IP Library › Granted Patent US 12,454,722
Granted Patent B2
US 12,454,722 · App. 18/142,512 · Granted Oct 28, 2025

Multiplexed method for the identification and quantitation of minor alleles and polymorphisms

Inventor: Anders Olof Herman Nygren (San Diego, CA)
Assignee: AGENA BIOSCIENCE, INC.
C12Q1/6858C12Q1/6827C12Q1/686
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,454,722
App. No.
18/142,512
Granted
Oct 28, 2025
Kind
B2
Abstract

Provided herein are products and processes for detecting the presence or absence of minor nucleic acid species in a sample containing a mixture of minor nucleic acid species and one or more major nucleic acid species, where the amount (frequency or copy number) of the minor nucleic acid species is less than that of the major nucleic acid species. Certain methods include amplifying the mixture and extending the resulting amplicons using chain terminating reagents and extension primers that specifically hybridize to the amplicons, where a chain terminating reagent specific for the major nucleic acid species has a concentration that is less than a chain terminating reagent that is specific for a minor nucleic acid species. Skewing the concentrations of the chain terminating reagents in favor of high concentrations of the chain terminating reagents specific for the minor nucleic acid species relative to a chain terminating reagent specific for a major nucleic acid species improves the detection limit (sensitivity) of detecting minor nucleic acid species present at low frequency or copy number in the mixture. In addition, the signals generated from the extension product of the major nucleic acid species amplicon can serve as a positive control and permit quantification of the minor nucleic acid species relative to the major nucleic acid species in the mixture.

Claims (34)

1. A method for identifying the presence or absence of one or more minor nucleic acid species in a sample, comprising:

(a) obtaining nucleic acids from a sample that includes a target nucleic acid, wherein the target nucleic acid has a major nucleic acid species and one or more minor nucleic acid species wherein each minor nucleic acid species is a lower frequency or copy number variant of the major nucleic acid species and is present at a frequency or copy number that is less than about 10% of the frequency or copy number of the major nucleic acid species, wherein “about” means±10% of the indicated value;

(b) contacting the nucleic acids of (a) with one or more extension primers, each of which comprises an oligonucleotide that hybridizes to the target nucleic acid, under extension conditions comprising a chain terminator specific for the major nucleic acid species and one or more chain terminators specific for the one or more minor nucleic acid species, wherein the concentration of the chain terminator specific for the major nucleic acid species is between 1% to 20%, or 0.5% to less than 20%, or 0.1% to 10%, or 0.01% to 10%, or 0.01% to 5% of the concentration of each of the chain terminator(s) specific for the minor nucleic acid species and wherein, if a ddNTP chain terminator is present in the extension conditions, the same dNTP is absent from the extension conditions, whereby the one or more extension primers are extended by the chain terminators, thereby generating chain terminated extension products corresponding to the minor nucleic acid species and/or chain terminated extension products corresponding to the major nucleic acid species; and

(c) analyzing the extension products of (b), thereby identifying the presence or absence of the one or more minor nucleic acid species.

2. The method of claim 1 , wherein the nucleic acids of (a) are obtained by amplifying the target nucleic acid in a sample with amplification primer pairs under amplification conditions comprising dNTPs.

3. The method of claim 1 , wherein:

the extension conditions comprise a chain terminator specific for each of a plurality of minor nucleic acid species of the same major nucleic acid species;

chain terminated extension products corresponding to each one of the plurality of minor nucleic acid species present in the nucleic acids of (a) are generated in a single reaction; and the presence or absence of each of the plurality of minor nucleic acid species that are all variants of the same major nucleic acid species is identified.

4. The method of claim 1 , wherein (b) is performed in a set of at least two reaction vessels or compartments, wherein:

a first vessel or compartment comprises extension conditions comprising the chain terminating reagent that is specific for the major nucleic acid species and not comprising a chain terminator that is specific for the one or more minor nucleic acid species; and

each of the remaining vessels or compartments comprises extension conditions: (a) comprising a single chain terminator specific for and common to one or more minor nucleic acid species, and (b) not comprising a chain terminator specific for the major nucleic acid species or a chain terminator specific for minor nucleic acid species that do not share the common, single chain terminator.

5. The method of claim 1 , wherein the sequences of the minor nucleic acid species and the major nucleic acid species differ by a single base and the primers are extended up to the single base that is different.

6. The method of claim 1 , wherein the sequences of the minor nucleic acid species and the major nucleic acid species differ by a single base and the primers are extended through the single base that is different.

7. The method of claim 1 , wherein the one or more minor nucleic acid species are each present in a frequency or copy number that is between 0.25% to less than 10%, or 0.5% to less than 10%, or 1% to less than 10% of the frequency or copy number of the major nucleic acid species.

8. The method of claim 1 , wherein the one or more minor nucleic acid species represents less than 30%, 20%, 15%, 10%, 8%, 5%, 4%, 3%, 2%, 1%, 0.8%, 0.75%, 0.5%, 0.1%, 0.05%, or 0.01% of the total nucleic acid.

9. The method of claim 1 , wherein the chain terminators are chain terminating nucleotides.

10. The method of claim 9 , wherein the chain terminating nucleotides independently are selected from among ddATP, ddGTP, ddCTP, ddTTP and ddUTP.

11. The method of claim 9 , wherein the chain terminating nucleotides specific for one or more of the minor nucleic acid species consist of one chain terminating nucleotide, two chain terminating nucleotides or three chain terminating nucleotides.

12. The method of claim 9 , wherein the chain terminators further comprise one or more acyclic terminators.

13. The method of claim 1 , wherein one or more chain terminators comprise a mass label, and the one or more minor nucleic acid species are identified by detection of the mass label.

14. The method of claim 13 , wherein detection of the label is by mass spectrometry.

15. The method of claim 1 , further comprising quantifying the one or more minor nucleic acid species by:

(1) detecting a detection signal corresponding to each of the extension products of the one or more minor nucleic acid species and a detection signal corresponding to the extension products of the major nucleic acid species, thereby determining the ratio of the amount(s) of extension products corresponding to each of the one or more minor nucleic acid species relative to the amount of extension product corresponding to the major nucleic acid species based on the proportion of the detection signal corresponding to each of the extension products of the one or more minor nucleic acid species relative to the detection signal corresponding to the extension products of the major nucleic acid species; and

(2) based on the ratio as determined in (1), and based on the concentration(s) of the chain terminators specific for the one or more minor nucleic acid species relative to the concentration of the chain terminator specific for the major nucleic acid species, quantifying the amount(s) of minor nucleic acid species relative to the amount of the major nucleic acid species using a normalization coefficient.

16. The method of claim 15 , wherein the normalization coefficient is inversely proportional to the ratio of the concentration of the chain terminator specific for the major nucleic acid species compared to the concentration of the chain terminator(s) specific for the minor nucleic acid species.

17. The method of claim 15 , wherein detecting the detection signal is by mass spectrometry and wherein the ratio of the amount(s) of extension products corresponding to each of the one or more minor nucleic acid species relative to the amount of extension product corresponding to the major nucleic acid species is determined as the ratio of the signal for the minor nucleic acid species generated by mass spectrometry analysis to the signal for the major nucleic acid species generated by mass spectrometry analysis.

18. The method of claim 1 , wherein the sequence of the minor nucleic acid species comprises an insertion or a deletion relative to the sequence of the major nucleic acid species, or the minor nucleic acid species is a single nucleotide polymorphism (SNP) variant of the major nucleic acid species.

19. The method of claim 1 , wherein the minor and major nucleic acid species are mutant and wild type alleles, respectively, of the same gene.

