`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
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`GENEOSCOPY, INC.,
`Petitioner,
`
`v.
`
`EXACT SCIENCES CORPORATION,
`Patent Owner.
`____________
`
`Case No.: IPR2024-01330
`U.S. Patent 11,970,746
`____________
`
`
`DECLARATION OF DUNCAN WHITNEY, Ph.D.
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`DECLARATION OF DUNCAN WHITNEY
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`2.
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`TABLE OF CONTENTS
`Introduction .................................................................................................... 1
`I.
`II. Qualifications and Experience ....................................................................... 2
`III. The Person of Ordinary Skill in the Art ........................................................ 5
`IV. Technical Background ................................................................................... 7
` Diagnostic Analysis of Biological Samples ............................... 8
`1.
`Diagnostic Tests Based on Detection of Biomarkers, such
`as Protein and DNA ....................................................... 10
`Sensitivity and Specificity as Measures of Diagnostic
`Performance ................................................................... 13
`Diagnostic Tests Commonly Measure Multiple Markers14
`3.
`Diagnostic Analyses Require Well-Preserved Samples 16
`4.
` Use of Fecal Diagnostic Tests to Diagnose Colorectal Cancer 24
`1.
`Fecal Occult Blood Tests ............................................... 24
`2.
`Fecal DNA-Based Tests ................................................. 28
`3.
`RNA Expression was also used to Diagnose Colorectal
`Cancer ............................................................................ 33
`Biomarker Panels Empower Broader and Earlier Detection of
`Colorectal Cancer ..................................................................... 34
`1.
`Panels of Different Fecal DNA biomarkers ................... 34
`2.
`Panels Combining DNA Biomarkers and FOBT ........... 35
` Home Collection of Fecal Samples .......................................... 39
`1.
`Collecting and Partitioning Stool Samples .................... 40
`2.
`Different Buffers were Used to Preserve Different
`Biomarkers in Fecal Samples......................................... 49
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`3.
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`2.
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`Partitioning Samples into Multiple Vessels for
`Stabilization during Shipment ........................................ 54
`Legal Standards ........................................................................................... 57
`V.
`VI. The Challenged Patent ................................................................................. 61
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`The ’746 Patent ........................................................................ 61
`
`Summary of the Claimed Subject Matter ................................. 65
`VII. SUMMARY OF SELECTED PRIOR ART REFERENCES ..................... 71
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`Lenhard (EX1004) .................................................................... 71
` Vilkin (EX1005) ....................................................................... 77
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`Itzkowitz (EX1006) .................................................................. 82
` Kanaoka (EX1007) ................................................................... 86
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`Shuber (EX1008) ...................................................................... 89
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`Inbar (EX1009) ......................................................................... 92
`VIII. OVERVIEW OF GROUNDS OF UNPATENTABILITY ......................... 97
`IX. THE CLAIMS OF THE ’746 PATENT ARE ANTICIPATED AND/OR
`OBVIOUS .................................................................................................... 98
`
`Lenhard in view of Itzkowitz and Vilkin renders claims 1-4 and
`14-19 obvious ........................................................................... 98
`1.
`A POSA would be motivated to use the iFOBT of Vilkin in
`place of the gFOBT of Lenhard ................................... 100
`A POSA would have been motivated to use the sample
`collection methodology of Itzkowitz in Lenhard’s process
` ...................................................................................... 104
`A POSA would have been motivated to use the DNA
`stabilizing buffer of Itzkowitz in Lenhard’s process ... 106
`Claim 1 ......................................................................... 110
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`3.
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`4.
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`5.
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`6.
`7.
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`8.
