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 statements (IDS) submitted on 01/23/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of Claims
This office action is in response to Applicant's Response to Election / Restriction filed on May 25, 2026. No claims amendment are made in the response filed on that date.
Claims 1-3 and 190-206 are currently pending, with claims 191 and 202-203 withdrawn.
Claims 1-3, 190, 192-201 and 204-206 are under consideration. This is the first action on the merits.
Election/Restrictions
Applicant’s election without traverse of the following species in the reply filed on May 25, 2026 is acknowledged:
Species of epidermal Nucleic acids: A) DNA (claim 201);
Species of nucleic acid modifying enzyme: i), ii) and iii) combined - i.e., an enzyme of a TET family, an enzyme of a UDP-glucose:DNA beta-D-glucosyltransferase family, and an enzyme of a deaminase family (claim 190);
Species of epidermal property: D) intrinsic epidermal age (claim 204);
Species of further assaying and determining steps: R) Further assaying for methylation level, and wherein (c) further comprises determining said epidermal property of said subject based at least partially on said methylation level (claim 195)1.
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Claims 191 and 202-203 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.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 1-3, 190, 192-201 and 204-206.
Priority
The priority date of the instant claims 1-3, 190, 192-201 and 204-206 is September 08, 2021, filling date of the UNITED KINGDOM Patent Application Number 2112817.8, to which the present application claims priority.
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 197-199 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.
A) Regarding claim 197, it recites "said methylation level" and "said reference methylation level" which lack antecedent basis. The base claim 193/192/1 does not recite these terms.
The term "a methylation level" is introduced in claim 195, but claim 197 does not depend therefrom.
The term "a reference methylation level" is introduced in claim 196, but claim 197 does not depend therefrom.
B) Claim 198 recites "said methylation level" and "said reference methylation level," which lack antecedent basis. The base claim 194/1 does not recite these terms.
The term "methylation level" is introduced in claim 195, but claim 198 does not depend therefrom.
The term "reference methylation level" is introduced in claim 196, but claim 198 does not depend therefrom.
C) Claim 199 recites "said reference methylation level" which lacks antecedent basis. The base claim 195/1 does not recite this term.
The term "reference methylation level" is introduced in claim 196, but claim 198 does not depend therefrom.
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, 192-201 and 204-206 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 are drawn to a method comprising steps of determining an epidermal property of a subject based on nucleic acid methylation levels.
Following the analysis below the claims are not patent eligible under 35 U.S.C. 101.
Step 1 - Whether the Claim is to a Statutory Category : YES. The claims are drawn to a method, therefore to one of the four statutory categories.
Step 2A Prong 1 - Whether the Claim Recite an Abstract idea, Law of Nature, or Natural Phenomenon: Yes. The claims recites steps to observe naturally occurring methylation profiles in a subject's DNA, and determining certain epidermal property, such as a disease, based on methylation level, which is a naturally occurring relationship.
As stated in MPEP 2106.04(b)(I), laws of nature and natural phenomena, as identified by the courts, include naturally occurring principles/relations and nature-based products that are naturally occurring or that do not have markedly different characteristics compared to what occurs in nature. A subject naturally possesses a methylation pattern in their epigenome, and the methylation level as biomarker comprised by the subject's epigenome is classified as naturally occurring principles/relations.
In conclusion, the claims recite laws of nature and natural phenomena.
Step 2A Prong 2- Whether the Claim Recite Additional Elements that Integrate the Judicial Exception into a Practical Application: No. The claim does not integrate the judicial exception into a practical application. The method steps in claim 1 merely observe the judicial exception and do not integrate it into a practical application. The method ends with determining a property of the subject based on the processed nucleic acid to analyze methylation level, which, by itself, is a mental process. There is no further action recited based on this determination.
Step 2B- Whether a Claim Amounts to Significantly More: No. In this instant case, the claims, when considered as a whole, do not recite any inventive concept with additional elements that amount to significantly more than the judicial exception.
Methods for observing methylation levels using nucleotide base-modifying enzymes are well known and commercially available in the field of molecular biology:
See Roberts (Importance of Methylation Analysis and Application Areas; May 2021;) discusses NEBNext® Enzymatic Methyl-seq (EM-seq™) from New England Biolabs;
See also Vaisvila (Vaisvila et al. EM-seq: detection of DNA methylation at single base resolution from picograms of DNA. BioRxiv. 2019 Dec 23:2019-12) pages 1-2, discusses ACE-seq, TET-assisted pyridine borane sequencing (TAPS) in Introduction;
See also Liu (Liu et al. Bisulfite-free direct detection of 5-methylcytosine and 5-hydroxymethylcytosine at base resolution. Nat Biotechnol. 2019 Apr;37(4):424-429. doi: 10.1038/s41587-019-0041-2. Epub 2019 Feb 25. PMID: 30804537);
See WO2017075436A1 - Compositions and methods for determining modified cytosines by sequencing; FIG. 1.
