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 01Jun2023 is acknowledged in which claim(s) 14 is/are canceled by Applicant.
Claim(s) 1-13, 15-21 is/are currently pending and presented for examination on the merits.
Specification
The use of trade name(s) or mark(s) used in commerce (e.g., ThermoFisher Scientific, Sigma Aldrich, Stem Cell Technologies, Lonza, FlowJo, Invivogen), 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.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (e.g., pg. 5, line 20; pg. 10, line 27). 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.
Claim Rejections - 35 USC § 112(a) – written description
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) 1-13 and 15-21 is/are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claimed Invention
Claim(s) 1-13 and 15-21, are drawn to method of reducing SIGLEC15 expression in lymph-node derived cells.
Breadth of Claims
The invention as disclosed in claim(s) 1-13 and 15-21 recite(s) “…S3. Reducing expression of SIGLEC15 in the extracted cells;…”. The claim(s) encompass a genus of methods which are claimed as having the function of specifically reducing SIGLEC15 expression in extracted cells. This means that the method genus includes any and all methods of reducing SIGLEC15 expression in extracted cells, which one of ordinary skill in the art would understand may include at least (1) small molecule inhibitors, (2) cytokine regulators, and (3) genetic silencing (e.g., siRNA, shRNA, sgRNA, etcetera). While the instant disclosure teaches six species of siRNA molecules with the demonstrated function of reducing SIGLEC15 expression in extracted cells, the instant disclosure does not provide an adequate number of species of siRNA to claim a SIGLEC15-reducing siRNA genus, nor does it provide any other species (e.g., small molecule inhibitor, shRNA, sgRNA, etc.) within the broader instant claimed genus of “reducing expression of SIGLEC15”. MPEP 2163.03(v) teaches “An original claim may lack written description support when…(2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc).”
Scope of Disclosed Species
The SIGLEC15 reducing siRNAs of SEQ ID NOs: 1-6 in the Applicant disclosure represents the SIGLEC15 expression reducing species that the applicant was in possession of at the time of filing.
State of the Prior Art
At the time of filing, SIGLEC15 expression was an emerging therapeutic target in the art, and one of ordinary skill in the art would have understood that commonly used approaches to inhibit a target gene include (1) small molecule inhibitors, (2) cytokine regulation, and (3) genetic silencing. It is understood by one of ordinary skill in the art that different expression modulating therapies each require function testing.
Small Molecule Inhibitors
At the time of filing, no small-molecule inhibitors were found in the prior art. However, post-filing, Ahmad et al. (Front. Immunol. 14:1254911, 06Oct2023; hereinafter “Ahmad”) teaches that multiple small molecule inhibitors of SIGLEC15 are known in the art and additionally taught a novel SHG-8 small molecule inhibitor of SIGLEC15 expression [e.g., title, abstract]. Ahmad’s post-filing disclosure supports that there are multiple small molecule species in the SIGLEC15 expression reducing genus.
Cytokine Regulation
At the time of filing, Wang et al. (Nature Medicine, Vol. 25, April 2019, 656-666; hereinafter “Wang”) taught IFNy inhibits SIGLEC15 expression in a variety of cell types [e.g., pg. 657, col. 2, ¶ 4; fig. 2].
Additionally, post-filing, Liu et al. (Acta Pharmaceutica Sinica B 2023;13(12):5048e5059; hereinafter “Liu”) teaches that IFNy loaded nanoparticles mediate SIGLEC15 silencing [e.g., title, abstract]. Liu’s post-filing disclosure supports the pre-filing teachings that SIGLEC15 expression is regulatable by IFNy and provides further evidence that additional species of SIGLEC15 expression reducing species exist.
Genetic Silencing
At the time of filing, Wang et al. (Nature Medicine, Vol. 25, April 2019, 656-666; hereinafter “Wang”) taught genetic ablation of SIGLEC15 [e.g., abstract, ¶ ; figs. 2-3, 5]. Additionally, Cao et al. (Signal Transduction and Targeted Therapy (2019) 4:10, hereinafter “Cao) taught SIGLEC15 knockout in macrophage cells [e.g., pg. 1, col. 2, ¶ 2]. Further, Sun et al. (Clin Cancer Res; 27(3) February 1, 2021, ePub 21Sep2020; hereinafter “Sun”) teaches SIGLEC15 siRNA for gene silencing is known in the art [e.g., tbl. 1].
