Case 1:20-cv-01580-LPS Document 44 Filed 03/05/21 Page 1 of 61 PageID #: 10085
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
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`GUARDANT HEALTH, INC.,
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`Plaintiff,
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`v.
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`FOUNDATION MEDICINE, INC.,
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`Defendant.
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`C. A. No. 20-cv-1580-LPS
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`DECLARATION OF GARY BENSON, PH.D IN SUPPORT
`OF DEFENDANT FOUNDATION MEDICINE, INC.’S OPPOSITION
`TO PLAINTIFF’S MOTION FOR PRELIMINARY INJUNCTION
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`PUBLIC VERSION
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`Confidential Version Filed: February 26, 2021
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`Public Version Filed: March 5, 2021
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`Case 1:20-cv-01580-LPS Document 44 Filed 03/05/21 Page 2 of 61 PageID #: 10086
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`Table of Contents
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`I.
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`II.
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`SCOPE ............................................................................................................................1
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`QUALIFICATIONS, COMPENSATION, AND BACKGROUND..................................1
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`III. MATERIALS CONSIDERED .........................................................................................5
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`IV.
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`LEGAL PRINCIPLES .....................................................................................................6
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`V.
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`CLAIM CONSTRUCTION .............................................................................................8
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`VI.
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`NON-INFRINGEMENT OF THE ASSERTED CLAIMS ...............................................9
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`VII. THE ASSERTED CLAIMS ARE ALSO INVALID UNDER SECTION 112 ................ 29
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`VIII. SIGNATURE ................................................................................................................ 34
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`Case 1:20-cv-01580-LPS Document 44 Filed 03/05/21 Page 3 of 61 PageID #: 10087
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`I, Gary Benson, Ph.D., hereby declare as follows:
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`I.
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`SCOPE
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`1.
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`I have been retained as an expert in this case by counsel for Defendant Foundation
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`Medicine, Inc. (“Foundation Medicine”). I have previously served as an expert for Foundation
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`Medicine in Guardant Health Inc. v. Foundation Medicine, Inc., No. 17-cv-1616-LPS-CJB (“the
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`1616 Action”), where I offered certain expert opinions regarding Foundation Medicine’s source
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`code and non-infringement.
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`2.
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`I offer this declaration in support of Foundation Medicine’s opposition to Plaintiff
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`Guardant Health, Inc.’s (“Guardant’s”) Motion for Preliminary Injunction. I expect to testify
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`regarding the matters set forth in this declaration if asked about these matters by the Court or by
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`the parties’ attorneys.
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`3.
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`I understand that on December 10, 2020, Guardant submitted the Declaration of
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`Gregory Cooper, Ph.D. (D.I. 10, the “Cooper Declaration” or “Cooper Dec.”), in which Dr.
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`Cooper asserts that the accused Foundation Medicine product – FoundationOne® Liquid CDx
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`(the “Accused Product”) – infringes Claim 1 of U.S. Patent No. 10,704,085 (the “’085 patent”)
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`and Claim 1 of U.S. Patent No. 10,704,086 (the “’086 patent”). Because Dr. Cooper only
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`analyzed Claim 1 of each of these patents (the “Asserted Claims”), I similarly only provide
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`opinions regarding these claims.
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`4.
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`For at least the reasons stated herein, I disagree with Dr. Cooper’s infringement
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`opinions. It is also my opinion that at least the “grouping” limitations of the Asserted Claims, as
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`described below, are indefinite and lack adequate written description support.
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`II.
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`QUALIFICATIONS, COMPENSATION, AND BACKGROUND
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`5.
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`I am currently an Associate Professor in the Program in Bioinformatics, the
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`Department of Computer Science, and the Department of Biology at Boston University. I am a
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`Case 1:20-cv-01580-LPS Document 44 Filed 03/05/21 Page 4 of 61 PageID #: 10088
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`core faculty member in the Program in Bioinformatics and serve in the leadership of that program.
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`I have been on the faculty at Boston University since 2003. My research involves the
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`development of efficient algorithms and software for the analysis of DNA sequencing data and
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`the use of that data to identify genetic variation in DNA repetitive sequences.
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`6.