Non-invasive sampling of a skin surface sample using adhesive tape is also well-known in the art:
See US20160024595A1 - Characterization of melanoma using a molecular signature; [0007];
See Taslimi (Taslimi et al. , A novel non-invasive diagnostic sampling technique for cutaneous leishmaniasis. PLoS Negl Trop Dis. 2017 Jul 13;11(7):e0005750. doi: 10.1371/journal.pntd.0005750. PMID: 28704463; PMCID: PMC5526608); Fig. 2;
See US20100267642A1 - Use of complex forms of calmodulin-like skin protein clsp; [0058];
WO2018161062A1 - Non-invasive methods for skin sample collection and analysis ; Figures 7A-7B;
US20050221334A1 - Tape stripping methods for analysis of skin disease and pathological skin state; Abstract;
US20150361509A1 - Diagnosis of melanoma and solar lentigo by nucleic acid analysis; [0009].
The claims do not appear to add markedly different characteristics that significantly modify or use the naturally occurring correlation in a manner that is not naturally occurring. The dependent claims 192-201 and 204-205 do not recite additional elements that amount to significantly more than the judicial exception, as they either further describe observing the judicial exception or represent mere general linkage of the judicial exception to the additional elements in the claims (MPEP § 2106.05(h)).
Dependent claim 206 recites: "further comprising (d) administering a therapeutic regimen to the subject based on said presence of said skin disease, disorder, or condition."
Even if a claim does recite a law of nature or natural phenomenon, it may still be eligible. See MPEP 2106.04. For example, claims reciting a naturally occurring relationship between a patient’s genotype and the risk of QTc prolongation (a law of nature) were held eligible as not "directed to" that relationship because they also recited a step of treating the patient with an amount of a particular medication that was tailored to the patient’s genotype. Vanda Pharms., 887 F.3d at 1134-36, 126 USPQ2d at 1279-81.
In this instant claim, however, the administering step of claim 206 does not render the claim patent-eligible under 35 U.S.C. 101 because it broadly recites administering a generic "therapeutic regimen" to a subject, without tailoring the treatment to any specific methylation level that correspond to a specific condition.
In conclusion, the claims 1-3, 192-201 and 204-206 are not patent eligible under 35 U.S.C. 101.
Applicant is advised that amending the independent claim to include all of the limitations of claim 190 would overcome this rejection. Claim 190 recites a step of treating nucleic acids with a combination of enzymes that is not considered well-known, routine, and conventional in the art, and therefore imposes a meaningful limitation on the judicial exception.
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.
Claims 1-3, 190, 192-201 and 205 are rejected under 35 U.S.C. 103 as being unpatentable over Dobak (WO2018191268A1 -- Non-invasive skin-based detection methods; Published on 2018-10-18; cited as Foreign Patent Document#1), in view of Vaisvila (Vaisvila et al. EM-seq: detection of DNA methylation at single base resolution from picograms of DNA. BioRxiv. 2019 Dec 23:2019-12).
A) Dobak teaches methods comprising determining skin epidermal layer methylation status using non-invasive sample collection with adhesive patch ([0009]; [0171]; [0131]).
Regarding claim 1, Dobak teaches a method for determining an epidermal property of a subject ([0009] detecting methylation status in a skin sample, which is an epidermal property; [0171] lines 1-7, non-invasive skin sample collection using skin patch and performing diagnostic assay; [0131] differentially methylated biomarkers in skin cancer), comprising:
(a) providing an epidermal sample of said subject that has been obtained non- invasively from said subject ([0171]; [0335] collecting skin surface sample using adhesive patch);
(b) processing at least a portion of nucleic acids derived from said epidermal sample of said subject ([0131]; [0132] “methylation analysis is carried out by any means known in the art”; [0135] Combined Bisulfite Restriction Analysis, where restriction enzyme digestion is used to reveal methylation- dependent sequence differences in PCR products of sodium bisulfite- treated DNA.); and
(c) determining said epidermal property of said subject based at least partially on said modified nucleic acids ([0131]; determining methylation status in a sample from subject).
Dobak teaches performing methylation analysis on collected skin samples, and that “methylation analysis is carried out by any means known in the art” ([0131]; [0132]).
