UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`HEI-MUN CHRISTINA FAN and STEPHEN QUAKE
`Junior Party
`(Patent 8, 195,415),
`
`v.
`
`YUK-MING DENNIS LO, ROSSA WAI KWUN CHIU, and KWAN CHEE CHAN
`Senior Party
`(Application 13/070,266).
`
`Patent Interference No. 105,922 (OK)
`(Technology Center 1600)
`
`DECLARATION OF STACEY BOLK GABRIEL, PH.D.
`
`STANFORD EXHIBIT 2115
`SEQUENOM v. STANFORD
`CASE IPR2013-00390
`
`

`

`TABLE OF CONTENTS
`
`I.
`
`II.
`
`III.
`
`IV.
`
`Introduction ........................................................................................................... 2
`
`Personal Background ........................................................................................... 3
`
`Summary of Opinions ......................................................................................... 11
`
`The Claimed Feature Is Described in the Lo ’266 Application ............................ 15
`
`A.
`
`B.
`
`“Windows” Are Predefined Subsections of a Chromosome ..................... 15
`
`The ’266 Application Describes Windows by Describing
`“Chromosomal Regions” and “a Specified Size Window” ........................ 18
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`“Chromosomal Regions” Are Predefined Subsections of a
`Chromosome ................................................................................ 19
`
`“Chromosomal Regions” Need Not Be of Same Length to
`Constitute Windows ...................................................................... 22
`
`The Lo ’266 Application Describes Normalization of
`Sequence Data ............................................................................. 24
`
`A “Chromosomal Region” Constitutes a Window, Not a
`Polynucleotide Sequence Whose Potential Imbalance Is
`Being Tested ................................................................................. 26
`
`The ’266 Application Discloses Using “a Specified Size
`Window” for Post-Sequencing Analysis ........................................ 27
`
`V.
`
`VI.
`
`The Claimed Feature Is Enabled by the Lo ’266 Application .............................. 28
`
`The Lo ’350 Application and ’181 Application Describe and Enable the
`Claimed Feature ................................................................................................. 31
`
`VII. Claim 14 of the ’415 Patent Would Have Been Obvious to a Person of
`Ordinary Skill in the Art Over the Count and the Knowledge in the Art as of
`September 20, 2008 ........................................................................................... 33
`
`A.
`
`B.
`
`C.
`
`Claim 14 ................................................................................................... 34
`
`Claim 14 Would Have Been Obvious Over the Subject Matter of the
`Count and the GC-Content Correction Taught by Shimkets .................... 35
`
`Claim 14 Would Have Been Obvious Over the Subject Matter of the
`Count and the GC-Content Correction Taught by Dohm ......................... 41
`
`

`

`
`
`I.
`
`I, Stacey Bolk Gabriel, declare as follows:
`
`Introduction
`
`1.
`
`I have been retained by Party Lo as an independent expert consultant in
`
`this proceeding before the United States Patent and Trademark Office. Although I am
`
`being compensated at a rate of $500 per hour for the time I spend on this matter, no
`
`part of my compensation is dependent on the outcome of this proceeding, and I have no
`
`other interest in this proceeding.
`
`2.
`
`I have been told that this proceeding is a patent interference between
`
`Fan’s U.S. Patent No. 8,195,415 (“the ’415 patent”) (2011) and Lo’s Application No.
`
`13/070,266 (“the ’266 application”) (2016).
`
`3.
`
`I have been told that the ’415 patent issued on June 5, 2012, from
`
`Application No. 12/696,509, filed on January 29, 2010.
`
`4.
`
`I have been told the ’266 application was filed on March 23, 2011, as a
`
`continuation of Application No. 12/614,350 (“the ’350 application”) (2008), filed on
`
`November 6, 2009, which is a continuation-in-part of Application No. 12/178,181
`
`(“the ’181 application”) (2009), filed on July 23, 2008, which in turn claims priority to
`
`Provisional Application No. 60/951,438, filed July 23, 2007. I understand that the
`
`disclosure of the ’266 application is identical to that of the ’350 application. I also
`
`understand that, in comparison to the ’181 application, the ’350 application contains
`
`additional disclosure.
`
`5.
`
`I previously provided declarations in three related patent interferences,
`
`that is, Interference Nos. 105,920, 105,923, and 105,924.
`
`
`
`2
`
`