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`Claim 2: “The method of claim 1, further comprising
`delivering the sealable vessel containing the first portion of
`the fecal sample and the stabilizing buffer and the sealable
`container containing the second portion of the fecal sample
`and the solution to a medical diagnostics laboratory” . 122
`Claim 3 ......................................................................... 123
`Claim 4: “The method of claim 3, wherein testing the
`nucleic acid comprises determining expression from a
`human gene.” ............................................................... 129
`Claim 14: “The method of claim 3, wherein testing for an
`amount of a blood protein present in the second portion
`comprises testing for a concentration of hemoglobin in the
`second portion, wherein a concentration of hemoglobin is
`indicative of a presence of blood in the fecal sample.” 131
`Claim 15: “The method of claim 14, wherein the testing for
`the concentration of hemoglobin comprises
`immunochemical detection of hemoglobin.” ............... 132
`10. Claims 16-19: “The method of claim 14, wherein the
`second portion of the fecal sample is considered positive
`for the presence of blood when the concentration of
`hemoglobin detected in the second portion is at least [5, 10,
`20, or 50] ng/ml.” ......................................................... 132
`Lenhard in view of Itzkowitz and Vilkin, in further view of
`Kanaoka renders obvious claims 12 and 13 ........................... 135
`1.
`Claim 12: “The method of claim 4, wherein determining
`expression from the human gene comprises measuring an
`amount of RNA expressed from the human gene.” ..... 135
`Claim 13: “The method of claim 12, wherein measuring an
`amount of RNA expressed from the human gene comprises
`reverse transcriptase polymerase chain reaction (RT-PCR)”
` ...................................................................................... 138
`Shuber and Vilkin render obvious claims 1-4, and 14-19...... 139
`1.
`Claim 1 ......................................................................... 144
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`2.
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`DECLARATION OF DUNCAN WHITNEY
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`2.
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`3.
`4.
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`5.
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`Claim 2: “The method of claim 1, further comprising
`delivering the sealable vessel containing the first portion of
`the fecal sample and the stabilizing buffer and the sealable
`container containing the second portion of the fecal sample
`and the solution to a medical diagnostics laboratory” . 151
`Claim 3 ......................................................................... 152
`Claim 4: “The method of claim 3, wherein testing the
`nucleic acid comprises determining expression from a
`human gene.” ............................................................... 155
`Claim 14: “The method of claim 3, wherein testing for an
`amount of a blood protein present in the second portion
`comprises testing for a concentration of hemoglobin in the
`second portion, wherein a concentration of hemoglobin is
`indicative of a presence of blood in the fecal sample.” 156
`Claim 15: “The method of claim 14, wherein the testing for
`the concentration of hemoglobin comprises
`immunochemical detection of hemoglobin.” ............... 157
`Claims 16-19: “The method of claim 14, wherein the
`second portion of the fecal sample is considered positive
`for the presence of blood when the concentration of
`hemoglobin detected in the second portion is at least [5, 10,
`20, or 50] ng/ml.” ......................................................... 157
`Shuber and Vilkin, in view of Kanaoka render obvious claims 12
`and 13 ..................................................................................... 160
`1.
`Claim 12 “The method of claim 4, wherein determining
`expression from the human gene comprises measuring an
`amount of RNA expressed from the human gene.” ..... 160
`Claim 13: “The method of claim 12, wherein measuring an
`amount of RNA expressed from the human gene comprises
`reverse transcriptase polymerase chain reaction (RT-PCR)
` ...................................................................................... 163
`Inbar anticipates claims 1 and 2 ............................................. 163
`1.
`Claim 1 ......................................................................... 171
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`6.
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`7.
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`2.
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`DECLARATION OF DUNCAN WHITNEY
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`2.
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`3.
`4.
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`5.
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`Claim 2: “The method of claim 1, further comprising
`delivering the sealable vessel containing the first portion of
`the fecal sample and the stabilizing buffer and the sealable
`container containing the second portion of the fecal sample
`and the solution ad the to a medical diagnostics laboratory”
` ...................................................................................... 181
`Inbar, Shuber, and Vilkin render obvious claims 1-4 and 14-19
` ................................................................................................ 181
`1.
`Claim 1 ......................................................................... 184
`2.
