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 Status
2. The amendment filed Dec. 4, 2025 has been entered. Claims 2, 5, 7, 10-11, 13-17, 20-21, 23, 25, 27, and 29-52 have been cancelled.
Election/Restrictions
3. Applicant’s election of Group A in the reply filed on Dec. 4, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 26 and 28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on Dec. 4, 2025.
4. Claims 1, 3-4, 6, 8-9, 12, 18-19, 22 and 24 are under consideration in this Office Action.
Information Disclosure Statement
5. The information disclosure statement (IDS) submitted on June 28, 2023, June 4, 2024 and Aug 8, 2024 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.
Claim Rejections - 35 USC § 112
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.
6. Claims 1, 4, 6, 12, and 18 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.
A) Claim 1b recites the limitations “the amount”; “…the at least one germline…”; “..the IL7 gene..”; “..the IL22RA1 gene..." “,,,the likelihood...”; “..the presence…” “..the absence..” in the claim. There is insufficient antecedent basis for this limitation in the claim.
B) It is unclear how to determine the metes and bounds of a “…germline variant near the IL7 gene..”. It is unclear how to define which germlines are near enough to be considered “near” and which are not “near”. It is unclear if “near” is a proximity marker, or if “near” includes biomarkers with specific familial syndrome . It is unclear how “near” a germline variants would be, in order to be deemed “near”. The germline variant near the IL22RA1 gene has the same issue. Thus the claim requires clarification to overcome the rejection.
C) It is unclear how to determine the metes and bounds of a “…germline variant
influencing IL7 splicing…”. The claims fails to recite the criteria necessary to define what and how the influencing will affect the IL7 splicing. It is unclear whether normal post-transcriptional processing is encompassed with the influenced splicing. The metes and bounds to determine whether splicing was influenced solely by the germline SNP or a different factor. It is unclear if the inherited variants in splicing regulatory regions would or would not be deemed as a germline. Thus the claim requires clarification to overcome the rejection.
D) Regarding claim 1, the phrase “…(SNP rsid rs7816685, or SNP rsid rs16906115, or other correlated SNPs),…” and “(SNP rsid rs75824728 or correlated SNPs)’…” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). It is unclear whether the SNPs within the parenthesis are specific examples of germline variants located near the IL7 or IL22RA1 interleukin gene or if Applicant is specifically claiming the SNP rsid rs7816685, SNP rsid rs16906115 or SNP rsid rs75824728. It is also unclear how to determine the metes and bounds of “other correlated SNPs”. It is unclear what the defining characteristics or criteria of an SNP to be deemed as correlated or not. Thus the claim requires clarification to overcome the rejection.
E) A germline biomarker is an inherited genetic alteration present in an individual’s healthy cells (from birth) that acts as an indicator for disease risk, prognosis, or therapeutic response, such as in cancer treatment selection. Therefore, it is unclear how a germline risk score for bladder cancer, for medication use and for blood cell counts is a germline biomarker. A risk score is not an inherited genetic alteration. Therefore it is unclear how a germline biomarker is a risk score. Thus, metes and bounds of the claims 1 and 18 are unclear and clarification is required to overcome the rejection.
F) Regarding claims 1 and 18, the phrase “… medication use (including anti-inflammatory or immunosuppressant medications)..” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). It is unclear whether the medication must include anti-inflammatory or immunosuppressant medications or if the anti-inflammatory or immunosuppressant are examples of possible medications. Therefore, clarification is required to overcome the rejection.
G) Claim 1 recites “…a significantly increased amount…” and “…a significantly decreased amount…” of a germline biomarker; however the metes and bounds of the phrase are unclear. It is unclear how to define what amount of increase or decrease is significant enough to be “significant”.
H) Claims 1 and 18 recite “…the presence” of the at least one germline biomarker; the claim appears to state that even minimal amounts of a biomarker identify the likelihood of developing an irAE within the claims. Ding et al., teach IL22RA1 is present in healthy patients (those without cancer). Therefore the mere presence of IL22RA1 alone would not indicate the increased likelihood of an irAE event, because IL22RA1 is normally present in a healthy human. Therefore, clarification is required to overcome the rejection.
I) Claim 4 recites “… developed irAE to an extent not exceeding a permissible level.” The metes and bounds for determining an extent not exceeding a permissible level is unclear. It is unclear how to define what a permissible level of irAE is. It is also unclear how to define what level of irAE is permissible. It is unclear what the permissible level is based upon, i.e., the severity of symptoms or the number of symptoms. Thus, the metes and bounds of the claim cannot be ascertained; thus clarification is required to overcome the rejection.
