Case 1:20-cv-01580-LPS Document 9-4 Filed 12/10/20 Page 1 of 61 PageID #: 859
`Case 1:20-cv-01580-LPS Document 9-4 Filed 12/10/20 Page 1 of 61 PageID #: 859
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`EXHIBIT 4
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`EXHIBIT 4
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`

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`United States Patent
`Talasaz et al .
`
`US 10,704,085 B2
`( 10 ) Patent No .:
`* Jul . 7 ,
`2020
`( 45 ) Date of Patent :
`
`US010704085B2
`
`( 54 )
`
`SYSTEMS AND METHODS TO DETECT
`RARE MUTATIONS AND COPY NUMBER
`VARIATION
`( 71 ) Applicant : GUARDANT HEALTH , INC . ,
`Redwood City , CA ( US )
`( 72 ) Inventors : Amir Ali Talasaz , Atherton , CA ( US ) ;
`Stefanie Ann Ward Mortimer , Morgan
`Hill , CA ( US )
`( 73 ) Assignee : GUARDANT HEALTH , INC . ,
`Redwood City , CA ( US )
`Subject to any disclaimer , the term of this
`patent is extended or adjusted under 35
`U.S.C. 154 ( b ) by 0 days .
`This patent is subject to a terminal dis
`claimer .
`( 21 ) Appl . No .: 16 / 575,079
`Sep. 18 , 2019
`( 22 ) Filed :
`( 65 )
`Prior Publication Data
`US 2020/0032323 A1 Jan. 30 , 2020
`
`( * ) Notice :
`
`Related U.S. Application Data
`( 63 ) Continuation of application No. 15 / 669,779 , filed on
`Aug. 4 , 2017 , which is a continuation of application
`No. 15 / 076,565 , filed on Mar. 21 , 2016 , now Pat . No.
`9,902,992 , which is a continuation of application No.
`14 / 855,301 , filed on Sep. 15 , 2015 , which is
`a
`continuation
`of
`application
`No.
`PCT / US2014 / 000048 , filed on Mar. 15 , 2014 .
`
`( 51 )
`
`Case 1:20-cv-01580-LPS Document 9-4 Filed 12/10/20 Page 2 of 61 PageID #: 860
`
`( 60 ) Provisional application No. 61 / 948,530 , filed on Mar.
`5 , 2014 .
`Int . Cl .
`( 2006.01 )
`C12P 19134
`( 2018.01 )
`C12Q 1/6827
`( 2018.01 )
`C12Q 1/6806
`( 2019.01 )
`G16B 30/00
`( 2018.01 )
`C12Q 1/6869
`U.S. CI .
`CPC
`C12Q 1/6827 ( 2013.01 ) ; C12Q 1/6806
`( 2013.01 ) ; G16B 30/00 ( 2019.02 ) ; C12Q
`1/6869 ( 2013.01 )
`Field of Classification Search
`C12Q 1/6806 ; C12Q 1/6869 ; C12Q
`CPC
`2521/501 ; C12Q 2525/191 ; C12Q
`2537/165 ; C12Q 2545/114 ; C12Q
`2565/514 ; C12Q 1/6827 ; C12Q 1/6886 ;
`C12Q 2600/158 ; C12Q 1/6874 ; C12Q
`2527/143 ; C12Q 2537/143 ; C12Q
`2600/118 ; C12Q 2600/156 ; C12Q
`2600/16 ; C12Q 2535/122
`See application file for complete search history .
`
`( 52 )
`
`( 58 )
`
`( 56 )
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,725,536 A
`4,942,124 A
`5,124,246 A
`5,149,625 A
`5,200,314 A
`5,424,186 A
`5,424,413 A
`5,445,934 A
`5,604,097 A
`5,635,352 A
`5,635,400 A
`5,648,245 A
`5,654,413 A
`5,656,731 A
`5,658,737 A
`5,714,330 A
`5,744,305 A
`5,759,778 A
`5,763,175 A
`5,800,992 A
`5,846,719 A
`5,854,033 A
`5,871,928 A
`5,925,525 A
`5,935,793 A
`5,952,170 A
`5,968,740 A
`
`2/1988 Fritsch et al .
`7/1990 Church
`6/1992 Urdea et al .
`9/1992 Church et al .
`4/1993 Urdea
`6/1995 Fodor et al .
`6/1995 Hogan et al .
`8/1995 Fodor et al .
`2/1997 Brenner
`6/1997 Urdea et al .
`6/1997 Brenner
`7/1997 Fire et al .
`8/1997 Brenner
`8/1997 Urdea
`8/1997 Nelson et al .
`2/1998 Brenner et al .
`4/1998 Fodor et al .
`6/1998 Li et al .
`6/1998 Brenner
`9/1998 Fodor et al .
`12/1998 Brenner et al .
`12/1998 Lizardi
`2/1999 Fodor et al .
`7/1999 Fodor et al .
`8/1999 Wong
`9/1999 Stroun et al .
`10/1999 Fodor et al .
`( Continued )
`FOREIGN PATENT DOCUMENTS
`102933721 A
`2/2013
`0799897 B1 6/2006
`( Continued )
`
`CN
`EP
`
`OTHER PUBLICATIONS
`Office action dated May 13 , 2019 for U.S. Appl . No. 15 / 669,779 .
`Park , et al . Discovery of common Asian copy number variants using
`integrated high - resolution array CGH and massively parallel DNA
`sequencing . Nat Genet . May 2010 ; 42 ( 5 ) : 400-5 . doi : 10.1038 / ng .
`555. Epub Apr. 4 , 2010 .
`Parkinson , N.J. et al . , “ Preparation of high - quality next - generation
`sequencing libraries from picogram quantities of target DNA , "
`Genome Res . 2012 , 22 ( 1 ) , 125-133 .
