Filed on behalf of: Sequenom, Inc.
`By:
`Steven P. O’Connor
`Michele C. Bosch
`
`FINNEGAN, HENDERSON, FARABOW,
`
`GARRETT & DUNNER, L.L.P.
`
`901 New York Avenue, NW
`
`Washington, DC 20001—4413
`Telephone: 202—408—4000
`Facsimile: 202—408-4400
`
`E—mail: Steven.oconnor@finnegan.com
`michele.bosch@finnegan.com
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`SEQUENOM, INC.
`Petitioner
`
`V.
`
`THE BOARD OF TRUSTEES OF
`
`THE LELAND STANFORD JUNIOR UNIVERSITY
`
`Patent Owner
`
`Patent 8,195,415
`
`
`
`DECLARATION OF STACEY BOLK GABRIEL
`
`SEQUENOM EXHIBIT 1010
`
`SEQUENOM EXHIBIT 1010
`
`

`

`Table of Contents
`
`Introduction ...................................................................................................... 1
`
`II.
`
`III.
`
`Qualifications ................................................................................................... 2
`
`Summary of Opinions .................................................................................... 11
`
`IV.
`
`Overview of the ’415 Patent .......................................................................... 14
`
`Claim Construction ........................................................................................ 15
`
`A
`
`B
`
`Chromosome Portion ........................................................................... 16
`
`Window ............................................................................................... 16
`
`C.
`
`Sliding Window ................................................................................... 17
`
`D
`
`E
`
`F
`
`Sequence Tag Density ......................................................................... 18
`
`Sequence Tag ...................................................................................... 18
`
`Massively Parallel Sequencing ............................................................ 19
`
`G. Mixed Sample ...................................................................................... 20
`
`VI.
`
`Certain References Teach All of the Claimed Features of the ’41 5
`
`Patent ............................................................................................................. 21
`
`A.
`
`L0 1] Discloses All of the Features of Claims 1—6 and 8—12 of
`
`the ’415 Patent ..................................................................................... 21
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`Claim 1 ...................................................................................... 21
`
`Claim 2 ...................................................................................... 27
`
`Claim 3 ...................................................................................... 3O
`
`Claim 4 ...................................................................................... 31
`
`Claim 5 ...................................................................................... 33
`
`Claim 6 ...................................................................................... 33
`
`Claim 8 ...................................................................................... 34
`
`

`

`8.
`
`9.
`
`Claim 9 ...................................................................................... 34
`
`Claim 10 .................................................................................... 35
`
`10.
`
`Claim 11 .................................................................................... 36
`
`ll.
`
`Claim 12 .................................................................................... 39
`
`L0 11 and Hillier and/0r Smith Teach All of the Features of
`
`Claim 7 of the ’415 patent ................................................................... 41
`
`L0 [1 and Wang Teach All of the Features of Claims 13 and 16
`of the ’415 patent ................................................................................. 43
`
`1.
`
`2.
`
`Claim 13 .................................................................................... 43
`
`Claim 16 .................................................................................... 52
`
`L0 [1, Shimkets, and/0r Dohm Teach All of the Features of
`Claim 14 of the ’415 patent ................................................................. 53
`
`L0 11 and Quake Teach All of the Features of Claim 15 of the
`’41 5 patent ........................................................................................... 54
`
`L0 [1, Wang, and Hillier and/0r Smith Teach All of the Features
`of Claim 17 ofthe ’415 patent ............................................................ 55
`
`L0 1] and Wang Teach All of the Features of Claims 1—6 and 8—
`12 ofthe ’415 patent ............................................................................ 57
`
`L0 11, Wang, and Hillier and/or Smith Teach All of the Features
`of Claim 7 of the ’415 patent .............................................................. 58
`
`L0 11, Wang, Shim/cets, and Hillier and/0r Smith Teach All of
`the Features of Claim 14 of the ’41 5 patent ........................................ 59
`
`L0 H, Wang, and Quake Teach All of the Features of Claim 15
`0f the ’415 patent ................................................................................. 59
`
`L0 1 and Shimkets Teach All of the Features of Claims 1—6 and
`
`8—12 of the ’415 patent ........................................................................ 60
`
`1.
`
`Claim 1 ...................................................................................... 62
`
`-ii—
`
`

