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 A) macrophage, B) Gene signature set combination including (a), (b), (c), (d), (e), and (f), and C) Gene signature matrix (a), in the reply filed on 1/9/2026 is acknowledged.
Claim Status
Claims 5, 7-8, 13-14, 16, 21-22, 25-26, 29, 31-32, 36-37, 40-41, 44-45, 51, 53, 57-59, 61-63, 65-69, 71, 73-74, and 211 are pending.
Claim 211 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 1/9/2026.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement (for example (not an exhaustive list): pg 20, ln 30-38 - pg 21, ln 1-9; pg 22, ln 14, 28-32; pg 24, ln 4-5; pg 25, ln 19). 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claim 45 is objected to because of the following informalities: “a tissue sample, tumor sample, whole blood sample, a plasma sample” should read “a tissue sample, a tumor sample, a whole blood sample, a plasma sample”. Appropriate correction is required.
Claim Rejections - 35 USC § 112b - Indefiniteness
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 5, 7-8, 21-22, 25-26, 29, 31-32, 36-37, 40-41, 44-45, 51, 53, 57-59, 61-63, 65-69, 71, 73-74 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 5 recites the limitation “wherein prior to treatment the amount or level of a macrophage biomarker in a sample from the patient has been determined to be above a reference macrophage biomarker amount or level”. It is unclear what this reference macrophage biomarker amount or level is with regards to calculation of this level and the reference population used to calculate this reference macrophage amount or level. As written, the reference macrophage amount or level could be calculated in any way and using any reference population (healthy individuals, individuals with cancer, individual specifically with lymphoma, etc.). Given that the reference population is undefined, “above a reference macrophage biomarker or level” is a relative term which is rendered indefinite by the lack of specifics regarding the “reference”. Therefore, the scope of the claim is unclear and clarification is required.
Claims 7-8, 21-22, 25-26, 29, 31-32, 36-37, 40-41, 44-45, 51, 53, 57-59, 61-63, 65-69, 71, 73-74 depend from claim 5, inherit this deficiency, and are rejected on the same basis.
Claim Rejections - 35 USC § 112d – Failure to Further Limit
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 21 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 21 is directed to the method of claim 5 “further comprising achieving an improvement of progression-free survival (PFS) or overall survival (OS)”. However, claim 5 contains the limitation of administering to the patient “an effective amount” of an anti-CD20 antibody. According to the instant specification, an “effective amount” of a compound is one which is the “minimum amount required to achieve the desired therapeutic result, such as a measurable increase in overall survival or progression-free survival” (pg 31, ln 1-4). Therefore, given that the anti-CD20 antibody is administered in an effective amount, the improvement of PFS or OS is already part of claim 5, and claim 21 fails to further limit. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112a – Scope of Enablement
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 the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 5, 7-8, 21-22, 25-26, 29, 31-32, 36-37, 40-41, 44-45, 51, 53, 57-59, 61-63, 65-69, 71, 73-74 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for
A method of treating a human patient having a lymphoma, the method comprising administering to the human patient an effective amount of an anti-CD20 antibody, wherein prior to treatment the amount or level of a macrophage biomarker in a sample from the human patient has been determined to be above a reference macrophage biomarker amount or level,
wherein the reference macrophage biomarker amount or level is:
(a) a median amount or level of the macrophage biomarker in a reference population; or
(b) an amount or level of a macrophage biomarker that is at the 25th percentile, 50th percentile, or 75th percentile of a reference population, and
wherein the reference population is a population of human patients having the lymphoma.
does not reasonably provide enablement for the treatment of a non-human mammalian patient based on the comparison of macrophage levels as compared to any reference population. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Nature of the invention and breadth of the claims
The invention is in the class of invention which the CAFC has characterized as "the unpredictable arts such as chemistry and biology." Mycogen Plant Sci., Inc. V. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The method of the rejected claims is broadly directed to assessing the level of a macrophage biomarker in a sample from a patient (human or non-human mammal, specification pg 34, ln 3-5) and comparing this amount or level of macrophage biomarker to any reference macrophage biomarker amount or level from any reference population. The method includes determining that the macrophage biomarker amount or level is greater than a reference macrophage biomarker amount or level (claim 5) via measurement of macrophage biomarkers through gene signature sets (claims 22 and 25) or gene signature matrices (claims 26 and 29).
