Case 1:20-cv-01580-LPS Document 1-6 Filed 11/23/20 Page 1 of 57 PageID #: 325
`Case 1:20-cv-01580-LPS Document 1-6 Filed 11/23/20 Page 1 of 57 PageID #: 325
`
`
`
`
`
`EXHIBIT 6
`
`EXHIBIT 6
`
`

`

`| HAO WANAT HA MARIA DEL CONTRA LA WA MIAKA MIT
`
`US009840743B2
`
`( 12 ) United States Patent
`Talasaz
`
`( 10 ) Patent No . :
`( 45 ) Date of Patent :
`
`US 9 , 840 , 743 B2
`* Dec . 12 , 2017
`
`( * ) Notice :
`
`( 2006 . 01 )
`( 2006 . 01 )
`( 2006 . 01 )
`( 2011 . 01 )
`
`( 52 )
`
`( 54 ) SYSTEMS AND METHODS TO DETECT
`RARE MUTATIONS AND COPY NUMBER
`VARIATION
`( 71 ) Applicant : Guardant Health , Inc . , Redwood City ,
`CA ( US )
`( 72 ) Inventor : Amir Ali Talasaz , Menlo Park , 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 . : 15 / 467 , 570
`( 22 ) Filed :
`Mar . 23 , 2017
`Prior Publication Data
`( 65 )
`US 2017 / 0218459 A1 Aug . 3 , 2017
`Related U . S . Application Data
`( 63 ) Continuation of application No . 14 / 425 , 189 , filed as
`application No . PCT / US2013 / 058061 on Sep . 4 ,
`2013 .
`( 60 ) Provisional application No . 61 / 845 , 987 , filed on Jul .
`13 , 2013 , provisional application No . 61 / 793 , 997 ,
`filed on Mar . 15 , 2013 , provisional application No .
`61 / 704 , 400 , filed on Sep . 21 , 2012 , provisional
`application No . 61 / 696 , 734 , filed on Sep . 4 , 2012 .
`( 51 ) Int . Ci .
`C12P 19 / 34
`C120 1 / 68
`C12N 15 / 10
`GO6F 19 / 22
`U . S . CI .
`CPC . . . . . . . C12Q 1 / 6886 ( 2013 . 01 ) ; C12N 15 / 1065
`( 2013 . 01 ) ; C12Q 1 / 6806 ( 2013 . 01 ) ; C120
`1 / 6869 ( 2013 . 01 ) ; C12Q 1 / 6874 ( 2013 . 01 ) ;
`GO6F 19 / 22 ( 2013 . 01 ) ; C12Q 2600 / 118
`( 2013 . 01 ) ; C12Q 2600 / 156 ( 2013 . 01 ) ; C12Q
`2600 / 158 ( 2013 . 01 ) ; C12Q 2600 / 16 ( 2013 . 01 )
`Field of Classification Search
`. . . . . . . 435 / 91 . 1 , 91 . 2
`USPC
`See application file for complete search history .
`References Cited
`U . S . PATENT DOCUMENTS
`4 , 725 , 536 A
`2 / 1988 Fritsch et al .
`4 , 942 , 124 A
`7 / 1990 Church
`5 , 124 , 246 A
`6 / 1992 Urdea et al .
`9 / 1992 Church et al .
`5 , 149 , 625 A
`4 / 1993 Urdea
`5 , 200 , 314 A
`6 / 1995 Fodor et al .
`5 , 424 , 186 A
`6 / 1995 Hogan et al .
`5 , 424 , 413 A
`8 / 1995 Fodor et al .
`5 , 445 , 934 A
`2 / 1997 Brenner
`5 , 604 , 097 A
`
`Case 1:20-cv-01580-LPS Document 1-6 Filed 11/23/20 Page 2 of 57 PageID #: 326
`
`. . . . . . .
`
`( 58 )
`
`( 56 )
`
`CN
`EP
`
`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
`5 , 981 , 176 A
`5 , 981 , 179 A
`
`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 .
`11 / 1999 Wallace
`11 / 1999 Lorinez et al .
`( Continued )
`FOREIGN PATENT DOCUMENTS
`102933721 A
`2 / 2013
`0799897 Al 10 / 1997
`( Continued )
`OTHER PUBLICATIONS
`Alkan , et al . Personalized copy number and segmental duplication
`maps using next - generation sequencing . Nat Genet . Oct .
`2009 ; 41 ( 10 ) : 1061 - 7 . doi : 10 . 1038 / ng . 437 . Epub Aug . 30 , 2009 .
`Andersson , et al . Bayesian detection of periodic mRNA time
`profiles without use of training examples . BMC Bioinformatics .
`Feb . 9 , 2006 ; 7 : 63 .
`Angeloni , D . Molecular analysis of deletions in human chromosome
`3p21 and the role of resident cancer genes in disease . Brief Funct
`Genomic Proteomic . Mar . 2007 ; 6 ( 1 ) : 19 - 39 . Epub May 24 , 2007 .
`Ansorge . Next - generation DNA sequencing techniques . New Bio
`technology , 25 ( 4 ) : 195 - 203 ( 2009 ) .
`Appel , Maryke . Part II : It ' s all about conversion . Kapa Biosystems .
`Accessed Mar . 29 , 2017 . Printed Apr . 11 , 2017 . 5 pages . URL : <
`https : / / www . kapabiosytems . com / ngs / part - ii - conversion / > .
`Ashford , Monica . NGS Error Correction Method Described at
`AACR as Excitement Grows for Early Cancer Detection .
`Genomeweb . com . Apr . 5 , 2017 . 3 pages . URL : < https : / / www .
`genomeweb . com / cancer / ngs - error - correction - method - described
`aacr - excitement - grows - early - cancer - detection > .
