DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/29/2026 has been entered.
Applicant’s arguments and amendments have been thoroughly reviewed and considered. Claims 16-32 remain withdrawn. Claim 12 has been canceled. Claims 1, 5-10, 13-15, and 33 are pending and are examined on the merits herein.
Response to Applicant’s Arguments and Amendments
Claims 1-3, 6, 10, 13-14, and 33 were rejected under 35 U.S.C. 103 as being unpatentable over Romanov et al. (US 2018/0111957 A1).
Claim 5 was rejected under 35 U.S.C. 103 as being unpatentable over Romanov et al. (US 2018/0111957 A1) in view of Bergren et al. (US 2017/0261313 A1).
Claim 7 was rejected under 35 U.S.C. 103 as being unpatentable over Romanov et al. (US 2018/0111957 A1) in view of Lopez et al. (US 2015/0316543 A1).
Claim 8 was rejected under 35 U.S.C. 103 as being unpatentable over Romanov et al. (US 2018/0111957 A1) in view of Liu et al. (Chem. Commun., 2018).
Claim 9 was rejected under 35 U.S.C. 103 as being unpatentable over Romanov et al. (US 2018/0111957 A1), hereby called Romanov 1, in view of Romanov et al. (CA 3,114,733 A1), hereby called Romanov 2.
Claim 12 was rejected under 35 U.S.C. 103 as being unpatentable over Romanov et al. (US 2018/0111957 A1), in view of Langlois et al. (US 2020/0080142 A1).
Claim 15 was rejected under 35 U.S.C. 103 as being unpatentable over Romanov et al. (US 2018/0111957 A1) in view of Sun et al. (US 2018/0258468 A1).
Applicant has amended instant claim 1 to incorporate the limitations of previously presented claim 12. Claim 12 was rejected over Romanov in view of Langlois. Applicant argues against this combination, particularly stating that Romanov teaches away from a two charge coupled device approach (Remarks, page 7). Applicant also argues that neither Romanov nor Langlois provide reason to modify Romanov in the manner claimed, particularly as the two references teach charge-coupled devices in different contexts, and thus altering Romanov as described in the action “changes the design architecture that Romanov I identifies as advantageous by suggesting that one of ordinary skill in the art would replace the simplified system from Romanov I with the more complicated system of Langlois,” (Remarks, pages 7-8 joining para.). Finally, Applicant states that the charge coupled device teachings of Romanov in view of Langlois do not utilize said device(s) in the manner presented in the instant specification or to the same effect (Remarks, page 8).
Regarding teaching away from a particular combination/teaching/limitation, MPEP 2145 X (D) 1 states, “"the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).” Applicant argues that Romanov teaches away from the claimed invention because the reference generally teaches the use of long stokes shift dyes in para. 10 and teaches an exemplary embodiment in para. 53 where a detection system may have a single detection channel. These teachings do not encompass the entirety of the scope of the reference, nor do these teachings specifically discredit or disparage the use of multiple detection channels. This is particularly true in view of the fact that Romanov teaches two or more distinct emission spectra (para. 46).
Thus, this argument is not considered persuasive.
Regarding motivation for combining Romanov and Langlois, it is noted that Romanov already teaches the use of charge-coupled devices (see para. 93, “each incorporated nucleotide can be “read” optically by suitable means, such as a charge-coupled device using laser excitation and suitable emission filters.”). Langlois specifically teaches an optics system for capturing fluorescence involving charge-coupled device detectors, and teaches that multiple detectors can each detect particular wavelengths (see para. 53 of the Final Rejection). Also, Romanov already makes obvious the use of nucleotides with three labels, where the first and third label have the same excitation wavelength and the second and third label have the same detection wavelength (see para. 26 of the Non-Final Rejection). In combining the references, para. 54 of the Final Rejection states, “Langlois teaches that the use of two detection wavelength can provide faster imaging and allow for simultaneous detection, which would cut down on sequencing time, making for an overall more efficient process and motivating the ordinary artisan. There would be a reasonable expectation of success because Romanov already teaches that charge-coupled detection devices can be used in their methods, and the charge-coupled devices of Langlois are used in a similar context and have the same function as those of Romanov.” This provides a motivation and a reasonable expectation of success.
