(12) Unlted States Patent
`(10) Patent No.:
`US 8,195,415 B2
`
`Fan et al.
`(45) Date of Patent:
`Jun. 5, 2012
`
`USOO8195415B2
`
`(54) NONINVASIVE DIAGNOSIS OF FETAL
`ANEUPLOIDY BY SEQUENCING
`Inventors: Hei-Mun Christina Fan, Fremont, CA
`(US); Stephen R. Quake, Stanford, CA
`(US)
`
`(75)
`
`.
`(73) A551gnee: The Board of Trustees of the Leland
`Stanford Junior University, Palo Alto,
`CA (Us)
`
`tal.
`
`2,377,332: 2
`,
`,
`5,153,117 A
`5,215,926 A
`5,296,375 A
`5,300,779 A
`5,304,487 A
`5,427,663 A
`5,427,946 A
`
`151338 filtfidy
`1
`llmura et a .
`10/1992 Simons
`6/1993 Et h 11,III
`3/1994 Krcicliaset a1.e
`4/1994 Hillman et al.
`4/1994 Wilding et al.
`6/1995 Austin et al.
`6/1995 Kr' k
`t
`1.
`C t'
`lcda e 3
`( on inue )
`FOREIGN PATENT DOCUMENTS
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`EP
`
`. 7/1997
`0637996 B1
`(Contlnued)
`OTHER PUBLICATIONS
`
`(21) APP1~ N0: 12/696s509
`
`(22)
`
`Filed:
`
`Jan. 29, 2010
`
`U.S.App1. No. 11/825,298, filed Jul. 5, 2007, Lopez etal.
`
`(Continued)
`
`(65)
`
`Prior Publication Data
`
`US 2010/0138165 A1
`
`Jun. 3, 2010
`
`Primary Examiner 7 Edward Raymond
`(74) Attorney, Agent, or Firm 7 David J. Aston; Peters
`Verny, LLP
`
`Related US. Application Data
`(62) Division Of application NO- 12/560,708, filed on Sep.
`16> 2009:
`(60) Provisional application No. 61/098,758, filed on Sep.
`20s 2008.
`
`(51)
`
`Int. Cl.
`(2006.01)
`gogF 19/00
`(52) US. Cl.
`........................................... 702/71; 435/6.1
`(58) Field of Classification Search .................... 702/20,
`702/1827185 71. 435/6
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`US. PATENT DOCUMENTS
`4 508 625 A
`4/1985 Graham
`4,675,286 A
`6/1987 Calenoff
`4,789,628 A
`12/1988 Nayak
`4,800,159 A
`1/1989 Mullis et al.
`
`ABSTRACT
`(57)
`Disclosed is a method to achieve digital quantification of
`DNA (i.e., counting differences between identical sequences)
`using direct shotgun sequencing followed by mapping to the
`chromosome of origin and enumeration of fragments per
`chromosome. The preferred method uses massively parallel
`sequencing, which can produce tens of millions of short
`sequence tags in a single run and enabling a sampling that can
`be statistically eValuated- By counting the number of
`sequence tags mapped to a Predefined Window in 621011 Chro'
`mosome, the over- or under-representation of any chromo-
`some in maternal plasma DNA contributed by an aneuploid
`fetus can be detected. This method does not require the dif-
`ferentiation of fetal versus maternal DNA. The median count
`of autosomal values is used as a normalization constant to
`
`account for differences in total number of sequence tags is
`used for comparison between samples and between chromo-
`SOIneS'
`
`17 Claims, 17 Drawing Sheets
`
`
`
`E i
`
`i
`
`Page 1 0f 48
`
`SEQUENOM EXHIBIT 1001
`
`Cotomcmom
`
`SEQUENOM EXHIBIT 1001
`
`Page 1 of 48
`
`

`

`US 8,195,415 B2
`
`Page 2
`
`US. PATENT DOCUMENTS
`
`5,432,054 A
`5,447,842 A
`5486335 A
`5’498’392 A
`2,288,888 2
`5’629’147 A
`’
`’
`2,828,888 2
`5,646,001 A
`5,676,849 A
`5,707,799 A
`5709943 A
`5,715,946 A
`28885888 2
`5766843 A
`’
`’
`288858423 2
`5,837,115 A
`5,840,502 A
`5,842,787 A
`5358549 A
`5,866,345 A
`5,879,883 A
`5,891,651 A
`5,928,880 A
`5952173 A
`5,962,234 A
`5’962’237 A
`5,962,332 A
`5,972,721 A
`5,993,665 A
`5,994,057 A
`2,888,288 2
`6,008,007 A
`6,013,188 A
`6,066,449 A
`9074327 A
`6,100,029 A
`6,143,496 A
`6,143,576 A
`8828888 2
`0,150,005 A
`6,176,962 B1
`6,184,043 B1
`6,186,660 B1
`6’197’523 Bl
`6,200,765 Bl
`8,318,288 E
`6’235’474 B1
`,
`,
`8,322,338 E
`6’300’077 B1
`,
`,
`8,888,888 3
`6,365,362 B1
`6,368,871 Bl
`8,888,888 3%
`6’387’707 B1
`,
`,
`2,394,923 3:
`6’399’364 B1
`6,432,630 B1
`6,440,706 B1
`6444 461 B1
`6’454’938 B2
`
`6,511,967 B1
`6,517,234 B1
`6,540,895 131
`6,576,478 B1
`6,582,904 B2
`6,582,969 B1
`
`7/1995 SfmndersetaL
`9/1995 5”.“an
`“1996 W!1d1.ng et 31'
`3/1996 W¥1d1ngetal'
`88888 $11131“ “3L
`5/1997 Aoumf’t
`1
`Sg‘me 3'
`8888;
`Ié‘igfii
`7/1997 Terstappen et 01.
