DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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.
Status of the Claims
Claims 1-14 were previously canceled. New claims 15-34 have been added. Claims 15-34 are pending and examined herein.
Priority
This application, 18/708,619, filed 05/09/2024, is a 371 of PCT/EP2022/081379 filed on 11/10/2022, and claims benefit of EP21306577.4 filed on 11/10/2021. This priority is acknowledged and the claims examined herein are treated as having an effective filing date of 11/10/2021.
Information Disclosure Statement
The Information Disclosure Statement filed on 05/09/2024 is acknowledged and has been considered.
Claim Objections
Claims 16, 33, and 34 are objected to because of the following informalities:
Claim 16 recites “…wherein CD4+CD25highCD39high T cell further…” when it should recite “T cells”.
Claims 33 and 34 recite “…which method comprises…” and is objected to due to the use of incorrect grammar.
Appropriate correction is required.
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.
Claims 15-34 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claims 15 and 23 recite “…two immunotherapeutic agents, in particular an anti-PD-1 monoclonal antibody and an anti-CTLA4 antibody…”. The recitation of “in particular” represents exemplary language that renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention, or represent a description of examples or preferences which can lead to confusion over the intended scope of the claim. See MPEP § 2173.05(d).
Claim 19 recites “…the anti-CTLA4 monoclonal antibody”. The terms lack antecedent basis because an anti-CTLA4 monoclonal antibody was not recited or defined previously in the claim or in claim 15 from which it depends.
Claims 22 and 31 recite “…a step of dosing via ELISA at least one marker selected from VEGFA, IL6, CXCL8, granzyme, in the supernatant…”. The claim is indefinite because there are multiple possible conflicting interpretations based on the claim language and table provided. For example, it is unclear if the claim language is to be interpreted as the dosage of immunotherapy is determined by measuring one of the recited markers via ELISA. Or alternatively, if interpretation of the claim language would be that the markers in the supernatant are dosed using ELISA. Furthermore, in this second interpretation, it is unclear how the markers could be dosed if they are already present in the sample supernatant. As there are multiple potential conflicting interpretations of the claim language, these claims are indefinite.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 15-34 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception and a law of nature without significantly more. Claim 15 recites a “An in vitro method of predicting, assessing or monitoring the sensitivity or resistance of a subject having a cancer to an immunotherapy combining at least two immunotherapeutic agents, in particular an anti-PD-1 monoclonal antibody and an anti-CTLA4 antibody, wherein the method comprises a step of determining, before any immunotherapeutic treatment step in the subject, in a tumor sample of the subject, the presence of CD4+CD25highCD39high T cells, the presence of CD4+CD25highCD39high T cells in the tumor sample being indicative of sensitivity of the subject to the immunotherapy, and the absence of CD4+CD25highCD39high T cells in the tumor sample being indicative of resistance of the subject to the immunotherapy”.
Similarly, claim 23 recites “An in vitro method of predicting, assessing or monitoring the sensitivity or resistance of a subject having a cancer to an immunotherapy combining at least two immunotherapeutic agents, in particular an anti-PD-1 monoclonal antibody and an anti-CTLA4 antibody, after one or several treatment steps with the immunotherapy in the subject, wherein the method comprises a step a) of determining, in a tumor sample of the subject, the expression level of CD4+CD25highCD39high T cells, and a step b) of comparing said CD4+CD25highCD39high T cells level to a CD4+CD25highCD39high T cells reference expression level, an expression level of CD4+CD25highCD39high T cells below the CD4+CD25highCD39high T cells reference expression level being indicative of sensitivity of the subject to the immunotherapy and an expression level of CD4+CD25highCD39high T cells above the CD4+CD25highCD39high T cells reference expression level being indicative of resistance of the subject to the immunotherapy”.
