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 .
Applicant's response to the previous Office action, dated April 6, 2026, has been received. By way of this submission, Applicant has amended claims 1, 4, 7, 22, and 31-32, and introduced new claims 33-42.
Claims 1-7, 11, and 21-42 are pending in the application. Claim 11 remains withdrawn from consideration, pursuant to the Restriction Requirement mailed February 27, 2025.
Claims 1-7 and 21-42 are therefore under examination before the Office.
The rejections of record can be found in the previous Office action, dated October 6, 2025.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on April 6, 2026 was filed after the mailing date of the first Office action on the merits on October 6, 2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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 1-7 and 21-42 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 is a new grounds of rejection, necessitated by Applicant’s amendment to the claims. This is a new matter rejection.
Applicant’s amendment, filed April 6, 2026, contains new matter in claims 1, 34, and 35, because the specification as-filed does not provide sufficient written description for the recitation of a "health-related output", "adjusting the cytosine methylation data based on the cell type fractions from the deconvolution", a "disease risk score", a "mortality risk assessment", a "biological age metric", an "immune function assessment", a "pace-of-aging metric", a "phenotypic measure estimate", or a "disease susceptibility classification".
There is no reference to any of these terms in the specification, nor does the specification offer any sort of definition as to what these terms are meant to mean. At no point was any "health related output" contemplated or defined in the specification.
As such, the claims now recite a limitation which was not clearly disclosed in the specification as-filed and now change the scope of the instant disclosure as-filed. Such a limitation recited in the present claims, which did not appear in the specification, as-filed, introduces a new concept and violates the description requirement of the first paragraph of 35 U.S.C. 112.
Claim 7 was previously 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.
Applicant's amendments to the claims have addressed this issue, and this rejection is hereby withdrawn.
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 1-7 and 21-42 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claims recite a natural phenomenon, a method of determining a deconvolution of cell-types in a saliva specimen. This judicial exception is not integrated into a practical application because the claimed data gathering steps do not add a meaningful limitation to the method as they are insignificant extra-solution activity. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
Applicant argues that claim 1 as amended recites additional elements that, when considered as an ordered combination, are not routinely performed by those of skill in the art; specifically, it is not routine or conventional to extract genomic DNA from a saliva specimen, determine cytosine methylation by performing a bisulfite conversion, or determining a deconvolution of cell-types in the saliva specimen.
Applicant's arguments have been considered fully but are not found to be persuasive.
The steps of genomic DNA extract from a saliva specimen, bisulfite conversion to determine cytosine methylation, and determining a deconvolution of cell-types in the saliva specimen were well-understood and conversional data gathering steps performed in the art. Zheng (Epigenomics. 2018 Jul;10(7):925-940, cited in IDS) teaches a method, comprising obtaining genomic DNA from a saliva specimen and performing bisulfite conversion on the genomic DNA, and that this method was used to create reference data from a group of subjects with which one may estimate fractions of epithelial and immune cells (i.e., determining a deconvolution of cell types in a saliva specimen) (page 936, last paragraph). Applicant's own specification at page 9 even concedes that their method is based upon the teachings of Zheng.
The use of an algorithm as recited in step (d) of claim 1 as amended also does not add significantly more, as an algorithm is merely a mathematical calculation that can be performed solely within the mind, and considered an abstract idea. MPEP 2106.04(a)(2).
The generation of a "health-related output" in steps (d) and (e) of claim 1 as amended also does not reach the threshold of an inventive concept. There is no explanation as to how the algorithm is used to create the health-related output, nor does Applicant provide any definition of what a "health-related output" is or how it relates to the data obtained in the previous steps. This step is merely an instruction to "apply" the exception, especially given the high level of generality of an unspecified "health-related output". MPEP 2106.05(f).
The claims as amended still recite judicial exceptions of a law of nature, without significantly more to establish an inventive concept. A mere instruction to generally apply the exception does not reach the threshold of an inventive concept.
This rejection is therefore maintained and extended to include new claims 33-42.
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.
Claim Rejections - 35 USC § 102
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.
Claims 1, 3-7, 21-34, and 42 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zheng (Epigenomics. 2018 Jul;10(7):925-940, cited in IDS), as evidenced by Infinium HD Methylation Assay Manual Workflow Checklist and Dor (WO2019159184A1).
