`references.
`
`
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`-5-
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`14. With respect to the ′394 patent, Petitioner does not identify any
`
`anticipatory prior art, but contends that the ′394 Patent is obvious in view of certain
`
`references, including Leary, which is Petitioner’s primary reference. Yet, as
`
`discussed herein, Leary is nowhere close to the ′394 Patent:
`
`
`
`DNA Sequencing is a process to discover the identity and the order
`
`of bases present in a duplex DNA structure. Leary only reported the
`
`sequence of short segments (25bp) at both ends of a much larger fragment
`
`(the mate pairing technique). Thus, Leary is not teaching whole genome
`
`sequencing and perhaps one could argue Leary is not even teaching general
`
`sequencing. However, there would be no argument that Leary is teaching a
`
`physical mapping method. Leary uses these disconnected short reads to
`
`identify guideposts in the genome that serve to identify gross chromosomal
`
`aberrations such as copy number changes and chromosomal rearrangements.
`
`It is very important to point out that the extent to which the human genome
`
`is mapped in this technique is provided by the term “physical coverage.”
`
`Physical coverage has been defined as “the number of DNA fragments of
`
`which both ends have been sequenced that on average overlie any position in
`
`the genome.” EX2162 at page 1. Thus, physical coverage should not be
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`confused with sequence coverage which means the average number of times
`
`that a base pair has been sequenced (identified).
`
`
`
` Nowhere does Leary mention whole genome sequencing. Petitioner’s
`
`contention that Leary teaches “whole genome sequencing” under the correct
`
`understanding of this term as used by the ′394 patent is, at best, based on a
`
`misunderstanding of Leary and, at worst, a distortion.
`
`
`
`Importantly, as confirmed by Dr. Quackenbush during his deposition,
`
`given that there is a large tract of missing sequence between the ends of the
`
`DNA fragments, Leary cannot even use the mapping method to report on the
`
`sequence of the aberrant chromosomal breakpoints. Such information about
`
`what genes are involved and whether the breakpoint has preserved or
`
`abolished the reading frame is what a POSA would expect.
`
`
`
`The Petitioner attempts to argue that the alleged “capture probes” (i.e.,
`
`PCR primers) and the resulting PCR amplification (that in Leary was merely
`
`used for confirmation of breakpoint status), are one and the same. The
`
`Petitioner attempts to argue that “capture probes”, a well-described entity
`
`which captures nucleic acids via a non-catalytic reaction, are synonymous
`
`with “Polymerase Chain Reaction Primer Capture Probes”. “Polymerase
`
`Chain Reaction Primer Capture Probes” is a term invented by Dr.
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`Quackenbush to illegitimately portray PCR primers as capture probes using
`
`improper hindsight. This is quite simply ridiculous. This argument is contrary
`
`to not just the intrinsic evidence, but also its own extrinsic evidence.
`
`15. Although Petitioner attempts to plug some of these gaps with a few
`
`secondary references, its secondary references simply confirm that Petitioner’s
`
`obviousness theory is without merit. For instance, while Petitioner contends that
`
`Chan can be combined with Leary to render obvious certain claims of the Personalis
`
`targeted approach based on the use of capture probes, Chan characterizes such an
`
`approach as offering only a “partial glimpse” of a tumor genome in cancer patients.
`
`EX1008 (Chan) at page 212. To the extent that Chan even considers such targeted
`
`approaches, it is only to vaguely speculate about them as future possibilities, thus
`
`confirming how ahead of its time the Personalis approach was. Indeed, an article
`
`published in the same issue as, and referring to, Chan teaches away from the use of
`
`personalized panels to detect recurrence and instead advocates for the continued use
`
`of shotgun sequencing (which is the sequencing of DNA fragments produced in a
`
`random unbiased protocol) so as to overcome the problem of tumor heterogeneity.
`
`See EX2003 (Swanton) at page 7 (“these data support the use of unbiased shotgun
`
`MPS approaches to ctDNA analysis”).