`( Continued )
`Primary Examiner — Cynthia B Wilder
`( 74 ) Attorney , Agent , or Firm — Timothy Hott
`( 57 )
`ABSTRACT
`The present disclosure provides a system and method for the
`detection of rare mutations and copy number variations in
`cell free polynucleotides . Generally , the systems and meth
`ods comprise sample preparation , or the extraction and
`isolation of cell free polynucleotide sequences from a bodily
`fluid ; subsequent sequencing of cell free polynucleotides by
`techniques known in the art ; and application of bioinfor
`matics tools to detect rare mutations and copy number
`variations as compared to a reference . The systems and
`methods also may contain a database or collection of dif
`ferent rare mutations or copy number variation profiles of
`different diseases , to be used as additional references in
`aiding detection of rare mutations , copy number variation
`profiling or general genetic profiling of a disease .
`30 Claims , 16 Drawing Sheets
`
`

`

`US 10,704,085 B2
`Page 2
`
`( 56 )
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`5,981,176 A
`5,981,179 A
`6,013,445 A
`6,020,124 A
`6,040,138 A
`6,046,005 A
`6,060,596 A
`6,117,631 A
`6,124,092 A
`6,138,077 A
`6,140,489 A
`6,172,214 B1
`6,197,506 B1
`6,235,475 B1
`6,242,186 B1
`6,268,152 B1
`6,284,460 B1
`6,300,077 B1
`6,309,822 B1
`6,309,823 B1
`6,326,148 B1
`6,355,431 B1
`6,355,432 B1
`6,395,491 B1
`6,406,848 B1
`6,440,667 B1
`6,440,706 B1
`6,451,536 B1
`6,458,530 B1
`6,468,744 B1
`6,489,114 B2
`6,492,121 B2
`6,498,012 B2
`6,503,718 B2
`6,512,105 B1
`6,514,699 B1
`6,544,739 B1
`6,551,784 B2
`6,576,424 B2
`6,582,908 B2
`6,586,177 B1
`6,600,996 B2
`6,629,040 B1
`6,653,077 B1
`6,753,147 B2
`6,849,403 B1
`6,849,404 B2
`6,852,488 B2
`6,858,412 B2
`6,964,846 B1
`7,163,789 B2
`7,208,275 B2
`7,406,385 B2
`7,410,764 B2
`7,424,368 B2
`7,424,371 B2
`7,537,897 B2
`7,700,286 B2
`7,704,687 B2
`7,727,720 B2
`7,803,929 B2
`7,811,757 B2
`7,822,555 B2
`7,824,889 B2
`7,838,647 B2
`7,915,015 B2
`7,935,487 B2
`7,937,225 B2
`7,957,913 B2
`7,972,817 B2
`7,981,612 B2
`8,094,312 B2
`8,168,385 B2
`8,195,415 B2
`8,209,130 B1
`
`11/1999 Wallace
`11/1999 Lorinez et al .
`1/2000 Albrecht et al .
`2/2000 Sorenson
`3/2000 Lockhart et al .
`4/2000 Ju et al .
`5/2000 Lemer et al .
`9/2000 Nilsen
`9/2000 O'Neill et al .
`10/2000 Brenner
`10/2000 Brenner
`1/2001 Brenner
`3/2001 Fodor et al .
`5/2001 Brenner et al .
`6/2001 Salonen
`7/2001 Fodor et al .
`9/2001 Fodor et al .
`10/2001 Shuber et al .
`10/2001 Fodor et al .
`10/2001 Cronin et al .
`12/2001 Pauletti et al .
`3/2002 Chee et al .
`3/2002 Fodor et al .
`5/2002 Fodor et al .
`6/2002 Bridgham et al .
`8/2002 Fodor et al .
`8/2002 Vogelstein et al .
`9/2002 Fodor et al .
`10/2002 Morris et al .
`10/2002 Cronin et al .
`12/2002 Laayoun et al .
`12/2002 Kurane et al .
`12/2002 Laken
`1/2003 Shuber et al .
`1/2003 Hogan et al .
`2/2003 O'Neill et al .
`4/2003 Fodor et al .
`4/2003 Fodor et al .
`6/2003 Fodor et al .
`6/2003 Fodor et al .
`7/2003 Shuber
`7/2003 Webster et al .
`9/2003 Goodlett et al .
`11/2003 Brenner
`6/2004 Vogelstein et al .
`2/2005 Shuber
`2/2005 Park et al .
`2/2005 Fodor
`al .
`2/2005 Willis et al .
`11/2005 Shuber
`1/2007 Chen et al .
`4/2007 Gocke et al .
`7/2008 Sorenson
`8/2008 Gocke et al .
`9/2008 Huang et al .
`9/2008 Kamentsky
`5/2009 Brenner et al .
`4/2010 Stroun et al .
`4/2010 Wang et al .
`6/2010 Dhallan
`9/2010 Melkonyan et al .
`10/2010 Shuber
`10/2010 Huang et al .
`11/2010 Vogelstein et al .
`11/2010 Hahn et al .
`3/2011 Vogelstein et al .
`5/2011 Gocke et al .
`5/2011 Mishra et al .
`6/2011 Chinitz et al .
`7/2011 Kopreski
`7/2011 Shuber et al .
`1/2012 Ulmer
`5/2012 Brenner
`6/2012 Fan et al .
`6/2012 Kennedy et al .
