FINAL ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Amendments and Status of the Claims
2. This action is in response to papers filed 17 March 2026 in which the specification and claims 7, 19, and 25 were amended, no claims were canceled, and no new claims were added. All of the amendments have been thoroughly reviewed and entered.
Any previous rejections not reiterated below are withdrawn in view of the amendments.
Applicant’s arguments have been thoroughly reviewed and are addressed following the new rejections necessitated by the amendments.
3. Claims 1-10 and 17-27 are under prosecution.
Information Disclosure Statement
4. The Information Disclosure Statement filed 16 March 2026 is acknowledged and has been considered.
Claim Rejections - 35 USC § 103
5. 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.
6. 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.
7. Claims 1-5, 17, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Ness et al. (U.S. Patent Application Publication No. US 2012/0194805 A1, published 2 August 2012) and Colston et al. (U.S. Patent Application Publication No. US 2010/0173394 A1, published 8 July 2010).
Regarding claims 1-3, Ness et al. teach methods comprising forming at least one million partitions, in the form of four million droplets, each including nucleic acids therein (paragraph 0004), performing single copy nucleic acid amplification therein (paragraph 0005) wherein the PCR amplification reagents are the claimed processing materials, and wherein a plurality of (i.e., multiple) nucleic acid targets are measured using different distinguishable fluorophores for teach target (paragraph 0006).
Ness et al. further teach using a detection subsystem (i.e., detector) for multicolor detection (paragraph 0025), comprising multiple detection units 552 each providing and detecting different wavelengths of light and each having collection optics and a detector (paragraphs 0129-0131 and Figures 14-16). Ness et al. also teach multiple filters (paragraph 0055), each of which is on a dedicated branch of an optical path, and that at least one filter (which encompasses two filters) is coupled to a detector (paragraph 0078). Thus, four detectors 552 (e.g., as shown in Figure 16) would comprise two filters each on a dedicated branch of an optical path, resulting in a total of 8 optical paths (i.e., claims 1-2). Ness et al. further teach identifying the target molecules by detecting their presence using a distinguishable fluorophore that identifies the droplet (paragraph 0006), and that the methods have the added advantage of allowing discrete study of nucleic acids in a massively high throughput manner (paragraph 0003). Thus, Ness et al. teach the known techniques discussed above.
Ness et al. do not teach each optical path is an optical channel.
However, Colston et al. teach methods comprising obtaining a sample comprising a plurality of nucleic acids (paragraph 0013), generating at least 1 million partitions, in the form of hundreds of millions of droplets (paragraph 0856), wherein each droplet comprises a single copy of a nucleic acid and amplification materials, in the form of digital PCR reagents, followed by amplification (paragraphs 0138-0139 and 0170) and generating counts by detecting signals from the plurality of partitions (paragraph 0856). Colston et al. teach detection of at least 25 targets (i.e., claims 1-3; paragraph 1148), and identifying droplets (paragraph 0179) and the nucleic acids therein (paragraph 1145). Colston et al. also teach obtaining the (fluorescent) signals from the droplets via optical paths (paragraph 0845), and that the emitted signals are detected independently of one another in different detection channels (paragraph 1089), which has the added advantage of allowing normalization of the data (paragraph 1093). Thus, Colston et al. teach the known techniques discussed above.
In addition, it is noted that the courts have held that mere duplication of parts has no patentable significance unless a new and unexpected result is produced (In re Harza, 274 F.2d 669, 124 USPQ 378 (CCPA 1960). See MPEP 2144.04 VI.B.
The courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists (see 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); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985) (see MPEP 2144.05.01).
The courts have further found that “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05 II.
Therefore, the claimed numbers of channels, filters, and targets merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
MPEP 716.01(c) makes clear that “[t]he arguments of counsel cannot take the place of evidence in the record” (In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965)). Thus, counsel’s mere arguments cannot take the place of evidence in the record.
It would therefore have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Ness et al. and Colston et al. to arrive at the instantly claimed methods with a reasonable expectation of success. The ordinary artisan would have been motivated to make the combination because said combination would have resulted in methods having the added advantages allowing discrete study of nucleic acids in a massively high throughput manner as explicitly taught by Ness et al. (paragraph 0003) and allowing normalization of the data as explicitly taught by Colston et al. (paragraph 1093). In addition, it would have been obvious to the ordinary artisan that the known techniques of the cited prior art could have been combined with predictable results because the known techniques of the cited prior art predictably result in reliable detection of nucleic acids.