`

`6.
`
`In this proceeding, I have been asked to provide my opinion as to whether
`
`a feature of the claims in the ’266 application reciting “using a number of windows of
`
`defined length within normally and abnormally distributed chromosome portions” (“the
`
`claim element” or “the claimed feature”) is described and enabled by the ’266
`
`application.
`
`7.
`
`I have been also asked to provide my opinion on whether the ’350 and
`
`’181 applications describe and enable an embodiment of Count 1 (“the Count”) of this
`
`interference containing the claimed feature.
`
`8.
`
`In addition, I have been asked to provide my opinion on whether claim 14
`
`of the ’415 patent would have been obvious to a person of ordinary skill in the art in
`
`view of the subject matter of the Count of this interference and the knowledge in the
`
`state of the art as of September 20, 2008.
`
`9.
`
`My opinions on these issues are set forth below.
`
`II.
`
`Personal Background
`
`10.
`
`I received a Bachelor of Sciences degree from Carnegie Mellon University
`
`in Molecular Biology in 1993. I received a Ph.D. in Genetics in 1998 from Case
`
`Western Reserve University. I conducted my thesis research projects under the
`
`direction of Dr. Aravinda Chakravarti using genomic mapping techniques and linkage
`
`analysis to identify genes involved in genetic diseases. My graduate research focused
`
`on characterizing genes involved in idiopathic congenital central hypoventilation
`
`syndrome, a rare disorder of respiratory control, and Hirschsprung (HSCR) disease, the
`
`most common cause of congenital intestinal obstruction.
`
`
`
`3
`
`

`

`11. My graduate research involved searching for sequence mutations in DNA
`
`by using techniques such as polymerase chain reaction (PCR), microsatellite
`
`genotyping, and DNA sequencing. I conducted genotyping on members from 61
`
`families containing individuals with and without HSCR to study the inheritance pattern of
`
`the disease. I performed fluorescent dye-terminator cycle sequencing (based on the first
`
`generation Sanger dideoxy sequencing method) using PCR with genomic DNA in a
`
`primer extension sequencing reaction. The PCR products were run out
`
`(electrophoresed) on a slab gel and an automated ABI 377 DNA Sequencer was used
`
`for data collection. I then performed linkage analyses of the data by comparing DNA
`
`sequences from HSCR affected and non-affected individuals to search for differences
`
`(polymorphisms) in the sequences. This study identified three important regions of the
`
`genome to explain the inheritance of HSCR (only one of these regions was previously
`
`known). It also showed that some of these mutations are in non-protein coding regions,
`
`suggesting the importance of noncoding variation. This experiment was an early
`
`example of complete genetic dissection of a multifactorial disorder.
`
`12.
`
`From November 1998 to February 2002, I was a Research Scientist in the
`
`Functional Genomics Program of the Whitehead Institute Center for Genome Research,
`
`now referred to as the Medical and Population Genetics Program of the Broad Institute
`
`of Harvard and MIT ("Broad Institute"). My responsibilities included laboratory work
`
`involving technology development for Single Nucleotide Polymorphism (SNP)
`
`genotyping, supervising technicians, and creating assays for SNP genotyping. During
`
`that time, I worked on the technical development and implementation of the first
`
`genotyping platforms to be used at our institute for high throughput SNP genotyping. All
`
`
`
`4
`
`

`

`of these platforms utilized the basic PCR technique or a variation of PCR at some step
`
`to amplify the individual pieces of DNA; however, each platform used a different
`
`strategy and method of detection. For example, I worked on TaqMan assays (assays
`
`that use allele specific fluorescent probes designed to increase the specificity of real-
`
`time PCR assays) and spotted array designs (hybridization techniques that use small
`
`fragments of PCR products that correspond to mRNAs) to genotype SNPs. Specifically,
`
`I helped design a method for parallel genotyping of SNPs called single base extension-
`
`tag array on glass slides (SBE-TAGS). This method uses techniques such as multiplex
`
`PCR (amplification of genomic DNA using multiple primers), primer extension using
`
`fluorescently labeled dideoxynucleotide triphosphates (ddNTPs), and DNA spotted
`
`microarrays. The ScanArray 5000 (GSI Luminonics) was used to scan the fluorescent
`
`signal for genotyping. With this study we were able to genotype over 100 SNPs,
`
`obtaining over 5,000 genotypes with approximately 99% accuracy.
`
`13. During my time as a Research Scientist in the Functional Genomics
`
`Program, I used the genotyping methods described above to investigate the haplotype
`
`structure of the human genome. I designed genotyping experiments in SNPs in 275
`
`individuals from Africa, Europe, and Asia. Using multiplex PCR followed by primer
`
`extension, the DNA sample was loaded onto a microarray chip (SpectroCHIP,
`
`Sequenom) and analyzed by matrix-assisted laser desorption ionization-time of flight
`
`(MALDI-TOF) using a Bruker Biflex III MALDI-TOF mass spectrometer
`
`(SpectroREADER, Sequenom). We characterized haplotype patterns across 51
`
`autosomal regions (spanning 13 megabases of the human genome) using this method.
`
`This research resulted in a first author Science publication (Gabriel et al. Science
`
`
`
`5
`
`

