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 with traverse of Group I (claims 1, 2, 4, 11, 18, 19, 21, 28, 35, 36, 38, 44, 50, 51, 53, 59, 66, 67, 69, 87, 88, 90, 108, 109, 113-115 and 125) with species, (biomarker): KIF1B in Tables 1 and 2; and (cancer): epithelial ovarian cancer in the reply filed on February 3, 2026 is acknowledged. The traversal is on the ground(s) that “…the claims of Group I and Group II may be searched together without significant burden”, see page 18. This is not found persuasive because the methods listed in Group I are independent and distinct from the one method listed in Group II. Group II reads on a library of cells, assays for sorting cells, sequencing nucleic acids and assessments of a DNA barcode. None of these valuations are set forth in the methods of Group I. Hence for the reasons of record noted in the Requirement mailed December 8, 2025, see page 7, segment 8 and the rationale set forth herein these two groups will not be searched, nor examined together.
Upon reconsideration, the cancer species election has been withdrawn and the biomarker species has been extended to B7-H6 (NCR3LG1) in Table 2 and ENTPD1 (CD39) in Tables 1, 2, B2 and C.
The requirement is still deemed proper and is therefore made FINAL.
3. Claims 1, 2, 4, 11, 18, 19, 21, 28, 35, 36, 38, 44, 50, 51, 53, 59, 65-67, 69, 87, 88, 90, 108, 109, 113-115 and 125 are pending.
Claim 65 is drawn to non-elected species are withdrawn from consideration.
Claims 3, 5-10, 12-17, 20, 22-27, 29-34, 37, 39-43, 45-49, 52, 60-64, 68, 70-86, 89, 91-107, 110-112, 116-124 and 126 have been cancelled.
Claims 1, 2, 4, 11, 18, 19, 21, 28, 35, 36, 38, 44, 50, 51, 53, 59, 66, 67, 69, 87, 88, 90, 108, 109, 113-115 and 125 with species, (biomarker): KIF1B in Tables 1 and 2, B7-H6 (NCR3LG1) in Table 2 and ENTPD1 (CD39) in Tables 1, 2, B2 and C are examined on the merits.
Claim Objections
4. Claims 4, 21, 38 and 53 are objected to because of the following informalities: step b) of each noted claim cites “optoinally”, which should be deleted and replace with the proper word, optionally.
Correction is required.
Claim Rejections - 35 USC § 112
5. 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, 2, 4, 11, 18, 19, 21, 28, 35, 36, 38, 44, 50, 51, 53, 59, 66, 67, 69, 87, 88, 90, 108, 109, 113-115 and 125 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. Claims 1, 18, 35 and 50 recite “…detecting…one or more values for one or biomarkers…” or “…selecting a subject identified as having one or more values for one or more biomarkers…”. However, it is not clear what or how a numerical amount for a biomarker is established. Accordingly, the metes and bounds cannot be determined.
b. Claims 11, 28, 44, 59, 66, 67, 69, 88, 109 and 113 recite “an antibody or a fragment thereof”. It is not clear what part of the fragment binds specifically to the target molecule. Applicant may obviate this rejection by deleting the said recitation and replacing it with the phrase,
an antibody or an antigen-binding fragment thereof.
c. Claims 66, 87 and 113 recites “…one or more biomarkers listed in Table 1 or a fragment thereof” on lines 3, 4; lines 2, 3; and line 2, respectively. It is not clear what part or portion of the biomarker should be assayed or targeted by an agent to facilitate killing the cancer cell bearing it. Accordingly, the metes and bounds cannot be determined.
d. Claim 1, 4, 11, 18, 21, 28, 35, 38, 44, 50, 53, 59, 66, 67, 87, 88, 108, 109, 113-115 and 125 reference numerous tables, Table 1, Table 2 and Table 3. Where possible, claims are to be complete in themselves. 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 than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant's convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations
omitted)., see MPEP 2173.05(s).
7. Claims 67 and 88 recite the limitation "the cancer cells" in step f). There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 101
8. 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.
