DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application is being examined under the pre-AIA first to invent provisions.
Claim status
2. Claims 1-2 are cancelled.
Claims 3-20 are currently pending and under exam herein.
Claims 3-20 are rejected.
Priority
3. This application is a continuation of U.S. Application No. 17/217,354, filed on March 30, 2021, which is a continuation of U.S. Application No. 16/430,064, filed on June 3, 2019 (now U.S. Patent No. 11,001,887), which is a continuation of U.S. Application No. 15/911,801 filed on March 5, 2018 (now U.S. Patent No. 10,329,611), which is a continuation of U.S. Application No. 15/214,737, filed on July 20, 2016 (now U.S. Patent No. 9,909,174), which is a continuation of U.S. Application No. 14/691,042, filed on April 20, 2015 (now U.S. Patent No. 9,434,989), which is a continuation of U.S. Application No. 13/305,415, filed on November 28, 2011 (now U.S. Patent No. 9,017,973), which is a continuation of U.S. Application No. 12/405,779, filed on March 17, 2009, which claims priority to, and the benefit of, U.S. Provisional Application No. 61/037,845, filed on March 19, 2008. The claimed benefit of U.S. Provisional Application 61/037,845, filed on 19 March 2008, is acknowledged. In this action, all claims are examined as though they had an effective filing date of 19 March 2008. In future actions, the effective filing date of one or more claims may change, due to amendments to the claims, or further analysis of the disclosure(s) of the priority application(s).
Information Disclosure Statement
4. The information disclosure statements (IDSs) submitted on 07 June 2024 and 09 June 2026 had references attached to the application are being considered by the examiner. The IDS submitted on 14 February 2020 had references attached to a parent application 17/217354 that are being considered by the examiner.
Drawings
5. The drawings submitted on 03 March 2023 are objected to by the examiner because Figure 12 is executed in color and because Figure 19 is illegible as the shades representing each line on the graph cannot be distinguished. Appropriate correction is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
7. Claims 3, 5-6, 9-14 and 19-20 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Banerjee et al. (WO2007123744A2, IDS 14 February 2004), in view of Model et al. (2001, Cytometry, Vol. 44, p. 309-316). The italicized text corresponds to the instant claim limitations.
Regarding claim 3 lines 2-5, Banerjee et al. discloses systems and devices for sequence by synthesis wherein polynucleotides are sequenced on beads attached to a planar solid substrate. Banerjee et al. further discloses doing this by incorporating fluorescent nucleotides to synthesize a sequence complementary to the polynucleotide of interest one base at a time, and detecting and recording the fluorescence emissions using a charge coupled device (CCD) or similar camera at each step to take a digital image containing a plurality of pixel intensities (Fig. 41A). Banerjee et al. further discloses that by this sequencing process, base calls are made (i.e. the identity of bases complementary to the labeled oligonucleotide are determined) and that the entire sequence of a target fragment is done by reading the chronological order of the bases (para. 0007-0012; 0063; Fig. 30; Fig. 32; Fig. 41A; a method for base calling of nucleotides during DNA sequencing, comprising: detecting a probe corresponding to a nucleotide in a nucleic acid sequence on a solid support to generate a raw image; obtaining a first data set of a plurality of pixel intensities of the raw image of the probe on the solid support).
Regarding claim 3 lines 6-7, Banerjee et al. further discloses a method of generating a smoothed digital image of the probe on the solid support: In capturing the image, one or more rotating waveplates are optionally used that mixes the optic modes of a multimode optical fiber in order to produce a spatially substantially uniform image in a desired timeframe. This is done by passing the optic modes of the fiber through one or more waveplates that are rotating at a speed faster than the image capture in the desired timeframe. This has the effect of generating a spatial profile that is averaged, resulting in uniform smoothing of the image results and such uniform smoothing is comparable to obtaining a larger number of images and averaging them (para. 0139-0142; obtaining a second data set of a plurality of pixel intensities of a smoothed image of the probe on the solid support).
Regarding claim 3 line 15, the synthesis of a second sequence complementary to the target polynucleotide is performed using labeled nucleotides and the identity of one or more bases complementary to the labeled oligonucleotide are determined using the imaging system described above (para. 0010; generating base calls based on the field flattened image).
