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 II, claims 8-9, 11, 13, and 52, and species anti-CD4 antibodies as the antibody and breast carcinoma as type of cancer, in the reply filed on June 23, 2026 is acknowledged.
Claims 2-4, 8-9, 11, 13-21, 23-26, 37-38, 45, 49, and 52 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 8-9, 11, 13, and 52 are under consideration in this office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The application is the national stage entry of PCT/US22/24067, which claims benefit to U.S. Provisional Application No. 63/172,977, filed April 9, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on June 7, 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS is being considered by the examiner.
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 8-9, 11, 13, and 52 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 8 recites a method for treating a tumor comprising administering a treatment to a subject if the density or number of three-cell structures in the tumor sample is above a baseline threshold. The phrase “baseline threshold” renders the claim indefinite because neither the claim nor the specification provide reasonable certainty as to its scope regarding how the baseline threshold is established or to what the reference against which the density or number of three-cell structures is compared. For example, it is unclear whether the baseline threshold is a predetermined numerical cutoff, a threshold derived from a reference population, or what the reference population is. Because there are no objective boundaries for determining the claimed baseline threshold, one of ordinary skill in the art would not be reasonably apprised of the metes and bounds of the claim. Thus, it is unclear when the claimed condition requiring the density or number of three-cell structures be above a baseline threshold is satisfied.
Claims 9, 11, 13, and 52 are included in this rejection for being dependent on a rejected base claim and for failing to cure the indefiniteness.
Claim Rejections - 35 USC § 112(a)
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.
Scope of Enablement
Claims 8-9, 11, 13, and 52 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 detecting in a tumor sample the presence of three-cell structures comprising a T cell, tumor-associated macrophage, and regulatory T cell, does not reasonably provide enablement for a method of treating a tumor comprising detecting thee-cell structures, calculating the density/number of three-cell structures, and administering a treatment if the density/number is above a baseline threshold.. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Case law holds that applicant’s specification must be “commensurately enabling [regarding the scope of the claims].” See Ex Parte Kung, 17 USPQ2d 1545, 1547 (Bd. Pat. Appl. Inter. 1989). Otherwise undue experimentation would be involved in determining how to practice and use applicant’s invention. Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described in In re Colianni, 195 USPQ 150 (CCPA 1977) and have been adopted by the Board of Patent Appeals and Interferences in Ex Parte Forman, 230 USPQ 546 (BPAI 1986). Among these factors are:
1. the nature of the invention,
2. the state of the prior art,
3. the predictability or lack thereof in the art,
4. the breath of the claims,
5. the amount of direction or guidance present, and
6. the presence or absence of working examples.
The following is an analysis of these factors in relationship to this application.
Nature of the invention/Breath of the claims
The nature of the invention is a method of treating a tumor by administering a treatment, wherein the patient receives the treatment if the density/number of three-cell structures is above a baseline threshold. With respect to claim breadth, the standard under 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. As such, the claims are directed to a broad method of treating all types of tumors with any treatment, wherein the treatment is administered if the density/number of three-cell structure is above a baseline threshold. The claims read on all tumor types and all treatment modalities, including pharmaceuticals, antibodies, surgery, and radiation.
State of the art/Predictability
The invention is related to a method of treating cancer, wherein treatment to be administered is determined by the presence of three-cell structures comprising a T cell (helper T cell or cytotoxic T cell), immunosuppressive regulator T cell (Treg), and immunosuppressive tumor-associated macrophage (M2 macrophage).
Oshi et al, published October 19, 2020 (instant PTO-892), teaches that regulatory T cells (Tregs) were associated with increased tumor infiltration of M2 macrophages and decreased infiltration of T helper type 1 cells. Further, responsiveness to neoadjuvant chemotherapy was associated with low Treg abundance in triple negative breast cancer (TNBC) but not in ER-positive/Her2-negative subtype (abstract). Oshi teaches that abundance of tumor-infiltrating lymphocytes (TILs) in breast cancer predicts response to neoadjuvant chemotherapy and better prognosis in TNBC (pg 2, section 1) and that Tregs suppress antitumor responses (pg 2, section 1). Oshi et al also teaches that high abundance of Tregs was associated with increased tumor infiltration of M2 macrophages. Oshi states that, “Because each breast cancer subtypes is biologically different, the impact of (TILs) on clinical outcome should be evaluated separately in each subtype” (pg 8, section 3).