`
`Case 1:20-cv-01580-LPS Document 9-4 Filed 12/10/20 Page 3 of 61 PageID #: 861
`
`8,216,789 B2
`8,236,532 B2
`8,361,726 B2
`8,383,338 B2
`8,383,345 B2
`8,455,193 B2
`8,470,996 B2
`8,481,292 B2
`8,603,749 B2
`8,685,678 B2
`8,697,408 B2
`8,704,165 B2
`8,715,967 B2
`8,722,368 B2
`8,728,766 B2
`8,741,606 B2
`8,775,092 B2
`8,835,358 B2
`8,865,410 B2
`9,018,365 B2
`9,085,798 B2
`9,260,753 B2
`9,340,830 B2
`9,376,719 B2
`9,404,156 B2
`9,476,095 B2
`9,598,731 B2
`9,752,188 B2
`9,834,822 B2
`9,840,743 B2
`9,920,366 B2
`10,287,631 B2
`10,370,713 B2
`10,385,393 B2
`10,388,403 B2
`2001/0053519 Al
`2002/0072058 A1
`2003/0003490 A1
`2003/0049616 A1
`2003/0104436 A1
`2003/0152490 A1
`2003/0165978 Al
`2003/0186251 A1
`2003/0207300 A1
`2004/0096892 Al
`2004/0146901 A1
`2004/0157243 A1
`2004/0209299 Al
`2004/0259118 Al
`2005/0164241 A1
`2005/0221314 A1
`2005/0250147 A1
`2006/0035258 Al
`2006/0046258 A1
`2006/0073506 A1
`2006/0211030 A1
`2007/0020640 A1
`2007/0065823 A1
`2007/0111233 A1
`2007/0128724 A1
`2007/0172839 A1
`2007/0172873 Al
`2008/0014146 Al
`2008/0124721 A1
`2008/0161420 A1
`2008/0261204 Al
`2008/0293055 Al
`2009/0029377 A1
`2009/0087847 Al
`2009/0098547 Al
`2009/0105959 Al
`2009/0162836 A1
`2009/0298075 Al
`2009/0298709 Al
`2009/0317818 A1
`2010/0041048 Al
`2010/0062494 Al
`2010/0069250 A1
`2010/0112575 Al
`
`7/2012 Disis et al .
`8/2012 Ronaghi et al .
`1/2013 Gocke et al .
`2/2013 Kitzman et al .
`2/2013 Shendure et al .
`6/2013 Travers et al .
`6/2013 Brenner
`7/2013 Casbon et al .
`12/2013 Gillevet
`4/2014 Casbon et al .
`4/2014 Kucera et al .
`4/2014 Huang
`5/2014 Casbon et al .
`5/2014 Casbon et al .
`5/2014 Casbon et al .
`6/2014 Casbon et al .
`7/2014 Colwell et al .
`9/2014 Fodor et al .
`10/2014 Shendure et al .
`4/2015 Brenner
`7/2015 Chee
`2/2016 Xie et al .
`5/2016 Lipson et al .
`6/2016 Eijk et al .
`8/2016 Hicks et al .
`10/2016 Vogelstein et al .
`3/2017 Talasaz
`9/2017 Schmitt et al .
`12/2017 Talasaz
`12/2017 Talasaz
`3/2018 Eltoukhy et al .
`5/2019 Salk et al .
`8/2019 Salk et al .
`8/2019 Salk et al .
`8/2019 Rava et al .
`12/2001 Fodor et al .
`6/2002 Voelker et al .
`1/2003 Fan et al .
`3/2003 Brenner et al .
`6/2003 Morris et al .
`8/2003 Trulson et al .
`9/2003 Firth et al .
`10/2003 Dunn et al .
`11/2003 Matray et al .
`5/2004 Wang et al .
`7/2004 Morris et al .
`8/2004 Huang et al .
`10/2004 Pinter et al .
`12/2004 Macevicz
`7/2005 Hahn et al .
`10/2005 Berlin et al .
`11/2005 Macevicz
`2/2006 Tadakamalla et al .
`3/2006 Lapidus et al .
`4/2006 Christians et al .
`9/2006 Brenner
`1/2007 McCloskey et al .
`3/2007 Dressman et al .
`5/2007 Bianchi et al .
`6/2007 Miles et al .
`7/2007 Smith et al .
`7/2007 Brenner et al .
`1/2008 Hoff et al .
`5/2008 Fuchs et al .
`7/2008 Shuber
`10/2008 Lexow
`11/2008 Freeman et al .
`1/2009 Lo et al .
`4/2009 Lo et al .
`4/2009 Ghosh
`4/2009 Braverman et al .
`6/2009 Widschwendter
`12/2009 Travers et al .
`12/2009 Ma
`12/2009 Ehrich et al .
`2/2010 Diehl et al .
`3/2010 Church et al .
`3/2010 White et al .
`5/2010 Fan et al .
`
`

`

`( 56 )
`
`References Cited
`U.S. PATENT DOCUMENTS
`6/2010 Lapidus
`2010/0143932 Al
`7/2010 Wong
`2010/0166744 Al
`8/2010 Sugarbaker et al .
`2010/0196898 A1
`2010/0264331 A1
`10/2010 Sacko et al .
`12/2010 Hamady et al .
`2010/0323348 A1
`12/2010 Robins et al .
`2010/0330571 Al
`1/2011 Jirtle et al .
`2011/0014607 A1
`6/2011 Fodor et al .
`2011/0160078 A1
`6/2011 Tewari
`2011/0160290 A1
`7/2011 Bhatt et al .
`2011/0171640 A1
`7/2011 Shuber
`2011/0177512 Al
`2011/0183330 A1
`7/2011 Lo et al .
`2011/0201507 Al
`8/2011 Rava et al .
`9/2011 Rava
`2011/0230358 A1
`9/2011 Stephan et al .
`2011/0230360 A1
`2011/0245482 A1
`10/2011 Hahn et al .
`10/2011 Chinitz et al .
`2011/0264376 A1
`11/2011 Byron et al .
`2011/0275084 A1
`2011/0281736 A1
`11/2011 Drmanac et al .
`2011/0319272 Al
`12/2011 Fan et al .
`2012/0003637 A1
`1/2012 Lo et al .
`2/2012 Sparks et al .