9. The claimed inventions (claims 1, 2, 4, 11, 18, 19, 21, 28, 35, 36, 38, 44, 50, 51, 53, 59, 108, 109, 113 and 115) are directed to judicial exception without significantly more. The claim(s) recite(s) methods of selecting a cancer patient with diagnosed cancer for immunotherapy based on the one or more values for one or more biomarkers; selecting a cancer cell identified as having one or more values for one or more biomarkers and method of determining a subject with cancer or at risk for developing a cancer benefit from inhibiting the copy number, amount and/or activity of at least biomarker comparing it with a control; and method for predicting the clinical outcome of a subject afflicted with a cancer expressing one or more biomarkers; monitoring the progression of a cancer in a subject is administered an agent that inhibits the copy number, amount and/or activity of at least biomarker an immunotherapy and comparing sample at different time points; and a method of assessing the efficacy of an agent that inhibits copy number, amount and/or activity of at least biomarker and an immunotherapy for treating comprising detecting and comparing samples from different time points; selecting a cancer cell identified as having one or more values and subjecting said cell to an immunotherapy based on the one or more value, wherein unidentified values, differences in these values between the patient and biomarker control thresholds and/or differences between these values at different time points is indicative of which patient should be selected for treatment based on unclear and unnamed values. This judicial exception is not integrated into a practical application because the claims describe a law of nature, namely the relationship between biomarker values and cancer diagnosis, selection for immunotherapy treatment, clinical outcome and benefit of immunotherapy. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because assaying mutations does not add significantly more and is not an inventive concept.
The analysis as set forth in the 2019 Guidance is as follows:
Step 1: Yes, claims are drawn to methods which are one of the four statutory categories, a process.
Step 2A, prong 1: Yes, the claims recite/describe a law of nature or natural phenomenon. Claim 1 describes the relationship between the values (copy number, expression level, activity or combination thereof) of one of the biomarkers and selection of a patient for treatment, a cancer diagnosis, at risk for developing cancer, benefit of inhibiting at least one of the said values, recommendation/prescribing/administering an immunotherapy, prediction of clinical outcome and progression of cancer and the efficacy of a treatment inhibiting an immunotherapy.
Step 2A, prong 2: No, the law of nature or natural phenomenon does not integrate into a practical application because there are no additional steps beyond the determination of a value and difference between one or more values for one or more biomarkers detected from a subject and a biomarker control threshold. This embodiment does not rely on or use the exception, this language does not integrate the law of nature or judicial exception into a practical application. There is observation of biomarker(s) and its value within a subject and one or more biomarker-specific control thresholds. In some claims thereafter, essentially one does nothing and there is a lack of action. In other claims one of ordinary skill in the art determines and/or selects (mental step(s)) there is an increased level of cancer antigen in the test sample and for all intents and purposes there is nothing further to do. Once one has the information regarding the values is detected from the subject, the subject is selected for treatment, determined to be susceptible to treatment or not, at risk for developing cancer and/or benefit from a treatment and/or predictive of progression of a cancer and/or assessing the efficacy of treatment.
Step 2B: There is no inventive concept present in the claims. The steps of analyzing for at least one biomarker and a value for one or more biomarker(s) is established by well understood, routine conventional methods, and in addition they are pre-solution activity, i.e. data gathering necessary to perform the correlation. The claims and steps inform one of ordinary skilled in the art whether or not an individual has cancer or not based on the increased level of antigen within an individual’s sample. The claims do not recite additional elements that amount to significantly more than the law of nature and are recited at a high level of generality, and are necessary data-gathering steps. Accordingly, these claims are not eligible under step 2A or step 2B.
Claims that describe the relation set forth a natural law. The claim limitations setting forth additional elements are insufficient to transform the identified natural law into a patentable process. The method for making such determinations were well known in the art and these activities are not sufficient to transform an unpatentable law of nature into a patent-eligible application of such law.
