Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claim status
Claims 1, 3-7, 9-19 are pending
Claims 13-17 and 19 are withdrawn
Claims 1, 3-7, 9-12, and 18 are under examination
Election/Restrictions
Applicant’s election of the following invention in the reply filed on 5/22/2026 is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
Group I, claims 1, 3-7, 9-12, and 18, drawn to a method for making a genetically modified neural stem cell, and kit thereof.
Claims 13-17 and 19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable linking claim.
Information Disclosure Statement
No information disclosure statement (IDS) has been submitted.
Applicant is reminded that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (p. 98, [0321]). Applicant is required to amend or delete the embedded hyperlink and/or other form of browser-executable code. For example, “www” can be replaced with “world wide web” as the URL code. See MPEP § 608.01.
Claim Objections
Claim 1 is objected to because of the following informalities: instant claim uses the abbreviations “IL2Rg” and “HBB”, which have not been spelled out upon first use. Although claims are allowed abbreviations, Applicant should only use abbreviations that are well known and would be apparent to someone who had not read the invention’s description.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claim 1, 3-4, 6-7, 9-10, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Maurer et al., (US2009/0305289, filed 7/07/2009, published 12/10/2009), in view of Maurer et al. (Proteome Sci, 2003, I:4), Kay et al., (2013/0280222, filed 3/15/2013, published 10/24/2013), Townes et al., (US2019/0144888, filed 6/17/2016, with priority to 62/181,138 filed 6/17/2015 and 62/266,316 filed 12/11/2015) and Rao et al., (US2016/0264999, filed 11/14/2014, published 9/15/2016)
Maurer (2009) teaches methods of drug screening, diagnosis, and treatment of neurodegenerative and/or ischemic diseases by influencing hemoglobin formation in neuronal cells (Abstract). Maurer teaches the realization forming the basis for the described invention is that hemoglobin formation in neurons is related to a protective effect that can be used for the treatment of human disease, especially neurological diseases [0024].
In regard to the cells of claims 1 and 18, Maurer (2009) teaches that for the neuronal cellular gene therapy methods (e.g., transplantation) a gene therapy construct is transfected into stem cells, especially adult stem cells [0035]. In addition, Maurer (2009) teaches the gene therapy is to treat neurodegenerative and/or ischemic diseases in humans [0029], and identifies HBB and HBA as part of the neuronal stem cell proteome (Table 1), thereby making obvious human adult stem cells. Finally, in the inventor’s earlier work, Maurer (2003) teaches that adult neuronal stem cells are capable of dividing and renewing themselves for long periods of time and have great therapeutic potential for a variety of human neurological diseases such as neurodegeneration and/or stroke (p. 2, Background, 2nd para.). Thus, Maurer (2009) in view of Maurer (2004) reasonably suggest genetic modification of human neuronal stem cells for at least cellular gene therapy purposes of human neurological diseases, and because of their ability to divide and expression of HBB making them obvious for use in a screening method.
In regard to the transgene cassette as per claims 1 and 18, Maurer (2009) teaches that for cellular gene therapy purposes a therapeutic hemoglobin and/or globin transgene or mutein or fusion protein thereof that promotes the absorption of the hemoglobin and/or globin by a neuron [0028-0029]. For screening purposes, Maurer teaches the neuronal cell comprising a reporter gene under the functional control of regulatory elements of at least one globin gene ([0023], see also claim 1 of Maurer).
In regard to vector comprising the transgene cassette as per claim 1, for the cellular gene therapy methods Maurer (2009) teaches the vector comprises regulatory sequences aimed to make possible the targeted expression of the transgene [0032], and suggest that the vector preferably contains the regulatory gene sequences assigned to the transgenes in question [0034] (i.e., a hemoglobin and/or globin transgene). Furthermore, for the screening methods, as stated supra, Maurer (2009) discloses a neuronal cell that comprises a reporter transgene under the functional control of the regulatory elements of the beta globin gene itself ([0023], see claims 9-11 of Maurer (2009)). Thus, Maurer (2009) reasonably suggests a transgene cassette that is under the control of regulatory elements of the beta globin gene.
