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 Formal Matters
This action is in response to papers filed 4/9/2026.
Claims 17-25 are pending.
Claims 1 has been amended.
Claim 25 has been added by amendment.
All previous rejection has been withdrawn as all previously rejected claims are canceled.
This action is final as the pending claims have been amended to no longer be improperly multiply dependent.
Priority
The instant application was filed 06/17/2023 and is a continuation in part of PCT/CN2021/137231 , filed 12/10/2021 and is a continuation in part of PCT/CN2021/086902 , filed 04/13/2021 which claims foreign priority to 202011496184.7, filed 12/17/2020 which claims foreign priority to 202210753404.2, filed 06/28/2022 and claims foreign priority to 202310565785.6, filed 05/19/2023.
Claim Objections
Claims 24 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from another multiply dependent cases. See MPEP § 608.01(n). Accordingly, the claims 24 not been further treated on the merits.
Response to Arguments
The response traverses the objection in view of the amendment. The objection of all claims except claim 24 has been withdrawn in view of the amendment. Claim 24 depends from claim 21 which is a multiply dependent claim.
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.
Claim 23 is 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 23 recites, “The reagent kit for detecting benignity or malignancy of a lung nodule as claimed in any of claims 17 to 20, characterized in that the reagent kit is applied to a test sample, the test sample being a respiratory tract sample selected from the group consisting of a lung tissue sample and a respiratory tract fluid sample.” The metes and bounds are unclear how this limits the independent claim as it appears to merely provide the intended use, but does not limit the structure.
Response to Arguments
This is a new ground of rejection necessitated by amendment.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 17-23 and 25 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural product without significantly more as the claims lack any limitation which require the hand of man. The claim(s) recite(s) the SEQ ID NO which encompass naturally occurring nucleic acids. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims provide no limitation which require the hand of man.
Claim analysis
The instant claim 17 is directed towards A reagent kit for detecting benignity or malignancy of a lung nodule,comprising a reagent for detecting a methylation level of one or more molecular markers for identifying DNA methylationwherein the one or more molecular markers are selected from at least one of the following: (a) the sequence of, or the completely complementary sequence to, SEQ ID NO:6; (b) the sequences of, or the completely complementary sequences to, SEQ ID NO:6 and SEQ ID 4(c) the sequences of, or the completely complementary sequences to, SEQ ID NO:6, SEQ ID NO:4, and SEQ ID NO:2: (d) the sequences of, or the completely complementary sequences to, SEQ ID NO:6 and SEQ ID no5 (e) the sequences of, or the completely complementary sequences to, SEQ ID NO:6, SEQ ID NO:4, and SEQ ID NO:5: (f) the sequences of, or the completely complementary sequences to, SEQ ID NO:6, SEQ ID NO:5, and at least one of SEQ ID NO:2 or SEQ ID NO:3; (g) the sequences of, or the completely complementary sequences to, SEQ ID NO:6, SEQ ID NO:5, and at least one of SEQ ID NO:1 or SEQ ID NO:3; (h) the sequences of, or the completely complementary sequences to, SEQ ID NO:6 and SEQ ID NO:1: (i) the sequences of, or the completely complementary sequences to, SEQ ID NO:6 and SEQ ID (j) the sequences of, or the completely complementary sequences to, SEQ ID NO:6, SEQ ID NO:1, and SEQ ID NO:2: (k) the sequences of, or the completely complementary sequences to, SEQ ID NO:6 and SEQ ID3 (1) the sequences of, or the completely complementary sequences to, SEQ ID NO:6, SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4: (m) the sequences of, or the completely complementary sequences to, SEQ ID NO:6, SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5: or (n) the sequences of, or the completely complementary sequences to, SEQ ID NO:1 to SEQ ID NO:6...
SEQ ID NO 6 is a naturally occurring nucleic acid from the gene ZSCAN31.
Dependent claims draw the invention to naturally occurring nucleic acids from HOXB4, (SEQ ID NO 1 and 2), PTGER4 (SEQ ID NO 3 and 4) and LHX9 (SEQ ID NO 5).
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case the Step 1 requirement is satisfied as the claims are directed towards a composition.
Step 2A Prong one. Does the claim recite a law of nature, a natural phenomenon or an abstract idea? Yes, natural phenomena or natural composition.
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? The answer is no as the claims provide no additional limitations.
Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No, the claims provide no limitations which require or demonstrate the hand of man has modified the nucleic acids from the way they occur in nature.
Tai (EP2966183) and Weiss (Journal of Thoracic Oncology (2016) Vol. 12 No. 1: 77-84) Homo sapiens prostaglandin E receptor 4 (subtype EP4), mRNA (cDNA clone MGC:126583 IMAGE:8069040), complete cds BC101534 submitted July 7, 2006), Lin (Lin et al. BMC Genomics 2014, 15:1079 http://www.biomedcentral.com/1471-2164/15/1079), Homo sapiens homeobox B4 (HOXB4), mRNA NM_024015 (https://www.ncbi.nlm.nih.gov/nuccore/1519245986?sat=47&satkey=4895528submitted 11/22/2018), Sakeda( Laboratory Investigation (2013) 93, 408–421), Houng Ly ( Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3515. doi:10.1158/1538-7445.AM2017-3515) Homo sapiens partial LHX9 gene for LIM-homeobox 9, exon 2 (AJ277916, July 26, 2016, https://www.ncbi.nlm.nih.gov/nucleotide/AJ277916.1?report=genbank&log$=nuclalign&blast_rank=1&RID=GTP785E4016 demonstrate the sequences are naturally occurring.
