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 .
Claim Status and Action Summary
This action is in response to the papers filed 7 May, 2026.
Claims 1-15 and 17-22 are pending, with claims 21-22 being newly added in the amendment dated 7 May 2026.
Claim 15 was withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-14 and 17-22 are under examination.
Any objections and rejections not reiterated below are hereby withdrawn.
Election/Restrictions
Applicant’s election without traverse of the invention of Group I, claims 1-14 and 17-20 in the reply filed on December 2, 2025 is acknowledged.
Priority
The present application, filed May 23, 2023 is a 371 of PCT/EP2021/082801, filed November 24, 2021, and claims foreign priority to EP 20209632.7, filed November 24, 2020.
Specification
The substitute specification filed on May 7, 2026 is acceptable.
Claim Rejections - 35 USC § 112(b)
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.
Claim 11 is 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.
This rejection has been updated as necessitated by the amendments to the claims.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). It is unclear what the term “sequenc-ing adapter” in claim 11 is intended to mean. The specification defines “the term “adapter” is a single-stranded, double-stranded, partly double-stranded, Y-shaped, or hairpin nucleic acid molecule that can be attached… to the end of other nucleic acids…” (specification, page 3, lines 5-15)(i.e. an “adapter” encompasses any nucleic acid molecule that can be attached to another nucleic acid). There is no clear definition in the specification or prior art of a subgenus “sequencing adapter” within the broader genus “adapter”. The term is indefinite because the specification does not clearly redefine the term. While the specification provides reference to “sequencing adapters, e.g. comprise a functional domain that allows for Oxford Nanopore Technologies or Ontera sequencing” (specification page 28, lines 25-26) and “barcoding adapters”, there is no limiting definition provided for either of these terms in the specification. There is no articulated, limiting structural difference recited, described, or known in the art between an “adapter” as defined by the special definition in the specification (page 3, lines 5-15) and a “sequencing adapter”. It appears, from the non-limiting examples on page 28 (see above) and (page 28, line 31-33) “preferably, the first and second adapter within a set each comprise compatible primer binding sequence, such that adapter ligated fragments are ready to be either amplified using a compatible primer pair or sequenced”, that “sequencing adapters” are distinguished in the specification (and the art) from “adapters” as defined by the specification in that they comprise a sequence that is suitable for initiating a sequencing process (i.e. they have a particular function of being suitable as primer binding sites). As such, essentially any nucleic acid sequence can be used as a “sequencing adapter”, dependent, for example, on a selected primer used in a sequencing by synthesis process (e.g. Sanger sequencing, “NGS” sequencing, etc.).
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 11 is rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends.
Claim 11 recites “wherein the adapter is a sequencing adapter”. However, the specification defines “the term “adapter” is a single-stranded, double-stranded, partly double-stranded, Y-shaped, or hairpin nucleic acid molecule that can be attached… to the end of other nucleic acids…” (specification, page 3, lines 5-15). There is no clear definition in the specification or prior art of a subgenus “sequence adapter” within the broader genus “adapter” (also see 112(b) rejection above). Therefore, the claim does not recite any further method steps or structures in addition to those recited by the claims upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Response to arguments
As discussed above in the 112(b) rejection of claim 11, there does not appear to be any recited method step or limitation or recited structural limitation conferred upon the claim term “adapter” by the addition of the intended use/function “sequencing adapter”. Therefore, it is unclear what specific structures are intended to be covered by “sequencing adapter” and it does not appear that claim 11 imparts any further limitations upon the claims from which it depends.
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.
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.
Claims 1-14 and 17-22 remain/are rejected under 35 U.S.C. 103 as being unpatentable over White et al., WO 2020/109412 (published June 4, 2020) (previously cited by applicant as Foreign Patent Document 1 “KEYGENE NV” on the IDS filed May 23, 2023) in view of Payne et al., “Nanopore adaptive sequencing for mixed samples, whole exome capture and targeted panels” bioRxiv 2020.02.03.926956; doi: 10.1101/2020.02.03.926956 (published February 3, 2020).
It is noted that the authorship of the White et al. reference is distinct from the inventorship of the instant application and that this rejection may be overcome by the filing of a 132 Katz-type declaration or a declaration under 37 CFR 1.130(a) (see In re Katz, 687 F.2d 450, 455, 215 USPQ 14, 18 (CCPA 1982) and MPEP 717.01(a)(1)(B) “Where the authorship of the prior art disclosure includes the inventor or a joint inventor named in the application, an “unequivocal” statement from the inventor or a joint inventor that he/she (or some specific combination of named joint inventors) invented the subject matter of the disclosure, accompanied by a reasonable explanation of the presence of additional authors, may be acceptable in the absence of evidence to the contrary.”)
This rejection has been updated as necessitated by the amendments to the claims.
Regarding claim 1, White et al. teach methods for sequencing target nucleic acid fragments comprising steps of “cleaving the nucleic acid sample with a first and a second… gRNA-Cas complex, thereby generating the target nucleic acid fragment and at least one non-target nucleic acid fragment. The generated fragments are subsequently contacted with an exonuclease, wherein the exonuclease digest only the non-target nucleic acid fragments. The invention further pertains to the use of the enriched target nucleic acid fragments for preparing an adapter ligated target fragment and for sequencing the target nucleic acid fragment (White et al., Abstract). Furthermore, White et al. claim 1 is identical to the instant claim 1 except in that the instant claim 1 further requires step (e): sequencing the target nucleic acid fragment by nanopore selective sequencing. (see White et al., claim 1 below) and the requirement for a desired result apparently inherent to the claimed methodological steps of “obtaining an at least 20-fold enrichment of target nucleic acid(s)… compared to… the non-target nucleic acid(s) reads.
