DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group in the reply filed on 07/09/2026 is acknowledged. Group II, claim 33, is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. The cancellation of claim 33 in the reply filed on 07/09/2026 is acknowledged.
A first office action on the merits of claims 1-3, 6-8, 14, 15, 19-25, 27, 28, 31, & 32 is set forth herein and claim 33 is withdrawn from consideration.
Information Disclosure Statement
Only the abstracts of the references in the IDS submitted on 08/20/2024 that are lined through, under the foreign patent documents section, were considered because an English copy of the full documents were not provided.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3, 6-8, 14, 15, 19-25, 27, 28, 31, & 32 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1, the recitation of “assigning each locus to a group based on mRNA or protein expression level of a gene associated with the locus in a healthy subject” in lines 8-9 of the claim is unclear what “based on” and what the relationship is between mRNA or protein expression level and how they are grouped. In addition, the recitation of “said at least said subset of said plurality of sequences” in lines 10-11 of the claim is unclear what “said at least said subset” is referring back to. If referring back to “(c) for at least a subset of said plurality of sequences” it is suggested to amend the recitation to “said at least subset of said plurality of sequences”.
Regarding claim 31, the recitations of “said at least said subset of said plurality of sequences” in lines 1-2 of the claim is unclear what “said at least said subset” is referring back to. If referring back to “(c) for at least a subset of said plurality of sequences” in claim 1, from which claim 31 depends from, it is suggested to amend the recitations to “said at least subset of said plurality of sequences”.
Regarding claim 32, the recitation of “said at least said subset of said plurality of sequences” in lines 1-2 of the claim is unclear what “said at least said subset” is referring back to. If referring back to “(c) for at least a subset of said plurality of sequences” in claim 1, from which claim 32 depends from, it is suggested to amend the recitation to “said at least subset of said plurality of sequences”.
Claims 2, 3, 6-8, 14, 15, 19-25, 27, & 28 are rejected due to their dependence on claim 1.
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 1-3, 6-8, 14, 15, 19-25, 27, 28, 31, & 32 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation/law of nature and an abstract idea without significantly more. This judicial exception is not integrated into a practical application and the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106. The unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, 561 U.S. 593, 601 (June 28, 2010) and Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014). See also Myriad v Ambry, CAFC 2014-1361, -1366, December 17, 2014. The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66, 71 (2012). “[L]aws of nature, natural phenomena, and abstract ideas” are not patentable. Dia-mond v. Diehr, 450 U. S. 175, 185 (1981); see also Bilski v. Kappos, 561 U. S. at 601 (2010).
Claims Analysis:
As set forth in MPEP 2106, the claims have been analyzed to determine whether they are directed to one of the four statutory categories (STEP 1).
The instant claims are directed to methods and therefore are directed to one of the four statutory categories of invention.
The claims are then analyzed to determine if they recite a judicial exception (JE) (STEP 2A, prong 1) [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)].
The claimed invention recites a method for identifying whether a subject has a disease comprising subjecting a plurality of nucleic acid molecules to sequencing, assigning each locus to a group, identifying a decrease or an increase in a number or concentration of the plurality of sequences, and upon identifying a decrease or an increase, electronically outputting a report that is indicative of said subject having said disease. This recitation is a natural correlation between increase or decrease in a number or concentration of a plurality of sequences relative to a healthy control and indicative of said subject having said disease. With regard to the natural correlation, as in Mayo, the relationship is itself a natural process that exists apart from any human action. The claimed invention also recites ”identifying a decrease or an increase in (i) a number or concentration of … said subset of said plurality of sequences” which is a recitation of an abstract idea because it encompasses conclusions and determinations which can occur entirely within the mind. It is therefore determined that the claims are directed to judicial exceptions.
The claims are then analyzed to determine whether they recite an element or step that integrates the JE into a practical application (STEP 2A, prong 2) [Vanda Pharmaceuticals Inc., v. West-Ward Pharmaceuticals, 887 F.3d 1117 (Fed. Cir. 2018)].
The claims recite steps of providing a plurality of nucleic acids molecules, subjecting a plurality of nucleic acid molecules to sequencing, for a subset of a plurality of sequences that are mappable to a locus assigning each locus to a group, identifying a decrease or an increase in a number or concentration of the plurality of sequences, and upon identifying a decrease or an increase, electronically outputting a report that is indicative of said subject having said disease, however this does not integrate the JE into a practical application because it is a mere data gathering step to use the correlation and does not add a meaningful limitation to the method.
