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 .
Priority
The instant application is claiming the benefit as a 35 U.S.C. 371 national phase application from, and claims priority to, International Application No. PCT/US2022/032124 filed 06/03/2022, which claims the benefit of the prior-filed United States Provisional Patent Application Nos. 63/235,496 filed 08/20/2021 and 63/197,060 filed 06/04/2021.
Status of Application/Claims
The preliminary amendment, filed 11/04/2024, is acknowledged. Claims 3-4, 11, 14-15, 18-26, 29, 31, 33-54, 59-64, 66-67, 69-70, and 72-112 are canceled. Claims 2, 5, 10, 12, 16-17, 27-28, 30, 58, 65, and 71 are currently amended. Claims 1-2, 5-10, 12-13, 16-17, 27-28, 30, 32, 55-58, 65, 68, and 71 are currently pending and are examined on the merits herein.
Information Disclosure Statements
The information disclosure statement (IDS) submitted on 11/28/2023 listed the reference “Scott, et al.” for which no pdf was provided; thus, this reference was not considered. The IDS submitted 11/28/2023 has otherwise been fully considered by the examiner.
Specification
The use of the terms Axis-Shield, Waters, Abcam, Quattro, MassLynx, ThermoFisher Scientific, Qubit, Agilent Technologies, Edinburgh, Illumina, TruSeq, NovaSeq, eBioscience, Roche, Sigma, Miltenyi, BioLegend, Alfa Aesar, Seurat, CellRanger, and 10x Genomics, which are trade names or marks used in commerce, have been noted in this application. The terms should be in all caps wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
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.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. 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.
Hyperlinks are found on the following pages. Each of the following hyperlinks contain a prefix (underlined) and/or is not limited to the top-level domain (see bold):
p.38:
“www.clinicaltrialsregister.eu/ctr-search/trial/2014-00438820/results#more informationSection”.
p.39:
“https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-004388-20/results”.
P.40
“https://www .clinicaltrialsregister.eu/ctr-search/trial/2014-004388-20/results”.
p.41
“github.com/ndu-UCSD/LJI_RNA_SEQ_FIPELINE_ V2”.
p.43
“github.com/vijaybioinfo/quality control” and “github.com/vijaybioinfo/ab_capture”.
Drawings
The drawings are objected to because of poor resolution in the following figures:
Fig.1A: axes and numbers
Fig.2F: axes, numbers, and legend
Fig.3: labels/text
Fig.4A: axes, numbers, and legend
Fig.4B: headings, axes, numbers, and label
Fig.4D: axes, numbers, and label
Figs.5A-B, E: headings, text/labels, numbers, and axes
Figs.5C-D: headings, axes, numbers
Fig.5F: headings
Fig.6B: axes, numbers, scale, headings, and legend
Fig.6D: axes and legend
Fig.7C-D: headings, text/labels, numbers
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 9, 10, 12, 28, 58, and 65 are objected to because of the following informalities:
Claims 9, 28, and 58 recite “CAL-101 (Idelalisib, GS-1101)” and “Zydelig” which are the same compound. Thus, the compound is listed in duplicate and one of the terms should be removed.
Claims 10 and 65 recite “TFR” in lines claim 10-line 6 and claim 65-line 4, which should be corrected to “TFR” for consistency.
Claim 12 recites “…wherein the method further comprises at least one of… or…” which should be corrected to “…wherein the method further comprises at least one of… and/or… “.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
Claims 1-2, 5-10, 12-13, 16-17, 27-28, 30, 32, 55-58, 65, 68, and 71 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea judicial exception without significantly more. The claims are drawn to methods comprising mental processes. The judicial exception is not integrated into practical application because the claims read on mental processes that fall under the judicial exception of being abstract ideas. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
The claims 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 drawn to a process, machine, manufacture or composition of matter?
Yes.
Claim 1 is drawn to a method/process of treating cancer in a patient which is one of the four statutory categories. Claims 2, 5-10, and 12-13 are dependent on claim 1 and do not overcome the issue.
