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 amendments and remarks filed 1-6-26 are acknowledged.
Claims 1-3, 6-19 and 22 are pending and under examination as they read on the elected the species of engineered immune cell
(i) wherein “the first antigen binding region is an scFv and the second antigen binding region is sdAb or a nanobody;”
(ii) wherein “the first and second antigen binding regions bind to Claudin18.2;” and
(iii) wherein “the first and second antigen binding regions are located on the same vector.”
Claims 3 and 14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species of invention, there being no allowable generic or linking claim.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1, 2, 6-13 and 15-19 stand rejected under 35 U.S.C. 103 as being unpatentable over Wang et al (WO2016008405) in view of Zhan et al. (J Clin Oncol 37, 2019 (suppl; abstr 2509); Maus et al. (WO2018191748) and Yao et al. (20220259303) as evidenced by Wang et al. (20200172613); Alexandra Flemming, “CAR Ts BiTE in brain,” Nature Reviews Immunology, page 535, 2019; DeSelm et al. (J Surg Oncol. 2017;116:63–74), Jefferis et al. (Immunology Letters 82 (2002) 57-65) and Fan et al. (WO2018028647)(all of record), essentially for the reasons of record.
Claim(s) 1, 2, 6-13, 15-19 and 22 stand rejected under 35 U.S.C. 103 as being unpatentable over Wang et al (WO2016008405) in view of Zhan et al. (J Clin Oncol 37, 2019 (suppl; abstr 2509), hereinafter “Zhan”); Maus et al. (WO2018191748) and Yao et al. (20220259303) as evidenced by Wang et al. (20200172613); Alexandra Flemming, “CAR Ts BiTE in brain,” Nature Reviews Immunology, page 535, 2019; DeSelm et al. (J Surg Oncol. 2017;116:63–74), Jefferis et al. (Immunology Letters 82 (2002) 57-65) and Fan et al. (WO2018028647), as applied to claims 1, 2, 6-13 and 15-19 above, and further in view of Tamada et al. (20200323920)(all of record), essentially for the reasons of record.
Applicant argues the rejections of record should be withdrawn because “…presently amended claim 1 recites specific features not taught or suggested by the cited references, employs a non-obvious solution to a problem not addressed in the art, and achieves unexpected, beneficial results. For at least these reasons, presently amended claim 1 is non-obvious and patentable over the cited references, whether taken alone or in combination.”
Applicant's arguments have been considered but have not been found convincing essentially for the reasons of record as described below.
With respect to the teachings of Wang and Zhan, applicant’s argues:
“…a POSITA considering Wang and Zhan would have no reasonable motivation to replace the inert eGFP reporter with a complex, functionally active immunomodulatory polypeptide like an Fc fusion protein (such as the one described in Yao), anticipating that this substitution would yield a synergistic therapeutic outcome without introducing new technical hurdles like secretion inefficiency,” the undersigned disagrees essentially for the reasons of record.
As set forth in the prior Office Action, the given the teachings of Wang in view of Zhan, it would have been obvious to one of ordinary skill in the art that treatment of gastric and pancreatic cancer by administering CLDN18.2-specific CAR T cells was in need of further improvement; moreover, given the teachings of Wang, Zhan, Yao and Maus it further would have been obvious to one of ordinary skill in the art that modification of the CAR T-cells of Wang to express a second agent that can provide further cancer cell killing activity, such as a CLDN18.2-binding, single-domain antibody fused to Fc as described by Yao, was one route to improve upon the cancer cell killing potency of the CAR T-cells of Wang.
Applicant’s assertion that the ordinarily skilled artisan would essentially be lead away from such a strategy because it would be “introducing new technical hurdles like secretion inefficiency,” appears to be a non-sequitur because the motivation to make use of a CLDN18.2-binding single-domain antibody Fc fusion as a second agent to improve upon the CLDN18.2-binding CAR T-cells of Wang is rooted at least in part in the notion that such a combination would not increase the risk of scFv – scFv mispairing problems, “as seen in engineered immune effector
cells co-expressing two or more scFv-based CARs.” (see Fan para 338).
Applicant further set forth the following arguments about the teachings of Yao, Maus and Fan (highlight added):
“Yao discloses that fusing a single-domain antibody (VHH/sdAb) to an Fc region can enhance its penetration and effector functions (ADCC, CDC, etc.), i.e., it describes the entity of a (VHH/sdAb )-Fc fusion polypeptide. However, Applicant submits that Yao's teachings are directed to the Fc-sdAb fusion as an independent soluble therapeutic agent, and Yao does not teach or suggest engineering a cell to coexpress this fusion protein alongside a CAR, let alone address the impact of antigen-binding domain format (scFv vs. sdAb) on the secretion efficiency of the co-expressed Fc fusion polypeptide within such a cellular context.”
