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 .
Claim Amendment
2. The amendment filed May 21, 2026 has been entered. Claims 1, 6, 9, 18, 24, and 24 have been amended. Clams 26 and 28 were withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions. Claims 2, 5, 7, 10-11, 13-17, 20-21, 23, 25, 27, and 29-52 have been cancelled.
Information Disclosure Statement
3. The information disclosure statement (IDS) submitted on May 21, 2026 were filed. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawal of Claim Rejections
4. The rejection of claims 1, 4, 6, 12, and 18 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in view of applicants amendments and arguments.
5. The rejection of claims 1, 3-4, 6, 8-9, 12, 18-19, 22 and 24 under 35 U.S.C. 102(a)(1) and/or (a)(2) as being anticipated by Allen et al., is withdrawn in view of applicants amendments and arguments.
Maintained Claim Objections
6. Claims 1 and 18-19 are objected to because of the following informalities:
With regard to claims 1 and 18, abbreviations like CNA, WAS, SNV, APC, BCOR, PIK3R1 and all the other abbreviations must be spelled out when used for the first time in a chain of claims.
With regard to claim 19, abbreviations like PD-1, PD-L1, PD-L2, TIM-3, LAG-3, CTLA-4 and other abbreviations must be spelled out when used for the first time in a chain of claims. Appropriate correction is required.
Response to Arguments
7. Applicant's arguments filed May 21, 2026 have been fully considered but they are not persuasive. Applicants response is that the abbreviations has been spelled out. However, claims 18 and 19 have not been amended. Therefore, the claim objection is maintained.
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.
8. Claims 1, 3, 6, 9, 12, 18-19, 22 and 24 are rejected under 35 U.S.C. 101 because: The claimed invention is directed to a method of identifying a likelihood of development of immune-related adverse events (irAE) in a subject due to receive immune checkpoint therapy, without significantly more. The claims recite a process. This judicial exception is not integrated into a practical application because the claimed invention is directed to a judicial exception (i.e., a process, machine manufacture or composition of matter). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because do not add significantly more to the judicial exception.
The claimed invention is directed to a judicial exception and/or natural phenomenon without significantly more. The claims recite methods of identifying a likelihood of development of immune-related adverse events (irAE) in a subject due to receive immune checkpoint therapy comprising a obtaining step, determining step wherein the presence of the at least one germline biomarker in the subject sample identifies the development of irAE due to immune checkpoint therapy as being more likely and wherein the absence of the at least one germline biomarker in the subject sample identifies the development of irAE due to immune checkpoint therapy as being less likely,and recommending, prescribing or administering the immune checkpoint therapy if the development of irAE due to immune checkpoint therapy is determined to be less likely or recommending, prescribing or administering an anti-cancer therapy other than the immune checkpoint therapy if the development of irAE due to immune checkpoint therapy is determined to be more likely.
This judicial exception is not integrated into a practical application because gathering information or recommending, prescribing or administering IL7 and/or IL22RA1 levels of candidate cancer biomarkers in a biological sample from a subject having cancer required to use the correlation do not add a meaningful limitation to the method as they are insignificant extra-solution activity. The claims does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because it does not recite something significantly different than a judicial exception. The rationale for this determination is explained below:
The analysis as set forth in the 2019 Guidance is as follows:
Step 1: Yes, claims are drawn to a method which is one of the four statutory categories, a process.
Step 2A, prong 1: Yes, the claims recite/describe/set forth a judicial exception. The claims describe the relationship between the level of determining at least one germline being present in a subject’s sample. Furthermore, comprising recommending, prescribing, or administering the immune checkpoint therapy if the development of irAE due to immune checkpoint therapy is determined to be less likely or administering an anti-cancer therapy other than the immune checkpoint therapy if the development of irAE due to immune checkpoint therapy is determined to be more likely. In the instant case, the rejected claims recite a mental step (comparing the amount of the biomarker to a control and assessing absence or presence of biomarker. The claims indicate a natural correlation between specific levels of biomarker and the absence or presence of the biomarker with respect to the likelihood of an irAE. The claim is then analyzed to determine whether it is directed to any judicial exception. The claims do not recites diagnosing the subject with any symptoms, determining onset, determining affected organs, frequency or severity based upon the presence or absence of a single biomarker. There is no correlation or relationship between the presence of biomarkers and the amount of biomarkers. There is no treatment intervention. This additional step does not constitute an improvement in the technology because the regimens that were known in the art at the time of filing and are not novel treatments.