The claims are directed to judicial exceptions, mainly they are abstract ideas, specifically, mental processes that can be performed in the human mind, and/or are merely observing naturally occurring correlations (laws of nature/natural correlation). These judicial exceptions are not integrated into a practical application because there is no practical application recited in the claims such as performing a treatment in a way that is particular, and not merely instructions to "apply" the exception in a generic way. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional steps amount to mere data gathering that does not go beyond well-understood, routine, and conventional activity; as detailed below.
Step 1 – Whether a claim is to a statutory category - YES
The instantly claimed invention is directed to in vitro methods of predicting, assessing or monitoring the sensitivity or resistance of a subject having a cancer to combined anti-PD-1 monoclonal antibody and an anti-CTLA4 antibody immunotherapy, before (claim 15) and after (claim 23) the treatment steps have occurred, by determining in a tumor sample of the subject the expression level of CD4+CD25highCD39high T cells. Therefore, the instantly claimed invention falls into one of the four statutory categories.
Step 2A Prong 1 – Whether the claim is directed to a judicial exception (i.e. Does the claim recite an abstract idea, law of nature, or natural phenomenon?) - YES
Claims 15 and 23 recite the following steps which fall under mental processes grouping of abstract ideas and/or laws of nature/natural correlation:
Claim 15 and 23 disclose to in vitro methods of predicting, assessing or monitoring the sensitivity or resistance of a subject having a cancer to combined anti-PD-1 monoclonal antibody and an anti-CTLA4 antibody immunotherapy, before (claim 15) and after (claim 23) the treatment steps have occurred. This is done by determining the presence (claim 15) or expression level (claim 23) of CD4+CD25highCD39high T cells in a cancer subjects tumor sample. In the method of claim 15, the mere presence or absence of CD4+CD25highCD39high T cells indicates immunotherapy sensitivity or resistance respectively. Whereas in the method of claim 23, expression levels of CD4+CD25highCD39high T cells are determined and compared to a reference expression level to determine immunotherapy sensitivity/resistance.
The broadest reasonable interpretation of these steps is measuring CD4+CD25highCD39high T cells in a tumor sample, and before treatment, if there is any amount of these cells detected the subject is predicted to be sensitive to immunotherapy. When the expression level of CD4+CD25highCD39high T cells is measured in a tumor sample after one or several immunotherapy treatment steps, and the level is any amount lower when compared to a reference expression level, that is indicative of sensitivity to the immunotherapy. These limitations recite a law of nature which is a judicial exception, because it is merely observing the correlation between a naturally occurring biomarker (CD4+CD25highCD39high T cells) and its relationship to a disease/disease state (cancer), and using these levels to make a determination of a subjects’ immunotherapy sensitivity, which are abstract ideas, specifically, abstract mental processes.
The “determining” steps can be regarded as a law of nature, namely, the naturally occurring correlation between levels of CD4+CD25highCD39high T cells and whether a subject’s cancer will be sensitive/resistance to immunotherapy. Regarding the identification of a correlation between the presence of a biomarker in a bodily sample and disease state the courts have held similar claims to be laws of nature and/or natural phenomena, as in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017) which involved claims to simply instruct a user to apply a natural law, by correlating naturally occurring enzyme levels with disease risk. In Mayo, the Supreme Court found that a claim was directed to a natural law, where the claim required administering a drug and determining the levels of a metabolite following administration, where the level of metabolite was indicative of a need to increase or decrease the dosage of the drug. See Mayo Collaborative Services V. Prometheus Labs., Inc., 566 U.S. 66, 74 (2012). The instant claims are similar to those in Mayo as they involve a "relation itself [which] exists in principle apart from any human action" (id. at 77). The instant claims do not recite administering an immunotherapy.
