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 .
Election/Restrictions
Applicant’s election without traverse of Group 1, claims 1-16 and 26 and species of tumor determination parameters of a) intratumoral infiltration by macrophages and b) proximity of lymphocytes to tumor cells (claims 1, 11, and 16) and an anti-angiogenic drug which is a tyrosine kinase inhibitor (claim 7) in the reply filed on June 4, 2026 is acknowledged.
Claims 17-22 and 24-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions and claims 14-15 and 26 are withdrawn as being drawn to non-elected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on June 4, 2026.
Claims 1-13 and 16 are examined on the merits.
Priority
The instant application is a 35 U.S.C 371 national stage filing of the International Application No. PCT/EP2021/062705 filed on May 12, 2021. The instant application claims foreign priority under 35 U.S.C 119(a)-(d) to European Patent Application EP20174467.9 filed on May 13, 2020. Receipt is acknowledged of a certified copy of the foreign patent application as required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on August 2, 2023 and December 20, 2024 is in compliance with the provisions of 37 CFR 1.97 and is being considered by the examiner.
Claim Objections
Claim 26 is objected to because of the following informalities: there should be a comma between Ramucirumab and Ziv-aflibercept. 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 1, 5, 10, 12-13, and 16 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.
Claim 1 recites the limitation "the prognosis" in line 1. There is insufficient antecedent basis for this limitation in the claim as there is no prior recitation of prognosis. Appropriate correction is required. It is recommended that Applicant ament claim 1 to recite “a prognosis”.
Claim 5, which depends from claim 1, recites the limitation "the sample" in line 3. There is insufficient antecedent basis for this limitation in the claim as the prior recitation is to “one or more samples”. As instantly claimed is not clear whether “the sample” is intended to refer to the same one or more samples as recited in claim 1 or a different sample. Appropriate correction is required.
Claim 10 which depends from claim 9, recites the limitation "wherein the binder, inhibitor, or antagonist" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim as the prior recitation is to “wherein the binder, inhibitor, or antagonist of at least one of CTLA-4, PD-1, PD-L1, LAG 3, TIM3, OX40 and/or TIGIT”. As instantly claimed is not clear whether “the binder, inhibitor, or antagonist” is intended to refer to the same binder, inhibitor, or antagonist of at least one of CTLA-4, PD-1, PD-L1, LAG 3, TIM3, OX40 and/or TIGIT as recited in claim 9 or a different binder, inhibitor, or antagonist. Appropriate correction is required.
Claim 12 recites the phrase "preferably" in lines 3 and 5 which 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). Appropriate correction is required.
Claim 12, which depends from claim 1, recites the limitation "the sample" in line 3. There is insufficient antecedent basis for this limitation in the claim as the prior recitation is to “one or more samples”. As instantly claimed is not clear whether “the sample” is intended to refer to the same one or more samples as recited in claim 1 or a different sample. Appropriate correction is required.
Claim 12, which depends from claim 1, recites the limitation "the tumor tissue identified therein" in lines 3 and 5. There is insufficient antecedent basis for this limitation in the claim as there is no prior recitation of a tumor tissue or limitation indicating that the one or more samples as recited in claim 1 must be from tumor tissue. Claim 1 recites that the sample could be from “a patient at risk of developing a solid tumor” which indicates the instantly claimed method could be performing in patients who do not have any tumor tissue. Appropriate correction is required.
Claim 12, which depends from claim 1, recites the limitation "the tumor" in line 5. There is insufficient antecedent basis for this limitation in the claim there is no prior recitation of a tumor. . Claim 1 recites that the sample could be from “a patient at risk of developing a solid tumor” which indicates the instantly claimed method could be performing in patients who do not have any tumor tissue. Appropriate correction is required.
Claim 13 recites the limitation "determining the distance between lymphocytes and cells…" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim as the prior recitations are to tumor cells. As claimed, it is unclear whether “cells” is intended to refer to the tumor cells as previously recited or a different cell type. Appropriate correction is required.
Claim 16 recites the phrases “low intratumoral infiltration” in line 2, “small distance” in line 3, “high likelihood” in line 7, and “better clinical outcome” in line 8 which are subjective terms which render the claim indefinite. A claim may be rendered indefinite by reference to subjective term (see MPEP 2173.05(b), IV). The phrases “low intratumoral infiltration”, “small distance”, and “high likelihood”, and “better clinical outcome” are not defined by the claim, the specification does not provide a standard for measuring the scope of the term, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Appropriate correction is required.
