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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/08/2025 has been entered.
Claims Status
Claims 5, 7, 8, 10, 14-16, 23, & 27 filed on 12/08/2025 are pending. Newly submitted claim 27 directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: claim 27 is directed to a polynucleotide, wherein the polynucleotide is a fragment of SEQ ID NO: 1, which is the amplification product of primers SEQ ID NO: 7 & SEQ ID NO: 8, in which Group II of the requirement for Restriction/Election (dated 11/18/2024) comprised claims directed to a polynucleotide, and Group II was not elected in the reply filed on 01/17/2025.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claim 27 withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Therefore, claims 11, 13, 17-22, & 24-27 are withdrawn from consideration as being drawn to a non-elected invention and claims 5, 7, 8, 10, 14-16, & 23 filed on 12/08/2025 are pending. The cancellation of claim 6 without prejudice or to disclaimer of the subject matter therein and the new claim 27 in the reply filed on 12/08/2025 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 Non-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
Claim 5 & 7 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 5, the recitation of “A pan-cancer detection method” in line 1 of the claim followed by the recitation of “wherein the tumor is a liver cancer, a breast cancer, a leukemia, a colorectal cancer, a lung cancer, a pancreatic cancer, an esophageal cancer” in lines 18-19 of the claim is unclear. It is unclear how a sample can comprise all of the tumor types lines in lines 18-19 of the claim, i.e. how can a sample contain a liver cancer, a breast cancer, a leukemia, a colorectal cancer, a lung cancer, a pancreatic cancer, and an esophageal cancer tumor? In addition, the claim recites the limitations of “the detection methods” in line 14 of the claim and “the tumor” in line 18 of the claim and there is insufficient antecedent basis for these limitations in the claim.
Claim 7 is rejected due to its dependence on claim 5.
Claim Rejections - 35 USC § 101
Claims 5 & 7 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation/law of nature 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 detecting a tumor by detecting 5-methylation modification on the CpG site(s) of a polynucleotide. This recitation is a natural correlation between detecting the presence of modified CpG site(s) in SEQ ID NO: 1 and detecting the sample is a tumor. With regard to the natural correlation, as in Mayo, the relationship is itself a natural process that exists apart from any human action.
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 treating DNA extracted from one or more samples comprising tumor cells with a reagent that modifies DNA in a methylation-specific manner and detecting a modification on the CpG site(s) of a polynucleotide by a tumor detection agent or kit, 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 detecting a modification on the CpG site(s) of a polynucleotide 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 amended claim 5 recites a step of treating DNA extracted from one or more samples comprising tumor cells with a reagent that modifies DNA in a methylation specific manner, thus, the claimed method recites specific steps for treating extracted DNA, thereby adding significantly more to the judicial exception. This argument has been thoroughly reviewed but was not found persuasive as the steps for treating extracted DNA are generally recited and the general recitation of detection of known nucleic acids is well understood, routine, and conventional activity (See MPEP 2106.05(d)(II)). Therefore, generally recited elements does not amount to significantly more than the judicial exception.
The response also asserts that amended claim 5 defines detection methods to be used in the claimed inventions and recites the categories of tumors detected by the claimed method and amended claim 5 recites a pan-cancer detection method capable of detecting a wide variety of cancers based on the methylation pattern of specific polynucleotides. Further, the response asserts that the claimed methods are therefore more than generalized limitations and amount to significantly more than the judicial exception. These arguments have been thoroughly reviewed but were not found persuasive. First, the recitation of “a pan-cancer detection method” in claim 5 as currently amended does not require detection of a variety of cancers. Second, as discussed above, the steps of detecting a modification on the CpG site(s) of a polynucleotide 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)). Therefore, generally recited elements does not amount to significantly more than the judicial exception.
The response also asserts that amended claim 5 is drawn to patent-eligible subject matter and each of claims 6 and 7 depend directly from claim 5, and therefore incorporate every limitation of amended claim 5 and that at least for the reason discussed supra, each of claims 6 & 7 are also drawn to patent-eligible subject matter. This argument has been thoroughly reviewed but was not found persuasive for the reasons set forth above. It is also noted that claim 6 was cancelled in the reply filed on 12/08/2025 and therefore the arguments on claim 6 are moot.
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) 5-7, 14-16, & 23 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wielscher (U.S. Patent Application Publication No. US 2017/0283887).
Regarding amended claim 5, Wielscher teaches a method determining the methylation status of 5-methyl cytosine that are methylated at a higher degree (hypermethylated) compared to a healthy state through determining the methylation status of more than one CpG dinucleotides of specific sequences (polynucleotide) through the treatment of the sequences with bisulfite to convert cytosine to uracil (treated extracted DNA from one or more samples comprising tumor cells with a reagent that modifies DNA in a methylation specific manner) (paragraph [0065] lines 1-6; paragraph [0067] lines 1-7; paragraph [0070] lines 3-11 & 23-27; paragraph [0137] lines 1-5; paragraph [0143] lines 1-6; paragraph [0145] lines 1-3), in which SEQ ID NO: 120 of Wielscher (bases 1150-1609) encompasses the nucleotide sequence of SEQ ID NO: 1 of the instant application therefore encompassing a nucleic acid complementary to the polynucleotide of (a) (embodiment (b)) (pg.129-133 SEQ ID NO: 120 sequence listing), which provides a means for diagnosing lung cancer (detecting a tumor) or the predisposition for lung cancer (high-risk of tumor) (paragraph [0145] lines 1-3; paragraph [0140] lines 1-6). In addition, Wielscher teaches the sample (tumor sample) comprises lung cancer (paragraph [0137] lines 1-5).