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`After beginning my undergraduate studies at the Massachusetts Institute of
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`Technology, I received a Bachelor of Science degree in Psychology from the University of
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`Maryland, College Park in 1976. In 1979, I received a Science and Mathematics Teacher
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`Certification from the University of Illinois at Chicago. I received a Master of Science degree in
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`Computer Science from the University of Maryland, College Park in 1989, and a Ph.D. in
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`Computer Science from the University of Maryland, College Park in 1992. During my graduate
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`studies at the University of Maryland, my thesis advisor was Prof. Amihood Amir, with whom I
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`worked on pattern matching algorithms. Between 1992 and 1994, I was a postdoctoral fellow in
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`Mathematical and Computational Biology in the Department of Mathematics at the University of
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`Southern California working, under the mentorship of Prof. Michael S. Waterman, on biological
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`sequence analysis algorithms.
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`7.
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`Before my current position, I was an Associate Professor and Assistant Professor
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`in the Department of Biomathematical Sciences and the Department of Human Genetics at the
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`Mount Sinai School of Medicine (now the Icahn School of Medicine at Mount Sinai) in
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`Manhattan, New York from 1994 to 2003. I was also an Instructor in the Department of Computer
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`Science and the Department of Mathematics at the University of Southern California in 1993. I
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`have been a Research Assistant, Summer Instructor, and Teaching Assistant in the Department of
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`Computer Science at the University of Maryland, College Park. I was also a Research Assistant
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`in a Neuroscience Laboratory at Northwestern University, and taught mathematics and computer
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`science at the high school level.
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`Case 1:20-cv-01580-LPS Document 44 Filed 03/05/21 Page 5 of 61 PageID #: 10089
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`8.
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`During my time at the Mount Sinai School of Medicine, I developed a widely-used
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`bioinformatics resource, the Tandem Repeats Finder (“TRF”) program, published in January
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`1999. This DNA analysis algorithm finds tandem repeats, or two or more contiguous,
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`approximate copies of a pattern of nucleotides, in genomic sequence data without the need to
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`specify either the pattern or pattern size. The TRF program has been cited in the scientific
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`literature 5,615 times (based on Google Scholar). While at Boston University and Mount Sinai,
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`I also developed nine other online software programs, eight of them related to bioinformatics.
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`9.
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`I have been training students in computational biology and bioinformatics at the
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`graduate level for over 25 years. From 2007 to 2014, I was the Director of a National Science
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`Foundation-funded Ph.D. training grant in Bioinformatics at Boston University. In Spring and
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`Summer 2019, I was acting Director of a National Institutes of Health-funded Ph.D. training grant
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`in Bioinformatics at Boston University. In Spring 2019, I was acting Director of the Program in
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`Bioinformatics at Boston University.
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`10. Since 1996, I have been funded by 18 federal grants from the National Science
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`Foundation and the National Institutes of Health to carry on my investigations of bioinformat ics,
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`sequencing data analysis, and computer science, and for student training in bioinformatics. Of
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`these 18 grants, I was the Principle Investigator on six research grants; the Co-Principle
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`Investigator or Co-Investigator on six research grants; the Principle Investigator on three
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`bioinformatics training grants, one for Ph.D. students and two for undergraduate students; and the
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`Co-Investigator on three grants for high school mathematics and biology curriculum development
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`and teacher training.
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`11.
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`I was the recipient of a Boston University Hariri Institute Research Incubation
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`Award in 2018, specifically for the Digital Health Initiative, for which I was the Principle
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`Investigator. The Hariri Institute supports research projects in various fields that apply
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`Case 1:20-cv-01580-LPS Document 44 Filed 03/05/21 Page 6 of 61 PageID #: 10090
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`computational and data-driven approaches. The Digital Health Initiative, in collaboration with
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`Boston University’s Institute for Health System Innovation & Policy, supports research
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`employing computing and data science technologies and methodologies to address modern
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`healthcare challenges.
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`12.
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`I have served on grant review panels for the National Institutes of Health, the
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`National Science Foundation, the Institut Pasteur in Paris, and the Boston University School of
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`Medicine. I have served on the National Science Foundation Advisory Committee on
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`DNA/Biomolecular Computing. I currently serve on the National Institutes of Health Training
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`and Workforce Development Subcommittee - B standing review committee.