A claim that requires the exercise of subjective judgment without restriction may render the claim indefinite. In re Musgrave, 431 F.2d 882, 893, 167 USPQ 280, 289 (CCPA 1970). Claim scope cannot depend solely on the unrestrained, subjective opinion of a particular individual purported to be practicing the invention. Datamize LLC v. Plumtree Software, Inc., 417 F.3d 1342, 1350, 75 USPQ2d 1801, 1807 (Fed. Cir. 2005)); see also Interval Licensing LLC v. AOL, Inc., 766 F.3d 1364, 1373, 112 USPQ2d 1188 (Fed. Cir. 2014) (holding the claim phrase "unobtrusive manner" indefinite because the specification did not "provide a reasonably clear and exclusive definition, leaving the facially subjective claim language without an objective boundary"). During prosecution, the applicant may overcome a rejection by amending the claim to remove the subjective term, or by providing evidence that the meaning of the term can be ascertained by one of ordinary skill in the art when reading the disclosure. However, "[f]or some facially subjective terms, the definiteness requirement is not satisfied by merely offering examples that satisfy the term within the specification." DDR Holdings, LLC v. Hotels.com, L.P., 773 F.3d 1245, 1261, 113 USPQ2d 1097, 1108 (Fed. Cir. 2014).
Claim 16, which depends from claim 1 recites the limitation "anti-angiogenesis therapy and/or immune checkpoint inhibition therapy" in line 9. There is insufficient antecedent basis for this limitation in the claim as claim 1 only recites use of an anti-angiogenic drug. Appropriate correction is required.
Claim 16 recites the phrase “…based on the therapeutic agents and regimens discussed herein elsewhere” which renders the scope of the claim indefinite. As instantly claimed, it is not clear which therapeutic agents and regimens discussed are intended to be encompassed by the claim. 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.
Claims 1-13, and 16 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Claim 1 recites a method for the prognosis of disease progression in a patient, said method comprising determining in one or more samples intratumoral infiltration by macrophages and proximity to lymphocytes wherein the prognosis is an assessment of the likelihood of efficacy of a therapy. Claims 3-13, and 16 depend from claim 1. Therefore claims 1-13 and 16 are drawn to the statutory category of a process and eligible under Step 1.
Claims 1 and 2 recite a method for the prognosis of disease progression in a patient, said method comprising determining in one or more samples intratumoral infiltration by macrophages and proximity to lymphocytes wherein the prognosis is an assessment of the likelihood of efficacy of a therapy. The method of claim 1 ultimately recites a determination of macrophage intratumoral infiltration and proximity of lymphocytes to tumor cells which is a mental process and using that determination to make an decision regard the likelihood of efficacy of a treatment which also a mental process. Therefore, claims 1 and 2 recite concepts which fall into the judicial exception of the mental processes group of abstract ideas (e.g., determining, assessing, deciding).
Claims 3-5 recite the method of claim 1 and further limit the types of tumor and samples to be used in the method.
Claim 6 recites the method of claim 1 further comprising determining the presence or absence of a type of tissue which is also drawn to a mental process.
Claims 7-10 recite the method of claims 2 and 1 and further limit the types of therapy for which the efficacy is to be determined by the method of claim 1.
Claims 11 and 12 recite the method of claim 1 and further limit the method of determining intratumoral infiltration by macrophages and proximity to lymphocytes.
Claim 13 recites the method of claim 1 wherein the proximity of lymphocytes to tumor cells is determined by determining the distance which is drawn to the judicial exception of either a mental process if “determining the distance” is based on a visual evaluation and decision or mathematical concepts if “determining the distance” is based on a measurement.
Claim 16 recites the method of claim 1 wherein low infiltration and small distances are indicative of high likelihood of survival and/or better clinical outcome, which are considered to be decisions and therefore are also drawn to a mental process.
Therefore, claims 1-13 and 16 are drawn to the judicial exception of abstract ideas under Step 2A, Prong One.