`Claim 2: “The method of claim 1, further comprising
`delivering the sealable vessel containing the first portion of
`the fecal sample and the stabilizing buffer and the sealable
`container containing the second portion of the fecal sample
`and the solution ad the to a medical diagnostics laboratory”
` ...................................................................................... 187
`Claim 3 ......................................................................... 188
`Claim 4: “The method of claim 3, wherein testing the
`nucleic acid comprises determining expression from a
`human gene.” ............................................................... 191
`Claim 14: “The method of claim 3, wherein testing for an
`amount of blood protein present in the second portion
`comprises testing for a concentration of hemoglobin in the
`second portion, wherein a concentration of hemoglobin is
`indicative of a presence ofblood in the fecal sample.” 191
`Claim 15: “The method of claim 14, wherein the testing for
`the concentration of hemoglobin comprises
`immunochemical detection of hemoglobin.” ............... 192
`Claims 16-19: “The method of claim 14, wherein the
`second portion of the fecal sample is considered positive
`for the presence of blood when the concentration of
`hemoglobin detected in the second portion is at least [5, 10,
`20, or 50] ng/ml.” ......................................................... 192
`Inbar, Shuber, and Vilkin, in further view of Kanaoka, render
`obvious claims 1 and 2 ........................................................... 193
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`6.
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`7.
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`DECLARATION OF DUNCAN WHITNEY
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`2.
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`1.
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`Claims 12 “The method of claim 4, wherein determining
`expression from the human gene comprises measuring an
`amount of RNA expressed from the human gene.” ..... 193
`Claim 13: “The method of claim 12, wherein measuring an
`amount of RNA expressed from the gene comprises
`reverse transcriptase polymerase chain reaction (RT-PCR)”
` ...................................................................................... 194
`SECONDARY CONSIDERATIONS OF NON-OBVIOUSNESS .......... 194
`X.
`XI. CONCLUSION .......................................................................................... 209
`APPENDIX A: LIST OF EXHIBITS ............................................................... 211
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`I.
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`DECLARATION OF DUNCAN WHITNEY
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`Introduction
`1.
`I have been asked by counsel for Geneoscopy, Inc.
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`(“Geneoscopy”) to offer my opinions as to whether claims 1-4 and 12-19 of
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`U.S. Patent No. 11,970,746 (EX1001; the “’746 patent”) would have been
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`anticipated and/or obvious to the person of ordinary skill in the art
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`(“POSA”) as of February 3, 2009, which I understand is the earliest priority
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`date claimed by the ’746 patent.
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`2.
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`I understand that my opinions in this Declaration will be
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`submitted as evidence in an inter partes review (“IPR”) proceeding before
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`the Patent Trial & Appeal Board in the U.S. Patent & Trademark Office
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`concerning the ’746 patent. I understand Geneoscopy is the Petitioner in this
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`proceeding and that Exact Sciences Corporation (“Exact”) is the Patent
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`Owner.
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`3.
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`I previously prepared a declaration as evidence for an IPR
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`proceeding No. IPR2024-00459, which concerned U.S. Patent No.
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`11,634,781 (“the ’781 patent). I understand the ’781 patent is the parent of
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`the ’746 patent.
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`4.
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`I am being compensated at my usual rate of $400 per hour plus
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`expenses for my work in connection with this IPR proceeding. My
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`compensation in no way depends on the outcome of this proceeding or on
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`DECLARATION OF DUNCAN WHITNEY
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`the opinions I express. The opinions and conclusions I express herein are
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`based on my review of the materials cited herein, as well as on (1) my
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`general knowledge of clinical diagnostic tests, including stool-based
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`diagnostic tests and sample handling processes, and (2) my years of
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`experience acquired working in this field. I reserve the right to supplement
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`or amend my opinions in response to opinions expressed by other experts, or
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`in light of any additional evidence, testimony, or other information that may
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`be provided to me after that date of this declaration.
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`II. Qualifications and Experience
`1. My current Curriculum Vitae is attached as EX1003. I have
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`summarized my educational and professional background below.
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`2.
