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 . Applicant’s preliminary amendment filed 11/17/2023 is acknowledged. Claims 1, 2, 3, 4, 12, 14, 15, 16, 17, 23, 25 and 26 have been amended. Claims 5-9, 11, 27 and 28 have been canceled. Claims 1-4, 10, 12-26 are pending and under examination.
Priority
This application is a 371 of PCT/CN2021/094016 filed 05/17/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/9/2024 and 11/17/2023 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
List of References in Specification
The Examiner notes that an information disclosure statement filed under the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 have been submitted with this application. It appears that Applicant has also cited a list of references in the specification at pages 19-21. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, applications, or other information submitted for consideration by the Office, and MPEP 609.04(a), subsection I, states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are objected to because the x-axes legends in Figures 2 and 4 read “100-specificity %”. Since the x-axes are labeled from 0-100%, it is not clear what the legends refer to or description in the specification at pages 4 and 5. Corrected drawing sheets in compliance with 37 CFR 1.121(d), or amendment to the specification to clarify the reference character(s) in the description in compliance with 37 CFR 1.121(b) 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. 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 1-4, 10, 12-26 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a law of nature (a natural correlation between the methylation biomarker and size of lung nodule), and the presence of lung cancer [NSCLC]) without significantly more. The claim(s) recite(s) predicting lung cancer based on the presence of the methylation marker biomarkers wherein the methylation markers genes are selected from or are PTGERA, RASSF1A and SHOX2. The claim(s) also recite kit comprising agents for detecting methylation levels of multiple methylation biomarker genes PTGER4, RASSf1A and SHOx3 wherein the agents are methylation specific primer pairs (natural phenomenon) for the genes and instructions for use.
These judicial exceptions are not integrated into a practical application because the additional elements of performing methylation-base amplification using methylation specific primer pairs, obtaining diameter size, using training coherts, using logistic regression modules and “calculating a probability” as well as instructions are data gather steps involving well-known methodologies and mathematical concepts as well as abstract ideas required to use the natural correlation or natural product.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because “general data gather steps” and “calculating a probability” were well-understood, routine and conventional steps known in the field of medical diagnostics.
The analysis of patent claims for eligibility under 35 USC 101 is discussed in MPEP 2106 (illustrated in a flowchart) and 2106.03-2106.05.
Step 1 of the analysis is to determine whether a claim is directed to a statutory category of invention (MPEP 2106.03(II)). In this case, the claims are directed to processes. Therefore, step 1 is satisfied.
Step 2A of the analysis is to determine whether a claim is directed to a judicial exception (MPEP 2106.04). Step 2A is divided into two prongs (MPEP 2106.04(II)(A)). The first prong is to determine whether the claim recites an abstract idea, law of nature or natural phenomenon, i.e. whether an abstract idea, law of nature or natural phenomenon is set forth or described in the claim. Here, the claims set forth the natural correlation and natural phenomenon that exists between the presence of methylation biomarkers in a plasma sample, the levels of the methylation biomarkers PTGER4, RASSF1A and SHOX in in a plasma sample, the size of the pulmonary nodule, and the presence of lung cancer along with a prediction models based on mathematical calculations.
Therefore, the claims are directed to a law of nature (a natural correlation; see examples of laws of nature identified by the courts at MPEP 2106.04(b)(I)) and abstract ideas based on Mathematical calculations (see MPEP 2106.04(a)(2).
The second prong of step 2A is to determine whether the claims recite additional elements that integrate the judicial exception into a practical application. MPEP 2106.04(d) discusses relevant considerations to take into account when determining whether any additionally recited steps, alone or in combination, integrate the judicial exception into a practical application. Here, the additionally-recited elements are data gathering steps using methylation specific primers (which are based on naturally occurring products (using results of quantitative RT-PCR (claims 13, 14, 25) measuring size of pulmonary nodules using CT and LDCT (claims 18 and 19), assessing prediction molecules using a training cohort, (including logistic regression model (claims 20 and 21) calculating prediction model using a probability calculation (claim 23) and limiting methylation primer pairs to SEQ ID NOS: 4-5, 8-9, 12-13, 20-21, and 24-25) (14 and 25).
