# US 2014/0194298 A1 · Methods and Apparatus for Detecting Molecular Interactions Using FET Arrays

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- Number: US 2014/0194298 A1
- Document ID: US20140194298A1
- Status: Published application
- Kind: A1
- Application number: 14/151,270
- Filed: 2014-01-09
- Published: 2014-07-10
- Earliest claimed: 2006-12-14
- Assignees: Life Technologies Corporation
- Applicants: Life Technologies Corporation
- Inventors: Jonathan Rothberg; Wolfgang Hinz
- Web page: https://patentgrep.com/patent/US20140194298A1

## CPC

- C12Q 1/6825: Nucleic acid detection involving sensors
- C12Q 1/6874: involving nucleic acid arrays, e.g. sequencing by hybridisation
- G01N 27/26: by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N 27/4145: {specially adapted for biomolecules, e.g. gate electrode with immobilised receptors}
- G01N 27/4148: {Integrated circuits therefor, e.g. fabricated by CMOS processing}
- G01N 33/54373: {involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings}
- G01N 33/6818: {Sequencing of polypeptides}
- H10D 30/60: Insulated-gate field-effect transistors [IGFET] (H10D30/40 takes precedence)
- H10D 30/68: Floating-gate IGFETs
- C12Q 1/6869: Methods for sequencing
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- H10D: INORGANIC ELECTRIC SEMICONDUCTOR DEVICES

## Abstract

Methods and apparatuses relating to large scale FET arrays for analyte detection and measurement are provided. ChemFET (e.g., ISFET) arrays may be fabricated using conventional CMOS processing techniques based on improved FET pixel and array designs that increase measurement sensitivity and accuracy, and at the same time facilitate significantly small pixel sizes and dense arrays. Improved array control techniques provide for rapid data acquisition from large and dense arrays. Such arrays may be employed to detect a presence and/or concentration changes of various analyte types in a wide variety of chemical and/or biological processes.

## Claims

### Claim at position 1

1-137. (canceled)

### Claim 138

A method for detecting bimolecular interactions, the method comprising:
providing a chemical detection circuit comprising a chemically-sensitive field effect transistor having a body terminal, a first terminal and a second terminal, the body terminal coupled to a body biasing voltage source line and the first terminal coupled to a first readout signal line; a first switch coupling the second terminal of the chemically-sensitive field effect transistor to a current source; and a second switch coupling the second terminal of the chemically-sensitive field effect transistor to a second readout signal line;
providing at least one molecular species to the chemical detection circuit; and
detecting a molecular interaction between the at least one molecular species and the a second molecular species by detecting the changes in electrical properties of the chemically-sensitive field effect transistor.

### Claim 139 (depends on 138)

The method of claim 138, further comprising disposing the at least one molecular species and the second molecular species in proximity to or in contact with the chemically-sensitive field effect transistor.

### Claim 140 (depends on 138)

The method of claim 138, wherein the change in at least one electrical property of at least a portion of the sensors of the array is the voltage or current change produced by a change in ion concentration or ion localization resulting from the interaction or reaction of the at least one molecular species with the second molecular species.

### Claim 141 (depends on 138)

The method of claim 138, wherein the at least one molecular species and the second molecular species are selected from the following combinations: a first protein and a second protein, a first nucleic acid and a second nucleic acid, a protein and a nucleic acid, an antibody and an antigen, an aptamer and a target, an enzyme and a substrate, an enzyme and an inhibitor, and enzyme and a cofactor.

### Claim 142 (depends on 141)

The method of claim 141, wherein the at least one molecular species comprises an enzyme, the second molecular species comprises a substrate for the enzyme, and the enzyme reacts with the substrate to effectuate a chance in the at least one electrical property of the sensors of the array.

### Claim 143 (depends on 138)

The method of claim 138, wherein the first and second switches are controlled by a selection signal common to the two switches.

### Claim 144 (depends on 138)

The method of claim 138, wherein the current source is common to the pixels of the column and adjustable by a bias voltage.

### Claim 145

A method for detecting bimolecular interactions, the method comprising:
providing a chemical detection device comprising a substrate of a first semiconductor type, and an array of chemical detection pixels, each chemical detection pixel including a chemically-sensitive field effect transistor formed in the substrate, the chemically-sensitive field effect transistor having a body terminal coupled to a body biasing voltage source line common to all chemical detection pixels of the array;
providing at least one molecular species to the chemical detection device; and
detecting a molecular interaction between the at least molecular species and a second molecular species by detecting the changes in electrical properties of the at least one chemically-sensitive field effect transistor.

### Claim 146 (depends on 145)

The method of claim 145, further comprising disposing the at least one molecular species and the second molecular species in proximity to or in contact with the chemically-sensitive field effect transistor.

### Claim 147 (depends on 145)

The method of claim 145, wherein the molecular interaction between the at least one molecular species and the second molecular species is a binding or coupling interaction or a hybridization or affinity interaction.

### Claim 148 (depends on 145)

The method of claim 145, wherein the change in at least one electrical property of at least a portion of the sensors of the array is the voltage or current change produced by a change in ion concentration or ion localization resulting from the interaction or reaction of the at least one molecular species with the second molecular species.

### Claim 149 (depends on 145)

The method of claim 145, wherein the at least one molecular species and the second molecular species are selected from the following combinations: a protein and a protein, a nucleic acid and a nucleic acid, a protein and a nucleic acid, an antibody and an antigen, an aptamer and a target, an enzyme and a substrate, an enzyme and an inhibitor, and enzyme and a cofactor.

### Claim 150 (depends on 145)

The chemical detection device of claim 145, wherein at least one of the first field effect transistor and the second field effect transistor has a body coupled to the body biasing voltage source line.

### Claim 151 (depends on 145)

The chemical detection device of claim 145, wherein the chemical detection pixel further includes a well of a second semiconductor type that is formed in the substrate, and the chemically-sensitive transistor, the first field effect transistor and the second field effect transistor are each formed in the well.

### Claim 152 (depends on 151)

The chemical detection device of claim 151, wherein the first field effect transistor and the second field effect transistor have a shared drain.

### Claim 153 (depends on 151)

The chemical detection device of claim 151, Wherein the chemical detection pixel further includes a highly doped region of the second semiconductor type to provide a body connection to the well, and wherein the body connection is coupled to a metal conductor around a perimeter of the chemical detection pixel.

### Claim 154

A method for detecting molecular interactions, the method comprising:
providing at least one molecular species into at least one of a plurality of reaction chambers, at least one reaction chamber of the plurality of reaction chambers coupled to at least one chemical-sensitive field effect transistor (chemFET) having a floating gate; and
detecting a molecular interaction between the at least one molecular species and a second molecular species by detecting a change in electrical properties of the chemFET.

### Claim 155 (depends on 154)

The method of claim 154, wherein the change in at least one electrical property of at least a portion of the sensors of the array is the voltage or current change produced by a change in ion concentration or ion localization resulting from the molecular interaction of the at least one molecular species with the second molecular species.

### Claim 156 (depends on 154)

The method of claim 154, wherein the at least one molecular species and the second molecular species are selected from the following pairs: a first protein and a second protein, a first nucleic acid and a second nucleic acid, a protein and a nucleic acid, an antibody and an antigen, an aptamer and a target, an enzyme and a substrate, an enzyme and an inhibitor, and enzyme and a cofactor.

### Claim 157 (depends on 154)

The method of claim 154, wherein the floating gate of the at least one chemFET is coupled to the at least one reaction chamber via an ion sensitive passivation layer sensitive.