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 claim 73-93, drawn to a method for providing hydroxymethylation state data, in the reply filed on 28 April 2026 is acknowledged.
Claim 94 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 28 April 2026.
Applicant’s election without traverse oligonucleotide adapters comprising 5-hydroxymethylcytosine (5hmC) nucleotides for election 1 of the Restriction Requirement mailed 27 March 2026 and the conversion condition comprising treatment with β-GT for election 2 of the Restriction Requirement mailed 27 March 2026 in the reply filed on 28 April 2026 is acknowledged.
Claims 78, 80, and 86 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 28 April 2026.
Information Disclosure Statement
The information disclosure statements (IDS) filed 8 April 2024, 11 July 2025, and 20 May 2026 are considered, initialed, and attached hereto.
Claim Status
Claims 73-94 are pending.
Claims 78, 80, 86, and 94 are withdrawn.
Claims 1-72 are canceled.
Claims 73-77, 79, 81-85, and 87-93 are under examination.
Specification
The use of terms such as Illumina, Swift Biosciences, and Ion Torrent, which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
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 89-93 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.
Claim 89 recites the limitation "the cell proliferative disorder" in line 4. There is insufficient antecedent basis for this limitation in the claim. Claims 90-93 are also rejected based on their dependency on claim 89.
Claim 90 recites the limitation "the cell proliferative disorder" in line 1. There is insufficient antecedent basis for this limitation in the claim, as it is unclear whether it refers to “the cell proliferative disorder” recited in line 4 of claim 89 or the separate “a cell proliferative disorder” recited in line 5 of claim 89.
Claim 91 recites the limitation "the cell proliferative disorder" in line 2. There is insufficient antecedent basis for this limitation in the claim, as it is unclear whether it refers to “the cell proliferative disorder” recited in line 4 of claim 89 or the separate “a cell proliferative disorder” recited in line 5 of claim 89.
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 88-93 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea (claims 88-93) and a law of nature (claims 89-93) without significantly more. While the claims are directed to a process, and therefore meet step 1 of the subject matter eligibility test (see MPEP §2106.03), the claims recite “using the hydroxymethylation state data of the nucleic acids to train a machine learning model” (claim 88, line 2), which is a mental process type of abstract idea since models like linear regressions can be trained by calculating the weights by hand (see MPEP §2106.04(a)(2)(III)), “processing the hydroxymethylation state data using a trained machine learning model” (claim 89, claims 90-93 due to depending on claim 89), which is a mental process type of abstract idea since the calculations to process data using a trained linear regression model can be done by hand, and “detecting a cell proliferative disorder in the subject based at least in part on the processing” (claim 89, claims 90-93 due to depending on claim 89), which is a law of nature because it recites a natural relationship between a subject’s hydroxymethylation state and the presence of a cell proliferative disorder in the subject (MPEP §2106.04(b)(I): “The courts have identified the following concepts and products as examples of laws of nature or natural phenomena: […] v. correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk, Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017)”).
Step 2A of the subject matter eligibility test require a two-pronged analysis. Prong One asks: does the claim recite an abstract idea, law of nature or natural phenomenon? As discussed in MPEP §2106.04(II)(A)(1), the meaning of “recites” is “set forth” or “describes”. That is, a claim recites a judicial exception when the judicial exception is “set forth” or “described” in the claim. In the instant case, the claims describe the abstract idea of training a machine learning model, the abstract idea of processing data using a trained machine learning model, and the law of nature of a correlation between a subject’s hydroxymethylation state and the presence of a cell proliferative disorder in the subject.
Prong Two of the analysis under step 2A asks: does the claim recite additional elements that integrate the judicial exception into a practical application of the judicial exception? As discussed in MPEP §2106.04(II)(A)(2):
Because a judicial exception is not eligible subject matter, Bilski, 561 U.S. at 601, 95 USPQ2d at 1005-06 (quoting Chakrabarty, 447 U.S. at 309, 206 USPQ at 197 (1980)), if there are no additional claim elements besides the judicial exception, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017) ("Adding one abstract idea (math) to another abstract idea (encoding and decoding) does not render the claim non-abstract"); Genetic Techs. Ltd. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016) (eligibility "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself."). For a claim reciting a judicial exception to be eligible, the additional elements (if any) in the claim must "transform the nature of the claim" into a patent-eligible application of the judicial exception, Alice Corp., 573 U.S. at 217, 110 USPQ2d at 1981, either at Prong Two or in Step 2B.