Regarding claim 3 lines 8-14, Banerjee et al. is silent to determining a field flattening intensity value for each of the plurality of pixels of the raw image based on the second data set; and generating a field flattened image of the probe on the solid support based on the field flattening intensity value for each of the plurality of pixels of the raw image, wherein a first correlation of pixel intensity of the plurality of pixels to their spatial location in the field flattened image is reduced in comparison to a second correlation of pixel intensity of the plurality of pixels to their spatial location in the raw image. However, these limitations were known in the art at the time of the effective filing date of the invention as taught by Model et al.
Pertaining to claim 3 lines 8-9, Model et al. teaches a method of correction of microscopic images for heterogeneity of illumination and detection within one single field (aka. shading or flat field correction), which is to divide the image of interest by the image of a uniform fluorescent sample. Model et al. teaches performing the classic flat field correction using this equation:
c
o
r
r
e
c
t
e
d
=
100
x
(
r
a
w
-
b
l
a
n
k
1
)
/
(
s
t
a
n
d
a
r
d
-
b
l
a
n
k
2
)
, wherein the standard image is produced by averaging several acquired images of the sample used as a standard;
b
l
a
n
k
1
is the mean gray level of the areas between the object and blank 2 is the image of a suitable blank sample and 100 is a scaling factor used so that the corrected images have the same average brightness as the corresponding raw image. Model et al. further discloses that in commonly used flat field correction formula, a variable multiplication factor is used so that the corrected images have the same average brightness as the corresponding raw images. In applying this technique to the method taught by Banerjee et al., retrospective flat field correction could be performed using the smoothed image in place of the standard image as both are averaged images and Model et al. recommends that a low pass filter image (i.e. a smoothed image) can be used in place of the standard, which has a similar averaging effect (p. 310, col. 1, para. 2-4; p. 311, col. 2, para. 1; p. 312, col. 2, para. 1; p. 314, col. 2, para. 1; determining a field flattening intensity value for each of the plurality of pixels of the raw image based on the second data set).
Pertaining to claim 3 lines 10-14, Model et al. discloses demonstrating that shading correction (i.e. flat field correction) reduced the correlation of fluorescence intensity with plate position with these details: A bead was imaged at five locations in an inhomogeneously illuminated field including dark locations and bright locations. Intensity of beads at the 5 positions were plotted as a function of their position. The results showed that shading correction using three different standards had reduced correlation of fluorescence with position compared to that of the raw image (Fig. 2; p. 312, col. 2, para. 2 – p. 313, col. 1, para. 1; generating a field flattened image of the probe on the solid support based on the field flattening intensity value for each of the plurality of pixels of the raw image, wherein a first correlation of pixel intensity of the plurality of pixels to their spatial location in the field flattened image is reduced in comparison to a second correlation of pixel intensity of the plurality of pixels to their spatial location in the raw image).
An invention would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Model et al. taught that applying flat field correction corrects for heterogeneity of illumination and detection within one single field (p. 310, col. 1, para. 2). Furthermore, Model et al. recommends that flat field correction can be used with a low pass filter image (such as the smoothed image of the instant application) as the standard (p. 314, col. 2, para. 1). Finally, Model et al. suggest this correction can be used in clinical analyses and laboratory practice (abstract). Therefore, one of ordinary skill in the art would have been motivated to utilize the flat field correction taught by Model et al. in the sequence by synthesis method taught by Banerjee et al. in order to correct for uneven illumination and detector response and to use the corrected data for base calling. Furthermore, one of ordinary skill in the art would predict that the flat field correction taught by Model et al. could be readily added to the system of Banerjee et al. with a reasonable expectation of success because, as disclosed by Banerjee et al., it is a classic correction method that can be used in any method that uses digital analysis of microscopy images (p. 310, col. 1, para. 2; p. 315, col. 2, para. 2). The invention is therefore prima facie obvious.
Regarding claim 5, Banerjee et al. discloses using several spectral filters including emission filters and bandwidth filters to detect four different fluorophores with overlapping wavelengths. For example, Banerjee et al. discloses that in some embodiments, a single laser excites two fluorophores, one with a narrow emission filter near the wavelength, and one with a wider band emission filter at longer wavelength in order to normalizes the relative intensities of the two dyes. Banerjee et al. further discloses that if the same bandwidth filters were used, the dye further from the laser wavelength would be much weaker. Both bandwidth filters and emission filters are spectral filters (para. 0147, 0154, 0070; the method of claim 3, wherein the detecting comprises use of a spectral filter).