20. A kit for analyzing a target nucleic acid, comprising:

one or more extension primers;

a chain terminating nucleotide specific for a major nucleic acid species of the target nucleic acid;

at least one chain terminating nucleotide specific for a minor nucleic acid species of the target nucleic acid, wherein the relative amounts of the chain terminating nucleotide specific for the major nucleic acid species and the chain terminating nucleotide specific for the minor nucleic acid species are present in solution such that the concentration of the chain terminating nucleotide specific for the major nucleic acid species is between 0.5% to less than 20% of the concentration of the chain terminating nucleotide(s) specific for the minor nucleic acid species; and

instructions for performing the method of claim 9 .

21. The kit of claim 20 , wherein the concentration of the chain terminating nucleotide specific for the major nucleic acid species is between 1% to 10% of the concentration of the chain terminating nucleotide(s) specific for the minor nucleic acid species.

Assignments (2)
SECURITY INTEREST Recorded Oct 5, 2023
From: MESA LABORATORIES, INC.; AGENA BIOSCIENCE, INC.
To: JPMORGAN CHASE BANK, N.A., AS ADMINISTRATIVE AGENT
Reel/Frame 065135/0174 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 11, 2023
From: NYGREN, ANDERS OLOF HERMAN
To: AGENA BIOSCIENCE, INC.
Reel/Frame 064565/0725 →
Continuity (7)
Continuation 17098993 · Nov 16, 2020
Continuation 16669311 · Oct 30, 2019
Continuation 16255718 · Jan 23, 2019
Continuation 15136024 · Apr 22, 2016
Provisional Application 62280951 · Jan 20, 2016
Provisional Application 62152697 · Apr 24, 2015
Related Publication 20230383340A1 · Nov 30, 2023
References Cited (389)
US 4515781A · Torrence et al. · 1985 [cited by applicant]
US 4582789A · Sheldon et al. · 1986 [cited by applicant]
US 4683195A · Mullis et al. · 1987 [cited by applicant]
US 4689405A · Frank et al. · 1987 [cited by applicant]
US 4711955A · Ward et al. · 1987 [cited by applicant]
US 5003059A · Brennan · 1991 [cited by applicant]
US 5013830A · Ohtsuka et al. · 1991 [cited by applicant]
US 5037882A · Steel · 1991 [cited by applicant]
US 5059654A · Hou et al. · 1991 [cited by applicant]
US 5064754A · Mills · 1991 [cited by applicant]
US 5118605A · Urdea · 1992 [cited by applicant]
US 5237016A · Ghosh et al. · 1993 [cited by applicant]
US 5242974A · Holmes · 1993 [cited by applicant]
US 5364760A · Chu et al. · 1994 [cited by applicant]
US 5380833A · Urdea · 1995 [cited by applicant]
US 5399857A · Doroshenko et al. · 1995 [cited by applicant]
US 5412083A · Giese et al. · 1995 [cited by applicant]
US 5480784A · Kacian et al. · 1996 [cited by applicant]
US 5489507A · Chehab · 1996 [cited by applicant]
US 5510270A · Fodor et al. · 1996 [cited by applicant]
US 5512439A · Hornes et al. · 1996 [cited by applicant]
US 5547835A · Koester · 1996 [cited by applicant]
US 5605798A · Koester · 1997 [cited by applicant]
US 5622824A · Koester · 1997 [cited by applicant]
US 5650489A · Lam · 1997 [cited by applicant]
US 5691141A · Koester · 1997 [cited by applicant]
US 5700642A · Monforte et al. · 1997 [cited by applicant]
US 5710028A · Eyal et al. · 1998 [cited by applicant]
US 5770272A · Biemann et al. · 1998 [cited by applicant]
US 5800984A · Vary · 1998 [cited by applicant]
US 5851765A · Koester · 1998 [cited by applicant]
US 5869242A · Kamb · 1999 [cited by applicant]
US 5872003A · Koester · 1999 [cited by applicant]
US 5885775A · Haff et al. · 1999 [cited by applicant]
US 5888819A · Goelet et al. · 1999 [cited by applicant]
US 5925520A · Tully et al. · 1999 [cited by applicant]
US 5965363A · Monforte et al. · 1999 [cited by applicant]
US 5976798A · Parker et al. · 1999 [cited by applicant]
US 5989871A · Grossman et al. · 1999 [cited by applicant]
US 6004744A · Goelet et al. · 1999 [cited by applicant]
US 6043031A · Koester et al. · 2000 [cited by applicant]
US 6074823A · Koester · 2000 [cited by applicant]
US 6194144B1 · Koester · 2001 [cited by applicant]
US 6197498B1 · Koester · 2001 [cited by applicant]
US 6221601B1 · Koester et al. · 2001 [cited by applicant]
US 6221605B1 · Koester · 2001 [cited by applicant]
US 6225450B1 · Koester · 2001 [cited by applicant]
US 6235478B1 · Koester · 2001 [cited by applicant]
US 6238871B1 · Koester · 2001 [cited by applicant]
US 6258538B1 · Koester et al. · 2001 [cited by applicant]
US 6268144B1 · Koester · 2001 [cited by applicant]
US 6277573B1 · Koester · 2001 [cited by applicant]
US 6300076B1 · Koester · 2001 [cited by applicant]
US 6428955B1 · Koester · 2002 [cited by applicant]
US 6500621B2 · Koester · 2002 [cited by applicant]
US 6602662B1 · Koester et al. · 2003 [cited by applicant]
US 6613509B1 · Chen · 2003 [cited by applicant]
US 7074563B2 · Koester · 2006 [cited by applicant]
US 7108974B2 · Ecker et al. · 2006 [cited by applicant]
US 7198893B1 · Koester et al. · 2007 [cited by applicant]
US 7217510B2 · Ecker et al. · 2007 [cited by applicant]
US 7226739B2 · Ecker et al. · 2007 [cited by applicant]
US 7255992B2 · Ecker et al. · 2007 [cited by applicant]
US 7419787B2 · Koester · 2008 [cited by applicant]
US 7759065B2 · Koester · 2010 [cited by applicant]
US 8003317B2 · Beaulieu et al. · 2011 [cited by applicant]
US 8153377B2 · Cantor et al. · 2012 [cited by applicant]
US 8349566B2 · Beaulieu et al. · 2013 [cited by applicant]
US 8586708B2 · Ting et al. · 2013 [cited by applicant]
US 9068223B2 · Beaulieu et al. · 2015 [cited by applicant]
US 9896724B2 · Beaulieu et al. · 2018 [cited by applicant]
US 10233489B2 · Nygren · 2019 [cited by applicant]
US 10513728B2 · Nygren · 2019 [cited by applicant]
US 10604791B2 · Honisch et al. · 2020 [cited by applicant]
US 10640817B2 · Nygren · 2020 [cited by applicant]
US 10865439B2 · Nygren · 2020 [cited by applicant]
US 11111530B2 · Beaulieu et al. · 2021 [cited by applicant]
US 11667958B2 · Honisch et al. · 2023 [cited by applicant]
US 11680289B2 · Nygren · 2023 [cited by applicant]
US 20030022225A1 · Monforte et al. · 2003 [cited by applicant]
US 20030027169A1 · Zhang et al. · 2003 [cited by applicant]
US 20030119004A1 · Wenz et al. · 2003 [cited by applicant]
US 20030203381A1 · Kambara et al. · 2003 [cited by applicant]
US 20040259105A1 · Fan et al. · 2004 [cited by applicant]
US 20050079521A1 · Beaulieu et al. · 2005 [cited by applicant]
