DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Applicant’s amendment filed on 06/10/2026 has been entered.
Amended claims 1, 79-97 and new claims 98-100 are pending in the present application.
Applicant elected previously the following species: (i) NME7 protein; (ii) a fibroblast; (iii) a reverted cell in a pluripotent state characterized by an increased expression profile of one or more genes selected from the group consisting of Oct4, Sox2, Klf-4, c-Myc, Nanog, and Lin28 as compared to a corresponding expression profile of the one or more genes of the terminally differentiated cell prior to the contacting; and (iv) in the presence of one or more exogenously introduced pluripotency factors selected from the group consisting of Oct4, Sox2, Klf-4, c-Myc, Nanog, and Lin 28.
Claims 81, 83-87, 89 and 91-94 were withdrawn previously from further consideration because they were directed to non-elected species.
Accordingly, amended claims 1, 79-80, 82, 88, 90 and 95-100 are examined on the merits herein with the above elected species.
Response to Amendment
1. The rejection under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, for New Matter was withdrawn in light of currently amended claim 1, and upon further consideration.
2. The rejection under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, for Scope of Enablement was withdrawn in light of currently amended claim 1, particularly at least with the limitation “reverting a mammalian somatic cell”.
3. The nonstatutory double patenting rejections over claims 1, 3-6, 8, 14 and 18 of U.S. Patent No. 11,976,295, drawn to a cell culture media for growth, maintenance, and induction of reversion of a less mature state of a cell comprising a recombinant NME7 protein that comprises a NDPK A domain and an NDPK B domain and does not comprise a targeting sequence, were withdrawn upon further considerations. It is also noted that U.S. Patent No. 11,976,295 is a DIV of U.S. Patent No. 11,591,565.
4. The provisional nonstatutory double patenting rejections as being unpatentable over claims 1, 3-6, 8, 14 and 18 of copending Application No. 19,322,00, drawn to a cell culture media for growth, maintenance, and induction of reversion of a less mature state of a cell comprising a recombinant NME7 protein that comprises a NDPK A domain and an NDPK B domain and does not comprise a targeting sequence, were withdrawn upon further considerations. It is also noted that the copending Application No. 19,322,00, is also a DIV of U.S. Patent No. 11,591,565.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
Amended claims 1, 79-80, 82, 88, 90, 96-97 and 99-100 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Bambad et al (US 2010/0093092; IDS) in view of Desvignes et al (BMC Evolutionary Biology 9:256; doi:10.1186/1471-2148-9-256, 25 pages; 2009) and evidenced by Hikita et al (PLoS ONE 3:e3312, doi:10.1371/journal.pone.003312, 13 pages, 2008; IDS). This is a slightly modified rejection necessitated by Applicant’s amendment.
The instant claims encompass a method for reverting a mammalian somatic cell, the method comprising: contacting the mammalian somatic cell with a culture medium composition, the culture medium composition: (i) comprising a human recombinant NME7 protein in monomeric form or a nucleic acid encoding the human recombinant NME7 protein in the monomeric form, wherein the recombinant human NME7 protein in monomeric form is devoid of amino acid residues 1 to 91 of SEQ ID NO: 13 and has two binding sites for a MUC1* receptor, and wherein the human recombinant NME7 protein in monomeric form dimerizes the MUC1* receptor; (ii) does not comprise serum, and (iii) does not comprise basic fibroblast growth factor, thereby reverting the mammalian somatic cell to a reverted cell having: a) a stem-like morphology; and b) increased expression of one or more genes selected from the group consisting of Oct4, KLf4, and Nanog compared to expression of the one or more genes in the somatic cell prior to the contacting. It is noted that the term “stem-like” morphology is defined by the instant specification to refer to a morphology that resembles that of a stem cell, a level of expression of one or more of the pluripotency genes, or an ability to differentiate into multiple cell types (paragraph 104).