Regarding claim 7, Wielscher teaches that lung cancer refers to any malignant disease affecting the tissue of the lung and that diseased cells comprise disease cells of lung tissue and circulating tumor cells and that the disease cells may be comprised and analyzed in the methods of the invention (sample comprising diseased cells of lung tissue) (Paragraph [0139] lines 1-11). Wielscher also teaches that the sample may comprise cell-free DNA obtained from plasma (blood sample) (paragraph [0141] lines 1-3).
Regarding amended claim 14, Wielscher teaches a method determining the methylation status (methylation profile) of 5-methyl cytosine that are methylated at a higher degree (hypermethylated) compared to a healthy state through taking a sample from an individual (providing the sample and extracting nucleic acid) and determining the methylation status of more than one CpG dinucleotide of specific sequences (polynucleotide) (paragraph [0067] lines 1-7; paragraph [0070] lines 3-11 & 23-27; paragraph [0137] lines 1-5; paragraph [0143] lines 1-6; paragraph [0145] lines 1-3), in which SEQ ID NO: 120 of Wielscher (bases 1150-1609) encompasses the nucleotide sequence of SEQ ID NO: 1 of the instant application therefore encompassing a nucleic acid complementary to the polynucleotide of (a) (embodiment (b)) (pg.129-133 SEQ ID NO: 120 sequence listing), which provides a means for diagnosing lung cancer or the predisposition for lung cancer (paragraph [0145] lines 1-3; paragraph [0140] lines 1-6).
Regarding claims 15, 16 & 23, Wielscher teaches that methods for DNA methylation analysis of 5-methyl cytosine relies on bisulfite conversion of DNA, which allows for the detection of single CpGs through the conversion of non-methylated cytosine to uracil (paragraph [0006] lines 1-3; paragraph [0065] lines 1-6 & 14-18; paragraph [0067] lines 1-7).
Response to Arguments
The response traverses the rejection. The response asserts that the larger sequence in Wielscher does not describe the currently claimed polynucleotide with sufficient specificity to anticipate the limitation of claim 5 and that Wielscher discloses its SEQ ID NO: 120, a 8,338 base pair sequence, and in contrast SEQ ID NO: 1 in the present application is a 460 base pair sequence only accounting for approximately 5.5% of the total length of the longer SEQ ID NO: 120 in Wielscher. Specifically, the response asserts that Wielscher does not draw any attention to this small claimed sequence beyond disclosing a much larger SEQ ID NO: 120 and, accordingly, no reasonable fact finder would conclude that Wielscher discloses the claimed polynucleotide in amended claim 5. These arguments have been thoroughly reviewed but were not found persuasive. First, embodiment (b) of amended claim 5 is directed towards a nucleic acid that is complementary to the polynucleotide of (a) in which a nucleic acid complementary to the polynucleotide of (a) encompasses longer sequences complementary to the polynucleotide of SEQ ID NO: 1. The amended claim 5 requires the detection of a 5-methylation modification on a CpG site of a polynucleotide according to embodiment (a) or (b) in which embodiment (b) is an open limitation that also encompasses detection of CpG site(s) outside of polynucleotide of SEQ ID NO: 1. Therefore, Wielscher teaches determining the methylation status of more than one CpG dinucleotides of specific sequences (polynucleotide) in which SEQ ID NO: 120 of Wielscher (bases 1150-1609) encompasses the nucleotide sequence of SEQ ID NO: 1 of the instant application therefore encompassing a nucleic acid complementary to the polynucleotide of (a) (embodiment (b)).
The response also asserts that Wielscher does not disclose a pan-cancer detection method applicable for a wide variety of tumors including “a liver cancer, a breast cancer, a leukemia, a colorectal cancer, a lung cancer, a pancreatic cancer, an esophageal cancer” as recited in amended claim 5. This argument was thoroughly reviewed but was not found to be persuasive as Applicant’s arguments rely on language solely recited in preamble recitations in newly amended claim 5. When reading the preamble in the context of the entire claim, the recitation "A pan-cancer detection method" is not limiting because the body of the claim describes a complete invention and the language recited solely in the preamble does not provide any distinct definition of any of the claimed invention’s limitations. Thus, the preamble of the claim(s) is not considered a limitation and is of no significance to claim construction. See Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999). See MPEP § 2111.02.
The response also asserts that for at least the reasons outlines supra for claim 5, that each of claims 6 & 7 are also not anticipated by Wielscher. There arguments have been thoroughly reviewed but were not found persuasive for the reasons set forth above. It is also noted that claim 6 was cancelled in the reply filed on 12/08/2025 and therefore the arguments on claim 6 are moot.
