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 March 30th, 2026 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Response to Amendment
The amendment filed July 23rd, 2026 is acknowledged. Regarding the Office Action mailed February 24th, 2026:
The objections to the claims are withdrawn in view of the amendments.
The rejections of claims 1-8, 10, 12-16 and 18 as set forth under 35 U.S.C. 112(b) are withdrawn in view of the amendments and cancellation of claim 12.
The rejection set forth under 35 U.S.C. 112(a) is withdrawn in view of the amendments.
Maintained, modified, or new rejections are set forth below, as necessitated by the amendments. Responses to arguments, if necessary, follow their respective rejection sections.
Claim Summary
Claims 1, 5, 9, and 18 have been amended. Claim 12 has been canceled. Claims 1-11 and 13-19 are pending. Claims 17 and 19 are withdrawn from consideration as being drawn to a non-elected invention/species. Claims 1-11, 13-16, and 18 are under examination and discussed in this Office action.
Claim Interpretation – Maintained
Claim 1 recites the limitation “isolating total nucleic acid from the sample”. Turning to the instant specification, “total nucleic acid” in the instant case has been defined as “nucleic acid isolated from a sample that has not been subjected for selection of methylated nucleic acid sequences” (see Page 6, lines 6-7 of the instant specification). Given this definition, reasonable interpretations of total nucleic acid could include genomic DNA isolated from a sample, etc. The provided definition from the instant specification will be applied for interpretation of the phrase “total nucleic acid” throughout this Office Action.
Claim 16 recites the limitation “an expanded FMR1 allele”. Turning to the instant specification, “an expanded FMR1 allele” in the instant case has been defined as “an allele of the FMRI gene that has an expanded CGG triplet repeat region as compared to a normal control. For example, an expanded allele may be classified as a premutation (PM) of about 55-200 CGG repeats, and/or full mutation (FM) of >200 CGG repeats alleles” (see Page 7, lines 1-5 of the instant specification). Given this definition, reasonable interpretations of an expanded FMR1 allele include any detected FMR1 with CGG repeats greater than 55. The provided definition from the instant specification will be applied for interpretation of the phrase “an expanded FMR1 allele” throughout this Office Action.
Claim 18 is drawn to a “system.” The specification recites a “system” wherein the “system” is defined in terms of structural limitations. In addition, the claims recite structural limitations of the “system.” Thus, the “system” is interpreted to encompass any collection of reagents and parts used together that are not necessarily part of a completely integrated single unitary device. Any further interpretation of the word is considered an “intended use” and does not impart any further structural limitation on the claimed subject matter.
Claim Interpretation – 112(f) – Maintained
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
The claims contain the following limitations:
Claim 18 recites “A system for determining methylation of an FMR] gene in a sample from a subject comprising: a component for isolating total nucleic acid from the sample; a component for fragmenting the isolated total nucleic acid to fragments having a size ranging from 2.4-3.2 kilobase pairs (kb); a component for contacting a first portion of the total fragmented nucleic acid with a methyl binding protein; a component for collecting from the first portion of the total fragmented nucleic acid contacted with the methyl binding protein a fraction of fragmented nucleic acid that is enriched for methylated nucleic acid and a fraction of fragmented nucleic acid that is enriched for unmethylated nucleic acid; a component to perform PCR amplification of the FMR] gene separately for the fraction of the fragmented nucleic acid that is enriched for methylated nucleic acid and the fraction of the fragmented nucleic acid that is enriched for unmethylated nucleic acid; and a component to determine if FMR] gene sequences are present in the nucleic acid fraction enriched for methylated nucleic acid and/or the nucleic acid fraction enriched for unmethylated nucleic acid or both”.
Thus, the cited limitations are drawn to generic means plus function. However, this limitation is not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because a review of the specification yields no limiting definition of the generically claimed means.
If applicant intends to have this limitation interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant should indicate where in the specification the specific structure is indicated.
Claim Rejections - 35 USC § 112(b) – New – Necessitated by Amendment
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 9 and 11 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.