“While Maus generically mentions the possibility of co-expressing an additional therapeutic agent ( e.g., a single-domain antibody) in a CAR-T cell, potentially from the same vector, it merely lists this as one among many possibilities. Applicant submits that Maus does not recognize the specific secretion obstacle arising from the structural format pairing of the antigen-binding regions when a CAR and an Fc fusion protein are co-expressed. Consequently, Maus provides no motivation for the POSITA to specifically select the "scFv + sdAb" or "sdAb + scFv" pairing as recited in presently amended claim 1 to overcome this unrecognized problem.”
“Fan discusses the potential for mispairing when multiple scFv-containing proteins are co-expressed and notes that co-expression of scFv with sdAb could potentially avoid such mispairing. However, Applicant submits that Fan's focus is solely on the problem of chain mispairing during protein assembly, and it does not address, teach, or suggest any issue related to the secretion efficiency of co-expressed proteins. Applicant notes that mispairing and secretion are distinct biological and technical challenges.”
Applicant concludes these argument as follows:
“Therefore, Applicant submits that the subject matter of the presently amended claims is not a mere predictable combination of prior art elements (Wang's CAR-T, Yao's Fc-sdAb, Maus's co-expression concept, Fan's compatibility note). Instead, it is based on the discovery of a specific, previously unrecognized problem---secretion impairment dictated by antigen-binding domain format in a CAR/Fc fusion protein co-expression system---and provides a non-obvious solution via the deliberate "scFv + sdAb/nanobody" combination.”
As a preliminary matter, note that the disclosure of alternative embodiment by Maus (see e.g. para 0004: “In various embodiments, the therapeutic agent is or includes an antibody reagent a single chain antibody, a single domain antibody (e.g., a camelid antibody), or a bispecific antibody reagent (e.g., a bispecific T cell engager (BiTE); also see below). In other embodiments, the therapeutic agent is or includes a cytokine”) does not “…constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971)…,” see MPEP § 2123; moreover, “PATENTS ARE RELEVANT AS PRIOR ART FOR ALL THEY CONTAIN “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)).” (see ibid).
Moreover, a premise of applicant’s arguments reproduced above appears to be that the teachings of the instant specification describe “a previously unrecognized problem---secretion impairment,” and that if this is true then the claimed invention must be non-obvious.
This argument is not found convincing for several reasons.
Firstly, the prior art need not necessary identify a “secretion impairment” issue, and in turn teach / suggest co-expression of a sdAb-Fc and scFv-CAR in the same cells as solution for said “secretion impairment” issue for the claimed immune cells to be prima facie obvious.
Indeed, as set forth in MPEP § 2144(IV), “The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991) (discussed below)….”
Consistent with the above, as set forth in the prior Office Action at page 5, last paragraph, given the teachings of Wang, Zhan, Yao and Maus it would have been obvious to one of ordinary skill in the art that modification of the CAR T-cells of Wang to express a second agent that can provide further cancer cell killing activity is one route to improve upon the cancer cell killing potency of the CAR T-cells of Wang. As further set forth in the prior Office Action at page 6, “…it would have been obvious to one of ordinary skill in the art to engineer an immune cells, such as a CTL comprising a CLD18A2-CAR described by Wang , to further comprise a CLDN18A2-binding, VHH antibody fused to an antibody Fc domain capable of mediating CDC, ADCC, ADPC and FcRn as taught by Yao, such that the gastric and pancreatic cancer killing activity of the CLD18A2-CAR CTLs of Wang is enhanced. The ordinarily skilled artisan would have been motivated to make such CTLs given the possibility that such a CLDN18A2-CAR expressing CTL will be able to recruit M1-type macrophage from, e.g., the pancreatic cancer TME, thereby boosting treatment with a CLDN18A2-CAR CTL cancer killing activity. Likewise, the ordinarily skilled artisan would have had a reasonable expectation of successfully making such enhanced CLDN18A2-CAR CTLs given the teachings of Maus as further evidenced by the teachings of Fan.”