Regarding claim 6, Model et al. teaches a method of correction of microscopic images for heterogeneity of illumination and detection within one single field (aka. shading or flat field correction), which is to divide the image of interest by the image of a uniform fluorescent sample. Model et al. taches performing the classic flat field correction using this equation:
c
o
r
r
e
c
t
e
d
=
100
x
(
r
a
w
-
b
l
a
n
k
1
)
/
(
s
t
a
n
d
a
r
d
-
b
l
a
n
k
2
)
, wherein the standard image is produced by averaging several acquired images of the sample used as a standard;
b
l
a
n
k
1
is the mean gray level of the areas between the object and blank 2 is the image of a suitable blank sample and 100 is a scaling factor used so that the corrected images have the same average brightness as the corresponding raw image. Banerjee et al. further discloses that in commonly used flat field correction formula, a variable multiplication factor is used so that the corrected images have the same average brightness as the corresponding raw images. In applying this technique to the method taught by Banerjee et al., retrospective flat field correction could be performed using the smoothed image in place of the standard image as both are averaged images and Model et al. recommends that a low pass filter can be used in place of the standard, which has a similar averaging effect. The terms 100, raw and standard of Model et al. are equivalent to the terms Mx0,y0 , Rx,y and Mx,y, in the instant application respectively (p. 310, col. 1, para. 2-4; p. 311, col. 2, para. 1; p. 312, col. 2, para. 1; p. 314, col. 2, para. The method of claim 3, wherein determining the field flattening intensity value for each of the plurality of pixels of the raw image based on the second data set comprises: using the equation:
F
x
,
y
=
R
x
,
y
M
x
0
,
y
0
M
x
,
y
,
where Fx,y is the field flattening intensity value of a pixel, Rx,y is the intensity of the pixel of the plurality of pixels in the raw image, Mx,y, is the intensity of the pixel of the plurality of pixels in the smoothed image, and Mx0,y0 is the intensity of a reference pixel in the smoothed image or a scaling factor of interest.
Pertaining to claim 9, Banerjee et al. discloses that the detection is done using sequence by synthesis with labeled nucleotides. Banerjee et al. further discloses that the labelled nucleotides can be fluorescently labeled triphosphates (para. 0010; the method of claim 3, wherein the probe is fluorescent).
Pertaining to claim 10, Banerjee et al. discloses that the invention relates to sequence analysis of nucleic acids such as short DNA sequences comprised of A, C, T and G (para. 0001, 0065; the method of claim 3, wherein the nucleotide comprises a base selected from Adenine (A), Guanine (G), Cytosine (C), Thymine (T), and Uracil (U)).
With respect to claim 11, Banerjee discloses that in some embodiments, the substrate can comprise a flowcell (flow cell) (para. 0009; the method of claim 3, wherein the solid support comprises a flow cell).
Pertaining to claim 12, Banerjee et al. discloses that the detection is done using sequence by synthesis with labeled nucleotides. Banerjee et al. further discloses that the labelled nucleotides can be fluorescently labeled triphosphates (para. 0010, 0064; the method of claim 3, wherein the method further comprises sequencing the nucleic acid sequence).
Regarding claim 13, Banerjee et al. discloses that the detection is done using sequence by synthesis with labeled nucleotides. Banerjee et al. further discloses that the labelled nucleotides can be fluorescently labeled triphosphates (para. 0010, 0064; the method of claim 12, wherein sequencing the nucleic acid sequence is performed by sequencing by synthesis).
Pertaining to claim 14, Banerjee discloses that the current invention utilizes sequencing-by- synthesis (SBS) wherein, four fluorescently labeled modified nucleotides are used to sequence dense clusters of amplified DNA present on the surface of a substrate (e.g., a flowcell) using a DNA polymerase to incorporate differently labeled nucleotides. Banerjee further discloses using a four-color DNA sequencing platform, wherein that the probes consist of four fluorescently labeled nucleotides that are differently labeled with using different colors (para. 0005, 0064-0065, 0240; the method of claim 12, wherein sequencing the nucleic acid sequence comprises using a polymerase to incorporate different nucleotides to the nucleic acid sequence, wherein each nucleotide is either a labeled or unlabeled nucleotide analog, and wherein each labeled nucleotide analog comprises a different probe corresponding to a different color).