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`13.
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`I have authored 68 publications in the areas of biological sequence analysis,
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`sequence comparison, pattern matching, and genetics.
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`14.
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`I served as the Executive Editor of the Annual Web Server Issue (“the Issue”) of
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`the peer-reviewed journal, Nucleic Acids Research, from 2007 through 2019. The Issue publishes
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`papers describing internet-based resources for analysis and visualization of biological data and
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`publishes an average of 95 papers per year. I have also edited three collections of research papers
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`relating to bioinformatics and computer science.
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`15. From 1992 to the present, I have presented over 60 lectures at a variety of academic
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`conferences, symposia, and universities. For example, in May 2016, I presented at the
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`International Conference on Genomics and Bioinformatics on “Tandem Repeat Variants in the
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`Human Genome” at the Izmir International Biomedicine and Genome Institute in Izmir, Turkey.
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`In April 2011, I gave a presentation entitled “Detecting Tandem Repeat Variants in Next-
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`Generation Sequencing Data” at the Stringology 2011 Conference at Haifa University. In October
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`2009, I gave a presentation about bioinformatics training methods at the National Institute of
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`Biomedical Imaging and Bioengineering and the Howard Hughes Medical Institute 2009
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`Case 1:20-cv-01580-LPS Document 44 Filed 03/05/21 Page 7 of 61 PageID #: 10091
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`Interdisciplinary Training Workshop. Also in October 2009, I was invited to speak on “Seeded
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`Search Techniques for DNA Homology Detection and Mapping of Next-Generation Sequencing
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`Reads” at Ben Gurion University’s Department of Computer Science. In September 2007, I
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`presented on “Copy number variation in the human genome based on analysis of whole genome
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`SNP arrays” at the Coriell Institute for Medical Research.
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`16.
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`I have expertise and am proficient in seven data science programming languages,
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`including C, Objective-C, C++, Perl, Python, SQL, and R. I have many years of experience with
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`C, including developing the major bioinformatics resource, Tandem Repeats Finder, in C. I taught
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`a summer course on using Objective-C for iPhone programming, and am familiar with C++ and
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`its use as an object-oriented alternative to C. I have used Perl extensively for internal database
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`interface development as well as in a graduate course that I taught at Boston University, entitled
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`Design of Biological Databases. I have also used Python for that course, in addition to using it
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`for data analytics. I have used SQL extensively, both for internal database development and as
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`part of my course on databases. I have used R for data visualization.
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`17. My background and experience is further detailed in my CV, which is attached as
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`Appendix A.
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`18.
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`I am compensated for my work on this case at the rate of
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` per hour. My
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`compensation does not depend in any way on the outcome of this litigation.
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`III. MATERIALS CONSIDERED
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`19.
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`In forming the opinions herein expressed, I have studied, reviewed, and/or relied
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`on:
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`a.
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`b.
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`The ’085 and ’086 patents;
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` of the source code pertaining to the Accused Product1;
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`1 The specific lines of source code cited herein are attached as Appendix B.
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`Case 1:20-cv-01580-LPS Document 44 Filed 03/05/21 Page 8 of 61 PageID #: 10092
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`c.
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`d.
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`e.
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`f.
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`g.
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`The additional references and documents cited herein;
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`The Cooper deposition transcript (1/28/2021) and certain exhibits;
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`Certain portions of the Cooper deposition transcript in the 1616 Action
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`(10/16/2019);
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`The Cooper Declaration and certain supporting documentation; and
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`My expertise in the field.
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`IV.
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`LEGAL PRINCIPLES
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`20.
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`I am not an attorney. I have not done any independent research on the law of patent
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`infringement or related principles. However, counsel for Foundation Medicine has informed me
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`about various legal standards that apply to the issues in my report. I have applied those standards
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`in arriving at my opinions.
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`21.
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`I have been informed by counsel that Guardant has the burden of proving
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`infringement by a preponderance of the evidence.
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`22.
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`I have also been informed by counsel that, to infringe a patent claim, every
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`limitation of the claim must be present in the accused product/system/method, either literally or,
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`if asserted by the patentee, under the ‘doctrine of equivalents.’ There is no infringement of a patent
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`claim if even only one limitation of that patent claim is not met.
