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 .
Detailed Action
This action is in response to the papers filed July 2, 2026.
Election/Restrictions
Applicant’s reply filed 07/02/2026 to the Requirement for Restriction/Election mailed 04/08/2026 is acknowledged.
Applicant elected without traverse the invention of:
Group 1, drawn to an engineered cell, a population of cells comprising thereof, and a composition comprising thereof;
beta islets, as the cell type;
increased expression of CD47 and reduced expression of CD142, B2M and CIITA, as the combination of modifications introduced into the engineered cell; and
diabetes, as the disease, condition or cellular deficiency to be treated.
Claims 461, 467-470 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claim Amendments
Applicant’s amendment to the claims filed 07/02/2026 is acknowledged.
Claims 1-450, 452-456 have been cancelled.
Claims 451, 457-470 are pending.
Claims 461, 467-470 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claims 451, 457-460, 462-466 are under examination.
Priority
The instant application 18/682,797 was filed on 02/09/2024. This application is a national stage of international application PCT/US2022/074870 filed 08/11/2022, claiming priority based on U.S. Provisional Application No. 63/353,527 filed 06/17/2022.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 03/17/2025 and 09/26/2025 have been considered.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, or by applicant in an information disclosure statement (IDS), they have not been considered.
Specification
The instant application was filed on or after 07/01/2022, and therefore the instant application is subject to the requirements of 37 C.F.R. 1.831 through 1.835.
The sequence rules embrace all nucleotide and amino acid sequences defined by:
(1) An unbranched sequence or linear region of a branched sequence containing 4 or more specifically defined amino acids, wherein the amino acids form a single peptide backbone; or
(2) An unbranched sequence or linear region of a branched sequence of 10 or more specifically defined nucleotides, wherein adjacent nucleotides are joined by:
(i) A 3' to 5' (or 5' to 3') phosphodiester linkage; or
(ii) Any chemical bond that results in an arrangement of adjacent nucleobases that mimics the arrangement of nucleobases in naturally occurring nucleic acids (i.e., nucleotide analogs).
Disclosed nucleotide or amino acid sequences that do not meet this definition must not be included in the Sequence Listing.
See 37 C.F.R. 1.831, and see guidance of WIPO ST.26 and MPEP 2412-2419.
Appropriate action is required so that the sequences disclosed in the application comply with the sequence rules. Examples found in the application which fail to comply with the sequence rules include the sequences disclosed in paragraph 282 of the specification.
Applicant should carefully review the entire specification to ensure compliance with the sequence rules. Applicant should provide a corresponding sequence identifier (SEQ ID NO) with every appearance of a sequence embraced by the sequence rules. Where a sequence is presented in a drawing, reference must be made to the sequence by use of the sequence identifier, either in the drawing or in the Brief Description of the Drawings, where the correlation between multiple sequences in the drawing and their sequence identifiers in the Brief Description is clear. For guidance on amending the Sequence Listing, see MPEP 2414. Appropriate action is required in reply to this Office action. See attached PTO-2301.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 451, 457-460, 462-466 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims recite an engineered cell comprising (i) one or more modifications that increase cell surface expression of CD47, (ii) one or more modifications that reduce CD142 expression, and (iii) one or more modifications that reduce expression of one or more MHC Class I or MHC Class II molecules, wherein the one or more MHC Class I or MHC Class II molecules include at least B2M and CIITA.
The “modifications” include any changes and alternations in a cell that impact gene expression. See, paragraph 144 of the specification. Accordingly, the claims broadly encompass both genetic modifications and non-genetic modifications that change or alter gene expression in a cell. Genetic modifications altering gene expression may be made within the coding sequence of the target gene or outside the coding sequence of the target gene. For example, genetic modifications would broadly embrace genomic changes to nontarget genes that have a downstream effect of altering expression of the target gene, e.g., via intracellular signaling pathways. Non-genetic modifications broadly encompass small molecule modulators, e.g., inhibitors and activators, inhibitory RNA, e.g., shRNA and splice-switching antisense oligonucleotides, and cell culture conditions, e.g., pH levels, O2 levels and temperature. Moreover, the modifications made to the expression of one or more MHC Class I or MHC Class II molecules include not only B2M and CIITA but rather any MHC Class I and MHC Class II molecules, e.g., TAP I, NLRC5, HLA-A, HLA-B, HLA-C, HLA-DP, HLA-DM, HLA-DOA, HLA-DOB, HLA-DQ, HLA-DR, RFX5, RFXANK, RFXAP, NFY-A, NFY-B and NFY-C. See, paragraph 190 of the specification. In addition, the modifications may be made to any cell type, e.g., beta islet cell, B cell, T cell, NK cell, retinal pigmented epithelium cell, hepatocyte, thyroid cell, skin cell, glial progenitor cell, neural cell, cardiac cell, blood cell, plasma cell, platelet, endothelial cell, epithelial cell, pluripotent stem cell, embryonic stem cell and red blood cell. See, paragraph 29 of the specification. Different cell types, due to difference in phenotype, would be expected to respond differentially to possible modifications, e.g., to treatment with different chemical inhibitors and activators.