Regarding claim 4, the method of clam 1 is discussed above. Colston et al. teach the droplets are provided in wells (paragraph 0208).
Regarding claim 5, the method of clam 1 is discussed above. Colston et al. teach the droplets are provided in a vessel (paragraph 0203).
Regarding claim 17, Ness et al. teach methods comprising forming at least 200,000 partitions, in the form of four million droplets, each including nucleic acids therein (paragraph 0004), performing single copy nucleic acid amplification therein (paragraph 0005) wherein the PCR amplification reagents are the claimed processing materials, and wherein a plurality of (i.e., multiple) nucleic acid targets are measured using different distinguishable fluorophores for teach target (paragraph 0006).
Ness et al. further teach using a detection subsystem (i.e., detector) for multicolor detection (paragraph 0025), comprising multiple detection units 552 each providing and detecting different wavelengths of light and each having collection optics and a detector (paragraphs 0129-0131 and Figures 14-16). Ness et al. also teach multiple filters (paragraph 0055), each of which is on a dedicated branch of an optical path, and that at least one filter (which encompasses two filters) is coupled to a detector (paragraph 0078). Thus, the four detectors 552 (e.g., as shown in Figure 16) would comprise two filters each on a dedicated branch of an optical path, resulting in a total of 8 optical paths each with its own filter. Ness et al. further teach identifying the target molecules by detecting their presence using a distinguishable fluorophore that identifies the droplet (paragraph 0006), and that the methods have the added advantage of allowing discrete study of nucleic acids in a massively high throughput manner (paragraph 0003). Thus, Ness et al. teach the known techniques discussed above.
Ness et al. do not teach each optical path is an optical channel.
However, Colston et al. teach methods comprising obtaining a sample comprising a plurality of nucleic acids (paragraph 0013), generating at least 200,000 partitions, in the form of hundreds of millions of droplets (paragraph 0856), wherein each droplet comprises a single copy of a nucleic acid and amplification materials, in the form of digital PCR reagents, followed by amplification (paragraphs 0138-0139 and 0170) and generating counts by detecting signals from the plurality of partitions (paragraph 0856). Colston et al. teach detection of at least 25 targets (paragraph 1148), thus exceeding the number of channels of Ness et al., and identifying droplets (paragraph 0179) and the nucleic acids therein (paragraph 1145).Colston et al. also teach obtaining the (fluorescent) signals from the droplets via optical paths (paragraph 0845), and that the emitted signals are detected independently of one another in different detection channels (paragraph 1089), which has the added advantage of allowing normalization of the data (paragraph 1093). Thus, Colston et al. teach the known techniques discussed above.
In addition, it is reiterated that the courts have held that:
Mere duplication of parts has no patentable significance unless a new and unexpected result is produced;
Where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists; and
Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Therefore, the claimed numbers of channels, filters, and targets merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
Applicant is again cautioned to avoid merely relying upon counsel’s arguments in place of evidence in the record, and that the Response above should not be construed as an invitation to file an after final declaration.
It would therefore have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Ness et al. and Colston et al. to arrive at the instantly claimed method with a reasonable expectation of success. The ordinary artisan would have been motivated to make the combination because said combination would have resulted in a method having the added advantages allowing discrete study of nucleic acids in a massively high throughput manner as explicitly taught by Ness et al. (paragraph 0003) and allowing normalization of the data as explicitly taught by Colston et al. (paragraph 1093). In addition, it would have been obvious to the ordinary artisan that the known techniques of the cited prior art could have been combined with predictable results because the known techniques of the cited prior art predictably result in reliable detection of nucleic acids.
Regarding claim 20, the method of claim 17 is discussed above. Ness et al. teach normalizing data from pairs of dyes (paragraph 0064). Colston et al. teach processing the signals against a set of pre-determined signal combinations to identify the target molecules; namely, values of one or more signals are transformed by subtracting baseline values (paragraph 1036-1037). Thus, subtracting baselines for the pairs of signal combinations would have been obvious.
8. Claims 6 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Ness et al. (U.S. Patent Application Publication No. US 2012/0194805 A1, published 2 August 2012) and Colston et al. (U.S. Patent Application Publication No. US 2010/0173394 A1, published 8 July 2010) as applied to claims 1 and 17 above, and further in view of Gordon et al. (U.S. Patent Application Publication No. US 2010/0323350 A1, published 23 December 2010).