Claim 9 recites the limitation “wherein the at least one primer used to generate an amplification product from the FMR1 gene from the fraction enriched for methylated nucleic acid and/or the fraction enriched for unmethylated nucleic acid each have the same sequence but are labeled with a different detectable moiety”. It is unclear from this recitation, if the option of having just one primer is exercised in performing the method, how there could be different detectable moieties for a multitude of amplification products. In other words, if there is only one primer, it is not possible for there to be different detectable moieties for each of an amplification product from the FMR1 gene from the fraction enriched for methylated nucleic acid and an amplification product from the FMR1 gene the fraction enriched for unmethylated nucleic acid. There would need to be at least two primers for the option of having the same sequence but different detectable moieties to be possible. This same issue is also noted for claim 11, wherein two labeled primers would have to be used to accomplish the method as claimed. For the purpose of compact prosecution, the recitation of “wherein the at least one primer used to generate an amplification product” is interpreted as requiring at least two primers.
Response to Arguments
Applicant's arguments filed July 23rd, 2026 have been fully considered but they are not persuasive.
The Applicant argues that one of skill in the art would understand the claim as amended (Page 9 of the Remarks filed July 23rd, 2026).
In response to this argument, it is noted that claim 9 still suffers from the same issue as previously indicated. While it is understood that each of the primers has a different moiety, there is still the option for only one primer to be used given the recitation of “at least one primer” and the optional “and/or”. To have different detectable moieties as the claim requires, there would need to be at least two primers. Therefore, the claim is still found indefinite and the argument is not persuasive.
Claim Rejections - 35 USC § 103 – Modified – Necessitated by Amendment
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.
Claims 1-11 and 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over Latham (US 20120107824 A1; previously cited), in view of McCarthy (MethylMeter(®): bisulfite-free quantitative and sensitive DNA methylation profiling and mutation detection in FFPE samples, Epigenomics, June 2016, 8, 747-765; cited on the IDS filed November 21st, 2024; previously cited) and Panteleeva (Optimizing DNA Shearing for Next Generation Sequencing Library Preparation with the Bioruptor® [online]. diagenode, [2010] [retrieved on February 12th, 2026]. Retrieved from: https://www.diagenode.com/files/posters/Poster-BR-A3-V2_22_06_10.pdf; previously cited), as evidenced by Applied Biosciences (DNA Fragment Analysis by Capillary Electrophoresis [online]. Applied Biosciences, [2014] [retrieved on February 13th, 2026]. Retrieved from: https://mugenomicscore.missouri.edu/PDF/fragment-analysis-chemistry-guide.pdf; previously cited).
Regarding instant claim 1, Latham teaches a method for determining methylation of an FMR1 gene in a sample from a human subject comprising the steps of: isolating total nucleic acid from the sample (Pages 10-11, paragraph [0103]), the total nucleic acid comprising both methylated nucleic acid and unmethylated nucleic acid (Page 10, paragraph [0101]; Pages 10-11, paragraph [0103]); contacting a first aliquot of isolated total nucleic acid with a methylation sensitive enzyme, thereby generating a nucleic acid fraction enriched for methylated nucleic acid (Page 11, paragraph [0105]); conducting PCR amplification of the FMR1 gene using an aliquot of nucleic acid from the fraction enriched for methylated nucleic acid (Page 11, paragraph [0106]); and determining the presence or absence of an FMR1 amplification product in the fraction enriched for methylated nucleic acid (Pages 11-12, paragraphs [0115]-[0119]).
Latham does not teach fragmenting the isolated total nucleic acid to fragments having a size ranging from 2.4-3.2 kilobase pairs (kb); contacting a first aliquot of the fragmented isolated total nucleic acid with a methyl binding protein, thereby generating a portion of unbound fragmented nucleic acid and a portion of bound fragmented nucleic acid within the first aliquot; isolating the unbound fragmented nucleic acid, thereby generating a nucleic acid fraction enriched for unmethylated nucleic acid; isolating the bound fragmented nucleic acid, thereby generating a nucleic acid fraction enriched for methylated nucleic acid; conducting PCR amplification of a target gene using an aliquot of nucleic acid from the fraction enriched for methylated nucleic acid; conducting PCR amplification of a target gene using an aliquot of nucleic acid from the fraction enriched for unmethylated nucleic acid; and determining the presence or absence of a target gene amplification product in both the fraction enriched for methylated nucleic acid and the fraction enriched for unmethylated nucleic acid.
