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 .
Claims Status
Claims 25-33, 42, & 45-50 filed on 04/15/2026 are pending. Claims 34-41, 43, & 44 are withdrawn from consideration as being drawn to a non-elected invention. Claims 25, 27-29, & 31 are currently under examination directed to the elected species of MROH6 gene in claims 25, 27, & 28, of MROH6 gene by using the primers of SEQ ID NO: 10 and SEQ ID NO: 11 and the probe sequence of SEQ ID NO: 28 in claim 29, and of blood sample in claim 31 (see response dated 09/25/2025). Claim 33 is rejoined with claims 25-32, 42, & 45-50. The cancellation of claims 34-41, 43, & 44 and the addition of new claims 45-50 in the reply filed on 04/15/2026 is acknowledged. All the amendments and arguments have been thoroughly reviewed but are deemed insufficient to place this application in condition for allowance. The following rejections are either newly applied, as necessitated by amendment, or are reiterated. They constitute the complete set being presently applied to the instant application. Response to Applicant’s argument follow. This action is FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.
Claim Rejections - 35 USC § 112
Claims 27-29, 33, 42, 49, & 50 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.
Regarding amended claim 27, although not elected, applicant is made aware of the recitation of “chr7: 129425301 genomic region and chr20: 1784267 genomic region” in lines 5-6 of the claim is unclear as to how “chr7: 129425301” and “chr20: 1784267” refer to a specific genomic region when only a particular single position in the genome is identified by chr7: 129425301” and “chr20: 1784267” and not a region in chromosome 7 and chromosome 20.
Regarding amended claim 29, although not elected, applicant is made aware of the recitation of “chr7: 129425301 genomic region and chr20: 1784267 genomic region” in lines 9 & 11 of the claim is unclear as to how “chr7: 129425301” and “chr20: 1784267” refer to a specific genomic region when only a particular single position in the genome is identified by chr7: 129425301” and “chr20: 1784267” and not a region in chromosome 7 and chromosome 20.
Regarding amended claim 42, although not elected, applicant is made aware of the recitation of “chr7: 129425301 genomic region and chr20: 1784267 genomic region” in lines 18 & 20 of the claim is unclear as to how “chr7: 129425301” and “chr20: 1784267” refer to a specific genomic region when only a particular single position in the genome is identified by chr7: 129425301” and “chr20: 1784267” and not a region in chromosome 7 and chromosome 20.
Regarding new claim 49, the claim recites the limitation “the DNA sample” in line 1 of the claim and there is insufficient antecedent basis for this limitation in the claim.
Regarding new claim 50, the claim recites the limitation “the DNA sample” in line 1 of the claim and there is insufficient antecedent basis for this limitation in the claim.
Claims 28 & 33 is rejected due to their dependence on claim 27.
Claim Rejections - 35 USC § 101
Claims 25-28, 30-33, 42, 45-50 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation/law of nature and an abstract idea without significantly more. This judicial exception is not integrated into a practical application and the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106. The unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, 561 U.S. 593, 601 (June 28, 2010) and Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014). See also Myriad v Ambry, CAFC 2014-1361, -1366, December 17, 2014. The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66, 71 (2012). “[L]aws of nature, natural phenomena, and abstract ideas” are not patentable. Dia-mond v. Diehr, 450 U. S. 175, 185 (1981); see also Bilski v. Kappos, 561 U. S. at 601 (2010).
Claims Analysis:
As set forth in MPEP 2106, the claims have been analyzed to determine whether they are directed to one of the four statutory categories (STEP 1).
The instant claims are directed to methods and therefore are directed to one of the four statutory categories of invention.
The claims are then analyzed to determine if they recite a judicial exception (JE) (STEP 2A, prong 1) [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)].
The claimed invention recites a method for quantifying the level of methylation of MROH6 gene wherein hypermethylation is indicative of lung cancer. This recitation is a natural correlation between level of methylation and indication of lung cancer. With regard to the natural correlation, as in Mayo, the relationship is itself a natural process that exists apart from any human action. The claimed invention also recites “indicative of lung cancer”, “comparing the level of methylation in (a) with the level of methylation for the same gene(s) or genomic region(s) in a control sample”, “comparing the level of methylation of the selected gene(s) or genomic region(s) to a reference value”, “comparing the level of methylation of MROH6 gene to a reference value”, and “comparing the level of methylation of the selected gene to a reference value” which is a recitation of an abstract idea because it encompasses conclusions and determinations which can occur entirely within the mind. It is therefore determined that the claims are directed to judicial exceptions.
The claims are then analyzed to determine whether they recite an element or step that integrates the JE into a practical application (STEP 2A, prong 2) [Vanda Pharmaceuticals Inc., v. West-Ward Pharmaceuticals, 887 F.3d 1117 (Fed. Cir. 2018)].