Claims 1, 2, 4, 11, 18, 19, 21, 28, 35, 36, 38, 44, 50, 51, 53, 59, 108, 109, 113 and 115 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: the claims recite/describe a law of nature or natural phenomenon. The claims describe the relationship between cancer biomarker(s) and diagnosis of cancer, selecting one for immunotherapy, at risk for developing cancer, determining patients that would benefit from therapeutic intervention, predicting clinical outcome of patient with cancer and/or assessing the efficacy of a therapeutic agent and immunotherapy at different time points.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because assaying differences in values between the values for one or more biomarker(s) from the subject and control thresholds at different time points, as well as before and after treatment 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. Detection of candidate cancer biomarker(s) has 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 a novel reagent, apparatus of 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 “selecting, “detecting”, “subjecting”, “determining”, “recommending”, “prescribing” and “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. 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 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 judicial exception. The claims do not "practically apply" the judicial expectation; rather, the claims "simply inform" the judicial exception to one performing routine active method steps and do not amount to significantly more than the judicial exception itself. In the instant case, the outcome of the claimed method is only a statement of the judicial exception, evaluating differences in the values of biomarker(s) between different time periods and different samples. Thus, the invention has not been practically applied. It is concluded that the instant claims are judicial exceptions to 35 U.S.C. 101 and are therefore not patent eligible. 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.
Claim Rejections - 35 USC § 102
10. 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.
11. Claim(s) 1, 2, 4, 11, 18, 19, 21, 28, 35, 36, 44, 50, 51, 59, 66, 67, 69, 87, 88, 90, 108, 109, 113-115 and 125 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Haining et al., US 2017/0233808 A1 (published August 17, 2017). Haining discloses methods of identifying a cell type, monitoring the progression of a disorder, based on “… a) determining the presence, copy number, amount, and/or activity of at least one biomarker listed in Table 1 [including CD39, which is also art known as ENTPD1] in a biological sample comprising CD8+ T cells; b) determining the presence, copy number, amount, and/or activity of the at least one biomarker in a control; and c) comparing the presence, copy number, amount, and/or activity of said at least one biomarker detected in steps a) and b); wherein the presence or a significant increase in the copy number, amount, and/or activity of the at least one biomarker in the biological sample relative to the control indicates that the biological sample comprises exhausted CD8+ T cells, is provided.”, see page 2, section 0008; and page 3, section 0012. Biomarker CD39 (ENTPD1) is cited in Applicant’s Table 1.
“The term “biomarker” refers to a measurable entity of the present invention that has been determined to be associated with a chronic immune disorder. Biomarkers can include, without limitation, nucleic acids, proteins, and metabolites, particularly those shown in Table 1.”, see page 7, section 0042.
The chronic immune disorder may be cancer, see page 3, 2nd column (col.) last 3 lines. The cancer may be epithelial ovarian cancer, see page 4, 1st col., 2nd to last sentence before “Brief…” segment; and page 9, section 0052.
“The term “altered amount” or “altered level” refers to increased or decreased copy number (e.g., germline and/or somatic) of a biomarker nucleic acid, e.g., increased or decreased expression level in a chronic immune disorder sample, as compared to the expression level or copy number of the biomarker nucleic acid in a control sample. The term “altered amount” of a biomarker also includes an increased or decreased protein level of a biomarker protein in a sample. e.g., a chronic immune disorder sample, as compared to the corresponding protein level in a normal, control sample. Furthermore, an altered amount of a biomarker protein may be determined by detecting posttranslational modification such as methylation status of the marker, which may affect the expression or activity of the biomarker protein.
“The amount of a biomarker in a subject is “significantly” higher or lower than the normal amount of the biomarker, if the amount of the biomarker is greater or less, respectively, than the normal level by an amount greater than the standard error of the assay employed to assess amount, and preferably at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 350%, 400%, 500%, 600%, 700%, 800%, 900%, 1000% or than that amount. Alternately, the amount of the biomarker in the subject can be considered “significantly” higher or lower than the normal amount if the amount is at least about two, and preferably at least about three, four, or five times, higher or lower, respectively, than the normal amount of the biomarker. Such “significance” can also be applied to any other measured parameter described herein, such as for expression, inhibition, cytotoxicity, cell growth, and the like.
The term “altered level of expression” of a biomarker refers to an expression level or copy number of the biomarker in a test sample, e.g., a sample derived from a patient suffering from a chronic immune disorder, that is greater or less than the standard error of the assay employed to assess expression or copy number, and is preferably at least twice, and more preferably three, four, five or ten or more times the expression level or copy number of the biomarker in a control sample (e.g., sample from a healthy subjects not having the associated disease) and preferably, the average expression level or copy number of the biomarker in several control samples. The altered level of expression is greater or less than the standard error of the assay employed to assess expression or copy number, and is preferably at least twice, and more preferably three, four, five or ten or more times the expression level or copy number of the biomarker in a control sample (e.g., sample from a healthy subjects not having the associated disease) and preferably, the average expression level or copy number of the biomarker in several control samples.