Regarding claims 6 and 18, the methods of claims 1 and 17 are discussed above in Section 7.
While Ness et al. teach detection of two or more colors (paragraph 0006), and Colston et al. teach four-color detection (paragraph 1089), neither Ness et al. nor Colston et al. teach the specifically claimed color channels.
However, Gordon et al. teach methods wherein four-color detection systems having one channel for each of blue, green, red and yellow is provided (paragraph 0427), which has the added advantage of allowing base calling for nucleic acid sequences (paragraph 0424). Thus, Gordon et al. teach the known techniques discussed above.
It would therefore have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Gordon et al. with Ness et al. and Colston et al. to arrive at the instantly claimed methods with a reasonable expectation of success. The ordinary artisan would have been motivated to make the combination because said combination would have resulted in methods having the added advantage of allowing base calling as explicitly taught by Gordon et al. (paragraph 0424). In addition, it would have been obvious to the ordinary artisan that the known techniques of Gordon et al. could have been combined with the cited prior art with predictable results because the known techniques of the Gordon et al. predictably result in useful channel configurations for nucleic acid detection.
9. Claims 7 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Ness et al. (U.S. Patent Application Publication No. US 2012/0194805 A1, published 2 August 2012) and Colston et al. (U.S. Patent Application Publication No. US 2010/0173394 A1, published 8 July 2010) as applied to claims 1 and 17 above, and further in view of Blainey et al. (U.S. Patent Application Publication No. US 2019/0049434 A1, published 14 February 2019).
Regarding claims 7 and 19, the methods of claims 1 and 17 are discussed above in Section 7.
Ness et al. teach detection of two or more colors (paragraph 0006) using FAM and ROX (paragraph 0064), and Colston et al. teach four-color detection (paragraph 1089), as well as the two (i.e., one or more) fluorescent probes associated with each target (i.e., claim 19; paragraph 0841).
However, Blainey et al. teach droplet based methods (paragraph 0092) comprising the use of the claimed dyes, which are specifically cited as being known to those skilled in the art and are used to create unique labels (paragraph 0130). Thus, Blainey et al. teach the known techniques discussed above.
It would therefore have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Blainey et al. with Ness et al. and Colston et al. to arrive at the instantly claimed methods with a reasonable expectation of success. The ordinary artisan would have been motivated to make the combination because said combination would have resulted in methods having the added advantage of utilizing dyes known by those of skill in the art that are used to create unique labels as explicitly taught by Blainey et al. (paragraph 0130). In addition, it would have been obvious to the ordinary artisan that the known techniques of Blainey et al. could have been combined with the cited prior art with predictable results because the known techniques of the Blainey et al. predictably result in useful labels for nucleic acid detection.
10. Claims 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Ness et al. (U.S. Patent Application Publication No. US 2012/0194805 A1, published 2 August 2012) and Colston et al. (U.S. Patent Application Publication No. US 2010/0173394 A1, published 8 July 2010) as applied to claim 1 above, and further in view of Shuber (U.S. Patent Application Publication No. US 2004/0110179 A1, published 10 June 2004).
Regarding claims 8-9, the method of claim 1 is discussed above in Section 7.
While Ness et al. teach detection using FRET (paragraph 0043) and Colston et al. teach FRET probes (paragraph 0178), neither Ness et al. nor Colston et al. teach the tandem FRET probes, as shown in Figure 3F and discussed in paragraph 0044 of the instant specification.
However, Shuber teaches methods comprising the use of the claimed tandem probes (i.e., claim 8; Figure 4C), which are a plurality of probes (i.e., claim 6) and which have the added advantage of identifying mutations indicative of disease (Abstract). Thus, Shuber teaches the known techniques discussed above.
It would therefore have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Shuber with Ness et al. and Colston et al. to arrive at the instantly claimed methods with a reasonable expectation of success. The ordinary artisan would have been motivated to make the combination because said combination would have resulted in methods having the added advantage of identifying mutations indicative of disease as explicitly taught by Shuber (Abstract). In addition, it would have been obvious to the ordinary artisan that the known techniques of Shuber could have been combined with the cited prior art with predictable results because the known techniques of the Shuber predictably result in useful probes for nucleic acid detection.
