DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The instant application is a national stage entry under 35 USC 371 of PCT/JP2021/013834, filed
31 March 2021. Acknowledgement is made of Applicant’s claim for foreign priority under 35 USC 119(a)-(d) to Japanese applications JP2020-219455, filed 28 December 2020, JP2020-165847, filed 30 September 2020, and JP2020-063477, filed 31 March 2020. Receipt is acknowledged of certified copies of papers, in a non-English language, required by 37 CFR 1.55.
Election/Restrictions
Applicant’s election of Group I encompassing claims 1-20 in the reply filed on 18 August 2025 is acknowledged. Because Applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse. See MPEP § 818.01(a).
Consequently, claims 21-38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 18 August 2025. Prosecution on the merits commences for claims 1-20.
Drawings
The replacement drawings sheets filed 24 March 2023 are acknowledged and entered into the application file.
However, the drawings filed 24 March 2023 are objected to for covering the sequences recited in Figures 16F, 21, and 25A with the sequence identifier label.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). More specifically, Figures 21B and 21C are missing sequence identifiers for the lox proteins, while Figure 27A is missing sequence identifiers for the listed primers. Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The amendments to the Specification filed 24 March 2023 are acknowledged and entered into the application file.
However, the instant Specification is objected to for referencing colors within the figures, when colored drawings have not submitted in the application. More specifically, the Specification references colors at least within Page 62 in reference to Figure 6A. Applicant is requested to review the Specification to identify any additional references to colors within the drawings and delete as appropriate since black and white drawings are submitted. The Specification must be amended to delete reference to specific colors within the text of the Specification.
Appropriate correction is required.
Claim Objections
Claim 12 is objected to because of the following informalities:
Regarding claim 12: The instant claim is objected to for failing to recite “wherein” in Line 4 prior to the recitation of “the mutant loxP sequence having a mutation sequence in the upstream repetitive sequence is located upstream of the selection marker gene”.
Appropriate correction is required.
Claim Interpretation
Instant claim 1 is directed to a cell preparation for treating central nervous system diseases/damages, wherein the cell preparation comprises neural stem cells that have been differentiated from pluripotent stem cells in which a suicide gene has been introduced. This is a product-by-process limitation. Product-by-process limitations are considered only in so far as the method of production affects the structure of the final product. In the instant case, there is no evidence that the differentiation of the neural stem cells from induced pluripotent stem cells imparts any particular structure or significance to the neural stem cells other than requiring the neural stem cells to comprise the introduced suicide gene. Thus, the claim will be interpreted as if a suicide gene-comprising neural stem cell derived from any source fulfills the recited claim limitation. See MPEP § 2113.
Instant claims 2-6 each recite an intended use limitation. Intended use limitations are considered only in so far as they physically limit the claimed cell preparation. Therefore, so long as the cell preparation is physically capable of being configured for use in the instantly recited treatments, it will read on each of the claims as written.
Instant claims 10-14 are directed to a cell preparation for treating central nervous system diseases/damages, wherein the neural stem cells that do not comprise a selection marker gene in the genome thereof are obtained by the methods recited in instant claims 10-12 and 14, or instant claim 13. These are product-by-process limitations. Product-by-process limitations are considered only in so far as the method of production affects the structure of the final product. In the instant case, there is no evidence that the insertion and subsequent removal of the selection marker gene within the induced pluripotent stem cells and differentiation into neural stem cells imparts any particular structure or significance to the neural stem cells other than the neural stem cells having to comprise the introduced suicide gene and not comprise a selection marker gene. Thus, the claims will be interpreted as if a neural stem cell comprising a suicide gene but lacking expression of a selection marker gene derived from any production method or source fulfills the recited claim limitations. See MPEP § 2113.
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 7-8, 13, and 16-20 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.
Regarding claims 7-8: The term “immediately” in instant claims 7-8 is a relative term which renders each claim indefinite. The term “immediately” is not defined by the claim, the Specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. See MPEP § 2173.05(b). More specifically, the ordinary artisan would not be readily apprised of the metes and bounds of what is considered a sequence linked “immediately” to another sequence, and if there can be any additional sequences between them.