Applicant uses para. 25 of Langlois to argue that the reference is drawn to splitting fluorescent emission with a dichroic and using different filters to detect two wavelength simultaneously or close in time. While it is true that a dichroic is taught in para. 25, which also teaches the use of two detectors, the ordinary artisan would be capable of reading the teaching, “The optics system 102 can include two detectors, a first detector coupled with a first filter for detecting fluorescent emissions at a first wavelength and a second detector coupled with a second filter for detecting fluorescent emissions at a second wavelength,” to determine that two detectors can generally be used in an optics system to detect two different emissions wavelengths. This, combined with the teaching in para. 23 that a detector can be a charge-coupled device, would also lead the ordinary artisan to the conclusion that two charge-coupled devices can be used as two detectors to detect two emission wavelengths. In combining these teachings with those of Romanov, the Final Rejection suggests “it would have been prima facie obvious for one of the ordinary skill in the art to use the teachings of Langlois in the method of Romanov, and specifically, to provide two charge-coupled devices to detect the first and second detection wavelengths.” It is not suggested that a dichroic system be used in Romanov, and as Romanov already teaches charge-coupled devices can be used (particularly during sequencing, see para. 93), the incorporation of such a device in Romanov in view of Langlois is not considered to change the detection architecture of Romanov.
MPEP 2141.03 I states, “A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396.” It is the Examiner’s position that the ordinary artisan, with ordinary skill, knowledge, and creativity in the art, would be capable of using charge-coupled devices as described in Langlois as optical detectors in the teachings of Romanov described in the previous rejection of claim 1, as Langlois simply provides additional details regarding optical detector methods that Romanov already alludes to using during sequencing.
Thus, these arguments are not considered persuasive.
As to the charge-coupled devices of the instant invention being used in a manner that is different than is taught in the reference, Applicant points to Figure 3 of the instant specification, and notes that this figure shows improved signal-to-noise ratios. Para. 109 of the instant specification describes this figure, and mostly focuses on the particular dyes used for nucleotides during sequencing. It is not clear how this figure relates to the use of charge-coupled devices specifically. It is also not clear that any improvements shown in the figure are particularly superior or unexpected. Applicant states that the “The specification expressly describes embodiments in which "the first detection wavelength is imaged by a first charge coupled device, and the second detection wavelength is imaged by a second charge coupled device." Specification at [0111]. The disclosed sequencing method also ties the claimed 2-wavelength detection scheme to the sequencing process, including detection of fluorescent emissions at the second detection wavelength from a long Stokes shift fluorescent dye. Specification at [0114],” (Remarks, page 3, para. 2). This very method is what is taught by Romanov in view of Langlois, where a long Stokes shift dye is used, and where two total excitation wavelengths and two total detection wavelengths are used. As long as the detection wavelengths of the dyes used are known, then there is no reason why these wavelengths could not be detected in Romanov in view of Langlois. The fact that Romanov in view of Langlois does not teach that such a method would provide reduced signal-to-noise ratios during sequencing is not pertinent to the obviousness rejection.
MPEP 2145 II states, “"The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985),” and MPEP 2144 IV states, “It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006).” Thus, even though Romanov in view of Langlois does not teach elements related to signal-to-noise measurements, because this combination generally teaches a motivation and reasonable expectation of success, the obviousness rejection is considered proper.
Thus, this argument is not considered persuasive.
Thus, overall, Applicant’s arguments were not considered persuasive to obviate the use of Romanov and Romanov in view of Langlois. The relevant portions of the rejections presented in the Final Rejection mailed 3/2/2026 are reiterated below. Because of Applicant’s amendments to the claims, all of the previously set forth 35 USC 103 Rejections have been withdrawn for all currently pending claims, but see new grounds of rejection below. Claim 12 has been canceled, and so this rejection has been rendered moot.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 112(a) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/325,057, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Specifically, this application does not describe any of the dyes recited in instant claims 9-10. Therefore, these claims will receive an effective filing date that is the filing date of the instant application, 3/27/2023.
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention 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 35 U.S.C. 103 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 the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 6, 10, 13-14, and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Romanov et al. (US 2018/0111957 A1) in view of Langlois et al. (US 2020/0080142 A1).
