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Patent Application
App. No. 11/232,335

Diagnosis of fetal aneuploidy

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Patent No.
US None
App. No.
11/232,335
Abstract

The invention relates to a method for the early non-invasive diagnosis of fetal aneuploidy. In particular, the invention concerns the diagnosis of fetal aneuploidy by identifying protein expression patterns characteristics of fetal aneuploidy in a maternal biological fluid, such as maternal serum or amniotic fluid.

Claims (68)

1 . A method for diagnosis of fetal aneuploidy, comprising comparing the proteomic profile of a test sample of a maternal biological fluid with a normal or a reference proteomic profile of the same type of biological fluid, and determining the presence of fetal aneuploidy if the proteomic profile of said test sample shows at least one unique expression signature representing at least one biomarker selected from the group consisting of the biomarkers listed in Tables 1-2 and 5-6, absent from said normal proteomic profile or present in said reference proteomic profile.

2 . The method of claim 1 wherein said test sample is obtained from a pregnant female human.

3 . The method of claim 1 wherein said proteomic profile is a mass spectrum.

4 . The method of claim 1 wherein test sample is maternal serum.

5 . The method of claim 4 wherein said unique expression signature is in one or more of molecular weight regions 16 to 20 kDa, 35 to 38 kDa, 38 to 42 kDa, 40 to 45 kDa, 50 to 55 kDa, 60 to 68 kDa, and 125 to 150 kDa.

6 . The method of claim 2 which is performed in the first trimester of pregnancy.

7 . The method of claim 2 which is performed in the second trimester of pregnancy.

8 . The method of claim 1 further comprising determining in said test sample the level of transcribed mRNA or the level of translated protein of at least one additional biomarker of fetal aneuploidy, and confirming the presence of fetal aneuploidy if said level of transcribed mRNA or level of translated protein is different relative to its level in a normal biological sample.

9 . The method of claim 8 wherein said fetal aneuploidy is Down's syndrome, trisomy 13, trisomy 18, X chromosome trisomy, X chromosome monosomy, Kleinfelter's syndrome (XXY genotype), or XYY syndrome (XYY genotype).

10 . The method of claim 1 wherein said fetal aneuploidy is Down's syndrome, trisomy 13, trisomy 18, X chromosome trisomy, X chromosome monosomy, Kleinfelter's syndrome (XXY genotype), or XYY syndrome (XYY genotype).

11 . The method of claim 8 wherein said additional biomarker is selected from the group consisting of PAPP-A, a-fetoprotein (AFP), human chorionic gonadotropin (bhCG), unconjugated estriol (uE3), and inhibin A.

12 . The method of claim 11 wherein the level of transcribed mRNA or the level of translated PAPP-A and bhCG are determined.

13 . The method of claim 12 wherein the level of transcribed mRNA or the level of translated AFP, bhCG, and uE3 are additionally determined.

14 . The method of claim 13 wherein the level of transcribed mRNA or the level of translated inhibin-A is additionally determined.

15 . The method of claim 2 further comprising subjecting the pregnant female human to one or more of additional diagnostic techniques.

16 . The method of claim 15 wherein said additional diagnostic techniques are selected from the group consisting of ultrasonography, techniques to test chromosomal abnormalities, and nuchal translucency (NT) measurement.

17 . The method of claim 1 comprising comparison of the unique expression signature of more than one of said biomarkers.