The nature of the claims thus requires knowledge of an association between macrophage biomarker amount or level and the benefit of treatment of a patient with lymphoma with an anti-CD20 antibody to achieve improved PFS or OS (claim 21). However, the claims encompass the analysis of any non-human mammal patient with lymphoma and generically encompass comparison to any reference macrophage amount or level.
Direction provided by the specification and working example
The specification teaches (pg 174-177) that, by using human patients with lymphoma as reference population, measuring macrophage biomarker amount or level in this reference population provides opportunity for dichotomization of the reference population into those with high amounts of macrophage biomarker and those with low amount of macrophage biomarker. Dichotomization of the reference population is achieved through usage of a statistical cutoff (reference macrophage biomarker amount or level) to distinguish between patients with high macrophage biomarker and low macrophage biomarker, and further analysis reveals that the high M1 macrophage biomarker subset of lymphoma patients were significantly associated with lower risk of progression and improved overall survival when treated with an anti-CD20 antibody (pg 174, ln 20-pg 174, ln 1-2).
The example provided by the specification teaches comparison to a reference macrophage biomarker amount or level derived from a human reference population with lymphoma and associated higher levels of macrophage biomarker as compared to the reference population derived cutoff with improved PFS and OS. The specification does not teach any other sort of reference population that would provide beneficial information regarding prognostic impact of macrophage biomarker levels.
The specification teaches that the methods encompass non-human mammalian subjects (pg 34, ln 3-5), but there are no teachings related to macrophage biomarker levels in any non-human mammalian subject.
State of the art, level of skill in the art, and level of unpredictability
While the state of the art and level of skill in the art with regard to detecting a biomarker in any particular sample is advanced, the unpredictability with regard to associating the amount or level of a biomarker with a prognostic impact is high. This unpredictability is demonstrated by the related art.
Because the claims encompass the analysis and treatment of any non-human mammal with lymphoma, whereas the instant specification provides only teachings of human macrophage biomarkers and samples, it is relevant to point out that there is a large amount of unpredictability with regard to comparing results from biomarker analysis data in humans to other, even closely related, animals. Enard et al. (2002) teaches that large numbers of quantitative changes in gene expression can be detected between closely related mammals (pg 342, col 2, last paragraph).
Because the claims encompass comparison of macrophage biomarker amount or level to any reference level or amount, it is relevant to note the unpredictability associated with reference levels determined from different reference populations. Riihijärvi et al. (2015) teaches that cutoff levels for accurately splitting reference populations to enable determination of prognostic impact of a biomarker significantly vary depending on the reference population used (pg 243, col 2, paragraph 2). Riihijärvi et al. also warn that in some instances, a genotype:phenotype association (gene expression/biomarker:prognostic outcome association) may not be statistically significant and may instead exist on a continuum (pg 243, col 2, paragraph 2).
Quantity of experimentation required
Given the level of unpredictability in terms of determining relevant prognostic impact of biomarkers in any human or non-human mammalian subject with comparison to any reference level, there would be an undue amount of experimentation required for one skilled in the art to perform the method of treatment as claimed.
Conclusion
After consideration of the teachings of the specification and the specific working examples, considering the breadth of the claims, and the unpredictability in the art, it is the conclusion that an undue and unreasonable amount of experimentation would be required to make and use the invention that is instantly claimed.
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.
Claims 5, 7, 21, 40-41, 51, 53, 57-59, 61-63, 65-69, 71, and 73-74 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Miyawaki (Miyawaki et al., EP 3674416 A1; cited on IDS of 7/20/2023).
Regarding claim 5: Miyawaki teaches a method of predicting the effectiveness of a treatment with anti-CD20 antibody by measuring the amount of macrophage biomarker in a sample from a patient (Abstract, paragraph [0009, 0012-0014, and 0017]). In particular, Miyawaki teach that the prognosis of the treatment with anti-CD20 antibody is favorable when determined to be above a cutoff value (reads on above a reference macrophage biomarker amount or level; paragraph [0015]). Miyawaki teach, after determining that the patient would respond well to treatment (i.e., that the amount of macrophage biomarker is above a reference macrophage biomarker amount), treating the patient with lymphoma with chemotherapy (which comprises an anti-CD20 antibody monotherapy; paragraphs [0041 and 0017]).
