DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. 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
2. Applicant’s election without traverse of Group IX (claim 44) in the reply filed on June 30, 2026 is acknowledged. Applicant’s election in the reply of June 30, 2026 of “the first 50 gene regions in Table PGI” as the species for examination is also acknowledged.
Applicant states in the response that claims 44-48 and 62-65 read on the elected invention and species. This is not entirely correct because claims 45 and 46 are drawn to non-elected species (i.e., different (larger) combinations of gene regions compared to the elected species 50 gene regions). Thus, claims 44, 47-48, and 62-65 read on the elected invention and species.
Claims 43, 45, 46, and 49-58 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (claims 43 and 49-58) or a nonelected species (claims 45 and 46), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on June 30, 2026.
Priority
3. The effective filing date of the claims under examination, considered with respect to the species election is August 17, 2021.
Information Disclosure Statement
4. Applicant’s submission of an Information Disclosure Statement on November 14, 2025 and June 17, 2026 is acknowledged. All of the cited references have been considered.
Drawings
5. The drawings filed on February 15, 2024 are acceptable.
Specification
6. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see para. 390 on page 161). 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.
Claim Interpretation
7. The specification contains explicit (i.e., limiting) definitions for several terms used in the claims under examination. These definitions include the following:
(i) gastrointestinal cancer or GI cancer = malignant conditions of the gastrointestinal tract (GI tract) and accessory organs of digestion, including the esophagus, stomach, biliary system, pancreas, small intestine, large intestine, rectum and anus (para. 40, page 6). This paragraph also includes hepatocellular carcinoma as an example of a GI cancer.
(ii) patient or subject = refers to a living organism suffering from or prone to a disease (i.e., cancer) that can be treated as described herein (para. 50, page 8). This paragraph gives human and non-human examples of patients/subjects.
(iii) healthy patient = patient who does not have cancer (para. 51, page 8).
(iv) standard control = the detected levels of DNA methylation in a biological sample from a subject not suffering from cancer or the detected levels of DNA methylation in a biological sample from healthy tissue (i.e., tissue that does not have cancerous cells) (para. 51, pages 8-9).
(v) gene region = any portion of a full length gene, including non-coding regions (para. 64, page 13).
Claim Objections
8. Claim 47 is objected to because of the following informality. Inserting the word “a” before “gastrointestinal cancer” in line 2 is suggested to improve consistency with claim 44. As well, deleting “wherein: (i)” is suggested.
Claim 48 is objected to because “comprise” in line 2 should be replaced with “comprises.”
Claim 62 is objected to because the hyphen after “free” in line 2 should be deleted.
Claim 65 is objected to because the word “cancer” should be inserted after “esophageal” to maintain consistency within the claim.
Claim Rejections - 35 USC § 101
9. 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 44, 47-48, and 62-65 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more.
Claim 44
Claim 44 is drawn to a method for detecting an increased level of DNA methylation in a patient at risk of developing a cancer, wherein the method comprises detecting an increased level of methylation at CpG sites relative to a standard control within a plurality of gene regions in a DNA sample from the patient. As noted above, Applicant has elected “gastrointestinal cancer” and “the first 50 gene regions in Table PGI” for examination.
Claim 44 recites two judicial exceptions. First, the claim recites a correlation between increased DNA methylation levels in the aforementioned gene regions and the presence or increased risk of developing a gastrointestinal cancer, which is a natural law. Second, the claim also recites an abstract idea since “detecting an increased level of methylation of CpG sites relative to a standard control” encompasses a mental step and/or mathematical calculation of comparing results obtained for a patient sample with a standard control. Thus, the claims are directed to judicial exceptions.
The judicial exceptions in claim 44 are not integrated into a practical application because the claim does not require using them in any sort of practical application (e.g., to treat a subject). Instead, the claim only recites the judicial exceptions.
Claim 44 also does not include additional elements that are sufficient to amount to significantly more than the judicial exception because nothing is required by the claim in addition to the judicial exception. As noted above, the “detecting” step encompasses a mental step and/or mathematical calculation and does not require performing any type of laboratory step (e.g., nucleic acid amplification or sequencing). And, even if “detecting” was construed to require a “wet lab” measurement step, the step is recited at such a high degree of generality as to be a mere instruction to apply the judicial exception.
Thus, claim 44 is rejected under 35 U.S.C. 101 as being directed to ineligible subject matter.
Claims 47, 48, and 62-65
Each of these claims depends directly or indirectly from claim 44.
Claim 47 depends from claim 44 and requires the cancer to be a gastrointestinal cancer.
Claim 48 depends from claim 47 and requires the plurality of gene regions to comprise the first 50 gene regions in Table PGI.
Claim 62 depends from claim 44 and requires at least 50% of the DNA in the DNA sample to be cell-free DNA.