White et al. teach that the target nucleic acid enriched, adapter-ligated libraries are sequenced by “Oxford Nanopore MinION system” (White et al., page 35-36).
White et al. teach methods (described above) obtain “reduction of complexity results in the enrichment of one or more specific target sequence or target nucleic acid fragments… while non-target sequences are reduced in amount by at least 20%... or 99% as compared to the amount of non-target sequences… in the starting material (White et al., page 10, lines 20-30). An at least 99% reduction in non-target sequences necessarily corresponds to an enrichment of 100X of the target sequences relative to non-target sequences because the non-target sequences are reduced in relative abundance to at most 0.01x of the total mixture.
White et al. do not teach that the nanopore sequencing is “nanopore selective sequencing”.
However, Payne et al. teach “Nanopore sequencers enable selective sequencing of single molecules in real time by individually reversing the voltage across specific nanopores” and an example wherein “we enrich panels including 25,600 exon targets from 10,000 human genes and 717 genes implicated in cancer… These methods can be
used to efficiently screen any target panel of genes without specialised sample preparation using a single computer and suitably powerful GPU.” (Payne et al., Abstract) Payne et al further teach that selective sequencing provides benefits in improved time-to-answer and enrichment benefits focused on specific subsets of reads (Payne et al., page 15-16 bridging paragraph).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the method taught by White et al. comprising steps of providing a sample comprising a target nucleic acid molecule, cleaving said target with a first and second gRNA-CAS complex, contacting the cleaved molecules with an exonuclease, optionally purifying the target nucleic acid, ligating adapters after the exonuclease treatment step, and sequencing the resulting target-sequence enriched libraries by nanopore sequencing by performing nanopore selective sequencing, rather than conventional nanopore sequencing as taught by Payne et al. The ordinary artisan would have been motivated to modify the sequencing step taught by White et al. because of the teaching of Payne et al. that nanopore selective sequencing beneficially improved time-to-answer and enrichment focused on specific subsets of reads (Payne et al., page 15-16 bridging paragraph). The ordinary artisan would have been reasonably confident that the nanopore selective sequencing method taught by Payne et al. would have successfully been used as a direct substitute for the conventional nanopore sequencing steps used by White et al. because Payne et al. expressly suggest “this method should be applicable to any MinION configuration with sufficient GPU to basecall a sequencing run in real time.” (Payne et al., page 16, paragraph 3).
Except for the further step (e) recited by the instant claim 1, the claims 2-14 of the present application and White et al. are identical in scope and/or language as follows:
Claim 2 is identical to White et al. claim 2.
Claim 3 is identical to White et al. claim 3, with the sole exception that the “preferred” conditions recited by White et al. claim 3 are recited by dependent claims 17-19: (“step b) is performed for about 60 minutes” (claim 17), “step b) and/or step c is performed at about 37 degrees C” (claim 18), and “step c) is performed for about 30 minutes”).
Claim 4 is identical to White et al., claim 4.
Claim 5 is identical to White et al., claim 5.
Claim 6 is identical to White et al., claim 6.
Claim 7 is identical to White et al., claim 7.
Claim 8 is identical to White et al., claim 8.
Claim 9 is identical to White et al., claim 9.
Claim 10 is identical to White et al., claim 10, with the sole exception that the instant claim further recites a sequencing the target nucleic acid fragment by nanopore selective sequencing after the ligation step.
Claim 11 is identical to White et al., claim 11.
Claim 12 is identical to White et al., claim 13.
Claim 13 is identical to White et al., claim 14.
Regarding claim 20, White et al. teach “us[ing] the enriched target nucleic acid fragments for preparing an adapter ligated target nucleic acid fragment and for sequencing the target nucleic acid fragment (i.e. the adapter ligation step follows the exonuclease treatment step c or optionally purifying step d) (White et al., abstract).
Regarding newly added claims 21-22, White et al. teach 100x enrichment of target nucleic acids can be obtained by the methods disclosed therein (White et al., page 10, lines 20-30), see also the rejection of claim 1 above.
Claims 1-14 and 17-22 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Ouellet et al., WO 2019/030306 (published February 14, 2019) (previously cited by applicant as Foreign Patent Document 3 “DEPIXUS” on the IDS filed May 23, 2023) in view of Payne et al., “Nanopore adaptive sequencing for mixed samples, whole exome capture and targeted panels” bioRxiv 2020.02.03.926956; doi: 10.1101/2020.02.03.926956 (published February 3, 2020).
This rejection has been updated as necessitated by the amendments to the claims.
Regarding claim 1, Ouellet et al. teach methods for sequencing a target nucleic acid fragment comprising providing a sample comprising the target nucleic acid, cleaving the target nucleic acid molecule with a first and second gRNA-Cas complex, contacting the cleaved nucleic acids with an exonuclease to digest the non-target nucleic acids, and preparing a sequencing library from the enriched target nucleic acids (Ouellet et al., page 61, line 18- page 62, line 7 and figures 9A and 13). Ouellet et al. further teach that the target nucleic acids are protected from degradation by exonucleases because Cas protein-gRNA complexes remain bound to their nucleic acid target(s), even after the Cas protein has cleaved the nucleic acid target (Ouellet et al., page 3, line 24-page 4, line 3). Ouellet et al. further teach sequencing libraries constructed from the isolated target nucleic acid molecules using methods comprising nanopore-based sequencing (Ouellet et al., page 47 line 11-30 ).
