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`Filed on behalf of: Junior Party FAN
`
`By:
`
`R. Danny Huntington, Esq.
`Sharon E. Crane, Ph.D., Esq.
`Rothwell, Figg, Ernst & Manbeck, PC.
`607 14‘h Street, N.W., Suite 800
`Washington, DC, 20005
`dhuntington@rfem.com
`scrane@rfem.com
`Main Telephone: (202) 783-6040
`Main Facsimile: (202) 783-6031
`
`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 131r070,266),
`
`Patent Interference No. 105,922 (DK)
`(Technology Center 1600)
`
`DECLARATION OF J. CHRIS DETTER, PILD.
`
`SEQUENOM EXHIBIT 1087
`SEQUENOM EXHIBIT 1087
`Sequenom v. Stanford
`Sequenom V. Stanford
`IPR2013-00390
`SEQUENOM EXHIBIT 1087
`
`IPR2013-00390
`
`

`

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`Filed on behalf of: Junior Party FAN
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`By:
`
`R. Danny Huntington, Esq.
`Sharon E. Crane, Ph.D., Esq.
`Rothwell, Figg, Ernst & Manbeck, PC.
`607 1-4111 Street, N.W., Suite 800
`Washington, DC, 20005
`dhuntington@rfem.com
`scrane@rfem.com
`Main Telephone: (202) 783-6040
`Main Facsimile: (202) 783-6031
`
`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 13070266),
`
`Patent Interference No. 105,922 (DK)
`(Technology Center 1600)
`
`DECLARATION OF J. CHRIS DETTER, PILD.
`
`EXHIBIT 2050
`
`QUAKE v. LO, Interference No. 105,920
`FAN v. L0, Interference No. 105,922
`LO v. QUAKE, Interference No. 105,923
`LO v. QUAKE, Interference No. 105,924
`
`

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`The undersigned, J. Chris Detter, Ph.D., does hereby declare and state that:
`
`1.
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`I make the following declaration based on my knowledge and belief.
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`My Educational and Professional Background
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`2.
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`I earned my B.S. in Biology at Baylor University in 1995 and my Ph.D. in
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`medical sciences (molecular genetics and microbiology) at University of Florida in Gainesville
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`in 1999.
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`3.
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`After receiving my Ph.D., I worked as the Team and Technical Leader for the
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`Research and Development Genomic Technology Group at the Lawrence Livermore National
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`Laboratory (“LLNL”) as part of the Joint Genome Institute from September, 1999 until May,
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`2001, where I developed DNA library creation protocols and methods for high-throughput
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`sequencing for the human genome sequencing project.
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`4.
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`From May, 2001 until September, 2005, I was the Group Leader in the
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`Genomics/Cloning Technology Group at LLNL, during which time I managed the high-
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`throughput library creation process for the Joint Genome Institute.
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`5.
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`From September, 2005 until February, 2009, I was the Team Leader for the
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`Sequencing Technology Team at the Joint Genome Technology Group (B-6) at the Los Alamos
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`National Laboratory (“LANL”), during which time I managed a highly automated sequencing
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`team focused on the genome finishing process. Also, from October, 2006 until April, 2007, I
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`was acting Group Leader for the Joint Genome Institute-Genome Technology Group (B-5) in the
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`Bioscience Division of LANL, where I managed a diverse genomic sequencing and
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`computational biology group.
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`6.
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`Since February, 2008, I have been the Genome Sciences Center Director and
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`Group Leader (B-6) at LANL, where I manage a diverse genomic sequencing and computational
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`biology group of about 45 individuals. In addition, since September, 2011, I have been the
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`Acting Bioscience Deputy Divisional Leader at LANL, in which position I assist the Division
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`Leader in programmatic, strategic and tactical mission areas for Bioscience. As of October 2012,
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`I am now the BioThreat, BioDefense Program Director for LANL.
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`7.
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`I received additional technical training an automated DNA sequencing at Perkin-
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`Elmer Corporation in 1997, at Amersham in 1999, at Applied Biosystems in 2000, at Affymetrix
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`in 2000, at 454 Life Sciences in 2006, and I consider myself to be an expert on high-throughput
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`sequencing on the Roche 454, Illumina and Pacific Biosciences (PacBio) platforms.