The claims recite steps of quantifying the level of methylation of a gene or geonic region through NGS or PCR and comparing the level of methylation of the selected at least one gene to a control, however, this does not integrate the JE into a practical application because it is a mere data gathering step to use the correlation and does not add a meaningful limitation to the method.
In the absence of steps or elements that integrate the JE into a practical application, the additional elements/steps are considered to determine whether they add significantly more to the JE either individually or as an ordered combination, to “’transform the nature of the claim’ into a patent eligible application” [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)] (STEP 2B).
In the instant situation, the steps of quantifying the level of methylation in at least one gene are generally recited and do not provide any particular reagents that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited. This step is not only a mere data gathering step, but the general recitation of detection of known nucleic acids is well understood, routine, and conventional activity (See MPEP 2106.05(d)(II)). Applicant is reminded that in Mayo, the Court found that “[i]f a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself." Further "conventional or obvious" "[pre]solution activity" is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law”. Flook, 437 U. S., at 590; see also Bilski, 561 U. S., at ___ (slip op., at 14) (“[T]he prohibition against patenting abstract ideas ‘cannot be circumvented by’ . . . adding ‘insignificant post-solution activity’” (quoting Diehr, supra, at 191–192)). The Court also summarized their holding by stating “[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.” Therefore these limitations/steps do not “‘transform the nature of the claim’ into a patent-eligible application.’” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
When viewed as an ordered combination, the claimed limitations are directed to nothing more than the determination that a natural correlation/phenomena exists. Any additional element consists of using well understood, routine and conventional activity, and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.
Accordingly, it is determined that the instant claims are not directed to patent eligible subject matter.
Response to Arguments
The response traverses the rejection. The response asserts that the claims as filed are not directed to a judicial exception. Further, the response asserts that in Illumina, the court determined that claims to a method preparing a fraction of cell-free DNA for analyzing a genetic locus was not directed to the discovered natural phenomenon, but, instead, exploited the discovery in a method for preparation of a mixture enriched in fetal DNA and that notably, the Illumina court rejected the notion that the steps of a patent eligible method need to be non-conventional. Specifically, the response asserts that since here, claim 25 is directed to patent eligible method comprising quantifying methylation of a specific gene and that this method includes steps that are performed in a laboratory to quantify the level of methylation of MROH6 gene in the sample of a subject. Further, the response asserts that the claims are directed to exploiting the discovered methylation pattern in MROH6 to the useful end of preparing DNA in which cytosine modifications are differentially enriched by bisulfite treatment and that in the claimed method the bisulfite conversion changes the composition of the DNA. Further, the applicants assert that the fact that bisulfite converting DNA might be considered routine or conventional by the office is of no consequence in step one of the Alice/Mayo test of whether a claim is directed to natural phenomenon and that the claims are directed to patent-eligible subject matter at step one and the analysis does not need to reach step two of the test. This argument has been thoroughly reviewed but was not found persuasive as the claimed invention recites a method for quantifying the level of methylation of MROH6 gene wherein hypermethylation is indicative of lung cancer. This recitation is a natural correlation between level of methylation and indication of lung cancer. With regard to the natural correlation, as in Mayo, the relationship is itself a natural process that exists apart from any human action. The claimed invention also recites “indicative of lung cancer”, “comparing the level of methylation in (a) with the level of methylation for the same gene(s) or genomic region(s) in a control sample”, “comparing the level of methylation of the selected gene(s) or genomic region(s) to a reference value”, “comparing the level of methylation of MROH6 gene to a reference value”, and “comparing the level of methylation of the selected gene to a reference value” which is a recitation of an abstract idea because it encompasses conclusions and determinations which can occur entirely within the mind. It is therefore determined that the claims are directed to judicial exceptions. Therefore, the claims are directed to judicial exceptions of natural correlation and abstract ideas and the analysis proceeds to step two as discussed above.
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Claim Rejections - 35 USC § 102
Claim(s) 25, 26, 30, 32, 42, 45-48 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cai (Cai et al.; Journal for ImmunoTherapy of Cancer, Vol. 7, pages 1-11, July 2019).
Regarding amended claim 25, Cai teaches a method for assessing DNA methylation profiles in lung cancer samples through the Infinium HumanMethylation 850K EPIC BeadChip array, in which the 850K encompasses the MROH6 gene (quantifying the methylation level in a biological sample from a subject that has or is suspected to have lung cancer of the patient of MROH6 gene), comparing to a control, and using the methylome-wide analysis for assessing clinical outcome with PD-L1 treatments (pg. 2 column 1 3rd full paragraph lines 1-15; pg. 3 column 1 1st full paragraph lines 1-24; pg. 3-4 paragraph bridging pg. 3 & 4 lines 1-28; pg. 9 column 1 1st full paragraph lines 1-21; pg. 9 paragraph bridging column 1 & 2 lines 15-29).
