DETAILED ACTION
Applicant’s amendment filed 6/28/2024 is acknowledged. Claims 4-9 are currently amended. Claims 18-23 are newly added. Claims 1-10 and 18-23 are pending in the instant application.
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
The instant application is a U.S. Continuation of PCT/EP2022/072744, filed on 8/15/2022, which claims foreign priority to EP21191417.1, filed 8/16/2021. Claims 1-10 and 18-23 find explicit support in the foreign application and are afforded an effective filing date of 8/16/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 6/28/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
In the specification as originally-filed, references 5-6, 10, 12-20, 23-37, 41, 44-52, 55, 60-62, and 66-67 on pp.33-38 comprise browser-executable code prefixes (http://) that need to be removed.
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required: the abbreviations “ASO”, “LNA”, and “CSF” appear throughout the specification but have not been fully spelled out in their first instance.
Duplicate Claims, Warning
Applicant is advised that should claim 1 be found allowable, claim 3 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Despite a slight difference in preamble wording, claims 1 and 3 are identical in claimed subject matter. Specifically, the claimed method steps a)-c) of claims 1 and 3 are identical in scope.
Claim Objections
Claims 1-6, 8, 18-20 and 22 are objected to because of the following informalities:
Claims 1-3 comprise a period after the recitation of “PSME3” in steps b), e), and b), respectively, which should be replaced by a comma followed by the conjunction “and”.
Claims 4 and 18 recite the abbreviation “CSF” without first fully spelling out the abbreviation.
Claims 6 and 20 recite the abbreviation “LNA” without first fully spelling out the abbreviation.
Claims 5 and 19 should not recite “Mass”, “Liquid”, or “Immunoassay” in capitalized form within the claim, since these limitations are not conventionally capitalized.
Claims 8 and 22 recite “UBLCP1and” in line 2, which is missing a space between “UBLCP1” and “and”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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 1-10 and 18-23 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 inventors, at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention.
Scope of the claimed genus. Claim 1 is directed to a method for measuring UBE3A protein expression modulation in a tissue sample comprising: a) providing a tissue sample of an animal or cell culture which has been treated with a UBE3A modulator, b) measuring a protein expression level in the sample of step a) of at least one protein selected from the group consisting of: TKT, DZANK1, ACYP1, UBLCP1, YARS, WARS, SOD2, and PSME3, and c) comparing the protein expression level of the at least one protein measured in step b) to the protein expression level of the at least one protein in a control, wherein a modulated protein expression level of the at least one protein measured in step b) compared to the protein expression level of the at least one protein in the control is indicative for UBE3A protein modulation. A tissue sample of an animal or cell culture and a UBE3A modulator are recited at a high level of generality.
Claim 2 is drawn to measuring UBE3A protein expression induction in a tissue sample. Claim 2 recites a tissue sample of an animal or cell culture and a UBE3A inducer at a high level of generality.
Claim 3 is drawn to a method for determining UBE3A target engagement of an UBE3A modulator comprising the steps: a) providing a tissue sample of an animal or cell culture which has been treated with a UBE3A modulator, b) measuring a protein expression level in the sample of step a) of at least one protein selected from the group consisting of: TKT, DZANK1, ACYP1, UBLCP1, YARS, WARS, SOD2 and PSME3, and c) comparing the protein expression level of the at least one protein measured in step b) to the protein expression level of the at least one protein in a control, wherein a modulated protein expression level of the at least one protein measured in step b) compared to the protein expression level of the at least one protein in the control is indicative for UBE3A target engagement of the UBE3A modulator. A tissue sample of an animal or cell culture and a UBE3A modulator are recited at a high level of generality.