This judicial exception is not integrated into a practical application because the additional method steps are no more than insignificant extra-solution activity and instructions to apply it. Claim 1 recites steps of determining intratumoral infiltration of macrophages and proximity of lymphocytes to tumor cells. Claim 1 does not provide limitations regarding how intratumoral infiltration of macrophages and proximity of lymphocytes is determined. Claims 11 and 12 recite methods by which the level macrophage infiltration of lymphocyte proximity is to be determined that comprise immunoassays or PCR (claim 11) and methods by which the level macrophage infiltration is to be determined by detection of CD163 or CD68 expression or detection of CD 163+ or CD68+ cells (claim 12). However, these additional method steps are performed in order to generate the conditions and/or data required for the use of the recited judicial exception of making a decision regarding the likelihood of efficacy of a therapy. Although claims 1 and 2 recite that the therapy comprises administration of a drug or drugs, the administration step is not considered to be positively recited as claims 1 and 2 are drawn to determining the prognosis of disease progression in a patient by making an assessment of the likelihood of the efficacy of administration of a particular therapy but does not recite that the assessment is used to effect a particular treatment or prophylaxis of those therapies for a particular patient (See MPEP 2106.04(d)).
Therefore, the judicial exceptions are not integrated into a practical application under Step 2A, Prong Two.
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception under Step 2B because the instant disclosure teaches well-understood, routine, and conventional methods which are implemented for the steps of determining intratumoral infiltration of by macrophages and proximity of lymphocytes (e.g., immunoassays, PCR, detection of expression) (See MPEP 2106.05(d)) as well as mere instructions to apply the judicial exemption without integration of the method into a practical application (See MPEP 2106.05(f)).
Claim Rejections - 35 USC § 102
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.
Claims 1, 3-6, and 11-12 are rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by Li and Franklin (WO 2015/117164 A1, hereafter “Li”).
With regard to claim 1, Li discloses an in vitro method for stratifying a subject suffering from a solid tumor as a candidate for therapy based on assessing cytotoxic phenotype (CD8+) tumor-associated lymphocytes in a biological sample derived from said patient (claim 1, Pg. 6; Pg. 18, 4th para.) and assessing the number of tumor associated macrophages (TAMs) in the sample (claim 6; Pg. 7, 5th para.). Assessing the number of macrophages in a biological sample, which Li discloses could be a tumor sample such as a biopsy (Pg. 16, 4th para.) is considered to reasonably read on intratumoral infiltration. Similarly, presence of cytotoxic lymphocytes in a biological sample, which Li discloses could be a tumor sample such as a biopsy (Pg. 16, 4th para.) is considered to reasonably read on assessment of infiltration of cytotoxic lymphocytes which a skilled artisan would understand that increased infiltration of cytotoxic lymphocytes would lead to increased proximity of those lymphocytes to tumor cells (See also Fig. 11).
Li also discloses an embodiment using determination of the density of cytotoxic lymphocytes within tumor tissue (Pg. 16, 1st para.) which is also considered to be related to proximity to tumor cells.
Li discloses that the method can be used to determine whether the subject is a suitable candidate for treatment with an immune checkpoint inhibitor (claims 1 and 6; Pg. 6; Pg. 18, 4th para.) and a suitable candidate for treatment with an Notch signaling pathway inhibitor or CSF-1 inhibitor (claim 12; Pg. 8-9 bridging para.). Li discloses that the Notch signaling pathway promotes angiogenesis (Pg. 34, 1st para.), therefore, a Notch signaling pathway inhibitor is considered to reasonably read on an anti-angiogenic drug. Li further discloses that stratifying patients includes determining the likelihood that a patient will respond to a certain therapy (Pg. 6, 1st para.; Pg. 16, 2nd para.) which is considered to reasonably read on an assessment of likelihood of efficacy of a therapy.
With regard to claims 3 and 4, Li discloses that the solid tumor can be from esophageal cancer (claim 5; Pg. 7, 4th para.)
With regard to claim 5, Li discloses that the biological sample can be a biopsy (Pg. 16, 4th para.), which a skilled artisan would recognize could be an esophageal biopsy based on Li’s teaching of the method for use in esophageal cancer (claim 5; Pg. 7, 4th para.).
