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 .
Response to Amendment
Amendments to the drawings, specification, and claims filed on 12 August 2026 are acknowledged. Claims 65 and 66 are amended, and claims 68-75, 77, and 78 are newly canceled. Claims 59-67 and 76 are pending; claim 76 is withdrawn; and claims 59-67 are examined herein on the merits.
In response to the amendment filed on 12 August 2026, the objections to the claims are withdrawn; the objections to the drawings are partially withdrawn; the objections to the specification are withdrawn; the rejections under 35 USC 112(b) are withdrawn; the rejections under 35 USC 112(a) are withdrawn; and the rejections under 35 USC 101 are maintained for the pending claims.
Information Disclosure Statement
The information disclosure statement filed 10 September 2025 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered.
Legible copies of numerous documents were missing from the information disclosure statements filed 10 September 2025. In remarks filed on 12 August 2026, Applicant states the following:
Applicant notes that copies of WO 2016097769, WO 2016112174, and WO 20162065960 were actually filed in the present application on September 10, 2025, as indicated by the Electronic Filing System Receipt dated September 10, 2025 (Exhibit A) submitted herewith, see pages 2 and 3. Copies of the remaining references are submitted along with this response; Applicant submits that the omission of copies of these references was inadvertent, and respectfully requests reconsideration of the Information Disclosure Statements filed on August 2, 2023 and September 10, 2025 under 37 CFR 1.97(f).
The foreign documents WO 2016097769, WO 2016112174, and WO 20162065960 have been considered, as reflected in the updated 1449 forms. WO 2016112174 had the wrong document code, which was a mistake of the Office. While WO 2016112174 and WO 20162065960 were listed on an IDS dated 2 August 2023, copies of WO 2016112174 and WO 20162065960 were first filed on September 10, 2025. The date of September 10, 2025 meets the requirements based on the time of filing of the IDS set forth in 37 CFR 1.97(b)(3), and therefore these documents have been considered.
Regarding the remaining references that have not been considered on the IDS filed on September 10, 2025, Applicant has not filed a new IDS with the fee required for consideration of an IDS filed after the period specified in 37 CFR 1.97(b). The requirements based on the time of filing of the IDS set forth in 37 CFR 1.97(b) would not be met by Applicant correction of the deficiency in the previously filed IDS via filing copies of documents on 12 August 2026. As set forth in MPEP609.05(a), "Applicant may then file a new information disclosure statement or correct the deficiency in the previously filed IDS, but the date that the new IDS or correction is filed will be the date of the IDS for purposes of determining compliance with the requirements based on the time of filing of the IDS (37 CFR 1.97)." A correction on 12 August 2026 does not meet the requirements based on the time of filing of the IDS set forth in 37 CFR 1.97(b).
Drawings
The drawings are objected to for the following reasons.
Regarding Figs. 4a and 6a, not all of the data lines cannot be distinguished from one another. Fig. 6a has been amended on 12 August 2026 such that two of the data lines are broken lines, but the key does not identify broken versus solid lines.
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.
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 59-67 are directed to natural products and a law of nature without significantly more.
Claims 59-67 recite a method for processing a human clinical blood sample, comprising quantifying a group of metabolites in a blood sample, the blood sample being obtained from a subject clinically assessed as having or suspected of having early-stage non-small cell lung cancer (NSCLC).
The metabolites recited in claims 59-67 are natural products. The location and existence of these metabolites in "a blood sample from a subject clinically assessed as having or suspected of having early-stage non-small cell lung cancer (NSCLC)" is a natural phenomenon and thus identifying their presence and quantify is merely claiming the natural phenomena itself. See discussion of Ariosa Diagnostics, Inc. v. Sequenom regarding process claims in MPEP 2106.04(c), I, C.
By reciting a step of quantifying a group of metabolites in a blood sample obtained from a subject clinically assessed as having or suspected of having early-stage non-small cell lung cancer (NSCLC), the claimed steps investigate a correlation between the group of metabolites and early-stage non-small cell lung cancer (NSCLC). A natural relationship between quantities of metabolites in a blood sample and the presence of a disease such as early-stage NSCLC is a law of nature. See MPEP 2106.04(b), I.
