DETAILED ACTION
The present Office Action is responsive to the Amendment received on June 10, 2026.
Preliminary Remark
Claims 1-33, 35-37, and 45-57 are canceled.
Claims 58-68 are new.
Claim Interpretation
The term, “methylation value” as it appears in claim 34, for example has been construed to mean a “methylation ratio” between a target locus and a control locus:
“determining a methylation value for each marker locus … by co-amplifying each marker locus and control locus … determining a methylation ratio for each of [marker locus] relative to the control locus based on the amplification products” (claim 34).
Claim Rejections - 35 USC § 112
The rejection of claims 1, 40, 41, 45, 50-53, 55, and 56 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to particularly point out and distinctly claim the subject matter, made in the Office Action mailed on June 10, 2026 is withdrawn in view of the Amendment received on June 10, 2026.
Rejection – New Grounds, 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 34, 38-44, and 58-68 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 34 is indefinite for reciting the phrase, “each marker locus selected from the group consisting of SEQ ID NO: 1 … 2 … 3” for the following reasons.
For the present rejection, the Office construes the members of the Markush group (i.e., SEQ ID NO: 1, 2, and 3) as being marker locus and the marker locus is what harbors the methylation.
The subject phrase recites that each marker locus is selected from the group consisting of SEQ ID Numbers 1, 2, and 3, which would appear to indicate that the method embraces an embodiment of using a single marker locus, that is, SEQ ID NO: 1, 2, or 3. However, the usage of the word, “each” confuses the phrase as appearing to require that the method employs all three loci (i.e., SEQ ID NO: 1, 2, and 3), and indeed Applicants’ arguments presented on page 5 of the response received on June 10, 2026 appears to argue this very point1. Therefore, the subject phrase is deemed indefinite.
However, claim 34 also recites the phrase, “comparing the methylation value for each of SEQ ID NO: 1 … 2 … and 3”, which appears to imply that the methylation was value was determined for all three loci. Therefore, the Office has construed the claim to determine the methylation value of each of SEQ ID NO: 1, 2, and 3.
Claim 34 is also indefinite for the following reasons.
Claim 34 recites that the methylation value of each locus (i.e., SEQ ID NO: 1, 2, or 3) in the cfDNA of a human subject sample and each control locus not containing a recognition site (of methylation-sensitive restriction endonuclease) is determined and that this determination step is made via the step of, “co-amplifying each marker locus and the control locus” so as to generate an amplification product for each locus. Generation of an amplification product for each locus, however, is not a methylation “value.” In addition, if the methylation “value” is the ratio between the marker locus and its control locus, then it would generate only methylation value for the subject’ sample not the control locus. It becomes unclear how the methylation value of the control locus is then generated.
Regardless, for the purpose of prosecution, the Office has construed the methylation value to refer to a “ratio”.
Claim 34 is also indefinite for reciting the phrase, “characterizing the cfDNA sample as having a methylation profile characteristic of a plurality of cancer types by comparing the methylation value … to at least one cancer reference vale and a non-cancer reference value, wherein the at least one cancer reference value is determined from cfDNA sample obtained from subjects representing a plurality of cancer types, wherein the plurality of cancer types are selected from lung cancer, breast cancer, … and sarcoma”. It is unclear whether the method concludes with the determination of whether the methylation value has “ties” to one of the cancers recited or the value can determine which of the cancers the subject has. Claims 61 and 65 are also indefinite for the same reason.
For the purpose of prosecution, the phrase has been construed to mean that a determined methylation value is compared to a cancer reference value that is unique to each of the recited cancers.
Claims 40-44 and 58-60 are indefinite by way of their dependency on claim 34.
Claim 41 is indefinite because it attempts to re-define a methylation value to DCq, where the parent claim had already defined the term (and Office construed) as a ratio.
Claims 61 and 65 are also indefinite for reasons discussed above for claim 34, adopting the term, “each marker locus selected from the group consisting of”.