Bambad et al already disclosed a method for inducing or maintaining pluripotency in a cell (e.g., dermal fibroblasts, rat 3Y1 fibroblasts, human MUC1-negative HCT-116 cells) comprising contacting the cell with a biological species that increases MUC1* activity, wherein the biological species is a protein which is a MUC1* ligand, preferably the ligand is NM23 (activating ligand of MUC1*) which includes NME7 or SEQ ID NOs. 12-13 (nucleotide and amino acid sequences of NME7, respectively) either alone OR in combination with gene products that are known to induce pluripotency such as OCT4, SOX2, KLF4, NANOG, c-myc and LIN28 (see at least Summary of the Invention; paragraphs 35-40, 46-47, 50, 55 and 64). SEQ ID NO: 13 is a human NME7 amino acid sequence comprising amino acids 1-91 that are identical to amino acids 1-91 of SEQ ID NO: 13 of the present application; and Example 4 discloses the use of recombinant human NM23. Bamdad et al also taught that the protein may also be an antibody, preferably bi-valent antibody that specifically recognizes the PSMGFR sequence of MUC1* (paragraph 10). Bamdad et al stated “NM23 is a ligand that activates MUC1* (Mahanta et al., 2008) (SEQ ID NOS:12-17 and 22-23)…..NM23 can be used to replace some or all of the previously identified pluripotency-inducing factors to induce and enhance the generation of iPS cells” (paragraph 36); “The invention involves reversing differentiation or maintaining stem-like characteristics by introducing to mature cells, or somewhat differentiated cells, genes or gene products that affect the expression of MUC1* and its associated factors….MUC1* associated factors include, but are not limited to, full-length MUC1, enzymes that cleave MUC1, MUC1* activating ligands and also transcription factors that affect the expression of MUC1 or MUC1*…Agents that affect expression of MUC1* or MUC1* associated factors can be added in combination with, or to replace one or more genes or gene products that are already known to induce pluripotency including OCT4, SOX2, KLF4, NANOG, c-myc and LIN28” (paragraph 38); “[l]igands that interact with MUC1 or MUC1* are added to somatic cells, dermal fibroblasts, fibroblasts, or somewhat differentiated cells to induce pluripotency either alone or in combination with other genes to induce or maintain pluripotency” (paragraph 46); and “NME-H1, -H2 or -7 can be used in their native state or in mutant forms that favor the dimeric state, such as the S120G mutation” (last sentence of paragraph 47) which indicates or suggests that NME7 protein can be used in native monomeric state. Bambad et al taught explicitly that NM23 or NME7 is introduced to a cell as a protein itself or as a protein bearing a leader sequence such as a poly-arginine tract to facilitate entry into the cell to aid in the induction or maintenance of pluripotency (paragraphs 47 and 50). In an exemplification, Bamdad et al demonstrated that wild-type recombinant NM23, mutant (S120G) NM23, or a bi-valent anti-MUC1* antibody (MUC1* ligands) does a better job of stimulating growth and pluripotency maintenance in pluripotent hESC colonies in “minimal stem cell medium” (media without feeder-conditioned medium) without bFGF than does conditioned medium plus bFGF OR minimal medium plus bFGF on Matrigel (paragraphs 18, 63; example 8 and Table 1). The minimal stem cell medium containing NM23 without feeder-conditioned medium and without FGF is also serum-free as evidenced by the “minimal stem cell medium” (hESC media without feeder-conditioned medium and without bFGF) of Hikita et al that consisted of DMEM/F12/GlutaMAX I with 30% Knockout Serum Replacement, 1% non-essential amino acids stock, 0.1 mM beta-mercaptoethanol (page 9, right column, first full paragraph; page 12, left column, first full paragraph). Since NM23 (e.g., NME-7) functions better in a serum-free, bFGF-free minimal stem cell culture medium for stimulating growth and pluripotency maintenance, it would have been obvious for an ordinary skill in the art that such minimal stem cell culture medium is also suitable in a method for inducing or maintaining pluripotency in a cell such as dermal fibroblasts, rat 3Y1 fibroblasts, human MUC1-negative HCT-116 cells. In example 12, Bambad et al stated “NM23 (NME-H1, NME-H2 or NME-7) enhances the induction or maintenance of pluripotency. NM23 is introduced along with previously identified pluripotency factors, including but not limited to OCT4, SOX2, KLF4, as well as others disclosed herein” (paragraph 72).
However, Bambad et al did not teach explicitly a method for reverting a human somatic cell using a culture medium composition comprising a human recombinant NME7 protein in monomeric form that lacks amino acid residues 1 to 91 of SEQ ID NO: 13 and has two binding sites for a MUC1* receptor.
At the effective filing date of the present application, Desvignes et al already characterized the Nme gene repertoire in vertebrates (Abstract). Figure 2 of the Desvignes reference depicts domains of human Nme proteins, including Nme1 (also known as NM23-HI; see Table 1 on page 3), Nme2/2a (also known as NM23-H2; see Table 1 on page 3) and Nme7, as shown below.
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Unlike human NM23-HI and NM23-H2 proteins (each has a single NDPk-1), human NME7 protein has NDPk7A and NDPk7B domains and the DUF1126 domain comprised of amino acid residues 2-91 that is not present either NM23-H1 or NM23H2 protein.
Accordingly, it would have been obvious for an ordinary skilled artisan to modify the teachings of Bamdad et al by also utilizing at least a recombinant human NME7 protein comprised of the two tandemly repeated full-length NDPK domains (NDPk7A domain and NDPk7B domain) or NME7-AB that shares a conserved NDPK domain in each of the NME-1 and NME-2 proteins, but lacking the DUF1126 domain as a MUC1* ligand for inducing pluripotency in a human somatic cell, in light of the teachings of Desvignes et al as presented above.
An ordinary skilled artisan would have been motivated to carry out the above modification because Desvignes et al disclosed that human NME7 protein possessing the DUF1126 domain followed by two tandemly repeated full-length conserved NDPK domains (NDPk7A domain and NDPk7B domain), whereas each of the NME-1 and NME-2 proteins possesses a single conserved NDPK domain and without the DUF1126 domain; and therefore the DUF1126 domain of human NME7 protein is not involved in their function as MUC1* ligands and is dispensable/deleted. Such a modified human NME7 protein would lack the amino acid residues 1 to 91 of SEQ ID NO: 1 of the present application. Please also note that the primary Bamdad reference teaches at least that NME-H1, -H2 or -7 can be used in their native state.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Bamdad et al and Desvignes et al; coupled with a high level of skill of an ordinary skilled artisan in the relevant art.
