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/CN2022/123409 (filed on 09/30/2022), which claims priority to CHINA 202111158620.4 (filed on 09/30/2021).
Election/Restrictions
Applicants elected without traverse of invention Group I, drawn to a method for trans-differentiating non-neuronal cells to functional neurons in a subject. Applicants fully complied with the restriction requirement. However, Applicants cancelled all previously presented claims and presented claims to a new invention: a method of treating or preventing Parkinson’s disease in a subject. This invention will be examined. Claims 119-135 read on the invention.
Claims Status
Claims 1-118 are cancelled.
Claims 119-135 are pending and have been examined on the merits.
Claim Objections
Claim 122 objected to because of the following informalities:
Claim is missing a period at the end.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 119-124 and 130-135 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claims 119-124: The method of claim 119 requires the administration to the subject an active substance capable of reducing the binding of REST to RE1/NRSE elements, wherein the active substance comprises a protein which can block the binding of REST and the RE1/NRSE element, or comprises a nucleic acid encoding the protein.
The issue at hand is the specification fails to provide sufficient information to show Applicants were in possession of the full scope of the genus of active substance(s) that would satisfy the physical and functional properties of the claims.
In claim 119, the active substance covers a genus of proteins (and nucleic acids encoding the proteins): any protein which can block the binding of REST and the RE1/NRSE element would satisfy the functional properties required by the claim. As the nucleic acids encoding the protein are defined by the protein they encode, this rejection will focus on ‘the protein’.
There are various proteins that block binding of REST and RE1/NRSE elements, including AAVs, antibodies, and Cas proteins. Thus the number of potential active substances covered by active substance is large. For example, Su et al (Frontiers in cell and development biology, 2022) teaches there are various ways to inhibit REST/NRSF such as C-terminal binding protein, DNA methyltransferase, SP3, CDYL, MED19, MED26, and REST-VP16 (See, p2 col 2 paragraph 2 and p8 col 2 paragraph 2).
To satisfy the written description aspect of 35 U.S.C. 112, first paragraph, for a claimed genus of molecules, it must be clear that: (1) the identifying characteristics of the claimed molecules have been disclosed, e.g., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed cor-relation between function and structure, or by a com-bination of such identifying characteristics; and (2) a representative number of species within the genus must be disclosed. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
In the instant case Applicants have disclosed a ‘REST variant’ as the protein that blocks RE1/NRSE element and competes with REST for binding RE1 (See, SPEC ¶ 98-99). Applicants further disclosed that the variant refers to a derivative sequence having one or more substitutions, additions, deletions, insertions or truncations, a fragment of REST protein or fusion protein of a fragment of REST protein with another protein (See, SPEC ¶ 99). The limited number of exemplary REST variant proteins listed in Specification ¶ 96-100 are not representative of the broad genus of proteins which are encompassed by the claims. Particular with regards to active substance, protein. While there are a few examples,RZFD-V1 (SEQ ID NO: 3), RZFD-V2 (SEQ ID NO:5 ), and RZFD-V3 (SEQ ID NO: 9), the examples encompass a single species of the broad genus of what the REST variant can be and thus is not considered representative of the broad breadth of the claims as written. Furthermore, the examples are not representative of all the active substances that are proteins or REST variants to cover the broad breadth of the claims as written.
Furthermore, Applicants have not provided any description of core features or structures of the active substance that couple with the function of being able to block the binding of REST and the RE1/NRSE element. The SPECIFICATION discloses that human endogenous zinc finger structure domain (RZFD) was used to target RE1 sequence, which was defined as amino acids 155-420 of REST (See, SPEC ¶113-114). The SPECIFICATION also discloses that three examples of RZFD-V1-3 for targeting the RE1 elements and binding. Applicants also disclosed that the RZFD-V2 has VP64 fused to the N or C-terminal of RZFD and RZFD-V3 has P65 and HSF1 also fused to the RZFD (See, SPEC ¶113). Therefore, this shows that only claim 125 recites the feature of amino acid sequence 155-420. Claim 130 recites the feature of having activation domain and claim 131 recites having the features VP64 or P65-HSF1. These are the only claims with these specific features but the rest of the claims are broader.