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`8.
`
`I have published numerous scientific research papers in the areas of chromosomal
`
`mapping and genome sequencing, as listed on my curriculum vitae, which is being submitted
`
`with this declaration as Exhibit 2051.
`
`My Understanding of this Proceeding
`
`9.
`
`I am informed that a patent interference, identified above, has been declared
`
`between a patent of Hei-Mun Christina Fan and Stephen Quake (collectively “Fan”) and an
`
`application of Yun-Ming Dennis Lo, Rossa Wai Kwun Chiu, and Kwan Chee Chan (collectively
`
`“Lo”).
`
`10.
`
`I am informed the Fan patent in the interference is U.S. Patent No. 8,195,415,
`
`which issued on June 5, 2012 (“the Fan ’415 patent”; Exhibit 2011) assigned to The Board of
`
`Trustees of the Leland Stanford Junior University (“Stanford”).
`
`11.
`
`I understand the Fan ’415 patent (Exhibit 2011) issued from U.S. Application
`
`Serial No. 12/696,509, filed on January 29, 2010 (“the Fan ’509 application”; Exhibit 2012),
`
`which published as U.S. Patent Publication No. 2010/0138165 on June 3, 2010 (“the Fan ’165
`
`publication”; Exhibit 2013).
`
`12.
`
`I am informed the Fan ’509 application (Exhibit 2012) is a divisional application
`
`from U.S Application Serial No. 12/560,708, filed on September 16, 2009 (“the Fan ’708
`3
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`

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`application”; Exhibit 2014), which published as U.S. Patent Publication No. 2010/0112575 on
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`May 6, 2010 (“the Fan ’575 publication”; Exhibit 2023).
`
`13.
`
`I am informed the Fan ’708 application (Exhibit 2014) claims the benefit of U.S.
`
`Provisional Application Serial No. 61/098,758, filed on September 20, 2008 (“the Fan ’758
`
`provisional”; Exhibit 2015).
`
`14.
`
`I understand that the Fan ’415 patent is involved in the above-captioned
`
`interference against U.S. Application Serial No. 13/070,266 filed on March 23, 2011 (“the Lo
`
`’266 application”; Exhibit 2016), which published as U.S. Patent Publication No. 2011/0003637
`
`on January 5, 2012 (“the Lo ’637 publication”; Exhibit 2017).
`
`15.
`
`I am informed the Lo ’266 application (Exhibit 2016) is a continuation application
`
`from U.S. Application Serial No. 12/614,350, filed on November 6, 2009, and published as U.S.
`
`Patent Publication No. 2010/0112590 on May 6, 2010 (“the Lo ’350 application”; Exhibit 2008),
`
`which is a continuation-in-part from U.S. Application Serial No. 12/178,181, filed on July 23,
`
`2008 (“the Lo ’181 application”; Exhibit 2009), and published as U.S. Patent Publication No.
`
`2009/0029377 on January 29, 2009 (“the Lo ’377 publication”; Exhibit 2020), which claims the
`
`benefit of U.S. Provisional Application Serial No. 60/951,438, filed on July 23, 2007 (“the Lo
`
`’438 provisional”; Exhibit 2010).
`
`Independent Witness
`
`16.
`
`I have been retained in this matter by Rothwell, Figg, Ernst & Manbeck, P.C. of
`
`Washington, D.C. (“Rothwell”).
`
`17. My main contacts at Rothwell are Sharon Crane, Ph.D., Esq., Seth Cockrum,
`
`Ph.D., Esq., and Danny Huntington, Esq.
`
`18.
`
`I have had no previous contact with Rothwell or these main contacts.
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`19.
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`I understand that the real parties in interest for party Fan is The Board of Trustees
`
`of the Leland Stanford University (“Stanford”), Fluidigm Corporation (“Fluidigm”), Verinata
`
`Health, Inc. (“Verinata”) and Illumina, Inc. (“Illumina”) and that the real parties in interest for
`
`party Lo are the Chinese University of Hong Kong (“the Chinese University”) and Sequenom,
`
`Inc. (“Sequenom”).