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`I received a B.A. in Chemistry from Colby College in 1981,
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`and a Ph.D. in Materials Sciences and Engineering from Massachusetts
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`Institute of Technology in 1987. My research advisor was Professor Gary
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`Wnek.
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`3.
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`I have held leadership positions in several companies
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`developing clinical diagnostics tests, with multiple responsibilities including
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`clinical trial design; conception of strategic research plans and specific
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`research approaches to address clinical unmet needs; scoping of analytical
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`and clinical experiments and data-generation plans, including review and
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`DECLARATION OF DUNCAN WHITNEY
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`interpretation of data; recruiting, training and management of research staff;
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`and working with other functional areas to gain regulatory and
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`reimbursement approvals as part of the test commercialization process. I
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`have authored or co-authored multiple peer-reviewed publications associated
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`with this work.
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`4. My current position is Chief Scientific Officer (CSO) of Gregor
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`Diagnostics (Madison, WI), since February of 2022. The company focuses
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`on development of improved clinical diagnostics tests for risk-management
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`of patients with prostate cancer. The company’s research has included
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`recruitment of patients in a multicenter study to collect specimens and
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`clinical data, which have been used to discover novel biomarkers using
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`various DNA and RNA-based sequencing methodologies. Prior to 2022, I
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`held the position of Vice President (VP) of Early Detection, within the Lung
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`Cancer Initiative at Johnson & Johnson (Boston, MA and New Brunswick,
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`NJ) for 3 years, leading research and clinical studies to advance ways to
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`diagnose and manage subjects with lung cancer.
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`5.
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`I held the position of VP of Research & Development (R&D) at
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`Allegro Diagnostics Corp. (Boston, MA) for 5 years. The goal of the
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`company was to develop novel diagnostics for pulmonary diseases,
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`including lung cancer. I led research programs to discover gene-expression
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`biomarkers from subjects at risk of lung cancer. A trial was completed
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`recruiting approximately 2000 subjects with indeterminate bronchoscopy
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`procedures, where normal-appearing bronchial epithelial cells were
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`collected, RNA was isolated, and the RNA was then profiled using
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`microarrays. Regression analysis of top genes, found to be differentially
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`expressed between subjects with and without cancer was validated and
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`published in top-tier, peer-reviewed journals, and was ultimately
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`commercialized as a clinical diagnostic test by Veracyte, Inc.
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`6.
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`I was involved in the sale of the company Allegro to Veracyte,
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`Inc. (South San Francisco, CA), which then hired me as VP of Discovery
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`R&D. In addition to completing studies to demonstrate analytical and
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`clinical validity of the lung cancer diagnostic test, initially developed by
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`Allegro, I also led a team to develop a second-generation thyroid cancer
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`diagnostic test using an RNA-sequencing methodology.
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`7. My initial professional experience developing clinical
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`diagnostics was at Exact Sciences Corporation, where I was employed for 5
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`years (2000-2005). I was initially hired as the Director of Technology
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`Development in the R&D group focusing on developing and optimizing
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`methods for isolation of human DNA from stool samples. I was
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`subsequently promoted to VP of Technology Development.
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`8.
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`I have authored 23 peer-reviewed publications spanning my
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`work conducted as part of my professional experiences. This includes five
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`publications from studies conducted while I was employed at Exact, focused
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`on stabilization of stool samples and recovery of human DNA from them for
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`non-invasive detection of colorectal cancer (“CRC”), and development of
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`CRC detection tests and technologies. I am also a named inventor on
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`numerous patents and patent applications, some of which originate from
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`studies I conducted while employed at Exact that focused on methods to
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`improve recovery of DNA from stool samples for applications in non-
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`invasive detection of CRC.
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`III. The Person of Ordinary Skill in the Art
`9.
`I have been informed that the person of ordinary skill in the art
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`(“POSA”) is a hypothetical person who is presumed to have known all of the
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`relevant art as of the priority date of the ’746 patent and is the person to
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`whom the subject matter of the Challenged Patents is directed.
