Optical system and assay chip for probing, detecting and analyzing molecules

• US 10,533,945 B2
• Filed: 11/10/2017
• Issued: 01/14/2020
• Est. Priority Date: 11/17/2013
• Status: Active Grant

• Current Assignee: Quantum-Si Incorporated
• Original Assignee: Quantum-Si Incorporated
• Inventors: Rothberg, Jonathan M., Kabiri, Ali, Sickler, Jason W., Gyarfas, Brett J., Lackey, Jeremy, Schmid, Gerard, Cipriany, Benjamin, Jewell, Jack, West, Lawrence C., Ferrigno, Michael, Glenn, Paul E., Cohen, Adam Ezra, Bellofiore, Anthony
• Primary Examiner(s): Bhat, Narayan K
• Application Number:
  US15/808,940
• Publication Number:
  US 20180088052A1
• Time in Patent Office: 795 Days
• CPC Class Codes: B01L 2200/12 Specific details about manufacturing devices
• CPC Class Codes: B01L 2300/0829 Multi-well plates; Microtitration plates
• CPC Class Codes: B01L 2300/0887 Laminated structure
• CPC Class Codes: B01L 2300/0893 having a very large number of wells, microfabricated wells
• CPC Class Codes: B01L 2300/168 Specific optical properties, e.g. reflective coatings
• CPC Class Codes: B01L 3/5085 for multiple samples, e.g. microtitration plates
• CPC Class Codes: C12Q 1/6869 Methods for sequencing
• CPC Class Codes: C12Q 1/6874 involving nucleic acid arrays, e.g. sequencing by hybridisation
• CPC Class Codes: C12Q 2521/101 DNA polymerase
• CPC Class Codes: C12Q 2525/101 incorporating non-naturally occurring nucleotides, e.g. inosine
• CPC Class Codes: C12Q 2537/157 A reaction step characterised by the number of molecules incorporated or released
• CPC Class Codes: C12Q 2563/107 fluorescence
• CPC Class Codes: C12Q 2565/607 being a sensor, e.g. electrode
• CPC Class Codes: G01N 2021/6419 Excitation at two or more wavelengths
• CPC Class Codes: G01N 2021/6441 with two or more labels
• CPC Class Codes: G01N 2021/6478 Special lenses
• CPC Class Codes: G01N 21/64 Fluorescence; Phosphorescence
• CPC Class Codes: G01N 21/645 Specially adapted constructive features of fluorimeters
• CPC Class Codes: G01N 21/6452 Individual samples arranged in a regular 2D-array, e.g. multiwell plates
• CPC Class Codes: G01N 21/6454 using an integrated detector array
• CPC Class Codes: G01N 21/648 : using evanescent coupling or surface plasmon coupling for the excitation of fluorescence
• CPC Class Codes: G01N 21/6486 : Measuring fluorescence of biological material, e.g. DNA, RNA, cells G01N21/6428 takes precedence
• CPC Class Codes: G01N 21/7743 : the reagent-coated grating coupling light in or out of the waveguide
• CPC Class Codes: G01N 21/7746 : the waveguide coupled to a cavity resonator
• CPC Class Codes: G01N 2201/02 : Mechanical
• CPC Class Codes: G01N 2201/06113 : Coherent sources; lasers
• CPC Class Codes: G01N 2201/0612 : Laser diodes
• CPC Class Codes: G01N 2201/062 : LED's
• CPC Class Codes: G01N 2201/068 : Optics, miscellaneous
• CPC Class Codes: G01N 2201/125 : Digital circuitry
• CPC Class Codes: Y10T 29/49016 : Antenna or wave energy "plumbing" making

Abstract

Apparatus and methods for analyzing single molecule and performing nucleic acid sequencing. An apparatus can include an assay chip that includes multiple pixels with sample wells configured to receive a sample, which, when excited, emits emission energy; at least one element for directing the emission energy in a particular direction; and a light path along which the emission energy travels from the sample well toward a sensor. The apparatus also includes an instrument that interfaces with the assay chip. The instrument includes an excitation light source for exciting the sample in each sample well; a plurality of sensors corresponding the sample wells. Each sensor may detect emission energy from a sample in a respective sample well. The instrument includes at least one optical element that directs the emission energy from each sample well towards a respective sensor of the plurality of sensors.