Regarding claim 7: Miyawaki teaches that the reference macrophage biomarker amount is a pre-assigned macrophage biomarker amount determined by ROC analysis (paragraph [0015]).
Regarding claim 21: Miyawaki teaches that an increased amount of macrophage biomarker indicates an association with a favorable prognosis, which indicates that treatment with an anti-CD20 antibody would achieve an improvement of PFS or OS (paragraphs [0009, 0015, and 0041-0042]).
Regarding claims 40 and 41: Miyawaki teaches that macrophage biomarker in the patient sample is determined using nucleic acid, and the nucleic acid expression level is an mRNA expression level (paragraph [0014]).
Regarding claim 45: Miyawaki teaches that the sample is a tumor sample (paragraph [0013]).
Regarding claim 51: Miyawaki teaches that the lymphoma is a diffuse large B-cell lymphoma (DLBCL; paragraph [0012]).
Regarding claim 53: Claim 53 is a limitation of an option of lymphoma type provided in claim 51, from which it depends. Because Miyawki teaches that the lymphoma is a DLBCL, the optional limitation of the B-cell lymphoma is automatically rejected.
Regarding claim 57: Miyawaki teaches that the DLCBL is a germinal-center B-cell-like (GCB) or activated B-cell-like (ABC) subgroup of DLBCL (paragraph [0070], Figure 7A and 7B).
Regarding claim 58: Miyawaki teaches that the lymphoma is a CD20-positive lymphoma (paragraph [0059] and Figure 3).
Regarding claim 59: Miyawaki teaches that the anti-CD20 antibody is a type II antibody or a type I antibody, in particular either obinutuzumab or rituximab, respectively (paragraph [0018]).
Regarding claims 61-63: Miyawaki teaches that the type II anti-CD20 antibody is Obinutuzumab (paragraph [0018]), which is comprised of SEQ ID NOs: 27-28 and 3-8.
Regarding claims 65-67: Miyawaki teaches that the type I anti-CD20 antibody is rituximab (paragraph [0018]), which is comprised of SEQ ID NOs: 11-16 and 25-26.
Regarding claims 68, 69, and 71: Miyawaki teaches administering an additional therapeutic agent (paragraph [0017]). Miyawaki teaches that the additional therapeutic agent is a chemotherapeutic agent, and in particular is cyclophosphamide, doxorubicin, vincristine and prednisone (also known as CHOP therapy; paragraph 10018-0029]).
Regarding claims 73 and 74: Miyawaki teaches that their methodology can be employed on patients to predict clinical outcome of “untreated” DLBCL (paragraph [0069]).
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 8, 13, 14, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Miyawaki (Miyawaki et al., EP 3674416 A1; cited on IDS of 7/20/2023) in view of Riihijärvi (Riihijärvi et al., Haematologica 2015; cited on IDS of 7/20/2023).
The teachings of Miyawaki in regards to the method of claim 5 (from which these claims depend) are detailed in the 102 rejections above. Briefly, and relevant to the instantly rejected claims, Miyawaki teaches a method of treating a patient with lymphoma with an anti-CD20 antibody when said patient has a macrophage biomarker amount or level that is above a reference macrophage biomarker amount or level.
Regarding claim 8: Miyawaki does not teach that the reference macrophage biomarker amount or level is an amount or level of a macrophage biomarker that is at the 25th percentile, 50th percentile, or 75th percentile of a reference population. However, using these percentile cutoffs to distinguish between groups of patients by prognostic outcome in terms of a macrophage biomarker is known in the art, as taught by Riihijärvi.
Riihijärvi teaches a method for assessing the prognostic impact of macrophages (expression levels of CD68 mRNA) on PFS and OS rates in patients with DLBCL (Abstract). Riihijärvi teaches using optimal cutoffs of 37% (pg 240, col 1, paragraph 2), 35% (pg 240, col 1, paragraph 3), and 23% (25th percentile; pg 240, col 1, paragraph 3). Riihijärvi teaches using multiple different cutoffs “because the optimal cutoff levels best discriminating the low and high [expression] subgroups varied between different cohorts”. With respect to determination of the optimal cutoff amount or level of a reference population for determining prognostic impact, it is noted that the courts have found that “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05 II.
