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 claims 1, 4, 6, 12, 15, 17-18, and 20 were amended, no claims were canceled, and no new claims were added. All of the amendments have been thoroughly reviewed and entered.
All previous objections and/or rejections not reiterated below are withdrawn in view of the amendments and the Terminal Disclaimer (as discussed below).
Applicant’s arguments have been thoroughly reviewed and are addressed following the rejections necessitated by the amendments.
Claims 1-20 are under prosecution.
Terminal Disclaimer
3. The terminal disclaimer filed on 17 March 2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent Application No. 19/192,017 and U.S. Patent Numbers 12,000,842, 12,265,088, and 12,540,948 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Information Disclosure Statement
4. The Information Disclosure Statement filed 19 April 2026 which is acknowledged and has been considered.
Claim Objections
5. Claim 4 is objected to because of the following informalities: claim 4 contains the recitation “generating the container is a a closed container.” Appropriate correction is required.
Claim Rejections - 35 USC § 112
6. Claim 3 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “minimal” in claim 3 is a relative term which renders the claim indefinite. The term “minimal” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim Rejections - 35 USC § 103
7. 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.
8. 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.
9. Claims 1-5, 7-13, 15, 17, and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Colston et al. (U.S. Patent Application Publication No. US 2010/0173394 A1, published 8 July 2010), Collins et al. (U.S. Patent Application Publication No. US 2018/0023124 A1, published 25 January 2018), and Liao et al. (bioRxiv 739243; doi: https://doi.org/10.1101/739243, pages 1-15, posted online 19 August 2019).
Regarding claims 1 and 13, Colston et al. teach digital methods comprising obtaining a sample comprising a plurality of nucleic acids (paragraph 0013), generating at least 5 million partitions, in the form of hundreds of millions of droplets (i.e., claims 1 and 13; 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. also teach the partitions (i.e., droplets) are stabilized in position (i.e., substantially static, as opposed to flowing) in the container (paragraph 0209), and that the methods have the added advantage of providing simple, easily analyzed samples with concomitant reductions in background and assay times (paragraph 0138). Thus, Colston et al. teach the known techniques discussed above.
Colston et al. do not teach the claimed number of counts.
However, Collins et al. teach methods utilizing droplet-based PCR (paragraph 0726), wherein detected signals are counted (paragraph 0030), and wherein at least 50,000 counts are obtained (paragraph 0327). Collins et al. also teach the methods have the added advantage of detecting genetic variation in genetic samples (paragraph 0001). Thus, Collins et al. teach the known techniques discussed above.
It is noted that 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 also 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 ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art, and the “stabilized” partitions merely represent routine optimization of the “substantially” static partitions to be totally static.
Applicant is advised that 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, Applicant should not merely rely upon counsel’s arguments in place of evidence in the record.
It is noted that the Response above should not be construed as an invitation to file an after final declaration. See MPEP 715.09.
Neither Colston et al. nor Collins et al. teach imaging cross sections of the container.
However, Liao et al. teach methods comprising imaging of digital PCR droplets (page 2) using light-sheet imaging, which images cross-sections of the container (Figure 1), which has the added advantage of a greatly increased dynamic range (Abstract). Thus, Liao 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 Colston et al., Collins et al., and Liao 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 of:
A. Providing simple, easily analyzed samples with concomitant reductions in background and assay times as explicitly taught by Coston et al. (paragraph 0138);
B. Detecting genetic variation in genetic samples as explicitly taught by Collins et al. (paragraph 0001); and
C. Providing a greatly increased dynamic range as explicitly taught by Liao et al. (Abstract).
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 2, the method of claim 1 is discussed above. Collins et al. teach the sample comprising sequences associated with genomic diseases (e.g., cancer; paragraph 0074). Colston et al. also teach diagnosing genetic diseases (paragraph 1138), including cancer (paragraph 1144), and Liao et al. teach detection of the Listeria genome (page 7)
Regarding claim 3, the method of claim 1 is discussed above. Collins et al. teach determining minimal residual disease (paragraph 0009).