The modified method resulting from the combined teachings of Bamdad et al and Desvignes et al as set forth above is indistinguishable and is encompassed by the presently claimed invention. As such, the modified method would result in a reverted human somatic cell having a stem-like morphology and an increased expression of at least one of Oct4, Klf4 and Nanog relative to the starting somatic cell.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments related to the above modified 103(a) rejection in the Amendment filed on 06/10/2026 have been fully considered, but they are respectfully not found persuasive for the reasons discussed below.
Applicant argued basically that Bamdad et al fails to teach or suggest the use of a human recombinant NME7 protein in monomeric form that is devoid of amino acid residues 1-91 of SEQ ID NO: 13; and Bamdad et al merely identified NME7 by its full-length amino acid sequence at SEQ ID NO: 13 as well as suggesting using NME7 “in their native state”. Applicant also argued that Desvignes et al fails to provide motivation to delete the DUF1126 domain from NME7 because the reference is a comparative evolutionary biology paper that characterizes the Nme gene repertoire across vertebrate species; and it does not discuss MUC1*, ligand function, and/or induction of pluripotency. Additionally, Desvignes et al expressly acknowledged that the function of the DUF1126 domain was unknown; and thereby an ordinary skilled in the art reading Desvignes et al would not have concluded that the DUF1126 domain is “dispensible” for NME7 function as a MUC1* ligand because Desvignes et al is silent about MUC1. Applicant also argued that NME1, NME2 and NME7 are different proteins with different structures and functions; with NME1 operates as a dimer with a single NDPK domain per monomer, while NME7 is a monomer with two NDPK domains and additionally a DUF1126 domain. Applicant further argued that the presence of a domain in one family member that is absent in another says nothing about whether the domain is required for the protein that possesses it to fold correctly, remain soluble, or maintain biological activity. Accordingly, an ordinary skilled artisan would have had no reason to assume that removing the DUF1126 domain from NME7 would yield a functional protein, let alone one with enhanced properties for inducing pluripotency. Applicant further argued that the present application demonstrates that native full-length NME7 expressed poorly in E. Coli and was largely insoluble, whereas NME7-AB (the construct consisting only of the NDPK A and B domains) expressed well with high yields and existed as a soluble protein. This was an unexpected and surprising result that could not have been predicted from the combined teachings of Bamdad et al and Desvinges et al. A person of ordinary skill in the art, even if motivated to truncate NME7 protein (lacking amino acid residues 1-91 or DUF1126 domain), would have had no reasonable expectation that the truncated NME7 protein would be properly folded and functional, retain the ability to bind to and dimerize MUC1*, function in a serum-free, bFGF-free culture medium, and successfully revert mammalian somatic cells to a stem-like state with increased pluripotency marker expression. Finally, Applicant argued that the claimed method requires a serum-free, bFGF-free culture medium, however, the evidence cited from Hikita et al shows the medium contains “30% Knockout Serum Replacement”.
First, since the above rejection was made under 35 U.S.C. 103(a) none of the cited references have to teach every limitation of the instant claims. For example, the primary Bamdad reference does not have to teach using a human recombinant NME7 protein in monomeric form that is devoid of amino acid residues 1-91 of SEQ ID NO: 13; or the Desvignes reference has to teach or discuss about MUC1*, ligand function and/or induction of pluripotency. It also appears that Applicant considers each of the cited references in total isolation, without taking into consideration the specific combination of Bamdad et al and Desvignes et al as set forth in the above modified 103(a) rejection.
Second, it is noted that the primary Bamdad reference already discloses the use of NME7 protein with the amino acid sequence of SEQ ID NO: 13 (containing amino acid residues 1-91 of SEQ ID NO: 13 of the present application + one binding site for a MUC1* receptor; and not a full-length NME7 protein with two binding sites for a MUC1* receptor as Applicant argued) for inducing or maintaining pluripotency in a cell (e.g., dermal fibroblasts, rat 3Y1 fibroblasts, human MUC1-negative HCT-116 cells). In addition to NME7, the primary Bamdad reference also teaches using NME-H1 and/or NME-H2 for inducing or maintaining pluripotency in a cell. Based on the protein domain characterization and comparison among NME-H1, NME-H2 and NME7 proteins as set forth in Figure 2 of the Desvignes reference, an ordinary skill in the art would reasonably deduce that since full-length human NME7 protein possesses the DUF1126 domain followed by two tandemly repeated full-length conserved NDPK domains (NDPk7A domain and NDPk7B domains), each of which is conserved with a single NDPK domain in each of the NME-1 and NME-2 proteins that lack the DUF1126 domain; the DUF1126 domain of human NME7 protein may not be involved in their function as MUC1* ligands. Accordingly, the DUF1126 domain (amino acid residues 1-91 of SEQ ID NO: 13) in human recombinant NME7 is dispensable/deleted regarding to its requirement in the function of NME7, NME-H1 and NME-H2 proteins as MUC1* ligands. The exact function of the DUF1126 domain is irrelevant in this context. Moreover, a truncated NME7 is stable (e.g., folding correctly and remaining functional as a MUC1* ligand) as evidenced at least by the teachings of the primary Bamdad reference with the NME7 of SEQ ID NO: 13 (containing amino acid residues 1-91 of SEQ ID NO: 13 of the present application + one binding site for a MUC1* receptor). Furthermore, since the primary Bamdad reference teaches at least that NME-H1, -H2 or -7 can be used in their native state, it does suggest that NME-7 protein with two conserved NDPK domains (NDPk7A domain and NDPk7B domains) can be used as MUC1* ligand.