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Miyawaki to assign he macrophage biomarkers at different percentiles of a reference population, as taught by Riihijärvi. One would be motivated to do so given the teaching by Riihijärvi that “The findings at multiple levels are important because the optimal cutoff levels best discriminating the low and high subgroups varied between different cohorts” and “true microenvironment-related differences exist between different populations of patients” (Discussion, paragraph 4). Additionally, Riihijärvi teaches that specific cutoff points for a reference population allows for accurate discrimination between low and high expression groups (thus different prognostic outcomes) as well as minimizing differences in the the two groups based on “age, stage, IPI scores or molecular subgroups” (pg 240, col 1, paragraphs 2-3). One would have a reasonable expectation of success given that Riihijärvi successfully applies these reference macrophage biomarker cutoffs to a reference population to distinguish prognostic outcomes in lymphoma patients based on macrophage biomarker levels.
Regarding claim 13: Riihijärvi teaches that the reference population of patients are patients with lymphoma (pg 239, col 1, paragraphs 3-5).
Regarding claim 14: Riihijärvi teaches that the references population of patients having the lymphoma were treated with anti-CD20 antibody (R-CHOP = rituximab plus chemotherapeutic agents) and the reference level of the biomarker was taken prior to initiating said treatment with the anti-CD20 antibody (pg 239, col 1, paragraph 2 and col 2, paragraph 1).
Regarding claim 16: Riihijärvi teaches that the reference macrophage biomarker amount or level significantly separates the reference population into a first set of patients who have benefitted from treatment with anti-CD20 antibody and a second set of patients who have not benefitted from the treatment with the anti-CD20 antibody (pg 239, col 1, paragraph 2; pg 240, col 1, paragraph 2).
Claims 22, 25, 32, 36-37, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Miyawaki (Miyawaki et al., EP 3674416 A1; cited on IDS of 7/20/2023) in view of Aran (Aran et al., Genome Biology 2017) and Riihijärvi (Riihijärvi et al., Haematologica 2015; cited on IDS of 7/20/2023).
The teachings of Miyawaki in regards to the method of claim 5 (from which these claims depend) are detailed in the 102 rejections above. Briefly, and relevant to the instantly rejected claims, Miyawaki teaches a method of treating a patient with lymphoma with an anti-CD20 antibody when said patient has a macrophage biomarker amount or level that is above a reference macrophage biomarker amount or level.
Regarding claims 22 and 25: Miyawaki does not teach that the macrophage biomarker is an average of M1 macrophage gene signature set scores of one or more M1 macrophage gene signature sets, or that the gene signature sets are sets (a)-(f) as listed in claim 25. However, use of M1 macrophage gene signature sets to determine an amount of M1 macrophage using one or more M1 macrophage gene signature sets as listed in claim 25 is known in the art, as taught by Aran.
Aran teaches using newly generated gene signatures for cells such as M1 macrophages to determine the enrichment scores on a linear scale and thus determine amount in tumor tissues (pg 2, col 1 last paragraph-col 2 1st paragraph). More specifically, Aran teaches that the macrophage biomarker is an average of one or more M1 macrophage gene signature sets, and each M1 macrophage gene signature set score is an average of the normalized expression level of one or more genes of an M1 macrophage gene signature set (pg 12, col 1-col 2 “Calculating scores for a mixture”). Aran teaches that the one or more M1 macrophage gene signature sets are (a)-(f) (as presented in claim 25; Additional File 3). Aran teaches that (a), (b), and (c) are the top 3 gene signature sets for M1 macrophages as derived from the Blueprint dataset, and (d), (e), and (f) are the top 3 gene signature sets for M1 macrophages as derived from the FANTOM5 data set (pg 11, col 2, paragraph 1; “From each data source the top three signatures were chosen. All together we chose 489 signatures corresponding to 64 cell types (across the six data sources we have 163 cell types; Additional file 3)).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Miyawaki to estimate the amount of M1 macrophages in the patient sample using the gene signature sets as taught by Aran. One would be motivated to look specifically at M1 macrophages given the teaching by Riihijärvi that M1 macrophages and M2 macrophages have different prognostic impacts on therapy in the context of lymphoma, with M1 being described as “good” and M2 having the opposite effect (Introduction, paragraph 4). One would be motivated to use the methodology of Aran given that Aran teaches that the use of these gene signature sets allows the discrimination between these two different types of macrophages (see Macrophage M1 signature sets vs. Macrophage M2 signature sets in Additional File 3). Additionally, Aran teaches that their methodology “robustly outperforms all available methods in predicting abundance of cell types” and enables “detection of subtle differences in the enrichment of a particular cell type in the tumor microenvironment with high confidence” (pg 9, col 1, paragraph 2). One would have a reasonable expectation of success given that Aran teaches successfully measuring the tumor microenvironment in cancer cells (Figure 4).