`10/1997 Sammons et 01.
`1/1998 Hansmann et al.
`“1998 Comma“ et 31'
`“998 RetlchenbaCh
`88888 311.81% etaL
`6/1998 Ag“arietal
`g
`'
`88888 8885:?:1, 3L
`11/1998 Austin et 01.
`11/1998 VanVlasselaer
`12/1998 Kopf-Silletal.
`“1999 ASgari et 31'
`2/1999 Wilding etal.
`3/1999 Benson “3L
`4/1999 Rocheetal.
`7/1999 Wilding et 01.
`9/1999 Hansmann et 01.
`10/1999 Golbus
`10/1999 TS,0 em
`10/1999 Singer etal.
`”“999 Bruno etaL
`11/1999 Terstappen etal.
`11/ 1999 MimSfield
`58888 18:12:15:th
`12/1999 Fruehaufet 01.
`1/2000 Terstappen et al.
`5/2000 Ditkoffetal.
`”000 Nelson et 31'
`8/2000 Lapidus et al.
`11/2000 Brown et al.
`“/2000 BPeChler
`58888 1183;011:031.
`00000 000000.
`1/2001 Soane etal.
`2/2001 Fodstad etal.
`2/2001 Kopf-Silletal.
`3/2001 Rim et 31'
`3/2001 MurPhYetaL
`28881 SKIS“ et 3L1
`”001 Feflflfgfta'
`g
`83881 1&0it a:
`31
`10/2001 $81115): eftal'
`~
`88883 $1381;fo
`4/2002 Terstappen et al.
`“002 ChriSteletaL
`”58388; if”? eta?
`5/2002 Sefi‘ipetyafta'
`~
`28883 30W“ “*8
`6/2002 1100323121
`8/2002 Blankenstein
`8/2002 Vogelstein etal.
`9/2002 Knapp et al.
`9,2002 Moon et 31.
`
`1/2003 Weissleder et 31.
`2/2003 Kopf-Sillet 31.
`4/2003 Spence et 31.
`6/2003 Wagner et 01.
`6/2003 Dahm
`6/2003 Wagner et al.
`
`Page 2 of 48
`
`6,596,144 B1
`6,596,545 B1
`6,613,525 B2
`6,618,679 B2
`6,632,619 B1
`6,632,652 B1
`6,637,463 B1
`6,645,731 B2
`6,664,056 B2
`6,664,104 B2
`88328:; E:
`6’685’841 B2
`6,689,615 B1
`6,746,503 B1
`6,753,147 B2
`6,783,928 B2
`6,818,184 B2
`6,830,936 B2
`6,858,439 B1
`8888851: 8%
`6,906,182 B2
`6’911’345 B2
`6,913,697 B2
`6’927’028 B2
`6,953,668 B1
`6’960’449 B2
`7’115’709 B1
`’
`’
`7,150,812 B2
`7,171,975 B2
`3888888 8%
`7,198,787 B2
`,
`,
`7,208,275 B2
`7,212,660 B2
`7,220,594 B2
`3%;888 E:
`7,250,256 B2
`7’252’976 B2
`7,258,987 B2
`7,262,177 B2
`7,262,269 B2
`7,264,972 B2
`7,272,252 B2
`30333053 3;
`7’442’506 B2
`7’476’363 B2
`7’645’576 B2
`7,655,399 B2
`2001/0007749 A1
`2001/0051341 A1
`2001/0053958 A1
`2002/0006621 A1
`2002/0009738 A1
`2002/0012930 A1
`2002/0012931 A1
`2002/0016450 A1
`ggggégggggi :1
`2002/0058332 A1
`2002/0076825 A1
`2002/0086329 A1
`2002/0110835 A1
`2002/0123078 A1
`2002/0137088 A1
`58838188888 :1
`2002/0172987 A1
`2003/0004402 A1
`
`2003/0022207 A1
`2003/0033091 A1
`2003/0044388 A1
`2003/0072682 A1
`2003/0077292 A1
`2003/0119077 A1
`
`'
`
`'
`
`7/2003 Regnier et al.
`7/2003 Wa ner et al.
`9/2003 Negonet 01.
`9/2003 Loehriein et 01.
`10/2003 Harrison et 01.
`10/2003 Austin et 01.
`10/2003 Lei et 01.
`11/2003 Terstappen et 01.
`12/2003 L0 etal.
`12/2003 Pourahmadi et 01.
`8388:: Eleglfit 8151
`2,2004 L82: e831 '
`2/2004 M5110 et al.
`6/2004 Benett et 01.
`6/2004 Vogelstein et 01.
`8/2004 HVichia et 01.
`11/2004 Fulwyleretal.
`12/2004 Anderson et al.
`2/2005 Xu et 01.
`88882 1133882318: 01
`6/2005 Ts’o etal
`6,2005
`ak 61
`7/2005 3: 00:61:11.
`8,2005 Loital
`'
`10/2005 Israeli e101
`11,2005 W
`t 1'
`10/2006 Gang: 8
`”lye 3'
`12/2006 Huangetal.
`2/2007 Mqonetal.
