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
Currently, claims 24, 26-30, 33, 35-38, 40-41, and 43-44, are pending in the instant application. Claims 37, 38, and 41 are withdrawn from consideration as being directed to non-elected species. Claims 24, 26-30, 33-36, 40, and 43-44 are currently under examination. 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 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.
Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.
Claim Rejections - 35 USC § 112
Claims 33, 35-36, 40, and 43-44 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention.
Amended claim 33 recites “pairing a DNA fragment of a methylated HOXB4 gene with a first probe and pairing a DNA fragment of a methylated SRC1N1 gene with a first probe”. It is not clear, however, if the sequence of the “first probe” is the same, or if this is a typographical error. Correction is required.
Amended claim 33 and its dependent claims also recite “the second probe” however this lacks sufficient antecedent basis because claim 33 does not recite a “second probe” previously, but only recites a “first probe”. Correction is required.
The claims have been amended to use the phrase “set forth in” in relation to nucleic acid sequences. This phrase indefinite because it is not clear if this encompasses sequences comprising the SEQ ID NO:, sequences consisting of the SEQ ID NO:, sequence fragments only within the SEQ ID NO:, sequence fragments within the SEQ ID NO: but also encompassing other sequences on either or both the 5’ and 3’ ends of the fragment, or all of the above. Accordingly, the metes and bounds of the encompassed probes and primers is unclear. Correction is required.
Claim Rejections - 35 USC § 103
Claims 24, and 27-30 are rejected under 35 U.S.C. 103 as being unpatentable over Daugaard (Daugaard et al; Scientific Reports, DOI: 10.1038/srep35807, pages 1-11, 2016) and Salhia (Salhia, Bodour; WO2019/035100).
Daugaard teaches methods of detecting lung adenocarcinoma (claims 29 and 30) by detecting methylation of a number of CpG islands including HOXB4 (see abstract). Daugaard teaches methylation analysis included extracting genomic DNA from a sample from a subject, performing bisulfite treatment and measuring the methylation levels of bisulfite treated DNA (see pages 8-9). Daugaard teaches measuring and comparing CpG methylation levels in tumor and normal lung tissue (claim 27), and detecting deviation in methylation levels between the samples. With regard to claim 28, Although Daugaard does not teach samples such as alveoli lavage fluid, it would have been prima facie obvious to the ordinary artisan prior to the effective filing date to have detected methylation levels in alveoli lavage because it is less invasive than tumor biopsy.
Daugaard does not teach detecting methylation levels of SRCIN1, or administering an anti-lung cancer drug, however Salhia teaches measuring methylation levels of a number of genes, including SRCIN1, for cancer detection, including lung cancer (see pages 65-110). Salhia also teaches treating a subject having cancer (para 0107). Therefore, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date, to have included the genes taught by Salhia in the methylation detection method of Daugaard for the benefit of analyzing a more comprehensive panel of genes differentially methylated in lung cancer. It would have further been prima facie obvious to one of ordinary skill in the art prior to the effective filing date to have treated lung cancer in patients taught by Daugaard, by administering an anti-lung cancer drug for the obvious benefit of treating the disease as taught by Salhia.
Claims 26, 33-36, 40, and 43-44 are rejected under 35 U.S.C. 103 as being unpatentable over Daugaard and Salhia as applied to claims 24, and 27-30 above, and further in view of Fackler (Fackler et al; Cancer Research, vol 64, pages 4442-4452, 2004).
The teachings of Daugaard and Salhia are set forth above. Daugaard and Salhia do not teach detecting methylation levels using quantitative methylation specific PCR, however Fackler teaches the successful analysis and measurement of CpG methylation in a number of genes from a single sample (see abstract, discussion). Fackler teaches designing primers and probes for the accurate measurement of CpG methylation levels (see page 4443-4444). Therefore, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date, to have using the quantitative methylation specific PCR method taught by Fackler, to analyze and measure the methylation levels of the genetic regions taught by Daugaard and Salhia because Fackler teaches the method can be used to accurately measure CpG hypermethylation in genes diagnostic of cancer. With regard to claims 33-36, 40, and 43-44, Daugaard and Salhia teach sequences and the location of CpG sites for analysis. Although the claims recite particular SEQ ID NOS, the scope of the primers and probes encompassed by the claims appears to be much broader, as outlined in the rejection under 35 USC 112(b) set forth above. Accordingly, absent secondary considerations, the broad scope of the possible primers and probes for methylation detection of HOXB4 and SRCIN1 encompassed by the claims are considered obvious over the teachings of the cited prior art.
Response to Arguments
The response traverses the rejection and asserts that the combination of the detection of methylation of HOXB4 and SRCIN1, is not obvious because the combination yields a synergistic effect significantly more than predictable results. The response asserts that the specification teaches that detection of the combination HOXB4 and SRCIN1 provides higher sensitivity and specificity compared with the combination of HOXB4, SRCIN1, PCDGHA12, and HOXD8, as well as different combinations, such as HOXB4 and PCDHGA12 (paragraphs 0164-0166, table 3). This argument, as well as the teachings of the specification have been thoroughly and carefully considered, however they are not persuasive to overcome the rejection because the claims are not commensurate in scope with the unpredictable results asserted in the response since the claims recite a method “comprising” which allows for methylation analysis of additional genes. This rejection can be overcome by amending the claims to recite “measuring the methylation levels of two genes, in the bisulfite treated DNA sample, wherein the two genes are HOXB4 and SRCIN1”.
Conclusion
No claims are allowed.
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 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
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