Ngiow et al, published July 28, 2020 (instant PTO-892), teaches the immunosuppressive phenotype of some tumors (abstract). Tumor-associated macrophages (TAMs) are innate immune cells that accumulate in the tumor microenvironment as tumors progress; the presence of immunosuppressive TAMs can interfere with T cell-mediated anti-tumor immune responses (pg 2, column 1, para 1). Also, Ngiow teaches that a higher effector/Treg ratio is associated with favorable outcomes in multiple solid cancers (pg 4, column 2, para 0). Ngiow teaches the importance of developing therapeutic approaches to limit the accumulation of immunosuppressive immune cells, like regulatory T cells (regs) and tumor-associated macrophages, while promoting effector T cell activity (abstract).
WO 2020/097495, published May 14, 2020 (“Purvis”; instant PTO-892) teaches a method related to performing single-cell phenotypic and functional analysis of cancer cells within the tumor microenvironment; the method allows for the determination of the functional status of tumor infiltrating lymphocytes (TILs) and whether a subject with a solid tumor is likely to respond to a particular immunomodulator ([0038]; abstract). For example, it would be possible to determine, for a given solid tumor sample, whether immune cells are activated or exhausted or whether immune cells are being suppressed within the tumor microenvironment by Tregs, M2 macrophages, and myeloid-derived suppressor cells (MDSCs). Furthermore, the methods and compositions also facilitate the quantification of TIL and tumor cell co-expression profiles of targetable immune modulatory receptors and their cognate ligands (e.g., PD-1 and PD-L1), thereby providing information about whether a particular immunomodulator may positively impact the TME and facilitate a positive treatment outcome with the immune-modulator, either alone or in combination with another cancer drug. The selection of a particular immunomodulator may reduce or eliminate the resistance a particular cancer cell may have to treatment with a particular cancer drug [0038].
Juncker-Jensen et al, presented April 2019 (IDS from 6/7/2024, pg 1) teaches that triple-negative breast cancers (TNBCs) are correlated with the presence of M2 tumor-associated macrophages (TAMs) and higher tumor proliferation (“Background and Results”). Juncker-Jensen found in a spatial nearest neighbor analysis that M2 TAMS were closer in proximity to both proliferating tumor cells and Tregs, suggesting that a pathway in which activated M2 TAMSs in TNBC tumors play a pro-tumorigenic role by stimulating proliferation of tumor cells and promoting an immunosuppressive tumor environment via promotion of Tregs (“Results”). Specifically, M2 TAMs (CD3-CD68+HLA-DRCD163+) were closer in proximity to T helper cells (CD3+CD4+), Tregs (CD3+CD4+FoxP3+), T cytotoxic cells (CD3+CD8+), and proliferating tumor cells (PanCK+Ki67+) in TNBC tumors versus ER-positive tumors. These data suggest a possible pathway in which TNBC cells induce TAM polarization toward a pro-tumorigenic M2 phenotype, thereby promoting an increase in tumor proliferation as well as indirectly creating an immuno-suppressive tumor environment via the recruitment of Tregs (“Conclusion”).
Seo et al, published December 2, 2016 (instant PTO-892) teaches that pancreatic ductal adenocarcinoma (PDA) affects CD4+ helper T-cell populations by driving differentiation away from the TH1 subtype towards TH2 cells, thus limiting antitumor efficacy and promoting chronic inflammation; the higher ratio of TH2 to TH1 subtypes in the PDA has been associated with worse survival (pg 110, column 2, para 5).