Response to Arguments
The response traverses the previous rejection n view of the amendment. This argument has been thoroughly reviewed but is not considered persuasive as the claims still read on naturally occurring nucleic acids.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 17, 23 is/are rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by Tai (EP2966183,).
Although claim 17-23 and 25 recites the term “kit”, the claim contains no structural requirements to distinguish it from a composition, nor is the term defined to be so limited in the specification. Accordingly, the claim has been given the reasonable interpretation to encompass a composition containing the claimed molecule.
Tai teaches method of detecting lung cancer including SEQ ID NO 2 which comprises instant SEQ ID NO 6 (nucleotides 1695-1884). Thus it anticipates the claims.
Claim 23 is rejected as it provides the intended use of the kit, but does not limit the reagents of the kit.
Response to Arguments
This is a new ground of rejection necessitated by amendment.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 17-20, 23, 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tai (EP2966183) and Weiss (Journal of Thoracic Oncology (2016) Vol. 12 No. 1: 77-84) Homo sapiens prostaglandin E receptor 4 (subtype EP4), mRNA (cDNA clone MGC:126583 IMAGE:8069040), complete cds BC101534 submitted July 7, 2006), Lin (Lin et al. BMC Genomics 2014, 15:1079 http://www.biomedcentral.com/1471-2164/15/1079), Homo sapiens homeobox B4 (HOXB4), mRNA NM_024015 (https://www.ncbi.nlm.nih.gov/nuccore/1519245986?sat=47&satkey=4895528submitted 11/22/2018), Sakeda( Laboratory Investigation (2013) 93, 408–421), Houng Ly ( Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3515. doi:10.1158/1538-7445.AM2017-3515) Homo sapiens partial LHX9 gene for LIM-homeobox 9, exon 2 (AJ277916, July 26, 2016, https://www.ncbi.nlm.nih.gov/nucleotide/AJ277916.1?report=genbank&log$=nuclalign&blast_rank=1&RID=GTP785E4016), Davidovic (Cent. Eur. J. Biol. • 9(12) • 2014 • 1127-1139), Henrandez (BioTechniques 55:181-197 (October 2013) )
Although claim 17-23 and 25 recites the term “kit”, the claim contains no structural requirements to distinguish it from a composition, nor is the term defined to be so limited in the specification. Accordingly, the claim has been given the reasonable interpretation to encompass a composition containing the claimed molecule.
Tai teaches method of detecting lung cancer including SEQ ID NO 2 which comprises instant SEQ ID NO 6 (nucleotides 1695-1884). Tai teaches methylation specific PCR (0037)
Tai does not teach SEQ ID NO 4 (PtGER4), HOXB4 (SEQ ID NO 2), LHX9 (SEQ ID NO 5)
However, Weiss teaches examination of PTGER 4 methylation with lung cancer (title). Homo sapiens prostaglandin E receptor 4 (subtype EP4), mRNA (cDNA clone MGC:126583 IMAGE:8069040), complete cds BC101534 submitted July 7, 2006) nucleotides 764-906 comprise SEQ ID NO 4 and nucleotides 538-711 comprise SEQ ID NO 3) Weiss teaches methylation specific PCR (blood sampling, sample preparation and methylation analysis)
Lin teaches a study of DNA methylation in non-small cell lung cancer. Lin teaches, “Genes related to the epithelial-to-mesenchymal transition, such as AXL, ESRP1, HoxB4, and SPINT1/2, were among the nearly 20% of the candidate genes that were differentially methylated between epithelial and mesenchymal cells. “ (abs)
Homo sapiens homeobox B4 (HOXB4), mRNA NM_024015 encompasses SEQ ID NO 2, nucleotides 254-74) and SEQ ID NO 1 (nucleotides 406-262).
Houng Ly teaches, “Oncogenic mutations of RAS are detected in approximately 30% of human cancers. KRAS is highly mutated in pancreatic, colorectal and lung cancers.” Houng Ly teaches, “We showed that LHX9 rescued KRAS suppression in multiple cell lines as well as xenograft. LHX9 overexpression substituted for KRAS in KRAS-driven xenograft. Moreover, in activated-MEK-overexpressing HA1E cells, LHX9 formed tumors as robustly as myristoylated AKT. LHX9 rescued KRAS suppression by both restoring KRAS-dependent pathways and activating KRAS-independent pathways.”
Sakeda teaches, “LHX9 were not expressed in the lung cancer cell lines examined.” (page 414, 2nd column, bottom 3rd full paragraph).