Claim 1, as amended, now recites the requirement of a desired result apparently inherent to the claimed methodological steps of “obtaining an at least 20-fold enrichment of target nucleic acid(s)… compared to… the non-target nucleic acid(s) reads. Relevant to this newly added limitation, Ouellet et al. teach the isolated (i.e. target) nucleic acid may be enriched by at least 10-fold, at least 20-fold,… at least 1,000,000-fold…” (Ouellet et al., page 7, lines 14-22).
Ouellet et al. do not teach that nanopore-based sequencing comprises “nanopore selective sequencing”.
However, Payne et al. teach “Nanopore sequencers enable selective sequencing of single molecules in real time by individually reversing the voltage across specific nanopores” and an example wherein “we enrich panels including 25,600 exon targets from 10,000 human genes and 717 genes implicated in cancer… These methods can be
used to efficiently screen any target panel of genes without specialised sample preparation using a single computer and suitably powerful GPU.” (Payne et al., Abstract) Payne et al further teach that selective sequencing provides benefits in improved time-to-answer and enrichment benefits focused on specific subsets of reads (Payne et al., page 15-16 bridging paragraph).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the method taught by Ouellet et al. comprising steps of providing a sample comprising a target nucleic acid molecule, cleaving said target with a first and second gRNA-CAS complex, contacting the cleaved molecules with an exonuclease, optionally purifying the target nucleic acid, ligating adapters after the exonuclease treatment step, and sequencing the resulting target-sequence enriched libraries by nanopore sequencing by performing nanopore selective sequencing, rather than conventional nanopore sequencing as taught by Payne et al. The ordinary artisan would have been motivated to modify the sequencing step taught by Ouellet et al. because of the teaching of Payne et al. that nanopore selective sequencing beneficially improved time-to-answer and enrichment focused on specific subsets of reads (Payne et al., page 15-16 bridging paragraph). The ordinary artisan would have been reasonably confident that the nanopore selective sequencing method taught by Payne et al. would have successfully been used as a direct substitute for the conventional nanopore sequencing steps used by Ouellet et al. because Payne et al. expressly suggest “this method should be applicable to any MinION configuration with sufficient GPU to basecall a sequencing run in real time.” (Payne et al., page 16, paragraph 3).
Regarding claim 2, Ouellet et al. teach that the target nucleic acids are protected from degradation by exonucleases because Cas protein-gRNA complexes remain bound to their nucleic acid target(s), even after the Cas protein has cleaved the nucleic acid target (Ouellet et al., page 3, line 24-page 4, line 3) (i.e. no further step of protecting the target nucleic acid prior to exonuclease digestion is necessary).
Regarding claims 3 and 17-18, Ouellet et al. teach a “General reaction protocol” for the method described above wherein the Cas-gRNA complexes are incubated (i.e. step b) for 1 hour at 37 degrees C to allow the complex to bind to the target region and the exonuclease treatment (i.e. step c) is performed for 1 hour at 37 degrees C. (Ouellet et al., page 62, line 29- page 63, line 13)
Regarding claim 4, Ouellet et al. teach the first and second gRNA-Cas complex comprise a Cas9 protein (Ouellet et al., Figure 1B).
Regarding claim 5, Ouellet et al. teach the gRNA-Cas complexes can comprise a sgRNA (Ouellet et al., page 14, lines 4-10)
Regarding claim 6, Ouellet et al. teach the gRNA-Cas complexes can comprise a crRNA and a tracrRNA as separate molecules (Ouellet et al., page 14, lines 15-16).
Regarding claims 7-8, Ouellet et al. teach the gRNA-Cas complexes comprise a wild-type Type II Cas protein (Ouellet et al., page 10, line 23-25) (i.e. are capable of inducing a DSB, “double strand break”)
Regarding claim 9, Ouellet et al. teach a first and second gRNA-Cas complex nicks the target DNA and an at least a third gRNA-Cas complex nicks the complement strand proximal (substantially complementary to) to the first nickase site (Ouellet et al., Figure 9 and page 11, lines 13-29).
Regarding claims 10 and 11, Ouellet et al. teach ligating sequencing adapters prior to sequencing the enriched target nucleic acid molecules (Ouellet et al., page 81, line 30-31).
Regarding claim 12, Ouellet et al. teach performing the method in parallel for multiple nucleic acid samples (Ouellet et al., page 81, line 20-31).
Regarding claim 13, Ouellet et al. teach the nucleic acid molecule is genomic DNA (Ouellet et al., page 81, line 20-31).
Regarding claim 14, Ouellet et al. teach the nucleic acid molecule is from human genomic DNA (i.e. is obtainable from an animal, a human) (Ouellet et al., page 81, line 10-15). Ouellet et al. further teach the sample comprising the target nucleic acid may be a biological sample obtained from bacteria (i.e. a microorganism), viruses, archaea, animals, plants, and/or fungi (Ouellet et al., page 4, line 23-30).
Regarding claim 19, Ouellet et al. teach incubation with exonuclease (i.e. step c) may be performed for 30 minutes at 37 degrees C (Ouellet et al., page 65, line 9-line 15).