`( Continued )
`Primary Examiner — Kenneth Horlick
`( 74 ) Attorney , Agent , or Firm — Wilson Sonsini Goodrich
`& Rosati
`ABSTRACT
`( 57 )
`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 .
`26 Claims , 16 Drawing Sheets
`
`

`

`( 56 )
`
`References Cited
`U . S . PATENT DOCUMENTS
`6 , 013 , 445 A
`1 / 2000 Albrecht et al .
`6 , 020 , 124 A
`2 / 2000 Sorenson
`6 , 040 , 138 A
`3 / 2000 Lockhart et al .
`6 , 046 , 005 A
`4 / 2000 Ju et al .
`6 , 060 , 596 A
`5 / 2000 Lerner et al .
`6 , 117 , 631 A
`9 / 2000 Nilsen
`6 , 124 , 092 A
`9 / 2000 O ' Neill et al .
`6 , 138 , 077 A
`10 / 2000 Brenner
`6 , 140 , 489 A
`10 / 2000 Brenner
`6 , 172 , 214 B1
`1 / 2001 Brenner
`6 , 197 , 506 B1
`3 / 2001 Fodor et al .
`6 , 235 , 475 B1
`5 / 2001 Brenner et al .
`6 , 242 , 186 B1
`6 / 2001 Salonen
`6 , 268 , 152 B1
`7 / 2001 Fodor et al .
`6 , 284 , 460 B1
`9 / 2001 Fodor et al .
`6 , 300 , 077 B1 10 / 2001 Shuber et al .
`6 , 309 , 822 B1 10 / 2001 Fodor et al .
`6 , 309 , 823 B1 10 / 2001 Cronin et al .
`6 , 326 , 148 B1 12 / 2001 Pauletti et al .
`6 , 355 , 431 B1 . 3 / 2002 Chee et al .
`6 , 355 , 432 B1
`3 / 2002 Fodor et al .
`6 , 395 , 491 B1
`5 / 2002 Fodor et al .
`6 , 406 , 848 B1 .
`6 / 2002 Bridgham et al .
`6 , 440 , 667 B1
`8 / 2002 Fodor et al .
`6 , 440 , 706 B1
`8 / 2002 Vogelstein et al .
`6 , 451 , 536 B1
`9 / 2002 Fodor et al .
`6 , 458 , 530 B1
`10 / 2002 Morris et al .
`6 , 468 , 744 B110 / 2002 Cronin et al .
`6 , 489 , 114 B2 12 / 2002 Laayoun et al .
`6 , 492 , 121 B2 12 / 2002 Kurane et al .
`6 , 498 , 012 B2 12 / 2002 Laken
`6 , 503 , 718 B21 / 2003 Shuber et al .
`6 , 512 , 105 B11 / 2003 Hogan et al .
`6 , 514 , 699 B1
`2 / 2003 O ' Neill et al .
`6 , 544 , 739 B1
`4 / 2003 Fodor et al .
`6 , 551 , 784 B2
`4 / 2003 Fodor et al .
`6 , 576 , 424 B2
`6 / 2003 Fodor et al .
`6 , 582 , 908 B2
`6 / 2003 Fodor et al .
`6 , 586 , 177 B1
`7 / 2003 Shuber
`6 , 600 , 996 B2
`7 / 2003 Webster et al .
`6 , 629 , 040 B1
`9 / 2003 Goodlett et al .
`6 , 653 , 077 B1 11 / 2003 Brenner
`6 , 753 , 147 B2
`6 / 2004 Vogelstein et al .
`6 , 849 , 403 B1
`2 / 2005 Shuber
`6 , 849 , 404 B2
`2 / 2005 Park et al .
`6 , 852 , 488 B2
`2 / 2005 Fodor et al .
`6 , 858 , 412 B2
`2 / 2005 Willis et al .
`6 , 964 , 846 B1 11 / 2005 Shuber
`7 , 163 , 789 B2
`1 / 2007 Chen et al .
`7 , 208 , 275 B2
`4 / 2007 Gocke et al .
`7 , 410 , 764 B2
`8 / 2008 Gocke et al .
`7 , 424 , 368 B2
`9 / 2008 Huang et al .
`7 , 424 , 371 B2
`9 / 2008 Kamentsky
`7 , 537 , 897 B2
`5 / 2009 Brenner et al .
`AN
`7 , 700 , 286 B2
`4 / 2010 Stroun et al .
`7 , 727 , 720 B2
`6 / 2010 Dhallan
`7 , 803 , 929 B2
`9 / 2010 Melkonyan et al .
`7 , 811 , 757 B2
`10 / 2010 Shuber
`7 , 822 , 555 B2 10 / 2010 Huang et al .
`7 , 824 , 889 B2 11 / 2010 Vogelstein et al .
`7 , 838 , 647 B2 11 / 2010 Hahn et al .
`7 , 915 , 015 B2
`3 / 2011 Vogelstein et al .
`7 , 935 , 487 B2
`5 / 2011 Gocke et al .
`7 , 937 , 225 B2
`5 / 2011 Mishra et al .
`7 , 957 , 913 B2
`6 / 2011 Chinitz et al .
`7 , 972 , 817 B2
`7 / 2011 Kopreski
`7 , 981 , 612 B2
`7 / 2011 Shuber et al .
`8 , 094 , 312 B2
`1 / 2012 Ulmer
`8 , 168 , 385 B2
`5 / 2012 Brenner
`8 , 195 , 415 B2
`6 / 2012 Fan et al .
`8 , 209 , 130 B1
`6 / 2012 Kennedy et al .
`8 , 216 , 789 B2
`7 / 2012 Disis et al .