Claim 16 is drawn to a method/process of stratifying cancer patients which is one of the four statutory categories. Claims 17, 27—28, 30, and 32 are dependent on claim 16 and do not overcome the issue.
Claim 55 is drawn to a method/process of treating a patient with a cancer vaccine which is one of the four statutory categories. Claims 56-58, 65, 68, and 71 are dependent on claim 55 and do not overcome the issue.
Step 2A, Prong One: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
Yes.
With respect to claims 1 and 55, the claims indicate that it is drawn to a method/process of treating cancer in a patient and a method of treating a patient with a cancer vaccine, respectively; and subparts (a)-(d) of the claims identify the steps of the methods with the following language: (a) providing or obtaining a sample from a patient; (b) determining a level or activity; (c) comparing the level or activity; and (d) if the patient has a high level or activity, administering a cancer therapy. Regarding step (b) “determining”: The instant disclosure provides that “determining” can be interpreted as “evaluating” results which is a mental process (p.18, [0037]). Regarding step (c) “comparing”: This limitation indicates that the claim is drawn to mental analyses of and a conclusions drawn from results. The mental activities of steps (b) and (c) represent abstract ideas according to MPEP 2106.04(a)(2) III. Regarding step (d) “if the patient has a high level or activity…”: This limitation is drawn to a correlation between a high level or activity and cancer. Such correlations fall under laws of nature according to MPEP 2106.
With respect to claim 16, the claim is indicated to be a method/process of stratifying cancer patients to select an effective cancer treatment comprising subparts (a) through (d) which identify the steps of the method with the following language: (a) providing or obtaining a sample from a patient; (b) determining; (c) comparing; and, (d) stratifying the patient into at least one of three groups. Thus, steps (b) and (c) indicate that the claim is drawn to mental analyses as applied above. The claim language of (d) describes “stratifying” which is considered an abstract idea interpreted to comprise evaluating and categorizing patients, which are mental processes. Such mental activities represent abstract ideas according to MPEP 2106.04(a)(2) III.
Step 2A, Prong Two: Does the claim recite additional elements that integrate the judicial exception (JE) into an application?
No. Claims 1 and 55 recite step (a) “obtaining a sample from the patient” which is considered data gathering and falls under an extra-solution step (see MPEP 2106.05(g)) and does not integrate the judicial exception. Step (d) of the claims sets forth a physical step of “administering,” but only “if the patient has a high level of activity.” However, as the claim as written also includes samples from all patients evaluated, the mental processes of steps (b) through (c) also apply to the “if not” patients who do not exhibit a high level or activity. See e.g., MPEP 2106.04(b). As there is no physical step performed for the patient who does not “have a high level or activity,” step (d) fails to overcome the issue for claims 1 and 55.
No. Claim 16 recites the additional limitations related to criteria for stratifying the patients but does not integrate the judicial exception into a practical application.
Step 2B: Does the claim recite additional elements that amount to significantly more than the judicial exception?
No. Claims 1, 16, and 55 recite step (a): “providing or obtaining a sample from a/the patient.” This is considered a data gathering step that is routine in the art and fails to add significantly more to the claims.
Accordingly, the claims are directed to judicial exceptions of abstract ideas. Because the claims do not include any additional features that integrate the mental processes into a practical application and/or do not add significantly more to the exceptions, the claims do not qualify as eligible subject matter under 35 U.S.C §101.
Claim Rejections - 35 USC § 112(b)
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 2, 16-17, 27-28, 58 is 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.
Regarding claim 2: Claim 2 recites the limitation “preferentially in a tumor microenvironment, in tumor-draining lymph nodes, or both” in line 4. The term “preferentially” renders the claim indefinite because it is not clear whether the limitations following the term are required.
[AltContent: textbox ([img-media_image1.png])]Regarding claim 16: Claim 16 recites the following method (see insert below) which comprises steps (a) through (d), wherein the relationship between steps (c) and (d) is not clear. It is unclear if applicant amendment was incorrectly applied or if applicant intended to change the verb/action/step in subpart (d). Thus, the claim is rendered indefinite. For further examination, step (d) of the claim is interpreted as “(d) stratifying the patient into at least one of the three groups…”.