`

`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`Claim 2 ...................................................................................... 69
`
`Claim 3 ...................................................................................... 71
`
`Claim 4 ...................................................................................... 72
`
`Claim 5 ...................................................................................... 73
`
`Claim 6 ...................................................................................... 73
`
`Claim 8 ...................................................................................... 74
`
`Claim 9 ...................................................................................... 74
`
`Claim 10 .................................................................................... 75
`
`10.
`
`Claim 11 .................................................................................... 76
`
`11.
`
`Claim 12 .................................................................................... 77
`
`L.
`
`M.
`
`N.
`
`0.
`
`P.
`
`L0 1, Shimkeis, and Hillier and/or Smith Teach Each and Every
`Feature of Claim 7 0f the ’41 5 patent ................................................. 78
`
`L0 1, Shimkets, and Wang Teach Each and Every Feature of
`Claims 13 and 16 of the ”415 patent ................................................... 79
`
`1.
`
`2.
`
`Claim 13 .................................................................................... 79
`
`Claim 16 .................................................................................... 86
`
`L0 1, Shimkeis, and/0r Dohm Teach Each and Every Feature of
`Claim 14 ofthe ’415 patent ................................................................. 87
`
`L0 1, Shimkets, and Quake Teach Each and Every Feature of
`Claim 15 of the ’415 patent ................................................................. 89
`
`L0 I, Shimkets, Wang, and Hillier and/0r Smith Teach Each and
`Every Feature of Claim 17 of the ’41 5 patent ..................................... 90
`
`VII. Conclusion ..................................................................................................... 91
`
`Appendices ............................................................................ 93—142
`
`—iii~
`
`

`

`1, Stacey Bolk Gabriel, declare as follows:
`
`I.
`
`Introduction
`
`1.
`
`I have been retained by Sequenom,
`
`Inc.
`
`(“Petitioner”)
`
`as an
`
`independent expert consultant in this proceeding before the United States Patent
`
`and Trademark Office. Although I am being compensated at my 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 understand that this proceeding involves U.S. Patent No. 8,195,415
`
`(“the ’415 patent”) (Ex. 1001), the application for which was filed on January 29,
`
`2010, as U.S. Patent Application No. 12/696,509, and issued on June 5, 2012.
`
`I
`
`also understand that the ’41 5 patent is what is referred to as a “divisional” of U.S.
`
`Patent Application No. l2/560,708, which was filed on September 16, 2009, which
`
`in turn claims priority to Provisional Application No. 61/098,758, filed September
`
`20, 2008.
`
`I further understand that the ’415 patent indicates it is assigned to the
`
`Board of Trustees of the Leland Stanford Junior University (“Patent Owner”).
`
`3.
`
`I have been asked to consider whether a person of ordinary skill in the
`
`art would have understood that certain references teach, either alone or in
`
`combination, the features recited in the claims of the ’415 patent. My opinions are
`
`set forth below.
`
`

`

`II.
`
`Qualifications
`
`4.
`
`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.
`
`5.
`
`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.
`
`6.
`
`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 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.
`
`7.
`
`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 (MALDl-TOF) using a Broker Biflex Ill 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 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 (Hap Map) 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.
`
`8.
`
`From February 2002 to May 2003, I was the Scientific Director of the
`
`SNP genotyping and Hap Map 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.
`
`9.
`
`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 Hap Map project, which had a $10 million budget.
`
`10.
`
`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, 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
`
`micro arrays 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.
`
`11.
`
`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 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.
`
`12.
`
`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.
`
`13.
`
`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 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.
`
`

`

`l4.
`
`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).
`
`15. 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.
`
`16.
`
`l 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 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 BX. 101 1.
`
`17.
`
`I have authored over 90 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.
`
`18.
`
`l have presented lectures at a variety of academic and industry
`
`conferences, and 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
`
`10
`
`

`

`Vision and Ophthalmology. These presentations were primarily focused on using
`
`genomics to understand the genetic basis of human disease.
`
`19.
`
`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 Ex. 1011.
`
`111.
`
`Summary of Opinions
`
`20.
`
`All of the opinions contained in this Declaration are based on the
`
`documents I reviewed and my knowledge and professional judgment.
`
`In forming
`
`the opinions expressed in this Declaration,
`
`I reviewed the (1) ’415 patent (BX.
`
`100]); (2) portions of the prosecution history for the ’415 patent; (3) US. Patent
`
`Application Publication No. 2009/0029377 to Lo et al. (“Lo 11”) (Ex. 1002); (4)
`
`US. Provisional Patent Application No. 60/951,438 to Lo et al.
`
`(“Lo 1”) (EX.
`
`1003); (5) US. Patent Application Publication No. 2005/0221341 to Shimkets er
`
`al. (“Shimkez‘s”) (Ex. 1004); (6) Tian-Li Wang et (11., “Digital karyotyping,” Proc.
`
`Natl. Acad. Sci. USA, 99(25):l6156—61 (“Wang”) (Ex. 1005); (7) LaDeana W.
`
`Hillier, “Whole—genome sequencing and variant discovery in C. elegans,” Nature
`
`Methods, 5(2):183—88 (and on—line supplementary information) (“Hillier”) (Ex.
`
`1006); (8) Juliane C. Dohm et (11., “Substantial biases in ultra—short read data sets
`
`from high—throughput DNA sequencing,” Nucleic Acids Res, 36(16):6105
`
`(“Do/1m”) (Ex. 1007); (9) us. Patent No. 7,888,017 to Quake and Fan (“Quake”)
`
`ll
`
`

