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 .
Status of Claims
Claims 1, 5, 11, 16-18, 20, 21, 23, 34-36, 57, and 59-61 are examined herein as directed to the elected species SESN3. Claims 31-33 and 58 are currently withdrawn from consideration as being directed to a non-elected species, there being no allowable generic or linking claim. 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 reiterated. They constitute the complete set being presently applied to the instant Application. Response to Applicant's arguments 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.
Rejections - 35 USC § 103
Claims 1, 5, 11, 16-18, 20, 21, 23, 34, 57, and 59-61 are rejected under 35 U.S.C. 103 as being unpatentable over Dor (US 2017/0121767 Pub 5/4/2017) in view of Hill (Hill et al; Molecular Cancer, vol 9, pages 1-13, 2010) and Accession number NM_001271594 (Genbank, NCBI, NLM, 2015).
Dor teaches obtaining cell-free DNA molecules from a first biological sample (plasma) (pg. 11, [0251]) of a subject having cancer (pg. 23). Dor teaches a method of detecting death of a tissue in a subject comprising determining whether cell-free DNA comprised in a fluid sample of the subject is derived from the tissue, wherein the determining is effected by ascertaining the methylation status of at least four methylation sites on a continuous sequence of the cell-free DNA, wherein a methylation status of each of the at least four methylation sites on the continuous sequence of the DNA characteristic of the tissue is indicative of death of the cell type or tissue (para 0008). Dor teaches that the ascertaining is affected by: (a) contacting the DNA in the sample with bisulfite to convert demethylated cytosines of the DNA to uracils; (b) amplifying the continuous sequence of DNA using oligonucleotides that hybridize to a nucleic acid sequence adjacent to the first and last of the at least four methylation sites on the continuous sequence of the DNA; and (c) sequencing the continuous sequence of DNA (pg. 2, [0029] - [0032]). Dor teaches the nucleic acid sequence comprising the four methylation sites are differentially methylated in a first cell of interest with respect to a second cell which is non-identical to the first cell of interest (pg. 2, [0013]) and where the methylation status is characteristic of a non-diseased cell type or tissue of interest (pg. 2, [0014]). Dor teaches a method of isolating cell free DNA molecules (pg. 11, [0251]). Dor teaches hybridizing the cell-free DNA molecule comprising the target sequence to a probe, and wherein the probe hybridizes to the target sequence when a methylation site of the target sequence is methylated in the first biological sample, or the probe hybridizes to the target sequence when a methylation site of the target sequence is unmethylated in the first biological sample (pg. 14, [0289] – [0290]). Dor teaches amplifying the cell-free DNA molecule using a pair of primers, wherein an affinity of hybridization of at least one primer of the pair of primers to the target sequence depends on the first methylation status of the target sequence, and wherein (i) the at least one primer of the pair of primers hybridizes to the target sequence when a methylation site of the target sequence is methylated in the first biological sample, or (ii) the at least one primer of the pair of primers hybridizes to the target sequence when a methylation site of the target sequence is unmethylated in the first biological sample (pg. 14, [0289], [0291]). Dor teaches a method wherein the assay comprises bisulfite conversion of unmethylated cytosine residues in the cell-free DNA molecule to uracil (pg. 2, [0030]). Dor teaches that ascertaining the methylation status of at least four or 5 methylation sites on cfDNA comprises sequencing ([0020], [0029]- [0032]). Dor discloses numerous sequencing methods that can be used (pg. 13, [0276]). These methods are considered to be "methylation aware sequencing" methods because they are sequencing methods that are capable of identifying if one or more sites of a nucleic acid molecule are methylated.
Dor does not teach analysis of methylation of SESN3, however Hill teaches that SESN3 was found to be differentially methylated in breast cancers (see whole document). Further, Accession number teaches the sequence of SESN3 mRNA which comprises “a polynucleotide sequence of SESN3” with at least 60% identity to SEQ ID NO: 8 and comprises one or more CpG sites of SEQ ID NO: 8. Therefor it would have been prima facie obvious to the ordinary artisan prior to the effective filing date to have performed analysis of the methylation of SESN3 as taught by Hill with the method of Dor for the obvious benefit of less invasive analysis of methylation in breast cancer patients.