The considerations to be used are set forth in MPEP §2106.05(a) through (c) and (e) through (h). Turning to those sections of the MPEP:
MPEP §2106.05(a) has to do with improvements to the functioning of a computer or to any other technology or technical field. The claims at issue do not improve the functioning of a computer. The claims do recite additional elements laid out in steps a)-d) of claim 73, which improve hydroxymethylation sequencing technologies by preserving fragment endpoint information.
MPEP §2106.05(b) has to do with whether the claims involve the use of a particular machine. In this case, the claims do not involve the use of a particular machine. No sensor, sequencer, or computing hardware is recited in these claims.
MPEP §2106.05(c) has to do with whether the claims involve a particular transformation. Here, none of the claims involve a particular transformation.
MPEP §2106.05(e) has to do with “other meaningful limitations”. The additional limitations imposed upon the abstract ideas and law of nature consist of steps a)-d) recited in claim 73. These additional limitations do not meaningfully limit the recited abstract ideas and law of nature as they amount to applying the abstract ideas and law of nature to data provided by a specific process consisting of steps a)-d).
MPEP §2016.05(f) raises the question as to whether the additional elements recited in the claim represent “mere instructions to apply an exception”. The steps a)-d) are data-gathering activity that serves as the input to the abstract ideas and law of nature. These additional elements therefore amount to mere instructions to apply the abstract ideas and law of nature to a particular context.
MPEP §2106.05(g) has to do with whether the additional elements of the claim amount of insignificant extra-solution activity. MPEP §2106.05(g) notes that “[d]etermining the level of a biomarker in blood” is an example of “mere data gathering” which the courts have found to be insignificant extra-solution activity. The steps a)-d) of providing hydroxymethylation data to be applied to the abstract ideas and law of nature is therefore mere data gathering and insignificant extra-solution activity.
MPEP §2106.05(h) has to do with whether the additional elements amount to more than generally linking the use of a judicial exception to a particular technological environment or field of use. The recitation of the method being applied to hydroxymethylation state data from sequencing represents a “field of use” limitation. However, as MPEP §2106.05(h) indicates, such limiting to a particular “field of use” does not confer patentability to otherwise ineligible subject matter.
In addition, the claims do not include additional elements that are sufficient to amount ot significantly more than the judicial exception (as set forth in step 2B of the subject matter eligibility test) because it was known in the prior art to provide hydroxymethylation state data by the steps a)-d) of claim 73, as shown in Kohli et al. (US 2025/0283170, effectively filed 12 July 2021), which teaches obtaining a biological sample containing nucleic acids, ligating adapters to the nucleic acids in the biological sample wherein the adapters comprise 5hmC nucleotides, subjecting the ligated nucleic acids to a conversion condition that converts C and 5mC but not 5hmC to U, and sequencing the converted nucleic acids (see 35 U.S.C. 102 rejection of claim 1 over Kohli et al. below for exact mapping of the limitations).
Having considered the factors discussed in MPEP §2106.05 as well as the prior art of Kohli et al., it is clear that the additional elements recited in the claims, whether considered individually or as a combination, do not integrate the judicial exceptions into a practical application of those exceptions in such a way as to provide meaningful limits on the use of the judicial exception and do not amount to significantly more than the judicial exception. Therefore, claims 88-93 are rejected here under 35 U.S.C. 101.
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)(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.
Claims 73-77, 79, 84, and 87 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Kohli et al. (US 2025/0283170, effectively filed 12 July 2021), herein Kohli.