Appropriate correction is required.
Regarding claim 13: The instant claim recites the limitation "the gene construct" in Line 4. There is insufficient antecedent basis for this limitation in the claim, as there is no prior recitation of a gene construct within the instant claim or parent claims 1 and 9.
Appropriate correction is required.
Regarding claim 16: The instant claim recites the limitation “which is used in combination with a prodrug that is converted to 5-fluorouracil by cytosine deaminase” in Lines 2-3. The scope of the claim is indefinite, as it is unclear if Applicant is requiring the conversion of the prodrug to 5-fluorouracil, or is simply describing the prodrug as one that is capable of being converted to 5-fluorouracil by cytosine deaminase. If the former interpretation is required, the claim is further rendered indefinite, as the recitation of method steps within a composition claim – or product and process limitations within the same claim – is impermissible. See MPEP § 2173.05(p). Therefore, the metes and bounds of the claim cannot be determined, thus rendering the claim indefinite.
Appropriate correction is required.
For purposes of compact prosecution, the Examiner will interpret the limitation as requiring a prodrug that is described as being capable of being converted to 5-fluorouracil by cytosine deaminase.
Regarding claims 17-18: The instant claims each recite the limitation “wherein the neural stem cells are neural stem cells in which the expression level of… been increased”. The term “increased” is a relative term which renders the claim indefinite. The term “increased” is not defined by the claim, the Specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. See MPEP § 2173.05(b). More specifically, the ordinary artisan would not be readily apprised of the metes and bounds of what is considered an “increased” expression level of the proteins within the neural stem cells, and with which the “increased” expression level is compared to.
Appropriate correction is required.
For the sake of compact prosecution, the instant claims will be interpreted as if the positive expression of the proteins within the neural stem cells is sufficient to read on the limitations.
Regarding claim 19: The instant claim recites the limitation, “wherein the neural stem cells are selected by using the expression level of at least one selected from ephrin A, ephrin A receptor, ephrin B receptor, ephrin B, and CXC motif chemokine receptor 4 as an indicator” (emphasis added). The scope of the claim is rendered indefinite, as it is unclear if the claim is requiring the active process of selecting the indicators. If so, the recitation of method steps within a composition claim – or product and process limitations within the same claim – is impermissible. See MPEP § 2173.05(p). Therefore, the metes and bounds of the claim cannot be determined, thus rendering the claim indefinite.
Appropriate correction is required.
For the sake of compact prosecution, the Examiner will interpret the limitation as not requiring the active selection of the indicators.
Regarding claim 20: The instant claim recites the limitation, “wherein the neural stem cells are selected by using ephrin A, ephrin A receptor, ephrin B receptor, ephrin B, and CXC motif chemokine receptor 4 as indicators” (emphasis added). The scope of the claim is rendered indefinite, as it is unclear if the claim is requiring the active process of selecting the indicators. If so, the recitation of method steps within a composition claim – or product and process limitations within the same claim – is impermissible. See MPEP § 2173.05(p). Therefore, the metes and bounds of the claim cannot be determined, thus rendering the claim indefinite.
Appropriate correction is required.
For the sake of compact prosecution, the Examiner will interpret the limitation as not requiring the active selection of the indicators.
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.
Claims 8 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.
Regarding claim 8: The instant claim recites the limitation “wherein a sequence coding for 2A peptide is linked immediately 3' to the translation region of β-actin gene in the pluripotent stem cell, and the suicide gene is linked 3' to the sequence coding for 2A peptide.” However, parent claim 7 recites the limitation “wherein the suicide gene is inserted immediately 3' to a translation region of β-actin gene in the pluripotent stem cell.” Therefore, instant claim 8 does not further limit parent claim 7, as it broadens the arrangement of the translation region of β-actin gene in relation to the suicide gene from being immediately linked 3’ to each other (claim 7) to having a sequence coding for 2A peptide between them (claim 8).
