DETAILED ACTION
Applicant’s amendment and Arguments/Remarks received on 08 October 2025 have been entered. Claims 1-2, 4-5, 10-19, and 21 were previously pending in the application. Claims 14-16 have been cancelled, and new claim 22 has been added by Applicant. Claims 1-2, 4-5, 10-13, 17-19, and 21-22 are currently pending in the application. Claim 1 is an independent claim.
Claims 1-2, 4-5, 10-13, 17-19, and 21-22 are currently pending and under examination in the instant application. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/IT2019/050177, filed 30 July 2019, which claims priority to Italy Application No. 102018000007601, filed 30 July 2018. Filing of a certified copy of the Italy Application No. 102018000007601, filed 28 January 2021 is acknowledged.
Thus, the earliest possible priority for the instant application is 30 July 2018.
Claim Objections
The objection to cancelled claim 15 for reciting “originate from one selected from” is withdrawn.
Claim Interpretation
Amended claim 1 newly recites, “the tCAR does not comprise all of intracellular signal transduction domains”, which has been afforded its broadest reasonable interpretation to encompass a tCAR which has some intracellular signal transduction domains, but does not have all possible intracellular signal transduction domains.
If Applicant intended for the amendment to indicate that the tCAR lacks intracellular signal domains, which is consistent with the apparently intended scope discussed in the interview held on 02 October 2025 and provided in Applicant’s Arguments and Remarks (page 7 line13: “the claimed tCAR missed the whole intracellular domain), Examiner recommends amending claim 1 to recite, “the tCAR does not comprise intracellular signal transduction domains” or “the tCAR does not comprise any intracellular signal transduction domains”.
Claim Rejections - 35 USC § 112(b)
The rejection of amended, previously presented, and cancelled claims 1-2, 4-5, 10-19, and 21 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for indefinite language is withdrawn in view of Applicant’s amendments to claims 1, 18, and 19.
**The following new rejection is necessitated by amendments to the claims.**
New claim 22 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
New claim 22 recites, “even when”, which is indefinite because it is unclear whether Applicant intends to claim that the tCAR remains anchored to a surface of PCs at other times or under other conditions that the condition of the TRAIL binding to a TRAIL receptor on a target tumor cell; and if so, then what other conditions are meant to be encompassed for the anchoring to remain or under what conditions the anchoring is allowed to discontinue. As such, the metes and bounds of the claim cannot be determined.
Claim Rejections - 35 USC § 103
The rejection of amended, previously presented, and cancelled claims 1-2, 4-5, and 10-19 under 35 U.S.C. 103 as being unpatentable over Balyasnikova et al. 2010, PLOS One, Vol. 5(3), e9750, 1-11, in view of Fakiruddin et al. 2018, Int. J. Molec. Sci., Vol. 19, 1-23, cited in a prior office action; Yuan et al. 2015, Cytotherapy, Vol. 17(7), 885-896, cited in a prior office action; Zhao et al. 2007, Journal of Immunology, Vol. 183(9), 5563-5574; Horta et al. 2016, Immunotherapy, Vol. 8(9), 1097-1117; Schott et al. 2015, Curr. Opin. Pharmacology, Vol. 24, 135-146, cited in a prior office action; and de Windt et al. 2017, Stem Cells, Vol. 35(8), 1984-1993, cited in a prior office action, is withdrawn over cancelled claims 14-16, maintained over amended and previously presented claims 1-2, 4-5, 10-13, 17-19 and newly applied to new claim 22. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant amended independent claim 1 to recite, “the tCAR does not comprise all of intracellular signal transduction domains”, which broadens the scope of the claim from the prior amendment in which the phrase “misses all of intracellular signaling domains” had been interpreted to a tCAR which comprises an scFV and transmembrane domain but which does not simultaneously comprise any intracellular signaling domains. Independent claim 1 additional incorporated a limitation previously included in cancelled claims 14-16. By broadening the scope of the claim to allow some signal transduction domains (but not “all”) within the tCAR, the amendment still encompasses a lack of any intracellular signaling domains and thus does not overcome the art of record.
Regarding new claim 22, Balyasnikova teaches that the scFv is expressed on the cell surface of the hMSCs [abstract, column 3 ¶ 2, column 11 ¶ 3- column 12 ¶ 1], and that the surface-expressed scFVEGFRvIII contributes to retention of MSCs in U87-EGFRvIII xenografts [column 12 ¶ 2-3, column 15 ¶ 3], indicating an enduring interaction between the hMSCs and the U87 glioma cells.
