Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Election/Restrictions
Applicant’s election of SEQ ID NO: 33 in the reply filed on 5/14/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
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 16, 18, 23, 24, and 26 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and a natural phenomenon without significantly more. The claim(s) recite(s) comparing (an abstract idea) and the relationship between certain methylation levels and the presence or recurrence of prostate cancer. This judicial exception is not integrated into a practical application because the treatment is recited at such a high level of generality it amounts to a statement to “apply” the judicial exceptions. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the only steps required in addition to the judicial exception are mere data gathering steps recited at such a high level of generality that they do not transform the judicial exceptions. Further, as evidenced by the commercially available methylation detection chips, such methods were also conventional.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claim 16, 18, 24, 25, 26, 28, and 30 is/are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Sherlock (WO 2012/138609) in view of Kobayashi et al. (2011. Genome Research, 21:1017–1027, including supplemental figures and figure descriptions) and NCBI Gene Expression Omnibus Platform record GPL16304, Illumina HumanMethylation450 BeadChip, public on March 4, 2013.
Sherlock teaches that methylation at cg19790294 and cg26537639 which are in the CYBA gene were identified as among the most predictive methylation sites in tumor versus benign adjacent tissue, and in particular that the CYBA promoter had two methylation sites listed Table 1 (see p. 15 and 17). The reference teaches diagnostic method for detecting prostate cancer based on the presence or one or more differentially methylated biomarkers in Table 1 (p. 10), and that the subject of the method could include previously treated patients, in which case the diagnostic method would have been one looking for biochemical recurrence, i.e. the presence of cancer cells (¶53). The reference teaches that in the case of a looking for cancer in a patient who is not presently receiving treatment but has undergone a previous course of treatment, the method is to determine whether a resumption of treatment is required (p. 12, ¶53). Sherlock teaches that treatments encompass radical proctectomy, and thus, a “previously treated” patient being screened for resumption of treatment encompasses a patient who had a radical proctectomy (¶30). Sherlock teaches determining a baseline value of methylation status in a normal control and comparing this with a value in the patient for a test response. Measured values in the patient may be compared with a control value (¶51-52). Thus, Sherlock teaches comparing with a threshold (i.e. control value) wherein the comparing is predictive of the presence or absence of prostate cancer. Sherlock teaches using the method to determine whether a treatment of prostate cancer is required (¶53), and also teaches that prostate cancer treatments include surgery, radiation, hormone, ultrasound, and chemotherapy (¶30). Sherlock teaches detecting methylation in samples using the Illumina Infinium HumanMethylation27 ¶81. Sherlock also teaches that methylation sites which are near cg19790294 are also differentially methylated in prostate tumor. See Figure 12, partially copied below, and ¶23.
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Sherlock does not teach assaying for cg0054525, which is also in the CYBA promoter. S
Kobayashi teaches substantially the same data as Sherlock (the two disclosures have common authors/inventors).
Kobayashi provides a figure identical to figure 12 of Sherlock where the lines appeared in color (Supplementary figure S7). The lines with increased methylation are in red in the figure, and these represent tumor samples with increased methylation relative to benign adjacent tissue (Supplementary figure S7 description). Kobayashi teaches that using the new Illumina HumanMethylation450 array will likely uncover additional sites of interest, probably including ones with better diagnostic and prognostic value (p. 1024).
Before the invention was made, Illumina provided the manifest for the HumanMethylation450 beadchip that was for sale.
The beadchip inherently included probes for the detection of cg19790294, cg26537639, cg00054525 which cg positions are located at positions 88717754, 88717373, and 88717586 of the human genome. This information is given in the publicly available data table for Illumina HumanMethylation450 BeadChip, that was made publicly available on March 4, 2013 (NCBI GOE Platform GPL16404). Thus, it is inherent also that the cg0005425 CpG position is between the two positions disclosed by Sherlock and Kobayashi.
