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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-13) in the reply filed on 12/12/2025 is acknowledged, however no claims are withdrawn because examiner did not require a restriction of groups and the groups are not deemed separate and distinct.
Applicants election without traverse of species (i) the lysosomal enzyme N-sulfoglucosamine sulfohydrolase (SGSH) is acknowledged.
Claims Status
No claims are withdrawn from consideration, and claims 1-27 have been considered on the merits.
Claim Objections
Regarding claims 22, 24: The claim recites “tracks”. Parent claim 1 recites “tracts”, which is considered the appropriate term for both white matter tracts and injection tracts. The term “tracks” is considered to be a typing error and replacement with the word “tracts” would overcome this objection.
Appropriate correction is required.
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 and 5-12 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Hazel et al (US 10,702,555 B2) as evidence by Merriam-Webster (Merriam-Webster [online]. Merriam-Webster corporation [retrieved on 04/01/2026]. Retrieved from the Internet: <URL: PATH STEM CELL Definition & Meaning - Merriam-Webster).
Regarding claims 1 and 5-12: The claim recites “neural stem cells”. The instant specification is silent on an explicit definition of this term. Merriam-Webster define stem cell as “an unspecialized cell that gives rise to differentiated cells”. Thus the broadest reasonable interpretation of “neural stem cell” is an unspecialized cell that gives rise to a neural cell. The claims are interpreted with the interpretation as stated.
Hazel teach treatment of neurodegenerative diseases or disorders using human neural stem cells comprising a vector containing an exogenous polynucleotide coding for insulin-like growth factor 1 (IGF-1) (abstract, claim 1). Hazel teach cells are injected into white matter (the fimbria fornix) (p29 col2 ln55-60) and the cells graft in the white-matter (Figure 9, p21 ln 40-45). This reads on depositing neural stem cells in a white matter tract. Hazel also teach the cells can engraft in the brain and/or spinal cord (p19 col2 ln20-27).
Hazel teach the human HK532 NSC lines are derived from human fetal tissue and are conditionally immortalized using c-myc fused with the human estrogen receptor (c-mycER) (p28 col 19/20 ln60-65/1-10). Hazel teach HK532 cells are cortical NSCs, and thus were derived from fetal cortical tissue (p30 col23 ln35-40).
Hazel also teach the neural stem cell is expandable for more than sixty cell doublings (claim 1).
Hazel teach migration of the cells is quantified using an in vitro assay and expression of IGF-I does not affect migration (Fig 2; p29 col21 ln 20-25). Thus the cells are migratory neural stem cells.
Hazel also teach cells are grown on flasks coated with poly-D-lysine. This reads on adherent neural stem cells of claim 8 because one of ordinary skill in the art would understand that flasks are coated with poly-D-lysine to promote cellular adherence.
Thus Hazel anticipates the invention as claimed.
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.
Claims 2-4 are rejected under 35 U.S.C. 103 as being unpatentable over Hazel et al (US 10,702,555 B2) as applied to claims 1 and 5-12 above, and further in view of Serginjenko et al (The American Society of Gene and Cell Therapy (2013) 21:10;1938-1949; cited in the IDS filed 09/08/2022).
Claims 1, 5-12 are anticipated by Hazel and thus are also rendered obvious (see above).
Regarding claims 2-4: The teachings of Hazel are described supra. Hazel teach treatment of neurodegenerative disease (ALS) by using HSCs to deliver IGF-1 to the central nervous system (p19 col1 ln19-30; ln 35-45). While Hazel teach the cells encode IGF-1, Hazel do not teach the protein encoded by the cells is the lysosomal enzyme M-sulfoglucosamine sulfohydrolase (SGSH).
Serginjenko teach mucopolysaccharidosis type IIIA (MPSIIIA) is a progressive neurodegenerative disorder cause by mutations in the lysosomal enzyme N-sulfoglucosamine sulfohydrolase (SGSH) (abstract). Serginjenko teach the mutations in SGSH result in a deficiency of SGSH (p1938 col1 ¶1). Serginjenko teach transduction of autologous MPSIIIA HSCs with an SGSH expression vector and subsequent autologous gene therapy normalized disease parameters in HPSIIIA mice (p1939 col1 ¶3).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Hazel drawn to treating a neurodegenerative disease such as ALS by depositing neural stem cells that express IGF1 in a white matter tract with the teachings of Serginjenko, to treat a neurodegenerative disease caused by a deficiency in SGSH by depositing neural stem cells that express SGSH.