Regarding claim 19 lines 2-5, Banerjee et al. discloses systems and devices for sequence by synthesis wherein polynucleotides are sequenced on beads attached to a planar solid substrate. Banerjee et al. further discloses doing this by incorporating fluorescent nucleotides to synthesize a sequence complementary to the polynucleotide of interest one base at a time, and detecting and recording the fluorescence emissions using a charge coupled device (CCD) or similar camera at each step to take a digital image containing a plurality of pixel intensities (Fig. 41A). Banerjee et al. further discloses that by this sequencing process, base calls are made (i.e. the identity of bases complementary to the labeled oligonucleotide are determined) and that the entire sequence of a target fragment is done by reading the chronological order of the bases (para. 0007-0012; 0063; Fig. 30; Fig. 32; Fig. 41A; a method for base calling of nucleotides during DNA sequencing, comprising: detecting a probe corresponding to a nucleotide in a nucleic acid sequence on a solid support to generate a raw image; obtaining a first data set of a plurality of pixel intensities of the raw image of the probe on the solid support).
Pertaining to claim 19 lines 8-9, Model et al. teaches a method of correction of microscopic images for heterogeneity of illumination and detection within one single field (aka. shading or flat field correction), which is to divide the image of interest by the image of a uniform fluorescent sample. Model et al. taches performing the classic flat field correction using this equation:
c
o
r
r
e
c
t
e
d
=
100
x
(
r
a
w
-
b
l
a
n
k
1
)
/
(
s
t
a
n
d
a
r
d
-
b
l
a
n
k
2
)
, wherein the standard image is produced by averaging several acquired images of the sample used as a standard;
b
l
a
n
k
1
is the mean gray level of the areas between the object and blank 2 is the image of a suitable blank sample and 100 is a scaling factor used so that the corrected images have the same average brightness as the corresponding raw image. Model et al. further discloses that in commonly used flat field correction formula, a variable multiplication factor is used so that the corrected images have the same average brightness as the corresponding raw images. In applying this technique to the method taught by Banerjee et al., retrospective flat field correction could be performed using the smoothed image in place of the standard image as both are averaged images and Model et al. recommends that a low pass filter image (i.e. a smoothed image) can be used in place of the standard, which has a similar averaging effect (p. 310, col. 1, para. 2-4; p. 311, col. 2, para. 1; p. 312, col. 2, para. 1; p. 314, col. 2, para. 1; determining a field flattening intensity value for each of the plurality of pixels of the raw image based on a smoothed image of the probe on the solid support).
Pertaining to claim 19 lines 10-14, Model et al. discloses demonstrating that shading correction (i.e. flat field correction) reduced the correlation of fluorescence intensity with plate position with these details: A bead was imaged at five locations in an inhomogeneously illuminated field including dark locations and bright locations. Intensity of beads at the 5 positions were plotted as a function of their position. The results showed that shading correction using three different standards had reduced correlation of fluorescence with position compared to that of the raw image (Fig. 2; p. 312, col. 2, para. 2 – p. 313, col. 1, para. 1; generating a field flattened image of the probe on the solid support based on the field flattening intensity value for each of the plurality of pixels of the raw image, wherein a first correlation of pixel intensity of the plurality of pixels to their spatial location in the field flattened image is reduced in comparison to a second correlation of pixel intensity of the plurality of pixels to their spatial location in the raw image).
Regarding claim 19 line 15, the synthesis of a second sequence complementary to the target polynucleotide is performed using labeled nucleotides and the identity of one or more bases complementary to the labeled oligonucleotide are determined using the imaging system described above (para. 0010; generating base calls based on the field flattened image).
The discussion of the limitations common to claim 3 is incorporated herein.
Regarding claim 20 lines 2-5, Banerjee et al. discloses systems and devices for sequence by synthesis wherein polynucleotides are sequenced on beads attached to a planar solid substrate. Banerjee et al. further discloses doing this by incorporating fluorescent nucleotides to synthesize a sequence complementary to the polynucleotide of interest one base at a time, and detecting and recording the fluorescence emissions using a charge coupled device (CCD) or similar camera at each step to take a digital image containing a plurality of pixel intensities (Fig. 41A). Banerjee et al. further discloses that by this sequencing process, base calls are made (i.e. the identity of bases complementary to the labeled oligonucleotide are determined) and that the entire sequence of a target fragment is done by reading the chronological order of the bases (para. 0007-0012; 0063; Fig. 30; Fig. 32; Fig. 41A; a method for base calling of nucleotides during DNA sequencing, comprising: detecting a probe corresponding to a nucleotide in a nucleic acid sequence on a solid support to generate a raw image; obtaining a first data set of a plurality of pixel intensities of the raw image of the probe on the solid support).