With regard to claim 6, Li discloses evaluation of tumor tissue (Pg. 42, 3rd para.; Example 11), which is considered to reasonably read on determining the presence or absence of tumor tissue.
With regard to claim 11, Li discloses use of PCR for detection of Mafb (Pg. 44, 3rd para.) and that Mafb expression can be used to identify TAMs (See Example 1) as well as use of immunofluorescence staining for detection of TAMs (Example 11, Fig. 11A) and assessment of the presence and density of cytotoxic lymphocytes within tumor tissue, which a skilled artisan would recognize increased presence/density would be related to proximity to tumor cells, and that presence can be determined by immunofluorescence (Example 11; Fig. 11B).
With regard to claim 12, Li discloses that presence of TAMs can be determined by detection of CD68 (Example 9).
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 2, 9-10, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Li and Franklin (WO 2015/117164 A1, hereafter “Li”).
With regard to claim 2, as detailed above, Li teaches a method for stratifying a subject suffering from a solid tumor as a candidate for therapy based on assessing cytotoxic phenotype (CD8+) tumor-associated lymphocytes in a biological sample derived from said patient (claim 1, Pg. 6; Pg. 18, 4th para.) and assessing the number of tumor associated macrophages (TAMs) in the sample (claim 6; Pg. 7, 5th para.). Assessing the number of macrophages in a biological sample, which Li teaches could be a tumor sample such as a biopsy (Pg. 16, 4th para.) is considered to reasonably read on intratumoral infiltration. Similarly, presence of cytotoxic lymphocytes in a biological sample, which Li teaches could be a tumor sample such as a biopsy (Pg. 16, 4th para.) is considered to reasonably read on assessment of infiltration of cytotoxic lymphocytes which a skilled artisan would understand that increased infiltration of cytotoxic lymphocytes would lead to increased proximity of those lymphocytes to tumor cells (See also Fig. 11). Li also teaches an embodiment using determination of the density of cytotoxic lymphocytes within tumor tissue (Pg. 16, 1st para.) which is also considered to be related to proximity to tumor cells.
Li teaches use of the method in order to determine whether the subject is a suitable candidate for treatment with an immune checkpoint inhibitor (claims 1 and 6; Pg. 6; Pg. 18, 4th para.) and a suitable candidate for treatment with a Notch signaling pathway inhibitor or CSF-1 inhibitor (claim 12; Pg. 8-9 bridging para.). Li teaches that the Notch signaling pathway promotes angiogenesis (Pg. 34, 1st para.), therefore, a Notch signaling pathway inhibitor is considered to reasonably read on an anti-angiogenic drug. Li further teaches that stratifying patients includes determining the likelihood that a patient will respond to a certain therapy (Pg. 6, 1st para.; Pg. 16, 2nd para.) which is considered to reasonably read on an assessment of likelihood of efficacy of a therapy.
Li teaches the method for stratifying patients based on likelihood of efficacy of a therapy could apply to combinations of drugs (Pg. 40, 1st para.) including combination therapy of drugs comprising a checkpoint inhibitor and another “target” inhibitor or conventional therapeutic modality which can be administered concomitantly or consecutively (Pg. 13, last para.). Li teaches both a therapy which is an immune checkpoint inhibitor and a therapy which is anti-angiogenic, although Li is silent as to the use of these specific therapies together. However, Li teaches that TAMs are promising targets for cancer immunotherapy (Pg. 29, 1st full para.) and that increased presence of TAMs is associated with a high number of lymphocytes which are dysfunctional and not able to perform cytotoxic functions (Pg. 16, 2nd para.; Pg. 37, 2nd para.).
Therefore, it would have been obvious to one having ordinary skill in the art, before the effective filing date of the claimed invention, to use a combination therapy of an anti-angiogenic drug and an immune checkpoint inhibitor based on the teachings of Li with a reasonable expectation of success. A skilled artisan would have been motivated to use this combination in order to decrease the number of TAMs, which Li teaches are “promising targets” for cancer immunotherapy (Pg. 29, 1st full para.) and prevent cytotoxic lymphocytes from properly functioning, in addition to use of the immune checkpoint inhibitor which Li teaches are useful as a cancer therapy for patients having a solid tumor (Pgs. 5-6, bridging para.). Additionally, MPEP 2144.06 states "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). One having ordinary skill in the art would have had a reasonable expectation of success as Li teaches that combination therapies can be useful in the treatment of cancer.
