DETAILED ACTION
The present Office Action is responsive to the Amendment received on May 14, 2026.
Preliminary Remark
Claim 4, 10-13, and 15-17 are canceled.
Claims 24 and 25 are new.
Claims 9 and 14 remain withdrawn1 from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on September 9, 2025.
Claim Rejections - 35 USC § 112
The rejection of claims 1-8 and 18-23 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point out and distinctly claim the subject matter, made in the Office Action mailed on November 14, 2025 is withdrawn in view of the Amendment received on May 14, 2026.
Rejection – New Grounds, Necessitated by Amendment
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 20 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 20 is indefinite because it is unclear how the claim further limits the parent claim. Claim 20 depends from claim 1. Claim 1 recites, inter alia, the step that one or more labeled probes is hybridized to a target cfDNA fragment or an amplification product thereof, within 500 nucleotides of at least four CpG sites. While claim 20 recites that the one or more labeled probes comprise one or more probe polynucleotides targeted to the at least four CpG sites, because claim 1 already recites that the one of more labeled probes is hybridized to a target cfDNA fragment that comprises at least four CpG sites, the fact that the probe is further described as a “polynucleotide” does not further limit claim 1, or if it does, it is unclear just exactly what that is, resulting in the vagueness in the metes and bounds of the claim.
Claim Rejections - 35 USC § 101
Maintained & Necessitated by Amendment
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.
The rejection of claims 1-3, 5-8 and 18-23 under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more as discussed in the Office Action mailed on November 14, 2025 is maintained for the reasons of record.
In addition claims 24 and 25 are rejected herein as being necessitated by Amendment (by their addition).
Applicants’ claim amendment and arguments presented in the Amendment received on May 14, 2026 have been carefully considered but they have not been found persuasive for the reasons discussed in the, “Response to Arguments” section.
The Rejection:
The claims recite a judicial exception of an inherent (or naturally occurring) methylation profile of genomic sequences that are present in cells of different tissue/organ. This judicial exception is not integrated into a practical application because this judicial exception is broadly captured by the generic recitation of a detection step that tantamount to capturing the judicial exception itself.
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception based on the analysis under the current Patent Eligibility Guidelines (herein, “PEG”) as discussed below.
Step 1 Inquiry under PEG
Step 1 inquiry under Patent Eligibility Guidelines (herein, “PEG”) determines whether or not the claimed invention is drawn to one of the recognized statutory classes of invention. Claims 1-8 and 18-23 satisfy the present inquiry as being drawn to a product.
Step 2A Inquiry under PEG
A recently revised PEG now performs step 2A inquiry under a 2-prong analysis, and the subject claims analyzed accordingly as follows:
Prong 1:
Prong-1 inquiry under step 2A determines whether the claim(s) recites an abstract idea, a law of nature, or a natural phenomenon. As stated above, the claims recite natural correlation (or phenomenon) which exists between a particular cell type and the methylation profile of the CpG sites therein.
This judicial exception is admitted in the application as filed as reproduced below:
“the methylation status of such CpG sites is different among other cells, thereby enabling the respective cell type(s) to be distinguished from other cell types. Each individual CpG dinucleotide is herein referred to as a ‘CpG site’” (section [0048])
“As demonstrated in the accompanying experimental examples, surprisingly, in every one of a large number of human cell types examined, a sufficient number of CpG clusters can be identified as having statistically different methylation status between a cell type and all other cell types. Such CpG clusters, also referred to as ‘methylation markers,’ allow identification of each cell type based on its DNA methylation status (section [0051])
The specification further evidences that the SEQ ID Numbers from which CpG site is selected or present in (see claim 1, step (1)(a) embodiment or (b) embodiment) are found in portions of genomic DNA sequences:
“It was discovered herein that some genomic locations are uniformly under-methylated or over-methylated in oral, larynx and esophageal cells as compared to all other cell types in the human (see, e.g., Table A). for instance, the genomic sequences as provided in SEQ ID NO: 1-15, 16-90, 91-92, or 102-125 (annotated with start and end locations on the respective chromosome) all have lower than 40% methylation percentages in oral, larynx or esophageal epithelial cells, and higher than 60^ methylation percentages in all other cell types. Likewise, the genomic sequences as provided in SEQ ID NO: 126-133, 134-134, or 135-150 all have relatively higher methylation percentages (>60%) in oral, larynx or esophageal epithelial cells and lower methylation percentages (<40%) in all other cell types” (section [0078])
Therefore, the unique methylation profile of CpG sites that are specific to a cell-type is naturally present (judicial exception) and claimed by recitation in the claim.
