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 the species election of nucleic acid in claim 43, of blood in claim 6, of colon cancer in claim 59, and of chemotherapy in claim 64 in the reply filed on 01/28/2026 is acknowledged. Claim 44 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
A first office action on the merits of claims 37, 38, 40-43, 45-48, 51, 52, 56, 58, 59, 61, 62, 64, 66, & 67 is set forth herein and claim 44 is withdrawn from consideration.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on pg. 27. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Information Disclosure Statement
Only the abstracts of the references in the IDS submitted on 07/21/2023 & 05/15/2025 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 42 & 43 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 42, the claim recites the limitation “said binding agent” in line 1 of the claim and there is insufficient antecedent basis for this limitation in the claim.
Regarding claim 43, the claim recites the limitation “said binding agent” in line 1 of the claim and there is insufficient antecedent basis for this limitation in the claim.
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 37, 38, 40-43, 45-48, 51, 52, 56, 58, 59, 61, 62, 64, 66, & 67 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 processing a plurality of nucleic acid molecule derived from a cell-free biological sample comprising determining a methylation state and determining a size for a nucleic acid molecule and processing the methylation state and size against a first and second database, respectively, to identify an association with at least a disease, determine that a subject has or is at risk of having a disease, or determining a disease level. This recitation is a natural correlation between methylation state and size of a nucleic acid molecule and having or risk of having a disease or disease level. 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 “determining a methylation state”, “determining a size”, “compare said first size with said second size”, and “compare said first end sequence with said second end sequence” which is a recitation of an abstract idea because it encompasses conclusions and determinations which can occur entirely within the mind. In addition, the claimed invention recites “processing (i) methylation state … against a first database, and (ii) said size … against a second database”, which is a recitation of an abstract idea because it encompasses the generic use of a computer to make comparisons 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 determining a methylation state for a nucleic acid molecule, determining a size for a nucleic acid molecule, processing methylation state and size of a nucleic acid against a first and second database, respectively, and identifying an association for a disease or comparing to references to determine the subject has or is at risk of having a disease, and further steps of circularizing the nucleic acid molecule, however this does not integrate the JE into a practical application because it is a mere data gathering step to use the correlation and to compare and does not add a meaningful limitation to the method.
Although the claims recite “administering a chemotherapy” to the subject, this step is conditional as it is based on the identified methylation state and size of a nucleic acid. Accordingly, these generally recited elements are considered nothing more than instructions to apply the law of nature because no particular conditions are required by the step of detecting methylation or size. As such, the “administering” step is merely a generalized “treat” limitation with no particularity that integrates the judicial exception into a practical application. The Supreme Court does acknowledge that it is possible to transform an unpatentable law of nature, but one must do more than simply state the law of nature while adding the words "apply it.” CLS BankInt’l, 134 S.Ct. at 2358; Prometheus, 132 S. Cl, at 1294.
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 detecting a methylation state and size of a nucleic acid 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. In addition, the steps of processing a methylation state and size of a nucleic acid against a first and second database, respectively, are generally recited and incorporates the use of a generic computer as a tool to perform a mental process (See MPEP 2106.04(a)(2)(III)(C)). These steps are not only a mere data gathering steps, 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) 37, 38, 40, 42, 45, 56, 58, 61, 62, & 64 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lo (United States Patent Application Publication US 2018/0149636 A1), as cited on the IDS dated 07/21/2023.
Regarding claim 37, Lo teaches a method for analyzing cell-free DNA for disease detection, comprising cancer detection, comprising measuring methylation levels of cell-free DNA in a sample (determining a methylation state for a nucleic acid molecule of a plurality of nucleic acid molecules) and measuring the size profile of cell-free DNA in a sample (determining a size for a nucleic acid molecule of a plurality of nucleic acid molecules) in which size profile analysis of cell-free DNA can identify sample with large portions of long fragments and methylation deconvolution (methylation state analysis) can identify origin of cell-free DNA fragments for disease analysis (identify an association of said methylation state and of said size with at least a disease) (paragraph [00006] lines 1-7; paragraph [0007] lines 1-11; paragraph [0008] lines 1-8; paragraph [0066] lines 1-31; paragraph [220] lines 1-9). Lo also teaches that the data obtained can be received at a computer and analyzed to accomplish the measurement and determine the sizes of the DNA fragments (processing said size for said nucleic acid molecule against a second database) (paragraph [0198] lines 1-7; paragraph [0328] lines 1-16) and that a computer system calculates a respective value comprising methylation level (methylation state) or a statistical value of size profile of a first group and normalize to a total or reference value (processing said methylation state for said nucleic acid molecule against a first database) (paragraph [0100] lines 1-4; paragraph [0263] lines 1-14; paragraph [0328] lines 1-16).