`2012/0034685 Al
`2/2012 Hyland et al .
`2012/0046877 A1
`2012/0053073 A1
`3/2012 Kassis
`3/2012 Hatchwell et al .
`2012/0059594 A1
`3/2012 Chee
`2012/0065081 A1
`4/2012 Halpern et al .
`2012/0095697 A1
`4/2012 Rava et al .
`2012/0100548 Al
`6/2012 Porreca et al .
`2012/0164630 A1
`2012/0165202 A1
`6/2012 Porreca et al .
`7/2012 Stuelpnagel et al .
`2012/0191367 Al
`8/2012 Downing et al .
`2012/0208706 Al
`8/2012 Sugarbaker et al .
`2012/0214163 A1
`2012/02 14678 A1
`8/2012 Rava et al .
`2012/0220478 Al
`8/2012 Shaffer
`2012/0231479 A1
`9/2012 Puskas et al .
`2012/0238464 A1
`9/2012 Koi et al .
`2012/0270212 A1
`10/2012 Rabinowitz et al .
`2012/0316074 A1
`12/2012 Saxonov
`12/2012 Kung et al .
`2012/0322681 A1
`1/2013 Anderson et al .
`2013/0005585 A1
`1/2013 Benz et al .
`2013/0017958 A1
`1/2013 Lapidus et al .
`2013/0022977 Al
`2013/0029852 Al
`1/2013 Rava et al .
`2013/0034546 Al
`2/2013 Rava et al .
`2013/0040824 A1
`2/2013 Lo et al .
`2/2013 Hubbell
`2013/0053256 A1
`2013/0060483 Al
`3/2013 Struble et al .
`2013/0078626 A1
`3/2013 Wasserstrom et al .
`4/2013 Deciu et al .
`2013/0085681 Al
`4/2013 Lee
`2013/0102485 Al
`2013/0102487 A1
`4/2013 Cos et al .
`5/2013 Schuetz et al .
`2013/0116127 A1
`5/2013 Fu et al .
`2013/0116130 A1
`5/2013 Morris et al .
`2013/0122499 Al
`2013/0130923 Al
`5/2013 Ehrich et al .
`5/2013 Shendure et al .
`2013/0137588 A1
`2013/0143747 A1
`6/2013 Gutin et al .
`2013/02 10643 A1
`8/2013 Casbon et al .
`8/2013 Volgelstein et al .
`2013/0210645 A1
`2013/0224743 A1
`8/2013 Casbon et al .
`2013/0237431 A1
`9/2013 Lo et al .
`2013/0237458 A1
`9/2013 Casbon et al .
`2013/0260381 A1
`10/2013 Ramakrishnan
`10/2013 Casbon et al .
`2013/0267424 Al
`12/2013 Deciu et al .
`2013/0338933 A1
`1/2014 Couronne
`2014/0011694 Al
`2014/0065609 A1
`3/2014 Hicks et al .
`2014/0065630 Al
`3/2014 Bubnoff et al .
`3/2014 Talasaz
`2014/0066317 A1
`2014/0100121 A1
`4/2014 Lo et al .
`8/2014 Boom et al .
`2014/0242588 Al
`9/2014 Raymond et al .
`2014/0274731 Al
`9/2014 Srinivasan et al .
`2014/0274740 A1
`10/2014 Domanus
`2014/0296094 A1
`
`Case 1:20-cv-01580-LPS Document 9-4 Filed 12/10/20 Page 4 of 61 PageID #: 862
`
`US 10,704,085 B2
`Page 3
`
`2014/0303008 A1
`2014/0336943 A1
`2014/0350130 A1
`2014/0357500 A1
`2015/0004158 Al
`2015/0024950 A1
`2015/0044687 Al
`2015/0050647 A1
`2015/0051085 A1
`2015/0065358 A1
`2015/0080266 A1
`2015/0087535 A1
`2015/0167069 Al
`2015/0197786 Al
`2015/0275289 A1
`2015/0299812 A1
`2015/0329917 Al
`2015/0344970 A1
`2015/0366866 Al
`2015/0368708 A1
`2016/0002739 A1
`2016/0002741 A1
`2016/0024576 A1
`2016/0026758 A1
`2016/0032396 Al
`2016/0040229 Al
`2016/0046986 A1
`2016/0053301 A1
`2016/0060691 Al
`2016/0071432 A1
`2016/0115553 Al
`2016/0130649 Al
`2016/0251704 A1
`2016/0319345 A1
`2016/0376647 A1
`2017/0051347 A1
`2017/0073774 Al
`2017/0145516 A1
`2017/0159120 A1
`2017/0211143 A1
`2017/02 18459 Al
`2017/02 18460 A1
`2018/0023125 A1
`2019/0271040 A1
`2019/0292597 A1
`2019/0338358 A1
`2019/0352714 Al
`
`10/2014 Schutz et al .
`11/2014 Pellini et al .
`11/2014 Sanborn et al .
`12/2014 Vigneault et al .
`1/2015 Shipp et al .
`1/2015 Bielas et al .
`2/2015 Schmitt et al .
`2/2015 Luo et al .
`2/2015 Vogelstein et al .
`3/2015 Comstock et al .
`3/2015 Volkmuth et al .
`3/2015 Patel
`6/2015 Schutz et al .
`7/2015 Osborne et al .
`10/2015 Otwinowski et al .
`10/2015 Talasaz
`11/2015 Shuber
`12/2015 Vogelstein et al .
`12/2015 Ali et al .
`12/2015 Talasaz
`1/2016 Schütz et al .
`1/2016 Kitano et al .
`1/2016 Chee
`1/2016 Jabara et al .
`2/2016 Diehn et al .
`2/2016 Talasaz et al .
`2/2016 Eltoukhy et al .
`2/2016 Raymond et al .
`3/2016 Giresi et al .