`

`296(5576):2225-2229 (2002)), which is widely regarded as laying the foundation for the
`
`International Human HapMap project. The International Human HapMap project is a
`
`multi-country collaboration to develop a haplotype map (HapMap) of the human genome
`
`based on SNP genotyping. The data is publicly released by researchers from
`
`participating countries and is a key resource for researchers to find genetic variants
`
`affecting health, disease, and responses to drugs and environmental factors.
`
`14.
`
`From February 2002 to May 2003, I was the Scientific Director of the SNP
`
`genotyping and HapMap Program of the Whitehead Institute Center for Genome
`
`Research. As Scientific Director, I was responsible for all aspects of the Center's
`
`contribution to the International HapMap Project. At the Whitehead HapMap Program I
`
`oversaw a team of 15 technicians, analysts and software engineers, played an active
`
`role in project design and quality control, and served on the International HapMap
`
`project Steering committee.
`
`15.
`
`From May 2003 to May 2004, I was the Associate Director of the High
`
`Throughput Biology, Medical and Population Genetics Program of the Whitehead
`
`Institute Center for Genome Research. As Associate Director, I spearheaded the
`
`expansion of SNP genotyping activity from targeted activity for the Human HapMap
`
`project to a centralized technology platform with dedicated activity in technology
`
`development, large-scale production, data management and analysis. I also oversaw
`
`the successful completion of the Whitehead Institute's contribution to the Human
`
`HapMap project, which had a $10 million budget.
`
`16.
`
`From May 2004 to January 2009, I was the Director of the Genetic
`
`Analysis Platform of the Broad Institute. As Director, I was responsible for creating,
`
`
`
`6
`
`

`

`scaling and directing the Genetic Analysis Platform of the Broad Institute. The Genetic
`
`Analysis Platform encompassed all production and data management activities related
`
`to nucleic acid analysis including gene expression, genotyping and re-sequencing.
`
`During the Platform's peak period from 2006 to 2008, I operated the platform with yearly
`
`revenues of $45 million, and oversaw a staff of 65 individuals including project
`
`managers, research scientists, software engineers and computational biologists. One
`
`of the key milestones of the Genetic Analysis Platform included producing microarray
`
`data on over 100,000 DNA samples over an 18-month period. I also directed data
`
`production for over 50 publications describing genome-wide association findings.
`
`Massively parallel sequencing using microarrays was used in many of these studies for
`
`SNP genotyping. DNA genomes of individuals with and without the disease of interest
`
`were compared to identify common variations in the genome that are associated with
`
`the disease. These studies focused on identifying genes involved in different diseases
`
`such as cancer, diabetes, arthritis, multiple sclerosis, and cardiovascular diseases. In
`
`contrast to other methods which specifically test one or a few genetic regions, these
`
`genome-wide association studies investigated the entire genome of individuals.
`
`17.
`
`From January 2009 to May 2012, I was Co-Director of the Genome
`
`Sequence and Analysis Program and Medical and Population Genetics Program of the
`
`Broad Institute. As the Co-Director, I was responsible for planning, execution and
`
`delivery of a portfolio of cancer and medical sequencing projects as part of the National
`
`Human Genome Research Institute (NHGRI) large-scale sequencing grant. I was also
`
`a Co-Principal Investigator with Eric Lander for a large-scale sequencing grant renewal.
`
`As Co-Director and Principal Investigator, I secured over $100 million in other NIH
`
`
`
`7
`
`

