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 .
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 final rejection. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/07/2025 has been entered.
Currently Claims 1, 3-5, 8-10,16-17, 32-33, 38-40, 44-47 are pending. Claims 2, 6-7, 11-15, 18-31, 34-37, 41-43 are cancelled.
The following rejections are Maintained. Response to arguments follows.
This action is FINAL.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention 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 the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 3-5, 8-10,16-17, 32-33, 38-40, 44-47 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zimmermann et al. (WO 2014/018080 January 30, 2014 as recited on the IDS) and in view of Makarov et al. (US Patent Application Publication 2003/0064376 April 3, 2003) and Dieh et al. (WO 2014/151117 September 25 2014 recited on the IDS).
With regard to claim 1, Zimmerman et al. teaches a method of forming a mixture comprising fragments from a nucleic acid library of cfDNA from a blood sample, a series of forward primers and a universal reverse primer (p 3, p 9 lines 1-20). Although Zimmerman et al. does not teach dNTPs or polymerase, the recitation of PCR method would include the reagents required by PCR methodologies to amplify. Therefore it would be prima facie obvious to one of ordinary skill in the art at the time of the effective filing date to modify the recitation of PCR assay of Zimmerman et al. to include reagents required for amplification (polymerase and dNTPs). Zimmerman et al. teaches that the cfDNA from blood samples can comprise circulating tumor DNA. (p 63 lines 15-20).
Zimmerman et al teaches that the DNA can be combined with 100 different forward and reverse primers (p. 24 lines 20-22). As such suggests that the forward primers can be 100 primers. Zimmerman et al teaches that sites of interest can be determined by aligning primers to regions 31 to 60 base pairs away, therefore Zimmerman et al. suggests that the primers can be hybridize to a region that is separated by 31 to 60 base pairs (p. 22). Zimmerman et al teaches PCR and therefore teaches conditions to generate amplicons. Zimmerman et al. teaches massively parallel sequencing (p 140 lines 28-32).
Zimmerman does not teach a one sided tiling multiplex PCR reaction using a universal primer and a tiled series of targets.
With regard to claim 3,9-10 Zimmerman et al. teaches that the PCR approach can involve a fully nested, heminested, semi nested, one sided fully nested, one sided heminested, or one sided semi nested PCR approach (p. 55). Therefore Zimmerman et al. suggests combinations of outer and inner primers that can tile a target regions. These series can be tiles such that a large number of primers can be used (more than 5) and the region of the target gene can be spaced apart.
Zimmerman et al. teaches a method of formation inner primer reactions and outer primer reactions in the combination of steps a and b. Zimmerman et al teaches that the DNA can be combined with 100 different forward and reverse primers (p. 24 lines 20-22). As such suggests that the forward primers can be 100 primers. Zimmerman et al teaches that sites of interest can be determined by aligning primers to regions 31 to 60 base pairs away, therefore Zimmerman et al. suggests that the primers can be hybridize to a region that is separated by 31 to 60 base pairs (p. 22).
With regard to claim 4, Zimmerman suggests that the inner and outer primers can overlap at 0 nucleotides (e.g. no overlap) (p 17 lines 20-25).
With regard to claim 5, Zimmerman teaches that in some embodiments a one sided nested PCR can be performed (p 70) and as such the reverse primers would be the same (outer and inner).
With regard to claim 6, Zimmerman et al. teaches that the target regions can be two genes (p 32 lines 25-28).
With regard to claims 7-8, Zimmerman et al. teaches that the primers forward sequences can overlap (p. 58) but does not detect that the target region is a fusion mutation.
With regard to claim 32, Zimmerman et al. suggests methods that can encompass binding and annealing steps at 40-80C (p 12 lines 14-25). Zimmerman et al teaches that sites of interest can be determined by aligning primers to regions 31 to 60 base pairs away, therefore Zimmerman et al. suggests that the primers can be hybridize to a region that is separated by 31 to 60 base pairs (p. 22). Zimmerman et al. teaches that the target region can be in 50-100 nucleotides in length and therefore teach a length within the recited range (p 4 lines 15-20).