Regarding claim 20, Ouellet et al. teach ligating sequencing adapters prior to sequencing the enriched target nucleic acid molecules and after exonuclease treatment (i.e. step c) and optionally purifying the protected nucleic acids (Ouellet et al., page 81, line 30-31).
Regarding newly added claims 21-22, Ouellet et al. teach the isolated (i.e. target) nucleic acid may be enriched by at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, … at least 1,000,000-fold…” (Ouellet et al., page 7, lines 14-22).
Claims 1-5, 7-8, 10-14, 17-18, and 20-22 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Stevens et al., “A novel CRISPR/Cas9 associated technology for sequence-specific nucleic acid enrichment” PLoS ONE 14(4): 30215441 (published April 18, 2019) in view of Payne et al., “Nanopore adaptive sequencing for mixed samples, whole exome capture and targeted panels” bioRxiv 2020.02.03.926956; doi: 10.1101/2020.02.03.926956 (published February 3, 2020).
This rejection has been updated as necessitated by the claim amendments.
Regarding claim 1, Stevens et al. teach methods of sequencing target nucleic acid fragments comprising providing a sample comprising the target nucleic acid molecule, cleaving the nucleic acid target with a first and second gRNA-Cas complex, contacting the cleaved molecules with an exonuclease, purifying the protected target nucleic acids, and sequencing the protected nucleic acids by nanopore sequencing (Stevens et al., Figure 5, see below)
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Claim 1, as amended, now recites the requirement of a desired result apparently inherent to the claimed methodological steps of “obtaining an at least 20-fold enrichment of target nucleic acid(s)… compared to… the non-target nucleic acid(s) reads. Relevant to this newly added limitation, Stevens et al. teach “as shown in figure 5, reads from the protected and exonuclease treated samples demonstrated 20x to 43x enrichment ratio enrichment when compared with the average of four unenriched genomes” (Stevens et al., page 7-8 bridging paragraph).
Stevens et al. do not teach that nanopore sequencing comprises “nanopore selective sequencing”.
However, Payne et al. teach “Nanopore sequencers enable selective sequencing of single molecules in real time by individually reversing the voltage across specific nanopores” and an example wherein “we enrich panels including 25,600 exon targets from 10,000 human genes and 717 genes implicated in cancer… These methods can be
used to efficiently screen any target panel of genes without specialised sample preparation using a single computer and suitably powerful GPU.” (Payne et al., Abstract) Payne et al further teach that selective sequencing provides benefits in improved time-to-answer and enrichment benefits focused on specific subsets of reads (Payne et al., page 15-16 bridging paragraph).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the method taught by Stevens et al. comprising steps of providing a sample comprising a target nucleic acid molecule, cleaving said target with a first and second gRNA-CAS complex, contacting the cleaved molecules with an exonuclease, optionally purifying the target nucleic acid, ligating adapters after the exonuclease treatment step, and sequencing the resulting target-sequence enriched libraries by nanopore sequencing by performing nanopore selective sequencing, rather than conventional nanopore sequencing as taught by Stevens et al. The ordinary artisan would have been motivated to modify the sequencing step taught by Stevens et al. because of the teaching of Payne et al. that nanopore selective sequencing beneficially improved time-to-answer and enrichment focused on specific subsets of reads (Payne et al., page 15-16 bridging paragraph). The ordinary artisan would have been reasonably confident that the nanopore selective sequencing method taught by Payne et al. would have successfully been used as a direct substitute for the conventional nanopore sequencing steps used by Stevens et al. because Payne et al. expressly suggest “this method should be applicable to any MinION configuration with sufficient GPU to basecall a sequencing run in real time.” (Payne et al., page 16, paragraph 3).
Regarding claim 2, Stevens et al. teach “We use the specificity of CRISPR-Cas9 single guide RNA (Cas9/sgRNA) complexes to define 50 and 30 termini of sequence-specific loci in genomic DNA, targeting 10 to 36 kb regions. The complexes were found to provide protection from exonucleases, by protecting the targeted sequences from degradation, resulting in enriched, double-strand, non-amplified target sequences suitable for next-generation sequencing library preparation or other downstream analyses.” (Stevens et al., Abstract) (i.e. no further step of protecting the target nucleic acid fragment was performed).
Regarding claims 3 and 17-18, Stevens et al. teach incubating the gRNA-Cas complexes with target DNA (i.e. step b) for 60 minutes at 37 degrees C and subsequently treating with exonuclease for 240 minutes at 37 degrees C (Stevens et al., page 2, paragraph 4).
Regarding claim 4, Stevens et al. teach the gRNA-Cas complexes comprise Cas9 protein (Stevens et al., Figure 5 and page 2, paragraph 3).
Regarding claim 5, Stevens et al. teach the gRNA-Cas complexes comprise sgRNA (Stevens et al., Figure 5 and page 2, paragraph 3).
Regarding claims 7-8, Stevens et al. teach the gRNA-Cas complexes are capable of inducing a DSB (Stevens et al., page 6, paragraph 1).
Regarding claims 10-11, Stevens et al. teach ligating sequencing adapters to the protected target DNA fragments prior to sequencing (Stevens et al., page 3, paragraph 3-4).
Regarding claim 12, Stevens et al. teach performing the method in parallel for multiple nucleic acid samples (i.e. multiplexing for multiple loci across multiple samples) (Stevens et al., page 8, paragraph 2).
Regarding claims 13-14, Stevens et al. teach the nucleic acid molecule is a human genomic DNA (e.g. a 10 kb locus comprised within the human CFTR gene) (Stevens et al., figure 5).
