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 .
Claims 84-107 are currently pending and under examination. Claims 1-83 are canceled.
Priority
The instant application 18/651,023 filed on 4/30/24 is a CON of 17/816,198 filed on 7/29/22, which is a CON of PCT/US21/16089 filed on 2/1/21, which claims domestic priority to provisional applications 62/988,859 filed 3/12/20; 62/987,232 filed 3/9/20; and 62/968,847 filed 1/31/20. The priority date is determined to be 1/31/20.
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 84-104 and 106-107 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims have been evaluated using the 2019 Revised Patent Subject Matter Eligibility Guidance (see Federal Register Vol. 84, No. 4 Monday, January 7, 2019).
Step 1: The claim is directed to the statutory category of a process.
Step 2A, prong one: The claim recites a judicial exception.
Claim 84 recitation of “performing a methylation analysis”; claim 85 recitation of “diagnosing, detecting, or monitoring”; claims 86-89 recitations of “diagnosing or detecting”; claims 90-91 recitations of “monitoring”; claims 97-98 recitations of “calculating”; claim 99 recitation of “detecting”; and claim 106 recitation of “performing a first analysis… and a second analysis” are all abstract ideas. These limitations are abstract mental processes and/or mathematical concepts (see MPEP 2106.04(a)). The abstract mental processes of analysis/diagnosis/detection/monitoring and calculation are concepts performed in the human mind.
Additionally, the claims are directed towards laws of nature and natural phenomena through the correlations of nucleic acid methylation levels (genotype) and cancer status (phenotype) (see MPEP 2106.04(b)).
Step 2A, prong two: The judicial exception is not integrated into a practical application.
Claims 84-104 and 106-107 recite insignificant extra-solution activities directed towards mere data gathering at high levels of generality (see MPEP 2106.05(g)). It is further noted that the claims are not directed to a particular treatment or prophylaxis (see MPEP 2106.04(d)(2)).
Claim 84 recites data-gathering limitations of sampling and enrichment, and does not expand upon the judicial exception of performing a methylation analysis beyond a high level of generality in which any technique or approach can be applied. Claim 85 ends with the judicial exceptions; claims 86-89 provide cancer stage/type limitations that do not integrate the judicial exceptions; claim 90 ends with the judicial exceptions; claim 91 recites treatment at a high-level of generality in which any therapeutic intervention can be applied; claims 92-96 recite data-gathering limitations of methylation analysis; claims 97-98 end with the judicial exceptions; claim 99 recites data-gathering limitations; claims 100-104 recite data-gathering limitations of target enrichment; and claims 106-107 end with the judicial exceptions recited at a high level of generality in which the analyses can be performed by any method applied.
Step 2B: The claim does not provide an inventive concept.
MPEP 2106.05(d)):
The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity:
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S.
at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health
Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir.
2017);
ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs.
Ltd. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir.
2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115
USPQ2d 1152, 1157 (Fed. Cir. 2015);
iii. Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78,
115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123
USPQ2d at 1088 (Fed. Cir. 2017);
iv. Immunizing a patient against a disease, Classen Immunotherapies, Inc. v.
Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
v. Analyzing DNA to provide sequence information or detect allelic
variants, Genetic Techs. Ltd., 818 F.3d at 1377, 118 USPQ2d at 1546;
vi. Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119
USPQ2d at 1375;
vii. Amplifying and sequencing nucleic acid sequences, University of Utah
Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d
1241, 1247 (Fed. Cir. 2014); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d
at 1247.
The claims end with the judicial exceptions. Additionally, methods of performing a methylation analysis are not inventive (Zhou et al. (2017; WO 2017/212428 A1); and Liu et al. (2018; "Targeted methylation sequencing of plasma cell-free DNA for cancer detection and classification". Ann Oncol. 2018 Jun 1;29(6):1445-1453. doi: 10.1093/annonc/mdy11)).
For the reasons set forth above, claims 84-104 and 106-107 are not directed to patent eligible subject matter.
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.
Claims 84-99 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou et al. (2017; WO 2017/212428 A1).
Relevant to claim 84, Zhou et al. Abstract teaches “Disclosed herein are methods and systems of utilizing sequencing reads for detecting and quantifying the presence of a tissue type or a disease type in cell-free DNA prepared from blood samples.”
Further relevant to claim 84, Zhou et al. paragraph 00258 teaches methods to “significantly amplify aberrant cfDNA signals”, reading on the instant performing a target enrichment.
Further relevant to claim 84, Zhou et al. paragraph 0009 teaches “In one aspect, provided herein is a method of characterizing a cell-free DNA (cfDNA) sample from a subject. In some embodiments, the method comprises the steps of receiving a plurality of sequencing reads for a cfDNA sample from the subject, wherein each sequencing read comprises methylation sequencing data obtained from a consecutive nucleic acid sequence of 50 or more nucleic acids; calculating a methylation pattern based on a sequencing read in the plurality, wherein the methylation pattern comprises a genomic region corresponding to the consecutive nucleic acid sequence and methylation status of one or more motifs in the genomic region; comparing the methylation pattern with each of one or more pre-established methylation signatures to compute one or more likelihood scores, wherein each of the one or more preestablished methylation signatures correlates with a biological composition, and wherein each pre-established methylation signature comprises at least one pre-determined signature region and pre-determined methylation rate associated therewith; and characterizing the sequencing read as containing the biological composition if at least one of the one or more likelihood scores exceeds a threshold value.”