Prong 2:
Prong-2 inquiry under step 2A determines whether or not the claims recite additional elements that integrate the judicial exception into a practical application in a manner that imposes a meaningful limit on the judicial exception.
Each of additional elements are addressed separately.
Detection means:
Claims 1 and 2 recite that the detection of the at least four CpG sites for the methylation status is achieved via generically recited means of a) hybridizing one or more polynucleotides to the target DNA fragments (harboring the CpG sites) or to an amplification product thereof within 500 nucleotides of the at least four CpG sites.
The use of such highly general language of using a polynucleotide to anneal to the target or its amplification product is not deemed to impose any meaningful limit on the judicial exception, but tantamount to “applying” the judicial exception itself as discussed by the Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories (566 U.S. 66 (2012)).2
Claims 3-8 further recites that he detection is for an elevated amount of cell-free DNA fragment while tying this phenomenon to a abnormal death of cell death of the cell type, or disease relating to the cell type (claim 3), or the identification that the subject has an injury, inflammation, or cancer of the tissue from which the cell-type is determined (claim 4), where the disease is pancreatic disease or condition (claim 7), or where the disease is diabetes, inflammation, or cancer. However, these are not additional element that impose a limitation to the judicial exception discussed above.
Rather, these are recitation of additional judicial exception pertaining to cell-free DNA that are known to be released when cell goes through apoptosis in normal, abnormal, or diseased conditions.
“Small fragments of nucleic acids, e.g., DNA, circulate freely in the peripheral blood of healthy and diseased individuals. These cell-free nucleic acids, such as DNA (cfDNA) molecules may originate from dying or damaged cells and thus reflect ongoing cell death or injuries taking place in the body. In recent years, such understanding has led to the emergence of diagnostic tools, which are impacting multiple areas of medicine. For instance, next-generation sequencing of fetal DNA circulating in maternal blood has allowed non-invasive prenatal testing of fetal chromosomal abnormalities; detection of donor-derived DNA in the circulation of organ transplant recipients can be used for early identification of graft rejection; and the evaluation of mutated DNA in circulation can be used to detect genotype and monitor cancer (section [0004])
Therefore, the present combination of one judicial exception with another judicial exception do not result in a meaningful limit on either/both of the judicial exceptions.
Claims 18-23 recite the additional elements of detecting genetic variations in the target DNA fragment (from which cell-type is identified, claim 18), or the one of more polynucleotides involved in the detection is one or more probe (claim 20), or primer (claim 21), or that the detection means is rendered via array/sequencing (claim 22), and that the methylation detection is detected via bisulfite means (which deaminates non-methylated cytosines, claims 23).
The recitation of a genetic variant to a condition is deemed a judicial exception, and does not add to the judicial exceptions presently discussed, and the usage of a general language “probes” and “primers” for detecting a nucleic acid sequence is not deemed significant nor impose any meaningful limit as such detection means are necessarily involved conventionally in array/amplification/sequencing reactions. Lastly, methylation detection also conventionally requires the deamination step with a bisulfite, converting unmethylated cytosine to uracil, and therefore is not deemed to meaningfully limit the judicial exception.
Step 2B Inquiry under PEG
Step 2B inquiry of the PEG determines whether or not additional elements are provided and whether such elements amount to significantly more than the judicial exception in the claims.
Presently, the additional elements are deemed routine and conventionally employed techniques in the art of molecule diagnostics.
For example, the means of detecting methylated CpG sites utilizing bisulfite-treatment in a PCR or array hybridization is well-known in the art as evidenced by Lee et al. (Cancer Letters, 2013, vol. 340, pages 171-178):
“methylation status of DNA can be analyzed by many different methods which utilize three basic principles … bisulfite treatment can convert unmethylated cytosine into uracil while leaving methylated cytosine unchanged. These principles have been integrated into high-throughput analytical applications such as microarray and next-generation sequencing (NGS) platforms” (page 172, 1st column, 1st para)
Lastly, claim 19 recites the additional element of “treating the subject for the disease by resection, surgery, radiation therapy, chemotherapy, or immunotherapy”. However, theses steps are not specific to any of the judicial exceptions recited. Rather, they are generalized concept of treating any patient that has a condition. Because the claimed judicial exception is not specifically tied and/or apply to the treatment step, this is not a specific and meaningful application of the judicial exception.