Summary
Thus, in view of the instant disclosure, prior art, and post-filing art, the SIGLEC15 expression reducing method genus is comprised of a number of patentably distinct structurally and/or mechanistically unrelated methods of SIGLEC15 expression reduction. Therefore, it would not be possible for a skilled artisan to envisage all of the various species of the genus of SIGLEC15 expression reducing methods.
Conclusion
As indicated by the art, the genus of method of reducing SIGLEC15 expression is comprised of various patentably distinct species. Written description can be met if the claim(s) recite the specific species of method of reducing expression of SIGLEC15. Specifically, Applicant claim(s) 1, 2, and 12 should be amended to recite “S3. Reducing expression of SIGLEC15 in the extracted cells wherein SIGLEC15 expression is reduced by siRNA transfection, wherein the siRNA comprises one of SEQ ID NOs: 1-6”; claim 20 should be amended to “A population SIGLEC15, wherein SIGLEC15 expression is reduced by siRNA transfection, wherein the siRNA comprises one of SEQ ID NOs: 1-6”; and claim 21 should be amended to “The population
Claim Rejections - 35 USC § 112(a) - enablement
Claim(s) 7-13 and 15-19 is/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 treating cancer comprising administration of the composition of claim 1 (e.g., claims 7-11, claims 12-13), or the composition of claim 2 (e.g., claims 15-19), does not reasonably provide enablement for treating cancer comprising administration of T cells having reduced SIGLEC15 expression. 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 use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation."' (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (A) The nature of the invention; (B) The breadth of the claims; (C) The amount of direction provided by the inventor; (D) The existence of working examples; (E) The state of the prior art; (F) The level of predictability in the art; (G) The quantity of experimentation needed to make or use the invention based on the content of the disclosure and (H) The level of one of ordinary skill. While all of these factors are considered, a sufficient amount for amount for a prima facie case are discussed below.
The nature of the invention
Claims 7-11, 12-13 and 15-19 are drawn to a method of treating cancer comprising administering a population of T cells with reduced expression of SIGLEC15.
The breadth of the claims
The specific method steps to obtain each specific composition for administration to a subject in each of claims 7-11, 12-13 and 15-19 do not contain any steps that require T cells specifically are engineered to have reduced SIGLEC15 expression, rather the method steps for each of the instant claimed compositions requires that “cells” extracted from lymph nodes are engineered to have reduced SIGLEC15 expression.
The instant disclosure and Applicant post-filing art does not provide support for the engineering of T cells specifically to have reduced SIGLEC15 expression, nor treatment of cancer with a SIGLEC15 reduced T cell population.
The amount of direction provided by the inventor/the existence of working examples
The examples of the instant disclosure include: a flow-chart illustrating the method for obtaining a population of T cells according to the present invention [e.g., fig. 1]; a flow-chart illustrating the method of treatment according to the present invention [e.g., fig. 2]; a relative expression of SIGLEC15 in sentinel and non-sentinel lymph nodes, respectively [e.g., fig. 3A]; relative expression of SIGLEC15 across cell types for sentinel lymph nodes [e.g., fig. 3B]; T cell functional cytokine release after SIGLEC15 knock-down [e.g., fig. 5]; relative expression of SIGLEC15 in sentinel and non-sentinel lymph nodes [e.g., tbl. 1]; relative expression of SIGLEC15 in sentinel lymph nodes before and after siRNA knockdown [e.g., tbl. 2]; expressed SIGLEC15 mRNA analyzed by RNAscope in sentinel and non-sentinel lymph nodes [e.g., tbl. 3]; siRNA sequences [e.g., tbl. 4]; SIGLEC15 MFI on live lymph node cells [e.g., tbl. 5]; and T cell functional cytokine release after SIGLEC15 knock-down [e.g., tbl. 6].