Romanov teaches fluorescent labels for nucleotides with applications for sequencing (Abstract). Their methods can be used to sequence template polynucleotides on clustered arrays utilizing modified nucleotides labeled with dye compounds (paras. 100-101). The excitation wavelength of any two dyes may be different from one another (paras. 47 and 110). The emission wavelengths for any two labels can also be different (para. 46). Romanov teaches that more than two labels can be used (para. 46). Three nucleotides can each be labeled with a unique fluorescent dye compounds, while the fourth dye can remain dark (para. 110). The A, T, G, and C dNTPs can use this unique labeling method during sequencing, where excitation may occur and then emission spectra are detected (paras. 92-93). The labels can include a dye that contains a Stokes shift, and particularly dyes with a long Stokes shift (paras. 48 and 50). The Stokes shift dyes of Romanov have shifts greater than 50 nm, overlapping with the range described in instant claim 6. Thus, it would be prima facie obvious to have the first, second, and third nucleotides contain single fluorescent labels, where the third label is a long Stokes shift dye. This would allow the first and third labels to be excited at the same wavelength but be detected at different wavelengths (e.g. para. 10). The second and third labels could then be designed to have the same detection wavelengths, as this would limit the number of detection channels needed in the sequencing method/device overall, and would still allow discrimination of the three labels from one another, as the overall optical spectra would be different for each label (i.e. each label would have a distinct overall curve shape in a graph as shown in Figure 1 and explained in para. 118). Taking this dye construction together with the sequencing described above would lead to the general method described by instant claim 1. This design and method would cut down on the components needed in the device, which would decrease cost and improve efficiency.
However, though Romanov teaches charge-coupled devices generally for detecting fluorescent signals (para. 93), the reference does not teach that the first and second detection wavelengths may be detected with separate charge-coupled devices.
Langlois teaches sequencing methods involving light sources and detectors (Abstract). The sequencing methods can include an optics system for capturing fluorescent images (e.g. para. 21). The optics system can include a detector, such as a charge-coupled device sensor (para. 23). The optics system can also include two detectors, where each detector operates at a particular wavelength (para. 25). This can allow simultaneous detection of two wavelengths, which can speed up the imaging process (para. 25).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the teachings of Langlois in the method of Romanov, and specifically, to provide two charge-coupled devices to detect the first and second detection wavelengths of Romanov. Langlois teaches that two detectors can be used in optical systems, and that detectors may be charge-coupled devices. The teachings of Romanov described above involve sequencing methods with the use of two emission wavelengths, both of which need to be distinctly detected for sequencing accuracy, and the reference specifically notes that charge-coupled devices can be used to read fluorescent signals. Thus, Langlois provides context that would indicate to the ordinary artisan that two charge-coupled detectors could be used in the sequencing methods of Romanov described above. Langlois teaches that the use of two detection wavelengths can provide faster imaging and allow for simultaneous detection, which would cut down on sequencing time, making for an overall more efficient process and motivating the ordinary artisan. There would be a reasonable expectation of success because Romanov already teaches that charge-coupled detection devices can be used in their methods, and the charge-coupled devices of Langlois are used in a similar context and have the same function as those of Romanov.
Thus, claims 1 and 6 are prima facie obvious over Romanov in view of Langlois.
Regarding claim 10, Romanov teaches the use of NR550S0 as a dye (paras. 118-119 and Figures 1-2), along with teaching the structure of the molecule between paras. 139 and 140. It is also shown as being compared with other dyes, where emission spectra can be distinguished between it and NR5201s (Figures 1 and 2). It would be prima facie obvious to use a dye described and used by Romanov in the invention of Romanov in view of Langlois, particularly if its fluorescent spectra is not identical to a similar dye such as NR5201s. As noted above, the method of Romanov in view of Langlois used in the rejection of claim 1 utilizes three different dyes for the first three labeled nucleotides. There are not particular requirements for the first two dyes in the method of Romanov, so long as they are distinguishable from one another. The ordinary artisan would thus recognize that NR550S0 could operate as the first or second nucleotide label in the method of Romanov in view of Langlois described above, with no change to the overall method other than the choosing of other dyes meeting the requirements of instant claim 1. As Romanov teaches many types of dyes (e.g. paras. 12-16), this would be possible for the ordinary artisan, and so it would be prima facie obvious to include NR550S0 as the first or second nucleotide label.