`
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`16. Consistent with this, the Ley reference relied upon by Petitioner as
`
`allegedly rendering obvious claims 1 and 4-5 expressly teaches against targeted
`
`approaches of the type claimed in the ′394 Patent as being “inherently limited” and
`
`likely to “miss key mutations:”
`
`Our results strongly support the notion that hypothesis driven (for
`example, candidate gene-based) examination of tumor genomes by
`PCR-directed or capture-based methods is inherently limited, and
`will miss key mutations.
`
`EX1012 (Ley) at page 70. Petitioner’s reliance on prior art which teaches that
`
`capture-based methods are “inherently limited” underscores the weakness of its
`
`positions in asserting that a POSA would have been motivated to use such capture-
`
`based methods to arrive at the invention claimed by the ′394 patent.
`
`17. Turning to the ′033 patent, Petitioner relies primarily on Forshew as an
`
`alleged anticipatory reference. Forshew, however, does not teach the use of capture
`
`probes, which is required by every limitation of claim 1 of the ′033 patent. Rather
`
`than using capture probes, Forshew relies upon PCR, a method that Petitioner’s own
`
`prior art repeatedly distinguishes. Importantly, Forshew refers to this method as
`
`PCR not as a “PCR primer capture probe” method. Indeed, Forshew itself
`
`distinguishes its PCR-based approach from the claimed capture probe methods of
`
`the ′033 Patent, criticizing the use of “expensive custom-designed probes” and
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`asserting that they “are difficult to implement on a routine basis.” EX1030 (Forshew)
`
`at page 10.
`
`18. While Petitioner asserts that a POSA would conflate PCR and capture
`
`probes, such an assertion is contradicted by the very exhibits cited by Petitioner. The
`
`additional obviousness theories that Petitioner presents based on the combination of
`
`Forshew and Wagle (or the combination of Wagle and Chan) also are unconvincing.
`
`Petitioner relies, for instance, on Wagle as disclosing capture probes. Yet, Wagle
`
`simply reports on the use of massively parallel sequencing to analyze samples from
`
`FFPE sections. Petitioner acknowledges that Wagle does not expressly disclose
`
`repeating steps (b)-(c) on a subsequently obtained sample from said individual. And
`
`it would not have been obvious to modify Wagle to repeat steps (b)-(c) on a
`
`subsequently obtained sample for several reasons discussed herein.
`
`19. The Chan reference relied upon by Petitioner does not render obvious
`
`the personalized approach claimed by the ′033 patent. Chan, in fact, criticizes
`
`personalized approaches like the claimed invention because they “might miss
`
`important information regarding imminent relapse or disease progression” as
`
`follows:
`
`These data suggest that for an accurate measurement of the total tumor
`load in a cancer patient, the use of a genomewide shotgun approach
`
`
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`might provide a more representative picture, compared with the more
`traditional approach of targeting specific tumor-associated mutations.
`For the latter approach, if only a subset of the tumor cells possesses
`the targeted mutations, one might miss important information
`regarding imminent relapse or disease progression caused by tumor
`cells not possessing the targeted mutations, or one might miss the
`emergence of a treatment-resistant clone.
`
`EX1008 (Chan) at page 222.
`
`20. For the many reasons discussed in detail in this declaration, the claims
`
`of the ′394 and ′033 patents are novel and nonobvious over the references cited by
`
`Petitioner.
`
`II. ENGAGEMENT
`21.
`I have been retained by counsel for Personalis, Inc. (“Personalis”) in
`
`the above-captioned IPR matters as an independent technical expert to review and
`
`evaluate claims of the ′394 Patent and ′033 Patent. My opinions are based on my
`
`skills, knowledge, training, education, and experience in matters of this nature, and
`
`my examination of the materials used in preparing this report.
`
`22.
`
`I am being compensated on an hourly basis for my work performed in
`
`connection with this matter. I have received no additional compensation for my
`
`work in this matter, and my compensation does not depend upon the contents of this
`
`report, any testimony I may provide, or the ultimate outcome of these matters.
`-11-
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`Personalis EX2031
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`III. BACKGROUND AND QUALIFICATIONS
`23.