`3/2016 Kurowski et al .
`4/2016 Stephan et al .
`5/2016 Xie et al .
`9/2016 Talasaz et al .
`11/2016 Gnerre et al .
`12/2016 Travers et al .
`2/2017 Vogelstein et al .
`3/2017 Lo et al .
`5/2017 Kopetz et al .
`6/2017 Eijk et al .
`7/2017 Shendure et al .
`8/2017 Talasaz et al .
`8/2017 Talasaz
`1/2018 Talasaz et al .
`9/2019 Salk et al .
`9/2019 Salk et al .
`11/2019 Salk et al .
`11/2019 Salk et al .
`
`FOREIGN PATENT DOCUMENTS
`6/2006
`1647600 A2
`10/2009
`2110442 A1
`9/2016
`3070177 A1
`6/2017
`3178941 A1
`1997007241 A1
`2/1997
`1997010365 Al
`3/1997
`6/1999
`1999028505 Al
`10/2000
`2000058516 A2
`7/2002
`2002056014 A2
`9/2005
`2005080604 A2
`11/2005
`2005111242 A2
`9/2006
`2006102264 A1
`4/2007
`2007037678 A2
`6/2008
`2008070144 A2
`12/2008
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`12/2009
`2009152928 A2
`5/2011
`2011060240 A1
`7/2011
`2011087760 A2
`2011091046 A1
`7/2011
`8/2011
`2011103236 A2
`2011140510 A2
`11/2011
`12/2011
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`1/2012
`2012012693 A2
`2/2012
`2012014877 A1
`2/2012
`2012019200 A2
`2012028746 A1
`3/2012
`3/2012
`2012038839 A2
`2012042374 A2
`4/2012
`4/2012
`2012048341 A1
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`
`References Cited
`FOREIGN PATENT DOCUMENTS
`
`2012054873 A2
`2012066451 A1
`2012071621 A1
`2012088348 A2
`2012106559 Al
`2012129363 A2
`2012142213 A2
`2012142611 A2
`2012103031 A3
`2013019075 A2
`2013033721 A1
`2013106737 A1
`2013123442 A1
`2013130512 A2
`2013130674 A1
`2013138510 Al
`2013142213 Al
`2013142389 Al
`2013148496 Al
`2013159035 A2
`2013173394 A2
`2013181170 A1
`2013188471 A2
`2013190441 A2
`2014004726 Al
`2014014497 A1
`2014015319 A1
`2014039556 A1
`2014093330 A1
`2014145078 A1
`2014151117 A1
`2014152990 A1
`2015159293 A2
`2016015058 A2
`2016040901 A1
`2017100441 A1
`2017181146 A1
`
`4/2012
`5/2012
`6/2012
`6/2012
`8/2012
`9/2012
`10/2012
`10/2012
`1/2013
`2/2013
`3/2013
`7/2013
`8/2013
`9/2013
`9/2013
`9/2013
`9/2013
`9/2013
`10/2013
`10/2013
`11/2013
`12/2013
`12/2013
`12/2013
`1/2014
`1/2014
`1/2014
`3/2014
`6/2014
`9/2014
`9/2014
`9/2014
`10/2015
`1/2016
`3/2016
`6/2017
`10/2017
`
`OTHER PUBLICATIONS
`Pel , J. et al . “ Duplex proximity sequencing ( pro - seq ) : A method to
`improve DNA sequencing accuracy without the cost of molecular
`barcoding redundancy ” bioRxiv ( 2017 ) https://doi.org/10.1101/
`163444 .
`Perakis , S. et al . “ Advances in Circulating Tumor DNA Analysis ”
`Adv Clin Chem ( 2017 ) pp . 1-81 .
`Pihlak , et al . Rapid genome sequencing with short universal tiling
`probes . Nature Biotechnology , 26 : 676-684 ( 2008 ) .
`Pinkel , et al . Comparative Genomic Hybridization . Annual Review
`of Genomics and Human Genetics , 6 : 331-354 ( 2005 ) .
`Pleasance , et al . A small - cell lung cancer genome with complex
`signatures of tobacco exposure . Nature . Jan. 14 , 2010 ; 463 ( 7278 ) : 184
`90. doi : 10.1038 / nature08629 . Epub Dec. 16 , 2009 .
`Pollack , et al . Genome - wide analysis of DNA copy - number changes
`using cDNA microarrays . Nat Genet . Sep. 1999 ; 23 ( 1 ) : 41-6 .
`Qiu , et al . DNA sequence - based “ bar codes ” for tracking the origins
`of expressed sequence tags from a maize cDNA library constructed
`using multiple mRNA sources . Plant Physiol . Oct. 2003 ; 133 ( 2 ) : 475
`81 .
`Quail , et al . A large genome center's improvements to the Illumina
`sequencing system . Nat Methods . Dec. 2008 ; 5 ( 12 ) : 1005-10 . doi :
`10.1038 / nmeth.1270 .
`Quinlan , A.R. et al . , " Pyrobayes : an improved base caller for SNP
`discovery in pyrosequences , ” Nat . Methods 2008 5 ( 2 ) , 179-181 .
`Rafi , I. et al . “ Cell - free fetal DNA and non - invasive prenatal
`diagnosis , ” Br . J. Gen. Pract . May 1 , 2009 ; 59 ( 562 ) : e146 - e148 .
`Rand , et al . Headloop suppression PCR and its application to
`selective amplification of methylated DNA sequences . Nucleic
`Acids Res . Aug. 9 , 2005 ; 33 ( 14 ) : e127 .
`Redon , R. et al . , “ Global variation in copy number in the human
`genome , ” Nature 2006 444 ( 7118 ) , 444-454 .
`
`Rizzo , J.M. et al . “ Key Principles and Clinical Applications of ‘ Next
`Generation ' DNA Sequencing , ” Cancer Prev . Res . , ( 2012 ) 5 , 887
`900 .
