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 .
Claim Status
Currently, claims 11-32 are pending in the instant application. Claims 1-10 have been canceled. Claims 21-32 have been added and claims 16-18, 21-24, 28-32 are withdrawn. This action is written in response to applicant' s correspondence submitted 07/06/2026. All the amendments and arguments have been thoroughly reviewed but were found insufficient to place the instantly examined claims in condition for allowance. The following rejections are either newly presented, as necessitated by amendment, or are reiterated from the previous office action. Any rejections not reiterated in this action have been withdrawn as necessitated by applicant' s amendments to the claims. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action. This action is FINAL.
Election/Restrictions
Newly submitted claims 21-24, 28-32 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: each of the genes and exons skipping events listed in claims 21-24 and 28-32 and structurally and functionally distinct, as set forth in the restriction requirement mailed 10/1/2025.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Applicant elected ITGAE in response to the restriction requirement among the structurally and functionally distinct exon skipping events on 12/01/2025. The newly added claims do not encompass the elected invention. Accordingly, claims 21-24, 28-32 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Claims 11-15, 17-20, 25-27 are under examination. Claim 13, 25, 27 is under examination with respect to ITGAE. Claim 14 and 18 are under examination with regard to CMS1.
Withdrawn Rejections/Objections
The object of claim 11, 14-15, 17-20 is withdrawn in view of the amendment to the claims.
Claim Objections
Claims 11, 14, 17, 18, 26, 27 are objected to because of the following informalities: each of the claims recite CMS. CMS should be written in its full term followed by abbreviation in parenthesis upon first mention in the claims. For example, claim 11 and claim 17 should recite consensus molecular subtype (CMS). Appropriate correction is required.
Declaration Under 37 CFR1.132
The declaration under 37 CFR 1.132 filed 07/08/2026 is insufficient to overcome the rejection of claims 11-15 and 17-20 based upon 35 USC 101 as directed to an abstract idea and law of nature without significantly more as set forth in the last Office action because the declaration while it addresses PSI values is not sufficient to overcome the rejection because while calculating PSI values may not be practices in a human mind, determining PSI values and converting PSI values to probabilities requires mathematical calculation and the claim recites mathematical equations which are an abstract idea. The declaration addresses that converting PSI values to determine disease outcome can not be calculated in the human mind, however this is not sufficient to overcome the rejection under 35 USC 101 as the claim recites additional judicial exceptions within the claim that are addressed below.
New Grounds of Rejection, Necessitated by Amendment to the claims
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 11-15, 17-20, 25-27 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. This rejection was previously presented and has been rewritten to address the amendment to the claims.
Claim 11 and 26 recites the limitation "the dot product", “the reference data set”, “the vector representations for PSI values”, “the linear combination”, “the intercept”, “the logistical function”, “the distance”, “the lowest distance” in step (c) of the claim. There is insufficient antecedent basis for these limitation in the claim. The claim does not recite or require a reference data set and the recitation of the reference data step in step c renders the claim indefinite. Additionally the claim does not require a dot product, vector representation, linear combination, intercept, logistical function and distance. It is unclear, for example, what is the dot product or the distance that is required for step c when the claim does not recite or require a dot product or distance in any preceding steps. For these reasons the claims are indefinite.
Claim 11 and 17 are vague and indefinite because it is unclear how converting PSI values determines disease outcome. Claim 11 recites converting PSI values to determine disease outcome, wherein PSI values are converted to CMS probabilities estimate by mathematical transformation. Neither claim 11 or claim 17 indicates how converting PSI values results in disease outcome. While claim 11 recites converting PSI values to CMS probabilities or CMS classification, this does not result in disease outcome but merely results in CMS probability or CMS classification. It is unclear what values are required for determining disease outcome. It is unclear how or when disease outcome is determined based on PSI values. The metes and bounds of the claimed invention are indefinite and one of ordinary skill in the art would not be apprised of infringing on the claimed method.
Claims 12-15, 18-20, 25 and 27 depend from claim 11 and claim 17 are indefinite for the reasons applied to claim 11 and claim 17.
Improper Markush Rejection
Claim 13 and 27 is 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. This rejection was previously presented and has been rewritten to address the amendment to the claims.