US 20050233381A1 · Liu et al. · 2005 [cited by applicant]
US 20050287533A1 · Ehrich et al. · 2005 [cited by applicant]
US 20050287592A1 · Kless · 2005 [cited by applicant]
US 20060003352A1 · Lipkin et al. · 2006 [cited by applicant]
US 20060166201A1 · Schatz et al. · 2006 [cited by applicant]
US 20070202514A1 · Koester et al. · 2007 [cited by applicant]
US 20070292861A1 · Thompson · 2007 [cited by applicant]
US 20080167197A1 · Schmidt et al. · 2008 [cited by applicant]
US 20080305479A1 · Van Den et al. · 2008 [cited by applicant]
US 20110165133A1 · Rabinovich et al. · 2011 [cited by applicant]
US 20120015826A1 · Beaulieu et al. · 2012 [cited by applicant]
US 20120046178A1 · Van Den et al. · 2012 [cited by applicant]
US 20120156685A1 · Cantor et al. · 2012 [cited by applicant]
US 20130017960A1 · Honisch et al. · 2013 [cited by applicant]
US 20130237428A1 · Beaulieu et al. · 2013 [cited by applicant]
US 20140011195A1 · Honisch et al. · 2014 [cited by applicant]
US 20160102347A1 · Beaulieu et al. · 2016 [cited by applicant]
US 20160312278A1 · Nygren · 2016 [cited by applicant]
US 20180298433A1 · Nygren · 2018 [cited by applicant]
US 20190153526A1 · Nygren · 2019 [cited by applicant]
US 20200123601A1 · Nygren · 2020 [cited by applicant]
US 20200318169A1 · Honisch et al. · 2020 [cited by applicant]
US 20210062254A1 · Nygren · 2021 [cited by applicant]
US 20220106637A1 · Beaulieu et al. · 2022 [cited by applicant]
US 20230407375A1 · Honisch et al. · 2023 [cited by applicant]
CN 1670222A · 2005 [cited by applicant]
CN 101194023A · 2008 [cited by applicant]
CN 103333952A · 2013 [cited by applicant]
CN 103602740A · 2014 [cited by applicant]
CN 103717751A · 2014 [cited by applicant]
CN 103131787B · 2014 [cited by applicant]
CN 104685064A · 2015 [cited by applicant]
EP 0269520A2 · 1988 [cited by applicant]
EP 0655501A1 · 1995 [cited by applicant]
EP 1176212A1 · 2002 [cited by applicant]
JP H07159404A · 1995 [cited by applicant]
JP H08256764A · 1996 [cited by applicant]
JP 2011501008A · 1999 [cited by applicant]
JP 2004527732A · 2004 [cited by applicant]
JP 2005336107A · 2005 [cited by applicant]
JP 2006320271A · 2006 [cited by applicant]
JP 2008531052A · 2008 [cited by applicant]
JP 2014515264A · 2014 [cited by applicant]
WO 8910977A1 · 1989 [cited by applicant]
WO 9111533A1 · 1991 [cited by applicant]
WO 9213969A1 · 1992 [cited by applicant]
WO 9400562A1 · 1994 [cited by applicant]
WO 9416101A2 · 1994 [cited by applicant]
WO 9630545A1 · 1996 [cited by applicant]
WO 9632504A2 · 1996 [cited by applicant]
WO 9737041A2 · 1997 [cited by applicant]
WO 03104420A2 · 2003 [cited by applicant]
WO 2004007773A1 · 2004 [cited by applicant]
WO 2005012578A1 · 2005 [cited by applicant]
WO 2006133840A1 · 2006 [cited by applicant]
WO 2010054110A2 · 2010 [cited by applicant]
WO 2010056513A2 · 2010 [cited by applicant]
WO 2011034115A1 · 2011 [cited by applicant]
WO 2012159089A1 · 2012 [cited by applicant]
WO 2014018080A1 · 2014 [cited by applicant]
WO 2016172571A1 · 2016 [cited by applicant]
WO 2016172579A1 · 2016 [cited by applicant]
Chinese Search Report issued in Chinese Patent Application No. 201680013462.4, mailed on Sep. 7, 2020, 2 pages of English Translation. [cited by applicant]
Ex Parte Quayle Action mailed on Apr. 20, 1999, in U.S. Appl. No. 08/617,256, filed Mar. 18, 1996. [cited by applicant]
Extended European Search Report mailed on Oct. 15, 2012, in European Patent Application No. 09826542.4, filed on Oct. 27, 2009, 8 pages. [cited by applicant]
Final Office Action mailed on Apr. 15, 1996, in U.S. Appl. No. 08/406,199, filed Mar. 17, 1995. [cited by applicant]
Final Office Action mailed on Apr. 19, 2005, in U.S. Appl. No. 09/686,148, filed Oct. 10, 2000, 6 pages. [cited by applicant]
Final Office Action mailed on Apr. 5, 1994, in U.S. Appl. No. 08/001,323, filed Jan. 7, 1993. [cited by applicant]
Final Office Action mailed on Aug. 3, 2018, in U.S. Appl. No. 13/551,486, filed Jul. 17, 2012, 24 pages. [cited by applicant]
Final Office Action mailed on Aug. 22, 1995, in U.S. Appl. No. 08/178,216, filed Jan. 6, 1994. [cited by applicant]
Final Office Action mailed on Aug. 27, 2003, in U.S. Appl. No. 09/686,148, filed Oct. 10, 2000, 8 pages. [cited by applicant]
Final Office Action mailed on Dec. 26, 2001, in U.S. Appl. No. 09/179,536, filed Oct. 26, 1998. [cited by applicant]
Final Office Action mailed on Dec. 30, 2015, in U.S. Appl. No. 13/551,486, filed Jul. 17, 2012, 23 pages. [cited by applicant]
Final Office Action mailed on Feb. 26, 2014, in U.S. Appl. No. 13/551,486, filed Jul. 17, 2012, 30 pages. [cited by applicant]
Final Office Action mailed on Jan. 20, 2017, in U.S. Appl. No. 13/551,486, filed Jul. 17, 2012, 21 pages. [cited by applicant]
Final Office Action mailed on Jun. 15, 2017, in U.S. Appl. No. 13/551,486, filed Jul. 17, 2012, 19 pages. [cited by applicant]
Final Office Action mailed on Nov. 16, 2009, in U.S. Appl. No. 12/163,923, filed Jun. 27, 2008, 6 pages. [cited by applicant]
Final Office Action mailed on Sep. 7, 2021, in U.S. Appl. No. 16/793,732, filed Feb. 18, 2020, 31 pages. [cited by applicant]
Final Office Action mailed on Nov. 6, 1997, in U.S. Appl. No. 08/617,256, filed Mar. 18, 1996. [cited by applicant]
Non-Final Office Action mailed on Jun. 29, 1993, in U.S. Appl. No. 08/001,323, filed Jan. 7, 1993. [cited by applicant]
Non-Final Office Action mailed on Sep. 8, 2000, in U.S. Appl. No. 09/495,444, filed Jan. 31, 2000. [cited by applicant]
Non-Final Office Action mailed on May 27, 2022, in U.S. Appl. No. 16/793,732, filed Feb. 18, 2020, 31 pages. [cited by applicant]
Non-Final Office Action mailed on Apr. 10, 2014, in U.S. Appl. No. 13/126,684, filed Oct. 12, 2011, 18 pages. [cited by applicant]
Office Action mailed on Apr. 10, 2002, in U.S. Appl. No. 09/879,341, filed Jun. 11, 2001. [cited by applicant]
Office Action mailed on Apr. 28, 2020, in U.S. Appl. No. 16/669,311, filed Oct. 30, 2019, 5 pages. [cited by applicant]
Office Action mailed on Aug. 8, 2001, in U.S. Appl. No. 09/297,576, filed Jun. 28, 1999. [cited by applicant]
Office Action mailed on Aug. 17, 1998, in U.S. Appl. No. 08/744,481, filed Nov. 6, 1996. [cited by applicant]
Office Action mailed on Aug. 21, 2000, in U.S. Appl. No. 09/431,613, filed Nov. 2, 1999. [cited by applicant]
Office Action mailed on Aug. 26, 2022, in U.S. Appl. No. 17/098,993, filed Nov. 16, 2020, 5 pages. [cited by applicant]
