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 No. 8,195,415
`Issued: June 5, 2012
`Filed: January 29, 2010
`Inventors: Hei-Mun Christina Fan and Stephen R. Quake
`Title: NONINVASIVE DIAGNOSIS OF FETAL ANEUPLOIDY BY
`SEQUENCING
`____________________
`
`Inter Partes Review No. 2014-00337
`__________________________________________________________________
`
`
`
`DECLARATION OF STACEY BOLK GABRIEL
`REGARDING U.S. PATENT 8,195,415
`
`
`
`Petitioner Sequenom - Ex. 1010, Cover Page
`
`

`

`Table of Contents
`
`I.
`
`II.
`
`Introduction ...................................................................................................... 4
`
`Qualifications ................................................................................................... 5
`
`III.
`
`Summary of Opinions .................................................................................... 14
`
`IV. Overview of the ’415 Patent .......................................................................... 17
`
`V.
`
`Claim Construction ........................................................................................ 19
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`G.
`
`“Chromosome Portion” ....................................................................... 19
`
`“Window” ............................................................................................ 20
`
`“Sliding Window” ............................................................................... 21
`
`“Sequence Tag Density” ..................................................................... 22
`
`“Sequence Tag” ................................................................................... 23
`
`“Massively Parallel Sequencing” ........................................................ 24
`
`“Mixed Sample” .................................................................................. 26
`
`VI. Patentability Analysis of the ’415 Patent ...................................................... 27
`
`A.
`
`Lo I and Shimkets Teach All of the Features of Claims 1-6 and
`8-12 of the ’415 Patent ........................................................................ 27
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`Claim 1 ...................................................................................... 30
`
`Claim 2 ...................................................................................... 38
`
`Claim 3 ...................................................................................... 39
`
`Claim 4 ...................................................................................... 40
`
`Claim 5 ...................................................................................... 41
`
`Claim 6 ...................................................................................... 42
`
`Claim 8 ...................................................................................... 42
`
`Petitioner Sequenom - Ex. 1010, p. 1
`
`

`

`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`G.
`
`8.
`
`9.
`
`Claim 9 ...................................................................................... 43
`
`Claim 10 .................................................................................... 43
`
`10. Claim 11 .................................................................................... 44
`
`11. Claim 12 .................................................................................... 45
`
`Lo I and Shimkets in Combination with Either One of Tarasaov,
`Hillier and/or Smith Teach Each and Every Feature of Claim 7
`of the ’415 Patent ................................................................................ 46
`
`Lo I, Shimkets, and Wang Teach Each and Every Feature of
`Claims 13 and 16 of the ’415 Patent ................................................... 48
`
`1.
`
`2.
`
`Claim 13 .................................................................................... 48
`
`Claim 16 .................................................................................... 55
`
`Lo I and Shimkets and/or Lo I, Shimkets, and Dohm Teach Each
`and Every Feature of Claim 14 of the ’415 Patent .............................. 56
`
`Lo I and Shimkets, and Quake Teach Each and Every Feature of
`Claim 15 of the ’415 Patent ................................................................. 57
`
`Lo I, Shimkets, and Wang in Combination with Either One of
`Tarasov, Hillier, and/or Smith Teach Each and Every Feature of
`Claim 17 of the ’415 Patent ................................................................. 58
`
`Lo I, Shimkets, and Green Teach All of the Features of Claims
`1-6 and 8-12 of the ’415 Patent ........................................................... 60
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`Claim 1 ...................................................................................... 61
`
`Claim 2 ...................................................................................... 70
`
`Claim 3 ...................................................................................... 71
`
`Claim 4 ...................................................................................... 72
`
`Claim 5 ...................................................................................... 73
`
`Claim 6 ...................................................................................... 74
`
`Petitioner Sequenom - Ex. 1010, p. 2
`
`