With regard to claim 9, Li teaches that the immune checkpoint inhibitor can be a PD-1 inhibitor (claim 4; Pg. 7, 3rd para.).
With regard to claim 10, Li teaches that the immune checkpoint inhibitor can be nivolumab (Table 1).
With regard to claim 16, Li teaches that high densities of tumor infiltrating lymphocytes are linked to improved clinical outcome and patient survival in various cancers and that tumor progression is characterized by accumulation of macrophages (Pg. 2, 2nd para.), specifically that macrophage density is associated with tumor growth (Pg. 4, 1st full para.). Li teaches that increased TAMs are associated with increased cytotoxic lymphocytes which are dysfunctional and are not able to perform cytotoxic functions (Pg. 16, 2nd para.; Pg. 37, 2nd para.) and that immune checkpoint inhibitors can be used to upregulate anti-tumor activity (Pg. 5). Ultimately, the entire teaching of Li suggests increasing cytotoxic lymphocytes and reducing TAMs is beneficial in the treatment of tumors. Therefore, Li teaches that low intratumoral macrophages and high infiltrating lymphocytes, which a skilled artisan would recognize would mean less distance between tumor cells and lymphocytes, are anti-tumorigenic and therefore would be considered indicators of improved outcome or higher likelihood of patient survival.
Claims 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Li as applied to claims 1 and 2 above, and further in view of Fukuoka et al. (2019, Regorafenib plus nivolumab in patients with advanced gastric (GC) or colorectal cancer (CRC): An open-label, dose-finding, and dose-expansion phase 1b trial (REGONIVO, EPOC1603), found in IDS dated 08/02/2023).
With regard to claims 7 and 8, as detailed above, Li teaches a method for stratifying a subject suffering from a solid tumor as a candidate for therapy based on assessing cytotoxic phenotype (CD8+) tumor-associated lymphocytes in a biological sample derived from said patient (claim 1, Pg. 6; Pg. 18, 4th para.) and assessing the number of tumor associated macrophages (TAMs) in the sample (claim 6; Pg. 7, 5th para.) which are considered to reasonably read on intratumoral infiltration proximity of lymphocytes to tumor cells. Li teaches use of the method in order to determine whether the subject is a suitable candidate for treatment with an immune checkpoint inhibitor (claims 1 and 6 , Pg. 6; Pg. 18, 4th para.) and a suitable candidate for treatment with an anti-angiogenic drug and Li’s teaching of anti-angiogenics and immune checkpoint inhibitors separately as well as use of combination therapies is considered to render obvious the use of a combination therapy comprising an anti-angiogenic drug and an immune checkpoint inhibitor. Li further teaches that stratifying patients includes determining the likelihood that a patient will respond to a certain therapy (Pg. 6, 1st para.; Pg. 16, 2nd para.) which is considered to reasonably read on an assessment of likelihood of efficacy of a therapy. Additionally, Li teaches use of the method in patients suffering from a solid tumor, which can be a colon carcinoma (Pg. 17, 2nd para.).
While Li teaches anti-angiogenics which are Notch signaling inhibitors and CSF-1 inhibitors (claim 12; Pg. 8-9 bridging para.), and that these anti-angiogenic are related to reduction of TAMS (See Pgs. 34 and 35), Li is silent as to an anti-angiogenic which is a tyrosine kinase inhibitor.
Fukuoka teaches that TAMs are associated with resistance to immune checkpoint inhibitors such as PD-1 and that regorafenib, an anti-angiogenic and oncogenic kinase inhibitor, reduces TAMs in in tumor models and could be combined with an anti-PD-1 therapy to provide better tumor growth suppression. Fukuoka teaches that use of a combination of regorafenib and nivolumab provided anti-tumor activity in patients having colorectal cancer and is a promising therapy (whole document).