The response also asserts that the applicant respectfully disagrees that Wielscher teaches a method of detecting the methylation profile of a sample wherein the target sequence is the claimed polynucleotide and that claims 15, 16, & 23 depends directly or indirectly from claim 14 and therefore incorporate each and every element of claim 14 and that, at least for the reasons discussed supra, each of claims 15, 16, & 23 are also not anticipated by the cited references. There arguments have been thoroughly reviewed but were not found persuasive for the reasons set forth 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 § 103
Claim(s) 8 & 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wielscher (U.S. Patent Application Publication No. US 2017/0283887).
Wielscher does not teach the method for designing a tumor detection agent for the detection of the modification on CpG(s) of the target sequence, a polynucleotide with a nucleotide sequence of SEQ ID NO: 1 or a nucleic acid complementary to the polynucleotide of SEQ ID NO: 1 (see claims 8 & 10).
However, regarding amended claim 8 & claim 10, Wielscher teaches a method of determining the methylation status (methylation profile) of cytosine that are methylated at a higher degree (hypermethylated) compared to a healthy state through taking a sample from an individual (providing the sample and extracting nucleic acid) and determining the methylation status of more than one CpG dinucleotide of specific sequences (polynucleotide) (paragraph [0070] lines 3-11 & 23-27; paragraph [0137] lines 1-5; paragraph [0143] lines 1-6; paragraph [0145] lines 1-3), in which SEQ ID NO: 120 of Wielscher (bases 1150-1609) encompasses the nucleotide sequence of SEQ ID NO: 1 of the instant application therefore encompassing a nucleic acid complementary to the polynucleotide of (a) (embodiment (b)) (pg.129-133 SEQ ID NO: 120 sequence listing), which provides a means for diagnosing lung cancer or the predisposition for lung cancer (paragraph [0145] lines 1-3; paragraph [0140] lines 1-6). Wielscher teaches determining the methylated DNA through preamplification of the methylated DNA with polymerase chain reaction (PCR) primers for methylation target loci (paragraph [0233] lines 6-10). Wielscher also teaches that DNA methylation changes can be detected in early cancer development providing a suitable method for early detection over mutation analysis (paragraph [0005] lines 4-8).
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 constructed a tumor detection agent for the analysis of CpG methylation in the sequence taught by Wielscher because Wielscher teaches PCR with primers specific to methylated DNA (polynucleotide) for the analysis of the methylation status of a cancer sample and Wielscher teaches the detection of DNA methylation changes can provide a suitable method for early cancer development over mutation analysis. Absent secondary considerations, these tumor detection agent and primers are considered obvious in view of the teachings of the prior art.
Response to Arguments
The response traverses the rejection. The response asserts that it would have not been obvious to one of ordinary skill in the art that detecting CpG modification(s) of a fragment of Wielscher’s SEQ ID NO: 120 would be useful for pan-cancer diagnostic purposes and that, as discussed supra, SEQ ID NO: 1 of the present application represents only a small portion of Wielscher’s SEQ ID NO: 120 and that further Wielscher discloses diagnostic tool in the context of lung cancer. Further, the response asserts that amended claim 8 is instead directed to a “pan-cancer detection method” with diagnostic utility across multiple tumor types and not just a single category of tumor and therefore a person of ordinary skill in the art would not have found it obvious to expect pan-cancer diagnostic utility when detecting modification of CpG(s) of a given fragment of Wielscher’s SEQ ID NO: 120. These arguments have been thoroughly reviewed but were not found persuasive. First, embodiment (b) of amended claim 8 is directed towards a nucleic acid that is complementary to the polynucleotide of (a) in which a nucleic acid complementary to the polynucleotide of (a) encompasses longer sequences complementary to the polynucleotide of SEQ ID NO: 1. The amended claim 8 requires the detection of a modification on a CpG site of a polynucleotide using said tumor detection agent according to embodiment (a) or (b) in which embodiment (b) is an open limitation that also encompasses detection of CpG site(s) outside of polynucleotide of SEQ ID NO: 1. Therefore, Wielscher teaches determining the methylation status of more than one CpG dinucleotides of specific sequences (polynucleotide) in which SEQ ID NO: 120 of Wielscher (bases 1150-1609) encompasses the nucleotide sequence of SEQ ID NO: 1 of the instant application therefore encompassing a nucleic acid complementary to the polynucleotide of (a) (embodiment (b)). Second, Applicant’s arguments rely on language solely recited in preamble recitations in newly amended claim 8. When reading the preamble in the context of the entire claim, the recitation "A pan-cancer detection method" is not limiting because the body of the claim describes a complete invention and the language recited solely in the preamble does not provide any distinct definition of any of the claimed invention’s limitations. Thus, the preamble of the claim(s) is not considered a limitation and is of no significance to claim construction. See Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999). See MPEP § 2111.02.
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.
Conclusion
Claims 5, 7, 8, 10, 14-16, & 23 are rejected.
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