IP Library › Granted Patent US 12,656,313
Granted Patent B2
US 12,656,313 · App. 18/663,889 · Granted Jun 16, 2026

Methods and devices for sequencing nucleic acids in smaller batches

Inventors: Steven Gordon (Weston, MA); Thomas Hagerott (Needham, MA); Edmund Golaski (Cambridge, MA); Jerzy Olejnik (Brookline, MA)
Assignee: IsoPlexis Corporation
G01N27/44791B01L3/502761C12Q1/6869G01N27/44726B01L3/502715B01L2200/0668B01L2300/0877B01L2400/0487
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Quick Facts
Patent No.
US 12,656,313
App. No.
18/663,889
Granted
Jun 16, 2026
Kind
B2
Abstract

The invention provides methods and compositions, including, without limitation, algorithms, computer readable media, computer programs, apparatus, and systems for determining the identity of nucleic acids in nucleotide sequences using, for example, data obtained from sequencing by synthesis methods. A plurality of smaller flow cells is employed, each with a relatively small area to be imaged, in order to provide greater flexibility and efficiency.

Claims (490)

1 . A method for identifying incorporation of a nucleotide analogue in a nucleic acid molecule during cycles of nucleotide incorporation via sequencing by synthesis of a target nucleic acid molecule, comprising:

providing:

I. at least one flow cell comprising an array of spots;

II. a moveable support, configured to move said at least one flow cell;

III. a reagent delivery mechanism in fluidic communication with said at least one flow cell;

IV. a plurality of reagent reservoirs configured to supply reagents including a plurality of nucleotide analogues comprising a detectable fluorescent label; and

V. an imaging platform configured to detect nucleotide analogues;

moving said at least one flow cell from an initial position to an imaging position aligned with said imaging platform;

performing a plurality of cycles of nucleotide incorporation, wherein performing an individual cycle of nucleotide incorporation comprises:

(a) incorporating at least one nucleotide analogue from the reagents into a nucleic acid molecule complementary to the target nucleic acid molecule associated with a spot of the array of spots of the at least one flow cell;

(b) washing non-incorporated nucleotide analogues from the at least one flow cell;

(c) detecting a first fluorescence intensity of a detectable fluorescent label from the spot comprising the complementary nucleic acid molecule; and

(d) detecting at least a second fluorescence intensity of a detectable fluorescent label from the spot comprising the complementary nucleic acid molecule; and

identifying the incorporation of the nucleotide analogue in the complementary nucleic acid molecule using the detected first fluorescence intensity and the second fluorescence intensity.

2 . The method of claim 1 , wherein only two fluorescence intensities are detected and the two fluorescence intensities comprise the first fluorescence intensity and the second fluorescence intensity.

3 . The method of claim 2 , wherein the first fluorescence intensity is detected in a first detector channel and the second fluorescence intensity is detected in a second detector channel.

4 . The method of claim 1 , wherein performing the individual cycle of nucleotide incorporation further comprises:

(e) detecting at least an additional third fluorescence intensity of a detectable fluorescent label from the spot comprising the complementary nucleic acid molecule.

5 . The method of claim 4 further comprising for each cycle of the plurality of cycles of nucleotide incorporation:

determining a contribution to the first fluorescence intensity of a nucleotide incorporated at an interrogation position of the complementary nucleic acid molecule from at least one of (i) a subsequent fluorescence intensity of at least one subsequent nucleic acid position of the complementary nucleic acid molecule and (ii) a prior fluorescence intensity of at least one preceding nucleic acid position of the complementary nucleic acid molecule; and

correcting for a sequence lead effect or a sequence lag effect based on the contribution to the first fluorescence intensity from at least one of the subsequent fluorescence intensity and the prior fluorescence intensity, wherein correcting the sequence lead or lag effect comprises determining and applying a lead or lag compensation.

