Status of the Claims
Claims 1, 3-6, 8-9, 13, 17, 19-20, 23, 26, 28, 30, 32, 36, and 39-41 are pending.
Claims 32, 36, and 39-41 are withdrawn.
Claims 1, 3-6, 8-9, 13, 17, 19-20, 23, 26, 28, and 30 are elected and examined herein.
Applicant's election without traverse of Group I in the Response filed on 06/30/2026 is acknowledged. Accordingly, claims 32, 36, and 39-41 are withdrawn from consideration as directed to non-elected inventions.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Objections
Claim 19 is objected to because of the following informalities: claim 19(h), line 4 contains a period before the end of the claim. Per MPEP 608.01(m), periods may only be used at the end of a claim, except for abbreviations. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3-6, 8-9, 13, 17, 19-20, 23, 26, 28, 30, 32, 36, and 39-41 are 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.
Regarding claims 1, 4-6, 8-9, 13, 17, 19-20, 26, 28, and 30, the term “preferably” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. As per MPEP 2173.05(c)-(d), “[i]f stated in a single claim, examples and preferences lead to confusion over the intended scope of the claim. In those instances where it is not clear whether the claimed narrower range is a limitation, a rejection under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph should be made.” Claims 3 and 23 are similarly rejected as being dependent on a rejected claim.
Claims 8 and 30 recite dependence on claims 1 to 7 or claims 20 to 22, respectively. However, claims 2, 7, 21, and 22 have been cancelled, rendering their recitation indefinite. For the purposes of examination, the claims will be interpreted as solely reciting dependence on pending claims. To overcome this rejection, the references to the cancelled claims can be removed.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 3, 4, 6, 13, 17, 19-20, 23, 26, 28, and 30 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Claim 1 recites “selecting a set of sequence reads” and “measuring microsatellite lengths”; claim 19 recites “establishing one or more provenances”; claim 20 recites “generating a distribution; claim 26 recites “estimating a confidence interval”; claim 28 recites “comparing the estimated confidence interval”; and claim 30 recites “calculating a K-eccentricity”. The listed limitations are all abstract ideas, specifically mental processes that could be performed in the human mind, or by a human using a pen and paper. Of note, the “measuring” recited in claim 1 is most similar to “counting”, and therefore qualifies as a mental process.
These judicial exceptions are not integrated into a practical application because the additional elements recited are insignificant extra-solution activity and there are no steps recited that apply or use the judicial exception. Additional elements recited in claims 1, 3-4, 6, 9, 13, and 17 constitute insignificant pre-solution activity as they are mere data gathering required for use of the judicial exception and are well-known in the art, as described below.
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements are well-understood, routine, and conventional. Specifically, the steps of partial mutagenesis, making a sequencing library, and sequencing are routine for sequencing microsatellites, as are mutagenesis via incorporation of nonstandard nucleotides (claims 3, 4), synthetic templates (6), mutational patterns (9), amplification (13), and single or paired end reads (17). This is demonstrated by their occurrence in the prior art, spanning numerous publications and upwards of 20 years. Each of these limitations are recapitulated by at least the following:
Keith et al. (NAR (2004), 32(3): e35);
Mitchelson (PCR Protocols, Meth. in Mol. Biol. (2011), 687: 75-88);
Sipos et al. (PLOS One (2012), 7(8): e43359).
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.
Imelfort et al. and Sipos et al.
Claims 1, 3-6, 9, 13, 17, 19, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Imelfort et al. (PG Pub No: 2021/0174905) in view of Sipos et al. (PLOS One (2012), 7(8): e43359).
Regarding claim 1, Imelfort discloses a method (Figure 16) comprising:
generating partially mutagenized templates by partial mutagenesis during production of first copies of the template (p. 14, ¶[208]);
making a sequencing library from the partially mutagenized templates (Figure 16);
sequencing the library (p. 16, ¶[0243-4]);
selecting a set of sequence reads (p. 17, ¶[0265]; p. 20, ¶[0305]) in which the error rate between matched pairs is minimized (p. 18-19, ¶[0284-6]: odds ratio); and
determining the sequence of the target (Figure 1: “sequencing analysis”).
Imelfort does not explicitly disclose the use of this method for the sequencing of microsatellites, but does teach that the sequence assembly aided by mutagenesis (SAM) method is useful for assembling sequences containing repeat regions (p. 1, ¶[003-6]). Sipos discloses a SAM method for targeted sequencing of tandem repeat regions (abstract; p. 3, col. 2), such as microsatellites (p. 7, 1st full ¶: “could be used even to sequence microsatellites”). It is clear from the disclosures of Imelfort and Sipos that the SAM method of Imelfort could be used to target microsatellites. This would require simple substitution of the target of Imelfort, which would have been obvious to one of ordinary skill in the art by the effective filing date and have a predictable result as SAM methods were known in the art and understood to be useful in the sequencing of microsatellites because they are repetitive regions that are traditionally difficult to sequence.
Imelfort does not explicitly disclose the measurement of the length of the target region. However, determining the sequence of a target region would necessarily result in measurement of the length of said sequence. Therefore, step (e) of the instant claim is encompassed by the disclosure of Imelfort in view of Sipos.