Based on the lack of disclosure of a representative number of species, as well as lack of description of core features or structures shared by the full genus of ‘active substances’ the application is determined to fail to provide written description for the genus of active substance/proteins covered by claim 119.
Regarding claims 120-124 which are dependent on 119, are included in the rejection due to their dependency. Claim 120 does not provide any additional information on the protein, and thus lacks written description for the reasons set forth above. Claims 121-122 define the protein as having the functional property of blocking binding (or competing for binding) with the REST protein, but this is functional limitation and there is no structure correlated with this function.
Regarding claims 130-135, which are dependent on claim 123, are included in the rejection due to their dependency. These claims further describe additional components (regulatory elements, activation domains, NLS, etc), but do not provide additional identifying information about the protein, per se. Therefore these claims, too, lack written description for the reasons set forth above.
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 128, 129 and 134 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 claim 128, there is insufficient antecedent basis for the limitation "the REST variant" in lines 2-3. It would seem claim 128 should depend on claim 123, which indicates the protein in the active substance is a REST variant.
Claim 129 depends from claim 128, inherits the deficiency, and is rejected on the same basis.
Regarding claim 134, the phrase “…said nuclear localization signal sequences is fused to the N-terminus and C-terminus of said REST variant, respectively”, renders the claim indefinite because the phrase, specifically the portion, ‘fused to the N-terminus and C-terminus of said REST variant’. It is not clear what the claim requires nor what the scope of the limitation is and any interpretation leads to the claims being indefinite. It is unclear if applicant is requiring a circular protein or 2 NLS with one at each terminus.
For examination purposes with respect to prior art, any method wherein at least one NLS is fused at each terminus of the REST variant will be considered within the metes and bounds of claim 134.
Appropriate correction or clarification is required.
Claim Rejections - 35 USC § 102
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.
Claims 119 and 120 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhou et al (Cell, 2020).
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. Zhou et al teaches that with this method one can convert glial cells in the striatum to dopaminergic neurons and Müller glia to retinal ganglion cells (RGCs) (See, Abstract). For the striatum glia conversion, AAV-CasRx 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, by injecting the Cas-Rx-mediated knockdown in the striatum of the mice, which showed that the method induces neurons showing features of dopaminergic neurons (See, p598 – p599).
Zhou et al teaches that the REST complex silences neuron-specific transcription factors and which is strongly inhibited by binding PTBP1 protein in non-neuronal cells (See, p 599 col 2 paragraph 3). Zhou et al teaches their knock down of Ptbp1 releases miR-124 activity which suppresses REST complex and leads to expression of neuron specific factors (See, p 599 col 2 paragraph 3).
Regarding claim 119: The method of Zhou et al reads on, a method for preventing and/or treating Parkinson’s disease in a subject. The AAV-CasRx reads on an active substance …comprising a nucleic acid encoding a protein that blocks the binding of REST and the RE1/NRSE element. Specifically, the Cas molecule is a protein. Zhou et al teaches the knockdown of PTBP1 via the CRISPR-Cas system results in miR-124 activity, which suppresses REST complex. Regarding claim 120: Following the discussion of claim 119 above, Zhou et al administer the AAV-CasRx into the striatum of the subject.
Therefore claims 119-120 are anticipated 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 119-124 and 130-134 are rejected under 35 U.S.C. 103 as being unpatentable over Watanabe et al (Genes and Development, 2004), and further in view of Zhou et al (Cell, 2020), evidenced by Immaneni et al (Nucleic acids research, 2000), Takarabio (pV16-construct) and Rodriquez-Pallares et al (Neural regeneration research, 2022).
Watanabe et al teaches that REST/NSRF contains a DNA-binding domain and two repressor domains, and it blocks transcription of its target genes by binding to a specific consensus RE1-binding site/neuron-restrictive silencer element (RE1/NRSE) (See, p890 col 1 paragraph 2). Watanabe et al teaches the use of REST-VP16, a recombinant transcription factor that replaced the repressor domains of REST/NRSF with the activation domain of the herpes simplex virus protein VP16 (which contains SV40 poly A, evidenced by Takarabio), such that the DNA binding domain of REST/NRSF is maintained. Watanabe et al also teaches that REST-VP16 competes with endogenous REST/NRSF for DNA binding and activates REST/NRSF target genes, thus functioning in the RE1/NRSE pathway (See, p890 col 1 paragraph 3 to p890 col 2 paragraph 2).