J) Regarding claim 6, the phrase "e.g.," renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
K) Claim 12 states the subject has been administered any anti-cancer treatment or inhibitor of an immune checkpoint. However the preamble of claim 1 is drawn to a method of identifying the likelihood of development of immune-related adverse events (irAE) in a subject due to immune checkpoint therapy comprising a subject having cancer. Therefore claim 1 defines the subject as 1) having cancer and 2) having had immune checkpoint therapy; thus making the subject susceptible to the development of irAE. Therefore, the claim is rejected because claim 12 seeks to broaden the subject population in a manner that is inconsistent with claim 1. Therefore, clarification is required to overcome the rejection.
Claim Objections
7. 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.
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, 3-4, 6, 8-9, 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 the likelihood of development of immune-related adverse events (irAE) in a subject due to 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.
Question #1: Is the claim to a process, Machine, Manufacture or Composition of Matter? The claims are drawn to a method of identifying the likelihood of development of immune-related adverse events (irAE) in a subject due to immune checkpoint therapy, the method comprising: a) obtaining or providing a subject sample from a subject having cancer;
b) measuring the amount of at least one germline biomarker in the subject sample, wherein the at least one germline biomarker is selected from: germline variant near the IL7 gene or influencing IL7 splicing (SNP rsid rs7816685, or SNP rsid rs16906115, or other correlated SNPs), germline variant near the IL22RA1 gene (SNP rsid rs75824728 or correlated SNPs), CNA deletion WAS, CNA deletion ARAF, SNV mutation in ARID1B, SNV mutation in PIK3R1, SNV mutation in APC, SNV mutation in SETD2, SNV mutation in B2M, SNV mutation in BCOR, SNV mutation in CASP8, SNV mutation in KDM6A, SNV mutation in MSH6, SNV mutation in ROS1, germline risk score for bladder cancer, germline risk score for medication use (including anti-inflammatory or immunosuppressant medications), and germline risk score for blood cell counts; and
c) comparing said amount of the at least one germline biomarker to a control, thereby identifying the likelihood of development of immune-related adverse events (irAE) in the subject due to immune checkpoint therapy, wherein the presence of or a significantly increased amount of the at least one germline biomarker in the subject sample, relative to the control, identifies the development of irAE due to immune checkpoint therapy as being more likely; and wherein the absence of or a significantly decreased amount of the at least one germline biomarker in the subject sample, relative to the control, identifies the development of irAE due to immune checkpoint therapy as being less likely, optionally further 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. Thus, the answer to question #1 from the PEG analysis is “Yes”, the rejected claims are directed to a process, which is a statutory category of invention.
The rejected claims do not positively specifically recite a step correlating the level, presence or absence of at least one germline biomarker in the subject sample, wherein the at least one germline biomarker is selected from: germline variant near the IL7 gene or influencing IL7 splicing (SNP rsid rs7816685, or SNP rsid rs16906115, or other correlated SNPs), germline variant near the IL22RA1 gene (SNP rsid rs75824728 or correlated SNPs), CNA deletion WAS, CNA deletion ARAF, SNV mutation in ARID1B, SNV mutation in PIK3R1, SNV mutation in APC, SNV mutation in SETD2, SNV mutation in B2M, SNV mutation in BCOR, SNV mutation in CASP8, SNV mutation in KDM6A, SNV mutation in MSH6, SNV mutation in ROS1, germline risk score for bladder cancer, germline risk score for medication use (including anti-inflammatory or immunosuppressant medications), and germline risk score for blood cell counts to a specific degree of likelihood of irAE.
However, in order to be a method, there must be some step where the actual diagnosis or monitoring is performed. The claims thus recite a judicial exception. This judicial exception is not integrated into a practical application because gathering information and treating an individual with a therapeutic regimen based on gathered information required to use the correlation do not add a meaningful limitation to the method as they are insignificant extra-solution activity. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because they do not recite something significantly different than a judicial exception. Therefore, these steps cannot be considered to add significantly more to the judicial exception. Thus, the only portions of the claims that add to the judicial exception are routine and conventional in the art and thus do not add significantly more to the judicial exception.
Question #2A-Prong I: Does the claim recite an abstract idea, law of nature, or natural phenomenon? Yes, the claims recite/describe/set forth a judicial exception. The instant claims describe the relationship between the measured germline biomarker and the presence, significant increased amount, absence or significant decrease of the biomarker from the sample relative to a control identified the likelihood of the development of an irAE. Optionally, further 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. The claimed therapeutic regimens are recited at such a high level of generality that it encompasses any means to treating. Furthermore, the decisions to render or not render treatment is conditional and optional. 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.
This limitation sets forth a judicial exception, because this type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo Collaborative Svcs. v. Prometheus Labs., 566 U.S. __, 132 S. Ct. 1289, 1297 (2012).