`

`7.
`
`8.
`
`9.
`
`Claim 8 ...................................................................................... 75
`
`Claim 9 ...................................................................................... 76
`
`Claim 10 .................................................................................... 76
`
`10. Claim 11 .................................................................................... 77
`
`11. Claim 12 .................................................................................... 78
`
`Lo I, Shimkets, and Green in Combination with Either One of
`Tarasov, Hillier and/or Smith Teach Each and Every Feature of
`Claim 7 of the ’415 Patent ................................................................... 79
`
`Lo I, Shimkets, Green, and Wang Teach Each and Every
`Feature of Claims 13 and 16 of the ’415 Patent .................................. 81
`
`1.
`
`2.
`
`Claim 13 .................................................................................... 81
`
`Claim 16 .................................................................................... 89
`
`Lo I, Shimkets, and Green and/or Lo I, Shimkets, Green, and
`Dohm Teach Each and Every Feature of Claim 14 of the ’415
`Patent ................................................................................................... 90
`
`Lo I, Shimkets, Green, and Quake Teach Each and Every
`Feature of Claim 15 of the ’415 Patent ............................................... 91
`
`Lo I, Shimkets, Green, and Wang in Combination with Either
`One of Tarasov, Hillier and/or Smith Teach Each and Every
`Feature of Claim 17 of the ’415 Patent ............................................... 92
`
`H.
`
`I.
`
`J.
`
`K.
`
`L.
`
`VII. Conclusion ..................................................................................................... 94
`
`Appendices ............................................................................................................... 95
`
`
`
`Petitioner Sequenom - Ex. 1010, p. 3
`
`

`

`I, 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 customary 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 ’415 patent is what is referred to as a “divisional” of U.S.
`
`Patent Application No. 12/560,708, 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 am the same Stacey Bolk Gabriel that submitted a declaration in IPR
`
`No. 2013-00390, which also involves the ’415 patent. I have been asked to
`
`consider whether a person of ordinary skill in the art would have understood that
`
`Petitioner Sequenom - Ex. 1010, p. 4
`
`

`

`certain additional 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
`
`Petitioner Sequenom - Ex. 1010, p. 5
`
`

`

`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
`
`Petitioner Sequenom - Ex. 1010, p. 6
`
`

`

`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 (MALDI-TOF) using a Broker Biflex III MALDI-TOF
`
`mass spectrometer (SpectroREADER, Sequenom). We characterized haplotype
`
`patterns across 51 autosomal regions (spanning 13 megabases of the human
`
`Petitioner Sequenom - Ex. 1010, p. 7
`
`

`

`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
`
`Petitioner Sequenom - Ex. 1010, p. 8
`
`

`

`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
`
`(“MPS”) 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.
`
`Petitioner Sequenom - Ex. 1010, p. 9
`
`

`

`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
`
`Petitioner Sequenom - Ex. 1010, p. 10
`
`

`

`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.
`
`Petitioner Sequenom - Ex. 1010, p. 11
`
`

`

`14. 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 MPS).
`
`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.
`
`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
`
`Petitioner Sequenom - Ex. 1010, p. 12
`
`

`

`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 Ex. 1011.
`
`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.
`
`I 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
`
`Petitioner Sequenom - Ex. 1010, p. 13
`
`

`

`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.
`
`III. 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 (Ex.
`
`1001); (2) portions of the prosecution history for the ’415 patent (Ex. 1015); (3)
`
`U.S. Provisional Patent Application No. 60/951,438 to Lo et al. (“Lo I”) (Ex.
`
`1003); (4) U.S. Patent Application Publication No. 2005/0221341 to Shimkets et
`
`al. (“Shimkets”) (Ex. 1004); (5) Tian-Li Wang et al., “Digital karyotyping,” Proc.
`
`Natl. Acad. Sci. USA, 99(25):16156-61 (2002) (“Wang”) (Ex. 1005); (6) LaDeana
`
`W. Hillier, “Whole-genome sequencing and variant discovery in C. elegans,”
`
`Nature Methods, 5(2):183-88 (2008) (and on-line supplementary information)
`
`(“Hillier”) (Ex. 1006); (7) Juliane C. Dohm et al., “Substantial biases in ultra-
`
`short read data sets from high-throughput DNA sequencing,” Nucleic Acids Res.,
`
`36(16):e105 (2008) (“Dohm”) (Ex. 1007); (8) U.S. Patent No. 7,888,017 to Quake
`
`and Fan (“Quake”) (Ex. 1008); (9) Andrew D. Smith et al., “Using quality scores
`
`Petitioner Sequenom - Ex. 1010, p. 14
`
`