Regarding claim 119 and 120, Watanabe et al teaches the conversion of myoblasts to functional neurons by direct activation of REST/NRSF target genes by REST-V16 (See, Abstract). Watanabe teaches that REST-V16 functionally counters endogenous REST/NRSF in myoblasts (See, Figure 1, p890 col 2 – p891 col 1). The REST-V16 reads on, active substance capable of reducing the binding of REST to RE1/NRSE elements, wherein the active substance comprises a protein which can block the binding of REST and the RE1/NRSE element
Watanabe et al does not teach a method for preventing or treating Parkinson’s disease in a subject or administering to the subject the active substance.
The teachings of Zhou et al are set forth above. Briefly, Zhou et al teaches a method of converting glial cell into functional neurons in the striatum through the downregulation of polypyrimidine tract-binding protein-1 (Ptbp1) using RNA targeting CRISPR system. Zhou et al performed the method of Ptbp1 knockdown in a Parkinson’s disease (PD) model, by injecting the Cas-Rx-mediated knockdown in the striatum of the mice, which showed that the method induces neurons showing features of dopaminergic neurons (See, p598 – p599). This reads on, a method for preventing and/or treating Parkinson’s disease in a subject, comprising administering to the subject…of claim 119 and wherein the active substance is administered locally to striatum of the subject… of claim 120.
Importantly, Zhou et al teaches that the REST complex silences neuron-specific transcription factors and which is strongly inhibited by binding PTBP1 protein in non-neuronal cells (See, p 599 col 2 paragraph 3). Zhou et al teaches their knock down of Ptbp1 releases miR-124 activity which suppresses REST complex and leads to expression of neuron specific factors (See, p 599 col 2 paragraph 3).
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the method of Watanabe et al to comprise directly administering the REST-VP16 to a subject in the striatum, as taught by Zhou et al. This conclusion of obviousness is based on teaching suggestion motivation rationale. One would have been motivated by Zhou et al to make this modification to prevent or treat Parkinson’s disease, evidenced by Rodriguez-Pallares et al which teaches that cell-based approaches to replacing dopamine or dopaminergic neuron to replace lost neurons in Parkinson’s disease as a treatment (See, Abstract), as Zhou et al demonstrated that targeting REST and inducing functional neurons in the striatum would improve outcomes for Parkinson’s disease. One would have had a reasonable expectation of success because the REST-VP16 from Watanabe et al was successful in reducing binding of REST and RE1/NRSE elements to transdifferentiate myoblasts to neurons and Zhou et al was successful in converting cells in the striatum by downregulating Ptbp1 and downregulating REST and RE1/NRSE elements to induce neurons in region, therefore administering REST-VP16 in the striatum in a subject, would provide successful results.
Regarding claim 121-123, following the discussion above, Watanabe et al teaches the use REST-VP16, a recombinant transcription factor that replaced the repressor domains of REST/NRSF with the activation domain of the herpes simplex virus protein VP16 such that the DNA binding domain of REST/NRSF is maintained.
Watanabe et al also teaches that REST-VP16 competes with endogenous REST/NRSF for DNA binding and activates REST/NRSF target genes, thus functioning in the RE1/NRSE pathway (See, p890 col 1 paragraph 3 to p890 col 2 paragraph 2). This reads on, wherein the protein binds to the RE1/NRSE element to block the binding of REST and the RE1/NRSE element of claim 121. This reads on, wherein the protein competes with REST for binding RE1/NRSE element of claim 122. This also reads on, wherein the protein is a REST variant of claim 123.