Dobak teaches modifying nucleotide bases by treating DNA with bisulfite (e.g., [0134]-[0135] DNA is modified by sodium bisulfite to convert unmethylated, but not methylated cytosines to uracil.)
Although Dobak does not explicitly teach modifying a nucleotide base using an enzyme, a skilled artisan would have found this feature obvious in view of the knowledge in the art, this is supported by Vaisvila.
Vaisvila teaches a methylation analysis method called Enzymatic Methyl-seq (EM seq):
“This method relies on two sets of enzymatic reactions. In the first reaction, TET2 and T4-bGT convert 5mC and 5hmC into substrates that cannot be deaminated by APOBEC3A. In the second reaction, APOBEC3A deaminates unmodified cytosines converting them to uracils. The protection of 5mC and 5hmC permits the discrimination of cytosines from 5mC and 5hmC. Over a range of DNA inputs, the overall fraction of 5mC and 5hmC in EM-seq libraries was similar to bisulfite libraries. However, libraries made using EM-seq outperformed bisulfite converted libraries in all specific measures examined including coverage, duplication, sensitivity and nucleotide composition.” (Abstract; see also Figure 4).
Therefore, a skilled artisan before the effective filing date of the claimed invention would have found it prima facie obvious to apply the EM seq methylation analysis approach of Vaisvila, to the method for determining skin epidermal layer methylation status using non-invasive sample collection with adhesive patch, as taught in Dobak, in order to leverage the superior performance of EM seq in methylation analysis, as suggested by Vaisvila.
The person of ordinary skill would have had a reasonable expectation of success because Dobak expressly permits use of any known methylation analysis method, and Vaisvila provides such method. Thus, the teachings are technically compatible.
Also, this modification would have been obvious as it aligns with the principle of KSR for a simple substitution of one known element for another to obtain predictable results, see MPEP 2141.
B) Regarding claim 2, Vaisvila teaches modifying in (b) comprises converting said base into a different base (Abstract; Figure 4).
Regarding claim 3, Vaisvila teaches an enzyme of a Ten- Eleven Translocation (TET) family (Figure 4, TET2).
Regarding claim 190, Vaisvila teaches processing nucleic acids using TET2 (Figure 4) or a functional equivalent derivative thereof, UDP-glucose:DNA beta-D-glucosyltransferase from E. coli or a functional equivalent derivative thereof (Figure 4, T4-phage b glucosyltransferase2 (T4-bGT)), and APOBEC3A or a functional equivalent derivative thereof (Figure 4, APOBEC3A).
Regarding claim 192, Dobak teaches obtaining said epidermal sample non- invasively from said subject ([0171]; [0335] collecting skin surface sample using adhesive patch).
Regarding claim 193, Dobak teaches applying an adhesive article comprising a skin tape to a skin area of said subject ([0171]; [0335] collecting skin surface sample using adhesive patch).
Regarding claim 194, Dobak teaches epidermal sample comprises cells from at least one of a stratum corneum and a stratum granulosum of said subject ([0077]).
Regarding claim 195, Dobak teaches determining a methylation level of at least a portion of said modified nucleic acids, and wherein (c) further comprises determining said epidermal property of said subject based at least partially on said methylation level ([0009]; [0171]; [0131]).
Regarding claim 196, Dobak teaches determining an epidermal property of a reference subject at least in part by determining a reference meth ylation level of at least a portion of nucleic acids derived from an epidermal sample of said reference subject, and wherein (c) further comprises determining said epidermal property of said subject based at least partially on said reference methylation level ([0131] “a gene of interest is differentially methylated in a skin cancer when compared to normal skin”; [0111] lines 1-10, teaches comparing measured values from the sample to a control from a healthy individual, in order to identification of the disease state, determining likelihood of treatment success for the given disease state, identification of progression of the disease state, or identification of the disease stage).
Regarding claim 197, Dobak teaches comparing said methylation level with said reference methylation level, and wherein (c) further comprises determining said epidermal property of said subject based at least partially on said comparing ([0131] “a gene of interest is differentially methylated in a skin cancer when compared to normal skin,” thus a skilled artisan would readily understand the differential methylation status of a gene is based on comparing a skin cancer sample and a reference methylation level of normal skin).
Regarding claim 198, Dobak teaches determining a hypermethylation or hypomethylation of said methylation level relative to said reference methylation level, and wherein (c) further comprises determining said epidermal property of said subject based at least partially on said hypermethylation or hypomethylation of said methylation level ([0131] “a gene of interest is differentially methylated in a skin cancer when compared to normal skin,” a skilled artisan would find it obvious that determination of whether a gene is hyper or hypomethylated is part of determining differential methylation status of a gene, meaning, a differentially methylated gene is either hyper or hypomethylated relatively to a reference).