Accordingly, the claims are directed to a vast, structurally-undisclosed genus of engineered cells, of any cell type, functionally-described as possessing (i) increased surface expression of CD47, (ii) reduced expression of CD142, and (iii) reduced expression of any MHC Class I and MHC Class II molecules, including at least B2M and CIITA.
An adequate written description of an engineered cell possessing modifications (i) through (iii), as outlined above, requires more than a mere statement that it is part of the invention. What is required is either (1) a description of a common core structure shared among the members (species) of the functionally described genus or (2) a disclosure of a representative number of species of the functionally described genus. It is not sufficient to define a genus of engineered cells solely by its desired biological property, i.e., as possessing modifications (i) through (iii), because disclosure of no more than that, as in the instant case, is simply a wish to know the identity of any one or more modifications capable of producing the desired effect. Also, naming a type of material generically known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material. Thus, claiming all cells possessing modifications (i) through (iii), as outlined above, without defining what means will do, or without disclosing a representative number of species, is not in compliance with the written description requirement.
The working examples (Example 1, pages 297-302) only exemplify making engineered human induced pluripotent stem cells (hiPSCs) by using CRISPR/Cas9 gene editing to introduce indel mutations into the coding sequence of B2M and CIITA and a lentiviral transduction to introduce a transgene encoding CD47, followed by differentiation of the B2Mindel/indel CIITAindel/indel CD47tg hiPSCs into endothelial cells. Examples 2-3 (pages 302-819), describing generation of CD142indel/indel B2Mindel/indel CIITAindel/indel CD47tg hiPSC and progeny beta islets therefrom, are merely prophetic. Accordingly, the present application only reduces to practice the generation of B2Mindel/indel CIITAindel/indel CD47tg hiPSCs and progeny endothelial cells therefrom using CRISPR/Cas9 gene editing to introduce indel mutations into the coding sequence of B2M and CIITA and a lentiviral transduction to introduce a transgene encoding CD47. No other cell types nor modifications are exemplified, including any modification to CD142 expression.
Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the broad, functionally-defined genus of engineered cells, as claimed, at the time the application was filed. Dependent claims are included in the basis of the rejection because they do not correct the deficiencies of the claim upon which they depend.
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.
Claims 451, 457-460, 462-466 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/018615 A2 to Schrepfer et al.; in view of US 2005/0255111 A1 to Korsgren et al.; and Kosinova et al. (2015) “Inhibition of tissue factor expression in pancreatic islets by SI-RNA” Acta Diabetol 52:211-212, Abstract from 5th EPITA Winter Symposium & 34th AIDPIT Workshop lgls/Innsbruck, Austria: 25-27 January 2015.
Schrepfer is relevant prior art for disclosing universally acceptable “off-the-shelf” hypoimmunogenic pluripotent cells and differentiated progeny thereof, including beta islet cells. The engineered cells possess reduced expression of B2M and CIITA and increased expression of CD47. CRISPR/Cas9 gene editing is used to disrupt or knockout expression of target genes in cells by introducing small deletions/insertions into the coding region of said target genes (B2M and CIITA), and nucleic acids encoding desired genes are introduced into cells to increase expression of said desired genes (CD47). The hypoimmunogenic pancreatic islets lack major immune antigens that trigger immune responses and avoid phagocytic endocytosis, and, accordingly, said hypo-immunogenic pancreatic islets useful for transplantation in the treatment of diabetes. See, e.g., Abstract, and paragraphs 9-10, 36-38, 119, 149, 182 and 212.
Schrepfer does not teach or fairly suggest modifying the cells to possess reduced expression of CD142 (i.e., tissue factor, TF), as instantly claimed.
Korsgren is relevant prior art for teaching inhibition of tissue factor (TF, CD142) in the treatment of diabetes. The risk of instant blood-mediated inflammatory reaction (IBMIR) for diabetic patients undergoing islet transplantation is associated with tissue factor expression by the endocrine cells of the islets of Langerhans, and, therefore, an inhibitor or antagonist against tissue factor can reduce the risk of IBMIR in the treatment of diabetic patients undergoing islet transplantation, as well as enhance the survival and avoid rejection of transplanted islets. See, e.g., Abstract, and paragraphs 3-8.