6 . The method of claim 1 further comprising for one or more cycles of nucleotide incorporation:

determining one or more spectral crosstalk factors associated with the at least one detectable fluorescent label, wherein the spectral crosstalk factor is assessed based on at least one of the first fluorescence intensity and the second fluorescence intensity; and

correcting crosstalk associated with the at least one detectable fluorescent label.

7 . The method of claim 1 , wherein a portion of the nucleotide analogues comprise a reversible terminator chemical moiety at the 3′-OH group and wherein the reversible terminator is reversibly terminated by an azidomethyl group, an allyl group, an aminoxy group, a methylaminoxy group, a disulfide group, or an O-allyl group at the 3′ position.

8 . The method of claim 1 , wherein the reagents further comprise a second plurality of nucleotide analogues that do not comprise a detectable label.

9 . The method of claim 1 , wherein the reagents further comprise a cleaving agent and cleaving agent scavenger.

10 . The method of claim 1 , further comprising moving said at least one flow cell while aligned with said imaging platform to facilitate focusing on one or more spots of said at least one flow cell.

11 . The method of claim 1 , wherein the at least one flow cell comprises a first flow cell comprising a first array of spots and a second flow cell comprising a second array of spots.

12 . The method of claim 11 , wherein, while the first flow cell is undergoing one or more of steps (c) or (d), a second flow cell is undergoing one or more of steps (a) or (b).

13 . The method of claim 9 , wherein said cleaving agent is: i) Catalytic hydrogenation over PtO 2 or Pd/C; ii) LiAlH 4 , HCO 2 NH 4 -10% Pd/C, NaBH 4 /CoCl 2 ·6 H 2 O, Zn/NH 4 Cl, or Fe/NH 4 Cl; or iii) tri-n-butyl-phosphine, (Tris-carboxyethyl)phosphine, triphenyl phosphine, tris(3-sulfophenyl)-phosphine, or Tris(2-carboxy-ethyl) phosphine.

14 . The method of claim 9 , wherein said cleaving agent scavenger does not contain a nucleic acid base.

15 . The method of claim 9 , wherein the cleaving agent scavenger comprises an aminoxy group, a thiol group or an azido group.

16 . The method of claim 15 , wherein the cleaving agent scavenger agent comprises hydroxylamine.

17 . The method of claim 15 , wherein the cleaving agent scavenger agent comprises cysteamine, cystamine, trans-1,2-Dithiane-4,5-diol, dimethyl disulfide, or diethyl disulfide.

18 . The method of claim 15 , wherein the cleaving agent scavenger comprises an azidomethyl group or an azidoethyl ether group.

19 . The method of claim 18 , wherein the cleaving agent scavenger comprises 11-Azido-3,6,9-trioxaundecan-1-amine, azidomethyl phenyl sulfide.

20 . The method of claim 1 , wherein the at least one detectable fluorescent label is BODIPY, rhodamine, carboxyrhodamine, cyanine, or a combination thereof.

21 . The method of claim 5 , wherein the lead or lag compensation is determined by applying equation to the data:

[

I

M

⁢

1

I

M

⁢

2

⋮

I

MN

]

=

K

Lead

/

Lag

[

I

A

⁢

1

I

A

⁢

2

⋮

I

AN

]

where

I M1 is a fluorescence intensity measured at position 1 of the nucleic acid molecule,

I M2 is a fluorescence intensity measured at position 2 of the nucleic acid molecule,

I MN is a fluorescence be intensity measured at position N of the nucleic acid molecule,

I A1 is the actual fluorescence intensity at position 1 of the nucleic acid molecule,

I A2 is the actual fluorescence intensity at position 2 of the nucleic acid molecule,

I AN is the actual fluorescence intensity at position N of the nucleic acid molecule.