`

`(Ex. 1008); and (10) Andrew D. Smith et (11., “Using quality scores and longer
`
`reads improves accuracy of Solexa read mapping,” BMC Bioinformatics, 9:128
`
`(“Smith ”) (Ex. 1009), while drawing on my experience and knowledge of genomic
`
`sequencing and related molecular biology techniques.
`
`21. My opinions have been also guided by my appreciation of how a
`
`person of ordinary skill in the art would have understood the claims of the ’415
`
`patent at the time of the alleged invention, which I have been asked to assume is
`
`September 20, 2008.
`
`22. At the time of the alleged invention, a person of ordinary skill in the
`
`art relevant to the subject matter of claims 1 through 17 of the ’415 patent 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 PhD.
`
`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 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.
`
`12
`
`

`

`23.
`
`It is my understanding that a claim is anticipated by the prior art if a
`
`prior art reference discloses each and every feature of the claim. Also,
`
`I
`
`understand that when the prior art discloses a species that falls within a genus, or
`
`range, a claim to the genus, or range, is anticipated by that prior art species.
`
`24.
`
`It is my understanding that a claim is unpatentable over the prior art if
`
`the differences between the features in the claim and the prior art are such that the
`
`subject matter of the claim as a whole would have been obvious at the time of the
`
`invention to a person having ordinary skill in the pertinent art.
`
`I understand that in
`
`some circumstances a teaching, suggestion, or motivation in the prior art would
`
`have led a person of ordinary skill in the art to modify a reference, or combine
`
`references, to arrive at the claimed invention.
`
`I also understand there may be other
`
`reasons why a claim would have been obvious. For example, I understand that it
`
`would be obvious for a person of ordinary skill in the art to use a known technique
`
`to improve a similar method in the same way and yield predictable results.
`
`I also
`
`understand it would be obvious for a person of ordinary skill in the art to combine
`
`prior art teachings to achieve a certain desired result with a reasonable expectation
`
`of success.
`
`25.
`
`Based on my experience and expertise, it is my opinion that certain
`
`references teach, alone or in combination, all of the features recited in the claims of
`
`the ’415 patent.
`
`13
`
`

`

`IV. Overview of the ’415 Patent
`
`26.
`
`I understand that the ”415 patent is directed to “a method to achieve
`
`digital quantification of DNA (i.e., counting differences between identical
`
`sequences) using direct
`
`shotgun sequencing followed by mapping to the
`
`chromosome of origin and enumeration of fragments per chromosome.”
`
`EX.
`
`1001, ’415 patent, Abstract. “Shotgun sequencing” refers to random sequencing of
`
`nucleic acid fragments in a sample.
`
`27. According to the ’415 patent, “[t]here is therefore a desire to develop
`
`non-invasive genetic tests for fetal chromosomal abnormalities.” 1d,, 1:52-54. The
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`’415 patent addresses that desire by providing methods for analyzing a maternal
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`sample, such as blood, which contains maternal and fetal DNA, for detecting fetal
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`aneuploidy. As explained in the ’415 patent, “[t]he abnormal distribution of a fetal
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`chromosome or portion of a chromosome (i.e., a gross deletion or insertion) may
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`be determined in the present method by enumeration of sequence tags as mapped
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`to different chromosomes.”
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`Id., 3:64—4zl. The methods entail “carr[ying] out
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`sequence determinations on the DNA fragments in the sample, obtaining sequences
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`from multiple chromosome portions of the mixed sample to obtain a number of
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`sequence tags of sufficient length of determined sequence to be assigned to a
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`chromosome location within a genome [by comparison to a reference sequence]
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`and of sufficient number to reflect abnormal distribution.” Id, 4:34—43.
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`14
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`