Office Action mailed on Aug. 5, 2005, in U.S. Appl. No. 10/375,714, filed Feb. 24, 2003, 8 pages. [cited by applicant]
Office Action mailed on Dec. 19, 2001, in U.S. Appl. No. 09/796,416, filed Feb. 28, 2001. [cited by applicant]
Office Action mailed on Feb. 6, 2009, in U.S. Appl. No. 12/163,923, filed Jun. 27, 2008, 6 pages. [cited by applicant]
Office Action mailed on Feb. 16, 2000, in U.S. Appl. No. 09/287,682, filed Apr. 6, 1999. [cited by applicant]
Office Action mailed on Feb. 20, 2008, in U.S. Appl. No. 11/541,871, filed Oct. 2, 2006, 9 pages. [cited by applicant]
Office Action mailed on Feb. 23, 1995, in U.S. Appl. No. 08/178,216, filed Jan. 6, 1994. [cited by applicant]
Office Action mailed on Feb. 28, 2013, in U.S. Appl. No. 13/551,486, filed Jul. 17, 2012, 27 pages. [cited by applicant]
Office Action mailed on Jan. 9, 2018, in U.S. Appl. No. 13/551,486, filed Jul. 17, 2012, 19 pages. [cited by applicant]
Office Action mailed on Jan. 27, 2021, in U.S. Appl. No. 16/793,732, filed Feb. 18, 2020, 24 pages. [cited by applicant]
Office Action mailed on Jul. 6, 2000, in U.S. Appl. No. 09/179,536, filed Oct. 26, 1998. [cited by applicant]
Non-Final Office Action mailed on Jul. 8, 2015, in U.S. Appl. No. 13/551,486, filed Jul. 17, 2012, 23 pages. [cited by applicant]
Non-Final Office Action mailed on Jul. 25, 2002, in U.S. Appl. No. 09/179,536, filed Oct. 26, 1998. [cited by applicant]
Non-Final Office Action mailed on Jul. 3, 2007, in U.S. Appl. No. 11/432,171, filed May 11, 2006, 11 pages. [cited by applicant]
Non-Final Office Action mailed on Jun. 6, 2019, in U.S. Appl. No. 15/568,701, filed Oct. 23, 2017, 6 pages. [cited by applicant]
Non-Final Office Action mailed on Jun. 28, 2000, in U.S. Appl. No. 09/287,681, filed Apr. 6, 1999. [cited by applicant]
Non-Final Office Action mailed on Jun. 28, 2002, in U.S. Appl. No. 09/724,877, filed Nov. 28, 2000. [cited by applicant]
Non-Final Office Action mailed on Mar. 8, 2019, in U.S. Appl. No. 13/551,486, filed Jul. 17, 2012, 25 pages. [cited by applicant]
Non-Final Office Action mailed on Mar. 28, 2001, in U.S. Appl. No. 09/179,536, filed Oct. 26, 1998. [cited by applicant]
Non-Final Office Action mailed on May 5, 2000, in U.S. Appl. No. 09/287,679, filed Apr. 6, 1999. [cited by applicant]
Non-Final Office Action mailed on May 8, 2002, in U.S. Appl. No. 09/297,576, filed Jun. 28, 1999. [cited by applicant]
Non-Final Office Action mailed on May 11, 2009, in U.S. Appl. No. 12/125,857, filed May 22, 2008, 11 pages. [cited by applicant]
Non-Final Office Action mailed on May 13, 2019, in U.S. Appl. No. 16/255,718, filed Jan. 23, 2019, 5 pages. [cited by applicant]
Non-Final Office Action mailed on May 20, 2009, in U.S. Appl. No. 12/163,915, filed Jun. 27, 2008, 12 pages. [cited by applicant]
Non-Final Office Action mailed on May 29, 2018, in U.S. Appl. No. 15/136,024, filed Apr. 22, 2016, 6 pages. [cited by applicant]
Non-Final Office Action mailed on Nov. 3, 2010, in U.S. Appl. No. 12/795,155, filed Jun. 7, 2010, 11 pages. [cited by applicant]
Non-Final Office Action mailed on Nov. 20, 2002, in U.S. Appl. No. 09/686,148, filed Oct. 10, 2000, 9 pages. [cited by applicant]
Non-Final Office Action mailed on Oct. 4, 2016, in U.S. Appl. No. 13/551,486, filed Jul. 17, 2012, 16 pages. [cited by applicant]
Non-Final Office Action mailed on Sep. 5, 2013, in U.S. Appl. No. 13/551,486, filed Jul. 17, 2012, 26 pages. [cited by applicant]
Non-Final Office Action mailed on Sep. 8, 2000, in U.S. Appl. No. 09/504,245, filed Feb. 15, 2000. [cited by applicant]
Non-Final Office Action mailed on Sep. 14, 1995, in U.S. Appl. No. 08/406,199, filed Mar. 17, 1995. [cited by applicant]
Non-Final Office Action mailed on Sep. 22, 2000, in U.S. Appl. No. 09/287,679, filed Apr. 6, 1999. [cited by applicant]
Non-Final Office Action mailed on Feb. 16, 2000, in U.S. Appl. No. 09/287,141, filed Apr. 6, 1999. [cited by applicant]
Non-Final Office Action mailed on May 5, 1997, in U.S. Appl. No. 08/617,256, filed Mar. 18, 1996. [cited by applicant]
Notice of Allowance mailed on Apr. 1, 1999, in U.S. Appl. No. 08/744,481, filed Nov. 6, 1996. [cited by applicant]
Notice of Allowance mailed on Apr. 28, 2006, in U.S. Appl. No. 09/686,148, filed Oct. 10, 2000, 7 pages. [cited by applicant]
Notice of Allowance mailed on Aug. 2, 2019, in U.S. Appl. No. 16/255,718, filed Jan. 23, 2019, 6 pages. [cited by applicant]
Notice of Allowance mailed on Aug. 18, 2020, in U.S. Appl. No. 16/669,311, filed Oct. 30, 2019, 6 pages. [cited by applicant]
Notice of Allowance mailed on Dec. 9, 2019, in U.S. Appl. No. 13/551,486, filed Jul. 17, 2012, 10 pages. [cited by applicant]
Notice of Allowance mailed on Feb. 23, 2010, in U.S. Appl. No. 12/125,857, filed May 22, 2008, 10 pages. [cited by applicant]
Notice of Allowance mailed on Feb. 25, 2000, in U.S. Appl. No. 09/287,681, filed Apr. 6, 1999. [cited by applicant]
Notice of Allowance mailed on Feb. 25, 2008, in U.S. Appl. No. 11/432,171, filed May 11, 2006, 7 pages. [cited by applicant]
Notice of Allowance mailed on Feb. 3, 2023, in U.S. Appl. No. 17/098,993, filed Nov. 16, 2020, 6 pages. [cited by applicant]
Notice of Allowance mailed on Jan. 2, 2001, in U.S. Appl. No. 08/744,481, filed Nov. 6, 1996. [cited by applicant]
Notice of Allowance mailed on Jan. 3, 2020, in U.S. Appl. No. 15/568,701, filed Oct. 23, 2017, 7 pages. [cited by applicant]
Notice of Allowance mailed on Jan. 10, 2006, in U.S. Appl. No. 10/375,714, filed Feb. 24, 2003, 7 pages. [cited by applicant]
Notice of Allowance mailed on Jun. 14, 2000, in U.S. Appl. No. 09/287,682, filed Apr. 6, 1999. [cited by applicant]
Notice of Allowance mailed on May 17, 2002, in U.S. Appl. No. 09/796,416, filed Feb. 28, 2001. [cited by applicant]
Notice of Allowance mailed on Nov. 3, 2000, in U.S. Appl. No. 09/495,444, filed Jan. 31, 2000. [cited by applicant]
Notice of Allowance mailed on Nov. 16, 2000, in U.S. Appl. No. 09/287,679, filed Apr. 6, 1999. [cited by applicant]
Notice of Allowance mailed on Nov. 27, 2002, in U.S. Appl. No. 09/879,341, filed Jun. 11, 2001. [cited by applicant]
Notice of Allowance mailed on Oct. 8, 2008, in U.S. Appl. No. 11/541,871, filed Oct. 2, 2006, 5 pages. [cited by applicant]
Notice of Allowance mailed on Oct. 10, 2000, in U.S. Appl. No. 09/431,613, filed Nov. 2, 1999. [cited by applicant]
