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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on April 22, 2026 has been entered. By way of this submission, Applicant has amended claims 1, 9, 14, 19, 25, 29-30, and 34-35, and cancelled claims 24 and 28.
Claims 1-9, 14, 19, 25-27, 29-31, and 33-35 are pending in the application. Claims 4 and 7 remain withdrawn from consideration, pursuant to the Restriction Requirement mailed March 4, 2022.
Claims 1-3, 5-6, 8-9, 14, 19, 25-27, 29-31, and 33-35 are therefore under examination before the Office.
The rejections of record can be found in the previous Office action, dated October 23, 2025.
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.
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 1-3, 5, 8-9, 14, 19, 24-25, 27-31 and 33 were previously rejected under 35 U.S.C. 103 as being unpatentable over Escobar (Sci Transl Med. 2014 Jan 1;6(217):217ra3, cited in IDS) in view of Picarda (Clin Cancer Res. 2016 Jul 153;22(14):3425-3431.
Claims 6 and 26 were previously rejected under 35 U.S.C. 103 as being unpatentable over Escobar and Picarda as applied to claim 1 above, and further in view of Chen (US20180362975A1).
Applicant argues that Escobar does not provide any suggestion that tumor-associated antigen-specific T cells are expanded by interferon. Applicant provides a Declaration under 37 CFR 1.132 from Dr. Luigi Naldini (the "fifth Naldini Declaration"), in support of this argument, which states that the statements of Escobar are introductory statements referring to the general properties of interferon in the context of immune cells and the immune response to tumors, and that these statements do not reflect the results of the study reported in Escobar, and they do not relate to the effects on T cells that the vectors in Escobar's study were reported to produce.
Applicant's arguments in view of the amendments to the claims have not addressed this issue fully. In the interest of compacting prosecution, the above rejections are withdrawn, and the following new grounds of rejection are issued, necessitated by Applicant's amendment to the claims:
Claims 1-3, 5, 8-9, 14, 19, 25, 27, 29-31, and 33-35 are rejected under 35 U.S.C. 103 as being unpatentable over Escobar (Sci Transl Med. 2014 Jan 1;6(217):217ra3, cited in IDS) in view of Picarda (Clin Cancer Res. 2016 Jul 153;22(14):3425-3431, Redeker (Front Immunol. 2016 Sep 6:7:345) and Verdegaal (Cancer Immunol Immunother. 2011 Jul;60(7):953-63).
Escobar teaches the use of hematopoietic stem/progenitor cells which were genetically modified with a vector comprising a transcriptionally targeted interferon-alpha transgene using enhancer/promoter sequences from the mouse Tie2/Tek gene (page 1, right column, second paragraph through page 2, right column). Escobar further teaches incorporating target sequences for miR-126 and miR-130a into the above vector to prevent chronic activation of the type I IFN pathway (page 4, left column, second paragraph), which is pertinent to claims 1, 8, 14, 19, 27, and 31. Escobar teaches that the above cell is useful for treating cancer (see, e.g., Figure 5).
Escobar further teaches that interferon-alpha is useful as a cancer treatment by various mechanisms, and it is desirable to target interferon-alpha to tumors by the above method, for example, to promote the survival, proliferation, and cytotoxicity of CD8+ T cells, as well as increasing the expression of tumor antigens on neoplastic cells to make them more immunogenic (page 1, right column, first and second paragraphs). Escobar further teaches that targeted delivery of interferon alpha to tumor cells reprograms the tumor microenvironment toward more effective dendritic cell activation and immune effector cell cytotoxicity (abstract). Escobar also teaches that interferon-alpha within a vector may be operably linked to a Tie2 promoter and miR-126 and miR-130a (Figure 2A), which is pertinent to claims 9, 14, 19, 25, 27, and 29-31.
Escobar further teaches that this method could also be combined with other immunotherapeutic approaches for treating cancer (page 11, right column, fourth paragraph).
However, Escobar does not teach combinations of the above cell with a chimeric antigen receptor (CAR)-bearing T cell that targets B7-H3 (CD276).
Picarda teaches that B7-H3 is aberrantly expressed in human cancers, including glioma (i.e., glioblastoma) (Table 1). Picarda further teaches that autologous (i.e., isolated from the patient) CAR-T cells which target B7-H3 are useful in treating cancers which overexpress this antigen (page 3429, left column, second paragraph), which is pertinent to claims 3, 5 and 33-35.
Picarda further teaches that combination therapies of anti-B7-H3 immunotherapy and other anticancer treatments, including immune checkpoint inhibitors, may also be useful (page 3429, left column, third paragraph through 3430), which is pertinent to claim 2.
