DETAILED ACTION Notice of Pre-AIA or AIA Status The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Election/Restrictions Applicant’s election without traverse of Group III (claims 3-6, 15-19, 23, 31, and 37) in the reply filed on 3/3/2026 is acknowledged. Claims 1-2, 10 , and 13- 14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Applicant has canceled claims 11-12 and 28 and added claims 54-59 that depend from claim 3. Thus, claims 3-6, 15-19, 23, 31, 37, and 54-59 are pending and are examined on the merits herein. Information Disclosure Statement The information disclosure statements (IDS) submitted on 11/8/2022, 5/9/2024, and 3/12/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. Nucleotide and/or Amino Acid Sequence Disclosures Summary of Requirements for Patent Applications Filed O n Or After July 1, 2022, T hat Have Sequence Disclosures 37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted: 1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying: a. the name of the XML file b. the date of creation; and c. the size of the XML file in bytes; or 2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying: a. the name of the XML file; b. the date of creation; and c. the size of the XML file in bytes. SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS: Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete. Specifically, this paragraph is missing in the instant specification. Required response - Applicant must: • Provide a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph, consisting of: • A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version); • A copy of the amended specification without markings (clean version); and • A statement that the substitute specification contains no new matter. Specification The disclosure is objected to because of the following informalities: the Sequence Incorporation by Reference paragraph is missing, as described above. Appropriate correction is required. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. 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. Specifically, hyperlinks appear in paras. 124 and 196 of the application as published. Drawings The drawings are objected to because Figure 4C is not legible, as the different cancers represented cannot be distinguished from one another . Figure 5 is also not legible, as the y-axis on the graph is unreadable. Figure 12 is also not legible, as the genes of interest appear as only black or white in color, and so are each indistinguishable from other genes in the same color. Figure 14 is also not legible. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance. It is noted that for at least Figure 3 and Figure 5, the specification refers to these figures as being in color (see paras. 31 and 33 of the application as published). However, these drawings do not appear in color. Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO p atent e lectronic f iling s ystem or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO p atent e lectronic f iling s ystem , and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification: The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2). Claim Objections Claims 3, 6, 23, and 54-59 are objected to because of the following identical informality: in each claim, when the increase in Oct4a expression is being discussed, the word “folds” should be amended to read “fold.” Appropriate correction is required. Claim 23 is objected to because of the following informalit y : in line 3, “the expression level” should read “the reference expression level” to match the format used throughout the claim set. Appropriate correction is required. 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. Claim s 3-6, 15-19, 23, 31, 37, and 54-59 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. The claim s recite a natural law . Claim 3 is directed to a method for in-vitro detection of cancer in a subject via measuring the expression of Oct-4a in very small embryonic like stem cells (VSELs) . The natural law recited is the expression level of Oct-4a and the presence of cancer in a subject. This judicial exception is not integrated into a practical application because there is no required active treatment step or other step that integrates the judicial exception into a practical application. See MPEP 2106.04(d)(2) . The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because it do es not amount to more than well-understood, routine, and conventional activity . The claimed method comprising obtaining a biological sample, enriching VSEL cells, obtaining nucleic acids, and then measuring the expression level of a biomarker for a target sample and comparing it to a reference expression level. These elements are taught by Shaikh et al. (Leukemia, 2015 ; cited in a previous Office Action ). This reference teaches the use of VSELs in human cord blood (Abstract). Cells were collected and enriched, and then quantitative real-time reverse transcription PCR was performed to measure the expression of several markers, including OCT4A (page 1910, “Flow cytometry analysis of human cord blood,” “Immunomagnetic enrichment of CD133- and SSEA4-positive cells,” and “Quantitative real-time reverse transcription-PCR”). Expression levels for these markers in cord blood cells (which