One of ordinary skill in the art would have been motivated to modify the method of Hazel with the teaching of Serginjenko, to treat the neurodegenerative disease MPSIII by administering neural stem cells that express SGSH because Serginjenko teach there is no treatment for MPSIII and evidence suggests successful treatment could be mediated by sufficient enzyme produced by donor-derived cells in the brain (p1938 col2 ¶2/3).
One would have had a reasonable expectation of success because the disclosures are drawn to treating neurodegenerative disease by introducing neural stem cells to deliver a transgene product to the brain.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Hazel et al (US 10,702,555 B2) as applied to claims 1 and 5-12 above, and further in view of Hong et al (Frontiers in Bioengineering and Biotechnology (2019) 7:400;1-17), and Glaser et al (PlosOne (2007) 3;1-4).
Regarding claim 13: The teachings of Hazel are discussed supra. Hazel also teach “neural stem cell” (NSC) refers to a multipotential stem cell that has the capacity to differentiate into neurons, astrocytes, and oligodendrocytes (p23 col9 ln40-46).
Hazel do not explicitly teach the neural stem cells are programmed to differentiate into neurons, astrocytes and oligodendrocytes.
Hong teach NSCs are tripotent cells that can differentiate into 3 neural lineage cell subtypes: neurons, astrocytes and oligodendrocytes (p2 col2 ¶1). Hong further teach the main types of nerve cells that comprise the central nervous system are neurons, astrocytes and oligodendrocytes (p2 col2 ¶2). Hong further teach differentiation of patient derived stem cells into specific neuronal cell types is a main concept in cell replacement therapies designed to cure neurodegenerative diseases (p3 col2 ¶1).
Glaser teach differentiation of a neural stem cell line into oligodendrocytes, astrocytes and neurons (abstract).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Hazel drawn to depositing neural stem cells in a white matter tract by using neural stem cells programmed to differentiate into neurons, astrocytes and oligodendrocytes as taught by Glaser.
One of ordinary skill in the art would have been motivated to modify the method of Hazel with the teaching of Glaser, to differentiate the neural stem cells into neurons, astrocytes and oligodendrocytes because Hong teach the three cell types are the main types of cells that comprise the central nervous system and that differentiation of patient derived stem cells into specific neuronal cell types is the main concept in cell replacement therapies.
One would have had a reasonable expectation of success because the disclosures are drawn to treating neurodegenerative disease by introducing neural stem cells.
Claims 14-22 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Hazel et al (US 10,702,555 B2, cited previously) in view of Serginjenko et al (The American Society of Gene and Cell Therapy (2013) 21:10;1938-1949; cited in the IDS filed 09/08/2022) and as evidenced by Merriam-Webster (Merriam-Webster [online]. Merriam-Webster corporation [retrieved on 04/01/2026]. Retrieved from the Internet: <URL: PATH STEM CELL Definition & Meaning - Merriam-Webster).
Regarding claim 14-22 and 27: Claim 14 recites “neural stem cells”. The instant specification is silent on an explicit definition of this term. Merriam-Webster define stem cell as “an unspecialized cell that gives rise to differentiated cells”. Thus the broadest reasonable interpretation of “neural stem cell” is an unspecialized cell that gives rise to a neural cell. The claims are interpreted as stated supra.
Hazel teach treatment of neurodegenerative diseases or disorders such as ALS by using human neural stem cells comprising a vector containing an exogenous polynucleotide coding for insulin-like growth factor 1 (IGF-1) for the treatment (abstract, claim 1). Hazel teach the cells are injected into white matter (the fimbria fornix) (p29 col2 ln55-60) and human cells graft in the white-matter (Figure 9, p21 ln 40-45). Hazel also teach neural stem cells transplanted into the cerebellum (p25 col13 ln 5-15). This reads on depositing neural stem cells in a white matter tract by intracerebral transplantation into the brain.