Additionally, Zhao was cited for teaching a truncated CAR (tCAR) construct targeting the tumor antigen ErbB2 (4D5-28D) in which the intracellular signaling domains have been completely removed and shows that expression of the tCAR lacking all of the intracellular signal transduction domains expresses at a higher level than the other CAR constructs which retain the intracellular signal transduction domains [abstract, column 8 ¶ 2, Figure 3].
Further, Horta teaches a direct connection between an expressed CAR on the surface of a cell with an antigen (e.g., GD2) on the surface of a target tumor cell [Figure 1].
Fakiruddin teaches that TRAIL ligand binds to the TRAIL receptor, which induces a variety of intracellular signaling pathways leading to apoptosis of the TRAIL receptor- expressing target cell [Figure 2].
None of the cited references teach or suggest that TRAIL ligand binding to the TRAIL receptor disrupts a GD2 antibody (e.g., GD2 CAR)- GD2 antigen interaction.
Therefore, given the teachings of Balyasnikova that a surface-expressed CAR induces a retention of the CAR-expressing cell proximal to target cells expressing the CAR-directed antigen; the teachings of Zhao of high expression levels of a truncated CAR which maintains the transmembrane domain; the teachings of Horta that CARs form direct physical interactions between the CAR-expressing cell and the target cell, wherein the CAR is anchored to a surface of the CAR-expressing cell and also bound to an antigen expressed on the target cell; and the teachings of Fakiruddin of a variety of intracellular signaling pathways induced by TRAIL-TRAIL receptor binding which does not include any indication of a disruption to a GD2 interaction; an ordinarily skilled artisan at the time of filing the instant application would expect that the GD2 tCAR remains anchored to a surface of the PCs even when the TRAIL expressed by the GD2 tCAR-expressing cell independently binds to a TRAIL receptor on a target tumor cell, absent evidence to the contrary. As such, it would have been prima facie obvious to an ordinarily skilled artisan at the time of filing the instant application that TRAIL binding to the TRAIL receptor would not remove the GD2 tCAR from the tCAR-expressing PC cell surface with a reasonable expectation of success.
Applicant argues that the cited art differs from the amended set of claims in several ways, including a) that the starting cells are mostly murine bone marrow cells instead of human AD-PCs; b) the pro-apoptotic molecule is not often TRAIL; c) the claimed tCAR is a truncated CAR which does not comprise all of intracellular signal transduction domains; and d) the tumor antigen is not GD2 but often HER2.
Applicant additionally argues unexpected results a) in that the fact that the Applicant is able to obtain an anti-cancer action in normal conditions (37oC, CO2 incubator) can be considered as surprising accounting for Balyasnikova 2 teaching away by teaching lower expression of scFv on the cells at 37oC; and b) in the fact that the method simultaneously allows the soluble payload release or direct cell-to-cell contact between the tumor cell and the mTRAIL, combined with truncated scFV-based CAR anchored to the membrane of adipose perivascular cells, which combination generates an anti-tumor effect that has never been proposed by others.
However, this is not agreed.
In response to applicant’s arguments against the references individually, it is noted that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Further, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In addition, 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).
Therefore, not every cited reference in an obviousness rejection under 35 U.S.C. 103 needs to include every limitation of a claimed invention.
Regarding a), Balyasnikova teaches human MSCs. Fakiruddin was cited for teaching that adipose-derived MSCs expressing TRAIL are capable of inducing apoptosis in glioblastoma (page 2 ¶ 2 and page 4 ¶ 3). Further, Fakiruddin et al. teaches that MScs are immunoprivileged, non-viral, and home in on the tumor microenvironment, thus making them good cells for allogenic transplantation which are safer than viruses for delivery of therapeutic molecules (page 4 ¶ 2-3). Therefore, Fakiruddin teaches the motivation to use adipose-derived MSCs/PCs.
Regarding b), Balyasnikova teaches hMSC cells which have been modified to express the therapeutic protein TRAIL [column 15 ¶ 1, column 20 ¶ 13].