include VSELs) was also done before and after 5-FU treatment (page 1910, “Effect of 5-FU treatment on cord blood cells in vitro”), where OCT4A expression was found to increase with treatment compared to control level expression (page 1915, column 1, para. 5). Thus, the claim is directed to a judicial exception without significantly more. Claims 4-5 depend on claim 3 and recite further performing a sequence-based assay, where claim 5 uses this assay to qualify the sample type. Th ese limitations do not integrate the judicial exception into a practical application because there is no required active treatment step or other step that integrates the judicial exception into a practical application. See MPEP 2106.04(d)(2) . The claim s also do not include additional elements that are sufficient to amount to significantly more than the judicial exception because they do not amount to more than well-understood, routine, and conventional activity . This is because MPEP 2106.05(d) II specifically notes that sequencing nucleic acids and analyzing sequence information is well-understood, routine, and conventional activity in the field of life science when they are claimed in a generic manner. The claims recite sequence-based assays at a high level of generality, and so this guidance applies. Thus, claims are directed to a judicial exception without significantly more for the same reasons described above for claim 3. Claim 6 depends on claim 3 and serves only to further the judicial exception, as it further limits the relationship between Oct-4a and the presence of cancer in the sample. This judicial exception is not integrated into a practical application because there is no required active treatment step or other step that integrates the judicial exception into a practical application. See MPEP 2106.04(d)(2) . The claim also does not include additional elements that are sufficient to amount to significantly more than the judicial exception because it does not amount to more than well-understood, routine, and conventional activity . Thus, the claim is directed to a judicial exception without significantly more for the same reasons described above for claim 3. Claim 15 depends on claim 3 and recites various methods for obtaining the biological sample from the subject. T his does not integrate the judicial exception into a practical application because there is no required active treatment step or other step that integrates the judicial exception into a practical application. See MPEP 2106.04(d)(2) . The claim also does not include additional elements that are sufficient to amount to significantly more than the judicial exception because it does not amount to more than well-understood, routine, and conventional activity in view of Tripathi et al. (US 2020/0370134 A1). This reference teaches measuring biomarkers of pluripotent stem cells for detecting cancer (Abstract). This reference particularly teaches the claimed extraction methods in paras. 86, 109, 120-121, 136, 156, 167, and 184). Thus, the claim is directed to a judicial exception without significantly more for the same reasons described above for claim 3. Claim 16 depends on claim 3 and recites various methods for assaying the nucleic acids to determine the expression level of Oct-4a in the sample. This does not integrate the judicial exception into a practical application because there is no required active treatment step or other step that integrates the judicial exception into a practical application. See MPEP 2106.04(d)(2) . The claim also do es not include additional elements that are sufficient to amount to significantly more than the judicial exception because it does not amount to more than well-understood, routine, and conventional activity . This is because MPEP 2106.05(d) II specifically notes that amplifying and sequencing nucleic acids and analyzing sequence information is well-understood, routine, and conventional activity in the field of life science when they are claimed in a generic manner. The claims recite amplification and sequencing at a high level of generality, and so this guidance applies. Regarding flow cytometry, this is taught in Shaikh et al. as a method for enrichment on page 1910, column 1, para. 2). Thus, the claim is directed to a judicial exception without significantly more for the same reasons described above for claim 3. Claim 17 depends on claim 3 and specifies the type of reference sample that must be used. T his does not integrate the judicial exception into a practical application because there is no required active treatment step or other step that integrates the judicial exception into a practical application. See MPEP 2106.04(d)(2) . The claim also does not include additional elements that are sufficient to amount to significantly more than the judicial exception because it does not amount to more than well-understood, routine, and conventional activity in view of Zha o et al. ( Blood Cells , Molecules and Diseases , 2015). The reference teaches measuring Oct-4a expression in bone marrow in association with leukemia, and compared this to expression in normal healthy subjects (Abstract). Thus, the claim is directed to a judicial exception without significantly more for the same reasons described above for claim 3. Claim 18 depends on