Regarding claims 32, 36, and 37: Aran teaches determining an amount of M1 macrophages wherein the amount of M1 macrophages is measured indirectly using nucleic acid measured using RNA-seq in a marker gene approach (pg 10, col 2, Signature data sources).
Regarding claim 44: Aran teaches that mRNA expression levels are determined through RNA-seq (pg 10, col 2, Signature data sources).
Claims 26, 29, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Miyawaki (Miyawaki et al., EP 3674416 A1; cited on IDS of 7/20/2023) in view of Finotello (Finotello et al., Genome Medicine 2019) and Riihijärvi (Riihijärvi et al., Haematologica 2015; cited on IDS of 7/20/2023).
The teachings of Miyawaki in regards to the method of claim 5 (from which these claims depend) are detailed in the 102 rejections above. Briefly, and relevant to the instantly rejected claims, Miyawaki teaches a method of treating a patient with lymphoma with an anti-CD20 antibody when said patient has a macrophage biomarker amount or level that is above a reference macrophage biomarker amount or level.
Regarding claims 26, 29, and 31: Miyawaki does not teach that the macrophage biomarker is a median gene expression value measured using a gene signature matrix, or that the gene signature matrix comprises the gene signature matrix as listed in claim 29(a) (consonant with Applicant’s election). However, use of gene expression values measured using a gene signature matrix to determine an amount of M1 macrophage using a gene signature matrix as listed in claim 29(a) is known in the art, as taught by Finotello.
Finotello teaches a method called quanTIseq, which uses bulk RNA-seq data to quantify fractions of immune cell types using deconvolution-based cell scores (Abstract). Finotello teaches using a gene signature matrix to determine absolute proportions of relevant immune cells types from RNA-seq data, and in particular, teaches the gene signature matrix as listed in claim 29(a) (Additional File 1). Finotello teaches specifically using the gene signature matrix of (a), which excludes 17 genes from the gene signature matrix of (b) (Methods – Restricted expression). Finotello teaches using the gene signature matrix of (a) to determine a number of M1 macrophages (Fig. 5).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Miyawaki to determine the amount of M1 macrophages in the patient sample using the gene signature matrix as taught by Finotello. One would be motivated to look specifically at M1 macrophages given the teaching by Riihijärvi that M1 macrophages and M2 macrophages have different prognostic impacts on therapy in the context of lymphoma, with M1 being described as “good” and M2 having the opposite effect (Introduction, paragraph 4). One would be motivated to use the methodology of Finotello given that Finotello teaches that the use of these gene signature matrices allows the discrimination between these two different types of macrophages (pg 9, col 1, paragraph 1; Fig 3a; Additional File 1). Additionally, Finotello teaches that this methodology enables high-throughput examination of gene expression as well as faithful quantitation of immune cell fractions (pg 16, col 1-col 2), and can be used in “the development of predictive markers for immunotherapy” (pg 18, col 1, paragraph 1). One would have a reasonable expectation of success given that Finotello successfully applies this technology to patient tissue samples (Methods - Leiden validation data set and Vanderbilt validation data sets).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAILEY E CASH whose telephone number is (571)272-0971. The examiner can normally be reached Monday-Friday 8:30am-6pm ET.
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/KAILEY ELIZABETH CASH/Examiner, Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683