The term “altered activity” of a biomarker refers to an activity of the biomarker which is increased or decreased in a disease state, e.g., in a chronic immune disorder sample, as compared to the activity of the biomarker in a normal, control sample. Altered activity of the biomarker may be the result of, for example, altered expression of the biomarker, altered protein level of the biomarker, altered structure of the biomarker, or, e.g., an altered interaction with other proteins involved in the same or different pathway as the biomarker or altered interaction with transcriptional activators or inhibitors.”, see page 6, section 0032-0034.
The determining step reads on Applicant’s step of selecting treatment for the subject, whom a biomarker(s) has been detected. Haining further teaches once it is determined targeted therapy will be administered against the disorder, immunotherapy including anti-immune checkpoint inhibitor therapy is selected as it is able to evoke and increase immune response against the disorder. “In most cases, the actual determination of the suitable treatment regimen for the subject will be performed by the attending physician or doctor.”, see page 10, section 0058.
“[D]etermining 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 chronic immune disorder 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 chronic immune disorder to provide immunotherapy that generally increases immune responses against the chronic immune disorder (e.g., anti-CD39 therapy with or without anti-immune checkpoint inhibitor therapy)… The determination can, in addition to the results of the analysis according to the present invention, be based on personal characteristics of the subject to be treated. In most cases, the actual determination of the suitable treatment regimen for the subject will be performed by the attending physician or doctor.”, see page 10, section 0058.
The immunotherapy is inclusive of an “immunotherapeutic agent”… any molecule, peptide, antibody or other agent which can stimulate a host immune system to generate an immune response against the chronic immune disorder in the subject.”, see page 16, section 0086. Non-limiting examples of anti-immune checkpoint inhibitor therapy taught in Haining are (e.g., anti-PD-1, anti-PD-L1, anti-PD-L2, and anti-CTLA4 therapies), see page 2, sections 0008-0010; page 11, section 0064-page 14, section 0074; page 50, sections 0283, 0286; page 52, section 0294; and page 57, section 0340. With the administration of the immunotherapy, it would naturally flow that primarily natural killer (NK) cells would be leveraged and modifies the biomarker(s).
Haining discloses “prognosis” includes a prediction of the probable course and outcome of [a] …disorder or the likelihood of recovery from the disease.”, see page 17, 0097. Haining teaches the “…diagnostic assays, prognostic assays, and monitoring clinical trials are used for prognostic (predictive) purposes to thereby treat an individual prophylactically. Accordingly, one aspect of the present invention relates to diagnostic assays for determining the amount and/or activity level of a biomarker listed in Table 1 in the context of a biological sample (e.g., blood, serum, cells, or tissue) to thereby identify the presence of exhausted CD8+ T cells and/or the status of an individual afflicted with a chronic immune disorder.”, see page 55, section 0324.
“As described [in Haining], a “pre-determined” biomarker amount and/or activity measurement(s) may be a biomarker amount and/or activity measurement(s) used to, by way of example only, evaluate a subject that may be selected for treatment, evaluate a response to a therapy (e.g., anti-CD39 therapy with or without anti-immune checkpoint inhibitor therapy), and/or evaluate a response to a combination of therapies. A pre-determined biomarker amount and/or activity measurement(s) may be determined in populations of patients with or without a chronic immune disorder. The pre-determined biomarker amount and/or activity measurement(s) can be a single number, equally applicable to every patient, or the pre-determined biomarker amount and/or activity measurement(s) can vary according to specific subpopulations of patients…”, see page 32, section 0125.
“The pre-determined biomarker amount and/or activity measurement(s) can be any suitable standard. For example, the pre-determined biomarker amount and/or activity measurement(s) can be obtained from the same or a different human for whom a patient selection is being assessed. In one embodiment, the pre-determined biomarker amount and/or activity measurement(s) can be obtained from a previous assessment of the same patient…[T]he progress of the selection of the patient can be monitored over time.”, see page 32, section 0126.