Regarding claim 124 and 130-133, Watanabe et al teaches that the REST-VP16 construction was previously disclosed by Immaneni et al (See, p 896). Immaneni et al teaches that REST1-VP16 was constructed by replacing the C-terminal sequence of REST beyond the DNA-binding domain with the activation domain of viral activator VP16 (which contains SV40 poly A, evidenced by Takarabio) but still contains N-terminus repressor domain. REST-VP16 was constructed by deleting the N terminus domain of the REST1-VP16, therefore it does not contain any REST repressor domain (See, p3404 and Figure 1). This reads on, wherein the REST variant comprises the DNA binding domain of REST but lacks the N-terminal and/or C-terminal repression domain of REST of claim 124. This reads on, wherein said REST variant further comprises an activation domain of claim 130. This reads on, wherein the activation domain comprises an epigenetic modification protein or gene activation regulatory element of claim 131, as VP16 is a gene activation regulatory element. This reads on, wherein the REST variant further comprises one or more nuclear localization signal sequences of claim 132, as VP16 has SV40 poly A included, which is a nuclear localization signal sequence. This reads on, wherein at least one of said nuclear localization signal sequence is fused to the C-terminus of said REST variant of claim 133, as the VP16 is in C-terminus of the REST variant.
Regarding claim 134, Watanabe et al teaches that REST-VP16 was constructed such that VP16 with the nuclear localization signal is in the C-terminus but not in the N-terminus.
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the REST variant of Watanabe et al to further comprise a nuclear localization signal (NLS) in the N-terminus. This conclusion of obviousness is based on teaching suggestion motivation rationale. One would have been motivated to include an NLS at the N-terminus of the REST variant to further ensure the nuclearization of the protein to increase efficacy. One would have had a reasonable expectation of success because increasing NLS, does not harm the protein but ensures its proper transport.
Therefore, claims 119-124 and 130-134 are rendered obvious over Watanabe et al in view of Zhou et al, evidenced by Takarabio, Rodriguez-Pallares et al, and Immaneni et al.
Claims 125-128 are rejected under 35 U.S.C. 103 as being unpatentable over Watanabe et al (Genes and Development, 2004) and Zhou et al (Cell, 2020), and further in view of Mandel et al (WO 96/29433-A1).
The teachings of Watanabe et al and Zhou et al are set forth above.
Regarding claims 125-127, Watanabe et al teaches a REST variant that lacks the N-terminal and/or C-terminal inhibitory domain of REST but does not teach amino acid sequence 155-420 of REST nor SEQ ID NO: 1,3,5, or 9 or having at least 50%,60%, or 70% identity percentage with anyone thereof.
Mandel et al disclosed an invention of nucleic acid encoding a protein and proteins that inhibit the expression of neural proteins in non-neural tissues that can be a suppressor domain of RE1-silencing transcription factor (REST) (See, Abstract).
Mandel et al disclosed amino acid sequence AAR99388 which is a 96.8% Query match with instant application SEQ ID NO: 3 (See, APPENDIX for alignment). This reads on, wherein the REST variant comprises the amino acid from 155-420 of REST of claims 125 and 126.
Mandel et al teaches the invention is related to REST protein that retain the ability to bind the RE1-promoter element and suppress the activity of a promoter to which the protein is bound (See, p 10 lines 5-10).
It would have been prima facie obvious to a person having ordinary skill in the art to substitute the amino acid sequence of Watanabe REST variant with the amino acid sequence of Mandel et al (AAR99388). The use of the amino acid sequence of Mandel et al would have a predictable result of success evidenced by Mandel et al utilizing it for pharmaceutical composition to retain or suppress REST activity. This rationale aligns with the principle of KSR for simple substitution of one known element for another to obtain predictable results (See, MPEP 2143).
Regarding claim 128, following the discussion above, Watanabe et al nor Zhou et al teach wherein the active substance comprises a nucleic acid sequence of SEQ ID NO: 2,4,6, or 10 or with 50%, 60% or 70% identity percentage.
Mandel et al disclosed sequence AAT41417, which is a 100% query match with instant SEQ ID NO: 2 (See, APPENDIX for alignment).
It would have been prima facie obvious to a person having ordinary skill in the art to modify the nucleic acid sequence of Watanabe et al REST variant with the sequence of Mandel et al (AAT41417). The use of the nucleic acid sequence of Mandel et al would have a predictable result of success evidenced by Mandel et al utilizing it for pharmaceutical composition to retain or suppress REST activity. This rationale aligns with the principle of KSR for simple substitution of one known element for another to obtain predictable results (See, MPEP 2143).