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.
For purposes of compact prosecution, the Examiner will interpret the limitation of instant claim 7 as requiring the suicide gene to be 3’ from the translation region of the β-actin gene.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-6 and 9-14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lee et al (J Neurooncol, 2013, of record).
Lee et al disclose neural stem cells that comprise the suicide genes of cytosine deaminase and tyrosine kinase for the treatment of a glioblastoma, a type of brain tumor (Abstract; Page 50, Engineering of...; Page 52, In vivo therapeutic effect...; Page 54, Discussion).
Lee et al further disclose that the suicide genes are inserted into the neural stem cells using Lipofectamine, wherein the vectors do not comprise a selection marker gene (Page 50, Engineering of…; Figure 1A).
Accordingly, Lee et al anticipate the claims as follows:
Regarding claim 1: The instant claim comprises a product-by-process limitation, as can be observed in the Claim Interpretation section above and is incorporated in its entirety herein.
Accordingly, Lee et al disclose neural stem cells that comprise the suicide genes of cytosine deaminase and tyrosine kinase for the treatment of a glioblastoma. As a glioblastoma is a type of central nervous system disease or damage, this therefore reads on the cell preparation of the instant claim.
Regarding claims 2-6: As aforementioned in the discussion of claim 1, Lee et al disclose neural stem cells that comprise the suicide genes of cytosine deaminase and tyrosine kinase for the treatment of a glioblastoma. As the neural stem cells are physically capable of being utilized for the treatment of brain dysfunctions (claim 2), traumatic brain damages (claim 3), spinal cord damages (claim 4), neurodegenerative diseases (claim 5), and brain tumors (claim 6), this therefore anticipates the cell preparation of the instant claims for the same reasons as discussed in the rejection of instant claim 1. See Claim Interpretation section for the discussion of the intended use limitations.
Regarding claim 9: Following the discussion of claim 1, Lee et al further disclose that the neural stem cells do not comprise a selection marker gene within their genome. This therefore reads on the cell preparation of the instant claim.
Regarding claims 10-14: The instant claims comprise product-by-process limitations, as can be observed in the Claim Interpretation section above and are incorporated in their entirety herein.
Accordingly, Lee et al disclose neural stem cells that comprise the suicide genes of cytosine deaminase and tyrosine kinase, and do not comprise a selection marker gene. This therefore reads on the cell preparation of instant claims 10-14.
Claims 1-6 and 9-16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Toda et al (WO 2019/098361 A1, translation provided by Espacenet). Toda et al has a publication date of 23 May 2019, which is greater than one year prior to the effective filing date of the instant invention.
Toda et al disclose a cell preparation for treating brain tumors and a method for producing
neural stem cells for use in the cell preparation (Paragraphs [0001], [0032], [0094]-[0098]).
As such, Toda et al disclose neural stem cells derived from pluripotent stem cells that have the inserted suicide genes of cytosine deaminase (CD) and uracil phosphoribosyltransferase (UPRT) (Paragraphs [0005], [0007], [0011]-[0012], [0017], [0019]-[0020], [0028]-[0029], [0036]-[0037]).
Toda et al further disclose that the CD-UPRT suicide gene is introduced to the pluripotent stem cells using a genome editing system, wherein the genome editing does not introduce a selection marker gene into the genome of the pluripotent stem cells (Paragraphs [0039]-[0042], [0050], [0058], [0064]-[0065], [0093]; Figure 18).
Toda et al further disclose that the cell preparation is used together with a prodrug that is converted to 5-fluorouracil by cytosine deaminase (Paragraphs [0009]-[0010], [0029], [0057], [0076]).
Accordingly, Toda et al anticipate the claims as follows:
Regarding claims 1 and 15: instant claim 1 comprises a product-by-process limitation, as can be observed in the Claim Interpretation section above and is incorporated in its entirety herein.