Regarding the step of “comparing” CD4+CD25highCD39high levels, the courts have held similar claims to be abstract mental processes, as in University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014) which involved claims to "comparing BRCA sequences and determining the existence of alterations," where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind. The claims are also similar to that in Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1067, 100 USPQ2d 1492, 1500 (Fed. Cir. 2011), which involved a claim to “collecting and comparing known information” (both of these court cases are discussed in MPEP 2106.04(a)(2) (II)(A)). The step of “determining” also constitutes an abstract mental process, involving assessing the comparison of expression levels of the biomarker in a test sample, and then making an evaluation or judgment as to the severity/state of a test subjects’ particular disease. The “comparing” and “determining” steps could be performed in the human mind, or by a human using pen and paper, insofar as it reads on comparing levels and drawing conclusions from this about the health status of a subject.
Thus, claims 15 and 23 fall into a judicial exception.
Step 2A: Prong 2 - Does the claim recite additional elements that integrate the judicial exception into a practical application? The Step 2A, Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception.
Claims 15-34 do not recite any additional element that integrate the exception into a practical application of the exception. The additional steps of measuring a T cell with additional markers (claims 16, 17, 25 and 26), specifying the immunotherapy treatment (claims 18, 19, 27, 28), selecting cancer type and tumor characteristics (claims 20, 21, 29, 30, and 32), dosing via ELISA (claims 22 and 31), and selecting an appropriate treatment or selecting/disqualifying a subject from a clinical trial (claims 33 and 34) are insufficient to integrate the exception into a practical application because the purpose is merely to obtain data and/or merely instructions to "apply" the exception in a generic way.
As in In re Grams, 888 F.2d 835, 839-40; 12 USPQ2d 1824, 1827-28 (Fed. Cir. 1989), such activity involving performing clinical tests on individuals constitutes mere data gathering, and does not go beyond insignificant extra-solution activity. See MPEP §§ MPEP 2106.04(d)(I) and 2106.05(g). There are no subsequent steps recited after the “determining” or “comparing” steps that would practically apply the method depending on the results of the measurements, e.g., treatment or other process steps that are performed after the test subject has been diagnosed with a disease.
In particular, of the claims indicated in the rejection heading, none of the additionally recited limitations amount to an additional element or combination of elements that apply, rely on, or use the judicial exceptions in a manner that impose meaningful limit on the judicial exceptions.
Step 2B; Whether the additional elements contribute an “inventive concept”. In the second step it is determined whether the claimed subject matter includes additional elements that amount to significantly more than the judicial exception. See MPEP 2106.05.
Briefly, claims 15-34 do not include additional elements that are sufficient to amount to significantly more than the judicial exception because of the following reasons. Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, has been found to be insufficient to add “significantly more” (MPEP 2106.05(I)(A)).
The additional steps recited above do not add a meaningful limitation to the instant method as they would have been routinely used by those of ordinary skill in the art as supported by Zitvogel et al. (WO2017140826A1), (herein referred to as Zitvogel), Retseck et al. (2018). “Long term impact of CTLA4 blockade immunotherapy on regulatory and effector immune responses in patients with melanoma”. Journal of Translational Medicine, 16(1), 184, (Retseck), Ottonello et al. (2020). “Association between response to nivolumab treatment and peripheral blood lymphocyte subsets in patients with non-small cell lung cancer”. Frontiers in Immunology, 11, 125, (herein referred to as Ottonello), and Gan et al. (2021). “Outcomes of patients with solid tumour malignancies treated with first-line immuno-oncology agents who do not meet eligibility criteria for clinical trials”. European Journal of Cancer, 151, 115-125, (published July 1, 2021), (herein referred to as Gan).
Zitvogel teaches an in vitro method of assessing the sensitivity of a subject having a cancer to an immunotherapy, in particular to an immunotherapy selected from anti-PD-1 monoclonal antibody, anti-PD-Ll monoclonal antibody, anti-CTLA-4 monoclonal antibody and a combination of anti- PD-1 and anti-CTLA-4 monoclonal antibodies, which method comprises a step a) of determining, in a biological sample from said subject which is a blood sample or a sample comprising tumor cells, the presence, absence or expression level of at least one biomarker, for example at least two biomarkers, and when the expression level is determined, a step b) of comparing said at least one expression level to a reference expression level or to a reference expression ratio, thereby predicting, assessing or monitoring whether the subject having a cancer is responsive or resistant to the immunotherapy (page 3, lines 29-32 – page 4, lines 1-17).