`8 , 236 , 532 B2
`8 / 2012 Ronaghi et al .
`8 , 361 , 726 B2
`1 / 2013 Gocke et al .
`8 , 383 , 345 B2 . 2 / 2013 Shendure et al .
`
`Case 1:20-cv-01580-LPS Document 1-6 Filed 11/23/20 Page 3 of 57 PageID #: 327
`
`US 9 , 840 , 743 B2
`Page 2
`
`6 / 2013 Travers et al .
`8 , 455 , 193 B2
`6 / 2013 Brenner
`8 , 470 , 996 B2
`7 / 2013 Casbon et al .
`8 , 481 , 292 B2
`8 , 603 , 749 B2 12 / 2013 Gillevet
`8 , 685 , 678 B2
`4 / 2014 Casbon et al .
`8 , 704 , 165 B2
`4 / 2014 Huang
`8 , 715 , 967 B2
`5 / 2014 Casbon et al .
`8 , 722 , 368 B2
`5 / 2014 Casbon et al .
`8 , 728 , 766 B2
`5 / 2014 Casbon et al .
`8 , 741 , 606 B2
`6 / 2014 Casbon et al .
`8 , 775 , 092 B2
`7 / 2014 Colwell et al .
`8 , 835 , 358 B2
`9 / 2014 Fodor et al .
`9 , 018 , 365 B2
`4 / 2015 Brenner
`9 , 085 , 798 B2
`7 / 2015 Chee
`9 , 260 , 753 B2
`2 / 2016 Xie et al .
`9 , 340 , 830 B2
`5 / 2016 Downing et al .
`9 , 376 , 719 B2
`6 / 2016 Eijk et al .
`9 , 404 , 156 B2
`8 / 2016 Hicks et al .
`9 , 598 , 731 B2
`3 / 2017 Talasaz
`2001 / 0053519 Al 12 / 2001 Fodor et al .
`2002 / 0072058 A1
`6 / 2002 Voelker et al .
`2003 / 0003490 A1 1 / 2003 Fan et al .
`2003 / 0049616 Al 3 / 2003 Brenner et al .
`2003 / 0104436 A1 6 / 2003 Morris et al .
`2003 / 0152490 A1
`8 / 2003 Trulson et al .
`2003 / 0165978 AL 9 / 2003 Firth et al .
`2003 / 0186251 Al 10 / 2003 Dunn et al .
`2003 / 0207300 AL 11 / 2003 Matray et al .
`2004 / 0096892 A15 / 2004 Wang et al .
`2004 / 0146901 A1 7 / 2004 Morris et al .
`2004 / 0157243 A1 8 / 2004 Huang et al .
`2004 / 0259118 Al 12 / 2004 Macevicz
`2005 / 0164241 A1 7 / 2005 Hahn et al .
`2005 / 0221314 Al 10 / 2005 Berlin et al .
`2005 / 0250147 A1 11 / 2005 Macevicz
`2006 / 0035258 Al 2 / 2006 Tadakamalla et al .
`2006 / 0046258 Al 3 / 2006 Lapidus et al .
`2006 / 0073506 A1 4 / 2006 Christians et al .
`2006 / 0211030 A1
`9 / 2006 Brenner
`2007 / 0020640 A1
`1 / 2007 McCloskey et al .
`2007 / 0065823 A1 3 / 2007 Dressman et al .
`2007 / 0128724 A1 6 / 2007 Miles et al .
`2007 / 0172839 Al 7 / 2007 Smith et al .
`2007 / 0172873 Al 7 / 2007 Brenner et al .
`2008 / 0014146 A1 1 / 2008 Von Hoff et al .
`2008 / 0124721 Al
`5 / 2008 Fuchs et al .
`2008 / 0161420 A1 7 / 2008 Shuber
`2008 / 0293055 Al 11 / 2008 Freeman et al .
`2009 / 0029377 A1
`1 / 2009 Lo et al .
`2009 / 0087847 A1 4 / 2009 Lo et al .
`2009 / 0098547 A1 4 / 2009 Ghosh
`2009 / 0105959 Al
`4 / 2009 Braverman et al .
`2009 / 0162836 Al 6 / 2009 Widschwendter
`2009 / 0298075 A1 12 / 2009 Travers et al .
`2009 / 0298709 Al 12 / 2009 Ma
`2010 / 0041048 AL 2 / 2010 Diehl et al .
`2010 / 0062494 Al 3 / 2010 Church et al .
`2010 / 0069250 A1 3 / 2010 White , III et al .
`2010 / 0143932 A1 6 / 2010 Lapidus
`2010 / 0166744 Al
`7 / 2010 Wong
`2010 / 0196898 Al 8 / 2010 Sugarbaker et al .
`2010 / 0323348 A1 12 / 2010 Hamady et al .
`2010 / 0330571 A1 12 / 2010 Robins et al .
`2011 / 0014607 Al
`1 / 2011 Jirtle et al .
`2011 / 0160078 A1 6 / 2011 Fodor et al .
`2011 / 0160290 A1 6 / 2011 Tewari
`2011 / 0171640 A1 7 / 2011 Bhatt et al .
`2011 / 0177512 A1
`7 / 2011 Shuber
`2011 / 0183330 A1
`7 / 2011 Lo et al .
`2011 / 0201507 A1
`8 / 2011 Rava et al .
`2011 / 0230358 A1
`9 / 2011 Rava
`2011 / 0230360 A1 9 / 2011 Stephan et al .
`2011 / 0245482 Al 10 / 2011 Hahn et al .
`2011 / 0264376 A1 10 / 2011 Chinitz et al .
`2011 / 0275084 Al 11 / 2011 Byron et al .
`2012 / 0003637 A1
`1 / 2012 Lo et al .