22 . The method of claim 21 , wherein the lead or lag compensation is determined by applying equation:

K

Lead

/

Lag

=

[

R

Lag

/

Lead

,

1

R

+

1

⁢

Lead

,

1

R

+

2

⁢

Lead

,

1

R

+

3

⁢

Lead

,

1

…

R

+

(

N

-

1

)

⁢

Lead

,

1

R

-

1

⁢

Lag

,

2

R

Lag

/

Lead

,

2

R

+

1

⁢

Lead

,

2

R

+

2

⁢

Lead

,

2

…

R

+

(

N

-

2

)

⁢

Lead

,

2

R

-

2

⁢

Lag

,

3

R

-

1

⁢

Lag

,

3

R

Lag

/

Lead

,

3

R

+

1

⁢

Lead

,

3

…

R

+

(

N

-

3

)

⁢

Lead

,

3

R

-

3

⁢

Lag

,

4

R

-

2

⁢

Lag

,

4

R

-

1

⁢

Lag

,

4

R

Lag

/

Lead

,

4

…

R

+

(

N

-

4

)

⁢

Lead

,

4

⋮

⋮

⋮

⋮

⋱

⋮

R

-

(

N

-

1

)

⁢

Lag

,

N

R

-

(

N

-

2

)

⁢

Lag

,

N

R

-

(

N

-

3

)

⁢

Lag

,

N

R

-

(

N

-

4

)

⁢

Lag

,

N

…

R

Lag

/

Lead

,

N

]

R Lag/Lead,1 is the ratio between reduced fluorescence intensity for nucleic acid at position 1 to actual fluorescence intensity at said nucleic acid at position 1,

R +1Lead,1 is the ratio contribution to fluorescence intensity at nucleic acid position 1 from a fluorescence intensity at nucleic acid position 2,

R +2Lead,1 is the ratio contribution to fluorescence intensity at nucleic acid position 1 from a fluorescence intensity at nucleic acid position 3,

R +3Lead,1 is the ratio contribution to fluorescence intensity at nucleic acid position 1 from a fluorescence intensity at nucleic acid position 4,

R +(N−1)Lead,1 is the ratio contribution to fluorescence intensity at nucleic acid position 1 from a fluorescence intensity at nucleic acid position 1+(N−1),

R −1Lag,2 is the ratio contribution to fluorescence intensity at nucleic acid position 2 from a fluorescence intensity at nucleic acid position 1,

R Lag/Lead,2 is the ratio between reduced fluorescence intensity for nucleic acid at position 2 to actual fluorescence intensity at said nucleic acid at position 2,

R +1Lead,2 is the ratio contribution to fluorescence intensity at nucleic acid position 2 from a fluorescence intensity at nucleic acid position 3,

R +2Lead,2 is the ratio contribution to fluorescence intensity at nucleic acid position 2 from a fluorescence intensity at nucleic acid position 4,

R +(N−2) Lead,2 is the ratio contribution to fluorescence intensity at nucleic acid position 2 from a fluorescence intensity at nucleic acid position 2+(N−2),

R −2Lag,3 is the ratio contribution to fluorescence intensity at nucleic acid position 3 from a fluorescence intensity at nucleic acid position 1,

R −1Lag,3 is the ratio contribution to fluorescence intensity at nucleic acid position 3 from a fluorescence intensity at nucleic acid position 2,

R Lag/Lead,3 is the ratio between reduced fluorescence intensity for nucleic acid at position 3 to actual fluorescence intensity at said nucleic acid at position 3,

R +1Lead,3 is the ratio contribution to fluorescence intensity at nucleic acid position 3 from a fluorescence intensity at nucleic acid position 4,

R +(N−3) Lead,3 is the ratio contribution to fluorescence intensity at nucleic acid position 3 from a fluorescence intensity at nucleic acid position 3+(N−3),

R −3Lag,4 is the ratio contribution to fluorescence intensity at nucleic acid position 4 from a fluorescence intensity at nucleic acid position 1,

R −2Lag,4 is the ratio contribution to fluorescence intensity at nucleic acid position 4 from a fluorescence intensity at nucleic acid position 2,

R −1Lag,4 is the ratio contribution to fluorescence intensity at nucleic acid position 4 from a fluorescence intensity at nucleic acid position 3,

R Lag/Lead,4 is the ratio between reduced fluorescence intensity for nucleic acid at position 4 to actual fluorescence intensity at said nucleic acid at position 4,

