DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
The amendment to the claims filed 3/4/2025 is acknowledged. New claims 176-186 are consideration in this office action.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 176-186 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.
When determining if a newly added recitation or amendment to the claims has adequate written description, the specification and claims, as originally filed, are examined to determine if sufficient explicit or implicit description is present.
A search of the originally filed claims and specification fails to provide a literal recitation for the amended and newly added claims. As such, the specification and claims fail to provide explicit written description for the amended and new claims.
Independent claim 176 newly recites in step (b) “determining DNA methylation of the promoter of Oct4 and/or promoter of Nanog in the somatic cell contact in steps (a) and (c) identifying the candidate reprogramming agent as a substitute for Klf4 in reprogramming somatic cells to a pluripotent state in combination with additional reprogramming agents if the DNA methylation level of the promoter of Oct4 and/or the promoter of Nanog in the somatic cells contacted in step (a) is about the same as a control level of DNA methylation, wherein the control level of DNA methylation is the level of DNA methylation in embryonic stem (ES) cells or induced pluripotent stem (iPS) cells.”
The closest disclosures in the originally filed application are found in the original claims:
176. A method of identifying an agent that reprograms somatic cells to a less differentiated state, the method comprising: (a) contacting somatic cells with a candidate reprogramming agent; (b) measuring DNA methylation of a region in the somatic cells; (c) identifying the candidate reprogramming agent as being likely to reprogram somatic cells to a less differentiated state by itself or in combination with additional agents if the DNA methylation of the region in the somatic cells is less than a reference level of DNA methylation.
177. The method of claim 176, wherein the DNA methylation in the somatic cells is measured by measuring the DNA methylation of the gene promoter of Oct 4.
178. The method of claim 176, wherein the DNA methylation in the somatic cells is measured by measuring the DNA methylation of the gene promoter of Nanog gene.
179. The method of claim 176, wherein the DNA methylation in the somatic cells is measured by measuring the DNA methylation of the gene promoter of Oct 4 and the gene promoter of Nanog gene.
180. The method of claim 176, wherein the reference level of DNA methylation is the DNA methylation level of the region in the somatic cells prior to contacting with the candidate reprogramming agent.
181. The method of claim 176, wherein the reference level of DNA methylation is a pre-determined level of DNA methylation.
While the originally filed claims are a method of screening a candidate agent for its ability to reprogram a somatic cells, it does not imply that the method is a method of identifying a substitute for Klf4 in a reprogramming method that reprograms to a pluripotent state as claimed. In original claim 176, it generically states that the candidate reprogramming agent is identify as being likely to reprogram somatic cells by itself or in combination with additional agents. However, this recitation does imply that other factors could be introduced to or contacted with the somatic cell in step (a). However, it does not imply that the other factors are specifically Sox2 and Oct4. Original dependent claims 177-179 specify measuring DNA methylation of the Oct4 promoter or Nanog promoter. However, the claims use a different point of reference as an indicator of the reprogramming agent. Base claim 176 recite “if the DNA methylation of the region in the somatic cells is less than a reference level of DNA methylation”. However, amended claim 176 recites, “wherein the control level of DNA methylation is the level of DNA methylation in embryonic stem (ES) cells or induced pluripotent (PS) cells”. As such, the originally filed claims use a completely different point of reference to identify a reprogramming factor than the amended claims. Therefore, the originally filed claims do not provide implicit support for the amended or new claims because the originally filed claims do not imply that the candidate reprogramming agent is a substitute for Klf4, that the somatic cells of step (a) are additionally and specifically contacted with Oct4 and Sox2, and that the point of references for identifying the substitute for Klf4 is the level of DNA methylation in embryonic stem (ES) cells or induced pluripotent (PS) cells. As such, the originally filed claims do not provide implicit support for the amended or newly added claims.
In conclusion, the amended and new claims constitute new matter because the specification as originally filed fails to provide explicit or implicit support for them.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 176-186 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 176 recites, “the DNA methylation level of the promoter of Oct4 and/or the promoter of Nanog in the somatic cell contacted in step (a) is about the same as a control level of DNA methylation”. The metes and bounds of “a control level of DNA methylation” are apparent because the claim does not specify what it the control is being measured for DNA methylation”. Is the control level of DNA methylation referring to total genome DNA methylation, regional DNA methylation, DNA methylation of the Oct4 promoter, DNA methylation of the Nanog promoter, etc.…?
Claims 177-186 depend upon claim 176. As such, these dependent claims are also indefinite for the reason discussed above.
Claim 177 recites, “the gene” in the somatic cell. However, base claim 176 does not expressly or implicitly refer back to any particular gene or genes. As such, it is not apparent to which gene “the gene” refers.
Claim 181 recites, “the control level of DNA methylation is a pre-determined level of DNA methylation”. However, base claim 176 already states, “the control level of DNA methylation is the level of DNA methylation in embryonic stem (ES) cells or induced pluripotent stem (iPS) cells”. As such, it is not apparent how the “pre-determined level” relates or is combined with the levels in ES cells or iPS cells.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 184 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 184 recites testing the “effect” of the candidate reprogramming agent and the additional reprogramming agents on reprogramming somatic cells. This is not further limiting because the somatic cells are contacted with a candidate agent and it is determined how contact leads to substituting Klf4 in reprogramming. As such, the method already inherent is testing such an effect as claimed in base claim 176 and therefore claim 184 is not further limiting. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Priority
Since the newly filed claims 176-184 are new matter, they have an effective filing date: 3/4/2025.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a) the invention was known or used by others in this country, or patented or described in a printed publication in this or a foreign country, before the invention thereof by the applicant for a patent.