`In general, I have knowledge and experience with both the general
`
`scientific contexts relevant to these litigation proceedings and specific details of the
`
`technologies employed. Based upon my experience, qualifications and expertise, I
`
`am qualified as an expert in the fields of nucleic acid biochemistry, the hybridization
`
`of DNA to RNA, DNA recombination, the isolation of human genes, the de novo
`
`sequencing and assembly of human DNA sequence, the use of PCR and DNA
`
`sequencing to identify mutations in human tumor tissue, the manipulation of gene
`
`expression by siRNAs and microRNAs, the mechanism of action of enzymes such
`
`as DNA ligase and DNA polymerase that are used in molecular biology protocols
`
`and the identification of SNPs in noncoding regions of the genome that regulate gene
`
`expression via microRNA.
`
`24.
`
`I have summarized in this section my educational background, career
`
`history, relevant publications, and other relevant qualifications. My full curriculum
`
`vitae has been submitted as Exhibit 2010 in this proceeding.
`
`25.
`
`I earned a Bachelor of Science in Biochemistry, with honors, from the
`
`University of Aberdeen (Scotland, United Kingdom) in 1975. This department was
`
`headed by Professor Hamish Keir, a student of Professor J.N Davidson, who wrote
`
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`the classic textbook “The Nucleic Acids”. Thus, this experience provided a rigorous
`
`introduction to nucleic acids.
`
`26.
`
`I earned a Ph.D. in Biochemistry, also from the University of Aberdeen,
`
`UK in 1978. My thesis work was on the structure and function of poly-ADP ribose,
`
`a novel nucleic acid that I discovered had novel effects upon RNA transcription. See
`
`Furneaux HM, Pearson CK: The effects of NAD+ on RNA synthesis in isolated
`
`nuclei from BHK cells. Biochem Soc. Trans, 6:753-755, 1978.
`
`27.
`
`In 1978, in a seminar given by Professor Ed Southern, I heard about the
`
`exciting hypothesis that mature eukaryotic mRNA might be spliced from a precursor
`
`mRNA. This mechanism was unknown and so I accepted a position in Jerry
`
`Hurwitz’s lab in New York, to try to establish a system that could recapitulate
`
`mRNA splicing in vitro. I was very fortunate to be trained by Dr Hurwitz who not
`
`only discovered many of the enzymes used in Molecular biology but also provided
`
`a very rigorous training environment. Indeed, several of Dr. Hurwitz’s trainees
`
`either won Nobel prizes, became members of the National Academy or attained
`
`comparable levels of achievement. We were amongst the first to recapitulate this
`
`reaction and the first to show that mRNA splicing required the action of a
`
`ribonucleoprotein complex. See Furneaux HM, Perkins KK, Freyer GA, Arenas J,
`
`
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`-13-
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`Personalis EX2031
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`Foresight Diagnostics v. Personalis
`IPR2023-00224 and IPR2023-00317
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`Hurwitz J: Isolation and characterization of two fractions from HeLa cells required
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`for mRNA splicing in vitro. Proc Natl. Acad. Sci, 82: 4351-4355, 1985.
`
`28. From 1984 to 1987, I was a Research Fellow in the Program in
`
`Molecular Biology at Sloan Kettering Institute, the experimental research arm of
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`Memorial Sloan Kettering Cancer Center in New York City. From 1987 to 1989, I
`
`was promoted to an Assistant Laboratory Member in the Program in Molecular
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`Pharmacology and Therapeutics. In this position, I pioneered the use of molecular
`
`biology techniques to address problems in Oncology. For example, my lab was
`
`amongst the first to perform PCR analysis on DNA from human Cerebral Spinal
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`Fluid (CSF) to identify a cancer-causing virus. See Henson J, Rosenblum M,
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`Armstrong D, Furneaux H: Amplification of JC virus DNA from brain and
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`cerebrospinal fluid of patients with progressive multifocal eucoencephalopathy.
`
`Neurology 41:1967-1971, 1991. My lab also pioneered the recovery of DNA from
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`archival paraffin embedded human tumor slides. My lab showed that this DNA
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`could be sequenced and we were amongst the first to identify recurrent mutations in
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`the p53 gene, that could be linked to benzopyrene. See Schlegel U, Rosenfeld M,
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`Voldanandt M, Rosenblum M, Furneaux HM: p53 Mutations in primary lung tumors
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`are conserved in brain metastasis. J Neuro-Oncology 14: 93-100, 1992.
