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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-6, 9-10, 12, 17, 19, 21, 26, 32, 35 and 39) in the reply filed on 2/17/2026 is acknowledged.
Claims 7-8, 11, 13-16, 20, 22-25, 27-31, 33-34, 36-38, 40, 42-54, 56-62, 64-67, 69-72, 74-76 have been canceled, claims 41, 55, 63, 68, 73 have been withdrawn from consideration as being drawn to non-elected subject matter, and claims 1-6, 9-10, 12, 17, 19, 21, 26, 32, 35 and 39 have been considered on the merits.
Information Disclosure Statement
The NPL reference by Au et al. (2018, ACS Nano) is duplicated, and the duplicate was lined through.
Claim Objections
Claim 17 is objected to because of the following informalities: Claim 17 discloses “TCO-MTZ” and “DBCO” in the structure. The full name of these abbreviation should be disclosed in the claim.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 17 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.
Claim 17 discloses structures in figures. It is not clear what the “x” and “y” intend to point out. The bracket is indicated with “x” and this could be understood that multiple numbers of the whole unit (conjugation) to the cells being in a linear repeat. Similarly, considering the content in the parenthesis, it appears that “y” intends to the number of the unit. Does this mean that the same unit of immune checkpoint molecule/PD-L1 or CD86 and linker being repeated in a linear form that is attached to the nanoparticle containing a cargo? Clarification is required.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-3 and 21 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Shirwan et al. (WO2007/067682A2; IDS ref.)
Regarding claims 1-2 and 21, Shirwan et al. teach that the engineered cells have cell surfaces being engineered to display an immune co-stimulatory polypeptide, and the method can be in vivo as well as in vitro (para. 8). Shirwan et al. teach a cell engineered with one or more of immune co-stimulatory polypeptide including CD86, PD-L1, PD-L2, B7-H3, B7-H4, etc.(para. 85). Shirwan et al. teach that the binding of the exogenous molecule to the cell surface can be effected by covalent bonding (para. 48), and the polypeptide and second member can be covalently bound to each other or conjugated to each other directly or through a linker (para. 90).
Regarding claim 3 directed to a cell type, Shirwan et al. disclose generally a cell being engineered for its cell surface (para. 8). A person skilled in the art would recognize that the scope of the “cell” taught by Shirwan et al. would encompass any known mammalian cells, and thus, the selection of any types of mammalian cells known in the art which would include those listed in claim 3 would be purview of a person skilled in the art at the time of filing. Therefore, it would have been obvious to a person skilled in the art would choose any known mammalian cell including those claimed for the surface engineering taught by Shirwan et al.
Thus, the reference anticipates the claimed invention.
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.
Claim(s) 1-6, 9-10, 12, 17, 21 and 39 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wen et al. (2008, Transplantation; IDS ref.) in view of Abbina et al. (2018, ACS Biomater. Sci. Eng.), Takayama et al. (2019, Molecules)
Wen et al. teach that the overexpression of PD-L1 on NIT-1 cells, insulin-producing insulinoma cell-line, i.e. beta cell line, markedly prolonged allograft survival in diabetic mice (Abstract). It is understood that PD-L1 overexpression taught by Wen et al. would express PD-L1 on the cell surface as PD-L1 is a receptor of PD-1. While the PD-L1 is attached to the cell membrane as a membrane receptor, however, Wen et al. do not teach the PD-L1 covalently attached to the cell surface.
Abbina et al. teach a method of surface engineering for cell-based therapies, and there are different approaches to provide cell surface modification including genetic engineering of cell surface proteins and broadly reactive chemical ligations and physical associations as well as controlled approaches as in genetic, enzymatic and metabolic engineering (Abstract; Fig. 2; Table 1). Abbina et al. teach that various cell-based therapeutics including islet cells, cancer cells, endothelial cells, stem cells, etc. (Abstract).
Abbina et al. discuss in detail about nonspecific strategies including covalent modification, physical association such as biotinylation, hydrophobic insertion; orthogonal strategies including genetic engineering, enzyme-mediated cell surface engineering and metabolic engineering.
Abbina et al. teach that metabolic engineering involving azides being installed on the cell surface using the synthetic azido sugar precursor N-azidoacetylmannosamine (AC4GalNaz). The precursors incorporated into the cell surface via the GalNAc salvage pathway, and the glycostructures are orthogonally labeled with a desired cargo (DBCO-cargo) (p.3670, Fig. 19). Abbina et al. also teach the use of maleimide/thiol conjugation in islet engineering, and (p.3662).