Step 2A, prong 2: No, the judicial exception is not integrated into a practical application. The claims do not rely on or use the exception here. None of the rejected claims appear to recite an additional element or elements that integrate the judicial exception (i.e. the mental step recited as the last step of the claims) into a practical application of the mental step. For example, the prior steps recited in each of the rejected claims appear to be nothing more than data gathering activity that is used to provide a basis for the mental process recited in the final step of each claim. There are no additional steps recited in any of the rejected claims that integrate the mental process recited in the final step of the claims to a practical application of the judicial exception. Additionally, the claimed steps could be performed by a human using mental steps or basic critical thinking, which are types of activities that have been found by the courts to represent abstract ideas (e.g., the mental comparison in University of Utah Research Foundation v. Ambry Genetics Corp., 774 F.3d 755 (Fed. Cir. 2014) or the diagnosing an abnormal condition by performing clinical tests and thinking about the results in Grams). Thus, the claim is directed to at least one exception (Step 2A: YES), which may be termed a law of nature, an abstract idea, or both. Note that although the claim recites several nature-based product limitations (e.g., the biological sample and biomarkers), the claim as a whole is focused on a process determining the presence of biomarkers, and is not focused on the products per se. Thus, there is no need to perform the markedly different characteristics analysis on the recited nature-based product limitations. Therefore, the answer to Question 2A-Prong II is “No”. Once the level of the IL7 and/or IL22RA1 is detected by conventional and art known means, there are no additional elements or combination of additional elements to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception.
Question #2B: Does the claim recite additional elements that amount to significantly more than the judicial exception? No, there is no inventive concept present in the clams. The steps of determining the presence of biomarker in a sample is established by well understood, routine conventional methods, as well as rendering therapeutic treatment and in addition they are pre-solution activity, i.e. data gathering necessary to perform the correlation. The following claims and steps inform one of ordinary skilled in the art the presence of biomarkers and aids in determining the likelihood of irAE. Each of the rejected claims recites data-gathering steps that are well-understood, routine and conventional in the art as well as the judicial exception. Besides the law of nature, the claim does not recite additional steps. No other additional elements are recited in the rejected claims. Obtaining a sample in order to perform tests is well-understood, routine and conventional activity for those in the field of diagnostics. Further, the steps are recited at a high level of generality such that it amounts to insignificant activity, e.g., a mere data gathering step necessary to use the correlation. Determining the biomarker in the sample merely instructs a scientist to use any detection technique with any generic antibody or other determination technique. When recited at this high level of generality, there is no meaningful limitation, such as a particular or unconventional machine or a transformation of a particular article, in this step that distinguishes it from well-understood, routine, and conventional data gathering activity engaged in by scientists prior to applicant’s invention, and at the time the application was filed, e.g., the routine and conventional techniques of determining the presence of a gene. Such activities are normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such law. Determination of candidate cancer biomarkers and recommending, prescribing or administering individuals with therapeutic regimens have been observed by applicant but not engineered by applicant. The claims do not add significantly more to the natural phenomenon because the claims do not require for example, a novel reagent, novel apparatus, or incorporate a novel treatment based on the correlation.
A claim that focuses on use of a natural principle must also include additional
elements or steps to show that the inventor has practically applied, and added something significant to, the natural principle itself. See Mayo, 101 USPQ2d at 1966. Recited elements such as “recommending” based on the natural principle impose no meaningful limit on the performance of the claimed invention. As set forth the claims do not impose meaningful limits on the performance of the claimed invention. Likewise, as well as equations and formulas based on the natural principle impose no meaningful limit on the performance of the claimed invention. Moreover, the concepts read on an abstract idea and do not recite any specific machine for performing the computational steps.
Furthermore, it is well established that the mere physical or tangible nature of additional elements such as the obtaining and detecting steps does not automatically confer eligibility on a claim directed to an abstract idea (see, e.g., Alice Corp. v. CLS Bank Int’l, 134 S.Ct. 2347, 2358-59 (2014)). Thus, the answer to Question #2B is “No” because none of the rejected claims recite any additional element or elements that make the claim as a whole read on something that is significantly more than the judicial element recited in the claim.