`8,388; 8811:8381
`4/2007 Fodstad e101
`oc eet al.
`4/2007 G k
`5/2007 Wetzelet
`5/2007 Foster et 01.
`8888; 8:88:32;
`7/2007 Reinhard e131
`8,2007 Lin et a1
`8/2007 Lamofiéet 01
`8/2007 Ts’o etal
`8/2007 Lam et 31'
`9/2007 Foster
`'
`9/2007 De La Torre-Bueno etal.
`13/533; 3mm
`10,2008 Dhaflan
`1,2009 Ungeretal
`1,2010 L0 em '
`2/2010 Cantor 6101.
`7/2001 Feinberg
`12/2001 L0 etal.
`12/2001 Rjedetal.
`1/2002 Bianchi
`1/2002 Houghton etal.
`1/2002 Rothberg et 01.
`1/2002 Waldman etal.
`2/2002 Laugharn et 01.
`8,388;
`811%};
`5/2002 Quake et 01.
`6/2002 Cheng et 01.
`7/2002 Shvets et 01.
`8/2002 Kumar
`9/2002 Seuletal.
`9/2002 Bianchi
`1
`18588; guak?
`rennsseta'
`11/2002 Terstappen et al.
`1/2003 Hitt etal.
`
`'
`
`'
`
`1/2003 Balasubramanian et 31.
`2/2003 Opalsky et al.
`3/2003 Dennis et a1.
`4/2003 Kikinis
`4/2003 Hanash etal.
`6/2003 Ts’o etal.
`
`Page 2 of 48
`
`

`

`US 8,195,415 B2
`
`Page 3
`
`2003/0119724 A1
`2003/0129676 A1
`2003/0153085 A1
`2003/0159999 A1
`2003/0165852 A1
`2003/0170631 A1
`2003/0170703 A1
`2003/0175990 A1
`2003/0186255 A1
`2003/0190602 A1
`2003/0199685 A1
`2003/0204331 A1
`2003/0206901 A1
`2003/0232350 A1
`2004/0005582 A1
`2004/0009471 A1
`2004/0018116 A1
`2004/0018509 A1
`2004/0043506 A1
`2004/0048360 A1
`2004/0053352 A1
`2004/0072278 A1
`2004/0096892 A1
`2004/0137452 A1
`2004/0137470 A1
`2004/0142463 A1
`2004/0144651 A1
`2004/0166555 A1
`2004/0171091 A1
`2004/0185495 A1
`2004/0197797 A1
`2004/0203037 A1
`2004/0214240 A1
`2004/0232074 A1
`2004/0241707 A1
`2005/0014208 A1
`2005/0019792 A1
`2005/0037388 A1
`2005/0042623 A1
`2005/0042685 A1
`2005/0049793 A1
`2005/0061962 A1
`2005/0118591 A1
`2005/0129581 A1
`2005/0145496 A1
`2005/0147977 A1
`2005/0153342 A1
`2005/0158754 A1
`2005/0164241 A1
`2005/0175996 A1
`2005/0181353 A1
`2005/0181410 A1
`2005/0181463 A1
`2005/0196785 A1
`2005/0207940 A1
`2005/0211556 A1
`2005/0214855 A1
`2005/0221341 A1
`2005/0221373 A1
`2005/0239101 A1
`2005/0244843 A1
`2005/0250111 A1
`2005/0250155 A1
`2005/0250199 A1
`2005/0252773 A1
`2005/0255001 A1
`2005/0262577 A1
`2005/0266433 A1
`2005/0272103 A1
`2005/0282196 A1
`2005/0282293 A1
`2005/0287611 A1
`2006/0000772 A1
`2006/0008807 A1
`2006/0008824 A1
`2006/0024756 A1
`2006/0046258 A1
`2006/0051265 A1
`2006/0051775 A1
`
`6/2003 Ts’o et a1.
`7/2003 Terstappen et al.
`8/2003 Leary et al.
`8/2003 Oakey et a1.
`9/2003 Schueler et al.
`9/2003 Houghton et al.
`9/2003 Piper et al.
`9/2003 Hayenga
`10/2003 Williams et al.
`10/2003 Pressman et al.
`10/2003 Pressman et al.
`10/2003 Whitney et al.
`11/2003 Chen
`12/2003 Afar et al.
`1/2004 Shipwash
`1/2004 Cao
`1/2004 Desmond et al.
`1/2004 Bianchi
`3/2004 Haussecker et a1.
`3/2004 Wada et a1.
`3/2004 Ouyang et al.
`4/2004 Chou et al.
`5/2004 Wang et a1.
`7/2004 Levett et al.
`7/2004 Dhallan
`7/2004 Walker et a1.
`7/2004 Huang et al.
`8/2004 Braff et al.
`9/2004 Lesko et a1.
`9/2004 Schueler et al.
`10/2004 Inoko et al.
`....................... 435/6
`10/2004 Lo et a1.
`10/2004 Cao
`11/2004 Peters et al.
`12/2004 Gao et al.
`1/2005 Krehan et a1.
`1/2005 McBride et al.
`2/2005 Antonarakis et al.
`2/2005 Ault-Riche et a1.
`2/2005 Albert et a1.
`3/2005 Paterlini-Brechot
`3/2005 Mueth et a1.
`6/2005 Tamak et al.
`6/2005 McBride et al.
`7/2005 Goodsaid et al.
`7/2005 Koo et al.
`7/2005 Chen
`7/2005 Puffenberger et al.