These additional elements do not integrate the judicial exception into a practical application for the following reasons:
These data gather steps of obtaining results using q-PCR and CT-derived diameters sized and LDCT-derived diameter size and well as performing mathematical calculations for predictions modules represent insignificant extra-solution activity required to use the natural correlation between the biomarker levels, nodule size and the presence or absence of NSCLC (MPEP 2106.05(g)). Obtaining results and calculating a probability constitute insignificant extra-solution activity as they were well-known (as discussed further below), and represent necessary data gathering and analysis steps for using the natural correlation.
Determining the size of pulmonary nodules and limiting the nodule to a particular type of carcinoma represent nothing more than limiting the application of the natural correlation to a particular field of use (MPEP 2106.05(h)). Limitations that amount to merely indicating a field of use or technological environment in which to apply a judicial exception do not amount to significantly more than the exception itself, and cannot integrate a judicial exception into a practical application.
The next step of the analysis, step 2B, is to determine whether the claims amount to significantly more than the judicial exception itself (MPEP 2106.05). The additional steps as noted above describe conventional steps of obtaining methylation level data and nodule size, which are then analyzed in the next step of the method using general computer algorithms and software to perform mathematical calculations. This further step is directed to an abstract idea of data analysis. As stated by MPEP 2106.04(a)(2)III and MPEP 2106.04(a)(2) III A:
“In Electric Power Group, the Federal Circuit explained that concepts of collecting and analyzing information fall within the “realm of abstract ideas” because information is intangible:
Information as such is an intangible. See Microsoft Corp. v. AT & T Corp., 550 U.S. 437, 451 n.12 (2007); Bayer AG v. Housey Pharm., Inc., 340 F.3d 1367, 1372 (Fed. Cir. 2003). Accordingly, we have treated collecting information, including when limited to particular content (which does not change its character as information), as within the realm of abstract ideas. See, e.g., Internet Patents, 790 F.3d at 1349; OIP Techs., Inc. v. Amazon.com, Inc., 788 F.3d 1359, 1363 (Fed. Cir. 2015); Content Extraction & Transmission LLC v. Wells Fargo Bank, Nat’l Ass’n, 776 F.3d 1343, 1347 (Fed. Cir. 2014); Digitech Image Techs., LLC v. Elecs. for Imaging, Inc., 758 F.3d 1344, 1351 (Fed. Cir. 2014); CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 1370 (Fed. Cir. 2011). In a similar vein, we have treated analyzing information by steps people go through in their minds, or by mathematical algorithms, without more, as essentially mental processes within the abstract-idea category. See, e.g., TLI Commc’ns, 823 F.3d at 613; Digitech, 758 F.3d at 1351; SmartGene, Inc. v. Advanced Biological Labs., SA, 555 F. App’x 950, 955 (Fed. Cir. 2014); Bancorp Servs., L.L.C. v. Sun Life Assurance Co. of Canada (U.S.),687 F.3d 1266, 1278 (Fed. Cir. 2012); CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 1372 (Fed. Cir. 2011); SiRF Tech., Inc. v. Int’l Trade Comm’n, 601 F.3d 1319, 1333 (Fed. Cir. 2010); see also Mayo, 132 S. Ct. at 1301; Parker v. Flook, 437 U.S. 584, 589–90 (1978); Gottschalk v. Benson, 409 U.S. 63, 67 (1972). And we have recognized that merely presenting the results of abstract processes of collecting and analyzing information, without more (such as identifying a particular tool for presentation), is abstract as an ancillary part of such collection and analysis. See, e.g., Content Extraction, 776 F.3d at 1347; Ultramercial, Inc. v. Hulu, LLC, 772 F.3d 709, 715 (Fed. Cir. 2014). Electric Power Group, LLC v. Alstom, S.A., 830 F.3d 1350, 1353-54, 119 USPQ2d 1739, 1741-42 (Fed. Cir. 2016).”