Claim 10 is drawn to a screening method for the identification of UBE3A protein expression modulators comprising the steps: a) providing a tissue sample of an animal or cell culture which has been treated with a test compound, b) measuring a protein expression level in the sample of step a) of at least one protein selected from the group consisting of: TKT, DZANK1, ACYP1, UBLCP1, YARS,WARS, SOD2 and PSME3, and c) comparing the protein expression level of the at least one protein measured in step b) to the protein expression level of the at least one protein in a control, wherein a modulated protein expression level of the at least one protein measured in step b) compared to the protein expression level of the at least one protein in the control is indicative for a UBE3A protein expression modulator. A test compound is extremely broad and the tissue sample is recited at a high level of generality.
Claims 4 and 18 limit the tissue sample to a blood sample, plasma sample, or a CSF sample.
Claims 6 and 20 limit the UBE3A modulator to an antisense oligonucleotide. Claims 7 and 21 loosely narrow the UBE3A modulator to a UBE3A protein expression level inducer for the treatment of Autism Spectrum Disorder, Angelman Syndrome, or 15qdup syndrome.
State of the prior art. The state of the art at the time of the invention recognized UBE3A as implicated in neurodevelopment disorders. However, the claimed protein biomarkers TKT, DZANK1, ACYP1, UBLCP1, YARS, WARS, SOD2 and PSME3 being modulated by UBE3A expression were not previously recognized.
Khatri et al. (Front. Mol. Neurosci., 2019, Vol. 12, Art. 109, pp.1-12; of record in IDS filed 6/28/2024) discloses that UBE3A is a gene implicated in the neurodevelopmental disorders that encodes the E3 ligase E6-associated protein (E6AP) (see Abstract, p.2, left column, last paragraph, passage bridging pp.2-3, and p.3, passage bridging left and right columns). UBE3A gene amounts are critical to normal brain development—evident from the number of neurological disorders associated with deletions, mutations, and copy number variations of the maternal UBE3A (see p.3, right column, 2nd passage). Khatri et al. teach that within the chromosome region 15q11-q13, the gene UBE3A is imprinted specifically in the brain, resulting in maternal expression of E6AP in human fetal brain and adult cortex, while the paternal copy is silenced by an antisense transcript, UBE3A-ATS (see passage bridging pp.2-3 and Fig. 1A,B). Imprinting of UBE3A is similar and exists in mice and rats and the general expression is mediated by the paternally expressed UBE3A-ATS. Khatri et al. describe that neuronal activity can alter expression of E6AP, such as membrane depolarization or glutamate receptor activation increasing E6AP mRNA expression or inhibitors of NMDA receptor, sodium channel, AMPA receptor decrease E6AP mRNA expression (see p.3, left column, last paragraph). Moreover, topoisomerase I and topoisomerase II inhibitors that unsilenced the paternal UBE3A allele have been demonstrated to restore the loss of E6AP expression (see passage bridging pp.3-4). Khatri et al. further express that since the primary function of E6AP is that of an E3 ligase and its function is mediated by protein ubiquitination, it is critical to identify its downstream targets (see paragraph bridging pp.5-6). Khatri et al. disclose that ubiquitination targets that have been identified include tumor suppressor p53, the PDZ- containing protein Scribble, the transcriptional repressor NFX1-91, the DNA-repair protein HHR23A, the AMPAR-trafficking regulator Arc, the RhoA guanine nucleotide exchange factor Ephexin5, the small-conductance potassium channel SK2, the mTORC1 regulating protein p18, and the inhibitor of apoptosis XIAP (see p.6,-p.8, left column, 1st paragraph, and Fig. 2).
Costa et al. (WO2020/148310; of record in IDS filed 6/28/2024) identifies novel UBE3A targets including the proteins CCDC88A, DST, FAM127A, FAM127B, FAM127C, PEG10, TCAF1, and PPID (see p.1, 4th paragraph). Costa et al. describe a method for measuring UBE3A protein expression modulation in a tissue sample by treating the tissue sample with a UBE3A modulator, measuring the protein expression level of at least one of: CCDC88A, DST, FAM127A, FAM127B, FAM127C, PEG10, TCAF1, and PPID, and comparing the measured expression levels to a control tissue sample. Costa et al. obtained neural stem cells from induced pluripotent stem cells and treated controls with UBE3A sense sequence targeting locked nucleic acids (LNA) 5’-TTTAcacctacttcttaaCA-3’ and treated Angelman Syndrome cells with UBE3A antisense targeting sequence 5’-CTttccatttatttccATTT-3’ and subjected the samples to proteomic analysis to discover the novel biomarkers (see p.9, last paragraph, p.10, 1st paragraph,-p.13, Tables 1-2).
