CTNF 18/726,384 CTNF 99545 Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. 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. Information Disclosure Statement The information disclosure statements (IDS) submitted on 07/02/2024 and 06/08/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. 12-151 AIA 26-51 12-51 Status of claims Claims 1--14, 16-18, 21, 26 and 27 are pending and under examination. 07-30-03-h AIA Claim Interpretation The term “genetically modified T-cells” under broadest reasonable interpretation can encompass a T-cell that comprises a localized modification that does not change the fundamental nature, function or structure of the claimed in vitro cluster of cells. Claim Rejections - 35 USC § 101 07-04-01 AIA 07-04 35 U.S.C. 101 reads as follows: Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title. Claims 1-7, 10, 16-18, 21 and 26 are rejected under 35 U.S.C. 101 because the claims are directed to naturally occurring substance without significantly more. Regarding claim 1 : The claims are directed to a cell cluster of lymphoid cells, derived from lymphoid tissue wherein the lymphoid tissue comprises genetically modified T cells (see claim interpretation). The claim is directed to a composition of matter, which is a statutory category of invention (Step 1: YES). The claim is then analyzed to determine whether it is directed to any judicial exception. The claim is directed to a cell cluster derived from lymphoid cells. As such the claim describes a naturally occurring product. Thus, the claim recites at least one exception, which may be termed a product of nature. (Step 2A prong 1: YES). The claim is then analyzed to determine if additional elements integrates the judicial exception into a practical application. The claimed cells are severed from its naturally occurring organ (lymph tissue) in order to isolate it from the organism in which it occurs in nature, but has the same cell composition and properties of the naturally occurring cells. The claimed cells have no functional characteristics distinct from the organs it occurs, i.e., look and function like the natural cells. In vitro collection of cells, which are otherwise unchanged is not eligible because they are not different enough from what exists in nature to avoid improperly tying up the future use and study of naturally occurring lymphoid cells. In other words, the claimed cells are different, but not markedly different, from their natural counterpart in its natural state, and thus are a “product of nature” exception. Furthermore “genetically modified T cells” as explained above, does not necessarily impart a cell cluster having markedly different characteristic from naturally occurring lymphoid tissue. The claim encompasses embodiments in which the modification is limited to a discrete genetic alteration that does not change the essential nature of the T cell as an immune cell, and does not alter its role within the germinal center, and does not produce a structurally distinct lymphoid cell cluster. As such the claim does not include any additional features that could add significantly more to the exception (Step 2B: NO). The claim does not qualify as eligible subject matter. Claims 2-7, 10, 16-18, 21, and 26 do not add markedly different characteristics for the purpose of product of nature analysis. Claim Rejections - 35 USC § 112 07-30-01 AIA 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. 07-31-01 Claim s 1-14, 16-18, 21, 26-27 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. Regarding claims 1-14, 16-18, 21, 26-27 : The claims encompass an in vitro cell cluster comprising any and all lymphoid tissue, including thymus, payer’s patches, bone marrow, among others. The claims further encompass any and all genetic modification in T-cells. It is noted that the specification provided support for in vitro clusters from tonsil organoids, lung-draining lymph nodes and spleen cultures. (See [0168]). It is further indicated that the specification does not reasonably convey possession of functional equivalence across full genus of lymphoid tissue sources. As such it is pointed that the specification lacks guidance that the system is universally applicable across all lymphoid tissue types without material modification. It is further pointed out that the specification disclosed specific genetic modifications, including FOXP3 knockout in Treg cells (Example 9); GZMB knockout (Example 11) and limited CRISPR perturbations. However, the claim encompasses all genetically modified T-cells, including knockouts, gene edits, and arbitrary gene modifications in any T-cell subset. The specification does not reasonably convey possession of full genus of genetic modifications across al T-cell types , or any modifications beyond those explicitly taught in the specification. Further the specification did not teach predictable applicability of all genetic modifications within a germinal center context. Instead genetic modification is disclosed as a specific experimental embodiment, not a generalized platform applicable to al T-cell