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 .
Applicant’s amendment and argument of 5/29/26 are entered.
Claims 63 and 75 are amended.
Claims 64-65, 67-68, 70-71, 73-74, and 76-77 are canceled.
Claim 78 is newly added.
Claims 63, 66, 69, 72, 75, and 78 are pending and considered herein.
Claim Status, Canceled Claims
In light of the cancelation of Claims 64-65, 67-68, 70-71, 73-74, and 76-77, all rejections/objections thereto, are withdrawn.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
In light of the office’s acceptance of the terminal disclaimer of 5/29/26, the rejections of the claims on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,673,964, are withdrawn.
Claim Rejections - 35 USC § 112
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.
Claims 63-77 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.
With the amendment of 5/29/26, Applicant has amended the first population of immune cells to T cells encoding a chimeric membrane protein with an antigen binding domain and a mutated endogenous CD5 gene, and the second population of immune cells to being T cells comprising a mutated CD5 gene. Thus, the previous rejection is herein modified to reflect the issues accordingly.
The claims are drawn to two generic populations of T cells, the first generic population of T cells comprising (i) a generic nucleic acid encoding a generic chimeric membrane protein with a generic antigen binding domain and a generic mutated endogenous CD5 gene, and (ii) the second generic population of T cells comprising a generic mutated endogenous CD5 gene. This may be seen in Claim 63. Claim 72 limits the expression of the endogenous CD5 to be lowered, indicating the broad claims encompass increased expression of the endogenous CD5. Claim 75 is drawn to the chimeric membrane protein having an antigen binding domain that does not bind to CD5, indicating the breadth of the antigen binding domain may be to any antigen. Claim 87 is to a Markush of targets for the antigen binding domain of the chimeric antigen binding protein of Claim 63.
In the context of the description, Applicant’s description teaches T cell lymphomas/leukemias have poor prognoses with few available treatments CAR T cell therapy has demonstrated efficacy for B cell neoplasms, but extending the same to T cell malignancies has been a problem, because most target antigens are shared between normal and malignant cells, leading to CAR T cell fratricide, as it binds to normal cells exhibiting the marker. Applicant proposes to rectify this problem of targeting T cell cancers with CAR T cells, and thereby eliminate T cell fratricide (Background of the Invention).
Throughout the specification, it is described to use CAR T cells, targeting CD2, CD5, or CD7, with concurrent administration of modified cells wherein the equivalent CD2, CD5, or CD7 has been knocked-out (e.g., Summary of the Invention). The specifications examples demonstrate the treatment of T cell malignancies, including in animal models, with the compositions so-made, i.e., the use of CAR T cells, with or without CD5 knocked out, and a second subset of T cells, with only CD5 knocked out (i.e., no CAR receptor). The CRISPR system was made with sgRNAs for one of CD2, CD5, or CD5, and utilized to knock out expression of these gene in jurkat cells (jurkat cells are a cell line of immortal human T cells, used in, e.g., the study of leukemia). Pages 69-70. Example 1 teaches that it is known to target CD19 in B cell lymphoma B-NHL, and here a parallel strategy is used to edit normal T cells to be CART resistant (e.g., Figure 2). It is stated that CART therapy becomes feasible when expression of CD2, CD5, or CD7 is temporarily stopped, thus avoiding CART-mediated killing and immunodeficiency that subsequently follows upon killing normal cells. Example 2. Teaches Anti-CD5 CART cells (CART5) and CD5 KO normal T cells can be used in a two-prong immunotherapy (e.g., Figure 3). Example 2 teaches anti-CD2 (CART2) and CD2 KO normal T cells, in parallel examples, following Figure 3. Example 4 teaches CART2 and CART5 testing, where they recognized and killed T cells expressing the appropriate marker, but did not kill themselves. Example 7 teaches similar with CART to CD7 (CART7) and normal CD7 KO T cells. Example 6 teaches dual specific CARS joined by a p2a sequence (i.e., CAR5 and CAR2). Example 6 teaches CD5 KO enhances CART immunotherapy, demonstrating the KO CD5 CART5 cells more effective than CART5 cells that express CD5.
