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 allowance 25 USPQ 74, 453 O.G. 213 (Comm'r Pat. 1935). 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, prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant's submission filed on 8/29/2025 has been entered.
Status of Claims and Prosecution
Currently, claims 1, 5-7, 9-10, 18, 20, 31, 32, 36, and 38-44 are pending in the instant application. With the RCE filed 8/29/2025, the claims have been extensively amended to broaden the previously claimed scope deemed allowable in the notice of allowance dated 6/10/2025. Consequently, the broadened claims are again subject to rejection in the instant office action. The rejections and prior art set forth in the instant office action have already been made of record during previous rounds of prosecution (prior to the RCE filed 8/29/2025) of the instant application. Accordingly, this action is made FINAL.
Claims 1, 5-7, 9-10, 18, 20, 31, 32, 36, and 38-44 are currently under examination. All the amendments have been thoroughly reviewed but are deemed insufficient to place this application in condition for allowance.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Rejections - 35 USC § 103
6. Claims 1, 6, 7, 9, 10, 20, 31-32, 36, and 39-44 are rejected under 35 U.S.C. 103 as being unpatentable over Taiwo (Taiwo et al., Nature Protocols. 2012. 7(4):617) in view of Schweiger (Schweiger et al., WO 2012/143481 A2).
Regarding claim 1, Taiwo teaches providing a sample of DNA from a subject (page 618, Table 1) and subjecting the sample to library preparation to permit subsequent sequencing of methylated DNA (page 619). Taiwo teaches generating methylated DNA immunoprecipitation, MeDIP-Seq libraries from genomic DNA, using custom methylated and unmethylated controls (page 620) , capturing the methylated DNA using antibodies (binder) directed against methylated cytosine (page 617) and sequencing the captured methylated nucleic acids (page 619, Fig. 3).
With regard to claims 1, 6, and 39, Taiwo does not teach identifying the presence or absence of one or more biomarkers associated with at least a portion of the captured DNA using a machine learning classifier, however, Schweiger teaches MeDIP-SEQ for prostate cancer analysis. Schweiger teaches identifying biomarkers based epigenetic cancer profiles based on fit using a statistical classifier (instant claim 39) known as the ‘nearest shrunken centroid’ method using the PAM classification protocol. Schweiger teaches that PAM is a supervised algorithm that performs sample classification (pg. 37, lines 25-26). Schweiger teaches using two most significantly differentially methylated regions for the classification analyses where samples with lower discriminatory power were clearly separated from other marker sets, showing that these marker sets have a potential to discriminate between benign and tumor tissues (pg. 42, lines 10-26). Schweiger teaches using diverse machine-learning techniques and statistical approaches to identify signatures of differential methylation which correctly differentiate between tumor and normal samples based on MeDIP-results (pg. 42, lines 20-23). Schweiger further teaches that a minimum of two genomic regions was sufficient to accurately discriminate between malignant and benign tissues (pg. 5-11, Table 1 and Table 2). Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filling date, to perform the method of Taiwo and included the use of a machine learning derived classifier to identify the presence or absence of a biomarker, as taught by Schweiger because Schweiger teaches that the use of diverse machine learning techniques and statistical classification were able to identify different classifiers and signatures of differential methylation which allowed the differentiation of tumor and normal samples based on MeDIP-Seq results (pg.42, lines 21-23).
With regard to claims 7 and 36, Taiwo teaches analysis of samples containing 50 and 5 ng of nucleic acid molecules (page 618, figure 1).
With regard to claims 9, 31, and 32 Taiwo teaches MeDIP-Seq and MBD-Seq, as enrichment based technologies which use methyl binding protein MBD2 for methyl capture (pg. 618, left column, 1st continuous paragraph). Since the protein used in the instant specification and that taught by Taiwo are the same, the reference is taken to necessarily meet the limitation of “capturing methylated nucleic acid molecules is performed at a specificity of at least 99%”.
With regard to claims 10, and 41, Taiwo teaches immunoprecipitating the methylated DNA using antibodies (binder) directed against methylated cytosine to precipitate methylated DNA fragments and methylated cytosines (pg. 617, Protocol development, Fig. 3). With regard to claim 40, Taiwo teaches diluting 1 uL of antibody (1.2 ug/uL) in 15 uL of water and using 2.4 uL of the diluted antibody, to arrive at 0.18 ug.
