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 .
Claims Status
The Amendment filed on 03Jun2026 is acknowledged in which claim(s) 1-16 were canceled by Applicant.
Applicant’s election without traverse of Group I (e.g., claims 17-30) in the reply filed on 03Jun2026 is acknowledged.
Claim(s) 31-36 is/are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03Jun2026.
Claim(s) 17-30 is/are presented for examination on the merits.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code [e.g., ¶ 0130-0131] . Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of trade name(s) or mark(s) used in commerce (e.g., EQ Four Element Calibration Beads, FlowJo), has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Interpretation
Claim(s) 23 recite(s) “determining the level of expression of FOLR2 gene in the patient tumor sample”. The broadest reasonable interpretation is considered to mean determining FOLR2 expression for any cells (e.g., TILs, macrophages, etc.) within a patient’s tumor sample.
Claim(s) 24 recite(s) “determining the level of expression of FOLR2 protein in the patient tumor sample”. The broadest reasonable interpretation is considered to mean determining FOLR2 protein level for any cells (e.g., TILs, macrophages, etc.) within a patient’s tumor sample.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
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.
Claim(s) 17-30 is/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(s) 17 (and dependent 18-30) recite(s) “comprising: determining the level of FOLR2+ macrophages in a patient tumor sample…correlates positively with outcome of cancer diseases or treatment…” in claim(s) 17. The claim(s) and the specification do not expressly and clearly define the meanings of the limitations within the above phrase. Specifically, in the phrase above it is unclear what the FOLR2+ macrophage levels are being compared to (e.g., FOLR2- macrophages, an unknown reference, etc.). For the purposes of compact prosecution, any measurement of FOLR2+ levels in tumor associated (e.g. stromal, tumor infiltrating, etc.) macrophages is considered to meet all of the limitations of instant claim(s) 17. This rejection may be overcome by amending claim(s) 17 to clearly recite the limitation(s) of the claim. Claim(s) 18-30 can overcome this rejection by amending claim(s) 17 as described above.
Claim(s) 18 recite(s) the phrase “elevated level of FOLR2+ macrophages…as compared to a reference” in line 2, rending the claim(s) indefinite. Specifically, it is unclear if the reference is (1) FOLR2- macrophages; (2) cancer cells; (3) non-macrophage stromal or tumor-infiltrating cells; or (4) something else. For the purposes of compact prosecution, the “reference” is considered to be a FOLR2- macrophage. Therefore, any FOLR2+ macrophages associated with tumor (e.g., stromal, tumor infiltrating, etc.) are considered to read on the instant claim. This rejection may be overcome by amending claim 18 to (1) remove the phrase “as compared to a reference”, or (2) otherwise clearly recite the limitation(s) of the instant claim.
Claim(s) 29 recite(s) the phrase “or a combination of chemotherapy agent and immunotherapy agent or endocrine therapy agent” in lines 2-3, rendering the claim(s) indefinite. Specifically, it is unclear if the phrase recited above means (1) a chemotherapy agent and either an immunotherapy or endocrine therapy agent; (2) coadministration of chemotherapy and immunotherapy agents or an endocrine therapy agent alone; or (3) something else. For the purposes of compact prosecution, the underlined portion of the phrase above is considered to mean (1) any chemotherapy in combination with an immunotherapy agent; or (3) any endocrine agent alone or in combination with a chemotherapeutic agent. This rejection may be overcome by amending claim(s) 29 to clearly recite the limitation(s) of the invention.
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.
Claim(s) 17-30 is/are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature (natural phenomenon) without significantly more.
Claims 17-30 are evaluated using the “Subject Matter Eligibility Test for Products and Processes” flow chart as shown in MPEP § 2106 (III).
Step 1: Is the claim to a process, machine, manufacture or composition of matter?
Yes. The claim is drawn to a process (method) which is one of the four statutory categories.