Homo sapiens partial LHX9 gene for LIM-homeobox 9, exon 2 comprises SEQ ID NO 5, nucleotides 116-236)
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to combine nucleotide sequences to known genes implicated in lung cancer including HOXB4, PTGER4, LHX( and ZSCAN31 into a kit. The artisan would be motivated to provide probes to isolate and further examine expression and methylation of the genes. The artisan would have a reasonable expectation of success as all the genes were known and implicated in lung cancer.
With regards to claim 18, Tia and Weiss teach methylation specific PCR.
Davidovic provides methylation specific PCR. Davidovic teaches how to determine locations (3.) Davidovic teaches rules and software for primer design (4.) Davidovic teaches in silico analysis of the primers suitability.
Hernadez provides a review on PCR based DNA methylation analysis including MethyLightand MS-HRM.
Designing methylation specific primers and probes, which are equivalents to those taught in the art is routine experimentation. The prior art teaches the parameters and objectives involved in the selection of oligonucleotides that function as probes, see Davidovic and Hernandez. The prior art is replete with guidance and information necessary to permit the ordinary artisan in the field of nucleic acid detection to design primers and probes. As discussed above, the ordinary artisan would be motivated to have designed and tested new methylation specific primers and probes to obtain additional oligonucleotides that function to detect methylation of SEQ ID NO 4 (PtGER4), HOXB4 (SEQ ID NO 2), LHX9 (SEQ ID NO 5)and identify oligonucleotides with improved properties. The ordinary artisan would have a reasonable expectation of success of obtaining additional primers and probes the teachings of Hernandez and Davidovic. Thus, for the reasons provided above, the ordinary artisan would have designed additional primers and probes using the teachings in the art at the time the invention was made. The claimed SEQ ID NOs are obvious over the cited prior art, absent secondary considerations.(claims 19-20, 23 and 25)
Claim 23 is rejected as it provides the intended use of the kit, but does not limit the reagents of the kit.
Claim(s) 21-22is/are rejected under 35 U.S.C. 103 as being unpatentable over Tai (EP2966183) and Weiss (Journal of Thoracic Oncology (2016) Vol. 12 No. 1: 77-84) Homo sapiens prostaglandin E receptor 4 (subtype EP4), mRNA (cDNA clone MGC:126583 IMAGE:8069040), complete cds BC101534 submitted July 7, 2006), Lin (Lin et al. BMC Genomics 2014, 15:1079 http://www.biomedcentral.com/1471-2164/15/1079), Homo sapiens homeobox B4 (HOXB4), mRNA NM_024015 (https://www.ncbi.nlm.nih.gov/nuccore/1519245986?sat=47&satkey=4895528submitted 11/22/2018), Sakeda( Laboratory Investigation (2013) 93, 408–421), Houng Ly ( Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3515. doi:10.1158/1538-7445.AM2017-3515) Homo sapiens partial LHX9 gene for LIM-homeobox 9, exon 2 (AJ277916, July 26, 2016, https://www.ncbi.nlm.nih.gov/nucleotide/AJ277916.1?report=genbank&log$=nuclalign&blast_rank=1&RID=GTP785E4016), Davidovic (Cent. Eur. J. Biol. • 9(12) • 2014 • 1127-1139), Hernandez (BioTechniques 55:181-197 (October 2013) ) as applied to claims 17-20, 23, 25 above, and further in view of Eads (Nucleic Acids Res. 2000 Apr 15;28(8):E32.)
The teachings of Tai, Weiss, Homo sapiens prostaglandin E receptor 4 (subtype EP4), mRNA (cDNA clone MGC:126583 IMAGE:8069040), complete cds BC101534 , Lin, Homo sapiens homeobox B4 (HOXB4), mRNA NM_024015, Sakeda, Houng Ly , Homo sapiens partial LHX9 gene for LIM-homeobox 9, exon 2 (AJ277916, July 26, 2016, Davidovic, Hernandez are set forth above.
The cited prior art does not specifically teach the use of ACTB as a reporter gene.
However, Eads teaches ACTB primers and probes as controls.
Designing methylation specific primers and probes, which are equivalents to those taught in the art is routine experimentation. The prior art teaches the parameters and objectives involved in the selection of oligonucleotides that function as probes, see Davidovic and Hernandez. The prior art is replete with guidance and information necessary to permit the ordinary artisan in the field of nucleic acid detection to design primers and probes. As discussed above, the ordinary artisan would be motivated to have designed and tested new methylation specific primers and probes to obtain additional oligonucleotides that function to detect methylation of SEQ ID NO 4 (PtGER4), HOXB4 (SEQ ID NO 2), LHX9 (SEQ ID NO 5)and identify oligonucleotides with improved properties. The ordinary artisan would have a reasonable expectation of success of obtaining additional primers and probes the teachings of Hernandez and Davidovic. Thus, for the reasons provided above, the ordinary artisan would have designed additional primers and probes using the teachings in the art at the time the invention was made. The claimed SEQ ID NOs are obvious over the cited prior art, absent secondary considerations.(claims 19-20, 23 and 25)
Response to Arguments
This is a new grounds of rejection necessitated by amendment.
Summary
No claims are allowed.
Conclusion
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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/Steven Pohnert/Primary Examiner, Art Unit 1683
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