DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. 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
2. Applicant’s election of Group I and the species of Elavl2 in the reply filed on 10 October 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim Status
3. Claims 1-5, 9-12, 14-17, 23, 25, 26, 28, 35 and 36 are pending.
Claims 11, 12, 14-17, 35 and 36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claim 9 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Note that claim 9 is considered to be directed to methods wherein the gene is one of the non-elected genes of Nek6, Pphlnl, Pdgfc, Pomtl, Sprbsl, Ssfa2, Rps6kb2, Cpeb4, Calu, Pard3, Ranpb3, Prx, 2810474019Rik, Mtdh, Arl6, Tbp, Slx4, Osbpl1a, Pex7, Camk1g, or Idnk (i.e., a gene other than the elected species of the Elavl2 gene).
Claims 1-5, 10, 23, 25, 26 and 28 read on the elected invention and have been examined herein. The claims have been examined to the extent that they read on the elected species of the Elavl2 gene. The claims encompass the non-elected species of genes other than Elavl2 and combinations of genes. Prior to the allowance of claims, any non-elected subject matter which has not been rejoined with the elected subject matter will be required to be removed from the claims.
Claim Rejections - 35 USC § 101
4. 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 1-5, 10, 23, 25, 26 and 28 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of a law of nature / natural phenomenon, and/or an abstract idea without significantly more. The judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Applicant' s attention is directed to MPEP 2106 “Patent Subject Matter Eligibility” which discusses the Alice/Mayo two-part test for evaluating subject matter eligibility.
Regarding Step 1 of the subject matter eligibility test set forth at MPEP 2106III, the claims are directed to the statutory category of a process.
Regarding Step 2A, prong one, the claims recite the judicial exception of a law of nature. The claims recite the correlation between the level of isoforms of the Elavl2 gene and pre-symptomatic ALS. That is, claims 1-5, and 10 recite “identifying the subject as having pre-symptomatic ALS if the absolute value of the ΔΨ score is not zero (0)” wherein the ΔΨ score is a score based on the level of isoforms of the ELavl2 gene. Claims 23, 25, 26 and 28 recite that “the subject has been characterized as having pre-symptomatic ALS by the method of claim 1” and thereby are considered to require characterizing a subject as having pre-symptomatic ALS based on a change in the level of isoforms of the Elavl2 gene. As in Mayo Collaborative Services v. Prometheus, the recited relationship is a natural phenomenon that exists apart from any human action. See also Cleveland Clinic Foundation v. True Health Diagnostic, LLC, 2018-1218 (Fed Cir. 2019) which states that “The re-phrasing of the claims does not make them less directed to a natural law.”
The claims also recite the judicial exception of an abstract idea and particularly mental processes.
MPEP 2106.04(a) states that the enumerated groupings of abstract ideas include:
“1) Mathematical concepts – mathematical relationships, mathematical formulas or equations, mathematical calculations (see MPEP § 2106.04(a)(2), subsection I);…
3) Mental processes – concepts performed in the human mind (including an observation, evaluation, judgment, opinion) (see MPEP § 2106.04(a)(2), subsection III).”
The claims require performing the steps of “calculating” a psi score; “comparing” a psi score to that of a control and “identifying” a subject as having pre-symptomatic ALS if the absolute value of the ΔΨ score is not zero (0).
Neither the specification nor the claims set forth a limiting definition for “calculating,” "comparing" or “identifying” and the claims do not set forth how these steps are accomplished. The broadest reasonable interpretation of the “comparing” step is that this step may be accomplished by critical thinking processes. Such “comparing” thereby encompasses only an abstract idea / process. Similarly, “identifying” may also be accomplished by critical thinking processes. “Identifying” may also be accomplished verbally. Such verbal communication is also abstract, having no particular concrete or tangible form.
The calculating step may also be accomplished by critical thinking processes or with the aid of pen and paper or a generic computer. Such calculating is considered to be an abstract idea. Note that the use of pen and paper or a generic computer or software program to implement an abstract idea does not itself impart patent eligibility.