Claim 63 depends from claim 62 and requires the cell-free DNA to be from plasma.
Claim 64 depends from claim 44 and requires the standard control to be a patient or population of patients that do not have cancer.
Claim 65 depends from claim 44 and requires the gastrointestinal cancer to be colorectal cancer, liver cancer, esophageal cancer, or pancreatic cancer.
Claims 47, 48, and 62-65 each recite two judicial exceptions for the same reason as claim 44. More specifically, the correlation between the measured DNA methylation levels and the presence of or risk of developing a gastrointestinal cancer is a natural law, and the “detecting” step in claim 44 encompasses at least one abstract idea (mental step and/or mathematical calculation).
Claims 47, 48, and 62-65 are not integrated into a practical application for the same reasons set forth above with respect to claim 44. That is, the claims do not use the judicial exceptions to perform any useful application (e.g., treating a subject). As well, claims 47, 48, and 62-65 do not contain any elements that would cause them to amount to significantly more than the judicial exception since they only further define the judicial exception in various ways. And more specifically, claims 47 and 48 only further define the judicial exception by reciting the elected invention (claim 47) or the elected species (claim 48). Claims 62-64 further define the judicial exception by limiting the sample type (claims 62 and 63) or the features of the standard control (claim 64). Claim 65 only further defines the judicial exception by limiting the types of gastrointestinal cancer.
Thus, claims 47, 48, and 62-65 are also rejected under 35 U.S.C. 101 as being directed to ineligible subject matter.
Claim Rejections - 35 USC § 112
10. 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.
Claims 44, 47, 48, and 62-65 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph because the specification fails to enable the full scope of the claimed methods.
As discussed in greater detail below, the specification enables a method in which the method of claim 44, considered in view of the species election, is practiced using cell-free DNA from a human plasma sample to detect an increased level of methylation at CpG sites in a human subject at risk of having an early-stage gastrointestinal cancer selected from colorectal cancer, hepatocellular carcinoma (HCC), esophageal squamous cell carcinoma (ESCC), gastric cancer, esophageal adenocarcinoma (EAC), and pancreatic ductal adenocarcinoma (PDAC).
The instant claims, even considered in view of the species election, are much broader, though, encompassing non-human subjects as well as human and non-human subjects at risk of having any stage of any gastrointestinal cancer. Also, with the exception of claim 63, the claims do not require analysis of cell-free DNA obtained from plasma and encompass the use of other bodily fluid samples (e.g., urine) as well as tissue samples. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use these broader aspects of the claimed 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
The instant claims are drawn to a method for detecting an increased level of DNA methylation in a patient at risk of developing a cancer, wherein the method comprises detecting an increased level of methylation at CpG sites relative to a standard control within a plurality of gene regions in a DNA sample from the patient. As noted above, Applicant has elected “gastrointestinal cancer” and “the first 50 gene regions in Table PGI” for examination.
The claimed invention is classified in the unpredictable arts of molecular biology and biochemistry.
Relative Skill of the Ordinary Artisan
The ordinary artisan typically holds a graduate degree and has at least several years of post-graduate laboratory and/or clinical experience.
Breadth of the Claims
Several aspects of the claims are very broad. First, the subject is not limited and encompasses human and non-human subjects (see also para. 50 on page 8 of the specification, where the term “subject” is defined as including human and non-human subjects). As well, with the exception of claims 62 and 63, which respectively require at least 50% of the DNA in the sample to be cell-free DNA and for the cell-free DNA to be from plasma, the sample type is unlimited. Lastly, the claims are not limited as to the stage of the gastrointestinal cancer and encompass detecting the risk of having an early or late-stage gastrointestinal cancer, wherein the gastrointestinal cancer may be hepatocellular carcinoma or any malignant condition of the gastrointestinal tract (GI tract) and accessory organs of digestion, including the esophagus, stomach, biliary system, pancreas, small intestine, large intestine, rectum and anus (para. 40, page 6).
State of the Prior Art
The prior art discloses methods for measuring CpG methylation levels in DNA samples, including cell-free DNA obtained from plasma samples, that have been obtained from subjects having or at risk of developing a gastrointestinal cancer. See, e.g., Moss et al. (Nature Communications 2018; 9: 5068; IDS reference) at the abstract, Figure 1, Figure 7, and pages 3 and 6-7. See also Qin et al. (Clinical Cancer Research 2019; 25: 7396-7404; IDS reference) at the abstract, Figure 1, and pages 4-6; Shen et al. (Nature 2018; 563: 579-583 + Extended Data; IDS reference) at the abstract and Figures 2-4; and Liu et al. (Science Translational Medicine 2020; 12: eaax7533; IDS reference) at the abstract, Figure 1, and pages 2-5.
The prior art does not teach or suggest using the elected combination of gene regions (i.e., the first 50 regions in Table PGI) to detect the risk of having a gastrointestinal cancer.