Throughout the specification, there is no discussion of why a CD5 marker should be mutated when the CAR T cells have a target that is NOT CD5, as is demonstrated by the claims. The purpose however is taught that: the CAR-T cells, by attacking normal T cells, including themselves, having CD19, a known marker for these T cells, would kill themselves and the endogenous T cells of the patient, specifically T cell lymphomas and leukemias, e.g., “Herein CRISPR-Cas editing is used to remove the target antigen from healthy T cells, protecting them CART cell therapy and eliminating the potentially fatal immunosuppression that would result from elimination of the T-cell compartment.” (e.g., pp. 22-23, paragraph bridging). Moreover, the temporary removal of CD5 from normal T cells avoids the CART-mediated killing and immunodeficiency that results from the same (pp. 70-71, paragraph bridging). From this it can be gleaned that (i) the generic chimeric membrane protein must target the antigen CD5, (ii) the mutated endogenous CD5 must be mutated to not be recognized, or not expressed, on the T cells, by the specific chimeric membrane protein, in order to not be targeted by the CAR-T cells, and (iii) the T cells claimed must be T cells that are cytotoxic T cells, as other cells of the T cell lineage would not attack, but prevent the attacking of the cancer cells.
Still further, there is a listing of antigens by the specification, now cloned into new claim 78, which includes a large list of antigens for the chimeric membrane antigen binding domain. Such is found to have antecedent basis in the specification, e.g., pp. 3-4, paragraph bridging and pp. 27-28, paragraph bridging. However, these antigens, when they are not CD5, do not make sense. If they are not CD5, the T cells do not require mutated CD5 to be expressed, nor do they require a second population of cells, as there is no fratricide of other T cells when the T cells recognize the receptor. This is a two-fold problem: (i) If the marker is expressed on another cell and not T cells, e.g., prostate specific antigen is not normally expressed by T cells, and thus, when targeting such, T cell fratricide is not expected and (ii) there is no reason to have a second population of T cells (nor the first population) which contain a mutated CD5 if there is no targeting of the T cells. I.e., because these two are tied, if one is not the target to the other, the reasoning for the dual population falls apart. Still further, if the CD5 marker is mutated to be overexpressed, there is no benefit, as the T cells would commit T-cell fratricide, and the second (and first) population would die and be of no benefit in pharmaceutical composition.
With regard to the T cell type, some T cells turn off the immune system. Thus, they would be expected to stop any immune response to cancer being targeted, when the antigen being targeted is CD5, thereby potentiating the T cell cancers. For example, T regulatory cells are well known to be therapeutic against autoimmune disease, not potentiate an autoimmune function needed (e.g., Goswami, et al. (2022) “Regulatory T cells (Tregs) and their therapeutic potential against autoimmune disorders – Advances and challenges”, Human Vaccines & Immunotherapeutics, 18(1): e20351117, 16 pages long, e.g., ABSTRACT). Here, the Treg cells would only exacerbate T cell cancer when targeting the CD5, not treat, as is taught throughout the specification.
With regard to the antigens, the Art recognizes that there exist many antigens. For example, in humans there should be at least about 20K genes (e.g., Ponomarenko, et al. (2016) “The Size of Human Proteome: The Width and Depth”, International Journal of Analytical Chemistry, Article ID 7436849, 6 pages long, p. 1, paragraph bridging columns). This is just in humans. Each of these proteins may have multiple epitopes, may be expressed inside a cell (e.g., DNA polymerase), may be secreted (e.g., glucocorticoids), or may be displayed on the surface of the cell (e.g., CD5). Moreover, one protein may display multiple antigenic sites (e.g., Berglund, et al. (2008) “The epitope space of the human proteome”, Protein Science, 17: 606-13, p. 606, col. 2, paragraph 2, demonstrating that myoglobin has 6-7 polar groups of amino acids in consecutive sequence, which may considered antigens; and pp. 607-608, paragraph bridging, teaching analyses of 10 million string comparisons (possible epitopes) per protein analyzed). From this, it may be gleaned that there exist a great many possible epitopes of proteins which may be recognized, a very great many. The complications exist in that many are intracellular and will not be recognized by a membrane displayed chimeric protein on a T cell. Other proteins, as shown above, are soluble, and thus the T cell, in recognizing the same would not be treating a cancer, but simply binding a soluble protein.