Regarding claim 17: Claim 17 recites “if the patient…selecting a cancer treatment that does not consist of administration of a PI3K inhibitor, or if the patient… further comprising at least one of…” followed by paragraphs 3, 4, and 5 of the claim. There should be a conjunction “and/or” between paragraphs 4 and 5 of the claim to clarify the options recited in paragraphs 3-5 when the alternative recited in paragraph 2 is selected. Additionally, claim 17 recites the limitation "the TFR cell depleting therapy" in lines 19 and 28. However, “a TFR cell depleting therapy” is recited in each of paragraphs 3, 4, and 5. There is insufficient antecedent basis for this limitation in the claim because it is uncertain which of the TFR cell depleting therapies is intended by the recitations in lines 19 and 28 (see MPEP 2173.05e).
Regarding claim 27: Similarly to claim 17, claim 27 recites the term “the TFR cell depleting therapy” which renders the claim indefinite as described for claim 17 above.
Regarding claim 28: Claim 28 recites “The method of claim 16, wherein the PI3K inhibitor…” in line 1. Claim 16 is canceled. Thus, claim 28 is rendered indefinite. For further examination, claim 28 is interpreted to be dependent on claim 17 which recites “a PI3K inhibitor.”
Regarding claim 58: Claim 58 recites the limitation “preferentially in a tumor microenvironment, in tumor-draining lymph nodes, or systemically” in lines 4-5. The term “preferentially” renders the claim indefinite because it is not clear whether the limitations following the term are required. Further, claim 58 recites The method of claim 55, wherein the method requires “at least one of” as it pertains to the agent of claim 55 wherein “the agent comprises a modified dosage or administration of a PI3K inhibitor that selectively or transiently depletes TFR ST2 Treg, highly suppressive Treg, activated Treg, or effector Treg cells preferentially in a tumor microenvironment, in tumor-draining lymph nodes, or systemically;…”. The remaining limitations recited in the claim render the claim indefinite because it is unclear which phrases are intended to be encompassed by the top level requirement of “at least one of” and which phrases are intended to be further limitations of the selected options. For further examination, the options for selection of “at least one of” are labeled as “1, 2, 3, and/or 4” as shown in the image below. As such, as option 4 is preceded by “or,” the limitation “the selective [AltContent: textbox ([img-media_image2.png])]Phophoinositide 3-kinase δ inhibitor” lacks antecedent basis in claim 55.
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.
Claims 1-2, 8-10, 12-13, 16, 27-28, 30, 32 are rejected under 35 U.S.C. 103 as being unpatentable over Ali, et al. Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer. Nature (2014), 510, p.407-411 (herein referred to as Ali); in further view of Lim, et al. Phosphoinositide 3-kinase δ is a regulatory T-cell target in cancer immunotherapy. Immunology (2019), 157, p.210-218 (herein referred to as Lim); further in view of Munoz-Erazo, et al. Tertiary lymphoid structures in cancer: Considerations for patient prognosis. Cellular & Molecular Immunology (2020), 17, p.570-575 (herein referred to as Munoz-Erazo); and, in further view of Song, et al. T follicular regulatory cells suppress Tfh-mediated B cell help and synergistically increase IL-10-producing B cells in breast carcinoma. Immunologic Research (2019), 67, p.416-423 (herein referred to as Song).