Regarding claim 199, it is obvious in view of Dobak and Vaisvila because it does not further limit the claimed method.
Claim 199 recites:
"wherein a difference between said methylation level and said reference methylation level is indicative of a difference in said epidermal property of said subject and said epidermal property of said reference subject."
Per MPEP 2111.04, a wherein clause can limit a method claim if it contributes meaning and purpose to the manipulative steps.
In this instant case, the wherein clause does not limit the method claim because it merely describe an desirable indication, without modifying any step of the claimed method. These limitations do not impose any manipulative difference in the claimed method, nor do they add any new active step.
Therefore, this claim language is interpreted as descriptive statement without any associated active steps and do not distinguish the claim from the prior art.
Regarding claim 200, Dobak teaches prior to (b), deriving nucleic acids from epidermal sample ([0291] lines 1-3; [0297]).
Regarding claim 201, Dobak teaches deoxyribonucleic acid (DNA) ([0291] lines 1-3; [0297] human gDNA).
Regarding claim 205, Dobak teaches a presence or an absence of a skin disease, disorder, or condition ([0131] skin cancer ).
Claims 204 and 206 are rejected under 35 U.S.C. 103 as being unpatentable over Dobak, in view of Vaisvila, as applied to claim 1 above and further in view of Boroni (Boroni et al. Highly accurate skin-specific methylome analysis algorithm as a platform to screen and validate therapeutics for healthy aging. Clin Epigenetics. 2020 Jul 13;12(1):105. doi: 10.1186/s13148-020-00899-1. PMID: 32660606; PMCID: PMC7359467).
A) Regarding claim 204, Although Dobak teaches performing methylation analysis using skin epidermal sample ([0009];[0077]; [0131-[0132]; [0171]), with the specific interest in analyzing differentially methylated genes in skin cancer, it does not explicitly teach intrinsic epidermal age. However, determining intrinsic epidermal age in the context of DNA methylation analysis for skin age and overall health would have been obvious in view of the knowledge in the art, this is supported by Boroni.
Boroni teaches highly accurate method for determining skin-specific, DNA methylation (DNAm) age, using DNA methylation data (Abstract).
Boroni teaches skin aging reflects both intrinsic and extrinsic processes:
“Even though the causes of the accumulation of epigenetic alterations in DNA are unknown, current knowledge points to the participation of both intrinsic (intracellular) and extrinsic (extracellular) processes. The skin is no different from other tissues in this sense, as its aging reflects both intrinsic and extrinsic processes, such as genetic and metabolic factors, as well as UV exposure and the general exposure to the greater environment [33]. As observed in other tissues, skin aging is generally accompanied by the accumulation of senescent cells [34, 35], reduced cellular proliferation/tissue renewal, and altered extracellular matrix, which are associated with skin wrinkling, sagging, altered pigmentation [36], and cancer [37].” (page 10-11)
Boroni further suggests that its “highly accurate skin-specific DNAm age predictor constitutes a holistic tool that will be of great use in the analysis of human skin health status/molecular aging, as well as in the analysis of the potential of established and novel compounds to alter DNAm age.” (Abstract) And that “since skin cancer has been correlated to age [37], DNAm analysis may also benefit skin cancer studies.” (Page 12, left-hand col, lines 27-28).
Accordingly, 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 modify the methylation analysis method using a skin epidermal sample in the combined teachings of Dobak and Vaisvila to further analyze the methylation data and determine the methylation age of the subject’s epidermal skin, in order to gain additional insight into the subject’s overall skin health status, as suggested by Boroni.
The person of ordinary skill would have had a reasonable expectation of success because Boroni’s skin-specific DNAm age predictor use DNA methylation data from skin samples as input, which the combined teachings of Dobak and Vaisvila already generate. In addition, the teaching of Boroni is specifically pertinent to the skin-cancer methylation-status analysis of Dobak, a skin cancer correlates with ago, as taught by Boroni.
B) Regarding claim 206, Boroni suggests administering a therapeutic regimen to the subject based on skin DNAm age (page 12, left-hand col, para 3).
Conclusion
No claims are allowed.
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/TIAN NMN YU/Examiner , Art Unit 1681
1 Claims 191 and 202-203 are withdrawn as being drawn to non-elected species Q and S.
2 T4-bGT is another name for UDP-glucose:DNA beta-D-glucosyltransferase;
See ExplorEnz – The Enzyme Database, EC2.4.1.27 ; Archived Feb 16, 2020 on WaybackMachine
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