The data in the beadchip data table provided with the GPL16404 platform record included this information about the cg probes:
cg19790294 88717754 88717756 88717755 88717805 IC .;chr16_IC:88716840-88717833 0 1 0 XY_NO A_NO 88717456 88717457 -298 CYBA AK097127 cg19790294. .
cg00054525 88717586 88717588 88717538 88717588 IC .;chr16_IC:88716840-88717833 0 1 1 XY_NO A_NO 88717456 88717457 -130 CYBA AK097127 cg00054525
cg26537639 88717373 88717375 88717374 88717424 rs8053867 1 IC .;chr16_IC:88716840-88717833 0 1 0 XY_NO A_NO 88717447 88717448 74 BC033739 BC033739 cg26537639
It would have been prima facie obvious to one having ordinary skill in the art to modify the method taught by Sherlock and Kobayashi references so as to have employed the Illumina HumanMethylation450 array for the detection of prostate cancer associated markers, and to use differentially methylated markers in the methods for detecting prostate cancer, as taught by Sherlock. One would have been motivated to use the larger array platform by the direct teaching of Kobayashi to do so. Furthermore, there would have been a reasonable expectation of success that additional methylation markers in CYBA would be identified since Sherlock teaches two markers in CYBA that were found to be methylated by array and additional markers near cg19790294 that were also differentially methylated in prostate tumors relative to benign tissue. Furthermore, upon the finding that a patient has evidence of prostate cancer cells, i.e. recurrence it would have been further obvious to follow the guidance of the Sherlock to treat the patient for the presence of prostate cancer using a known means for treating prostate cancer, including surgery, chemotherapy, hormone therapy or radiation. Following all of this, the claimed invention would have obvious before the invention was made.
Claim 23 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Sherlock (WO 2012/138609) in view of Kobayashi et al. (2011. Genome Research, 21:1017–1027, including supplemental figures and figure descriptions) as applied to claims 16, 18, 24, 25, 26, 28, and 30 above, and further in view of Lee et al. (Cancer Letters 340(2013)171-178).
The teachings of Sherlock in view of Kobayashi et al. as they are relevant to claim 16, from which claim 23 depends are given previously in this Office action and fully incorporated here.
The references do not teach a method which comprises detecting methylation of a plurality of CpG loci within at least 20 contiguous base pairs of the at least one cytosine.
Lee teaches targeted bisulfite conversion next generation sequencing in which a region of interest is amplified and then sequenced to determine the methylation status of all CpG within the region. As Kobayashi et al. teach the methylation of both cg19790294 and cg26537639 within CYBA and additionally teaches in Figure 12 that other CpG near these are differentially methylated in an informative way in prostate cancer, it would have been obvious to one having ordinary skill in the art to have carried out targeted bisulfite sequencing of at least the genomic region bounded by the two disclosed informative CpG sites, in order to identify additional CpG which are informative for prostate cancer. Such a method would have necessarily included sequencing all of the region corresponding to SEQ ID NO: 33, including two CpG that are within 20 nucleotides of one another.
Response to Remarks
Any rejection not reiterated or otherwise addressed in this Office action was overcome by amendment. The 101 rejection was traversed. However, the treatment step appended to the claims is not sufficiently specific to overcome the 101 rejection of record, as discussed in the rejection. Applicant argues that the instant claim does not recite any recognized exception, but the examiner cannot agree for the reasons et forth in the rejection.
Applicant argues that a person or ordinary skill would not have had a reasonable expectation of success because the data table for the array discloses hundreds of thousands of CpG. However, this is not persuasive because the primary reference directs to a limited set of genes with CpG informative for prostate cancer, naming CYBA as one of only two with multiple CpG identified as associated. Therefore, one skilled in the art would not have looked to all of the CpG on the array but the ones specifically taught as being in the same genomic region. Applicant’s argument is a piecemeal analysis. The rejection is maintained.
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 Juliet Switzer whose telephone number is (571)272-0753. The examiner can normally be reached Monday to Thursday, 8:00 AM-3:30 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Winston Shen can be reached at (571)-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Juliet Switzer
Primary Examiner
Art Unit 1682
/JULIET C SWITZER/Primary Examiner, Art Unit 1682