Regarding claim 20 lines 6-7, Model et al. teaches a method of correction of microscopic images for heterogeneity of illumination and detection within one single field (aka. shading or flat field correction), which is to divide the image of interest by the image of a uniform fluorescent sample. Model et al. taches performing the classic flat field correction using this equation:
c
o
r
r
e
c
t
e
d
=
100
x
(
r
a
w
-
b
l
a
n
k
1
)
/
(
s
t
a
n
d
a
r
d
-
b
l
a
n
k
2
)
, wherein the standard image is produced by averaging several acquired images of the sample used as a standard;
b
l
a
n
k
1
is the mean gray level of the areas between the object and blank 2 is the image of a suitable blank sample and 100 is a scaling factor used so that the corrected images have the same average brightness as the corresponding raw image. Model et al. further discloses that in commonly used flat field correction formula, a variable multiplication factor is used so that the corrected images have the same average brightness as the corresponding raw images. In applying this technique to the method taught by Banerjee et al., retrospective flat field correction could be performed using the smoothed image in place of the standard image as both are averaged images and Model et al. recommends that a low pass filter image (i.e. a smoothed image) can be used in place of the standard, which has a similar averaging effect. In this method the baseline intensity of the instant claim corresponds to the standard of the reference, which can be either the smoothed image or another averaged image as disclosed (p. 310, col. 1, para. 2-4; p. 311, col. 2, para. 1; p. 312, col. 2, para. 1; p. 314, col. 2, para. 1; determining a field flattening intensity value for each of the plurality of pixels of the raw image based on a baseline intensity at said pixel).
Pertaining to claim 20 lines 8-12, Model et al. discloses demonstrating that shading correction (i.e. flat field correction) reduced the correlation of fluorescence intensity with plate position with these details: A bead was imaged at five locations in an inhomogeneously illuminated field including dark locations and bright locations. Intensity of beads at the 5 positions were plotted as a function of their position. The results showed that shading correction using three different standards had reduced correlation of fluorescence with position compared to that of the raw image (Fig. 2; p. 312, col. 2, para. 2 – p. 313, col. 1, para. 1; generating a field flattened image of the probe on the solid support based on the field flattening intensity value for each of the plurality of pixels of the raw image, wherein a first correlation of pixel intensity of the plurality of pixels to their spatial location in the field flattened image is reduced in comparison to a second correlation of pixel intensity of the plurality of pixels to their spatial location in the raw image).
Regarding claim 20 line 13, the synthesis of a second sequence complementary to the target polynucleotide is performed using labeled nucleotides and the identity of one or more bases complementary to the labeled oligonucleotide are determined using the imaging system described above (para. 0010; generating base calls based on the field flattened image).
The discussion of the limitations common to claim 3 is incorporated herein.
8. Claim 4 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Banerjee et al. (WO2007123744A2, IDS 14 February 2004), in view of Model et al. (2001, Cytometry, Vol. 44, p. 309-316) as applied to claims 3, 5-6, 9-14 and 19 and 20 above, further in view of Frost et al. (US20030086608A1). The italicized text corresponds to the instant claim limitations.
The limitations of claims 3, 5-6, 9-14 and 19-20 are taught by Banerjee et al. and Model et al. above.
Regarding claim 4, Banerjee et al. disclose two image modifications that are used to smooth the image and gain a more spatially uniform illumination field including using a rotating wave plate as discussed above and using a diffuser, which also produces a more uniform illumination field (para. 0140-0142). However, Banerjee et al. and Model et al. are silent to: the method of claim 3, wherein the smoothed image of the probe on the solid support is generated using a low-pass filter. However, this limitation was known in the art at the time of the effective filing date of the invention as taught by Frost et al.
Regarding claim 4, Frost et al. teaches a computational method of processing image samples from a flow imaging instrument to segment objects from background. Frost et al. discloses a method of processing of the images that include objects of interest and background, that the image is segmented into a region of interest and a background region. In this method, the filtering operations employed for object detection include a low pass filtering operation. Frost et al. further teaches that the 2D low pass filter is applied to improve the signal-to noise ratio and that the low pass filter is applied on the premise that the object detection can rely on the spatial frequencies that define the general size and shape of the object and that the highest frequencies in the object, such as those representing fine texture and sharp breaks in the object boundaries, can be removed (abstract; para. 0004-0008; para. 0086; the method of claim 3, wherein the smoothed image of the probe on the solid support is generated using a low-pass filter.