As such, each of the rejected claims recite a mental process that is reasonably considered in this case to be a mental process. Thus, the answer to Question #2A-Prong I is “Yes” because each of the claims recites a judicial exception (i.e. a mental step and/or a natural correlation).
Question #2A-Prong II: Does the claim recite additional elements that integrate the judicial exception into a practical application? 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”.
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 analyzing the presence or/ and level 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/amount/ abundance 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 step is 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. Detecting levels of 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 protein. Such activities are normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such law. Detection of candidate cancer biomarkers and treating 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 “comparing” 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 mathematical concepts read on an abstract idea and include mathematical formulas, equations and calculations 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.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
9. Claims 1, 3-4, 6, 8-9, 12, 18-19, 22 and 24 are rejected under 35 U.S.C. 102(a)(1) and/or (a)(2) as being anticipated by Allen et al., (WO 2018132369 published July 19, 2018; priority to Jan 11, 2017).
The claims are drawn to a method of identifying the likelihood of development of immune-related adverse events (irAE) in a subject due to immune checkpoint therapy, the method comprising: a) obtaining or providing a subject sample from a subject having cancer; b) measuring the amount of at least one germline biomarker in the subject sample, wherein the at least one germline biomarker is selected from: germline variant near the IL7 gene or influencing IL7 splicing (SNP rsid rs7816685, or SNP rsid rs16906115, or other correlated SNPs), germline variant near the IL22RA1 gene (SNP rsid rs75824728 or correlated SNPs), CNA deletion WAS, CNA deletion ARAF, SNV mutation in ARID1B, SNV mutation in PIK3R1, SNV mutation in APC, SNV mutation in SETD2, SNV mutation in B2M, SNV mutation in BCOR, SNV mutation in CASP8, SNV mutation in KDM6A, SNV mutation in MSH6, SNV mutation in ROS1, germline risk score for bladder cancer, germline risk score for medication use (including anti-inflammatory or immunosuppressant medications), and germline risk score for blood cell counts; and c) comparing said amount of the at least one germline biomarker to a control, thereby identifying the likelihood of development of immune-related adverse events (irAE) in the subject due to immune checkpoint therapy, wherein the presence of or a significantly increased amount of the at least one germline biomarker in the subject sample, relative to the control, identifies the development of irAE due to immune checkpoint therapy as being more likely; and wherein the absence of or a significantly decreased amount of the at least one germline biomarker in the subject sample, relative to the control, identifies the development of irAE due to immune checkpoint therapy as being less likely, optionally further 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.
Allen et al., teach the identification of novel biomarkers predictive of responsiveness to anti-immune checkpoint therapies [abstract]. Allen et al., teach that alterations in multiple oncogenic signaling pathways, including SWI/SNF pathway but also other chromatin modifiers, such as KDM6A, and EGFR signaling, predict response or resistance to immune checkpoint therapies, including (but not limited to) monoclonal antibodies targeting PD-1, PD-L1, and CTLA-4, across multiple cancer types. The SWI/SNF chromatin remodeling complex, which contains ARID1A, ARID1B, ARID2, SMARCA2, SMARCA4, SMARCB1, and PBRM1 subunits, among other subunits, plays a role in replication, transcription, DNA repair, and control of cell proliferation and differentiation [para 3]. Although alterations in SWI/SNF subunits are known to play a role in the pathogenesis of ˜20% of human cancers, including clear cell renal cell carcinoma, colorectal cancer, and pancreatic cancer, a mutation in one or more subunits of the SWI/SNF complex (e.g., mutations in one or more subunits of the PBAF complex, such as PBRM1 and ARID2), is predictive of response to immune checkpoint inhibitors. Thus teaching claim 22.
A method of identifying the likelihood of a cancer in a subject to be responsive to an immune checkpoint therapy, the method comprising a) obtaining or providing a subject sample from a patient having cancer; b) measuring the amount or activity of at least one biomarker listed in Table 1 in the subject sample; and c) comparing said amount or activity of the at least one biomarker listed in Table 1 in a control sample, wherein the absence of or a significantly decreased amount or activity of the at least one biomarker listed in Table 1 in the subject sample and/or the presence of or a significantly increased amount or activity of the at least one biomarker listed in Table 1 having a loss of function mutation in the subject sample, relative to the control sample identifies the cancer as being more likely to be responsive to the immune checkpoint therapy; and wherein the presence of or a significantly increased amount or activity of the at least one biomarker listed in Table 1 in the subject sample and/or the absence of or a decreased amount or activity of the at least one biomarker listed in Table 1 having a loss of function mutation in the subject sample, relative to the control sample identifies the cancer as being less likely to be responsive to the immune checkpoint therapy, is provided [para 4]. Thus teaching claim 24. In still another embodiment, the control sample is a cancerous or non-cancerous sample from the patient obtained from an earlier point in time than the patient sample. In yet another embodiment, the control sample is obtained before the patient has received immune checkpoint therapy and the patient sample is obtained after the patient has received immune checkpoint therapy. In another embodiment, the control sample described herein comprises cells or does not comprise cells. In still another embodiment, the control sample comprises cancer cells known to be responsive or non-responsive to the immune checkpoint therapy [para 6]. Thus teaching claim 4. In another embodiment, the at least one biomarker listed in Table 1 is human ARID2, KDM6A, ARID1A, ARID1B, or a fragment thereof. In still another embodiment, the immune checkpoint therapy described herein comprises at least one antibody selected from the group consisting of anti-PD-1 antibodies, anti-CTLA-4 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies, and combinations thereof [para 10]. Thus teaching claim 19.