Retseck teaches the long-term impact of CTLA4 blockade immunotherapy on regulatory and effector immune responses in patients with melanoma (abstract). Retseck teaches that patients were treated with ipilimumab given at 10 mg/kg IV every 3 weeks for 2 doses bracketing surgery, and that blood specimens were collected at baseline and during treatment for up to 9 months. Retseck also teaches that immune responses were tested at 3, 6, and 9 months utilizing multicolor flow cytometry, and the comparison of frequencies of circulating regulatory T cells, including CD4+CD25hi+CD39+, and MDSC on-study to baseline levels, as well as frequencies of CD4+ and CD8+ T cells specific to shared tumor-associated antigens (abstract). Additionally, Retseck teaches that lower baseline levels of circulating CD4+CD25hi+CD39+ were significantly associated with better relapse free survival (abstract).
Ottonello teaches the performance of a high-dimensional flow cytometry analysis to investigate the distribution of different lymphocyte subsets in the peripheral blood of NSCLC patients prior and during anti-PD-1 immunotherapy, with the aim of verifying whether specific immune cell signatures could be related to the clinical outcomes (page 2, column 2, 1st paragraph). Ottonello teaches the study blood samples collected at baseline and during treatment in a cohort of advanced NSCLC patients (n = 74) treated with nivolumab (abstract). Additionally, Ottonello teaches the investigation of the impact of regulatory CD4+CD25+CD127negFoxp3+ Tcells (Tregs), including those co expressing CD39 (CD39+Tregs) in their samples because of their key role in the modulation of immune responses (page 5, column 1, 2nd paragraph – page 5, column 2, 1st paragraph). Ottonello also teaches that higher baseline levels of these T cells co expressing CD39 were correlated with controlled disease/clinical benefit of treatment, and also that patients displaying longer overall survival had significantly higher level of these T cells (page 7, column 1, 4th paragraph; page 9, column 1, 2nd full paragraph; page 9, column 2, 1st full paragraph).
Gan teaches an examination of the outcomes of patients with solid tumour malignancies treated with first-line immuno-oncology agents who do not meet eligibility criteria for clinical trials (title). Gan teaches that immuno-oncology (IO)–based therapies have been approved based on randomized clinical trials, yet a significant proportion of real-world patients are not represented in these trials (abstract). Additionally, Gan teaches that patients with advanced RCC, non–small-cell lung cancer (NSCLC) or melanoma treated with 1L PD-(L)1 inhibition–based therapy were included in the study (abstract). Gan teaches that trial eligibility was retrospectively determined based on inclusion and exclusion criteria selected based on the most commonly used criteria across currently published phase III 1L IO-based registration clinical trials of patients with advanced RCC, NSCLC and melanoma (page 116, column 2, 5th paragraph).
For all of these reasons, the claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s).
Therefore, the instantly rejected claims are not drawn to eligible subject matter as they are directed to a law of nature and abstract idea without significantly more. For additional guidance, applicant is directed generally to MPEP § 2106.
Claim Rejections - 35 USC § 103
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.
Claims 15, 18-24, 27-33 are rejected under 35 U.S.C. 103 as being unpatentable over Zitvogel et al. (WO2017140826A1), (herein referred to as Zitvogel), in view of Retseck et al. (2018). “Long term impact of CTLA4 blockade immunotherapy on regulatory and effector immune responses in patients with melanoma”. Journal of Translational Medicine, 16(1), 184, (Retseck), as evidenced by TIP (2010). “ELISA technical guide and protocols”. Thermo Fisher Scientific Inc USA, Bartlesville, OK, (herein referred to as TIP).