Guidance Presented in the Application & Working Examples
The specification contains guidance relevant to the claimed methods. First, consistent with the “State of the Prior Art” above, the specification states that “Methods for extracting DNA for a cell-free sample of blood, plasma, or serum to obtain cell-free DNA are known in the art” (page 14, para. 68).
Second, the working examples, which begin on page 155 and extend to the end of the specification, are relevant to the claimed methods. Here, the specification describes development of a “pan-gastrointestinal” (panGI) assay comprising a panel of CpG sites useful for detecting the presence of any of a plurality of gastrointestinal cancers (see, especially, paras. 371-372, 376, 380-382, and 386-388; see paras. 390-399 for more specific method details).
The teachings in the examples are limited relative to the breadth of the claims in several ways. First, the examples only describes results obtained in human subjects. It is not clear that the results will extend to any of the many non-human subjects encompassed by the claims. Second, although Figure 3 shows correlation between tissue and plasma samples, it is not clear that any of the many other samples encompassed by the claims will show the same relationship. Third, the example contains results for six gastrointestinal cancers (HCC, ESCC, EAC, GC, PDAC, and CRC), but the claims more broadly encompass additional gastrointestinal cancers. It is not clear that the results will extend to all gastrointestinal cancers encompassed by the claims. Fourth, the results describe early-stage detection (para. 379), but the claims more broadly encompass any stage of gastrointestinal cancer. It is not clear that the results will extend to assessing the risk of having a late-stage gastrointestinal cancer.
Thus, although the specification provides some guidance as to the claimed methods, the claimed methods are much broader, and it is not clear that the results presented in the disclosure will extend over the full scope of the claims.
Quantity of Experimentation & Unpredictability
In view of the limitations in the specification and prior art, the ordinary artisan would have to conduct a large quantity of highly unpredictable experimentation to enable practice of the claimed methods. In particular, the ordinary artisan would have to determine that the elected set of gene regions is capable of being used to detect increased DNA methylation levels indicative of an increased risk of having any stage of any gastrointestinal cancer irrespective of the sample type (i.e., in tissue samples and other bodily fluid samples) and type of subject (i.e., human or non-human subjects). This experimentation would be highly unpredictable, especially with nonhuman subjects, given the differences in physiology between species. As well, different samples may not contain any or all of the required nucleic acids, which would preclude use of the elected set of gene regions for those samples. And, results obtained for one sample or type of nonhuman subject may not extend to any other sample or nonhuman subject. Still further, it is not clear that the results observed for early-stage cancers would extend to late-stage cancers, particularly since altered methylation can differ between early and late-stage patients. See, e.g., Gao et al. (Carcinogenesis 2008; 29: 1901-1910) at pages 1901 and 1908-1909 as well as Kupcinskaite-Noreikiene et al. (BMC Cancer 2016; 16: 40) at the abstract and pages 4 and 6-7. Lastly, it is not clear that the results presented in the application would extend to gastrointestinal cancers other than colorectal cancer, gastric cancer, HCC, PDAC, ESCC, and EAC since each different type of gastrointestinal cancer has a different etiology and progression.
The ordinary artisan would have to conduct the required experimentation with minimal guidance from the specification and would have no guarantee of success. The post-filing art of Kandimalla et al. (Clinical Cancer Research 2021; 27: 6135-6144) also supports the conclusion that the full scope of the claims is not enabled. This post-filing art reference, which includes the inventors of the instant application as authors, describes a “pan-GI assay” that uses DNA methylation levels measured in cell-free DNA obtained from human plasma samples to detect the presence of early-stage gastrointestinal cancers (abstract, Figure 1, and pages 6136-6137) and does not teach or suggest that the disclosed methods are capable of being used as broadly as recited in the instant claims.
Thus, it is clear that a very large amount of complex and highly unpredictable experimentation would be required to practice the full scope of the claimed methods, and claims 44, 47, 48, and 62-65 are rejected for failing to comply with the enablement requirement.
Claim Rejections - 35 USC § 112
11. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 44, 47, 48, and 62-65 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.
Claims 44 and 48 are indefinite because they make reference to a table in the specification. As discussed in MPEP 2173.05(s), “Incorporation by reference to a specific figure or table ‘is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference rather than duplicating a drawing or table into the claim.” In this case, the invention can be defined in words and need not incorporate the table by reference.
Claims 47 and 62-65 are also indefinite since they depend from claim 44 and do not correct its indefiniteness issue.
Conclusion
12. No claims are currently allowable. The elected species is free of the prior art, but the claims have been rejected for other reasons.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Angela Bertagna whose telephone number is (571)272-8291. The examiner can normally be reached 8-5, M-F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gary Benzion can be reached at 571-272-0782. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ANGELA M. BERTAGNA/Primary Examiner, Art Unit 1681
