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
This application is a national stage entry under 35 USC 371 of PCT/CN2022/075823 (filed on 02/10/2022), which claims priority to CHINA 2022110185323.2 (filed on 02/10/2021). There is no certified translation of the foreign priority application on record.
Claim Status
Claims 40-49 are pending, all of which have been considered on the merits.
Claim Interpretation
For clarity of record the following comments are made regarding claim interpretation under broadest reasonable interpretation:
Claim 40 is drawn to a method of producing functional dopamine neurons from glial cells, comprising using a REST inhibitor. Though the claim does not specify how the REST inhibitor is used, the most reasonable interpretation is that the REST inhibitor is applied to/contacted with the glial cells.
Claim 43 is drawn to a method of producing functional retinal ganglion cells or photoreceptor cells from Müller glia, comprising using a REST inhibitor. Though the claim does not specify how the REST inhibitor is used, the most reasonable interpretation is that the REST inhibitor is applied to /contacted with the Müller glia.
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 41,42,44, and 45 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 claim 41, claim 40 is drawn to a method of producing functional dopamine neurons from glial cell from glial cells, comprising using a REST inhibitor. Claim 41 states the REST inhibitor can be used to prevent and/or treat a disease associated with loss of function or death of functional dopamine neurons. It is unclear if/how claim 41 further limits parent claim 40. It appears claim 41 simply states an intended use of a REST inhibitor, while not integrating the intended use into the method claim.
Regarding claim 42, following the discussion of claim 41, it is unclear if/how claim 42 further limits parent claims 41 and 40. It appears claim 42 simply states diseases associated with loss of function or death of functional dopamine neurons, while not integrating the intended use into the method claim.
Regarding claim 44, claim 43 is drawn to a method of producing functional retinal ganglion cells or photoreceptor cells from Müller glia, comprising using a REST inhibitor. Claim 44 states the REST inhibitor could prevent or treat a visual system disease associated with loss of function or death of RGCs or photoreceptor cells. It is unclear if/how claim 44 further limits parent claim 43. It appears claim 44 simply states an intended use of a REST inhibitor, while not integrating the intended use into the method claim.
Regarding claim 45, following the discussion of claim 44, it is unclear if/how claim 45 further limits parent claims 44 and 43. It appears claim 45 simply states visual system diseases associated with loss of function or death of RGCs, while not integrating the intended use into the method claim.
Regarding claim 44, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 45 depends from claim 44, and thus inherits the deficiency and is rejected on the same basis.
Appropriate correction or clarification 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.
(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.
Applicant cannot rely upon the certified copy of the foreign priority application to overcome this rejection because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
Claims 40-46 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhou et al (Cell, 2020).
Zhou et al teaches that with this method one can convert glial cells in the striatum to dopaminergic neurons and Müller glia (MG) to retinal ganglion cells (RGCs) (See, Abstract).
Regarding claims 40-42: Zhou et al teaches a method that converts glial cells into functional neurons through the downregulation of polypyrimidine tract-binding protein-1 (Ptbp1) using RNA targeting CRISPR system (See, Abstract). Zhou et al also teaches that the REST complex activity is suppressed by miR-124, which is strongly inhibited by the binding protein PTBP1 in non-neuronal cells, thus downregulating PTBP1 releases miR-124, which inhibits REST (See, p 599 col 2 ¶3). For the striatum glia conversion, AAV-GFAP-CasRx-Ptbp1 induced knockdown of Ptbp1 was completed in WT mice and there was an increase in mature neuron markers after 1 month (See, p595 c2 and 598 c1). Zhou et al confirmed there was a mixed population of glutamatergic neurons and dopaminergic neurons via immunostaining (See, p598 c1). Zhou et al performed the method of Ptbp1 knockdown in a Parkinson’s disease (PD) model and showed that the method induces neurons showing features of dopaminergic neurons (See, p598 – p599). The AAV-GFAP-CasRx-Ptbp1 reads on an “inhibitor of REST” as the knockdown of Ptab1 results in “reduced activity of a REST gene”. As such, the method reads on, “method for producing dopamine neurons from glial cells…by using a REST inhibitor, wherein the REST inhibitor reduces the expression or activity of a REST gene….wherein the glial cells are astrocytes from striatum,” of claim 40. This also reads on the, “wherein the REST inhibitor could be used to prevent/treat disease associated with loss of function or death of functional dopamine neurons..” of claim 41. Finally, this reads on, “ wherein the disease associated with lose of function or death of functional dopamine neurons is…. Parkinson’s disease,” of claim 42.