With regard to claim 33, Zimmerman et al. suggests methods that can encompass annealing times that can be longer than 60 minutes (and therefore encompass reagents that are between 60 minutes and 90 minutes) (p. 47 lines 15-25). Zimmerman et al. suggests methods that can encompass binding and annealing steps at 40-80C (p 12 lines 14-25). Zimmerman et al. teaches that 5 cycle runs can be performed at longer annealing times (p. 47 lines 28-31).
With regard to claims 38-39, 47, Zimmerman et al. teaches a method of forming a mixture comprising fragments from a nucleic acid library of cfDNA from a blood sample from a human, a series of forward primers and a universal reverse primer (p 3, p 9 lines 1-20). Zimmerman et al. teaches that the cfDNA from blood samples can comprise circulating tumor DNA. (p 63 lines 15-20).Zimmerman et al teaches that the DNA can be combined with 100 different forward and reverse primers and nested (p. 24 lines 20-22). As such suggests that the forward primers can be 100 primers. Zimmerman et al teaches that sites of interest can be determined by aligning primers to regions 31 to 60 base pairs away, therefore Zimmerman et al. suggests that the primers can be hybridize to a region that is separated by 31 to 60 base pairs (p. 22). Zimmerman et al teaches PCR and therefore teaches conditions to generate amplicons. Zimmerman et al. teaches massively parallel sequencing (p 140 lines 28-32). Zimmerman et al. suggests methods that can encompass annealing times that can be longer than 60 minutes (and therefore encompass reagents that are between 60 minutes and 90 minutes) (p. 47 lines 15-25). Zimmerman et al. suggests methods that can encompass binding and annealing steps at 40-80C (p 12 lines 14-25). Zimmerman et al. teaches that 5 cycle runs can be performed at longer annealing times (p. 47 lines 28-31).
With regard to claim 40, Zimmerman teaches that in some embodiments a one sided nested PCR can be performed (p 70) and as such the reverse primers would be the same (outer and inner).
With regard to claim 44, Zimmerman et al. suggests methods that can encompass annealing times that can be longer than 60 minutes (and therefore encompass reagents that are between 60 minutes and 90 minutes) (p. 47 lines 15-25).
With regard to claim 45, Zimmerman et al teaches that the DNA can be combined with 100 different forward and reverse primers (p. 24 lines 20-22). As such suggests that the forward primers can be 100 primers. Zimmerman et al teaches that sites of interest can be determined by aligning primers to regions 31 to 60 base pairs away, therefore Zimmerman et al. suggests that the primers can be hybridize to a region that is separated by 31 to 60 base pairs (p. 22).
With regard to claim 46, Zimmerman et al. teaches a method of forming a mixture comprising fragments from a nucleic acid library of cfDNA from a blood sample, a series of forward primers and a universal reverse primer (p 3, p 9 lines 1-20). Although Zimmerman et al. does not teach dNTPs or polymerase, the recitation of PCR method would include the reagents required by PCR methodologies to amplify. Therefore it would be prima facie obvious to one of ordinary skill in the art at the time of the effective filing date to modify the recitation of PCR assay of Zimmerman et al. to include reagents required for amplification (polymerase and dNTPs). Zimmerman et al. teaches that the cfDNA from blood samples can comprise circulating tumor DNA. (p 63 lines 15-20).
Zimmerman et al teaches that the DNA can be combined with 100 different forward and reverse primers (p. 24 lines 20-22). As such suggests that the forward primers can be 100 primers. Zimmerman et al teaches that sites of interest can be determined by aligning primers to regions 31 to 60 base pairs away, therefore Zimmerman et al. suggests that the primers can be hybridize to a region that is separated by 31 to 60 base pairs (p. 22). Zimmerman et al teaches PCR and therefore teaches conditions to generate amplicons. Zimmerman et al. teaches massively parallel sequencing (p 140 lines 28-32). Zimmerman et al. teaches that the PCR approach can involve a fully nested, heminested, semi nested, one sided fully nested, one sided heminested, or one sided semi nested PCR approach (p. 55). Therefore Zimmerman et al. suggests combinations of outer and inner primers that can tile a target regions. These series can be tiles such that a large number of primers can be used (more than 5) and the region of the target gene can be spaced apart.
Zimmerman et al. teaches a method of formation inner primer reactions and outer primer reactions in the combination of steps a and b.