“In another aspect, a method of monitoring the progression of a chronic immune disorder in a subject, comprising a) detecting at a first point in time the presence, copy number, amount, and/or activity of at least one biomarker listed in Table 1 in CD8+ T cells from a subject sample; b) repeating step a) during at least one subsequent point in time after administration of a therapeutic agent; and c) comparing the presence, copy number, amount, and/or activity detected in steps a) and b), wherein the presence or a significantly increased copy number, amount, and/or activity of the at least one biomarker listed in Table 1 in the CD8+ T cells from the first subject sample relative to at least one subsequent subject sample, indicates that the agent treats the chronic immune disorder in the subject, is provided. In one embodiment, the method further comprises determining the copy number, level of expression, and/or level of activity of at least one immune checkpoint inhibitor in the CD8+ T cells from the first subject sample; determining the copy number, level of expression, and/or level of activity of the at least one immune checkpoint inhibitor in the CD8+ T cells from the at least one subsequent subject sample; and comparing the differences in the copy number, level of expression, and/or level of activity of the at least one immune checkpoint inhibitor between the samples, wherein a significant decrease in the copy number, level of expression, and/or level of activity of the at least one immune checkpoint inhibitor in the at least one subsequent subject sample relative to the first subject sample further indicates that the agent treats the chronic immune disorder in the subject. In another embodiment, the method further comprises determining T cell effector function of the CD8+ T cells in the first subject sample; determining T cell effector function of the CD8+ T cells in the at least one subsequent subject sample; and comparing the T cell effector function determinations, wherein a significant increase in the T cell effector function of the CD8+ T cells in the at least one subsequent subject sample relative to the first subject sample further indicates that the agent treats the chronic immune disorder in the subject. In still another embodiment, the subject has undergone treatment, completed treatment, and/or is in remission for the chronic immune disorder in between the first point in time and the subsequent point in time. In yet another embodiment, the subject has undergone anti-immune checkpoint inhibitor therapy in between the first point in time and the subsequent point in time. 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 chronic immune disorder. 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.”, page 3, section 0012.
Claim Rejections - 35 USC § 103
12. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
13. Claim(s) 1, 2, 4, 11, 18, 19, 21, 28, 35, 36, 38, 44, 50, 51, 53, 59, 66, 67, 69, 87, 88, 90, 108, 109, 113-115 and 125 is/are rejected under 35 U.S.C. 103 as being unpatentable over Munirajan et al. (The Journal of Biological Chemistry 283(36): 24426-24434, September 5, 2008), and further in view of Semeraro et al., (OncoImmunology 4:11, e1042202-1 to e1042202-3, November 2015/ IDS reference CB submitted September 22, 2022) and Haining et al., US 2017/0233808 A1 (published August 17, 2017). Munirajan teaches “expression of KIF1B was markedly down-regulated in advanced stages of tumors (p < 0.001)”, see Abstract on page 24426. “Overexpression of KIF1B in Neuroblastomas-induced Apoptotic Cell Death—“, see page 24428. “The tumors formed by cells lacking KIF1B expression were histologically diagnosed as poorly differentiated invasive ductal carcinoma and frequently metastasized to the lung (Fig.4). Thus, it is likely that KIF1B exerts tumor-suppressive function in vivo.”, see page 24429, last two sentences before “LOH…” segment. The KIF1B marker is cited in Applicant’s Tables 1 and 2.
“Decreased Expression of KIF1Bb Is Associated with Monoallelic Loss of the Gene in Primary Neuroblastomas—We examined expression levels of KIF1Bb mRNA in 102 primary neuroblastomas by using both semi-quantitative and quantitative real time PCRs. As shown in Fig.5, A and B [see at bottom of page 24430], expression levels of KIF1Bb mRNA were significantly higher in tumors at favorable stages (1, 2, and 4s, 1.654 + 0.257, mean S.E., n=60) than in those at advanced stages (3 and 4, 0.503 + 0.180, n = 42, p 0.001).”…tumors with monoallelic loss of KIF1Bb gene locus expressed significantly lower levels of KIF1B mRNA (0.126 + 0.092, n = 13) as compared with those with two KIF1Bb alleles (0.364 + 0.035, n = 16, p = 0.019). These results suggest that KIF1Bb is a haploinsufficient tumor suppressor gene in high risk neuroblastomas.”, see page 24430, paragraph (para.) bridging both columns (cols.) .