Therefore, the state of the art at the time of the invention was still in development to understand the downstream targeting of E6AP encoded by UBE3A and has only identified a handful of targets, none of which are presently claimed. Furthermore, the prior art only identified agents that target the paternal antisense transcript as UBE3A modulators, specifically, topoisomerase I and topoisomerase II inhibitors and the UBE3A antisense targeting sequence 5’-CTttccatttatttccATTT-3’. Additionally, only neuronal tissue has been identified to be imparted with UBE3A.
Summary of species disclosed in the original specification. MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The instant disclosure provides examples of performing the claimed invention in Angelman Syndrome-induced rat and Angelman Syndrome-induced mice brain tissue and neurons obtained from induced pluripotent stem cells which were all treated with 5’-TTTAcacctacttcttaaCA-3’ or 5’-TTGaataagtggaTGT-3’ (see paragraphs [0098]-[00107] and [00120]-[00124]). Angelman Syndrome was induced by deletion of UBE3A (see paragraph [0092]-[0094]). The specification does not demonstrate the claimed invention in any other tissue beside brain tissue and does not disclose any other UBE3A modulator than 5’-TTTAcacctacttcttaaCA-3’ and 5’-TTGaataagtggaTGT-3’. Given the potential variability encompassed by the genus of tissues and UBE3A modulators, this disclosure cannot be considered representative of the genus of tissues and UBE3A modulators as claimed.
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. As noted above, the art teaches that UBE3A is imparted in the brain of animals and the development of the research is still in its infancy with regards to targets of UBE3A and the downstream targets of EP6A encoded by UBE3A.
For all the reasons presented above, one of skill in the art would not know which of the possible UBE3A modulators and test compounds that Applicant was in possession of other than 5’-TTTAcacctacttcttaaCA-3’ and 5’-TTGaataagtggaTGT-3’. Therefore, the skilled artisan would not reasonably conclude that the inventors, at the time the application was filed, had full possession of the genus UBE3A modulators and test compounds as broadly claimed.
Given the lack of disclosure of a representative population of UBE3A modulators and test compounds, the description of only two antisense modulator species, and the fact the species that were described cannot be considered representative of the broad genus, applicant was not in possession of the invention as claimed.
Applicant may overcome this rejection by amending claims 1, 2, and 3 to require a brain tissue sample and 5’-TTTAcacctacttcttaaCA-3’ and 5’-TTGaataagtggaTGT-3’ as modulators of UBE3A. With regards to claim 10, Applicant may amend the claim to require a brain tissue sample and the test compound to be a locked nucleotide acid (LNA) antisense oligonucleotide compound.
Claim Rejections - 35 USC § 112(b)
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 1-10 and 18-23 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.
Claim 1 recites “providing a tissue sample of an animal or cell culture which has been treated with a UBE3A modulator” in step a). Claim 2 recites “providing a tissue sample of an animal or cell culture which has been treated with a UBE3A inducer” in step d). Claim 3 recites “providing a tissue sample of an animal or cell culture which has been treated with a UBE3A modulator” in step a). Claim 10 recites “providing a tissue sample of an animal or cell culture which has been treated with a test compound” in step a). These recitations are indefinite because it is not clear when the tissue sample of an animal or cell culture of each respective claim is treated with the respective agents. The claim rejections may be overcome by separately reciting “providing a tissue sample of an animal or cell culture,” and “treating the tissue sample with a [respective agent],” which would require active method steps that clarify when the tissue sample is treated.
Claims 4-9 and 18-23 are also rejected for being dependent on a rejected base claim and failing to remedy the issue set forth above.
