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 .
Status of Application
In view of further search and consideration, finality of the previous Office action is withdrawn, and prosecution has been reopened. The following rejections are applicable, although not necessitated by Applicant’s amendments.
Rejections and/or objections not reiterated from the previous office action are hereby withdrawn due. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Arguments applicable to newly applied rejections to amended or newly presented claims are addressed below. Rejections not reiterated here are withdrawn in light of Applicant’s amendments and/or arguments.
Status of Claims
Applicant’s response and amendment filed on June 13th, 2025, are acknowledged and entered. Applicant has amended claims 21, 102, 109-110, and 114-116, claims 1-20, 24-28, 31-34, 36-77, 79-89, 91-92, 94-99, and 111-113 are canceled, and claims 90 and 93 are withdrawn.
Currently, claims 21-23, 29-30, 35, 78, 100-110 and 114-116 are under consideration.
Claim Rejections - 35 USC § 103
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.
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.
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.
Claims 21, 29, 78, 100, 102-103, 109, and 114-116 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (US 2019/0262399 A1, Application US16/331,410, priority date 09/07/2017, prior art of record) in view of Pereira, Renata M., et al. (Journal of leukocyte biology 102.3: 601-615, published Sept. 2017, hereinafter as “Pereira”), Sekiya, et al. (Nature immunology 14.3: 230-237, published 2013, prior art of record), Golz et al., (WO2005/075983A2, published 2005, hereinafter as “Golz”), Nowyhed, et al. (The Journal of Immunology 195.8: 3515-3519, published 2015, prior art of record), and Cheng et al. (The EMBO journal, published 1997, prior art of record).
This is a new rejection in response to Applicants After-final filed on Oct. 16, 2025. Any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
Regarding claim 21, 109, and 115, Wang teaches a method of detecting and using immune cells like CD8+ T cells, which can be protective against disease control (Abstract, claims 1, 49, 52, 56, and 68, para. 6-8). Wang teaches an immune cell can be engineered to comprise a tumor-specific chimeric antigen receptors (CAR)(para. 154, 183, 186, 208, 231, 250-254, 257). Further, Wang teaches a CAR comprising a chimeric antigen receptor (CAR) comprising: (a) an antigen binding domain; (b) a hinge domain; (c) a transmembrane domain; (d) and an intracellular domain (para. 257-258, 260).
Regarding claim 21, 109 and 115, Wang teaches the method of detecting a dysfunctional immune cells comprising detection of a gene expression signature selected from: NR4A1(Nur77), NR4A2(Nurr1), and NR4A3(Nor1)(see e.g. claims 1, 19, and 49; para. 25, 41). Further, Wang teaches an isolated immune cell modified to comprise an altered expression or activity of or modified to comprise an agent capable of inducible altered expression or activity of a gene (claim 49, para. 54), such as a knockout of the NR4A1 (i.e. Nur77)(see e.g. para. 855-856; Example 9).
Wang does not explicitly teach the preferred embodiment of the reduction or elimination of expression of NR4A3 (i.e. NOR-1).
However, the prior art of Pereira discloses that Nr4a3 is expressed more highly in tumor-infiltrating cells (i.e. tumor Ag-reactive OT-I (exhausted) cells than in bystander (non-exhausted) P14 cells (i.e. CD8+ T cells) in the tumor model (see e.g. page 607).