As stated in MPEP 2106.04(a)(2) III “The courts do not distinguish between mental processes that are performed entirely in the human mind and mental processes that require a human to use a physical aid (e.g., pen and paper or a slide rule) to perform the claim limitation” and that “Nor do the courts distinguish between claims that recite mental processes performed by humans and claims that recite mental processes performed on a computer.”
The claims also recite the judicial exception of a mathematical concept of the formula that is used to calculate the psi score and delta psi score. See MPEP 2106.04(a)(2):
“A claim that recites a mathematical calculation, when the claim is given its broadest reasonable interpretation in light of the specification, will be considered as falling within the “mathematical concepts” grouping. A mathematical calculation is a mathematical operation (such as multiplication) or an act of calculating using mathematical methods to determine a variable or number, e.g., performing an arithmetic operation such as exponentiation. There is no particular word or set of words that indicates a claim recites a mathematical calculation. That is, a claim does not have to recite the word “calculating” in order to be considered a mathematical calculation. For example, a step of “determining” a variable or number using mathematical methods or “performing” a mathematical operation may also be considered mathematical calculations when the broadest reasonable interpretation of the claim in light of the specification encompasses a mathematical calculation.”
Regarding Step 2A, prong two, having determined that the claims recite a judicial exception, it is then determined whether the claims recite additional elements that integrate the judicial exception into a practical application.
Herein, the claims do not recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). The additionally recited step of detecting levels of two or more isoforms of ELavl2 in a biological sample from a subject is part of the data gathering process necessary to observe the judicial exception. These steps do not practically apply the judicial exception.
Regarding claims 23, 25 and 26, these claims recite “administering to the subject a therapeutic agent,” including agents that are any peptide, protein (or any antibody in claim 28), nucleic acid or small molecule. These treatments are recited at a high degree of generality and encompass treatments that are not for pre-symptomatic ALS or ALS per se. Accordingly, the administering step is merely an “apply it” limitation and is not a practical application of the judicial exception.
Regarding specific treatments, see MPEP 2106.04(d)(2):
When determining whether a claim applies or uses a recited judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition, the following factors are relevant.
a. The Particularity Or Generality Of The Treatment Or Prophylaxis
The treatment or prophylaxis limitation must be "particular," i.e., specifically identified so that it does not encompass all applications of the judicial exception(s). For example, consider a claim that recites mentally analyzing information to identify if a patient has a genotype associated with poor metabolism of beta blocker medications. This falls within the mental process grouping of abstract ideas enumerated in MPEP § 2106.04(a). The claim also recites "administering a lower than normal dosage of a beta blocker medication to a patient identified as having the poor metabolizer genotype." This administration step is particular, and it integrates the mental analysis step into a practical application. Conversely, consider a claim that recites the same abstract idea and "administering a suitable medication to a patient." This administration step is not particular, and is instead merely instructions to "apply" the exception in a generic way. Thus, the administration step does not integrate the mental analysis step into a practical application….
b. Whether The Limitation(s) Have More Than A Nominal Or Insignificant Relationship To The Exception(s)
The treatment or prophylaxis limitation must have more than a nominal or insignificant relationship to the exception(s). For example, consider a claim that recites a natural correlation (law of nature) between blood glucose levels over 250 mg/dl and the risk of developing ketoacidosis (a life-threatening medical condition). The claim also recites "treating a patient having a blood glucose level over 250 mg/dl with insulin". Insulin acts to lower blood glucose levels, and administering insulin to a patient will reduce the patient’s blood glucose level, thereby lowering the risk that the patient will develop ketoacidosis. Thus, in the context of this claim, the administration step is significantly related to the recited correlation between high blood glucose levels and the risk of ketoacidosis. Because insulin is also a "particular" treatment, this administration step integrates the law of nature into a practical application. Alternatively, consider a claim that recites the same law of nature and also recites "treating a patient having a blood glucose level over 250 mg/dl with aspirin." Aspirin is not known in the art as a treatment for ketoacidosis or diabetes, although some patients with diabetes may be on aspirin therapy for other medical reasons (e.g., to control pain or inflammation, or to prevent blood clots). In the context of this claim and the recited correlation between high blood glucose levels and the risk of ketoacidosis, administration of aspirin has at best a nominal connection to the law of nature, because aspirin does not treat or prevent ketoacidosis. This step therefore does not apply or use the exception in any meaningful way. Thus, this step of administering aspirin does not integrate the law of nature into a practical application.(Emphasis added).