`
`20.
`
`I do not have any financial interest in any of the real parties in interest or in the
`
`outcome of this proceeding.
`
`21.
`
`I have had no previous personal contact with the Fan inventors or the Lo
`
`inventors.
`
`22.
`
`I believe that I can provide an independent witness opinion in this matter as
`
`independent expert witness.
`
`My Opinions and Their Bases
`
`23.
`
`I have been asked to give my opinion on whether a person of ordinary skill in the
`
`art reading the Lo ’266 application would have determined that Lo was in possession of the
`
`invention of the Count, and whether the specification of the Lo ’266 application enables a person
`
`of ordinary skill in the art to make or use the invention of the Count, at the time of filing the Lo
`
`’266 application and should therefore be entitled to claim the subject matter of the Lo claims 24-
`
`49. I have reviewed the language of all of Claims 24-49, and thus my opinions discussed in this
`
`declaration relate to all of these claims.
`
`24.
`
`I have also been asked to give my opinion on whether a person of ordinary skill in
`
`the art reading the Lo ’350 application and the Lo ’181 application would have determined that
`
`Lo was entitled to claim the benefit of the filing dates of those applications for the invention of
`
`the Count.
`
`5
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`25.
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`I have also been asked to give my opinion on whether a person of ordinary skill in
`
`the art would understand that Fan claim 14 does not correspond to the invention of the Count.
`
`26.
`
`I have also been asked to give my opinion on whether a person of ordinary skill in
`
`the art reading the Fan ’758 provisional application would have determined that it disclosed at
`
`least one species within the scope of the Count. I understand that such a species would be a
`
`method that is within the scope of the method defined by the Count..
`
`27.
`
`As a part of these opinions, I considered the level of ordinary skill in the art
`
`around July 2007, the date of the Lo ’438 provisional application that represents the earliest date
`
`to which the Lo ’266 application can claim priority. One of ordinary skill in the art relevant to
`
`the Fan ’415 patent would have a multi-disciplinary background. That person would have at
`
`least a bachelor’s degree in a life science area (e.g., biology, cell biology, genetics, molecular
`
`biology) and understand both the operation and application of massively parallel DNA
`
`sequencing platforms. Further, one of ordinary skill in the art would understand the operation
`
`and application of basic bioinformatics techniques, including at least techniques for aligning
`
`sequence reads to a reference genome. One of skill in the art could acquire an understanding of
`
`such techniques by, for example, earning a degree in computational biology or a related
`
`discipline or through carrying out relevant research activities that involve the use of such
`
`bioinformatics techniques.
`
`28.
`
` I have reviewed the Declaration of Stacey Polk Gabriel submitted in Lo U.S.
`
`Application Serial No. 13/070,275 (Exhibit 2048). I note that in paragraph 48 of that
`
`Declaration, Dr. Gabriel defines a person of ordinary skill in the art as someone with:
`
`“at least a bachelor’s degree in a life science area (e.g., biology cell biology,
`genetics, molecular biology) and at least a master’s degree or Ph.D. in
`computational biology, mathematics or statistics, or equivalent training. One of
`ordinary skill in the art should understand both the operation and application of
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`

`

`massively parallel DNA sequencing platforms, and have significant direct
`experience at performing and applying these techniques. Further, one 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.”
`
`29.
`
`I have also reviewed Dr. Gabriel’s education, experience, and list of publications.
`
`Given my education, experience, and additional training discussed above, I consider myself at
`
`least as qualified as Dr. Gabriel to speak to what a person of ordinary skill in the art that is
`
`associated with the Counts in the interferences would understand at the relevant time frame
`
`regarding the matters I have been asked to address.
`
`30.
`
`I will refer to certain Exhibits in my discussion of my opinions and their bases. I
`
`have reviewed the exhibits cited in this Declaration as part of my analysis.
`
`The Subject Matter of the Count
`
`31.
`
`I understand the Count of an interference is the subject matter that is being
`
`contested in an interference.
`
`32.
