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 filed on 17-27 & 31-34 are pending. Claim 18 is currently under examination directed to the elected species of cervical cancer, rejoined with prostate cancer (see response dated 12/04/2024 and office action dated 12/30/2024) and claim 19 is currently under examination directed to the species of tissue samples (see response dated 12/04/2024). The cancellation of claims 28-30 and 35-37 without prejudice in the reply filed on 04/30/2025 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 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Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.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 § 101
Claims 17-21 & 23 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 modification on the CpG site(s) of a polynucleotide. This recitation is a natural correlation between detecting the presence of modified CpG sites 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. 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 detecting a modification on the CpG site(s) of a polynucleotide by a tumor detection agent or kit, which comprises primers or probes, 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 17 recites detecting modifications on the CpG sites of the claimed polynucleotide using a tumor detection agent or kit which is a primer or probe and that the claimed method uses specific primers to detect specific modifications to specific polynucleotides. The response also 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 as only claim 22 recites the specific primers (SEQ ID NO: 5 and 6; or SEQ ID NO: 7 and 8) to detect CpG modifications of the claimed polynucleotide and claim 22 is not included in the rejection under 35 U.S.C. 101. Therefore, the rejected claims under 35 U.S.C. 101 (claims 17-21 & 23), are generally recited to include the steps of detecting a modification on the CpG site(s) of the claimed polynucleotide with the use of general tumor detection agents comprising primers or probes and are not recited to include the use of the specific primers of SEQ ID NO: 5 and 6 or SEQ ID NO: 7 and 8. Therefore, generally recited elements does not amount to significantly more than the judicial exception.
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 claim.
Claim Rejections - 35 USC § 102
Claim(s) 17-21, & 31-34 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Schweiger (U.S. Patent Application Publication US 2014/0051082), as cited in the IDS dated 12/14/2021.
Regarding claim 17, Schweiger teaches detection of cytosines that are hypermethylated in prostate cancer samples such that the quantification of the methylation status of specific genomic regions (polynucleotide) (Table 1), in which SEQ ID NO: 23 of Schweiger (bases 1700-2171) encompasses the nucleotide sequence of SEQ ID NO: 1 of the instant application therefore encompassing a fragment comprising residues of 286-316 of SEQ ID NO: 1 of the instant application (embodiment (b)) (Table 1; pg. 28-29 SEQ ID NO: 23 sequence listing), provides a means for accurate and reliable diagnosis of prostate cancer (paragraph [0018] lines 1-6; paragraph [0019] lines 1-8; paragraph [0032] lines 1-7). Schweiger also teaches that the methylation status of a genomic region may be analyzed through conventional technologies including real time PCR analysis (amplifying nucleic acids in a sample) (paragraph [0160] lines 1-2; paragraph [0161 lines 1-6).
Regarding claims 18 & 19, Schweiger teaches the sample (tumor sample) comprises prostate tissue sample (a gynecological and reproductive system tumor) (paragraph [0049] lines 1-5).
Regarding claims 20 & 21, Schweiger teaches genomic region specific primers (tumor detection agent) hybridize to a target sequence (specific genomic region polynucleotide) to be amplified for the detection of at least one CpG position to analyze the methylation status of that specific genomic region (paragraph [0041] lines 1-4 & 10-21).
Regarding claim 31, Schweiger teaches detection of cytosines that are hypermethylated (methylation profile) in prostate cancer samples through extraction of DNA from tumor tissue samples (paragraph [0210] lines 1-2) and quantification and analysis of the methylation status of specific genomic regions (polynucleotide) (Table 1), in which SEQ ID NO: 23 of Schweiger (bases 1700-2171) encompasses the nucleotide sequence of SEQ ID NO: 1 of the instant application (paragraph [0018] lines 1-6; paragraph [0019] lines 1-8; Table 1; pg. 28-29 SEQ ID NO: 23 sequence listing).
Regarding claims 32-34, Schweiger teaches analyzing the methylation status comprises means and methods useful for assessing and quantifying the methylation status which encompasses bisulfite sequencing where the DNA (extracted nucleic acid) is treated with bisulfite thereby converting nonmethylated cytosine residues into uracil while the methylated cytosines remain unchanged (paragraph [0037] lines 1-7; Paragraph [0051] lines 1-9; paragraph [0162] lines 1-12).