Notice of Allowance mailed on Oct. 20, 2000, in U.S. Appl. No. 09/504,245, filed Feb. 15, 2000. [cited by applicant]
Notice of Allowance mailed on Oct. 21, 1998, in U.S. Appl. No. 08/617,256, filed Mar. 18, 1996. [cited by applicant]
Notice of Allowance mailed on Oct. 22, 2018, in U.S. Appl. No. 15/136,024, filed Apr. 22, 2016, 5 pages. [cited by applicant]
Notice of Allowance mailed on Sep. 8, 2000, in U.S. Appl. No. 09/397,766, filed Sep. 15, 1999. [cited by applicant]
Notice of Allowance mailed on Sep. 10, 1999, in U.S. Appl. No. 08/617,256, filed Mar. 18, 1996. [cited by applicant]
Notice of Allowance mailed on Sep. 19, 2002, in U.S. Appl. No. 09/724,877, filed Nov. 28, 2000. [cited by applicant]
Notice of Allowance mailed on Feb. 3, 1998, in U.S. Appl. No. 08/617,256, filed Mar. 18, 1996. [cited by applicant]
Notice of Allowance mailed on May 30, 2000, in U.S. Appl. No. 09/287,141, filed Apr. 6, 1999. [cited by applicant]
Office Action mailed on Apr. 22, 2016, in U.S. Appl. No. 13/790,996, filed Mar. 8, 2013. [cited by applicant]
Office Action mailed on Aug. 1, 2003, in U.S. Appl. No. 08/467,208, filed Jun. 6, 1995. [cited by applicant]
Office Action mailed on Aug. 19, 1998, in U.S. Appl. No. 08/467,208, filed Jun. 6, 1995. [cited by applicant]
Office Action mailed on Aug. 22, 2019, in U.S. Appl. No. 13/126,684, filed Oct. 12, 2011, 23 pages. [cited by applicant]
Office Action mailed on Aug. 27, 2002, in U.S. Appl. No. 09/783,881, filed Feb. 13, 2001. [cited by applicant]
Office Action mailed on Dec. 16, 2016, in U.S. Appl. No. 13/790,996, filed Mar. 8, 2013. [cited by applicant]
Office Action mailed on Dec. 26, 2014, in U.S. Appl. No. 13/126,684, filed Oct. 12, 2011. [cited by applicant]
Office Action mailed on Feb. 7, 2019, in U.S. Appl. No. 13/790,996, filed Mar. 8, 2013. [cited by applicant]
Office Action mailed on Jan. 12, 1999, in U.S. Appl. No. 08/467,208, filed Jun. 6, 1995. [cited by applicant]
Office Action mailed on Jan. 17, 2017, in U.S. Appl. No. 13/126,684, filed Oct. 12, 2011. [cited by applicant]
Office Action mailed on Jan. 17, 2018, in U.S. Appl. No. 13/790,996, filed Mar. 8, 2013. [cited by applicant]
Office Action mailed on Jan. 29, 2016, in U.S. Appl. No. 13/126,684, filed Oct. 12, 2011. [cited by applicant]
Office Action mailed on Jan. 6, 2016, in U.S. Appl. No. 13/790,996, filed Mar. 8, 2013. [cited by applicant]
Office Action mailed on Jul. 16, 2001, in U.S. Appl. No. 08/467,208, filed Jun. 6, 1995. [cited by applicant]
Office Action mailed on Jul. 18, 2017, in U.S. Appl. No. 13/126,684, filed Oct. 12, 2011. [cited by applicant]
Office Action mailed on Jul. 29, 2002, in U.S. Appl. No. 08/467,208, filed Jun. 6, 1995. [cited by applicant]
Office Action mailed on Jul. 31, 2000, in U.S. Appl. No. 08/467,208, filed Jun. 6, 1995. [cited by applicant]
Office Action mailed on Jun. 19, 2015, in U.S. Appl. No. 13/790,996, filed Mar. 8, 2013. [cited by applicant]
Office Action mailed on Jun. 27, 2017, in U.S. Appl. No. 13/790,996, filed Mar. 8, 2013. [cited by applicant]
Office Action mailed on Jun. 28, 2018, in U.S. Appl. No. 13/126,684, filed Oct. 12, 2011. [cited by applicant]
Office Action mailed on Mar. 20, 1997, in U.S. Appl. No. 08/467,208, filed Jun. 6, 1995. [cited by applicant]
Office Action mailed on Mar. 26, 2001, in U.S. Appl. No. 08/467,208, filed Jun. 6, 1995. [cited by applicant]
Office Action mailed on Nov. 15, 2017, in U.S. Appl. No. 13/126,684, filed Oct. 12, 2011. [cited by applicant]
Office Action mailed on Nov. 16, 2018, in U.S. Appl. No. 13/126,684, filed Oct. 12, 2011. [cited by applicant]
Office Action mailed on Oct. 13, 1999, in U.S. Appl. No. 08/467,208, filed Jun. 6, 1995. [cited by applicant]
Office Action mailed on Oct. 28, 1997, in U.S. Appl. No. 08/467,208, filed Jun. 6, 1995. [cited by applicant]
Office Action mailed on Oct. 3, 2014, in U.S. Appl. No. 13/790,996, filed Mar. 8, 2013, 19 pages. [cited by applicant]
Office Action mailed on Oct. 3, 2016, in U.S. Appl. No. 13/126,684, filed Oct. 12, 2011. [cited by applicant]
Office Action mailed on Oct. 4, 2016, in U.S. Appl. No. 13/551,486, filed Jul. 17, 2012. [cited by applicant]
Office Action mailed on Sep. 8, 2005, in U.S. Appl. No. 08/467,208, filed Jun. 6, 1995. [cited by applicant]
Office Action mailed on Sep. 9, 2004, in U.S. Appl. No. 08/467,208, filed Jun. 6, 1995. [cited by applicant]
Office Action mailed on Sep. 8, 2014, in U.S. Appl. No. 13/099,236, filed May 2, 2011. [cited by applicant]
International Preliminary Report on Patentability mailed on May 12, 2011, in International Patent Application No. PCT/US2009/062239, filed on Oct. 27, 2009, 8 pages. [cited by applicant]
International Preliminary Report on Patentability mailed on Nov. 2, 2017, in International Patent Application No. PCT/US2016/028971, filed on Apr. 22, 2016, 10 pages. [cited by applicant]
International Preliminary Report on Patentability mailed on Nov. 2, 2017, in International Patent Application No. PCT/US2016/028980, filed on Apr. 22, 2016, 8 pages. [cited by applicant]
International Preliminary Report on Patentability mailed on Nov. 28, 2013, in International Patent Application No. PCT/US2012/038710, filed on May 18, 2012, 7 pages. [cited by applicant]
International Search Report and Written Opinion mailed on Jul. 9, 2010, in International Patent Application No. PCT/US2009/062239, filed on Oct. 27, 2009, 10 pages. [cited by applicant]
International Search Report and Written Opinion mailed on Jul. 15, 2016, in International Patent Application No. PCT/US2016/028971, filed on Apr. 22, 2016, 12 pages. [cited by applicant]
International Search Report and Written Opinion mailed on Jun. 22, 2016, in International Patent Application No. PCT/US2016/028980, filed on Apr. 22, 2016, 10 pages. [cited by applicant]
International Search Report and Written Opinion mailed on Sep. 5, 2012, in International Patent Application No. PCT/US2012/038710, filed on May 18, 2012, 10 pages. [cited by applicant]
Adler, et al., “Cell Membrane Coating with Glutaraldehyde: Application to a versatile Solid-Phase Assay for Thyroid Membrane Proteins and Molecules Interacting with Thyroid Membranes”, Analytical Biochemistry, 1985, 148… [cited by applicant]
Anker, et al. “Tetranucleotide Repeat Polymorphism at the Human Thyroid Peroxidase (hTPO) Locus”, Human Molecular Genetics, 1992, 1:137. [cited by applicant]
