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 .
Status of Claims
Claims 1-14 are pending in the instant application and the subject of this non-final office action.
Priority
It is noted that the default priority date is the actual filing date of the application. See MPEP 2152.01. To properly claim benefit to a provisional application under 35 USC 119(e), the claims must be fully supported under 35 USC 112.
As discussed in further detail in the 112(a) section below, claims 1-14 lack support for “diagnosing” and claims 1-10 lack support for predicting any phenotype. Thus, these claims are not entitled to the date of the provisional application.
Claim Interpretation
In evaluating the patentability of the claims presented in this application, claim terms have been given their broadest reasonable interpretation (BRI) consistent with the specification, as understood by one of ordinary skill in the art, as outlined in MPEP 2111.
Regarding claims 1 and 11, “relative expression” is defined as “the exon expression relative to the expression of other exons of the same gene” (para [0018]). Para [0018] further states: “Exon expression is calculated from the total amount of mRNA containing the exon expressed.” It is noted that para [0028] states that “Reads overlapping introns were not counted.” The artisan would understand that “the total amount of mRNA containing the exon expressed” would be interpreted to exclude possible retained introns and alternative 5’ and 3’ splice sites that are labeled as “intronic” under such an exon annotation. This is further supported by Supplementary Figure 2 of Chiang (Chiang AH, et al. Exons as units of phenotypic impact for truncating mutations in autism. Mol Psychiatry. 2021 May;26(5):1685-1695. Epub 2020 Oct 27), which was intended to be incorporated by reference.
The term “phenotype dosage sensitivity” is defined as “the slope of the fitted regression between the relative expression of a target exon and the effect of a mutation” (para [0015]). Para [0015] further defines “PDS is a parameter which quantifies the relationship between changes in a gene's dosage and changes in a given disease phenotype”.
The terms "predicting" or "prediction" are defined as “forecasting of likely or expected phenotypes, traits, symptoms, conditions, or survival associated with an illness or condition” (para [0017]).
The terms "diagnosing" or "diagnose" are defined as “detecting and identifying a disease/disorder in a subject”.
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 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 “predicting” non-verbal IQ in samples from individuals with ASD/autism, does not reasonably provide enablement for “diagnosing” (diseases/disorders) or predicting any phenotype in any sample/individual. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Regarding claims 1-10, the applicant’s disclosure lacks sufficient detail to enable one of
ordinary skill in the art to use the full scope of the claimed invention, as required under 35 U.S.C. 112(a). See MPEP 2164.01(a) for the factors considered.
Under the applicant’s definition of “diagnosing” (see Claim Interpretation above), identification and detecting a disease/disorder of a subject is required. In contrast to this, the applicant provides a working example with data in Fig. 1 and para [0023-24] and [0031-38] that provides a linear regression between normalized nonverbal IQ and relative expression of “exon containing LGD mutation” in individuals from an ASD cohort. Thus, while predicting IQ in ASD individuals is enabled, the disclosure fails to provide guidance, direction, or working examples of a phenotype dosage sensitivity regression model being utilized to detect just any disease/disorder (i.e., “diagnose”).
The invention is in the class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The prior art describes unpredictability of the effects of “mutations” within exons. Rivas (Rivas MA, et al. Effect of predicted protein-truncating genetic variants on the human transcriptome. Science. 2015 May 8;348(6235):666-9.) teaches that protein truncating variants (PTV) [i.e., likely gene disrupting/loss of function] are abundant in the genome of healthy individuals, indicating that they often do not have major phenotypic consequence (pg. 666, para 1). Rivas teaches that while PTVs are often described as in most cases their precise molecular effect has not been characterized (pg. 666, para 1). Rivas further teaches that PTVs that generate premature stop codons may trigger nonsense-mediated decay (NMD), wherein such variants are often recessive and [NMD] may protect against detrimental phenotype effects but [NMD] may alternatively cause disease via haploinsufficiency or a dominant-negative or gain-of-function truncated protein (pg. 667, col 2, para 1). This indicates that “mutations” in exons are not predicable, based on the prior art, for their molecular or clinical effects—specifically, that expression cannot broadly predict whether the result will be phenotypically positive or negative for a subject (i.e., due to the mixed potential for haploinsufficiency, dominant-negative, or gain-of-function absent other functional data).
Additionally, Rivas provides two examples of allele-specific expression, wherein one has heterogenous effects across different tissue type (Fig. 2E) and the other has more uniform allele-specific expression across all tested tissues (Fig. 2F). This indicates that the effects of “mutations” in exons on expression are not predictable, based on the prior art, across sample types.
The specification fails to provide a clear indication of what tissues/sources the expression data comes from. Para [0031] states that “Gene expression changes due to LGD variants in GTEx”, and para [0036] states that “separate analyses are performed for each tissue” (in the context of parameter estimation). However, no indication was found of the tissue/RNA-seq sample origins utilized in the PDS regression model in either the specification or Chiang.