The Markush grouping of ITGAE, CCNDBP1, CPT1B, CDC16, PTPN6, ACCS, EXOSC9, ZNF611, MRRF, NUP153, WARS, D2HGDH, LUC7L, EPB41, DGUOK, MDM4, PTP4A2, MKNK2, CCDC112, FRYL, CEP78, FNBP1, ECT2, ANKRD26, ZMIZ2, C6orf48, USPL1, RBM39, MIS12, AFMID, MACROD1, FN1, WBP1, XPO1, PTPN18, ARHGAP27, C16orfl3, FCGRT, DOCK6, EXOC7, BPTF, PXN, EXOC1, PLOD2, CD47, ARHGEF 11, PBRM1, MAGI1, MBNL1, TNC, ENAH, BAZ2B, RAI14, FNIP1, MAP3K7, ERBIN, SULF2, SORBS1, SRSF6, WASH3P, OPAl, GOLGB1, APLP2, CPNE1, WIPF1, ATG9A, NUBP2, ANO1, AURKA, EPB41L3, KALRN, ADAM15, KRAS, SLC39A14, MYO9A, TPM1, MYO6, KIAA1217, GIT2, MYL6, MYH1l, NUMB, TEAD1, SPAG9, FAT1, TNS1, ESYT2, SLMAP, AKAP9, RUBCN, ATP2B4, LRRFIP2, TBC1D23, EHBP1, SLK, WDFY3, SMARCC2, KIF13A, MPRIP, LRRFIP1, NIN, RPS24, ACTN1, CTNND1, CD44, APBB2, SEC31A, SYTL2, MYOF, NAV2, GAB1, PLEKHM2, CLSTN1, GOLGA4, PBX1 and FKBP14 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use.
The Markush grouping of ITGAE in exon with genomic coordinates chr17:3723287-3723383, CCNDBP1 in exon with genomic coordinates chr15:43194080-43194137, CPT1B in exon with genomic coordinates chr22:50573807-50573921, CDC16 in exon with genomic coordinates chr13:114236644- 114236699, PTPN6 in exon with genomic coordinates chr12:6951458-6951520, PTPN6 in exon with genomic coordinates chr12:6951463-6951520, ACCS in exon with genomic coordinates chr11:44073446-44073517, EXOSC9 in exon with genomic coordinates chr4:121816143- 121816194, EXOSC9 in exon with genomic coordinates chr4:121816368-121816447, ZNF611 in exon with genomic coordinates chr19:52707468-52707542, MRRF in exon with genomic coordinates chr9:122285779-122285946, NUP153 in exon with genomic coordinates chr6:17668974-17669028, WARS in exon with genomic coordinates chrl4:100375282- 100375350, WARS in exon with genomic coordinates chrl4:100375282-100375403, WARS in exon with genomic coordinates chr14:100375282-100375406, D2HGDH in exon with genomic coordinates chr2:241748864-241749929, LUC7L in exon with genomic coordinates chri6:228332-228402, EPB41 in exon with genomic coordinates chrl:29058588-29058645, DGUOK in exon with genomic coordinates chr2:73938909-73939022, MDM4 in exon with genomic coordinates chrl:204537429-204537497, MDM4 in exon with genomic coordinates chrl:204537458-204537497, PTP4A2 in exon with genomic coordinates chrl:31915894- 31915987, MKNK2 in exon with genomic coordinates chr19:2039630-2039856, CCDC 1[2 in exon with genomic coordinates chr5:115269702-115269798, FRYL in exon with genomiccoordinates chr4:48593929-485940 16, CEP78 in exon with genomic coordinates chr9:78265858- 78265906, FNBP I in exon with genomic coordinates chr9:129923843-129923996, FNBP I in exon with genomic coordinates chr9:129923843-129924026, ECT2 in exon with genomic coordinates chr3:172752149-172752472, ECT2 in exon with genomic coordinates chr3:172755482-172755575, ANKRD26 in exon with genomic coordinates chr10:27044156-27044190, ZMIZ2 in exon with genomic coordinates chr7:44760150-44760228, C6orf48 in exon with genomic coordinates chr6:31836423-31836517 and USPL1 in exon with genomic coordinates chr13:30621072-30621239.