Third, a human recombinant NME7 protein could be produced in a mammalian expression system (e.g., CHO, HEK 293, COS-7, NSO and Sp2/O cells) and not necessarily limited only to an E. Coli expression system at the effective filing date of the present application. Moreover, the instant claims are not drawn to a method of producing a human recombinant NME7 protein; nor do the claims require that the human recombinant NME7 protein must be generated from an E. Coli expression system.
Fourth, an ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Bamdad et al and Desvignes et al; coupled with a high level of skill of an ordinary skilled artisan in the relevant art. Please also refer to the Examiner’s responses in preceding paragraphs. Please also note that the standard under 35 U.S.C. 103(a) is a “reasonable” expectation of success.
Fifth, a culture medium containing “30% Knockout Serum Replacement” is considered by an ordinary skilled in the art as a serum-free culture medium.
Claim 95 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Bambad et al (US 2010/0093092; IDS) in view of Desvignes et al (BMC Evolutionary Biology 9:256; doi:10.1186/1471-2148-9-256, 25 pages; 2009) as applied to claims 1, 79-80, 82, 88, 90, 96-97 and 99-100 above, and further in view of Bamdad (US 2010/0316688; IDS).
The teachings of Bambad et al and Desvignes et al were presented above. However, none of the cited references taught explicitly that the method further comprises culturing the somatic cell on a surface comprising an anti-MUC1* antibody, even though Bambad et al already taught that a bi-valent antibody that specifically recognizes the PSMGFR sequence of MUC1* is a biological species to be used in a method for inducing or maintaining pluripotency in a cell such as dermal fibroblasts, rat 3Y1 fibroblasts, human MUC1-negative HCT-116 cells.
At the effective filing date of the present application, Bamdad already taught a method of culturing, expanding or growing stem or stem-like cells or induced pluripotent stem cells on a surface, including attaching the cells to the surface through a ligand that binds to the surface and the cells, wherein the ligand may specifically bind to a polypeptide that is expressed on the stem or stem-like cells or induced pluripotent stem cells (e.g., MUC1 or MUC1*) and the ligand may be an antibody, preferably an anti-MUC1* antibody that induces dimerization of MUC1* (Abstract; Summary of the Invention; particularly paragraphs [0007], [0016] and [0072]-[0074]). Bamdad also stated “These surfaces are particular useful for culturing non-adherent cells, stem cells and stem-like cells, including induced pluripotent stem (iPS) cells and some progenitor cells. Methods disclosed herein solve the problem of how to retain valuable cells while exchanging cell culture media” (paragraph [0059]).
Accordingly, it would have been obvious for an ordinary skilled artisan to further modify the teachings of Bamdad et al and Desvignes et al by also culturing the somatic cell (e.g., a fibroblast) on a surface coated with anti-MUC1* antibody for further inducing or maintaining pluripotency in the somatic cell undergoing induction to pluripotency with a culture medium composition comprising an NME7 in monomeric form that lacks a DUF1126 domain and has two binding sites for MUC1* receptor, in light of the teachings of Bamdad as presented above with a reasonable expectation of success.
An ordinary skilled artisan would have been motivated to carry out the above modification because Bamdad already taught a method of culturing, expanding or growing stem or stem-like cells or induced pluripotent stem cells on a surface, including attaching the cells to the surface through a ligand that binds to the surface and the cells, wherein the preferable ligand is an anti-MUC1* antibody that induces dimerization of MUC1*. Moreover, the primary Bamdad reference stated clearly “[l]igands that interact with MUC1 or MUC1* are added to somatic cells, dermal fibroblasts, fibroblasts, or somewhat differentiated cells to induce pluripotency either alone or in combination with other genes to induce or maintain pluripotency” (paragraph 46). Thus, the anti-MUC1* antibody coated surface is useful for further inducing pluripotency in somatic cells, along with culturing and retaining stem or stem-like cells while exchanging culture media.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Bamdad et al, Designes et al and Bamdad; coupled with a high level of skill of an ordinary skilled artisan in the relevant art.
The modified method resulting from the combined teachings of Bamdad et al, Desvignes et al and Bamdad as set forth above is indistinguishable and is encompassed by the presently claimed invention.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments related to the above modified 103(a) rejection in the Amendment filed on 06/10/2026 have been fully considered, but they are respectfully not found persuasive for the reasons discussed below.
Applicant argued basically the additional Bamdad reference does not cure the deficiencies of the primary Bamdad et al and Desvignes et al as discussed above.