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`28.
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`The
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`’415 patent
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`applies conventional
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`statistical data
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`analysis
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`techniques to the sequencing data obtained from the methods.
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`For example,
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`according to the ’415 patent one may normalize the data obtained from the
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`methods to provide more robust and statistically significant results.
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`In one
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`approach, non—uniform distribution of sequence tags to different chromosomal
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`portions may be corrected by using windows of defined length to subdivide the
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`chromosomes.
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`16]., 4:51—67. This same approach to data analysis can be used to
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`correct for the known bias resulting from the G/C content of the maternal and fetal
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`DNA sequenced in the methods claimed in the ’41 5 patent. Id, 5:23—30.
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`V.
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`Claim Construction
`
`29.
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`I understand that in this type of proceeding before the United States
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`Patent
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`and Trademark Office,
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`a
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`claim receives
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`the broadest
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`reasonable
`
`interpretation in light of the specification of the patent in which it appears.
`
`I also
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`understand that, at
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`the same time, claim terms are given their ordinary and
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`accustomed meaning as would be understood by a person of ordinary skill in the
`
`art. But I also understand that a patentee may act as his own lexicographer in
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`redefining the meaning of particular claim terms away from their ordinary
`
`meaning.
`
`I have followed these principles in my analysis.
`
`I discuss a few terms
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`below and what I understand to be Petitioner’s constructions of these terms, which
`
`I agree with.
`
`15
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`

`

`A.
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`Chromosome Portion
`
`30.
`
`Each of independent claims 1 and 13 recites testing for or determining
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`a “chromosome portion.” Ex. 1001, 33:53-34:58; 36:1—17.
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`I understand that the
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`Petitioner has offered the broadest
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`reasonable
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`construction of
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`the
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`term
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`“chromosome portion” consistent with the specification as “either an entire
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`chromosome or a significant fragment of a chromosome.”
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`I have used this
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`construction in my analysis and agree with it because the ”415 patent specifically
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`defines the term this way. See id., 4:5—7.
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`B. Window
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`31.
`
`Independent claim 1
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`recites determining values for a number of
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`sequences tags using “a number of windows of defined length.” Ex. 1001, 33:33—
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`34:58. The ”415 patent treats the terms “window” and “bin” as equivalent. Ex.
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`1001, 7:37.
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`I understand that the Petitioner has offered the broadest reasonable
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`construction of the term “window” or “bin” consistent with the specification as a
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`“predefined subsection of a chromosome.”
`
`1 have used this construction in my
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`analysis and agree with it because the specification of the ’415 patent supports
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`such an interpretation:
`
`0 “Each autosome (chr. 1-22) is computationally segmented into
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`contiguous, non—overlapping windows” and “[e]ach window is of
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`sufficient length to contain a significant number of reads (sequence
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`16
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`

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`tags, having about 20—100 [bp] of sequence)....” EX. 1001, 5:4—9.
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`0 “The present method also involves correcting for nonuniform
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`distribution [of] sequence tags to different chromosomal portions
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`[using windows].” Id, 4:51—52.
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`0 “[A] number of windows of defined length are created along a
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`chromosome, the windows being on the order of kilobases in length,
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`whereby a number of sequence tags will fall into many of the
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`windows and the windows covering each entire chromosome in
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`question, with exceptions for non—informative regions, e.g.,
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`centromere regions and repetitive regions.” Id, 4:53—59.
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`C.
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`Sliding Window
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`32.
`
`Independent
`
`claim 13
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`recites
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`that
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`each chromosomal portion
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`comprises “a sliding window of a predetermined length.” Ex. 1001, 3621—17.
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`I
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`understand that the Petitioner has offered the broadest reasonable construction of
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`the term “sliding window” consistent with the specification as “contiguous,
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`overlapping or non—overlapping, predefined subsections of a chromosome.” 1 have
`
`used this construction in my analysis and agree with it because the specification of
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`the ’41 5 patent supports such an interpretation:
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`0 “Each autosome (chr. 1—22) is computationally segmented into
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`contiguous, non—overlapping windows. (A sliding window could also
`
`17
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`

`

`be used).” Ex. 1001, 5:4—6.
`
`0 “Because the distribution of sequence tags across each chromosome
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`was non—uniform (possibly technical artifacts), we divided the length
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`of each chromosome into non-overlapping sliding window[s] with a
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`fixed width (in this particular analysis, a 50 kbp window was used),
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`skipping regions of genome assembly gaps and regions with known
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`microsatellite repeats.” 16