claim 3 and recites a particular sample type and enrichment method. T his does not integrate the judicial exception into a practical application because there is no required active treatment step or other step that integrates the judicial exception into a practical application. See MPEP 2106.04(d)(2) . The claim also does not include additional elements that are sufficient to amount to significantly more than the judicial exception because it does not amount to more than well-understood, routine, and conventional activity in view of Shaikh et al. On page 1910, column 1, para. 2 and the Supplemental Section of this reference , it is explain ed that blood samples were used, where blood was diluted in a 1:1 ratio of phosphate buffered saline, centrifuged to obtain an RBC pellet, and then the pellet was washed and lysed (Supplementary Section, “Ficoll-Hypaque centrifugation”). This was done to enrich VSELs (page 1909, column 2, para. 3). Thus, the claim is directed to a judicial exception without significantly more for the same reasons described above for claim 3. Claim 19 depends on claim 18 and requires a particular processing step for the enrichment of claim 18. T his does not integrate the judicial exception into a practical application because there is no required active treatment step or other step that integrates the judicial exception into a practical application. See MPEP 2106.04(d)(2) . The claim also does not include additional elements that are sufficient to amount to significantly more than the judicial exception because it does not amount to more than well-understood, routine, and conventional activity . In the rejection of claim 18 above, it is already noted that lysing and washing are recited by Shaikh et al. Regarding additional centrifugation, Tripathi et al. teaches sequential centrifugation to obtain pluripotent stem cells (paras. 114, 125-126, and 221). Thus, the claim is directed to a judicial exception without significantly more for the same reasons described above for claim 3. Claim 23 depends on claim 3 and serves to only further the judicial exception, as it further limits the relationship between Oct-4a and the presence of cancer in the sample. This judicial exception is not integrated into a practical application because there is no required active treatment step or other step that integrates the judicial exception into a practical application. See MPEP 2106.04(d)(2) . The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because it does not amount to more than well-understood, routine, and conventional activity . Thus, the claim is directed to a judicial exception without significantly more for the same reasons described above for claim 3. Claim 31 depends on claim 3 and provides specific enriching methods. T his does not integrate the judicial exception into a practical application because there is no required active treatment step or other step that integrates the judicial exception into a practical application. See MPEP 2106.04(d)(2) . The claim also does not include additional elements that are sufficient to amount to significantly more than the judicial exception because it does not amount to more than well-understood, routine, and conventional activity . In the rejection of claim 18 above, it is already noted that Shaikh et al. teaches flow cytometry methods. StemCell Technologies (“Cell Separation and Cell Isolation Methods,” 2019) also teaches various well-known methods for cell separation . This includes immunomagnetic cell separation, microfluidic cell separation, aptamer cell sorting, buoyancy-activated cell sorting, and microfiltration (under “Microfluidic Cell Separation). Thus, the claim is directed to a judicial exception without significantly more for the same reasons described above for claim 3. Claim 37 depends on claim 3 and requires the use of particular nucleic acids. This serves to only further the judicial exception, as the expression of Oct-4a and its relation ship to cancer exists for all types of nucleic acids that encode Oct-4a. This judicial exception is not integrated into a practical application because there is no required active treatment step or other step that integrates the judicial exception into a practical application. See MPEP 2106.04(d)(2) . The claim also does not include additional elements that are sufficient to amount to significantly more than the judicial exception because it does not amount to more than well-understood, routine, and conventional activity . Thus, the claim is directed to a judicial exception without significantly more for the same reasons described above for claim 3. Claims 54-59 each depend on claim 3, and each serve to only further the judicial exception of claim 3, as they further limit the relationship between Oct-4a and the presence of cancer in the sample. This judicial exception is not integrated into a practical application because there is no required active treatment step or other step that integrates the judicial exception into a practical application. See MPEP 2106.04(d)(2) . The claim s also do not include additional elements that are sufficient to amount to significantly more than the judicial exception because they do not amount to more than well-understood, routine, and conventional activity . Thus, the claims are