Regarding claim 38, Lo teaches measuring methylation levels of cell-free DNA in a sample (determining a methylation state) comprises whole-genome bisulfite sequencing (sequencing said nucleic acid molecule of plurality of nucleic acid molecules) (paragraph [0100] lines 1-4; paragraph [0101] lines 4-6; paragraph [0142] lines 1-3).
Regarding claim 40, Lo teaches measuring methylation levels of cell-free DNA in a sample (determining a methylation state) comprises treatment with a methylation-binding protein followed by microarray analysis or DNA sequencing (contacting said nucleic acid molecule to a binding agent that bind specifically to methylated nucleic acids or a derivative thereof) (paragraph [0142] lines 3-10).
Regarding claim 42, Lo teaches the binding agent comprises an anti-methylcytosine antibody (binding agent comprises an antibody) (paragraph [0142] lines 3-10).
Regarding claim 45, Lo teaches a method for analyzing cell-free DNA for disease detection (plurality of nucleic acid molecule comprises a DNA molecule) (paragraph [00006] lines 1-7; paragraph [0007] lines 1-11; paragraph [0008] lines 1-8).
Regarding claim 56, Lo teaches the cell-free DNA sample (cell-free biological sample) comprises a blood sample) (paragraph [0006] lines 1-7).
Regarding claim 58, Lo teaches that a computer system calculates a respective value comprising methylation level (methylation state) or a statistical value of size profile of a first group and normalize to a total or reference value comprising comparing methylation levels of cancer samples compared to a reference methylome (processing said methylation state against a plurality of reference methylation states to identify said methylation state to at least a subset of said plurality of reference methylation states) and comparing and normalizing size profiles of samples with and without cancer (reference) (processing said size against a plurality of sizes to identify said size as corresponding to at least a subset of reference sizes) as a method to detect cancer (thereby determining that a subject has or is at risk of having a disease) (paragraph [0100] lines 1-4; paragraph [0104] lines 1-6; paragraph [0208] lines 1-5; paragraph [0209] lines 1-14; paragraph [0263] lines 1-14; paragraph [0328] lines 1-16).
Regarding claim 61, Lo teaches that the data obtained can be received at a computer and analyzed to accomplish the measurement and determine the sizes of the DNA fragments and that a computer system calculates a respective value comprising methylation level (methylation state) or a statistical value of size profile of a first group and normalize to a total or reference value and as a result a level of cancer can be determined (using said methylation state and said size identified to output an electronic report indicating that said subject has or is at risk of having a disease) (paragraph [0100] lines 1-4; (paragraph [0198] lines 1-7; paragraph [0218] lines 1-3; paragraph [0219] lines 1-5; paragraph [0220] lines 1-5; paragraph [0221] lines 1-2; paragraph [0263] lines 1-14; paragraph [0328] lines 1-16).
Regarding claim 62, Lo teaches that based on the level of cancer determined through size and methylation analysis a treatment plan can be devised (using said methylation state and said size identified to provide a therapeutic intervention to said subject for a disease) (paragraph [0220] lines 1-5; paragraph [0221] lines 1-2).
Regarding claim 64, Lo teaches the cancer may be treated by chemotherapy (said subject is treated by administering a chemotherapy) (paragraph [0220] lines 1-5; paragraph [0221] lines 1-3).
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) 41, 43, 46-48, 51, 52, 66, & 67 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lo (United States Patent Application Publication US 2018/0149636 A1), as cited on the IDS dated 07/21/2023, in view of Weng (United States Patent Application Publication US 2018/0363039 A1), as cited on the IDS dated 07/21/2023.
The teachings of Lo with respect to claim 37 is discussed above and incorporated herein.
Regarding claim 41, Lo teaches measuring methylation levels of cell-free DNA in a sample (determining a methylation state) comprises treatment with a methylation-binding protein followed by microarray analysis or DNA sequencing (bringing plurality of nucleic acid molecules in contact with a plurality of binding agents to provide a first subset of nucleic acid molecules coupled to said plurality of binding agents) (paragraph [0142] lines 3-10).
Lo does not teach circularizing a nucleic acid molecule from said first subset of said plurality of nucleic acid molecules to obtain a circularized nucleic acid molecule.