Thus, claim 10 is prima facie obvious over Romanov in view of Langlois.
Regarding claim 13, Romanov notes that for sequencing-by-synthesis methods that may be used with the dyes of the invention, nucleotides may be added sequentially to the strand complementary to the template nucleic acid being sequenced (para. 91). In the embodiment of Romanov described in the rejection of claim 1 over Romanov in view of Langlois above, the first and third labels are excited at the same wavelength but detected at different wavelengths. When combining this teaching with sequencing-by-synthesis methods, it would still be prima facie obvious to add each nucleotide sequentially and separately, thereby meeting the limitations of instant claim 13. This would ensure that sequencing data is as accurate as possible, and that only a single type of nucleotide is incorporated into the complementary strands at one time. If multiple nucleotides are added to the array at once, multiple nucleotides may be incorporated into a single strand at the same time, which could lead to missed base incorporations within the sequencing data.
Thus, claim 13 is prima facie obvious over Romanov in view of Langlois.
Regarding claim 14, Romanov teaches that when using Stokes shift dyes, a single excitation wavelength can be used with a range of detection wavelength measurements, so as to pick up emission wavelengths from two dyes (para. 10). The reference also discusses being able to tell different dyes apart through optical distinguishing (paras. 47 , 110, and 119). Because in the embodiment of Romanov described in the rejection of claim 1 over Romanov in view of Langlois above, the first and third labels are excited at the same wavelength but detected at different wavelengths, it would be prima facie obvious to detect these signals simultaneously on the clustered array. This would mean that two labeled nucleotides can be used for sequencing simultaneously, but could still be distinguished from one another in the optical data due to Stokes shifts. By taking advantage of these detection properties, sequencing of multiple different clusters of sequences could occur faster, as not every nucleotide would need to be introduced to the array individually. There would be a reasonable expectation of success as this would not change the sequencing analysis, it would just alter the way the nucleotides are introduced to the array.
Thus, claim 14 is prima facie obvious over Romanov in view of Langlois.
Regarding claim 33, in the teachings of Romanov in view of Langlois described above in the rejection of claim 1, three different fluorescent dyes are used, where the third dye is a long Stokes shift dye. This third dye has the same emission wavelength as the second dye, while the first dye has its own emission wavelength. This three-dye method is capable of use in sequencing with a fourth unlabeled nucleotide. Romanov teaches that when two dyes have the same emission wavelength, they may be detected with the same emission channel during sequencing, which cuts down on the complexity of the sequencing device as less emission filters are needed (paras. 10-11 and 53). Para. 142 of the reference notes that traditional sequencing platforms may use four detection channels. Thus, given the teachings of Romanov described above, it would be prima facie obvious that the device required to perform sequencing with the three different fluorescent dyes described above in Romanov in view of Langlois would require two detection channels – one for the first dye and one for the second and third dye, based on their emission wavelengths. The unlabeled nucleotide would not require a detection channel. This would still cut down on the traditional number of detection channels needed for sequencing from four to two, thus allowing for a less complex device to be used, which may lower sequencing error and noise. This setup would also allow the dyes to still function as intended, thus maintaining the benefits of the use of the dyes described above in the rejection of claim 1. As Romanov teaches such detection channels, and that the use of multiple detection channels is already known in the art, there would be a reasonable expectation of success in utilizing such a sequencing device.
Thus, claim 33 is prima facie obvious over Romanov in view of Langlois.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Romanov et al. (US 2018/0111957 A1), in view of Langlois et al. (US 2020/0080142 A1), and further in view of Bergren et al. (US 2017/0261313 A1).
Romanov in view of Langlois teaches the methods of claims 1, 6, 10, 13-14, and 33, as described above. Though Romanov does provide many teachings about long Stokes shift dyes, it does not specify that the long Stokes shift dye may have a shift ranging from about 300 meV to 850 meV.
Bergren teaches a fluorescent liquid penetrant (Abstract). Specifically, the liquid can contain fluorophores that have a Stokes shift of more than 300 meV or more than 400 meV (para. 73).
MPEP 2144.05 I states, “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)… Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).” Applicant has not provided evidence that the energy range recited in claim 5 is critical, as the instant specification simply mentions the same limitation as the instant claim (para. 118). In light of the teachings of Romanov, which recite long Stokes shift dyes and Bergren, which recite said dyes with a shift in the claimed range, the energy range recited in claim 5 is considered routine optimization, and the specific claimed parameters are not viewed as inventive.