`7/2005 Hahn et al.
`8/2005 Chen
`8/2005 Rao et al.
`8/2005 Shaffer et al.
`8/2005 Rao et al.
`9/2005 Quake et al.
`9/2005 Butler et al.
`9/2005 Childers et al.
`9/2005 Wagner et al.
`10/2005 Shimkets et al.
`10/2005 Enzelberger et al.
`10/2005 Sukumar et al.
`11/2005 Chen et al.
`11/2005 Xie et al.
`11/2005 Lesko et a1.
`11/2005 Anderson et al.
`11/2005 McBride et al.
`11/2005 Padmanabhan et al.
`11/2005 Guelly et al.
`12/2005 Kapur et al.
`12/2005 Chen
`12/2005 Costa
`12/2005 Cosman et al.
`12/2005 Nugent et a1.
`1/2006 Sano et al.
`1/2006 O’Hara et al.
`1/2006 Ronaghi et al.
`2/2006 Tibbe et al.
`3/2006 Lapidus et al.
`3/2006 Mohamed et a1.
`3/2006 Bianchi et al.
`
`Page 3 0f 48
`
`2006/0060767 A1
`2006/0072805 A1
`2006/0073125 A1
`2006/0094109 A1
`2006/0121452 A1
`2006/0121624 A1
`2006/0128006 A1
`2006/0134599 A1
`2006/0160105 A1
`2006/0160150 A1
`2006/0160243 A1
`2006/0183886 A1
`2006/0205057 A1
`2006/0223178 A1
`2006/0252054 A1
`2006/0252061 A1
`2006/0252068 A1
`2006/0252071 A1
`2006/0252087 A1
`2007/0015171 A1
`2007/0017633 A1
`2007/0026381 A1
`2007/0026413 A1
`2007/0026414 A1
`2007/0026415 A1
`2007/0026416 A1
`2007/0026417 A1
`2007/0026418 A1
`2007/0026419 A1
`2007/0026469 A1
`2007/0037172 A1
`2007/0037173 A1
`2007/0037273 A1
`2007/0037275 A1
`2007/0042238 A1
`2007/0042339 A1
`2007/0042360 A1
`2007/0042368 A1
`2007/0048750 A1
`2007/0054268 A1
`2007/0054287 A1
`2007/0059680 A1
`2007/0059683 A1
`2007/0059716 A1
`2007/0059718 A1
`2007/0059719 A1
`2007/0059737 A1
`2007/0059774 A1
`2007/0059781 A1
`2007/0059785 A1
`2007/0065845 A1
`2007/0065858 A1
`2007/0071762 A1
`2007/0072228 A1
`2007/0072290 A1
`2007/0077578 A1
`2007/0092444 A1
`2007/0092881 A1
`2007/0092917 A1
`2007/0099207 A1
`2007/0099219 A1
`2007/0099289 A1
`2007/0105105 A1
`2007/0105133 A1
`2007/0110773 A1
`2007/0117158 A1
`2007/0122856 A1
`2007/0122896 A1
`2007/0128655 A1
`2007/0131622 A1
`2007/0134658 A1
`2007/0134713 A1
`2007/0135621 A1
`2007/0141587 A1
`2007/0141588 A1
`2007/0141717 A1
`2007/0154928 A1
`2007/0154960 A1
`2007/0160503 A1
`
`3/2006 Wang et al.
`4/2006 Tsipouras et al.
`4/2006 Clarke et al.
`5/2006 Trainer
`6/2006 Dhallan
`6/2006 Huang et al.
`6/2006 Gerhardt et al.
`6/2006 Toner et al.
`7/2006 Dhallan
`7/2006 Seilhamer et al.
`7/2006 Tang et al.
`8/2006 T’so et a1.
`9/2006 Wayner et al.
`10/2006 Barber et al.
`11/2006 Lin et al.
`11/2006 Zabeau et al.
`11/2006 Lo et a1.
`11/2006 Lo et a1.
`11/2006 Tang et al.
`1/2007 Bianchi et al.
`1/2007 Tonkovich et al.
`2/2007 Huang et al.
`2/2007 Toner et al.
`2/2007 Fuchs et al.
`2/2007 Fuchs et al.
`2/2007 Fuchs
`2/2007 Fuchs et al.
`2/2007 Fuchs et al.
`2/2007 Fuchs et al.
`2/2007 Fuchs et al.
`2/2007 Chiu et al.
`2/2007 Allard et a1.
`2/2007 Shuler et al.
`2/2007 Shuler et al.
`2/2007 Kim et a1.
`2/2007 Toner et al.
`2/2007 Afar et al.
`2/2007 Zehentner-Wilkinson et al.
`3/2007 Peck et al.
`3/2007 Sutherland et a1.
`3/2007 Bloch
`3/2007 Kapur et a1.
`3/2007 Barber et al.
`3/2007 Balis et al.
`3/2007 Toner et al.
`3/2007 Grisham et al.
`3/2007 Baker et a1.
`3/2007 Grisham et al.
`3/2007 Kapur et a1.
`3/2007 Bacus et al.
`3/2007 Baker et a1.
`3/2007 Haley
`3/2007 Ts’o et a1.
`3/2007 Brauch
`3/2007 HVichia
`4/2007 Penning et a1.
`4/2007 Benos et al.
`4/2007 Ohnishi et al.
`4/2007 Guyon
`5/2007 Fuchs et al.
`5/2007 Teverovskiy et a1.
`5/2007 Irimia et al.