The natural product judicial exception of claims 59-67 is not integrated into a practical application because claims 59-67 do not recite any application of the metabolites or the quantities of the metabolites. The broadly recited "obtaining" and "quantifying" steps amount to merely identifying the presence and levels of the natural product itself. See discussion of Ariosa Diagnostics, Inc. v. Sequenom regarding process claims in MPEP 2106.04(c), I, C.
The natural law judicial exception of claims 59-67 is not integrated into a practical application because claims 59-67 do not recite any application of a natural relationship between quantities of metabolites in a blood sample and the presence of early-stage NSCLC.
Claims 59-67 do not include additional elements that are sufficient to amount to significantly more than the judicial exceptions. The broadly recited "obtaining" and "quantifying" steps of independent claim 59 are in addition to the judicial exceptions but are mere data gathering steps that are insignificant extra-solution activity. See MPEP 2106.05(g). The courts have recognized that determining the level of a biomarker in blood is well-understood, routine, conventional activity in the life science arts when it is claimed in a merely generic manner (e.g., at a high level of generality) or is insignificant extra-solution activity. See MPEP 2106.05(d), II and Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017).
Response to Arguments
Applicant's arguments filed on 12 August 2026 have been considered and are not fully persuasive.
Regarding the rejection under 35 USC 101 because the claims are directed to a law of nature, Applicant argues that the office action does not identify language in claim 59 itself that recites a correlation. In response, the rejection points out that the blood sample from which the group of metabolites is quantified is obtained "from a subject clinically assessed as having or suspected of having early-stage non-small cell lung cancer (NSCLC)." A correlation between the quantified group of metabolites and early-stage non-small cell lung cancer (NSCLC) is implicit to the language of claim 59. As set forth in MPEP 2106.04(II)(A), "there are two ways in which an exception can be recited in a claim." The first way is "clearly stated laws of nature," and as an example of the second way, "the claims in Alice Corp., 573 U.S. at 218, 110 USPQ2d at 1982, described the concept of intermediated settlement without ever explicitly using the words 'intermediated' or 'settlement' " [MPEP 2106.04(II)(A)].
Regarding the rejection under 35 USC 101 because the claims are directed to natural products, Applicant argues the following:
The Office Action separately asserts that the recited metabolites are natural products, and that identifying their presence in a blood sample from the recited patient population "is merely claiming the natural phenomena itself," citing Ariosa Diagnostics, Inc. v. Sequenom, MPEP 2106.04(c)(I)(C). This ground fails for a related reason: claim 59 does not recite merely "identifying" the metabolites' presence. It recites quantifying them, i.e., generating numeric values for a defined multi-component panel. The facts of Sequenom are materially different. In Sequenom, detection of the paternally-inherited cffDNA fragment was the diagnostic endpoint; presence or absence of the fragment answered the diagnostic question directly, and the claimed method did nothing more than detect it. Claim 59 is different in kind: it quantifies (i.e., generates numeric measurements for) a panel of six specifically enumerated metabolites without reciting any correlation or other mental step drawn from those values. The Office Action has not explained how quantifying a defined multi-component panel is equivalent to merely identifying the presence of a single DNA fragment, as in Sequenom.
The claims at issue in Ariosa Diagnostics, Inc. v. Sequenom were claims 1, 2, 4, 5, 8, 19-22, 24, and 25 of US 6,258,540, which the court held to be invalid under 35 USC 101 for not being directed to patent eligible subject matter. Dependent claim 13 of US 6,258,540, which recites a step of "determining the concentration of the foetal nucleic acid sequence in the maternal serum or plasma," was not at issue in this appeal. The Sequenom claim 1 recites steps of "amplifying a paternally inherited nucleic acid from the serum or plasma sample" and "detecting the presence of a paternally inherited nucleic acid of fetal origin in the sample." Dependent claim 5 recites that "the presence of a foetal nucleic acid sequence from the Y chromosome is detected." Dependent claim 8 recites that "the presence of a foetal nucleic acid from a paternally-inherited non-Y chromosome is detected." In other words, the invalidated Sequenom claims include claims directed to detecting different paternally inherited nucleic acids of fetal origin.