Applicant argues that Zheng does not teach every limitation of the claims as amended; specifically, Zheng does not teach determining cell type fractions from deconvolution or generating a health-related output for a subject.
Applicant's arguments have been considered but are not found to be persuasive.
Zheng teaches the use of the EpiDISH algorithm to estimate cell-type fractions for epithelial cells and various types of immune cells (page 926: "Estimating the cell-type fractions using hierarchical EpiDISH (HEpiDISH)"), which is pertinent to new claim 33.
Zheng further teaches the use of a reference matrix of DNA methylation values derived from a reference group, which defines epithelial cells and immune cells (page 926: "Finally, the DNAm reference was obtained by averaging DNAm values for the 716 DMCs and for each of the three main cell types (Epi, Fib and IC), resulting in a 716 × 3 reference matrix, we call 'EpiFibIC'.").
Zheng further teaches that this method is useful in determining immune cell infiltration across epithelial tissues (page 933, fourth paragraph and Figure 5), and to infer differentially methylated CpG loci in cancer cells (page 937, third paragraph), which is pertinent to new claim 34. Under the broadest reasonable interpretation of the term, this is a "health-related outcome".
Zheng further teaches that the immune cells detected may be neutrophils, eosinophils, monocytes, CD4+ and CD8+ T cells, B cells and natural killer [NK] cells (page 926, second paragraph), which is pertinent to new claim 42.
This rejection is therefore maintained and extended to encompass new claims 33-34 and 42.
Claim Rejections - 35 USC § 103
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.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Zheng as applied to claim 1 above, and further in view of Nishitani (Epigenetics. 2018;13(4):352-362).
Applicant argues that Nishitani does not overcome the alleged deficiencies of Zheng. This is not found persuasive, for reasons defined supra.
This rejection is therefore maintained.
Claims 1-7, 21-40, and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Zheng (Epigenomics. 2018 Jul;10(7):925-940, cited in IDS) in view of Horvath (WO2019232320A1), as evidenced by Infinium HD Methylation Assay Manual Workflow Checklist and Dor (WO2019159184A1). This is a new grounds of rejection, necessitated by Applicant’s amendment to the claims.
Zheng teaches a method, comprising obtaining genomic DNA from a saliva specimen, performing bisulfite conversion on the genomic DNA, and profiling the DNA methylation with a beadchip and imaging the beadchip (page 928, last paragraph), which is pertinent to claims 1, 3, and 30-31.
Zheng further teaches the use of a regression algorithm to compare samples to the reference data (Figure 1), which is pertinent to claim 4.
Zheng further teaches that this method was used to create reference data from a group of subjects with which one may estimate fractions of epithelial and immune cells (i.e., determining a deconvolution of cell types in a saliva specimen) (page 936, last paragraph), which is pertinent to claim 6.
Zheng further teaches that this method is useful for detecting epithelial cells, neutrophils, monocytes, eosinophils, CD4+ T cells, CD8+ T cells, NK cells and B cells (Figure 6), which is pertinent to claims 22-29.
Zheng teaches the use of the EpiDISH algorithm to estimate cell-type fractions for epithelial cells and various types of immune cells (page 926: "Estimating the cell-type fractions using hierarchical EpiDISH (HEpiDISH)"), which is pertinent to new claim 33.
Zheng further teaches the use of a reference matrix of DNA methylation values derived from a reference group, which defines epithelial cells and immune cells (page 926: "Finally, the DNAm reference was obtained by averaging DNAm values for the 716 DMCs and for each of the three main cell types (Epi, Fib and IC), resulting in a 716 × 3 reference matrix, we call 'EpiFibIC'.").
Zheng further teaches that this method is useful in determining immune cell infiltration across epithelial tissues (page 933, fourth paragraph and Figure 5), and to infer differentially methylated CpG loci in cancer cells (page 937, third paragraph), which is pertinent to new claim 34. Under the broadest reasonable interpretation of the term, this is a "health-related outcome".
Zheng further teaches that the immune cells detected may be neutrophils, eosinophils, monocytes, CD4+ and CD8+ T cells, B cells and natural killer [NK] cells (page 926, second paragraph), which is pertinent to new claim 42.