The Markush groupings of the claimed genes and genomic coordinates is improper because the because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use.
The members of the improper Markush grouping do not share a substantial feature and/or common use that flows from the substantial structural feature because each member of the claimed genes are structurally unique relative to one another. There is no disclosed common substantial structural feature and the genes do not share a single structural similarity, as each gene represents a different gene and each chromosomal region represented a distinct location on the chromosome with different genes and chromosomes that has no substantial common nucleotide sequence. The only structurally similarity present is that each gene comprises nucleic acid molecules. The fact that the genes and chromosomal regions comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising a nucleotide alone is not essential to the common activity of being correlated to classifying a sample. Accordingly while the different genes and chromosomal regions are asserted to have the property of one exon skipping event that is indicative of colorectal cancer it is not clear from their very nature or from the prior art that all of them possess this property. The nature of different genes and chromosomal regions is that they are differently expressed with different alternative splicing events in different disorders. 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.
Response to Arguments
The response traverses the rejection on page 18 of the remarks mailed 07/06/2026. The response asserts that the claims are directed to specific exon skipping events not general intron/exon architecture of the listed genes. The response asserts that each member of the group shares necessarily a similar structure that results in a PSI value predictive of colorectal cancer outcomes. The response asserts that the genes share a common function of predicting colorectal cancer outcomes when each gene undergoes exon-skipping events that product quantifiable differences in PSI values. This response has been reviewed but not found persuasive. Markush group applies when there is an expectation from the knowledge in the art that the members of the class will behave in the same way in the context of the claimed invention i.e. each member could be substituted one for the other, with the expectation that the same intended result would be achieved. There is no evidence of any similar structure that results in similar PSI values for each of the claimed genes or genomic coordinates. There is no evidence that the members of the claimed class encompassing a wide range of genes and genomic coordinates will comprise similar splicing events that will have a similar PSI and will behave the same way in the context of the claimed invention. There is no common use that flows from a substantial structure feature. See MPEP 2117 (II) B, in the instant case there is no structure feature that is common to a specific PSI value or that is specific for disease outcome. The common structural feature of splicing event with a similar PSI can be measured in a sample, however the value of PSI and the splicing event is dependent on unique structures and therefore do not comprise a common structure. There is not a similar structure that is shared among the genes or genomic coordinates such that there is knowledge in the prior art that each of the genes and genomic coordinates will have same PSI values.
It appears that applicant is asserting that each of the genes and genomic coordinates will have similar PSI values, however there is no evidence of record to establish that it is clear from their very nature that the different genes and genomic coordinates will have similar PSI values. If each of the claimed genes and genomic coordinates have similar PSI values, applicant should provide evidence of record. It is noted the specification provides no PSI values for the claimed genes or genomic coordinates. This should not be construed as an invitation for providing evidence. Applicant is reminded of the timely submission of evidence as stated in MPEP 716.01
For these reasons and reasons of record this rejection is maintained.
Claim Rejections - 35 USC § 112
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 11-15 and 25-27 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. This is a new grounds of rejection. This is a new matter rejection.
The amendment to claims 11 and 26 to recite PSI and Θ changes the scope of the claim
and raises the issue of new matter. The amendment to the claims to recite
PNG
media_image1.png
146
819
media_image1.png
Greyscale
introduces new matter. The “…” between PSI and Θ raises the issue of new matter. While the specification teaches:
PNG
media_image2.png
116
487
media_image2.png
Greyscale
the specification does not teach … between PSI and Θ. There is no support in the disclosure that results in an equation that has “…” between PSI and Θ. As such the equation recited in the claims introduces new matter.
Claim Rejections - 35 USC § 112-Scope of Enablement
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 11-15 and 25-27 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 predicting percent spliced in values for a colorectal sample comprising a) collecting said sample from a tumor of the subject and b) determining PSI values in said sample by measuring using RT-PCR, multiplex assays, or targeted sequencing, does not reasonably provide enablement for the claims as written. 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 and use the invention commensurate in scope with these claims.