R +(N−4) Lead,4 is the ratio contribution to fluorescence intensity at nucleic acid position 4 from a fluorescence intensity at nucleic acid position 4+(N−4),

R −(N−1)Lag,N is the ratio contribution to fluorescence intensity at nucleic acid position N from a fluorescence intensity at nucleic acid position N−(N−1),

R −(N−2)Lag,N is the ratio contribution to fluorescence intensity at nucleic acid position N from a fluorescence intensity at nucleic acid position N−(N−2),

R −(N−3)Lag,N is the ratio contribution to fluorescence intensity at nucleic acid position N from a fluorescence intensity at nucleic acid position N−(N−3),

R −(N−4)Lag,N is the ratio contribution to fluorescence intensity at nucleic acid position N from a fluorescence intensity at nucleic acid position N−(N−4), and

R Lag/Lead,N is the ratio between reduced fluorescence intensity for nucleic acid at position N to actual fluorescence intensity at said nucleic acid at position N.

23 . The method of claim 22 , wherein one or more of the following terms are negligible and set to zero:

R Lag/Lead,1 is the ratio between reduced fluorescence intensity for nucleic acid at position 1 to actual fluorescence intensity at said nucleic acid at position 1,

R +1Lead,1 is the ratio contribution to fluorescence intensity at nucleic acid position 1 from a fluorescence intensity at nucleic acid position 2,

R +2Lead,1 is the ratio contribution to fluorescence intensity at nucleic acid position 1 from a fluorescence intensity at nucleic acid position 3,

R +3Lead,1 is the ratio contribution to fluorescence intensity at nucleic acid position 1 from a fluorescence intensity at nucleic acid position 4,

R +(N−1)Lead,1 is the ratio contribution to fluorescence intensity at nucleic acid position 1 from a fluorescence intensity at nucleic acid position 1+(N−1),

R −1Lag,2 is the ratio contribution to fluorescence intensity at nucleic acid position 2 from a fluorescence intensity at nucleic acid position 1,

R Lag/Lead,2 is the ratio between reduced fluorescence intensity for nucleic acid at position 2 to actual fluorescence intensity at said nucleic acid at position 2,

R +1Lead,2 is the ratio contribution to fluorescence intensity at nucleic acid position 2 from a fluorescence intensity at nucleic acid position 3,

R +2Lead,2 is the ratio contribution to fluorescence intensity at nucleic acid position 2 from a fluorescence intensity at nucleic acid position 4,

R +(N−2)Lead,2 is the ratio contribution to fluorescence intensity at nucleic acid position 2 from a fluorescence intensity at nucleic acid position 2+(N−2),

R −2Lag,3 is the ratio contribution to fluorescence intensity at nucleic acid position 3 from a fluorescence intensity at nucleic acid position 1,

R −1Lag,3 is the ratio contribution to fluorescence intensity at nucleic acid position 3 from a fluorescence intensity at nucleic acid position 2,

R Lag/Lead,3 is the ratio between reduced fluorescence intensity for nucleic acid at position 3 to actual fluorescence intensity at said nucleic acid at position 3,

R +1Lead,3 is the ratio contribution to fluorescence intensity at nucleic acid position 3 from a fluorescence intensity at nucleic acid position 4,

R +(N−3)Lead,3 is the ratio contribution to fluorescence intensity at nucleic acid position 3 from a fluorescence intensity at nucleic acid position 3+(N−3),

R −3Lag,4 is the ratio contribution to fluorescence intensity at nucleic acid position 4 from a fluorescence intensity at nucleic acid position 1,

R −2Lag,4 is the ratio contribution to fluorescence intensity at nucleic acid position 4 from a fluorescence intensity at nucleic acid position 2,

R −1Lag,4 is the ratio contribution to fluorescence intensity at nucleic acid position 4 from a fluorescence intensity at nucleic acid position 3,

R Lag/Lead,4 is the ratio between reduced fluorescence intensity for nucleic acid at position 4 to actual fluorescence intensity at said nucleic acid at position 4,