“[Munirajan has] shown that the KIF1B gene is hemizygously deleted especially in aggressive primary neuroblastoma tumors, and its mutation is infrequent. The expression of KIF1B was kept at quite a low level in aggressive neuroblastoma subsets, even though no methylation of its promoter region was observed.”, see page 24432, col. 2., 1st para.
Munirajan does not teach once the level of expression was detected and differences were observed, the patient was treated with immunotherapy. Munirajan does not teach other values, copy number, the activity or combination thereof of the biomarker(s) may be assayed. Nor, does Munirajan teach one of the biomarkers detected is B7-H6 (NCR3LG1) cited in Applicant’s Tables 1, 2; CD39 (ENTPD1), cited in Applicant’s Table 1, 2; and CSF1 cited in Applicant’s Table 3.
However, Semeraro teaches “…neuroblastoma cells express the NKp30 ligand B7-H6, which can be shed from the tumor cells. Elevated soluble B7-H6 levels contained in patient sera inhibited NK functions in vitro and correlated with downregulation of NK-p30 on NK cells,”, see abstract on page 1.
The caption for figure 1 on page e1042202-2 states “[t]wo possible scenarios describe the NKp30 involvement in controlling high-risk neuro-blastoma (HR-NB): in the first one, a favorable ratio of the NKp30B over the immunosuppressiveNKp30C isoform (NKp30DBChigh) is associated with tumor growth control. In particular, the NKp30/B7-H6 recognition between NK lymphocytes and neuroblasts and/or monocytes elicits a Th1 response with consequent cytotoxic, cytostatic and anti-angiogenic effects. In the second possible scenario, the presence of a predominant immunosuppressive NKp30 isoform (NKp30DBClow) induces IL-10 production with a consequent immunosuppressive environment resulting in tumor growth.”
Two possible scenarios describe the NKp30 involvement in controlling high-risk neuroblastoma (HR-NB): in the first one, a favorable ratio of the NKp30B over the immunosuppressiveNKp30C isoform (NKp30DBChigh) is associated with tumor growth control. In particular, the NKp30/B7-H6 recognition between NK lymphocytes and neuroblasts and/or monocytes elicits a Th1response with consequent cytotoxic, cytostatic and anti-angiogenic effects. In the second possible scenario, the presence of a predominant immunosuppressive NKp30 isoform (NKp30DBClow) induces IL-10 production with a consequent immunosuppressive environment resulting in tumor growth.
Moreover, Haining discloses methods of identifying a cell type, monitoring the progression of a disorder, based on “… a) determining the presence, copy number, amount, and/or activity of at least one biomarker listed in Table 1 [including CD39, which is also art known as ENTPD1] in a biological sample comprising CD8+ T cells; b) determining the presence, copy number, amount, and/or activity of the at least one biomarker in a control; and c) comparing the presence, copy number, amount, and/or activity of said at least one biomarker detected in steps a) and b); wherein the presence or a significant increase in the copy number, amount, and/or activity of the at least one biomarker in the biological sample relative to the control indicates that the biological sample comprises exhausted CD8+ T cells, is provided.”, see page 2, section 0008; and page 3, section 0012. Biomarker CD39 (ENTPD1) is cited in Applicant’s Table 1. Haining also teaches additional markers in Table 4, CSF1 on page 68 and KIF1B on page 71.
“The term “biomarker” refers to a measurable entity of the present invention that has been determined to be associated with a chronic immune disorder. Biomarkers can include, without limitation, nucleic acids, proteins, and metabolites, particularly those shown in Table 1.”, see page 7, section 0042.
The chronic immune disorder may be cancer, see page 3, 2nd column (col.) last 3 lines. The cancer may be epithelial ovarian cancer, see page 4, 1st col., 2nd to last sentence before “Brief…” segment; and page 9, section 0052.
“The term “altered amount” or “altered level” refers to increased or decreased copy number (e.g., germline and/or somatic) of a biomarker nucleic acid, e.g., increased or decreased expression level in a chronic immune disorder sample, as compared to the expression level or copy number of the biomarker nucleic acid in a control sample. The term “altered amount” of a biomarker also includes an increased or decreased protein level of a biomarker protein in a sample. e.g., a chronic immune disorder sample, as compared to the corresponding protein level in a normal, control sample. Furthermore, an altered amount of a biomarker protein may be determined by detecting posttranslational modification such as methylation status of the marker, which may affect the expression or activity of the biomarker protein.
