DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/21/2025 has been entered.
Amended claims 1 and 79-97 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Claims 81, 83-87, 89 and 91-94 were withdrawn previously from further consideration because they were directed to non-elected species.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 95-97 are examined on the merits herein with the above elected species.
Response to Amendment
The rejection under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, for Lack of Written Description was withdrawn in light of currently amended independent claim 1, particularly with the limitation “wherein the NME7 protein in the monomeric form is devoid of amino acid residues 1 to 91 of SEQ ID NO: 13”.
Claim Rejections - 35 USC § 112 (New Matter)
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.
Amended claims 1, 79-80, 82, 88, 90 and 95-97 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. This is a new ground of rejection.
Amended independent claim 1 recites the new limitation “an NME7 protein in monomeric form or a nucleic acid encoding the NME7 protein in the monomeric form, wherein the NME7 protein in the 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”. The claims encompass a method for reverting a somatic cell, the method comprising: contacting the somatic cell with a culture medium composition, wherein the culture medium composition: (i) comprises an NME7 protein in a monomeric form obtained from any source (e.g., human NME7 protein, murine NME7 protein, or zebrafish NME7) or a nucleic acid encoding the NME7 protein in the monomeric form, wherein the NME7 protein in the 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 NME7 protein in the monomeric form dimerizes the MUC1* receptor; (ii) does not comprise serum, and (iii) does not comprise basic fibroblast growth factor, 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. The as-filed specification does not have a written support for the above new limitation.
As an initial matter, currently amended claims 1, 79-80, 82, 88, 90 and 95-97 have been introduced in the Amendment filed on 11/21/2025, so the claims themselves are not part of the original disclosure. 37 CFR § 1.115(a)(2). “New or amended claims which introduce elements or limitations that are not supported by the as-filed disclosure violate the written description requirement. . . . While there is no in haec verba requirement, newly added claims or claim limitations must be supported in the specification through express, implicit, or inherent disclosure. . . . The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed.” MPEP § 2163, part (I)(B); see also MPEP § 2163.02. In this case, the original specification does not convey the particular invention recited in claims 1, 79-80, 82, 88, 90 and 95-97 with reasonable clarity to skilled artisans. “The trouble is that there is no such disclosure, easy though it is to imagine it.” MPEP § 2163.05, part (II) (quoting In re Ruschig, 379 F.2d 990, 995, 154 USPQ 118, 123 (CCPA 1967)).
In the Amendment filed on 11/21/2025 (at page 6, first paragraph), Applicant simply stated “Support for the claim amendment can be found throughout the application as filed. No new matter is added by any of these amendments”. However, upon careful examination of the as-filed specification apart from the disclosed NME7-AB of SEQ ID NO: 35 (encoded by the nucleotide sequence of SEQ ID NO: 34) that is devoid of the “M leader sequence” (page 34, last sentence continues to first two lines on page 35) and the generic statement “[t]he NME family member is NME7 which may optionally consist of subunits A and B, devoid of the “M” leader sequence: NME7-AB (SEQ ID NOs: 34-35) (page 33, lines 21-22), there is no definition or description of the M leader sequence and/or the M leader sequence is constituted of which particular amino acid sequence in a NME7 protein that is in monomeric form and has two binding sites for a MUC1* receptor. There is no indication or suggestion whatsoever that the amino acid residues 1-91 of SEQ ID NO: 13 which is the 283-amino acid NME7 sequence containing only a single binding site for a MUC1* receptor constitutes the M leader sequence (last 4 lines at page 17 continues to first two lines at page 18; and Applicant-initiated Interview Summary dated 01/17/2025 with Mr. Eric A. Grobe and SPE James D. Schultz). In the Amendment filed on 11/21/2025 (at pages 6-7), Applicant cited the Desvignes publication (BMC Evol Biol 9:256, 2009; Exhibit A) and argued that Desvignes et al disclosed that NME7 contains a leader peptide sequence followed by two nucleoside diphosphate kinase (NDPK) domains, A and B, as shown in Fig. 2 for human (left diagram) and zebrafish NME7 (right diagram) proteins below; and assumed that the M-leader sequence is residues 1-91 of SEQ ID NO: 13 of the present application that is presumably supported by Fig. 2 of the Desvignes reference.
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However, it is noted that Desvignes et al did not describe any leader peptide sequence; rather amino acid residues 2-91 constitute the DUF1126 domain of human NME7 protein while amino acid residues 1-89 constitute the DUF1126 domain of zebrafish NME 7 protein. Desvignes et al al also stated clearly “The zebrafish Nme7, as human NME7, contains a DUF1126 domain, belonging to the DM10 family, and an NDPk-7A and an NDPk-7B domain (Fig. 2). Very little is known about the function of DUF1126 domain and its DM10 family” (left paragraph at page 19). Accordingly, the as-filed specification does not have a written support for the amino acid residues 1-91 of SEQ ID NO: 13 (the 283-amino acid NME7 sequence containing only a single binding site for a MUC1* receptor) of the present application as the M leader sequence to be devoid of or deleted from NME7 protein derived from any source (human NME7 protein, zebrafish NME7 protein, or any other vertebral NME7 protein) as long as the resulting NME7 is in a monomeric form and has two binding sites for a MUC1* receptor as encompassed by currently amended claims. Certainly, there is no written support whatsoever for the concept to devoid of/deletion of amino acid residues 1-91 of SEQ ID NO: 13 from zebrafish NME7 protein, let alone for other vertebral NME7 proteins as encompassed broadly by the instant claims.