`
`I understand the Count in this interference is claim 1 of the Fan ’415 patent
`
`(Exhibit 2011), namely:
`
`1. 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, 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 within
`normally and abnormally distributed chromosome portions to obtain a first value
`and a second value therefrom; and
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`(d) using the values from step (c) to determine a differential, between the
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`first value and the second value, which is determinative of whether or not the
`abnormal distribution exists.
`
`33.
`
`I understand that claims designated as corresponding to the Count are the claims
`
`which are involved in this interference. I further understand that Fan claims 1-17, and Lo claims
`
`24-49, have been designated as corresponding to the Count.
`
`The Fan ’415 Patent Specification
`
`
`
`General Method Described by the Fan ’415 Patent Specification
`
`34.
`
`The Fan ’415 patent specification discloses methods of testing for abnormal
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`distributions of chromosome portions comprising, among other things, sequencing a mixed
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`sample of normally and abnormally distributed chromosome portions obtain from a subject, such
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`as a mixture of fetal and maternal DNA in a maternal plasma sample obtained from a pregnant
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`woman. Unlike prior art methods, the methods of the Fan ’415 patent do not require that the
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`maternal and fetal DNA be separated or distinguished from each other. Rather, a fetal
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`chromosomal aneuploidy, if present, may be detected by quantitating chromosome sequences of
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`maternal and fetal DNA in the mixture of fetal and maternal DNA. (Exhibit 2011, col. 3 – 4).
`
`35.
`
`The Fan ’415 patent methods also do not rely on sequence differences between
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`maternal and fetal DNA because the summed contribution of both maternal and fetal sequences
`
`in a particular chromosome, or chromosome portion, will be different as between an intact,
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`diploid chromosome and an aberrant chromosome, i.e., with an extra copy, missing portion or
`
`the like. For this reason, the Fan ’415 method does not rely on previously known sequence
`
`information that would distinguish fetal DNA from maternal DNA. In other words, the Fan ’415
`
`patent methods allow one of ordinary skill in the art to analyze a genome in one sequencing run
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`rather than being limited to analyzing specifically targeted areas of interest. (Exhibit 2011, cols.
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`3 – 4).
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`36.
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`The maternal and fetal DNA in the mixed sample is sequenced using a method
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`that gives a large number of typically short reads, referred to as “sequence tags.” (Exhibit 2011,
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`cols. 3 – 4). Sequence tags are defined in the Fan ’415 specification as “a DNA sequence of
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`sufficient length that it may be assigned specifically to one of chromosomes 1-22, X or Y.”
`
`(Exhibit 2011, col. 8). Accordingly, each sequence tag is unique to a given chromosome.
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`(Exhibit 2011, cols. 3 – 4).
`
`37.
`
`The sequence tags described in the Fan ’415 patent specification may precisely
`
`match the sequence on a chromosome to which they are mapped. In the alternative, the sequence
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`tag may contain up to one mismatch. A mismatch occurs when the order of nucleotides of the
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`sequence tag does not precisely match the order of bases on the chromosome. (Exhibit 2011,
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`cols. 3 – 4). A single mismatch is permitted to account for minor polymorphisms that may exist
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`between the reference genome and the maternal and fetal genomes being mapped. (Exhibit
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`2011, col. 8).
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`38.
`
`The Fan ’415 patent describes an example wherein the total number of sequence
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`tags obtained during a sequencing reaction was about ten million. Of the ten million tags
`
`obtained from that sequencing reaction, approximately five million were mapped uniquely to the
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`human genome with at most one mismatch. In this example, approximately 4% of the entire
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`human genome was matched with a sequence tag. (Exhibit 2011, col. 14, Table 1, Table 2).
`
`39.
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`As noted above, the sequence tags are mapped to specific positions in the human
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`genome, e.g., chromosomes 1-22, X or Y. Mapping a sequence to a specific portion in the
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`human genome can be done using an alignment program. For example, in certain embodiments,
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`the Fan ’415 patent utilizes the Solexa ELAND alignment program. (Exhibit 2011, col. 22).
`
`40.