Nature of the invention and breadth of the claims
The claimed methods are drawn to predicting disease outcome indication for a subject suffering from colorectal cancer using percent spliced in values by collecting a sample, determining PSI values, and converting PSI values to determine disease outcome wherein the PSI values are converted to CMS probabilities estimates or the CMS classification by the claimed mathematical formulas.
The claims encompass predicting disease outcome based on PSI values. The claims encompass PSI values converted to CMS probabilities or classification. The claims encompass any alternative splice event in any gene. The claims further encompass PSI values to determine treatment. The claims recite a PSI equation that is not described in the specification.
Additional claims encompass exon skipping event in the elected gene, ITGAE.
The claims thus require knowledge of reliable and robust association between the PSI values, colorectal classification by CMS, disease outcome and response to cancer therapy for any splicing event.
Direction provided by the specification and working example
The instant specification provides a method that encompasses collecting a sample from a tumor of a subject and determining PSI values. The specification teaches a CMS identifier was constructed and validated using data from detectable alternative splicing events in 675 human colorectal cancers. The specification asserts CMS labels were derived from expression data quantified at gene-level and selection was achieved through bootstrapping and L1- penalized estimation, which was used to train multiple logistic models. The specification asserts the model performance was evaluated on unseen CRC from two sources and CRC subtype identifier, CRCi was developed based on 29 exon-skipping events and outperformed expression based CMS classified (see pg. 4-5). However the specification provides no information on the 29 exon skipping events or their PSI values that were identified in this study nor does the study use PSI values to identify CMS classification (see pg. 5-6). The specification provides no information on how the PSI values were calculated for CMS classification to determine disease outcome.
The specification asserts that figure 1 demonstrated a strength of association between clusters emerging from NMF-based consensus clustering of PSI values and CMS, however this figure demonstrates association between CMS and NMF clusters to NMF clusters, there is no indication of PSI values in any figures.
The specification teaches the subject encompasses any human or animal including all vertebrates (See pg. 7, lines 10-15). The specification teaches PSI refers to exon-inclusion ratio and is a known statistic value for measuring alternative splicing events. The specification teaches the PSI value is based on at least 5, 10, 50, 141 alternative splicing events or combination (see pg. 8).
The specification asserts the colorectal cancer subtype identifier classifies tumors as CMS1, CMS2, CMS3, or CMS4. However the specification provides no guidance on how the PSI value classifies tumors as CMS1, CMS2, CMS3 or CMS4. The specification asserts that at least 1, especially at least 25 exon skipping events are present for identification of CMS1 (See pg. 9). The specification asserts that for identification of CMS2 at least 1, at least 15 exon skipping events are present (see pg. 10-11). For identification of CMS3 at least 1, at least 41 are present (see pg. 11-13) and for CMS4 at least 1, especially at least 55 are present (pg. 13-15). However the specification provides no values for PSI for any of the chromosome regions or genes that identify CMS1-4. The claims encompass any alternative splicing event however the specification only discloses on exon skipping events and provides no PSI values for the disclosed exon skipping events to classify CMS1-4.
While the specification teaches PSI values are estimated from RNA-seq data using computational tools, the specification does not teach how PSI values determine disease outcome or classify CMS to determine disease outcome. The specification asserts that PSI values are converted to CMS probabilities by mathematical transformation and provides mathematical equations (See pg. 19-20), however the claims do not recite the same mathematical equations recites within the specification. Additionally the specification provides no analysis of identified PSI values converted to CMS subtypes. The specification is merely prophetic that PSI values can be used in the mathematical equations to identify CMS subtypes.
It is inconclusive based on the guidance in the specification if CMS subtypes could be identified based on PSI values. The specification provides no analysis of PSI values identified in samples and identified as CMS subtypes.
Relevant to the breadth of the claims, there is no analysis of any non-human subjects. There is no analysis of any therapy in any subject identified with disease outcome based on PSI values and CMS classifier. There is no analysis of exon skipping or alternative skipping of ITGAE in tumor samples from subjects with colorectal cancer. There is no statistically significant analysis, including data analysis with p values, of using PSI values of alternative splicing, including exon skipping to classify CMS1-4 or disease outcome.