Regarding claims 15, 23, and 24, Zitvogel teaches an in vitro method of assessing the sensitivity of a subject having a cancer to an immunotherapy, in particular to an immunotherapy selected from anti-PD-1 monoclonal antibody, anti-PD-Ll monoclonal antibody, anti-CTLA-4 monoclonal antibody and a combination of anti- PD-1 and anti-CTLA-4 monoclonal antibodies, which method comprises a step a) of determining, in a biological sample from said subject which is a blood sample or a sample comprising tumor cells, the presence, absence or expression level of at least one biomarker, for example at least two biomarkers, selected from PD-1+CD4+ T cells, CD8+ T cells and CD25+CD127 CD4+ T cells, CD95+CD4+ T cells, CD95+CD8+ T cells, PD-L1+CD4+ T cells, PD-L1+CD8+ T cells, CLA+CD8+TEM cells, CD137L+CD4+ T cells, CD137L+CD8+ T cells, CD137+CD4+ T cells and CD137+CD8+ T cells, and, when the expression level is determined, a step b) of comparing said at least one expression level to a reference expression level or to a reference expression ratio, thereby predicting, assessing or monitoring whether the subject having a cancer is responsive or resistant to the immunotherapy (page 3, lines 29-32 – page 4, lines 1-17). For one embodiment, Zitvogel teaches that in step b) of comparing said levels to their respective reference expression levels, an expression level above the reference expression level being indicative of resistance of the subject to the immunotherapy, and an expression level below the reference expression level being indicative of sensitivity of the subject to the immunotherapy (page 16, lines 12-23). Zitvogel also teaches that typically, the "reference value" or "reference expression level" is the concentration of the biomarker in a control sample derived from one or more subjects (reference population) having a cancer (page 12, lines 11-14). Zitvogel teaches that for CD4+FoxP3+ Treg, a biological response was defined as a >1.5 fold decrease compared with the baseline levels in responders compared to non-responders (page 67, lines 30-32 – page 68, lines 1-2).
However, Zitvogel does not teach determining the presence or expression level of CD4+CD25highCD39high T cells specifically.
Retseck teaches the long-term impact of CTLA4 blockade immunotherapy on regulatory and effector immune responses in patients with melanoma (abstract). Retseck teaches that patients were treated with ipilimumab given at 10 mg/kg IV every 3 weeks for 2 doses bracketing surgery, and that blood specimens were collected at baseline and during treatment for up to 9 months. Retseck also teaches that immune responses were tested at 3, 6, and 9 months utilizing multicolor flow cytometry, and the comparison of frequencies of circulating regulatory T cells, including CD4+CD25hi+CD39+, and MDSC on-study to baseline levels, as well as frequencies of CD4+ and CD8+ T cells specific to shared tumor-associated antigens (abstract). Additionally, Retseck teaches that lower baseline levels of circulating CD4+CD25hi+CD39+ were significantly associated with better relapse free survival (abstract). Retseck teaches that the significant increase in Treg (CD4+CD25hi+Foxp3+ and CD4+CD25hi+CD39+) at 6 weeks reversed starting 3 months, and that CD4+CD25hiCD39+ Treg and HLA-DR+lowCD14+ MDSC may be baseline markers of immunotherapeutic benefit and warrant further study (page 9, column 2, 1st paragraph). Additionally, Retseck teaches that levels of the intracellular transcription factor Foxp3 is an accepted marker for regulatory T cells, there is evidence that CD39, which interacts with CD73, may also be critically informative (page 3, column 2, 3rd paragraph – page 4, column 1, 1st paragraph). CD4+CD25hiCD39+ Treg produce adenosine and therefore may possess more immunosuppressive function, and they are also found in increased levels in cancer patients (page 4, column 1, 1st paragraph).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the in vitro method of assessing the sensitivity of a subject having a cancer to an immunotherapy, as taught by Zitvogel, to detect the presence of CD4+CD25highCD39high T cells, as taught by Retseck, as a matter of using a known technique to improve similar devices in the same way. Both Zitvogel and Retseck, along with the instant application, are in the same field of endeavor of methods of predicting, assessing or monitoring a cancer patients’ response to immunotherapy by detecting T cells, representing the base method. Furthermore, both Zitvogel and Retseck teach the use of ipilimumab as the immunotherapy being used. Retseck teaches lower baseline levels of circulating CD4+CD25hi+CD39+ acted as a biomarker of better relapse free survival, therefore, measuring CD4+CD25hi+CD39+ in the method of Zitvogel would improve the base device. Addition of this significant biomarker to the in vitro method of predicting, assessing or monitoring a cancer patients’ response to immunotherapy could help make better informed treatment decisions which can improve patient outcomes. A person of ordinary skill in the art could have made this modification and the results would have been predictable because: both Zitvogel and Retseck teach the use of flow cytometry to measure the T cell biomarkers which is a well-understood, routine, and conventional activity in the art, and both also teach melanoma as the cancer that the patients have teach the use of ipilimumab as the immunotherapy.