Regarding claim 73, Kohli teaches a method for providing hydroxymethylation state data of nucleic acids in a biological sample (“workflows presented in FIG. 7A” [0128]; “Sequence for 5hmC” FIG. 7A spACE-Seq (solid-phase ACE-Seq) step 7), the method comprising: a) obtaining the biological sample containing the nucleic acids (“three substrates pooled together were used: unmethylated lambda DNA (acting as a C control), methylated pUC19 (acting as an 5mC control), and T4-5hmC genomic DNA (acting as a 5hmC control)” [0128]; “Shear + end repair DNA” FIG. 7A spACE-Seq step 1); b) ligating oligonucleotide adapters to at least a portion of the nucleic acids in the biological sample, wherein the oligonucleotide adapters comprise 5-hydroxymethylcytosine (5hmC) nucleotides, the species elected from Election 2, thereby generating ligated nucleic acids (“Ligate adaptors” FIG. 7A spACE-Seq step 2; “A notable modification for all workflows evaluated being that A3A-resistant adapters were used” [0128]; “5pyC, 5hmC, 5hmC+βGT, and 5pyrC adapters amplified with efficiency demonstrating their appropriateness for a pre-deamination workflow” [0115]); subjecting at least a portion of the ligated nucleic acids or a derivative thereof to a conversion condition that converts unmethylated and methylated cytosine nucleotides but not hydroxymethylated cytosine nucleotides of the ligated nucleic acids into uracil nucleotides, thereby generating converted nucleic acids (“Denature + A3A” FIG. 7A spACE-Seq step 5; “APOBEC3A (A3A)” [0053]); d) sequencing at least a portion of the converted nucleic acids to obtain a nucleic acid sequence of the converted nucleic acids, thereby providing the hydroxymethylation state data of the nucleic acids (“Sequence for 5hmC” FIG. 7A spACE-Seq step 7).
Regarding claim 74, Kohli teaches the method of claim 73 (see 35 U.S.C. 102 rejection of claim 73 above), wherein the oligonucleotide adapters do not comprise cytosine nucleotides in flow cell binding regions or primer binding sites of the oligonucleotide adapters (“As shown in FIG. 2, natural cytosine variants are not compatible with enzymatic deamination, while bulky modifications to the 5-position make the cytosine resistant to enzymatic deamination. These resistant cytosines can be built into DNA molecules that can be ligated to target DNA samples in the form of adapters. The sequences of a few representative adapters compatible with Illumina next-generation sequencing are shown (FIG. 2B)” [0113]; FIG. 2B; SEQ ID NOs: 7 and 8 in [0103]).
Regarding claim 75, Kohli teaches the method of claim 73 (see 35 U.S.C. 102 rejection of claim 73 above), further comprising subjecting at least a portion of the ligated nucleic acids to glucosylation by β-glycosyltransferase (β-GT)/UDP-glucose to convert 5hmC nucleotides into 5gmC nucleotides after b) or prior to c) (“βGT” FIG. 7A spACE-Seq step 4; “converting all 5hmC to 5ghmC with UDP-glucose and T4-βGT” [0063] teaching that βGT converts 5hmC to 5ghmC/5gmC).
Regarding claim 76, Kohli teaches the method of claim 73 (see 35 U.S.C. 102 rejection of claim 73 above), wherein the conversion condition comprises enzymatic treatment (“Denature + A3A” FIG. 7A spACE-Seq step 5; “APOBEC3A (A3A)” [0053]). Kohli also teaches a separate embodiment wherein the conversion condition comprises bisulfite treatment and enzymatic treatment (FIG. 8C schematic branch ending in “Sequence 5hmC”).
Regarding claim 77, Kohli teaches the method of claim 73 (see 35 U.S.C. 102 rejection of claim 73 above), wherein the oligonucleotide adapters comprise 5hmC nucleotides (“5pyC, 5hmC, 5hmC+βGT, and 5pyrC adapters amplified with efficiency demonstrating their appropriateness for a pre-deamination workflow” [0115]).
Regarding claim 79, Kohli teaches the method of claim 73 (see 35 U.S.C. 102 rejection of claim 73 above), wherein the conversion condition comprises treatment with βGT (“βGT” FIG. 7A spACE-Seq step 4; “Denature + A3A” FIG. 7A spACE-Seq step 5; steps 4 and 5 are considered to jointly make up the conversion condition as the conversion condition is not limited to any one single step or enzyme).
Regarding claim 84, Kohli teaches the method of claim 73 (see 35 U.S.C. 102 rejection of claim 73 above), further comprising amplifying at least a portion of the ligated nucleic acids prior to the sequencing (“Index PCR” FIG. 7A spACE-SEQ step 6).
Regarding claim 87, Kohli teaches the method of claim 73 (see 35 U.S.C. 102 rejection of claim 73 above), further comprising aligning the nucleic acid sequence to a reference genome (“Reads were aligned with Bismark and deduplicated with Picard” [0108]; “For solid-phase ACE-Seq […] Bioinformatic analysis was performed as described above” [0109]).
Therefore, claims 73-77, 79, 84, and 87 are anticipated by Kohli.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 82-83 are rejected under 35 U.S.C. 103 as being unpatentable over Kohli et al. (US 2025/0283170, effectively filed 12 July 2021), herein Kohli, as applied to claims 73-77, 79, 84, and 87 above.