`5/2007 Clelland et al.
`5/2007 Clarke et al.
`5/2007 Asina et al.
`5/2007 Coumans et al.
`5/2007 Georges et al.
`5/2007 Shuler et al.
`6/2007 Obata
`6/2007 Oakey et a1.
`6/2007 Bohmer et al.
`6/2007 Cao
`6/2007 Bourel et al.
`6/2007 Baker et a1.
`6/2007 Baker et a1.
`6/2007 Carpenter et al.
`7/2007 Mack et al.
`7/2007 Connelly et a1.
`7/2007 Sethu et al.
`
`Page 3 of 48
`
`

`

`US 8,195,415 B2
`
`Page 4
`
`7/2007 Sidhu et a1.
`2007/0160974 A1
`7/2007 Huang et a1.
`2007/0160984 A1
`7/2007 Kinch et a1.
`2007/0161064 A1
`7/2007 Hsieh et a1.
`2007/0166770 A1
`7/2007 Rubel
`2007/0170811 A1
`7/2007 Toner etal.
`2007/0172903 A1
`8/2007 Mar'er et a1.
`2007/0178067 A1
`8/2007 O’Brien et a1.
`2007/0178458 A1
`8/2007 Huang et a1.
`2007/0187250 A1
`8/2007 Schwartz et a1.
`2007/0196663 A1
`8/2007 Kapur et a1.
`2007/0196820 A1
`8/2007 Roca et a1.
`2007/0196840 A1
`8/2007 Perez etal.
`2007/0196869 A1
`8/2007 Palucka etal.
`2007/0202106 A1
`8/2007 Nakarnura et a1.
`2007/0202109 A1
`8/2007 Quake et a1.
`2007/0202525 A1
`8/2007 Yamanishietal.
`2007/0202536 A1
`9/2007 Christensen et a1.
`2007/0207351 A1
`9/2007 Cantor et a1.
`2007/0207466 A1
`9/2007 Bianchi et a1.
`2007/0212689 A1
`9/2007 Bendele et a1.
`2007/0212698 A1
`9/2007 Clarke et a1.
`2007/0212737 A1
`9/2007 Haley etal.
`2007/0212738 A1
`10/2007 Toner etal.
`2007/0231851 A1
`10/2007 Barrett et a1.
`2007/0238105 A1
`11/2007 Toner etal.
`2007/0259424 A1
`11/2007 Toner etal.
`2007/0264675 A1
`11/2007 L0 etal.
`2007/0275402 A1
`1/2008 Mitchell et a1.
`2008/0020390 A1
`1/2008 Inglis etal.
`2008/0023399 A1
`1/2008 Stoughton etal.
`2008/0026390 A1
`2/2008 Bischoffetal.
`2008/0038733 A1
`2/2008 Stoughton etal.
`2008/0050739 A1
`3/2008 Stoughton etal.
`2008/0070792 A1
`3/2008 Hahn et a1.
`2008/0071076 A1
`4/2008 Shoemaker et a1.
`2008/0090239 A1
`4/2008 Quake
`2008/0096216 A1
`4/2008 Lee
`2008/0096766 A1
`5/2008 Fuchs
`2008/0124721 A1
`6/2008 Kapur et a1.
`2008/0138809 A1
`6/2008 L0 etal.
`2008/0153090 A1
`7/2008 Bianchi
`2008/0182261 A1
`8/2008 Mann et a1.
`2008/0193927 A1
`9/2008 Brody et a1.
`2008/0213775 A1
`9/2008 Shoemaker et a1.
`2008/0220422 A1
`12/2008 Oeth et a1.
`2008/0299562 A1
`1/2009 L0 etal.
`2009/0029377 A1
`4/2009 L0 etal.
`2009/0087847 A1
`7/2009 Quake et a1.
`2009/0170113 A1
`7/2009 Quake et a1.
`2009/0170114 A1
`11/2009 Stoughton etal.
`2009/0280492 A1
`11/2009 Stoughton etal.
`2009/0291443 A1
`5/2010 L0 etal.