Regarding claim 4, the method of claim 1 is discussed above. Liao et al. teach detection within a closed container (Figure 1).
In addition, it is noted that the courts have held that any order of performing process steps is prima facie obvious in the absence of new or unexpected results (In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930); Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959)). See MPEP §2144.04 IV C. Thus, closing the container at any point in the claimed method is an obvious variant of the steps 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.
Regarding claim 5, the method of claim 1 is discussed above. Liao et al. teach detection within a clear emulsion (page 11).
Regarding claim 7, the method of claim 1 is discussed above. Collins et al. teach detection of sets of chromosomes (paragraph 0090), as do Colston et al. (paragraph 1140).
Regarding claim 8, the method of claim 7 is discussed above. Collins et al. teach maternal samples with low fetal fractions (paragraph 0151), as well as detection of fractions less than 1% in analogous samples (paragraph 0176). Thus it would have been obvious to try using a maternal sample having a fetal fraction of less than 1%.
It is reiterated that 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, and 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.
Therefore, the claimed ranges 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.
Regarding claim 9, the method of claim 1 is discussed above. Collins et al. teach the sample is derived from plasma (paragraph 0077), as do Colston et al. (paragraph 0156).
Regarding claim 10, the method of claim 1 is discussed above. Collins et al. teach the sample is derived from blood (paragraph 0077), as do Colston et al. (paragraph 0156) and Liao et al. (page 13).
Regarding claim 11, the method of claim 1 is discussed above. Collins et al. teach the targets comprise single nucleotide polymorphisms (paragraph 0060), as do Colston et al. (paragraph 1137).
Regarding claim 12, the method of claim 1 is discussed above. Collins et al. teach scanning in less than 180 minutes (paragraph 0149).
It is reiterated that 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, and 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.
Therefore, the claimed ranges 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.
Regarding claim 15, Colston et al. teach digital methods comprising obtaining a sample comprising a plurality of nucleic acids (paragraph 0013), generating at least 10 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. also teach the partitions (i.e., droplets) are stabilized in position (i.e., substantially static, as opposed to flowing) in the container (paragraph 0209), and that the methods have the added advantage of providing simple, easily analyzed samples with concomitant reductions in background and assay times (paragraph 0138). Thus, Colston et al. teach the known techniques discussed above.
While Colston et al. discuss rare targets (paragraph 1082), Colston et al. do not teach the claimed sensitivity.
However, Collins et al. teach methods utilizing droplet-based PCR (paragraph 0726), wherein detected signals are counted (paragraph 0030), as well as detection with at least 99% sensitivity; i.e., detection of a rare molecule, in the form of a mutant alleles present at only 0.1% (paragraph 0427). Collins et al. also teach the methods have the added advantage of detecting genetic variation in genetic samples (paragraph 0001). Thus, Collins et al. teach the known techniques discussed above.
It is reiterated that 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, and 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.
Therefore, the claimed ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art, and the “stabilized” partitions merely represent routine optimization of the “substantially” static partitions to be totally static.
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.
Neither Colston et al. nor Collins et al. teach imaging cross sections of the container.
However, Liao et al. teach methods comprising imaging of digital PCR droplets (page 2) using light-sheet imaging, which images cross-sections of the container (Figure 1), which has the added advantage of a greatly increased dynamic range (Abstract). Thus, Liao 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 Colston et al., Collins et al., and Liao 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 of:
A. Providing simple, easily analyzed samples with concomitant reductions in background and assay times as explicitly taught by Coston et al. (paragraph 0138);
B. Detecting genetic variation in genetic samples as explicitly taught by Collins et al. (paragraph 0001); and
C. Providing a greatly increased dynamic range as explicitly taught by Liao et al. (Abstract).
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 17, the method of claim 15 is discussed above. Liao et al. teach detection within a closed container (Figure 1) and that amplifying (i.e., PCR) is performed with a closed container (page 9).
In addition, it is reiterated that the courts have held that any order of performing process steps is prima facie obvious in the absence of new or unexpected results. Thus, closing the container at any point in the claimed method is an obvious variant of the steps 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.