“The amount of a biomarker in a subject is “significantly” higher or lower than the normal amount of the biomarker, if the amount of the biomarker is greater or less, respectively, than the normal level by an amount greater than the standard error of the assay employed to assess amount, and preferably at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 350%, 400%, 500%, 600%, 700%, 800%, 900%, 1000% or than that amount. Alternately, the amount of the biomarker in the subject can be considered “significantly” higher or lower than the normal amount if the amount is at least about two, and preferably at least about three, four, or five times, higher or lower, respectively, than the normal amount of the biomarker. Such “significance” can also be applied to any other measured parameter described herein, such as for expression, inhibition, cytotoxicity, cell growth, and the like.
The term “altered level of expression” of a biomarker refers to an expression level or copy number of the biomarker in a test sample, e.g., a sample derived from a patient suffering from a chronic immune disorder, that is greater or less than the standard error of the assay employed to assess expression or copy number, and is preferably at least twice, and more preferably three, four, five or ten or more times the expression level or copy number of the biomarker in a control sample (e.g., sample from a healthy subjects not having the associated disease) and preferably, the average expression level or copy number of the biomarker in several control samples. The altered level of expression is greater or less than the standard error of the assay employed to assess expression or copy number, and is preferably at least twice, and more preferably three, four, five or ten or more times the expression level or copy number of the biomarker in a control sample (e.g., sample from a healthy subjects not having the associated disease) and preferably, the average expression level or copy number of the biomarker in several control samples.
The term “altered activity” of a biomarker refers to an activity of the biomarker which is increased or decreased in a disease state, e.g., in a chronic immune disorder sample, as compared to the activity of the biomarker in a normal, control sample. Altered activity of the biomarker may be the result of, for example, altered expression of the biomarker, altered protein level of the biomarker, altered structure of the biomarker, or, e.g., an altered interaction with other proteins involved in the same or different pathway as the biomarker or altered interaction with transcriptional activators or inhibitors.”, see page 6, section 0032-0034.
The determining step reads on Applicant’s step of selecting treatment for the subject, whom a biomarker(s) has been detected. Haining further teaches once it is determined targeted therapy will be administered against the disorder, immunotherapy including anti-immune checkpoint inhibitor therapy is selected as it is able to evoke and increase immune response against the disorder. “In most cases, the actual determination of the suitable treatment regimen for the subject will be performed by the attending physician or doctor.”, see page 10, section 0058.
“[D]etermining 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 chronic immune disorder 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 chronic immune disorder to provide immunotherapy that generally increases immune responses against the chronic immune disorder (e.g., anti-CD39 therapy with or without anti-immune checkpoint inhibitor therapy)… The determination can, in addition to the results of the analysis according to the present invention, be based on personal characteristics of the subject to be treated. In most cases, the actual determination of the suitable treatment regimen for the subject will be performed by the attending physician or doctor.”, see page 10, section 0058.
The immunotherapy is inclusive of an “immunotherapeutic agent”… any molecule, peptide, antibody or other agent which can stimulate a host immune system to generate an immune response against the chronic immune disorder in the subject.”, see page 16, section 0086. Non-limiting examples of anti-immune checkpoint inhibitor therapy taught in Haining are (e.g., anti-PD-1, anti-PD-L1, anti-PD-L2, and anti-CTLA4 therapies), see page 2, sections 0008-0010; page 11, section 0064-page 14, section 0074; page 50, sections 0283, 0286; page 52, section 0294; and page 57, section 0340. With the administration of the immunotherapy, it would naturally flow that primarily natural killer (NK) cells would be leveraged and modifies the biomarker(s).
Haining teaches “prognosis” includes a prediction of the probable course and outcome of [a] …disorder or the likelihood of recovery from the disease.”, see page 17, 0097. Haining teaches the “…diagnostic assays, prognostic assays, and monitoring clinical trials are used for prognostic (predictive) purposes to thereby treat an individual prophylactically. Accordingly, one aspect of the present invention relates to diagnostic assays for determining the amount and/or activity level of a biomarker listed in Table 1 in the context of a biological sample (e.g., blood, serum, cells, or tissue) to thereby identify the presence of exhausted CD8+ T cells and/or the status of an individual afflicted with a chronic immune disorder.”, see page 55, section 0324.