In the absence of steps or elements that integrate the JE into a practical application, the additional elements/steps are considered to determine whether they add significantly more to the JE either individually or as an ordered combination, to “’transform the nature of the claim’ into a patent eligible application” [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)] (STEP 2B).
In the instant situation, the steps of subjecting a plurality of nucleic acid molecules to sequencing and identifying a decrease or an increase in a number or concentration of at least a subset of said plurality of sequences relative to a control are generally recited and do not provide any particular reagents that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited. This step is not only a mere data gathering step, but the general recitation of detection of known nucleic acids is well understood, routine, and conventional activity (See MPEP 2106.05(d)(II)). Applicant is reminded that in Mayo, the Court found that “[i]f a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself." Further "conventional or obvious" "[pre]solution activity" is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law”. Flook, 437 U. S., at 590; see also Bilski, 561 U. S., at ___ (slip op., at 14) (“[T]he prohibition against patenting abstract ideas ‘cannot be circumvented by’ . . . adding ‘insignificant post-solution activity’” (quoting Diehr, supra, at 191–192)). The Court also summarized their holding by stating “[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.” Therefore these limitations/steps do not “‘transform the nature of the claim’ into a patent-eligible application.’” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
When viewed as an ordered combination, the claimed limitations are directed to nothing more than the determination that a natural correlation/phenomena exists. Any additional element consists of using well understood, routine and conventional activity, and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.
Accordingly, it is determined that the instant claims are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-3, 6, 7, 14, 15, 19, 21-25, 27, 28, & 32 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Arensdorf (United States Patent Application Publication US 2020/0123616 A1, April 2020), as cited on the IDS dates 08/20/2024.
Regarding claim 1, Arensdorf teaches a method of evaluating the risk of pancreatic cancer in a patient comprising obtaining a cell-free DNA (cfDNA) sample from the patient (providing a plurality of nucleic acid molecules derived from a cell-free nucleic acid sample of a subject), enriching for hydroxymethylated DNA in the sample, quantifying the nucleic acids in the enriched sample that map to each of a plurality of loci in a reference hydroxmethylated profile, in which quantifying the nucleic acids in the enriched sample comprises amplifying the cfDNA and sequencing the amplicons and quantifying the nucleic acids that map to the reference loci from the sequence reads, and comparing at each locus (each locus group) the hydroxymethylation level in the reference profile (subjecting said plurality of nucleic acid molecules to sequencing and for at least a subset of said plurality of sequences that are mappable to a locus or loci of a reference genome, assigning each locus to a group based on mRNA or protein expression level of a gene associated with the locus in a healthy subject), and calculating an index value representing a risk that lesion in pancreatic cancer from the comparison step as a fold change (decrease or increase) (identifying a decrease or an increase in (i) a number or concentration of said at least said subset of said plurality if sequences assigned to said group relative to (ii) a number or concentration of at least a subset of a plurality of additional sequences from a healthy control that are mappable to said locus of loci or said group and identifying a decrease and an increase in a number or concentration relative to a healthy control) in which the index value can be calculated through data analysis and transforming raw data to develop a predictive model that classifies the sample and is provided in a report (upon identifying said decrease or increase, electronically outputting a report that is indicative said subject having said disease (paragraph [0023] lines 1-21; paragraph [0027] lines 1-4; paragraph [0028] lines 10-14; paragraph [0170] lines 1-9; paragraph [0213] lines 1-10; paragraph [0214] lines 1-8; paragraph [0215] lines 1-11).
Regarding claims 2 & 3, Arensdorf teaches the loci may be contained within a gene body such as a DNA binding site comprising transcription factor binding sites (said locus comprises a binding site for DNA-binding molecule and said DNA binding molecule comprises a transcription factor (paragraph [0158] lines 11-21).
Regarding claim 6, Arensdorf teaches the sequencing comprises sequencing by synthesis, sequencing by ligation, or nanopore sequencing (paragraph [0136] lines 1-11).
Regarding claim 7, Arensdorf teaches quantifying the nucleic acids in the enriched sample that map to each of a plurality of loci in a reference hydroxmethylated profile, in which quantifying the nucleic acids in the enriched sample comprises amplifying the cfDNA and sequencing the amplicons and quantifying the nucleic acids that map to the reference loci from the sequence reads (prior to sequencing subjecting said plurality of nucleic acids to nucleic acid amplification to generate a plurality of amplification products in which plurality of amplification products is sequencing to generate said plurality of sequences) (paragraph [0028] lines 10-14).