Still further, it is well known in the Art that CAR-T cells, when not targeting a protein they display, do not require a second population of T cells, and don’t require both the CAR-T cell and the second population of T cells having a mutated CD5. For example, several cancers are treated with CAR-T cell therapy, including CD19 specific T cells, and several other antigens, all of which are displayed on the surface of the cancer, and do not require the CAR-T cell carry a mutated CD5, or a second population that does (e.g., Tokarew, et al. (2018) “Teaching an old dog new tricks: next-generation CAR T cells”, British Journal of Cancer, 120: 26-37, p. 27, col. 2).
Moreover, the structure required is not even known, for the targeting of these proteins. Lastly, it should be noted that the Art recognizes that CAR-T cells are generally known to be cytotoxic T cells (e.g., Davila, et al. (2016) “CD19-Targeted CAR T Cells as Novel Cancer Immunotherapy for Relapsed and Refactory B-Cell Acute Lymphoblastic Leukemia”, Clinical Advances in Hematological Oncology, 14(10): 802-808, provided as an HHS Public Access Author Manuscript, 11 pages long, from https://pmc.ncbi.nlm.nih.gov/articles/PMC5536094/pdf/nihms886576.pdf). See pages 4-5.
Thus, given these teachings by Applicant and the Art, the Artisan would not have understood Applicant to have been in possession of pharmaceutical compositions where:
the first population of T cells express other than an chimeric membrane protein targets other than the CD5 protein of a cancer;
the first and second populations of T cells have a mutated endogenous CD5 gene which does not remove expression of normal CD5 on the T cells;
the first and second populations of T cells being other than cytotoxic T cells,
Response to Argument – written description
Applicant’s argument of 5/29/26 has been considered but is not found persuasive.
Applicant argues that that the Examiner’s statement of the “the Art” which is not technically grounded analysis, and the specification provides sufficient written description (p. 4, paragraph 9).
Such is not persuasive. The Examiner has to take some level of knowledge as known, as it is impossible to build the world with every application that comes through. However, to directly answer Applicant’s argument as best possible, to citations of Art, the following have been found in the office action of 2/2/26:
“The Art, however, recognizes many forms of immune cell.” As well as the next sentence “The Art does not teach which of these are treated due to expression of CD5, and would benefit from such CART therapy, much less how the T cells will replace the loss of these cells, for the T cells that are knocked out for CD5”. This is followed by a sentence citing a web page, for “the Art”.
“Further, with regard to the Art, it is also well known that there exist many many proteins, millions, and they may not even be displayed on the immune cell to target a CD5, or to have some undefined function to make another immune cells work against a cancerous cell.” The Art is admittedly not provided here, but to argue it is not technically grounded analysis is a little beyond the pale. There are a great many proteins expressed on cell surfaces, for distinct purposes, and cause binding to different molecules, including other proteins on other cells, soluble proteins, and other. This is basic biochemistry. However, if Applicant wishes an example of Art, Wojdyla, et al. (2020) “Cell-Surface Proteomics Identifies Differences in Signaling and Adhesion Protein Expression between Naïve and Primed Human Pluripotent Stem Cells”, Stem Cell Reports, 14: 972-988, gives examples of proteins that are expressed on a pluripotent stem cells, much less all the types expressed by all cells of the human body. See, for example, Figure 1.