However, with regard to claims 1 and 38 and 46, Zimmerman et al. is directed to determining polymorphic positions and not detection of fusion. Further Zimmerman does not teach a one sided tiling multiplex PCR reaction using a universal primer and a tiled series of targets.
With regard to claims 1, 38, 46, Makarov et al. teaches methods of amplifying regions using a one sided PCR tiling technique (para 11-14). Makarov et al. teaches that using universal primers allows for a one sided PCR that can be used using a combination of unique and non-unique primers to determine and walk libraries (para 230-244).
With regard to claim 1,38, and 46, Dieh et al. teaches a method of detection in cfDNA of mutations associate with tumors (para 2). Dieh et al. teaches that these can be detected and analyzed using massively parallel sequencing (para 722). Dieh et al. teaches that the mutations can include fusions (para 722).
With regard to claims 16,Dieh et al. teaches a method wherein EML4-ALK fusions, SLC34A2-ROS1 are detected (para 451-459)
With regard to claims 17, Dieh et al. teaches a method wherein chromosomal translocation of SLC34A2-ROS1 (para 451).
Therefore it would be prima facie obvious to one of ordinary skill in the art at the time of the effective filing date to modify the method of Zimmerman et al. to specifically detect fusion mutations as taught by Dieh et al. in order to detect known tumor mutations that are detectable in cfDNA using one sided PCR techniques as taught by Makarov. The ordinary artisan would have a reasonable expectation of success as Dieh et al. teaches that there’s mutations can be analyzed by PCR and massively parallel sequencing (para 722). Massively parallel sequencing of fragments is the same method of analyzing which is performed by Zimmerman to detect mutational regions. Furthermore one of ordinary skill in the art at the time of the effective filing date to modify the PCR method of Zimmerman et al. to use a known technique of one sided PCR in order to screen a region of cfDNA from library in order to determine and walk over the sequences of a library.
Response to Arguments
The reply traverses the rejection. A summary of the arguments has been provided below with response to arguments following. A summary of the arguments is provided below with response to arguments following. The reply asserts that what is not taught is that one sided tiling PCR can be performed on cf or circulating tumor DNA to detect gene fusion (p 8). The reply asserts that Makarov does not teach one sided tiling but rather chromosome walking and does not teach cf DNA (p. 8-9). The reply asserts that paragraphs 11-14 provide various prior art teaching that chromosome walking is disadvantageous and includes all one sided PCR methods but rather Makarov teaches nick translation molecules (p. 9). The reply asserts that paragraphs 230-244 of Makarov only provides nick translation library and does not teach one sided tiling multiplex PCR (p. 9). The reply asserts that paragraphs 234-244 discourage using shorter DNA fragments and asserts that that the selected DNA is amplified by using one sequence specific and one universal primer resulting in the amplification of a limited number of molecules (pl 10). The reply asserts that paragraph 240-244 are drawn to sequence analysis by fractionation and does not provide that cfDNA can be used but rather teaches size fractionated to obtain larger DNA molecules for sequencing (p 10). The reply asserts that Zimmerman and Diehn does not cure the deficiencies (p. 11). These arguments have been fully reviewed but have not been found persuasive. The reply appears to be arguing Markov individually without the combination with Zimmerman. Zimmerman suggests one sided semi nest PCR approach (p. 55) which can be interpreted as a tiling method. Furthermore Zimmerman teaches using cfDNA from a blood sample to perform a series of primers that are nested (tiled) (p 3). However, what is not taught is using a universal primer in a tiling technique. Makarov teaches using universal primers in a one sided PCR tiling technique. Although as exemplified by Makarov there are disadvantages such as bias towards shortest DNA fragments and overlap between the adapter sequence (para 231-232), Markarov teaches there are 4 different approaches which help with these issues (par 235-246) which includes fractionation, nick translation and suppression PCR. These issues with one sided PCR tiling are known and Zimmerman particularly teaches that one sided PCR can be performed. It would be well within the skills of an ordinary artisan to optimize the reaction of Zimmerman with the universal primer such that the adapter regions are not overlapping. Furthermore Zimmerman et al teaches that cfDNA can be used in a PCR based technique. As such the rejection has been maintained.
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 KATHERINE D SALMON whose telephone number is (571)272-3316. The examiner can normally be reached 9-530.
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/KATHERINE D SALMON/Primary Examiner, Art Unit 1682