Regarding amended claim 26, Cai teaches a method for assessing DNA methylation profiles in lung cancer samples through the Infinium HumanMethylation 850K EPIC BeadChip array, in which the 850K encompasses the MROH6 gene, in which the Infinium HumanMethylation 850 EPIC BreadChip array requires pretreatment of the samples with bisulfite (obtaining a biological sample from the patient, preparing DNA from the biological sample, bisulfite converting the prepared DNA, and quantifying the methylation level of the MROH6 gene) (pg. 2 column 1 3rd full paragraph lines 1-15; pg. 3 column 1 1st full paragraph lines 1-24; pg. 3-4 paragraph bridging pg. 3 & 4 lines 1-28; pg. 9 column 1 1st full paragraph lines 1-21; pg. 9 paragraph bridging column 1 & 2 lines 15-29).
Regarding amended claim 30, Cai teaches a method for assessing DNA methylation profiles in lung cancer samples through the Infinium HumanMethylation 850K EPIC BeadChip array, in which the 850K encompasses the MROH6 gene, in which standard protocol of the Infinium HumanMethylation 850 EPIC BreadChip array comprises amplification of the samples (level of methylation is quantified by qPCR or dPCR) (pg. 2 column 1 3rd full paragraph lines 1-15; pg. 3 column 1 1st full paragraph lines 1-24; pg. 3-4 paragraph bridging pg. 3 & 4 lines 1-28; pg. 9 column 1 1st full paragraph lines 1-21; pg. 9 paragraph bridging column 1 & 2 lines 15-29).
Regarding amended claim 32, Cai teaches assessing DNA methylation profiles in lung cancer samples through the Infinium HumanMethylation 850K EPIC BeadChip array covering CpG sites across the human whole genome (the level of methylation of at least two genes is quantified simultaneously in the biological sample of the patient) (pg. 3-4 paragraph bridging pg. 3 & 4 lines 1-5).
Regarding amended claim 42, Cai teaches a method for assessing DNA methylation profiles in lung cancer samples through the Infinium HumanMethylation 850K EPIC BeadChip array, in which the 850K encompasses the HOXB4 gene (quantifying the level of methylation in a biological sample of the patient of at least one gene or genomic region selected from one of the groups consisting of HOXB4 gene) (pg. 2 column 1 3rd full paragraph lines 1-15; pg. 3 column 1 1st full paragraph lines 1-24; pg. 3-4 paragraph bridging pg. 3 & 4 lines 1-28; pg. 9 column 1 1st full paragraph lines 1-21; pg. 9 paragraph bridging column 1 & 2 lines 15-29).
Regarding new claim 45, Cai teaches a method for assessing DNA methylation profiles in lung cancer samples through the Infinium HumanMethylation 850K EPIC BeadChip array, in which the 850K encompasses the HOXB4 gene (quantifying the level of methylation of at least one gene or genomic region selected from HOXB4 gene) (pg. 2 column 1 3rd full paragraph lines 1-15; pg. 3 column 1 1st full paragraph lines 1-24; pg. 3-4 paragraph bridging pg. 3 & 4 lines 1-28; pg. 9 column 1 1st full paragraph lines 1-21; pg. 9 paragraph bridging column 1 & 2 lines 15-29).
Regarding new claim 46, Cai teaches a method for assessing DNA methylation profiles in lung cancer samples through the Infinium HumanMethylation 850K EPIC BeadChip array, in which the 850K encompasses the MROH6 gene (obtaining a biological sample from a patient and quantifying the methylation level in a biological sample of the patient of the MROH6 gene), comparing to a control (comparing the level of methylation of MROHG gene to a reference value), and using the methylome-wide analysis for assessing clinical outcome with PD-L1 treatments (predicting clinical outcome on the basis of the comparison step) (pg. 2 column 1 3rd full paragraph lines 1-15; pg. 3 column 1 1st full paragraph lines 1-24; pg. 3-4 paragraph bridging pg. 3 & 4 lines 1-28; pg. 9 column 1 1st full paragraph lines 1-21; pg. 9 paragraph bridging column 1 & 2 lines 15-29).
Regarding new claim 47, Cai teaches a method for assessing DNA methylation profiles in lung cancer samples through the Infinium HumanMethylation 850K EPIC BeadChip array, in which the 850K encompasses the HOXB4 gene (quantifying the level of methylation of at least one gene or genomic region selected from HOXB4 gene) comparing to a control (comparing the level of methylation of said one gene or genomic region to a reference value), and using the methylome-wide analysis for assessing clinical outcome with PD-L1 treatments (predicting clinical outcome on the basis of the comparison step) (pg. 2 column 1 3rd full paragraph lines 1-15; pg. 3 column 1 1st full paragraph lines 1-24; pg. 3-4 paragraph bridging pg. 3 & 4 lines 1-28; pg. 9 column 1 1st full paragraph lines 1-21; pg. 9 paragraph bridging column 1 & 2 lines 15-29).
