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 .
Claim Status
Claims 3-4, 7-8, 12-34, 37, 39-41, 52, 55-56, 60-62, 64-65 and 67-69 are canceled.
Claims 1-2, 5-6, 9-11, 35-36, 38, 42-51, 53-54, 57-59, 63, and 66 are pending and under examination herein.
Claims 1-2, 5-6, 9-11, 35-36, 38, 42-51, 53-54, 57-59, 63, and 66 are rejected.
Priority
The instant application filed 02/25/2021 claims priority to US provisional application 62/983404, filed 02/28/2020. However, the priority application does not discloses amplifying non-complementary forward and reverse strands in different extents, as recited in the instant claims. As such, the effective filing date of the claims is 02/25/2021. The effective filing date of the claims has be updated after further consideration.
Drawings
The drawings remain objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following reference character(s) not mentioned in the description:
30 and 32 (fig 1),
108 and 110 (fig 2),
Steps 1 – 5 (fig 11),
328 and 332 (fig 3B)
214 (fig 3C).
The drawings remain objected to as failing to comply with 37 CFR 1.84(p)(5) because they do not include the following figure and reference sign(s) mentioned in the description:
Fig 14B, Reference signs 1432, 1434, 1438, 1440, 1442, 1444, 1446
Corrected drawing sheets in compliance with 37 CFR 1.121(d), or amendment to the specification to add the reference character(s) in the description in compliance with 37 CFR 1.121(b) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Response to applicant’s arguments
Applicant stated they will consider amending the drawings and specification to expedite the prosecution in the case where the claims are otherwise found patentable (Applicant’s Arguments filed 11/19/2024, p 11, para 3). The examiner acknowledged this statement in the office action mailed 02/28/2025.
Specification
The use of the term “Illumina”, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
This is not an exhaustive list of all trademarks in the application. Applicant is reminded of their duty to review disclosure and correct other informalities.
Response to applicant’s arguments
Applicant stated they will consider amending the drawings and specification to expedite the prosecution in the case where the claims are otherwise found patentable (Applicant’s Arguments filed 11/19/2024, p 11, para 3). The examiner acknowledged this statement in the office action mailed 02/28/2025.
Claim Interpretation
Claim 1 recites limitations for “storing” data, which is interpretated as storing data on a generic computer.
Claim Rejections - 35 USC § 112
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.
Claims 1-2, 5-6, 9-11, 35-36, 38, 42-51, 53-54, 57-59, 63, and 66 are 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 rejection is newly recited after further consideration.
The step in claim 1, and all claims dependent thereon, for amplifying non-complementary forward and reverse strands in different extents, is not supported by the instant disclosure or the priority applications. While the instant application discloses amplification of hybridized nucleic acid fragments in para 00222, it is silent on the amplifying non-complementary forward and reverse strands in different extents.
Claim Rejections - 35 USC § 101
The rejection of claims 1-2, 5-6, 9-11, 35-36, 38, 42-51, 53-54, 57-59, 63, and 66 under 35 U.S.C. 101 is withdrawn in view of Applicant’s Arguments filed 02/10/2026 (p 1, para 5-p 4, last paragraph) that bisulfite sequencing is known to introduce a unique technical problem: during bisulfite treatment, unmethylated cytosines are converted to uracils, resulting in forward and reverse strands that are no longer complementary, and these strands are then amplified to different extents, leading to uneven sequencing depth, strand bias, and reduced accuracy at allelic positions of interest, and the instant invention address that problem by computing distinct conditional probabilities for forward and reverse strands, and by evaluating these probabilities in combination with population-based priors, the claimed method improves the accuracy of variant calling and methylation level determination under conditions where conventional, strand-agnostic approaches fail by amplifying noncomplementary forward and reverse strands in different extents, excluding bases affected by cytosine conversion, generating strand-specific base count sets, and determining separate forward and reverse conditional probabilities, which are all important to compensate for known biochemical artifacts, and therefore provides an improvement to the technical reliability of methylation sequencing outputs generated by a biochemical assay under Step 2A, Prong 2. This was found to be persuasive.
Claim Rejections - 35 USC § 102
The rejection under 35 U.S.C. 102(a)(1) as being anticipated by Liu et al. (IDS (02/25/2022) reference A34; previously cited) were withdrawn in the office action mailed 12/26/2024 in view of claim amendments filed 08/30/2023, as the cited prior art does not appear to disclose excluding bases that could be affected by the conversion of methylated or unmethylated cytosine when performing variant calling. Liu et al. instead appears to disclose finding SNPs at potentially methylated sites.
Claim Rejections - 35 USC § 103
The rejection under 35 U.S.C. 103 as being unpatentable over Liu et al. (IDS (02/25/2022) reference A34; previously cited) further in view of Barturen et al. (F1000Research 2013, 2, 217; previously cited) were withdrawn in the office action mailed 12/26/2023 in view of claim amendments filed 08/30/2023, as the cited prior art does not appear to disclose excluding bases that could be affected by the conversion of methylated or unmethylated cytosine when performing variant calling; Liu et al. and Barturen et al. instead appear to disclose finding SNPs at potentially methylated sites.
Prior Art
Claims 1-2, 5-6, 9-11, 35-36, 38, 42-51, 53-54, 57-59, 63, and 66 appear to remain free from prior art as the prior art does not teach or fairly suggest cited prior art does not appear to disclose excluding bases that could be affected by the conversion of methylated or unmethylated cytosine when performing variant calling or expressing the variant threshold as a log-likelihood of the reference genotype of the allelic position and the variant threshold is less than -10 or between -25 and -5. The closest prior art is Liu et al. (IDS (02/25/2022) reference A34), which discloses finding SNPs at potentially methylated sites and calculating a likelihood score expressed as a log likelihood and that calls at varying stringencies were generated by adjusting the Bis-SNP score cutoff, which is defined as the odds ratio between the first and second most likely genotype and discloses calculating a cutoff score with,
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where G is genotype and D represents base calls at a particular genomic position, and discloses optimizing execution by evaluating only the subset of the 10 possible diploid genotypes that are possible given the sequences read (p 5, col 1, para 3; p 10, col 1, para 2-col 2, para 2). However, Liu et al. appears to be silent on excluding bases that could be affected by the conversion of methylated or unmethylated cytosine when performing variant calling or the threshold being less than -10 or between -25 and -5.
Conclusion
No claims are allowed.
Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIDHI DHARITHREESAN whose telephone number is (571)272-5486. The examiner can normally be reached Monday - Friday 9:00 - 5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Larry D Riggs II can be reached on (571) 270-3062. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/N.D./ Examiner, Art Unit 1686
/Karlheinz R. Skowronek/Supervisory Patent Examiner, Art Unit 1687
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