Accordingly, Toda et al disclose neural stem cells derived from pluripotent stem cells that comprise the suicide genes of cytosine deaminase and uracil phosphoribosyltransferase (claim 15) for the treatment of a brain tumor. As a brain tumor is a type of central nervous system disease or damage, this therefore reads on the cell preparation of the instant claim.
Regarding claims 2-6: As aforementioned in the discussion of claim 1, Toda et al disclose neural
stem cells that comprise the suicide genes of cytosine deaminase and uracil phosphoribosyltransferase for the treatment of a brain tumor. As the neural stem cells are physically capable of being utilized for the treatment of brain dysfunctions (claim 2), traumatic brain damages (claim 3), spinal cord damages (claim 4), neurodegenerative diseases (claim 5), and brain tumors (claim 6), this therefore anticipates the cell preparation of the instant claims for the same reasons as discussed in the rejection of instant claim 1. See Claim Interpretation section for the discussion of the intended use limitations.
Regarding claim 9: Following the discussion of claim 1, Toda et al further disclose that the neural stem cells do not comprise a selection marker gene within their genome. This therefore reads on the cell preparation of the instant claim.
Regarding claims 10-14: The instant claims comprise product-by-process limitations, as can be observed in the Claim Interpretation section above and are incorporated in their entirety herein.
Accordingly, Toda et al disclose neural stem cells that comprise the suicide genes of cytosine deaminase and uracil phosphoribosyltransferase, and do not comprise a selection marker gene. This therefore reads on the cell preparation of instant claims 10-14.
Regarding claim 16: Following the discussion of claim 15, Toda et al further disclose that the cell preparation is used together with a prodrug that is converted to 5-fluorouracil by cytosine deaminase. This therefore reads on the cell preparation of the instant claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-16 are rejected under 35 U.S.C. 103 as being unpatentable over Toda et al (WO 2019/098361 A1, translation provided by Espacenet) in view of Martin et al (Nat Commun, 2020).
The discussion of Toda et al regarding claim 1 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Toda et al anticipate claims 1-6 and 9-16. Martin et al is considered prior art under 35 USC 102(a)(1).
Regarding claims 7-8: Following the discussion of claim 1, Toda et al further disclose that the CD-UPRT suicide gene is inserted into a housekeeping gene within the pluripotent stem cell, wherein the housekeeping gene is β-actin (Paragraphs [0007], [0013]-[0014], [0021]-[0022], [0040]).
Toda et al further disclose that the CD-UPRT suicide gene is linked 3’ to a sequence coding for a 2A peptide (Figure 18).
Toda et al do not disclose that the suicide gene is inserted immediately 3’ to a translation region of a β-actin gene within the pluripotent stem cell, as required by instant claim 7.
Martin et al, however, disclose the insertion of a thymidine kinase (TK) suicide gene into a β-actin gene, wherein the β-actin translation region (as evidenced by the black box in Figure 4B) and suicide gene are separated by a T2A self-cleaving peptide, such that the regions are situated 5’ to 3’ as follows: β-actin translation region, T2A peptide, and TK suicide gene (Page 5, Eliminating hPSC-derived cell populations in vivo by ACTBTK; Page 10; Figure 4B).
Therefore, it would have been prima facie obvious to modify the pluripotent stem cell of Toda et al such that the CD-UPRT suicide gene and 2A peptide sequence are inserted 3’ of the β-actin translation region, as detailed in Martin et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to insert the sequences into the β-actin gene and specifically next to a β-actin translation region, as β-actin is a constitutively active gene that is endogenously expressed in human pluripotent stem cells, thus making it an effective gene to house an inducible safety switch (Martin et al: Pages 2, 9, 11). Furthermore, the ordinary artisan would have had a reasonable expectation of success due to the fact the disclosure of Toda et al reasonably suggests the insertion of the CD-UPRT suicide gene into the β-actin gene, thus there would be minimal adaptability required between the two disclosures. See MPEP § 2143(I)(G).