With regard to claim 20, Schweiger teaches the biomarker comprises circulating cell free tumor DNA (pg. 24, lines 18, 21, 23). It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filling date that the method of Taiwo could be practiced with cell free DNA as taught by Schweiger with a reasonable expectation of success because Taiwo teaches the method is optimized to work with as little as 50 ng DNA, making it applicable to a much wider range of samples and studies (Taiwo, pg. 617, right column, last full paragraph).
With regard to claims 42 and 43, Taiwo teaches adding an amount of control DNA to assess the efficiency of the MeDIP reaction (pages 619-620, 622-624). The claims do not provide any definition of “second amount” of control DNA and as such, this recitation does not differentiate the claims from the teachings of Taiwo.
With regard to claim 44, Schweiger teaches monitoring the efficacy of treatment of a prostate cancer patient (pg. 24, lines 14-16). Schweiger teaches analyzing methylated DNA of known therapeutic cancer biomarkers such as GSTP1, multidrug resistance protein 1 (MDR1), O-6-methylguanine-DNA methyltransferase (MGMT), Ras association domain family member 1 (RASSFI), retinoic acid receptor beta (RARB), adenomatous polyposis coli (APC), androgen receptor (AR), cyclin-dependent kinase inhibitor 2A (CDKN2A), E-cadherin (CDH1) and/or CD44 (page 29, lines 11-21).
Claim 38 is rejected under 35 U.S.C. 103 as being unpatentable over Taiwo (Taiwo et al., Nature Protocols. 2012. 7(4):617) in view of Schweiger (Schweiger et al., WO 2012/143481 A2) as applied to claim 1 above, further in view of Chiu (US 2016/0017419 A1).
The teachings of Taiwo and Schweiger are set forth above. Taiwo and Schweiger do not teach that the sample is from plasma. However, Chiu teaches cell free DNA sample is from plasma of the subject (page 43). Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filling date to modify the method of Taiwo and Schweiger to use plasma of the subject as taught by Chiu because using plasma to detect circulating cell free DNA is less invasive.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Taiwo (Taiwo et al., Nature Protocols. 2012. 7(4):617) in view of Schweiger (Schweiger et al., WO 2012/143481 A2) as applied to claim 1 above, and further in view of Hughey (Hughey et al., Nucleic Acid Research, 2015, Vol. 43, Issue 12).
The teachings of Taiwo and Schweiger are set forth above. Taiwo and Schweiger do not teach the classifier is an elastic net classifier. However, Hughey teaches that an elastic net classifier is a powerful and versatile method for classification, builds a multivariate predictive model, and performs in a way where one can use cross-validation and can assimilate continuous and categorical features. Hughey teaches that the elastic net is used in numerous and diverse applications including identification of genomic markers of drug sensitivity, development of a predictor of age based on DNA methylation and it is well suited for genome scale data (pg. 1, right column, middle paragraph). Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filling date to have modified the method of Taiwo and Schweiger by incorporating the powerful and versatile classifier, such as the elastic net classifier taught by Hughey. A person of ordinary skill in the art would be motivated to use such a powerful method of classification which has found use in many applications as taught by Hughey.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Taiwo (Taiwo et al., Nature Protocols. 2012. 7(4):617) in view of Schweiger (Schweiger et al., WO 2012/143481 A2) as applied to claim 1 above, and further in view of Bupathi (Bupathi et al., Journal of Gastrointestinal Oncology, 2016; 7(5):713-720).
The teachings of Taiwo and Schweiger are set forth above. Taiwo and Schweiger do not teach the therapeutic biomarker is CpG methylation phenotype – high (CIMP-high) phenotype. Bupathi teaches a method of identifying CIMP-high tumors by performing genome wide DNA methylation analysis. Bupathi teaches CIMP-high tumors does not correlate with a stage of tumor but has been associated with a shorter overall survival (pg. 718, first continued paragraph, left side). Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filling date to have modified the method of Taiwo and Schweiger by incorporating using CIMP-high phenotype as taught by Bupathi. One of ordinary skill in the art would be motivated to use the CIMP-high phenotype as a biomarker because Bupathi teaches that prognostically it is associated with overall survival.
Conclusion
No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 examiner Jehanne Sitton whose telephone number is (571) 272-0752. The examiner is a hoteling examiner and can normally be reached Mondays-Fridays from 8:00 AM to 2:00 PM Eastern Time Zone.
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/JEHANNE S SITTON/Primary Examiner, Art Unit 1682