11. Claims 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over Ness et al. (U.S. Patent Application Publication No. US 2012/0194805 A1, published 2 August 2012) and Colston et al. (U.S. Patent Application Publication No. US 2010/0173394 A1, published 8 July 2010) as applied to claim 1 above, as evidenced by, or further in view of Biglia (U.S. Patent Application Publication No. US 2016/0076089 A1, published 17 March 2016).
It is noted that while claim 9 has been rejected as described above, the claim isa also obvious using the interpretation outlined below.
Regarding claims 9-10, the method of claim 1 is discussed above in Section 7.
While Ness et al. teach detection using FRET (paragraph 0043) and detection of multiple different targets using different reporters (paragraph 0006); thus it would have been obvious to bind different FRET probes to different targets. Colston et al. also teach FRET probes (paragraph 0178), as well as having each droplet have a target and probes (paragraph 0819).
Colston et al. also teach the use of Taqman probes (e.g., paragraph 1154), which are hydrolysis probes as evidenced by Biglia (paragraph 0064); it is noted that the method does not actually require any hydrolysis step.
Alternatively, Biglia teaches methods using the Taqman probes as hydrolysis probes, which have the added advantage of increasing the signal (i.e., reporter fluorescence) at a rate proportional to the amount of template (paragraph 0064). Thus, Biglia teaches the known techniques discussed above.
It would therefore have alternatively been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Biglia with Ness et al. and Colston et al. to arrive at the instantly claimed methods with a reasonable expectation of success. The ordinary artisan would have been motivated to make the combination because said combination would have resulted in methods having the added advantage of increasing the signal at a rate proportional to the amount of template as explicitly taught by Biglia (paragraph 0064). In addition, it would have alternatively been obvious to the ordinary artisan that the known techniques of Biglia could have been combined with the cited prior art with predictable results because the known techniques of the Biglia predictably result in useful probes for nucleic acid detection.
12. Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Ness et al. (U.S. Patent Application Publication No. US 2012/0194805 A1, published 2 August 2012) and Colston et al. (U.S. Patent Application Publication No. US 2010/0173394 A1, published 8 July 2010) as applied to claim 17 above, and further in view of Cheng et al. (U.S. Patent Application Publication No. US 2002/0102690 A1, published 1 August 2002).
It is noted that while claim 19 has been rejected as described above, the claim isa also obvious using the interpretation outlined below.
Regarding claim 19, the method of claim 17 is discussed above in Section 7.
Ness et al. teach detection of two or more colors (paragraph 0006) using FAM and ROX (paragraph 0064), and Colston et al. teach four-color detection (paragraph 1089), as well as the two (i.e., one or more) fluorescent probes associated with each target (paragraph 0841).
Neither Ness et al. nor Colston et al. teach Cyanine 5.
However, Cheng et al. teach methods comprising the use of the multi-color detection using probes including Cyanine 5 (i.e., Cy5) as a label, which has the added advantage of allowing rapid and simultaneous differentiation expression analysis of independent samples (paragraph 0179). Thus, Cheng et al. teach the known techniques discussed above.
It would therefore have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Cheng et al. with Ness et al. and Colston et al. to arrive at the instantly claimed method with a reasonable expectation of success. The ordinary artisan would have been motivated to make the combination because said combination would have resulted in a method having the added advantage of allowing rapid and simultaneous differentiation expression analysis of independent samples as explicitly taught by Cheng et al. (paragraph 0179). In addition, it would have been obvious to the ordinary artisan that the known techniques of Cheng et al. could have been combined with the cited prior art with predictable results because the known techniques of the Cheng et al. predictably result in useful labels for nucleic acid detection.
13. Claims 21-27 are rejected under 35 U.S.C. 103 as being unpatentable over Ness et al. (U.S. Patent Application Publication No. US 2012/0194805 A1, published 2 August 2012), Colston et al. (U.S. Patent Application Publication No. US 2010/0173394 A1, published 8 July 2010) and Shuber (U.S. Patent Application Publication No. US 2004/0110179 A1, published 10 June 2004).
Regarding claim 21, Ness et al. teach methods comprising forming at least 200,000 partitions, in the form of four million droplets, each including nucleic acids therein (paragraph 0004), performing single copy nucleic acid amplification therein (paragraph 0005) wherein the PCR amplification reagents are the claimed processing materials, and wherein a plurality of (i.e., multiple) nucleic acid targets are measured using different distinguishable fluorophores for teach target (paragraph 0006).