Ali teaches a method of treating cancer via inactivation of PI(3)K p110δ, which breaks regulatory T-cell-mediated immune tolerance to cancer (title), including solid tumors. Ali teaches that inhibitors against the p110δ isoform of PI3K have shown remarkable therapeutic efficacy in some human leukaemias; and, that inactivation in mice protects against a broad range of cancers, including non-haematological solid tumours (p.1, col.1 para.1). Ali’s study demonstrates that p110δ inactivation in regulatory T cells unleashes CD8+ cytotoxic T cells and induces tumor regression; and, that such inhibitors can break tumour-induced immune tolerance and should be considered for wider use in oncology (p.1, col.1, para.1). Ali teaches that mice expressing constitutively inactive PI3Kδ were more resistant to B16 melanoma and prevented growth of Lewis lung carcinoma, EL4 thymoma, and 4T1 breast cancer cells (p.1, col.1, para.2). Ali also shows that FOXP3+ CD4+ Tregs in the draining lymph nodes of 4T1 tumour-bearing KO mice did not expand as robustly as in wild-type mice (p.1, col.1, para.3). Ali’s data demonstrate that p110δ inactivation in Tregs is both necessary and sufficient to confer tumour resistance (p.2, col1, para.1). Additionally, Ali teaches that PI-3065 is a small molecule inhibitor with selectivity toward the p110δ isoform of PI3K; and, that administration of PI-3065 suppressed tumor growth and metastasis in 4T1 breast cancer bearing mice (p.3, col.2, para.1).
Lim teaches that PI3Kδ is a regulatory T-cell target in cancer immunotherapy (title). Lim teaches that tumour infiltration by Tregs contributes to suppression of the anti-tumour response, which limits the efficacy of immune-mediated cancer therapies (abstract). Lim teaches that Treg cells were initially identified as a CD25hi T-cell subset with immunosuppressive function and assume critical roles in the prevention of autoimmunity (p210, col.1, para.1). Lim further teaches that therapeutic targeting of tumour Treg cells to enhance anti-tumour immunity is an active area of research (p.210, col.1, para.1). Lim teaches that evidence of T suppressor cells first emerged a half-century ago, and that detailed study of defined T-cell subsets began around 1995, citing Sakaguchi et al (p.211, col.1, para.2). Lim teaches that Foxp3 is a transcription factor that is a master regulator of the Treg cell lineage (p.211, col.1, para.2). Lim teaches that the proportion of Treg cells within the tumour immune infiltrate often far outstrips homeostatic proportions in circulation (p.211, col.1, para.4). Lim also teaches the importance of Tregs in dampening inflammation driving oncogenic progression in colorectal cancer. Lim teaches that Treg-mediated immunosuppression has been held accountable for the reduced anti-tumour functionality of CD8+ and CD4+ conventional T cells in the tumour (p.211, col.2, para.1). Lim also teaches molecular dimerization of subunits in immune and non-immune cells, teaching that the regulatory subunit 110δ of PI3K is largely dominant in immune cells rather than non-immune cells which express other regulatory subunits (p.212, col.1, para.3). Lim teaches that in vitro treatment of T cells with inhibitors of the PI3K/Akt pathway has been shown to improve in vivo persistence and anti-tumour efficacy when transfused into tumour-bearing mice (p.212, col.2, para.1). Lim teaches that PI3Kδ activity is necessary for Treg cell suppressive function. Lim also cites a study identifying clear defects in human Treg cell activation on and suppressive function under idelalisib-treated patients (i.e., with a selective PI3Kδ inhibitor; p.212, col.2, para.3). Lim cites that whereas some studies show that PI3Kδ inhibition preferentially incapacitates Treg cells over effector T cells, another study showed that loss of PI3Kδ activity abrogated tumour elimination by CD8+ T cells; and, further teaches that enhancement of anti-tumour immunity by PI3Kδ inactivation occurs in spite of concurrent impairment of CD8+ T-cell cytotoxicity and correlates with the dependence of the tumour on Treg-mediated immunosuppression (p.212, col.2, para.4). Importantly, Lim suggests that Treg cells have varying requirements for PI3Kδ signaling throughout their lifespan, with reduced activity during development, but dependence on PI3Kδ in delivering immune suppression as mature regulators. Importantly, Lim suggests that this bifurcation represents an intriguing therapeutic potential to selectively target highly activated effector Treg cells in the tumour while leaving the homeostatic pool of resting Treg cells intact (p.213, col1., para.2; also, see Fig.1 below). Lim also teaches that there is known PI3Kδ involvement in signaling downstream of the TCR, CD28, ICOS, and possibly the IL-2 receptor, each of which regulates Treg cell homeostasis and function (p.214, col.1, para.2). Lim also teaches that checkpoint receptor molecules such as CTLA-4 and PD-1 are often up-regulated in highly activated effector T cells to limit collateral damage to self-tissue in the wake of pathogen-induced immune [AltContent: textbox (Lim, et al. Fig.1: Effect of PI3Kδ inhibition on activated/effector Tregs vs. homeostatic Tregs.