`2012 / 0034685 Al 2 / 2012 Sparks et al .
`2012 / 0046877 A1
`2 / 2012 Hyland et al .
`2012 / 0053073 A1
`3 / 2012 Kassis
`
`

`

`US 9 , 840 , 743 B2
`Page 3
`
`( 56 )
`
`References Cited
`U . S . PATENT DOCUMENTS
`2012 / 0059594 A1
`3 / 2012 Hatchwell et al .
`2012 / 0065081 A1
`3 / 2012 Chee
`2012 / 0095697 Al 4 / 2012 Halpern et al .
`2012 / 0100548 A1 4 / 2012 Rava et al .
`2012 / 0164630 Al
`6 / 2012 Porreca et al .
`2012 / 0208706 A1
`8 / 2012 Downing et al .
`2012 / 0214163 Al 8 / 2012 Sugarbaker et al .
`2012 / 0214678 AL 8 / 2012 Rava et al .
`2012 / 0220478 Al
`8 / 2012 Shaffer
`2012 / 0231479 Al
`9 / 2012 Puskas et al .
`2012 / 0238464 AL
`9 / 2012 Koi et al .
`2012 / 0270212 Al 10 / 2012 Rabinowitz et al .
`2012 / 0316074 Al 12 / 2012 Saxonov
`2013 / 0005585 A1
`1 / 2013 Anderson et al .
`2013 / 0017958 Al 1 / 2013 Benz et al .
`2013 / 0022977 Al
`1 / 2013 Lapidus et al .
`2013 / 0029852 Al
`1 / 2013 Rava et al .
`2013 / 0034546 A1
`2 / 2013 Rava et al .
`2013 / 0040824 A1 2 / 2013 Lo et al .
`2013 / 0053256 A1 2 / 2013 Hubbell
`2013 / 0060483 A1
`3 / 2013 Struble et al .
`2013 / 0078626 A1 3 / 2013 Wasserstrom et al .
`2013 / 0085681 A1
`4 / 2013 Deciu et al .
`2013 / 0102485 A1 4 / 2013 Lee
`2013 / 0102487 Al
`4 / 2013 Gironella I Cos et al .
`2013 / 0116127 A1 5 / 2013 Schuetz et al .
`2013 / 0116130 A1
`5 / 2013 Fu et al .
`2013 / 0122499 A1 5 / 2013 Morris et al .
`2013 / 0130923 Al
`5 / 2013 Ehrich et al .
`2013 / 0137588 A1
`5 / 2013 Shendure et al .
`2013 / 0143747 A1 6 / 2013 Gutin et al .
`2013 / 02 10643 A1 8 / 2013 Casbon et al .
`2013 / 0210645 A1
`8 / 2013 Volgelstein et al .
`2013 / 0224743 A1
`8 / 2013 Casbon et al .
`2013 / 0237431 A1 9 / 2013 Lo et al .
`2013 / 0237458 AL
`9 / 2013 Casbon et al .
`2013 / 0260381 AL 10 / 2013 Ramakrishnan
`2013 / 0267424 Al 10 / 2013 Casbon et al .
`2013 / 0338933 A1 * 12 / 2013 Deciu
`. . . . . . . . . . . . . . . . . . G06F 19 / 22
`702 / 20
`2014 / 0065609 Al
`3 / 2014 Hicks et al .
`2014 / 0065630 Al
`3 / 2014 Von Bubnoff et al .
`2014 / 0066317 A13 / 2014 Talasaz
`C12Q 1 / 6886
`2014 / 0100121 A1 *
`4 / 2014 LO . . . . . .
`506 / 2
`2014 / 0242588 A1 *
`8 / 2014 Van Den Boom . . . C12Q 1 / 6827
`435 / 6 . 11
`2014 / 0274740 A1 9 / 2014 Srinivasan et al .
`2014 / 0296094 Al 10 / 2014 Domanus
`2014 / 0303008 A
`10 / 2014 Schutz et al .
`2014 / 0336943 AL 11 / 2014 Pellini et al .
`2014 / 0350130 AL 11 / 2014 Sanborn et al .
`2015 / 0004158 A1
`1 / 2015 Shipp et al .
`2015 / 0024950 A1
`1 / 2015 Bielas et al .
`2015 / 0044687 Al 2 / 2015 Schmitt et al .
`2015 / 0050647 Al
`2 / 2015 Luo et al .
`2015 / 0051085 Al
`2 / 2015 Vogelstein et al .
`2015 / 0065358 Al 3 / 2015 Comstock et al .
`2015 / 0087535 A1
`3 / 2015 Patel
`2015 / 0275289 Al 10 / 2015 Otwinowski et al .
`2015 / 0344970 A1 12 / 2015 Vogelstein et al .
`2015 / 0368708 A1 12 / 2015 Talasaz et al .
`2016 / 0024576 AL
`1 / 2016 Chee
`2016 / 0026758 A1
`1 / 2016 Jabara et al .
`2016 / 0032396 A1
`2 / 2016 Diehn et al .
`2016 / 0040229 A1
`2 / 2016 Talasaz et al .
`2016 / 0046986 A1
`2 / 2016 Eltoukhy et al .
`2016 / 0053301 A1 2 / 2016 Raymond et al .
`2016 / 0060691 Al 3 / 2016 Giresi et al .
`2016 / 0130649 Al
`5 / 2016 Xie et al .
`2016 / 0251704 A
`9 / 2016 Talasaz et al .
`2016 / 0319345 AL 11 / 2016 Gnerre et al .
`2016 / 0333417 AL 11 / 2016 Talasaz
`2017 / 0051347 A12 / 2017 Vogelstein et al .
`2017 / 0073774 A1
`3 / 2017 Lo et al .