For these reasons, the additional elements recited in the claims are not deemed significantly more than just inclusion of means which are commonly used, routine and conventional in the art.
Therefore, the present claims lack patent eligibility.
Response to Arguments:
Applicants traverse the rejection.
Applicants’ arguments are addressed in the order they were presented.
Applicants state that claims are not directed to judicial exception, “if the claim as a whole integrates the recited judicial exception into a practical application of that exception” where if the claims as a whole “improve the functioning of” and “technological field” (page 14, Response).
Applicants also state that claims 1-8 and 18-23 also recite methods and products that improve the functioning of the technical field of cell-free DNA analysis in a manner that impose meaningful limits on the operation of the recited steps (page 14, Response).
Various sections of the specification are alluded where Applicants assert a surprising discovery/findings that a sufficient number of CpG clusters can be identified as having statistically different methylation between a cell type and all other cell types (page 15, Response).
Applicants also contend that claim 1 as amended recites such CpG clusters (in SEQ IDs in groups (1)-(7) which have statistically different methylation between one specific cell type and all other types and that the Office has failed to point out where such methylation markers having specific threshold methylation status for minority cell types of a particular tissue, much less across the diversity of tissues recited in claim 1, are described in prior art (page 16, Response).
These statements and arguments have been carefully considered but they have not been found persuasive.
The “surprising” finding that some sufficient numbers of CpG clusters with their methylation status being correlated with a particular cell type is a naturally existing phenomenon. The fact that Applicants “discovered” this correlation does not in itself does not render that discovery a patentable feature when that correlation (i.e., judicial exception) is applied in a practical and meaningful way.
Claim 1 as presently recited involves the step of: (1) hybridizing one or more labeled probes to a target cell-free DNA fragment (i.e., cfDNA) in a biological sample (or its amplification product) within the vicinity of at least four CpG sites; and (2) detecting the methylation status of the at least four CpG sites of the target cfDNA, and recites the judicial exception that the target cfDNA, based on its methylation status of the CpG sites indicates the origin form which the cfDNA came from. The CpG sites are represented by their SEQ ID numbers, but they are sequences that are found in the naturally existing sample.
Therefore, claim 1 recites a judicial exception that exists between a methylation status of a CpG site of a cfDNA and the cell from which the cfDNA came from.
While Applicants make much of the discovery of this correlation, such is nevertheless a naturally existing phenomenon, analogous to the facts of Mayo.
In Mayo, a method directed to optimization of a therapeutic efficacy for treatment of an immune-mediated gastrointestinal discover was under dispute wherein the method contained the following steps:
(a) administering a drug providing 6-thioguanine to a subject having said immune-mediated gastrointestinal disorder; and
(b) determining the level of 6-thioguanine in said subject having said immune-mediated gastrointestinal disorder,
wherein the level of 6-thioguanine less than about 230 pmol per 8x108 red blood cells indicates a need to increase the amount of said drug subsequently administered to said subject and
wherein the level of 6-thioguanine greater than about 400 pmol per 8x108 red blood cells indicates a need to decrease the amount of said drug subsequently administered to said subject [from claim 1 of the litigated patent 6,355,623]
The naturally existing correlation was the level of a drug metabolite in a patient’s system whether or not the administered drug amount was effective.
Similarly, the instant claim 1 recites the naturally existing correlation that ties the methylation profile of CpG sites in cfDNA and their origin. While the instant claim 1 recites the additional steps of hybridizing one or more labeled probes and detecting the methylation status of the CpG sites, these steps are analogous to the administration of the drug and determination of the drug metabolite steps in Mayo, to which the Court characterized as no more than a drafting effort that attempts to monopolize the law of nature itself:
“The question before us is whether the claims do significantly more than simply describe these natural relations. To put the matter more precisely, do the patent claims add enough to their statements of the correlations to allow the processes they describe to qualify as patent-eligible processes that apply natural laws? We believe that the answer to this question is no.”
“If 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 drafting effort designed to monopolize the law of nature itself.”
“First, the ‘administering’ step simply refers to the relevant audience, namely doctors who treat patients with certain diseases with thiopurine drugs. That audience is a pre-existing audience; doctors used thiopurine drugs to treat patients suffering from autoimmune disorders long before anyone asserted these claims. In any event, the ‘prohibition against patenting abstract ideas ‘cannot be circumvented by attempting to limit the use of the formula to a particular technological environment.’ Bilski, supra, at __ (slip op., at 14) (quoting Diehr, 450 U.S., at 191-192).”