“Another example is University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 113 USPQ2d 1241 (Fed. Cir. 2014). The patentee in Ambry Genetics claimed methods of screening a human’s genome for an altered BRCA gene, comprising comparing the sequence of the human’s BRCA gene with the sequence of the wild-type gene, and identifying any differences that arise. 774 F.3d at 763-764, 113 USPQ2d at 1246. The Federal Circuit determined that these claims were directed to the concept of “comparing BRCA sequences and determining the existence of alterations”, which was an “abstract mental process”. Id.”
“Other examples of this type of concept include:
i. collecting and comparing known information, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1067, 100 USPQ2d 1492, 1500 (Fed. Cir. 2011); and
ii. diagnosing an abnormal condition by performing clinical tests and analyzing the results, In re Grams, 888 F.2d 835, 840, 12 USPQ2d 1824, 1828 (Fed. Cir. 1989); see CyberSource, 654 F.3d at 1372 n.2, 99 USPQ2d at 1695 n.2 (describing the abstract idea in Grams).”
The next question to ask is whether the claims include an inventive concept, which amounts to “significantly more” and therefore make the claims patent-eligible under 35 U.S.C. 101. As stated in MPEP 2106.05 IA:
“Limitations that the courts have found to qualify as “significantly more” when recited in a claim with a judicial exception include:
i. Improvements to the functioning of a computer, e.g., a modification of conventional Internet hyperlink protocol to dynamically produce a dual-source hybrid webpage, as discussed in DDR Holdings, LLC v. Hotels.com, L.P., 773 F.3d 1245, 1258-59, 113 USPQ2d 1097, 1106-07 (Fed. Cir. 2014) (see MPEP § 2106.05(a));
ii. Improvements to any other technology or technical field, e.g., a modification of conventional rubber-molding processes to utilize a thermocouple inside the mold to constantly monitor the temperature and thus reduce under- and over-curing problems common in the art, as discussed in Diamond v. Diehr, 450 U.S. 175, 191-92, 209 USPQ 1, 10 (1981) (see MPEP § 2106.05(a));
iii. Applying the judicial exception with, or by use of, a particular machine, e.g., a Fourdrinier machine (which is understood in the art to have a specific structure comprising a headbox, a paper-making wire, and a series of rolls) that is arranged in a particular way to optimize the speed of the machine while maintaining quality of the formed paper web, as discussed in Eibel Process Co. v. Minn. & Ont. Paper Co., 261 U.S. 45, 64-65 (1923) (see MPEP § 2106.05(b));
iv. Effecting a transformation or reduction of a particular article to a different state or thing, e.g., a process that transforms raw, uncured synthetic rubber into precision-molded synthetic rubber products, as discussed in Diehr, 450 U.S. at 184, 209 USPQ at 21 (see MPEP § 2106.05(c));
v. Adding a specific limitation other than what is well-understood, routine, conventional activity in the field, or adding unconventional steps that confine the claim to a particular useful application, e.g., a non-conventional and non-generic arrangement of various computer components for filtering Internet content, as discussed in BASCOM Global Internet v. AT&T Mobility LLC, 827 F.3d 1341, 1350-51, 119 USPQ2d 1236, 1243 (Fed. Cir. 2016) (see MPEP § 2106.05(d)); or
vi. Other meaningful limitations beyond generally linking the use of the judicial exception to a particular technological environment, e.g., an immunization step that integrates an abstract idea of data comparison into a specific process of immunizing that lowers the risk that immunized patients will later develop chronic immune-mediated diseases, as discussed in Classen Immunotherapies Inc. v. Biogen IDEC, 659 F.3d 1057, 1066-68, 100 USPQ2d 1492, 1499-1502 (Fed. Cir. 2011) (see MPEP § 2106.05(e)).”