Kosinova is relevant prior art for teaching that pancreatic islet (PI) transplantation is hindered by the instant blood-mediated inflammatory reaction (IBMIR) when treating diabetic patients, which is triggered by tissue factor (TF, CD142) expression on the surface of islet cells. Temporary inhibition of tissue factor expression can reduce the IBMIR and improve the engraftment of islet cells after infusion.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the engineered cells of Schrepfer to further possess reduced expression of CD142, in view of Korsgren and Kosinova, with a reasonable expectation of success because inhibition of CD142 would be expected to reduce the IBMIR and improve the engraftment of islet cells after infusion into diabetic patients.
For these reasons, claims 451, 457-460, 462-466 would have been prima facie obvious over the prior art.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 451, 457-460, 462-466 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 12,221,622 or 12,492,382; in view of the secondary references Schrepfer, Korsgren and Kosinova, as cited above.
The reference claims recite engineered, pancreatic islet cells comprising one or more modifications that increase expression of CD47 and decrease expression of B2M and CIITA.
The reference claims do not recite further modifying the cells to possess reduced expression of CD142.
The teachings of the secondary references Schrepfer, Korsgren and Kosinova have been provided above and hereby incorporated by reference.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the engineered cells of the reference claims to further possess reduced expression of CD142, in view of the secondary references, with a reasonable expectation of success because inhibition of CD142 would be expected to reduce the IBMIR and improve the engraftment of islet cells after infusion into diabetic patients.
For these reasons, claims 451, 457-460, 462-466 would have been prima facie obvious over the references claims and secondary references.
Claims 451, 457-460, 462-466 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending U.S. Application No. 17/997,103 (claim listing filed 08/05/2026), 18/021,036 (claim listing filed 08/05/2026), 18/449,625 (claim listing filed 06/15/2026), 18/682,778 (claim listing filed 08/27/2025), 19/671,233 (claim listing filed 05/08/2026), or 19/376,675 (claim listing filed 01/14/2026); in view of the secondary references Schrepfer, Korsgren and Kosinova, as cited above.
The reference claims recite engineered, pancreatic islet cells comprising one or more modifications that increase expression of CD47 and decrease expression of B2M and CIITA.
The reference claims do not recite further modifying the cells to possess reduced expression of CD142.
The teachings of the secondary references Schrepfer, Korsgren and Kosinova have been provided above and hereby incorporated by reference.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the engineered cells of the reference claims to further possess reduced expression of CD142, in view of the secondary references, with a reasonable expectation of success because inhibition of CD142 would be expected to reduce the IBMIR and improve the engraftment of islet cells after infusion into diabetic patients.
For these reasons, claims 451, 457-460, 462-466 would have been prima facie obvious over the references claims and secondary references.
Claims 451, 457-460, 462-466 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending U.S. Application No. 18/579,148 (claim listing filed 01/13/2025) or 18/727,670 (claim listing filed 09/03/2025).
Claims 451, 457-460, 462-466 are found to be anticipated by the references claims. The reference claims recite engineered, pancreatic islet cells comprising one or more modifications that increase expression of CD47 and decrease expression of B2M and CIITA. Since the nucleic acid encoding CD47 is inserted into the CD142 locus, expression of CD142 would be disrupted.
Claims 451, 457-460, 462-466 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending U.S. Application No. 18/682,798 (claim listing filed 11/26/2024) or 18/682,782 (claim listing filed 11/18/2024); in view of the secondary references Schrepfer, Korsgren and Kosinova, as cited above.
Claims 451, 457-460, 462-466 are found to be anticipated by the references claims. The reference claims recite engineered, pancreatic islet cells comprising one or more modifications that increase expression of CD47 and decrease expression of CD142, B2M and CIITA.
Conclusion
Rejections will not be held in abeyance. Applicant is respectfully reminded that a complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims or the filing of a terminal disclaimer in accordance with 37 CFR 1.321 in the pending application(s) with a reply to the Office action (see MPEP § 1490 for a discussion of terminal disclaimers). Such a response is required even when the nonstatutory double patenting rejection is provisional. See, MPEP 804(I)(B)(1).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES J GRABER whose telephone number is (571)270-3988. The examiner can normally be reached Monday-Thursday: 9:00 am - 4:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James D Schultz can be reached at (571)272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAMES JOSEPH GRABER/Examiner, Art Unit 1631
Prosecution Insights