Regarding Step 2B, the next question is whether the remaining elements/steps – i.e., the non-patent-ineligible elements/steps - either in isolation or combination, amount to significantly more than the judicial exception.
Herein, the claims as a whole are not considered to recite any additional steps or elements that amount to significantly more than routine and conventional activity and do not add something “significantly more” so as to render the claims patent-eligible. The additionally recited step in claim 1 of detecting the level of isoforms of Elavl2 in a biological sample obtained from a subject is recited at a high degree of generality, covering any method of detecting nucleic acids. Methods of detecting and quantifying nucleic acids, including methods of RNA sequencing (RNA-seq; see claim 14) were well-known, routine and conventional in the prior art. This finding is supported by the teachings in the specification at para [0059] and [0119-0120] (note that paragraph numbering herein is with respect to the published application), which disclose that methods of RNA sequencing, including next generation sequencing, were well-known in the prior art. This finding is also supported by the teachings of Akerman et al (WO 2019/226804; cited in the IDS) which teaches well-known RNA-seq platforms for detecting alternative splicing of RNA transcripts (e.g., para [075] and [0162]); the teachings of Katz et al (Nature Methods. 2010. 7(12): 1009-1015; cited in the IDS) which teaches methods of RNA sequencing to identify RNA isoforms present in a mixture of isoforms (e.g., abstract and p. 2); and the teachings of Prudencio et al (Nature Neuroscience. 2015. 18: 1175; cited in the IDS) which teaches the use of RNA-seq to screen for alternative splicing transcripts in brain tissue of subjects having ALS (e.g., p. 1175, col. 2 to p. 1176 col. 1).
See also MPEP 2106.05(d) II which states that:
The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
iii. Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
iv. Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
v. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
vi. Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
vii. Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
Note that while the claims recite detecting isoforms of a particular gene (i.e., the Elavl2 gene), the identity of the gene is part of the judicial exception and not something in addition to the recited judicial exceptions. The claims do not require using a particular non-conventional reagent, such as a particular, non-conventional probe or primer consisting of or comprising a specific nucleotide sequence so as to add something ‘significantly more’ to the recited judicial exceptions.
Further, to the extent that a computer may be intended to be used to accomplish the calculating step, MPEP 2106.05(a) states that ”Limitations that the courts have found not to be enough to qualify as “significantly more” when recited in a claim with a judicial exception include: i. Adding the words “apply it” (or an equivalent) with the judicial exception, or mere instructions to implement an abstract idea on a computer, e.g., a limitation indicating that a particular function such as creating and maintaining electronic records is performed by a computer, as discussed in Alice Corp., 134 S. Ct. at 2360, 110 USPQ2d at 1984 (see MPEP § 2106.05(f))”
In Mayo v. Prometheus, the Supreme Court stated: "[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately."
This is similar to the present situation wherein the additional steps and elements are recited at a high degree of generality and are all routine, well understood and conventional in the prior art. The recited steps and elements do not provide the inventive concept necessary to render the claims patent eligible. See also Genetic Technologies Ltd. v. Merial L.L.C. 818 F.3d at 1377, 1379 (Fed. Cir. 2016).
For the reasons set forth above, when the claims are considered as a whole, the claims are not considered to recite something significantly more than a judicial exception and thereby are not directed to patent eligible subject matter.