Regarding claim 82, Kohli teaches the method of claim 73 (see 35 U.S.C. 102 rejection of claim 73 above), further comprising performing sequence enrichment (FIG. 5D having steps of processing a nucleic acid to obtain a sample, ligating a DNA deaminase resistant sequencing adapter to the sample, treating with A3A to convert C and mC but not 5hmC or 5ghmC, and sequencing the converted nucleic acid, this differs from the embodiment used in the 102 rejection in that it tethers the genetic information to the epigenetic information; “A strength of the methods where the genetic information is tethered to the epigenetic information in the same read, is that these reads can be enriched using probe oligonucleotides that are complementary to the DNA regions of interest” [0134]) and that the tethered genetic and epigenetic information that enables sequence enrichment is made before step b) (FIG. 5D 3rd step).
However, Kohli does not teach that the sequence enrichment is specifically performed after step a) or prior to step b). Doing the sequence enrichment step taught by Kohli after step b) or prior to step c) would be obvious to one of ordinary skill in the art because “selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results” (MPEP §2144.04 IV. C., In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946)).
Regarding claim 83, Kohli teaches the method of claim 82 (see 35 U.S.C. 103 rejection of claim 82 above), wherein the sequence enrichment comprises a target capture hybridization (“these reads can be enriched using probe oligonucleotides that are complementary to the DNA regions of interest” [0134]).
Therefore, claims 82-83 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
Claim 81 is rejected under 35 U.S.C. 103 as being unpatentable over Kohli et al. (US 2025/0283170, effectively filed 12 July 2021), herein Kohli, as applied to claims 73-77, 79, 84, and 87 above, and in view of Rao et al. (US 2011/0236894, published 29 September 2011, effectively filed 26 September 2008), herein Rao.
Regarding claim 81, Kohli teaches the method of claim 73 (see 35 U.S.C. 102 rejection of claim 73 above). However, Kohli does not teach treating the oligonucleotide adapters with a TET enzyme after a) or prior to b). This deficiency is made up for in the teachings of Rao.
Regarding claim 81, Rao teaches a kit for the conversion of 5-methylcytosine residues in nucleic acids to hydroxymethylcytosine using TET enzymes, which possesses the advantage of ease of use due to including instructions (“one or more catalytically active TET family enzymes, functional TET family derivatives, or TET catalytically active fragments thereof are provided in a kit to generate nucleic acids containing hydroxymethylcytosine from nucleic acids containing 5-methylcytosine or other oxidized pyrimidines from appropriate free or nucleic acid precursors. In all such embodiments of the aspect, the kit includes packaging materials and instructions therein to use said kits” [0182]). In the combination of Rao’s method of making a nucleic acid comprising 5hmC nucleotides as a method of generating the oligonucleotide adapters comprising 5hmC nucleotides used in the method of Kohli, the TET treatment would necessarily be done prior to step b), since TET treatment after adapter ligation would lead to conversion of 5mC to 5hmC in the sample, as taught by Kohli in FIG. 7A rEM-Seq step 4 where treatment of sample ligated to adapters protects both 5mC (black nucleotide) and 5hmC (grey nucleotide) from conversion by A3A.
One of ordinary skill in the art would be motivated to combine the teachings of Rao and Kohli because Rao teaches a kit for producing nucleic acids consisting of 5hmC nucleotides, thereby providing the advantage of an easy-to-use way to obtain the oligonucleotides consisting of 5hmC nucleotides required in the method of Kohli (MPEP §2143 I. G.). One of ordinary skill in the art would have a reasonable expectation of success in this combination because using a specific kit to generate a material used in the method of Kohli would not be expected to negatively impact the functioning of the method of Kohli. Therefore, claim 81 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
Claim 85 is rejected under 35 U.S.C. 103 as being unpatentable over Kohli et al. (US 2025/0283170, effectively filed 12 July 2021), herein Kohli, as applied to claims 73-77, 79, 84, and 87 above, and in view of Dai et al. (“Preparation of DNA Containing 5-Hydroxymethyl-2′-Deoxycytidine Modification Through Phosphoramidites with TBDMS as 5-Hydroxymethyl Protecting Group” Curr Protoc Nucleic Acid Chem 47:4.47.1-4.47.18 (2011)), herein Dai.