`............................ 435/6
`2010/0112590 A1*
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`EP
`EP
`EP
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`EP
`EP
`EP
`EP
`EP
`EP
`
`0405972 B1
`1262776 A2
`0994963 B1
`0970365 B1
`783694 B1
`1262776 A3
`1388013 B1
`0920627 B1
`1418003 A1
`0739240 B1
`1462800 A1
`0919812 B1
`1561507 A1
`1409727 B1
`1272668 B1
`1754788 A2
`1757694 A2
`1409745 B1
`1754788 A3
`1770171 Al
`1313882 B1
`1803822 A1
`951645 B1
`1813681 A2
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`5/1999
`12/2002
`5/2003
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`1832661 A1
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`WO 2005/084374 A2
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`WO 2005/084380 A2
`W0 W0 2005/085476 A1
`W0 W0 2005/085861 A2
`W0 W0 2005/098046 A2
`
`9/2007
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`WO 2005/108621
`WO 2005/109238
`WO 2005/028663
`WO 2005/098046
`WO 2005/116264
`WO 2005/118852
`WO 2005/121362
`WO 2005/085861
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`2006097049
`WO 2006/076567
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`WO 2007/028146
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`WO 2007/034221
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`WO 2007/036025
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`WO 2007/030949
`WO 2007/034221
`WO 2007/050495
`WO 2007/053142
`WO 2007/053648
`WO 2007/053785
`WO 2007/059430
`WO 2007/062222
`WO 2005/058937
`WO 2007/067734
`WO 2007/048076
`WO 2007/053648
`WO 2007/075879
`WO 2007/076989
`WO 2007/079229
`WO 2007/079250
`WO 2007/080583
`WO 2007/082144
`WO 2007/082154
`WO 2007/082379
`WO 2007/050495
`WO 2007/075879
`WO 2007/087612
`WO 2007/089880
`WO 2007/089911
`WO 2007/090670
`WO 2007/092713
`WO 2007/098484
`WO 2006/100366
`WO 2007/100684
`WO 2007/101609
`WO 2007/033167
`WO 2007/038264
`WO 2007/044690
`WO 2007/053785
`WO 2007/059430
`WO 2005/084374
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`
`11/2005
`11/2005
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`WO 2007/035414 A3
`WO 2007/044091 A3
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`WO 2007/082379 A3
`WO 2007/098484 A3
`WO 2007/062222 A3
`WO 2007/100684 A3
`WO 2007/075836 A3
`WO 2008/017871 A1
`WO 2007/089911 A3
`WO 2007/028146 A3
`WO 2007/067734 A3
`WO 2007/126938 A3
`WO 2007/082154 A3
`WO 2007/087612 A3
`WO 2007/082144 A3
`WO 2007/092713 A3
`2009013492 A1
`2009013496 A1
`WO 2007/079229 A3
`WO 2007/080583 A3
`WO 2007/079250 A3
`WO 2007/041610 A3
`WO 2009/019455 A3
`
`11/2007
`11/2007
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`11/2007
`11/2007
`11/2007
`12/2007
`12/2007
`1/2008
`1/2008
`2/2008
`2/2008
`5/2008
`6/2008
`8/2008
`10/2008
`11/2008
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`12/2008
`12/2008
`1/2009
`1/2009
`1/2009
`2/2009
`3/2009
`4/2009
`4/2009
`
`OTHER PUBLICATIONS
`
`U.S. Appl. No. 11/825,677, filed Jul. 5,2007, Lopez et al.
`U.S.App1.No. 11/909,959, filed Sep. 27, 2007, Duff.
`U.S. Appl. No. 60/764,420, filed Feb. 2, 2005, Quake.
`U.S. Appl. No. 60/949,227, filed Jul. 11, 2007, Kapur.
`Adinolfi, et al. Gene Amplification to Detect Fetal Nucleated Cells in
`Pregnant Women. The Lancet. Aug. 5, 1989:328-329.
`Adinolfi, et al. Rapid detection of aneuploidies by microsatellite and
`the quantitative fluorescent polymerase chain reaction. Prenat.
`Diagn. 1997; 17(13):1299-311.
`Adinolfi, M. On a Non-Invasive Approach to Prenatel Diagnosis
`based on the detection of Fetal Nucleated Cells in Maternal Blood
`Samples. Prenatal Diagnosis. 1991;11:799-804.
`Ahn, et al. A fully integrated micromachined magnetic particle sepa-
`rator. Journal of Microelectromechanical Systems. 1996; 5(3):151-
`158.
`Andrews, et al. Enrichment of fetal nucleated cells from maternal
`blood: model test system using cord blood. Prenatal Diagnosis. 1995;
`1 5 :9 13-9 19.
`Applicant’s Amendment and Response dated Jun. 17, 2009 to Exam-
`iner Carla J. Myers Non-Final Office Action ofJan. 28, 2009 re U.S.
`App1.No. 11/701,686.
`Ariga, et al. Kinetics of fetal cellular and cell-free DNA in the
`maternal circulation during and after pregnancy: implications for
`noninvasive prenatal diagnosis. Transfusion. 2001; 41: 1524-1530.
`Arnould, et al. Agreement between chromogenic in situ hybridisation
`(CISH) and FISH in the determination of HER2 status in breast
`cancer. Br J Cancer. 2003; 88(10):1587-91. (Abstract only).
`Babochkina, et al. Direct detection of fetal cells in maternal blood: a
`reappraisal using a combination of two different Y chromosome-
`specific FISH probes and a single X chromosome-specific probe.
`Arch Gynecol Obstet. Dec. 2005;273(3):166-9. (Abstract only).
`Babochkina, T. I. Ph. D. DissertationiFetal cells in maternal circu-
`lation: Fetal cell separation and FISH analysis. University of Basel,
`Switzerland. Dec. 8, 2005. (123 pages).
`Balko, et al. Gene expression patterns that predict sensitivity to
`epidermal growth factor receptor tyrosine kinase inhibitors in lung
`cancer cell lines and human lung tumors. BMC Genomics. Nov. 10,
`2006;7:289 (14 pages).
`using
`hybridization
`genomic
`Barrett,
`et
`al. Comparative
`oligonucleotide microarrays and total genomic DNA. Proc Natl Acad
`Sci U S A. 2004; 101(51):17765-70.
`Basch, et al. Cell separation using positive immunoselective tech-
`niques. Journal of Immunological Methods. 1983;56:269-280.
`Bauer,
`J. Advances in cell separation:
`recent developments in
`counterflow centrifugal elutriation and continuous flow cell separa-
`tion. Journal of Chromatography. 1999;722:55-69.
`
`Page 5 of 48
`
`

`

`US 8,195,415 B2
`
`Page 6
`
`Becker, et al. Fabrication ofMicrostructures With High Aspect Ratios
`and Great Structural Heights by Synchrotron Radiation Lithography,
`Galvanoforming, and Plastic Moulding (LIGA Process). Microelec-
`tronic Engineering. 1986;4:35-56.