Therefore, it would have been obvious to one having ordinary skill in the art, before the effective filing date of the claimed invention to choose the anti-angiogenic regorafenib for treatment of colorectal cancer as taught by Fukuoka in the method of determining the likelihood of efficacy of a combination treatment comprising an anti-angiogenic drug and an immune checkpoint inhibitor which can be used for patients having colon carcinoma as taught by Li with a reasonable expectation of success. A skilled artisan would have been motivated to choose the anti-angiogenic regorafenib because Fukuoka teaches regorafenib is a potent anti-angiogenic which is effective for treatment of colorectal cancer and would have had a reasonable expectation of success as both Li and Fukuoka teach combination therapies comprising an anti-angiogenic and an immune checkpoint inhibitor (i.e., nivolumab) as tumor therapies.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Li as applied to claim 1, and further in view of Barua et al. (2018, Spatial interaction of tumor cells and regulatory T cells correlates with survival in non-small cell lung cancer. Lung Cancer, 117, 73-79, hereafter “Barua”).
With regard to claim 13, as detailed above, Li teaches a method for stratifying a subject suffering from a solid tumor as a candidate for therapy based on assessing cytotoxic phenotype (CD8+) tumor-associated lymphocytes in a biological sample derived from said patient (claim 1, Pg. 6; Pg. 18, 4th para.) and assessing the number of tumor associated macrophages (TAMs) in the sample (claim 6; Pg. 7, 5th para.) which are considered to reasonably read on intratumoral infiltration proximity of lymphocytes to tumor cells. Li also teaches an embodiment using determination of the density of cytotoxic lymphocytes within tumor tissue (Pg. 16, 1st para.) which is also considered to indicate proximity to tumor cells. Further, Li teaches use of immunofluorescence to evaluate cytotoxic lymphocytes (Example 11, Fig. 11B). Li teaches the method can be used in order to determine whether the subject is a suitable candidate for treatment with an Notch signaling pathway inhibitor or CSF-1 inhibitor (claim 12; Pg. 8-9 bridging para.), which is considered to reasonably read on an anti-angiogenic drug. Li further teaches that stratifying patients includes determining the likelihood that a patient will respond to a certain therapy (Pg. 6, 1st para.; Pg. 16, 2nd para.) which is considered to reasonably read on an assessment of likelihood of efficacy of a therapy.
While Li teaches assessment of lymphocyte infiltration and use of determining the density of cytotoxic lymphocytes in a tumor and use of fluorescent staining, Li is silent as to determining the distance between lymphocytes and cells characterized by the presence of a tumor marker.
Barua teaches measurement of the abundance and spatial location of immune cells including CD8+ cells in the tumor microenvironment via staining of various types of cells, assignment of coordinates for each type of stained cell in tumor samples, and use of the G-cross spatial distance method to determine the probability of finding an immune cell within a given proximity to a tumor cell (Abstract). Barua teaches the G-cross method is a quantitative measure of spatial proximity between tumor and T cells (Pg. 74, left col., 3rd para.), which is considered to reasonably read on determining proximity by determining the distance between lymphocytes and tumor cells, and use of staining for cytokeratin (Pg. 74, right col., 1st full para.), which is considered to reasonably read on a tumor marker. Barua teaches that increased infiltration of CD8+ lymphocytes in tumor regions is associated with improved survival (Abstract) and that the spatial context of immune cells in the tumor microenvironment, which goes beyond methods such as counting or density, is an important determinant for prognostic value (Pg. 77, right col., 1st full para.).
Therefore, it would have been obvious to one having ordinary skill in the art, before the effective filing date of the claimed invention, to use the G-cross method of to determine spatial distance of lymphocytes to tumor cells as taught by Barua in the method of assessing the likelihood of efficacy of a therapy based on infiltration of macrophages and lymphocytes in a tumor as taught by Li with a reasonable expectation of success. A skilled artisan would have been motivated to use the G-cross method as Barua teaches that existing measurements of lymphocyte infiltration in the tumor microenvironment such as density are overly simplistic and do not allow for spatial context which is important predictor of prognosis. One having ordinary skill in the art would have had a reasonable expectation of success as both Li and Barua teach evaluation of CD8+ cells in tumor samples as predictors of prognosis.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIN V PAULUS whose telephone number is (571)272-6301. The examiner can normally be reached Mon-Fri 8 AM-5 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Doug Schultz can be reached at 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ERIN V PAULUS/Examiner, Art Unit 1631
/ARTHUR S LEONARD/Examiner, Art Unit 1631
Prosecution Insights