DETAILED ACTION
The present Office Action is responsive to the Amendment received on August 6, 2026.
Preliminary Remark
Claim 13 is canceled.
Claims 5-8, 11, 12, and 17-20 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on March 11, 2026.
Claim Rejections - 35 USC § 112
The rejection of claims 2-4, 9, 10, and 13-16 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to particularly point out and distinctly claim the subject matter, made in the Office Action mailed on May 7, 2026 is withdrawn in view of the Amendment received on August 6, 2026.
The scope of enablement rejection of claims 2 and 13-16 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, for reasons discussed in the Office Action mailed on May 7, 2026, is withdrawn in view of the Amendment received on August 6, 2026.
The written description rejection of claims 2 and 13-16 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, for reasons discussed in the Office Action mailed on May 7, 2026, is withdrawn in view of the Amendment received on August 6, 2026.
Claim Rejections - 35 USC § 102
The rejection of claims 1-4, 9, 10, and 13-16 under 35 U.S.C. 102(a)(1) as being anticipated by Wei et al. (CN108642154A, published October 12, 2018; IDS ref1), made in the Office Action mailed on May 7, 2026 is withdrawn in view of the Amendment received on August 6, 2026.
Claim Rejections - 35 USC § 103
The rejection of claim 2 and 13-16 under 35 U.S.C. 103 as being unpatentable over Wei et al. (CN108642154A, published October 12, 2018; IDS ref) in view of Lin et al. (CN101445829A, published June 2009, using machine-translated English document via Google Patents), made in the Office Action mailed on May 7, 2026 is withdrawn in view of the Amendment received on August 6, 2026. However, the rejection is withdrawn for format reasons as the limitation of claim 13 was incorporated into parent claim 1. The rejection rationale, however, is maintained and Applicants’ arguments presented in the Amendment received on August 6, 2026 is addressed in the, “Response to Arguments” section.
Rejection – New Grounds, Necessitated by Amendment
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.
Claim 1-4, 9, 10, and 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over Wei et al. (CN108642154A, published October 12, 2018; IDS ref) in view of Lin et al. (CN101445829A, published June 2009, using machine-translated English document via Google Patents).
The present rejection is for the embodiment directed to the primer/probes comprising the recited SEQ ID numbers for the elected species, E746_A750del deletion mutation.
With regard to claim 1, Wei et al. teach a primer and probe composition for detecting EGFR gene mutation (“invention provides use of the primer-probe combination … in detecting EGFR mutations”, section [0077]), comprising a combination of primers and probes for G719S point mutation at exon 18, E746_A750del deletion mutation at exon 19, T790M point mutation at exon 20, and L858R point mutation at exon 21 (“mutations in exon 18, exon 19, exon 20, and exon 21 of the EGFR gene”, section [0008]; also “G719X (G719S, G719A, G719C) …”, section [0073]); also “19Del”, section [0176]; also “T790M … probe primer set”, section [0073]; also “L858R point mutation (“L858R … probe primer set”, section [0072]).
With regard to claim 2, the embodiment directed to “a nucleotide sequence in which one or more nucleotides are substituted, deleted, added and inserted would without any limitation (i.e., “one or more … nucleotides are substituted, deleted, added and inserted”) would necessarily arrive at any sequence, including those disclosed by Wei et al. (see for example, primers and probe set disclosed for G719X (sections [0010]-[0015]). Because the primers and probes of Wei et al. are directed to the same mutations, the limitation is met based on the language of the claim. In addition, the artisans teach labeling the probe with a fluorescent moiety at the 5’ end and a 3’ end MGB (see sections [0118]-[0127]).
With regard to claim 3, Wei et al. teach a kit comprising their primer-probe composition (“present invention provides a kit for detecting EGFR mutation sites … kit includes the aforementioned primer-probe combination”, section [0059]).
With regard to claim 4, the kit comprises dNTP mix, Taq enzyme and Mg2+ (see section [0070]).
With regard to claim 9, the method and kit as disclosed is broadly construed as directed to a “system” (also “[c]onfigure a droplet digital PCR reaction system”, section [0082]).
With regard to claim 10, Wei et al. teach a device for detecting the mutation comprising the system (since the droplet digital PCR reaction system comprises the primer-probe and reagent mixture therein).
With regard to claims 14-15, the recited primers and probes are: 1) non-elected species; and 2) are not actively required because the parent claim simply requires primers and probe directed to the “one or more” mutations recited.
With regard to claim 16, the fluorophore moiety and the quencher/acceptor are different (as a FRET dye pair, see Cy5 with NFQ or BHQ, or FAM with BHQ, claim 1).
Wei et al., while explicitly teaching the primers/probe set for the mutations found on EGFR gene (as discussed above), do not teach the primers/probe set directed to E746_A750del deletion mutation at exon 19 comprising the mutant probe sequence of SEQ ID NO: 12.
Lin et al. teach a mutation specific probe (20-mer) for the mutation found on exon 19 of EGFR, “exon 19 del E746-A750” having SEQ ID NO: 6 that contains 100% of the probe of instant SEQ DI NO: 12:
Query Match 100.0%; Score 19; Length 20;
Best Local Similarity 100.0%;
Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
SEQ ID NO: 12 1 GGAGATGTTTTGATAGCGA 19
|||||||||||||||||||
SEQ ID NO: 6 (Lin et al.) 2 GGAGATGTTTTGATAGCGA 20
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Wei et al. and Lin et al., thereby arriving at the invention as claimed for the following reasons.