Regarding claims 18 and 27, Zitvogel teaches that the anti-PD-1 monoclonal antibody is selected from nivolumab and pembrolizumab (page 7, lines 10-13).
Regarding claims 19 and 28, Zitvogel teaches that the anti-CTLA4 monoclonal antibody is selected from ipilimumab and tremelimumab (page 7, lines 18-20).
Regarding claims 20 and 29, Zitvogel teaches that the cancer or tumor is typically selected from melanoma, lung, in particular non-small cell lung cancer or small cell lung cancer, head and neck cancer, bladder cancer, in particular a bladder cancer with lymph nodes (LN) metastasis, mesothelioma cancer, oesophagus cancer, stomach cancer, hepatocarcinoma cancer, kidney or renal cancer, and breast cancer (page 8, lines 9-15).
Regarding claims 21 and 30, Zitvogel teaches that using a system biology approach aimed at defining immunometrics relevant for prediction of in situ response to classical therapeutic cytokines and novel mAb (agonistic and blockers of immune checkpoints) on freshly resected stage III melanoma (page 3, lines 1-5).
Regarding claims 22 and 31, Zitvogel teaches that a cell surface biomarker expression can easily be determined by FACS and a molecule cell release can easily be determined by ELISA (page 18, lines 27-30). Zitvogel teaches that the chemokine expression measured in the described "mLN assay" can be selected from CCL2, CCL3, CCL4, CCL5, CXCL8, CXCL9, CXCL10, and the interleukins measured can be selected from IL1B, IL2, IL6, IL10, IL12p70, or IL13 (page 19, lines 3-8). Zitvogel also teaches that metastatic lymph nodes containing 4-98% melanoma tumor cells (CD45+ cells) were resected, freshly mechanically and enzymatically dissociated for 1 hour at 37°C under rotation (2 incubation steps of 30 minutes) (page 24, lines 7-10). Additionally, Zitvogel teaches that the cytokine/chemokine accumulation in the 18-24 hrs supernatant can be measured by multiplex array and ELISA (page 34, lines 2-6). Zitvogel teaches that in the method of ELISA, after a period of incubation sufficient to allow the formation of antibody-antigen complexes, the plate(s) can be washed to remove unbound moieties and a detectably labelled secondary binding molecule added (page 21, lines 20-23). In one embodiment, Zitvogel teaches a CXCL10 dosage by ELISA on patients' lesions (Fig. 2A-E). Zitvogel teaches the use of a commercial ELISA kits (page 68, lines 15-18), which generally use an incubation step of at least one minute, as evidenced by TIP (page 9, Fig. step 7).
Regarding claim 32, Zitvogel teaches that metastatic lymph nodes (mLN) containing 4-98 % melanoma tumor cells (CD45+ cells) were resected, freshly mechanically and enzymatically dissociated using the Gentle MACs Miltenyi equipment for 1 hour at 37°C under rotation (2 incubation steps of 30 minutes) (page 24, lines 7-16).