Weng teaches a method of identifying a sequence variant, comprising methylation, in a nucleic acid sample comprising a plurality of cell-free DNA polynucleotides comprising analyzing methylation patterns of polynucleotides through treating with bisulfite prior to circularization followed by forming a plurality of ligation products formed by ligating a cell-free polynucleotide to a single stranded adapter that is hybridized to a capture probe (binding agent) to form a polynucleotide complex (provide a first subset of said plurality of nucleic acid molecule coupled to said plurality of binding agents), in which the polynucleotide complexes can be isolated by binding of a selective binding agent immobilized on a support attached to the capture probe (first subset) to separate any polynucleotide hybridized to capture probe from the other contents of the reaction (second subset) (separating said first subset coupled to binding agents from said second subset of nucleic acid molecules not coupled to binding agents), and then circularizing the plurality of ligation products to yield circular target polynucleotides (circularizing a nucleic acid molecule derived from said first subset of said plurality of nucleic acid molecules to obtain a circularized nucleic acid molecule), and sequencing and identifying a sequence of the circular target polynucleotides (identifying said circularized nucleic acid molecule or derivative thereof) (paragraph [0005] lines 1-34; paragraph [0078] lines 1-19; paragraph [0105] lines 1-15). Weng also teaches that this method improves efficiency in the generation of ligation products to detect polynucleotide targets and can be used to determine locations of methylated cytosines at a single nucleotide resolution (paragraph [0003] lines 1-5; paragraph [0105] lines 12-15).
Lo and Weng are considered to be analogous to the claimed invention because they are all in the same field of methylation analysis with a cell-free DNA sample. 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 measuring methylation levels of cell-free DNA in a sample (determining a methylation state) comprises treatment with a methylation-binding protein in Lo to incorporate the circularizing a plurality of nucleic acid ligation products (plurality of nucleic acid molecules) from a first subset of said plurality of nucleic acid molecules to obtain and identify a circularized target polynucleotide (circularized nucleic acid molecule) as taught in Weng because Weng teaches that doing so would improves efficiency in the generation of ligation products to detect polynucleotide targets and can be used to determine locations of methylated cytosines at a single nucleotide resolution.
Regarding claim 43, Weng teaches forming a plurality of ligation products formed by ligating a cell-free polynucleotide to a single stranded adapter that is hybridized to a capture probe (binding agent) to form a polynucleotide complex followed by circularizing in which the capture probe (binding agent) hybridizes to one or more polynucleotides and comprises nucleotides (binding agent comprises a nucleic acid) (paragraph [0043] lines 1-12).
Regarding claim 46, Weng teaches circularizing comprises ligating ends of a target polynucleotide complex (nucleic acid molecule) hybridized to an adapter on the 5’ end and 3’ end of the cell-free DNA polynucleotide (ligating a 5’ end and a 3’ end of said nucleic acid molecule to one another) (paragraph [0005] lines 10-17; paragraph [0073] lines 1-8).
Regarding claim 47, Weng teaches circularizing comprises ligating ends of a target polynucleotide complex (nucleic acid molecule) that are hybridized to an adapter on the 5’ end and 3’ end of the cell-free DNA polynucleotide (circularizing comprises coupling an adapter to both a 5’ end and a 3’ end of said nucleic acid molecule) (paragraph [0005] lines 10-17).
Regarding claim 48, Weng teaches that circularization may be followed by one or more amplification reactions (subjecting said circularized nucleic acid molecule to nucleic acid amplification to generate a plurality of amplification products of said circularized nucleic acid molecule to identify plurality of nucleic acid amplification products) (paragraph [0005] lines 1-34; paragraph [0078] lines 1-19).
Regarding claim 51, Weng teaches the amplification primers can comprise a primer with a random sequence (nucleic acid amplification comprises contacting said circularized nucleic acid molecule to an amplification reaction mixture comprising random primers) (paragraph [0078] lines 1-19; paragraph [0084] lines 1-23).
Regarding claim 52, Weng teaches that that multiple target-specific primer for a plurality of targets can be used in the same reaction for amplification (nucleic acid amplification comprises contacting said circularized nucleic acid molecule to an amplification reaction mixture comprising one or more primers, each of which hybridizes to a different target sequence via sequence complementarity (paragraph [0078] lines 1-19; paragraph [0084] lines 1-13; paragraph [0086] lines 1-10).