The same claim interpretation has been made (i.e., method embraces the use of single marker locus from SEQ ID NO: 1, 2, or 3).
Claims 62-64 and 66-68 are indefinite by way of their dependency on claims 61 and 65 (respectively).
Rejection – New Grounds, Necessitated by Amendment
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 34, 38-44, and 58-68 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 Written Description Rejection.
Independent claims 34, 61, and 65 have been amended (and newly submitted) to include that a comparing a methylation value for the three loci represented by SEQ ID NOs: 1-3 against a cancer reference value, wherein the cancer reference value is determined from a list of cancer including: lung cancer, breast cancer, colorectal cancer, hepatocellular carcinoma, leukemia, lymphoma, esophageal cancer, gastric cancer, head and neck cancer, ovarian cancer, uterine cancer, pancreatic cancer, and sarcoma.
The written description requirement ensures that, “an applicant invented the subject matter which is claimed. Further, the written description requirement for a claimed genus may be satisfied through a sufficient description of a representative number of species by 1) reduction to practice; 2) reduction to drawing; or 3) disclosure of relevant identifying characteristics (i.e., structure of other physical and/or chemical properties, functional characteristics coupled with a known or disclosed correlation between function and structure) (MPEP 2163 at II(A)(3)(a)(ii)).
Reduction to Practice
The Federal Circuit reiterated that mere use of the same words in the specification and the claim (an in ipsis verbis test) is not sufficient to establish written description.
The specification discloses that three genomic loci harboring a methylation region, represented by SEQ ID Numbers 1, 2, and 3 have been determined to show increased methylation levels in cell-free DNA in cancer patients, said cancer being in various types and stages:
“The present invention is based, in part on identification of three human genomic loci as DNA methylation markers for the detection of multiple types in cell-free DNA samples. These genomic loci, set forth herein as SEQ ID NO: 1 … 2 … 3 were found to have increased methylation levels in cell-free DNA of cancer patients of various types and stages compared to cell-free DNA of subjects with no cancer. (page 5)
The specification also teaches that three genomic loci harboring a methylation region, represented by SEQ ID NO: 4, 5, and 6 were previously discovered by applicants as being hypermethylated in lung cancer samples, and later further discovered that the level of the methylation can be utilized to distinguish between lung cancer and other types of cancers:
“The present invention is further based on the surprising finding that human genomic loci, set forth herein as SEQ ID NO: 4 … 5 … 6, that were previously disclosed by the inventors of the present invention to be hypermethylated in lung cancer DNA compared to normal DNA, also have increased methylation levels in cancer types other than lung cancer, and are therefore useful as general markers of cancer. The inventors of the present invention identified that a certain increase in methylation levels of these marker loci is common to a variety of cancer types and stages, and thus serves as a general indication for the presence of cancer in a subject (page 5)
“The inventors of the present invention identified that methylation levels of these marker loci above a first threshold are common to a variety of cancer types and stages, and thus serve as a general indication for the presence of cancer in a subject” (page 64)
“The inventors of the present invention identified that methylation levels of these marker loci above a first threshold are common to a variety of cancer types and stages and thus serve as a general indication for the presence of cancer in a subject. A further increase in methylation levels, above a second threshold, is specifically indicative for the presence of lung cancer in the subject” (page 65)
The specification provides threshold that provides a delineation between lung cancer and based on a specific formula that pertains to a value of DCq which is a value normalized against a cancer of a specific tissue against a control locus:
“the step of co-amplifying from the restriction endonuclease-treated DNA the at least one marker locus and a control locus is performed using real-time PCR … In some embodiments, the ratio between the signal intensities of the amplification products of each of said at least one marker locus and the control locus is calculated by determining the quantification cycle (Cq) of reach locus and calculating 2(Cq control locus-Cq marker locus) (page 9)
“The restriction sites within the marker loci are differentially methylated between cancer and non-cancer DNA. Methylation-sensitive restriction endonucleases cleave their restriction site only if it is unmethylated. Thus, the degree of digestion of each locus by HinPII and AcI depends on its level of methylation in a tested DNA sample, where increased methylation results in less digestion” (page 65)
“The numerical value obtained for a given marker locus with respect to the control locus represents a ratio between the signal intensities of the amplification products of this marker locus and the control locus, and reflects the methylation ratio between this marker locus and the control locus in the DNA sample … the highest signal ratio is scored 100 and the lowest signal ratio is scored 0. Altogether, six marker scores were calculated for each DNA sample. The six individual marker scores obtained for each DNA sample were combined into a single sample score, term “EpiScore” which is a number between 0 and 100, reflecting the overall relative methylation level of the DNA sample at the panel of six marker loci. A threshold EpiScore below the threshold classified the DNA sample as negative for cancer” (page 67)
The specification, however, provides such a threshold value which can only be distinguished between lung and: (i) colorectal cancer; (ii) liver cancer; (iii) breast cancer; and (iv) hematological cancers (see pages 70-72).
