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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/20/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The disclosure is objected to because page 57, in para [0073], line 7 of the specification contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The disclosure is objected to because of the following informalities:
The use of the following trade names or marks 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.
[0034] line 3 "SOLiD"
[0034] line 5: "SMRT"
[0034] line 9: "454"
[0082] line 3: "Ion Torrent"
[0082] line 2: "QuantStudio"
Page 60, line 3: "DNeasy"
Page 60, line 2: "Triton X-100"
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.
Status of Claims
This office action is in response to Applicant's Response to Election / Restriction filed on December 17, 2025.
Claims 1-10, 12-21, and 23-44 are currently pending, with claims 1-10, 12-21, and 23-42 withdrawn.
Claims 43-44 are under examination. This is the first action on the merits.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-10, 12-21, 23-32, and 41-44) in the reply filed on December 17, 2025 is acknowledged1. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicant’s election without traverse of the following species in the reply filed on December 17, 2025 is acknowledged:
Species of methods analyzing differential DNA methylation region (DMR): B) wherein a number of determined DMRs are sufficient to determine, from a process comprising the comparing and employing a computer, whether the human male subject, or an offspring of the human male subject, has or is at increased risk of having autism or autism spectrum disorder, or determine a severity of autism spectrum disorder (Claim 20, 43) 2.
Species of method for processing DNA: D) wherein DNA is required to be fragmentated (Claim 43) 3.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-10, 12-21, and 23-42 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Examination on the merits commences on claims 43-44.
Priority
Regarding claims 43-44, the earliest priority is 08/18/2021 because the priority document (PCT/US2021/046422 ) filed that date is the first to disclose "a number of determined DMRs are sufficient to determine, from a process comprising the comparing and employing a computer, whether the human male subject, or an offspring of the human male subject, has or is at increased risk of having autism or autism spectrum disorder, or determine a severity of autism spectrum disorder."
Claim Rejections - 35 USC § 112(b)
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.
Claims 43-44 are rejected under 35 U.S.C. 112(b), 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 claim 43, it recites "wherein a number of determined DMRs are sufficient to determine, from a process comprising the comparing and employing a computer, whether the human male subject, or an offspring of the human male subject, has or is at increased risk of having autism or autism spectrum disorder, or determine a severity of autism spectrum disorder." This wherein clause is indefinite for several reasons.
First, the use of "or" introduces multiple alternative scenarios without clearly defining their scope. The wherein clause appears to encompass the following:
whether the human male subject has autism;
whether the human male subject is at increased risk of having autism;
whether an offspring of the human male subject has autism;
whether an offspring of the human male subject is at increased risk of having autism; or
determine a severity of autism spectrum disorder.
It is unclear to which of the preceding scenarios "determine a severity of autism spectrum disorder" applies. It is ambiguous whether severity refers to the subject or the offspring, and whether it is predictive (i.e., determining risk of having autism with certain level of severity) or diagnostic (i.e. determining whether a subject or offspring has autism with certain level of severity). It is also unclear how an offspring can be diagnosed with autism based on methylation level of parental sperm. The grammatical construction does not resolve this ambiguity, and the metes and bounds of these alternative scenarios cannot be reasonably determined.
Second, the phrase "wherein a number of determined DMRs are sufficient to determine…" is indefinite because it is unclear what "a number of determined DMRs" refers to in the context of the claim. The claim does not previously recite any step of determining a number of DMRs. Instead, it only recites determining a methylation level of a single DMR. Therefore, this limitation is indefinite.
Third, it is unclear what number of DMRs qualifies as "sufficient." The application's disclosure does not define what number of DMRs is considered sufficient for any of the listed scenarios. According to the specification, the disclosure was designed to identify a sperm epigenetic biomarker to assess a father's ability to transmit autism susceptibility to his offspring (see, e.g., [0016]; [0070]), but it does not define or describe any number of DMRs as sufficient, nor provide criteria or methodology to determine what would be sufficient for any of the scenarios recited in the claim. Without such guidance, this claim language is indefinite.
Fourth, the phrase "a process comprising the comparing and employing a computer" is indefinite because "the comparing and employing a computer" lacks antecedent basis. This language appears to refer to another process separate from what is claimed, yet the use of "the" creates confusion.
Per MPEP 2111.04, a wherein clause can limit a method claim if it contributes meaning and purpose to the manipulative steps. In the instant claim, however, this wherein clauses does not incorporate any additional step into the method claim nor does it modify any existing method step in the claim. In other words, it merely describes a number of determined DMRs that does not modify any existing steps in the claim and makes no manipulative difference.
Therefore, for the purpose of compact prosecution and applying prior art under 35 USC§ 102 and 103, this wherein clause is interpreted as descriptive statements without any associated active steps and do not further limit the scope of the claim.
Claim 44 is rejected for depending from claim 43 and not remedying the indefiniteness.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim 43 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Feinberg (Feinberg et al. US20180291450A1 - Method of identifying risk for autism; Published on 2018-10-11; cited as US Patent Application Publication # 2 in IDS filed 01/20/2023).