Hazel do not teach the neurodegenerative disease is due to a lack of a lysosomal enzyme in the brain, or that the neural stem cell express an enzyme that is deficient in the brain.
Serginjenko teach mucopolysaccharidosis type IIIA (MPSIIIA) is a progressive neurodegenerative disorder cause by mutations in the lysosomal enzyme N-sulfoglucosamine sulfohydrolase (SGSH) (abstract). Serginjenko teach the mutations in SGSH result in a deficiency of SGSH (p1938 col1 ¶1). Serginjenko teach transduction of autologous MPSIIIA HSCs with an SGSH expression vector and subsequent autologous gene therapy (administration of cells) normalized disease parameters in HPSIIIA mice (p1939 col1 ¶3). Serginjenko teach the SGSH is human SGSH and thus the vector comprises a recombinant human SGSH coding sequence (Figure 2b).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Hazel drawn to treating a neurodegenerative disease such as ALS by depositing neural stem cells that express IGF1 in a white matter tract with the teachings of Serginjenko, to treat a neurodegenerative disease caused by a deficiency in SGSH by depositing neural stem cells that express SGSH.
One of ordinary skill in the art would have been motivated to modify the method of Hazel with the teaching of Serginjenko, use neural stem cells that express SGSH because Serginjenko teach there is no treatment for MPSIII and evidence suggests successful treatment could be mediated by sufficient enzyme produced by donor-derived cells in the brain (p1938 col2 ¶2/3).
One would have had a reasonable expectation of success because the disclosures are drawn to treating neurodegenerative disease by introducing neural stem cells.
Regarding claim 22: The teachings of Hazel are discussed supra. Hazel also teach NSCs are injected at between 5 and 50 sites (tracks) (p 27 col 18 ln 60-67).
MPEP 2131.03 reads “"[W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated' if one of them is in the prior art." Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985)”
Thus the teaching of Hazel renders obvious the invention as claimed.
Claims 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over Hazel et al (US 10,702,555 B2, cited previously) in view of Serginjenko et al (The American Society of Gene and Cell Therapy (2013) 21:10;1938-1949; cited in the IDS filed 09/08/2022) and Tamaki et al (Cell Stem Cell (2009) 5:310-319).
Regarding claim 23: The teachings of Hazel are discussed supra. While Hazel teach the stem cells are injected into the fimbria fornix (part of the cerebrum), Hazel do not teach the injections are made in two stages.
Tamaki teach transplantation of neural stem cells to deliver the lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1) to reduce impairment is a neurodegenerative mouse model (abstract). Tamaki further teach to deliver a higher dose of neural stem cells, mice were transplanted multiple times (p314 col1 ¶4). Tamaki teach the mice received transplants at multiple locations and at different stages- as neonates and as juveniles (p314 col1 ¶4). This reads on two stages as required by the instant claim 23.
It would have been obvious to one of ordinary skill in the art to adapt the methods of Hazel, drawn to treating a neurodegenerative disease by depositing neural stem cells that express a transgene, with the teaching of Tamaki, to make the injections in two stages.
One of ordinary skill in the art would have been motivated to modify the method of Hazel with the teaching of Tamaki, to make the injections in two stages, because Tamaki teach injecting at multiple locations at different stages allowed an assessment of different dosages of the stem cells because the volume of cells that could be physically introduced at one time is limited (p314 col1 ¶4).
One would have had a reasonable expectation of success because the disclosures are drawn delivering neural stem cells expressing a transgene to white matter tracts and Tamaki show successful delivery of the transgene and a dose dependent effect (Fig 5D).
Regarding claim 24: The claim recites “about 2-8 weeks”. The broadest reasonable interpretation of the term includes fewer than two weeks and greater than 8 weeks.
The teachings of Hazel are discussed supra. Hazel teach the stem cells are injected bilaterally into the fimbria fornix (a part of the cerebrum) at three sites for a total of 6 injections (first stage) (p29 col22 ln55-60). Hazel do not teach the first stage is followed by injections at two cerebellar tracts about 2-8 weeks after the injections of the first stage.