`Ryan , et al . A prospective study of circulating mutant KRAS2 in the
`serum of patients with colorectal neoplasia : strong prognostic
`indicator in postoperative follow up . Gut . Jan. 2003 ; 52 ( 1 ) : 101-8 .
`Rygaard , et al . Abnormalities in structure and expression of the
`retinoblastoma gene in small cell lung cancer cell lines and xenografts
`in nude mice . Cancer Res . Sep. 1 , 1990 ; 50 ( 17 ) : 5312-7 .
`Sanger , F. et al . “ DNA sequencing with chain - terminating inhibi
`tors ” PNAS ( 1977 ) 74 ( 12 ) : 5463-5467 .
`Sausen , M. et al . “ Integrated genomic analyses identify ARIDIA
`and ARIDIB alterations in the childhood cancer neuroblastoma ” ,
`Nature Genetics 2013 , 45 ( 1 ) , 12-17 .
`Schmitt et al . Supplemental Information http://www.pnas.org/content/
`suppl / 2012 / 08 / 01 / 1208715109 . DCSupplemental .
`Schmitt , et al . Detection of ultra - rare mutations by next - generation
`sequencing . Proc Natl Acad Sci USA . Sep. 4 , 2012 ; 109 ( 36 ) : 14508
`13. doi : 10.1073 / pnas.1208715109 . Epub Aug. 1 , 2012 .
`Schwarzenbach , et al . A critical evaluation of loss of heterozygosity
`detected in tumor tissues , blood serum and bone marrow plasma
`from patients with breast cancer . Breast Cancer Res . 2007 ; 9 ( 5 ) : R66 .
`Schwarzenbach , et al . Cell - free tumor DNA in blood plasma as a
`marker for circulating tumor cells in prostate cancer . Clin Cancer
`Res . Feb. 1 , 2009 ; 15 ( 3 ) : 1032-8 . doi : 10.1158 / 1078-0432.CCR - 08
`1910 .
`Schwarzenback , H. et al . “ Cell - free nucleic acids as biomarkers in
`cancer patients ” Nature Reviews Cancer ( 2011 ) 11 : 426-437 .
`Schweiger et al . , “ Genome - wide massively parallel sequencing of
`formaldehyde fixed - paraffin embedded ( FFPE ) tumor tissues for
`copy - number- and mutation - analysis , ” PLoS One 2009 , 4 ( 5 ) , e5548 .
`Sebat , et al . Large - Scale Copy Number Polymorphism in the
`Human Genome . Science , 305 : 525-528 ( 2004 ) .
`Sehnert , A.J. et al . “ Optimal Detection of Fetal Chromosomal
`Abnormalities by Massively Parallel DNA Sequencing of Cell - Free
`Fetal DNA from Maternal Blood ” Clin Chem ( 2011 ) 57 ( 7 ) : 1042
`1049 .
`Shaw et al . Genomic analysis of circulating cell - free DNA infers
`breast cancer dormancy . Genome Research 22 ( 2 ) : 220-231 ( Feb.
`2012 ) .
`Shaw , et al . Microsatellite alterations plasma DNA of primary breast
`cancer patients . Clin Cancer Res . Mar. 2000 ; 6 ( 3 ) 1119-24 .
`Shendure , J. et al . “ Next - generation DNA sequencing , " Nat . Biotechnol .
`2008 26 ( 10 ) , 1135-1145 .
`Shinozaki , et al . Utility of circulating B - RAF DNA mutation in
`serum for monitoring melanoma patients receiving biochemotherapy .
`Clin Cancer Res . Apr. 1 , 2007 ; 13 ( 7 ) 2068-74 .
`Shiroguchi , et al . Digital RNA sequencing minimizes sequence
`dependent bias and amplification noise with optimized single
`molecule barcodes . Proc Natl Acad Sci US A. Jan. 24 ,
`2012 ; 109 ( 4 ) : 1347-52 . doi : 10.1073 / pnas.1118018109 . Epub Jan. 9 ,
`2012 .
`Shoemaker , et al . Quantitative phenotypic analysis of yeast deletion
`mutants using a highly parallel molecular bar - coding strategy .
`Nature Genetics , 14 : 450-456 ( 1996 ) .
`Simpson , et al . Copy number variant detection in inbred strains from
`short read sequence data . Bioinformatics . Feb. 15 , 2010 ; 26 ( 4 ) : 565
`7. doi : 10.1093 / bioinformatics / btp693 . Epub Dec. 18 , 2009 .
`Smith , et al . Highly - multiplexed barcode sequencing : an efficient
`method for parallel analysis of pooled samples . Nucleic Acids
`Research , 38 ( 13 ) : e142 ( 2010 ) .
`Smith , T.F. et al . “ Comparison of Biosequences ” Adv App Math
`( 1981 ) 2 : 482-489 .
`Sorenson , et al . Soluble normal and mutated DNA sequences from
`single - copy genes in human blood . Cancer Epidemiol Biomarkers
`Prev . Jan. - Feb . 1994 ; 3 ( 1 ) : 67-71 .
`Sparks , et al . Selective analysis of cell - free DNA in maternal blood
`for evaluation of fetal trisomy . Prenat Diagn . Jan. 2012 ; 32 ( 1 ) : 3-9 .
`doi : 10.1002 / pd . 2922. Epub Jan. 6 , 2012 .
`Stein , et al . “ The case for cloud computing in genome informatics ” ,
`Genome Biol . 2010 ; 11 ( 5 ) : 207 . Epub May 5 , 2010 .
`Steinman . Free DNA in serum and plasma from normal adults . J
`Clin Invest . Aug. 1975 ; 56 ( 2 ) : 512-5 .