Response to Arguments
The response traverses the rejection. The response asserts that Schweiger does not disclose each element in the amended claim 17 and that, in particular, Schweiger does not disclose the sequence of SEQ ID NO: 1 in the present application, nor does Schweiger disclose a fragment comprising residues 286-316 of SEQ ID NO: 1 in amended claim 17 as SEQ ID NO: 1 in the present application is a 472 base pair sequence that only partially overlaps with the 2,749 base pair sequence of SEQ ID NO: 23 of Schweiger. These arguments have been thoroughly reviewed but were not found persuasive. First, Schweiger does disclose the sequence of SEQ ID NO: 1 of the instant application that fully overlaps from positions 1700-2171 of SEQ ID NO: 23 of Schweiger. Therefore, Schweiger also discloses a fragment comprising residues 286-316 of SEQ ID NO: 1 in amended claim 17. Second, the amended claim 17 requires the detection of a modification of a CpG site of a polynucleotide according to embodiment (a), (b), and/or (c), in which embodiment (b) requires detection of a CpG site of a fragment comprising residues 286-316 of SEQ ID NO: 1 which is an open limitation that can also encompass detection of CpG site(s) outside of residues 286-316 of SEQ ID NO: 1 of the instant application. Therefore, Schweiger teaches quantification and analysis of the methylation status of specific genomic regions (polynucleotide) which includes SEQ ID NO: 23 that encompasses the instant applications SEQ ID NO: 1 further encompassing a fragment comprising residues of 286-316 of SEQ ID NO: 1 of the instant application (embodiment (b)).
The response also asserts that SEQ ID NO: 23 is only one of the 110 hypermethylated genomic regions identified by Schweiger and that Table 2 of Schweiger highlights grouped pairs to be used for prostate cancer diagnosis and that Schweiger’s SEQ ID NO: 23 only appears in Groups 13, 23, and 72. Further, the response asserts that Schweiger only mentions genomic region pairs comprising SEQ ID NO: 23 as part of a second embodiment in the specification but does not indicate that SEQ ID NO: 23 is a preferred embodiment or that none of the genomic pairs in Schweiger’s claim 2 include SEQ ID NO: 23 as one of the paired sequences. These arguments have been thoroughly reviewed but were not found to be persuasive as it is not required that the limitations of a claim be taught in a preferred embodiment or in a claim of a patent document.
Finally, the response asserts that for the same reasons outlined supra for claim 17, that that the applicant disagrees that Schweiger teaches the limitations in claim 31. Further, the response asserts that claims 18-21 and 32-34 are also not anticipated by the cited reference at least for the reasons discussed supra. These arguments have been thoroughly reviewed but were not found to be persuasive. First, with regard to claim 31, the amended claim 31 requires detection of a methylation profile comprising detecting modification on CpG site(s) of a target sequence wherein the target sequence is a polynucleotide comprising (a) the polynucleotide of SEQ ID NO: 1, (b) a fragment comprising residues 286-316 of SEQ ID NO: 1, and/or (c) a nucleic acid complementary to the polynucleotide of fragment (a) or (b). Therefore, the amended claim 31 is a comprising claim that does not exclude the detection of additional CpG sites outside of SEQ ID NO: 1 in embodiment (a), (b), and (c). In addition, these arguments were not found to be 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) 18 & 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schweiger (U.S. Patent Application Publication US 2014/0051082), as cited in the IDS dated 12/14/2021, in view of Zhang (Zhang et al.; Japanese Journal of Clinical Oncology, vol. 46, pages 427-434, February 5th, 2016).
The teachings of Schweiger with respect to claim 17 is discussed above and incorporated herein.
Regarding claims 18 & 23, Schweiger fails to teach the tumor comprises cervical cancer and the modification on the CpG site comprises 5-methylation, 5-hydroxymethylation, 5-formylcytosine or 5-carboxylcytosine.
Zhang teaches detecting the expression of 5-methylcytosine in cervical squamous cell carcinoma tumor tissue samples as a means for assessing the clinical outcome of the tumor samples (abstract lines 7-10; pg. 429 paragraph bridging column 1 & 2 lines 1-5; pg. 431 paragraph bridging column 1 & 2 lines 5-7). Zhang also teaches that the detection of increased 5-methylcytosine provides insight on stage, histological grade, metastatic lymph node, and vascular invasion of the cervical cancer tumor (pg. 432 column 2 4th full paragraph lines 1-4).