Regarding claim 85, Kohli teaches the method of claim 73 (see 35 U.S.C. 102 rejection of claim 73 above), wherein the oligonucleotide adapters are chemically synthesized (“DNA oligonucleotides forming the adapters were synthesized by standard phosphonamidite chemistry by commercial vendors (Integrated DNA Technologies, IDT or Biomers). Some non-standard building blocks for synthesis were obtained from Glen Research” [0103]). However, Kohli does not specifically teach that the oligonucleotide adapters are synthesized using 5hmC phosphoramidites. This deficiency is made up for in the teachings of Dai.
Regarding claim 85, Dai teaches 5hmC phosphoramidite building blocks for oligonucleotide synthesis that are particularly advantageous because their protecting groups can be removed following oligonucleotide synthesis under mild conditions (“it is highly desirable to develop new 5-hmC phosphoramidites using protecting groups that can be cleanly removed under mild conditions. Herein we report the efficient syntheses of two 5-hmC phosphoramidite building blocks (III and IV), and demonstrate the advantages in the removal of the protecting groups following oligo synthesis” page 2 paragraph 1; entire Abstract).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to perform the simple substitution of the 5hmC phosphoramidite building blocks taught by Dai for the more generically recited non-standard building blocks in the chemical synthesis of the oligonucleotide adaptors in the method of Kohli (MPEP §2143 I. B.). One of ordinary skill in the art would also be motived to use the 5hmC phosphoramidites taught by Dai in order to gain the advantages taught by Dai that they provide in oligonucleotide synthesis of oligonucleotides comprising 5hmC nucleotide (MPEP §2143 I. G.). One of ordinary skill in the art could have performed this substitution and would have found the results of this substitution predictable because using a specific method to produce the adapter oligonucleotides comprising 5hmC nucleotides would not be expected to impact the ability of the adapter oligonucleotides to function in the method of Kohli. Therefore, the invention as a whole of claim 85 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
Claims 88-93 are rejected under 35 U.S.C. 103 as being unpatentable over Kohli et al. (US 2025/0283170, effectively filed 12 July 2021), herein Kohli, as applied to claims 73-77, 79, 84, and 87 above, and in view of Arensdorf et al. (U.S. Patent Document Cite No 27 in IDS filed 8 April 2024)(US 2020/0123616, published 23 April 2020, effectively filed 19 September 2018), herein Arensdorf.
Regarding claim 88, Kohli teaches the method of claim 73 (see 35 U.S.C. 102 rejection of claim 73 above). However, Kohli does not teach the method further comprising using the hydroxymethylation state data of the nucleic acids to train a machine learning model configured to generate hydroxymethylation state data. This deficiency is made up for in the teachings of Arensdorf.
Regarding claim 88, Arensdorf teaches using hydroxymethylation state data to train a machine learning prediction model configured to generate hydroxymethylation state data (“To generate a predictive model for pancreatic cancer, a robust data set, comprising known control samples and samples corresponding to pancreatic cancer, is used in a training set” [0214]; “Of particular use in combining hydroxymethylation levels at various biomarker loci and clinical parameters, optionally in further combination with other factors (e.g., non-hydroxymethylation biomarkers), are linear and non-linear equations and statistical classification analyses to determine the relationship between hydroxymethylation levels at the biomarker loci detected in a patient sample and the patient's risk of having or developing pancreatic cancer. In panel and combination construction, of particular interest are structural and syntactic statistical classification algorithms, and methods of risk index construction, utilizing pattern recognition and machine learning features” [0151]).
Regarding claim 89, Kohli teaches the method of claim 73 (see 35 U.S.C. 102 rejection of claim 73 above), wherein the biological sample is obtained or derived from a subject (“The term “biological sample” includes, without limitation, cell-containing bodily fluids, peripheral blood, tissue homogenates, aspirates, and any other source of rare cells or polynucleotides that are obtainable from a human subject” [0042]). Arensdorf teaches processing hydroxymethylation state data, such as that provided by the method of Kohli, using a trained machine learning model configured to distinguish between subjects with a cell proliferative disorder and subjects without the cell proliferative disorder, and detecting the cell proliferative disorder in the subject based at least in part on the processing (“Among the provided diagnostic, prognostic, and predictive methods are those which employ statistical analysis and biomathematical algorithms and predictive models to analyze the detected hydroxymethylation information” [0190]; “In another aspect, the hydroxymethylation levels at each of the biomarker loci are used to identify the presence of pancreatic cancer or a risk of developing pancreatic cancer for the first time” [0193]; “the methods of the invention apply the mathematical formulations, algorithms or models to distinguish between normal and cancerous samples” [0206]; [0151] as cited regard claim 88 above).