Regarding claim 20, Stevens et al. teach the adapter ligation step follows the exonuclease treatment and purification steps and precedes the sequencing step (Stevens et al.,
Regarding newly added claims 21-22, Stevens et al. teach “as shown in figure 5, reads from the protected and exonuclease treated samples demonstrated 20x to 43x enrichment ratio enrichment when compared with the average of four unenriched genomes” (Stevens et al., page 7-8 bridging paragraph).
Claims 1-2, 4-5, 7-11, 13-14, and 20-22 remain/are rejected under 35 U.S.C. 103 as being unpatentable over “Shuber A”, US 2019/0382824 A1 (published December 19, 2019) in view of Payne et al., “Nanopore adaptive sequencing for mixed samples, whole exome capture and targeted panels” bioRxiv 2020.02.03.926956; doi: 10.1101/2020.02.03.926956 (published February 3, 2020)
This rejection has been updated as necessitated by the amendments to the claims.
Regarding claim 1, Shuber A teaches a method for enriching and sequencing target nucleic acid fragments comprising providing a sample comprising a target nucleic acid molecule, cleaving the target nucleic acid molecule with a first and second gRNA-Cas complex, contacting the cleaved nucleic acid molecules with an exonuclease, purifying the protected fragments, and sequencing the target nucleic acid molecules by Nanopore sequencing. (Shuber A, Figure 5, see below, paragraph 0054 and paragraph 0067).
Claim 1, as amended, now recites the requirement of a desired result apparently inherent to the claimed methodological steps of “obtaining an at least 20-fold enrichment of target nucleic acid(s)… compared to… the non-target nucleic acid(s) reads.
Shuber A teaches “One or more exonuclease is used to digest unprotected nucleic acid…[for example]… ExoIII and ExoVII destroy all DNA that does not include both binding/protecting sites (Shuber A, paragraph 0070, emphasis added). “destr[uction of] all DNA that does not include both binding/protecting sites” would result in an enrichment ratio approaching infinity because the denominator (i.e. the number of reads derived from non-target sequences that do not include the protecting sites) approaches zero as the destruction of DNA that does not include both binding sites approaches “destruction of all DNA that does not include both binding/protecting sites”.
Shuber A does not teach that nanopore sequencing comprises “nanopore selective sequencing”.
However, Payne et al. teach “Nanopore sequencers enable selective sequencing of single molecules in real time by individually reversing the voltage across specific nanopores” and an example wherein “we enrich panels including 25,600 exon targets from 10,000 human genes and 717 genes implicated in cancer… These methods can be
used to efficiently screen any target panel of genes without specialised sample preparation using a single computer and suitably powerful GPU.” (Payne et al., Abstract) Payne et al further teach that selective sequencing provides benefits in improved time-to-answer and enrichment benefits focused on specific subsets of reads (Payne et al., page 15-16 bridging paragraph).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the method taught by Shuber A comprising steps of providing a sample comprising a target nucleic acid molecule, cleaving said target with a first and second gRNA-CAS complex, contacting the cleaved molecules with an exonuclease, optionally purifying the target nucleic acid, ligating adapters after the exonuclease treatment step, and sequencing the resulting target-sequence enriched libraries by nanopore sequencing by performing nanopore selective sequencing, rather than conventional nanopore sequencing as taught by Shuber A. The ordinary artisan would have been motivated to modify the sequencing step taught by Shuber A because of the teaching of Payne et al. that nanopore selective sequencing beneficially improved time-to-answer and enrichment focused on specific subsets of reads (Payne et al., page 15-16 bridging paragraph). The ordinary artisan would have been reasonably confident that the nanopore selective sequencing method taught by Payne et al. would have successfully been used as a direct substitute for the conventional nanopore sequencing steps used by Shuber A because Payne et al. expressly suggest “this method should be applicable to any MinION configuration with sufficient GPU to basecall a sequencing run in real time.” (Payne et al., page 16, paragraph 3).
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Regarding claim 2, Shuber A teaches “binding of the proteins (i.e. the gRNA-Cas complexes) to the ends of the segment provides protection against exonuclease digestion (i.e. no further step of protecting the target nucleic acid fragment is performed) (Shuber A, paragraph 0045).
Regarding claim 4, Shuber A teaches the first and second gRNA-Cas complexes comprise Cas9 protein (Shuber A , paragraph 0054).
Regarding claim 5, Shuber A teaches that the first and second gRNA-Cas complexes comprise sgRNA (Shuber A, paragraph 0094).
Regarding claims 7-8, Shuber A teaches that the two gRNA-Cas complexes are either wildtype (i.e. catalytically active, capable of inducing a DSB), or may be catalytically inactive (Shuber A, paragraph 0008).
Regarding claim 9, Shuber A teaches the two Cas endonuclease complexes (or sets of complexes if nickases are used) define the locus [to be protected] (i.e. at least a third nickase in addition to the first and second nickase) (Shuber A, paragraph 0070-0071).
Regarding claims 10-11 and 20, Shuber A teaches the protected segment may be detected by any means known in the art including sequencing (i.e. ligating a sequencing adapter to the protected nucleic acid segment after nuclease treatment and prior to the sequencing step).
Regarding claims 13 and 14, Shuber A teaches the nucleic acid sample is a genomic DNA obtainable from a human, an animal, a plant, or microorganism (Shuber A, paragraph 0058-0060).