“Lastly, it should be noted that the Art recognizes that CAR-T cells are generally known to be cytotoxic T cells (e.g., Davila, et al. (2016) “CD19-Targeted CAR T Cells as Novel Cancer Immunotherapy for Relapsed and Refactory B-Cell Acute Lymphoblastic Leukemia”, Clinical Advances in Hematological Oncology, 14(10): 802-808, provided as an HHS Public Access Author Manuscript, 11 pages long, from https://pmc.ncbi.nlm.nih.gov/articles/PMC5536094/pdf/nihms886576.pdf). See pages 4-5.” Provides the Art.
Hopefully this assuages Applicant’s belief the Argument is made and not supported by the Art.
Applicant argues the wrong legal standard has been followed, and the inquiry is to directed to the claimed subject matter, not unrecited functional or efficacy requirements, citing MPEP 2163.
Such is not persuasive. The specification is looked to, to understand why something is done. Without that, the advancement in the Art is not known, and a specification would not even be required. The specification makes clear it is meant to be analogous system to the CD19 replacement for B cells, but Applied to the T cells (see rejection). How is this not important?
Applicant argues that the claims is to the two populations, and has no therapeutic requirement and thus the Examiner is importing limitations into the claims (p. 5, paragraph 2).
Such is not persuasive. Applicant’s claims are to a “pharmaceutical composition”. Necessarily then, they must be possessed for therapeutic outcomes. Moreover, the only purpose of these compositions taught in the specification is for treating T cell lymphomas and leukemias (see modified rejection above).
Applicant argues that the negation of effect which T regulatory cells may have on cancer improperly imports efficacy into the claims, and no authority is provided by the Examienr why it is relevant to the analysis (p. 5, paragraph 3).
Such is not persuasive. Even assuming Applicant’s argument is on point, the claims are to a pharmaceutical composition.
Applicant argues that proteins displayed that do not target CD5, is also irrelevant, and importing functional language into the claims (p. 5, last paragraph).
Such is not persuasive. Even assuming Applicant’s argument is right, the claims are to a pharmaceutical composition.
Applicant argues that proof of every embodiment is not required and the functional and efficacy requirements are not required of the claims (pp. 5-6 paragraph bridging).
Such is not persuasive. Again, Applicant has claimed a pharmaceutical composition. To be possessed it must be efficacious against something, and that needs to be described.
Applicant again states the examiner requires every embodiment to be in the specification, and that this wrong, and that only enough is required for possession (p. 6, paragraph 2).
Such is not persuasive. Even assuming, arguendo, the claims are not read in light of the specification, it must be possessed as pharmaceutical composition.
Applicant recaps and requests a declaration (pp. 6-7, paragraph bridging).
Such is not persuasive. The Art was cited, and the single instance it wasn’t provided, the Examiner provided herein another piece of art. Moreover, it seems like a waste of time and money to argue about things that are basic to the science.
Applicant argues that claim 78 provides illustrative targets, none of which are required in Claim 63, but demonstrates possession (p. 7, paragraph 2).
Such is not persuasive. As has been shown in the rejection again, the invention is to a pharmaceutical composition and the only instance, in the Art and Applicant’s specification, where CD5 should be mutated, is because the membrane protein is on a cytotoxic T cell that targets CD5, and thus, prevents T-cell fratricide, as shown in the Argument above.
Applicant avers the wrong legal standard is applied and the application supports the claims (p. 7, paragraph 3).
Such is not persuasive, for the reasoning given above.
Applicant argues that new claim 78 is now presented, and it depends from Claim 63, which they believe allowable (p. 8, penultimate paragraph).
Such is not persuasive. The claim is rejected under written description, as is now incorporated into the rejection due to amendment.
Conclusion
No claim is 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 ROBERT M KELLY whose telephone number is (571)272-0729. The examiner can normally be reached M-F: 8a-5p.
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, Tracy Vivlemore can be reached at 571-272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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ROBERT M. KELLY
Examiner
Art Unit 1638
/ROBERT M KELLY/Primary Examiner, Art Unit 1638
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