The fact that the person of ordinary skill in the art could have carried out the claimed invention without undue experimentation based on applicants’ disclosure is inadequate to meet this requirement. “The Federal Circuit has pointed out that, under United States law, a description that merely renders a claimed invention obvious may not sufficiently describe the invention for the purposes of the written description requirement of 35 U.S.C. 112.” MPEP § 2163, part (I)(A).
Therefore, given the lack of sufficient guidance provided by the originally filed specification, it would appear that Applicants did not contemplate or have possession of invention as now broadly claimed at the time the application was filed.
Claim Rejections - 35 USC § 112 (Scope of Enablement)
Amended claims 1, 79-80, 82, 88, 90 and 95-97 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
A method for reverting a mammalian somatic cell, the method comprising: contacting the mammalian somatic cell with a culture medium composition, wherein the culture medium composition: (i) comprises a mammalian NME7 protein in a monomeric form or a nucleic acid encoding the mammalian NME7 protein in the monomeric form, wherein the NME7 protein in the monomeric lacks a DUF1126 domain and has two binding sites for a MUC1* receptor, and wherein the NME7 protein in the monomeric form dimerizes the MUC1* receptor; (ii) does not comprise serum, and (iii) does not comprise basic fibroblast growth factor, 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;
does not reasonably provide enablement for a method of reverting any other somatic cell as claimed broadly. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims. This is new ground of rejection.
The factors to be considered in the determination of an enabling disclosure have been summarized as the quantity of experimentation necessary, the amount of direction or guidance presented, the state of the prior art, the relative skill of those in the art, the predictability or unpredictability of the art and the breadth of the claims. Ex parte Forman, (230 USPQ 546 (Bd Pat. Appl & Unt, 1986); In re Wands, 858 F.2d 731, 8 USPQ 2d 1400 (Fed. Cir. 1988)).
The instant specification is not enabled for the instant broadly claimed invention for the reasons discussed below.
1. The breadth of the claims
The instant claims encompass a method for reverting any somatic cell derived from any source (e.g., a human, rodent, flies, fish, frog, chicken, or a plant), the method comprising: contacting the somatic cell with a culture medium composition, wherein the culture medium composition: (i) comprises a NME7 protein in a monomeric form obtained from any source (e.g., a human, rodent, zebrafish, or other vertebral animals) or a nucleic acid encoding the NME7 protein in the monomeric form, wherein the NME7 protein in the 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 NME7 protein in the monomeric form dimerizes the MUC1* receptor; (ii) does not comprise serum, and (iii) does not comprise basic fibroblast growth factor, 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. The instant specification defines the term “stem-like” morphology to refer to a morphology that resembles that of a stem cell, a level of one or more of the pluripotency genes, or an ability to differentiate into multiple cell types” (paragraph [00104]).
2. The state and the unpredictability of the prior art
Before the effective filing date of the present application (08/14/2012), little was known about a method for reverting a somatic cell obtained from any source using a culture medium composition containing any NME7 protein in monomeric form or a nucleic acid encoding the NME7 protein, wherein the NME7 protein 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 NME7 protein in the monomeric form dimerizes the MUC1* receptor as claimed broadly by the present application as evidenced at least by the teachings 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) and Boissan et al (Mol. Cell Biochem. 329:51-62, 2009). The physiological art is recognized as unpredictable (MPEP 2164.03).
3. The amount of direction or guidance provided
Apart from disclosing that NM23-MM alone causes human fibroblasts to form ES-like colonies; NME7 in contact with human iPS cells or human ES cells cultured over a surface coated with anti-MuC1* antibody caused an increase in the expression of MUC1*, which coincided with an increase in the percentage of cells that stained positive for pluripotency markers; along with NME7-AB of SEQ ID NO: 35 (encoded by the nucleotide sequence of SEQ ID NO: 34) that is devoid of the “M leader sequence” (see at least page 34, last sentence continues to first two lines on page 35; examples 10 and 15); the instant specification failed to provide sufficient guidance for an ordinary skilled artisan on how to revert any non-mammalian somatic cell (including a plant somatic cell) as encompassed broadly by the instant claims. Particularly, the specification teaches specifically that the portions of MUC1 that are membrane proximal are highly conserved among mammals, and because of the great sequence conservation, ligands that recognize human MUC1* receptor (e.g., NM23 such as H1 or H6 dimers, or NME7), also recognize murine MUC1* receptor (paragraphs [00130]-[00134]). There is no evidence of record indicating any mammalian NME7 in the monomeric form that is devoid of amino acid residues 1 to 91 of SEQ ID NO: 13 and has two binding sites for a MUC1* receptor is capable of reverting any non-mammalian somatic cell, including a plant somatic cell, to a reverted cell having the recited characteristics (a stem-like morphology and increased expression of one or more genes selected from the group consisting of Oct4, Klf4 and Nanog). There is also no evidence of record indicating or suggesting that a non-mammalian NME7 protein is capable of recognizing the portions of MUC1 that are membrane proximal and are highly conserved among mammals.