[img-media_image3.png])]responses and to prevent autoimmune damage (p.214, col2, para.2).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to combine the teachings of Ali with the teachings of Lim by using the selective PI3Kδ inhibitor PI-3065 (taught by Ali) or Idelalisib (taught by Lim) for the treatment of a solid tumor such as breast cancer, melanoma, or lung cancer (taught by Ali), in order to receive the expected benefit that treating with a PI3Kδ inhibitor (taught by Ali) would selectively target highly activated effector Treg cells in a tumour having a high proportion of activated Tregs, while leaving the homeostatic pool of resting Treg cells intact (taught by Lim). One of ordinary skill would have a reasonable expectation of success because Lim teaches that PI3Kδ activity is necessary for Treg cell suppressive function; that PI3Kδ inhibition preferentially incapacitates Treg cells over effector T cells; that Treg cells within the tumour immune infiltrate outnumber homeostatic proportions in circulation; and, that p110δ inactivation in regulatory T cells unleashes CD8+ cytotoxic T cells and induces tumor regression to break immune tolerance.
The combination of Ali/Lim does not teach determining and comparing the level or activity of highly suppressive/activated/follicular regulatory Tregs in order to administer a modified dosage of the PI3Kδ inhibitor. Regarding determining and comparing the level or activity of highly suppressive/activated/follicular regulatory Tregs and administering a modified dosage of the PI3Kδ inhibitor: The instant specification does not provide an explicit reference dosage or administration from which a “modified” dosage or administration would be determined. However, from the context of the disclosure, it is interpreted that the dosage or administration is a “tailored” dosage or administration wherein the dosage or administration would be higher for a patient having a high level or activity of TFR/ST2 Treg/highly suppressive Treg/activated Treg/effector Treg than a dosage or administration for a patient having lower levels or activity of these “activated Tregs.”
Munoz-Erazo teaches the role of tertiary lymphoid structures (TLSs) in cancer (title); and, that TLSs are comprised of various cell densities of certain immune cell populations, including TFRs. Munoz-Erazo teaches a review and consideration of the TLS as part of a prognostic armamentarium for human cancer; that TLSs likely play a direct role in influencing the immune response (p.570, col.2, para.3); and, that TLSs are discrete, structured organizations of infiltrating immune cells that are induced in chronically inflamed locations, such as persistent pathogen infection, autoimmune disorders, allograft rejection, and cancer (p.570, col.1, para.1-2). Munoz-Erazo teaches that TLSs are very similar to lymph nodes in structure and development; that TLSs can be simple lymphocyte aggregates or more organized structures; and, that well-developed TLSs contain B-cell follicles with actively replicating B-cell germinal centers (GCs) surrounded by T-cells, but, that TLSs are not encapsulated and occur within various nonlymphoid tissues (p.570, col.1, para.2—col.2, para.1). Munoz-Erazo teaches that tumor-associated TLSs are often associated with good prognostic outcome in most cancers, including breast, CRC, and lung cancer; and, that negative associations of TLS with cancer may be a result of compositionally different TLS (p.570, col.2, para.2). Munoz-Erazo also provides Table 1, which shows that Tregs are an immune cell population that is more likely to vary in TLSs; and, cites studies suggesting the analysis of TLS as a prognostic tool, which can vary by tissue of origin, tumor subtype, tumor location, and tumor stage (p.571, col.1, para.1). Munoz-Erazo provides a review of studies that have used various RNA- and protein-based methods for assessing cell-specific populations within TLSs (see Table 2 and section: Methods for Evaluating TLS in Cancer). Munoz-Erazo teaches studies that have evaluated cellular composition of TLSs to determine the effect of TLS cell types on disease recurrence in CRC and lung cancer, citing that Kim et al. studied and stratified lung cancer patients using a tiered approach which was based on the presence or absence of TLS, low or high TLS, and presence or absence of GC in TLS (p.573, col.1, para.1). Munoz-Erazo further teaches that the collective data suggest that the predictive effect of TLS may be due not only to the number and composition but also to the function and activity of the cells inside, which in turn is affected or controlled by the site of such a localized immune reaction (p.573, col.2, para.5). Munoz-Erazo also cites Gobert et al., teaching that Tregs in infiltrating primary breast cancer were not associated with tumor growth, but Tregs within TLS had an activated phenotype (p.574, col.1, para.1). Munoz-Erazo additionally teaches that TLSs are likely clinically important in patient prognosis and that understanding the sequence of immunological events in TLS will assist with identifying which patients may require more aggressive management and identifying patients likely to benefit from existing immunotherapies (p.547, col.1, para.5). Munoz-Erazo includes Table 3 which teaches that better characterization of TLS subtype features may assist with patient selection for existing therapies (second row).