Consequently, Toda et al as modified by Martin et al render obvious a cell preparation comprising neural stem cells derived from pluripotent stem cells into which a CD-UPRT suicide gene has been introduced into a β-actin gene, wherein the CD-UPRT is located 3’ to a sequence encoding a 2A peptide, which is located immediately 3’ to the β-actin translation region (claim 8). This therefore renders obvious the cell preparation of instant claim 7 given the claim interpretation presented in the 35 USC 112(d) section above.
Claims 1-6 and 9-20 are rejected under 35 U.S.C. 103 as being unpatentable over Toda et al (WO 2019/098361 A1, translation provided by Espacenet) in view of Vescovi et al (US 2012/0083454 A1) and Zhang et al (Neuroscience, 2016).
The discussion of Toda et al regarding claim 1 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Toda et al anticipate claims 1-6 and 9-16. Vescovi et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2). Zhang et al is considered prior art under 35 USC 102(a)(1).
Regarding claims 17-20: As aforementioned in the discussion of claim 1, Toda et al disclose neural stem cells derived from pluripotent stem cells that comprise the CD-UPRT suicide gene for the treatment of a brain tumor.
Toda et al do not disclose the expression profile of the neural stem cells, as required by instant claims 17-20.
Vescovi et al, however, disclose that human neural stem cells (HNSCs) have a positive expression of ephrin A receptors, ephrin A ligands, ephrin B receptors, and ephrin B ligands (Paragraphs [0017], [0114]-[0138]; Figure 1A).
In addition, Zhang et al disclose that neural stem cells derived from human pluripotent stem cells have an upregulated expression of CXCR4 when compared to the human pluripotent stem cell expression (Pages 89, 92-94).
Therefore, it would have been prima facie obvious for the neural stem cells of Toda et al to express an ephrin A receptor, ephrin A ligand, ephrin B receptor, ephrin B ligand, and CXCR4 – or CXC motif chemokine receptor 4, as detailed in Vescovi et al and Zhang et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to select and utilize neural stem cells that have an expression profile synonymous with the wild-type expression of neural stem cells, thereby verifying that they are indeed utilizing cells that have been properly differentiated into neural stem cells, and would have had a reasonable expectation of success since the techniques to measure expression of a protein are well-known in the art (see, for example, Paragraph [0119] of Vescovi et al). See MPEP § 2143(I)(G).
Consequently, Toda et al as modified by Vescovi et al and Zhang et al render obvious a cell preparation, wherein the neural stem cells express are selected for using the expression of an ephrin A receptor, ephrin A ligand, ephrin B receptor, ephrin B ligand, and CXCR4. This therefore renders obvious the cell preparation of instant claims 17-20 given the claim interpretation presented in the 35 USC 112(b) section above.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,090,172 B2 in view of Toda et al (WO 2019/098361 A1, translation provided by Espacenet) in view of Martin et al (Nat Commun, 2020), Vescovi et al (US 2012/0083454 A1), and Zhang et al (Neuroscience, 2016).
Although the claims at issue are not identical, they are not patentably distinct from each other because the patent claim either anticipates or renders obvious the instant claims. More specifically, the patent claim is not identical because no single patent claim discloses all of the limitations of a portion of the instant claims; however, each of the limitations of the instant claims are disclosed the patent claim, or rendered obvious by the accompanying prior art.
Patent claim 1 is directed to a cell preparation for treating brain tumors used in combination with a prodrug that is converted to 5-fluorouracil by cytosine deaminase, wherein the cell preparation comprises neural stem cells derived from pluripotent stem cells having a cytosine deaminase gene and an uracil phosphoribosyltransferase gene. Therefore, patent claim 1 reads on instant claims 1-6 and 15-16 given the aforementioned claim interpretations.
With that, instant claims 7-14 and 17-20 are known from the prior art and can be further incorporated into the cell preparation anticipated by patent claim 1:
Martin et al teach the limitations recited in instant claim 7-8.
Toda et al teach the limitations recited in instant claims 9-14.
Vescovi et al and Zhang et al teach the limitations recited in instant claim 17-20.
Conclusion
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/ALYSSA G WESTON/Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633