Accordingly, it would have been obvious to one of ordinary skill in the art to modify the methods as taught by Wang and substitute the NR4A1 (as taught by Wang) with the NR4A3 as suggested by Pereira for the reduction or elimination of expression of NR43, because Pereira discloses that Nr4a3 is highly expressed in tumor exhausted CD8+ T cells (see e.g. page 607). Additionally, the prior art of Sekiya discloses the loss of NR4a3(Nor1) expression in regulatory T cells (see e.g. page 231, Supplemental Fig. 1a), and Golz et al. discloses that the inhibition of activity of NR4A3 for treating diseases was known in the prior art (see e.g. abstract). Further, the prior art of Nowyhed discloses that the loss of NR4A1 expression CD8+ T cells exhibit increased effector function (see e.g. page 3515). Furthermore, Sekiya cites the prior art of Cheng, which discloses that Nr4a1 and Nr4a3 share extensive homology (e.g. more than 90% homology in their DNA binding domains)(see e.g. page S61). Thus, it would have been obvious to one of ordinary skill in the art to modify the methods as taught by Wang and substitute the NR4A1 (as taught by Wang) with the NR4A3 as suggested by Pereira for the reduction or elimination of expression of NR43 in order have increased effector function of CD8+ T cells. Moreover, a person would have had a reasonable expectation of success of substituting one NR4A family member for another. Further, Wang discloses methods to modulating cells, such that the cells are resistant to exhaustion or dysfunction (see e.g. para. 7-9, 235, 237, and 281). Therefore, it would have been obvious to one of ordinary skill in the art to substitute one known element for another to obtain predictable results with a reasonable expectation of success. In the instant case, both Nr4a1 and Nr4a3 are cited in the prior art for immunotherapy and one of ordinary skill could have substituted one element for another with predictable results, and a reasonable expectation of success. Furthermore, an artisan of ordinary skill in the art of (e.g. immune therapy) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding claim 29, Wang teaches wherein the immune cell comprises a polynucleotide encoding the CAR (Figure 1;page 6384, col. 1, para. 3).
Regarding claim 78, Wang discloses a pharmaceutical composition comprising a carrier and an immune cells, such as CD8+ T-cells, as discussed above (see e.g. claims 19, 31, 34, 41,49, and 73, and para. 475-477, and 492).
Regarding claim 100, Wang teaches wherein the CD8+ T cell expresses a receptor that binds to at least one tumor antigen (para. 154, 177, 238, 249, 253-254, 794).
Regarding claims 102 and 110, as discussed above, Wang teaches a method of detecting and using immune cells like CD8+ T cells, which can be protective against disease control (Abstract, claims 1, 49, 52, 56, and 68, para. 6-8). Wang teaches an immune cell can be engineered to comprise a tumor-specific chimeric antigen receptors (CAR)(para. 154, 183, 186, 208, 231, 250-254, 257). Wang teaches a CAR comprising a chimeric antigen receptor (CAR) comprising: (a) an antigen binding domain; (b) a hinge domain; (c) a transmembrane domain; (d) and an intracellular domain (para. 257-258, 260). As discussed above, Wang teaches the method of detecting a dysfunctional immune cells comprising detection of a gene expression signature selected from: NR4A1, NR4A2, and NR4A3 (see e.g. claims 1, 19, and 49; para. 25, 41). Wang teaches factors regulating dysfunction in CD8+ T-cells (Example 9). Further, Wang teaches an isolated immune cell (e.g. CD8+ T-cells) modified to comprise an altered expression or activity of or modified to comprise an agent capable of inducible altering expression or activity of NR4A3 (see e.g. para. 54, 188, 193-195, para. 861, 865, claims 1, and 49). Additionally, Wang teaches regulating dysfunction of CD8+ T-cells with NR4A1 (see e.g. para. 855-856; Example 9).
Wang does not explicitly state wherein the CD8+ T cells being further engineered to reduced or eliminate expression and/or function of NR4A2 (Nurr1).
However, the prior art of Pereira, et al. discloses that Nr4a2 and Nr4a3 are expressed more highly in tumor-infiltrating cells (i.e. tumor Ag-reactive OT-I (exhausted) cells than in bystander (non-exhausted) P14 cells (i.e. CD8+ T cells) in the tumor model (see e.g. page 607). Furthermore, the Sekiya discloses eliminating expression and/or function of NR4a1 (Nur77), NR4a2(Nurr1), and NR4a3(Nor1) in a CD8+ T cell (Supplemental Fig. 4a).