`
`Case 1:20-cv-01580-LPS Document 9-4 Filed 12/10/20 Page 5 of 61 PageID #: 863
`
`

`

`US 10,704,085 B2
`Page 5
`
`( 56 )
`
`References Cited
`OTHER PUBLICATIONS
`Stitziel , et al . Computational and statistical approaches to analyzing
`variants identified byexome sequencing . Genome Biol . Sep. 14 ,
`2011 ; 12 ( 9 ) : 227 . doi : 10.1186 / gb - 2011-12-9-227 .
`Stroun , M , et al , “ About the possible orgin and mechanism of
`circulating DNA apoptosis and active DNA release " , Clin Chim
`Acta , vol . 313 , No. 1-2 , pp . 139-142 , ( 2001 ) .
`Stumm , M. et al . “ Noninvasive prenatal detection of chromosomal
`aneuploidies using different next generation sequencing strategies
`and algorithms ” Prenatal Diagnosis ( 2012 ) 32 : 569-577 .
`Taback , et al . Detection of tumor - specific genetic alterations in bone
`marrow from early - stage breast cancer patients . Cancer Res . Apr.
`15 , 2003 ; 63 ( 8 ) : 1884-7 .
`Tan , et al . Genome - wide comparison of DNA hydroxymethylation
`in mouse embryonic stem cells and neural progenitor cells by a new
`comparative hMeDIP - seq method . Nucleic Acids Res . Apr.
`2013 ; 41 ( 7 ) : e84 . doi : 10.1093 / nar / gkt091 . Epub Feb. 13 , 2013 .
`Taudien , et al . Haplotyping and copy number estimation of the
`highly polymorphic human beta - defensin locus on 8p23 by 454
`amplicon sequencing . BMC Genomics . Apr. 19 , 2010 ; 11 : 252 . doi :
`10.1186 / 1471-2164-11-252 .
`Teer , J.K. et al . “ Systematic comparison of three genomic enrich
`ment methods for massively parallel DNA sequencing ” Genome
`Res ( 2010 ) 20 ( 10 ) : 1420-1431 .
`Tie , J. et al . , “ Circulating tumor DNA analysis detects minimal
`residual disease and predicts recurrence in patients with stage II
`colon cancer , ” Sci . Transl . Med . 2016 , 8 ( 346 ) : 346ra92 .
`Tomaz , et al . Differential methylation as a cause of allele dropout at
`the imprinted GNAS locus . Genet Test Mol Biomarkers . Aug.
`2010 ; 14 ( 4 ) : 455-60 . doi : 10.1089 / gtmb.2010.0029 .
`Tomlinson , et al . A genome - wide association scan of tag SNPs
`identifies a susceptibility variant for colorectal cancer at 8q24.21 .
`Nat Genet . Aug. 2007 ; 39 ( 8 ) : 984-8 . Epub Jul . 8 , 2007 .
`IPR2019-00130 , Preliminary Response to Petition for Inter Partes
`Review U.S. Pat . No. 9,598,731 , filed Mar. 6 , 2019 .
`IPR2019-00634 , Decision Instituting Inter Partes Review U.S. Pat .
`No. 9,840,743 , dated Aug. 19 , 2019 .
`IPR2019-00634 , Petition for Inter Partes Review of U.S. Pat . No.
`9,840,743 , dated Feb. 1 , 2019 .
`IPR2019-00636 & 637 , Exhibit 3001 Memo for Inter Partes Review
`of U.S. Pat . No. 9,902,992 , dated Jul . 1 , 2019 .
`IPR2019-00636 & 637 , Order Conduct of the Proceedings for
`Inter Partes Review of U.S. Pat . No.9,902,992 , dated Jul . 22 , 2019 .
`IPR2019-00636 and IPR 2019-00637 , Decision Denying Inter Partes
`Review U.S. Pat . No. 9,902,992 , issued Aug. 20 , 2019 .
`IPR2019-00636 , Petition for Inter Partes Review of U.S. Pat . No.
`9,902,992 , dated Feb. 1 , 2019 .
`IPR2019-00637 , Petition for Inter Partes Review of U.S. Pat . No.
`9,902,992 , dated Feb. 1 , 2019 .
`IPR2019-00652 , Decision Granting Inter Partes Review U.S. Pat .
`No. 9,834,822 , issued Aug. 19 , 2019 .
`IPR2019-00652 , Petition for Inter Partes Review of U.S. Pat . No.
`9,834,822 , dated Feb. 1 , 2019 .
`IPR2019-00653 , Decision Denying Inter Partes Review U.S. Pat .
`No. 9,834,822 , issued Aug. 19 , 2019 .
`IPR2019-00653 , Petition for Inter Partes Review of U.S. Pat . No.
`9,834,822 , dated Feb. 1 , 2019 .
`Jabara , C. Capturing the cloud : High throughput sequencing of
`multiple individual genomes from a retroviral population . Biology
`Lunch Bunch Series , Training Initiatives in Biomedical & Biologi
`cal Sciences of the University of North Carolina at Chapel Hill , Apr.
`23 , 2010 .
`Jabara , et al . Accurate sampling and deep sequencing of the HIV - 1
`protease gene using a Primer ID . ( Paper # 665 ) , The 18th Annual
`Conference on Retroviruses and Opportunistic Infections , Boston ,
`Massachusetts , Mar. 2011 .
`Jabara , et al . Accurate sampling and deep sequencing of the HIV - 1
`protease gene using a Primer ID . Proc Natl Acad Sci USA . Dec.
`13 , 2011 ; 108 ( 50 ) : 20166-71 . doi : 10.1073 / pnas.1110064108 . Epub
`Nov. 30 , 2011 .
`
`Jahr , et al . DNA fragments in the blood plasma of cancer patients :
`quantitations and evidence for their origin from apoptotic and
`necrotic cells . Cancer Res . Feb. 15 , 2001 ; 61 ( 4 ) : 1659-65 .