Step 2A, Prong One: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
Yes. The claims are directed towards an a natural phenomenon and an abstract idea because the claims require (a) determining the FOLR2+ ‘level’ on macrophages in cancer (e.g., a natural phenomenon), (b) deducing therefrom whether the outcome of cancer disease or treatment is likely to be favorable or unfavorable (e.g., an abstract idea), and (c) “administering an appropriate treatment to the patient depending on whether the outcome of cancer disease or treatment is likely to be favorable or not…” (e.g., a natural phenomenon).The natural phenomenon is correlating FOLR2+ level in macrophages with cancer, and the abstract idea is deducing favorable vs unfavorable outcomes in cancer based on FOLR2+ levels.
Step 2A, Prong Two: Does the claim recite additional elements that integrate the judicial exception into a practical application?
No. While claim 17 recites “determining the level oof FOLR2+ macrophages in a patient sample, wherein the level of tumor associated FOLR2+ macrophages correlates positively with outcome of cancer disease or treatment in the patient; deducing therefrom whether the outcome of cancer disease or treatment is likely to be favorable or unfavorable to the patient; and administering an appropriate treatment to the patient depending on whether the outcome of cancer disease or treatment is likely to be favorable or not in the patient” and discloses purposes (a method of treating cancer) for doing so, these do not integrate the judicial exception into a practical application. Specifically, the treatment step is not practically applying the natural phenomenon, because it is generic and does not require any particular treatment and is equivalent to an “apply it” step (see MPEP 2106.04(d)(2)). Additionally, the measurement of FOLR2+ in macrophages and the treatment of cancer based on FOLR2+ macrophages was known in the art at the time of filing, as evidenced by WO 2018/183921 A1 [e.g., abstract; ¶ 0008-0009, 022,0044,0067,0131,0320, 0342,0343; see 102 rejection below for details]. Therefore, the recited method steps of claim 17 are considered routine and conventional (see MPEP 2106.04(b), 2106.07(a)), and as such fail to integrate the judicial exception(s) into a practical application.
Step 2B: Does the claim recite additional elements that amount to significantly more than the judicial exception?
No. The judicial exception is recited without additional limitations amounting to significantly more than the exception. While the act of determining the biomarker level (e.g. macrophage FOLR2+ level) in the sample from a patient could require performance of an assay, this is considered to be necessary data gathering steps for the judicial exception and, therefore, do not amount to significantly more than the judicial exception that is claimed. Additionally, the administration step is not considered to practically apply the natural phenomenon because the administration step is a conditional limitation that does not require the administration to be performed and recites a generic method of applying any appropriate treatment to the patient depending on whether the treatment is likely to be favorable to the patient, which is how a skilled artisan determines a course of treatment for a patient in a routine treatment course (e.g., only applying a treatment expected to be favorable to the patient). There is no clear link between the natural phenomenon and the expected outcome of treatment, and there is no specific treatment or prophylaxis linked to the natural phenomenon recited in the claims, and therefore the administration step amounts to no more than ‘apply it’ and as such does not amount to significantly more than the judicial exception that is claimed.
Claim(s) 18-30, which depend from claim 17, act to further limit the FOLR2+ level control reference; favorable outcome indicators; determining FOLR2+ density; additional macrophage marker(s) characterization; FOLR2+ tumor characterization; macrophage gene signature characterization; therapeutics administered to ‘favorable’ or ‘unfavorable’; and/or specific cancer indication(s). The limitations do not amount to significantly more than the judicial exception.
As the instant claim(s) 17-30 recite judicial exceptions and claim method of treating a population of subjects for which the judicial exception is not integrated into a practical application, and no elements that amount to significantly more than the judicial exception are recited, the claims were found not to be drawn to eligible subject matter under 35 USC § 101.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 17, 20-21, 23-26, 30 is/are rejected under 35 U.S.C. 102(a)(1) as anticipated by WO 2018/183921 A1 (hereinafter “WO921”).