Thus, claim 5 is prima facie obvious over Romanov, in view of Langlois, and further in view of Bergren.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Romanov et al. (US 2018/0111957 A1), in view of Langlois et al. (US 2020/0080142 A1), and further in view of Lopez et al. (US 2015/0316543 A1).
Romanov in view of Langlois teaches the methods of claims 1, 6, 10, 13-14, and 33, as described above. Though Romanov does provide many teachings about long Stokes shift dyes, it does not specify that the long Stokes shift dye may be excited at about 300 nm. It is noted that Langlois also provides information about long Stokes shift dyes (e.g. paras. 17 and 35), but also does not state that long Stokes shift dye may be excited at about 300 nm.
Lopez teaches luminescent complexes for detection of compounds (Abstract). The reference teaches that it is possible to have a long Stokes shift dye that is excited at 300 nm, where the emission wavelength is 600 nm and the Stokes shift is 300 nm (para. 83).
Romanov teaches that with long Stokes shift dyes, detection emissions may be between 550-570 nm (para. 10), and that Stokes shifts may be greater than 150 nm (para. 42) Thus, prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to substitute a long Stokes shift dye such as the one described by Lopez for the third labeled nucleotide in the invention of Romanov in view of Langlois, as said dye would overlap with the teachings of long Stokes shift dyes of Romanov. MPEP 2143 I (B) states, “The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.” The teachings of Lopez would provide the ordinary artisan with evidence that such a long Stokes shift dye could be obtained and used for fluorescence detection, and as fluorescence dyes are well known in the art, as evidenced by Lopez, Langlois, and Romanov, the results of using such dyes would be predictable.
Thus, claim 7 is prima facie obvious over Romanov, in view of Langlois, and further in view of Lopez.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Romanov et al. (US 2018/0111957 A1), in view of Langlois et al. (US 2020/0080142 A1), and further in view of Liu et al. (Chem. Commun., 2018).
Romanov in view of Langlois teaches the methods of claims 1, 6, 10, 13-14, and 33, as described above. However, neither reference teaches the use of a chromenoquinoline dye.
Liu teaches the use of chromenoquinoline dyes for staining cellular components (Abstract). Depending on the specific dye used, a variety of fluorescence spectra can be obtained (Figure 2). Particular chromenoquinoline dyes also showed large Stokes shifts, which are taught to be beneficial for fluorescent microscopy (page 1510, column 1, para. 3). Generally, Liu teaches that these dyes can have “relatively high quantum yields, large absorption extinction coefficients, large Stokes shifts and good water solubility,” (page 1511, column 2, para. 4).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to substitute a chromenoquinoline dye into the method of Romanov in view of Langlois as the third labeled nucleotide, as this nucleotide is already described as a long Stokes shift dye. MPEP 2143 I (B) states, “The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.” Chromenoquinoline dyes are known and can be used in fluorescent detection methods, as evidenced by Liu, and as their emission spectra are known, it would be possible to use them in sequencing methods. Utilizing this dye in Romanov in view of Langlois, which already teaches the use of long Stokes shift dyes, would produce similar results to the methods of Romanov in view of Langlois alone, as the chromenoquinoline would be capable of detection and discrimination from other dyes. As noted above, the method of Romanov used in the rejection of claim 1 over Romanov in view of Langlois above utilizes three different dyes for the first three labeled nucleotides, where the third dye is a long Stokes shift dye. There are no other particular requirements for the three dyes, so long as they are distinguishable from one another. The ordinary artisan would thus recognize that a chromenoquinoline dye could operate as the third nucleotide label with no change to the overall method other than the choosing of other dyes that meet the requirements of instant claim 1. As Romanov teaches many types of dyes (e.g. paras. 12-16), this would be possible for the ordinary artisan, and so it would be prima facie obvious to use a chromenoquinoline dye as the third nucleotide label.
Thus, claim 8 is prima facie obvious over Romanov, in view of Langlois, and further in view of Liu.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Romanov et al. (US 2018/0111957 A1), hereby called Romanov 1, in view of Langlois et al. (US 2020/0080142 A1), and further in view of Romanov et al. (CA 3,114,733 A1), hereby called Romanov 2.