As discussed above Wei et al. teach a plurality of primer pairs and probe composition which are for amplifying and detecting mutations found on EGFR gene, wherein the artisans teach utilizing them in a digital PCR reaction:
“present invention aims to provide a multiplex droplet digital PCR kit for detecting EGFR mutation sites” (section [0006])
While Wei et al. did not teach the exact mutation probe having the presently claimed nucleotide sequence (i.e, SEQ ID NO: 12), because the EGFR gene and the mutations had been well-known and characterized in the art before the effective filing date of the claimed invention, one of ordinary skill in the art would have been capable of deriving at a probe annealing to the mutation found on exon 19 of the EGFR gene (i.e., exon 19 del E746-A750).
Indeed, this is explicitly demonstrated by Lin et al. who teach a 20-mer probe specific for the same mutation having the entirety of the instant 19-mer probe of SEQ ID NO: 12 (see above alignment).
Therefore, based this probe, one of ordinary skill in the art would have been motivated to provide a primer pair flanking the region of the probe, so as to provide a detectable signal during a digital PCR reaction.
Designing a pair of flanking primers surrounding a probe that is demonstrated to be specific for the target sequence has been well-established in the art of real-time PCR and digital PCR, involving the generation of candidate primers followed by their empirical testing.
Therefore, the pair of primers of SEQ ID numbers 9 or 10 that flank the probe of Lin et al. would have been obvious to arrive at based on such conventional determination, yielding no more than a predictable outcome.
In KSR, the Supreme Court particularly emphasized “the need for caution in granting a patent based on the combination of elements found in the prior art,” Id. at 415, 82 USPQ2d at 1395, and discussed circumstances in which a patent might be determined to be obvious. Importantly, the Supreme Court reaffirmed principles based on its precedent that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” Id. at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are “[t]hree cases decided after Graham [that] illustrate this doctrine.” Id. at 416, 82 USPQ2d at 1395. (1) “In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.”
As to the primer-probe directed to the other mutations (non-elected species), the claims presently read one the composition having “one or more” of the recited primer/probe for the listed mutations (i.e., all of them primers/probe are not required).
For these reasons, the invention as claimed is deemed prima facie obvious over cited references.
Response to Arguments:
Applicants traverse the rejection (page 10, Response).
Applicants reiterate that claim 1 now recites that primer pairs comprise SEQ ID NO: 9 and 10 and probes comprise SEQ ID Numbers 11 and 12 (page 10, Response).
Applicants further state that Lin et al. do not teach a probe of SEQ ID NO: 11 that is directed a wildtype counterpart of the mutation probe that Lin et al. teach.
Applicants further contend that both mutant and wildtype strand have signals and a mutation abundance of 0.1% can be detected using the digital droplet PCR (ddPCR) that enable reliable detection of EGFR mutations at a mutant abundance as low as 0.5%, and that this sensitivity is significantly higher than that of Sanger sequencing, HRMA (page 10, Response).
These arguments have been carefully considered but they have not been found persuasive.
Preliminarily, the claims are directed to a product, not a method. Therefore, the sensitivity of the assay which is reliant on the actual assay conditions cannot distinguish the products of the instant claims. This is because the same primers and probes combination can be employed to perform a conventional TaqMan PCR. The usage of such combination would not observe the same kind of sensitivity as the instantly argued sensitivity of the assay is produced via digital PCR, which has been generally known to increase the sensitivity yield due to their isolation of single molecules in isolated environments, shielding from background noise produced from non-related molecules and inhibitors. Therefore, argument based on their context of usage is not persuasive.
As to the contention that wild-type probe is not discussed by Lin et al., the Office contends that Lin et al. clearly suggest of such a probe:
“probe sequence of EGFR detection in Gene Mutation, it is characterized in that: include: Be selected from SEQ ID NO: 1~SEQ ID NO: 3 any, at the wild-type probe of Exon 19 exon, and be selected from SEQ E NO: 4 ~ SEQ ID NO: 6, any, at del E746-A470(1) mutant probe of Exon 19 exon …” (page 2)
Therefore, Lin et al. clearly suggest that a probe targeting a wild-type location for the probe targeting a mutation is included.
The actual sequence of the probe for this wild-type has not been disclosed by Lin et al. as being SEQ ID NO: 11.
However, given that Lin et al. clearly taught a probe that anneals to the same mutation as that which is targeted by Applicants (see above), one of ordinary skill in the art would have had arrived at a region that also covers the wild-type counterpart of the mutation targeted by the probe of Lin et al. since the EGFR exon 19 gene has already been well-characterized.
Similarly, designing a pair of primers that flank a probe known to be specific for a mutation would have been an obvious application in view of the well-known real-time PCR reactions, such as TaqMan® (or 5’ nuclease PCR), and arriving at such pairs would have involved empirical determination involving the use of commercially available primer/probe software2, yielding no more than a predictable outcome.
Therefore, Applicants’ arguments are not deemed persuasive, and the rejection is maintained.
Conclusion
No claims are allowed.
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.
Inquiries
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Young J. Kim whose telephone number is (571) 272-0785. The Examiner can best be reached from 7:30 a.m. to 4:00 p.m (M-F). The Examiner can also be reached via e-mail to Young.Kim@uspto.gov. However, the office cannot guarantee security through the e-mail system nor should official papers be transmitted through this route.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's supervisor, Gary Benzion, can be reached at (571) 272-0782.
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/YOUNG J KIM/Primary Examiner
Art Unit 1637 October 9, 2026
/YJK/
1 The referenced teachings are made against the IDS document of English translation from EPO.
2 Gervais et al. NAR, June 2010, vol. 38, pages W308-W312, evidences computerized generation candidate primers/probes, their algorithmic based rankings, and experimental validation.
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