18 . The method of claim 1 wherein said biomarker or biomarkers are selected from the group consisting of complement factor H (CFAH_HUMAN, SwissProt Accession No. P08603); pregnancy zone protein (PZP_HUMAN; SwissProt Accession No. P20741); afamin (AFAM_HUMAN; SwissProt Accession No. P43652); angiotensinogen (ANGT_HUMAN; SwissProt Accession No. P01019); alpha-2-hs-glycoprotein (A2HS_HUMAN; SwissProt Accession No. P02765); clusterin (CLUS_HUMAN; SwissProt Accession No. P10909); apolipoprotein AI (APA1_HUMAN; SwissProt Accession No. P02647); apolipoprotein AIV (APA4_HUMAN; SwissProt Accession No. P06727); apolipoprotein E (APE_HUMAN; SwissProt Accession No. P02649); pigment epithelium-derived factor (PEDF_HUMAN; SwissProt Accession No. P36955); serum amyloid A protein (SAA_HUMAN; SwissProt Accession No. P02735); AMBP protein (AMBP_HUMAN; SwissProt Accession No. P02760); plasma retinol binding protein (RETB_HUMAN; SwissProt Accession No. P02753); serotransferrin precursor (TRFE_HUMAN; SwissProt Accession No. P02787); alpha-1-antitrypsin precursor (A1AT_HUMAN; SwissProt Accession No. P01009); alpha-2-macroglobulin precursor (A2MG_HUMAN; SwissProt Accession No. P01023); complement C3 precursor (CO3_HUMAN; SwissProt Accession No. P01024); angiotensinogen precursor (ANGT_HUMAN; SwissProt Accession No. P01019); ceruloplasmin precursor (CERU_HUMAN; SwissProt Accession No. P00450); haptoglobin precursor (HPT_HUMAN; SwissProt Accession No. P00738); antithrombin-III precursor (ANT3_HUMAN; SwissProt Accession No. P01008); hemopexin precursor (HEMO_HUMAN; SwissProt Accession No. P02790); alpha-1-acid glycoprotein 1 precursor (A1AG_HUMAN; SwissProt Accession No. P02763); apolipoprotein A-I precursor (APA1_HUMAN; SwissProt Accession No. P02647); alpha 1b-glycoprotein (SwissProt Accession No. P04217); kininogen precursor (KNG_HUMAN; SwissProt Accession No. P01042-2); inter-alpha-trypsin inhibitor heavy chain H2 precursor (ITH2_HUMAN; SwissProt Accession No. P19823); alpha-2-hs-glycoprotein precursor (A2HS_HUMAN; SwissProt Accession No. P02765); alpha-1-antichymotrypsin precursor (AACT_HUMAN; SwissProt Accession No. P01011); inter-alpha-trypsin inhibitor heavy chain H4 precursor (ITH4_HUMAN; SwissProt Accession No. Q14624-2); complement factor H precursor (CFAH_HUMAN; SwissProt Accession No. P08603-1); plasma protease C1 inhibitor precursor (IC1_HUMAN; SwissProt Accession No. P05155); heparin cofactor II precursor (HEP2_HUMAN SwissProt Accession No. P05546); complement factor B precursor (CFAB_HUMAN; SwissProt Accession No. P00751-1); alpha-2-glycoprotein 1, zinc (ZA2G_HUMAN; SwissProt Accession No. P25311); vitronectin precursor (VTNC_HUMAN SwissProt Accession No. P04004); inter-alpha-trypsin inhibitor heavy chain H1 precursor (ITH1_HUMAN; SwissProt Accession No. P19827); complement component C9 precursor (CO9_HUMAN; SwissProt Accession No. P02748); fibrinogen alpha/alpha-E chain precursor (FIBA_HUMAN; SwissProt Accession No. P02671-1); fibrinogen beta chain precursor (FIBB_HUMAN; SwissProt Accession No. P02675); fibrinogen gamma chain precursor (FIBG_HUMAN; SwissProt Accession No. P02679-1); prothrombin precursor (THRB_HUMAN; SwissProt Accession No. P00734); clusterin precursor (CLUS_HUMAN; SwissProt Accession No. P10909); alpha-1B-glycoprotein precursor (A1BG_HUMAN; SwissProt Accession No. P04217); alpha-1-acid glycoprotein 2 precursor (A1AH_HUMAN; SwissProt Accession No. P19652); apolipoprotein D precursor (APOD_HUMAN; SwissProt Accession No. P05090); pregnancy zone protein precursor (PZP_HUMAN; SwissProt Accession No. P20742); histidine-rich glycoprotein precursor (HRG_HUMAN; SwissProt Accession No. P04196); sex hormone-binding globulin precursor (SHBG_HUMAN; SwissProt Accession No. P04278-1); plasminogen precursor (PLMN_HUMAN; SwissProt Accession No. P00747); apolipoprotein C-III precursor (APC3_HUMAN; SwissProt Accession No. P02656); leucine-rich alpha-2-glycoprotein precursor (A2GL_HUMAN; SwissProt Accession No. P02750); apolipoprotein E precursor (APE_HUMAN; SwissProt Accession No. P02649); fetuin-B precursor (FETB_HUMAN; SwissProt Accession No. Q9UGM5); myosin-reactive immunoglobulin light chain variable region (SwissProt Accession No. Q9UL83); complement C1S component precursor (C1S_HUMAN; SwissProt Accession No. P09871); ambp protein precursor (AMBP_HUMAN; SwissProt Accession No. P02760); and complement C4 precursor (CO4_HUMAN; SwissProt Accession No. P01028).