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`23.
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`I have been informed by counsel that a process claim is properly limited to a certain
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`order of steps when the claim language, as a matter of logic or grammar, requires that the steps be
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`performed in the order written, or the specification directly or implicitly requires an order of steps.
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`24.
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`I have been informed by counsel that infringement is decided based on a claim-by-
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`claim analysis. I am also informed by counsel that, if an independent claim is not infringed, its
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`dependent claims are also not infringed.
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`Case 1:20-cv-01580-LPS Document 44 Filed 03/05/21 Page 9 of 61 PageID #: 10093
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`25.
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`I have been informed by counsel that when literal infringement does not exist
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`because an accused method does not meet a claim limitation exactly, infringement, in certain
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`limited circumstances, may nevertheless be found under a judicially-created doctrine called the
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`‘doctrine of equivalents.’
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`26.
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`I have been informed by counsel that, under Federal Circuit precedent, an accused
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`product that does not literally infringe a patent claim may still infringe under the doctrine of
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`equivalents only if the differences between an individual limitation of the claimed invention and
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`an element of the accused product are insubstantial. Substantiality is assessed from the perspective
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`of a person of ordinary skill in the art (a “POSA”).
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`27.
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`I have been informed by counsel that one way to determine whether a feature of the
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`accused product or process is only insubstantially different from a patent’s claim limitation is to
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`determine whether the feature performs the same function as the claim limitation, in the same
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`way as the claim limitation, to achieve the same result as the claim limitation. Also, that the
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`accused product achieves the same “result” does not create a presumption that it does so in the
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`same “way.”
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`28.
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`I have been informed by counsel that a patentee is barred from asserting
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`infringement under the doctrine of equivalents where the patentee defines the claim, or the claim
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`is construed, in a way that clearly excludes certain subject matter, thereby implicitly disclaiming
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`the subject matter that was excluded. The doctrine of equivalents cannot broaden a claim to cover
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`a feature that is the opposite of, or inconsistent with, the recited limitation.
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`29.
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`I have been informed that a patent claim is invalid if the patent claim is indefinite.
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`I have also been informed that a patent claim is indefinite if, when viewed in light of the
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`specification and the prosecution history, the claim fails to inform a POSA with reasonable
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`certainty about the scope of the invention. I further understand that a claim term may be indefinite
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`Case 1:20-cv-01580-LPS Document 44 Filed 03/05/21 Page 10 of 61 PageID #: 10094
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`if it is neither a term of art nor defined by the patentee, and there exist multiple methods to
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`determine its scope, which may result in substantially different results such that a POSA would
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`not understand the scope of the invention.
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`30.
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`I have been informed and understand that a patent claim is invalid if the patent fails
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`to provide adequate written description for the claim. I understand that to satisfy the written
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`description requirement, the disclosure of the specification must convey with reasonable clarity
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`to those skilled in the art that, as of the priority date, the inventor was in possession of the
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`invention. I understand that the invention is, for purposes of the written description inquiry,
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`whatever is claimed. I further understand that the description must do more than merely disclose
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`that which would render the claimed invention obvious.
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`V.
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`CLAIM CONSTRUCTION
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`31.
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`I have been informed that claims are to be construed to have their plain and ordinary
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`meaning. I have also been informed by counsel that the meanings of the claim terms are viewed
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`from the perspective of a POSA at the time of the invention. I have been informed by counsel that,
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`when interpreting patent claims, subsequent use of the definite articles “the” or “said” in a claim
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`is interpreted to refer back to the same term recited earlier in the claim.
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`32.
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`I have also been informed that the Court has not yet issued any claim construction
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`decisions in this proceeding, but that the Court has previously issued claim constructions for
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`certain terms of related patents in the 1616 Action. For example, I understand the Court construed
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`the term “sequence reads,” which appeared in the claims of the related ’992 patent in the 1616
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`Action, as “the order of the bases of a polynucleotide determined by a sequencer.” 2
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`33. Where relevant, and for the sole purposes of this declaration and the preliminary
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`injunction proceeding, I applied the Court’s prior construction, and have also construed certain
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`2 1616 Action, D.I. 207; id., D.I. 262.