Ness et al. further teach using a detection subsystem (i.e., detector) for multicolor detection (paragraph 0025), comprising multiple detection units 552 each providing and detecting different wavelengths of light and each having collection optics and a detector (paragraphs 0129-0131 and Figures 14-16). Ness et al. also teach multiple filters (paragraph 0055), each of which is on a dedicated branch of an optical path, and that at least one filter (which encompasses two filters) is coupled to a detector (paragraph 0078). Thus, the four detectors 552 (e.g., as shown in Figure 16) would comprise two filters each on a dedicated branch of an optical path, resulting in a total of 8 optical paths each with its own filter. Ness et al. further teach identifying the target molecules by detecting their presence using a distinguishable fluorophore that identifies the droplet (paragraph 0006), and that the methods have the added advantage of allowing discrete study of nucleic acids in a massively high throughput manner (paragraph 0003). Thus, Ness et al. teach the known techniques discussed above.
Ness et al. do not teach each optical path is an optical channel.
However, Colston et al. teach methods comprising obtaining a sample comprising a plurality of nucleic acids (paragraph 0013), generating at least 200,000 partitions, in the form of hundreds of millions of droplets (paragraph 0856), wherein each droplet comprises a single copy of a nucleic acid and amplification materials, in the form of digital PCR reagents, followed by amplification (paragraphs 0138-0139 and 0170) and generating counts by detecting signals from the plurality of partitions (paragraph 0856). Colston et al. teach detection of at least 25 targets (paragraph 1148), thus exceeding the number of channels of Ness et al., and identifying droplets (paragraph 0179) and the nucleic acids therein (paragraph 1145).Colston et al. also teach obtaining the (fluorescent) signals from the droplets via optical paths (paragraph 0845), and that the emitted signals are detected independently of one another in different detection channels (paragraph 1089), which has the added advantage of allowing normalization of the data (paragraph 1093). Thus, Colston et al. teach the known techniques discussed above.
In addition, it is reiterated that the courts have held that:
Mere duplication of parts has no patentable significance unless a new and unexpected result is produced;
Where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists; and
Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Therefore, the claimed numbers of channels, filters, and targets merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
Applicant is again cautioned to avoid merely relying upon counsel’s arguments in place of evidence in the record, and that the Response above should not be construed as an invitation to file an after final declaration.
It would therefore have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Ness et al. and Colston et al. to arrive at the instantly claimed method with a reasonable expectation of success. The ordinary artisan would have been motivated to make the combination because said combination would have resulted in a method having the added advantages allowing discrete study of nucleic acids in a massively high throughput manner as explicitly taught by Ness et al. (paragraph 0003) and allowing normalization of the data as explicitly taught by Colston et al. (paragraph 1093). In addition, it would have been obvious to the ordinary artisan that the known techniques of the cited prior art could have been combined with predictable results because the known techniques of the cited prior art predictably result in reliable detection of nucleic acids.
Ness et al. teach fluorophore labeled probes that give signal upon amplification (i.e., Taqman probes; paragraph 0064). Colston et al. also teach Taqman probes, as well as forward and reverse primers (paragraph 1066).
Neither Ness et al. nor Colston et al. teach the adapter sequences on the probes, as shown in Figure 3E and discussed in section 2.1.3 of the instant specification.
However, Shuber teaches methods comprising the use of the claimed adapter probes (Figure 4C), which are a plurality of probes having adapter sequences, in the form of the portions of Q and R that hybridize to one another in the absence of the target (paragraph 0098), and which have the added advantage of identifying mutations indicative of disease (Abstract). Thus, Shuber teaches the known techniques discussed above.
It would therefore have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Shuber with Ness et al. and Colston et al. to arrive at the instantly claimed method with a reasonable expectation of success. The ordinary artisan would have been motivated to make the combination because said combination would have resulted in a method having the added advantage of identifying mutations indicative of disease as explicitly taught by Shuber (Abstract). In addition, it would have been obvious to the ordinary artisan that the known techniques of Shuber could have been combined with the cited prior art with predictable results because the known techniques of the Shuber predictably result in useful probes for nucleic acid detection.