Claim 2 recites “in a control” in step f). Claim 2 depends from claim 1, which also recites a control in step c). It is not clear if the control of step f) in claim 2 should be a separate control or if it is intended to refer to the control of claim 1 since it references the proteins measured in step b). Consequently, the metes and bounds of the claim limitation cannot be determined by a person of ordinary skill in the art. Applicant may amend claim 1 to recite “a control tissue sample that is not treated with a UBE3A modulator” and claim 2 to recite “a control tissue sample that is not treated with a UBE3A inducer” to overcome this rejection.
Claim 2 recites “measuring a protein expression level in the sample of step a) of at least one protein selected from the group consisting of: TKT, DZANK1, ACYP1, UBLCP1, YARS, WARS, SOD2 and PSME3” and “comparing the protein expression level of the at least one protein measured in step b) to the protein expression level of the at least one protein in a control, wherein a decreased protein expression level of the at least one protein measured in step b) compared to the protein expression level of the at least one protein in the control is indicative for UBE3A protein expression induction” in steps e) and f), respectively. Claim 2 depends from claim 1. Claim 1 steps b) and c) recite the same limitations of steps e) and f) in claim 2. It is not clear if steps e) and f) are intended to be repeated on the tissue sample of step a) and how this is both generally indicative of UBE3A protein expression modulation as recited in step c) and induction as recited in step f). Therefore, a person of ordinary skill in the art would not be able to determine the metes and bounds of the claimed invention.
Regarding claims 6 and 20, the phrase "in particular" renders the claim indefinite because it is unclear whether the limitation following the phrase is part of the claimed invention. See MPEP § 2173.05(d). It is not clear if the limitation “a LNA antisense oligonucleotide” is a required limitation or any antisense oligonucleotide would satisfy the invention of claims 6 and 20.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-10 and 18-23 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more.
Claim 1 recites a method for measuring UBE3A protein expression modulation in a tissue sample comprising: a) providing a tissue sample of an animal or cell culture which has been treated with a UBE3A modulator, b) measuring a protein expression level in the sample of step a) of at least one protein selected from the group consisting of: TKT, DZANK1, ACYP1, UBLCP1, YARS, WARS, SOD2, and PSME3, and c) comparing the protein expression level of the at least one protein measured in step b) to the protein expression level of the at least one protein in a control, wherein a modulated protein expression level of the at least one protein measured in step b) compared to the protein expression level of the at least one protein in the control is indicative for UBE3A protein modulation.
Claim 3 recites a method for determining UBE3A target engagement of an UBE3A modulator comprising the steps: a) providing a tissue sample of an animal or cell culture which has been treated with a UBE3A modulator, b) measuring a protein expression level in the sample of step a) of at least one protein selected from the group consisting of: TKT, DZANK1, ACYP1, UBLCP1, YARS, WARS, SOD2 and PSME3, and c) comparing the protein expression level of the at least one protein measured in step b) to the protein expression level of the at least one protein in a control, wherein a modulated protein expression level of the at least one protein measured in step b) compared to the protein expression level of the at least one protein in the control is indicative for UBE3A target engagement of the UBE3A modulator.
Claim 10 recites a screening method for the identification of UBE3A protein expression modulators comprising the steps: a) providing a tissue sample of an animal or cell culture which has been treated with a test compound, b) measuring a protein expression level in the sample of step a) of at least one protein selected from the group consisting of: TKT, DZANK1, ACYP1, UBLCP1, YARS,WARS, SOD2 and PSME3, and c) comparing the protein expression level of the at least one protein measured in step b) to the protein expression level of the at least one protein in a control, wherein a modulated protein expression level of the at least one protein measured in step b) compared to the protein expression level of the at least one protein in the control is indicative for a UBE3A protein expression modulator.