This so-called “Click Chemistry” is well established in the art as shown by Takayama et al. (see entire document). Takayama et al. teach various compounds utilized in click chemistry and glycoengineering in vitro (Table 1), including AC4ManNAz, cyclooctyne such as TCO and DBCO, etc. Takayama et al. teach that the azide-modified cells (AC4GalNaz incorporated) are labeled with DBCO-coated nanoparticles via SPAAC reaction (Fig. 2). The teachings of Abbina et al. and Takayama et al. are identical to the structure of nanoparticle covalently attached to the cell surface via DBCO-Azide as shown in the structure of claim 17. Takayama et al. also teach the use of nanoparticles composed of polyamidoamine dendrimers as a means to provide high concentration of drug being delivered (p.3661, 2nd col.). Takayama et al. teach DBCO modified polymeric nanoparticles, DBCO-conjugated PEGylated liposome and a peptide conjugated with trans-cyclooctene (TCO) (Table 2).
It would have been obvious to a person skilled in the art to use the cell surface modification technologies including metabolic engineering taught by Abbina et al. and Takayama et al. utilizing linkers DBCO, TCO and metabolic incorporation of azide using AC4ManNAz, and polyamidoamine dendrimer, etc. to replace the genetic engineering to overexpress PD-L1 on the surface of NIT-1 cells taught by Wen et al. A person of ordinary skilled in the art would have been motivated to do so because Abbina et al. teach that chemical modification including metabolic engineering is a known alternative to genetic engineering for the cell surface modification. Thus, replacing a known technique with another known technique is obvious. Furthermore, as taught by Abbina et al. and Takayama et al., the technology utilized by the claimed method are well known in the art and one skilled in the art would readily utilize the known technique for having the NIT-1 cells to have PD-L1 attached to the cell surface for the purpose of inhibit the undesired immune response with a reasonable expectation of success.
By combining the teachings of Abbina et al. and Takayama et al. with Wen et al., one skilled in the art would attach PD-L1 using various linker molecules known in the art including, for example, PD-L1 would be attached to the polyamidoamine dendrimer and the use of metabolic incorporation of AC4ManNAz via a transmembrane glycoprotein would provide a means to attach the dendrimer using cyclooctyne-azide linkage (e.g. DBCO-azide).
Regarding claim 3 directed to the beta cell, while the NIT-1 is a cell line derived from insulinoma, i.e. beta cell line, and the instant specification discloses NIT-1 as beta cells. Thus, the teaching of Wen et al. would meet the claim 3.
Regarding claims 4 and 6 directed to the glycoengineered moiety comprising an amide of mannosamine, the combined teachings of Wen et al. in view of Abbina et al. and Takayama et al. would meet the limitation because the use of AC4ManNAz taught by Abbina et al. and Takayama et al. as AC4ManNAz is N-azidoacetyl-mannosamine.
Regarding claims 5, 9, 10 directed to the immune checkpoint molecule-functionalized nanoparticle, a residue of a dendrimer, and the dendrimer being a polyamidoamine dendrimer, as discussed above, the combined teachings of Abbina et al. and Takayama et al. for cell surface modification of PD-L1 utilizing polyamidoamine dendrimer would meet the limitation.
Regarding claim 12 directed to the MW of polyamidoamine dendrimer being about 500-1,000,000, while Abbina et al. and Takayama et al. do not teach the MW of polyamidoamine dendrimer, however, it would be inherent that the polyamidoamine dendrimer of Abbina et al. and Takayama et al. would have the identical MW as claimed because the claimed dendrimer is identical to the polyamidoamine dendrimer of Abbina et al. and Takayama et al.
Regarding claim 17, as discussed above, it would have been obvious to a person skilled in the art such that the combined teachings of Wen et al. in view of Abbina et al. and Takayama et al. would arrive the structure as claimed.
Regarding claim 21, the combined teachings of Wen et al. in view of Abbina et al. and Takayama et al. would meet PD-L1.
Regarding claim 39 directed to the composition comprising the functionalized cell and a pharmaceutically acceptable excipient, while the cited references do not particularly teach the use of a pharmaceutically acceptable excipient, however, one skilled in the art would utilize any known pharmaceutically acceptable excipient in order to inject/transplant the NIT-1 cells modified/functionalized by using the glycoengineering technology known in the art as taught by Abbina et al. and Takayama et al. As PBS is well known solution or pharmaceutically acceptable excipient for such a purpose, the use of pharmaceutically acceptable excipient along with the glycoengineered NIT-1 cells with PD-L1 attached would be within the purview of a person skilled in the art.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim(s) 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wen et al. in view of Abbina et al. and Takayama et al. as applied to claims 1-6, 9-10, 12, 17, 21 and 39 above, and further in view of Ilinskaya et al. (2014, British Journal of Pharmacology).