19 . The method of claim 18 comprising comparison of the unique expression signature of more than one of said biomarkers.

20 . The method of claim 1 wherein said biomarkers are complement factor H (CFAH_HUMAN, SwissProt Accession No. P08603); and pregnancy zone protein (PZP_HUMAN; SwissProt Accession No. P20741).

21 . The method of claim 1 wherein said biomarkers are complement factor H (CFAH_HUMAN, SwissProt Accession No. P08603); and afamin (AFAM_HUMAN; SwissProt Accession No. P43652).

22 . The method of claim 1 wherein said biomarkers are pregnancy zone protein (PZP_HUMAN; SwissProt Accession No. P20741); and alpha-2-hs-glycoprotein (A2HS_HUMAN; SwissProt Accession No. P02765).

23 . The method of claim 1 wherein said biomarkers are complement factor H (CFAH_HUMAN, SwissProt Accession No. P08603); angiotensinogen (ANGT_HUMAN; SwissProt Accession No. P01019); and clusterin (CLUS_HUMAN; SwissProt Accession No. P10909).

24 . The method of claim 1 wherein said biomarkers are apolipoprotein E (APE_HUMAN; SwissProt Accession No. P02649); AMBP protein (AMBP_HUMAN; SwissProt Accession No. P02760); and plasma retinol binding protein (RETB_HUMAN; SwissProt Accession No. P02753).

25 . The method of claim 1 wherein said biomarkers are complement factor H (CFAH_HUMAN, SwissProt Accession No. P08603); afamin (AFAM_HUMAN; SwissProt Accession No. P43652); angiotensinogen (ANGT_HUMAN; SwissProt Accession No. P01019); and clusterin (CLUS_HUMAN; SwissProt Accession No. P10909).

26 . The method of claim 1 wherein said biomarkers are complement factor H (CFAH_HUMAN, SwissProt Accession No. P08603); afamin (AFAM_HUMAN; SwissProt Accession No. P43652); pigment epithelium-derived factor (PEDF_HUMAN; SwissProt Accession No. P36955); serum amyloid A protein (SAA_HUMAN; SwissProt Accession No. P02735); angiotensinogen (ANGT_HUMAN; SwissProt Accession No. P01019); and clusterin (CLUS_HUMAN; SwissProt Accession No. P10909).

27 . The method of claim 1 wherein said biomarkers are apolipoprotein E (APE_HUMAN; SwissProt Accession No. P02649); AMBP protein (AMBP_HUMAN; SwissProt Accession No. P02760); plasma retinol binding protein (RETB_HUMAN; SwissProt Accession No. P02753); serotransferrin precursor (TRFE_HUMAN; SwissProt Accession No. P02787); alpha-2-macroglobulin precursor (A2MG_HUMAN; SwissProt Accession No. P01023); and histidine-rich glycoprotein precursor (HRG_HUMAN; SwissProt Accession No. P04196).

28 . The method of claim 1 wherein said biomarkers are inter-alpha-trypsin inhibitor heavy chain H1 precursor (ITH1_HUMAN; SwissProt Accession No. P19827); complement component C9 precursor (CO9_HUMAN; SwissProt Accession No. P02748); fibrinogen alpha/alpha-E chain precursor (FIBA_HUMAN; SwissProt Accession No. P02671-1); apolipoprotein C-III precursor (APC3_HUMAN; SwissProt Accession No. P02656); leucine-rich alpha-2-glycoprotein precursor (A2GL_HUMAN; SwissProt Accession No. P02750); apolipoprotein E precursor (APE_HUMAN; SwissProt Accession No. P02649); fetuin-B precursor (FETB_HUMAN; SwissProt Accession No. Q9UGM5); and complement C4 precursor (CO4_HUMAN; SwissProt Accession No. P01028).