McCarthy, in a reasonably pertinent field, teaches fragmenting isolated total nucleic acid (Page 756, column 1, paragraph 5 to column 2, paragraph 1); contacting the fragmented isolated total nucleic acid with a methyl binding protein, thereby generating a portion of unbound fragmented nucleic acid and a portion of bound fragmented nucleic acid (Figure 1; Page 756, column 2, paragraphs 3-4); isolating the unbound fragmented nucleic acid, thereby generating a nucleic acid fraction enriched for unmethylated nucleic acid (Figure 1; Page 756, column 2, paragraphs 3-4); isolating the bound fragmented nucleic acid, thereby generating a nucleic acid fraction enriched for methylated nucleic acid (Figure 1; Page 756, column 2, paragraphs 3-4); conducting PCR amplification of a target gene using an aliquot of nucleic acid from the fraction enriched for methylated nucleic acid (Figure 1; Page 756, column 2, paragraphs 3-4); conducting PCR amplification of a target gene using an aliquot of nucleic acid from the fraction enriched for unmethylated nucleic acid (Figure 1; Page 756, column 2, paragraphs 3-4); and determining the presence or absence of a target gene amplification product in both the fraction enriched for methylated nucleic acid and the fraction enriched for unmethylated nucleic acid (Figure 1; Page 756, column 2, paragraphs 3-4).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Latham with the method of McCarthy. Since McCarthy teaches on detecting methylation for target genes, which is reasonably pertinent to the method of Latham, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. With regard to the methyl binding protein, one of ordinary skill in the art would have been motivated to make this modification because methyl binding proteins are highly specific for CpG islands and unaffected by the sequencing context of a methylated CpG site (McCarthy, Page 748, column 2, paragraph 2). With regard to also looking at an unmethylated nucleic acid fraction, one of ordinary skill in the art would have been motivated to make this modification because measuring both a methylated and unmethylated fraction allows for determination of methylation percentage (McCarthy, Figure 1). In addition, it would have been obvious to the ordinary artisan that the known techniques of McCarthy could have been applied to the method of Latham with predictable results because the known techniques of McCarthy predictably result in both methylated and unmethylated fractions of input nucleic acid being available for downstream applications, including gene specific PCR (see MPEP 2141(III)). Finally, use of an unmethylated fraction produced by the method of McCarthy, which leaves unmethylated DNA intact, in the method of Latham would amount to simple substitution of one known element for another to obtain predictable results given that the method of Latham is intended to detect intact FMR1 gene (Latham, Page 10, paragraph [0101]); see MPEP 2141(III)).
Neither Latham nor McCarthy teach fragmenting the isolated total nucleic acid to fragments having a size ranging from 2.4-3.2 kilobase pairs (kb).
Panteleeva, in a reasonably pertinent field, teaches on sonication optimization for specific fragment sizes, including mean fragment sizes of 3000bp (e.g. 3.0kb) (Abstract).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the fragment of Latham, in view of McCarthy, with the sonication of specific fragment sizes of Panteleeva. Since Panteleeva teaches optimizing DNA shearing, which is reasonably pertinent to the fragmenting of Latham, in view of McCarthy, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because sonication is ideal to fractionate chromatin for epigenetics studies and is capable of highly reproducible fragment distributions (Abstract).
Regarding instant claim 2, Latham, in view of McCarthy and Panteleeva, teaches the method of claim 1. Latham further teaches the method further comprising determining the size of the FMR1 amplification product in a fraction enriched for methylated nucleic acid (Pages 11-12, paragraph [0115]-[0117]). As evidenced by Applied Biosciences, capillary electrophoresis can enable size of an amplification product to be determined via comparison with a size standard (Page 42), such as ROX 1000 (Page 43, size standard table). Latham teaches on using a ROX 1000 ladder (Page 11, paragraph [0115]).
Regarding instant claim 3, Latham, in view of McCarthy and Panteleeva, teaches the method of claim 2. Latham further teaches the method further comprising determining the number of CGG repeats at the FMR1 gene for the amplification product in the fraction enriched for methylated nucleic acid (Pages 11-12, paragraphs [0115]-[0118]; Figures 4A-D, bottom graphs; Figures 5A-D, bottom graphs).
Regarding instant claim 4, Latham, in view of McCarthy and Panteleeva, teaches the method of claim 1. Latham further teaches the method further comprising performing PCR amplification of the FMR1 gene using a second aliquot of nucleic acid from the total nucleic acid (Page 11, paragraph [0105]) and determining the size of at least one FMR1 amplification product (Pages 11-12, paragraph [0115]-[0117]). As evidenced by Applied Biosciences, capillary electrophoresis can enable size of an amplification product to be determined via comparison with a size standard (Page 42), such as ROX 1000 (Page 43, size standard table). Latham teaches on using a ROX 1000 ladder (Page 11, paragraph [0115]).