Therefore claims 125-128 are rendered obvious by Watanabe et al and Zhou et al in further view of Mandel et al.
Claim 129 is rejected under 35 U.S.C. 103 as being unpatentable over Watanabe et al (Genes and Development, 2004), Zhou et al (Cell, 2020), and Mandel et al (WO 96/29433-A1), and further in view of Fotin-Mleczek et al (WO 2017/191274-A2).
The teachings of Watanabe et al, Zhou et al and Mandel et al are set forth above.
Regarding claim 129, Watanabe et al, Zhou et al , and Mandel et al do not teach wherein the nucleic acid encoding the REST variant is codon-optimized or SEQ ID NO: 15.
Fotin-Mleczek et al disclosed an invention of pharmaceutical compositions of novel RNAs and proteins for gene therapy for the treatment or prophylaxis of inherited diseases (See, Abstract).
Fotin-Mleczek disclosed SEQ ID NO: 22558, which is an 83% query match for SEQ ID NO: 15 of the instant app (See, APPENDIX for alignment).
It would have been prima facie obvious to a person having ordinary skill in the art to modify the sequence of Watanabe et al REST variant with the codon-optimized sequence of Fotin-Mleczek (SEQ ID NO: 22558). This conclusion of obviousness is based on teaching suggestion motivation rationale. One would have been motivated to use the optimized codon sequence of Fotin-Mleczek et al because it would have been advantageous to use a known sequence in the art to achieve the same goal. One would have had a reasonable expectation of success evidence by Fotin-Mleczek et al.
Therefore, claim 129 is rendered obvious by Watanabe et al, Zhou et al, and Mandel et al, in further view of Fotin-Mleczek et al.
Claim 135 is rejected under 35 U.S.C. 103 as being unpatentable over Watanabe et al (Genes and Development, 2004) and Zhou et al (Cell, 2020), and further in view of Liu et al (WO 2018/071868-A1).
The teachings of Watanabe et al and Zhou et al are set forth above.
Regarding claim 135, Watanabe et al does not teach wherein the nuclear localization sequence of SV40 in REST-VP16 is SEQ ID NO: 13 or 41-58.
Liu et al disclosed compositions delivering Cas9 protein or a nuclease edit to cells (See, ¶0004). Liu et al disclosed SEQ ID NO: 375, which is a 100% query match for instant SEQ ID NO: 13 (See, APPENDIX for alignment).
It would have been prima facie obvious to a person having ordinary skill in the art to modify the sequence of Watanabe et al REST variant with SV40 NLS, with amino acid sequence of Liu et al for NLS. This conclusion of obviousness is based on teaching suggestion motivation rationale. One would have been motivated to use the amino acid sequence of Liu et al for the NLS because it would have been advantageous to use a known sequence in the art to achieve the same goal. One would have had a reasonable expectation of success evidence by Liu et al.
Therefore, claim 135 is rendered obvious by Watanabe et al, Zhou et al, and Mandel et al, in further view of Liu et al.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Caroline M Lara whose telephone number is (571)272-4262. The examiner can normally be reached 7:00 to 4:30pm M-Th.
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/CAROLINE M LARA/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
APPENDIX
SEQUENCE ALIGNMENTS
RE: Mandel et al (WO 96/29433-A1)
Query (instant SEQ ID NO: 3) vs Subject (reference SEQ ID NO: AAR99388)
PNG
media_image1.png
491
623
media_image1.png
Greyscale
Query (instant SEQ ID NO: 2 ) vs Subject (reference SEQ ID NO: AAT41417 )
PNG
media_image2.png
486
616
media_image2.png
Greyscale
RE: Fotin-Mleczek et al (WO 2017/191274-A2)
Query (instant SEQ ID NO: 15) vs Subject (reference SEQ ID NO:22558)
PNG
media_image3.png
497
617
media_image3.png
Greyscale
RE: Liu et al (WO2018071868-A1)
Query (instant SEQ ID NO: 13) vs Subject (reference SEQ ID NO:375)
PNG
media_image4.png
157
635
media_image4.png
Greyscale
Prosecution Insights