Regarding claim 33, Zitvogel teaches that another particular method herein described is a method of selecting an appropriate chemotherapeutic treatment for a subject, which method comprises a step of predicting or assessing the sensitivity of a subject having a cancer or a malignant tumor to an immunotherapy using a method according to the present invention as described herein above. Zitvogel teaches that if the subject is identified as resistant to the proposed immunotherapy, the method further advantageously comprises an additional step of selecting a distinct chemotherapeutic treatment of cancer more appropriate for the subject (page 5, lines 11-17).
Claims 16, 17, 25 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Zitvogel in view of Retseck as applied to claim 15 above, and further in view of Ottonello et al. (2020). “Association between response to nivolumab treatment and peripheral blood lymphocyte subsets in patients with non-small cell lung cancer”. Frontiers in Immunology, 11, 125, (herein referred to as Ottonello).
The teachings of Zitvogel in view of Retseck are incorporated herein.
Regarding claims 16, 17, 25 and 26, Zitvogel in view of Retseck teaches all the limitations of claim 1 of the instant application, but does not teach that that the CD4+CD25highCD39high T cell further expresses at least one additional marker selected from CD3, CD45, CD 127 and Foxp3, or that the CD4+CD25highCD39high T cell is a CD127low T cell.
Ottonello teaches the performance of a high-dimensional flow cytometry analysis to investigate the distribution of different lymphocyte subsets in the peripheral blood of NSCLC patients prior and during anti-PD-1 immunotherapy, with the aim of verifying whether specific immune cell signatures could be related to the clinical outcomes (page 2, column 2, 1st paragraph). Ottonello teaches the study blood samples collected at baseline and during treatment in a cohort of advanced NSCLC patients (n = 74) treated with nivolumab (abstract). Additionally, Ottonello teaches the investigation of the impact of regulatory CD4+CD25+CD127negFoxp3+ Tcells (Tregs), including those co expressing CD39 (CD39+Tregs) in their samples because of their key role in the modulation of immune responses (page 5, column 1, 2nd paragraph – page 5, column 2, 1st paragraph). Ottonello also teaches that higher baseline levels of these T cells co expressing CD39 were correlated with controlled disease/clinical benefit of treatment, and also that patients displaying longer overall survival had significantly higher level of these T cells (page 7, column 1, 4th paragraph; page 9, column 1, 2nd full paragraph; page 9, column 2, 1st full paragraph). It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the in vitro method of predicting, assessing or monitoring the sensitivity or resistance of a subject having a cancer to an immunotherapy combining at least two immunotherapeutic agents, as taught by Zitvogel in view of Retseck, so the CD4+CD25highCD39high T cell expresses at least one additional marker and is a CD127low T cell, as taught by Ottonello, as a matter of using a known technique to improve similar devices in the same way. Zitvogel, Retseck and Ottonello, along with the instant application, are in the same field of endeavor of methods of predicting, assessing or monitoring a cancer patients’ response to immunotherapy by detecting T cells, representing the base method. Furthermore, both Zitvogel and Ottonello teach the use of nivolumab as the immunotherapy being used. Ottonello teaches that the T cell expressing CD4+CD25highCD39high and CD127low can act as a biomarker of controlled disease/clinical benefit of treatment and overall survival, therefore, measuring these T cells in the method of Zitvogel in view of Retseck would improve the base device. Addition of this significant biomarker to the in vitro method of predicting, assessing or monitoring a cancer patients’ response to immunotherapy could help make better informed treatment decisions which can improve patient outcomes. A person of ordinary skill in the art could have made this modification and the results would have been predictable because: both Zitvogel, Retseck and Ottonello teach the use of flow cytometry to measure the T cell biomarkers which is a well-understood, routine, and conventional activity in the art, and both also teach melanoma as the cancer that the patients have teach the use of ipilimumab as the immunotherapy.