Claim(s) 176-181 and 184-186 is/are rejected under pre-AIA 35 U.S.C. 102(a)(1) as being anticipated by Feng (Feng et al. Nature Cell Biology 11(2):197-203 and Supplementary Information pp. 1-5, 2009).
Regarding claim 1, Feng discloses we started by identifying factor(s) that could
replace Klf4 in the presence of Oct4, Sox2 and c‑Myc (p. 197, col 2). These disclosure expressly disclose A method of identifying an agent that substitutes Klf4 in reprogramming somatic cells to a pluripotent state as claimed. Feng discloses contacting mouse embryonic fibroblast (MEF; i.e. a somatic cell) comprising exogenous reprogramming factors Oct-4 and Sox-2 (i.e. in combination with additional reprogramming agents Oct-4 and Sox-2) with we observed that the orphan nuclear receptor, Esrrb (i.e. a candidate reprogramming agent that substitutes klf-4). See Figure 1 and p. 197 col 2). We assessed the status of DNA methylation at
Nanog and Pou5f1 promoters by bisulphite sequencing in ES cells, MEFs
and our OSCE‑ and OSE‑reprogrammed cell‑lines. The results show
that DNA methylation, which was present in the Nanog and Pou5f1
promoter regions in MEFs, were largely absent in the OSCE‑ and OSE
reprogrammed cell‑lines (Fig. 3a), consistent with reactivation of Nanog
and Pou5f1 in the reprogrammed cells. See. 198, col 2). These disclosure expressly disclose the determining steps (b) and (c). ES-cell-specific genes such as Nanog and Pou5f1 are highly expressed in ES cells and their promoter regions are hypomethylated. In MEFs, these genes are silenced and their promoters become hypermethylated. Previous work has shown that reprogramming leads to the erasure of DNA methylation (p. 198, col 2). These disclosure disclose the limitations of the ES cell or iPS cell controls. As such, Feng expressly discloses all of the limitations of claim 176.
Regarding claim 177, Feng expressly discloses determining methylation by bisulphite sequence analysis as discussed above.
Regarding claims 178 and 179, Feng discloses methylation analysis of the Nanog gene promoter (claim 178) and the oct4 gene promoter (claim 179) as discussed above.
Regarding claim 180, Feng discloses methylation analysis of both ES cell and iPSC as controls as discussed above.
Regarding claim 181, Feng does not expressly state control levels of DNA methylation is a pre-determined Level of DNA methylation. However, by choosing both ES cells and established iPSC as the control standard, it has been pre-determined that the levels of DNA-methylation are the control or point of comparison levels. As such, Feng discloses the limitations of claim 181 as well.
Regarding claim 182, Feng discloses that Oct-4, Sox-2 and the candidate agent effectively reprogram the MEF as discussed above.
Regarding claim 183, Feng discloses iPS cells as controls as discussed above.
Regarding claim186, Feng includes iPS cells induce with klf-4 present as controls (see figure).
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.
Claims 182-183 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Feng (Feng et al. Nature Cell Biology 11(2):197-203 and Supplementary Information pp. 1-5, 2009) as applied to claim 176-181 and 184-186 above, and further in view of Hannah (Hannah et al Cell 133:250-264, 2008).
Feng teaches the screening method as discussed above. Feng does not teach that the somatic cell is an immune cell (claim 182) or a B-cell (claim 183).
However, at the time of effectively filing, Hannah teaches successfully reprogramming mouse B cells with the Yamanaka factors (see abstract). Further Hannah teaches development of cells along the B cell lineage allows us to ad dress these questions because sequential intrinsic genetic DNA rearrangements in the heavy and light chain immunoglobulin loci genetically mark the different consecutive stages of B cell maturation. To define the susceptibility of differentiated cells to nuclear reprogramming we used cells from this highly ordered developmental pathway that carry distinct, sequentially acquired genetic ‘‘fingerprints’’ that would allow accurate retrospective assessment of the developmental stage of the donor B cell nucleus that was able to generate the respective monoclonal iPS line. Paragraph bridging p. 250 and 252).
Thus, at the time of effectively filing, it would have been obvious to an artisan of ordinary skill to use mouse B-cell, as taught by Hannah, as the somatic cell with the screening method of Feng to predictably arrive at the limitations of the claims. An artisan would have a reasonable expectation of success because means of added any or all of the reprogramming agent to the B-cell and determining methylation status of the Oct-4 and Nanog promoters was successful as exemplified by Feng. Further an artisan would be motivated to use particularly a B-cell because B-cells have this highly ordered developmental pathway that carry distinct, sequentially acquired genetic ‘‘fingerprints’’ that would allow accurate retrospective assessment of the developmental stage of the donor B cell nucleus that was able to generate the respective monoclonal iPS line, as taught by Hannah. As such, Feng in view of Hannah render the claims obvious.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARCIA STEPHENS NOBLE whose telephone number is (571)272-5545. The examiner can normally be reached M-F 9-5:30.
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MARCIA S. NOBLE
Primary Examiner
Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632
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