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`claim language consistent with what I understand to be the plain and ordinary meaning of the
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`patent terms, the specification of the Asserted Patents, and the prosecution history of the Asserted
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`Patents. I understand neither Guardant nor Dr. Cooper has offered any specific constructions for
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`the terms of the Asserted Claims. I expressly reserve the right to supplement or revise my opinions
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`following the issuance of any claim construction decision(s) by the Court, or in response to any
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`disputed constructions offered by Guardant or Dr. Cooper.
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`VI. NON-INFRINGEMENT OF THE ASSERTED CLAIMS
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`34.
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`It is my opinion that the Accused Product – FoundationOne® Liquid CDx – does
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`not perform all of the steps required by Claim 1 of the ’085 or ’086 patent (the “Asserted Claims”).
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`My opinions are based, in particular, on my analysis of Foundation Medicine’s source code,
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`which controls the bioanalytical operation of its products. I understand that Dr. Cooper,
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`Guardant’s expert, has previously testified that this source code is the controlling evidence with
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`respect to the bioinformatics steps of Foundation Medicine’s accused tests.
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`Q. What is -- in a bioinformatics process, what does source code do?
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`A. I mean, I think source code in any process is the instructions to
`the computer to do whatever it is you want the computer to do.
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`Q. Is it fair to say that the source code controls how the bioanalytical
`steps are carried out on that computer?
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`A. Source code controls the bioanalytical steps -- I mean, ultimately
`that’s a person choosing to use different implementations of source
`code. But, yes, source code is ultimately the instructions that are
`given to the computer.
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`Ex. 116 (Deposition Transcript of Gregory Cooper, Ph.D., 10/16/2019), at 798:25-799:14.
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`35.
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`In forming my opinions, I specifically reviewed
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` of FMI’s source code,
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`which I understand controls the bioinformatics steps of Foundation Medicine’s liquid biopsy
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`assays. I understand that Foundation Medicine produced this version of the code in the preceding
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`Case 1:20-cv-01580-LPS Document 44 Filed 03/05/21 Page 12 of 61 PageID #: 10096
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`case between these parties involving related patents. See Guardant Health, Inc. v. Foundation
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`Medicine, Inc., No. 17-cv-1616 (D. Del. Nov. 9, 2017). I understand that Dr. Cooper agrees that
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`the newly accused product, FoundationOne® Liquid CDx, “is based on FoundationOne[®]
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`Liquid and FoundationACT, and the workflow of all three assays is substantially similar[.]”
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`Cooper Dec. ¶69. Thus, my opinions are based on my understanding that the source code for
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`FoundationOne® Liquid/FoundationACT® is substantially similar to the source code for
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`FoundationOne® Liquid CDx. I am not aware at this time of any material differences that are
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`relevant to my analysis as set forth herein, but expressly reserve my rights to supplement or
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`change my opinions as stated in this declaration and to rely on any additional documents and/or
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`testimony that may be produced after the date of this declaration.
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`36.
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`I understand that Foundation Medicine also asserts that Claim 1 of each patent is
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`invalid and unenforceable. While it is my opinion that Claim 1 of each patent is invalid because
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`the “grouping” limitations are indefinite and lack adequate written description support (see infra
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`Section VII), I have not analyzed, nor have I expressed an opinion about, whether Claim 1 of
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`either the ’085 or ’086 patent is valid or enforceable for any other reason.
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`1.
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`’085 Patent
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`37.
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`I understand that Dr. Cooper asserts that the Accused Product infringes Claim 1 of
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`the ’085 patent. See Cooper Dec. ¶17 and Section X.