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`10.
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`I have been asked to opine as to the qualifications of the POSA
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`to which the claims of the ’746 patent are directed. For the purpose of
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`rendering an opinion on this question, I have further been instructed to
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`assume that the priority date of the ’746 patent to be February 3, 2009 (the
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`“Priority Date”).
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`11.
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`I have been informed that factors that may be considered in
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`determining the level of ordinary skill may include: (1) the educational level
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`of the inventor; (2) the type of problems encountered in the art; (3) prior art
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`solutions to those problems; (4) the rapidity with which innovations are
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`made; (5) the sophistication of the technology; and (6) the educational level
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`of active workers in the field. I have further been informed that the POSA
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`may possess the education, skills, and experience of multiple actual people
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`who would work together as a team to solve a problem in the field.
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`12.
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`In my opinion, a POSA relevant to the ’746 Patent would have
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`a Ph.D. in chemistry, biochemistry, biology, or a related field and at least
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`five years of experience designing and performing diagnostic assays on fecal
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`samples. I have applied this understanding in offering my present opinions.
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`13.
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`I am aware that in the Patent Owner’s Preliminary Response
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`filed by Exact in IPR2024-00459, Exact argued that a POSA relevant to the
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`’781 patent (the parent of the ’746 patent) would have a doctoral degree in
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`medicine, chemistry, biochemistry, biology, or a related field and 1-2 years
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`of experience in the processing and analysis of biological samples, including
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`fecal samples, where the POSA could have been an individual or a member
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`of a team of scientists addressing fecal sample processing and analysis.1 My
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`opinions offered here would not change if I applied Exact’s definition of a
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`POSA in place of my own.
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`IV. Technical Background
`14. The disputed technology in this matter relates to the collection
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`of human clinical specimens and recovery of informative biomarkers from
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`fecal specimens for use in the diagnosis of disease, particularly the diagnosis
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`of CRC.
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`15. The claims of the ’746 patent concern a method of processing a
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`fecal sample, wherein the sample is collected at home and divided in two
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`portions: a first portion that is combined with stabilizing buffer, and a
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`second portion that is combined with a solution that prevents denaturation or
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`degradation of blood proteins. The first portion can be analyzed for a nucleic
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`acid, such as methylated DNA. The second portion can be tested for the
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`presence of a blood protein, like hemoglobin.
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`16. Processing fecal samples for detection of nucleic acids and
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`blood proteins was routine in the art well before the Priority Date, February
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`3, 2009. As I explain below in section IV(B), fecal tests for detecting nucleic
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`1 IPR2024-00459 Patent Owner’s Preliminary Response (EX1032) p. 47.
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`acids and blood protein as recited in the ‘746 patent claims were known and
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`routine well before the Priority Date. Moreover, as I explain in sections
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`IV(C) and IV(D), below, separating a fecal sample so that two separate and
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`complementary tests can be performed (e.g., for nucleic acids and for blood
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`proteins) had been reported throughout the prior art. The method claimed by
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`the ’746 patent amounts to no more than the routine use of standard methods
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`to prepare a fecal sample for performance of well-established,
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`complementary diagnostic assays.
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` Diagnostic Analysis of Biological Samples
`17. Diagnostic testing has long been a basic tenet of modern
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`medicine. For many diseases, timely diagnosis can be a prerequisite to
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`effective treatment. In the absence of accurate and convenient diagnostic
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`methods, many otherwise curable diseases can remain life-threatening due to
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`shortfalls in detection. Further, early detection of a disease, such as CRC,
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`can result in its diagnosis at an earlier (and more treatable) stage, resulting in
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`reduced mortality.