Regarding instant claim 5, Latham, in view of McCarthy and Panteleeva, teaches the method of claim 4. Latham further teaches the method further comprising determining the number of CGG repeats at the FMR1 gene for the at least one amplification product obtained from the second aliquot of nucleic acid from the total nucleic acid (Pages 11-12, paragraphs [0115]-[0118]; Figures 4A-D, top graphs; Figures 5A-D, top graphs).
Regarding instant claim 6, Latham, in view of McCarthy and Panteleeva, teaches the method of claim 2. Latham does not directly teach wherein determining the size of the FMR1 amplification product in at least one of the fraction enriched for methylated nucleic acid and the fraction enriched for unmethylated nucleic acid comprises comparing the size of the amplification products for the fraction enriched for methylated nucleic acid and/or the fraction enriched for unmethylated nucleic acid to the size of the at least one FMR1 amplification product for total nucleic acid. However, Latham does teach that the total nucleic acid amplification product is mixed with a ROX 1000 ladder as a part of capillary electrophoresis (Page 11, paragraph [0115]). As evidenced by Applied Biosciences, capillary electrophoresis can enable size of an amplification product to be determined via comparison with a size standard (Page 42), such as ROX 1000 (Page 43, size standard table). Therefore, the size of the amplification products of the total nucleic acid would be known. It would then be obvious to compare the amplification products for the fraction enriched for methylated nucleic acid and/or the fraction enriched for unmethylated nucleic acid to the known sizes of the FMR1 amplification product for total nucleic acid to determine the size of the amplification products in other fractions.
Regarding instant claim 7, Latham, in view of McCarthy and Panteleeva, teaches the method of claim 6. Latham further teaches wherein the size of the FMR1 amplification product in the fraction enriched for methylated nucleic acid is determined to be the size of the at least one FMR1 amplification product for total nucleic acid (Pages 11-12, paragraphs [0115]-[0118]; Figure 4C; Figure 5B).
Regarding instant claim 8, Latham, in view of McCarthy and Panteleeva, teaches the method of claim 1. Latham further teaches wherein at least one primer used to generate an FMR1 amplification product is labeled with a detectable moiety (Page 11, paragraph [0106]).
Regarding instant claim 9, Latham, in view of McCarthy and Panteleeva, teaches the method of claim 8. Latham teaches on contacting a first portion that is enriched for methylated nucleic acid and a second portion of sample DNA with amplification primers having the same sequence, but different labels for each portion (Page 11, paragraph [0106]).
However, Latham does not teach that these portions are a fraction enriched for methylated nucleic acid and a fraction enriched for unmethylated nucleic acid.
McCarthy, in a reasonably pertinent field, teaches separating target DNA into two fractions, one enriched for methylated nucleic acid and one enriched for unmethylated nucleic acid, and performing PCR on these fractions (Page 756, column 2, paragraphs 3-4).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the portions of Latham with the portions of McCarthy. Since McCarthy teaches on detecting methylation for target genes, which is reasonably pertinent to the method of Latham, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because it amounts to simple substitution of one known element for another with predictable results (see MPEP 2141(III)). Because both Latham and McCarthy teach on analyzing portions/fractions that originate from the same sample to determine methylation, it would be obvious the unmethylated fraction of McCarthy could serve as the second portion in the method of Latham. Furthermore, one of ordinary skill in the art would have been motivated to make this modification because measuring both a methylated and unmethylated fraction allows for determination of methylation percentage (McCarthy, Figure 1).
Regarding instant claim 10, Latham, in view of McCarthy and Panteleeva, teaches the method of claim 8. Latham further teaches wherein the detectable moiety is a fluorescent dye (Page 11, paragraph [0106]). Latham earlier teaches that both FAM and HEX are fluorescein dyes (Page 9, paragraph [0089]).