State of the art, level of skill in the art, and level of unpredictability
While the state of the art and level of skill in the art with regard to identifying alternative splice events in human samples is high, the unpredictability in associating any particular splice event with a specific phenotype, or identifying treatment, as is encompassed by the claims, is even higher. The unpredictability is demonstrated by the related art and the instant specification.
Because the claims encompass any subject organism, while the specification teaches only the analysis of human subjects, it is relevant to point out the unpredictability in extrapolating alternative splicing, or its association with any phenotype, from one animal to any other different animal.
The claims encompass identifying PSI values based on alternative splice events in samples from subjects with colorectal cancer and identifying disease outcome. The claims include any alternative splice event. The art demonstrates the unpredictability of PSI values with disease outcomes. Lin (Bioinformatics, 35 (23) 2019, 5048-5054) teaches PSI values and comparison of different tools to calculate PSI. Lin teaches rMATS has significantly lower recall (See pg. 5049, 2nd paragraph). Lin demonstrates the limitations of different tools to calculate PSI.
Takeruji (Gatroenterology, May 2025, vol 168, p 1035-1036) addresses applicant own prior art, Ambreskovic (Gastroenterology, 2024, 167:13587-1370e12) similar in content to the instant specification. Takeruji teaches that the approach by Ambreskovic using L1-penalized estimation has an inherent risk of overlooking important features due to limitations associated with linear and parametric modeling, which is relevant when the analysis involved correlated relationships among features. Takeruji teaches L1-penalized estimation, which is disclosed in specification, can lead to omission of significant predicators that favor sparsity and arbitrarily select one feature over others, which could comprise overall effectiveness of the model to capture essential interactions and dependencies, impacting subtyping framework. Takeruji teaches that nonlinear and nonparametric methods should be considered and would provide a comprehensive evaluation of feature importances to capture complexities inherent in relationships within high dimensional data. Takeruji teaches these strategies could enhance feature selection and optimize overall performance of the subtyping framework yielding accurate and clinically relevant insights. Takauji further teaches that it is critical to evaluate data distribution, investigate relationships among variables and conduct rigorous statistical validation through P values.
Quantity of experimentation required
A large and prohibitive amount of experimentation would be required to make and use the claimed invention. Given that the claims generically encompass any splicing event with any PSI value and classifying to CMS, one would have to perform large case: control studies, and validation of any results, to determine PSI value that may be reliably and robustly associated with CMS subtypes and determine therapeutic outcome. While the claims recite a regression model, the art demonstrated the unpredictability of using linear models. One would have to perform large case:control studies and validation of a large genus of alternative splicing events to determine which PSI values would predictably classify CMS and identify therapy and analyze data among different classification models. Even for the particular elected gene, ITGAE disclosed in the specification, given the lack of data with regard to PSI values, CMS classification and therapeutic response, one would have to perform an analysis to see if alternative splicing events are robustly and reliably associated with CMS subtype and therapeutic response.
Conclusion
Taking into consideration the factors outlined above, including the nature of the invention and breadth of the claims, the state of the art, the level of skill in the art and its high level of unpredictability, and the particular guidance in the specification including the examples, it is the conclusion that an undue amount of experimentation would be required to make and use the invention as claimed.
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 11-15, 17-20, 25-27 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and law of nature without significantly more. This rejection was previously presented and has been rewritten to address the amendment to the claims.
Claims 11, 17, and 26 recite determining PSI values and converting PSI values to determine disease outcome indication. This step encompasses a data analysis process that encompasses mathematical concepts that recite mathematical formula, equations and calculations. These recitations are an abstract idea.
Claims 11, 14, 17 and 18 recite a law of nature/natural phenomenon and an abstract idea. Claim 11 and 17 recites an abstract idea that is a mental process and includes mathematical concepts. The recitation of converting PSI values to determine disease outcome indication is a mental process. The recitation of determining PSI values is a mathematical concept that encompasses a mathematical calculation. The recitation of converting PSI values to CMS probabilities or CMS classification recites a mathematical formula and is a mathematical grouping of an abstract idea judicial exception. The recitation of to determine disease outcome results in a mental analysis of the PSI conversion to determine disease outcome after determining the probability or classification of CMS using mathematical equations. Neither the claims nor the specification set forth limiting definitions for determining and the claims do not set forth how determining PSI is accomplished, the claims set forth mathematical equations for determining probability, which is an abstract idea. The broadest reasonable interpretation of determining is a step that can be accomplished mentally by evaluating data and critical thinking process wherein one mentally reads information in a database or report regarding PSI levels. Additionally the claim recites mathematical equations, formulas and calculations to determine CMS probabilities of PSI values using splicing events and this encompasses an abstract idea.