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`38. Claim 1 of the ’085 patent reads:
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`1. A method for generating a genetic profile of a tumor from a blood sample of
`double-stranded cell-free deoxyribonucleic acids (cfDNA) from a subject having
`cancer or suspected of having a cancer, the method comprising:
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`(a) obtaining a population comprising the double-stranded cfDNA
`molecules from the blood sample from the subject;
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`(b) ligating a set of molecular barcodes to both ends of a plurality of the
`double-stranded cfDNA molecules using more than a 30x molar excess of
`molecular barcodes relative to the double-stranded cfDNA molecules to
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`Case 1:20-cv-01580-LPS Document 44 Filed 03/05/21 Page 13 of 61 PageID #: 10097
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`produce tagged parent polynucleotides, wherein a given molecular barcode
`is a member of a set of molecular barcodes comprising 2 to 1,000,000
`different molecular barcode sequences, wherein at least 20% of the double-
`stranded cfDNA molecules from the population of cfDNA molecules are
`attached to molecular barcodes;
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`(c) amplifying a plurality of the tagged parent polynucleotides to produce
`progeny polynucleotides with associated molecular barcodes;
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`(d) selectively enriching a subset of the progeny polynucleotides for target
`regions associated with cancer, whereby enriched progeny polynucleotides
`are generated;
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`(e) sequencing a portion of the enriched progeny polynucleotides to produce
`sequencing reads of the progeny polynucleotides with associated molecular
`barcodes;
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`(f) aligning a plurality of the sequencing reads to a reference sequence;
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`(g) grouping a plurality of the sequencing reads into a plurality of families
`based at least on sequence information of the molecular barcodes, a start
`base position of a given sequencing read from among the sequencing reads
`at which the given sequencing read is determined to start aligning to the
`reference sequence, and a stop base position of the given sequencing read
`at which the given sequencing read is determined to stop aligning to the
`reference sequence, wherein a family of the plurality of families is
`representative of a cell-free nucleic acid molecule in the sample;
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`(h) detecting, from among the families, the presence or absence of somatic
`genetic variants; and
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`(i) quantifying a plurality of somatic genetic variants detected as present to
`generate the genetic profile of the tumor.
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`2.
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`’086 Patent
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`39.
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`I understand that Dr. Cooper asserts that the Accused Product infringes Claim 1 of
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`the ’086 patent. See Cooper Dec. ¶17 and Section IX.
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`40. Claim 1 of the ’086 patent reads:
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`1. A method for detecting a presence or absence of one or more somatic genetic
`variants in cell-free deoxyribonucleic acid (cfDNA) molecules from a bodily fluid
`sample of a subject, comprising:
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`(a) non-uniquely tagging a plurality of cfDNA molecules from a population
`of cfDNA molecules obtained from the bodily fluid sample with molecular
`barcodes from a set of molecular barcodes to produce non-uniquely tagged
`parent polynucleotides, wherein the non-uniquely tagging comprises
`ligating molecular barcodes from the set of molecular barcodes to both ends
`of a cfDNA molecule from the plurality of cfDNA molecules using more
`than a 10× molar excess of molecular barcodes relative to the population of
`cfDNA molecules, wherein the cfDNA molecules that map to a mappable
`base position of a reference sequence are tagged with a number of different
`molecular barcodes ranging from at least 2 and fewer than a number of
`cfDNA molecules that map to the mappable base position, and wherein at
`least 20% of the cfDNA molecules from the population of cfDNA
`molecules are attached to molecular barcodes;
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`(b) amplifying a plurality of the non-uniquely tagged parent polynucleotides
`to produce progeny polynucleotides with associated molecular barcodes;
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`(c) sequencing a plurality of the progeny polynucleotides to produce
`sequencing reads of the progeny polynucleotides with associated molecular
`barcodes;
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`(d) mapping a plurality of the sequencing reads to the reference sequence to
`generate mapped sequencing reads;
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`(e) grouping a plurality of the mapped sequencing reads into a plurality of
`families based on sequence information from the molecular barcodes and at
`least (1) a start base position of a given mapped sequencing read from
`among the mapped sequencing reads at which the given mapped sequencing
`read is determined to start mapping to the reference sequence and/or (2) a
`stop base position of the given mapped sequencing read at which the given
`mapped sequencing read is determined to stop mapping to the reference
`sequence; and
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`(f) detecting, from among the mapped sequencing reads in a plurality of the
`families, the presence or absence of the one or more somatic genetic
`variants.
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`3.