`

`awards over a period of 5 years aimed at large scale genotyping and sequencing. As
`
`Co-Director, I directed the activity of cross-disciplinary teams totaling 60 people,
`
`including project managers, analysts, computational biologists and software engineers
`
`in the analysis of massively parallel sequence data as applied to an array of cancer
`
`genomics and medical genetics projects. As Co-Director, I served as co-chair of the
`
`Data Production committee for the International 1000 Genomes Project, as well as
`
`serving as a member of the Executive and Steering committee for The Cancer Genome
`
`Atlas.
`
`18. As Co-Director, I was involved in developing a technique called Solution
`
`Hybrid Selection (SHS), which is used to prepare specific regions of the genome for
`
`massively parallel sequencing using the Illumina platform. Because of the large size of
`
`the human genome, it is more feasible in some cases to sequence only certain regions
`
`of the genome. The SHS technique uses RNA "baits" to "fish" pieces of DNA out of a
`
`"pond" of DNA fragments. PCR is used at two different stages to amplify the DNA.
`
`Additionally, quantitative PCR is used to quantify the final amount of DNA that was
`
`"caught" by the "bait." The resulting DNA was sequenced using the Illumina platform,
`
`but this technique can be used on any sequencing platform. This method has been
`
`commercialized by Agilent Technologies as "SureSelect" and is the leading product for
`
`genome selection today.
`
`19. Since May 2012, I have been the Director of the Genomics Platform of the
`
`Broad Institute. As Director, I am in charge of the Broad Institute's largest platform, and
`
`the largest US genome center, comprising 180 people dedicated to all sample handling,
`
`microarray, genotyping, and sequencing activities. I am responsible for a $90 million
`
`
`
`8
`
`

`

`annual budget for genomic activities. I oversee project management and data analysis
`
`activities, primarily in support of cancer and medical genetics, as well as technology
`
`development and evaluation and implementation of new technology platforms. I also
`
`maintain all the leadership activities I described above as Co-Director of the Genome
`
`Sequence and Analysis Program and Medical and Population Genetics Program.
`
`20.
`
`Throughout my research experience I have used a variety of genomic
`
`tools including PCR, genotyping (for example by single base extension, hybridization, or
`
`oligo ligation), and sequencing (for example by Sanger sequencing or massively parallel
`
`sequencing). All of the genomic technologies use methods such as template
`
`preparation (preparation of pieces of DNA to be sequenced), sequencing and imaging,
`
`and data analysis. However, the unique combination of specific techniques used within
`
`these methods is what distinguishes one technology from another. I have had the
`
`opportunity to use and help develop numerous platforms that utilize very different
`
`techniques. I have participated in the development and use of multiple sequencing
`
`platforms, including both Sanger type sequencers and massively parallel DNA
`
`sequencers that utilize different strategies to sequence DNA.
`
`21.
`
`I have served and continue to serve on various editorial and advisory
`
`boards related to genomic research. For example, from February 2007 to the present, I
`
`have served on the External Advisory Committee for National Heart, Lung, and Blood
`
`Institute (NHLBI) Resequencing and Genotyping Service. From July 2009 to June
`
`2013, I was a standing member of the NIH Study Section of Genomics, Computational
`
`Biology and Technology. From May 2010 to the present, I have served on the Scientific
`
`Advisory Board of Genome Canada. I have served on the editorial boards of Human
`
`
`
`9
`
`

`

`Genetics and Genome Research. My additional peer review and other professional
`
`activities are set forth on my curriculum vitae, a copy of which is submitted herewith as
`
`1033.
`
`22.
`
`I have authored over 100 peer-reviewed publications. As my research has
`
`been primarily directed to genome sequencing, most of these publications involve the
`
`application of sequencing technology to the study of human disease. DNA sequences
`
`of individuals with and without a specific disease were compared in order to determine
`
`whether there is a common genetic variable in those individuals with the disease.
`
`These publications resulted in the identification of genes and mutations that are
`
`associated with diseases including cancer, diabetes, arthritis, multiple sclerosis, and
`
`cardiovascular diseases. Additionally, I have published protocols for methods that I
`
`have helped develop to prepare DNA for use in massively parallel sequencing.
`
`23.
`
`I have presented lectures at a variety of academic and industry
`
`conferences, and I lecture about 6 to 8 times a year at conferences involving genomics.
`
`For example, I have presented at conferences held by the International Congress of
`
`Human Genetics, the American Society of Human Genetics, the American Association
`
`for Cancer Research, the American Heart Association, the Multiple Myeloma Research
`
`Foundation, and the Association for Research in Vision and Ophthalmology. These
`
`presentations were primarily focused on using genomics to understand the genetic
`
`basis of human disease.
`
`24.
`
`I am not an attorney and offer no legal opinions. My curriculum vitae,
`
`which includes a more detailed summary of my background, experience, and
`
`publications, is attached as 1033.
`
`
`
`10
`
`