`
`Once the sequence tags have been aligned to each chromosome, they are counted
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`by using a number of windows of defined length within normally and abnormally distributed
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`chromosome portions as discussed in greater detail below. The number of sequence tags present
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`on a suspected aneuploid chromosome (i.e., suspected abnormally distributed chromosome), or
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`chromosome portion, is then compared to the number of sequence tags present on a normally
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`distributed chromosome, or chromosome portion. By comparing the two, an over- or under-
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`representation of any chromosome, or chromosome portion, can be determined. (Exhibit 2011,
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`cols. 3 – 4).
`
`41.
`
`The Fan ’415 patent specification notes this method was successfully used to
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`detect fetal aneuploidy at a gestation stage as early as fourteen weeks. (Exhibit 2011, col. 10).
`
`Specifically, the Fan ’415 patent notes the method was able to detect all 9 cases of trisomy 21, 2
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`cases of trisomy 18, and 1 case of trisomy 13 out of a mixed population of normal and
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`aneuploidy pregnancies. (Exhibit 2011, col. 17).
`
`The Claimed Methods of the Fan ’415 Patent Specify “Using a Number of Windows
`of Defined Length within Normally and Abnormally Distributed Chromosome
`Portions” to Count the Sequence Tags Mapped to the Chromosomes
`
`42.
`
`The claims of the ’415 patent specify the “using a number of windows of defined
`
`length within normally and abnormally distributed chromosome portions.” (Exhibit 2011, e.g.
`
`claim 1). In my opinion, the use of these “windows” is an integral part of the method described
`
`in the Fan ’415 patent. I have been informed that because claim 1 of the Fan ’415 patent defines
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`the subject matter of the Count, the use of “windows” is also an integral part of the Count.
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`10
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`43.
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`The Fan ’415 patent specification describes a window as unit of defined length
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`covering specific informative regions along a chromosome. For example, each chromosome is
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`computationally segmented into contiguous, non-overlapping windows. Another embodiment of
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`the Fan ’415 patent describes sliding windows, and their specific use. In either embodiment, the
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`windows will be applied across the entirety of each chromosome except that windows are not
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`applied across non-informative regions of the chromosome. Examples of non-informative
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`regions include centromere regions and repetitive regions. (Exhibit 2011, cols. 3 – 4, 22).
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`44.
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`As described in the Fan ’415 patent specification, the sequence tags generated by
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`the sequencing method are mapped to each predefined window of defined length on each
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`chromosome. Using windows in this manner allows a comparison in sequence tag coverage
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`among the different chromosomes. In other words, by counting sequence tags within a series of
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`predefined windows of equal lengths along different chromosomes, more robust and statistically
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`significant results may be obtained. The windows enable an improved statistically significant
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`comparison because they eliminate the over- or under- representation of a particular
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`chromosome, or chromosome portion, that is due to bias, such as sequencing bias, and not due to
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`aneuploidy. As discussed below, it is my opinion that the Fan ’415 patent specification describes
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`in detail how the windows described in the Fan ’415 patent are used to produce such improved
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`statistically significant results.
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`45.
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`An additional advantage of using “windows of defined length” is to mitigate the
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`computational demand of whole genome sequencing. By looking at isolated, predefined
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`windows of equal length, the mapping of millions of sequence tags that can be generated by
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`sequencing becomes more manageable. Notably, the computational results achieved by using
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`“windows of defined length” are also more informative. The results are more informative
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`because the examination of smaller amounts of information at a time makes it easier to identify
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`the presence of an abnormal distribution of chromosomes, or chromosome portions.
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`46. Window size can vary between 10 – 100 kilobases (“kb”) (Exhibit 2011, col. 5).
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`A 50 kb window is utilized in the examples. (Exhibit 2011, col. 22, Figure 9). The Fan ’415
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`patent specification notes that smaller windows may be used to account for a larger number of
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`reads, and to give a more detailed picture of the chromosome. Alternatively, the specification
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`also makes clear that larger windows may be used to account for a smaller number of reads.
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`Larger windows are still suitable for the detection of gross chromosome deletions, omissions or
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`duplications. (Exhibit 2011, col. 17).
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`47.
