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 .
This action is in response to papers filed 6/09/2026.
Applicant’s election without traverse of Group III and the species of ZIC4 and cg211227068 in the reply filed on 11/14/2025 is acknowledged.
Claims 1-14, 18-19 and 21, 99-102 are pending. Claims 15-17, 20 and 22-98 have been cancelled.
Claims 1-14, 18-19 are withdrawn as being drawn to a nonelection.
The following rejections are modified or newly applied as necessitated by amendment. Response to arguments follows.
The following action for claims 21, 99-102 is FINAL.
Withdrawn Rejections
The 35 USC 112b rejection made in the previous office action is withdrawn based upon amendments to the claims.
The 35 USC 102 rejections made in the previous office action is withdrawn based upon amendments to the claims.
Newly Applied Claim Rejections - 35 USC § 112
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 21, 99-102 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.
Claims 21, 99-102 are indefinite as it is not clear if the claims intend biomarkers for each of the cancer types to be measured or if the claims intend to only screen one biomarker to a particular cancer type. Furthermore it is note clear if these “reference value ranges” is intended to be a comparison to one biomarker to data of that same biomarker for the reference or if the claims encompass any types of reference value ranges.
Claim 101 is indefinite over the recitation of the recited cg markers –. The recited markers are acronyms used by Illumina. There is no fixed and well-accepted meaning in the art for what constitutes the cg numbers. The information provided at Internet sites and in databases is continually changing and can be deleted. The disclosure of the Illumina nomenclature at a current Internet address does not ensure that this information will remain available overtime or is well-known (utilized or referenced) in the art. Also, the chromosomal positions provided in the Illumina document to be downloaded vary over time and there is no fixed location or meaning for the listed nucleotide positions. The meaning of the nucleotide positions requires knowledge of the nucleotide sequence provided in a particular NCBI Database build. Accordingly, the metes and bounds of what is encompassed by the recited cg numbers is not unclear.
Modified Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 21, 99-102 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of one or more of the genes in each of ai-av listed is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
The recited alternative species in the groups set forth here do not share a single structural similarity, as each method relies on detection of different biomarker position. Each biomarker that could be detected is itself located in a separate region of the genome and has its own structure. The nature of genes is that they are differences within a population. The only structural similarity present is that all detected positions are part the nucleic acid structure. The fact that the markers comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising a nucleotide alone is not essential to the common activity of being correlated with treatment. For example, the biomarker APC has a distinct chemical structure as compared to, for example, ZIC4 since the gene can only be understood within the context of the nucleotides, which are structurally dissimilar. Accordingly, while the different markers are asserted to have the property of being indicative of treatment, they do not share a single structural similarity. Nor is the functionality is clear from the very nature of the biomarkers.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Response to Arguments
The reply traverses the rejection. A summary of the arguments is provided below with response to arguments follows. The reply asserts that the biomarkers genes within each disease specific panel share a single structural similarity for each are tumor suppressor genes containing CpG signals in the promoter regions that become hypermethylated (p. 10). The reply asserts that these are essential structural characteristics common for all members of each group (p. 10). The reply asserts that each comprise a common use (p 10).
These arguments have been reviewed but have not been found persuasive.
In particular the asserted functionality and structure appear to be based on the data provided by the specification. Therefore the genes are not described as having a structural similarity from “their very nature”. The genes would have to first be detected to be correlated to cancer subtypes, which would involve lab determinations. There is no evidence by this very nature that the biomarkers would share a single structural similarity.
Modified 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 21, 99, 101-102 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation without significantly more. The claim(s) recite(s) a judicial exception of correlation of diagnosis and CpG methylation expression. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims do not integrate the judicial exception to steps that are not considered routine and conventional steps.
These judicial exceptions are not integrated into a practical application because the claims only recite the natural correlation and routine and convention steps, wherein the routine and convention steps does not integrate the judicial expectation. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the steps are considered general and routine knowledge in the prior art as exemplified by the prior (as discussed below).
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case the Step 1 requirement is satisfied as the claims are directed towards a process.
Step 2A Prong one. Does the claim recite a law of nature, a natural phenomenon or an abstract idea? Yes, a natural phenomenon
The correlation of methaytlion CpG data and diagnosis is considered a natural correlation. The step of providing determining the methylation expression in the sample are considered a routine and conventional step as detailed below.
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? The answer is no as the steps require only routine and convention steps and does not integrate the judicial exception to a practical application.
Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No as the claims do not require any elements that integrate the judicial exception. Feber et al. (US Patent Application 2018/0305765).teaches a method of measuring levels of methylation by CpG detection in ZIC4 promoter using cfDNA from a blood sample (paragraph 38 and table 1).
These methods are considered generic recitations of general methods of methylation determination that do not overcome the rejection.
Response to Arguments
The reply traverses the rejection. A summary of the arguments is provided below with response to arguments follows. The reply asserts that the claims integrate a natural relationship to practical application by applying a specific diagnostic process that transforms raw methylation data into a concrete diagnostic determination for a particular cancer (p. 12). The reply asserts that the amended claims further require a defined panels of signatures biomarkers discovered through the LAMB methodology and as such claim 21 requires specific cgs (p. 12).
These arguments have been reviewed but have not been found persuasive.
It is noted that claim 21 does not require any particular methylation assay (e.g. LAMB) nor does the claim require any particular cpgs, except that these regions are within the promoter region. As noted above although the claims require steps of measuring levels , comparing, and determining these are not sufficient to integrate judicial exceptions. The comparing and determining steps are considered judicial exceptions themselves as these steps are considered “abstract” as the steps are considered mental steps. The step of measuring levels of methylation is considered a well-known routine and conventional step of measuring naturally occurring regions of the sample and using well known methaytlion assays to measure the methylation level data. As such the rejection has been maintained.
Modified Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 21,99-102 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pfeifer et al. (US Patent Application Publication 20090305256 December 10, 2009) in view of Lo et al. (US patent Application Publication 2019/0241979 August 8, 2019).
With regard to claims 21 and 99 and 102, Pfeifer et al. teaches diagnosis of lung squamosas cell carcinoma by detection of increased methaytlion of CpG sites in the promoter of ZIC4 (para 12, 57-58 and table 2). Pfeifer et al. teaches that the region that is detected is promoter associated CpGs (para 31). Pfeifer et al. teaches comparison to normal levels (para 27) which would encompass the limitation of reference value ranges”. Pfeifer et al. teaches use of blood but does not teach cfDNA (para 24).
With regard to claim 100, Pfeifer et al does not specifically recite cg211227068, however, as noted by the 35 USC 112b above, it is not clear the region this recitation encompasses. As Pfeifer et al. teaches the detection of the promoter region, Pfeifer et al. teaches screening this region that would be encompassed.
With regard to claim 101, Pfeifer et al. teaches an assay that encompasses methaytlion based PCR (para 27).
However Pfeifer et al. does not teach of cfDNA from blood.
With regard to claim 21, Lo et al teaches screening of cfDNA derived from blood samples from adenocarcinoma lung patients to measure levels of methylation (para 333,466,557). Lo et al. teaches that this screening includes probes on the Illumina Infinium Human Methylation 450K bead chip array (para 557). As indicated by the specification ZIC4 used in the specification is the probe cg21127068 on this bead chip array.
Therefore it would be prima facie obvious to one of ordinary skill in the art at the time of the effective filing date to modify the method of Pfeifer et al. to screen other known sample types such as the one taught by Lo et al. to make determinations on expression of Zin4 methylation. The ordinary artisan would be motivated to use cfDNA as taught by Lo et al. because Lo teaches that this gene is on known arrays for methylation detection and the obtaining cfDNA is non-invasive as compared to the tissue isolation of Pfeifer et al.
Response to Arguments
The reply traverses the rejection. A summary of the arguments is provided below with response to arguments follows. The reply asserts that claims require measuring, comparing, and determining steps and asserts that Feber does not anticipate these steps. As noted above the combination of Feber and Lo tech the required steps. It is noted that the rejection is based on Pfeifer and not Feber. The reply asserts that neither Lo or Pfeifer teach the recited genes and subtypes (p. 15). It is noted that Lo is used for detection of cfDNA. Furhtermore the claims as amended only require the analysis of one of the recited biomarkers to a subtype (which is taught by Pfeifer). The reply asserts that there are no reasons to combine (p. 16). However, it would be obvious to use a known sample type (cfDNA) which has been shown to be measurable with regard to detectable methylation levels in a method of Pfeifer, which teaches blood samples. The ordinary artisan would be motivated to use cfDNA as taught by Lo et al. because Lo teaches that this gene is on known arrays for methylation detection and the obtaining cfDNA is non-invasive as compared to the tissue isolation of Pfeifer et al.
Conclusion
No claims are 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE D SALMON whose telephone number is (571)272-3316. The examiner can normally be reached 9-530.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu Cheng (Winston) Shen can be reached at 5712723157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KATHERINE D SALMON/Primary Examiner, Art Unit 1682
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