There are no other threshold values provided against which all types of cancers can be distinguished by comparison to a reference value as presently claimed method embodies.
Therefore, the specification only contains description that provides a reference value which allow the distinction of lung cancer vs. (i) colorectal cancer; (ii) liver cancer; (iii) breast cancer; and (iv) hematological cancers, as no such methylation reference values are disclosed.
Reduction to Drawing
The specification disclose the evidence of threshold methylation values represented by DCq value against the cancers discussed immediately above (see Figures 3A-3D).
Disclosure of Relevant Identifying Characteristics
While one could argue that a skilled artisan would be able to identify the “representative number of species” of the DCq threshold value so as to specifically identify all of the listed cancers recited in the claims, such a method would not satisfy the written description for the genus claims when, “the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional in the art or known to one of ordinary skill in the art” (MPEP 2163(I)(A)). For the claims at issue, such essential or critical feature is the DCq reference value that can clearly delineate one cancer over the other cancers based on the methylation levels. Applicants simply have not disclosed enough number of species within the claimed genus nor even demonstrated that such can be feasible based strictly on the methylation levels of the three loci that contain methylation region (i.e. CpG region).
As stated in University of California v. Eli Lilly and Co. at page 1404:
An adequate written description of a DNA ... "requires a precise definition, such as by structure, formula, chemical name, or physical properties," not a mere wish or plan for obtaining the claimed chemical invention. Fiers v. Revel, 984 F.2d 1164, 1171, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993). Accordingly, "an adequate written description of a DNA requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it; what is required is a description of the DNA itself." Id. at 1170, 25 USPQ2d at 1606.
Therefore, for the foregoing reasons, the genus embraced by the claims is not sufficiently described by the number of species disclosed in the specification, and therefore, the specification lacks written description of the claims.
Claim Rejections - 35 USC § 101
The rejection of claim 1, 34, 37-39, 45, and 56 under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception/abstract idea (i.e., data manipulation) without significantly more, made in the Office Action mailed on March 10, 2026 is withdrawn in view of the Amendment received on June 10, 2026.
Rejection – New, Necessitated by Amendment
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 61-68 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract idea (i.e., data manipulation) without significantly more.
The claims recite steps of data observation and manipulation. This judicial exception is not integrated into a practical application as discussed below.
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception based on the analysis under the current Patent Eligibility Guidelines (herein, “PEG”) as discussed below.
Step 1 Inquiry under PEG
Step 1 inquiry under Patent Eligibility Guidelines (herein, “PEG”) determines whether or not the claimed invention is drawn to one of the recognized statutory classes of invention. Claims 61-68 satisfy the present inquiry as being drawn to a method.
Step 2A Inquiry under PEG
A recently revised PEG now performs step 2A inquiry under a 2-prong analysis, and the subject claims analyzed accordingly as follows:
Prong 1:
Prong-1 inquiry under step 2A determines whether the claim(s) recites an abstract idea.