The prior art teaches that the relationship between IQ and the disorder of autism/ASD is heterogenous. Wolff (Wolff N, et al. Autism Spectrum Disorder and IQ - A Complex Interplay. Front Psychiatry. 2022 Apr 18;13:856084) teaches that the number of autistic individuals with intellectual disability has seemingly decreased from 70% to 30% over the past 50 years (pg. 2, col 1, para 1), in part due to changes in disorder classification taxonomy, which now includes individuals with higher IQs (pg. 2, Heterogeneity as Effigy of an Altered Autism Spectrum Disorder Taxonomy). Wolff further teaches that the diagnosis of autism is complicated by questions of the validity of the IQ tests for individuals with autism (pg. 4, col 1, para 1-2) and the propensity of the ADOS-2 to over classify individuals below average IQ and misclassify those with above average IQ (pg. 4, col 1, para 3, spanning col 2). Wolff teaches that the distributions of IQ levels of ASD, non-ASD, and exemplary “norm” samples overlap (Fig. 1). Thus, the prior art teaches that IQ is not a predictable proxy for a diagnosis of autism or ASD.
The claims are broad and encompass any one or more exon and predicting one or more phenotype or diagnosis. However, as discussed, only data is provided for exons being used to generative a predictive model for IQ in an autism/ASD cohort.
Thus, given the breath of the claims and the limited working example; the prior art teachings of unpredictability in 1) the positive or negative effects on clinical outcomes of expression for a given “mutation”, 2) the effects of such “mutations” comprising at least PTVs on expression in different sample types, and 3) the ability for IQ to serve as a proxy for diagnosis of autism/ASD; and the limited direction provided, balanced only against the high skill of one in the art, the quantity of experimentation needed to use the invention is considered to be undue. Therefore, while the specification supports prediction non-verbal IQ in individuals with ASD/autism, it not enabled for predictions of other phenotypes or the diagnosis (i.e., detection and identification of a disease/disorder).
Claims 11-14 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Regarding claims 11-14, claim 11 recites a method for diagnosing a genetic disorder comprising diagnosing one or more potential phenotypes by fitting a phenotype dosage sensitivity regression model.
The same unpredictability rationales and citations applied in claims 1-10 apply here.
Thus, given the breath of the claims to diagnosing any genetic disorder and the limited working example; the prior art teachings of unpredictability in 1) the positive or negative effects on clinical outcomes of expression for a given “mutation”, 2) the effects of such “mutations” on expression in different sample types, and 3) the ability for IQ to serve as a proxy for diagnosis of autism/ASD; and the limited direction provided, balanced only against the high skill of one in the art, the quantity of experimentation needed to use the invention is considered to be undue. Therefore, while the specification supports prediction non-verbal IQ in individuals with ASD/autism, it not enabled for the diagnosis of genetic disorders.
Claims 1-14 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 claim(s) contains 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 inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claims 1-14, claim 1 requires diagnosing or predicting one or more potential phenotypes and claim 10 requires diagnosing one or more potential phenotypes in a method for diagnosing a genetic disorder. The instant specification and Chiang provide only the working example of the prediction of non-verbal IQ in an autism/ASD population. This species is not sufficient to represent all possible phenotypes and/or genetic disorders, not least in view of the same considerations taught by Rivas as discussed in the rejection of 1-10 above under the enablement requirement, in particular the diversity of mutation types (gain-of-function, dominant negative, etc.) and clinical impact.
For this reason, and given the breath of genes and phenotypes/disease/disorders, claims 1-14 lack written description support sufficient to convey to a skilled artisan that the Applicant had possession of the of the full breadth of the claimed invention at the time of filing.
Regarding claim 6, the claim requires that relative expression is calculated from a mutation’s location in a gene. This same relative expression for each exon containing mutations is then used in predicting one or more phenotypes in a PDS. The instant specification is silent as to terms including “location”, “distance”, and “position” (outside of the x-axis/y-axis descriptions). Chiang describe an analyses separate from a prediction in which the position of the mutations is analyzed, but neither a calculation of “relative expression” or incorporation into the relative expression analysis was identified.
For this reason, claims 1-14 lack written description support sufficient to convey to a skilled artisan that the Applicant had possession of claimed invention of “the relative expression is calculated from a mutation’s location in a gene” at the time of filing.
It is noted that the incorporation by reference of Chiang in para [0043] of the instant specification is not effective under 35 CFR 1.57 as it 1) is not a US patent or US patent application publication and 2) provides support for claimed features including the additional phenotype of behavior predicted in Fig. 6 of Chiang, i.e., “essential material”. All material required to support the claimed inventions must be amended into the specification. See 35 CFR 1.57(d) and the noted potential required support in the rejections below.