An invention would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Frost et al. taught 2D low pass filter is applied to improve the signal-to noise ratio of images by removing the highest frequencies in the object representing fine texture and sharp breaks in the object boundaries (para. 0086). Therefore, one of ordinary skill in the art would have been motivated to utilize the low pass filter taught by Frost et al. in the sequence by synthesis method taught by Banerjee et al. in order to improve signal to noise in imaging. Furthermore, one of ordinary skill in the art would predict that the low pass filter taught by Frost et al. could be readily added to the system of Banerjee et al. with a reasonable expectation of success because both are directed to detecting and processing digital fluorescence images. The invention is therefore prima facie obvious.
9. Claims 7 and 8 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Banerjee et al. (WO2007123744A2, IDS 14 February 2004), in view of Model et al. (2001, Cytometry, Vol. 44, p. 309-316), as applied to claims 3, 5-6, 9-14 and 19-20 above, further in view of Izmailov et al. (Electrophoresis, 2002. Vol 23, p. 2720-2728, IDS 14 February, 2014). The italicized text corresponds to the instant claim limitations.
The limitations of claims 3, 5-6, 9-14 and 19-20 are taught by Banerjee et al. and Model et al. above.
Banerjee et al. and Model et al. are silent to: the method of claim 3, wherein the base calls contain fewer errors than base calls generated based on the raw image (claim 7); and the method of claim 7, wherein the errors are generated due to color cross-talk, dephasing, or a combination thereof (claim 8). However, these limitations were known in the art at the time of the effective filing date of the invention as taught by Izmailov et al.
Pertaining to claim 7, Izmailov et al. disclose that In the majority of multicolor automated DNA sequencers, the emission spectra of different fluorescent dyes display a significant amount of spectral overlap and above a certain level of relative intensity, lack of compensation for cross-talk may lead to
errors in base-calling. Izmailov et al. further discloses methods for cross-talk compensation exist using a cross-talk compensation matrix with coefficients (p. 2724, col. 1, para. 2; the method of claim 3, wherein the base calls contain fewer errors than base calls generated based on the raw image).
Pertaining to claim 8, Izmailov et al. disclose that In the majority of multicolor automated DNA sequencers, the emission spectra of different fluorescent dyes display a significant amount of spectral overlap and above a certain level of relative intensity, lack of compensation for cross-talk may lead to
errors in base-calling (p. 2724, col. 1, para. 2; the method of claim 7, wherein the errors are generated due to color cross-talk, dephasing, or a combination thereof).
An invention would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Izmailov et al. taught the light emitted by one fluorophore is simultaneously collected by several detection channels, dictating a
necessity for cross-talk compensation to prevent errors in base calling in sequencing electropherograms. Izmailov et al. further discloses the existence of cross-talk compensation matrices with coefficients that correct for cross-talk (p. 2724, col. 1, para. 2). Therefore, one of ordinary skill in the art would have understood that improvement to base calling by implementing cross talk correction would also apply to the solid-support sequence by synthesis method taught by Banerjee et al. and Model et al. Furthermore, one of ordinary skill in the art would predict that the relationship between base-call errors and cross-talk correction taught by Izmailov et al. could be readily added to the system of Banerjee et al. and Model et al. with a reasonable expectation of success because both are directed to detecting and processing a fluorescence readout from four color sequencing. The invention is therefore prima facie obvious.
10. Claims 15 and 17 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Banerjee et al. (WO2007123744A2, IDS 14 February 2004), in view of Model et al. (2001, Cytometry, Vol. 44, p. 309-316) as applied to claims 3, 5-6, 9-14 and 19-20, further in view of Kheterpal et al. (Electrophoresis, 1996, Vol. 17, 1852-1859). The italicized text corresponds to the instant claim limitations.
The limitations of claims 3, 5-6, 9-14 and 19-20 are taught by Banerjee et al. and Model et al. above.
Pertaining to claim 15, Banerjee et al. and Model et al. are silent to: the method of claim 14 further comprising correcting color cross-talk between the different probes corresponding to different colors (claim 15); and the method of claim 3, wherein generating the base calls based on the field flattened image comprises generating the base calls based on the field flattened image subsequent to the correcting color cross-talk between the different probes corresponding to different colors (claim 17). However, these limitations were known in the art at the time of the effective filing date of the invention as taught by Kheterpal et al.