Consideration of the additional elements as a combination also adds no other meaningful limitations to the exception not already present when the elements are considered separately. Unlike the eligible claim in in which the elements limiting the exception are individually conventional, but taken together act in concert to improve a technical field, the claim here does not invoke any of the considerations that courts have identified as providing significantly more than an exception. Even when viewed as a combination, the additional elements fail to transform the exception into a patent-eligible application of that exception. Thus, the claim as a whole does not amount to significantly more than the exception itself. The claim is not eligible. Given the analysis provided above, it is apparent that each of the rejected claims encompasses embodiments that are not directed to statutory subject matter. The claims do not recite additional elements that amount to significantly more than the judicial exception. Accordingly, these claims are not be eligible under step 2A or step 2B. Thus, the technology used by the instant claims is well-known in the art and does not contribute significantly more to the judicial exception. See the 2019 Revised Patent Subject Matter Eligibility Guidance and Federal Register
https://www.federalregister.gov/documents/2019/10/18/2019-22782/october-2019-patent-
eligibility-guidance-update; and FDsys.gov.
Therefore, claims 1, 3-4, 6, 8-9, 12, 18-19, 22 and 24 are rejected under 35 U.S.C. 101 as being directed to ineligible subject matter.
Response to Arguments
9. Applicant's arguments filed May 21, 2026 have been fully considered but they are not persuasive. Despite Applicants amendments, the rejected claims are drawn to a non-statutory method having a "natural principle" as a limiting element or step without reciting additional elements/steps that integrate the natural principle into the claimed invention such that the natural principle is practically applied, and are sufficient to ensure that the claim amounts to significantly more than the natural principle itself. In the instant case, the "natural principle" is: determining whether at least one germline biomarker is present in the subject sample. Additionally, the claim recites the conditional term “if”, it is not clear how the clinician should proceed. The judicial exception is not integrated into a practical application because gathering information required to use the correlation does not add a meaningful limitation to the method as they are insignificant extra-solution activity. The claims do not add significantly more to the natural phenomenon because the claims do not require for example , a novel reagent, novel apparatus or incorporate a novel treatment based on the correlation. The claims do not “practically apply” the natural principle; rather the claims “simply inform” the natural principle to one performing routine active method steps and do not amount to significantly more than the natural principle itself; contrary to Applicants arguments.
Finally, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because assaying for candidate biomarkers does not add significantly more and is not an inventive concept. Because methods for making such determinations were well known in the art, these steps simply tell researchers to engage in well-understood, routine, conventional activity previously engaged in by scientists in the field. Such activities are normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such law.
A claim that focuses on use of a natural principle must also include additional elements or steps to show that the inventor has practically applied, and added something significant to, the natural principle itself. See Mayo, 101 USPQ2d at 1966. Recited elements such as “determining”, “recommending”, “prescribing” and “determining”, based on the natural principle impose no meaningful limit on the performance of the claimed invention. As set forth the claims do not impose meaningful limits on the performance of the claimed invention. Patents cannot be obtained on subject matter identified by the courts as being exempted from eligibility (i.e., laws of nature, natural phenomenon, and abstract ideas). Further, the active method steps are conventional and routine in the art for the reasons stated above and the claims do not amount to significantly more than the recited natural principle. The claims do not "practically apply" the natural principle; rather, the claims "simply inform" the natural principle to one performing routine active method steps and do not amount to significantly more than the natural principle itself. Thus, the technology used by the instant claims is well-known in the art and does not contribute significantly more to the judicial exception. See the 2019 Revised Patent Subject Matter Eligibility Guidance and Federal Register https://www.federalregister.gov/documents/2019/10/18/2019-22782/october-2019-patent-eligibility-guidance-update; and FDsys.gov.