Accordingly, it would have been obvious for one of ordinary skill in the art at the time of the effective filing date to have modified the CD8+ T cells as taught by Wang and combine the reduction or elimination of expression with the NR4a2 as taught by Pereira and Sekiya because Sekiya discloses that the Nr4a receptors, especially Nr4a2, act as the key initiation factors for thymic Treg cell development (see e.g. pg 236, fig. 4,6). Further, Wang et al teaches NR4a2 from a limited genus of exhaustion markers for CD8 T cell. Thus, it would have been obvious to one of ordinary skill in the art to modify the methods as taught by Wang and substitute the NR4A1 (as taught by Wang) with the NR4A2 as suggested by Pereira for the reduction or elimination of expression of NR42 in order have increased effector function of CD8+ T cells. Moreover, a person would have had a reasonable expectation of success of substituting one NR4A family member for another. Therefore, it would have been obvious to one of ordinary skill in the art to substitute one known element for another to obtain predictable results with a reasonable expectation of success. Regarding the rationale for combining prior art elements according to known methods to yield predictable results, all of the claimed elements were known in the prior art and one skilled in the art could have combined the element as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of filing of the invention. As discussed above, each of the elements (modified CD8 CART cells, NR4A2, and NR4A3 modifications, gene editing methods and formulations) are taught by Wang and further they are taught in various combinations and are shown to be used in a method for producing CD8+ T cells comprising a CAR with reduced or eliminated expression of NR4A3 and/or NR4A2. Furthermore, an artisan of ordinary skill in the art of (e.g. immune therapy) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding claim 103, as discussed above, Wang discloses methods to modulating cells, such that the cells are resistant to exhaustion or dysfunction (see e.g. para. 7-9, 235, 237, and 281). Further, Wang discloses that NR4A3 is suited for targeting as a modulation and detecting dysfunctional immune cells (see e.g. para. 865, claim 1). Additionally, the prior art of Sekiya discloses eliminating expression and/or function of NR4a1 (Nur77), NR4a2(Nurr1), and NR4a3(Nor1) in a CD8+ T cell (Supplemental Fig. 4a).
Wang does not explicitly state exhibiting decreased exhaustion as compared to a corresponding wild-type CD8+ T cell.
However, Pereira discloses that Nr4a3 is highly expressed in tumor exhausted CD8+ T cells (see e.g. page 607).
Nevertheless, it would have been obvious to one of ordinary skill in the art to have the modified the CD8+ T cells as taught by Wang with the reduction or elimination of expression with the NR4a3 as suggested by Pereira and Sekiya, which would naturally exhibiting decreased exhaustion as compared to a corresponding wild-type CD8+ T cell because Wang discloses methods for modulating cells, such that the cells are resistant to exhaustion or dysfunction (see e.g. para. 7-9, 235, 237, and 281).
Accordingly, it would have been obvious for one of ordinary skill in the art at the time of the effective filing date to have modified the CD8+ T cells as taught by Wang and substitute the NR4A1 with the NR4a3 as taught by Pereira and Sekiya because Pereira discloses that Nr4a3 is highly expressed in tumor exhausted CD8+ T cells (see e.g. page 607). Thus, a person of ordinary skill in the art would have had a reasonable expectation of success because Wang et al teaches NR4a receptors are from a limited genus of exhaustion markers for CD8 T cell so a person of ordinary skill in the art would have envisioned this modified CD8 T cell from the limited genus of options. Thus, it could have been done with a reasonable expectation of success. Furthermore, Wang discloses methods for downregulating or abolishing, the expression or activity of the expression of genes (i.e. NR4a receptors) that can inhibit induction of dysfunction or exhaustion (see e.g. para. 237).
Regarding claim 114, Wang discloses regulating CD4+ T cell function (see e.g. para. 205).
