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 .
Election/Restrictions
Applicant’s election without traverse of Group I, and species E746_A750del, and lung cancer, in the reply filed on March 11, 2026 is acknowledged.
Claims 5-8, 11, 12, and 17-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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.
Information Disclosure Statement
The IDS received on March 25, 2024 is proper and is being considered by the Examiner.
Drawings
The drawings received on September 25, 2023 are acceptable.
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 2-4, 9, 10, and 13-16 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.
Claim 2 is indefinite for the following reasons.
Claim 2 recites the phrase, “a nucleotide sequence in which one or more nucleotides are substituted, deleted, added, and inserted in the nucleotide sequence shown in SEQ ID NO: 5 or 6”, which is then followed by the phrase, “wherein a first fluorescent group is conjugated to the 5’ end of the SEQ ID NO: 5 and a minor groove binder is conjugated to the 3’ end of the probe of SEQ ID NO: 5, wherein a second fluorescent group is conjugated to the 5’ end of the probe of SEQ ID NO: 6 and a minor groove binder is conjugated to the 3’ end of the probe of SEQ ID NO: 6.”
This is indefinite. Claim 2 contains two separate embodiments for each probe: 1) one that comprises the SEQ ID Number (e.g., SEQ ID NO: 5 or 6); and 2) one that comprises any number of insertion/deletion/substituted into the same SEQ ID Number, which is no longer the claimed SEQ ID Number. The phrase which later further limits the probe with the fluorescent group and the minor groove binder results in the confusion in whether this further limitation only applies to the probe of the embodiment 1) or both embodiments 1 and 2 (because embodiment 2) is not the SEQ ID Number.
For the purpose of prosecution, the first embodiment is construed, that is, the limitation involving the fluorescent group and minor groove binder are found only on the embodiment of probe comprising SEQ ID Numbers, and not the embodiment of the probe having insertion/deletion/substituted therein.
Claims 13-15 are indefinite for the same reason.
Claim 16 is indefinite by way of its dependency on claim 15.
Claim 3 is indefinite for reciting the phrase, “wherein the gene mutation is selected from one or more of G719S point mutation … L858R point mutation at exon 21,” because this limitation is already present in the parent claim 1 from which claim 3 depends. Therefore, it is unclear what additional limitation is imposed by this redundant recitation.
Claim 4 is indefinite by way of its dependency on claim 3.
Claims 9 and 10 are indefinite for the same reason as claims 3 and 4 discussed above.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 2 and 13-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a primer-probe composition for detecting an EGFR gene mutation involving probes of SEQ ID NO: 6 (for G719S point mutation); SEQ ID NO: 12 (for E746_A750del mutation); SEQ ID NO: 18 (for T790M point mutation); and SEQ ID NO: 24 (for L858R point mutation), does not reasonably provide enablement for the composition comprising SEQ ID NO: 5, 11, 17, and 23 (respectively). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The specification discloses that the SEQ ID NOs: 5, 11, 17, and 23 are associated with a wild-type sequence of the markers currently recited whereas SEQ ID Numbers 6, 12, 18, and 24 are associated with mutants (see pages 3-5).
Claims currently embrace the embodiment that comprises only the wild-type probes with the intended usage of “for detecting EGFR gene mutation”. As discussed above, these probes are incapable of detecting the recited mutations and thus are not enabled for its intended purposes recited in the claims.
Claims 2 and 13-16 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a Written Description.
The written description requirement ensures that, “an applicant invented the subject matter which is claimed. Further, the written description requirement for a claimed genus may be satisfied through a sufficient description of a representative number of species by 1) reduction to practice; 2) reduction to drawing; or 3) disclosure of relevant identifying characteristics (i.e., structure of other physical and/or chemical properties, functional characteristics coupled with a known or disclosed correlation between function and structure) (MPEP 2163 at II(A)(3)(a)(ii)).
Reduction to Practice
The Federal Circuit reiterated that mere use of the same words in the specification and the claim (an in ipsis verbis test) is not sufficient to establish written description.