Regarding claim 19, the method of claim 15 is discussed above. Collins et al. teach the sample is derived from blood (paragraph 0077), as do Colston et al. (paragraph 0156) and Liao et al. (page 13).
Regarding claim 20, the method of claim 15 is discussed above. Colston et al. teach the partitions (i.e., droplets) are in a chamber (paragraph 0208), which is explicitly listed as an alternative to wells.
Liao et al. teach the partitions are in a tube (Figure 1).
In addition, Collins et al. teach the use of nanovials and nanowells (paragraph 0004), which are not microwells.
10. Claims 6 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Colston et al. (U.S. Patent Application Publication No. US 2010/0173394 A1, published 8 July 2010), Collins et al. (U.S. Patent Application Publication No. US 2018/0023124 A1, published 25 January 2018), and Liao et al. bioRxiv 739243; doi:
https://doi.org/10.1101/739243, pages 1-15, posted online 19 August 2019) as applied to claims 5 and 15 above, and further in view of Fricke et al. (U.S. Patent Application Publication No. US 2013/0217797 A1, published 22 August 2013).
Regarding claims 6 and 18, the methods of claims 5 and 15 are discussed above in Section 9.
While Liao et al. teach detection within a clear emulsion (page 11), neither Colston et al., Collins et al., nor Liao et al. discuss not matching refractive indexes.
However, Fricke et al. microemulsions are clear emulsions, which are achieved on the size of the particles and index of refraction (paragraph 0009). Thus, it would have been obvious to have a clear microemulsion based on particle size without exact matching of the refractive indexes, and Fricke et al. teach the known techniques discussed above.
It is reiterated that the courts have 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.
Therefore, the claims merely represent an obvious variant and/or routine optimization of the conditions 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 Fricke et al. with Colston et al., Collins et al., and Liao et al. to arrive at the instantly claimed method with a reasonable expectation of success. It would have been obvious to the ordinary artisan that the known techniques of Fricke et al. could have been combined with the cited prior art with predictable results because the known techniques of the Fricke et al. predictably result in reliable formation of microemulsions.
11. Claims 14 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Colston et al. (U.S. Patent Application Publication No. US 2010/0173394 A1, published 8 July 2010), Collins et al. (U.S. Patent Application Publication No. US 2018/0023124 A1, published 25 January 2018), and Liao et al. bioRxiv 739243; doi:
https://doi.org/10.1101/739243, pages 1-15, posted online 19 August 2019) as applied to claims 1 and 15 above, and further in view of Chiu et al. (U.S. Patent Application Publication No. US 2016/0096172 A1, published 7 April 2016).
Regarding claims 14 and 16, the methods of claims 1 and 15 are discussed above in Section 9.
Neither Colston et al., Collins et al., nor Liao et al. discuss dead volumes.
However, Chiu et al. teach methods of forming droplets without any dead volume, which has the added advantage of not having any loss of sample (paragraph 0016). Thus, Chiu 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 Chiu et al. with Colston et al., Collins et al., and Liao 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 preventing loss of sample as explicitly taught by Chiu et al. (paragraph 0016). In addition, it would have been obvious to the ordinary artisan that the known techniques of Chiu et al. could have been combined with the cited prior art with predictable results because the known techniques of the Chiu et al. predictably result in reliable formation of sample droplets.
Response to Arguments
12. 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. Applicant argues on pages 6-7 of the Remarks that the term “minimal residual disease” is a well understood term, citing a www.cancer.gov as evidence.
However, a single citation does not establish a term as being readily recognized by the ordinarily skilled artisan.
In addition, Applicant’s citation specifically refers to genomic disease, which is not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
The rejection is therefore maintained.
B. As noted above, all of the double patenting rejections are withdrawn in view of the Terminal Disclaimer.
C. Applicant’s remaining arguments have been considered but are moot in view of the new rejections necessitated by the amendments.
Conclusion
13. No claim is allowed.
14. 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).
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.
15. 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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Robert T. Crow
Primary Examiner
Art Unit 1683
/Robert T. Crow/Primary Examiner, Art Unit 1683
Prosecution Insights