Secondly, while the specification describes at page 34, 1st full paragraph, e.g., the apparent lack of scFv-Fc expression in Figure 4 as “no significant expression of scFv-Fc was detected in either Fite-CAR T cell supernatant compared to Con-CAR T and NT cells,” and that “…this might due to the fact that the antigen-binding regions in the two Fite-CART were both scFv structures, which caused the adhesion of the VL and VH domains in the two scFv structures with each other, thus affecting the normal secretion of scFv-Fc,” the stated lack of normal secretion of scFv-Fc merely describes the lack of scFv-Fc being detected via the ELISA assay that was used in Fig. 4. There is nothing in the specification that shows, e.g., which particular step or steps – translation, insertion into the ER lumen, protein folding, vacuolar transport to the golgi, Fc glycosylation, and/or secretory vesicle fusion with the plasma membrane) – fail to occur as normal thereby diminishing “normal secretion” of the scFv-Fc. Indeed, it is possible that the aggregation and mispairing of scFv domains displayed, e.g., on the first page of CN109641948 (cited on an IDS) is occurring the context of, e.g., soluble scFv-Fc and an scFv-based CAR, including at the cell surface. If so, scFv-Fc may be considered by some ordinarily skilled artisans to have completed the “normal secretion” process even if the soluble scFv-Fc never makes it into the supernatant because it has aggregated at the cell surface.
Whatever the mechanism by which two or more scFv comprising proteins can unfold, undergo variable chain mispairing, and in turn form aggregates, it remains the examiner’s position, by contrast to applicant’s argument, that given the teachings of Wang in view of Zhan, Yao and Maus (as evidenced by Flemming, DeSelm, Jefferis and Fan), it would have been obvious to one of ordinary skill in the art to engineer an immune cells, such as a CTL comprising a CLD18A2-CAR described by Wang ‘405, to further comprise a CLDN18A2-binding, VHH antibody fused to an antibody Fc domain capable of mediating CDC, ADCC, ADPC and FcRn as taught by Yao, such that the gastric and pancreatic cancer killing activity of the CLD18A2-CAR CTLs of Wang would be enhanced. Moreover, as described above, the ordinarily skilled artisan would have been motivated to make such CTLs given the possibility that such a CLDN18A2-CAR expressing CTL will be able to recruit M1-type macrophage from, e.g., the pancreatic cancer TME, thereby boosting treatment with a CLDN18A2-CAR CTL cancer killing activity. Likewise, the ordinarily skilled artisan would have had a reasonable expectation of successfully making such enhanced CLDN18A2-CAR CTLs given the teachings of Maus as further evidenced by the teachings of Fan.
Finally, applicant’s argument that “[a]s supported by the experimental data in the specification (e.g., Fig. 8), the claimed combination (e.g., Claudinl8.2-specific CAR-T cell co-expressing a secreted Claudinl8.2 sdAb-Fc) achieves a synergistic effect through dual mechanisms: direct tumor cell killing via the CAR and recruitment/activation of bystander immune effector cells (e.g., NK cells, macrophages) via the secreted Fc fusion protein. This synergistic outcome would not have been predicted from the cited references,” pointing to Figs. 4, 5 and 8 of the specification is not found convincing for the reasons set forth below.
First, Figs. 4 and 5, and the disclosure of the instant specification underlying said figures, are not relevant to applicant’s assertion (“achieves a synergistic effect through dual mechanisms: direct tumor cell killing via the CAR and recruitment/activation of bystander immune effector cells”) as Figs. 4 and 5 merely show the amount of scFv-Fc or sdAb-Fc expression as compared to control cells not expressing the Fc fusion proteins rather than showing “a synergistic effect through dual mechanisms: direct tumor cell killing via the CAR and recruitment/activation of bystander immune effector cells.”
Second, Fig. 8 cannot show anything about an allegedly “synergistic effect through dual mechanisms…” since the active agent being tested is “Fite-CAR(l8.2-18.2)X T cell supernatant” and not Fite-CAR(l8.2-18.2)X T cells, per se. By contrast to applicant’s argument, the ordinarily skilled artisan aware of the reference teachings and considering Fig. 8 of the specification would not be surprised to see that a Claudin18.2-binding sdAb-Fc is capable of redirecting NK cells to lyse Claudin18.2-expressing target cells.
Furthermore, if anything, Figure 6 of the instant specification seems to contradict applicant’s assertion that “the claimed combination (e.g., Claudinl8.2-specific CAR-T cell co-expressing a secreted Claudinl8.2 sdAb-Fc) achieves a synergistic effect through dual mechanisms: direct tumor cell killing via the CAR and recruitment/activation of bystander immune effector cells (e.g., NK cells, macrophages) via the secreted Fc fusion protein.” See also page 35, 5th paragraph of the specification, “[a]s shown m Fig. 6…T cells comprising Fite-CAR(l8.2-18.2)X were able to kill target cells… and the killing efficiency was comparable to that of Con-CART cells.”
In conclusion, when Applicant’s arguments are taken as a whole and weighed against the evidence supporting the prima facie case of unpatentability, the instant claims, by a preponderance of evidence, remain unpatentable. See M.P.E.P. §§ 716.01(d) and 2142.
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 ZACHARY S SKELDING whose telephone number is (571)272-9033. The examiner can normally be reached M-F 9-5 EST.
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644