directed to a judicial exception without significantly more for the same reasons described above for claim 3. Claim Rejections - 35 USC § 112 (a) The following is a quotation of the first paragraph of 35 U.S.C. 112(a): (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. Claim s 3-6, 15-19, 23, 31, 37, and 54-59 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the enablement requirement. The claim s contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands , 8 USPQ2d 1400 (CA FC 1988). These factors include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. Each of these factors is discussed below. Nature of the Invention Claims 3-6, 15-19, 23, 31, 37, and 54-59 are drawn to an in-vitro method for detecting the presence of cancer in a subject by measuring the expression of the biomarker Oct-4a in very small embryonic like stem cells and comparing this expression to that of a reference sample. The claimed methods are classified in the unpredictable arts of molecular biology and biochemistry. Breadth of the Claims Claim 3 is broad in scope as it encompasses any type of cancer. The dependent claims do not further limit this broad aspect of the claims. Level of Skill in the Art The ordinary artisan typically holds at least a master’s degree has several years of experience. State of the Prior Art & Unpredictability Concerning the claimed invention, what was (and is) unpredictable in the prior art is the precise relationship between Oct-4a expression in VSELs in relation to cancer generally and to particular cancers . Therefore, it is not possible to know a priori the quantitative relationship of Oct-4a expression in a particular cancer compared to that of a reference sample. Bhartiya ( Indian J Med Res , 2015) notes that Oct-4 generally has been implicated as a pluripotent marker in various cancers (see Table on page 159) , but the references in this table do not discuss Oct-4a in the context of VSELs. Samardzija et al. ( Journal of Ovarian Research , 2012) discusses VSELs, and teaches that they are positive for Oct4 and are present in many body tissues (page 2, column 2, para. 2). Page 5, column 2, para. 3 states that VSELs are likely implicated in tumor development, and Figure 2 shows that mRNA expression of Oct-4a is present in cancer cells, and has higher expression levels in cancer patients with recurrent disease, although this analysis was not performed on VSELs (page 7, column 1, para. 3). The reference also mentions that Oct4 and Oct4a have been implicated in cancer, but the references cited do not discuss VSELs (page 6, column 1, para. 1 and page 7, column 1, para. 1). Bhartiya et al. ( Journal of Cancer Stem Cell Research , 2016) discusses VSELs and Oct-4 expression (Abstract) . On page 5, column 1, para. 2, the reference discusses various references and reaches the conclusion that Oct-4a expression is likely increased in VSELs in leukemia, but does not provide data for this point. Parte et al. ( Stem Cells and Development , 2017) focuses on ovarian cancer, and examines VSELs and OCT4 expression (Abstract and page 1782, column 1, para. 3) . Figure 2 shows that VSELs expressing OCT4 are potentially in both normal samples and high grade ovarian cancer samples , but this finding does not focus on Oct-4a nor does it specifically quantify any expression differences . Shaikh et al. ( Leukemia , 2015 ; cited in previous Office Action ) discusses enrichment methods for VSELs and examines Oct-4a expression (Abstract). They mention that VSELs likely play a role in ovarian and pancreatic cancers (page 1909, column 1, para. 1) , but neither this reference nor the references cited in this paragraph mention quantitative measures of Oct-4a expression in VSELs of cancer patients. Ratajczak et al. ( Stem Cell Rev and Rep , 2010; cited in previous Office Action) discusses VSELs and markers associated with them (Abstract). They state that Oct-4 is generally highly expressed at the mRNA and protein levels in VSELs (page 313, column 2, para. 3) , where this is based on data from Shin et al. ( Leukemia , 2009). Shin shows this data in Figure 1b and 1 c and explain s on page 2044, column 2, para. 2. Shin however, does not discuss cancer. Taken together, though the prior art appears to agree that Oct-4 is expressed in VSELs, and there appears to be a correlation of higher Oct-4/Oct-4a expression in VSELs in at least some cancers, there has been little research done precisely quantifying expression in particular cancers, and a wide range of cancers has not been studied with regard to VSELs and Oct-4a expression. Guidance in the Specification and Examples The citations provided in this section all utilize the paragraph numbers from Applicant’s application as published (US 2023/0212688 A1). Applicant recites in para. 53 that “cancer” as used in the present disclosure encompass an incredibly large variety of diseases/conditions, including benign tumors, and notes that this recited list is non-limiting. In Applicant’s working examples, para. 128 notes that 180 samples were collected for VSEL enrichment and Oct-4a expression/cancer analysis to correlate expression with cancer stage and create the HrC scale . However, para. 134 states that 120 samples were used to collect this data, so the number of samples initially used is