“Second, the ‘wherein’ clauses simply tell a doctor about the relevant natural laws, at most adding a suggestion that he should take those laws into account when treating his patient. That is to say, these clauses tell the relevant audience about the law while trusting them to use those laws appropriately where they are relevant to their decisionmaking (rather like Einstein telling linear accelerator operators about his basic law and then trusting them to use it where relevant).”
“Third, the ‘determining’ step tells the doctor to determine the level of the relevant metabolites in the blood, through whatever process the doctor or the laboratory wishes to use. As the patents state, methods for determining metabolite levels were well known in the art. ‘623 patent, col. 9, ll. 12-65, 2. App. 11. … Thus, this step tells doctors to engage in well-understood, routine, conventional activity previously engaged in by scientists who work in the field. Purely ‘ 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)).”
“Fourth, to consider the three steps as an ordered combination adds nothing to the laws of nature that is not already present when the steps are considered separately… Anyone who wants to make use of these laws must first administer a thiopurine drug and measure the resulting metabolite concentrations, and so the combination amounts to nothing significantly more than an instruction to doctors to apply the applicable laws when treating their patients.”
Therefore, instant claim 1 does not add more than the judicial exception with purely conventional pre-solution activity that are not deemed significant to place a meaningful limit on the judicial exception itself.
As regard to Applicants’ contention that “improved accuracy” being held by Fe. Circuit as “improved functioning to a technology or technical field” when determining patentable subject matter eligibility (page 17, Response), the Office respectfully disagrees. While a naturally existing phenomenon may improve a field of endeavor (such as in the case of Mayo, where the improvement is better drug efficacy determination and treatment decision), when that naturally existing phenomenon is not applied in a significantly meaningful way, such would not be sufficient to place the judicial exception to patent eligible subject matter.
Re: claims 24 and 25:
While new claims 24 and 25 recite the means by which the methylation status is determined, that is, via bisulfite treatment that convers the non-methylated cytosines to uracil, the use of bisulfite to distinguish a methylated vs. non-methylated cytosine in a nucleic acid sequence has been well-known and routine practice in the art and therefore, is no more than a pre-solution activity.
Therefore, the instant claims do not satisfy patent eligibility requirement.
Claim Rejections - 35 USC § 103
The rejection of claims 1-8 and 18-23 under 35 U.S.C. 103 as being unpatentable over Dor et al. (WO 2015/159292 A2, published October 2015, IDS ref) in view of Fortin et al. (Bioinformatics, 2017, vol. 33, no. 4, pages 558-560), made in the Office Action mailed on November 14, 2025 is withdrawn in view of the Amendment received on May 14, 2026.
Applicants have canceled the CpG regions that pertain to liver hepatocytes, pancreatic acinar cell, alpha cell, beta cell in the amendment.
Rejection - New Grounds, Necessitated by Amendment
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-3, 5-8 and 18-25 are rejected under 35 U.S.C. 103 as being unpatentable over Dor et al. (WO 2015/159292 A2, published October 2015, IDS ref, herein, “Dor-1”) in view of Dor et al. (US2020/0340057, published October 29, 2020, herein, “Dor-2”), and Fortin et al. (Bioinformatics, 2017, vol. 33, no. 4, pages 558-560).
Regarding claim 1, Dor-1 teaches a well-known known means of typing a cell/tissue based on the cell’s/tissue’s unique methylation pattern:
“Despite having an identical nucleotide sequence, the DNA of each cell type in the body carries unique epigenetic marks correlating with its gene expression profile … Methylation patterns are unique to each cell type, conserved among cells of the same type in the same individual and between individuals, and are highly stable under physiologic or pathologic conditions. Therefore, it may be possible to use the DNA methylation pattern of cfDNA to determine its tissue of origin and hence to infer cell death in the source organ” (page 1, line 31 to page 2, line 5)
“detecting death of a cell type or tissue in a subject comprising determining whether cell-free DNA comprised in a fluid sample of the subject is derived from the cell type or tissue, wherein the determining is effected by ascertaining the methylation status of at least four methylation sites on a continuous sequence of the cell-free DNA, the sequencing comprising no more than 300 nucleotides, wherein a methylation status of each of the at least four methylation sites on the continuous sequence of the DNA characteristic of the cell type or tissue is indicative of death of the cell type or tissue” (page 2, line 29 to page 3, line 4)
In determining the methylation status, the method employs “methylation-dependent oligonucleotide” to hybridize to at least one of the four methylation sites (page 4, lines 22-24), or via use of primers (“amplifying the continuous sequence of DNA using oligonucleotides that hybridize to a nucleic acid sequence adjacent to the first and last of the at least four methylation sites on the continuous sequence of the DNA”, page 5, lines 5-7; “typical amplification reaction is carried out by contacting a forward and reverse primer pair (a primer pair)”, page 32, lines 5-6).