R +(N−4)Lead,4 is the ratio contribution to fluorescence intensity at nucleic acid position 4 from a fluorescence intensity at nucleic acid position 4+(N−4),

R −(N−1)Lag,N is the ratio contribution to fluorescence intensity at nucleic acid position N from a fluorescence intensity at nucleic acid position N−(N−1),

R −(N−2)Lag,N is the ratio contribution to fluorescence intensity at nucleic acid position N from a fluorescence intensity at nucleic acid position N−(N−2),

R −(N−3)Lag,N is the ratio contribution to fluorescence intensity at nucleic acid position N from a fluorescence intensity at nucleic acid position N−(N−3),

R −(N−4)Lag,N is the ratio contribution to fluorescence intensity at nucleic acid position N from a fluorescence intensity at nucleic acid position N−(N−4), and

R Lag/Lead,N is the ratio between reduced fluorescence intensity for nucleic acid at position N to actual fluorescence intensity at said nucleic acid at position N.

24 . The method of claim 23 , wherein at least the following terms are negligible and are set to zero and N is greater than 4:

R +2Lead,1 ,

R +3Lead,1 ,

R +(N−1)Lead,1 ,

R +2Lead,2 ,

R +(N−2)Lead,2 ,

R −2Lag,3 ,

R +(N−3)Lead,3 ,

R −3Lag,4 ,

R −2Lag,4 ,

R −(N−1)Lag,N ,

R −(N−2)Lag,N , and

R −(N−3)Lag,N .

25 . The method of claim 6 , wherein the one or more crosstalk factors comprise a spectral crosstalk ratio determined by calculating the ratio between the first fluorescence intensity detected in a first detector channel and the second fluorescence intensity in a second detector channel.

26 . The method of claim 25 , wherein the one or more spectral crosstalk factors are used to determine a spectral crosstalk matrix.

27 . The method of claim 26 , wherein the spectral crosstalk matrix is determined using equation:

[

M

A

M

B

]

=

K

[

A

B

]

⁢

where

⁢

K

=

[

1

R

AB

R

B

⁢

A

1

]

wherein:

M A is a detected fluorescence intensity of a first detectable fluorescent label,

M B is a detected fluorescence intensity of a second detectable fluorescent label,

A is an actual fluorescence intensity of the first detectable fluorescent label,

B is an actual fluorescence intensity of the second detectable fluorescent label,

R AB is a ratio between (a) a portion of fluorescence intensity for the first detectable fluorescent label that is contributed by the second detectable fluorescent label, and (b) the actual fluorescent intensity of the second detectable fluorescent label,

and

R BA is the ratio between (a) a portion of fluorescence intensity for the second detectable fluorescent label that is contributed by the first detectable fluorescent label, and (b) the actual fluorescent intensity of the first detectable fluorescent label.

28 . The method of claim 27 , wherein the equation is solved to determine spectral crosstalk matrix K −1 using equation

[

A

B

]

=

K

-

1

[

M

A

M

B

]

.

29 . The method of claim 26 , wherein the spectral crosstalk matrix is determined using equation:

[

M

A

M

B

M

C

]

=

K

[

A

B

C

]

⁢

where

⁢

K

=

[

1

R

AB

0

R

BA

1

R

BC

0

R

CB

1

]

wherein:

M A is a detected fluorescence intensity of a first detectable fluorescent label,

M B is a detected fluorescence intensity of a second detectable fluorescent label,

M C is a detected fluorescence intensity of a third detectable fluorescent label,

A is an actual fluorescence intensity of the first detectable fluorescent label,

B is an actual fluorescence intensity of the second detectable fluorescent label,

C is an actual fluorescence intensity of the third detectable fluorescent label,

R AB is a ratio between (a) a portion of fluorescence intensity for the first detectable fluorescent label that is contributed by the second detectable fluorescent label, and (b) an actual fluorescent intensity of the second detectable fluorescent label,