`

`III.
`
`Summary of Opinions
`
`25. All of the opinions contained in this Declaration are based on the
`
`documents I reviewed and my knowledge and professional judgment based on my
`
`experience. In forming the opinions expressed in this Declaration, I reviewed the ’415
`
`patent (2011), the ’266 application (2016), the ’181 application (2009), the ’350
`
`application (2008), the Declaration of Dr. John Christopher Detter (“Dr. Detter”) signed
`
`July 31, 2013 (2050), U.S. Patent Application Publication No. 2005/0221341 to
`
`Shimkets et al. published on October 6, 2005 (“Shimkets”) (2044); Dohm et al. (2008)
`
`“Substantial biases in ultra-short read data sets from high-throughput DNA sequencing,”
`
`Nucleic Acids Res., 36(16):e105 (“Dohm”) (2043); Fan et al. (2008), “Noninvasive
`
`diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood,” Proc.
`
`Natl. Acad. Sci. USA, 105(42):16266-16271 (“Fan PNAS Paper”) (2056); and the
`
`transcript of Dr. Detter’s deposition of November 15, 2013 (1061).
`
`26. My opinions have been also guided by my appreciation of how a person of
`
`ordinary skill in the art would have understood the Count and the claims of the ’415
`
`patent and the ’266 application.
`
`27. As explained in my declarations submitted in the related interferences, in
`
`my opinion, in approximately 2008, a person of ordinary skill in the art relevant to the
`
`subject matter of this interference would have a multi-disciplinary background. That
`
`person would have at least a bachelor’s degree in a life sciences area (e.g., biology, cell
`
`biology, genetics, and molecular biology) and at least a master’s degree or a Ph.D. in
`
`computational biology, mathematics or statistics, or equivalent training. A person of
`
`ordinary skill in the art should understand both the operation and application of
`
`
`
`11
`
`

`

`massively parallel DNA sequencing platforms, and have significant direct experience at
`
`performing and applying these techniques. Further, a person of ordinary skill in the art
`
`should understand and have experience with techniques for aligning sequence reads
`
`generated by massively parallel sequencing to a reference genome.
`
`28.
`
`I have been told that, in general, claims involved in an interference are
`
`given their broadest reasonable interpretation in light of the patent application or patent
`
`in which the claims appear. I also understand that when a party challenges written
`
`description support for a copied claim in an interference, the originating disclosure
`
`provides the meaning of the pertinent claim language. I have been told that the claims
`
`of the ’266 application were copied from the ’415 patent claims, and so the meaning of
`
`the ‘266 claim language is based on the content of the ’415 patent.
`
`29.
`
`I have been told that the claimed feature is an element of the Count (which
`
`corresponds to claim 1 of the ’415 patent) and also of claim 24 of the ’266 application.
`
`Claim 24 recites in its entirety:
`
`A method of testing for an abnormal distribution of a specified
`chromosome portion in a mixed sample of normally and abnormally
`distributed chromosome portions obtained from a subject, the method
`comprising:
`
`(a) sequencing DNA from the mixed sample to obtain sequences from
`multiple chromosome portions, wherein said sequences comprise a
`number of sequence tags of sufficient length of determined sequence to
`be assigned to a chromosome location within a genome;
`
`(b) assigning the sequence tags to corresponding chromosome portions
`including at least the specified chromosome by comparing the determined
`sequence of the sequence tags to a reference genomic sequence;
`
`(c) determining values for numbers of sequence tags mapping to
`chromosome portions by using a number of windows of defined length
`
`
`
`12
`
`