Banerjee, et al., “inhA, a Gene Encoding a Target for Isoniazid and Ethionamide in [cited by applicant]
Beckmann, et al., “Survey of Human and Rat Microsatellites”, Genomics, 1992, 12:627-631. [cited by applicant]
Binladen, et al., “The Use of Coded PCR Primers Enables High-Throughput Sequencing of Multiple Homolog Amplification Products by 454 Parallel Sequencing”. Plos One, 2007, 2(2): e197:1-9. [cited by applicant]
Bird, Adrian, “DNA Methylation Patterns and Epigenetic Memory”, Genes Development, 2002, 16:6-21. [cited by applicant]
Caruthers, et al., “Chemical Synthesis of Deoxyoligonucleotides by the Phosphoramidite Method”, Methods in Enzymology, 1987, 154:287-313. [cited by applicant]
Caruthers, Marvin H., “Gene Synthesis Machines: DNA Chemistry and Its Use”, Science, Oct. 18, 1985, 230:281-285. [cited by applicant]
Caskey, et al., “Triplet Repeat Mutations in Human Disease”, Science, May 8, 1992, 256(5058):784-789. [cited by applicant]
Chakrabarti, et al., “Sequence of Simian Immunodeficiency Virus from Macaque and Its Relationship to Other Human and Simian Retroviruses”, Nature, Aug. 6, 1987, 328:543-547. [cited by applicant]
Chee, M., “Enzymatic Multiples DNA Sequencing”, Nucleic Acids Research, 1991, 19(12):3301-3305. [cited by applicant]
Cook, et al., “Synthesis and Hybridization of a Series of Biotinylated Oligonucleotides”, Nucleic Acids Research, 1988, 16:4077-4095. [cited by applicant]
Deisingh, et al., “Sequences of [cited by applicant]
Ding, et al., “MS Analysis of Single-nucleotide Differences in Circulating Nucleic Acids: Application to Noninvasive Prenatal Diagnosis”, PNAS, 2004, 101(29):10762-10767. [cited by applicant]
Ding, Chunming, “Qualitative and Quantitative DNA and RNA Analysis by Matrix-Assisted Laser Desorption/ionization Time-of-Flight Mass Spectrometry”, Methods in Molecular Biology, 2006, 336:59-71. [cited by applicant]
Doktycz, et al., “Analysis of Polymerase Chain Reaction-Amplified DNA Products by Mass Spectrometry Using Matrix-Assisted Laser Desorption and Electrospray: Current Status”, Analytical Biochemistry, 1995, 230:205-214. [cited by applicant]
Donovan, et al., “Increase in the Stability of Avidin Produced by Binding of Biotin. A Differential Scanning Calorimetric Study of Denaturation by Heat”, Biochemistry, 1973, 12(3):512-517. [cited by applicant]
Dubiley, et al., “Polymorphism Analysis and Gene Detection by Minisequencing on an Array of Gel-Immobilized Primers”, Nucleic Acids Research, 1999, 27(18):1-6. [cited by applicant]
Duffield, et al., “Simultaneous Determination of Multiple mRNA Levels Utilizing MALDI-TOF Mass Spectrometry and Biotinylated Dideoxynucleotides”, RNA, Jun. 2010, 16(6):1285-1291. [cited by applicant]
Eckstein, “Oligonucleotides and Analogues: A Practical Approach”, Oxford University Press, 1991, 56-57,137-139, 256-259. [cited by applicant]
Edwards, “Dinucleotide Repeat Polymorphism in Human GLUT2/liver Facilitative Glucose Transporter Gene on Chromosome 3”, Nucleic Acids Research, 1991, 19(17):4791. [cited by applicant]
Fan, et al., “Parallel Genotyping of Human Snps Using Generic High-Density Oligonucleotide Tag Arrays 11”, Genome Research, Jan. 1, 2000, 10(6):853-860. [cited by applicant]
Fitzgerald, et al., “Basic Matrices for the Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry of Proteins and Oligonucleotides”, Analytical Chemistry, 1993, 65:3204-3211. [cited by applicant]
Ganem, et al., “Detection of Oligonucleotide Duplex Forms by lon-Spray Mass Spectrometry”, Tetrahedron Letters, 1993, 34(9):1445-1448. [cited by applicant]
Gardner, et al., “Acyclic and Dideoxy Terminator Preferences Denote Divergent Sugar Recognition by Archaeon and Taq DNA Polymerases”, Nucleic Acids Res., Jan. 15, 2002, 30(2):605-613. [cited by applicant]
German, et al., “ Blood's Syndrome. XII. Report from the Registry for 1987”, Clinical Genetics, 1989, 35:57-69. [cited by applicant]
Gust, et al., “Taxonomic Classification of Hepatitis a Virus”, Intervirology, 1983, 20:1-7. [cited by applicant]
Guyader, et al., “Genome Organization and Transactivation of the Human Immunodeficiency Virus Type 2”, Nature, Apr. 16, 1987, 326(6114):662-669. [cited by applicant]
Haff, et al., “Multiplex Genotyping of PCR Products with Mass Tag-Labeled Primers”, Nucleic Acids Research, 1997, 25(18):3749-3750. [cited by applicant]
Haff, et al., “Single-Nucleotide Polymorphism Identification Assays Using a Thermostable DNA Polymerase and Delayed Extraction MALDI-TOF Mass Spectrometry”, Genome Research, Apr. 1, 1997, 7(4):378-388. [cited by applicant]
Hartmer, et al., “RNase T1 Mediated Base-Specific Cleavage and MALDI-TOF MS for High-Throughput Comparative Sequence Analysis”, Nucleic Acids Res., 2003, 31(9): e47:1-10. [cited by applicant]
Heym, et al., “Implications of Multidrug Resistance for the Future of Short-Course Chemotherapy of Tuberculosis: A Molecular Study”, Lancet, 1994, 344(8918):293-298. [cited by applicant]
Hirsch, et al., “Easily Reversible Desthiobiotin Binding to Streptavidin, Avidin, and Other Biotin-Binding Proteins: Uses for Protein Labeling, Detection, and Isolation”, Analytical Biochemistry, Sep. 2, 2015, 308(2):34… [cited by applicant]
Hirschhorn, et al., “SBE-TAGS: An Array-Based Method for Efficient Single-Nucleotide Polymorphism Genotyping 11”, PNAS, Oct. 24, 2000, 97(22):12164-12169. [cited by applicant]
Hitchcock, et al., “Cleavage of Deoxyoxanosine-Containing Oligodeoxyribonucleotides by Bacterial Endonuclease V”, Nucleic Acids Research, 2004, 32(13):4071-4080. [cited by applicant]
Holmberg, et al., “The Biotin-streptavidin Interaction can be Reversibly Broken Using Water at Elevated Temperatures”, Electrophoresis, 2005, 26:501-510. [cited by applicant]
Jacobson, et al., “Applications of Mass Spectrometry to DNA Sequencing”, Genet. Anal. Tech. Appl., 1991, 8(8):223-229. [cited by applicant]
Jeffreys, et al., “Hypervariable ‘Minisatellite’ Regions in Human DNA”, Nature, Mar. 7, 1985, 314:67-73. [cited by applicant]
Khrapko, et al., “A Method for DNA Sequencing by Hybridization with Oligonucleotide Matrix”, J. DNA Sequencing and Mapping, 1991, 1:375-388. [cited by applicant]
Kim, et al., “Digital Genotyping Using Molecular Affinity and Mass Spectrometry”, Nature Review Genetics, 2003, 4:1001-1008. [cited by applicant]
