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, 3, 5-7, 13, 15, 20, 21, 23-25, 28-30, and 38-39) in the reply filed on 05/18/2026 is acknowledged. Calims 1, 3, 5-7, 13, 15, 20, 21, 23-25, 28-30, 38-41, 44-51, and 55-67 are pending; claims 40-41, 44-51, and 55-67 are withdrawn from prosecution for being drawn to non-elected subject matter.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/12/2023 was considered by the examiner.
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.
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 1, 3, 20, 38 and 39 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.
Specifically, a protein is a regarded as a chemical compound, which must be defined with reference to technical features such as a sequence or a reasonable degree of homology. Neither the term "J domain" nor "TDP-43-binding domain" have a meaning in the art that would allow the skilled person to put the invention into practice.
As such, the metes and bounds of the claims could not be determined.
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, 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 1, 3, 5-7, 13, 15, 20 and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Pozzi et al. (Virus-mediated delivery of antibody targeting TAR DNA-binding protein-43 mitigates associated neuropathology. J. Clin. Invest., 129, 1581-1595, 2019 -cited by Applicant) in view of Chen et al. (The heat shock response plays an important role in TDP-43 clearance: evidence for dysfunction in amyotrophic lateral sclerosis, Brain,139, 1417-1432, 2016 (cited by Applicant).
The claims are drawn to an isolated fusion protein comprising a J domain of a J protein (which may be of human origin) and a TDP-43-binding domain. The structure of the fusion may be described by the formula DNAJ-X-T with different permutations of the DNAJ (J domain of a J protein), T (TDP-43-binding domain) and X (a linker). The fusion protein is further described by the effect that it might had in a cell.
Pozzi et al. described single-chain (scFv) antibodies against the RNA recognition motif 1 (RRM1) of TDP-43, which is involved in abnormal protein self-aggregation and interaction with p65 NF-κB. The cytoplasmic aggregation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of degenerating neurons in amyotrophic lateral sclerosis (ALS) and subsets of frontotemporal dementia (FTD). Virus-mediated delivery into the nervous system of a scFv antibody, named VH7Vk9, reduced microgliosis in a mouse model of acute neuroinflammation and mitigated cognitive impairment, motor defects, TDP-43 proteinopathy, and neuroinflammation in transgenic mice expressing ALS-linked TDP-43 mutations. These results suggest that antibodies targeting the RRM1 domain of TDP-43 might provide new therapeutic avenues for the treatment of ALS and FTD (abstract). TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA-binding protein that is highly and ubiquitously expressed, with main localization in the cell nucleus. Thanks to its 2 RNA recognition domains (RRM1 and RRM2), the protein is a multifunctional factor involved in different aspects of RNA metabolism such as transcription, splicing, stabilization, and transport. More than 90% of ALS cases show a pathological behavior of this protein called TDP-43 proteinopathy, described as a consistent mislocalization and aggregation of the protein in the cytoplasm where TDP-43 can form hyperphosphorylated, fragmented, and ubiquitinated inclusions that impair the physiological function of the protein (introduction).
The scFv antibody against TDP-43 (VH7Vk9 scFv) specifically targeted the RRM1 domain of TDP-43, a region implicated in the cytosolic mislocalization and aggregation of the protein. Virus-mediated delivery of VH7Vk9 in the CNS of transgenic mice expressing mutant hDP-43 succeeded in ameliorating cognitive and motor deficits as well as in reducing TDP- 43 proteinopathy and neuroinflammatory changes. Cytoplasmic accumulation of TDP-43 is cytotoxic and protein levels of TDP-43 were found to be increased in CNS tissues and peripheral cells of patients with sALS. While factors triggering the initial mislocalization of TDP-43 in pathologies are largely unknown, reduction of cytoplasmic TDP-43 levels can rescue neurons from death. TDP-43 can be degraded through proteasomal and autophagic pathways and both of these pathways can act on the soluble TDP-43 present in the cytoplasm, with the proteasome contributing to the degradation of monomers and autophagy promoting the degradation of early oligomers, microaggregates, or late macroaggregates (conclusion; figs. 6-8).
The reference does not address the role of J domain of a J protein or a fusion of it with a specific TDP-43 binding domain.
Chen et al. attacked the persistent problem of cytoplasmic TDP-43 from another angle. The reference underscored that detergent-resistant, ubiquitinated and hyperphosphorylated Tar DNA binding protein 43 neuronal cytoplasmic inclusions are the pathological hallmark in ~95% of amyotrophic lateral sclerosis and ~60% of frontotemporal lobar degeneration cases. The role for the heat shock response in the clearance of insoluble TDP-43 in a cellular model of disease and findings in transgenic mice and human amyotrophic lateral sclerosis tissues was sought after. The heat shock response is a stress-responsive protective mechanism regulated by the transcription factor heat shock factor 1 (HSF1), which increases the expression of chaperones that refold damaged misfolded proteins or facilitate their degradation. Manipulation of the heat shock response by expression of dominant active HSF1 results in a dramatic reduction of insoluble and hyperphosphorylated TDP-43 that enhances cell survival, whereas expression of dominant negative HSF1 leads to enhanced TDP- 43 aggregation and hyperphosphorylation. To determine which chaperones were mediating TDP-43 clearance, a range of heat shock proteins (HSPs) were over-expressed and identified DNAJB2a (encoded by DNAJB2, and also known as HSJ1a) as a potent antiaggregation chaperone for TDP-43. DNAJB2a has a J domain, allowing it to interact with HSP70, and ubiquitin interacting motifs, which enable it to engage the degradation of its client proteins. Using functionally deleted DNAJB2a constructs it was demonstrated that TDP-43 clearance was J domain-dependent and was not affected by ubiquitin interacting motif deletion or proteasome inhibition. This indicates that TDP-43 is maintained in a soluble state by DNAJB2a, leaving the total levels of TDP-43 unchanged. The levels of HSF1 and heat shock proteins are significantly reduced in affected neuronal tissues from a TDP-43 transgenic mouse model of amyotrophic lateral sclerosis and patients with sporadic amyotrophic lateral sclerosis indicating that the HSF1-mediated DNAJB2a/HSP70 heat shock response pathway is compromised in amyotrophic lateral sclerosis. Defective refolding of TDP-43 is predicted to aggravate the TDP-43 proteinopathy. The finding that the pathological accumulation of insoluble TDP-43 can be reduced by the activation of HSF1/HSP pathways presents an exciting opportunity for the development of novel therapeutics (abstract).
A person of ordinary skill in the art, considering the two facets of the same problem, namely reducing the deleterious effect of accumulation of cytoplasmic TDP-43 (aggregated of incorrectly folded) would have sought after the solution of considering the seminal references of Pozzi and Chen and come to the conclusion that specifically binding TDP-43 in combination with a J domain role in correctly folding would cooperate in drastically reducing the level of cytoplasmic TDP-43. Coupling a J domain of a J protein like DNAJ with a TDP-binding domain would thus seems obvious and within the bailiwick of a skilled artisan. The J domain of the J protein business end of the fusion would force the interaction with the HSP 70 chaperone and thus address the misfolding and the TDP-43 binding domain part of the fusion would assure specificity of the folding/unfolding process toward the desired TDP-43 in order to attain the goal of treating the devastating consequences of the TDP-43 pathology.
Allowable Subject Matter
Claims 21, 23-25, and 28-30 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claims are allowed.
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ELLY-GERALD STOICA
Primary Examiner
Art Unit 1647
/Elly-Gerald Stoica/Primary Examiner, Art Unit 1647
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