`Becker, et al. Planar quartz chips with submicron channels for two-
`dimensional capillary electrophoresis applications. J. Micromech
`Microeng.1998;9:24-28.
`Beebe et al. Functional Hydrogel Structures for Autonomous Flow
`Control Inside Microfluidic Channels. Nature. 2000; 404:588-590.
`Bennett,
`et
`al. Toward the
`1,000 dollars human genome.
`Pharmacogenomics. 2005; 6(4):373-82.
`Berenson, et al. Cellular Immunoabsorption Using Monoclonal Anti-
`bodies. Transplantation.1984;38:136-143.
`Berenson, et al. Positive selection of viable cell populations using
`avidin-biotin immunoadsorption. Journal of Immunological Meth-
`ods.1986;91:11-19.
`Berg, H. C. Random Walks in Biology, Ch. 4. Princeton University
`Press. Princeton, NJ. 1993. pp. 48-64.
`Berger, et al. Design of a microfabricated magnetic cell separator.
`Electrophoresis. Oct. 2001;22(18):3883-92.
`Bianchi, et al. Isolation of fetal DNA from nucleated erythrocytes in
`maternal blood. Medical Sciences. 1990;87:3279-3283.
`Bianchi, et al. Demonstration of fetal gene sequences in nucleated
`erythrocytes isolated from maternal blood. American Journal of
`Human Genetics. 1989;45:A252.
`Bianchi, et al. Fetal gender and aneuploidy detection using fetal cells
`in maternal blood: analysis of NIFTY I data. Prenatal Diagnosis.
`2002; 22:609-615.
`Bianchi, et al. Fetal nucleated erythrocytes (FNRBC) in maternal
`blood: erythroid-specific anitbodies improve detection. The Ameri-
`can Journal of Human Genetics. Oct. 1992. Supplemental to vol. 51,
`No. 4: 996.
`Bianchi, et al. Isolation of Male Fetal DNA from Nucleated Eryth-
`rocytes (NRBC) in Maternal Blood. The American Pediatric Society
`and Society for Pediatric Research, Mar. 1989; 818:139A.
`Bianchi, et al. Possible Effects of Gestational Age on the Detection of
`Fetal Nucleated Erythrocytes in Maternal Blood. Prenatal Diagnosis.
`1991;11:523-528.
`Bignell, et al. High-resolution analysis of DNA copy number using
`oligonucleotide microarrays. Genome Research. 2004; 14(2):287-
`295.
`Blake, et al. Assessment of multiplex fluorescent PCR for screening
`single cells for trisomy 21 and single gene defects. Mol. Hum.
`Reprod. 1999; 5(12):1166-75.
`Bode, et al. Mutations in the tyrosine kinase domain of the EGFR
`gene are rare in synovial sarcoma. Mod Pathol. Apr. 2006;19(4):541-
`7.
`Boehm, et al. Analysis of Defective Dystrophin Genes with cDNA
`Probes: Rearrangement Polymorphism, Detection of Deletions in
`Carrier Females, and Lower Than Expected Frequency of Carrier
`Mothers in Isolated Cases of Delections. Pediatric Research. Apr.
`1989: 139A-820.
`Bohmer, et al. Differential Development of Fetal and Adult
`Haemoglobin Profiles in Colony Culture: Isolation of Fetal Nucle-
`ated Red Cells by Two-Colour Fluorescence Labelling. Br.
`J.
`Haematol. 1998; 103:351-60.
`Brison, et al. General Method for Cloning Amplified DNA by Dif-
`ferential Screening with Genomic Probes. Molecular and Cellular
`Biology. 1982;2:578-587.
`Brody, et al. Deformation and Flow of Red Blood Cells in a Synthetic
`Lattice: Evidence for an Active Cytoskeleton. Biophys. J. 68:2224-
`2232 (1995).
`Caggana, M. Microfabricated devices for sparse cell isolation. CNF
`Project #905-00. Cornell NanoScale Facility. 2003; pp. 38-39.
`Caggana, M. Microfabricated devices for sparse cell isolation. CNF
`Project #905-00. Cornell NanoScale Facility. 2004-2005; pp. 32-33.
`Calin, et al. A microRNA signature Associated with prognosis and
`progression in chronic lymphocytic leukemia. New England Journal
`of Medicine. 2005; 353: 1793-1801.
`Cha, The utility of an erythroblast scoring system and gender-inde-
`pendent short tandem repeat (STR) analysis for the detection of
`aneuploid fetal cells in maternal blood. Prenat. Diagn. 2005;
`25(7):586-91.
`
`Page 6 0f 48
`
`Chamberlain, et al. Deletion screening of the Duchenne muscular
`dystrophy locus via multiplex DNA amplification. Nucleic Acids
`Research. 1988;16:11141-11156.
`Chan, et al. Size distributions of maternal and fetal DNA in maternal
`plasma. Clin Chem. Jan. 2004;50(1):88-92.
`Chang, et al. Biomimetic technique for adhesion-based collection
`and separation of cells in a microfluidic channel. Lab Chip. 2005;
`5:64-73.
`Cheung, et al. Development and validation of a CGH microarray for
`clinical cytogenetic diagnosis. Genet Med. 2005; 7(6):422-32.