While Zheng does not explicitly teach that the subject is human, Zheng teaches the method used is the Infinium MethylationEPIC BeadChip (page 928, last paragraph). According to InfiniumTM MethylationEPIC v2.0 BeadChip data sheet, the beadchip is designed for evaluation of human DNA (page 2). Zheng therefore inherently teaches the subject matter of claim 5.
While Zheng does not explicitly teach staining the beadchip, Infinium HD Methylation Assay Manual Workflow Checklist teaches staining the beadchip prior to imaging (page 5). Zheng therefore inherently teaches the subject matter of claim 7.
While Zheng does not explicitly teach the various CG loci that are recited in claim 21, Dor teaches CG loci that are part of the Infinium Human MethylationEPIC Beadchip array and relevant to discerning cell types in a sample, including cg25599673 and cg02661764 (Table 1 and para. 0084, 0176, and 0188). A person using Infinium Human MethylationEPIC Beadchip array would inherently determine cytosine methylation at these loci. Zheng therefore inherently teaches the subject matter of claim 21.
However, Zheng does not teach disease risk score, loss of cell function, or biological age of the subject.
Horvath teaches that DNA methylation is a useful biomarker of aging (page 2, line 16), and that algorithms based on this data are useful for both estimating age and age-related diseases (page 2, lines 20-25). Under the broadest reasonable interpretation of the term, age-related disease is a "loss of cell function".
Horvath further teaches DNA methylation-based biomarkers allow one to estimate the epigenetic age of an individual, especially when methylation is assessed in sorted cell types (page 3, lines 9-21).
Horvath further teaches DNA methylation-based biomarkers of aging are useful for predicting mortality (page 15, lines 8-26), which is pertinent to claim 35.
Horvath further teaches that lifestyle changes can affect accelerated aging, such a physical exercise (page 31, lines 7-15), which is pertinent to claims 38-40.
Horvath further teaches the use of methylation-specific polymerase chain reaction (PCR) based on a chemical reaction of sodium bisulfite with DNA (page 20, lines 17-23), which is pertinent to claim 2.
It would have been prima facie obvious for a person of ordinary skill in the art as of the effective filing date to combine the teachings of Zheng and Horvath to arrive at the claimed invention. An ordinary artisan would have been motivated to do so, and have a reasonable expectation of success, since both Zheng and Horvath are concerned with analysis of DNA methylation. Methods of cell deconvolution in a saliva sample based upon methylation patterns were known in the art according to Zheng. Horvath teaches that one such use for this information is to determine biological age and assess disease risk. One of ordinary skill could perform the methods of deconvolution according to Zheng and use this data to make assessments based upon the teachings of Horvath, with each component of the combination performing its known, expected function to affect a predictable result.
Claim 41 is rejected under 35 U.S.C. 103 as being unpatentable over Zheng and Horvath as applied to claim 37 above, and further in view of Cheishvili (WO2020240511A1). This is a new grounds of rejection, necessitated by Applicant’s amendment to the claims.
The teachings of Zheng and Horvath have been described supra. However, Zheng and Horvath do not teach declining skin elasticity.
Cheishvili teaches that aging of skin (i.e. declining skin elasticity) is a parameter that predicts biological aging (page 2, lines 13-16).
Cheishvili further teaches the use of a DNA methylation profile from a saliva specimen to determine a biological age (page 5, lines 10-16).
Cheishvili further teaches lifestyle changes that might impact the patient's healthy aging (page 9, lines 5-30).
It would have been prima facie obvious for a person of ordinary skill in the art as of the effective filing date to combine the teachings of Zheng, Horvath, and Cheishvili to arrive at the claimed invention. As stated above, methods of generating health-related output from DNA methylation profiles were known in the art, according to Zheng and Horvath. Cheishvili further teaches that aging skin is another related metric when calculating biological age. Cheishvili further teaches the use of DNA methylation data to generate a biological age, as well as suggesting appropriate lifestyle changes. One of ordinary skill could apply the teachings of Cheishvili to the assay of Zheng and Horvath to arrive at the claimed invention, with each component of the combination performing its known, expected function to affect a predictable result.
Double Patenting
Claims 1-7 and 30 and 32 were previously provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 and 18 of copending Application No. 18/741,311 (reference application).
Applicant's amendments to the claims have addressed this issue, and this rejection is hereby withdrawn.
Conclusion
No claim is allowed.
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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/PETER JOHANSEN/Examiner, Art Unit 1644
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