The specification discloses that the invention is directed to a plurality of primer-probe sets that are designed to target the mutations on EGFR gene that consist of G719S point mutation, E746_A750del mutation, T790M point mutation and L858R point mutation:
“in one aspect, the present disclosure provides a primer-probe composition for detecting an epidermal growth factor receptor (EGFR) gene mutation, comprising a combination of primers and probes for one of more of the following gene mutations: 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” (page 3, 2nd paragraph)
The specification discloses a single set of primer pair and a pair of probes for each of the mutations targeted on the EGFR gene:
I - G719S mutation: SEQ ID Numbers: 3 and 4 (forward and reverse primer, respectively) and SEQ ID Numbers 5 and 6 (for wildtype and mutant, respectively);
II – E746_A750del deletion mutation: SEQ ID Numbers: 9 and 10 (forward and reverse primer, respectively) and SEQ ID Numbers 11 and 12 (for wildtype and mutant, respectively);
III – T790M mutation: SEQ ID Numbers 15 and 16 (forward and reverse primer, respectively) and SEQ ID Numbers 17 and 18 (for wildtype and mutant, respectively); and
IV – L858R mutation: SEQ ID Numbers 21 and 22 (forward and reverse primer, respectively) and SEQ ID Numbers 23 and 24 (for wildtype and mutant, respectively).
The specification does not disclose any other variant or sequence homologs to the disclosed primers and probes that can comprise any number of base addition, deletion, substitution and insertions.
Therefore, the specification lacks the reduction to practice for disclosing a reasonable number of such species primer-probe sequences that are encompassed in the genus of the claims.
Therefore, the single primer-probe combination recited by their specific SEQ ID numbers, would not reasonably represent the number of species encompassed by the claimed genus of that comprise any number of base additions, deletion, substitution and deletions based on the SEQ ID numbers.
Reduction to Drawing
The specification do not disclose any additional primer-probe other than the above-discussed primers and probes having specific SEQ ID numbers.
Disclosure of Relevant Identifying Characteristics
While one could argue that a skilled artisan would be able to identify the “representative number of species” of the primers and probe by designing and testing such species, such method would not satisfy the written description for the genus claims when, “the claims require an essential or critical feature which is not adequately described in the specification” (MPEP 2163(I)(A)). For the claims at issue, such essential or critical feature is the actual sequences of the primers and probes. Applicants have not disclosed enough number of species within the claimed genus so as to justify the genus.
As stated in University of California v. Eli Lilly and Co. at page 1404:
An adequate written description of a DNA ... "requires a precise definition, such as by structure, formula, chemical name, or physical properties," not a mere wish or plan for obtaining the claimed chemical invention. Fiers v. Revel, 984 F.2d 1164, 1171, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993). Accordingly, "an adequate written description of a DNA requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it; what is required is a description of the DNA itself." Id. at 1170, 25 USPQ2d at 1606.
Therefore, for the foregoing reasons, the genus embraced by the claims is not sufficiently described by the number of species disclosed in the specification, and therefore, the specification lacks written description of the claims.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-4, 9, 10, and 13-16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wei et al. (CN108642154A, published October 12, 2018; IDS ref1).
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 13-15, 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 claims.
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).
Therefore, the invention as claimed is anticipated by Wei et al.
Claim Rejections - 35 USC § 103
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 2 and 13-16 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.
The teachings of Wei et al. have already been discussed above.
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.
Conclusion
No claims are allowed.
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.
Papers related to this application may be submitted to Art Unit 1681 by facsimile transmission. The faxing of such papers must conform with the notice published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 CFR 1.6(d)). NOTE: If applicant does submit a paper by FAX, the original copy should be retained by applicant or applicant’s representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED, so as to avoid the processing of duplicate papers in the Office. All official documents must be sent to the Official Tech Center Fax number: (571) 273-8300. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600.
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/YOUNG J KIM/Primary Examiner
Art Unit 1637 May 4, 2026
/YJK/
1 The referenced teachings are made against the IDS document of English translation from EPO.
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