However, in regard to genomic locus of the transgene cassette as per claim 1 claims 1and 18, as stated supra, although Maurer (2009) states that the transgene is under the functional control of the regulatory elements of the beta globin gene, they are silent with respect to genomically integrating the transgene cassette into the human beta globin (HBB) locus.
Kay teaches methods and compositions for genomically integrating a transgene of interest into a target locus of an endogenous gene such that the transgene of interest is spatially and temporally expressed the same as the endogenous gene while maintaining expression of the endogenous gene at the target locus (Abstract). Specifically in regard to claims 1 and 18, Kay teaches the method of inserting a transgene into the human beta-globin (HBB) locus of a cell ([0006, 0020, 0022, 0092, Example 5, see Figs. 7 & 9). Kay teaches the cell is a stem cell or neural cell induced from stem cells ([0012, 0108], see claims 35-38 of Kay).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time of filing to practice the method of generating genetically modified human neural stem cells comprising a transgene cassette that is under the control of regulatory elements of the beta globin gene as suggested by Maurer et al, and choose the regulatory elements of the endogenous HBB locus as taught by Kay with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Kay because doing so would express the transgene of Maurer in a spatial and temporal pattern that is the same as the endogenous HBB gene in neuronal stem cells while maintaining expression of the endogenous HBB gene at the target locus in order to treat a disease and/or for biotechnology and research purposes [0004, 0137-0147].
However, in regard to the method of generating the genetically modified human neural stem cell as per claims 1 and 18, although Mauer suggests using genetic mutation through homologous recombination in stem cells [0035-0036], they are silent to genetically modifying a human neural stem by homologous recombination with (a) a donor template comprising the transgene cassette and (b) a CRISPR/Cas9 nuclease.
Townes (2019) teaches methods and compositions for using CRISPR-Cas for homologous recombination based targeting (HDR) of a genomic locus, wherein the method comprises:
A donor repair template comprising (i) a transgene cassette (e.g., PGKNeo or CAR or corrected portion of a gene), and (ii) two non-overlapping homologous portions of the target locus located at the 5’ and 3’ of the transgene cassette;
A CRISPR-Cas9 DNA nuclease capable of creating a double-strand break in the target locus to induce insertion of the transgene by homologous recombination (priority document ‘316, p. 7, Detailed Description to p. 9, 1st para., p. 10, 3rd para., p. 18, 4th para., p. 24, last para, see also Fig. 3A).
Importantly, Townes et al. (2019) teaches methods for successful CRISPR/Cas9 nuclease mediated integration of a donor template into the HBB locus using a sgRNA (priority document ‘316, Examples 2 & 3, pgs. 32-54).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time of filing to practice a method of generating genetically modified human neural stem cells by homologous recombination of a transgene that is under the functional control of the HBB locus as suggested by Maurer et al., and conduct the method with (a) a donor template comprising the transgene and 5’ and 3’ homology arms targeting the HBB locus, and (b) a CRISPR/Cas nuclease as taught by Townes with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Townes et al. (2019) because the CRISPR/Cas system allows efficient targeting by homologous recombination to a specific target locus with efficiency as high as 100% with two guide RNAs are used (see Fig. 3C). In regard to the reasonable expectation of success for targeting an isolated a human neural stem cell as per claim 1, Rao (2016) teaches methods for generating a genetically modified human neural stem cell comprising introducing to said cell (a) a donor template comprising (i) a transgene cassette, and (ii) two non-overlapping homologous portions of the target locus ([0009, 0013, 0020-0022, 0094, 0131]) located at the 5’ and 3’ of the transgene cassette (e.g., see Fig.1); and (b) a DNA nuclease (e.g., CRISPR) capable of creating a double-strand break in the target locus to induce insertion of the transgene by homologous recombination, thereby generating a genetically modified human neural stem cell ([0010, 0028, 0125, 0127], see also pgs. 68-70, Example 1).
Finally, in regard to claim 18, although Maurer is silent to a kit comprising these elements, Rao suggests a kit [0011, 0134] comprising polynucleotides, transfection/nucleofection agents, and selection agents.