`

`within normally and abnormally distributed chromosome portions to
`obtain a first value and a second value therefrom; and
`
`(d) using the values from step (c) to determine a differential, between the
`first value and the second value, which is determinative of whether or not
`the abnormal distribution exists.
`
`Paper 7 (Lo Clean Copy of Claims) (emphasis added.)
`
`30.
`
`I have been told that Lo copied the claim element from the ’415 patent
`
`claims and thus the term “windows” should be interpreted in view of the ’415 patent
`
`disclosure.
`
`31.
`
`I have been told that a claim meets the written description requirement if
`
`the disclosure of the application in which the claim is pending reasonably conveys to a
`
`person of ordinary skill in the art that the inventors of the application had possession of
`
`the claimed subject matter as of the filing date of the application. I have also been told
`
`that all claim terms do not have to appear literally in a patent or application in order for a
`
`person of ordinary skill in the art to understand that the inventors had possession of the
`
`claimed invention.
`
`32.
`
`I have also been told that the enablement requirement of a claim is
`
`satisfied when a person skilled in the art, after reading the application, using his
`
`knowledge and experience, could practice the claimed invention without undue
`
`experimentation.
`
`33.
`
`In my opinion, the broadest reasonable interpretation of the claim term
`
`“windows,” in view of the disclosure of the ’415 patent, is predefined subsections of a
`
`chromosome.
`
`
`
`13
`
`

`

`34.
`
`It is my opinion that the Lo ’266 application discloses “chromosome
`
`regions,” which constitute windows, and discloses “a specified size window” for post-
`
`sequencing analysis. A person of ordinary skill in the art would understand that the Lo
`
`inventors had possession of each of the claims in the ’266 application, including the
`
`claimed feature, as of the March 23, 2011, filing date of the ’266 application.
`
`35.
`
`It is my opinion that the claims of the ’266 application, including the
`
`claimed feature, are enabled by the ’266 application because the claimed feature was
`
`known in the art before the filing date of the ’266 application and a person of ordinary
`
`skill in the art would have been able to practice the claimed feature without undue
`
`experimentation.
`
`36.
`
`It is my opinion that the ’350 application, which has the same disclosure
`
`as the ’266 application, describes and enables an embodiment of the Count, including
`
`the claimed feature, as of the November 6, 2009, filing date of the ’350 application.
`
`37.
`
`It is my opinion that the ’181 application, which provides essentially
`
`identical disclosure regarding “chromosomal regions” and “a specified size window” as
`
`the ’266 application, describes and enables an embodiment of the Count, including the
`
`claimed feature, as of the filing date of the ’181 application, i.e., July 23, 2008.
`
`38.
`
`It is my opinion that claim 14 of the ’415 patent would have been obvious
`
`over the subject matter of the Count and the GC-bias correction taught by Shimkets or
`
`Dohm as of September 20, 2008.
`
`
`
`14
`
`

`

`IV.
`
`The Claimed Feature Is Described in the Lo ’266 Application
`
`39.
`
`I understand it is Dr. Detter’s opinion that the ’266 application does not
`
`describe the claimed feature and would not convey to a person of ordinary skill in the art
`
`that Lo was in possession of the claimed feature. 2050, ¶ 55-91.
`
`40.
`
`I disagree with Dr. Detter. In my opinion, a person of skill in the art would
`
`understand that the “chromosomal regions” disclosed in the ’266 application constitute
`
`predefined subsections of a chromosome, such as segments of a chromosome, and
`
`therefore the ’266 application describes “windows” as that term is properly interpreted
`
`based on disclosure in the ’415 patent. In addition, the ’266 application also discloses
`
`“a specified size window” for post sequence analysis.
`
`A.
`
`“Windows” Are Predefined Subsections of a Chromosome
`
`41.
`
`In my opinion, Dr. Detter’s conclusion on written description is based on
`
`his incorrect interpretation of the meaning of “windows.”
`
`42. Dr. Detter, in his declaration, interprets “windows” as units of defined
`
`length covering specific informative regions along a chromosome or defined units of
`
`equal length within a chromosomal regions or chromosome portions. 2050, ¶¶ 43-45,
`
`48, 84. Dr. Detter clarifies in his cross-examination that, in his opinion, “defined length
`
`does absolutely mean equal length.” 1061, 210:2-3
`
`43.
`
`In my opinion, Dr. Detter’s interpretation of the term “windows” is incorrect
`
`because it is not the broadest reasonable interpretation in view of the disclosure of the
`
`’415 patent. The broadest reasonable interpretation of the claim term, in my opinion, is
`
`predefined subsections of a chromosome, such as regions or segments of a
`
`
`
`15
`
`