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`
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`-14-
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`Personalis EX2031
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`
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`Foresight Diagnostics v. Personalis
`IPR2023-00224 and IPR2023-00317
`
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`29. From 1989 to 1995, I was promoted to Assistant Member and Head of
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`the Laboratory of Molecular Neuro-Oncology at Sloan Kettering. Concurrently, I
`
`was also an Assistant Professor of Neuroscience at the Cornell University Graduate
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`School of Medical Sciences (now known as the Weill Cornell Graduate School of
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`Medical Sciences). In this phase of my career, my lab focused on the isolation of
`
`the genes that encoded human tumor antigens. This was an innovative project, since
`
`the conventional dogma at that time was that the immune system did not recognize
`
`tumors. My lab was the first to clone the human paraneoplastic tumor antigen genes,
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`HuD, HuR, LEMS and CDR62. In addition, the cloned tumor antigens provided an
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`ELISA assay for the early detection of lung cancer and neurological disease, which
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`was patented and licensed to Quest Diagnostics. These studies involved cDNA
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`library expression cloning, extensive DNA sequence analysis, gene expression by
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`RT-PCR and an innovative immunohistochemical technique that we devised to
`
`directly visualize the expression of tumor antigens and antigen-reactive T cells in
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`human tumor tissue. See Szabo A, Dalmau J, Manley G, Rosenfeld M, Wong E,
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`Henson J, Posner JB, Furneaux HM: HuD a paraneoplastic encephalomyelitis
`
`antigen contains RNA binding domains and is homologous to Elav and Sex-Lethal.
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`Cell 67: 325-333, 1991; Fathallah-Shaykh H, Wolf S, Wong E, Posner JB, Furneaux
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`HM: Cloning of a leucine zipper protein recognized by the sera of patients with
`-15-
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`
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`Personalis EX2031
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`
`
`Foresight Diagnostics v. Personalis
`IPR2023-00224 and IPR2023-00317
`
`
`antibody-associated paraneoplastic cerebellar degeneration. Proc Nat Acad. Sci,
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`88:3451-3454, 1991.
`
`30. From 1996 to 2000, I was promoted to Associate Member.
`
`Concurrently, I was also an Associate Professor of Neuroscience at the Cornell
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`University Graduate School of Medical Sciences. In this phase, my lab continued
`
`to focus on the structure and function of the HuD and HuR tumor antigens and
`
`demonstrated their role in regulation of gene expression via their interaction with the
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`AU-rich elements in the 3’UTR of mRNA. See Chung S, Jiang L, Cheng S, and
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`Furneaux HM*. Purification and properties of HuD, a neuronal RNA binding
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`protein. J. Biol. Chem. 271:11518-11524, 1996. It is important to note that mutation
`
`of these noncoding elements is a driver of carcinogenesis.
`
`31.
`
`In 2000, I accepted the position of Associate Professor of Molecular,
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`Microbial and Structural Biology at the University of Connecticut School of
`
`Medicine. Beginning in 2003 and through 2009, I was also the Director of the
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`Molecular Biology and Biochemistry Graduate Program at the University of
`
`Connecticut School of Medicine. In this phase, my lab continued studies on HuR,
`
`and HuD. My lab also pursued studies on the structure and function of microRNAs.
`
`This included innovative studies on the regulation of gene expression by SNPs
`
`present in microRNA target sites in non-coding regions. See Jensen KP, Covault J,
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`
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`Personalis EX2031
`
`
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`Foresight Diagnostics v. Personalis
`IPR2023-00224 and IPR2023-00317
`
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`Conner TS, Tennen H, Kranzler HR, Furneaux HM. A common polymorphism in
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`serotonin receptor 1B mRNA moderates regulation by miR-96 and associates with
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`aggressive human behaviors. Molecular Psychiatry 2009 14(4):381-9.
`
`32.
`
`In 2009 I left academia to create a company (Clonegene LLC) that
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`could generate income to fund my basic science resear
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