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 .
DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 9/04/2025 has been entered.
3. Applicant's election without traverse of Group I and the species of the combination of genes in table 1 (SEQ ID No. 1-398) and the combination of primers in table 2 (SEQ ID no 399-1194) in the reply filed on 8/23/2023 is acknowledged. It is noted that the election is deemed to be free of the art and 35 USC 112. Namely the interpretation that Claim 21 requires all of SEQ ID NO. 399-1194 would be in condition for allowance. Therefore the examiner will move to the next species. The next species that is searched is one primer pair and one gene from the list of genes.
4. Claims 21-32, 34-35 are pending. Claims 1-20, 33 are cancelled.
5. The following rejections are newly applied. The 35 USC 103(a) rejection made in the previous office action is withdrawn.
6. This action is NONFINAL.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 21-32, 34-35 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 21-32, 34-35 are indefinite over the method of claim 21. In particular the claims require that the plurality of primer pair reagents are selected from the group consisting of SEQ ID No. 399-1194, whereas the newly applied amendment requires that each primer pair reagents have at least one nucleotide that is replaced with a non-native nucleotide cleavable group. As such it is not clear if the primer pair reagents “are selected” from the seq id numbers or if the primer pair regarded comprise the nucleotides of the sequences. Therefore the metes and bounds are unclear.
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) 21-25,31-32,34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Alarcon et al. (US Patent Publication 2015/0024952 Jan 22, 2015) in view of Dieffenbach (PCR methods and Applications (1993) volume 3, pages S30-S37), Roux et al(PCR Methods and Applications (1995) volume 4, pages s185-s194) and Stapleton et al (US Patent Application 2016/0152972 June 2, 2016).
With regard to claim 21, Alarcon et al. teaches a method of measuring mRNA expression of VEGFA and CD33 expression in a human and comparing the expression to a control to determine changes in expression (para 264). Alacon et al. teaches that RT PCR in a multiplex is used for expression detection (para 264). Alacon et al. teaches further measuring a housekeeping gene (para 136). As such, Alarcon et al. teaches detection of one of the genes associated with immune response activity. However, Alacon et al. does not teach the primer pairs of VEGFA and CD33 as recited in the claims.
With regard to claim 21, the instant specification detection that uracil DNA glycosylase (UDG or UNG) can be consider a non-native nucleotide that is cleaved (para 138). Alacrcon et al. teaches that the multiplex design is made with UDG (para 500), but does not teach that these are on the primer pairs.
With regard to claim 22, Alarcon teaches that these genes are associated with tumor markers (para 264).
With regard to claims 23-24, Alarcon et al. teaches a method of measuring mRNA expression of VEGFA and CD33 expression (para 264).
With regard to claim 25, as Alarcon et al. teaches measuring expression of the genes of CD33 and VEGFA these genes would encompass the target sequences of the recited sequences directed to these genes.
With regard to claim 31, Alacon et al. teaches that the biological sample can comprise tumor (11).
With regard to claim 32, Alacon et al. teaches that the sample and the control can be from the same individual (para 124).
With regard to claim 34, Alacon et al. teaches that the expression level is normalized against a housekeeping gene (para 124).
However, Alacon et al. does not teach the primer pairs of VEGFA as recited in the claims.
With regard to claim 21, although Alacon et al. does not teach a pair of primers and the target sequences, the prior art teaches that these would be well known, Dieffenbach and Roux et al. teach constraints to designing oligonucleotides. Dieffenbach teaches parameters and principles of promoter design include primer length, terminal nucleotide, GC content, melting temperature, PCR product length, and placement of target sequence (s30-s34). Dieffenbach teaches PCR software was known (s35).
Roux teaches optimization of PCR by the presence of enhancing agents, Mg2+, annealing temperature, primer design, cycle number, hot start PCR (s185-s194).
With regard to claim 21, the art teaches that UDG can be added to the ends of primers for a cleavable site. Stapleton et al teaches that in multiplex RT PCR primers can be designed with an uracil on the ends and cleaved (para 10 and 104. 326 and 331).
Designing oligonucleotides to hybridize to specific targets, which are equivalents to those taught in the art is routine experimentation. The prior art teaches the parameters and objectives involved in the selection of oligonucleotides that function as primers, see Dieffenbach and Roux. The prior art is replete with guidance and information necessary to permit the ordinary artisan in the field of nucleic acid detection to design primers. As discussed above, the ordinary artisan would be motivated to have designed and tested oligonucleotides from VEFGA and CD33 to obtain additional oligonucleotides that function to detect expression and identify oligonucleotides with improved properties for such detection. Furthermore the ordinary artisan would be motivated to add uracil to increases the efficiency of the primer amplification (para 326 Stapleton et al). Thus, for the reasons provided above, the ordinary artisan would have designed additional oligonucleotides using the teachings in the art at the time the invention was made including oligonucleotides that comprise the primers pairs for each gene. As such the recited oligonucleotides are obvious over the cited prior art, absent secondary considerations
Claim(s) 30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Alarcon et al. (US Patent Publication 2015/0024952 Jan 22, 2015) and Dieffenbach (PCR methods and Applications (1993) volume 3, pages S30-S37), Roux et al(PCR Methods and Applications (1995) volume 4, pages s185-s194) and Stapleton et al (US Patent Application 2016/0152972 June 2, 2016) as applied to claims 21-25, 31-32 and 34 and in view of Simmini et al. (US Patent Application Publication 2024/0376436 November 14, 2024).
Alarcon et al. teaches a method of measuring mRNA expression of VEGFA and CD33 expression in a human and comparing the expression to a control to determine changes in expression (para 264). Alacon et al. teaches that RT PCR in a multiplex is used for expression detection (para 264). Alacon et al. teaches further measuring a housekeeping gene (para 136). Dieffenbach and Roux teach the obviousness of using equivalent primer pairs to amplify genes of interest. Stapleton et al teaches UDG primers (para 326). As such, Alarcon et al. teaches detection of one of the genes associated with immune response activity.
Alacon et al. teaches that the expression level is normalized against a housekeeping gene (para 124) but does not teach TBP as a housekeeping gene.
With regard to claim 30, Simmini et al. teaches using the housekeeping of TBP for determination of mRNA expression levels (para 98).
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 housekeeping gene of Alacon et al. combination with TBP of Simmini et al. The ordinary artisan would be motivated to use one of the finite number of housekeeping genes of TBP as it shows the smallest standard deviation amongst panels of housekeeping genes (para 98).
Conclusion
No claims are allowed. It is noted that the combination of all SEQ ID Number 399-1194 appear to be free of the prior art. However, the examiner has not moved on to the next species in light of the rejections set forth above for the election.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu Cheng (Winston) Shen can be reached on 5712723157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KATHERINE D SALMON/Primary Examiner, Art Unit 1682