unclear. Data to obtain this scale is not explicitly shown. Once the scale was created, 1,000 subjects were used for validation, where 500 had cancer and 500 did not. To enrich the VSELs, blood samples were taken and underwent various centrifugations (para. 129). Oct-4a expression was then measured via qRT-PCR (para. 130) . The HrC scale developed (and shown in Figure 1) is stated to be “ double the fold change in the expression of Oct4A analyzed from the blood samples of the test subject as compared to a housekeeping gene or Oct4A analyzed from the blood sample of a healthy subject ,” (para. 134). In the study of the 1,000 patients, 25 cancers were analyzed (para. 136). Figure 2 shows the distribution of cancers in 500 patients, where as few as five or less patients were utilized for a single group (and notably, only 1 patient with a gastrointestinal cancer was examined). Para. 137 states that of the cancer patients, “ 11 were in stage I cancer, 94 were in stage II cancer, 133 were in stage III cancer, and 257 were in stage IV cancer ,” (see also Figure 3). No clear data is provided matching particular cancer types with stage (e.g. how many of the 59 breast cancer samples are Stage I, Stage II, Stage III, etc.) . This data appears to be provided in Figure 4C, but as noted in the “Drawings” section above, this figure is not legible. Given the small sample size for Stage I cancers in particular, there are several cancer groups represented by the study at large that do not have any Stage I patients. Furthermore, even if each studied cancer was equally represented in the remaining stages (which is not the case, particularly given the low samples sizes for some cancers), there would be only ~4 patients with Stage II cancer for each cancer, ~5 patients with Stage III cancer for each cancer, and ~10 patients with Stage IV cancer for each cancer, which would be relatively low sample sizes with a skew towards worse prognosis cancers. Figure 4A shows high HrC values in all cancers as compared to non-cancer samples, but this appears to combine all stages of cancer, and so is skewed by the proportionally higher amount of Stages III-IV cancer samples present in the study. Figure 4B groups all cancer stages together for each cancer, and so shows a similar high cancer stage skew as in Figure 4A . Figure 5 (which appears to plot HrC on the y-axis based on the guidance pf para. 33) clearly shows an increase in HrC as cancer stage increases, but the y-axis is not legible, and so conclusions about specific ranges for each cancer stage cannot be drawn. Figures 6-9 are more legible and do align with the data provided in Figure 1, but it is unclear if the y-axis for these figure s are the same as that of Figure 5. The x-axis on these figures also only shows the sex and age of each patient, and not the particular type of cancer they may have. Additionally, while HrC value does steadily increase as cancer stage increases, it is unclear if the changes between stages are significantly different from one another, which would bolster the utility of utilizing the scoring method of the disclosure (and thus, Oct-4a expression) to actually distinguish between different cancer stages, at least for the cancers analyzed. It is noted that in the instant claims, the subject has a single cancer (see “a cancer” and “the cancer” language in instant claim 3). Applicant does not appear to have provided any data concerning patients with multiple cancers. Thus, in Applicant’s disclosure, data is provided for only a small sample of the cancers that are encompassed by the cancers of the invention as a whole, and it is unclear if the provided method is supported for all cancers. Additionally, for the cancers that are disclosed in the working examples, some have very little data due to low sample size, and there is no clear data linking cancer stage to Oct-4a expression for individual cancers. Thus, i t is not clear that Applicant’s specification has successfully demonstrated the use of the claimed biomarker (Oct-4a) in the claimed sample type (very small embryonic like stem cells) as a means to detect any type of cancer in a subject , particularly in view of the low sample sizes , lack of clear data categorized by cancer type , and unpredictability in the prior art discussed above. Additionally, g iven the lack of clarity regarding the different stages of cancer presented (e.g. the lack of data presented for the stages of different cancers, as well as no statistical data comparing the cancer stages), it is not clear that distinguishing between any cancer stage is enabled by the instant disclosure. Quantity of Experimentation The ordinary artisan would have to conduct a very large quantity of highly unpredictable experimentation before being able to successfully practice the full scope of the claimed methods. Specifically, the ordinary artisan would have to determine for every cancer sample encompassed by the claims, including those not described in Applicant’s working examples, that Oct-4a expression patterns are as claimed when compared to reference samples. With regard to claims 23 and 57-59, the ordinary artisan would additionally have to determine that Oct-4a expression levels for each cancer stage of each cancer are as claimed when compared to reference samples. Based