DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/10/2025 has been entered.
Claims 1, 4-15, 17-20 are pending. Claims 11-13, 17-19 are withdrawn. Claims 1, 4-10, 14, 15 and 20 are currently under examination.
All previous rejection not reiterated in this office action are withdrawn.
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, 4-10, 14, 15 and 20 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 1, the recitation of “expressing a recombinant ribosome comprising a deleted or mutated ribosomal protein comprising an animo acid exchange or deletion” renders the claim indefinite because it is unclear how a deleted ribosomal protein can comprise an amino acid exchange or deletion.
The recitation of “wildtype control cell” in step c) renders the claim indefinite because it is unclear whether it is referring to a wildtype cell that has not defective translation of the target gene, a recombinant eukaryotic yeast cell that do not express target cell, or a wild type yeast cell expresses the target gene but not the recombinant ribosome comprising deleted ribosomal protein?
The recitation of “the eukaryotic cell” in step h) is confusing because it is unclear whether it is referring to the yeast eukaryotic cell that expresses the target gene, other eukaryotic cells that expresses the target gene, or the eukaryotic cell that expresses defective translation of the target gene.
The recitation of “identifying the at least one small organic molecule compound as ameliorating or reverting the defective translation of the target gene based on said measured change in step h)” renders the claim indefinite because it is unclear what forms the basis for such identification. In other words, it is unclear whether a change indicates the compound as ameliorating or reverting the defective translation of the target gene or not ameliorating or reverting the defective translation of the target gene.
Dependent claims 4-10, 14, 15 and 20 are rejected for same reason because they depend on claim 1 but do not remedy the indefiniteness.
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 1, 4-10, 14, 15 and 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method for identifying a small organic molecule compound that ameliorates or reverts a defective translation of a target gene in a eukaryotic cell comprising the steps of a) selecting at least one target gene that shows a defective translation in a eukaryotic cell; b) providing a screening system comprising at least one recombinant eukaryotic yeast cell i) expressing a recombinant ribosome comprising a deleted ribosomal protein; ii) expressing a first reporter construct comprising the at least one target gene of a) coupled to a first luciferase reporter group to be co-expressed with said target gene, and iii) expressing a second reporter construct comprising a second luciferase reporter as an internal control; c) determining translation of the target gene in recombinant eukaryotic yeast cell; identifying the deleted ribosomal protein as having an effect on the translation of the target gene; e) providing a non-mutated ribosomal protein of the deleted ribosomal protein; f) contacting the ribosomal protein as provided in step e) with at least one small organic molecule compound that potentially ameliorates or reverts the defective translation of the target gene; g) identifying a binding of the at least one candidate small organic molecule compound to the ribosomal protein of step e); h) contacting the small organic compound identified in step g) with the eukaryotic cell that shows defective translation of the target gene; and measuring a change in the translation of the target gene in the presence of said compound; i) identifying the at least one small organic compound as ameliorating or reverting the defective translation of the target gene when the defective translation is restored in said eukaryotic cell; wherein the target gene is selected from the group consisting of COL17A1, LAMB3, Keratin , Keratin 14, LAMB2, LAMA3, LAMC2, INTβ4, alpha6, plectin, Col1, and Col7, does not reasonably provide enablement for the claimed method wherein the recombinant ribosome comprises a mutated ribosomal protein, or the claimed method with any other target gene. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to: (a) the nature of the invention; (b) the breadth of the claims; (c) the state of the prior art; (d) the amount of direction provided by the inventor; (e) the existence of working examples; (f) the relative skill of those in the art; (g) whether the quantity of experimentation needed to make or use the invention based on the content of the disclosure is "undue"; and (h) the level of predictability in the art (MPEP 2164.01 (a)).
The nature of the invention
The claimed method of claim 1 is drawn to a method for identifying a compound that ameliorates or reverts a defective translation of a target gene in a eukaryotic cell comprises providing a screen system that comprises a eukaryotic cell expressing a recombinant ribosomal comprising a deleted or mutated ribosomal protein or a ribosomal protein showing altered expression; expressing a first reporter that comprises said target gene coupled to a reporter; and a second reporter; determining translation of the target gene in the cell that comprises the recombinant ribosome, that comprises at least one deleted or mutated ribosomal protein or ribosomal protein showing altered expression; identify the deleted or mutated ribosomal protein or ribosomal protein having altered expression as having an effect on the translation of the target gene based on the determining; providing a non-mutated ribosomal protein as identified in step d) and contacting said non-mutated ribosomal protein with a compound to identify binding of the compound to said ribosomal protein; measuring the translation of the target gene in the presence of said at least one compound compared to the translation of said target gene in the asence of said at least one compound, and identifying the compound to revert or ameliorate the defective translation of the target gene based on said measuring.
The breath of the claim
The scope of the claim is rather broad. The broadest claim encompasses identifying a compound of ameliorate or reverts a defective translation of a target gene, which includes a large number of genes without limitation. Claim 4 recites the target genes encode proteins related to a large number of different disease or condition. Claim 1 also encompasses all of the eukaryotic ribosomal protein that comprises a wide range of mutation or deletion.