29 . The method of claim 1 wherein said proteomic profiles include at least one glycoprotein.

30 . The method of claim 29 wherein said at least one glycoprotein is selected from the group consisting of sialic acid glycoproteins, mannose binding glycoproteins, and O-linked glycoproteins.

31 . The method of claim 1 wherein said fetal aneuploidy is an autosomal aneuploidy.

32 . The method of claim 31 wherein said autosomal aneuploidy is a trisomy of chromosomes 13, 18, or 21.

33 . The method of claim 1 wherein said fetal aneuploidy is a sex chromosome aneuploidy.

34 . The method of claim 33 wherein said sex chromosome aneuploidy is selected from the group consisting of: X chromosome trisomy, X chromosome monosomy, Kleinfelter's syndrome (XXY genotype), and XYY syndrome (XYY genotype).

35 . A method for diagnosis of fetal aneuploidy, comprising comparing the proteomic profile of a test sample of a maternal biological fluid with a normal or a reference proteomic profile of the same type of biological fluid, and determining the presence of fetal aneuploidy if the proteomic profile of said test sample shows at least one unique expression signature representing at least one biomarker selected from the group consisting of the biomarkers listed in Table 3, absent from said normal proteomic profile or present in said reference proteomic profile.

36 . The method of claim 35 wherein said test sample is obtained from a pregnant female human.

37 . The method of claim 35 wherein said proteomic profile is a mass spectrum.

38 . The method of claim 35 wherein the test sample is maternal amniotic fluid.

39 . The method of claim 38 wherein said unique expression signature is in one or both of molecular weight regions of 6 to 7 kDa and 8 to 10 kDa.

40 . The method of claim 36 which is performed in the first trimester of pregnancy.

41 . The method of claim 36 which is performed in the second trimester of pregnancy.

42 . The method of claim 35 further comprising determining in said test sample the level of transcribed mRNA or the level of translated protein of at least one additional biomarker of fetal aneuploidy, and confirming the presence of fetal aneuploidy if said level of transcribed mRNA or level of translated protein is different relative to its level in a normal biological sample.

43 . The method of claim 2 wherein said fetal aneuploidy is Down's syndrome, trisomy 13, trisomy 18, X chromosome trisomy, X chromosome monosomy, Kleinfelter's syndrome (XXY genotype), or XYY syndrome (XYY genotype).

44 . The method of any one of claim 42 wherein said fetal aneuploidy is Down's syndrome, trisomy 13, trisomy 18, X chromosome trisomy, X chromosome monosomy, Kleinfelter's syndrome (XXY genotype), or XYY syndrome (XYY genotype).

45 . The method of claim 42 wherein said additional biomarker is selected from the group consisting of PAPP-A, a-fetoprotein (AFP), human chorionic gonadotropin (bhCG), unconjugated estriol (uE3), and inhibin A.

46 . The method of claim 45 wherein the level of transcribed mRNA or the level of translated PAPP-A and bhCG are determined.

47 . The method of claim 46 wherein the level of transcribed mRNA or the level of translated AFP, bhCG, and uE3 are additionally determined.

48 . The method of claim 47 wherein the level of transcribed mRNA or the level of translated inhibin-A is additionally determined.

49 . The method of claim 36 further comprising subjecting the pregnant female human to one or more of additional diagnostic techniques.

50 . The method of claim 49 wherein said additional diagnostic techniques are selected from the group consisting of ultrasonography, techniques to test chromosomal abnormalities, and nuchal translucency (NT) measurement.

51 . The method of claim 35 comprising comparison of the unique expression signature of more than one of said biomarkers.