Additionally, the instant disclosure teaches that SIGLEC15 expression was only monitored via bulk RNA sequencing in lymph node tissue before and after siRNA engineering, not in T cells specifically [e.g., pg. 8, lines 18-32]; and the “T cell functional cytokine release” after SIGLEC15 knockdown was performed in control lymph nodes (LN) versus S15-96, S15-965, and S15-138 which are siRNA treated LN tissues (not isolated T cells) [e.g., pg. 11, lines 6-11]. Therefore, there is no evidence in the Applicant disclosure to support that SIGLEC15 reduced T cells specifically treat cancer.
The Applicant disclosure is missing the controls and/or experiments required to meet the instant claim limitations of administering SIGLEC15 reduced T cells to treat cancer. Specifically, Applicant would need to demonstrate that (1) lymph node derived T cells were specifically isolated; (2) isolated T cells demonstrated decreased SIGLEC15 expression after siRNA engineering (relative to un-engineered T cell isolates from the same sample); and (3) isolated SIGLEC15 reduced T cell administration treats cancer.
The examples provided do not demonstrate that T cells with reduced SIGLEC15 expression were isolated and used to treat cancer. Additionally, the disclosure does not discuss, or demonstrate through working examples, a method that could be used to determine that reduced SIGLEC15 expression on T cells specifically is responsible for the anti-tumor effects of the SIGLEC15 knockdown lymph node cells in treating cancer.
The state of the art/the level of predictability in the art
At the time of filing, SIGLEC15 expression on cells other than T cells (e.g., cancers, myeloid cells, etc.) were well-known in the art to suppress/inhibit T cell function. Specifically, Wang et al. (Nature Medicine, Vol. 25, Apr2019, 656-666; hereinafter “Wang”) taught SIGLEC15 is a critical immune suppressor that is expressed on some myeloid cells, that SIGLEC15 suppresses antigen-specific T cell responses in vitro and in vivo, that genetic ablation of SIGLEC15 amplifies anti-tumor immunity in the TME and inhibits tumor growth, and that SIGLEC15 is a potential target for cancer immunotherapy [e.g., title, abstract].
There are no methods to establish that SIGLEC15 knockdown or knockout T cells treat cancer in the prior art. However, the prior art (as discussed above) teaches methods of increasing T cell anti-cancer activity comprising inhibiting SIGLEC15 on other cells from interacting with and suppressing/inhibiting T cell anti-tumor function.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
Therefore, based on the instant disclosure and prior art, it would be unclear to one of ordinary skill in the art if the SIGLEC15 knockdown composition of the instant invention treats cancer because (1) as described in Wang above, decreased SIGLEC15 expression on other lymph node cells results in increased T cell anti-cancer activity; (2) if a composition comprising only T cells with reduced SIGLEC15 expression is an effective anti-cancer therapeutic; or (3) something else.
Based on the instant disclosure and prior art, there is no known method through which one of ordinary skill in the art would have been able to reliably predict that SIGLEC15 reduced T cell administration treats cancer. Therefore, in order to practice the invention as claimed, one of ordinary skill in the art would have to perform undue experimentation to develop a method which (1) produces SIGLEC15 reduced T cells, and (2) demonstrates SIGLEC15 reduced T cells treat cancer. Applicant is enabled for treatment of treating cancer comprising administration of the composition of claim 1 (e.g., claims 7-11, claims 12-13), or the composition of claim 2 (e.g., claims 15-19)
Conclusion
In view of the Wands factors as discussed above, one of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the instant claimed invention. As such, instant claims 7-13 and 15-19 were determined to not meet the scope of enablement requirement of 35 USC § 112(a).
Enablement can be met by amending claims 7, 12, and 15 to recite “…a population of [[T]] cells…”. Dependent claims 8-11, 13, and 16-19 can overcome this rejection by amending claims 7, 12, and 15 as described above.
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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/AMY M. CHATTIN/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643