Since the prior art before the effective filing date of the present application failed to provide sufficient guidance regarding to the aforementioned issues, it is incumbent upon the present application to do so. Given the state of the prior art, coupled with the lack of sufficient guidance provided by the present application, it would have required undue experimentation for a skilled artisan to make and use the instant invention as claimed broadly.
As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112, first paragraph requires:
That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; in cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws; in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.
Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maizel.).
Accordingly, due to the lack of sufficient guidance provided by the specification regarding to the issues set forth above, the state and unpredictability of the relevant art, and the breadth of the instant claims, it would have required undue experimentation for one skilled in the art to make and use the instant broadly claimed invention.
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 and 96-97 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 new ground of rejection.
The instant claims encompass a method for reverting a somatic cell, the method comprising: contacting the somatic cell with a culture medium composition, the culture medium composition: (i) comprising an NME7 protein in monomeric form or a nucleic acid encoding the NME7 protein in the monomeric form, wherein the 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 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 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). 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 somatic cell using a culture medium composition comprising an 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 human 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 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 noting 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 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.
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 and 96-97 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.
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 95-97 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.
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 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 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 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 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 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 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 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 95-97 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, 88 and 96-97 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, 8, 14 and 18 of U.S. Patent No. 11,976,295.
Although the conflicting claims are not identical, they are not patentably distinct from each other because a cell culture media for growth, maintenance, and induction of reversion to a less mature state of a cell comprising 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 (e.g., SEQ ID NO: 39 which is the human NME7-AB that does not contain amino acid residues 1-91 of the present application; claim 18); wherein the cell is a mature, somatic, or progenitor cell (claim 3); wherein the cell is human (claim 4); wherein the cell culture media does not comprise basic fibroblast growth factor (bFGF), transforming growth factor beta (TGF-beta), or both (claim 5); wherein the cell culture media is free of serum (claim 6); wherein the recombinant NME7 is characterized by a molecular weight of about 25-33 kilodaltons (kDa) (claim 8); wherein the recombinant NME7 is the only growth factor in the cell culture media (claim 14) would render a method for reverting a somatic cell of the present application to be obvious, and such method would also result in a reverted somatic cell to have a stem-like morphology and increased expression of one or mor 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. Please also note that a mature cell can be considered to be a terminally differentiated cell.
Amended claims 82 and 90 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, 8, 14 and 18 of U.S. Patent No. 11,976,295 as applied to claims 1, 79-80, 88 and 96-97 above, and further in view of Bambad et al (US 2010/0093092; IDS).
The instant claims differ from claims 1, 3-6, 8, 14 and 18 of U.S. Patent No. 11,976,295 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 use the cell culture media in claims 1, 3-6, 8, 14 and 18 of U.S. Patent No. 11,976,295 for reverting a human fibroblast cell to a less mature state, as well as including exogenous pluripotent factors such as Oct4, Sox2 and Klf4 in the cell culture media for introducing these pluripotent factors 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, 88 and 96-97 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, 8, 14 and 18 of copending Application No. 19,322,00.
Although the conflicting claims are not identical, they are not patentably distinct from each other because a cell culture media for growth, maintenance, and induction of reversion to a less mature state of a cell comprising 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 (e.g., SEQ ID NO: 39 which is the human NME7-AB that does not contain amino acid residues 1-91 of the present application; claim 18); wherein the cell is a mature, somatic, or progenitor cell (claim 3); wherein the cell is human (claim 4); wherein the cell culture media does not comprise basic fibroblast growth factor (bFGF), transforming growth factor beta (TGF-beta), or both (claim 5); wherein the cell culture media is free of serum (claim 6); wherein the recombinant NME7 is characterized by a molecular weight of about 25-33 kilodaltons (kDa) (claim 8); wherein the recombinant NME7 is the only growth factor in the cell culture media (claim 14) would render a method for reverting a somatic cell of the present application to be obvious, and such method would also result in a reverted somatic cell to have a stem-like morphology and increased expression of one or mor 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. Please also note that a mature cell can be considered to be a terminally differentiated cell.
This is a provisional nonstatutory double patenting rejection.
Amended claims 82 and 90 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, 8, 14 and 18 of copending Application No. 19,322,00 as applied to claims 1, 79-80, 88 and 96-97 above, and further in view of Bambad et al (US 2010/0093092; IDS).
The instant claims differ from claims 1, 3-6, 8, 14 and 18 of copending Application No. 19,322,000 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