`
`5 / 2017 Kopetz et al .
`2017 / 0145516 A1
`2017 / 0159120 A16 / 2017 Van Eijk et al .
`2017 / 02 18460 AL
`8 / 2017 Talasaz
`FOREIGN PATENT DOCUMENTS
`1647600 A2
`4 / 2006
`2110442 A1 10 / 2009
`WO - 9707241 AL
`2 / 1997
`WO - 9710365 A1
`3 / 1997
`WO - 9928505 AL
`6 / 1999
`WO - 0058516 A2
`10 / 2000
`WO - 02056014 A2
`7 / 2002
`WO - 2005080604 A2
`9 / 2005
`WO - 2005111242 A2
`11 / 2005
`WO - 2006102264 Al 9 / 2006
`WO - 2007037678 A2
`4 / 2007
`WO - 2008070144 A2
`6 / 2008
`WO - 2008154317 A1 12 / 2008
`WO - 2009 152928 A2 12 / 2009
`WO - 2009152928 A3
`2 / 2010
`WO - 2011060240 Al 5 / 2011
`WO - 2011087760 A2
`7 / 2011
`WO - 2011091046 Al
`7 / 2011
`WO - 2011103236 A2
`8 / 2011
`WO - 2011140510 A2
`11 / 2011
`WO - 2011155833 A2 12 / 2011
`WO - 2012012693 A2
`1 / 2012
`WO - 2012014877 Al 2 / 2012
`WO - 2012019200 A2
`2 / 2012
`WO - 2012028746 A1 3 / 2012
`WO - 2012038839 A2
`3 / 2012
`WO - 2012042374 A2
`4 / 2012
`WO - 2012048341 Al
`4 / 2012
`WO - 2012054873 A2
`4 / 2012
`WO - 2012066451 A1
`5 / 2012
`WO - 2012088348 A2
`6 / 2012
`WO - 2012106559 Al 8 / 2012
`WO - 2012129363 A2
`9 / 2012
`WO - 2012142213 A2 10 / 2012
`WO - 2012103031 A3
`1 / 2013
`WO - 2013019075 A2
`2 / 2013
`WO - 2013033721 A1
`3 / 2013
`WO - 2013106737 A1
`7 / 2013
`WO - 2013123442 Al
`8 / 2013
`WO - 2013130512 A2
`9 / 2013
`WO - 2013130674 Al 9 / 2013
`WO - 2013138510 Al
`9 / 2013
`WO - 2013142213 Al
`9 / 2013
`WO - 2013142389 Al
`9 / 2013
`WO - 2013148496 A
`10 / 2013
`WO - 2013159035 A2
`10 / 2013
`WO - 2013173394 A2
`11 / 2013
`WO - 2013181170 AL 12 / 2013
`WO - 2013188471 A2 12 / 2013
`WO - 2013190441 A2 12 / 2013
`WO - 2014004726 A1
`1 / 2014
`WO - 2014014497 A
`1 / 2014
`WO - 2014015319 Al
`1 / 2014
`WO - 2014039556 A1 3 / 2014
`WO - 2014093330 A1 6 / 2014
`WO - 2014145078 A1
`9 / 2014
`WO - 2014151117 A1
`9 / 2014
`WO - 2014152990 A1 9 / 2014
`WO - 2015159293 A2 10 / 2015
`WO - 2016040901 A1 3 / 2016
`WO - 2017100441 A16 / 2017
`
`EP
`EP
`WO
`wo
`WO
`WO
`WO
`WO
`Wo
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`Wo
`WO
`wo
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`wo
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`wo
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`Wo
`WO
`
`OTHER PUBLICATIONS
`Atanur , et al . The genome sequence of the spontaneously hyper
`tensive rat : Analysis and functional significance . Genome Res . Jun .
`2010 ; 20 ( 6 ) : 791 - 803 . doi : 10 . 1101 / gr . 103499 . 109 . Epub Apr . 29 ,
`2010 .
`Audic , et al . The Significance of Digital Gene Expression Profiles .
`Genome Research , 7 : 986 - 995 ( 1997 ) .
`Barzon , et al . Evaluation of circulating thyroid - specific transcripts
`as markers of thyroid cancer relapse . Int J Cancer . Jul . 20 ,
`2004 ; 110 ( 6 ) : 914 - 20
`
`Case 1:20-cv-01580-LPS Document 1-6 Filed 11/23/20 Page 4 of 57 PageID #: 328
`
`

`

`US 9 , 840 , 743 B2
`Page 4
`
`( 56 )
`
`References Cited
`OTHER PUBLICATIONS
`Bendich , et al . Circulating DNA as a possible factor in oncogenesis .
`Science . Apr . 16 , 1965 ; 148 ( 3668 ) : 374 - 6 .
`Bonaldo , et al . Normalization and subtraction : two approaches to
`facilitate gene discovery . Genome Res . Sep . 1996 ; 6 ( 9 ) : 791 - 806 .
`Bowcock , et al . Exclusion of the retinoblastoma gene and chromo
`some 134 as the site of a primary lesion for human breast cancer .
`Am J Hum Genet . Jan . 1990 ; 46 ( 1 ) : 12 - 7 .
`Braha , et al . Simultaneous stochastic sensing of divalent metal ions .
`Nature Biotechnology , 18 : 1005 - 1007 ( 2000 ) .
`Bremnes , et al . Circulating tumour - derived DNA and RNA markers
`in blood : a tool for early detection , diagnostics , and follow - up ?
`Lung Cancer . Jul . 2005 ; 49 ( 1 ) : 1 - 12 .
`Brenner , et al . Gene expression analysis by massively parallel
`signature sequencing ( MPSS ) on microbead arrays . Nature Biotech
`nology , 18 : 630 - 634 ( 2000 ) .