Regarding claims 43-45: Following the discussion above, Zhou et al teaches that for Müller glia (MG) conversion, AAV-GFAP-CasRx-Ptbp1 induced knockdown of Ptbp1 was completed in 5 week mice retinas that concluded with the loss of glial characteristics in cells and an increase in a variety of markers for RGCs, that indicated MGs were able to convert into different subtypes of RGCs(See, p592 c1). Zhou et al explored the MG to RGC conversion in a retinal injury mouse model (See, p593 to p594). The results show that in an injured retina, MG via Ptbp1 knockdown can convert into functional RGCs (See, Figure 4 p593). The injury was NMDA induced injury in the retina, which causes near complete loss of RGCs (See, p593 c1). Again, the AAV-GFAP-CasRx-Ptbp1 reads on “an inhibitor of REST” as the knockdown of Ptab1 results in “reduced activity of a REST gene”. As such, the method reads on, “method for producing functional RGCs or photoreceptor cells by using REST inhibitor,…transdifferentiating MG…, wherein the REST inhibitor reduces the expression or activity of REST gene…, wherein the photoreceptors comprise of rod and cone cells,” of claim 43. This also reads on, “ wherein the REST inhibitor could prevent or treat a visual system disease associated with loss of function or death of RGCs…,” of claim 44. This lastly reads on, “ wherein the visual system disease associated with loss of function or death of RGCs is selected from the group consisting of visual impairment due to death of RGCs…,” of claim 45.
Regarding claim 46: Following the above discussion, the use of AAV-GFAP-CasRx-Ptbp1 induced knockdown of Ptbp1 to complete the method of producing functional dopamine neurons, reads on “ wherein the REST inhibitor is selected from:… gene editors,” of claim 46.
Therefore, claims 40-46 are rejected as being anticipated by Zhou et al.
Claims 40-46 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fu et al (US 2015/0299698 A1), and evidenced by Zhou et al (Cell, 2020).
The teachings of Zhou et al are set forth above.
Fu et al discloses an in vitro method for trans-differentiation of or re-programming mammalian cells to functional neurons. They also disclose a method for direct reprogramming of cells to a second phenotype or differentiated phenotype (See, Abstract).
Regarding claims 40-42: Fu et al discloses an in vitro method trans-differentiating, re-differentiating, or re-programming a mammalian cell to a neuronal cell, where method includes reducing or lowering the level of expression of or activity of or inactivating an RE1-Silencing Transcription factor (REST) by contacting a mammalian cell with a compound that comprise a protein, a peptide, an antibody, a nucleic acid, an antisense miRNA, or a small molecule (See, ¶0006-0017).
Fu et al further discloses that the mammalian cell before trans-differentiation or re-programming can be an adult stem cell, a glial cell, an astrocyte, neural cell, or a Müller cell, among others (See, ¶0023). The embodiment wherein the mammalian cell to be trans-differentiated is a glial cell, specifically an astrocyte, is relied upon for this rejection. While Fu et al does not specify the kind of functional neuron is generated by the method disclosed, Zhou et al, follows a method that inhibits REST activity through the gene editing of Ptbp1 in a glial cell that in turn transdifferentiates into a mixed population with dopaminergic neurons (See, p598 c1). Therefore, Fu et al teaches the same process of producing dopaminergic neurons as in the current application, and thus the functional neuron formed by Fu et al are one and the same as the dopaminergic neuron formed in the current application, evidence by Zhou et al.
This reads on, “wherein, the glial cells are astrocytes from striatum,” of claim 40. Although where the glial cells are derived from is not specified in Fu et al, the method does not change based on the origin of the glial cells. This reads on, “a method for producing functional dopamine neurons from glial cells, comprising transdifferentiating or reprogramming the glial cells into functional dopamine neurons by using a REST inhibitor, wherein the REST inhibitor reduces the expression or activity of a REST gene, an RNA thereof, or an encoding protein thereof..,” of claim 40, as evidenced by Zhou et al.
The limitations of claims 41-42 include those from claim 40, it is included in the rejections stated above and is also read on by Fu et al disclosing that the invention provides method for treating or ameliorating a neurodegenerative disease or injury or neurodegenerative condition; such as Parkinson’s disease and stroke (See, ¶0030-0045).
Regarding claims 43: Fu et al discloses an in vitro method trans-differentiating, re-differentiating, or re-programming a mammalian cell to a neuronal cell, where method includes reducing or lowering the level of expression of or activity of or inactivating an RE1-Silencing Transcription factor (REST) by contacting a mammalian cell with a compound that comprise a protein, a peptide, an antibody, a nucleic acid, an antisense miRNA, or a small molecule(See, ¶0006-0017). Fu et al further discloses that the mammalian cell before trans-differentiation or re-programming can be an adult stem cell, a glial cell, an astrocyte, neural cell, or a Müller cell, among others (See, ¶0023). The embodiment wherein the mammalian cell to be trans-differentiated is a Müller cell is relied upon for this rejection.
This reads on, “…wherein the Müller glia are from retina, and wherein the photoreceptor cells comprise rod cells and cone cells,” of claim 43. Although where the Müller cells are derived from is not specified in Fu et al, the method does not change based on the origin of the Müller cells. While Fu et al does not specify the kind of functional neurons generated by the method disclosed, Zhou et al, follows a method that inhibits REST activity through the gene editing of Ptbp1 in a Müller glia that in turn transdifferentiates into a mixed population of functional RGCs (See, Figure 4 p593). Therefore, Fu et al teaches the same process of producing functional RGCs or photoreceptors as in the current application, and thus the functional neuron formed by Fu et al are one and the same as the functional RGCs or photoreceptors formed in the current application, evidence by Zhou et al.