`Jeronimo , et al . Quantitative GSTP1 hypermethylation in bodily
`fluids of patients with prostate cancer . Urology . Dec. 2002 ; 60 ( 6 ) : 1131
`5 .
`Jiang , H. et al . , " SeqMap : mapping massive amount of oligonucle
`otides to the genome , ” Bioinformatics 2008 , 24 ( 20 ) : 2395-2396 .
`Kanagawa . Bias and artifacts in multitemplate polymerase chain
`reactions ( PCR ) , 2003 , Journal of Bioscience and Bioengineering ,
`vol . 96 , No. 4 , p . 317-323 .
`Kao , W - C . et al . , “ BayesCall : A model - based base - calling algorithm
`for high - throughput short - read sequencing , " Genome Res . 2009
`19 ( 10 ) , 1884-1895 .
`Karow , J. “ Hopkins Team Develops Method to Improve Rare
`Mutation Detection for Early Cancer Dx ” Genome Web ( 2011 ) 3
`pages .
`Kennedy , S.R. et al . , “ Detecting ultralow - frequency mutations by
`Duplex Sequencing , ” Nat . Protoc . 2014 , 9 ( 11 ) , 2586-2606 .
`Kimura , et al . EGFR mutation status in tumour - derived DNA from
`pleural effusion fluid is a practical basis for predicting the response
`to gefitinib . Br J Cancer . Nov. 20 , 2006 ; 95 ( 10 ) : 1390-5 . Epub Oct.
`24 , 2006 .
`Kinde , et al . Detection and quantification of rare mutations with
`massively parallel sequencing . Proc Natl Acad Sci US A. Jun . 7 ,
`2011 ; 108 ( 23 ) : 9530-5 . doi : 10.1073 / pnas.1105422108 . Epub May
`17 , 2011 .
`Kinde , et al . Supplemental Information , Detection and quantifica
`tion of rare mutations with massively parallel sequencing . Proc Natl
`Acad Sci US A. Jun . 7 , 2011 ; 108 ( 23 ) : 1-10 .
`Kinde , I. et al . , “ Evaluation of DNA from the Papanicolaou Test to
`Detect Ovarian and Endometrial Cancers , ” Sci . Transl . Med . 2013 ,
`5 ( 167 ) : 167ra4 .
`Kinde , I. et al . , “ FAST - SeqS : a simple and efficient method for the
`detection of aneuploidy by massively parallel sequencing , ” PLOS
`One 2012 , 7 ( 7 ) , e41162 .
`Kircher , M. et al . , “ Improved base calling for the Illumina Genome
`Analyzer using machine learning strategies , ” Genome Biol . 2009 ,
`10 ( 8 ) , R83 .
`Kirsch , S. et al . “ Sequence error storms and the landscape of
`mutations in cancer , ” Proc . Natl . Acad . Sci . USA 2012 , 109 ( 36 ) ,
`14289-14290 .
`Kivioja , T. , et al . Counting absolute numbers of molecules using
`unique molecular identifiers . Nat Methods . Nov. 20 , 2011 ; 9 ( 1 ) : 72-4 .
`doi : 10.1038 / nmeth.1778 .
`Koboldt , D.C.et al . , “ The next - generation sequencing revolution
`and its impact on genomics , ” Cell 2013 , 155 ( 1 ) , 27-38 .
`Koboldt , et al . Massively parallel sequencing approaches for char
`acterization of structural variation . Aug. 12 , 2011. Methods Mol
`Biol . 2012,838 : 369-84 . doi : 10.1007 / 978-1-61779-507-7_18 .
`Kolble , et al . Microsatellite alterations in serum DNA of patients
`with colorectal cancer . Lab Invest . Sep. 1999 ; 79 ( 9 ) : 1145-50 .
`Konig , et al . iCLIP reveals the function of hnRNAP particles in
`splicing at individual nucleotide resolution , Jul . 2010 , Nature Struc
`tural & Molecular Biology , 17 ( 7 ) : 909-916 .
`Kopreski , et al . Detection of mutant K - ras DNA in plasma or serum
`of patients with colorectal cancer . Br J Cancer . 1997 ; 76 ( 10 ) : 1293-9 .
`Korbel , J.O. et al . , “ Paired - end mapping reveals extensive structural
`variation in the human genome , ” Science 2007 , 318 ( 5849 ) , 420
`426 .
`Koyanagi , et al . Association of circulating tumor cells with serum
`tumor - related methylated DNA in peripheral blood of melanoma
`patients . Cancer Res . Jun . 15 , 2006 ; 66 ( 12 ) : 6111-7 .
`Krimmel , J.D. et al . , “ Ultra - deep sequencing detects ovarian cancer
`cells in peritoneal fluid and reveals somatic TP53 mutations in
`noncancerous tissues , ” Proc . Natl . Acad . Sci . USA 2016 , 113 ( 21 ) ,
`6005-6010 .
`Kukita , Y. et al . “ High - fidelity target sequencing of individual
`molecules identified using barcode sequences : de novo detection
`and absolute quantitation of mutations in plasma cell - free DNA
`from cancer patients ” DNA Research ( 2015 ) 22 ( 4 ) : 269-277 .
`
`Case 1:20-cv-01580-LPS Document 9-4 Filed 12/10/20 Page 6 of 61 PageID #: 864
`
`

`

`US 10,704,085 B2
`Page 6
`
`( 56 )
`
`References Cited
`OTHER PUBLICATIONS
`Lam , et al . Plasma DNA as a prognostic marker for stroke patients
`with negative neuroimaging within the first 24 h of symptom onset .
`Resuscitation . Jan. 2006 ; 68 ( 1 ) : 71-8 . Epub Dec. 1 , 2005 .
`Lanman , et al . , Analytical and Clinical Validation of a Digital
`Sequenci