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 1-14 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 claims 1 and 11, the claims recite “v) diagnosing…by fitting the relative expression into a…PDS…regression mode, and vi) optionally, if a PDS is unknown for an exon, then calculating a PDS linear regression model for said exon”. It is unclear how one may first fit the relative expression for each exon into a PDS regression model if a PDS may be unknown. Additionally, it is unclear if vi) is intended to be truly optional or merely conditional.
The claims recite “identifying mutations in one or more exons…for each exon containing mutations”. It is not clear whether the exons in question must contain plural (i.e., two or more) “mutations” or if the “mutations” are referring to the collective set of mutations in the one or more exons.
Claims 2-10 and 12-14 are indefinite for depending from claims 1 or 11 and not rectifying the deficiency.
Regarding claims 1 and 4, claim 1 recites “identifying mutations in one or more exons” and claim 4 recites “wherein the mutations comprise one or more of the following…splice acceptor variants, splice donor variants”. As would be recognized by one of skill in the art, the splice donor and acceptor motifs span both exonic and intronic nucleotides, and indeed the most critical sites are in the intron for most introns (Yeo G, Burge CB. Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J Comput Biol. 2004;11(2-3):377-94.: Fig. 6 and 8; pg. 382, 3.1. Construction of transcript data, para 1). Thus, it is not clear if claim 1 is attempting to redefine the term “exon” to encompass the exon and the adjacent splice sites when the term of art means “a region of RNA that is retained after introns are spliced out“ (i.e., excludes splice sites), or, alternatively, if claim 4 is attempting to redefine splice donor/acceptor as only those nucleotides present within the exon.
The specification fails to provide guidance regarding this. It recites only the generic “splice-site” mutation (para [0014]), wherein such a mutation is not limited by location, implying the former interpretation. It is noted that Supplementary Fig. 2 of Chiang, ineffectually incorporated by reference, appears to support the former interpretation.
Claims 2-10 are indefinite for depending from claim 1 and not rectifying the deficiency.
Regarding claim 6, the claim recites “the relative expression is calculated from a mutation’s location in a gene”. The nexus to the defined calculation of relative expression is unclear (i.e., is it intended to replace or be included in a larger calculation?), as is the connection between data on “location in a gene” to “expression”. It is noted that no examples or guidance is provided in the instant specification.
Regarding claim 10, the claim recites “the potential phenotype”. There is insufficient antecedent basis for this limitation in the claim. Claim 1 recites “the one or more potential phenotype”. It is unclear which potential phenotype is being referred to.
Regarding claim 11, the claim recites “diagnosing a genetic disorder” but fails to recite an active step in which a genetic disorder is diagnosed.
Claims 12-14 are indefinite for depending from claim 11 and not rectifying the deficiency.
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 1-14 rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. The claim(s) recite(s) natural phenomena/abstract ideas. This judicial exception is not integrated into a practical application. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
The following three inquiries are used to determine whether a claim is drawn to patent-eligible subject matter:
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter?
Yes, the claims 1-14 are directed to a process.
Step 2A, prong 1. Does the claim recite a law of nature, a natural phenomenon, or an abstract idea (recognized judicial exceptions)?
Claims 1 and 11 recite calculations of relative expression and of a regression model and using these together to diagnose (or predict in claim 1) one or more phenotypes based on expression. Therefore, the claims are directed to an abstract idea, including mathematical calculation (encompassing calculating relative expression and “fitting” a regression model, both of which may be performed by hand) and mental processes (identifying mutations and diagnosing/predicting). See MPEP 2106.04(a). The claims also recite the natural phenomenon between expression levels of one or more exons and one or more phenotypes.
Step 2A, prong 2. Is the judicial exception integrated into a practical application?
Regarding claim 1, the claim further recites steps of collecting a sample and sequencing nucleic acids. As discussed in MPEP 2106.04(d), the courts have identified that adding c is not sufficient to integrate the judicial exception into a practical application. Recited at a high level of generality, collecting a sample and sequencing nucleic acids amount to mere data gathering. See 2106.05(g).
Regarding claims 2, 4, and 10, claim 2 recites sample types, claim 4 recites classes of identified mutations, and claim 10 recites phenotypes. Therefore, these amount to choices of data and insignificant extra-solution activity.
Regarding claim 3, the claim recites general, well-known classes of “sequencing” methods such the limitation amounts to necessary data gathering when recited at such a high generality. See MPEP 2106.05(g).
Regarding claim 5-9, the claims recite calculation limitations encompass choices of data and/or methods of calculation. Therefore, these fail to integrate the claims into a practical limitation.
Regarding claim 11, as with claim 1, the steps of collecting a sample and sequencing, recited at a high level of generality, are insufficient to integrate the claim into a practical application as they are insignificant extra-solution activity.