Applicant's argument that a step of detecting the presence of a natural product is materially different from a step of quantifying a natural product with respect to the subject matter guidance provided by Ariosa Diagnostics, Inc. v. Sequenom and MPEP 2106.04(c), I, C is unpersuasive. MPEP 2106.04(c), I, C is reproduced in full below, with added bolding:
C. Process Claims
For a process claim, the general rule is that the claim is not subject to the markedly different analysis for nature-based products used in the process. This is because the analysis of a process claim should focus on the active steps of the process rather than the products used in those steps. For example, when evaluating a claimed process of cryopreserving hepatocyte cells comprising performing density gradient fractionation to separate viable and non-viable hepatocytes, recovering the viable hepatocytes, and cryopreserving the recovered viable hepatocytes, the court did not subject the claim to the markedly different characteristics analysis for the nature-based products (the hepatocytes) used in the process. Rapid Litig. Mgmt. v. CellzDirect, Inc., 827 F.3d 1042, 1049, 119 USPQ2d 1370, 1374 (Fed. Cir. 2016) (claims are directed to a process of creating a preparation of multi-cryopreserved hepatocytes, not to the preparation itself).
However, in the limited situation where a process claim reciting a nature-based product is drafted in such a way that there is no difference in substance from a product claim, the claim is subject to the markedly different analysis for the recited nature-based product. These types of claims are drafted in a way that focuses on the product rather than the process steps. For example, consider a claim that recites, in its entirety, "a method of providing an apple." Under the broadest reasonable interpretation, this claim is focused on the apple fruit itself, which is a nature-based product. Similarly, claims to detecting naturally occurring cell-free fetal DNA (cffDNA) in maternal blood were held to be directed to the cffDNA, because the "existence and location of cffDNA is a natural phenomenon [and thus] identifying its presence was merely claiming the natural phenomena itself." Rapid Litig. Mgmt., 827 F.3d at 1048, 119 USPQ2d at 1374, (explaining the holding in Ariosa Diagnostics, Inc. v. Sequenom, 788 F.3d 1371, 115 USPQ2d 1152 (Fed. Cir. 2015)).
The instant rejected claims are drafted in a way that focuses on the group of metabolites rather than the process steps, which are very general ("obtaining" and "quantifying"). The quantity of a natural product is an attribute of a similar type to the "existence" and "location" of the natural product. According, the quantity of a group of metabolites is a natural phenomenon and thus quantifying a group of metabolites is merely claiming the natural phenomenon itself. Furthermore, the court in Ariosa Diagnostics, Inc. v. Sequenom quoted Mayo that methods determining metabolite levels were well known:
In Mayo, the patents at issue claimed a method for measuring metabolites in the bloodstream in order to calibrate the appropriate dosage of thiopurine drugs in the treatment of autoimmune diseases. 132 S.Ct. at 1294. The respondent contended that the claimed method was a patent eligible application of. a natural law that described the relationship between the concentration of certain metabolites and the likelihood that the drug dosage will be harmful or ineffective. Methods for determining metabolite levels, however, were already “well known in the art.” Id. at 1298. Further, the process at issue amounted to “nothing significantly more than an instruction to doctors to apply the applicable laws when treating their patients.” Id. In that case, “[s]imply appending conventional steps, specified at a high level of generality,” was not enough to supply an inventive concept. Id. at 1300.