Regarding instant claim(s) 17, 23-24, WO921 teaches a method of treating cancer in subjects (e.g., patients), comprising identifying gene signatures for predicting response to immune checkpoint blockade therapy (e.g., deducing favorable or unfavorable outcomes correlated with FOLR2+ macrophages; see 112(b) rejection above) [e.g., abstract; ¶ 0008-0009]. WO921 further teaches that the predictive gene signature of tumor associated macrophages comprises one or more genes or polypeptides (e.g., protein) including FOLR2 (e.g., determining level of FOLR2+ macrophages; see claim interpretations above) [e.g., pg. 314, claim 17; ¶ 0022, 0044, 0067, 0131, 0342-0343]; and that clinically predictive signatures (e.g. of macrophages) can be used to develop novel therapeutic strategies (e.g., administering appropriate treatment based on predicted favorable or unfavorable responses) that could overcome immunotherapy resistance [e.g., ¶ 0009, 0320].
Regarding instant claim(s) 20-21, 23, WO921 teaches density clustering on two-dimensional t-SNE analysis (e.g. of IHC using antibodies), including of macrophages (e.g., FOLR2+ cells) [e.g., ¶ 0483; fig. 6A-B].
Regarding instant claim(s) 25-26, WO921 teaches the macrophage gene signature comprises FOLR2, SEPP1, and SLC40A1 genes [e.g., ¶ 0022], and that RNAseq (e.g., of mRNA) was used to assess FOLR2 levels in macrophages [e.g., ¶ 0061, 0483; figs. 1, 6].
Regarding instant claim(s) 30, WO921 teaches the cancer is breast cancer [e.g., ¶ 0063, 0070, 0098, 0109, 0358].
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claim(s) 18-19, 22, and 27-29 is/are rejected under 35 U.S.C. 103 as obvious over WO 2018/183921 A1 (hereinafter “WO921”) as applied to claims 17 and 20 above, as evidenced by the instant specification.
The teachings of WO921 as recited above.
Regarding instant claim(s) 18-19, WO921 teaches that the cancer is breast cancer [e.g., ¶ 0063, 0070, 0098, 0109, 0358].
WO921 does not expressly teach the method wherein an elevated FOLR2+ macrophage in the patient tumor sample as compared to a reference indicates that the outcome of cancer disease or treatment is likely to be favorable to the patient.
It would have been prima facie obvious, at the time of filing, to perform a method of treating cancer comprising 1) measuring the level of FOLR2 in tumor associated macrophages, 2) correlating the gene signature of the tumor associated macrophages (wherein the gene signature comprises the level of FOLR2 macrophages); and 3) choosing a favorable treatment such as immune checkpoint blockade therapy and/or other therapy based on the immune signature as taught by WO921. While WO921 does not expressly teach correlative relationships observable between FOLR2+ macrophages and breast cancer outcome, FOLR2+ macrophages are an independent prognostic factor which positively correlates with patient survival (e.g., favorable) in breast cancer and across at least six other types of cancer, as evidenced by the instant specification [e.g., ¶ 0010]. Therefore, performing the active method steps as taught by WO921 would naturally result in the instant method because a skilled artisan, in comparing the gene signatures as taught by WO921, would arrive at the instant relationship. The Examiner notes that "wherein an elevated level of FOLR2+ macrophages in the patient tumor sample as compared to a reference" is a limitation that does not require the active step of comparing, and that there is no specific prophylaxis or treatment that is likely or unlikely to be favorable; therefore a skilled artisan has a reasonable expectation of success because it was routine to choose a treatment with a favorable outcome to the patient as taught by WO921.
Regarding instant claim(s) 22, WO921 teaches macrophage signatures includes TREM2 [e.g., ¶ 0044].
WO921 does not expressly teach an FOLR2+/TREM2- or FOLR2+/TREM2low macrophage population.
It would have been prima facie obvious, at the time of filing, to perform a method of treating cancer comprising 1) measuring the level of FOLR2 and TREM2 in tumor associated macrophages, 2) correlating the gene signature of the tumor associated macrophages (wherein the gene signature comprises the level of FOLR2 macrophages); and 3) choosing a favorable treatment such as immune checkpoint blockade therapy and/or other therapy based on the immune signature as taught by WO921. While WO921 does not expressly teach FOLR2+/TREM2- or FOLR2+/TREM2low macrophage populations, there are no active steps to create these populations of cells, but rather the instant claimed populations are simply observed, naturally occurring in tumor associated macrophages. Therefore, performing the active method steps as taught by WO921 would naturally result in the instant method because a skilled artisan, in comparing reviewing the gene signatures (e.g., single cell RNAseq) as taught by WO921, would observe the above naturally-occurring macrophage populations. The Examiner notes that "wherein the FOLR2+ cells are further TREM2- or TREM2low" is a limitation that does not require an active step; therefore a skilled artisan has a reasonable expectation of success because it was routine to assess the FOLR2 and TREM2 gene signatures of tumor associated macrophages as taught by WO921.