`

`chromosome. And unlike Dr. Detter’s view, in my opinion, the ’415 patent does not
`
`require that windows be the same length.
`
`44.
`
`In reaching his interpretation of windows, Dr. Detter relies on select
`
`exemplary embodiments, but does not give consideration to the ’415 patent disclosure
`
`as a whole, which supports an interpretation of the term that is broader than the
`
`interpretation reached by Dr. Detter.
`
`45.
`
`For example, Dr. Detter cites to an exemplary schematic in Figure 9 of the
`
`’415 patent and description thereof to illustrate how the sequence tag distribution across
`
`windows of 50 kb can be used to detect the over- or under-representation of a
`
`chromosome by normalizing the sequence tags originating from those windows. 2050,
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`¶¶ 47, 48; 2011, 7:25-8:6, Fig. 9.
`
`46. Dr. Detter also cites to Figure 10 and Example 8 of the ’415 patent, noting
`
`how windows of 20 kb may be used to compensate for sequence bias that may arise as
`
`a result of nucleotide content, such as GC content. 2050, ¶¶ 51-54; 2011, 25:30-26:59,
`
`Fig. 10.
`
`47. While those embodiments that Dr. Detter relies upon are informative as to
`
`how windows can be used for aneuploidy detection, e.g., in some preferred manner, the
`
`’415 patent provides a broader disclosure of windows.
`
`48.
`
`For example, the ’415 patent as a whole does not require that windows be
`
`of equal length. In my opinion, Dr. Detter improperly relies on selected exemplary
`
`embodiments in the ’415 patent to reach the unduly narrow interpretation of “windows”
`
`as “defined units of equal length.”
`
`
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`16
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`

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`49.
`
`In my opinion, the ’415 patent as a whole supports a broader interpretation
`
`of “windows,” as meaning predefined subsections of a chromosome.
`
`50.
`
`For example, the ’415 patent discloses that aneuploidies can be
`
`determined by “analyzing sequence tag density in predefined subsections of
`
`chromosomes (e.g., 10 to 100 kb windows).” 2011, 4:9-10. In my opinion, a person of
`
`ordinary skill in the art reading this disclosure would understand the reference in this
`
`passage to “predefined subsections of a chromosome” as a description of windows.
`
`Those predefined subsections may vary in length from 10-100 kb. Such a person would
`
`also understand that this disclosure does not require windows to be of equal length
`
`because there is no language in this passage imposing such a requirement.
`
`51.
`
`In my opinion, and as further explained below, a person of ordinary skill in
`
`the art would understand that, for example, windows on a chromosome suspected of
`
`aneuploidy (e.g., each window on chromosome 21) need not be of equal length, but, for
`
`the purpose of determining dosage imbalance, each window on the chromosome
`
`suspected of aneuploidy should be of equal length to a corresponding window on a
`
`reference chromosome (e.g., a window on chromosome 12) in order for a fair
`
`comparison to occur.
`
`52.
`
`The ’415 patent further discloses:
`
`Each autosome (chr. 1-22) is computationally segmented into contiguous,
`non-overlapping windows. (A sliding window could also be used). Each
`window is of sufficient length to contain a significant number of reads
`(sequence tags, having about 20-100 by [sic] of sequence) and not still
`have a number of windows per chromosome. Typically, a window will be
`between 10 kb and 100 kb, more typically between 40 and 60 kb.
`
`2011, 5:4-11.
`
`
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`17
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`53.
`
`In my opinion, a person of ordinary skill in the art reading this disclosure
`
`would understand that windows are predefined subsections of a chromosome, e.g.,
`
`contiguous, non-overlapping segments, typically between 10 kb and 100 kb, more
`
`typically between 40 and 60 kb. Such a person would also understand that this
`
`disclosure does not require windows to be of equal length because there is no language
`
`in this passage imposing such a requirement.
`
`54.
`
`Indeed, Dr. Detter, in his cross-examination, admits that the disclosure at
`
`col. 4:9-10 of the ’415 patent shows that “[a window] is a predefined subsection of a
`
`chromosome.” 1061, 228:21 to 229:3. Dr. Detter, referring to col. 4:9-10 of the ’415
`
`patent, states that “[t]hat’s the way it’s being used here and I think that’s what I
`
`mentioned earlier, is that a window can be – it’s a region, a window is a region. So here
`
`it’s a predefined subsection of a chromosome, 100 kb window so that’s how it’s
`
`being used here, correct.” 1061, 228:21 to 229:3 (emphasis added).
`
`55. Considering the ’415 patent in its entirety, in my opinion, the broadest
`
`reasonable interpretation of “windows” is predef