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`The Fan ’415 patent specification provides an exemplary schematic illustrating
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`how the sequence tag distribution across windows of defined length can be used to detect the
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`over- or under-representation of a chromosome. A chromosome is first segmented into windows
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`that are mapped to chromosome coordinates representing the position of the sequence read along
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`the chromosome. For example, chromosome 1 consists of approximately 2.8 x 108 base pairs
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`which is divided into 50 kb windows. The sequence tags obtained from sequencing the mixed
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`sample of maternal and fetal genomic DNA are then plotted to chromosome 1 by comparing the
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`determined sequence of the sequence tags to a reference genomic sequence for chromosome 1.
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`The sequence tags that uniquely map to the chromosome are then counted. The mapped sequence
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`tag data are then replotted to show the distribution of the number of sequence tags per 50 kb
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`window. The distributions of sequence tags within windows for a chromosome of interest can be
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`compared and a representative value of sequence tags for the chromosome of interest, e.g., a
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`median or mean value of sequence tags, can be determined. (Exhibit 2011, Cols. 7 - 8, Figure
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`9).
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`48.
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`The process of plotting sequence tag data described above using chromosome 1 as
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`an example is conducted for all chromosomes, and a representative number of sequence tags for
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`each chromosome is determined. By taking the representative number of sequence tags for all
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`autosomes, i.e., chromosomes 1 – 22, a normalization constant can be calculated. The
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`normalization constant can be then be used to obtain the sequence tag density for each
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`chromosome by dividing the representative number of sequence tags for a given chromosome by
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`the normalization constant. An advantage to the calculation of a normalization constant in this
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`manner, i.e., with the use of defined windows of equal length, is that an external standard is not
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`required. (Exhibit 2011, cols. 8-9). By comparing the sequence tag density of each chromosome
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`it is also possible to compare different patient samples even though the total number of sequence
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`tags for each patient sample may be different. (Exhibit 2011, cols. 7 – 8).
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`49.
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`The Fan ’415 patent specification also discloses how windows may be used to
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`compensate for sequence bias that may arise as a result of nucleotide content. For example, it
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`was observed that certain chromosomes have large variations in the number of sequence tags
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`counted for each chromosome. It was also observed that this variation is strongly dependent on
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`the nucleotide content, specifically content of the guanine and cytosine (“G/C content”), of the
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`chromosome. (Exhibit 2011, col. 11).
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`50.
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`The practical consequence of the G/C content bias observed in the Fan ’415
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`method is a loss of aneuploidy detection sensitivity from chromosome to chromosome. For
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`example, Figure 1A of the Fan ’415 patent illustrates the chromosome to chromosome variation
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`that results from G/C content bias. Figure 1A depicts the sequence tag densities from eighteen
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`different samples that represent the plasma DNA of five different genotypes: woman with a
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`trisomy 21 fetus, woman with Trisomy 18 fetus, woman with Trisomy 13 fetus, woman with
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`normal fetus, and a normal adult male. The chromosomes in Figure 1A are ordered by
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`increasing G/C content. As can be clearly seen from the Figure, the sequence tag density of a
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`particular chromosome shows an increase in variability as correlated with increasing G/C
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`content. (Exhibit 2011, cols. 5 and 11, Figure 1).
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`51.
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`The most common human aneuploidies, e.g., chromosome 13, chromosomes 18,
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`and chromosome 21, exhibit a low variation and thus can be detected without reducing the G/C
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`content bias. However, if the G/C content bias is reduced, then the detection sensitivity of those
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`common aneuploidies is even greater. In addition, the reduction of G/C content bias allows for
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`the detection of aneuploidy in G/C rich or G/C poor chromosomes. Accordingly, the reduction of
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`G/C content bias enables the detection of fetal aneuploidy with even greater statistical
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`confidence. (Exhibit 2011, cols. 11, 19-20, Figure 1, Figure 10).
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`52.