Schweiger and Zhang are considered to be analogous to the claimed invention because they are all in the same field of detection of methylation modification in tumor 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 detecting the methylation status of a specific genomic region (encompassing polynucleotide of SEQ ID NO: 23 of Schweiger) as taught in Schweiger to include the analysis of the methylation modification of 5-methylcytosine in cervical cancer tumor samples as well, because Zhang teaches that doing so would provide valuable information on the tumor status (stage, histological grade, etc.) for assessing the clinical outcome of a tumor sample.
Claim(s) 22 & 24-27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schweiger (U.S. Patent Application Publication US 2014/0051082), as cited in the IDS dated 12/14/2021.
The teachings of Schweiger with respect to claims 17, 20, & 21 is discussed above and incorporated herein.
Schweiger does not teach primers shown in SEQ ID NO: 5 AND 6 or the primers shown in SEQ ID NO: 7 and 8 (see claims 22 & 27). In addition, Schweiger does not teach the method for preparing the genomic region specific primers (tumor detection agent) (see claim 24).
However, regarding claims 22 & 24-27, Schweiger teaches genomic region specific primers (tumor detection agent) hybridize to a target sequence (specific genomic region polynucleotide) to be amplified for the detection of at least one CpG position for analysis of the methylation status of that specific genomic region (polynucleotide) (paragraph [0041] lines 1-4 & 10-21). Schweiger also teaches that it would be obvious to the skilled person that the sequence of the primer depends on the hybridization position and that part of the sequence of the hybridization position may be converted by bisulfite in which the primers then may be adapted accordingly to enable hybridization (paragraph [0041] lines 14-21).
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 methylation specific primers, including primers show in SEQ ID NO: 5-8, for the analysis of CpG methylation in the sequence taught by Schweiger because Schweiger teaches Methylation specific PCR can be used to analyze the methylation status of a tumor sample treated with bisulfite and Schweiger also teaches how to construct such primers. Absent secondary considerations, these 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 Schweiger teaches a 2,749 base pair sequence that only partially overlaps with SEQ ID NO: 1 in the present invention and that the deficiencies of Schweiger are not remedied by Zhang. This argument has been thoroughly reviewed but was not found persuasive. Schweiger does disclose the sequence of SEQ ID NO: 1 of the instant application that fully overlaps from positions 1700-2171 of SEQ ID NO: 23 of Schweiger. Therefore, Schweiger also discloses a fragment comprising residues 286-316 of SEQ ID NO: 1 in amended claim 17.
The response also asserts that it was not shown that it would have been obvious that the diagnostic utility of detecting methylation would be retained across the diverse tumor types in amended claim 18 and that is was not shown that it would have been obvious that the epigenetic modifications listed in amended claim 23 would all have similar diagnostic utility. Further, the response asserts that Zhang indicates that a practitioner would not have found it obvious that the methylation status of a given sequence would be similar across diverse types of tumors and therefore, Zhang does not teach or suggest the claimed invention. These arguments were thoroughly reviewed but were not found persuasive. First, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Second, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., retaining of diagnostic utility across tumor types and epigenetic modifications having similar diagnostic utility) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
The response also asserts that that it would have not been obvious to one or ordinary skill in the art that locating primers targeting a small, diagnostically useful portion of Schweiger’s SEQ ID NO. 23 sequence would be possible without unpredictable and extensive experimentation. Further, the response asserts that difficulties in creating primers would become even more pronounced for shorter fragments such as residues 286-316 of SEQ ID NO: 1 of the present invention as in amended claims 17 and 24. These arguments have been thoroughly reviewed but not found to be persuasive. First, the arguments presented cannot take place evidence in the record. Second, Schweiger teaches that it would be obvious to the skilled person that the sequence of the primer depends on the hybridization position and that part of the sequence of the hybridization position may be converted by bisulfite in which the primers then may be adapted accordingly to enable hybridization (paragraph [0041] lines 14-21) indicating the routine nature of creating primers that target specific sequences. Therefore, creating primers would be possible without unpredictable and extensive experimentation.
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 17-27 & 31-34 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