Like the patentee in Mayo, Sequenom contends that the claimed methods are patent eligible applications of a natural phenomenon, specifically a method for detecting paternally inherited cffDNA. Using methods like PCR to amplify and detect cffDNA was well-understood, routine, and conventional activity in 1997. The method at issue here amounts to a general instruction to doctors to apply routine, conventional techniques when seeking to detect cffDNA. Because the method steps were well-understood, conventional and routine, the method of detecting paternally inherited cffDNA is not new and useful. The only subject matter new and useful.as of the date of the application was the discovery of the presence of cffDNA in maternal plasma or serum.
Applicant's argument that a method directed to plural natural products is materially different from a method directed to a single natural product with respect to the subject matter guidance provided by Ariosa Diagnostics, Inc. v. Sequenom and MPEP 2106.04(c), I, C is clearly unpersuasive. Applicant does not supply any precedent or legal rationale for treating plural different natural products as outside the judicial exception identified by the courts as "products of nature." Moreover, as mentioned above, invalidated claims 5 and 8 of the Sequenom patent are directed to detecting different natural products.
Applicant argues, in the alternative, that claim 59 integrates any judicial exception into a practical application by stating that the claim "is directed to clinical sample preparation activity that is upstream of any diagnosing step and concern a practical implementation of the invention." In response, it is contrary to the ordinary meaning of "application" to characterize an upstream activity as an application of a downstream activity. Logically, an application must be downstream of what is being applied.
Applicant argues that the reliance on Mayo is insufficient for the finding that determining the level of a biomarker in blood is well-understood, routine, conventional activity in the life science arts when it is claimed in a merely generic manner (e.g., at a high level of generality) or is insignificant extra-solution activity. It is noted that the rejection also cites MPEP 2106.05(d), II and Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017).
Applicant argues that "there is no evidence of record to support an assertion that quantifying this specific five/six-component panel … was well-understood, routine, and conventional as of the filing date." Applicant's arguments emphasize the combination of claimed metabolites as being non-conventional. In response, Applicant has not articulated any technical reason why quantifying a group of metabolites, as claimed, must be different from quantifying each of the metabolites separately. The scope of the claim does not require that a single aliquot of the blood sample, having a particular volume, is used to quantify all of the group of metabolites in a single analytical run. Furthermore, the scope of the claim does not require that a single analytical technique is used to quantify all of the group of metabolites. Instead, the scope of the claim permits any conventional analytical technique be used to quantify each of the group of metabolites, and the scope of the claim permits combinations of different analytical techniques to be used for the quantifying step.
The following prior art mentioned in the non-final office action disclose quantifying metabolites of the claimed group of metabolites:
Bahado-Singh (US 2017/0003291; previously cited) discloses quantifying a group of metabolites in the blood sample, the group of metabolites comprising: (a) β-hydroxybutyric acid (3-hydroxybutyric acid, Table 4, page 12); (b) PC ae C40:6 (Table 5, page 14); and (c1) LysoPC 20:3 (Table 5, page 13), and (c2) citric acid (Table 4, page 12) and carnitine (Table 4, page 12).
Holcapek (US 2020/0363419; previously cited) discloses quantifying a group of metabolites in the blood sample, the group of metabolites comprising: (b) PC ae C40:6 (PC O-40:6, Table 3, where "PC O-" is equivalent to PC alkyl-acyl, Table 1) and (c1) LysoPC 20:3 (LPC 20:3, Table 3, where "LPC" is equivalent to LysoPC, Table 1).
Puchades-Carrasco ("Serum metabolomic profiling facilitates the non-invasive identification of metabolic biomarkers associated with the onset and progression of non-small cell lung cancer," Oncotarget. 2016; previously cited) discloses quantifying a group of metabolites in the blood sample, the group of metabolites comprising:(a) β-hydroxybutyric acid (3-hydroxybutyrate, Table 1B); and (c2) citric acid (citrate, Table 1B).
Conclusion
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHELLE ADAMS whose telephone number is (571)270-5043. The examiner can normally be reached M, T, Th, and F, 12-4 P.M.
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/MICHELLE ADAMS/ Examiner, Art Unit 1797
/JENNIFER WECKER/Primary Examiner, Art Unit 1797