Regarding claim 43, Feinberg teaches a method comprising:
obtaining a sperm sample from a human male subject ([0079]; [0084]);
isolating deoxyribonucleic acid (DNA) from the sample ([0084]; [0016]; );
fragmenting the DNA ([0086] “Genomic sperm DNA (4 µg) was sheared on a Hydro Shear
Plus” );
isolating fragmented methylated DNA ([0086] gel purification of sheared DNA; hybridized to array);
determining a methylation level of a differential DNA methylation region (DMR) comprised in the isolated fragmented methylated DNA ([0034]; [0065]; [0072]; [0114]); and
comparing the methylation level of the DMR to a reference level of a corresponding reference DMR ([0065]line 4-8; [0064]; [0125] lines 4-9; [0101-0102]):
wherein:
the comparing comprises comparing employing a computer comprising a computer processor and computer readable memory comprising computer readable instructions contained thereon ([0069]; [0090]; [0102] running the software packages such as CHARM Package™ (v.2.8.0) in R (version 3.0.3), and FlowSorted.DLPFC.450 k Bioconductor inherently requires a computer;
the determining comprises employing an array ([0030]; [0045]; [0055]; [0076]; [0086] lines 10-18).
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.
Claim 44 is rejected under 35 U.S.C. 103 as being unpatentable over Feinberg (Feinberg et al. US20180291450A1 - Method of identifying risk for autism; Published on 2018-10-11; cited as US Patent Application Publication # 2 in IDS filed 01/20/2023), in view of Taiwo (Taiwo et al. ; Methylome analysis using MeDIP-seq with low DNA concentrations. Nat Protoc. 2012 Mar 8;7(4):617-36. doi: 10.1038/nprot.2012.012. PMID: 22402632).
The teachings of Feinberg are recited above and applied as for base claim 43.
Feinberg teaches methods for methylation based testing, more specifically to sperm DNA methylation as a predictive marker of autism risk (entire document).
Regarding claim 44, although Feinberg does not disclose the use of MeDIP, it expressly states that its teachings are not limited to any particular assay for detecting DNA methylation, and that numerous methods for analyzing methylation status may be used:
"While the present invention exemplifies the CHARM assay for detection of methylation, in fact numerous methods for analyzing methylation status (hypomethylation or hypermethylation) may be utilized." ([0046]).
Taiwo teaches MeDIP-seq (methylated DNA immunoprecipitation followed by sequencing) as an improved method for analyzing DNA methylation (entire document). Taiwo further highlights the advantages of MeDIP-seq, such as providing high specificity and enrichment efficiency, cost-effective, suitable for low-input DNA, and applicable to analyzing all currently known forms of mammalian DNA methylation (see Abstract; see also page 618, "Application of the method").
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the CHARM assay for analyzing methylation in Feinberg with the MeDIP-seq method taught by Taiwo.
Both references are in the same field of analyzing DNA methylation, particularly in mammalian samples. While Feinberg does not specifically disclose MeDIP, it expressly allows for alternative methylation analysis methods, thereby providing a reason for a skilled artisan to consider MeDIP-seq as a substitute.
The skilled artisan would have been motivated to make this substitution in view of the advantages of MeDIP-seq, as suggested by Taiwo.
The person of ordinary skill would have had a reasonable expectation of success in making the modification to Feinberg's methods for analyzing sperm DNA methylation as a predictive marker of autism risk, by substituting the CHARM assay with Taiwo's MeDIP-seq assay, because both assays share the same purpose and function ꟷ analyzing DNA methylation in a sample ꟷ and a skilled artisan would recognize that substituting one known methylation analysis assay for another would predictably yield the same outcome, i.e., results on methylation levels in the sample.
This rationale aligns with the principle of KSR for a simple substitution of one known element for another to obtain predictable results, see MPEP 2141.
Prior Art
Other prior art also teach assessing autism risk using sperm DNA methylation levels:
Feinberg JI, et al. Paternal sperm DNA methylation associated with early signs of autism risk in an autism-enriched cohort. Int. J. Epidemiol. 2015:1–12. doi: 10.1093/ije/dyv028;
US20160208327A1 - Systems and methods for determining impact of age related changes in sperm epigenome on offspring phenotype;
Denomme et al., "The inherited methylome landscape is directly altered with paternal aging and associated with offspring neurodevelopmental disorders", AGING CELL, vol. 19, no. 8, 1 July 2020 (2020-07-01), pages 1-13.
Conclusion
No claims are allowed.
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/TIAN NMN YU/Examiner , Art Unit 1681 /AARON A PRIEST/Primary Examiner, Art Unit 1681
1 Claims 33-40 are withdrawn as being drawn to non-elected group II.
2 Claims 1-10, 12-19, 32 and 41-42 are withdrawn as being drawn to non-elected species A.
3 Claims 20-21 and 23-31 are withdrawn as being drawn to non-elected species C.