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 .
This is responsive to papers filed 11/26/2026.
Claim 1 has been amended. Claim 6 has been newly added and no claims have been newly canceled.
Claims 1-6 are currently pending.
Claim 5 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected specie, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/24/2024.
Claims 1-4 and 6 have been examined on their merits.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim(s) 1-4 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over June et al (WO 2012/079000-previously cited) in view of Aggarwal et al (US 2008/0095749-previously cited) and as evidenced by Baghaei et al (Gastroenterol Hepatol Bed Bench, 2017).
Regarding claims 1-4 and 6, June disclose a method of expanding a population of genetically engineered T cells in a human diagnosed with cancer comprising administering to the human a T cell genetically engineered to express a CAR wherein the CAR comprises an antigen binding domain, and the T cel is an autologous T cell (page 101 claims 61 and 63), or an allogeneic CAR-T cell (page 52 lines 20-27). The CAR-T cells may be administered in combination with other components such as cytokines or other cell populations (page 53 lines 16-19). Cancers to be treated include solid tumors (page 50 lines 10-14).
June do not specifically teach wherein the additional cell population is a bone marrow derived CD34- mesenchymal stem cell.
Aggarwal teach a method of treating cancer by administering mesenchymal stem cells to a subject with cancer, including cancers with solid tumors such as pancreatic cancer (page 4 para 48-49). The mesenchymal stem cells are derived from the bone marrow and cultured as adherent cells (page 2 para 14, pages 8-9 Example 1) and are thus inherently CD34- as evidenced by Baghaei (page 209 column 1). The MSCs may be autologous or allogeneic (page 2 para 16). The MSCs when used therapeutically, such as with cancer treatment, may be employed in combination with other therapeutic agents, growth factors, cytokines and cells other than mesenchymal stem cells (page 7 para 100-101).
Baghaei teach that regardless of isolation method that isolated MSC should fulfill certain criteria such as being plastic-adherent cells and should lack expression of CD34 (page 209, column 1).
Therefore, one of ordinary skill in the art would have been motivated to include CD34- mesenchymal stem cells in combination with the CAR-T cells of June for the treatment of solid tumors because Aggarwal teach and suggest that adherent MSCs derived from marrow are suitable for use in the treatment of solid cancers and in combination with other therapeutic agents (cytokines, growth factors) and other cells. One of ordinary skill in the art would have had a reasonable expectation of success because June specifically state that other agents and cells can be combined with their CAR-T cells and both June and Aggarwal teach the treatment of solid cancer such as pancreatic cancer.
Therefore, the combined teachings of June et al and Aggarwal et al render obvious Applicant’s invention as claimed.
Response to Arguments
Applicant's arguments filed 11/26/2026 have been fully considered but they are not persuasive.
Applicant argues that there was a commonly accepted understanding in the scientific community that MSCs had an immunosuppressive effect on T cell proliferation and activation. Applicant asserts that this would be the opposite effect to what would be intended and required in the treatment of a solid tumor. Applicant asserts that there is neither motivation nor a reasonable expectation of success to combine administration of unmodified MSCs with CAR-T cells in achieving enhanced CAR-T cell function.
This is not found persuasive. Haddad and Saldanha-Araujo disclose that MSCs are able to promote the generation of classic CD4+ Tregs (page 3, column 2). Duffy also disclose that Treg number and activity is enhanced in vitro and in vivo by support of MSCs (page 5 of 9, column 2).
Further evidence that it is not unexpected to combine MSCs and immune cells, such as T lymphocytes, for cell therapy is also disclosed by Qi et al (CN 102641298 B, machine translation). Qi specifically disclose the combination of MSCs with T lymphocytes (a variant that is also a key factor of combatting cancer cells) for therapeutic administration (paragraph 35). Engela et al (Frontiers in Immunology, 2012) also disclose the beneficial combining of MSCs and CD4+ Treg cells and how MSC administration allows for these T cells to have a positive effect upon administration (pages 4-5). Lim et al (Cell Transplantation 2014-from IDS filed 10/25/2022) also disclose the combination of genetically unmodified MSCs derived from bone marrow with CD4+ T cells (page 705, column 2).