on the teachings in the art, this would be an inventive and unpredictable undertaking, requiring extensive experimentation in which there is no guarantee of success. The large quantity of experimentation and its unpredictability constitute undue experimentation. Conclusion In view of the foregoing, it is clear that the specification fails to enable the full scope of the claimed methods, and claims 3-6, 15-19, 23, 31, 37, and 54-59 are rejected under 35 U.S.C. 112(a) for failing to comply with the enablement requirement. Claim Rejections - 35 USC § 112 (b) 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 appl icant regards as his invention. Claim s 5, 15, and 18-19 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 5 is rejected because it states that a “sequence-based assay” detects a particular type of cancer in a subject. However, the term “sequence-based assay” is not defined by the instant specification, and so is taken to include any assay that relies on the sequence of a nucleic acid (e.g. PCR, next-generation sequencing, LAMP, etc.). It is unclear, given the method described in claim 3, how performing such an assay , particularly in view of the broadness of said assays, would detect a particular type of cancer. The published application at paras. 79 and 90 notes that sequence-based assays can detect mutations in a cancer-related marker of a sample that may not be present in a reference sample, but no use of mutations is described or required in claims 3 or 5. Thus, the scope of the claim is indefinite relative to the claimed method. Additionally, it is noted that in claim 5 (and claim 4, from which this claim depends), the sequence-based assay is performed in addition to the steps of the method of claim 3, as evidenced by the language of claim 4 stating that the method of claim 3 further comprises performing a sequence-based assay. This indicates that this assay is distinct from sequence-based assays that may be performed in the method of claim 3, in step (d), for example. This does not render the scope of either claim indefinite, but is noted for clear claim interpretation. Claim 15 is rejected because the claim is directed to methods of obtaining a biological sample, but the methods listed appear to be methods of nucleic acid extraction. Thus, it is unclear how these extraction methods could be used to obtain a biological sample, which likely contains more than nucleic acids. It will be interpreted as though this is a typographical error, and that the claim is intended to recite the obtaining of step c) of claim 3 , which recites obtaining of nucleic acids specifically . Claim 18 is rejected because the claim recites “The method of claim 3, further comprising… ” (emphasis added) and then g oes on to describe obtaining a blood sample from a subject and a particular process of enriching the very small embryonic like stem cells. The obtaining of a sample and the enrichment of these cells is already described in claim 3, from which this claim depends, and due to the language of claim 18 , the claim describes second obtaining and enriching steps. It is unclear what the purpose of said second obtaining and enriching steps would be within the larger method of claim 3, and this lack of clarity renders the scope of the claim indefinite. It is recommended, if it is Applicant’s intent, to amend claim 18 to recite “The method of claim 3, wherein the biological sample is a blood sample, and wherein step b) comprises…” and then recite i)-iii) of the claim. Claim 19 is rejected due to its dependence on rejected claim 18. Double Patenting The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg , 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman , 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi , 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum , 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel , 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington , 418 F.2d 528, 163 USPQ 644 (CCPA 1969). A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b). The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13. The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA/25, or PTO/AIA/26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer . Claim s 3- 6 , 15-16 , 23, and 54-59 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 30, 32-33, 36 , and 40 of copending Application No. 18/681,811 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because claim 30 of the ‘811 application is encompassed by instant claim 3. Claim 30 recites the use of a blood sample, which is encompassed by the biological sample of the instant claim, and recites the use of RNA, which is encompassed by the general nucleic acids of the instant claim. Steps (b)-(g) of claim 30 are recited as a method of enriching very small embryonic like stem cells (see para. 8 of the instant specification), and so these steps read on instant steps (b) and (c). Claim 30 then performs the same assaying and comparison to a reference sample as the instant claim, and notes the same conclusions when Oct4a has a 5 fold or higher increase in expression in the biological sample. Thus, claim 30 reads on each limitation of the instant claim. Claim 30 also overlaps in scope with the fold increases described in instant claims 6 and 