Response to Arguments
The response traverses the rejection. The response asserts that none of the references disclose assaying methylation of the particular targets in cell free DNA. This argument has been thoroughly reviewed but was not found persuasive because one cannot show non-obviousness 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). The response also asserts that the references do not provide a basis for reasonably predicting results of doing so. This argument has been thoroughly reviewed but was not found persuasive because the claims do not require any particular results. The recitation of “to measure, for each of the one or more DMR’s, an amount of the cell free DNA molecules” is an intended use limitation and does not require the measurement of any particular amount of cell free DNA comprising a first methylation status of a target sequence in the DMR. The response also asserts that establishing a prima facie case requires that the alleged modifications of the cited references would have produced results that “would have been predictable to one of ordinary skill in the art”, and that the standard has not been met. The response asserts that:
“Just because a particular differentially methylated sequence may serve as a marker for distinguishing DNA when extracted from tissue, does not provide a basis for reasonably predicting whether that particular target will still be useful as a marker for distinguishing different samples in cell-free DNA. At the very least, the Office has not provided evidence to establish a contrary assumption. Moreover, Dor actually provides an illustration in Example 10 of the challenge in attempting to predict performance based on tissue results. Specifically, Dor discloses having "identified and validated three methylation markers of skeletal muscle that are unmethylated in skeletal muscle and are methylated in other tissues," being "TNN, TPO, and MAD 1," but that only "two of these markers (unmethylated TPO and TNN) in the plasma of healthy controls are very low, reflective of very low turnover of muscle at baseline" (Dor, para. [0391]; emphasis added). According to these results of Dor, MAD1 was useful as a marker at the tissue level, but not characterized as among the useful markers when analyzing DNA from plasma. This illustrates the point that utility as a tissue marker does not allow one to reasonably predict utility as a marker in cell-free DNA.”
This argument has been thoroughly reviewed but was not found persuasive because the teachings of the prior art provide ample motivation for the ordinary artisan to perform a method of measuring cytosine methylation at one or more DMRs comprising SESN3 in cell free DNA. That is all that is actually required by the claims. The claims do not provide any requirement that a particular measurement be achieved or any further analysis of the measurement itself requiring any particular result. Given that the ordinary artisan would have been motivated to assess methylation in cell free DNA which is less invasive that procuring tissue samples, as well as the fact that Hill teaches that SESN3 was differentially methylated in breast cancers, the art provides ample motivation to measure cytosine methylation at one or more DMRs comprising SESN3 in cell free DNA. At the very least, the ordinary artisan would have been motivated to conduct the measurement to screen for possible cell free DNA methylation markers. The argument that even an “obvious to try” requires selection from among predictable solutions has been thoroughly reviewed but was not found persuasive because the art does provide predictable solutions, in the instant case, although Hill ultimately did not use SESN3 among targets due to the results of gene expression analysis, this does not negate the fact that Hill does teach that SESN3 was differentially methylated in breast cancers. Therefore, the art does in fact provide a reason to assess the measurement of methylation levels of DMRs comprising SESN3. For example, claim 1 simply requires 2 steps: obtaining a cell free DNA and performing an assay that measures the level of DNA methylation in a particular target. Performing this method does not require knowledge that SESN3 methylation levels in cell free DNA are diagnostic, but rather provides motivation to conduct the analysis. This type of routine analysis is in fact exemplified by the teachings of Dor. Since the claim does not actually require actual active steps after the measuring step, the arguments regarding a “predictable solution” is not found persuasive because the claim does not recite any steps that use the measurement in any active way requiring any type of “predictable solution”. The rejection is maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 5, 11, 16-18, 20, 21, 23, 34-36, 57, and 59-61 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,884,966. Although the claims at issue are not identical, they are not patentably distinct from each other because they are coextensive in scope, requiring methylation analysis of the same gene (SESN3) in cancer metastasis. The response does not traverse the rejection.
Conclusion
Claims 35 and 36 are free of the cited prior art.
Claims 1, 5, 11, 16-18, 20, 21, 23, 34, 57, and 59-61 are rejected.
THIS ACTION IS MADE FINAL. 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.
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/JEHANNE S SITTON/Primary Examiner, Art Unit 1682