`Brenner , et al . In vitro cloning of complex mixtures of DNMA on
`microbeads : physical separation of differentially expressed cDNAs .
`Proc Natl Acad Sci US A . Feb . 15 , 2000 ; 97 ( 4 ) : 1665 - 70 .
`Campbell , et al . Identification of somatically acquired rearrange
`ments in cancer using genome - wide massively parallel paired - end
`sequencing . Nat Genet . Jun . 2008 ; 40 ( 6 ) : 722 - 9 . doi : 10 . 1038 / ng .
`128 . Epub Apr . 27 , 2008 .
`Caramazza , et al . Chromosome 1 abnormalities in myeloid malig
`nancies : a literature survey and karyotype - phenotype associations .
`Eur J Haematol . Mar . 2010 , 84 ( 3 ) : 1 91 - 200 . doi : 10 . 1111 / j . 1600
`0609 . 2009 . 01392 . x . Epub Nov . 30 , 2009 .
`Carr , et al . Inferring relative proportions of DNA variants from
`sequencing
`electropherograms .
`Bioinformatics . Dec .
`15 ,
`2009 ; 25 ( 24 ) : 3244 - 50 . doi : 10 . 1093 / bioinformatics / btp583 . Epub
`Oct . 9 , 2009 .
`Casbon , et al . A method for counting PCR template molecules with
`application to next - generation sequencing . Nucleic Acids Res . Jul .
`2011 ; 39 ( 12 ) : e81 . doi : 10 . 1093 / nar / gkr217 . Epub Apr . 13 , 2011 .
`Castle , et al . DNA copy number , including telomeres and mito
`chondria , assayed using next - generation sequencing . BMC Genom
`ics . Apr . 16 , 2010 ; 11 : 244 . doi : 10 . 1186 / 1471 - 2164 - 11 - 244 .
`Chang , et al . Detection of allelic imbalance in ascitic supernatant by
`digital single nucleotide polymorphism analysis . Clin Cancer Res .
`Aug . 2002 ; 8 ( 8 ) : 2580 - 5 .
`Chee . Enzymatic multiplex DNA sequencing . Nucleic Acids
`Research , 19 ( 12 ) : 3301 - 3305 ( 1991 ) .
`Chee , et al . Accessing genetic information with high - density DNA
`arrays . Science , 274 : 610 - 614 ( 1996 ) .
`Chen , et al . Microsatellite alterations in plasma DNA of small cell
`lung cancer patients . Nat Med . Sep . 1996 ; 2 ( 9 ) : 1033 - 5 .
`Chin , et al . A SNP in a let - 7 microRNA complementary site in the
`KRAS 3 ' untranslated region increases non - small cell lung cancer
`risk . Cancer Res . Oct . 15 , 2008 ; 68 ( 20 ) : 8535 - 40 . doi : 10 . 1158 / 0008
`5472 . CAN - 08 - 2129 .
`Chiu , et al . Non - invasive prenatal assessment of trisomy 21 by
`multiplexed maternal plasma DNA sequencing : large scale validity
`study . BMJ . Jan . 11 , 2011 ; 342 : c7401 . doi : 10 . 1136 / bmj . c7401 .
`Chiu , et al . Quantitative analysis of circulating mitochondrial DNA
`in plasma . Clin Chem . May 2003 ; 49 ( 5 ) : 719 - 26 .
`Church , et al . Multiplex DNA sequencing . Science , 240 : 185 - 188
`( 1988 ) .
`Cook , et al . Methylated DNA labels for marking objects . Biotechnol
`Lett . Jan . 2003 ; 25 ( 1 ) : 89 - 94 .
`Co - pending U . S . Appl . No . 15 / 348 , 481 , filed Nov . 10 , 2016 .
`Costello , et al . Discovery and characterization of artifactual muta
`tions in deep coverage targeted capture sequencing data due to
`oxidative DNA damage during sample preparation . Nucleic Acids
`Res . Apr . 1 , 2013 ; 41 ( 6 ) : e67 . doi : 10 . 1093 / nar / gks1443 . Epub Jan . 8 ,
`2013 .
`Coulet , et al . Detection of plasma tumor DNA in head and neck
`squamous cell carcinoma by microsatellite typing and p53 mutation
`analysis . Cancer Res . Feb . 1 , 2000 ; 60 ( 3 ) : 707 - 11 .
`Cox ,
`J . Bar coding objects with DNA . Analyst . May
`2001 ; 126 ( 5 ) : 545 - 7 .
`
`Craig , et al . Identification of genetic variants using bar - coded
`multiplexed sequencing . Nat Methods . Oct . 2008 ; 5 ( 10 ) : 887 - 93 . doi :
`10 . 1038 / nmeth . 1251 . Epub Sep . 14 , 2008 .
`Daines , et al . High - throughput multiplex sequencing to discover
`copy number variants
`in
`Drosophila . Genetics . Aug .
`2009 ; 182 ( 4 ) : 935 - 41 . doi : 10 . 1534 / genetics . 109 . 103218 . Epub Jun .
`15 , 2009 .
`D ' Antoni , et al . Rapid quantitative analysis using a single molecule
`counting approach . Anal Biochem . May 1 , 2006 ; 352 ( 1 ) : 97 - 109 .
`Epub Feb . 10 , 2006 .
`Daser , et al . Interrogation of genomes by molecular copy - number
`counting ( MCC ) . Nature Methods , 3 ( 6 ) : 447 - 453 ( 2006 ) .
`De Saizieu , et al . Bacterial transcript imaging by hybridization of
`total RNA to oligonucleotide arrays . Nature Biotechnology , 16 :
`45 - 48 ( 1998 ) .