Regarding claim 116, Wang teaches wherein the antigen binding domain is a tumor-specific antigen binding domain, such as an anti-ROR1 binding domain; the transmembrane domain comprises a CD28 or a CD8 a transmembrane domain; and the intracellular domain comprises a region selected from a CD28 costimulatory signaling region, a 4-1BB costimulatory signaling region, an ICOS costimulatory signaling region, and an OX40 costimulatory region; and a CD3 zeta signaling domain (see e.g. para. 249, 254, 257-260). In regard to choosing ROR1, Wang teaches that targeting this antigen can treat a variety of cancers including non-small lung cancer, triple negative breast cancer, pancreatic cancer, prostate cancer, ALL, CLL, or MCL [0254]). Claim Interpretation Broadest Reasonable Interpretation: the ROR1 as taught by Wang reads on the claimed tumor antigen binding domain (see Spec. pg. 31, para. 109).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal:
In Applicant’s arguments filed Jan. 12, 2026, Applicant argues that “Wang and Mullican 2003 fails to teach or suggest each and every element of the claims and teaches away from reducing or eliminating expression of NR4A3 as presently claimed. Likewise, Cheng, Sekiya, Beard, Nowyhed, Mullican 2007, Hudecek, and Kim additionally fail to remedy the deficiencies of Wang and Mullican 2003 in rendering the claimed invention obvious” (Remarks, page 4).
Applicant’s arguments, see Remarks, filed Jan. 12, 2026, with respect to the rejection(s) of the claim(s) under Wang et al. (US 2019/0262399 Al, Application US16/33 l,410) in view of Mullican et al. (US2003/0220288 Al, "Mullican 2003"), Cheng et al. (The EMBOJournal), Sekiya, et al. (Nature Immunology 14.3: 230-237,), Beard et al (Cellular Signalling 27.2: 257-266,), Nowyhed, et al. (The Journal oflmmunology 195.8: 3515-3519), and Mullican, et al. (Nature Medicine 13.6: 730-735, "Mullican 2007" have been fully considered and are persuasive due to Mullican et al (2003) disclosing increase expression. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Wang et al. (US 2019/0262399 A1, Application US16/331,410, priority date 09/07/2017, prior art of record) in view of Pereira, Renata M., et al. (Journal of leukocyte biology 102.3: 601-615, published Sept. 2017, hereinafter as “Pereira”), Sekiya, et al. (Nature immunology 14.3: 230-237, published 2013, prior art of record), Golz et al., (WO2005/075983A2, published 2005, hereinafter as “Golz”), Nowyhed, et al. (The Journal of Immunology 195.8: 3515-3519, published 2015, prior art of record), and Cheng et al. (The EMBO journal, published 1997, prior art of record).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicants argument, Sekiya, Cheng, Nowyhed, Hudecek, nor Kim are cited for teaching the modified CAR-T cell or NR4A3. As discussed above, Wang is cited for teaching the modified CD8+ T cells. As discussed above, the prior art of Pereira, Renata M., et al., and Golz et al., (WO2005/075983A2, published 2005, hereinafter as “Golz”), are cited for disclosing reduced or eliminated of expression and/or function of NR4A3.
Applicant asserts that “Sekiya discloses that mice deficient in both NR4A1 and NR4A3 have fewer T cells and develop autoimmunity, suggesting that additionally knocking out NR4A3 undesirably leads to T cell underdevelopment and dysfunction” (Remarks, page 5).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicant argument, it is noted that Sekiya discloses that mice deficient in both NR4A1 and NR4A3 have fewer T cells and develop autoimmunity. As discussed above, Sekiya is not cited for reducing expression of both NR4A1 and NR4A3 in a CD8+ T cell. Contrary to Applicants assertion the claims do not require reducing or eliminating expression of both NR4A1 and NR4A3. Furthermore, a person of ordinary skill in the art would understand that knocking out both NR4A1 and NR4A3 would have a different effect than knocking out NR4A3 alone absent evidence to the contrary (see Sekiya e.g. pages 231-232).