The methods of claims 1, 3, and 10 are directed to a judicial exception of correlating a protein expression level of at least one of TKT, DZANK1, ACYP1, UBLCP1, YARS,WARS, SOD2 and PSME3 to modulation of UBE3A protein expression, which is a natural phenomenon. This judicial exception is not integrated into a practical application because the claims are considered to be directed to the natural phenomenon and the additional elements are insignificant extra-solution data gathering activity. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements are directed to insignificant extra-solution data gathering activity or abstract mental processes.
Claims 1, 3, and 10 require providing a tissue sample of an animal or cell culture which has been treated with a UBE3A modulator (claims 1 and 3) or a test compound (claim 10). Treatment with a UBE3A modulator or test compound are recited so broadly as to include natural modulations of UBE3A in animal tissue. Khatri et al. (Front. Mol. Neurosci., 2019, Vol. 12, Art. 109, pp.1-12; of record in IDS filed 6/28/2024) describe that neuronal activity can alter expression of E6AP, such as membrane depolarization or glutamate receptor activation increasing E6AP mRNA expression or inhibitors of NMDA receptor, sodium channel, AMPA receptor decrease E6AP mRNA expression (see p.3, left column, last paragraph). Thus, the claimed inventions embrace tissue samples naturally altered in E6AP (UBE3A) at any previous time point without significantly more. The steps of measuring a protein expression level in the sample of step a) of at least one protein selected from the group consisting of: TKT, DZANK1, ACYP1, UBLCP1, YARS,WARS, SOD2 and PSME3 is considered to be directed to the natural phenomenon and insignificant extra-solution data gathering activity, since the alterations in these protein expression levels necessarily naturally occurs. The steps of comparing the protein expression level of the at least one protein measured in step b) to the protein expression level of the at least one protein in a control, wherein a modulated protein expression level of the at least one protein measured in step b) compared to the protein expression level of the at least one protein in the control is indicative for a UBE3A protein expression modulator is an abstract process that can be practically performed in the human mind. Thus, claims 1, 3, and 10 are directed to correlating a change in expression level of at least one of TKT, DZANK1, ACYP1, UBLCP1, YARS,WARS, SOD2 and PSME3 to a change in the expression of UBE3A, which is a natural process.
Claim 2 recites providing a tissue sample of an animal or cell culture which has been treated with a UBE3A inducer. Similarly, this step is so broadly recited so as to embrace natural induction of UBE3A in animal tissue for the same reasons as provided above. Additionally, the step of measuring a protein expression level in the sample of step a) of at least one protein selected from the group consisting of: TKT, DZANK1, ACYP1, UBLCP1, YARS, WARS, SOD2 and PSME3 is considered to be directed to the natural phenomenon and insignificant extra-solution data gathering activity, since the alterations in these protein expression levels necessarily naturally occurs. The steps of comparing the protein expression level of the at least one protein measured in step b) to the protein expression level of the at least one protein in a control, wherein a modulated protein expression level of the at least one protein measured in step b) compared to the protein expression level of the at least one protein in the control is indicative for a UBE3A protein expression induction is an abstract process that can be practically performed in the human mind. Thus, claim 2 is directed to the natural phenomenon without significantly more.
Claims 4 and 18 recite wherein the tissue sample is a blood sample, a plasma sample or a CSF sample, which is directed to the natural phenomenon without significantly more. Khatri et al. teach that within the chromosome region 15q11-q13, the gene UBE3A is imprinted specifically in the brain, resulting in maternal expression of E6AP in human fetal brain and adult cortex, while the paternal copy is silenced by an antisense transcript, UBE3A-ATS (see passage bridging pp.2-3 and Fig. 1A,B). Thus, the recited tissue embraces naturally occurring tissues that undergo the claimed natural phenomenon.
Claims 5 and 19 recite wherein the protein expression level is measured using western blotting, mass spectrometry (MS), Liquid chromatography-mass spectrometry (LC-MS) or immunoassays, which are directed to insignificant extra-solution data gathering activity. Thus, claims 5 and 19 are directed to the natural phenomenon without significantly more.