52 . The method of claim 35 wherein said biomarker or biomarkers are selected from the group consisting of complement factor H (CFAH_HUMAN, SwissProt Accession No. P08603); pregnancy zone protein (PZP_HUMAN; SwissProt Accession No. P20741); afamin (AFAM_HUMAN; SwissProt Accession No. P43652); angiotensinogen (ANGT_HUMAN; SwissProt Accession No. P01019); alpha-2-hs-glycoprotein (A2HS_HUMAN; SwissProt Accession No. P02765); clusterin (CLUS_HUMAN; SwissProt Accession No. P10909); apolipoprotein AI (APA1_HUMAN; SwissProt Accession No. P02647); apolipoprotein AIV (APA4_HUMAN; SwissProt Accession No. P06727); apolipoprotein E (APE_HUMAN; SwissProt Accession No. P02649); pigment epithelium-derived factor (PEDF_HUMAN; SwissProt Accession No. P36955); serum amyloid A protein (SAA_HUMAN; SwissProt Accession No. P02735); AMBP protein (AMBP_HUMAN; SwissProt Accession No. P02760); plasma retinol binding protein (RETB_HUMAN; SwissProt Accession No. P02753); serotransferrin precursor (TRFE_HUMAN; SwissProt Accession No. P02787); alpha-1-antitrypsin precursor (A1AT_HUMAN; SwissProt Accession No. P01009); alpha-2-macroglobulin precursor (A2MG_HUMAN; SwissProt Accession No. P01023); complement C3 precursor (CO3_HUMAN; SwissProt Accession No. P01024); angiotensinogen precursor (ANGT_HUMAN; SwissProt Accession No. P01019); ceruloplasmin precursor (CERU_HUMAN; SwissProt Accession No. P00450); haptoglobin precursor (HPT_HUMAN; SwissProt Accession No. P00738); antithrombin-III precursor (ANT3_HUMAN; SwissProt Accession No. P01008); hemopexin precursor (HEMO_HUMAN; SwissProt Accession No. P02790); alpha-1-acid glycoprotein 1 precursor (A1AG_HUMAN; SwissProt Accession No. P02763); apolipoprotein A-I precursor (APA1_HUMAN; SwissProt Accession No. P02647); alpha 1b-glycoprotein (SwissProt Accession No. P04217); kininogen precursor (KNG_HUMAN; SwissProt Accession No. P01042-2); inter-alpha-trypsin inhibitor heavy chain H2 precursor (ITH2_HUMAN; SwissProt Accession No. P19823); alpha-2-hs-glycoprotein precursor (A2HS_HUMAN; SwissProt Accession No. P02765); alpha-1-antichymotrypsin precursor (AACT_HUMAN; SwissProt Accession No. P01011); inter-alpha-trypsin inhibitor heavy chain H4 precursor (ITH4_HUMAN; SwissProt Accession No. Q14624-2); complement factor H precursor (CFAH_HUMAN; SwissProt Accession No. P08603-1); plasma protease C1 inhibitor precursor (IC1_HUMAN; SwissProt Accession No. P05155); heparin cofactor II precursor (HEP2_HUMAN SwissProt Accession No. P05546); complement factor B precursor (CFAB_HUMAN; SwissProt Accession No. P00751-1); alpha-2-glycoprotein 1, zinc (ZA2G_HUMAN; SwissProt Accession No. P25311); vitronectin precursor (VTNC_HUMAN SwissProt Accession No. P04004); inter-alpha-trypsin inhibitor heavy chain H1 precursor (ITH1_HUMAN; SwissProt Accession No. P19827); complement component C9 precursor (CO9_HUMAN; SwissProt Accession No. P02748); fibrinogen alpha/alpha-E chain precursor (FIBA_HUMAN; SwissProt Accession No. P02671-1); fibrinogen beta chain precursor (FIBB_HUMAN; SwissProt Accession No. P02675); fibrinogen gamma chain precursor (FIBG_HUMAN; SwissProt Accession No. P02679-1); prothrombin precursor (THRB_HUMAN; SwissProt Accession No. P00734); clusterin precursor (CLUS_HUMAN; SwissProt Accession No. P10909); alpha-1B-glycoprotein precursor (A1BG_HUMAN; SwissProt Accession No. P04217); alpha-1-acid glycoprotein 2 precursor (A1AH_HUMAN; SwissProt Accession No. P19652); apolipoprotein D precursor (APOD_HUMAN; SwissProt Accession No. P05090); pregnancy zone protein precursor (PZP_HUMAN; SwissProt Accession No. P20742); histidine-rich glycoprotein precursor (HRG_HUMAN; SwissProt Accession No. P04196); sex hormone-binding globulin precursor (SHBG_HUMAN; SwissProt Accession No. P04278-1); plasminogen precursor (PLMN_HUMAN; SwissProt Accession No. P00747); apolipoprotein C-III precursor (APC3_HUMAN; SwissProt Accession No. P02656); leucine-rich alpha-2-glycoprotein precursor (A2GL_HUMAN; SwissProt Accession No. P02750); apolipoprotein E precursor (APE_HUMAN; SwissProt Accession No. P02649); fetuin-B precursor (FETB_HUMAN; SwissProt Accession No. Q9UGM5); myosin-reactive immunoglobulin light chain variable region (SwissProt Accession No. Q9UL83); complement C1S component precursor (C1S_HUMAN; SwissProt Accession No. P09871); ambp protein precursor (AMBP_HUMAN; SwissProt Accession No. P02760); and complement C4 precursor (CO4_HUMAN; SwissProt Accession No. P01028).