The teaching from the specification and the presence of working examples
The specification does not teach a method of identifying a compound that ameliorate or reverts a defective translation of a target gene, following steps a)-i) as recited in claim 1 and dependent claims thereof. The teaching from the specification teaches engineering yeast strains that comprises a specific type of reporter, premature termination codons (PTC). The specification gives example of wild type and 4 ribosomal protein (RP) deletion strains RPL10/ΔRPL10, RPL4A/ΔRPL4A, RPL25/ΔRPL25 and RPL19A/ΔRPL19A, transformed with a first reporter construct comprising a CYH2-FF, CYH2-PTC-FF, LAMB3-FF or LAMB3-PTC-FF, and a second RF as internal control in yeast cells. The specification does not teach any other type of mutation(s) or combinations thereof in other RP or a combination of mutations in a number of RPs in eukaryotic cells (other than yeast) which causes defective or undesired translational read-through of a target gene bearing a PTC, or other types of defective translation. However, the specification fails to teach how to use this system to identify compound following steps a)-h) of claim 1. The specification fails to any “basis” for identifying the defective ribosomal protein in step c) for comparing to a wildtype control, and for identifying the compound in step i) for what type of change indicates the compound may revert the defective translation. The specification does not provide any substantive evidence that a small compound composition binds to a non-mutant form of a ribosomal protein may reverse the defective form of same ribosomal protein that causes defective translation. As such, whether following steps a)-h) of claim 1 would lead to identification of a compound that can revert or ameliorate many different types of translation defect is unpredictable. Moreover, claim 4 recites a large number of target genes encoding proteins related to a large number of condition or disease. The specification fails to teach what those genes encompasses. Without knowing what those genes are, whether a skilled artisan would know which ribosomal protein is responsible for such target gene translation is unpredictable. It is also unpredictable what type of mutation(s) or amino acid exchange would result in defective translation in one or a group of target gene.
The state of prior art and the level of predictability in the art
The state of prior art at the time of filing does not teach a method for identifying compounds that can ameliorate or revert translation defect as claimed in claim 1. The prior art does not provide sufficient information on mutation(s) within one or more RP in a wide variety of eukaryotic cells that causes translational read-through or other types of translation defect in respective target genes. In fact, Gopanenko et al (International Journal of Molecular Sciences, 2021, Vol.2, 4531, pages 1-16) teach mammalian cells contain subpopulations of active ribosomes, heterogeneous in protein composition, are specialized ribosomes, which preferentially translate different subset of mRNAs (page 1, 1st paragraph, last 4 lines). Gopanenko et al. reported identification of 150 genes that has altered translation efficiency when eL38 RP is knocked out in HEK293 cells, and finding from identification of genes with altered translational efficiencies and from analysis of the pathways may shed light on the possible causes of some abnormalities in mammals deficient in eL38 RP (page 16, last paragraph). The teaching from prior art suggests that whether deletion of different RP(s) or mutations within different RPs would cause read-through PTC or other types of translation defect in target gene is unpredictable. Whether following steps a)-h) of claim 1 would lead to identification of a compound that ameliorate or revert a translational defect in a wide range of target genes is unpredictable. Moreover, many genes encoding proteins related to disease or condition as recited in claim 4 are not in the prior art. For example, it is unclear what are genes encoding protein related to aging, CNS, mental retardation disease, neurodegenerative disease…giantism, dwarfism…wrinkles, sunburn…undesired hair growth…etc. As such, whether such condition is caused by defective translation is unpredictable.
The amount of experimentation required
In view of lack of teaching from both the specification and prior art, a skilled artisan would have to engage in undue amount of experimentation to find mutations (other than the yeast RP deletion strains) or combination thereof in one or more eukaryotic RPs that causes translational read-through PTC or other types of translational defect in specific target gene(s). The skilled artisan then has to engage in undue experimentation to determine whether such eukaryotic cell may be used to screen a compound following steps a)-h) of claim 1. Therefore, the claimed method is only enabled to the scope as indicated above.
Response to Arguments
Applicant argues that amended claims relate to one target gene at a time, and assaying one target gene does not involve undue experimentation. Applicant asserts that the specification discloses around 80 ribosomal protein known in the art, and techniques for modifying the ribosomal protein are known in the art, as the use of a bank of 80 mutated ribosomal proteins in yeast. Applicant concludes that the experimentation would have been routine.
The above arguments have been fully considered but deemed unpersuasive. The claimed method of identifying a compound that ameliorates or reverts a defective translation of a target gene in a eukaryotic cell not only requires each gene that encodes 80 different ribosomal protein, but also what mutation, in a wide variety of eukaryotic cells would cause defective translation in a large number of so called target genes. Even though only one target gene is assayed at one time, a skilled artisan would have to assay not only at least about 80 deletion of ribosomal protein in a yeast cell, but also mutation (including deletion, insertion and/or substitution) or combination of such mutations thereof and determine whether it causes defective translation of said selected target gene. The list in Table 1 is ribosomal deletion strains of yeast cells, which does not include other type(s) of mutation or combination of mutations thereof. The data presented in example is directed to one specific type of mutation, translational readthrough, with such yeast deletion strains. In view of the very broad claim scope (as discussed in the rejection above), whether this specific example can expand the predictability to a wide range of other types of mutation(s) or alteration that would cause defective translation is unpredictable. Therefore, the claimed method is only enabled to the scope as indicated above.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CELINE X QIAN whose telephone number is (571)272-0777. The examiner can normally be reached M-F (8-4:00).
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/CELINE X QIAN/Primary Examiner, Art Unit 1637