Regarding claims 22-24, Ness et al. teach methods comprising forming at least 200,000 partitions, in the form of four million droplets (i.e., claim 24), each including nucleic acids therein (paragraph 0004), performing single copy nucleic acid amplification therein (paragraph 0005) wherein the PCR amplification reagents are the claimed processing materials, and wherein a plurality of (i.e., multiple) nucleic acid targets are measures using different distinguishable fluorophores for teach target (paragraph 0006), as well as imaging (paragraph 0043).
Ness et al. further teach using a detection subsystem (i.e., detector) for multicolor detection (paragraph 0025), comprising multiple detection units 552 each providing and detecting different wavelengths of light and each having collection optics and a detector (paragraphs 0129-0131 and Figures 14-16). Ness et al. also teach multiple filters (paragraph 0055), each of which is on a dedicated branch of an optical path, and that at least one filter (which encompasses two filters) is coupled to a detector (paragraph 0078). Thus, the four detectors 552 (e.g., as shown in Figure 16) would comprise two filters each on a dedicated branch of an optical path, resulting in a total of 8 optical paths each with its own filter. Ness et al. further teach identifying the target molecules by detecting their presence using a distinguishable fluorophore that identifies the droplet (paragraph 0006), and that the methods have the added advantage of allowing discrete study of nucleic acids in a massively high throughput manner (paragraph 0003). Thus, Ness et al. teach the known techniques discussed above.
Ness et al. do not teach each optical path is an optical channel.
However, Colston et al. teach methods comprising obtaining a sample comprising a plurality of nucleic acids (paragraph 0013), generating at least 200,000 partitions, in the form of hundreds of millions of droplets (i.e., claim 24; paragraph 0856), wherein each droplet comprises a single copy of a nucleic acid and amplification materials, in the form of digital PCR reagents, followed by amplification (paragraphs 0138-0139 and 0170) and generating counts by detecting signals from the plurality of partitions (paragraph 0856), as well as imaging (paragraph 0210). Colston et al. teach the droplets are provided in a vessel (paragraph 0203). Colston et al. teach detection of at least 25 targets (paragraph 1148), thus exceeding the number of channels of Ness et al., and identifying droplets (paragraph 0179) and the nucleic acids therein (paragraph 1145). Colston et al. also teach obtaining the (fluorescent) signals from the droplets via optical paths (paragraph 0845), and that the emitted signals are detected independently of one another in different detection channels (paragraph 1089), which has the added advantage of allowing normalization of the data (paragraph 1093). Thus, Colston et al. teach the known techniques discussed above.
In addition, it is reiterated that the courts have held that:
Mere duplication of parts has no patentable significance unless a new and unexpected result is produced;
Where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists; and
Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Therefore, the claimed numbers of channels, filters, and targets merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
Applicant is again cautioned to avoid merely relying upon counsel’s arguments in place of evidence in the record, and that the Response above should not be construed as an invitation to file an after final declaration.
It would therefore have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Ness et al. and Colston et al. to arrive at the instantly claimed methods with a reasonable expectation of success. The ordinary artisan would have been motivated to make the combination because said combination would have resulted in methods having the added advantages allowing discrete study of nucleic acids in a massively high throughput manner as explicitly taught by Ness et al. (paragraph 0003) and allowing normalization of the data as explicitly taught by Colston et al. (paragraph 1093). In addition, it would have been obvious to the ordinary artisan that the known techniques of the cited prior art could have been combined with predictable results because the known techniques of the cited prior art predictably result in reliable detection of nucleic acids.
Ness et al. teach fluorophore labeled probes that give signal upon amplification (i.e., Taqman probes; paragraph 0064). Colston et al. also teach Taqman probes, as well as forward and reverse primers (paragraph 1066) and quenchers (i.e., claim 23; paragraph 0178).
Neither Ness et al. nor Colston et al. teach the adapter sequences on the probes, as shown in Figure 3E and discussed in section 2.1.3 of the instant specification.
However, Shuber teaches methods comprising the use of the claimed adapter probes (Figure 4C), which are a plurality of probes having adapter sequences, in the form of the portions of Q (quencher 34) and R (i.e., reporter 32) that hybridize to one another in the absence of the target (paragraph 0098). Shuber also teaches imaging (paragraph 0091), and that the methods have the added advantage of identifying mutations indicative of disease (Abstract). Thus, Shuber teaches the known techniques discussed above.