Pertinent Art
10. The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure.
Jia et al., (J Exp Clin Cancer Res 39, 284 (2020) teach immune checkpoint inhibitors (ICIs), an efficient tumor treatment model different from traditional treatment, is based on their unprecedented antitumor effect, but the occurrence of immune-related adverse events (irAEs) is an obstacle to the prospect of ICI treatment. IrAEs are a discrete toxicity caused by the nonspecific activation of the immune system and can affect almost all tissues and organs. Currently, research on biomarkers mainly focuses on the gastrointestinal tract, endocrine system, skin and lung. Several potential hypotheses concentrate on the overactivation of the immune system, excessive release of inflammatory cytokines, elevated levels of pre-existing autoantibodies, and presence of common antigens between tumors and normal tissues. This review lists the current biomarkers that might predict irAEs and their possible mechanisms for both nonspecific and organ-specific biomarkers. However, the prediction of irAEs remains a major clinical challenge to screen and identify patients who are susceptible to irAEs and likely to benefit from ICIs.
Ding et al., studied effective molecular markers to evaluate colon cancer differentiation grade, screening of effective molecular markers for the diagnosis and treatment of colon cancer is of great significance. IL22RA1 gene was derived from the intersection of obtained gene and colon tissue-specific genes. Ding et al., analyzed the expression level of IL22RA1 in various tissue cells, and analyzed the correlation between IL22RA1 and the survival of colon cancer patients, and then used the ROC curve to analyze the specificity and sensitivity of IL22RA1 diagnosis of differentiated colon cancer. Ding et al., found that both RNA and protein levels of IL22RA1 were higher in colon tissues and colon cancer tissues than in other normal and cancer tissues. A comparison of IL22RA1 expression in different cancer cells found that IL22RA1 expression was significantly higher in CACO-2 colon cancer cells than in other cancer cells. Survival analysis showed that IL22RA1 gene expression was positively correlated with the overall survival rate of colon cancer patients (P=0.0224). ROC curve analysis revealed that IL22RA1 expression had good specificity and sensitivity to stage II colon cancer. These findings teach that IL22RA1 serves as a specific molecular marker for the differentiation of colon cancer.
Liudahl et al., (J Clin Invest 2018: 128(2):577-579. Feb 1, 2018) Immune checkpoint inhibitors are becoming a cornerstone of cancer immunotherapy as a result of their clinical success in relieving immune suppression and driving durable antitumor T cell responses in certain subsets of patients. Unfortunately, checkpoint inhibition is also associated with treatment-related toxicities that result in a myriad of side effects, ranging from mild and manageable to severe and debilitating. In this issue of the JCI, Das and colleagues report an association between early therapy-induced changes in circulating B cells and an increased risk of high-grade immune-related adverse events (IRAEs) in patients treated with checkpoint inhibitors that target cytotoxic T lymphocyte–associated antigen-4 (CTLA4) and programmed cell death protein 1 (PD1). These findings identify potential predictive biomarkers for high-grade IRAEs that may be leveraged to improve patient monitoring and may prompt new treatment strategies to prevent IRAEs.
Nakamura et al., (Front. Med., 28 May 2019 Sec. Dermatology Volume 6 – 2019).Teach numerous factors have been reported as potential biomarkers for tumor response to ICIs, factors for predicting irAE have been less reported. In this review, we show recent advances in the understanding of biomarkers for tumor response and occurrence of irAEs in cancer patients treated with ICIs.
Passtoors et al., (IL7R gene expression network associates with human healthy ageing. Immun Ageing 12, 21 (2015). The level of expression of the interleukin 7 receptor gene in blood has recently been found to be associated with familial longevity and healthy ageing. Therefore the mere presence of IL7 would not indicate the increased likelihood of an irAE event.
Gaudino et al., (Nature Comm. 15, Article number:1597(2024). A key role of intestinal epithelium-specific IL-22RA1 signaling in regulating intestinal metabolism and alleviating systemic obesity-associated disorders.
Edman et al., (Otolaryngol Head Neck Surg. 2009 May;140(5):741-7). Stimulation of interleukin-22 receptor alpha-1 (IL22RA1) was reported to increase the innate immune responses in inflammatory diseases. Moreover, a reduced level of IL22RA1 was found in patients with recalcitrant CRS with nasal polyps.
Conclusion
11. No claims allowed.
12. 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.
13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JA-NA A HINES whose telephone number is (571)272-0859. The examiner can normally be reached Monday thru Thursday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor Peter Paras, can be reached on 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JANA A HINES/Primary Examiner, Art Unit 1645
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