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 12May2026 is acknowledged in which claim(s) 3 and 14 is/are canceled by Applicant.
Claim(s) 1-2, 4-13, 15-21 is/are presented for examination on the merits.
Response to Amendment
The objection(s) to the specification have been withdrawn in view of the Amendment filed on 12May2026.
All previous rejections of claim(s) 3 are moot in view of claim cancelation.
The previously set forth rejection(s) of claim(s) 1-2, 4-13, and 15-21 under 35 U.S.C. § 112(a) written description have been withdrawn in view of the recent claim amendment filed on 12May2026, which added new limitations to the claims, that were not considered in the previous rejections.
All other previously presented rejection(s) and objection(s) are maintained and/or maintained in modified form as necessitated by amendment, for reasons provided below. Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Rejections Maintained/Modified as Necessitated by Claim Amendments
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) 1-2, 4-13 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) 1-2, 4-13 and 15-21, are drawn to method of reducing SIGLEC15 expression in lymph-node derived and/or a population of reduced SIGLEC15 expression T cells.
Breadth of Claims
The invention as disclosed in claim(s) 1-13 and 15-19 recite(s) “…S3. Reducing expression of SIGLEC15 in the extracted cells; by downregulating expression of a gene encoding SIGLEC15 by siRNA transfection, shRNA transfection, or CRISPR-mediated gene editing…”, and claim(s) 20-21 recites “population of T cells with reduced expression of SIGLEC15”. The claim(s) encompass a genus of methods which are claimed as having the function of specifically reducing SIGLEC15 expression in a population of T cells via siRNA transfection or shRNA transfection. A skilled artisan would understand that shRNA and siRNA sequences for gene silencing require function testing, and further that the active steps (S1-S4) do not necessarily result in a composition of only T cells (e.g., would result in a population comprising T cells).
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, it is understood by one of ordinary skill in the art that different expression modulating (e.g., SIGLEC15 reducing) siRNA and shRNA sequences each require function testing.
Fellmann and Lowe (Nat Cell Biol. 2014 January ; 16(1): 10–18. doi:10.1038/ncb2895; hereinafter “Fellmann”) teaches stable RNA interference rules for silencing genes in mammalian systems [e.g., title, abstract]. Fellmann further teaches that validation is required of siRNA and shRNA sequences, even for computer generated RNAi molecules (e.g., shRNAs or siRNAs) [e.g., pg. 4, “identifying the right shRNA”].
Thus, in view of the instant disclosure and prior art, the SIGLEC15 expression reducing method genus is comprised of an unknown plurality of patentably distinct, structurally unrelated (e.g., different sequences) shRNA or siRNA molecules with the function of SIGLEC15 expression reduction, which require target gene validation because the effects in cells are unpredictable. 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 using siRNA or shRNA 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 T cells with reduced expression of 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 of claim 20, wherein”. Dependent claims 4-11, 13, and 15-19 can meet written description by amending claims 1, 2, and/or 12 as described above. Note, the above recommendations are based on the written description support within the instant disclosure.
Response to Arguments
Applicant argues that the previous rejection does not take into account the current amended claim(s) language, and that the amendment should overcome the previous art rejection because the specification has support for pGPu6 vectors carrying SIGLEC15 shRNA, and clearly demonstrates possession.
In response, Applicant amendment overcame one of the issues in the previous rejection, but failed to fully incorporate the suggested amendments (e.g., currently unincorporated, previously provided amended wording suggestions are bolded above). Specifically, the applicant does not have written description for all possible (e.g., including unknown) shRNA and/or siRNA molecules, but rather would be limited to those disclosed in the instant specification, and the resultant composition is not considered to be only a population of T cells but rather a composition comprising T cells (e.g., may consist of more than just T cells). A new/modified rejection is provided above based on the claim(s) in the Amendment filed on 12May2026 (see above for details).
Applicant arguments have been thoroughly reviewed but are not persuasive. The rejection(s) of claim(s) 1-2, 4-13, and 15-21 is/are maintained in modified form, as necessitated by amendment.
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.
Response to Arguments
Applicant argues:
The specification provides instruction for expanding T cells specifically: (a) dependent claim 5 and the specification recite “the conditions favouring T cell expansion comprise maintenance of the cells in the present of IL-2”, (b) instant disclosure further describes that “single cells” with reduced expression of SIGLEC15 suspensions are re-suspended in serum-free cell culture medium in the present of IL2 and/or other cytokines, (c) that cells are stimulated by the tumor antigens together with APCs during cell culture, (d) these conditions are well-known in the art to favor T cell expansion, and (e) that instant figure 5 and table 6 show SIGLEC15 knockdown results in increased release of IL2, TNFa, and IFNy, arguing that this demonstrates that a skilled artisan would recognize that the modified T cells are responsible for the cancer-fighting effect, and that such cytokine results are “indicative of enhanced anti-tumor T cell activity”.
In response to (a-b), there are no steps in the instant claimed steps S1-S4 in either claim 1 or 2 that require the separation of T cells from other lymph node extracted cells, nor is there a requirement for single-cell suspension. Further (b), it is not made clear in the specification that the single cells in suspension are T cells. Further (a, c-d), S4 specifically requires expanding under conditions favoring T cell expansion, but not that it prevents expansion of other cell types, or that T cells in fact are expanded. A skilled artisan would understand that while IL2 and antigen primed/exposed APCs are utilized for T cell expansion that they are not entirely unique thereto. For example, IL2 is recognized in the art to promote proliferation (e.g., expansion) of activated B cells, as evidenced by Mingari et al. (Nature 312, 641–643 (1984)) [e.g., title, abstract]. Further, IL2 and/or APCs is/are also known in the art to expand NK cells, as evidenced by Cho and Champana (Korean J Lab Med. 2009 Apr;29(2):89–96) [e.g., pg. 2, “cytokines and stimulants”; pgs. 2-3, “expansion of NK cells with accessory cells”]. Therefore, based on the recited steps of the instant claims, one of ordinary skill in the art would not expect the reduced SIGLEC15 expression cells expanded in IL2 supplemented media to contain only T cells. Applicant is reminded that they are enabled for administration of a population comprising T cells with reduced SIGLEC15 expression.
Lastly, regarding (e), B cells are also known to secrete IL2, IFN, and TNFa, as evidenced by Wojciechowski et al. (Immunity. 2009 March 20; 30(3): 421–433) [e.g., pg. 2, ¶ 2], and IL2 primed (e.g., exposed) NK cells were shown to secrete IL2, TNFa, and IFNy, as evidenced by Sanctis et al. (Immunology 1997 90 526-533) [e.g., title, abstract; figs. 3-4].
Therefore, without further testing and/or additional data outside of that present in the instant disclosure, there is no way for a skilled artisan to conclude that the provided data can only come from T cells, and the method for the reasons provided above, is not considered to result in a composition comprising only T cells.
Applicant arguments have been thoroughly reviewed but are not persuasive. The rejection(s) of claim(s) 7-13 and 15-19 is/are maintained.
Conclusion
No claims are currently allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/AMY M. CHATTIN/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643
Prosecution Insights