Tamaki teach injecting at multiple locations at different stages to allow delivery of higher doses of cells than could be physically introduced at one time due to injection volume limitations (p314 col1 ¶4). Tamaki teach juvenile mice received a second injection bilaterally in the brain parenchyma (part of the cerebellum) (Sup p2 ¶1). Injections bilaterally reads on injections at two cerebellar tracts. One of ordinary skill in the art would understand a juvenile mouse is typically 3-6 weeks old, therefore injection of a juvenile mouse after injection of a neonate, as taught by Tamaki, reads on about 2-8 weeks after the first stage.
It would have been obvious to one of ordinary skill in the art to adapt the methods of Hazel, drawn to treating a neurodegenerative disease by depositing neural stem cells that express a transgene at a single stage, with the teaching of Tamaki, to include a second stage comprising injections at two cerebellar tracts about 2-8 weeks after the first stage.
One of ordinary skill in the art would have been motivated to modify the method of Hazel with the teaching of Tamaki, to include a second stage comprising injections at two cerebellar tracts about 2-8 weeks after the first stage because Tamaki teach injecting at multiple locations at different stages allows injection of a higher dosage of cells (p314 col1 ¶4). Tamaki also show a that transgene activity increases in a dose dependent manner (Fig 5D).
One would have had a reasonable expectation of success because the disclosures are drawn delivering a neural stem cells expressing a transgene to white matter tracts and Tamaki show successful delivery of the transgene and a dose dependent effect (Fig 5D).
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Hazel et al (US 10,702,555 B2, cited previously) in view of Serginjenko et al (The American Society of Gene and Cell Therapy (2013) 21:10;1938-1949; cited in the IDS filed 09/08/2022) and Ravi et al (Journal of Stem Cells and Regenerative Medicine (2011) 7:1;1-13).
Regarding claim 25: The claim recites “about 20- to about 300-fold higher than physiological activity”. This is interpreted to include values below 20-fold and above 300-fold because the term “about” includes values outside of the stated range.
The teachings of Hazel and Serginjenko are discussed supra. Hazel also teach the vector is a lentiviral vector with expression of the transgene driven by the human ubiquitin C promoter (p28 col20 ln 5-15). Hazel teach the stem cells comprising the vector are characterized by determining IGF-1 expression (p28 col20 ln39-40).
Hazel do not teach the promoter is an EF1α promoter or that the stem cells are characterized by activity of expressed SGSH protein between about 20- about 300-fold higher than physiological activity of SGSH protein.
Regarding the activity of the expressed SGSH protein; as discussed supra Serginjenko teach transplantation of HSCs transduced with a lentivirus vector for expression of SGSH for treatment (reduction of symptoms) of MPSIIIA mice (p1939 col1 ¶3). Serginjenko characterize the activity of the expressed SGSH protein in multiple tissues (Fig 3). The activity of SGSH is compared to that of WT (set to 100%). MPSIIA mice without SGSH expressing NSCs had SGSH activity of ~1-5% compared to WT (Fig 3 a-d). The SGSH activity of the MPSIIIA mouse is considered physiologic because it is activity of endogenously expressed SGSH, thus 5% wild type is considered 1-fold expression of SGSH expression from the MPSIIIA mouse.
The transgenic NSCs were transduced into MPSIIIA mice. Activity of the expressed SGSH expressed from the NSCs in various tissues ranged from 8% (compared to WT; Figure 2d) to 600% (compared to WT, Figure 2a). Thus the activity of the expressed SGSH compared to the endogenously expressed SGSH of the MPSIIIA mouse ranges from 1.6 fold (8%/5%) to 120 fold (600%/5%).
MPEP 2131.03 reads “"[W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated' if one of them is in the prior art." Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985)”.
It would have been obvious to one of ordinary skill in the art to adapt the combined method of Hazel and Serginjenko, drawn to treating the neurodegenerative disease MPSIIIA by depositing neural stem cells that comprise a lentiviral vector expressing a SGSH in the white matter, by characterizing the activity of the expressed SGSH protein as further taught by Serginjenko.
One of ordinary skill in the art would have been motivated to modify the combined method of Hazel and Serginjenko, with the further teaching of Serginjenko that SGSH activity is protein between about 20- about 300-fold higher than physiological activity of SGSH protein, because Serginjenko teach previous treatment failure for MPSIIIA was likely due to insufficient enzyme produced by donor-derived cells (p1938 col1 ¶3).