Claim 11, 14, 17 and 18 recites a law of nature/natural phenomenon. Claim 11 and 17 recite PSI values to determine the disease outcome. PSI values as based on the occurrence of at least one alternative splicing event. Claims 14 and 18 add an additional judicial exception, an abstract idea, as the claim recites the conversion of PSI values to determine disease outcome indication classifies the tumors as CMS1, CMS2, CMS3 or CMS4. These recited relationships are a natural phenomenon that exists apart from any human action. This type of correlation is a consequence of a natural process.
This judicial exception is not integrated into a practical application because the claims do not recite additional steps or elements that integrate the recited judicial exceptions into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the steps in addition to the judicial exception are data gathering steps recited at a high level of generality employing techniques that were well-established, routine and conventional at the time of the invention. For example, the claims do not practically apply the judicial exception by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
An additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing; and
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
While claim 11 and claim 17 recite determining PSI values, the claims generically recites PSI values with no additional elements for determining PSI. Claim 11 and 27 further recite mathematical equations which are an abstract idea. Additionally PSI values were well known routine and conventional in the art taught by Xiong (EBioMedicine, 2018, 26:183-195).
Claims 12-13 recite the alternative splicing event is skipping exons and the gene is ITGAE. These claims only limit the judicial exceptions. However, it was routine in the art to determine PSI and identifying exon skipping in ITGAE, as taught by Xiong (EBioMedicine, 2018, 26:183-195) (see supplemental table 2).
Claims 15-16 further limit the PSI conversion to decide treatment or surveillance, which is an additional judicial exception since deciding treatment or surveillance is a mental process. There is no step of administering a treatment. It is noted that treating a subject with active surveillance would encompass a mental process.
Claim 19-20 limit the subject, thus is a field of use limitation which does not amount to significantly more.
Response to Arguments
The response traverses the rejection on pages 18-20 of the remarks mailed 07/06/2026. The response asserts the process of determining PSI values cannot be performed by the human mind. The response asserts that the calculations to convert PSI values are recited in claim 11 and claim 26 and cannot be practically performed in the human mind. The response asserts that the claims recite more than a mere mental process and require calculations that cannot practically be performed by the human mind. The response points to the declaration filed on 7/8/2026. This response and declaration has been thoroughly considered but not found persuasive. The claims as amended recite a mathematical calculation. The recitation of a mathematical calculation and mathematical formula, as recited in claim 1 and claim 26 are an abstract idea, specifically mathematical groupings (See MPEP 2106.04(a)(2)(I)). As such the recitation of PSI value and converting PSI values to disease outcome by converting to CMS probability and CMS classification is an abstract idea.
The response asserts that determination of treatment renders the claims patentable. The response asserts that claim 17 and dependent claim 15 are analogous to examples 43 of the subject Matter Eligibility Examples from October 2019. The response asserts that the claims are also analogous to hypothetical claim 5 and 6 of ex 29. The response asserts that claims 15 and 17 recite a practical application of the claimed process by determination of whether the subject is subjected to treatment by anti-tumor therapy or surveillance of progress of colorectal cancer. This response has been reviewed but not found persuasive. In example 29 and example 43 of the Pct 2019 guidelines, there is a particular treatment that is being administered for a disease. In the instant case, claim 15 and claim 17 recite whether a subject is subjected to a treatment by anti-tumor therapy and/or surveillance of progress of colorectal cancer. Surveillance of progress of colorectal cancer is not a treatment step that involves administering a particular treatment for a disease. Surveillance encompasses a watch and watch, which does not integrate the judicial exception into a practical application because this merely encompasses mental analysis or data gathering. Additionally the step of determine whether the subject is subjected to a treatment by anti-tumor therapy does not integrate the judicial exception because this is a mental process, an abstract idea. The step of “is used to decide whether the subject is subjected to a treatment by anti-tumor therapy and/or surveillance” does not require performing experimental or clinical steps and be performed entirely in one’s mind to decide to subject a subject to treatment. This step is not a particular treatment. The claims do not recite or require which PSI values or outcome results in treatment with anti-tumor therapy. The claims do not recite or require any specific anti-tumor therapy and the recitation of anti-tumor therapy encompasses any and all cancer therapy. Additionally the recitation of “whether” is conditional and does not apply the treatment to a particular subject. The treatment steps recites in claim 15 and 17 are not similar to the examples provides as the examples includes a particular treatment limitation that was more than a nominal relationship the expectation and was not extra solution activity, unlike instant claim 15 and 17 which recites a further judicial exception.