`

`and longer reads improves accuracy of Solexa read mapping,” BMC
`
`Bioinformatics, 9:128 (2008) (“Smith”) (Ex. 1009); (10) Richard E. Green, et al.,
`
`“Analysis of one million base pairs of Neanderthal DNA,” Nature, 444:330-36
`
`(2006) (“Green”) (Ex. 1012); (11) Valery Tarasov, et al., “Differential Regulation
`
`of microRNAs by p53 Revealed by Massively Parallel Sequencing,” Cell Cycle,
`
`6:1586-93 (2007) (“Tarasov”) (Ex. 1013); (12) Claim Construction Order, Aria
`
`Diagnostics, Inc. v. Sequenom, Inc., Case No. C 11-06391 SI, Natera, Inc., et al. v.
`
`Sequenom, Inc., et al., Case No. C 12-00132 SI, and Verinata Health, Inc., et al. v.
`
`Sequenom, Inc., et al., Case No. 12-00865 SI (NDCA) (October 16, 2013); and
`
`(13) Decision Institution of Inter Partes Review, IPR2013-00390, Paper 7
`
`(December 9, 2013), 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
`
`Petitioner Sequenom - Ex. 1010, p. 15
`
`

`

`molecular biology) and at least a master’s degree or Ph.D. in computational
`
`biology, mathematics or statistics, or equivalent training. A person of ordinary
`
`skill in the art would have understood both the operation and application of
`
`massively parallel DNA sequencing platforms, and would have had significant
`
`direct experience at performing and applying these techniques. Further, a person
`
`of ordinary skill in the art would have understood and would have had experience
`
`with techniques for aligning sequence reads generated by massively parallel
`
`sequencing to a reference genome.
`
`23.
`
`It is my understanding that a claim is anticipated by the prior art if a
`
`prior art reference discloses, either by its express disclosure or an inherent feature
`
`or characteristics of the express disclosure, 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
`
`Petitioner Sequenom - Ex. 1010, p. 16
`
`

`

`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 have been 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 have been obvious for a person of ordinary skill
`
`in the art to combine prior art teachings to achieve a certain desired result if the
`
`combination would have been undertaken by the person of ordinary skill in the art
`
`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.
`
`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
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`at Abstract. “Shotgun sequencing” refers to random sequencing of nucleic acid
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`fragments in a sample.
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`27. According to the ’415 patent, “[t]here is … a desire to develop non-
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`invasive genetic tests for fetal chromosomal abnormalities.” Id. at 1:52-54. The
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`Petitioner Sequenom - Ex. 1010, p. 17
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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.” Id. at 3:64-4:1. 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. at 4:34-43.
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`28. The ’415 patent applies conventional statistical data analysis
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`techniques to the sequencing data obtained from the methods. 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. 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. Id. at 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 ’415 patent. Id. at 5:23-30.
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`Petitioner Sequenom - Ex. 1010, p. 18
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`

`V. Claim Construction
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`29.
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`I understand that in this type of proceeding before the United States
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`Patent and Trademark Office, a claim receives the broadest reasonable
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`interpretation in light of the specification of the patent in which it appears. I also
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`understand that, at 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
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`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
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`meaning. I have been asked to follow these principles in my analysis of what the
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`claims terms mean. I discuss a few terms below and what I understand to be
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`Petitioner’s constructions of these terms, which I agree with.
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`A.
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`“Chromosome Portion”
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`30. Each of independent claims 1 and 13 recites testing for or determining
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`a “chromosome portion.” Ex. 1001 at 33:53-34:58; 36:1-17. I understand that the
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`Petitioner has offered the broadest reasonable construction of the 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.” 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. at 4:5-7.
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`Petitioner Sequenom - Ex. 1010, p. 19
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`

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`31.
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`In addition, I note that the Patent Trial and Appeal Board (“Board”)
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`adopted this construction of the term “chromosome portion” in a previous decision
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`instituting inter partes review of the ’415 patent, IPR No. 2013-00390.
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`B.
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`32.
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`“Window”
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`Independent claim 1 recites determining values for a number of
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`sequences tags using “a number of windows of defined length.” Ex. 1001 at
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`33:53-34:58. The ’415 patent treats the terms “window” and “bin” as equivalent.
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`Id. at 7:37. I understand that the Petitioner has offered the broadest reasonable
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`construction of the term “window” or “bin