This reads on, “a method for producing functional retinal ganglion cells (RGCs) or photoreceptor cells from Muller glia (MG), comprising transdifferentiating or reprogramming Muller glia into functional RGCs or photoreceptor cells by using a REST inhibitor, wherein the REST inhibitor reduces the expression or activity of a REST gene, an RNA thereof, or an encoding protein thereof…,” of claim 43.
Regarding claims 44-45: Following the discussion above, the limitations of claims 44-45 are included in the rejections stated above and is read on by the teachings of Fu et al.
Regarding claims 46: Following the discussion above, Fu et al discloses, the use of a compound that comprise a protein, a peptide, an antibody, a nucleic acid, an antisense miRNA, or a small molecule(See, ¶0006-0017) for the method. This reads on, “wherein the REST inhibitor is selected from:… antibodies, small molecule compounds, microRNA, siRNA, shRNA, , REST binding proteins and protein domains, polypeptides, aptamers, gene editors…,” of claim 46.
Therefore, claims 40-46 are anticipated by Fu et al and evidenced by Zhou et al.
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 47,48, and 49 are rejected under 35 U.S.C. 103 as being unpatentable over Fu et al, evidenced by Zhou et al, as applied to claims 40-46 above, and further in view of Young et al (WO 2017/075406 A1).
The teachings of Fu et al and Zhou et al are set forth above.
Regarding claim 47: Following the discussion above, Fu et al discloses, the use of a compound that comprise a protein, a peptide, an antibody, a nucleic acid, an antisense miRNA, or a small molecule(See, ¶0006-0017) for inhibiting REST. Fu et al further discloses, that nucleic acids can be used to practice this invention, whether RNA, iRNA, gDNA, vectors, viruses or hybrids thereof (See, ¶0084).
Fu et al does not teach the use of CRISPR or wherein the gRNA is a DNA or an RNA guiding the gene editing protein to specifically bind to REST gene.
Young et al teaches a method of modulating binding between RNA transcription from at least one regulatory element of a target gene and a transcription factor which binds to both the RNA and at least one regulatory element (See, p1 L31 – p2 L5). Young et al teaches that in some embodiments, the transcription factor is selected from a group consisting of REST and other factors (See, p2 L29-31). Young et al further teaches that the modulating can be done with RNA interfering agents such as, gRNA, siRNA, shRNA, mRNA, and CRISPR RNA (See, p4 L7-12). In some embodiments, the composition comprises a genomic editing system such as, CRISPR/Cas, ZFNs, and TALENs (See, p4 L16-19). Young et al teaches that in some embodiments, the composition comprises a CRISPR/Cas system , which relies upon the nuclease activity of the Cas9 protein coupled with synthetic guide RNA (gRNA) to make specific modifications in a genome (See, p91 L21-24).
Given that Fu et al and Young et al both teach modes of inhibit REST, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the siRNA or other RNA editor in Fu et al in the method of trans-differentiation of glial cells into functional neurons with CRISPR/Cas9 and gRNAs, taught by Young et al for a similar purpose. Both Fu et al and Young et al teach methods of interfering REST activity.
The use of CRISPR/Cas9 with gRNAs that bind to REST in place of the siRNA and other nucleic acids in Fu et al, is a predictable use of prior art elements according to their established functions, leading to the predictable result interfering with REST activity in cells.
This rationale aligns with the principle of KSR for a simple substitution of one known element for another to obtain predictable results, see MPEP 2143.
Regarding claim 48-49: Following the discussion above, Fu et al does not teach wherein the gRNA guides the gene-editing protein to specifically bind to nucleotides at positions 867-1103.
Young et al teaches that in some embodiments, the composition comprises a CRISPR/Cas system, which relies upon the nuclease activity of the Cas9 protein coupled with synthetic guide RNA (gRNA) to make specific modifications in a genome (See, p91 L21-24). Young et al teaches that in light of the disclosed embodiments and the general level of skill in the art, that numerous changes, modifications and alterations can be employed without departing from the scope of the disclosed subject matter (See, p107 L23-27). Young et al differs from the claims in that the limitation gRNA guides the gene-editing protein to specifically bind to nucleotides at positions 867-1103 of REST coding sequence or sequence selected from SEQ ID Nos: 4-20 and 83-118 or comprises a sequence encoded by sequences set forth in SEQ ID Nos: 55-62 and 71-76, of claims 48 and 49 respectively.
However, each of these differences are considered prima facie obvious, as the limitation about the specific gRNA to inhibit REST in the method of the instant claims are rendered obvious by Fu et al in view of Young et al. Young et al teaches that those with general skill in the art can make modifications without departing from the scope. One of ordinary skill in the art can select a sequence for the guide RNAs to best bind to REST coding sequence and inhibit REST activity. Because Young et al provides motivation to modify portions of the method, it would have been obvious to create or select a gRNA to fulfill these limitations without undo experimentation. As such, selecting the gRNA for this method would have been a matter of routine optimization. See MPEP 2144.05.
Therefore, claims 47-49 are rejected as being rendered obvious by Fu et al in view of Young et al.
Conclusion
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/CAROLINE M LARA/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633