`Diehl , et al . Circulating mutant DNA to assess tumor dynamics . Nat
`Med . Sep . 2008 ; 14 ( 9 ) : 985 - 90 . doi : 10 . 1038 / nm . 1789 . Epub Jul . 31 ,
`2007 .
`Diehl , et al . Detection and quantification of mutations in the plasma
`of patients with colorectal tumors . Proc Natl Acad Sci US A . Nov .
`8 , 2005 ; 102 ( 45 ) : 16368 - 73 . Epub Oct . 28 , 2005 .
`Ding , et al . Clonal evolution in relapsed acute myeloid leukaemia
`revealed by whole - genome sequencing . Nature .
`Jan . 11 ,
`2012 ; 481 ( 7382 ) : 506 - 10 . doi : 10 . 1038 / nature10738 .
`Ehrich , et al . Noninvasive detection of fetal trisomy 21 by sequenc
`ing of DNA in maternal blood : a study in a clinical setting . Am J
`Obstet Gynecol . Mar . 2011 ; 204 ( 3 ) : 205 . el - 11 . doi : 10 . 1016 / j . ajog .
`2010 . 12 . 060 . Epub Feb . 18 , 2011 .
`Eisenmann , et al . 5q - myelodysplastic syndromes : chromosome 5q
`genes direct a tumor - suppression network sensing actin dynamics .
`Oncogene . Oct . 1 , 2009 ; 28 ( 39 ) : 3429 - 41 . doi : 10 . 1038 / onc . 2009 .
`207 . Epub Jul . 13 , 2009 .
`Elshire , et al . A robust , simple genotyping - by - sequencing ( GBS )
`approach for high diversity species . PLoS One . May 4 ,
`2011 ; 6 ( 5 ) : e19379 . doi : 10 . 1371 / journal . pone . 0019379 .
`European search report and search opinion dated Mar . 29 , 2016 for
`EP Application No . 13834427 . 0 .
`Fan , et al . Microfluidic digital PCR enables rapid prenatal diagnosis
`of fetal aneuploidy . Am Obstet Gynecol . 2009 ; 200 : 543 . el - 543 . e7 .
`Fan , et al . Noninvasive diagnosis of fetal aneuploidy by shotgun
`sequencing DNA from maternal blood . Proc Natl Acad Sci US A .
`Oct . 21 , 2008 ; 105 ( 42 ) 16266 - 71 . doi : 10 . 1073 / pnas . 0808319105 .
`Epub Oct . 6 , 2008 .
`Fan , et al . Non - invasive prenatal measurement of the fetal genome .
`Nature . Jul . 19 , 2012 ; 487 ( 7407 ) : 320 - 4 . doi : 10 . 1038 / nature11251 .
`Fan , et al . Parallel Genotyping of Human SNPs Using Generic
`High - density Oligonucleotide Tag Arrays . Genome Research , 10 :
`853 - 860 ( 2000 ) .
`Fonatsch , C . The role of chromosome 21 in hematology and
`oncology . Genes Chromosomes Cancer . Jun . 2010 ; 49 ( 6 ) : 497 - 508 .
`doi : 10 . 1002 / gcc . 20764 .
`Forster , et al . From next - generation sequencing alignments to
`accurate comparison and validation of single - nucleotide variants :
`the pibase software . Nucleic Acids Res . Jan . 7 , 2013 ; 41 ( 1 ) : e16 . doi :
`10 . 1093 / nar / gks836 . Epub Sep . 10 , 2012 .
`Fournie , et al . Plasma DNA as a marker of cancerous cell death .
`Investigations in patients suffering from lung cancer and in nude
`mice bearing human tumours . Cancer Lett . May 8 , 1995 ; 91 ( 2 ) : 221
`Freeman , et al . Profiling the T - cell receptor beta - chain repertoire by
`massively
`parallel
`sequencing .
`Genome Res .
`Oct .
`2009 ; 19 ( 10 ) : 1817 - 24 . doi : 10 . 1101 / gr . 092924 . 109 . Epub Jun . 18 ,
`2009 .
`Fu , et al . Counting individual DNA molecules by the stochastic
`attachment of diverse labels . Proc Natl Acad Sci US A . May 31 ,
`2011 ; 108 ( 22 ) : 9026 - 31 . Epub May 11 , 2011 .
`Fujiwara , et al . Identification of epigenetic aberrant promoter
`methylation in serum DNA is useful for early detection of lung
`cancer . Clin Cancer Res . Feb . 1 , 2005 ; 11 ( 3 ) : 1219 - 25 .
`Fujiwara , et al . Plasma DNA microsatellites as tumor - specific
`markers and indicators of tumor progression in melanoma patients .
`Cancer Res . Apr . 1 , 1999 ; 59 ( 7 ) : 1567 - 71 .
`
`Case 1:20-cv-01580-LPS Document 1-6 Filed 11/23/20 Page 5 of 57 PageID #: 329
`
`

`

`US 9 , 840 , 743 B2
`Page 5
`
`( 56 )
`
`References Cited
`OTHER PUBLICATIONS
`Gerry , et al . Universal DNA microarray method for multiplex
`detection of low abundance point mutations . Journal of Molecular
`Biology , 292 ( 2 ) : 251 - 262 ( 1999 ) .
`Gillespie . Exact stochastic simulation of coupled chemical reac
`tions . The Journal of Physical Chemistry , 81 ( 25 ) : 2340 - 2361
`( 1977 ) .
`Gordian , et al . Serum free circulating DNA is a useful biomarker to
`distinguish benign versus malignant prostate disease . Cancer
`Epidemiol Biomarkers Prey . Aug . 2010 ; 19 ( 8 ) : 1984 - 91 . doi :
`10 . 1158 / 1055 - 9965 . EPI - 10 - 0287 . Epub Jul . 20 , 2010 .