With respect to the deficiencies of the primary Bamdad et al and Desvignes et al, please refer to the Examiner’s responses for the 103(a) rejection of claims 1, 79-80, 82, 88, 90, 96-97 and 99-100. The additional Bamdad reference was cited primarily to supplement the combined teachings of the primary Bamdad et al and Desvignes et al for the limitation recited in dependent claim 95.
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 §§ 706.02(l)(1) - 706.02(l)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Amended claims 1, 79-80, 88 and 95-100 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11,591,565. This is a modified rejection necessitated by Applicant’s amendment.
Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons.
The claims of the present application differ from claims 1-19 of U.S. Patent No. 11,591,565 in reciting specifically at least “thereby reverting the somatic cell to a reverted cell, wherein the reverted cell has: a) a stem-like morphology; and b) increased expression of one or more genes selected from the group consisting of Oct4, Klf4, and Nanog compared to expression of the one or more genes in the somatic cell prior to the contacting”; and “wherein the human recombinant NME7 protein in monomeric form is devoid of amino acid residues 1 to 91 of SEQ ID NO: 13 and has two binding sites for a MUC1* receptor, and wherein the human recombinant NME7 protein in monomeric form dimerizes the MUC1* receptor”.
However, it would have been obvious to an ordinary skilled artisan that a method for stimulating growth of stem or progenitor cells or for inducing cells (e.g., mature, somatic or progenitor cells, claim 5) to revert to a less mature state comprising contacting cells with cell culture media that comprises a recombinant NME7 protein that comprises a nucleotide diphosphate kinase (NDPK) A domain and an NDPK B domain and does not comprise a targeting sequence, including the cell culture media contain the recombinant NME7 (e.g., NME7 comprises the amino acid sequence of SEQ ID NO: 39 which is 100% identical to SEQ ID NO: 35 of the present application; claim 13 and attached sequence search below) as the only growth factor (claim 3), the cell culture media do not comprise bFGF and TGF-beta (claim 4), the cell culture media are serum-free (claim 7), the cells are human cells (claim 6), and the stem or progenitor cells are grown or the cells are induced to revert to the less mature state on a surface coated with anti-MUC1* antibody (claim 2) as encompassed in claims 1-19 of U.S. Patent No. 11,591,565 would also result in human somatic cells (e.g., mature, somatic or progenitor cells) being reverted to cells that have a stem-like morphology and increased expression of one or more genes selected from the group consisting of Oct4, Klf4, and Nanog compared to expression of the one or more genes in the somatic cells prior to the contacting to a culture medium composition comprising an NME7 protein in monomeric form that is devoid of amino acid residues 1-91 of SEQ ID NO: 13 and has two binding sites for a MUC1* receptor with a reasonable expectation of success because the methods in claims 1-19 of U.S. Patent No. 11,591,565 are indistinguishable and encompassed by the method for reverting a mammalian somatic cell of the present application.
Please note that a “mature” cell can be considered to be a terminally differentiated cell, and there is no indication and/or suggestion that recombinant NME7 protein that comprises a nucleotide diphosphate kinase (NDPK) A domain and an NDPK B domain and does not comprise a targeting sequence in U.S. Patent No. 11,591,565 is in any form other than in a monomeric form. Additionally, with respect to the functional wherein limitations “wherein the human recombinant NME7 protein in monomeric form is devoid of amino acid residues 1-91 of SEQ ID NO: 13 and has two binding sites for a MUC1* receptor, and wherein the human recombinant NME7 protein in monomeric form dimerizes the MUC1* receptor”, since the recombinant NME7 protein in U.S. Patent No. 11,591,565 that includes the NME7 protein comprising the amino acid sequence of SEQ ID NO:39 (human NME7-AB; claims 13-14 and col. 21 of issued Patent) which is identical to the NME7-AB protein of SEQ ID NO:35 of the present application, the recombinant NME7 protein in U.S. Patent No. 11,591,565 is necessarily in a monomeric form that is devoid of amino acid residues 1-91 of SEQ ID NO: 13 as well as necessarily possesses the recited properties in the functional wherein limitations.
Moreover, please also note that where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product. See In re Ludtke. Whether the rejection is based on "inherency" under 35 USC 102, or "prima facie obviousness" under 35 USC 103, jointly or alternatively, the burden of proof is the same, and its fairness is evidenced by the PTO's inability to manufacture products or to obtain and compare prior art products. In re Best, Bolton, and Shaw, 195 USPQ 430, 433 (CCPA 1977) citing In re Brown, 59 CCPA 1036, 459 F.2d 531, 173 USPQ 685 (1972).
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Amended claims 82 and 90 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11,591,565 as applied to claims 1, 79-80, 88 and 95-100 above, and further in view of Bambad et al (US 2010/0093092; IDS).
The instant claims differ from claims 1-19 of U.S. Patent No. 11,591,565 in reciting specifically “wherein the terminally differentiated human cell is a fibroblast” (claim 82), and “said method further comprises exogenously introducing into the somatic cell pluripotency factors of Oct4, Sox2, and Klf4,” (claim 90).