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`As noted above, the Fan ’415 patent specification explicitly teaches how to use
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`“windows” to correct for the sequencing bias resulting from G/C content. Again, the first step
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`in using windows to correct for G/C content bias is to divide each chromosome into windows of
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`predetermined length. After the chromosome is divided into windows, the G/C content of each
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`window is then calculated. In Example 8 of the Fan ’415 patent, the G/C content of a 20 kilobase
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`window is calculated using the hgG/Cpercent script of the UCSC Genome Browser’s “kent
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`source tree.” The output of this file contains the chromosome coordinate of each 20 kilobase
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`window, and the associated G/C content. (Exhibit 2011, cols. 25 – 26).
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`53.
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`The relationship between sequence coverage and G/C content is then determined
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`by counting the number of sequence tags in each window and calculating the average number of
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`sequence tags per window for every 0.1% of G/C content in the window. In calculating the
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`average number of sequence tags, windows with no sequence tags, windows with zero G/C
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`content, and windows with an over-abundance of sequence tags were ignored. The reciprocal of
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`the average number of sequence tags for a particular G/C content percent relative to the global
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`average number of sequence tags per window is used to calculate the weight. Each sequence tag
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`is then assigned a weight depending on the G/C content percent that it falls into. The results are
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`then plotted. For example, Figure 11 represents a scatter plot showing the weight given to
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`different sequence samples according to percentage of G/C content. Lower weight is given to
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`those sequence tags with higher G/C content, and greater weight is given to those sequence tags
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`with lower G/C content. (Exhibit 2011, cols. 25-26, Figure 11).
`
`54.
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`Using the G/C content bias correction detailed in the Fan ’415 patent
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`specification, a person of ordinary skill in the art would be able to reduce variations in sequence
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`tag density observed in chromosomes with higher G/C content. For example, the results plotted
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`in Figure 1A may be improved with this method. Figure 10 is a scatter plot showing sequence
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`tag density relative to the corresponding value of genomic control (similar to that depicted in
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`Figure 1A), but the G/C content bias has been reduced. Accordingly, use of this method results
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`in a greater statistical significance. As a result, aneuploidy that may not otherwise have been
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`detected may be observed. (Exhibit 2011, cols. 19-20, Figure 10).
`
`The Lo ’266 Application Does Not Demonstrate Possession of At Least the Claim Feature
`“Using a Number of Windows of Defined Length within Normally and Abnormally
`Distributed Chromosome Portions”
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`55.
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`I have been informed that an assessment of whether an application contains
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`written description to support a claim is based on whether a person of ordinary skill would
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`appreciate that the applicant was in possession of the invention being claimed at the time the
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`application was filed. I have also been informed that the question is not whether a person of
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`ordinary skill in the art might be able to construct the invention based on the disclosure of the
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`application, but whether one of ordinary skill in the art would immediately be able to envisage
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`the invention from the disclosure.
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`56.
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`I have further been informed that the claims of the Lo ’266 application involved
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`in the interference are to be interpreted in view of the Fan ’415 patent specification. I have been
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`informed this is because the Lo claims were copied from the Fan ’415 patent.
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`57.
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`I have reviewed the Lo ’266 application as well as the prosecution file history of
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`the Lo ’266 application. It is my opinion that the Lo application would not convey to a person of
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`ordinary skill in the art that Lo was in possession of at least the claim feature “using a number of
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`windows of predefined length within normally and abnormally distributed chromosome
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`portions” as that term is set forth in the Fan ’415 patent specification.
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`Lo Cited No Support When Copying the Fan ’415 Patent Claims
`
`58.
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`As noted above, I have reviewed the prosecution file history of the Lo ’266
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`application. (Exhibit 2059). In particular, I have reviewed an amendment dated October 10,
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`2012 submitted by Lo during prosecution of the ’266 application. (Exhibit 2041). The
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`amendment canceled the claims previously filed by Lo and replaced them with claims that
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`substantially copied the Fan ’415 patent claims. The amendment also states that the copied
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`claims are presented for provoking an interference with the Fan ’415 patent. However, the Lo
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`applicants never set forth support for any of the Lo claims submitted to provoke an interference
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`with the Fan ’415 patent. In addition, support for claims Lo copied from the Fan ’415 patent to
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`provoke an interference was never analyzed by an examiner in an office action considering the
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`patentability of those Lo claims. (Exhibit 2059). Accordingly, it is unclear what Lo believes
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