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`’085 patent, Claim 1(g)/’086 patent, Claim 1(e)
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`(g) grouping a plurality of the sequencing reads into a plurality of families
`based at least on sequence information of the molecular barcodes, a start
`base position of a given sequencing read from among the sequencing
`reads at which the given sequencing read is determined to start aligning
`to the reference sequence, and a stop base position of the given
`sequencing read at which the given sequencing read is determined to stop
`aligning to the reference sequence, wherein a family of the plurality of
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`families is representative of a cell-free nucleic acid molecule in the sample;
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`(e) grouping a plurality of the mapped sequencing reads into a plurality of
`families based on sequence information from the molecular barcodes and
`at least (1) a start base position of a given mapped sequencing read from
`among the mapped sequencing reads at which the given mapped
`sequencing read is determined to start mapping to the reference sequence
`and/or (2) a stop base position of the given mapped sequencing read at
`which the given mapped sequencing read is determined to stop mapping
`to the reference sequence;
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`41. For the reasons stated below, I disagree with Dr. Cooper that the Accused Product
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`performs Claim 1(g) of the ’085 patent, or Claim 1(e) of the ’086 patent, which I refer to as the
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`“grouping” steps or “grouping” limitations. See Cooper Dec. ¶¶124-129 (Dr. Cooper’s opinion
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`with respect to Claim 1(e) of the ’086 patent).
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`42. First, I note that the grouping steps are specific in that they require the use of a
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`“start” and[/or] “stop” “position” of a single “given sequencing read” (or a “given mapped
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`sequencing read”) “at which” the sequencing read is actually determined, by an aligner, to start
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`or stop aligning to a reference sequence. ’085 patent, 64:17-27; ’086 patent, 64:19-28. While the
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`patents do not seem to provide any guidance as to what is meant by grouping based on “start” or
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`“stop” “positions” at which the given sequencing read is determined to start mapping/aligning to
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`the reference sequence (see infra Section VII), Dr. Cooper and I both agree that the plain language
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`of both claims requires (1) that the “start” and “stop” positions must be from the same read (not
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`two different reads), and (2) that the “position…at which the given [/mapped] sequencing read is
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`determined to start [/stop] mapping [/aligning] to the reference sequence” is a position where a
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`given aligner is able to actually map/align (i.e., match) a base of a given sequence read to a
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`corresponding base in the reference sequence. Ex. 134 (Deposition Transcript of Gregory Cooper,
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`Ph.D., 1/28/2021 (“Cooper Dep.”)), at 344:8-19; id. at 229:6-11 (“they generate an alignment to
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`the reference genome, and that allows them to further subset to build a finer-grain resolution that
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`says here are reads that have the same barcode and have the same start and stop as deriving from
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`the same fragment.”); id. at 232:12-233:1 (“what is used to make the grouping is . . . It’s a
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`combination of the barcodes that are applied to each fragment and then their start-and-stop . . .
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`it’s the intersection of the read location and the barcode associated with those reads”) (emphases
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`added); id. at 233:13-18 (“So the claim element requires a combination of barcode and mapping
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`information[.]”) (emphasis added); id. at 275:12-276:8 (“So basically it’s just saying where within
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`the read do you start mapping and where within the reference does that mapping start”); id. at
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`276:10-22 (“I mean, rephrasing some there, but it’s basically the end of where the alignment is.
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`So the end coordinate within the read and within the reference.”).
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`43. For example, both Dr. Cooper and I agree that not every base of a sequence read
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`will align to a reference sequence, and thus the recited “start” and “stop” positions of the Asserted
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`Claims must be positions where the aligner determines a base does (not should) align. See id. at
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`238:6-11 (“Q: Do sequence reads always align or map perfectly to a reference sequence? . . . A:
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`No. There are a variety of reasons why a read might have mismatches, indels, et cetera, in
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`comparison to a reference.”); id. at 266:1-267:5 (referring to an example where a read will not
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`map perfectly to a reference sequence and noting that “the read representing that fragment would
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`align more poorly because it has these bases on the end that actually aren’t present in the sample”);
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`id. at 283:16-284:8 (“[I]f my aligner determined that the read stops mapping at Position 99
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`because there is this indel in Position 100, then that is the stop base position that I would be using
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`for this claim; is that correct? A: Right. Exactly.”); see also id. at 271:10-272:3, 274:3-284:17,
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`294:16-298:5.
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`44.
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`45. As explained below, Foundation Medicine’s source code demonstrates
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`46.
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`47.
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`“Soft-clipping” generally refers to a process in which the aligning tool “masks” or
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`“ignores” portions of the sequencing read that do not align to a reference during