Regarding claim 12, as with claim 10, a particular phenotype/genetic disorder amounts to a choice of data and does not integrate the claim into a practical application.
Regarding claims 13 and 14, MPEP 2106.04(d)(2) discusses the three factors for determining whether a treatment for a disease is sufficient to integrate a judicial exception into a practical application. In the instant case, “administering a treatment” in claim 13 is recited at such a high level of generality that amounts to mere instructions to “apply” the exception. The limitation of claim 14 that the therapy be “personalized” fails to sufficiently reduce the generality of the treatment; further, it encompasses treatments that have only a nominal or insignificant relationship to the exception.
Step 2B. Does the claim amount to significantly more?
Regarding claims 1-14, the claims do not recite additional elements that are sufficient to amount to significantly more than the judicial exception because the practical steps of the claims are well understood, routine, and convention in the related art, as cited in Step 2A Prong Two. In the instant case, the additional elements are data gathering steps, calculation steps, or selections of specific data. The treatment discussed above is not particular or is limited to treatments that have more than a nominal or insignificant relationship to the exceptions.
Therefore, the claims include no additional elements sufficient to represent significantly more.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-5 and 7-10 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chiang (Chiang AH, et al. Exons as units of phenotypic impact for truncating mutations in autism. Mol Psychiatry. 2021 May;26(5):1685-1695. Epub 2020 Oct 27), evidenced by Fischbach (Fischbach GD, Lord C. The Simons Simplex Collection: a resource for identification of autism genetic risk factors. Neuron. 2010 Oct 21;68(2):192-5).
Regarding claims 1-3, Chiang teaches collecting a sample from a subject and sequencing nucleic acids from a sample, evidenced by Fischbach. While Chiang does not explicitly teach sample collection and sequencing it is inherently taught because Chiang teaches that the genetic and phenotypic data was collected in the database of Fischbach (Introduction, para 1) and the exome sequencing was used (Supplementary Methods, SSC sequencing and phenotype data, para 1; instant claim 3) and Fischbach collected a blood sample from each study participant (pg. 193, Resources Available to the Research Community, para 1; instant claim 2) and states pending availability of high-throughput DNA sequencing for additional mutations (pg. 194, Looking Ahead, para 1). Thus it follows that the DNA/exome sequencing was inherently performed.
Chiang teaches mutations in one or more exons of the exome sequencing were obtained [i.e., had been identified from the sequencing] ((Supplementary Methods, SSC sequencing and phenotype data, para 1).
Chiang teaches calculating a relative expression for each exon containing mutations (Supplementary Materials, pg. 55, Gene expression changes due to LGD variants in GTE, spanning pg. 57, Changes in total gene expression due to LGD variants; pg. 59, Methods Fig. 1; Fig. 4).
Chiang teaches predicting the effect of LGD mutations [in exons] on the phenotype of non-verbal IQ (Fig. 4: “predicting the effects of LGD mutations on NVIQ”).
Regarding claim 4, Chiang teaches that the mutations include nonsense variants, frameshift indels, splice acceptor variants, and splice donor variants (Supplementary Materials, SSC sequencing and phenotype data, para 2).
Regarding claim 5, Chiang teaches identifying likely gene-disrupting mutations (Supplementary Materials, SSC sequencing and phenotype data, para 2), wherein “LGD” mutations were used for subsequent analyses, including the calculation of relative expression (e.g., Supplementary Materials, pg. 55, Gene expression changes due to LGD variants in GTE, spanning pg. 57, Changes in total gene expression due to LGD variants; pg. 59, Methods Fig. 1; Fig. 4). Thus, it follows that non-LGD mutations were removed from the analyses.
Regarding claim 7, Chiang teaches that the NVIQ prediction model was calculated with the SSC data (Fig. 4), wherein the SSC data includes genetic and phenotype data [i.e., paired mutations and phenotypes dataset] (Introduction, para 1), and relative expression (Fig. 4), wherein relative expression was calculated using exon-level expression (pg. 55, Gene expression changes due to LGD variants in GTEx; pg. 59, Methods Fig. 1).
Regarding claims 8 and 9, Chiang teaches that the phenotypic effects were normalized (pg. 59, Methods Fig. 1, para 3) and that raw scores were adjusted using score transformation that included gender [i.e., a sex identity] (pg. 53, Adjustment of phenotype scores for gender and age; instant claim 9).
Regarding claim 10, Chiang teaches that the phenotype is non-verbal IQ (Fig. 4).
For at least these reasons, claims 1-5 and 7-10 are anticipated by Chiang.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMMA R HOPPE whose telephone number is (703)756-5550. The examiner can normally be reached Mon - Fri 11:00 am - 7:00 pm.
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/EMMA R HOPPE/ Examiner, Art Unit 1683
/ANNE M. GUSSOW/ Supervisory Patent Examiner, Art Unit 1683