Applicant argues that the Office improperly blends the art together by picking and choosing various components of the prior art (i.e. Wang, Mullican 2003, Cheng, Sekiya, Beard, Nowyhed, Mullican 2007, Hudecek, and Kim) and is using an impermissible hindsight-driven obviousness rejection (Remarks, page 5-6).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In the instant case, the prior art of Mullican 2003, Beard, and Mullican 2007, are no longer cited for disclosing NR4A3. Rather the prior art of Pereira is cited for disclosing that Nr4a3 is expressed more highly in tumor-infiltrating cells (i.e. tumor Ag-reactive OT-I (exhausted) cells than in bystander (non-exhausted) P14 cells (i.e. CD8+ T cells) in the tumor model (see e.g. page 607). Therefore, it would have been obvious to one of ordinary skill in the art to modify the methods as taught by Wang and substitute the NR4A1 (as taught by Wang) with the NR4A3 as suggested by Pereira for the reduction or elimination of expression of NR43, because Pereira discloses that Nr4a3 is highly expressed in tumor exhausted CD8+ T cells (see e.g. page 607). Furthermore, the prior art of Golz et al. discloses that the inhibition of activity of NR4A3 for treating diseases was known in the prior art (see e.g. abstract). Thus, it would have been obvious to one of ordinary skill in the art to modify the methods as taught by Wang and substitute the NR4A1 (as taught by Wang) with the NR4A3 as suggested by Pereira for the reduction or elimination of expression of NR43 in order have increased effector function of CD8+ T cells. Moreover, a person would have had a reasonable expectation of success of substituting one NR4A family member for another. Furthermore, an artisan of ordinary skill in the art of (e.g. immune therapy) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Further, Applicant argues that the Specification, paragraph [0026] and FIG. 14 show that “the results surprisingly demonstrate that not only does reduce expression ofNR4A3 represent a novel strategy for increasing immune cell function, but also that reduced expression of NR4A3 is comparable to NR4A TKO” (Remarks, page 7).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e. increasing immune cell function) are not explicitly stated in the claims. Applicant’s response is reminded that although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). It is noted that, the reduced expression of NR4A3 is comparable to NR4A TKO. However, it is unclear how fig. 14 is comparable to what Wang (i.e. the closest prior art) shows regarding to the knockout. Therefore, the surprising results do not overcome the issue of nonobviousness of the claimed subject matter.
Applicant argues that on June 13, 2025, Applicant filed a declaration under 37 CFR 1.132 by Dr. Anjana Rao (Remarks, page 7-8 and see Affidavit filed June 13, 2025). Applicant reiterates the argument that Dr. Rao’s Declaration and Exhibit A demonstrates “increased anti-tumor activity of immune cells modified to decrease expression of NR4A3” (Remarks, page 7). Applicant reiterates the argument that “In particular, the data provided in Exhibit A shows that degradation of NR4A3 via dTAG mediated degradation improves the tumor killing capacity of immune cells. See Rao Declaration, at paragraphs 7-9; see also Exhibit A, FIG. 5C” (Remarks, page 7-8).
As previously stated in the final office action sent on Oct. 16, 2025, the declaration under 37 CFR 1.132 filed on June 13, 2025, is acknowledged and has been considered.
The declaration under 37 CFR 1.132 filed by Dr. Rao on 6/3/2025 is insufficient to overcome the rejection of instant claims based upon 35 U.S.C 103 as set forth in this Office action for the following reasons: the invention works as intended which includes statements which amount to an affirmation that the claimed subject matter (i.e. CD8+ T cell) functions as it was intended to function (i.e. reducing expression of NR4A3). Additionally, the statements amount to affirmation that the affiant has never seen the claimed subject matter before. These issues are not relevant to the issue of nonobviousness of the claimed subject matter and provides no objective evidence thereof. See MPEP § 716.
It is acknowledged that that the CD8+ CAR T cells decreased tumor growth (see fig. 5b) and CD8+ CAR T cells with NR4A3 inhibited tumor growth (see fig. 5c) (reproduced below, Exhibit A). Applicants’ response is reminded that in submitting evidence asserted to establish unobvious results, there is a burden on an applicant to indicate how the examples asserted to represent the claimed invention are considered to relate to the examples intended to represent the prior art and, particularly, to indicate how those latter examples do represent the closest prior art. See In re Borkowski, 595 F.2d 713, 184 USPQ 29 (CCPA 1974); In re Goodman, 339 F.2d 228, 144 USPQ 30 (CCPA 1964). It should also be established that the differences in the results are in fact unexpected and unobvious and of both statistical and practical significance. In re Merck, 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986); In re Longi, 759 F. 2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Klosak, 455 F2d 1077, 173 UAPQ 14 (CCPA 1972); In re D’Ancicco, 429 F.2d 1244, 169 USPQ 303 (CCPA 1971 ). Ex parte Gelles, 22 USPQ2d 1318 (BPAI 1992). It is unclear if the results and declaration indicant that the subjects administered cells treated with CD8+ CAR T cells and having reduced expression of NR4A3 demonstrated “statistically significantly” reduced cancer cell growth compared to cells treated with DMSO controls (see fig. 5). Although the figure legend indicates that a statistical treatment with p<0.0001 is four stars (i.e.****), there are no stars indicated on the graphs of B and C (e.g. like the stars as seen fig. 4b of Exhibit A and in Applicant’s drawings). The declaration discloses a “significant improvement” but does not recite a statistically significant improvement. Therefore, it is unclear if the results of figure 5c are in fact unexpected and unobvious and of both statistical and practical significance.