Regarding instant claim 11, Latham, in view of McCarthy and Panteleeva, teaches the method of claim 10. Latham further teaches wherein the fluorescent dye used for detection of the amplification products from the total nucleic acid is hexachlorofluorescein (HEX) and the dye used for detection of the amplification product from the fraction enriched for methylated nucleic acid is 6-carboxyfluorescein (FAM) (Page 11, paragraph [0106]), which is the reverse of what is claimed. However, it is taught both are able to be used together (Page 11, paragraph [0106]). It is also taught that the reverse primer they are bound to is the same sequence, and therefore the primers can be used interchangeably on the different fractions (Page 11, paragraph [0106]). Therefore, it would be obvious that they could be used interchangeably for detection of the amplification products of the total nucleic acid and the methylated nucleic acid as this would amount to simple substitution of one known element for another to obtain predictable results (see MPEP 2141(III)).
Regarding instant claim 14, Latham, in view of McCarthy and Panteleeva, teaches the method of claim 1. Latham further teaches wherein the size of the FMR1 amplification product in the fraction enriched for methylated nucleic acid is measured by capillary electrophoresis (Pages 11-12, paragraph [0115]-[0117]). As evidenced by Applied Biosciences, capillary electrophoresis can enable size of an amplification product to be determined via comparison with a size standard (Page 42), such as ROX 1000 (Page 43, size standard table). Latham teaches on using a ROX 1000 ladder (Page 11, paragraph [0115]). Latham does not teach that a fraction enriched for unmethylated nucleic acid is measured by capillary electrophoresis. However, given the methods already taught by Latham for the fraction enriched for methylated nucleic acid, as well as the obviousness of an unmethylated fraction in view of McCarthy, it would be obvious to do the same for the fraction enriched for unmethylated nucleic acid because it would amount to simple substitution of one known element for another to obtain predictable results (see MPEP 2141(III)).
Regarding instant claim 15, Latham, in view of McCarthy and Panteleeva, teaches the method of claim 1. Latham further teaches the method further comprising determining whether the subject has full methylation of FMR1 (Page 13, paragraph [0132]; Page 16, paragraph [0137]; Table 5: FM=full methylation; Figures 5A-B).
Regarding instant claim 16, Latham, in view of McCarthy and Panteleeva, teaches the method of claim 15. Latham further teaches the method further comprising determining whether the subject has full methylation of an expanded FMR1 allele (Page 13, paragraph [0132]; Page 16, paragraph [0137]; Table 5: FM=full methylation; Figures 5A-B).
Response to Arguments
Applicant's arguments filed July 23rd, 2026 have been fully considered but they are not persuasive.
The Applicant first summarizes the Examiner’s previous rejection (Page 10 of the Remarks filed July 23rd, 2026). The Applicant then reiterates the criteria for establishing obviousness, stating that the amended claims are not obvious because one of skill in the art would not have had a reason to combine the cited art to arrive at amended claims 1 and 18 (Page 10 of the Remarks file July 23rd,m 2026). The Applicant summarizes the amendment to claim 1, stating that it derives from original claim 12 (Page 10 of the Remarks filed July 23rd, 2026). The Applicant summarizes the cited teachings of Latham and McCarthy, and particularly notes that Latham and McCarthy are admitted to not teach or disclose size-specific fragmentation of isolated nucleic acid (Page 11 of the Remarks filed July 23rd, 2026). Instead, they use enzymes that result in fragments that range from tens to hundreds of base pairs, not thousands (Page 11 of the Remarks filed July 234rf, 2026). With regard to Panteleeva, the Applicant argues that it fails to provide a rationale for why one skilled in the art would have opted to fragment the isolated total nucleic acid to have fragment sizes from 2.4-3.2 kb (Page 11 of the Remarks filed July 23rd, 2026). The Applicant cites the specification, stating that “using an optimized fragment sized based on the size of the PCR product that is expected based on the largest FMR1 allele in the sample, i.e., the claimed 2.4-3.2 kb fragment size, increases the specificity of the claimed assay. See para. [0067] of the specification as published” (Page 11 of the Remarks filed July 23rd, 2026). The Applicant argues that Latham and McCarthy also do not mention optimization of fragment size, produce fragments smaller than those claimed, and do not provide teachings or disclosures the would encourage generating 2.4-3.2 kb fragments (Pages 11-12 of the Remarks filed July 23rd, 2026). The Applicant argues that Applied Biosciences does not cure the alleged deficiencies of Lathem, McCarthy, or Panteleeva (Page 12 of the Remarks filed July 23rd, 2026).