At the effective filing date of the present application, Bambad et al already disclosed a method for inducing or maintaining pluripotency in a cell (e.g., dermal fibroblasts, rat 3Y1 fibroblasts, human MUC1-negative HCT-116 cells) comprising contacting the cell with a biological species that increases MUC1* activity, wherein the biological species is a protein which is a MUC1* ligand, preferably the ligand is NM23 (activating ligand of MUC1*) which includes NME7 or SEQ ID NOs. 12-13 (nucleotide and amino acid sequences of NME7, respectively) either alone OR in combination with gene products that are known to induce pluripotency such as OCT4, SOX2, KLF4, NANOG, c-myc and LIN28 (see at least Summary of the Invention; paragraphs 35-40, 46-47, 50, 55 and 64). Bamdad et al stated “NM23 is a ligand that activates MUC1* (Mahanta et al., 2008) (SEQ ID NOS:12-17 and 22-23)…..NM23 can be used to replace some or all of the previously identified pluripotency-inducing factors to induce and enhance the generation of iPS cells” (paragraph 36); “[l]igands that interact with MUC1 or MUC1* are added to somatic cells, dermal fibroblasts, fibroblasts, or somewhat differentiated cells to induce pluripotency either alone or in combination with other genes to induce or maintain pluripotency” (paragraph 46); and “NME-H1, -H2 or -7 can be used in their native state or in mutant forms that favor the dimeric state, such as the S120G mutation” (last sentence of paragraph 47).
Accordingly, it would have been obvious to an ordinary skilled artisan to further modify the method for inducing cells to revert to a less mature state in claims 1-19 of U.S. Patent No. 11,591,565 by also selecting and using a human fibroblast cell to revert to a less mature state, as well as further exogenously introducing pluripotent factors such as Oct4, Sox2 and Klf4 into the fibroblast with a reasonable expectation of success; in light of the teachings of Bambad et al as presented above.
An ordinary skilled artisan would have been motivated to carry out the above modifications because Bambad et al already taught a method for inducing or maintaining pluripotency in a cell (e.g., dermal fibroblasts, rat 3Y1 fibroblasts, human MUC1-negative HCT-116 cells) comprising contacting the cell with a biological species that increases MUC1* activity, wherein the biological species is a protein which is a MUC1* ligand, preferably the ligand is NM23 (activating ligand of MUC1*) which includes NME7 or SEQ ID NOs. 12-13 (nucleotide and amino acid sequences of NME7, respectively) either alone OR in combination with gene products that are known to induce pluripotency such as OCT4, SOX2, KLF4, NANOG, c-myc and LIN28.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Amended claims 1, 79-80, 82, 88, 90, 95-97 and 99-100 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11-18 of U.S. Patent No. 11,898,160 in view of Bambad et al (US 2010/0093092; IDS), Desvignes et al (BMC Evolutionary Biology 9:256; doi:10.1186/1471-2148-9-256, 25 pages; 2009), Bamdad (US 2010/0316688; IDS) and evidenced by Hikita et al (PLoS ONE 3:e3312, doi:10.1371/journal.pone.003312, 13 pages, 2008; IDS). This is a modified rejection necessitated by Applicant’s amendment.
Claims 11-18 of U.S. Patent No. 11,898,160 are drawn to a method for inducing pluripotency in a cell comprising: (i) contacting the cell with transcription factors Oct4, Sox2, and Nanog, and (ii) contacting the cell with an exogenous nucleoside diphosphate protein kinase 7 (NME7); wherein the NME7 is a polypeptide (claim 2); wherein the cell is a fibroblast (claim 3); wherein the cell is a human cell (claim 14); wherein the said contacting occurs in vitro (claim 16); further comprising contacting the cell with one or more transcription factors selected from Klf4, c-Myc, and Lin28 (claim 17).
The instant claims differ from claims 11-18 of U.S. Patent No. 11,898,160 at least in reciting contacting a somatic cell with a culture medium composition comprising a recombinant human NME7 protein in monomeric form, wherein the recombinant human NME7 is devoid of amino acid residues 1 to 91 of SEQ ID NO: 13 and has two binding sites for a MUC1* receptor; and wherein the culture medium does not comprise bFGF and serum; and further comprising culturing the mammalian somatic cell on a surface comprising an anti-MUC1* antibody (claim 95).