Romanov 1 in view of Langlois teaches the methods of claims 1, 6, 10, 13-14, and 33, as described above. However, neither reference teaches the use of NR455BoC as a dye or label.
Romanov 2 teaches detection of fluorescent dyes in the context of labeled nucleotides (Abstract). The reference teaches the use of NR455BoC in exemplary dye sets (see the table at the top of page 108), teaches the structure of an NR455BoC dye (see the figure before the table of page 108), and shows the successful detection of this dye in Figures 9-11 and 13. Particularly, it is noted that NR455BoC can be used in sequencing methods that detect all four nucleotides, can be used in multiplex imaging methods (paras. 18-19 and 21), and can be used in methods where a fourth nucleotide is unlabeled (para. 334).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to substitute NR455BoC into the method of Romanov 1 in view of Langlois as one of the first two labeled nucleotides. MPEP 2143 I (B) states, “The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.” NR455BoC is a known dye for use in nucleotide fluorescent detection methods, as evidenced by Romanov 2, and its use in sequencing methods to produce detectable and categorizable emission spectra is known. Utilizing this dye in Romanov 1 in view of Langlois would produce the similar results to the methods of Romanov 1 in view of Langlois alone, as the methods of Romanov 1 and Romanov 2 are very similar. As noted above, the method of Romanov 1 used in the rejection of claim 1 over Romanov 1 in view of Langlois above utilizes three different dyes for the first three labeled nucleotides. There are no particular requirements for the first two dyes, so long as they are distinguishable from one another. The ordinary artisan would thus recognize that NR455BoC could operate as either the first or second nucleotide label with no change to the overall method other than the choosing of other dyes the meet the requirements of instant claim 1. As Romanov 1 teaches many types of dyes (e.g. paras. 12-16), this would be possible for the ordinary artisan, and so it would be prima facie obvious to use NR455BoC as either the first or second nucleotide label.
Thus, claim 9 is prima facie obvious over Romanov 1, in view of Langlois, and further in view of Romanov 2.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Romanov et al. (US 2018/0111957 A1), in view of Langlois et al. (US 2020/0080142 A1), and further in view of Sun et al. (US 2018/0258468 A1).
Romanov in view of Langlois teaches the methods of claims 1, 6, 10, 13-14, and 33, as described above. However, neither reference teaches the use of a time delay imaging system for detecting the nucleotide labels.
Sun teaches imaging systems associated with samples (Abstract). Specifically, the reference teaches imaging systems in relation to sequencing, and teaches optical sequencers that incorporate time delay integration to detect fluorescence emissions from a sample flowcell (paras. 2-3). Such an imaging system can be used with light beams hitting a sample, where said sample can be on a an array (para. 6-9 and 69). This type of imaging can enable high throughput scanning of fluorescence emissions (para. 3).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to utilize the time delay integration taught by Sun in the method of Romanov in view of Langlois to detect the labeled nucleotides. Romanov teaches the use of arrays and light excitation sources (e.g. paras. 46 and 100-101), and also notes sequencing methods (Abstract), similar to the teachings of Sun. Romanov teaches that the particular base added to a sequence can be determined in an imaging step (para. 91), and generally teaches imaging devices (para. 102), but does not provide specifics on the structure or use of these devices. Given that Romanov in view of Langlois already utilizes charge coupled devices for detecting, it would be prima facie obvious that the time delay integration of Sun could be combined with these devices for the imaging methods of Romanov in view of Langlois. MPEP 2143 I (A) states, “The rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art.” Charge coupled devices are focused on sending electrical signals from emitted light based on wavelength, while the time delay integration sensor sends signals based on molecule movement. Combined, these techniques would provide additional signal information for each nucleotide, and could thus be used to more accurately determine sequence information. As both techniques are focused on different aspects of signal generation, their use together would not interfere with one another. The use of time delay integration was known, as evidenced by Sun, and could be successfully and predictably used in sequencing methods to detect fluorescent emissions, providing evidence of predictable results in the method of Romanov in view of Langlois.
Thus, claim 15 is prima facie obvious over Romanov, in view of Langlois, and further in view of Sun.
Conclusion
No claims are currently allowable.
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/F.F.G./Examiner, Art Unit 1681
/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681
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