In response to the Applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, it is noted that appropriate motivation has been provided for the combination of Panteleeva with Latham and McCarthy. As indicated above, Panteleeva states sonication is ideal to fractionate chromatin for epigenetics studies and is capable of highly reproducible fragment distributions (Panteleeva, Abstract). These distributions include the fragment sizes as instantly claimed.
In addition, it is also noted that the Supreme Court ruling for KSR Int' l Co. v. Teleflex, Inc. (No 04-1350 (US 30 April 2007) forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See Ex parte Smith (USPQ2d, slip op. at 20 (Bd. Pat. App. & Interf. June 25, 2007).
While the Applicant further argues that there would be no reason to opt for the claimed range, the reason for doing so included by the Applicant is provided from the specification and is not claimed. It is noted that the features upon which the Applicant relies (i.e., the claimed size range being chosen based on the largest FMR1 allele) are 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). Therefore, because fragmentation is only required to be within a specific range with no connection to ideal sizes based on FMR1 alleles, the method of Panteleeva is capable of achieving the claimed range with appropriate motivation and the arguments are not found persuasive.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Latham (US 20120107824 A1; previously cited), McCarthy (MethylMeter(®): bisulfite-free quantitative and sensitive DNA methylation profiling and mutation detection in FFPE samples, Epigenomics, June 2016, 8, 747-765; cited on the IDS filed November 21st, 2024; previously cited) and Panteleeva (Optimizing DNA Shearing for Next Generation Sequencing Library Preparation with the Bioruptor® [online]. diagenode, [2010] [retrieved on February 12th, 2026]. Retrieved from: https://www.diagenode.com/files/posters/Poster-BR-A3-V2_22_06_10.pdf; previously cited), as evidenced by Applied Biosciences (DNA Fragment Analysis by Capillary Electrophoresis [online]. Applied Biosciences, [2014] [retrieved on February 13th, 2026]. Retrieved from: https://mugenomicscore.missouri.edu/PDF/fragment-analysis-chemistry-guide.pdf; previously cited), as applied to claims 1-11 and 15-16 above, and further in view of Rehli (US 20210371901 A1; previously cited).
Regarding instant claim 13, Latham, in view of McCarthy and Panteleeva, teaches the method of claim 1.
None of these references teach wherein the methyl binding protein is a bifunctional polypeptide comprising: (i) an Fc portion of an antibody; (ii) a short flexible peptide linker; and (iii) a DNA-binding domain of an MBD2 protein.
Rehli, in a reasonably pertinent field, teaches a methyl binding protein of a bifunctional polypeptide comprising: (i) an Fc portion of an antibody (Page 18, paragraph [0150]); (ii) a short flexible peptide linker (Page 18, paragraph [0150]); and (iii) a DNA-binding domain of an MBD2 protein (Page 18, paragraph [0150]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the methyl binding protein of Latham, in view of McCarthy, with the methyl binding protein of Rehli. Since Rehli teaches on methods for detecting methylated DNA, which is reasonably pertinent to the method of Latham, in view of McCarthy, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because a bifunctional polypeptide as described has a high affinity and high avidity to methylated DNA (Rehli, Page 5, paragraph [0037]).
Response to Arguments
Applicant's arguments filed July 23rd, 2026 have been fully considered but they are not persuasive.
The Applicant argues that because claim 13 depends from claim 1, which has been deemed not obvious in the earlier arguments, it is also not obvious (Page 12 of the Remarks filed July 23rd, 2026). The Applicant also argues the Rehli does not cure the deficiencies of the earlier cited references (Page 12 of the Remarks filed July 23rd, 2026).
Applicant’s arguments regarding claim 13 rely on alleged deficiencies previously addressed, which are unpersuasive for the reasons discussed above. Therefore, the claim remains rejected based on the prior art citations presented in the above rejection.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over McCarthy (MethylMeter(®): bisulfite-free quantitative and sensitive DNA methylation profiling and mutation detection in FFPE samples, Epigenomics, June 2016, 8, 747-765; cited on the IDS filed November 21st, 2024; previously cited), in view of Panteleeva (Optimizing DNA Shearing for Next Generation Sequencing Library Preparation with the Bioruptor® [online]. diagenode, [2010] [retrieved on February 12th, 2026]. Retrieved from: https://www.diagenode.com/files/posters/Poster-BR-A3-V2_22_06_10.pdf; previously cited).