Regarding claim 14, Arensdorf teaches enriching for hydroxymethylated DNA in the sample, quantifying the nucleic acids in the enriched sample that map to each of a plurality of loci in a reference hydroxmethylated profile, in which quantifying the nucleic acids in the enriched sample comprises amplifying the cfDNA and sequencing the amplicons and quantifying the nucleic acids that map to the reference loci from the sequence reads, and comparing at each locus (each locus group) the hydroxymethylation level in the reference profile (prior to sequencing subjecting said plurality of nucleic acid molecules to enrichment to yield an additional plurality of nucleic acid molecules which are sequenced to generate a plurality of sequences) (paragraph [0023] lines 1-21; paragraph [0028] lines 10-14).
Regarding claim 15, Arensdorf teaches the enrichment step comprises ligating adapters with an affinity tag onto the cfDNA to allow selective capture of the tagged cfDNA (enrichment is performed with targeted primers/capture probes) (paragraph [0028] lines 1-5).
Regarding claim 19, Arensdorf teaches obtaining a cell-free DNA (cfDNA) sample from the patient (plurality of nucleic acid molecules comprises cell-free deoxyribonucleic acid) (paragraph [0027] lines 1-4).
Regarding claim 21, Arensdorf teaches tumor and normal cell DNA is released into cfDNA and further obtaining this cfDNA from a blood sample or a pancreatic lesion sample (from a tumor) from the patient (paragraph [0009] lines 1-4; paragraph [0027] lines 1-4).
Regarding claim 22, Arensdorf teaches this method can monitor a patient with a pancreatic lesion progressing towards cancer and monitor effectiveness of treatment of a patient (monitoring a progression or regression of said disease in a subject in response to treatment) (paragraph [0029] lines 1-7; paragraph[0052] lines 1-3).
Regarding claims 23 & 24, Arensdorf teaches the cfDNA sample if from a blood sample or a sample of pancreatic lesion fluid obtained from the patient (cell-free nucleic acid sample is from a bodily fluid wherein the bodily fluid is blood) (paragraph [0027] lines 1-4).
Regarding claim 25, Arensdorf teaches this method for enriching and quantifying hydroxymethylation levels in cell-free nucleic acids (identify an epigenetic modification selected from methylation) through quantification through a variety of predictive model analysis (computer processing a plurality of sequences to identify an epigenetic modification in said plurality of sequences) (paragraph [0009] lines 1-8; paragraph [0023] lines 1-21; paragraph [0213] lines 1-10; paragraph [0214] lines 1-8; paragraph [0215] lines 1-11).
Regarding claim 27, Arensdorf teaches the disease is pancreatic cancer (disease is a cancer selected from pancreatic cancer) (paragraph [0023] lines 1-21).
Regarding claim 28, Arensdorf teaches calculating an index value representing a risk that lesion in pancreatic cancer from the comparison step as a fold change (decrease or increase) through differential analysis if hydroxymethylation levels that are increased and decreased in which a fold change of 1.5 from cancer to non-cancer samples was determined (said decrease or increase in (i) relative to (ii) is at least 0.5%) (paragraph [0170] lines 1-9; paragraph [0227] lines 1-11).
Regarding claim 32, Arensdorf teaches the nucleic acids that map to each of the plurality of selected loci (group by loci) in a reference hydroxymethylation profile are quantified (prior to identifying a decrease or increase mapping said at least said subset of said plurality of sequences to said locus) (paragraph [0170] lines 1-9).
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.
Claim(s) 8, 20, & 31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Arensdorf (United States Patent Application Publication US 2020/0123616 A1, April 2020), as cited on the IDS dated 08/20/2024, in view of Namsaraev (WO 2018/031808 A1, February 2018).
The teachings of Arensdorf with respect to claim 1 are discussed above and incorporated herein.
Regarding claim 8, Arensdorf teaches quantifying the nucleic acids in the enriched sample that map to each of a plurality of loci in a reference hydroxmethylated profile, in which quantifying the nucleic acids in the enriched sample comprises amplifying the cfDNA and sequencing the amplicons and quantifying the nucleic acids that map to the reference loci from the sequence reads (prior to sequencing subjecting said plurality of nucleic acids to nucleic acid amplification to generate a plurality of amplification products) (paragraph [0028] lines 10-14).
Arensdorf does not teach subjecting said plurality of nucleic acid molecules to circularization to generate a plurality of circularized nucleic acid molecules and subjecting to rolling circle amplification.