Regarding c), Zhao was cited for teaching a truncated CAR (tCAR) construct targeting the tumor antigen ErbB2 (4D5-28D) in which the intracellular signaling domains have been completely removed and shows that expression of the tCAR lacking all of the intracellular signal transduction domains expresses at a higher level than the other CAR constructs which retain the intracellular signal transduction domains [abstract, column 8 ¶ 2, Figure 3]. Therefore, Zhao teaches the motivation to use a truncated CAR.
Regarding d), Horta was cited for teaching the motivation to use an scFv directed towards the tumor antigen GD2 in a method of producing engineered cells targeting GD2+ positive cancers to direct those cells to specifically target the tumor cells [abstract, column 1 ¶ 1, column 18 ¶ 1- column 20 ¶ 1, column 21 ¶ 1, Figure 1, Executive summary].
Regarding Applicant’s assertion of unexpected results, note that Applicant has not provided or referenced any data in support of the assertion, either by reference to the specification or by means of a declaration or affidavit. As such, the arguments amount to arguments of counsel. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). See MPEP § 716.01(c) for examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration. Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. MPEP 716.01(c). Attorney argument is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See MPEP § 2129 and § 2144.03 for a discussion of admissions as prior art.
It is also noted that any evidence of unexpected results must be commensurate in scope with the claimed invention, and that a greater, or greater than additive, effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected MPEP 716.02 (a) and (d). Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980).
Specifically, Applicant argues that Applicant is able to obtain an anti-cancer action in normal conditions (e.g., at 37oC and 5% CO2). However, the claimed method is a method of making bifunctional cells, not a method of treating cancer, wherein the function of treating cancer is only claimed as an intended use in claim 18. Additionally, the temperature or % CO2 conditions are not claimed limitations. As such, Applicant’s arguments are not commensurate in scope with the claimed limitations.
Applicant also argues that the fact that the claimed methods simultaneously allow the soluble payload release or direct cell-to-cell contact between the tumor cell and the mTRAIL, combined with truncated scFV-based CAR anchored to the membrane of adipose perivascular cells, which combination generates an anti-tumor effect that has never been proposed by others, is evidence of a surprising effect associated with the method. However, Applicant does not provide any data to support that the effect observed is greater than what would have been expected given the teaches of the cited art, which provide teachings and/or motivations for each of the claimed limitations. Figure 8 of the instant drawings shows anti-tumor activity of bifunctional PC sTRAIL in a 3D model with respect to spheroids of TC71 tumor cells in vitro. However, anti-tumor activity would be expected for a cell which expresses sTRAIL, as taught by Fakiruddin, which was cited for teaching that TRAIL is a potent anti-tumor agent, has apoptotic effects, and can either be a soluble ligand and secreted by the MSCs or attached as a transmembrane protein by a hydrophobic amino acid bond (page 7 ¶ 1-3, page 8 ¶ 3, page 9 ¶ 1-page 10 ¶ 2, and page 12 ¶ 1, and Figure 2).
Therefore, Applicant’s arguments do not overcome a finding of obviousness over Balyasnikova, Fakiruddin, Yuan, Zhao, Horta, Schott, and de Windt under 35 U.S.C. 103.
The rejection of amended, previously presented, and cancelled claims 1-2, 4-5, 10-19, and 21 under 35 U.S.C. 103 as being unpatentable over Prapa et al. 2015, Oncotarget, 6(28), 24884-24894; in view of Balyasnikova et al. 2010, PLOS One, Vol. 5(3), e9750, 1-11, cited in a prior office action; Horta et al. 2016, Immunotherapy, Vol. 8(9), 1097-1117, cited in a prior office action; Fakiruddin et al. 2018, Int. J. Molec. Sci., Vol. 19, 1-23, cited in a prior office action; Yuan et al. 2015, Cytotherapy, Vol. 17(7), 885-896, cited in a prior office action; Zhao et al. 2007, Journal of Immunology, Vol. 183(9), 5563-5574, cited in a prior office action; Schott et al. 2015, Curr. Opin. Pharmacology, Vol. 24, 135-146, cited in a prior office action; and de Windt et al. 2017, Stem Cells, Vol. 35(8), 1984-1993, cited in a prior office action, is withdrawn over cancelled claims 14-16, maintained over amended and previously presented claims 1-2, 4-5, 10-13, 17-19, and 21, and newly applied to new claim 22. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant amended independent claim 1 to recite, “the tCAR does not comprise all of intracellular signal transduction domains”, which broadens the scope of the claim from the prior amendment in which the phrase “misses all of intracellular signaling domains” had been interpreted to a tCAR which comprises an scFV and transmembrane domain but which does not simultaneously comprise any intracellular signaling domains. Independent claim 1 additional incorporated a limitation previously included in cancelled claims 14-16. By broadening the scope of the claim to allow some signal transduction domains (but not “all”) within the tCAR, the amendment still encompasses a lack of any intracellular signaling domains and thus does not overcome the art of record.