At the effective filing date of the present application, Bambad et al already disclosed a method for inducing or maintaining pluripotency in a cell (e.g., dermal fibroblasts, rat 3Y1 fibroblasts, human MUC1-negative HCT-116 cells) comprising contacting the cell with a biological species that increases MUC1* activity, wherein the biological species is a protein which is a MUC1* ligand, preferably the ligand is NM23 (activating ligand of MUC1*) which includes NME7 or SEQ ID NOs. 12-13 (nucleotide and amino acid sequences of NME7, respectively) either alone OR in combination with gene products that are known to induce pluripotency such as OCT4, SOX2, KLF4, NANOG, c-myc and LIN28 (see at least Summary of the Invention; paragraphs 35-40, 46-47, 50, 55 and 64). SEQ ID NO: 13 is a human NME7 amino acid sequence comprising amino acids 1-91 that are identical to amino acids 1-91 of SEQ ID NO: 13 of the present application; and Example 4 discloses the use of recombinant human NM23. Bamdad et al also taught that the protein may also be an antibody, preferably bi-valent antibody that specifically recognizes the PSMGFR sequence of MUC1* (paragraph 10). Bamdad et al stated “NM23 is a ligand that activates MUC1* (Mahanta et al., 2008) (SEQ ID NOS:12-17 and 22-23)…..NM23 can be used to replace some or all of the previously identified pluripotency-inducing factors to induce and enhance the generation of iPS cells” (paragraph 36); “The invention involves reversing differentiation or maintaining stem-like characteristics by introducing to mature cells, or somewhat differentiated cells, genes or gene products that affect the expression of MUC1* and its associated factors….MUC1* associated factors include, but are not limited to, full-length MUC1, enzymes that cleave MUC1, MUC1* activating ligands and also transcription factors that affect the expression of MUC1 or MUC1*…Agents that affect expression of MUC1* or MUC1* associated factors can be added in combination with, or to replace one or more genes or gene products that are already known to induce pluripotency including OCT4, SOX2, KLF4, NANOG, c-myc and LIN28” (paragraph 38); “[l]igands that interact with MUC1 or MUC1* are added to somatic cells, dermal fibroblasts, fibroblasts, or somewhat differentiated cells to induce pluripotency either alone or in combination with other genes to induce or maintain pluripotency” (paragraph 46); and “NME-H1, -H2 or -7 can be used in their native state or in mutant forms that favor the dimeric state, such as the S120G mutation” (last sentence of paragraph 47) which indicates or suggests that NME7 protein can be used in native monomeric state. Bambad et al taught explicitly that NM23 or NME7 is introduced to a cell as a protein itself or as a protein bearing a leader sequence such as a poly-arginine tract to facilitate entry into the cell to aid in the induction or maintenance of pluripotency (paragraphs 47 and 50). In an exemplification, Bamdad et al demonstrated that wild-type recombinant NM23, mutant (S120G) NM23, or a bi-valent anti-MUC1* antibody (MUC1* ligands) does a better job of stimulating growth and pluripotency maintenance in pluripotent hESC colonies in “minimal stem cell medium” (media without feeder-conditioned medium) without bFGF than does conditioned medium plus bFGF OR minimal medium plus bFGF on Matrigel (paragraphs 18, 63; example 8 and Table 1). The minimal stem cell medium containing NM23 without feeder-conditioned medium and without FGF is also serum-free as evidenced by the “minimal stem cell medium” (hESC media without feeder-conditioned medium and without bFGF) of Hikita et al that consisted of DMEM/F12/GlutaMAX I with 30% Knockout Serum Replacement, 1% non-essential amino acids stock, 0.1 mM beta-mercaptoethanol (page 9, right column, first full paragraph; page 12, left column, first full paragraph). Since NM23 (e.g., NME-7) functions better in a serum-free, bFGF-free minimal stem cell culture medium for stimulating growth and pluripotency maintenance, it would have been obvious for an ordinary skill in the art that such minimal stem cell culture medium is also suitable in a method for inducing or maintaining pluripotency in a cell such as dermal fibroblasts, rat 3Y1 fibroblasts, human MUC1-negative HCT-116 cells. In example 12, Bambad et al stated “NM23 (NME-H1, NME-H2 or NME-7) enhances the induction or maintenance of pluripotency. NM23 is introduced along with previously identified pluripotency factors, including but not limited to OCT4, SOX2, KLF4, as well as others disclosed herein” (paragraph 72).
Additionally, Desvignes et al already characterized the Nme gene repertoire in vertebrates (Abstract). Figure 2 of the Desvignes reference depicts domains of human Nme proteins, including Nme1 (also known as NM23-HI; see Table 1 on page 3), Nme2/2a (also known as NM23-H2; see Table 1 on page 3) and Nme7, as shown below
PNG
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475
304
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0
Unlike human NM23-HI and NM23-H2 proteins (each has a single NDPk-1), human NME7 protein has NDPk7A and NDPk7B domains and the DUF1126 domain comprised of amino acid residues 2-91 that is not present either NM23-H1 or NM23H2 protein.
Moreover, Bamdad also taught a method of culturing, expanding or growing stem or stem-like cells or induced pluripotent stem cells on a surface, including attaching the cells to the surface through a ligand that binds to the surface and the cells, wherein the ligand may specifically bind to a polypeptide that is expressed on the stem or stem-like cells or induced pluripotent stem cells (e.g., MUC1 or MUC1*) and the ligand may be an antibody, preferably an anti-MUC1* antibody that induces dimerization of MUC1* (Abstract; Summary of the Invention; particularly paragraphs [0007], [0016] and [0072]-[0074]). Bamdad also stated “These surfaces are particular useful for culturing non-adherent cells, stem cells and stem-like cells, including induced pluripotent stem (iPS) cells and some progenitor cells. Methods disclosed herein solve the problem of how to retain valuable cells while exchanging cell culture media” (paragraph [0059]).