Accordingly, Maurer et al. teach all of the components that would comprise a kit for genetic modification of neural stem cells and similar kits as taught by Rao were well known in the art at the time of filing of the. Therefore, it would have been obvious to combine said components into a kit for the purposes of convenience and economy.
In regard to claims 3-4, as stated supra, Maurer teaches the transgene encodes a therapeutic hemoglobin and/or globin transgene or mutein or fusion protein, which is a neuroprotective or neuroregenerative protein. In regard to claim 3, Maurer (2009) teaches that the hemoglobin and/or globin gene are associated with numerous genetic disorders of the central nervous system [0027].
In regard to claims 6 and 7, as stated supra, Townes teaches a single guide RNA, which is a chimera of the nucleotide sequence complementary to the target locus (e.g., HBB) and a sequence that interacts with the Cas nuclease, and would have been obvious to one of ordinary skill to use in the method so as to allow the ideal stoichiometry to be reached between the Cas and sgRNA ([0065, 0097, 0134] of ‘888 application, see priority document ‘316 p. 33, Guide RNA Preparation, p. 46, 2nd para.).
In regard to claims 9-10, as stated supra, both Townes and Rao teach the donor template comprises selective markers (e.g., PGKNeo) (see also [0026, 0647, 0657], p. 71, last para. and Fig. 16 of Rao), which would have been obvious to one of ordinary skill to use in the method so as to allow rapid selection of the genetically modified human neuronal stem cells.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Maurer et al., (US2009/0305289, filed 7/07/2009, published 12/10/2009), in view of Maurer et al. (Proteome Sci, 2003, I:4), Kay et al., (2013/0280222, filed 3/15/2013, published 10/24/2013), Townes et al., (US2019/0144888, filed 6/17/2016, with priority to 62/181,138 filed 6/17/2015 and 62/266,316 filed 12/11/2015) and Rao et al., (US2016/0264999, filed 11/14/2014, published 9/15/2016), as applied to claim 1, in further view of Wu et al., (Cell Stem Cell, 2013, 13:659-662).
As discussed previously, Maurer et al. suggest a method for generating a genetically modified human neural stem cell comprising a transgene targeted by CRISPR/Cas9 to the HBB locus.
However, Maurer (2009) et al. are silent the CRISPR/Cas9 is encoded by a mRNA.
With respect to claim 5, Wu teaches a method of genetically modifying stem cells by HDR comprising a donor template, a CRISPR-Cas9 mRNA, and sgRNA (Summary, p. 660, Fig. 1).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time of filing to practice the method of generating genetically modified human neural stem cells as taught by Maurer and choose a mRNA that encodes the Cas9 nuclease as taught by Wu with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Wu because the mRNA exhibited a low toxicity (p. 661, 2nd para.). Furthemore, it would have been understood that mRNA can produce sustained levels of Cas9 compared to the protein loading method of Townes, yet eliminates the risk of random integration by the DNA method of Rao. Finally, Wu explicitly suggests that the Cas9 mRNA based method for gene-correction be used in human stem cells (p. 662, last para.).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Maurer et al., (US2009/0305289, filed 7/07/2009, published 12/10/2009), in view of Maurer et al. (Proteome Sci, 2003, I:4), Kay et al., (2013/0280222, filed 3/15/2013, published 10/24/2013), Townes et al., (US2019/0144888, filed 6/17/2016, with priority to 62/181,138 filed 6/17/2015 and 62/266,316 filed 12/11/2015) and Rao et al., (US2016/0264999, filed 11/14/2014, published 9/15/2016), as applied to claims 1 and 9, in further view of DeMaria et al., (Biotech Prog, 2007, 23:465-472).
As discussed previously, Maurer et al. suggest a method for generating a genetically modified human neural stem cell comprising a transgene targeted by CRISPR/Cas9 to the HBB locus.
However, although both Townes and Rao et al. teach the use of genetically encoded selectable markers, they are silent with respect to a CD20 selectable marker.