Regarding new claim 22, Balyasnikova teaches that the scFv is expressed on the cell surface of the hMSCs [abstract, column 3 ¶ 2, column 11 ¶ 3- column 12 ¶ 1], and that the surface-expressed scFVEGFRvIII contributes to retention of MSCs in U87-EGFRvIII xenografts [column 12 ¶ 2-3, column 15 ¶ 3], indicating an enduring interaction between the hMSCs and the U87 glioma cells.
Additionally, Zhao was cited for teaching a truncated CAR (tCAR) construct targeting the tumor antigen ErbB2 (4D5-28D) in which the intracellular signaling domains have been completely removed and shows that expression of the tCAR lacking all of the intracellular signal transduction domains expresses at a higher level than the other CAR constructs which retain the intracellular signal transduction domains [abstract, column 8 ¶ 2, Figure 3].
Further, Horta teaches a direct connection between an expressed CAR on the surface of a cell with an antigen (e.g., GD2) on the surface of a target tumor cell [Figure 1].
Fakiruddin teaches that TRAIL ligand binds to the TRAIL receptor, which induces a variety of intracellular signaling pathways leading to apoptosis of the TRAIL receptor- expressing target cell [Figure 2].
None of the cited references teach or suggest that TRAIL ligand binding to the TRAIL receptor disrupts a GD2 antibody (e.g., GD2 CAR)- GD2 antigen interaction.
Therefore, given the teachings of Balyasnikova that a surface-expressed CAR induces a retention of the CAR-expressing cell proximal to target cells expressing the CAR-directed antigen; the teachings of Zhao of high expression levels of a truncated CAR which maintains the transmembrane domain; the teachings of Horta that CARs form direct physical interactions between the CAR-expressing cell and the target cell, wherein the CAR is anchored to a surface of the CAR-expressing cell and also bound to an antigen expressed on the target cell; and the teachings of Fakiruddin of a variety of intracellular signaling pathways induced by TRAIL-TRAIL receptor binding which does not include any indication of a disruption to a GD2 interaction; an ordinarily skilled artisan at the time of filing the instant application would expect that the GD2 tCAR remains anchored to a surface of the PCs even when the TRAIL expressed by the GD2 tCAR-expressing cell independently binds to a TRAIL receptor on a target tumor cell, absent evidence to the contrary. As such, it would have been prima facie obvious to an ordinarily skilled artisan at the time of filing the instant application that TRAIL binding to the TRAIL receptor would not remove the GD2 tCAR from the tCAR-expressing PC cell surface with a reasonable expectation of success.
Applicant argues that the cited art differs from the amended set of claims in several ways, including a) that the starting cells are mostly murine bone marrow cells instead of human AD-PCs; b) the pro-apoptotic molecule is not often TRAIL; c) the claimed tCAR is a truncated CAR which does not comprise all of intracellular signal transduction domains; and d) the tumor antigen is not GD2 but often HER2.
Applicant additionally argues unexpected results a) in that the fact that the Applicant is able to obtain an anti-cancer action in normal conditions (37oC, CO2 incubator) can be considered as surprising accounting for Balyasnikova 2 teaching away by teaching lower expression of scFv on the cells at 37oC; and b) in the fact that the method simultaneously allows the soluble payload release or direct cell-to-cell contact between the tumor cell and the mTRAIL, combined with truncated scFV-based CAR anchored to the membrane of adipose perivascular cells, which combination generates an anti-tumor effect that has never been proposed by others.
However, this is not agreed.
In response to applicant’s arguments against the references individually, it is noted that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Further, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In addition, 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).
Therefore, not every cited reference in an obviousness rejection under 35 U.S.C. 103 needs to include every limitation of a claimed invention.