With regard to claim 3, the biological sample comprises, “blood, plasma, sperm, milk, urine, saliva and cerebral spinal fluid” (page 4, lines 18-19)
With regard to claim 4, the target DNA fragment is a cell-free DNA fragment (“the invention is cell-free DNA”, page 4, line 7).
With regard to claim 5, the Dor-1 teaches determining the amount of cell-free DNA from the cell type or tissue (“method further comprises analyzing the amount of cell-free DNA derived from the cell type or tissue”, page 5, lines 12-13; “when the amount of cell free DNA derived from the cell type or tissue is above the predetermined level, it is indicative that there is a predetermined level of cell death … level of cell death is above a predetermined level, it is indicative that the subject has the disease or pathological state”, page 47, lines 15-18).
With regard to claim 6, the Dor-1 further teach identifying the subject human as having cancer, inflammation, or cancer (“a wide variety of pathologies, including but not limited to cancers, trauma …”, page 14, lines 1-2).
With regard to claims 20 and 22, the detection means is via hybridization to a DNA array which comprises probes or sequenced (“DNA may be sequenced using any methods known in the art”, page 36, lines 24-25; “Illumina 450k array”, page 55, line 32, see also page 61, lines 10-11).
With regard to claim 21, the Dor-1 teaches amplifying the at least for CpG sites (“amplifying the continuous sequence of DNA using oligonucleotides that hybridize to a nucleic acid sequence adjacent to the first and last of the at least four methylation sites on the continuous sequence of the DNA”, page 5, lines 5-7).
With regard to claim 23, the target DNA fragment comprises one or more deaminated cytosines (i.e., cytosines are deaminated to uracil when treated with bisulfite, “[m]ethods of determining the methylation status of a methylation site are known in the art and includes the use of bisulfite … which converts cytosine residues to uracil … but leaves 5-methylcytosine residues unaffected …”, page 30, lines 21-25).
With regard to claims 24 and 25, Dor-1 teaches a well-known means of treating the sample with bisulfite to convert unmethylated cytosines to uracils (“contacting the DNA in the sample with bisulfite to convert demethylated cytosines of the DNA to uracils”, page 5, lines 3-4).
Dor-1 teaches a plurality of SEQ ID Numbers of interest containing CpG sites, sequences of which expand to 1496 different SEQ ID Numbers (pages 16-28_, some of which are discussed below:
“SEQ ID NO: 1-27 and 1241-1244 comprise sequences which include at least 4 methylation sites in a continuous sequence of no more than 300 nucleotides that are unmethylated in pancreatic beta cells and methylated in other cells” (page 16, lines 27-29)
SEQ ID NO: 28-50 comprise sequences which include at least 4 methylation sites in continuous sequence of no more than 300 nucleotides that are methylated in pancreatic beta cells and unmethylated in other cells (page 17, lines 1-3)
SEQ ID NO: 51-100 comprise sequences which include at least 4 methylation sites in a continuous sequence of no more than 300 nucleotides that are unmethylated in pancreatic ductal cells and methylated in other cells (page 17, lines 12-14)
While the Dor-1 further teach that the amount of cell death in a particular cell population can be used to diagnose a particular pathological state (e.g., disease) or condition (e.g., trauma) (see page 45, line 28 to page 46, line 2, also “when the amount of cell free DNA derived from the cell type or tissue is above the predetermined level, it is indicative that there is a predetermined level of cell death … level of cell death is above a predetermined level, it is indicative that the subject has the disease or pathological state”, page 47, lines 15-18), the artisans do not explicitly teach that the increase in the cell-free DNA is linked to pancreatic cell type, wherein disease is diabetes, inflammation, or cancer (claims 7 and 8).
Dor-1 teach that their method is used for the detection of conditions, and monitoring treatment (“death of the cell type is associated with a pathological process, the method further comprise diagnosing the pathological process, page 4, lines 5-7; “method can be used for diagnosis, monitoring disease progression and assessment of response to therapy”, page 14, lines 2-3), but do not explicitly teach that genetic mutation is examined (claim 18) or that treatment of surgery, resection, radiation therapy, chemotherapy, or immunotherapy is administered (claim 19).