Picarda also teaches that an immunosuppressive tumor microenvironment is a barrier to effective CAR-T-based therapy (page 3429, left column, second paragraph).
Redeker teaches that interferon alpha is useful for promoting T cell expansion in the context of adoptive cell therapy (i.e., infusion of tumor-specific T cells) (page 8, left column, second paragraph: “IFN-α is known for its direct anti-tumor effect and is currently a frequently used cytokine for the treatment of cancer. It has also been recognized that IFN-α promotes T cell activation, survival, expansion, and memory formation through activation and differentiation of DCs”).
Verdegaal teaches a combination of adoptive transfer of tumor-reactive T cells and interferon alpha for the treatment of cancer (page 954, left column, first paragraph).
Verdegaal also teaches that this combination results in expansion of tumor-specific adoptively transferred T cells in vivo (Figure 2).
It would have been prima facie obvious for a person of ordinary skill in the art as of the effective filing date to combine the teachings of Escobar, Picarda, Redeker, and Verdegaal to arrive at the claimed invention. The individual components of the claimed invention were known in the art, as described above. Picarda also teaches a known obstacle of an immunosuppressive tumor microenvironment for effective CAR-T therapy, while Escobar teaches a possible solution to this problem by targeted delivery of interferon-alpha to the tumor cells. Both Escobar and Picarda also teach that it is advantageous to combine their respective therapies with other cancer immunotherapies. Likewise, Redeker and Verdegaal teach that interferon alpha is useful for T cell expansion in the context of adoptive cell therapy. As Escobar teaches a solution to the problem recited by Picarda, it would be obvious to combine the teachings of these references, especially with guidance from Redeker and Verdegaal. The skilled artisan could do so by known methods, with each component in the combination performing its known, usual function, to affect a predicable result.
Claims 6 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Escobar, Picarda, Redeker, and Verdegaal as applied to claim 1 above, and further in view of Chen (US20180362975A1).
The teachings of Escobar, Picarda, Redeker, and Verdegaal have been discussed supra. However, Escobar, Picarda, Redeker, and Verdegaal do not teach an engineered T cell comprising a disruption in a major histocompatibility complex (MHC) gene.
Chen teaches chimeric antigen receptor (CAR)-bearing T cells which have been modified to inactivate or delete an exogenous MHC gene (see, e.g., para. 0133). Chen further teaches that it is useful to reduce or eliminate expression of MHC molecules in a CAR-T cell to reduce or eliminate the host versus graft disease response upon administration of the cell (para. 0575). Chen further teaches that this approach could be used to generate “off the shelf” T cells (para. 0574).
Chen further teaches that the CAR may target B7-H3 (CD276) (para. 0385).
Chen further teaches that the cancer to be treated may be glioblastoma (para. 0330).
It would have been prima facie obvious for a person of ordinary skill in the art as of the effective filing date to combine the teachings of Escobar, Picarda, Redeker, Verdegaal and Chen to arrive at the claimed invention. An ordinary artisan would have been motivated to do so, and have a reasonable expectation of success, since Chen teaches that reducing or eliminating expression of an MHC gene is a useful improvement to CAR-T therapy by eliminating graft-versus-host disease. The benefits of such a modification to the CAR-bearing T cell and methods of doing so were known in the art, as evidenced by Chen. The application of a known technique to a known device (method, or product) ready for improvement to yield predictable results is prima facie obvious. MPEP 2143(1)(D). A person of ordinary skill could combine the teachings of Escobar, Picarda, Redeker, Verdegaal, and Chen by known methods to arrive at the claimed invention, with each component of the combination performing its known, usual function, and the combination would yield nothing more than predictable results.
In response to Applicant's arguments, the ability of interferon alpha to expand adoptively transferred T cells is expressly taught by Redeker and Verdegaal.
Applicant's arguments concerning the teachings of Escobar are limited to Escobar in isolation. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually. MPEP 2145(IV). The ability of the combination treatment of the claimed hematopoietic stem cell and the claims TAA-specific T cell is a latent result of following the step of administering both cells.
Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979). "The fact that appellant 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." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). MPEP 2145(II).
Products of identical chemical composition cannot have mutually exclusive properties. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. MPEP 2112.01(II). Since the cells administered in the claimed method are identical to the cells of Escobar and Picarda, this creates a prima facie presumption that the cells would possess an identical function when used in combination.
It is also noted that Dr. Naldini is listed as one of the authors in the Escobar publication.
Conclusion
No claim is allowed.
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/PETER JOHANSEN/ Examiner, Art Unit 1644
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