Song teaches that TFRs suppress TFH-mediated B cell help in breast cancer (title). Song teaches sorting of Treg subtype populations and distinguishes TFR-like (i.e., CD25+CXCR5+) from Treg-like (i.e., CD25+CXCR5-) and TFH-like (i.e., CD25-CXCR5+) cell populations (abstract) in obtained human samples (p.417, col.1, para.4; i.e., including TFR isolation and determination). Song further teaches that TFR-like cells expressed intermediate levels of Foxp3 and Bcl6; whereas Treg-like cells had high Foxp3 and low Bcl-6; and, TFH-like cells were high in Bcl-6 but low in Foxp3 (abstract). Song also teaches that TFR- and Treg-like cells were elevated in breast cancer patients and that TFRs in breast cancer patients expressed higher levels of Foxp3 than controls. Song uses protein-based FACS in conjunction with anti-human antibodies toward CD3, CD4, CXCR5, and CD25 to distinguish subtypes (p.417, col.2, para.1).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Ali/Lim with the teachings of Munoz-Erazo and Song by stratifying patients according to their TLS (as taught by Munoz-Erazo) and Treg (taught by Song) profiles and further stratifying patients according to their comparative levels of highly suppressive/activated (i.e., TFR) cells versus homeostatic Tregs and TFHs in order to receive the expected benefit of effectively identifying (i.e., through determination and comparing relative TFR levels) and treating patients having higher relative levels or activities of TFRs in order to better tailor them toward more aggressive management (taught by Munoz-Erazo) and benefit from existing therapies like the PI3Kδ inhibitors (taught by the combination of Ali and Lim) that selectively inhibit highly suppressive/activated/follicular regulatory Tregs (taught by Ali and Lim) in order to relieve suppression of anti-tumor activities in cytotoxic T cells (taught by Lim) and TFH cells (taught by Song) . One of ordinary skill would have a reasonable expectation of success because Munoz-Erazo teaches that TLSs differ in composition and that Treg contribution varies depending on cancer type and individual; Song teaches how to distinguish TFRs from homeostatic Tregs and TFHs using cell-specific marker profiles; Lim teaches that TFRs suppress cytotoxic T cells; and, Song teaches that TFRs suppress TFHs in cancer.
Claims 5-7 are rejected under 35 U.S.C. 103 as being unpatentable over Ali, Lim, Munoz-Erazo, and Song, as applied to claim 1 above, and further in view of Page, et al. Two may be better than one: PD-1/PD-L1 blockade combination approaches in metastatic breast cancer. Breast Cancer (2019), 5:34, p. 2-9 (herein referred to as Page).
The combination of Ali/Lim/Munoz-Erazo/Song teaches a method of treating cancer by obtaining a patient sample, determining the level or activity of activated suppressive Tregs, and treating patients with high levels or activity of activated suppressive Tregs with tailored/modified, more aggressive PI3Kδ inhibitor, as applied to claim 1.
The combination of Ali/Lim/Munoz-Erazo/Song does not teach that the inhibitor is provided in conjunction with an additional cancer therapy (instant claims 5 and 17); that the additional cancer therapy is a checkpoint inhibitor or other immunotherapy (instant claim 6); or, that the immune checkpoint inhibitor or immunotherapy comprises an antibody against PD-L1.