`Chiu, et al. Patterned Deposition of Cells and Proteins Onto Surfaces
`by Using Three-Dimensional Microfluidic Systems. Proceedings of
`the National Academy of Sciences of the United States of America.
`2000; pp. 2408-2413.
`Choesmel, et al. Enrichment methods to detect bone marrow
`micrometastases in breast carcinoma patients: clinical relevance.
`Breast Cancer Res. 2004;6(5):R556-569.
`Choolani,
`et
`al. Characterization of First Trimester Fetal
`Erythroblasts for Non-Invasive Prenatal Diagnosis. Mol. Hum.
`Reprod. 2003; 9:227-35.
`Chou, et al. A Microfabricated Device for Sizing and Sorting DNA
`Molecules. Proceedings of the National Academy of Sciences of the
`United States ofAmerica. 1999; pp. 11-13.
`Chou, et al. Sorting by diffusion: An asymmetric obstacle course for
`continuous molecular
`separation. PNAS. 1999; 96(24):13762-
`13765.
`Christel, et al. High aspect ratio silicon microstructures for nucleic
`acid extraction. Solid-state sensor and actuator workshop. Hilton
`Head, SC. Jun. 8-11, 1998; 363-366.
`Christensen, et al. Fetal Cells in Maternal Blood: A Comparison of
`Methods for Cell Isolation and Identification. Fetal Diagn. Ther.
`2005; 20:106-12.
`Chueh, et al. Prenatal Diagnosis Using Fetal Cells from the Maternal
`Circulation. West J. Med. 159:308-311 (1993).
`Chueh, et al. Prenatal Diagnosis Using Fetal Cells in the Maternal
`Circulation. Seminars in Perinatology. 1990;14:471-482.
`Chueh, et al. The search for fetal cells in the maternal circulation. J
`Perinat Med. 1991;19:411-420.
`Cirigliano, et al. “Clinical application of multiplex quantitative fluo-
`rescent polymerase chain reaction (QF-PCR) for the rapid prenatal
`detection of common chromosome aneuploidies,” Molecular Human
`Reproduction, 2001, vol. 7, No. 10, 1001-1006.
`Clayton, et al. Fetal Erythrocytes in the Maternal Circulation of
`Pregnant Women. Obstetrics and Gynecology. 1964;23:915-919.
`Collarini, et al. Comparison of methods for erythroblast selection:
`application to selecting fetal erythroblasts from maternal blood.
`Cytometry. 2001; 45:267-276.
`Cremer, et al. Detection of chromosome aberrations in human
`interphase nucleus by visualization of specific target DNAs with
`radioactive and non-radioactive in situ hybridization techniques:
`diagnosis of trisomy 18 with probe L1.84. Human Genetics.
`1986;74:346-352.
`Cremer, et al. Detection of chromosome aberaations in metaphase
`and interphase tumor cells by in situ hybridization using chromo-
`some-specific library probes. Human Genetics.1988;80:235-246.
`Das, et al. Dielectrophoretic segregation ofdifferent human cell types
`on microscope slides. Anal. Chem. 2005; 77:2708-2719.
`De Alba, et al. Prenatal diagnosis on fetal cells obtained from mater-
`nal peripheral blood:
`report of 66 cases. Prenat Diagn. Oct.
`1999;19(10):934-40.
`De Kretser, et al. The Separation of Cell Populations using
`Monoclonal Antibodies attached to Sepharose. Tissue Antigens.
`1980;16:317-325.
`Delamarche, et al. Microfluidic Networks for Chemical Patterning of
`Substrates: Design and Application to Bioassays. Journal of the
`American Chemical Society. 1998; 120:500-508.
`Delamarche, et al. Patterned Delivery of Immunoglobulins to Sur-
`faces Using Microfluidic Networks. Science. 1997; 276:779-781.
`Deng, et al. Enumeration and microfluidic chip separation of circu-
`lating fetal cells early in pregnancy from maternal blood. American
`Journal of Obstetrics & Gynecology. Dec. 2008 (vol. 199, Issue 6, p.
`S134).
`
`Page 6 of 48
`
`

`

`US 8,195,415 B2
`
`Page 7
`
`al. Continuous Micromixer With Pulsatile
`et
`Deshmukh,
`Micropumps. Solid-State Sensor and Actuator Workshop. Hilton
`Head Island, South Carolina; Jun. 4-8, 2000:73-76.
`Di Naro, et al. Prenatal diagnosis of beta-thalassaemia using fetal
`erythroblasts enriched from maternal blood by a novel gradient. Mol
`Hum Reprod. 2000; 6(6):571-4.
`Dilella, et al. Screening for Phenylketonuria Mutations by DNA
`Amplification with the Polymerase Chain Reaction. The Lancet. Mar.
`5, 1988:497-499.
`Doyle, et al. Self-Assembled Magnetic Matrices for DNA Separation
`Chips. Science 295:2237 (2002).
`Eigen, et al. Sorting Single Molecules: Application to Diagnostics
`and Evolutionary Biotechnology. Proceedings of the National Acad-
`emy of Sciences of the United States of America. 1994; 91:5740-
`5747.
`Emanuel, et al. Amplification of Specific Gene Products from Human
`Serum. GATA, 1993, vol. 10, No. 6, 144-146.
`European search report dated Nov. 9, 2009 for Application No.
`77844421
`European search report dated Dec. 21, 2009 for Application No.
`077985794.
`European search report dated Dec. 22, 2009 for Appllication No.
`077985802.
`European search report dated Dec. 22, 2009