At the time the application was filed, it was generally understood in the art that tumors exhibiting an immunosuppressive tumor environment, including the presence of Tregs an TAMs, were associated with suppression of anti-tumor immune responses, promotion of tumor progression, and reduced responsiveness to immunotherapies. The prior art recognizes that these immune cell population contribute to immune evasion by inhibiting effector T-cell activity and fostering a tumor-permissive inflammatory microenvironment. Although the art suggests that tumors enriched in these immunosuppressive cell types may exhibit diminished therapeutic responses, it did not establish that a specific density or number of colocalized helper T cells, regulator T cells, and TAMs above a base threshold should be used to select patients for treatment, nor did it identify any threshold values or specific treatment regimen based on such determination.
Guidance/working examples
The disclosure details a method for determining an appropriate therapy of a tumor based on the density/number of three-cell structures comprising a regulatory T cell, a tumor-associated macrophage, and a cytotoxic T cell [0004]. The helper T cells are inactive PD1-LAG3-CD8+ T cells or exhausted PD1+LAG3+CD8+ T cells, the tumor-associated macrophages are CD68+, CD68+TIM3+, CD163+, or CD163+TIM3+ tumor-associated macrophages, and the regulatory T cells are CD4FOXP3+ regulatory T cells [0005]. According to the specification, a density of 5 or more, 10 or more, 15 or more, or 20 or more three-cell structures per mm2 in the perivascular space indicates that the tumor will not respond to a anti-cancer therapy [0005]. As shown in Figure 3, in triple negative breast cancer, there is perivascular accumulation of tumor-associated macrophages and Tregs in untreated and chemotherapy-treated tumors [0015]. This close contact of T cells and Tregs and TAMs may inhibit T cell anti-tumor function, where T cells encounter a high density of at least two immunosuppressive cell types in the perivascular niche, could lead to T cell inactivation before the T cells can migrate further into tumors, thereby reducing anti-tumor immunity [0055]. Also, presence of the three-cell structures may limit the efficacy of cancer immunotherapies mediated by activated T cells [0055]. These conclusions are extended to any cancer, any solid tumor, and any cancer associated with the presence of a perivascular space [0059].
The claims are drawn to a method based on this threshold for treating any cancer with any treatment based on the presence of three-cell structures. The specification, while providing insight into the relationship between the presence of three-cell structures and tumor disease severity, fails to reasonably provide enablement for a method of treating cancer based on administering a treatment if the three-cell structure density/number is greater than a baseline threshold.
Specifically, applicant’s disclosure lacks guidance regarding which cancers and which treatments, and the scope of the claims is broader than the enabling disclosure.
The standard for determining whether the specification meets the enablement requirement is whether the experimentation needed to practice the invention is undue or unreasonable. To be fully enabled, one of ordinary skill in the art should be able to make and use the invention without undue experimentation. The claims are drawn to a potentially novel metric for determining responsiveness of a subject with cancer to a given therapy; however, the specification provides no method for using the claimed invention that bears a reasonable correlation to the entire scope of the claim. Applicant’s disclosure, does not define what constitutes a baseline threshold or teach one of ordinary skill how to select the appropriate baseline threshold.
A skilled artisan would not know how to use the method with a reasonable expectation of success based solely what is disclosed in the specification and the art at the time the application was filed for the treatment of a tumor. The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use it with a reasonable expectation of success. The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution. Given that the nature of the invention is directed to in vivo treatment of a tumor, a person having ordinary skill in the art would have to perform multiple in vivo experiments in different models of cancer to overcome the unpredictability within the disclosure. The amount of further experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine’ within the art, and constitutes undue further experimentation in order to discover how to use the method with a reasonable expectation of success.
Therefore, claims 8-9, 11, 13, and 52 are rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER BENAVIDES whose telephone number is (571)272-0545. The examiner can normally be reached M-F 9AM-5PM (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at (571)272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Jennifer Benavides
Examiner
Art Unit 1675
/JENNIFER A BENAVIDES/ Examiner, Art Unit 1675
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