For these reasons and reasons of record this rejection is maintained.
Maintained Rejections
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 17-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Xiong (EBioMedicine, 2018, 26:183-195).
Xiong teaches alternative splicing in colorectal cancer. Xiong teaches obtaining CRC tissue from a human subject and determining PSI values (see materials and methods, 2.2) (claim 19-20). Xiong teaches CRC patients were divided into groups based on PSI values to determine hazard ratios, overall survival and disease free survival (see fig 1). Xiong teaches the alternative splicing events are disclosed in supplementary table S2. Table S2 discloses exon skipping for ITGAE (claim 12-13). Xiong discloses the prognostic value of differential expression alternative splicing events in CRC (see 3.5). Xiong teaches clustering of different CMS, TNM stage, and survival status in CRC samples between clusters from PSI values aligned (see figure 8 and 3.6) (conversion of PSI values classifies CMS1) (claim 14 and 18). Xiong teaches determining PSI values and conversion of PSI values to determine disease outcome.
With regard to claims 17, 18 and 20, the preamble of claim 17 recites a method for treating a subject suffering from colorectal cancer using PSI values however the only active process steps of the claims are collecting a sample, determining PSI values and conversion of PSI values to determine disease outcome. The recitation in the preamble of “treating a subject” in the context of the present claim does not result in a manipulative difference, none of the process steps require treating a subject. Accordingly the process steps are able to stand alone and the preamble limitation in not accorded patentable weight. Xiong teach of the active steps of claim 17.
Claims 17, 19-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Epstein (WO2021101452A2)
Epstein teaches a method of identifying splicing alternations in colorectal cancer. Epstein teaches determining PSI values for each sample. Epstein teaches PSI values can be used for treatment of CRC patient (see fig 21 and pg. 16) (claim 17). Epstein teaches alternative splicing by increased exon skipping compared to normal samples (see fig 22 and pg17). Epstein teaches the method characterizing a medical condition and characterizing a cancer. Epstein teaches the subject or patient includes humans (see pg. 73)
Response to Arguments
The response traverses the rejection on pages 21-22 of the remarks mailed 07/26/2026. The response asserts that neither Xiong or Epstein teacher methods to determine treatment plans. This response has been thoroughly reviewed but not found persuasive. The claims do not require a step of treating a subject. Claim 17 recites conversion of the PSI values to determine a disease outcome indication, wherein the conversion of PSI values to determine disease outcome indication is used to decide whether the subject is subjected to a treatment by anti-tumor therapy and/or surveillance of progress of colorectal cancer. This recitation is an intended use of the PSI values and does not require performing experimental or clinical steps or any other steps that are transformative. The specification does not provide a limiting definition for how surveillance of progress of colorectal cancer is to be accomplished. Thereby the step may be performed entirely in one’s mind as the claim only requires PSI values used to decide whether the subject is subjected to treatment. As such Xiong and Epstein anticipate the claimed invention as there is no active process step of administering a treatment to a subject.
Conclusion
No claims are allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAE L BAUSCH whose telephone number is (571)272-2912. The examiner can normally be reached M-F 9a-4p.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Fereydoun Sajjadi can be reached at 571-272-3311. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SARAE L BAUSCH/ Primary Examiner, Art Unit 1699
Prosecution Insights