“As described [in Haining], a “pre-determined” biomarker amount and/or activity measurement(s) may be a biomarker amount and/or activity measurement(s) used to, by way of example only, evaluate a subject that may be selected for treatment, evaluate a response to a therapy (e.g., anti-CD39 therapy with or without anti-immune checkpoint inhibitor therapy), and/or evaluate a response to a combination of therapies. A pre-determined biomarker amount and/or activity measurement(s) may be determined in populations of patients with or without a chronic immune disorder. The pre-determined biomarker amount and/or activity measurement(s) can be a single number, equally applicable to every patient, or the pre-determined biomarker amount and/or activity measurement(s) can vary according to specific subpopulations of patients…”, see page 32, section 0125.
“The pre-determined biomarker amount and/or activity measurement(s) can be any suitable standard. For example, the pre-determined biomarker amount and/or activity measurement(s) can be obtained from the same or a different human for whom a patient selection is being assessed. In one embodiment, the pre-determined biomarker amount and/or activity measurement(s) can be obtained from a previous assessment of the same patient…[T]he progress of the selection of the patient can be monitored over time.”, see page 32, section 0126.
“In another aspect, a method of monitoring the progression of a chronic immune disorder in a subject, comprising a) detecting at a first point in time the presence, copy number, amount, and/or activity of at least one biomarker listed in Table 1 in CD8+ T cells from a subject sample; b) repeating step a) during at least one subsequent point in time after administration of a therapeutic agent; and c) comparing the presence, copy number, amount, and/or activity detected in steps a) and b), wherein the presence or a significantly increased copy number, amount, and/or activity of the at least one biomarker listed in Table 1 in the CD8+ T cells from the first subject sample relative to at least one subsequent subject sample, indicates that the agent treats the chronic immune disorder in the subject, is provided. In one embodiment, the method further comprises determining the copy number, level of expression, and/or level of activity of at least one immune checkpoint inhibitor in the CD8+ T cells from the first subject sample; determining the copy number, level of expression, and/or level of activity of the at least one immune checkpoint inhibitor in the CD8+ T cells from the at least one subsequent subject sample; and comparing the differences in the copy number, level of expression, and/or level of activity of the at least one immune checkpoint inhibitor between the samples, wherein a significant decrease in the copy number, level of expression, and/or level of activity of the at least one immune checkpoint inhibitor in the at least one subsequent subject sample relative to the first subject sample further indicates that the agent treats the chronic immune disorder in the subject. In another embodiment, the method further comprises determining T cell effector function of the CD8+ T cells in the first subject sample; determining T cell effector function of the CD8+ T cells in the at least one subsequent subject sample; and comparing the T cell effector function determinations, wherein a significant increase in the T cell effector function of the CD8+ T cells in the at least one subsequent subject sample relative to the first subject sample further indicates that the agent treats the chronic immune disorder in the subject. In still another embodiment, the subject has undergone treatment, completed treatment, and/or is in remission for the chronic immune disorder in between the first point in time and the subsequent point in time. In yet another embodiment, the subject has undergone anti-immune checkpoint inhibitor therapy in between the first point in time and the subsequent point in time. 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 chronic immune disorder. 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.”, page 3, section 0012.
It would have been obvious to one of ordinary skill in the art before
the effective filing date of the claimed invention to combine the teachings of the references to assay biological samples for several different types potential biomarkers in cancer, as well as survey different values that yield information regarding cancer diagnosis, cancer prognosis, progression and monitoring of cancer, best treatment and/or efficacy of treatment, see all references in their entirety. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in all references, there are several art known methods in the art that can be efficiently and reproducibly implemented to analyze several candidate biomarkers for and discern their impact on a cancer patient’s clinical outcome, see all references in their entirety.
Conclusion
14. Any inquiry concerning this communication or earlier communications from the Examiner should be directed to ALANA HARRIS DENT whose telephone number is (571)272-0831. The Examiner works a flexible schedule, however she can generally be reached between the hours, 8AM-8PM, Monday through Friday.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Julie Wu can be reached on 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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ALANA HARRIS DENT
Primary Examiner
Art Unit 1643
Alana Harris Dent
13 March 2026
/Alana Harris Dent/
Primary Examiner, Art Unit 1643