Relevant to claim 85, Zhou et al. paragraph 0003 teaches “The invention disclosed herein generally relates to method for analyzing sequencing data of nucleic acid samples (e.g., cell-free DNA samples). It also relates to methods of cancer diagnosis and prognosis, including the identification, origin, and location of a cancer.”
Relevant to claims 86-87, Zhou et al. paragraph 0035 teaches embodiments wherein the cancer “may be Stage I, II<III, or IV.”
Relevant to claims 88-89, Zhou et al. paragraph 0035 teaches cancer type embodiments.
Relevant to claim 90, Zhou et al. paragraph 00115 teaches “In some embodiments, multiple blood samples can be taken from the same patient over a period of time. Methylation patterns derived from these blood samples can be used to monitor disease onset for high risk population. Alternatively, methylation patterns derived from these blood samples can be used to monitor disease progression; e.g., cancer prognosis.”
Relevant to claim 91, Zhou et al. paragraph 0086 teaches “In one aspect, methods disclosed herein can also be used to monitor cancer treatment for identifying driver clones, driver genes and driver regulatory pathways.”
Relevant to claims 92-94, Zhou et al. paragraph 00162 teaches “Cell-free DNA (cfDNA) isolation and Whole Genome Bisulfite Sequencing (WGBS)” methodologies which include treatment with methylation assay reagents, bisulfite and enzymatic treatments.
Relevant to claim 95, Zhou et al. Figure 22 depicts interrogating methylation status of 1 marker for a cancer.
Relevant to claim 96, Zhou et al. paragraph 00100 teaches interrogation of differentially methylated regions (DMRs).
Relevant to claim 97, Zhou et al. paragraph 00199 teaches calculating methylation fractions.
Relevant to claim 98, Zhou et al. paragraph 00168 teaches calculating methylation density.
Relevant to claim 99, Zhou et al. paragraph 0028 teaches detecting a disease based on counts of hyper-methylated molecules.
Zhou et al. does not teach a specific embodiment having all the claimed elements. That being said, however, it must be remembered that "[w]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious." KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. AG. Pro, 425 U.S. 273, 282 (1976)). "[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious," the relevant question is "whether the improvement is more than the predictable use of prior art elements according to their established functions." (Id.). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR at 1741. The Court emphasized that "[a] person of ordinary skill is... a person of ordinary creativity, not an automaton." Id. At 1742.
Consistent with this reasoning, it would have been prima facie obvious to have selected various combinations of various disclosed elements — including cancers, monitoring, reagents, and analyses — for a method of performing a methylation analysis, to arrive at compositions "yielding no more than one would expect from such an arrangement."
Claims 100-107 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou et al. (2017; WO 2017/212428 A1), as applied to claims 84-99 above, and further in view of Raymond (2010; WO 2010/030683 A1; FOR citation 3 in IDS filed 4/30/24).
The teachings of Zhou et al. are applied to instantly rejected claims 100-107 as they were previously applied to claims 84-99 above as rendering obvious a method of performing a methylation analysis. Zhou et al. is silent to specifics regarding target enrichment by hybridization. However, these limitations were known in the prior art and taught by Raymond.
Relevant to claim 100, Raymond Abstract teaches “The invention provides compositions and methods for generating a target enriched, sequencing ready library for resequencing at least one target region of interest from a nucleic acid containing sample.”
Relevant to claims 100-101, Raymond teaches "EXAMPLE 4: This example describes solution-based capture using indirect capture via chimeric capture oligos with a gene-specific region and a region that hybridizes to a universal biotinylated adaptor oligo, with a set of indirect oligos that are specific for a set of 5 genes of interest" (page 78, lines 1-5). The method is displayed in Raymond Figure 5.
Further relevant to claim 101, Raymond teaches "double-stranded nucleic acid fragments 10 are combined with the first 20 and second 30 stem-loop linker oligonucleotides in a ligation reaction" (page 13, lines 23-24).
The Raymond "double-stranded nucleic acid fragments” are equivalent to the instant target sequence of a molecule.
Further relevant to claim 101, Raymond teaches a "chimeric capture probe 200, 200' with a first region 202 that hybridizes to a target nucleic acid sequence 10, 10' in the library" (page 78, lines 23-25).
The Raymond "chimeric capture probe" is equivalent to the instant first/second bridge probe.
Further relevant to claim 101, Raymond teaches "As shown in FIGURE 5, in another embodiment of the method of this aspect of the invention, the capture probes 200 comprise a target-sequence specific binding region 202, 202' and a capture reagent binding region 204 that hybridizes to a universal adaptor oligonucleotide 300 comprising a moiety 310 that binds to a capture reagent 400" (page 19, lines 32- 33 continued to page 20, lines 1-2).