In another embodiment, the first and/or at least one subsequent sample is selected from the group consisting of ex vivo and in vivo samples. In still another embodiment, the first and/or at least one subsequent sample is obtained from an animal model of the cancer. In yet another embodiment, the first and/or at least one subsequent sample is a portion of a single sample or pooled samples obtained from the subject para 8]. The subject sample is selected from the group consisting of serum, whole blood, plasma, urine, cells, cell lines, and biopsies [para 10]. Thus teaching claim 9. The term “single nucleotide polymorphism” (SNP) refers to a polymorphic site occupied by a single nucleotide, which is the site of variation between allelic sequences. The site is usually preceded by and followed by highly conserved sequences of the allele (e.g., sequences that vary in less than 1/100 or 1/1000 members of a population). A SNP usually arises due to substitution of one nucleotide for another at the polymorphic site. SNPs can also arise from a deletion of a nucleotide or an insertion of a nucleotide relative to a reference allele. Typically the polymorphic site is occupied by a base other than the reference base. For example, where the reference allele contains the base “T” (thymidine) at the polymorphic site, the altered allele can contain a “C” (cytidine), “G” (guanine), or “A” (adenine) at the polymorphic site. SNP's may occur in protein-coding nucleic acid sequences, in which case they may give rise to a defective or otherwise variant protein, or genetic disease. Such a SNP may alter the coding sequence of the gene and therefore specify another amino acid (a “missense” SNP) or a SNP may introduce a stop codon (a “nonsense” SNP). When a SNP does not alter the amino acid sequence of a protein, the SNP is called “silent.” SNP's may also occur in noncoding regions of the nucleotide sequence. This may result in defective protein expression, e.g., as a result of alternative spicing, or it may have no effect on the function of the protein [para 181]. Thus teaching claim 8.
The efficacy of immune checkpoint therapy is predicted according to biomarker amount and/or activity associated with a cancer in a subject according to the methods described herein. In one embodiment, such immune checkpoint therapy or combinations of therapies (e.g., anti-PD-1 antibodies) can be administered once a subject is indicated as being a likely responder to immune checkpoint therapy. In another embodiment, such immune checkpoint therapy can be avoided once a subject is indicated as not being a likely responder to immune checkpoint therapy and an alternative treatment regimen, such as targeted and/or untargeted anti-cancer therapies can be administered [para 292]. The term “determining a suitable treatment regimen for the subject” is taken to mean the determination of a treatment regimen (i.e., a single therapy or a combination of different therapies that are used for the prevention and/or treatment of the cancer in the subject) for a subject that is started, modified and/or ended based or essentially based or at least partially based on the results of the analysis according to the present invention. One example is determining whether to provide targeted therapy against a cancer to provide immunotherapy that generally increases immune responses against the cancer (e.g., immune checkpoint therapy). Another example is starting an adjuvant therapy after surgery whose purpose is to decrease the risk of recurrence, another would be to modify the dosage of a particular chemotherapy [para 99]. Thus teaching claims 3 and 12. The activity or level of a biomarker protein can be detected and/or quantified by detecting or quantifying the expressed polypeptide. The polypeptide can be detected and quantified by any of a number of means well known to those of skill in the art. Aberrant levels of polypeptide expression of the polypeptides encoded by a biomarker nucleic acid and functionally similar homologs thereof, including a fragment or genetic alteration thereof (e.g., in regulatory or promoter regions thereof) are associated with the likelihood of response of a cancer to an immune checkpoint therapy. Any method known in the art for detecting polypeptides can be used. Such methods include, but are not limited to, immunodiffusion, immunoelectrophoresis, radioimmunoassay (MA), enzyme-linked immunosorbent assays (ELISAs), immunofluorescent assays, Western blotting, binder-ligand assays [para 261]. Thus teaching claim 6. Thus, the rejected claims are anticipated by Allen et al.
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
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