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 .
Applicant’s amendment and response filed on 6/25/2026 has been received and entered into the case.
Claims 5, 7-8, 11, 13-16, 18, 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27-31, 33-34, 36-38, 40, 42-54, 56-62, 64-67, 69-72, 74-76 have been canceled, claims 41, 55, 63, 68, 73 have been withdrawn from consideration as being drawn to non-elected subject matter, and claims 1-4, 6, 9-10, 12, 17, 19, 21, 26, 32, 35 and 39 have been considered on the merits. All arguments have been considered.
The claim rejection under 35 USC 112 has been withdrawn due to the instant amendment.
The claim rejection under 35 USC 102 has been withdrawn due to the instant amendment.
Claim Objections
Claim 17 is objected to because of the following informalities: Claim 17 discloses the term “ix” in the wherein clause. It appears this term is a typographical error of “is”. It is also noted that the structures disclosed in claim 17 are not clear as the text in the drawing is not clearly visible.
Appropriate correction is required.
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) 1-4, 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 (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 1-4, 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 1-4, 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 1-4, 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.
Response to Arguments
Applicant’s arguments with respect to the 102 rejection based on Shirwan have been fully considered and are persuasive. The 102 rejection has been withdrawn.
Applicant's arguments with regard to the 103 rejection have been fully considered but they are not persuasive.
Applicant asserted that Wen’s teachings relate to in vitro cell modification, followed by administration of the modified cells, and Abbina’s process involves modifying a cancer cell in vivo, and applicant has concluded that one of ordinary skill in the art would not have been motivated to apply Abbina's teachings to Wen's in vitro modifications of cells for subsequent administration.
The Examiner respectfully disagrees with the applicant’s argument. One skilled in the art would understand that the in vivo modification (metabolic labeling) taught by Abbina would be readily available for in vitro modification according to Takayama et al. as discussed in the claim rejection.
Applicant argued that Abbina explicitly teaches that the solution to immunologic issues involved in administration of pancreatic islet cells is a PVA coating, not addition of an immune checkpoint molecule-functionalized nanoparticle or polymer. The claim rejection does not state that Abbina teaches the use of an immune checkpoint molecule-functionalized nanoparticle or polymer, rather the teaching of Abbina as well as Takayama is directed to the known technology (i.e. click chemistry) for cell surface engineering for cell-based therapies, and Abbina teaches that the chemical modification including metabolic engineering is a known alternative to genetic engineering for the cell surface protein modification (see Abstract; p.3367, 3. Orthogonal Strategies). Abbina et al. teach that genetic engineering, enzyme-mediated cell surface engineering, and metabolic engineering are known strategies for orthogonal modification of cell surface (p.3367-3673). Thus, it would have been obvious to a person skilled in the art to replace the cell surface modification to express PD-L1 by genetic engineering taught by Wen et al. with other known alternatives, i.e. enzyme-mediated cell surface engineering or metabolic engineering taught by Abbina et al.
As discussed above, metabolic engineering can be carried out in vitro as well as in vivo according to Takayama et al. and in fact, the instant specification discloses that metabolic glycoengineering and biorthogonal click chemistry are tools available for chemical decoration of immune checkpoint molecules onto the targeted cells (para. 117). It is understood that the click chemistry taught by Abbina and Takayama is the identical technology utilized in the instant application.
Thus, it is the Examiner’s position that the combined teachings of the cited references render the claimed cell surface modification using immune checkpoint molecule-functionalized nanoparticle or polymer with a reasonable expectation of success.
Conclusion
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 TAEYOON KIM whose telephone number is (571)272-9041. The examiner can normally be reached 9-5 EST Monday-Friday.
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/TAEYOON KIM/Primary Examiner, Art Unit 1631
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