Regarding claim 90, the combination of Kohli and Arensdorf teach the method of claim 89 (see 35 U.S.C. 103 rejection of claim 89 above), and Arensdorf further teaches that the cell proliferative disorder comprises pancreatic cancer (“present invention is predicated on the discovery of a set of hydroxymethylation biomarkers that in combination with one or more clinical parameters and optionally one or more other types of biomarkers and/or patient-specific risk factors, exhibits a hydroxymethylation level that correlates in some way with pancreatic cancer”).
Regarding claim 91, the combination of Kohli and Arensdorf teach the method of claim 89 (see 35 U.S.C. 103 rejection of claim 89 above), and Arensdorf further teaches that the trained machine learning model is tailored to detect the cell proliferative disorder at a pre-selected sensitivity and specificity (“As is known in the art, the relative sensitivity and specificity of a predictive model can be adjusted to favor either the selectivity metric or the sensitivity metric” [0212]).
Regarding claim 92, the combination of Kohli and Arensdorf teach the method of claim 89 (see 35 U.S.C. 103 rejection of claim 89 above), and Arensdorf further teaches featurizing the hydroxymethylation state data and processing the featurized hydroxymethylation state data using the trained machine learning model to classify the biological sample according to a pre-determined biological property of the subject (“Raw data can be initially analyzed by measuring the hydroxymethylation level for each biomarker. The data can be manipulated, for example, raw data can be transformed using standard curves, and the average of multiple measurements, if made, can be used to calculate the average and standard deviation for each patient. The data are then input into a selected predictive model, which will classify the sample” [0213]; “transforming any qualitative features to quantitative features” [0215]; “5hmC gene features” [0234]).
Regarding claim 93, the combination of Kohli and Arensdorf teach the method of claim 92 (see 35 U.S.C. 103 rejection of claim 92 above), and Arensdorf further teaches that the pre-determined biological property comprises a presence or absence of pre-cancer, a presence or absence of cancer, a stage of cancer, or a prognosis of cancer in the subject (“the methods of the invention apply the mathematical formulations, algorithms or models to distinguish between normal and cancerous samples, and between various sub-types, stages, and other aspects of disease or disease outcome. In another aspect, the methods are used for prediction, classification, prognosis, and treatment monitoring and design” [0206]; “the method is a non-invasive way of enabling the practitioner to identify changes in a previously identified pancreatic lesion and thereby determine, for example, whether the lesion is progressing toward cancer” [0029]).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to perform the simple substitution of the method of providing hydroxymethylation state data taught by Kohli for the hydroxymethylation information used as the input into the method for diagnosing pancreatic cancer taught by Arensdorf (MPEP §2143 I. B.). Furthermore, Kohli teaches that their method of obtaining hydroxymethylation state data possesses significant advantages in the rapidity and efficiency of epigenomic sequencing (“An advantage of the solid-phase immobilized enzymatic deamination method is that the same DNA molecule can potentially be interrogated more than once in library constructs” [0035]; “using cytosine analogs that are resistant to DNA deaminases provides significant advantages for rapid and efficient epigenomic sequencing, can be used to resolve multiple different DNA modification states in the same DNA molecule, or to simultaneously resolve genetic and epigenetic information” [0036]), so one of ordinary skill in the art would be motivated to modify the method of Arensdorf with the method of Kohli in order to improve the method of Arensdorf with these advantages. One of ordinary skill in the art could have performed this substitution and would have found the results of this substitution predictable because simply swapping out one method for obtaining the data used in an analytical method for another method of obtaining the data would not be expected to negatively impact the ability of the analytical method to provide the desired analysis. Therefore, the invention as a whole of claims 88-93 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
Conclusion
Claims 73-77, 79, 81-85, and 87-93 are rejected. Claims 1-72 are canceled. Claims 78, 80, 86, and 94 are withdrawn.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jeffrey Lawrence Bellah whose telephone number is (571)272-1024. The examiner can normally be reached M-Th, 7:30-5 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, Anne Gussow can be reached at (571)272-6047. 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.
/JEFFREY BELLAH/Examiner, Art Unit 1683
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683
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