Applicant argues that June makes no mention of combining MSCs with CAR-T cells as the combination would not have been obvious or reasonably expected to succeed. Applicant argues that passage cited by the Examiner on page 53 of June is a generic disclosure listing the mere theoretical possibility of potential combinations with other cell populations. Applicant argues that there is no guidance as to which cells should be combined or for which reason or a specific suggestion for combining MSCs with CAR-T cells.
This is not found persuasive. In response to applicant's arguments against the references individually, 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).
Therefore, one of ordinary skill in the art would have been motivated to include CD34- mesenchymal stem cells in combination with the CAR-T cells of June for the treatment of solid tumors because Aggarwal teach and suggest that adherent MSCs derived from marrow are suitable for use in the treatment of solid cancers and in combination with other therapeutic agents (cytokines, growth factors) and other cells. One of ordinary skill in the art would have had a reasonable expectation of success because June specifically state that other agents and cells can be combined with their CAR-T cells and both June and Aggarwal teach the treatment of solid cancer such as pancreatic cancer.
Applicant argues that Aggarwal makes no mention of combining MSCs with CAR-T cells and asserts that this combination would not have been obvious or reasonably expected to succeed. Applicant argues that passage cited by the Examiner at paragraph 100 of Aggarwal is a generic disclosure listing the mere theoretical possibility of potential combinations of MSCs with cells other than mesenchymal stem cells, such as dendritic cells. Applicant argues that there is no specific suggestion for combining MSCs with CAR-T cells.
This is not found persuasive. In response to applicant's arguments against the references individually, 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).
Therefore, one of ordinary skill in the art would have been motivated to include CD34- mesenchymal stem cells in combination with the CAR-T cells of June for the treatment of solid tumors because Aggarwal teach and suggest that adherent MSCs derived from marrow are suitable for use in the treatment of solid cancers and in combination with other therapeutic agents (cytokines, growth factors) and other cells. One of ordinary skill in the art would have had a reasonable expectation of success because June specifically state that other agents and cells can be combined with their CAR-T cells and both June and Aggarwal teach the treatment of solid cancer such as pancreatic cancer.
Applicant argues that Aggarwal emphasizes different predicted effects and properties of MSCs as relevant in the proposed therapeutic applications. Applicants to the summary of the invention in paragraphs 6-8 of Aggarwal as evidence for effects unrelated to CAR-T cell modulation and that they do not suggest compatibility with enhancing T cell proliferation and function. Applicant asserts that even if Aggarwal suggests MSCs as a potential cancer treatment that the combination of MSCs with CAR-T cells is not suggested and would not have been obvious or expected to succeed.
This is not found persuasive. In response to applicant's argument that the prior art does not teach that MSCs enhance CAR-T cell proliferation and activation, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
The fact that the references describe different beneficial effects than those that Applicant has focused on does not negate the fact that there was motivation and a reasonable expectation of success to combine the two cell types for the treatment of solid tumors as described above.
Applicant argues that the cited documents June and Aggarwal are per se unrelated and could only be combined in hindsight after considering the presently claimed method. Applicant asserts that the prior art specifically taught that MSCs have the opposite effect on T cells as would be desired and required in an adjuvant to a CAR T cell therapy.
This is not found persuasive. 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 current case, the obviousness rejection is based on the teachings of the cited references and the explicit teachings to combine the cell therapy methods with other cells be administered for the same purpose of treating a solid tumor. It is prima facie obvious to combine products known for the same purpose in order to provide a combined product for the very same purpose.
Applicant argues that it is a surprise finding that unmodified WT-MSCs have a significant supporting and stimulatory effect on CAR-T cell proliferation and activity. Applicant asserts that the declaration of Dr. Stangl and the two attached references of Haddad and Saldanha-Araujo and Duffy et al outline the established expectation that MSCs would be immunosuppressive towards T cells and thus would lead to a suppression of the CAR-T properties (proliferation and activation against cancer cells) that are important in obtaining a therapeutic effect. Applicant asserts that the administration of unmodified WT-MSCs in combination with CAR-T cells was initially as a negative control and to show the desired stimulatory effect of genetically modified MSCs expressing transgenic IL-7 and IL-21 and it was surprising that the unmodified WT-MSCs had a significant supporting and stimulatory effect on CAR-T cell proliferation and activity.
This is not found persuasive. The references cited by Applicant (Haddad and Saldanha-Araujo and Duffy et al) refer to various T cells, but do not refer to CAR-T cells at all and thus they are not commensurate in scope with the claimed method which explicitly requires CD4+ CAR-T cells. Also, the claims do not recite wild type MSCs, only genetically-unmodified MSCs, and thus assertions regarding WT-MSCs are also not commensurate in scope with the claims.