The Raymond "capture reagent binding region… that hybridizes to a universal adaptor oligonucleotide" is equivalent to the instant first/second adaptor landing sequence of the first/second bridge probe is bound to a first/second bridge binding sequence of an adaptor anchor probe.
Relevant to claims 102-103, Raymond teaches "The universal adaptor oligonucleotide 300 is present at an equal concentration as the capture probes 200, and hybridize to the capture reagent binding region 204. The moiety 310 (e.g., biotin) attached to the universal oligo adaptor 300 is then contacted with a capture reagent 400 (e.g., a magnetic bead) having a binding region 410 (e.g., streptavidin coating) and the complex is pulled out of solution with a sorting device 500 (e.g., a magnet) that binds to the capture reagent 400" (page 20, lines 6-11).
Relevant to claim 104, Raymond Figure 5 depicts attaching adaptors to the 5’ end or the 3’ ends.
Relevant to claims 105-107, Raymond Figure 6 and associated text (last paragraph of page 21 – third paragraph of page 22) teaches sequential enrichment and a first analysis of sequence analysis.
Relevant to claim 107, Zhou et al. teaches methylation analyses, as described in above rejections of claims 84-99.
Although Zhou et al. does not explicitly teach the Raymond target enrichment by hybridization, it would have been prima facie obvious to the skilled artisan. Zhou et al. and Raymond are analogous disclosures in the field of nucleic acid analysis.
The skilled artisan would be motivated to combine the analogous art. Zhou et al. teaches that “Early detection of cancer – before it has had a chance to metastasize – presents the best strategy for increasing cancer survival. Recently, cancer detection using cell-free DNA (cfDNA) from blood has attracted significant interest due to its non-invasive nature. However, tumor cfDNA levels are very low in most early-stage and many advanced stage cancer patients [citations]. Therefore, the major challenge in cfDNA-based early cancer diagnostics is how to identify the tiny amount of tumor cfDNAs out of total cfDNAs in blood” (paragraph 0007).
To this end of overcoming the challenge of detection of very lowly concentrated cfDNA, the skilled artisan would find it obvious to use the Raymond target enrichment by hybridization because Raymond teaches that “As described in Examples 3-5, the solution-based capture methods according to the various embodiments described herein may be used to produce a level of target fragment specific enrichment in the range of 500- to 900-fold in the first round of enrichment, with a 50-fold higher level of enrichment in the second round (i.e., 25,000- to 45,000-fold total enrichment levels)” (page 22, lines 21-25).
Thus, the skilled artisan would be motivated to include the Raymond target enrichment within the Zhou et al. methodology to overcome the detection challenges associated with low concentrations of cfDNA, thus enriching the nucleic acids to detectable levels. The skilled artisan would have a reasonable expectation of success based on the disclosures of Zhou et al., and further in view of Raymond.
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.
Claims 84-107 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 84-103 of copending Application No. 17/816,198 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to forming a nucleic acid complex for the detection of a target nucleic acid.
Instant claim 101 teaches a method which has steps that include all of the limitations of copending claim 84. Although the copending claims do not teach a single claim that includes all of the limitations of instant claim 84+, it would have been prima facie obvious to the skilled artisan to have modified any one of the copending claims so as to have applied it to the formation of a nucleic acid detection complex since this is a specifically named embodiment of the invention in claims 84+ in the copending application. Since all the claims in the copending application are directed toward the formation of this nucleic acid complex, it would have been obvious to combine the methods of the copending claims to achieve the predictable outcome of forming a nucleic acid complex.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 84-107 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 170, 172-182, and 190-192 of copending Application No. 17/326,475 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to forming a nucleic acid complex for the detection of a target nucleic acid.
Instant claim 101 teaches a method which has steps that include all of the limitations of copending claim 170. Although the copending claims do not teach a single claim that includes all of the limitations of instant claim 84+, it would have been prima facie obvious to the skilled artisan to have modified any one of the copending claims so as to have applied it to the formation of a nucleic acid detection complex since this is a specifically named embodiment of the invention in claims 170+ in the copending application. Since all the claims in the copending application are directed toward the formation of this nucleic acid complex, it would have been obvious to combine the methods of the copending claims to achieve the predictable outcome of forming a nucleic acid complex.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 84-107 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/839,303 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to forming a nucleic acid complex for the detection of a target nucleic acid.
Instant claim 101 teaches a method which has steps that include all of the limitations of copending claim 1. Although the copending claims do not teach a single claim that includes all of the limitations of instant claim 84+, it would have been prima facie obvious to the skilled artisan to have modified any one of the copending claims so as to have applied it to the formation of a nucleic acid detection complex since this is a specifically named embodiment of the invention in claims 1+ in the copending application. Since all the claims in the copending application are directed toward the formation of this nucleic acid complex, it would have been obvious to combine the methods of the copending claims to achieve the predictable outcome of forming a nucleic acid complex.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/SARAH JANE KENNEDY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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