With respect to claims 11 and 12, DeMaria teaches the use of the CD20 based cell surface marker for transfected cells (p. 465, col 2, p. 467, Materials & Methods).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time of filing to practice the method of generating genetically modified human neural stem cells as suggested by Maurer et al. and include a CD20 cell surface maker as taught by DeMaria with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by DeMaria because of the advantages of CD20 based immunosorting such as rapid and early stage identification of transfected cells producing high levels of a therapeutic protein (Abstract, p. 471, Discussion).
Hence, 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 obviousness-type 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); and 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 a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims 1, 6-7, and 18 are rejected on the grounds of nonstatutory double patenting over claim 1-4, 7, 11-12, 16-29, and 31, 34, 38-44 of U.S. Patent No. 12,584,149 (Dever et al., Patented 3/24/2026).
The subject matter claimed in the instant application is fully disclosed in the referenced patent as follows: the method for generating a genetically modified neural stem cell comprising a donor template, CRISPR-Cas9, and sgRNA that targets the HBB locus (i.e., SEQ ID NO:1), and kit thereof anticipates and/or makes obvious the method and kit of instant application. It is clear that all the elements of the cited patent claims are to be found in instant claims. The difference between the cited patent claims and the instant claims lies in the fact that the cited patent claims are much more specific with respect to the site in the HBB locus (i.e., SEQ ID NO:1). Thus the invention of said claims of the cited patent are in effect “species” of the “generic” invention of the instant claim. It has been held that the generic invention is “anticipated” by the “species”. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993).
Since the instant application claims are anticipated by and/or obvious over cited patent claims, said claims are not patentably distinct.
Claims 3-4 are rejected on the grounds of nonstatutory double patenting over claim 1-4, 7, 11-12, 16-29, and 31, 34, 38-44 of U.S. Patent No. 12,584,149 (Dever et al., Patented 3/24/2026), in view of Maurer et al. (Proteome Sci, 2003, I:4).
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the method for generating a genetically modified neural stem cell comprising a donor template, CRISPR-Cas9, and sgRNA that targets the HBB locus (i.e., SEQ ID NO:1), makes obvious the method of instant application. It is clear that elements of the cited patent claims are to be found in instant claims. The difference between the cited patent claims and the instant claims lies in the fact that the instant claims limit the transgene cassette to a sequence associated with a genetic disorder of the CNS and is neuroprotective. Nevertheless, claiming a transgene for neural stem cells that encodes a sequence associated with a genetic disorder of the CNS and is neuroprotective would have been obvious considering the therapeutic potential of neuronal stem cells for a variety of genetic disorders of the CNS such as neurodegenerative disorders, Alzheimer’s and Parkinson’s disease as taught by Maurer (2003) (p. 2, Background, 2nd para.).
Since the instant application claims are obvious over cited patent claims in view of Maurer, said claims are not patentably distinct.
Claims 9-12 are rejected on the grounds of nonstatutory double patenting over claim 1-4, 7, 11-12, 16-29, and 31, 34, 38-44 of U.S. Patent No. 12,584,149 (Dever et al., Patented 3/24/2026) in view of DeMaria et al., (Biotech Prog, 2007, 23:465-472).
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the method for generating a genetically modified neural stem cell comprising a donor template, CRISPR-Cas9, and sgRNA that targets the HBB locus (i.e., SEQ ID NO:1), makes obvious the method of instant application. It is clear that elements of the cited patent claims are to be found in instant claims. The difference between the cited patent claims and the instant claims lies in the fact that the instant claims combine the transgene cassette with a CD20 marker. Nevertheless, claiming a CD20 cell surface maker would have been obvious considering DeMaria teaches the advantages of CD20 based immunosorting such as rapid and early stage identification of transfected cells producing high levels of a therapeutic protein (Abstract, p. 471, Discussion).
Since the instant application claims are obvious over cited patent claims in view of DeMaria, said claims are not patentably distinct.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ARTHUR S LEONARD whose telephone number is (571)270-3073. The examiner can normally be reached on Mon-Fri 9am-5pm.
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/ARTHUR S LEONARD/Examiner, Art Unit 1631
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