Namsaraev teaches a method of analyzing cell-free nucleic acids in a sample comprising enriching for cell-free nucleic acid fragments that are mappable to one or more loci and comprising ligating the first end of the cell-free nucleic acid molecule to the second end of the cell-free nucleic acid molecule thereby forming a circularized cell-free nucleic acid molecule and determining an amount of the circularized cell-free nucleic acid comprising through rolling circle amplification to determine the disease of cancer (subjecting said plurality of nucleic acid molecules to circularization and subjecting said plurality of circularized nucleic acid molecules to rolling circle amplification) (paragraph [0008] lines 1-5, 11-15, & 19-23). In addition, Namsaraev teaches that this method enables enrichment and amplification of target nucleic acids in a sample while preserving the sequence information at the ends of the target nucleic acids which is useful in disease prognostics and diagnostics (paragraph [0002] lines 11-15).
Arensdorf and Namsaraev are considered to be analogous to the claimed invention because they are all in the same field of quantification of sequenced cell-free nucleic acid molecules mappable to loci. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of amplifying the cfDNA and sequencing the amplicons and quantifying the nucleic acids that map to the reference loci from the sequence reads in Arensdorf to incorporate the circularization and rolling circle amplification of circularized nucleic acid molecules mappable to loci as taught in Namsaraev because Namsaraev teaches that doing so would provide a method that enables enrichment and amplification of target nucleic acids in a sample while preserving the sequence information at the ends of the target nucleic acids which is useful in disease prognostics and diagnostics.
Regarding claim 20, Arensdorf teaches obtaining a cell-free DNA (cfDNA) sample from the patient (plurality of nucleic acid molecules comprises cell-free deoxyribonucleic acid) (paragraph [0027] lines 1-4).
Arensdorf does not teach the plurality of nucleic acid molecules comprises cell-free ribonucleic acid.
Namsaraev teaches a method of analyzing cell-free nucleic acids in a sample comprising enriching for cell-free nucleic acid fragments that are mappable to one or more loci comprising cell-free RNA (cell-free ribonucleic acid) to determine the disease of cancer in which reverse transcription PCR can be used to determine the cell-free nucleic acids (said plurality of nucleic acid molecules is generated at least in part using reverse transcription) (paragraph [0008] lines 1-5, 11-15, & 19-23; paragraph [0036] lines 1-4; paragraph [0110] lines 5-7). In addition, Namsaraev teaches that this method enables enrichment and amplification of target nucleic acids in a sample while preserving the sequence information at the ends of the target nucleic acids which is useful in disease prognostics and diagnostics (paragraph [0002] lines 11-15).
Arensdorf and Namsaraev are considered to be analogous to the claimed invention because they are all in the same field of quantification of sequenced cell-free nucleic acid molecules mappable to loci. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of amplifying the cfDNA and sequencing the amplicons and quantifying the nucleic acids that map to the reference loci from the sequence reads in Arensdorf to incorporate enriching for cell-free nucleic acid fragments that are mappable to one or more loci comprising cell-free RNA using reverse-transcription PCR as taught in Namsaraev because Namsaraev teaches that doing so would provide a method that enables enrichment and amplification of target nucleic acids in a sample while preserving the sequence information at the ends of the target nucleic acids which is useful in disease prognostics and diagnostics.
Regarding claim 31, Arensdorf does not teach wherein said at least said subset of said plurality of sequences have a size(s) above or below a threshold.
Namsaraev teaches a method of analyzing cell-free nucleic acids in a sample comprising enriching for cell-free nucleic acid fragments that are mappable to one or more loci comprising cell-free nucleic acids to determine the disease of cancer two sizes of targets were analyzed (at least said subset of said plurality of sequences have size(s) above or below a threshold) (paragraph [0008] lines 1-5, 11-15, & 19-23; paragraph [0132] lines 8-12). In addition, Namsaraev teaches that this method enables enrichment and amplification of target nucleic acids in a sample while preserving the sequence information at the ends of the target nucleic acids which is useful in disease prognostics and diagnostics (paragraph [0002] lines 11-15).
Arensdorf and Namsaraev are considered to be analogous to the claimed invention because they are all in the same field of quantification of sequenced cell-free nucleic acid molecules mappable to loci. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of amplifying the cfDNA and sequencing the amplicons and quantifying the nucleic acids that map to the reference loci from the sequence reads in Arensdorf to incorporate targets above or below a size threshold as taught in Namsaraev because Namsaraev teaches that doing so would provide a method that enables enrichment and amplification of target nucleic acids in a sample while preserving the sequence information at the ends of the target nucleic acids which is useful in disease prognostics and diagnostics.
Conclusion
Claims 1-3, 6-8, 14, 15, 19-25, 27, 28, 31, & 32 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BAILEY C BUCHANAN whose telephone number is (703)756-1315. The examiner can normally be reached Monday-Friday 8:00am-5:00pm ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Winston Shen can be reached at (571) 272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