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`18. Disease diagnosis is often based on the analysis of analytes
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`originating from the affected cells or tissue to distinguish afflicted
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`individuals from healthy ones. For example, in the diagnosis of colon
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`cancer, procedures such as colonoscopy or sigmoidoscopy allow the
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`sampling of suspicious looking tissue directly from the colon. The tissue is
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`then examined to determine the presence of abnormal-appearing cells
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`associated with malignancy, stage, and cell-type associated with a cancer
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`diagnosis and prognosis. Alternatively, it may be determined that no
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`abnormal cells are present. Also, it may be determined that abnormal cells
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`may be present that are associated with pre-malignant lesions, such as
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`adenomas. The process of directly sampling tissue from human subjects is
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`typically considered to be invasive.
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`19. Various non-invasive diagnostic methods have also been
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`developed. Non-invasive diagnostic testing involves procedures that do not
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`break the skin or physically enter the body.
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`20. Some common non-invasive diagnostic methods use imaging
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`techniques (such as MRI, X-ray, ultrasound, etc.) to observe targeted tissues.
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`These methods can be effective, but also have limited resolution which
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`depends on the imaging technique. For instance, X-rays typically are only
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`able to detect lesions (such as tumors) that are at least a few millimeters in
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`diameter, and therefore may miss small and early-stage cancers.
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`21. Other non-invasive techniques involve collection of bodily
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`fluids or other extruded bodily samples, such a fecal samples, which can be
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`analyzed for the presence of disease indicators (sometimes called
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`“biomarkers”). The goal of such approaches, in general, is to retrieve and
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`detect in the extruded sample either diseased cells, or analytes originating
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`from diseased cells.
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`22. Diagnostics based on bodily samples, such as fecal samples,
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`can be particularly attractive because they are non-invasive and relatively
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`convenient, particularly when compared to invasive alternatives like
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`colonoscopy or sigmoidoscopy. Diagnostic tests that analyze bodily samples
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`therefore contribute to treatment efficiency and can improve patient
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`experience and increase patient compliance by reducing the need for
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`invasive testing.
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`1. Diagnostic Tests Based on Detection of Biomarkers, such
`as Protein and DNA
`23. Many non-invasive diagnostic tests provide medical
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`information by detecting and/or measuring disease-associated biomarkers in
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`patient samples. When applied to cancer diagnosis, non-invasive detection
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`methods may involve analysis of cancer cells using methods either to
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`directly examine such cells, or methods to extract analytes from the cells that
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`are specifically associated with disease. For instance, PAP smear procedures
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`are designed to detect cervical cancer by taking a swab of the cervix to
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`collect cells and directly examine them to detect the presence of abnormal-
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`appearing cells. Methods have also been developed to non-invasively detect
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`or monitor cancer in the body by collecting circulating cancerous cells in the
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`blood stream using, for example, immunoaffinity-capture. These methods
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`are often referred to as a form of liquid biopsy. Direct enumeration of these
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`cells can be indicative of cancer. In other approaches, DNA is extracted
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`from these cells, which can be analyzed for cancer-associated mutations.
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`These tests are often used in detection or monitoring of breast, prostate, and
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`colorectal cancers. Other forms of liquid biopsy tests involve directly
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`isolating and analyzing nucleic acids originating from cancerous cells in the
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`blood stream.
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`24.
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`In other cases, it may be sufficient to directly isolate analytes
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`associated with cancerous cells without first isolating the cells themselves.
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`There are multiple examples of these kinds of approaches, where analytes
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`are collected from a variety of bodily fluids. These range from single
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`analytes, such as the measurement of prostate-specific antigen (PSA) in
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`blood, to more complex analyses, such as DNA-mutation analysis in
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`multiple genes in DNA recovered from stool samples.