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over Zitvogel and Retseck in view of Gan et al. (2021). “Outcomes of patients with solid tumour malignancies treated with first-line immuno-oncology agents who do not meet eligibility criteria for clinical trials. European Journal of Cancer, 151, 115-125”, (published July 1, 2021), (herein referred to as Gan).
The teachings of Zitvogel and Retseck as applied above are incorporated herein.
Regarding claim 34, Zitvogel and Retseck teach the method of predicting or assessing the sensitivity of a subject having a cancer to an immunotherapy combining at least two immunotherapeutic agents of claim 15.
However, Zitvogel and Retseck do not teach a method of selecting or disqualifying a subject having a cancer for inclusion in a clinical trial, the clinical trial being for evaluating an immunotherapy combining at least two immunotherapeutic agents.
Gan teaches an examination of the outcomes of patients with solid tumour malignancies treated with first-line immuno-oncology agents who do not meet eligibility criteria for clinical trials (title). Gan teaches that immuno-oncology (IO)–based therapies have been approved based on randomized clinical trials, yet a significant proportion of real-world patients are not represented in these trials (abstract). Additionally, Gan teaches that patients with advanced RCC, non–small-cell lung cancer (NSCLC) or melanoma treated with 1L PD-(L)1 inhibition–based therapy were included in the study (abstract). Gan teaches that trial eligibility was retrospectively determined based on inclusion and exclusion criteria selected based on the most commonly used criteria across currently published phase III 1L IO-based registration clinical trials of patients with advanced RCC, NSCLC and melanoma (page 116, column 2, 5th paragraph). Gan teaches that seven factors were chosen as the exclusion criteria: Karnofsky performance status (KPS) < 70% or Eastern Cooperative Oncology Group (ECOG) performance status > 1, haemoglobin (Hb) < 9 g/dL, the presence of brain metastases, estimated glomerular filtration rate (eGFR) < 40 mL/min, platelets < 100,000/mm3, neutrophils < 1500/mm3 and no clear-cell component on pathology specimen (for RCC only) (page 117, column 1, 1st paragraph). Furthermore, Gan teaches that clinical trial eligibility criteria may be duplicated from historical study protocols that examined chemotherapy or targeted therapy, which may not be appropriate in the era of IO therapy (page 120, column 2, 2nd paragraph).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of predicting or assessing the sensitivity of a subject having a cancer to an immunotherapy combining at least two immunotherapeutic agents as taught by Zitvogel and Retseck, to use the data to select or disqualify a subject having a cancer for inclusion in an immunotherapy clinical trial, as taught by Gan, as a matter of combining prior art elements according to known methods to yield predictable results. Gan demonstrates that using a patient’s data/physiological markers (based on previous data regarding those markers) to determine inclusion/exclusion of a cancer patient into an immunotherapy clinical trial a well-understood, routine, and conventional activity in the art. Zitvogel and Retseck also the use of biomarkers (T cells) to determine/predict a cancer patients’ response to immunotherapy.
There is nothing prohibiting the combination of the method of Zitvogel and Retseck using the method of Gan, as it would merely require using the determined significant associations of the T cells measured and treatment sensitivity to determine cutoff values for trial inclusion. Therefore, each element merely performs the same function as it does separately. Using the method of Zitvogel and Retseck to select or disqualify patients from clinical trials may improve clinical trial eligibility criteria to help make better informed treatment decisions, as Gan teaches that the current eligibility criteria may be duplicated from historical study protocols that examined chemotherapy or targeted therapy, which may not be appropriate in the era of IO therapy. A person of ordinary skill in the art could have made this modification and the results would have been predictable because: all references teach melanoma patients as the subjects and teach the use of CTLA-4 inhibitors as one of the used immunotherapies for these patients.
Conclusion
For all the reasons discussed above, claims 15-34 are rejected and therefore no claims are allowed.
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/ALEXANDER J. HOFFMAN/ Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 August 7, 2026
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