Regarding newly added claims 21-22, Shuber A teaches “One or more exonuclease is used to digest unprotected nucleic acid…[for example]… ExoIII and ExoVII destroy all DNA that does not include both binding/protecting sites (Shuber A, paragraph 0070, emphasis added). “destr[uction of] all DNA that does not include both binding/protecting sites” would result in an enrichment ratio approaching infinity because the denominator (i.e. the number of reads derived from non-target sequences that do not include the protecting sites) approaches zero as the destruction of DNA that does not include both binding sites approaches “destruction of all DNA that does not include both binding/protecting sites”.
Claims 1-2, 4-8, 10-11, 13-14, and 20-22 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Shuber et al. 2018, US 10,081,829 B2 (Issued Sept. 25, 2018) in view of Payne et al., “Nanopore adaptive sequencing for mixed samples, whole exome capture and targeted panels” bioRxiv 2020.02.03.926956; doi: 10.1101/2020.02.03.926956 (published February 3, 2020).
This rejection has been updated as necessitated by the amendments to the claims.
Regarding claim 1, Shuber et al. 2018 teach methods of sequencing target nucleic acids comprising providing a sample comprising the target nucleic acid, cleaving the target nucleic acid with a first and second gRNA-Cas complex, generating target fragments that are protected against exonuclease cleavage, contacting the cleaved nucleic acids with exonuclease, purifying and detecting the protected target fragments (Shuber et al. 2018, Abstract and column 3) by sequencing, such as by Nanopore sequencing (Shuber et al. 2018, column 8, line 25-44).
Claim 1, as amended, now recites the requirement of a desired result apparently inherent to the claimed methodological steps of “obtaining an at least 20-fold enrichment of target nucleic acid(s)… compared to… the non-target nucleic acid(s) reads.
Shuber et al. 2018 teaches “degrad[ing] substantially all nucleic acid in a sample except for the nucleic acid of interest” Shuber et al. 2018, abstract) and further teaches “digestion may destroy all or substantially all nucleic acids in the population other than the target. For example, at least 90%... at least 99%, at least 99.9% of nucleic acids may be digested” (Shuber et al. 2018, column 7, lines 60-65). Destruction of 99% of nucleic acids results in a 100X enrichment of the remaining nucleic acids (i.e. the target nucleic acids) and destruction of 99.9% results in a 1000x enrichment of the remaining nucleic acids (i.e. the target nucleic acids).
Shuber et al. 2018 do not teach that nanopore sequencing comprises “nanopore selective sequencing”.
However, Payne et al. teach “Nanopore sequencers enable selective sequencing of single molecules in real time by individually reversing the voltage across specific nanopores” and an example wherein “we enrich panels including 25,600 exon targets from 10,000 human genes and 717 genes implicated in cancer… These methods can be
used to efficiently screen any target panel of genes without specialised sample preparation using a single computer and suitably powerful GPU.” (Payne et al., Abstract) Payne et al further teach that selective sequencing provides benefits in improved time-to-answer and enrichment benefits focused on specific subsets of reads (Payne et al., page 15-16 bridging paragraph).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the method taught by Shuber et al. 2018 comprising steps of providing a sample comprising a target nucleic acid molecule, cleaving said target with a first and second gRNA-CAS complex, contacting the cleaved molecules with an exonuclease, optionally purifying the target nucleic acid, ligating adapters after the exonuclease treatment step, and sequencing the resulting target-sequence enriched libraries by nanopore sequencing by performing nanopore selective sequencing, rather than conventional nanopore sequencing as taught by Shuber et al. 2018. The ordinary artisan would have been motivated to modify the sequencing step taught by Shuber et al. 2018 because of the teaching of Payne et al. that nanopore selective sequencing beneficially improved time-to-answer and enrichment focused on specific subsets of reads (Payne et al., page 15-16 bridging paragraph). The ordinary artisan would have been reasonably confident that the nanopore selective sequencing method taught by Payne et al. would have successfully been used as a direct substitute for the conventional nanopore sequencing steps used by Shuber et al. 2018 because Payne et al. expressly suggest “this method should be applicable to any MinION configuration with sufficient GPU to basecall a sequencing run in real time.” (Payne et al., page 16, paragraph 3).
Regarding claim 2, Shuber et al. 2018 teach the bound Cas endonuclease complexes are used to protect the nucleic acid of interest from exonuclease digestion (i.e. no further step of protecting is performed) (Shuber et al. 2018, Abstract).
Regarding claim 4, Shuber et al. 2018 teach the gRNA-Cas complexes comprise Cas9 protein (Shuber et al. 2018, column 3, paragraph 2).
Regarding claims 5 and 6, Shuber et al. 2018 teach the gRNA-Cas complexes comprise sgRNA or crRNA and tracrRNA as separate molecules (Shuber et al. 2018, column 3, paragraph 4).
Regarding claims 7 and 8, Shuber et al. 2018 teach one or both of the Cas complexes may be catalytically active (i.e. capable of cleaving the substrate, inducing a DSB) or inactive (Shuber et al. 2018, column 3, paragraph 3-5).
Regarding claims 10-11 and 20, Shuber et al. 2018 teach sequencing the protected target nucleic acids protected from exonuclease digestion (i.e. ligating sequencing adapters prior to the sequencing step and after the exonuclease digestion step) (Shuber et al. 2018, column 3, paragraph 3-6).
Regarding claims 13 and 14, Shuber et al. 2018 teach the target nucleic acid is genomic DNA from a human, non-human animal, plant, pathogen, mitochondria, chloroplast, etc. (Shuber et al. 2018, column 2, line 50-column 3, line 10).