It would therefore have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Shuber with Ness et al. and Colston et al. to arrive at the instantly claimed method with a reasonable expectation of success. The ordinary artisan would have been motivated to make the combination because said combination would have resulted in a method having the added advantage of identifying mutations indicative of disease as explicitly taught by Shuber (Abstract). In addition, it would have been obvious to the ordinary artisan that the known techniques of Shuber could have been combined with the cited prior art with predictable results because the known techniques of the Shuber predictably result in useful probes for nucleic acid detection.
Regarding claim 25, the method of claim 22 is discussed above. Colston et al. teach the primer is shorter than the target region (i.e., template; paragraph 0177), and that the primer annealing and extension temperature is 55oC (paragraph 0707). Thus, having the melting temperature above 55oC, which is necessary for the denaturation step in PCR, would be obvious and overlaps the claimed range.
It is noted that the courts have held that optimization through routine experimentation, and in particular, when related to differences in temperature, do not support patentability (In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)). Thus, the claimed temperature range is merely represents routine optimization of the melting temperature of the reverse primer.
Applicant is again cautioned to avoid merely relying upon counsel’s arguments in place of evidence in the record, and that the Response above should not be construed as an invitation to file an after final declaration.
Regarding claims 26-27, the method of claim 22 is discussed above. Ness et al. teach polymerase (paragraph 0041). Colston et al. teach polymerase and dNTPs (paragraph 0159).
Claim Rejections - 35 USC § 112
14. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
15. Claim 25 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
This is a new matter rejection necessitated by the amendments.
Claim 25 is amended to recited a revers primer that is “shorter than the target region.” Applicant has provided no citation of support for the amendment. While a review of the specification reveals a teaching of reverse primers shorter than forward primers (e.g., paragraph 0106), the specification does not teach revers primers shorter than the target region. Thus, the amendments include new matter.
Response to Arguments
16. Applicant's arguments filed 17 March 2026 (hereafter the “Remarks”) have been fully considered but they are not persuasive for the reasons discussed below
A. Page 9 of the Remarks summarizes the amendments and refers to the previous indefiniteness rejections, which are withdrawn in view of the amendments.
However, contrary to Applicant’s assertion on page 9 of the Remarks, claims 1, 4, 6, 12, 15, 17, 18 and 20 were not amended; only claims 7, 19, and 25 were amended.
B. Applicant argues on pages 10-11 of the Remarks that Ness et al. do not teach the claimed number of channels.
In response to Applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Specifically, as noted in the rejections above, Ness et al clearly teach multiple detection units each providing and detecting different wavelengths of light and each having collection optics and a detector (paragraphs 0129-0131 and Figures 14-16).
Ness et al. also teach multiple filters (paragraph 0055), each of which is on a dedicated branch of an optical path, and that at least one filter (which encompasses two filters) is coupled to a detector (paragraph 0078).
Ness et al. also teach embodiments wherein a detection subsystem comprises four detectors 552 (e.g., Figure 16) which each comprise two filters each on a dedicated branch of an optical path.
The combination of the cited teachings of Ness et al. therefore clearly suggests, and would result in, a total of 8 optical paths each with its own filter; i.e., four detectors, each detector having two filters, resulting in a total of 8 optical paths.
As noted above, Colston et al. teach the emitted signals are detected independently of one another in different detection channels (paragraph 1089), which has the added advantage of allowing normalization of the data (paragraph 1093).
Thus, the combination of the references results in eight channels arising from 8 optical paths.
C. Applicant argues on page 11 of the Remarks that there is no expectation of success because Ness et al. allegedly teaches problems inherent with LEDs.
However, Applicant’s own citation of paragraph 0131 of Ness et al. explicitly refers to “an alternative light source,” and paragraph 0046 of Ness et al. discusses other light sources (e.g., lasers). Thus, the teachings of Ness et al. are not limited to LEDs.
It is also reiterated that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. Paragraph 0825 of Colston et al. teach non-LED sources of light.
Thus, the combination of the cited art is not limited to LEDs as light sources.
D. Applicant’s remaining arguments rely on alleged deficiencies previously addressed, which are unpersuasive for the reasons discussed above. Therefore, the claims remained rejected based on the prior art citations presented in the rejections.
Conclusion
17. No claim is allowed.
18. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
19. A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
20. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Robert T. Crow whose telephone number is (571)272-1113. The examiner can normally be reached M-F 8:00-4:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Anne Gussow can be reached at 571-272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Robert T. Crow
Primary Examiner
Art Unit 1683
/Robert T. Crow/Primary Examiner, Art Unit 1683
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