Regarding a), Balyasnikova teaches human MSCs. Fakiruddin was cited for teaching that adipose-derived MSCs expressing TRAIL are capable of inducing apoptosis in glioblastoma (page 2 ¶ 2 and page 4 ¶ 3). Further, Fakiruddin et al. teaches that MScs are immunoprivileged, non-viral, and home in on the tumor microenvironment, thus making them good cells for allogenic transplantation which are safer than viruses for delivery of therapeutic molecules (page 4 ¶ 2-3). Therefore, Fakiruddin teaches the motivation to use adipose-derived MSCs/PCs.
Regarding b), Balyasnikova teaches hMSC cells which have been modified to express the therapeutic protein TRAIL [column 15 ¶ 1, column 20 ¶ 13]. Prapa was cited for teaching a method of producing bifunctional cells, comprising engineering human T cells to obtain engineered T cells contemporarily expressing both TRAIL and a CAR directed against GD2, wherein the CAR comprises an scFv directed toward the GD2 [abstract, column 4 ¶ 4, column 13 ¶ 1-column 14 ¶ 2].
Regarding c), Zhao was cited for teaching a truncated CAR (tCAR) construct targeting the tumor antigen ErbB2 (4D5-28D) in which the intracellular signaling domains have been completely removed and shows that expression of the tCAR lacking all of the intracellular signal transduction domains expresses at a higher level than the other CAR constructs which retain the intracellular signal transduction domains [abstract, column 8 ¶ 2, Figure 3]. Therefore, Zhao teaches the motivation to use a truncated CAR.
Regarding d), Horta was cited for teaching the motivation to use an scFv directed towards the tumor antigen GD2 in a method of producing engineered cells targeting GD2+ positive cancers to direct those cells to specifically target the tumor cells [abstract, column 1 ¶ 1, column 18 ¶ 1- column 20 ¶ 1, column 21 ¶ 1, Figure 1, Executive summary].
Regarding Applicant’s assertion of unexpected results, note that Applicant has not provided or referenced any data in support of the assertion, either by reference to the specification or by means of a declaration or affidavit. As such, the arguments amount to arguments of counsel. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). See MPEP § 716.01(c) for examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration. Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. MPEP 716.01(c). Attorney argument is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See MPEP § 2129 and § 2144.03 for a discussion of admissions as prior art.
It is also noted that any evidence of unexpected results must be commensurate in scope with the claimed invention, and that a greater, or greater than additive, effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected MPEP 716.02 (a) and (d). Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980).
Specifically, Applicant argues that Applicant is able to obtain an anti-cancer action in normal conditions (e.g., at 37oC and 5% CO2). However, the claimed method is a method of making bifunctional cells, not a method of treating cancer, wherein the function of treating cancer is only claimed as an intended use in claim 18. Additionally, the temperature or % CO2 conditions are not claimed limitations. As such, Applicant’s arguments are not commensurate in scope with the claimed limitations.
Applicant also argues that the fact that the claimed methods simultaneously allow the soluble payload release or direct cell-to-cell contact between the tumor cell and the mTRAIL, combined with truncated scFV-based CAR anchored to the membrane of adipose perivascular cells, which combination generates an anti-tumor effect that has never been proposed by others, is evidence of a surprising effect associated with the method. However, Applicant does not provide any data to support that the effect observed is greater than what would have been expected given the teaches of the cited art, which provide teachings and/or motivations for each of the claimed limitations. Figure 8 of the instant drawings shows anti-tumor activity of bifunctional PC sTRAIL in a 3D model with respect to spheroids of TC71 tumor cells in vitro. However, anti-tumor activity would be expected for a cell which expresses sTRAIL, as taught by Prapa and Fakiruddin, which were cited for teaching that anti-GD2 CAR-expressing T cells elicited a robust and specific anti-tumor activity in culture with neuroblastoma cells which included release of the pro-apoptotic molecule TRAIL, such that the anti-GD2 CAR effectively targeted the T cells against GD2 expressed on the surface of the neuroblastoma cells [Prapa abstract, column 11 ¶ 3]; and that TRAIL is a potent anti-tumor agent, has apoptotic effects, and can either be a soluble ligand and secreted by the MSCs or attached as a transmembrane protein by a hydrophobic amino acid bond (page 7 ¶ 1-3, page 8 ¶ 3, page 9 ¶ 1-page 10 ¶ 2, and page 12 ¶ 1, and Figure 2).
Therefore, Applicant’s arguments do not overcome a finding of obviousness over Prapa, Balyasnikova, Horta, Fakiruddin, Yuan, Zhao, Schott, and de Windt under 35 U.S.C. 103.
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.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634