genetic alterations. Further, regarding claim 8, the claim encompasses genetically modified T-cells with all FOX family transcription factors, including, but not limited to: all members of FOXP family, FOXO, FOXA, FOXB, among others. It is generally known that transcription factors have general and diverse roles in T-cell development, metabolic regulation, apoptosis lineage of differentiation, immune homeostasis. (See Golson et al). The specification only provides support for FOXP3 knockout in regulatory T-cells, FOXP3-associated modulation of immune tolerance, FOXP3 effects in immune responses. It is noted that the specification only provided a single species within the FOX transcription factor family. As such there is no representative sampling of the full genus. Neither does the specification demonstrate that the FOX transcription factors are interchangeable. Thus, Applicants were not in possession of the full scope of the claimed invention at the time of filing of the instant invention. Claim Rejections - 35 USC § 103 07-06 AIA 15-10-15 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. 07-20-aia AIA 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. 07-23-aia AIA 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. 07-20-02-aia AIA This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention. 07-21-aia AIA Claim s 1, 3-6, 10, 12, 14, 16, 17-18, 21, 26, 27 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al (US20050191743A1;Published September 1, 2005; hereinafter "Wu;" See IDS of 07/02/2024) . Regarding claim 1, 3, 17-18 : Wu taught methods of culturing antigen-specific lymphocytes in the presence of antigens. Wu taught that antigen may be selected from a wide variety of antigen types, including peptides, carbohydrates, glycoproteins, lipopolysaccharides and any combination thereof (See Wu claim 27). Wu further stated that cultured antigen-specific lymphocytes can may be B-cells, or T-cells or combinations thereof (See Wu claim 33). Wu further stated that “[t]hese cells cultured in the bioreactors can be obtained from autologous, allogeneic, or xenogeneic sources to carry out specific therapeutic functions. Furthermore, they may be genetically engineered to carry a gene for replacing the defective one or augmenting the therapeutic effect of the cells.” (See Wu [0120]). Wu indicated that the organoid comprises “B lymphocytes which may be generated and maintained by the methods of the present invention include, for example, CD19 + , IgD + , CD23 + (follicular B2 cells); IgM hi , CD23 − (B 1 cells); IgM hi , CD23 + , CD21 + (marginal zone B cells), CD19+, PNA+, GL-7+(germinal center cells and plasma cells).” (See Wu [0064-0065]). It would have been obvious for a person of ordinary skill in the art to incorporate genetically modified T-cells into the lymphoid cell culture system of Wu. Wu expressly taught that lymphoid organ cells, including T lymphocytes may be genetically modified using well established techniques such as transfection. One of ordinary skill in the art would have been motivated to genetically modify T-cells within the lymphoid culture system of Wu in order to satisfy immune cell behavior and augmenting the therapeutic effect of the cells using known gene transfer techniques as they would have been expected to yield predictable results, namely altered T-cell function within the lymphoid cell culture system. Regarding claim 4, 5 : Claim 9 of Wu taught that the antigen is a tumor antigen. Regarding claim 6 : Wu taught a method of screening vaccine candidates comprising culturing peripheral lymphoid organ cells in a container on a three-dimensional scaffolding which is covered or surrounded with culture medium under conditions effective to generate and maintain mature and functional peripheral lymphoid organ cells, wherein said three-dimensional scaffolding allows the peripheral lymphoid organ cells in the culture medium to have cell to cell contact in three dimensions, adding a vaccine candidate to the container; and determining whether the vaccine candidate elicits an immune response in the cultured peripheral lymphoid organ cells. (See claim 38 of Wu). As such it is pointed out that Wu expressly taught system for evaluating immunogenicity of candidate vaccines in vitro. Regarding claim 10, 21 : Wu taught that “[e]xamples of T lymphocytes which may be generated and maintained by the methods of the present invention include, for example, CD4 + and CD8 + cells.” Regarding claim 12 : Claim 26 of Wu taught a method of adding an adjuvant to the cell culture Regarding claim 14 : Wu taught that the lymphoid system is cultured with an antigen or a fragment to induce antigen-specific lymphocytes, under conditions effective to permit clonal selection, expansion, and/or affinity maturation of lymphocytes. (See Wu claim 25). Regarding claim 16 : Wu taught that “cultured peripheral lymphoid organ cells are selected from the group consisting of spleen cells, lymph node cells, thymus cells, Peyer's patches cells, and combinations thereof.” (See Wu claim 17). Regarding claim 26 : Wu taught that “the