As discussed above, the declaration only compares the CD8+ CAR T cells with NR4A3 inhibited tumor growth to the control (i.e. DMSO)(see fig. 5) and does not compare the CD8+ CAR T cells with NR4A3 inhibited tumor growth (see fig. 5c) to what Wang (i.e. the prior art) shows regarding to the knockout (see declaration sections a-b). Therefore, the declaration (i.e. Exhibit A) does not overcome the issue of nonobviousness of the claimed subject matter.
It is noted that the features upon which applicant relies (i.e. significantly improved tumor killing capacity and reduction in tumor area) are not explicitly stated in the claims. Furthermore, the features of significantly improved tumor killing capacity and reduction in tumor area do not add either a manipulative or structural difference to the claimed composition. Therefore, even if the Applicant added these features as a claim limitation the features would not advance prosecution.
In response to Dr. Rao’s declaration, as discussed above, Mullican (2007) is no longer cited for teaching NR4a3, therefore the argument is considered moot.
Further, Applicant asserts that the skilled artisan “would have expected any reduction in NR4A3 to have the opposite effects in a CD8+ T cell based on the teachings of Mullican 2003, Mullican 2007, and Sekiya, which indicate that a reduction in NR4A3 leads to the progression of cancer” (Remarks, page 8). Applicant argues that “the claimed CD8+ T cell possesses surprising and unexpected characteristics that could not have been anticipated based on the teachings of the prior art” (Remarks, page 8).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
As discussed above, the Applicant’s arguments, see Remarks, filed Jan. 12, 2026, with respect to the rejection(s) of the claim(s) under Wang et al. in view of Mullican et al. Cheng et al., Sekiya, et al., Beard et al, Nowyhed, et al. and Mullican, et al. have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Wang et al. in view of Pereira, Renata M., et al., Sekiya, et al., Golz et al., Nowyhed, et al. and Cheng et al.. Furthermore, it is noted that the Office has presented an obviousness rejection and has not asserted that “the claimed CD8+ T cell possesses surprising and unexpected characteristics that could not have been anticipated based on the teachings of the prior art” (Remarks, page 8).
