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 .
Response to Amendment
Claims 1, 5, 9-10, 14, and 17 have been amended; Claim 21 has been cancelled, as requested in the amendment filed on 20 July 2026. Following the amendment, claims 1-3, 5-12, 14-17, and 20 are pending in the instant application.
Claims 10-12, 14-17, and 20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions, there being no allowable generic or linking claim.
Claims 1-3 and 5-9 are under examination in the instant office action.
Claim Rejections - 35 USC § 103 (New, Necessitated by Amendment)
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.
Claims 1-3 and 5-9 are rejected under 35 U.S.C. 103 as being unpatentable over Gazit, J Inherit Metab Dis, 39: 483-488, 2016; in view of Di Gregorio et al., Frontiers in Mol Neurosci, 11(394), October 2018 and Shaham-Niv et al. Sci. Adv, 1: e1500137, 2015.
Regarding claim 1, the Gazit et al. prior art reference teaches that it was known since 2012 that a single amino acid, phenylalanine, can form amyloid fibrils (Abstract). Specifically, X-ray crystallography demonstrated the formation of supramolecular β-sheet-like organization by phenylalanine at its zwitterionic form. The authors explicitly suggest “that the observed amyloid formation could explain some of the symptoms observed in phenylketonuria (PKU) upon the accumulation of phenylalanine. … In 2015, it was reported that other metabolites involved in metabolic disorders, including adenine, uracil, tyrosine, and orotic acid, could form amyloid-like assemblies. It was further demonstrated that the assemblies induce apoptotic cell death. Taken together, we suggest a new hypothesis to understand the etiology of degenerative processes observed in inborn error of metabolism disorders and indicate new avenues for treatment” (Abstract). Thus, the Gazit prior art teaches : “accumulation and aggregation of at least one metabolite forming intracellular metabolite aggregates comprising fibrillary structures, wherein accumulation and aggregation of said at least one metabolite is associated with at least one inborn error of metabolism (IEM) disorder; and (b) at least one reagent or means for determining at least one of, the accumulation and aggregation of said metabolite and at least one phenotype associated with accumulation and aggregation of said metabolite, wherein said metabolite is any one of: (i) a nucleobase, nucleoside, nucleotide, or any derivative or any intermediate product thereof, or (ii) an amino acid residue, or any derivative or any intermediate product thereof”.
Regarding Claim 3, Gazit teaches a phenotype associated with accumulation and aggregation of said metabolite is at least one of cell toxicity and fibril formation, namely phenylalanine, adenine, uracil, tyrosine, and orotic acid that form amyloid-like assemblies that lead to cytotoxicity and cell apoptosis (see pg. 486, Table 1, first column). Table 1 discloses these are assessed by MTT colorimetric assay (a.k.a. spectrometric assay of the instant claim) or FACS analysis (a.k.a. flow cytometry).
Regarding Claims 5 and 6, Gazit teaches accumulation of a metabolite is at least one nucleobase, namely adenine and uracil. Adenine teaches the specific purine nucleobase of instant claim 6 and explicitly suggests assays that are involved in metabolic disorders.
Regarding Claim 8, Gazit et al. teach accumulation of phenylalanine and tyrosine (see Figures 1a and c; and explicitly suggests the accumulation of these as a model for inborn errors of metabolism (Title and abstract).
The only elements that are missing from Gazit is (a) a yeast cell and/or yeast cell line, and/or yeast cell population, that carry at least one manipulation in at least one yeast metabolic pathway, that leads to said accumulation and aggregation (instant Claim 1); specifically, the adenine phosphoribosyltransferase pathway of instant Claim 7; and screening compounds for treating, ameliorating, reducing or delaying the deficiency associated with accumulation and aggregation of at least one of adenine, tyrosine, or phenylalanine (instant Claim 9).
The Di Gregorio et al. prior art remedies these deficiencies by teaching, “The cellular processes that involve protein misfolding and in turn the cellular response to protein misfolding, i.e., cellular stress response pathways, are highly conserved between humans and yeast (Winderickx et al., 2008). As a consequence, many yeast models of protein misfolding diseases recapitulate the general patterns of mislocalization, aggregation and cellular quality control mechanisms (Figure 1; Winderickx et al., 2008). Additionally, cellular quality control mechanisms, including the HSR and the UPR, are heavily conserved. While the focus of this review article is on impaired RNA metabolism and protein misfolding, yeast models also recapitulate many other essential mechanisms of eukaryotic biology. Cell cycle regulation, organelle function, and DNA metabolism are all examples of highly tractable process that can be aptly studied in yeast (Figure 2)” (pg. 4, second column, first full paragraph). Thus, the prior art teaches a system comprising: (a) a yeast cell and/or yeast cell line, and/or yeast cell population, that carry at least one manipulation in at least one yeast metabolic pathway, that leads to accumulation and aggregation of at least one metabolite forming intracellular metabolite aggregates comprising fibrillary structures.
It would have been obvious to a person, having ordinary skill in the art before the effective filing date of the application, to use the yeast system of Di Gregorio et al. to study metabolite amyloid formation. Motivation to do so is explicit in the prior art wherein Gazit teaches the metabolites of phenylalanine, adenine, uracil, tyrosine, and orotic acid have been successfully shown to accumulate as amyloid fibrils and Di Gregorio discloses the cellular processes involved are “highly conserved between humans and yeast”.
Regarding Claim 2, the Di Gregorio prior art teaches at least one means for validating selected from (a) at least one unicellular organism that displays accumulation and aggregation of said metabolite; (b) at least one multicellular eukaryotic organism that displays accumulation and aggregation of said metabolite; (c) at least one mammalian cell that displays accumulation and aggregation of said metabolite; and (d) at least one mammalian animal model that displays accumulation and aggregation of said metabolite; wherein it discloses yeast models that can be used to study accumulation of proteins within yeast (see Table 2, third column, titled ‘Aggregation’).
Regarding Claim 7, while the Gazit prior art discloses systems whereby nucleobases and amino acids are accumulated it does not specifically disclose genetic modification in at least one of Adenine phosphoribosyl transferase or Adenine deaminase genes. The Shaham-Niv prior art builds upon the Gazit study and discloses the specific genetic modifications that lead to the accumulation of each metabolite (see table at Figure 1B). Shaham-Niv et al explicitly teach adenine phosphoribosyl transferase deficiency underlies adenine accumulation.
Regarding Claim 9, Di Gregorio et al. discloses “Yeast high-throughput screens” can be used to identify genetic modifiers of cell toxicity (pg. 6, paragraph bridging columns; and pg. 7, second paragraph) and Shaham-Niv et al. states: “Such insights should enable specific directed drug design, which may present a new innovational approach of treatment for these metabolic disorders.” Thus, the prior art references explicitly suggest the use of metabolite accumulation and the yeast system of the claims as means for identifying candidate therapeutic compounds.
Therefore, the invention of instant claims 1-9 fails to distinguish over the system disclosed in the prior art references, and the claims are rejected.
Conclusion
No claim is allowed.
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/STACEY N MACFARLANE/Examiner, Art Unit 1675
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