mammalian peripheral lymphoid organ cells are human cells” Regarding claim 27 : Claim 6 of Wu taught “culturing peripheral lymphoid organ cells on a three-dimensional scaffolding which is covered or surrounded with culture medium under conditions effective to generate and maintain mature and functional peripheral lymphoid organ cells, wherein said three-dimensional scaffolding allows cells in the culture medium to have cell to cell contact in three dimensions.” (see claim 1) wherein “wherein the culture medium contains exogenous growth factors, cytokines, lymphokines, hormones, chemokines, interleukins, mitogens, antigens or antigenic fragments thereof, or combination thereof” (See claim 6). Claim 41 taught that the “culturing is carried out with an antigen or antigenic fragment thereof in the culture medium and under conditions effective to produce antigen-specific lymphocytes” “under conditions effective to permit the antigen-specific lymphocytes to produce antibodies” (See claim 31). Wu further taught producing hybridomas and producing antibodies from the hybridomas (See claim 36). Ass such Wu taught every aspect of the claimed invention. One of ordinary skill in the art would have been motivated to arrive at the claimed invention using the techniques taught by Wu . 07-21-aia AIA Claim 2 is r ejected under 35 U.S.C. 103 as being unpatentable over W u et al (US20050191743A1;Published September 1, 2005; hereinafter "Wu;" See IDS of 07/02/2024) as evidenced by Houghton et al (J Clin Invest. 2004 Aug; hereinafter "Houghton;" See PTO-892). R egarding claim 2 : The teachings of Wu are indicated above. It is submitted that Wu did not teach self-antigens explicitly. However as noted above, Wu taught a method of using cancer/tumor antigen. As evidenced by Houghton et al (J Clin Invest. 2004 Aug) Most antigens expressed by human cancer cells and recognized by host T cells and antibodies are nonmutated self-antigens — molecules also expressed on the surface of normal cells. As such Wu implicitly taught self-antigens . 07-21-aia AIA Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Wu et al (US20050191743A1; Published September 1, 2005; hereinafter "Wu;" See IDS of 07/02/2024) in view of He et al (Hum Vaccin Immunother. 2015; hereinafter "He;" See PTO-892) . Regarding claim 13 : The teachings of Wu are set forth above. Wu did not expressly teach aluminum hydroxide or imiquimod as an adjuvant. It is pointed out that Wu taught the addition of an adjuvant to the cell culture. (See Wu claim 110). It is however pointed out that aluminum hydroxide adjuvants are widely used. For example, He taught “Aluminum hydroxide, aluminum phosphate and alum constitute the main forms of aluminum used as adjuvants. Among these, aluminum hydroxide is the most commonly used chemical as adjuvant.” (See He Abstract). It would have been obvious to one of ordinary skill in the art at the time of the invention to incorporate aluminum hydroxide into Wu’s organoid system. He established aluminum hydroxide as a commonly used adjuvant. Therefore its use in any in vitro immune model designed to evaluate antibody production would be expected . 07-21-aia AIA Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Wu et al (US20050191743A1; Published September 1, 2005; hereinafter "Wu;" See IDS of 07/02/2024) as evidenced by (Wei et al (Blood. 2006 Jul 15; hereinafter "Wei;" See PTO-892) . Regarding claim 7 : The teachings of Wu are set forth above. Wu did not expressly teach Treg cells. It is however pointed out that Treg cells are present in lymphoid tissue such as the thymus (See Wei Abstract). As such it is submitted that the claimed invention is inherently taught in Wu, due to the inherent properties of lymphoid tissue. Conclusion Claims 8-9 and 11 appear free of art, but have 112(a) written description issue. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAGAMYA VIJAYARAGHAVAN whose telephone number is (703)756-5934. The examiner can normally be reached 9:00a-5:00p. 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, Christopher M. Babic can be reached at 571-272-8507. 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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /JAGAMYA NMN VIJAYARAGHAVAN/Examiner, Art Unit 1633 /EVELYN Y PYLA/Primary Examiner, Art Unit 1633 Application/Control Number: 18/726,384 Page 2 Art Unit: 1633 Application/Control Number: 18/726,384 Page 3 Art Unit: 1633 Application/Control Number: 18/726,384 Page 4 Art Unit: 1633 Application/Control Number: 18/726,384 Page 5 Art Unit: 1633 Application/Control Number: 18/726,384 Page 6 Art Unit: 1633 Application/Control Number: 18/726,384 Page 7 Art Unit: 1633 Application/Control Number: 18/726,384 Page 8 Art Unit: 1633 Application/Control Number: 18/726,384 Page 9 Art Unit: 1633 Application/Control Number: 18/726,384 Page 10 Art Unit: 1633 Application/Control Number: 18/726,384 Page 11 Art Unit: 1633 Application/Control Number: 18/726,384 Page 12 Art Unit: 1633 Application/Control Number: 18/726,384 Page 13 Art Unit: 1633
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