As discussed above, the prior art of Pereira, et al. discloses that Nr4a2 and Nr4a3 are expressed more highly in tumor-infiltrating cells (i.e. tumor Ag-reactive OT-I (exhausted) cells than in bystander (non-exhausted) P14 cells (i.e. CD8+ T cells) in the tumor model (see e.g. page 607). Furthermore, the Sekiya discloses eliminating expression and/or function of NR4a1 (Nur77), NR4a2(Nurr1), and NR4a3(Nor1) in a CD8+ T cell (Supplemental Fig. 4a). Accordingly, it would have been obvious for one of ordinary skill in the art at the time of the effective filing date to have modified the CD8+ T cells as taught by Wang and combine the reduction or elimination of expression of NR4A3 and NR4a2 as taught by Pereira and Sekiya because Pereira discloses that Nr4a2 and Nr4a3 are expressed more highly in tumor-infiltrating cells (i.e. tumor Ag-reactive OT-I (exhausted) cells P14 cells (i.e. CD8+ T cells) (see e.g. page 607). Further, Wang discloses that NR4a receptors are from a limited genus of exhaustion markers for CD8+ T cell. As discussed above, each of the elements (modified CD8 CART cells, NR4A2, and NR4A3 modifications, gene editing methods and formulations) are taught by Wang et al., and further they are taught in various combinations and are shown to be used in a method for producing CD8+ T cells comprising a CAR with reduced or eliminated expression of NR4A3 and NR4A2. Furthermore, an artisan of ordinary skill in the art of (e.g. immune therapy) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Claims 22, 23, and 104-108 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (US 2019/0262399 A1, Application US16/331,410, priority date 09/07/2017, prior art of record) in view of Pereira, Renata M., et al. (Journal of leukocyte biology 102.3: 601-615, published Sept. 2017, hereinafter as “Pereira”), Sekiya, et al. (Nature immunology 14.3: 230-237, published 2013, prior art of record), Golz et al., (WO2005/075983A2, published 2005, hereinafter as “Golz”), Nowyhed, et al. (The Journal of Immunology 195.8: 3515-3519, published 2015, prior art of record), and Cheng et al. (The EMBO journal, published 1997, prior art of record), as applied to claims 21, 29, 78, 100, 102-103, 109, and 114-116 above, and further in view of Hudecek et al. (Blood, The Journal of the American Society of Hematology 116.22: 4532-4541, published 2010– prior art of record), and Kim et al. (PLoS One. 2011;6(4):e18556. Epub, published 2011 – prior art of record).
This rejection is repeated with regard to claims 22, 23, 104-108 for the same reasons of record as set forth in the Official action mailed on Dec. 3, 2024. A response to applicant' s traversal follows the reiterated rejection below.
The teachings of Wang et al and Nowyhed et al apply here as indicated above.
Regarding claims 22 and 104, Wang teaches the immune cell of claim 21, wherein the antigen binding domain comprises: (a) an anti-ROR1 binding domain; the transmembrane domain comprises a CD28 or a CD8 a transmembrane domain; and the intracellular domain comprises a region selected from a CD28 costimulatory signaling region, a 4-1BB costimulatory signaling region, an ICOS costimulatory signaling region, and an OX40 costimulatory region; and a CD3 zeta signaling domain (para. 249, 254, 257-260). In regard to choosing ROR1, Wang teaches that targeting this antigen can treat a variety of cancers including non-small lung cancer, triple negative breast cancer, pancreatic cancer, prostate cancer, ALL, CLL, or MCL [0254]).
Regarding claim 23 and 108 Wang teaches wherein CAR comprises a single-chain variable fragment (scFv) (page 6383, col. 2, last para.).
Regarding claim 105, Wang et al, as discussed supra, teaches wherein the transmembrane domain comprises a CD28 transmembrane domain or a CD8 transmembrane domain (para. 257-260).
Regarding claim 106, Wang et al, as discussed supra, teaches wherein the intracellular domain comprises a CD28 costimulatory signaling region, a 4-lBB costimulatory signaling region, an ICOS costimulatory signaling region, or an OX40 costimulatory region (para. 257-260).
Regarding claim 107, Wang et al, as discussed supra, teaches further comprising a CD3 zeta signaling domain (para. 257-260).
However, Wang et al are silent to a preferred embodiment of the NR4A1 KO CD8+ T-cell comprising an anti-ROR1 scFV CAR.
Regarding instant claims, Hudecek teaches the scFv against receptor tyrosine kinase-like orphan receptor (ROR1) can be expressed in a CAR (abstract, p. 4535, last para.).
Accordingly, it would have been obvious for one of ordinary skill in the art at the time of the invention to prepare the NR4A1 KO CD8 T cell comprising an anti-ROR1 scFV CAR as suggested by Wang et al with a reasonable expectation of success. Further the artisan would be motivated to use an scFV anti-ROR1 binding domain of the CAR for several reasons. First, Wang suggests as much. Furthermore, Hudecek et al provides an enabling disclosure of a scFV anti-ROR1 binding domain of the CAR that could be predictably expressed in the CD8 T cells of Wang. Finally, similar to Wang, Kim et al. (2011) teaches that ROR1 has the potential to target tumor cells for adoptive T-cell therapy (abstract, page 4532, 4540).