In addition, the references cited by Applicant indicate that certain T cell types, specifically Treg cells (regulatory T cells), have a different interaction with MSCs than other T cell types. Haddad and Saldanha-Araujo disclose that MSCs are able to promote the generation of classic CD4+ Tregs (page 3, column 2). Duffy also disclose that Treg number and activity is enhanced in vitro and in vivo by support of MSCs (page 5 of 9, column 2).
The declaration of Dr. Manfred Stangl under 37 CFR 1.132 filed 11/26/2025 is insufficient to overcome the rejection of claims 1-4 and 6 based upon June and Aggarwal applied under 35 USC 103 as set forth in the last Office action because:
The evidence shown is not commensurate in scope with the claims and the evidenced of obviousness is deemed greater than the evidence of nonobviousness.
The declaration gives the same reasons as described above and cites the same references as evidence that it is scientifically unfounded to assert that a skilled person would have been motivated to combine CD34- MSCs in combination with CAR-T cells to enhance CAR-T cell proliferation and activation with a reasonable expectation of success. The declaration states that it was commonly considered that MSCs had suppressive properties towards T cell proliferation and activation and were generally considered immunosuppressive. The declaration points to Figures 2 and 4 as evidence of the in vitro effects that WT-MSCs have on CAR-T cells.
This is not found persuasive. The references cited by Applicant (Haddad and Saldanha-Araujo and Duffy et al) refer to various T cells, but do not refer to CAR-T cells at all and thus they are not commensurate in scope with the claimed method which explicitly requires CD4+ CAR-T cells. Also, the claims do not recite wild type MSCs, only genetically-unmodified MSCs, and thus assertions regarding WT-MSCs are also not commensurate in scope with the claims.
In addition, the references cited by Applicant indicate that certain T cell types, specifically Treg cells (regulatory T cells), have a different interaction with MSCs than other T cell types. Haddad and Saldanha-Araujo disclose that MSCs are able to promote the generation of classic CD4+ Tregs (page 3, column 2). Duffy also disclose that Treg number and activity is enhanced in vitro and in vivo by support of MSCs (page 5 of 9, column 2). So while some T cells are shown to be inhibited or suppressed by MSCs, not all T cells show this effect (such as Treg cells and CAR-T cells).
In response to applicant's argument that the prior art does not teach that MSCs enhance CAR-T cell proliferation and activation, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
The obviousness rejection is based on the combination of two cell therapies known for the same purpose of treating solid tumors. “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (MPEP 2144.06).
Further evidence that it is not unexpected to combine MSCs and immune cells, such as T lymphocytes, for cell therapy is also disclosed by Qi et al (CN 102641298 B, machine translation). Qi specifically disclose the combination of MSCs with T lymphocytes (a variant that is also a key factor of combatting cancer cells) for therapeutic administration (page 5 paragraph 35). Engela et al (Frontiers in Immunology, 2012) also disclose the beneficial combining of MSCs and CD4+ Treg cells and how MSC administration allows for these T cells to have a positive effect upon administration (pages 4-5). Lim et al (Cell Transplantation 2014-from IDS filed 10/25/2022) also disclose the combination of genetically unmodified MSCs derived from bone marrow with CD4+ T cells (page 705, column 2).
Therefore, it appears to be generally understood in the prior art that the combination of unmodified MSCs and T cells are suitable and beneficial in the art of cell therapy.
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.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Batten et al., “Human Mesenchymal Stem Cells Induce T Cell Anergy and Downregulate T Cell Allo-Responses via the TH2 Pathway: Relevance to Tissue Engineering Human Heart Valves”, TISSUE ENGINEERING, 2006, Volume 12, Number 8, pp. 2263-2273.
Engela et al., “On the interactions between mesenchymal stem cells and regulatory T cells for immunomodulation in transplantation”, Frontiers in Immunology, 2012, Vol. 3, pp. 1-8.
Qi et al (CN 102641298 B, machine translation).
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 LAURA J SCHUBERG whose telephone number is (571)272-3347. The examiner can normally be reached 8:30-5:00 EST.
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LAURA J. SCHUBERG
Primary Examiner
Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631