Regarding claim 66, Lo teaches a method for analyzing cell-free DNA for disease detection, comprising cancer detection, comprising measuring methylation levels of cell-free DNA in a sample (determining a methylation state for a nucleic acid molecule of a plurality of nucleic acid molecules) and measuring the size profile of cell-free DNA in a sample (determining a size for a nucleic acid molecule of a plurality of nucleic acid molecules) in which size profile analysis of cell-free DNA can identify sample with large portions of long fragments and methylation deconvolution (methylation state analysis) can identify origin of cell-free DNA fragments for disease analysis (identify an association of said methylation state and of said size with at least a disease) (paragraph [00006] lines 1-7; paragraph [0007] lines 1-11; paragraph [0008] lines 1-8; paragraph [0066] lines 1-31; paragraph [220] lines 1-9). Lo also teaches that the data obtained can be received at a computer and analyzed to accomplish the measurement and determine the sizes of the DNA fragments and that a computer system calculates a respective value comprising methylation level (methylation state) or a statistical value of size profile of a first group and normalize to a total or reference value and as a result a level of cancer can be determined (paragraph [0100] lines 1-4; (paragraph [0198] lines 1-7; paragraph [0218] lines 1-3; paragraph [0219] lines 1-5; paragraph [0220] lines 1-5; paragraph [0221] lines 1-2; paragraph [0263] lines 1-14; paragraph [0328] lines 1-16).
Lo does not teach circularizing a nucleic acid molecule from said first subset and a second subset and sequencing to obtain a first size and a second size from the circularized nucleic acid molecules.
Weng teaches a method of identifying a sequence variant, comprising methylation, in a nucleic acid sample comprising a plurality of cell-free DNA polynucleotides comprising forming a plurality of ligation products formed by ligating a cell-free polynucleotide to a single stranded adapter that is hybridized to a capture probe (binding agent) to form a polynucleotide complex (provide a first subset of said plurality of nucleic acid molecule coupled to said plurality of binding agents), in which the polynucleotide complexes can be isolated by binding of a selective binding agent immobilized on a support attached to the capture probe (first subset) to separate any polynucleotide hybridized to capture probe from the other contents of the reaction (second subset) (separating said first subset coupled to binding agents from said second subset of nucleic acid molecules not coupled to binding agents), and then circularizing the plurality of ligation products to yield circular target polynucleotides (circularizing a nucleic acid molecule derived from said first subset of said plurality of nucleic acid molecules to obtain a circularized nucleic acid molecule), and sequencing and identifying a sequence of the circular target polynucleotides (identifying said circularized nucleic acid molecule or derivative thereof) (paragraph [0005] lines 1-34; paragraph [0078] lines 1-19; paragraph [0105] lines 1-15). Weng also teaches that this method improves efficiency in the generation of ligation products to detect polynucleotide targets (paragraph [0003] lines 1-5; paragraph [0105] lines 12-15).
Lo and Weng are considered to be analogous to the claimed invention because they are all in the same field of disease analysis with a cell-free DNA sample. 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 measuring the size profile of cell-free DNA in a sample to determine level of a cancer (disease) with a first and second size in Lo to incorporate the circularizing a plurality of nucleic acid ligation products (plurality of nucleic acid molecules) from a first subset and second subset of said plurality of nucleic acid molecules to obtain, sequence, and identify a circularized target polynucleotide (circularized nucleic acid molecule) as taught in Weng because Weng teaches that doing so would improves efficiency in the generation of ligation products to detect polynucleotide targets.
Regarding claim 67, Lo teaches a method for analyzing cell-free DNA for disease detection, comprising cancer detection, comprising measuring methylation levels of cell-free DNA in a sample (determining a methylation state for a nucleic acid molecule of a plurality of nucleic acid molecules) and measuring the size profile of cell-free DNA in a sample comprising tumor specific fragment end patterns (determining a size comprising an end sequence for a nucleic acid molecule of a plurality of nucleic acid molecules) in which size profile analysis of cell-free DNA can identify sample with large portions of long fragments, methylation deconvolution (methylation state analysis), and fragment end patterns (end sequence) can identify origin of cell-free DNA fragments for disease analysis (identify an association of said methylation state and of said size with at least a disease) (paragraph [00006] lines 1-7; paragraph [0007] lines 1-11; paragraph [0008] lines 1-8; paragraph [0066] lines 1-31; paragraph [220] lines 1-9; paragraph [0307] lines 1-19). Lo also teaches that the data obtained can be received at a computer and analyzed to accomplish the measurement and determine the sizes of the DNA fragments and that a computer system calculates a respective value comprising methylation level (methylation state) or a statistical value of size profile of a first group and normalize to a total or reference value and as a result a level of cancer can be determined (paragraph [0100] lines 1-4; (paragraph [0198] lines 1-7; paragraph [0218] lines 1-3; paragraph [0219] lines 1-5; paragraph [0220] lines 1-5; paragraph [0221] lines 1-2; paragraph [0263] lines 1-14; paragraph [0328] lines 1-16). Lo also teaches that tumor specific fragment end analysis (end sequence) may be used to determine a level of cancer (paragraph [0307] lines 1-19).