Hence, the claimed invention as a whole was prima facia obvious in the absence of evidence to the contrary.
Response to Traversal:
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive, and have been addressed supra.
Claim 30 is rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (US 2019/0262399 A1, Application US16/331,410, priority date 09/07/2017, prior art of record) in view of Pereira, Renata M., et al. (Journal of leukocyte biology 102.3: 601-615, published Sept. 2017, hereinafter as “Pereira”), Sekiya, et al. (Nature immunology 14.3: 230-237, published 2013, prior art of record), Golz et al., (WO2005/075983A2, published 2005, hereinafter as “Golz”), Nowyhed, et al. (The Journal of Immunology 195.8: 3515-3519, published 2015, prior art of record), and Cheng et al. (The EMBO journal, published 1997, prior art of record), as applied to claims 21, 29, 78, 100, 102-103, 109, and 114-116 above, and further in view of Hudecek et al. (Blood, The Journal of the American Society of Hematology 116.22: 4532-4541, published 2010 – prior art of record), and Kim et al. (PLoS One. 2011;6(4):e18556, Epub, published 2011 – prior art of record).
This rejection is repeated with regard to claim 30 for the same reasons of record as set forth in the Official action mailed on Dec. 3, 2024. A response to applicant' s traversal follows the reiterated rejection below.
The teachings of Wang et al apply here as indicated above.
Regarding claim 30, Wang et al is silent regarding a 2A self-cleaving peptide (T2A) encoding polynucleotide sequence.
However, Hudecek teaches the polynucleotide further comprises: a promoter operatively linked to the polynucleotide to express the polynucleotide in said immune cell; a 2A self-cleaving peptide (T2A) encoding polynucleotide sequence located downstream of a polynucleotide encoding the anti-ROR1 antigen binding domain; a polynucleotide encoding a signal peptide located downstream of a polynucleotide encoding the anti-ROR1 anti CD 19 antigen binding domain; or a combination thereof (abstract).
Hudecek is silent regarding a 2A self-cleaving peptide (T2A) located upstream of a polynucleotide encoding the anti-ROR1 antigen binding domain.
However, Kim teaches that the self-cleaving 2A peptide could be a good candidate to replace IRES because of its small size and high cleavage efficiency between genes upstream and downstream of the 2A peptide (abstract).
Accordingly, it would have been obvious for one of ordinary skill in the art at the time of the invention to incorporate the 2A self-cleaving peptide (T2A) located upstream of a polynucleotide encoding the anti-ROR1 antigen binding domain as taught by Hudecek et al into the CAR construct taught by Wang et al to predictably arrive at the limitations of claim 30. T2A sequences are an established means of expressing two separate proteins from the same transcript as demonstrated by Hudecek and Kim. Thus, an artisan would have a reasonable expectation of successfully using a T2A sequence. Further the artisan would be motivated to use a T2A sequence because Kim teaches that T2A has a small size and high cleavage efficiency.
Hence, the claimed invention as a whole was prima facia obvious in the absence of evidence to the contrary.
Response to Traversal:
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive, and have been addressed supra.
Allowable Subject Matter
SEQ ID NO: 1 and 2 are free of prior art, therefore Claims 35 and 101 are objected to as being dependent upon a rejected base claim but would be allowable if rewritten in the independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claim is allowed.
Prior art made of record: Scott-Browne JP, et al., (Immunity. 2016 Dec 20;45(6):1327-1340. doi: 10.1016/j.immuni.2016.10.028. Epub, published 2016); Murphy (US20020049151 A1, published 2002), and Martinez, Gustavo J., et al. (Immunity 42.2 (2015): 265-278, published 2015).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPHINE GONZALES whose telephone number is (571)272-1794. The examiner can normally be reached M-Th: 9AM - 5:00PM (EST).
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, Doug Schultz can be reached at 571-272-0763. 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.
JOSEPHINE GONZALES
Examiner
Art Unit 1631
/JOSEPHINE GONZALES/ Examiner, Art Unit 1631
/JAMES D SCHULTZ/ Supervisory Patent Examiner, Art Unit 1631