Regarding new claim 48, Cai teaches a method for assessing DNA methylation profiles in lung cancer samples through the Infinium HumanMethylation 850K EPIC BeadChip array, in which the 850K encompasses the MROH6 gene, in which the Infinium HumanMethylation 850 EPIC BreadChip array requires pretreatment of the samples with bisulfite (obtaining a biological sample from the patient, preparing DNA from the biological sample, bisulfite converting the prepared DNA, and quantifying the methylation level of at least one gene selected from MROH6 gene) (pg. 2 column 1 3rd full paragraph lines 1-15; pg. 3 column 1 1st full paragraph lines 1-24; pg. 3-4 paragraph bridging pg. 3 & 4 lines 1-28; pg. 9 column 1 1st full paragraph lines 1-21; pg. 9 paragraph bridging column 1 & 2 lines 15-29).
Response to Arguments
The response traverses the rejection. The response asserts that Cai does not anticipate the claimed invention ad none of the differentially methylated regions of Table S3 or top 3000 methylation variable positions of Table S4 taught by Cai include the genomic location of the MROH6 gene and therefore, even though the BeadChip array assay may contain MROH6, Cai does not teach differential methylation of the MROH6 gene, let alone MROH6 gene hypermethylation as indicative of lung cancer and, therefore, Cai fails to disclose each and every element arranged as in the claims and does not anticipate the claims. This argument has been thoroughly reviewed but was not found persuasive as the only active step of amended claim 25 is quantifying the level of methylation of MROH6 gene in a biological sample of a subject that has or is suspected of having lung cancer or has had lung cancer. The recitation of “wherein hypermethylation is indicative of lung cancer” is not an active step as recited in claim 25 as currently amended. Further, Cai teaches a method for assessing DNA methylation profiles in lung cancer samples through the Infinium HumanMethylation 850K EPIC BeadChip array, in which the 850K encompasses the MROH6 gene (quantifying the methylation level in a biological sample from a subject that has or is suspected to have lung cancer of the patient of MROH6 gene) (pg. 2 column 1 3rd full paragraph lines 1-15; pg. 3 column 1 1st full paragraph lines 1-24; pg. 3-4 paragraph bridging pg. 3 & 4 lines 1-28; pg. 9 column 1 1st full paragraph lines 1-21; pg. 9 paragraph bridging column 1 & 2 lines 15-29). Therefore, Cai teaches each and every element of claim 25 as currently amended.
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Claim Rejections - 35 USC § 103
Claim(s) 31, 49, & 50 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cai (Cai et al.; Journal for ImmunoTherapy of Cancer, Vol. 7, pages 1-11, July 2019), in view of Pathak (Pathak et al.; Clinical Chemistry, Vol. 52, pages 1833-1842, December 2005).
The teachings of Cai with respect to claim 25 is discussed above and incorporated herein.
Regarding amended claim 31 and new claims 49 & 50, Cai does not teach that the biological sample is a blood sample (see claim 31) or that the DNA sample is cell-free DNA or circulating tumor DNA (see claims 49 & 50).
Pathak teaches a method of screening lung cancer through determining methylation in serum/plasma (blood) samples comprising circulating cell-free DNA (abstract background lines 1-6; pg. 1833-1834 paragraph bridging pg. 1833 & 1834 lines 1-22; pg. 1838 column 1 2nd full paragraph lines 1-9; pg. 1838 paragraph bridging column 1 & 2 lines 6-23). In addition, Pathak teaches that use of serum/plasma (blood) samples comprising circulating cell-free DNA is a simple and non-invasive method to manage and screen lung cancer (abstract background lines 1-6; pg. 1833-1834 paragraph bridging pg. 1833 & 1834 lines 1-22).
Cai and Pathak are considered to be analogous to the claimed invention because they are all in the same field of detection of biomarkers in lung cancer samples. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of assessing DNA methylation profiles in lung cancer samples through the Infinium HumanMethylation 850K EPIC BeadChip array in Cai to incorporate the use of a serum/plasma (blood) sample comprising circulating cell-free DNA from lung cancer patients as taught in Pathak because Pathak teaches that doing so would provide a simple and non-invasive method to manage and screen lung cancer.
Conclusion
Claims 25-33, 42, & 45-50 are 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BAILEY C BUCHANAN whose telephone number is (703)756-1315. The examiner can normally be reached Monday-Friday 8:00am-5:00pm ET.
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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
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