Page teaches that antibodies blocking PD-1 or PD-L1 are associated with modest response rates in breast cancer, but are well tolerated and are safe when administered with a variety of systemic chemotherapies, targeted therapies, and radiotherapy (abstract). Page teaches that several studies suggest that inhibition of PI3K decreases Tregs and promotes CD8+ memory T cell differentiation; and that the addition of anti-PD-1 was found to enhance the benefit of dual blockade of PI3K and CDK4/6 (p.4, col.2, para.2).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Ali/Lim/Munoz-Erazo/Song with the teachings of Page by concurrently administering an anti-PD1 and/or anti-PD-L1 antibody (taught by Page) with a PI3K inhibitor (taught by Page) that is selective toward PI3Kδ for breast cancer (taught by the combination of Ali/Lim/Munoz-Erazo/Song) in order to receive the expected benefit that the combination therapy would enhance treatment efficacy. One of ordinary skill in the art would have a reasonable expectation of success because Page teaches that anti-PD-1 and/or anti-PD-L1 antibody therapies are safe and well tolerated when administered with targeted therapies; and, the combination of Ali/Lim/Munoz-Erazo/Song teaches that PI3Kδ inhibitors selectively target highly suppressive activated Tregs.
Claims 55-58, 65, 68, and 71 are rejected under 35 U.S.C. 103 as being unpatentable over Ali, Lim, Munoz-Erazo, and Song, as applied to claim 1 above, and further in view of Morse, et al. Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines (herein referred to as Morse).
The combination of Ali/Lim/Munoz-Erazo/Song teaches a method of treating cancer by obtaining a patient sample, determining the level or activity of activated suppressive Tregs, and treating patients with high levels or activity of activated suppressive Tregs with tailored/modified, more aggressive PI3Kδ inhibitor, as applied to claim 1. Additionally, the combination of Ali/Lim/Munoz-Erazo/Song teaches tailoring of the PI3Kδ administration that selectively depletes highly activated suppressive Tregs (instant claim 58); that the selective inhibitor is PI-3065 or Idelalisib (instant claim 58); that TFR cells are CD3+CD4+FOXP3+BCL6+ and can also express CTLA-4, CXCR5, and PD-1 (instant claim 65); that the cancer is melanoma, lung, or breast cancer (instant claim 68); and stratifying patients according to the level or activity of highly activated suppressive Tregs in the tumor (instant claim 71).
The combination of Ali/Lim/Munoz-Erazo/Song does not teach that the treatment is with a cancer vaccine (instant claim 55); that the cancer vaccine is an antigen vaccine (instant claim 56); or, that the antigen is CEA (instant claim 57). or, that the immune checkpoint inhibitor or immunotherapy comprises an antibody against PD-L1.
Morse teaches that Tregs limit antigen-specific immune responses are a cause of suppressed anticancer immunity. Morse demonstrates that using an agent to suppress Treg-cell function enhanced antitumor immune responses in patients with CEA-expressing malignancies using the rF-CEA(6D)-TRICOM CEA antigen cancer vaccine (abstract). More generally, Morse conceives of “combining Treg-cell depletion with anticancer vaccines to enhance tumor antigen-specific immune responses (abstract).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Ali/Lim/Munoz-Erazo/Song with the teachings of Morse by using the PI3Kδ inhibitor (taught by Ali and Lim) as a Treg depleting agent in a combination therapy with a CEA-antigen cancer vaccine (taught by Morse) in order to receive the benefit that the PI3Kδ inhibitor would enhance tumor antigen-specific immune responses to an antigen cancer vaccine (taught by Morse). One of ordinary skill in the art would have a reasonable expectation of success because the combination of Ali/Lim/Munoz-Erazo/Song teaches how to identify and stratify patients who have an increased level or activity of highly suppressive activated Tregs and who are likely to benefit from PI3Kδ inhibitor treatment.
Conclusion
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/JAMI MICHELLE GURLEY/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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