54-56, as the claim recites “at least 5 folds.” It is noted that such a use of the reference application specification is considered proper under MPEP 804 II (B) 1, where the reference specification may be used to determine the scope/broadest reasonable interpretation of claim language, and to “ provide support for the reference claims … when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application (as distinguished from an obvious variation of the subject matter disclosed in the reference patent or application). In re Vogel, 422 F.2d 438, 441-42, 164 USPQ 619, 622 (CCPA 1970). The court in Vogel recognized "that it is most difficult, if not meaningless, to try to say what is or is not an obvious variation of a claim," but that one can judge whether or not the invention claimed in an application is an obvious variation of an embodiment disclosed in the patent or application which provides support for the claim …’” Claim 32 of the ‘811 application lists the same means for nucleic acid extraction as instant claim 15, and so reads on this claim. Note that this rejection relies on the interpretation of instant claim 15 described above in the 35 USC 112(b) Rejections. Claim 33 of the ’811 application lists the same assay methods of instant claim 16, and so reads on this claim. Claim 36 of the ‘811 application requires the use of a sequence-based assay that can detect a particular cancer, and so reads on the limitations of instant claims 4-5. Claim 40 of the ‘811 application recites a n increase in Oct4a in the sample of 5-20+, thus reading on claims 3 , 6, and 54-56. Claim 40 also recites expression levels of Oct4a that correlate with cancer stages, and th u s reads on the limitations of claim s 23 and 57-59. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Clai ms 3- 4, 6 , 15-17, and 37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 1 , 4, 15, 24, 67, and 69 of Application No. 17/314,442 (reference application) . Although the claims at issue are not identical, they are not patentably distinct from each other because claim 1 of the ‘442 application is encompassed by instant claim 3. Claim 1 recites the use of a blood sample, which is encompassed by the biological sample of the instant claim, and recites the use of mRNA, which is encompassed by the general nucleic acids of the instant claim. Steps (b)-(d) of claim 1 are recited as a method of enriching very small embryonic like stem cells (see para. 96 of the instant specification), and so these steps read on instant steps (b) and (c). Claim 1 then performs the same assaying and comparison to a reference sample as the instant claim, and notes the same conclusions when Oct4a has a 5 to less than 10 fold increase in expression in the biological sample. Thus, claim 1 reads on each limitation of the instant claim. Claim 1 also reads on instant claim 6, which describes a fold increase in the range of 5-10 and thus overlaps with that of claim 1. It is noted that such a use of the reference application specification is considered proper under MPEP 804 II (B) 1, where the reference specification may be used to determine the scope/broadest reasonable interpretation of claim language, and to “ provide support for the reference claims … when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application (as distinguished from an obvious variation of the subject matter disclosed in the reference patent or application). In re Vogel, 422 F.2d 438, 441-42, 164 USPQ 619, 622 (CCPA 1970). The court in Vogel recognized "that it is most difficult, if not meaningless, to try to say what is or is not an obvious variation of a claim," but that one can judge whether or not the invention claimed in an application is an obvious variation of an embodiment disclosed in the patent or application which provides support for the claim …’” Claim 4 of the ‘442 application recites using a sequencing method, and so reads on instant claim 4. It is noted that the assaying of claim 4 of the ‘442 application comprises sequencing, and so may include other elements, thus meaning the claim can overlap in scope with the further comprising language of instant claim 4, as more than sequencing may be included in the assay of claim 4 of the ‘442 application. Claim 15 of the ‘442 application recites the same means for nucleic acid extraction as instant claim 15, and so reads on this claim. Note that this rejection relies on the interpretation of instant claim 15 described above in the 35 USC 112(b) Rejections. Claim 24 of the ‘442 application recites the use of a cancer-free subject as a reference, and therefore reads on instant claim 17. Claim 67 of the ‘442 application recites the use of qPCR, and so reads on instant claim 16, which also recites the use of PCR. Claim 69 of the ‘442 application recites the use of cDNA, and so reads on instant claim 37, which also recites the use of cDNA. At the time of the mailing of this Office Action, the issue fee for the ‘442 application has been paid, but a patent has not been issued, and so no U.S. Patent Number is available. Thus, while this is a provisional nonstatutory double patenting rejection, it will likely not be provisional if maintained in further actions. Conclusion No claims are currently allowable. 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