Regarding instant claim(s) 27, WO921 teaches macrophage gene signatures comprising FOLR2+, that macrophage signatures can predict tumor response to immunotherapy, and that predictive signatures (e.g. of macrophages) can be used to develop novel therapeutic strategies (see 102 rejection above for details and citations).
Regarding instant claim(s) 28, WO921 teaches that if an immune checkpoint resistance (ICR) is not detected (e.g., favorable), that an immunotherapy may be administered to the cancer patient [e.g., pg. 315, “20.”], and that the immunotherapy comprises an immune checkpoint inhibitor (e.g., immune checkpoint ‘blockage’ agent) [e.g., pg. 316, “28”]. WO9221 teaches macrophage gene signatures comprising FOLR2 are predictive of ICR [e.g., ¶ 0022, 0044].
Regarding instant claim(s) 29, WO921 teaches the administration of a cell cycle inhibitor to the patient if ICR is detected (e.g., unfavorable) [e.g., pg. 315, “20”-“21”].
WO921 does not expressly teach (1) a step of classifying the patient specifically into “favorable” or “unfavorable” categories, or (2) administering chemotherapy to “unfavorable” patients.
It would have been prima facie obvious, at the time of filing, to perform a method of treating cancer comprising 1) measuring the level of FOLR2 and TREM2 in tumor associated macrophages, 2) correlating the gene signature of the tumor associated macrophages (wherein the gene signature comprises the level of FOLR2 macrophages); and 3) choosing a treatment such as immune checkpoint blockade therapy (e.g., to favorable subjects) or a chemotherapeutic cell cycle inhibitor (e.g., to unfavorable subject) based on the immune signature as taught by WO921. While WO921 does not expressly teach (1) a step of classifying the patient specifically into “favorable” or “unfavorable”, or (2) administering chemotherapy to “unfavorable” category patients, WO921 specifically teaches (1) a predictive and prognostic relationship between the macrophage gene signature and the ability to adapt treatment based on the observed macrophage gene signature (e.g., would naturally require predicting favorable or unfavorable responses to individual treatments such as ICR), and (2) administration of a cell cycle inhibitor to subjects deemed not eligible for (e.g., unfavorable) other therapies. A skilled artisan would understand chemotherapy is a commonly employed anti-cancer therapy that is a known in the art cell-cycle inhibitor, as evidenced by Dana Farber (“How Does Chemotherapy Affect Cancer Cells?”, published online 06Mar2019), and therefore would be obvious to substitute in place of the generic “cell cycle inhibitor” taught by WO921. Additionally, regarding the favorable/unfavorable categories, there are no active steps to create these populations of cells, or to alter their relationship/correlation with cancer disease or treatment outcome, but rather the instant claimed correlations (e.g., favorable or unfavorable outcomes based on macrophage gene signature) are simply observed, naturally occurring. Therefore, performing the active method steps as taught by WO921 would naturally result in the instant method because a skilled artisan, in comparing the gene signatures as taught by WO921, would arrive at the instant relationship. A skilled artisan has a reasonable expectation of success because it was routine to choose a treatment based on predicted favorable/unfavorable outcomes to the patient as taught by WO921, and the administration of chemotherapeutic cell-cycle inhibitors are well known in the art to treat a variety of cancers, as evidenced by Dana Farber.
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Conclusion
No claims are currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY M CHATTIN whose telephone number is (571)270-0646. The examiner can normally be reached T-F 0600-1600 PST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at (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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/AMY M. CHATTIN/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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