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`25. Biomarkers used in non-invasive diagnostics include proteins,
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`nucleic acids (e.g., DNA or RNA), and chemical metabolites. Scientists have
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`been identifying useful biomarkers and developing non-invasive diagnostic
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`tests based on such biomarkers for over a century. For example, in 1841 a
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`scientist named Karl Trommer developed a diagnostic test for diabetes
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`which involved subjecting a patient’s urine sample to acid hydrolysis. Fecal
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`hemoglobin protein levels were associated with bowel cancer by 1901, and a
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`diversity of diagnostic tests measuring hemoglobin protein levels in feces
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`were developed during the first part of the 1900s.2 More sophisticated occult
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`hemoglobin assays were in widespread clinical use for diagnosis of CRC by
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`the 1970s.3
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`26. With the advent of more modern molecular biology techniques
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`in the 1980s, DNA-based biomarkers began to be used with increasing
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`frequency. For example, fecal testing for DNA-containing mutations
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`associated with cancer has been used for the diagnosis of CRC since at least
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`1992.4
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`27. By the early 2000s, fecal diagnostics based on epigenetic
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`markers associated with cancer had been developed. Epigenetics refers to
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`changes to DNA that do not alter its sequence of bases but affect whether
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`genes encoded by the DNA are expressed. One type of epigenetic
`
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`2 Simon (EX1034) p.822.
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`3 Id. p. 823.
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`4 Sidransky (EX1035).
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`modification that has been used in fecal CRC diagnostics is DNA
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`methylation. In DNA methylation, a methyl group is added to certain
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`cytosine bases in DNA. When the DNA in a gene or its promoter is
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`methylated it tends to prevent that gene from being expressed. Methylation
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`of certain genes and their promotors are associated with CRC, and detection
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`of such methylated sequences has been used in CRC diagnostics since at
`
`least 2004.5
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`2. Sensitivity and Specificity as Measures of Diagnostic
`Performance
`28. Sensitivity and specificity are important metrics of diagnostic
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`assay performance.
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`29. Sensitivity refers to the frequency at which a diagnostic test
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`successfully detects disease in subjects (the true positive rate). A false-
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`negative result refers to subjects with disease that are not detected by the
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`diagnostic test. Thus, a test with high sensitivity will produce few false-
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`negative results. Having a high sensitivity is particularly important in fecal
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`CRC tests, where the consequence of false-negative results is that CRC
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`patients do not receive needed cancer treatment, leading to a worse
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`prognosis and potentially death.
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`5 Müller (EX1036); Schuebel (EX1037); Shen (EX1038).
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`30. Specificity refers to the frequency at which the test result is
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`negative in subjects without disease (the true negative rate). A false-positive
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`result refers to subjects without disease that are indicated as having the
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`disease by the diagnostic test. Thus, a test with high specificity will produce
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`few false-positive results (i.e., patients who incorrectly test positive who do
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`not have the disease being tested for). Having a high specificity is desirable
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`in fecal CRC tests, because patients who wrongly test positive are often
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`subjected to an unnecessary medical procedures and potentially unnecessary
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`treatment.
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`3. Diagnostic Tests Commonly Measure Multiple Markers
`31. Effective diagnostic tests must be sensitive and specific for the
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`disease of interest. In the case of cancer diagnostics, the disease itself may
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`be polyclonal within individuals, meaning that there may be different cell
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`populations with aberrant malignant growth, which in turn are driven by
`
`distinct molecular pathways. The presence and/or level of a particular
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`biomarker in a patient’s samples may also vary over time. Across a
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`population of affected individuals, the presence of multiple disease pathways
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`within a certain cancer type will be even more pronounced. The impact of
`
`this non-homogeneity is that measurement of different biomarkers may be
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`required for detection of the same disease in different individuals, or in the
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`same individual tested at different times.
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`32. Testing for multiple biomarkers in the same test will therefore
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`often increase that test’s sensitivity. For example, if a given biomarker can
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`be detected in 40% of diseased subjects, that alone may not be sufficient to
`
`be an effective diagnostic test. However, if a second biomarker is also
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`detectable in 40% of disease subjects, and there is incomplete overlap in the
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`individuals detected using the two analytes, then the overall detection
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`sensitivity of the assay will be higher when both analytes are detected as
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`compared to when either analyte is detected individually. This approach can
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`be extended to include more than two biomarkers.
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`33. For this reason, by the Priority Date, diagnostic tests, including
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`fecal tests, f