Regarding newly added claims 21-22, Shuber et al. 2018 teaches “degrad[ing] substantially all nucleic acid in a sample except for the nucleic acid of interest” Shuber et al. 2018, abstract) and further teaches “digestion may destroy all or substantially all nucleic acids in the population other than the target. For example, at least 90%... at least 99%, at least 99.9% of nucleic acids may be digested” (Shuber et al. 2018, column 7, lines 60-65). Destruction of 99% of nucleic acids results in a 100X enrichment of the remaining nucleic acids (i.e. the target nucleic acids) and destruction of 99.9% results in a 1000x enrichment of the remaining nucleic acids (i.e. the target nucleic acids).
Claims 1-2, 4-8, 10-11, 13-14, and 20-22 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Shuber et al. 2019, US 10,370,700 B2 (Issued Aug 6, 2019) in view of Payne et al., “Nanopore adaptive sequencing for mixed samples, whole exome capture and targeted panels” bioRxiv 2020.02.03.926956; doi: 10.1101/2020.02.03.926956 (published February 3, 2020).
This rejection has been updated as necessitated by the claim amendments.
Regarding claim 1, Shuber et al. 2019 teach methods of sequencing target nucleic acids comprising providing a sample comprising the target nucleic acid, cleaving the target nucleic acid with a first and second gRNA-Cas complex, generating target fragments that are protected against exonuclease cleavage, contacting the cleaved nucleic acids with exonuclease, purifying and detecting the protected target fragments (Shuber et al. 2019, Abstract and column 3) by sequencing, such as by Nanopore sequencing (Shuber et al. 2019, column 8, line 25-44).
Claim 1, as amended, now recites the requirement of a desired result apparently inherent to the claimed methodological steps of “obtaining an at least 20-fold enrichment of target nucleic acid(s)… compared to… the non-target nucleic acid(s) reads.
Shuber et al. 2019 teaches “degrad[ing] substantially all nucleic acid in a sample except for the nucleic acid of interest” Shuber et al. 2019, abstract) and further teaches “digestion may destroy all or substantially all nucleic acids in the population other than the target. For example, at least 90%... at least 99%, at least 99.9% of nucleic acids may be digested” (Shuber et al. 2019, column 7, lines 60-65). Destruction of 99% of nucleic acids results in a 100X enrichment of the remaining nucleic acids (i.e. the target nucleic acids) and destruction of 99.9% results in a 1000x enrichment of the remaining nucleic acids (i.e. the target nucleic acids).
Shuber et al. 2019 do not teach that nanopore sequencing comprises “nanopore selective sequencing”.
However, Payne et al. teach “Nanopore sequencers enable selective sequencing of single molecules in real time by individually reversing the voltage across specific nanopores” and an example wherein “we enrich panels including 25,600 exon targets from 10,000 human genes and 717 genes implicated in cancer… These methods can be
used to efficiently screen any target panel of genes without specialised sample preparation using a single computer and suitably powerful GPU.” (Payne et al., Abstract) Payne et al further teach that selective sequencing provides benefits in improved time-to-answer and enrichment benefits focused on specific subsets of reads (Payne et al., page 15-16 bridging paragraph).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the method taught by Shuber et al. 2019 comprising steps of providing a sample comprising a target nucleic acid molecule, cleaving said target with a first and second gRNA-CAS complex, contacting the cleaved molecules with an exonuclease, optionally purifying the target nucleic acid, ligating adapters after the exonuclease treatment step, and sequencing the resulting target-sequence enriched libraries by nanopore sequencing by performing nanopore selective sequencing, rather than conventional nanopore sequencing as taught by Shuber et al. 2019. The ordinary artisan would have been motivated to modify the sequencing step taught by Shuber et al. 2019 because of the teaching of Payne et al. that nanopore selective sequencing beneficially improved time-to-answer and enrichment focused on specific subsets of reads (Payne et al., page 15-16 bridging paragraph). The ordinary artisan would have been reasonably confident that the nanopore selective sequencing method taught by Payne et al. would have successfully been used as a direct substitute for the conventional nanopore sequencing steps used by Shuber et al. 2019 because Payne et al. expressly suggest “this method should be applicable to any MinION configuration with sufficient GPU to basecall a sequencing run in real time.” (Payne et al., page 16, paragraph 3).
Regarding claim 2, Shuber et al. 2019 teach the bound Cas endonuclease complexes are used to protect the nucleic acid of interest from exonuclease digestion (i.e. no further step of protecting is performed) (Shuber et al. 2019, Abstract).
Regarding claim 4, Shuber et al. 2019 teach the gRNA-Cas complexes comprise Cas9 protein (Shuber et al. 2019, column 3, paragraph 3).
Regarding claims 5 and 6, Shuber et al. 2019 teach the gRNA-Cas complexes comprise sgRNA or crRNA and tracrRNA as separate molecules (Shuber et al. 2019, column 3, paragraph 4).
Regarding claims 7 and 8, Shuber et al. 2019 teach one or both of the Cas complexes may be catalytically active (i.e. capable of cleaving the substrate, inducing a DSB) or inactive (Shuber et al. 2019, column 3, paragraph 3-5).
Regarding claims 10-11 and 20, Shuber et al. 2019 teach sequencing the protected target nucleic acids protected from exonuclease digestion (i.e. ligating sequencing adapters prior to the sequencing step and after the exonuclease digestion step) (Shuber et al. 2019, column 3, paragraph 3-6).