53 . The method of claim 52 comprising comparison of the unique expression signature of more than one of said biomarkers.

54 . The method of claim 35 wherein said biomarkers are complement factor H (CFAH_HUMAN, SwissProt Accession No. P08603); and pregnancy zone protein (PZP_HUMAN; SwissProt Accession No. P20741).

55 . The method of claim 35 wherein said biomarkers are complement factor H (CFAH_HUMAN, SwissProt Accession No. P08603); and afamin (AFAM_HUMAN; SwissProt Accession No. P43652).

56 . The method of claim 2 wherein said biomarkers are pregnancy zone protein (PZP_HUMAN; SwissProt Accession No. P20741); and alpha-2-hs-glycoprotein (A2HS_HUMAN; SwissProt Accession No. P02765).

57 . The method of claim 2 wherein said biomarkers are complement factor H (CFAH_HUMAN, SwissProt Accession No. P08603); angiotensinogen (ANGT_HUMAN; SwissProt Accession No. P01019); and clusterin (CLUS_HUMAN; SwissProt Accession No. P 10909).

58 . The method of claim 2 wherein said biomarkers are apolipoprotein E (APE_HUMAN; SwissProt Accession No. P02649); AMBP protein (AMBP_HUMAN; SwissProt Accession No. P02760); and plasma retinol binding protein (RETB_HUMAN; SwissProt Accession No. P02753).

59 . The method of claim 2 wherein said biomarkers are complement factor H (CFAH_HUMAN, SwissProt Accession No. P08603); afamin (AFAM_HUMAN; SwissProt Accession No. P43652); angiotensinogen (ANGT_HUMAN; SwissProt Accession No. P01019); and clusterin (CLUS_HUMAN; SwissProt Accession No. P10909).

60 . The method of claim 2 wherein said biomarkers are complement factor H (CFAH_HUMAN, SwissProt Accession No. P08603); afamin (AFAM_HUMAN; SwissProt Accession No. P43652); pigment epithelium-derived factor (PEDF_HUMAN; SwissProt Accession No. P36955); serum amyloid A protein (SAA_HUMAN; SwissProt Accession No. P02735); angiotensinogen (ANGT_HUMAN; SwissProt Accession No. P01019); and clusterin (CLUS_HUMAN; SwissProt Accession No. P10909).

61 . The method of claim 2 wherein said biomarkers are apolipoprotein E (APE_HUMAN; SwissProt Accession No. P02649); AMBP protein (AMBP_HUMAN; SwissProt Accession No. P02760); plasma retinol binding protein (RETB_HUMAN; SwissProt Accession No. P02753); serotransferrin precursor (TRFE_HUMAN; SwissProt Accession No. P02787); alpha-2-macroglobulin precursor (A2MG_HUMAN; SwissProt Accession No. P01023); and histidine-rich glycoprotein precursor (HRG_HUMAN; SwissProt Accession No. P04196).

62 . The method of claim 2 wherein said biomarkers are inter-alpha-trypsin inhibitor heavy chain H1 precursor (ITH1_HUMAN; SwissProt Accession No. P19827); complement component C9 precursor (CO9_HUMAN; SwissProt Accession No. P02748); fibrinogen alpha/alpha-E chain precursor (FIBA_HUMAN; SwissProt Accession No. P02671-1); apolipoprotein C-III precursor (APC3_HUMAN; SwissProt Accession No. P02656); leucine-rich alpha-2-glycoprotein precursor (A2GL_HUMAN; SwissProt Accession No. P02750); apolipoprotein E precursor (APE_HUMAN; SwissProt Accession No. P02649); fetuin-B precursor (FETB_HUMAN; SwissProt Accession No. Q9UGM5); and complement C4 precursor (CO4_HUMAN; SwissProt Accession No. P01028).