Claims 61 and 65:
Claims 61 and 65 recite the step of “determining” a cfDNA methylation value for recited marker loci, represented by SEQ ID NO: 1, 2, or 3 which tantamount to the uploading or looking at the data value and the step of “comparing” the value to a reference value. Such steps are considered no more than looking or loading of the data and comparison of the data, which is deemed data manipulation without a significant application of the abstract idea.
Claims 62-64 and 66-68 identify the source from which the data are generated, but fail to provide any additional elements.
Prong 2:
Prong-2 inquiry under step 2A determines whether or not the claims recite additional elements that integrate the judicial exception into a practical application in a manner that imposes a meaningful limit on the judicial exception.
Claims 62-64 and 66-68:
Claims 62-64 and 66-68 recite the additional element in the form of the number of samples from which the data was generated, or the identity of the samples. However, these are identification of the data and do not add any additional elements to apply data collection and manipulation steps in a significant way.
Step 2B Inquiry under PEG
Step 2B inquiry of the PEG determines whether or not additional elements are provided and whether such elements amount to significantly more than the judicial exception in the claims.
As stated above, claims 62-64 and 66-68 do not recite additional elements.
Therefore, the present claims lack patent eligibility.
Claim Rejections - 35 USC § 103
The rejection of claims 1, 37, 45, 51, and 52 under 35 U.S.C. 103 as being unpatentable over Frumkin et al. (WO 2019/142193 A1, published July 2019) in view of Pfeifer et al. (US 2009/0305256 A1, published December 2009), made in the Office Action mailed on March 10, 2026, is withdrawn in view of the Amendment received on June 10, 2026, canceling the rejected claims.
The rejection of claims 50 and 56 under 35 U.S.C. 103 as being unpatentable over Frumkin et al. (WO 2019/142193 A1, published July 2019) in view of Pfeifer et al. (US 2009/0305256 A1, published December 2009) as applied to claims 1, 34, 37-45, 51, and 52 above, and further in view of Chapman et al. (Lung Cancer, December 2016, vol. 102, pages 122-134), made in the Office Action mailed on March 10, 2026, is withdrawn in view of the Amendment received on June 10, 2026, canceling the rejected claims.
The rejection of claims 53 and 55 under 35 U.S.C. 103 as being unpatentable over Frumkin et al. (WO 2019/142193 A1, published July 2019) in view of Pfeifer et al. (US 2009/0305256 A1, published December 2009) as applied to claims 1, 34, 37-45, 51, and 52 above, and further in view of Ilie et al. (Virchows Arch., 2016, vol. 468, pages 511-525) or Croce et al. (WO 2011/119553 A1, published September 2011), made in the Office Action mailed on March 10, 2026, is withdrawn in view of the Amendment received on June 10, 2026, canceling the rejected claims.
Conclusion
No claims are allowed.
Claims are free of prior art as the prior art does not teach or suggest for a method which compares a methylation profile of the three marker loci represented by SEQ ID NOs: 1, 2, and 3.
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.
Inquiries
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Young J. Kim whose telephone number is (571) 272-0785. The Examiner can best be reached from 7:30 a.m. to 4:00 p.m (M-F). The Examiner can also be reached via e-mail to Young.Kim@uspto.gov. However, the office cannot guarantee security through the e-mail system nor should official papers be transmitted through this route.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's supervisor, Gary Benzion, can be reached at (571) 272-0782.
Papers related to this application may be submitted to Art Unit 1681 by facsimile transmission. The faxing of such papers must conform with the notice published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 CFR 1.6(d)). NOTE: If applicant does submit a paper by FAX, the original copy should be retained by applicant or applicant’s representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED, so as to avoid the processing of duplicate papers in the Office. All official documents must be sent to the Official Tech Center Fax number: (571) 273-8300. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600.
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/YOUNG J KIM/Primary Examiner
Art Unit 1637 September 1, 2026
/YJK/
1 “As an initial matter, claim 34 as amended … requires determining a methylation ratio for each of SEQ ID NO: 1 … 2 … 3 … All three loci are required.”, page 5, Response received on June 10, 2026.
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