Improper Markush Grouping Rejection
5. Claims 1-5, 10, 23, 25, 26 and 28 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush groupings of the genes recited in claim 1 and combinations thereof are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
It is first noted that MPEP 2117 states that “A Markush claim may be rejected under judicially approved "improper Markush grouping" principles when the claim contains an improper grouping of alternatively useable members. A Markush claim contains an "improper Markush grouping" if either: (1) the members of the Markush group do not share a "single structural similarity" or (2) the members do not share a common use. Supplementary Guidelines at 7166 (citing In re Harnisch, 631 F.2d 716, 721-22, 206 USPQ 300, 305 (CCPA 1980)). “ Members of a Markush group share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class (prong 1) and the members of a Markush group share a common function or use when they are disclosed in the specification or known in the art to be functionally equivalent (prong 2).
The phrase “significant structural element is shared by all of the alternatives” refers to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity.
A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved.” (see MPEP 2117IIA).
Herein, the recited alternative species do not share a single structural similarity, as each gene has a different chemical structure in that it consists of a different nucleotide sequence. The only structural similarity present is that all of the genes comprise nucleotides. The fact that the genes comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising nucleotides alone is not essential to the asserted common activity of having a change in a psi score for the level of isoforms of the genes and risk of pre-symptomatic ALS. Accordingly, while the different genes are asserted to have the property of being correlated with pre-symptomatic ALS, they do not share a substantial structural similarity essential to this activity. Note that the teachings in the specification make clear that not any gene can be used in the claimed methods but only “certain genes.” For instance, the specification states at para [0039] “The disclosure is based, in part, on the recognition that isoforms of certain genes as described herein undergo alternative splicing changes that are detectable (e.g., quantifiable) in a biological sample obtained from a subject having or at risk of having pre-symptomatic ALS/FTD.”
Further, the recited genes do not belong to a chemical or art-recognized class because there is no expectation from the knowledge in the prior art that the genes behave in the same manner and can be substituted for one another with the same intended result achieved. There is no evidence of record to establish that it is clear from their very nature that the recited genes possess the common property of having a level of two or more isoforms that ais diagnostic of pre-symptomatic ALS.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
6. 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 1-5, 10, 23, 25, 26 and 28 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.
Claims 1-5, 10, 23, 25, 26 and 28 are indefinite over the use of the acronym “psi” score. This term has not been clearly defined in the specification or claims. The use of an acronym renders the claims indefinite because the acronym may have many different meanings in the art. For instance, “psi” can refer to Pneumonia Severity Index or Pounds per square inch. This rejection may be overcome by amendment of the claim 1 at (ii) to recite “Percent Spliced-In (PSI).”
Claim Rejections - 35 USC § 112(d) / Fourth paragraph
7. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 23, 25, 26 and 28 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 23, 25, 26 and 28 are drawn to a method of treating pre-symptomatic ALS comprising administering to the subject a therapeutic agent, wherein the subject has been characterized as having pre-symptomatic ALS by the method of claim 1. Claim 1 is drawn to a “method for identifying a subject as having pre-symptomatic amyotrophic lateral sclerosis (ALS)” and does not include steps of characterizing a subject as having pre-symptomatic ALS. While claims 23, 25, 26 and 28 depend from claim 1, they only define the subject in terms of one who has been characterized as having pre-symptomatic ALS by the method of claim 1. Claims 23, 25, 26 and 28 do not require performing each of the process steps of claim 1 from which they depend. Also, claim 1 is not limited to only methods that identify a subject as having ALS because in the method of claim 1 the subject is identified as having pre-symptomatic ALS “if” the absolute value of the ΔΨ score is not zero (0), and thereby the claim includes methods wherein the ΔΨ score is not zero. Thereby, claims 23, 25, 26 and 28 fail to include all the limitations of the claim upon which it depends and do not properly depend from claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
8. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Bandyopadhyay et al (PLoS ONE. 03 Jan 2013. 8(1): e53575) discloses methods for identifying RNAs that are alternatively spliced in a presymptomatic ALS mouse strain transgenic for a mutant human SOD1 (G85R; e.g., abstract). Bandyopadhyay performed whole transcriptome RNA-seq analysis of samples from the presymptomatic SOD ALS mouse strain and compared the sequencing data to that of a control mouse (e.g., p. 6, col. 2). The reference (p. 4, col. 1) states:
“Recent studies using a Tdp43 knockdown model for ALS have suggested that misregulation of RNA-splicing is a major contributor to ALS onset and progression in that setting [18]. In contrast, the effect here of transgenic G85R SOD1-YFP on motor neuron RNA splicing was minimal. We detected only 8 of the 287 aberrant splicing events identified in the Tdp43 study in either wild-type or G85R transcriptomes. Of these, only three genes, Eif4h, Hisppd2a, and Spp1, showed evidence of differential
splicing exclusively in the G85R strain (validated by qRT-PCR; Table S5), suggesting that mutant SOD1 is associated with a different mechanism of disease causation.”