Lo does not teach circularizing a nucleic acid molecule from said first subset and a second subset and sequencing to obtain a first end sequence and a second sequence from the circularized nucleic acid molecules.
Weng teaches a method of identifying a sequence variant, comprising methylation, in a nucleic acid sample comprising a plurality of cell-free DNA polynucleotides comprising forming a plurality of ligation products formed by ligating a cell-free polynucleotide to a single stranded adapter that is hybridized to a capture probe (binding agent) to form a polynucleotide complex (provide a first subset of said plurality of nucleic acid molecule coupled to said plurality of binding agents), in which the polynucleotide complexes can be isolated by binding of a selective binding agent immobilized on a support attached to the capture probe (first subset) to separate any polynucleotide hybridized to capture probe from the other contents of the reaction (second subset) (separating said first subset coupled to binding agents from said second subset of nucleic acid molecules not coupled to binding agents), and then circularizing the plurality of ligation products to yield circular target polynucleotides (circularizing a nucleic acid molecule derived from said first subset of said plurality of nucleic acid molecules to obtain a circularized nucleic acid molecule), and sequencing and identifying a sequence of the circular target polynucleotides (identifying said circularized nucleic acid molecule or derivative thereof) (paragraph [0005] lines 1-34; paragraph [0078] lines 1-19; paragraph [0105] lines 1-15). Weng also teaches that this method improves efficiency in the generation of ligation products to detect polynucleotide targets (paragraph [0003] lines 1-5; paragraph [0105] lines 12-15).
Lo and Weng are considered to be analogous to the claimed invention because they are all in the same field of disease analysis with a cell-free DNA sample. 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 measuring the size profile of cell-free DNA in a sample to determine level of a cancer (disease) with a first and second end sequence in Lo to incorporate the circularizing a plurality of nucleic acid ligation products (plurality of nucleic acid molecules) from a first subset and second subset of said plurality of nucleic acid molecules to obtain, sequence, and identify a circularized target polynucleotide (circularized nucleic acid molecule) as taught in Weng because Weng teaches that doing so would improves efficiency in the generation of ligation products to detect polynucleotide targets.
Claim(s) 59 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lo (United States Patent Application Publication US 2018/0149636 A1), as cited on the IDS dated 07/21/2023, in view of Petit (Petit et al.; Journal of Surgical Research, Vol. 236, pages 184-197, December 2018).
The teachings of Lo with respect to claims 37 & 58 are discussed above and incorporated herein.
Regarding claim 59, Lo teaches measuring methylation level (methylation state) and a statistical value of size profile of cancer (disease) samples (paragraph [0100] lines 1-4; paragraph [0104] lines 1-6; paragraph [0208] lines 1-5; paragraph [0209] lines 1-14; paragraph [0263] lines 1-14; paragraph [0328] lines 1-16).
Lo does not teach that the disease is colon cancer.
Petit teaches analysis of cell-free DNA comprising methylated cell-free DNA to detect colorectal cancer (abstract background lines 1-7; abstract conclusions lines 1-8). In addition, Petit teaches that analysis of methylation in cell-free DNA is a promising and noninvasive method to diagnose colorectal cancer, monitor therapy response, and provide information on prognosis (abstract background lines 1-7; abstract conclusions lines 1-8).
Lo and Petit are considered to be analogous to the claimed invention because they are all in the same field of methylation analysis with a cell-free DNA sample. 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 measuring methylation level (methylation state) and a statistical value of size profile of cancer (disease) samples in Lo to incorporate measuring and analyzing cell-free DNA samples in colorectal cancer samples as taught in Petit because Petit teaches that doing so would provide a promising and noninvasive method to diagnose colorectal cancer, monitor therapy response, and provide information on prognosis.
Conclusion
Claims 37, 38, 40-43, 45-48, 51, 52, 56, 58, 59, 61, 62, 64, 66, & 67 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.
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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
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