Claims

1. An apparatus comprising:

an array of sample wells arranged on a surface of a chip, wherein individual sample wells in the array are configured to receive a sample; and

a plurality of lenses formed in the chip, wherein individual lenses of the plurality of lenses are configured to focus light emitted from a sample well in the array, wherein the plurality of lenses include a plurality of refractive lenses.

2. The apparatus of claim 1, wherein individual lenses of the plurality of lenses correspond to individual sample wells in the array.

3. The apparatus of claim 2, wherein individual lenses of the plurality of lenses are positioned to direct light emitted from the corresponding sample well in the array towards a sensor.

4. The apparatus of claim 2, wherein individual lenses in the plurality of lenses overlap with the corresponding sample well in the array.

5. The apparatus of claim 4, wherein individual lenses in the plurality of lenses are centered below the corresponding sample well.

6. The apparatus of claim 5, wherein individual lenses of the plurality of lenses are disposed approximately 5 microns below the corresponding sample well.

7. The apparatus of claim 1, wherein individual lenses of the plurality of lenses have a convex surface proximate to the array of sample wells and a planar surface distal from the array of sample wells.

8. The apparatus of claim 1, wherein the plurality of lenses are formed within a lens layer of the chip.

9. The apparatus of claim 8, further comprising a layer of dielectric material positioned between the lens layer and the array of sample wells.

10. The apparatus of claim 9, wherein the layer of dielectric material includes silicon oxide and the lens layer includes silicon nitride.

11. The apparatus of claim 9, wherein the layer of dielectric material has a thickness of approximately 5 microns.

12. An apparatus comprising:

an array of sample wells arranged on a surface of a chip, wherein individual sample wells in the array are configured to receive a sample;

a plurality of lenses formed within a lens layer of the chip, wherein individual lenses of the plurality of lenses are configured to focus light emitted from a sample well in the array; and

a layer of dielectric material positioned between the lens layer and the array of sample wells, wherein the layer of dielectric material includes silicon oxide and the lens layer includes silicon nitride.

13. A method of forming an apparatus comprising:

forming an array of sample wells arranged on a surface of a chip, wherein individual sample wells in the array are configured to receive a sample; and

forming a plurality of lenses in the chip, wherein individual lenses of the plurality of lenses are configured to focus light emitted from a sample well in the array, wherein the plurality of lenses include a plurality of refractive lenses.

14. The method of claim 13, wherein forming the plurality of lenses further includes forming individual lenses of the plurality of lenses positioned to direct light emitted from a corresponding sample well in the array towards a sensor.

15. The method of claim 14, wherein forming the plurality of lenses further includes forming individual lenses in the plurality of lenses to overlap with the corresponding sample well in the array.

16. The method of claim 15, wherein forming the array of sample wells further includes forming individual sample wells in the array that are aligned to a corresponding lens of the plurality of lenses.

17. The method of claim 13, wherein forming the plurality of lenses further includes forming individual lenses of the plurality of lenses to have a convex surface proximate to the array of sample wells and a planar surface distal from the array of sample wells.

18. The method of claim 13, further comprising forming a layer of dielectric material positioned between the plurality of lenses and the array of sample wells.

19. The method of claim 13, wherein forming the plurality of sample wells further comprises:

forming, over an optically transparent layer, a stack of materials that includes at least one metal layer; and

etching through at least the stack of materials to form the plurality of sample wells.

20. The method of claim 19, wherein the etching further comprises etching tapered sidewalls for individual sample wells of the plurality of sample wells.