One would have had a reasonable expectation of success because the disclosures are drawn to expression of transgenes in neural stem cells using a lentiviral vector and Serginjenko demonstrates successful characterization of the SGSH activity of the expressed SGSH protein.
Regarding the promoter: Ravi teach lentiviral transduction in stem cells is often associated with low levels of transgene expression (abstract). Ravi evaluate different promoters to drive expression of transgenes and teach the EF1α promoter robustly drives transgene expression while the ubiquitin promoter only induced low levels of transgene expression (abstract).
It would have been obvious to one of ordinary skill in the art to adapt the combined method of Hazel and Serginjenko, drawn to treating a neurodegenerative disease depositing neural stem cells that comprise a lentiviral vector with a ubiquitin promoter with the teachings of Ravi, to use the EF1α promoter.
One of ordinary skill in the art would have been motivated to modify the combined method of Hazel and Serginjenko with the teaching of Ravi, to use the EF1α promoter in place of the ubiquitin promoter to drive transgene expression, because Ravi teach the EF1α promoter showed high-level stable transgene expression while the Ubiquitin C promoter induced very low level of transgene expression.
One would have had a reasonable expectation of success because the disclosures are drawn to expression of transgenes in stem cells, and one of ordinary skill in the art would understand changing functional components of an expression vector, such as a promoter, uses routine molecular biology methodology and would have a high expectation of success.
Claim 26 is rejected under 35 U.S.C. 103 as being unpatentable over Hazel et al (US 10,702,555 B2, cited previously) in view of Serginjenko et al (The American Society of Gene and Cell Therapy (2013) 21:10;1938-1949; cited in the IDS filed 09/08/2022) and Kober et al (Biotechnology and Bioengineering (2012) 4;1-10).
Regarding claim 26: The claim recites SGSH secretion is increased by “about 20% to about 200%. Values above and below the 20%-200% are interpreted to read on the claimed range because the term “about” includes values greater than 200% and less than 20% and the instant specification is silent on an explicit definition of the term.
The claim recites “artificial signal sequence”. The instant specification is silent on an explicit definition of “artificial”. The term artificial in the context of a signal sequence is interpreted as “non-native” in relation to the transgene.
The combined teachings of Hazel and Serginjenko are discussed supra. Hazel and Serginjenko do not teach the human SGSH coding sequence comprises an artificial secretory sequence wherein the secretion of SGSH is increased by about 20%- about 200% compared to the native secretory signal of SGSH.
Kober teach secretion efficiency of recombinant proteins can be improved by optimizing signal peptides. Figure 5 teaches the signal peptide sequence of Azurocidn preproptein (peptide E) increases recombinant protein concentration by ~150% (Fig 5A, Table 1). Kober teach that the signal peptide can be used to generate cell lines with improved recombinant protein production rates and that the improved rates are independent of the recombinant protein (rates are product-independent) (p9 col2 ¶2).
It would have been obvious to one of ordinary skill in the art to adapt the combined method of Hazel and Serginjenko, drawn to treating a neurodegenerative disease depositing neural stem cells that comprise a lentiviral vector expressing a transgene, with the teachings of Kober, to use the artificial (non-native) secretory signal sequence of the Azurocidn preproptein (peptide E) for improved secretion of the transgene (SGSH).
One of ordinary skill in the art would have been motivated to modify the method of Hazel and Serginjenko with the teaching of Kober, to use the artificial (non-native) secretory signal sequence of the Azurocidn preproptein (peptide E) for improved secretion of the transgene (SGSH) because Kober teach the peptide improves protein (product) secretion by ~150% and one of ordinary skill in the art would understand that a cell with improved protein secretion represents a more efficient therapy. One would also have been motivated because Serginjenko teach previous treatment failure for MPSIIIA was likely due to insufficient enzyme produced by donor-derived cells (p1938 col1 ¶3).
One would have had a reasonable expectation of success because Kober teach the improved protein production is product independent, and thus one of ordinary skill in the art would have a reasonable expectation of an improvement of production when fusing the artificial signal peptide to SGSH.
Conclusion
No claims are allowed.
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/ANDREA LYNNE MORRIS SPENCER/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631