Regarding claim 19 directed to the nanoparticle containing a cargo in claim 17 being an immunosuppressive agent, Wen et al. in view of Abbina et al. and Takayama et al. do not particularly teach the limitation.
Ilinskaya et al. teach that nanoparticles such as dendrimers can be used for delivery of anti-inflammatory drugs (p.3992, 1st col., last para.), and PAMAM dendrimers have also been used to deliver methotrexate and indomethacin to reduce inflammation in the rat model of arthritis (p.3992, 2nd col., 1st para.).
It would have been obvious to a person skilled in the art to use an immunosuppressive agent as a cargo of the polyamidoamine dendrimer (PAMAM) taught by Abbina et al. and Takayama et al. in the glycoengineering to modify NIT-1 cells to present PD-L1 on the cell surface in order to reduce immune response and inflammatory response when the cells are transplanted to treat diabetes in a subject.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim(s) 17, 26 and 32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wen et al. in view of Abbina et al. and Takayama et al. as applied to claims 1-6, 9-10, 12, 17, 21 and 39 above, and further in view of Muraki et al. (2017, BMC Biotechnology)
Regarding claims 26 and 32 directed to the functionalized dendrimer comprising a structure of the dendrimer, a linker 2, a cyclooctyne and an azide containing molecule, Wen et al. in view of Abbina et al. and Takayama et al. do not particularly teach the linker 2 between cyclooctyne and dendrimer.
Muraki et al. teach the use of TCO-MTZ conjugation and MTZ (methyltetrazine) functionalized rabbit IgG-Fab’ fragment (rFab’-MTZ) as an example (Fig. 1). The rFab’-MTZ would conjugate with its reaction partner, a TCO-modified agent, via TCO-MTZ reaction. This is consistent with the linker, TCO-MTZ, of the third structure disclosed in claim 17.
It would have been obvious to a person skilled in the art to use dendrimer functionalized with either TCO or MTZ and reacted with nanoparticle, i.e. dendrimer, functionalized with MTZ or TCO for the conjugation reaction via TCO-MTZ reaction taught by Muraki et al. for the PD-L1 functionalized dendrimer taught by Wen et al. in view of Abbina et al. and Takayama et al. A person of ordinary skilled in the art would have been motivated to do so because the linker system of TCO-MTZ is known in the art and thus, the use of known technique for the purpose of conjugation of protein and dendrimer would be obvious.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim(s) 35 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wen et al. in view of Abbina et al. and Takayama et al. as applied to claims 1-6, 9-10, 12, 17, 21, 26 and 39 above, and further in view of Ma et al. (2019, J. Proteom Res.)
Regarding claim 35 directed to an acellular pancreatic extracellular matrix comprising the functionalized cell, Wen et al. in view of Abbina et al. and Takayama et al. do not teach the limitation.
Ma et al. teach that the pancreatic ECM obtained decellularized human pancreas represents a natural scaffold that may be capable of recapitulating the in vivo environment of islets to enhance survival and function of the cells throughout the isolation, culture and transplantation process (p.3156, Introduction). Ma et al. teach that the matrisome proteins have roles in survival, proliferation, differentiation of β cells and insulin secretion have been implicated in previous studies, making them important components of scaffolds in transplantation and tissue engineering (p.3160).
It would have been obvious to a person skilled in the art to use the decellularized extracellular matrix protein for transplanting the NIT-1 cells of Wen et al. modified to present PD-L1 on the cell surface by the method of Abbina et al. and Takayama et al. for treating diabetes with a reasonable expectation of success. A person of ordinary skilled in the art would have been motivated to do so because Ma et al. teach that decellularized pancreatic ECM protein (matrisome) is beneficial in the islet cells’ survival, proliferation and differentiation of β cells and insulin secretion.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Relevant Prior Art
The following prior art is relevant to the subject matter of the claimed invention but not cited in the claim rejection:
CN 110055218 (Liu et al.): NK cell surface modification of PD-L1 aptamer using click chemistry.
Conclusion
No claims are allowed.
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/TAEYOON KIM/Primary Examiner, Art Unit 1631