Regarding claims 13 and 14, Shuber et al. 2019 teach the target nucleic acid is genomic DNA from a human, non-human animal, plant, pathogen, mitochondria, chloroplast, etc. (Shuber et al. 2018, column 2, line 50-column 3, line 10).
Regarding newly added claims 21-22, Shuber et al. 2019 teaches “degrad[ing] substantially all nucleic acid in a sample except for the nucleic acid of interest” Shuber et al. 2019, abstract) and further teaches “digestion may destroy all or substantially all nucleic acids in the population other than the target. For example, at least 90%... at least 99%, at least 99.9% of nucleic acids may be digested” (Shuber et al. 2019, column 7, lines 60-65). Destruction of 99% of nucleic acids results in a 100X enrichment of the remaining nucleic acids (i.e. the target nucleic acids) and destruction of 99.9% results in a 1000x enrichment of the remaining nucleic acids (i.e. the target nucleic acids).
Response to arguments
The response asserts that the claims as amended distinguish the claimed invention from the prior art because “a person of skill in the art looking for a way to obtain an at least 20-fold enrichment of the target nucleic acids… would not have a motivation to combine any of [the cited primary references above] with Payne since the enrichment observed using read until sequencing in Payne is relatively modest”.
This argument has been thoroughly reviewed and is not persuasive. As described above, the combination of the enrichment methods taught by the primary references comprising enrichment comprising targeted binding and protection of gRNA-CAS complex(es) with target nucleic acids with the subsequent enrichment methods taught in Payne comprising nanopore “selective sequencing” would have been expected to further enrich target sequences enriched by the Cas-binding/protection methods taught by the primary references because Payne teaches nanopore selective sequencing improves upon prior nanopore sequencing methods utilized in the primary references. Furthermore, as described in the updated rejections above, the newly added requirements of desired results apparently inherent to the claimed methodological steps of “obtaining an at least 20-fold enrichment of target nucleic acid(s)… compared to… the non-target nucleic acid(s) reads” does not distinguish the claimed invention from the cited prior art references for the reasons described in the body of the updated 103 rejections above.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 12 of copending Application No. 17297859 (herein referred to as ‘859) in view of Payne et al., “Nanopore adaptive sequencing for mixed samples, whole exome capture and targeted panels” bioRxiv 2020.02.03.926956; doi: 10.1101/2020.02.03.926956 (published February 3, 2020).
Claim 1 of ‘859 recites a method comprising steps of providing a sample comprising a target nucleic acid molecule, cleaving the target using a first and second gRNA-Cas complex, contacting the cleaved nucleic acid molecules with an exonuclease, and optionally purifying the target nucleic acid molecules.
In contrast, present claim 1 is identical save for the recited step e) “sequencing the target nucleic acid fragment by nanopore selective sequencing” and the newly added requirement of desired results apparently inherent to the claimed methodological steps of “obtaining an at least 20-fold enrichment of target nucleic acid(s)… compared to… the non-target nucleic acid(s) reads”.
Claim 12 of ‘859 further recites optionally ligating adapters to the target nucleic acid fragment and sequencing the target nucleic acid fragment.
The claims of ‘859 do not recite “nanopore selective sequencing”.
However, Payne et al. teach “Nanopore sequencers enable selective sequencing of single molecules in real time by individually reversing the voltage across specific nanopores” and an example wherein “we enrich panels including 25,600 exon targets from 10,000 human genes and 717 genes implicated in cancer… These methods can be
used to efficiently screen any target panel of genes without specialised sample preparation using a single computer and suitably powerful GPU.” (Payne et al., Abstract) Payne et al further teach that selective sequencing provides benefits in improved time-to-answer and enrichment benefits focused on specific subsets of reads (Payne et al., page 15-16 bridging paragraph).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the method recited by claims 1 and 12 of ‘859 comprising steps of providing a sample comprising a target nucleic acid molecule, cleaving said target with a first and second gRNA-CAS complex, contacting the cleaved molecules with an exonuclease, optionally purifying the target nucleic acid, ligating adapters after the exonuclease treatment step, and sequencing the resulting target-sequence enriched libraries by nanopore sequencing by performing nanopore selective sequencing, rather than generic “sequencing” recited by claims 1 and 12 of ‘859. The ordinary artisan would have been motivated to modify the sequencing step recited by claims 1 and 12 of ‘859 because of the teaching of Payne et al. that nanopore selective sequencing beneficially improved time-to-answer and enrichment focused on specific subsets of reads (Payne et al., page 15-16 bridging paragraph). The ordinary artisan would have been reasonably confident that the nanopore selective sequencing method taught by Payne et al. would have successfully been used as a direct substitute for the generic “sequencing” recited by claims 1 and 12 of ‘859 because Payne et al. expressly suggest “this method should be applicable to any MinION configuration with sufficient GPU to basecall a sequencing run in real time.” (Payne et al., page 16, paragraph 3).
This is a provisional nonstatutory double patenting rejection.
Response to arguments
The response requests that the double patenting rejection be held in abeyance until allowable subject matter is reached. This request has been noted, however MPEP 804(I)(b)(1) and 37 C.F.R. 1.111(b), which allows that some objections may be held in abeyance, includes no provision for holding rejections in abeyance. Thus, for the reasons above and those already of record, the rejection is maintained.
Conclusion
No claim is 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.
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/Z.M.T./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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