Dor-1 does not teach the CpG regions whose methylation status is specific to oral, larynx or esophageal cells.
Dor-2 similarly teaches additional CpG regions of different target DNA specific for oral cavity cell type, colon cell type (see Table 1).
Fortin et al. teach a well-known commercial availability of methylation detection assays, such as HumanMethylation 450, or “450k” solid via Illumina®.
“In 2015, Illumina released their next generation methylation array, the HumanMethylationEPIC (‘EPIC’) array … We have extended … to convert EPIC array to a virtual 450k array …” (page 558)
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 combine the teachings of Dor-1 and Dor-2 with Fortin et al. and the suggestions made by Dor-1 and Dor-2, thereby arriving at the invention as claimed for the following reasons.
As discussed above, Dor-1 and Dor-2 already teach that methylation profiles of DNA (in particular cell-free DNA) from samples are cell-type specific and can be used to identify the origin from which the cell-free DNA was released. And as discussed above, the artisans explicitly list thousands of target DNA fragments (by SEQ ID Numbers) comprising at least 4 CpG sites thereon. However, as noted above, the nature of the application and the prior art is that the thousands of SEQ ID numbers disclosed by Dor et al. and instant application, the comparison of such sheer numbers of SEQ ID numbers cannot be made. However, the Office notes the analysis of determining cell-type specific methylation patterns employed by Dor-1 and Dor-2 and instant application employed the same commercially available platform, Illumina 450k array (see above). Therefore, the Office asserts that at least one of the target DNA fragment sequences represented in the instant claim is represented in the thousands of cell-free DNA fragments containing CpG sites disclosed by Dor-1 and Dor-2, absent evidence to the contrary.
And based on this rationale, one of ordinary skill in the art would have had a reasonable motivation to identify a cell type based on the methylation pattern observed in the many of the target DNA fragments harboring CpG sites disclosed by Dor-1 and Dor-2.
With regard to identifying that the increased cell-free DNA is an indication of a pancreatic disease such as diabetes, one of ordinary skill in the art would have been clearly capable of concluding and arriving at such an application because Dor-1 and Dor-2 explicitly teach that the list of cell-free DNA is related back to the original source being a hepatocyte (see page 5, line 18, Dor-1) and Oral cells (Dor-2). Because Dor-1 and Dor-2 teach that the increased cell-free DNA above a predetermined level is indicative of cell death and disease (“when the amount of cell free DNA derived from the cell type or tissue is above the predetermined level, it is indicative that there is a predetermined level of cell death … level of cell death is above a predetermined level, it is indicative that the subject has the disease or pathological state”, page 47, lines 15-18), one of ordinary skill in the art would have been motivated and would have had a reasonable expectation of success at concluding that the rise of cell-free DNA level that originated from hepatocytes would be reason for screening for diabetes.
As to the detection of genetic variation in cell-free DNA for mutations that relate to diseases such as cancer, and concluding that proper treatment is applied (such as surgery, radiation therapy, etc.), such a conclusion would have also been obvious as such a practice has been long precited in the art of molecular diagnostics, where mutation markers are detected to render a diagnosis, followed by an appropriate treatment, requiring no more than a common sense.
In KSR International Co. v. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421, 82 USPQ2d at 1397 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”).
Therefore, the invention as claimed is deemed prima facie obvious over the cited references.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Inquiries
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Young J. Kim whose telephone number is (571) 272-0785. The Examiner can best be reached from 7:30 a.m. to 4:00 p.m (M-F). The Examiner can also be reached via e-mail to Young.Kim@uspto.gov. However, the office cannot guarantee security through the e-mail system nor should official papers be transmitted through this route.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's supervisor, Gary Benzion, can be reached at (571) 272-0782.
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/YOUNG J KIM/Primary Examiner
Art Unit 1637 July 21, 2026
/YJK/
1 Applicants’ election canceled claims 10-13 and 15-17, dependent on the independent claims 9 and 14, respectively.
2 “to transform an unpatentable law of nature into a patentable eligible application of such a law, a patent
must to more than simply state the law of nature while adding the words ‘apply it.’ See, e.g.,
Gottschalk v. Benson, 409, U.S. 63, 71-72. It must limit its reach to a particular, inventive application
of the law.” (Id. at 60)
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