`Gormally , et al . Amount of DNA in plasma and cancer risk : a
`prospective study . Int J Cancer . Sep . 20 , 2004 ; 111 ( 5 ) : 746 - 9 .
`Grant , et al . SNP genotyping on a genome - wide amplified DOP
`PCR template . Nucleic Acids Res . Nov . 15 , 2002 ; 30 ( 22 ) : e125 .
`Grutzmann , et al . Sensitive detection of colorectal cancer in periph
`eral blood by septin 9 DNA methylation assay . PLoS One .
`2008 ; 3 ( 11 ) : e3759 . doi : 10 . 1371 / journal . pone . 0003759 . Epub Nov .
`19 , 2008 .
`Gundry , et al . Direct , genome - wide assessment of DNA mutations
`in single cells . Nucleic Acids Res . Mar . 2012 ; 40 ( 5 ) : 2032 - 40 . doi :
`10 . 1093 / nar / gkr949 . Epub Nov . 15 , 2011 .
`Gundry , et al . Direct mutation analysis by high - throughput sequenc
`ing : from germline to low - abundant , somatic variants . Mutat Res .
`Jan . 3 , 2012 ; 729 ( 1 - 2 ) : 1 - 15 . doi : 10 . 1016 / mrfmmm . 2011 . 10 . 001 .
`Epub Oct . 12 , 2011 .
`Hacia , et al . Determination of ancestral alleles for human single
`nucleotide polymorphisms using high - density oligonucleotide
`arrays . Nature Genetics , 22 : 164 - 167 ( 1999 ) .
`Hamady , et al . Error - correcting barcoded primers for pyrosequenc
`ing hundreds of samples in multiplex . Nat Methods . Mar .
`2008 ; 5 ( 3 ) : 235 - 7 . doi : 10 . 1038 / nmeth . 1184 . Epub Feb . 10 , 2008 .
`Hensel , et al . Simultaneous identification of bacterial virulence
`genes by negative selection . Science . Jul . 21 , 1995 ; 269 ( 5222 ) : 400
`3 .
`Hiatt , et al . Parallel , tag - directed assembly of locally derived short
`sequence reads . Nat Methods . Feb . 2010 ; 7 ( 2 ) : 119 - 22 . doi : 10 . 1038 /
`nmeth . 1416 . Epub Jan . 17 , 2010 .
`Hiatt , et al . Single molecule molecular inversion probes for targeted ,
`high - accuracy detection of low - frequency variation . Genome Res .
`May 2013 ; 23 ( 5 ) : 843 - 54 . doi : 10 . 1101 / gr . 147686 . 112 . Epub Feb . 4 ,
`2013 .
`Hibi , et al . Molecular detection of genetic alterations in the serum
`of colorectal cancer patients . Cancer Res . Apr . 1 , 1998 ; 58 ( 7 ) : 1405
`Holdenrieder , et al . Circulating nucleosomes and cytokeratin
`19 - fragments in patients with colorectal cancer during chemo
`therapy . Anticancer Res . May - Jun . 2005 ; 25 ( 3A ) : 1795 - 801 .
`Holies , et al . A stochastic approach to count RNA molecules using
`DNA sequencing methods . Lecture Notes in Computer Science ,
`2812 : 55 - 62 ( 2003 ) .
`Hoque , et al . Detection of aberrant methylation of four genes in
`plasma DNA for the detection of breast cancer . J Clin Oncol . Sep .
`10 , 2006 ; 24 ( 26 ) : 4262 - 9 . Epub Aug . 14 , 2006 .
`Howe , et al . Retinoblastoma growth suppressor and a 300 - kDa
`protein appear to regulate cellular DNA synthesis . Proc Natl Acad
`Sci USA . Aug . 1990 ; 87 ( 15 ) : 5883 - 7 .
`Hug , et al . Measurement of the number of molecules of a single
`mRNA species in a complex mRNA preparation . J Theor Biol . Apr .
`21 , 2003 ; 221 ( 4 ) : 615 - 24 .
`Hyland , et al . The normal and tumor spectrum of copy number
`variation : Copy number alterations correlate with changes in gene
`expression in tumor transcriptome . Nov . 15 , 2009 . 1 page . Retreived
`from :
`https : / / tools . thermofisher . com / contents / sfs / posters / cms _ _
`073633 . pdf > .
`Iafrate , et al . Detection of large - scale variation in the human
`genome . Nat Genet . Sep . 2004 ; 3 ( 9 ) : 949 - 51 . Epub Aug . 1 , 2004 .
`Ikeguchi , et al . Detection of loss of heterozygosityat microsatellite
`loci in
`esophageal squamous - cell
`carcinoma . Oncology .
`1999 ; 56 ( 2 ) : 164 - 8 .
`
`Ingolia , et al . Genome - wide analysis in vivo of translation with
`nucleotide resolution using ribosome profiling . Science . Apr . 10 ,
`2009 ; 324 ( 5924 ) : 218 - 23 . Epub Feb . 12 , 2009 .
`International search report and written opinion dated Apr . 3 , 2015
`for PCT / US2014 / 072383 .
`International search report and written opinion dated May 7 , 2012
`for PCT / IB2011 / 003160 .
`International search report and written opinion dated Jun . 6 , 2012
`for PCT / US2011 / 065291 .
`“ International search report and written opinion dated Jul . 15 , 2015
`for PCT / US2015 / 030639 . ”
`International search report and written opinion dated Sep . 5 , 2014
`for PCT / US2014 / 000048 .
`International search report and written opinion dated Nov . 18 , 2013
`for PCT / US2013 / 058061 .
`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