In Supplemental Table S5, Bandyopadhyay discloses splice variants that were detected in wild-type and G85R motor neurons. Table S5 includes the entry “2663” for Elavl2 and the occurrence of 1 splice variant in the G85R replicate 1 (see below). In contrast, Table S5 shows that multiple isoforms / spliced variants of EIF4H were detected in wildtype samples as compared to G85R samples (entries 2764-2767 below) and that multiple isoforms / spliced variants of SPP1 were detected in either wildtype samples or in G85R SOD mutant samples (entries 26912-26917 below):
PNG
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18
990
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Greyscale
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20
1014
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Versus EIF4H:
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64
1010
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Greyscale
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122
884
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Greyscale
Bandyopadhyay does not teach the detection of two or more isoforms of Elavl2 in samples from the asymptomatic ALS mouse and does not teach or suggest calculating a percent spliced-in (psi) score for Elavl2 in the sample from the mouse and comparing the psi score to a psi score of Elavl2 in a control sample to produce a delta psi score and identifying a subject as having pre-symptomatic / asymptomatic ALS if the absolute value of the delta psi score is not zero.
van Blitterswijk et al (PLoS ONE. April 2013. 8(4): e60788 and Supporting Information, 37 pages total) discloses methods for identifying RNAs that are differentially spliced in amyotrophic lateral sclerosis wherein the methods comprise performing RNA-seq to analyze the RNAs present in HEK-293T cells having R521G or R522G FUS mutations as compared to wildtype cells (e.g., abstract and p. 2 col. 2 to p. 3 col. 1). The reference states “To study the effects of wild-type and mutant forms of FUS, we utilized RNA-Seq analysis to investigate alterations in gene expression and alternative splicing” (p. 4, col. 2). Alterations in exon skipping were detected in the RPS24 and PRPF8 genes in cells carrying mutant FUS (Table 4 and p. 6 col. 1 “Among the specific molecular targets that were affected by FUS, we validated the expression patterns of RBM25, TAF15, TARS, TPR, and APP, and the alternative splicing of PRPF8 and RPS24”).
Smith et al (U.S. 20160265057) teaches methods for identifying differentially spliced genes in cells in response to serum from presymptomatic ALS mice as compared to serum from aged-matched normal mice (para [0035]). CK1γ2 was identified as a significantly differentially spliced gene in those cell samples contacted with serum from presymptomatic ALS mice as compared samples contacted with serum from age-matched normal mice (para [0036]). Smith (para [0035]) states “These data suggest differential splicing of CK1γ2 in response to presymptomatic ALS serum.” It is stated that the methods disclosed therein can be used to develop a “classifier for detection of presymptomatic ALS using human serum.” The genes used to train the classifier for detecting presymptomatic ALS are set forth in para [0046].
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/CARLA J MYERS/Primary Examiner, Art Unit 1682