Finally, Imelfort does not disclose that the microsatellite of a set of reads exceeds a disruption index, nor that the error rate between matched pairs is less than 2%. However, Imelfort does disclose that its “odds ratio” would exceed a threshold in order to determine what reads are in a set. Imelfort further teaches that the threshold can be set “at any level”, based on the requirements of the practitioner (p. 19, ¶[0287]), and that some of the factors to which the threshold is responsive is the mutation rate (p. 19, ¶[0289]) and the error rate (p. 19, ¶[0292]). Additionally, Imelfort teaches that under-mutated reads are unusable for the purpose of determining target sequence, and should be disregarded (p. 21, ¶[0331]). Therefore, it would have been obvious to one of ordinary skill in the art to adjust the threshold of the odds ratio of Imelfort to ensure a baseline level of mutagenesis so that the error rate between the matched pairs is minimized. Furthermore, as Imelfort discloses that the threshold can be set at any level depending on the experimental requirements and that it is desirable to minimize the error rate between matched pairs, it would have been a matter of routine optimization to arrive at an odds ratio where the error rate between matched pairs to less than 2%, as per MPEP 2144.05.
Regarding claims 3-4, Imelfort further discloses that the partial mutagenesis comprises deamination of cytosines by bisulfite mutagenesis (p. 15, ¶[0225]), enzymatic mutagenesis (p. 15, ¶[0226]), or incorporation of standard and nonstandard nucleotides in the presence of a mixed pool of standard and nonstandard nucleotides (p. 25, ¶[0377] ([claim 13]p. 23, ¶[0347-8]) ([claim 17] p. 13, ¶[0202]).
Regarding claim 5, Imelfort discloses mutagenesis via an error-prone DNA polymerase using primers that bind to the flanking portions of the nucleic acid template, and therefore protect the flanking portions from partial mutagenesis (p. 15, ¶[0229]).
Regarding claim 6, Imelfort further discloses that the nucleic acid templates are from a biological sample (p. 4, ¶[0081]).
Regarding claim 8, Imelfort further discloses generating first copies of the partially mutagenized templates, wherein adaptors are added to the copies that comprise tags and universal primer binding sites (p. 2, ¶[0050]: “This step also introduces (i) sample tags and (ii) an additional adapter sequence at the template ends to facilitate downstream amplification of products”).
Regarding claim 9, Imelfort discloses that the initial nucleic acid templates and/or first copies thereof comprise one or more individual identifiers (p. 21, ¶[0324]).
Regarding claims 13 and 17, Imelfort further discloses amplification of the partially mutagenized templates (p. 23, ¶[0350]) and that the sequence reads are single or paired end reads (p. 13, ¶[0202]).
Regarding claim 19, Imelfort further discloses establishing provenances of the sequence reads, wherein the provenances are established from an initial nucleic acid template with a specific individual identifier (p. 21, ¶[0324]: “allows target template nucleic acid molecules to be differentiated from one another”).
Regarding claim 23, Imelfort discloses selecting sequence reads based on the estimated replication error (p. 19, ¶[0292]), as discussed in relation to claim 1.
Imelfort et al., Sipos et al., and Fungtammasan et al.
Claims 20, 26, and 28 are rejected under 35 U.S.C. 103 as being obvious over Imelfort in view of Sipos and further in view of Fungtammasan et al. (Genome Res. (2015), 25(5): 736-749; cited in IDS of 03/07/2024).
Regarding claim 20, the limitations of claim 1 are rendered obvious by the disclosures of Imelfort and Sipos, as discussed above. However, neither Imelfort nor Sipos disclose generating a distribution of microsatellite read lengths.
Fungtammasan discloses generating a distribution of microsatellite read lengths by counting the number of microsatellites of a given length across all measured microsatellite lengths in a set of sequence reads from the same locus (p. 17, Tool for STR length profiling; p. 20, Profiling STR length at each locus). Additionally, Fungtammasan teaches that the lengths of microsatellites are an important property that can potentially be used to diagnose diseases (p. 3, 1st ¶).
Therefore, it would have been obvious to one of ordinary skill in the art to apply the method of generating a distribution of microsatellite lengths of Fungtammasan to the method of Imelfort and Sipos, based on the motivation of Fungtammasan. There would have been a reasonable expectation of success in doing so as the method of Fungtammasan also uses data derived from NGS.
Regarding claim 26, Fungtammasan further discloses estimating a confidence interval for the length of a microsatellite at a specific locus of a single sample based on the error rate (p. 20-21, Construction of bootstrap confidence intervals). Additionally, Imelfort discloses the use of disruption and error rates determined from a prior experiment as a benchmark (p. 19, ¶[0293-7; 0301]). Though neither Fungtammasan nor Imelfort disclose using the disruption rate of the microsatellite to estimate the error rate in order to estimate a confidence interval, it would have been obvious to one of ordinary skill in the art based on the above disclosures as the error rate of Fungtammasan could be derived from the disruption and error rates of Imelfort.
Regarding claim 28, Fungtammasan further suggests that the lengths of microsatellites can be used to diagnose diseases (p. 3, 1st ¶). Diagnosis of a disease necessarily involves comparison between the “diseased” state and the “healthy” state, and therefore comparing the resulting confidence intervals of microsatellite length between two samples would also be suggested to one of ordinary skill in the art by Fungtammasan.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Alexandra Olson whose telephone number is (571)272-7519. The examiner can normally be reached Monday-Friday 9-5pm.
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, Heather Calamita can be reached at (571) 272-2878. 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.
/ALEXANDRA OLSON/Examiner, Art Unit 1684
/JEREMY C FLINDERS/Primary Examiner, Art Unit 1684