Accordingly, it would have been obvious to an ordinary skilled artisan to modify the method for inducing pluripotency in a cell such as a fibroblast in claims 11-18 of US 11,898,160 by also at least selecting a serum-free, bFGF-free culture media containing human recombinant NME7 protein comprised of the two tandemly repeated full-length NDPK domains (NDPk7A domain and NDPk7B domain) that shares a conserved NDPK domain in each of the NME-1 and NME-2 proteins, but lacking the DUF1126 domain as a MUC1* ligand for inducing pluripotency in a human fibroblast, and further culturing the fibroblast on a surface coated with anti-MUC1* antibody for further inducing or maintaining pluripotency in the fibroblast, in light of the teachings of Bambad et al, Desvignes et al and Bamdad as presented above.
An ordinary skilled artisan would have been motivated to carry out the above modifications because: (i) Bambad et al taught that NM23 (e.g., NME-7) functions better in a serum-free, bFGF-free minimal stem cell culture medium for stimulating growth and pluripotency maintenance, it would have been obvious for an ordinary skill in the art that such minimal stem cell culture medium is also suitable in a method for inducing or maintaining pluripotency in a cell such as dermal fibroblasts, rat 3Y1 fibroblasts, human MUC1-negative HCT-116 cells; (ii) Desvignes et al disclosed that human NME7 protein possessing the DUF1126 domain followed by two tandemly repeated full-length conserved NDPK domains (NDPk7A domain and NDPk7B domain), whereas each of the NME-1 and NME-2 proteins possesses a single conserved NDPK domain and without the DUF1126 domain; and therefore the DUF1126 domain of human NME7 protein is not involved in their function as MUC1* ligands and is dispensable/deleted. Such a modified human NME7 protein would lack the amino acid residues 1 to 91 of SEQ ID NO: 1 of the present application; and (iii) Bamdad already taught a method of culturing, expanding or growing stem or stem-like cells or induced pluripotent stem cells on a surface, including attaching the cells to the surface through a ligand that binds to the surface and the cells, wherein the preferable ligand is an anti-MUC1* antibody that induces dimerization of MUC1*. Moreover, Bamdad et al stated clearly “[l]igands that interact with MUC1 or MUC1* are added to somatic cells, dermal fibroblasts, fibroblasts, or somewhat differentiated cells to induce pluripotency either alone or in combination with other genes to induce or maintain pluripotency” (paragraph 46). Thus, the anti-MUC1* antibody coated surface is useful for further inducing pluripotency in somatic cells, along with culturing and retaining stem or stem-like cells while exchanging culture media.
An ordinary skilled artisan would have a reasonable expectation of success in light of claims 11-18 in US 11,898,160 along with the teachings of Bamdad et al, Desvignes et al and Bamdad; coupled with a high level of skill of an ordinary skilled artisan in the relevant art.
The modified method resulting from the combination of claims 11-18 in US 11,898,160 and the teachings of Bamdad et al, Desvignes et al and Bamdad as set forth above is indistinguishable and encompassed by the presently claimed invention.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
It is noted that in the Amendment filed on 06/10/2026 (last two pages), Applicant simply traversed the above nonstatutory double patenting rejections and requested that these rejections are held in abeyance until allowable subject matter is indicated in the present application.
Conclusions
No claim is allowed.
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 Quang Nguyen, Ph.D., at (571) 272-0776.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s SPE, James Douglas (Doug) Schultz, Ph.D., may be reached at (571) 272-0763.
To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Group Art Unit 1631; Central Fax No. (571) 273-8300.
Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to (571) 272-0547.
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/QUANG NGUYEN/Primary Examiner, Art Unit 1631
Sequence 39, Application US/14254749 (US 11,591,565)
Human NME7-AB
Query Match 100.0%; Score 1492; DB 80; Length 286;
Best Local Similarity 100.0%;
Matches 286; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MEKTLALIKPDAISKAGEIIEIINKAGFTITKLKMMMLSRKEALDFHVDHQSRPFFNELI 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MEKTLALIKPDAISKAGEIIEIINKAGFTITKLKMMMLSRKEALDFHVDHQSRPFFNELI 60
Qy 61 QFITTGPIIAMEILRDDAICEWKRLLGPANSGVARTDASESIRALFGTDGIRNAAHGPDS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 QFITTGPIIAMEILRDDAICEWKRLLGPANSGVARTDASESIRALFGTDGIRNAAHGPDS 120
Qy 121 FASAAREMELFFPSSGGCGPANTAKFTNCTCCIVKPHAVSEGLLGKILMAIRDAGFEISA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 FASAAREMELFFPSSGGCGPANTAKFTNCTCCIVKPHAVSEGLLGKILMAIRDAGFEISA 180
Qy 181 MQMFNMDRVNVEEFYEVYKGVVTEYHDMVTEMYSGPCVAMEIQQNNATKTFREFCGPADP 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 MQMFNMDRVNVEEFYEVYKGVVTEYHDMVTEMYSGPCVAMEIQQNNATKTFREFCGPADP 240
Qy 241 EIARHLRPGTLRAIFGKTKIQNAVHCTDLPEDGLLEVQYFFKILDN 286
||||||||||||||||||||||||||||||||||||||||||||||
Db 241 EIARHLRPGTLRAIFGKTKIQNAVHCTDLPEDGLLEVQYFFKILDN 286
Prosecution Insights