63 . The method of claim 2 wherein said proteomic profiles include at least one glycoprotein.

64 . The method of claim 63 wherein said at least one glycoprotein is selected from the group consisting of sialic acid glycoproteins, mannose binding glycoproteins, and O-linked glycoproteins.

65 . The method of claim 2 wherein said fetal aneuploidy is an autosomal aneuploidy.

66 . The method of claim 65 wherein said autosomal aneuploidy is a trisomy of chromosomes 13, 18, or 21.

67 . The method of claim 2 wherein said fetal aneuploidy is a sex chromosome aneuploidy.

68 . The method of claim 67 wherein said sex chromosome aneuploidy is selected from the group consisting of: X chromosome trisomy, X chromosome monosomy, Kleinfelter's syndrome (XXY genotype), and XYY syndrome (XYY genotype).

Assignments (7)
CORRECTIVE ASSIGNMENT TO CORRECT THE INCORRECT PATENT NO. 8081301 PREVIOUSLY RECORDED AT REEL: 028810 FRAME: 0745. ASSIGNOR(S) HEREBY CONFIRMS THE SECURITY AGREEMENT. Recorded Nov 9, 2017
From: HOLOGIC, INC.; BIOLUCENT, LLC; CYTYC CORPORATION; CYTYC SURGICAL PRODUCTS, LIMITED PARTNERSHIP; SUROS SURGICAL SYSTEMS, INC.; THIRD WAVE TECHNOLOGIES, INC.; GEN-PROBE INCORPORATED
To: GOLDMAN SACHS BANK USA
Reel/Frame 044432/0565 →
CORRECTIVE ASSIGNMENT TO CORRECT THE INCORRECT PATENT NO. 8081301 PREVIOUSLY RECORDED AT REEL: 035820 FRAME: 0239. ASSIGNOR(S) HEREBY CONFIRMS THE SECURITY INTEREST RELEASE. Recorded Nov 9, 2017
From: GOLDMAN SACHS BANK USA, AS COLLATERAL AGENT
To: HOLOGIC, INC.; BIOLUCENT, LLC; CYTYC CORPORATION; CYTYC SURGICAL PRODUCTS, LIMITED PARTNERSHIP; SUROS SURGICAL SYSTEMS, INC.; THIRD WAVE TECHNOLOGIES, INC.; GEN-PROBE INCORPORATED
Reel/Frame 044727/0529 →
SECURITY INTEREST RELEASE REEL/FRAME 028810/0745 Recorded Jun 4, 2015
From: GOLDMAN SACHS BANK USA, AS COLLATERAL AGENT
To: HOLOGIC, INC.; BIOLUCENT, LLC; CYTYC CORPORATION; CYTYC SURGICAL PRODUCTS, LIMITED PARTNERSHIP; SUROS SURGICAL SYSTEMS, INC.; THIRD WAVE TECHNOLOGIES, INC.; GEN-PROBE INCORPORATED
Reel/Frame 035820/0239 →
SECURITY AGREEMENT Recorded Aug 1, 2012
From: HOLOGIC, INC.; BIOLUCENT, LLC; CYTYC CORPORATION; CYTYC SURGICAL PRODUCTS, LIMITED PARTNERSHIP; SUROS SURGICAL SYSTEMS, INC.; THIRD WAVE TECHNOLOGIES, INC.; GEN-PROBE INCORPORATED
To: GOLDMAN SACHS BANK USA
Reel/Frame 028810/0745 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 19, 2011
From: PROTEOGENIX, INC.
To: PROTEOGENIX (ASSIGNMENT FOR THE BENEFIT OF CREDITORS) LLC
Reel/Frame 026149/0524 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 10, 2011
From: PROTEOGENIX (ASSIGNMENT FOR THE BENEFIT OF CREDITORS) LLC
To: HOLOGIC, INC.
Reel/Frame 025931/0472 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 22, 2007
From: ROSENFIELD, RON; NAGALLA, SRINIVASA
To: PROTEOGENIX, INC.
Reel/Frame 018836/0651 →