Regarding claim 15, Kheterpal et al. teaches the design and operation of a four-color capillary array electrophoresis scanner for DNA sequencing, including collecting fluorescence data, generating four-color image files from the data, reducing the images to four-color line plots followed by base calling. Kheterpal et al. discloses that data processing includes low-pass Gaussian filtering to remove the noise, color separation to remove the cross-talk due to spectral overlap, mobility shift corrections from the use of different fluorophores, baseline subtraction, second and fourth derivative Fourier filtering to deconvolute overlapping peaks followed by Gaussian filtering of the output and finally the base calling. The steps of color separation and Fourier filtering are equivalent to correcting color cross-talked in the instant application (p. 1852, col. 2, para. 3; p. 1855, col. 2, para. 3; Table I; the method of claim 14 further comprising correcting color cross-talk between the different probes corresponding to different colors).
Regarding claim 17, Kheterpal et al. discloses that color separation to remove the cross-talk due to spectral overlap and second and fourth derivative Fourier filtering to deconvolute overlapping peaks are done before base calling (p. 4531, col. 2, para. 2; the method of claim 3, wherein generating the base calls based on the field flattened image comprises generating the base calls based on the field flattened image subsequent to the correcting color cross-talk between the different probes corresponding to different colors).
An invention would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Kheterpal et al. taught that their method using energy transfer primers and various steps of correction enables DNA sequencing with four colors with a single excitation wavelength, simplifying optical systems and dramatically improves fluorescence signal strengths (p. 1852, col. 2, para. 1-2). Therefore, one of ordinary skill in the art would have been motivated to utilize the cross-talk correction taught by Kheterpal et al. in the sequence by synthesis method taught by Banerjee et al. and Model et al. in order to simplify instrumentation and improve signal strength. Furthermore, one of ordinary skill in the art would predict that the cross-talk correction taught by Kheterpal et al. could be readily added to the system of Banerjee et al. and Model et al. with a reasonable expectation of success because both are directed to DNA sequencing with four fluorescence probes. The invention is therefore prima facie obvious.
Double patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
11. Claims 3-6, 910 and 12-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2 and 4 of patent US 9,879,309 B2.
Although the conflicting claims are not identical, they are not patentably distinct from each other as indicated below.
Claim 3 of the instant application is taught by claim 1 of the reference application as indicated below:
Claim 3 lines 2-3 are taught by claim 1 b)1) of the reference
Claim 3 lines 4-5 are taught by claim 1 b)2) of the reference
Claim 3 lines 6-7 (and claim 4) are taught by claim 1 b)4) of the reference
Claim 3 lines 8-9 are taught by claim 1 b)5) of the reference
Claim 3 lines 10-14 are taught by claim 1 b)6) of the reference
Claim 3 line 15 is taught by claim 1 f) of the reference
Claim 4 of the instant application is taught by claim 1 b)3) of the reference application
Claim 5 of the instant application is taught by claim 1 b)1) of the reference application
Claim 6 of the instant application is taught by claim 1 b)5) of the reference application
Claim 9 of the instant application is taught by claim 2 of the reference application
Claim 10 of the instant application is taught by claim 4 of the reference application (because the utilization of uracil in the instant application is optional)
Claim 12 of the instant application are taught by claim 1a of the reference application
Claim 13 of the instant application are taught by claim 1a of the reference application
Claim 14 of the instant application are taught by claim 1a of the reference application
Claim 15 of the instant application is taught by claim 1 c) of the reference
Claim 16 of the instant application is taught by claim 1 d) of the reference
Claim 17 of the instant application is taught by claim 1 e) and f) of the reference
Claim 18 of the instant application is taught by claim 1 e) and f) of the reference
Claim 19 of the instant application is taught by claim 1 of the reference application as indicated below:
Claim 19 lines 2-3 are taught by claim 1 b)1) of the reference
Claim 19 lines 4-5 are taught by claim 1 b)2) of the reference
Claim 19 lines 6-7 are taught by claim 1 b)5) of the reference
Claim 19 lines 8-12 are taught by claim 1 b)6) of the reference
Claim 19 line 13 is taught by claim 1 f) of the reference
Claim 20 of the instant application is taught by claim 1 of the reference application as indicated below:
Claim 20 lines 2-3 are taught by claim 1 b)1) of the reference
Claim 20 lines 4-5 are taught by claim 1 b)2) of the reference
Claim 20 lines 6-7 are taught by claim 1 b)5) and claim 16 of the reference
Claim 20 lines 8-12 are taught by claim 1 b)6) of the reference
Claim 20 line 13 is taught by claim 1 f) of the reference
This is a nonstatutory double patenting rejection.