Kim, et al., “Multiplex Genotyping of the Human Beta2-Adrenergic Receptor Gene Using Solid-Phase Capturable Dideoxynucleotides and Mass Spectrometry”, Analytical Biochemistry, May 1, 2003, 316(2):251-258. [cited by applicant]
Kim, et al., “Solid Phase Capturable Dideoxynucleotides for Multiplex Genotyping Using Mass Spectrometry”, Nucleic Acids Research, Aug. 15, 2002, 30(16): e85. (6 pages.). [cited by applicant]
Lefmann, et al., “Novel Mass Spectrometry-Based Tool for Genotypic Identification of Mycobacteria”, Journal of Clinical Microbiology, Jan. 1, 2004, 42(1):339-346. [cited by applicant]
Leonard, et al., “High-Resolution Structure of Mutagenic Lesion in DNA”, Proc. Nat. Acad. Sci. Biochemistry, 1990, 87:9573-9576. [cited by applicant]
Li, et al., “Single Nucleotide Polymorphism Determination Using Primer Extension and Time-of-flight Mass Spectrometry”, Electrophoresis, Jun. 1999, 20(6):1258-1265. [cited by applicant]
Litt, et al., “Dinucleotide Repeat Polymorphism at the D11S35 Locus”, Nucleic Acids Research, 1990, 18:5921. [cited by applicant]
Litt, et al., “Dinucleotide Repeat Polymorphism at the D6S89 Locus”, Nucleic Acids Research, 1990, 18:4301. [cited by applicant]
Luty, et al., “Dinucleotide Repeat Polymorphism at the D14S45 Locus”, Nucleic Acids Research, 1991, 19(15):4308. [cited by applicant]
Luty, et al., “Five Polymorphic Microsatellite VNTRs on the Human XChromosome”, Am. J. Hum. Genet., 1990, 46:776-783. [cited by applicant]
Matthews, et al., “Analytical Strategies for the Use of DNA Probes”, Analytical Chemistry, 1988, 169:1-25. [cited by applicant]
McKinnon, P.J., “Ataxia-Telangiectasia: An Inherited Disorder of Ionizing-Radiation Sensitivity in Man”, Human Genetics, 1987, 75(3):197-208. [cited by applicant]
Mizusawa, et al., “Improvement of the Dideoxy Chain Termination Method of DNA Sequencing by Use of Deoxy-7-Deazaguanosine Triphosphate in Place of DGTP”, Nucleic Acids Research, 1986, 14(3):1319-1325. [cited by applicant]
Morris, et al., “Molecular Mechanisms of Multiple Drug Resistance in Clinical Isolates of [cited by applicant]
Morrison, et al., “Organic Chemistry”, Published by Allyn and Bacon., Boston, Massachusetts, USA, 1973, 406-409. [cited by applicant]
Mosko, et al., “Ultrasensitive Detection of Multiplexed Somatic Mutations Using MALDI-TOF Mass Spectrometry”, The Journal of Molecular Diagnostics, 2016, 18:23-31. [cited by applicant]
Muddiman, et al., “Length and Base Composition of PCR-Amplified Nucleic Acids Using Mass Measurements from Electrospray Ionization Mass Spectrometry”, Analytical Chemistry, Apr. 15, 1997, 69(8):1543-1549. [cited by applicant]
Mullis, “The Unusual Origin of the Polymerase Chain Reaction”, Scientific American, 1990, 262(4):56-61. [cited by applicant]
Naito, et al., “Molecular Mass Measurement of Polymerase Chain Reaction Products Amplified from Human Blood DNA by Electrospray Ionization Mass Spectrometry”, Rapid Communications in Mass Spectrometry, 1995, 9:1484-1486. [cited by applicant]
Nakamura, et al., “Variable Number of Tandem Repeat (VNTR) Markers for Human Gene Mapping”, Science, 1987, 235:1616-1622. [cited by applicant]
Naomi, et al., “Rapid Mass Spectrometric Identification of Human Genomic Polymorphisms Using Multiplexed Photocleavable Mass-Tagged Probes and Solid Phase Capture”, Organic and Biomolecular Chemistry, Jan. 1, 2007, 5(12… [cited by applicant]
Nguyen, et al., “Mild Conditions for Releasing Mono and Bis-Biotinylated Macromolecules from Immobilized Streptavidin”, Biomolecular Engineering, Oct. 1, 2005, 22(4):147-150. [cited by applicant]
Nishimura, et al., “A Tetranucleotide Repeat for The F13B Locus”, Nucleic Acids Research, 1992, 20(5):1167. [cited by applicant]
Nordhoff, et al., “Matrix-assisted Laser Desorption/Ionization Mass Spectrometry of Nucleic Acids with Wavelengths in the Ultraviolet and Infrared”, Rapid Communications in Mass Spectrometry, Dec. 1992, 6(12):771-776. [cited by applicant]
Oeth, et al., “SEQUENOM® Application Note, Document No. 8876-006, R04”, Nov. 10, 2006, 12 pages. [cited by applicant]
Overberg, et al., “Matrix-Assisted Laser Desorption of Large Biomolecules with a TEA-CO.sub.2-Laser”, Rapid Communications in Mass Spectrometry, 1991, 5(3):128-131. [cited by applicant]
Palejwala, et al., “Quantitative Multiplex Sequence Analysis of Mutational Hot Spots. Frequency and Specificity of Mutations Induced by a Site-Specific Ethenocytosine in M13 Viral DNA”, Biochemistry, 1993, 32:4105-4111. [cited by applicant]
Pieles, et al., “Matrix-assisted Laser Desorption Ionization Time-of-flight Mass Spectrometry: A Powerful Tool for The Mass and Sequence Analysis of Natural and Modified Oligonucleotides”, Nucleic Acid Research, 1993, 2… [cited by applicant]
Pierce, et al., “Comparison of the GenMark Diagnostics eSensor Respiratory Viral Panel to Real-Time PCR for Detection of Respiratory Viruses in Children”, Journal of Clinical Microbiology, Nov. 2012, 50(11):3458-3465. [cited by applicant]
Ploos, et al., “Tetranucleotide Repeat Polymorphism in the VWF Gene”, Nucleic Acids Research, 1990, 18(16):4957. [cited by applicant]
Polymeropoulos, et al., “Trinucleotide Repeat Polymorphism at the Human Pancreatic Phospholipase A-2 Gene (PLA2)”, Nucleic Acids Research, 1990, 18(24):7468. [cited by applicant]
Polymeropoulos, et al., “Tetranucleotide Repeat Polymorphism at the Human C- Fes/fps Proto-Oncogene (FES)”, Nucleic Acids Research, 1991, 19(14):4018. [cited by applicant]
Polymeropoulos, et al., “Tetranucleotide Repeat Polymorphism at the Human Aromatase Cytochrome p. 450 Gene (CYP19)”, Nucleic Acids Research, 1991, 19(1):195. [cited by applicant]
Polymeropoulos, et al., “Tetranucleotide Repeat Polymorphism at the Human Coagulation Factor XIII a Subunit Gene(F13A1)”, Nucleic Acids Research, 1991, 19(15):4306. [cited by applicant]
Ratner, et al., “Complete Nucleotide Sequence of AIDS Virus, HTLV-III”, Nature, 1985, 313:227-284. [cited by applicant]
Reymer, et al., “A Lipoprotein Lipase Mutation (Asn291Ser) Is Associated with Reduced HDL Cholesterol Levels in Premature Atherosclerosis”, Nature Genetics, 1995, 10(1):28-34. [cited by applicant]
Rosli, et al., “Quantitative Recovery of Biotinylated Proteins from Streptavidin-Based Affinity Chromatography Resins”, Methods in Molecular Biology, 2008, 418:89-100. [cited by applicant]