Claims 6 and 20 recite wherein the UBE3A modulator is an antisense oligonucleotide, in particular a LNA antisense oligonucleotide. Khatri et al. teach that within the chromosome region 15q11-q13, the gene UBE3A is imprinted specifically in the brain, resulting in maternal expression of E6AP in human fetal brain and adult cortex, while the paternal copy is silenced by an antisense transcript, UBE3A-ATS (see passage bridging pp.2-3 and Fig. 1A,B). Thus, Khatri demonstrates that UBE3A is naturally inhibited by UBE3A-ATS. Therefore, claims 6 and 20 further embrace the natural phenomenon without significantly more.
Claims 7 and 21 recite wherein the UBE3A modulator is an UBE3A protein expression level inducer for the treatment of Autism Spectrum Disorder, Angelman Syndrome, or 15qdup syndrome. The claimed inducers embrace naturally occurring inducers since Khatri et al. describe that neuronal activity can alter expression of E6AP (UBE3A), such as membrane depolarization or glutamate receptor activation increasing E6AP mRNA expression or inhibitors of NMDA receptor, sodium channel, AMPA receptor decrease E6AP mRNA expression (see p.3, left column, last paragraph). Khatri et al. further discloses that UBE3A is a gene implicated in the neurodevelopmental disorders that encodes the E3 ligase E6-associated protein (E6AP) such as Autism Spectrum Disorder, Angelman Syndrome, and 15qdup syndrome (see paragraph bridging pp.3-4 and p.4, left column, 1st paragraph,-right column, 1st passage). Therefore, the claimed limitations embrace a natural phenomenon without significantly more.
Claims 8 and 22 recite wherein the protein in step b) is selected from the group consisting of TKT, DZANK1, UBLCP1, and PSME3 and the expression level of these proteins inversely correlates to the UBE3A expression level, which is an abstract process that can be practically performed in the human mind. Thus, claims 8 and 22 are further directed to the natural phenomenon without significantly more.
Claims 9 and 23 recite wherein the protein in step b) is selected from the group consisting of ACYP1, YARS, WARS, and SOD2 and the expression level of these proteins directly correlates to the expression level of UBE3A protein expression level, which is an abstract process that can be practically performed in the human mind. Thus, claims 9 and 23 are further directed to the natural phenomenon without significantly more.
Therefore, the claimed inventions are directed to the natural phenomenon correlating a change in expression level of at least one of TKT, DZANK1, ACYP1, UBLCP1, YARS,WARS, SOD2 and PSME3 to a change in expression level of UBE3A, which is a natural process. The additional elements recited in the claimed inventions do not amount to more than the judicial exception because the additional elements are directed to insignificant extra-solution data gathering activity and an abstract idea. The dependent claims do not recite anything that amounts to more than the exception because the additional claims are directed to the natural phenomenon, abstract ideas, or insignificant extra-solution data gathering activity.
Closest Prior Art
The closest prior art to the claimed invention is to Costa et al. (WO2020/148310; of record in IDS filed 6/28/2024) identifies novel UBE3A targets including the proteins CCDC88A, DST, FAM127A, FAM127B, FAM127C, PEG10, TCAF1, and PPID (see p.1, 4th paragraph). Costa et al. describe a method for measuring UBE3A protein expression modulation in a tissue sample by treating the tissue sample with a UBE3A modulator, measuring the protein expression level of at least one of: CCDC88A, DST, FAM127A, FAM127B, FAM127C, PEG10, TCAF1, and PPID, and comparing the measured expression levels to a control tissue sample. The instantly claimed invention differs from Costa et al. in that the protein expression level of at least one of: TKT, DZANK1, ACYP1, UBLCP1, YARS, WARS, SOD2 and PSME3 is/are measured, which are not disclosed in Costa. The Examiner has not found any teaching or suggestion in the prior art to measure the protein expression level of at least one of: TKT, DZANK1, ACYP1, UBLCP1, YARS, WARS, SOD2 and PSME3 to correlate to an expression level or modulation of expression of UBE3A. Therefore, the claimed invention is free of the prior art.
Conclusion
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/J.P.S./Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651