Upon review of the above conditions, Applicant’s claims do not present any steps that amount to “significantly more” than the judicial exception, since the steps of obtaining a biological sample and determining methylation level of genes are data gathering steps were well-known, conventional and routine in the art. As stated by MPEP 2106.05(d) II:
“The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
i. Determining the level of a biomarker in blood by any means, 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);
ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
iii. Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
iv. Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
v. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
vi. Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
vii. Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics,774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.”
Therefore, considering the MPEP guidance and court cases, the judicial exceptions are not integrated into a practical application because the recited steps of lung cancer diagnosis were well known, routine and conventional in the art as evidence by Applicant’s own specification at page 2 which teaches that the methylation of the biomarkers PTGER4, RASSF1A and SHOX2, have been separately identified as valuable biomarkers for lung cancer diagnoses in several research studies and cites the following citations as evidence at page 20 (citations 9-12 of specification, respectively):
Weiss G, Schlegel A, Kottwitz D, K6nig T, Tetzner R. Validation of the SHOX2/PTGER4 DNA methylation marker panel for plasma-based discrimination between patients with malignant and nonmalignant lung disease. J Thorac Oncol. 2017;12(1):77-84.
Zhang C, Yu W, Wang L, et al. DNA Methylation Analysis of the SHOX2 and RASSFlA Panel in Bronchoalveolar Lavage Fluid for Lung Cancer Diagnosis. J Cancer. 2017;8(17):3585-91. Published 2017 Sep 30.
Kneip C, Schmidt B, Seegebarth A, et al. SHOX2 DNA methylation is a biomarker for the diagnosis of lung cancer in plasma. J Thorac Oncol. 2011;6(10):1632-8.
Hu H, Zhou Y, Zhang M, Ding R. Prognostic value of RASSFlA methylation status in non-small cell lung cancer (NSCLC) patients: a meta-analysis of prospective studies. Biomarkers. 2019;24(3):207-16.
Further machine models for analyzing cancers, including lung cancers are also well-known and conventional in the art as evidence by Shippe et al (Journal of Thoracic Disease, 2019; 11 (supplemental 4): S574-S584). For the reasons discussed above, claims 1-4, 10, 12-26 are found to be patent-ineligible subject matter under 35 USC 101.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-4, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 23, 24 and 26 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Xing et al., (BMC Cancer, 21:263, 1-11, March 10, 2021). Regarding claim 1-4, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 23, 24 and 26, Xing et al teach a method of predicting and identifying lung cancer in a subject, the method comprising assessing three DNY methylation biomarkers (PTGER4, RASSF1A and SHOX2) and clinically-relevant variables in a training cohort of 110 individuals with pulmonary nodules (PN). Four machine-learning-based prediction models were established and compared, including the K-nearest neighbors, random forest, support vector machine and logistic regression algorithms (Abstract,). Xing et al teaches nodule radiographic characteristic comprised of maximum traverse size, location and nodule type. Xing teaches detecting pulmonary nodules on CT scans and LDCT-derived nodule diameter between 4 and 35 mm. The radiologic characteristics of PN were obtained from the radiology report, documentation provided by an attending pulmonologist or thoracic surgeon and by review of imaging by the research team (see section entitled “patient cohorts and study design”). Xing et al teach DNA methylation analysis using real-time PCR (see “DNA methylation analysis”). Xing teaches statistical analysis using training cohorts and machine learning approaches, including logistic regression (see pages 4-9). Thus, Xing meets the limitations of the claims recited above.
Conclusion
No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CYNTHIA B WILDER whose telephone number is (571)272-0791. The examiner can normally be reached Flexible.
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/CYNTHIA B WILDER/Primary Examiner, Art Unit 1681