R BA is the ratio between (a) a portion of fluorescence intensity for the second detectable fluorescent label that is contributed by the first detectable fluorescent label, and (b) an actual fluorescent intensity of the first detectable fluorescent label,

R BC is the ratio between (a) a portion of fluorescence intensity for the second detectable fluorescent label that is contributed by the third detectable fluorescent label, and (b) an actual fluorescent intensity of the third detectable fluorescent label,

R CB is the ratio between (a) a portion of fluorescence intensity for the third detectable fluorescent label that is contributed by the second detectable fluorescent label, and (b) an actual fluorescent intensity of the second detectable fluorescent label.

30 . The method of claim 29 , wherein the equation is solved to determine the spectral crosstalk matrix K −1 comprises:

[

A

B

C

]

=

K

-

1

[

M

A

M

B

M

C

]

.

31 . The method of claim 12 , wherein while the second flow cell is undergoing one or more of steps (a) or (b), step (c) or (d) for the first flow cell further comprises moving the first flow cell while aligned with said imaging platform to facilitate focusing on one or more spots of the first flow cell.

32 . The method of claim 1 , wherein at least a portion of the reagents are recovered for re-use in one or more subsequent cycles of nucleotide incorporation.

33 . The method of claim 5 , wherein the plurality of cycles includes at least a majority of the cycles of nucleotide incorporation during the sequencing by synthesis of the target nucleic acid molecule.

34 . The method of claim 3 further comprising for each cycle of the plurality of cycles of nucleotide incorporation:

determining a contribution to the first fluorescence intensity of a nucleotide incorporated at an interrogation position of the complementary nucleic acid molecule from at least one of (i) a subsequent fluorescence intensity of at least one subsequent nucleic acid position of the complementary nucleic acid molecule and (ii) a prior fluorescence intensity of at least one preceding nucleic acid position of the complementary nucleic acid molecule; and,

correcting for a sequence lead effect or a sequence lag effect based on the contribution to the first fluorescence intensity from at least one of the subsequent fluorescence intensity and the prior fluorescence intensity, wherein correcting the sequence lead or lag effect comprises determining and applying a lead or lag compensation;

wherein the plurality of cycles includes at least a majority of the cycles of nucleotide incorporation during the sequencing by synthesis of the target nucleic acid molecule; and

wherein the reagents further comprise a second plurality of nucleotide analogues that do not comprise a detectable label.

Assignments (4)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 16, 2024
From: GORDON, STEVEN; HAGEROTT, THOMAS; GOLASKI, EDMUND; OLEJNIK, JERZY
To: INTELLIGENT BIO-SYSTEMS, INC.
Reel/Frame 067432/0363 →
RESOLUTION ADOPTING CHANGE OF NAME Recorded May 16, 2024
From: INTELLIGENT BIO-SYSTEMS, INC.
To: QIAGEN WALTHAM, INC.
Reel/Frame 067432/0781 →
PATENT PURCHASE AGREEMENT Recorded May 16, 2024
From: QIAGEN SCIENCES, LLC
To: ISOPLEXIS CORPORATION
Reel/Frame 067432/0805 →
MERGER Recorded May 16, 2024
From: QIAGEN WALTHAM, INC.
To: QIAGEN SCIENCES, LLC
Reel/Frame 067432/0821 →
Continuity (13)
Continuation 18436656 · Feb 8, 2024
Continuation 17194850 · Mar 8, 2021
Continuation 16292819 · Mar 5, 2019
Continuation 15656307 · Jul 21, 2017
Continuation 14708675 · May 11, 2015
Continuation 14463211 · Aug 19, 2014
Continuation 13786895 · Mar 6, 2013
Continuation 12719469 · Mar 8, 2010
Continuation In Part 12405694 · Mar 17, 2009
Continuation In Part 12020284 · Jan 25, 2008
Provisional Application 61037845 · Mar 19, 2008
Provisional Application 60899454 · Feb 5, 2007
Related Publication 20250052717A1 · Feb 13, 2025
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