The courts have held that “while features of an apparatus may be recited either structurally or functionally, claims directed to an apparatus must be distinguished from the prior art in terms of structure rather than function.” In re Schreiber, 128 F.3d 1473, 1477-78, 44 USPQ2d 1429, 1431-32 (Fed. Cir. 1997). In addition, “[A]pparatus claims cover what a device is, not what a device does.” Hewlett-Packard Co. v. Bausch & Lomb Inc., 909 F.2d 1464, 1469, 15 USPQ2d 1525, 1528 (Fed. Cir. 1990) (emphasis in original). Therefore, the various uses recited in claim 18 (e.g., performing PCR amplification specifically of FMR1 gene in methylated and unmethylated fractions of nucleic acids) fail to define additional structural elements of the claimed system. See MPEP § 2114. As long as the components of the system have structure capable of performing the generic action of the component as claimed, any further description of the component is considered an “intended use” and does not impart any further structural limitation on the claimed subject matter.
Regarding instant claim 18, McCarthy teaches a system for determining methylation of an FMR1 gene in a sample from a subject comprising: a component for isolating total nucleic acid from the sample (Page 751, column 1, paragraph 5: centrifuge to spin down samples); a component for contacting a first portion of the total fragmented nucleic acid with a methyl binding protein (Page 751, column 2, paragraph 5: “[m]agnetic beads bearing the MethylMagnet GST-MBD2 fusion protein were distributed to 1.7 ml microcentrifuge tubes”); a component for collecting from the first portion of total fragmented nucleic acid contacted with the methyl binding protein a fraction of fragmented nucleic acid that is enriched for methylated nucleic acid and a fraction of fragmented nucleic acid that is enriched for unmethylated nucleic acid (Page 751, column 2, paragraph 5 to Page 752, column 1, paragraph 1: “beads were pelleted with a magnet”); a component to perform PCR amplification of the FMR1 gene separately for the fraction of the fragmented nucleic acid that is enriched for methylated nucleic acid and the fraction of the fragmented nucleic acid that is enriched for unmethylated nucleic acid (Page 754, column 1, paragraph 2: qPCR machine); and a component to determine if FMR1 gene sequences are present in the nucleic acid fraction enriched for methylated nucleic acid and/or the nucleic acid fraction enriched for unmethylated nucleic acid or both (Page 754, column 1, paragraph 2: FAM-BHQ1-labeled molecular beacon).
McCarthy does not teach a component for fragmenting the isolated total nucleic acid to fragments having a size ranging from 2.4-3.2 kilobase pairs (kb).
Panteleeva, in a reasonably pertinent field, teaches on a sonicator and sonication optimization for specific fragment sizes, including mean fragment sizes of 3000bp (e.g. 3.0kb) (Abstract: “Bioruptor sonicator”).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the system of McCarthy with the sonicator for fragmenting nucleic acid to a specific size range of Panteleeva. Since Panteleeva teaches optimizing DNA shearing, which is reasonably pertinent to the system of McCarthy, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because sonicators are ideal to fractionate chromatin for epigenetics studies and is capable of highly reproducible fragment distributions (Abstract).
Response to Arguments
Applicant's arguments filed July 23rd, 2026 have been fully considered but they are not persuasive.
The Applicant argues that amended claim 18 is not obvious for the same reasons set forth for claim 1 (Page 13 of the Remarks filed July 23rd, 2026). The Applicant further argues that neither McCarthy nor Panteleeva include any disclosures regarding FMR1 (Page 13 of the Remarks filed July 23rd, 2026).
Applicant’s arguments regarding claim 18 as being not obvious for the same reasons as claim 1 rely on alleged deficiencies previously addressed, which are unpersuasive for the reasons discussed above. With regard to McCarthy and Panteleeva lacking teachings regarding FMR1, as previously noted, everything claimed in the system recites an intended use of each component and is merely generically claimed. As long as the components of the system have structure capable of performing the generic action of the component as claimed, any further description of the component is considered an “intended use” and does not impart any further structural limitation on the claimed subject matter. This includes any reference to FMR1, the inclusion of which is a specific intended use for the generic action of each component in which it is referenced. The claim remains rejected based on the prior art citations presented in the above rejection.
Conclusion
All claims stand rejected.
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.
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/ALLISON E SCHLOOP/Examiner, Art Unit 1683
/Robert T. Crow/Primary Examiner, Art Unit 1683
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