12. Claims 3-6, 9-10, 12-13, 15 and 19-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 12, 14, 15 and 20 of patent US 8612161 B2
Although the conflicting claims are not identical, they are not patentably distinct from each other as indicated below.
Claim 3 of the instant application is taught by claims 1, 12, 14-15 and 20 of the reference application as indicated below:
Claim 3 lines 2-3 are taught by claim 1 a) and b) of the reference
Claim 3 lines 4-5 are taught by claim 14 a) of the reference
Claim 3 lines 6-7 are taught by claim 14 b) of the reference
Claim 3 lines 8-9 are taught by claim 14 c) of the reference
Claim 3 lines 10-14 are taught by claim 14 d) of the reference
Claim 3 line 15 is taught by claim 5 of the reference
Claim 4 of the instant application is taught by claim 14 b) of the reference application
Claim 5 of the instant application is taught by claim 14 a) of the reference application
Claim 6 of the instant application is taught by claim 15 of the reference application
Claim 9 of the instant application is taught by claim 1 a) of the reference application
Claim 10 of the instant application is taught by claim 12 of the reference application (because the utilization of uracil in the instant application is optional)
Claim 12 of the instant application are taught by claim 1a) of the reference application
Claim 13 of the instant application are taught by claim 1 a) of the reference application
Claim 15 of the instant application is taught by claim 20 of the reference
Claim 19 of the instant application is taught by claims 1 and 14 of the reference application as indicated below:
Claim 19 lines 2-3 are taught by claim 1 a) and b) of the reference
Claim 19 lines 4-5 are taught by claim 14 a) of the reference
Claim 19 lines 6-7 are taught by claim 14 c) and claim 15 of the reference
Claim 19 lines 8-12 are taught by claim 14 d) of the reference
Claim 19 line 13 is taught by claim 5 of the reference
Claim 20 of the instant application is taught by claims 1, 5 and 14 of the reference application as indicated below:
Claim 20 lines 2-3 are taught by claim 1 a) and b) of the reference
Claim 20 lines 4-5 are taught by claim 14 a) of the reference
Claim 20 lines 6-7 are taught by claim 14 c) and claim 15 of the reference
Claim 20 lines 8-12 are taught by claim 14 d) of the reference
Claim 20 line 13 is taught by claim 5 of the reference
This is a nonstatutory double patenting rejection.
Conclusion
13. No claims are allowed.
Claims 16 and 18 are free from the prior art. The claims are directed to the method of claim 3 further comprising correcting dephasing in multiple sequencing cycles (claim 16); and the method of claim 3, wherein generating the base calls based on the field flattened image comprises generating the base calls based on the field flattened image subsequent to the correcting dephasing in multiple sequencing cycles (claim 18), which pertain to correcting for molecules within a colony falling behind or jumping ahead during sequencing cycles. While there were algorithms used to correct dephasing (aka phasing or prephasing) in fields outside of DNA sequencing that were known in the art of ‘signal processing correction’ such as inter-symbol interferences (ISI) equations used in digital communications, it would not be obvious to a person having ordinary skill in the art at the time of the effective filing date to apply these algorithms to correct phasing in DNA sequencing.
Claims 3-20 were examined for subject matter eligibility under 35 U.S.C. 101 and were found to be eligible at Step 2A prong 2. Whereas claims 3, 19 and 20 claims recite concepts that equate to an abstract idea (both mathematical concepts and mental processes), they also recite additional elements that add meaningful limitations that transform the judicial exception into patent-eligible subject matter (see MPEP 106.05(e)). These additional elements are limitations directed to generating an output image from the nucleic acid sequencing method that has background noise from uneven illumination corrected, which would otherwise lead to spatial biases in the signal (specification p. 59 line 21 – p. 60 line 13). These limitations include ‘generating a field flattened image of the probe on the solid support based on the field flattening intensity value for each of the plurality of pixels of the raw image’ and ‘generating base calls based on the field flattened image’. Field flattening is a technique known to reduce noise from uneven illumination across an image that had not previously been applied to correct images in nucleic acid sequencing data. Therefore, these steps reduce noise in the sequencing data by generating field flattened images for base calling add meaningful limitations beyond generally linking the use of the judicial exception to a particular technological environment to transform the judicial exception into patent-eligible subject matter. Claims 4-18 are also considered to be eligible subject matter by virtue of their dependence on claim 3.
E-mail Communications Authorization
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/J.J.S./Examiner, Art Unit 1685
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685
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