Rybak, et al., “Purification of Biotinylated Proteins on Streptavidin Resin: A Protocol for Quantitative Elution”, Proteomics, 2004, 4(8):2296-2299. [cited by applicant]
Sano, et al., “Intersubunit Contacts Made by Tryptophan 120 with Biotin Are Essential for Both Strong Biotin Binding and Biotin-Induced Tighter Subunit Association of Streptavidin”, PNAS, 1995, 92(8):3180-3184. [cited by applicant]
Schächter, et al., “Genetic Associations with Human Longevity at the APOE and ACE loci”, Nature Genetics, 1994, 6:29-32. [cited by applicant]
Schlesinger, “Macromolecular Sequencing and Synthesis: Selected Methods and Applications”, Alan R. Liss, Inc., New York, 1988, 127-149. [cited by applicant]
Singer-Sam, “A Sensitive, Quantitative Assay for Measurement of Allele-specific Transcripts Differing by a Single Nucleotide”, Genome Research, 1992, 1:160-163. [cited by applicant]
Si-Yuan, et al., “Principal and Development of SNP Genotyping Technology”, Letters in Biotechnology, English Abstract Only, May 2003, 14(3):218-221. [cited by applicant]
Smith, et al., “Immobilization of Nucleic Acids Using Biotin-Strept(avidin) Systems”, Topics in Current Chemistry, 2005, 261:63-90. [cited by applicant]
Stahl, et al., “Solid Phase DNA Sequencing Using the Biotin-Avidin System”, Nucleic Acids Research, 1988, 16(7):3025-3039. [cited by applicant]
Stanssens, et al., “High-Throughput MALDI-TOF Discovery of Genomic Sequence Polymorphisms”, Genome Research, 2004, 14(1):126-133. [cited by applicant]
Takenaka, et al., “Multiplex Single-Base 1-39 Extension Typing to Identify Nuclear Genes Required for RNA Editing in Plant Organelles”, Nucleic Acid Research, Dec. 5, 2008, 37(2): e13. [cited by applicant]
Tautz, et al., “Hypervariability of Simple Sequences as a General Source for Polymorphic DNA Markers”, Nucleic Acids Research, 1989, 17(16):6463-6471. [cited by applicant]
Thompson, et al., “ Electrospray Ionisation-Cleavable Tandem Nucleic Acid Mass Tag-Peptide Nucleic Acid Conjugates: Synthesis and Applications to Quantitative Genomic Analysis Using Electrospray Ionisation-MS/MS ”, Nucl… [cited by applicant]
Tost, et al., “Genotyping Single Nucleotide Polymorphisms by Mass Spectrometry”, Mass Spectrometry Reviews, 2002, 21(6):388-418. [cited by applicant]
Trainor, “Dna Sequencing, Automation, and the Human Genome”, Anal. Chem., 1990, 62:418-426. [cited by applicant]
Tsang, et al., “Mass Spectrometry-Based Detection of Hemoglobin E Mutation by Allele-Specific Base Extension Reaction”, Clinical Chemistry, 2007, 53(12):2205-2209. [cited by applicant]
Tuschihashi, et al., “Progress in High Throughput SNP Genotyping Methods”, The Pharmacogenomics Journal, Jan. 1, 2002, 2(2):103-110. [cited by applicant]
Uhlmann, et al., “Antisense Oligonucleotides: A New Therapeutic Principle, Chemical Reviews”, Chemical Reviews, 1990, 90(4):544-583. [cited by applicant]
Vallone, et al., “Genotyping SNPs Using a UV-Photocleavable Oligonucleotide in MALDI-TOF Mvallon”, Methods in Molecular Biology, 2005, 297:169-178. [cited by applicant]
Vivante, et al., “High-Throughput, Sensitive and Quantitative Assay for the Detection of BCR-ABL Kinase Domain Mutations”, Leukemia, 2007, 21(6):1318-1321. [cited by applicant]
Wain, et al., “Nucleotide Sequence of the AIDS Virus, LAV”, Cell, 1985, 40(1):9-17. [cited by applicant]
Wang, et al., “Large-Scale Identification, Mapping, and Genotyping of Single-Nucleotide Polymorphisms in the Human Genome”, Science, 1998, 280(5366): 1077-1082. [cited by applicant]
Weber, et al., “Abundant Class of Human DNA Polymorphisms Which Can Be Typed Using the Polymerase Chain Reaction”, American Journal of Human Genetics, 1989, 44(3):388-396. [cited by applicant]
Weissenbach, et al., “A Second-Generation Linkage Map of the Human Genome”, Nature, 1992, 359(6398):794-801. [cited by applicant]
Wenzel, et al., “Genosnip: SNP Genotyping by MALDI-TOF MS Using Photocleavable Oligonucleotides”, Nucleosides, nucleotides nucleic acids, 2003, 22(5-8):1579-1581. [cited by applicant]
Wu, et al., “Matrix-Assisted Laser Desorption Time-of-Flight Mass Spectrometry of Oligonucleotides Using 3-Hydroxypicolinic Acid as an Ultraviolet-Sensitive Matrix”, Rapid Communications in Mass Spectrometry, 1993, 7(2)… [cited by applicant]
Wunschel, et al., “Analysis of Double-Stranded Polymerase Chain Reaction Products from the Bacillus Cereus Group by Electrospray Ionization Fourier Transform lon Cyclotron Resonance Mass Spectrometry”, Rapid Communicati… [cited by applicant]
Yao, et al., “Interaction of Deoxyinosine 3′-Endonuclease from [cited by applicant]
Yao, et al., “Purification and Characterization of a Novel Deoxyinosine-Specific Enzyme, Deoxyinosine 3′ Endonuclease, from [cited by applicant]
Yao, et al., “Strand-Specific Cleavage of Mismatch-Containing DNA by Deoxyinosine 3′- Endonuclease from [cited by applicant]
Ying, et al., “Design of a Reversible Biotin Analog and Applications in Protein Labeling, Detection, and Isolation”, Chemical Communications, 2011, 47:8593-8595. [cited by applicant]
Yolov, et al., “Synthesis of RNA Using T7 Rna Polymerase and Immobilized DNA in a Stream Type Reactor”, Biooraanicheskala Khhimia, Jun. 1991, 17(6):789-794. [cited by applicant]
Zuliani, et al., “Tetranucleotide Repeat Polymorphism in the LPL Gene”, Nucleic Acids Research, 1990, 18(16):4958. [cited by applicant]
Office Action mailed on Jan. 9, 2001, in U.S. Appl. No. 09/431,613, filed Nov. 2, 1999. [cited by applicant]
Office Action mailed on May 8, 2002, in U.S. Appl. No. 09/783,881, filed Feb. 13, 2001. [cited by applicant]
Hammond et al., “Rapid Mass Spectrometric Identification of Human Genomic Polymorphisms Using Multiplexed Photocleavable Mass-Tagged Probes and Solid Phase Capture”, Organic & Biomolecular Chemistry, May 10, 2007, pp. 1… [cited by applicant]
Mengel-Jergensen et al., “Typing of Multiple Single-Nucleotide Polymorphisms Using Ribonuclease Cleavage of DNA/RNA Chimeric Single-Base Extension Primers and Detection by MALDI-TOF Mass Spectrometry”, Analytical Chemis… [cited by applicant]
Sanchez et al., “Typing of Y Chromosome SNPs with Multiplex PCT Methods”, Methods in Molecular Biology, vol. 297, Dec. 31, 2005, pp. 209-228. [cited by applicant]
Office Action in co-pending U.S. Appl. No. 18/139,303, dated Dec. 13, 2024, 18 pages. [cited by applicant]
Final Office Action in co-pending U.S. Appl. No. 18/139,303, dated Apr. 22, 2024, 15 pages. [cited by applicant]