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 .
Election/Restrictions
Applicant’s election without traverse of species (a) in the reply filed on 12/18/2025 is acknowledged.
Upon further search and consideration, the requirement for species election is withdrawn.
Status of Claims
Applicant’s amendment filed 06/02/2023 is acknowledged. Claims 69-87 have been added. Claims 1-68 have been cancelled. Claims 69-87 are pending in the instant application and the subject of this non-final office action.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892 or marked as a considered on a submitted IDS, they have not been considered.
Specification
The use of terms including “IPA”, which is a trade name or a mark used in commerce, has been noted in this application. Such terms should be accompanied by the generic terminology; furthermore such terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 80 and 84 are objected to because of the following informalities:
Claims 80 and 84 recite “KIAA01O0” and “MAG11”. These appear to be OCR errors. The genes are “KIAA0100” (two ending zeros) and “MAGI1” (ending with letter “i” one). Also, claim 80 lacks a space before “KIAA0100”.
Appropriate correction is required.
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 69, 73, 76-77, 79-80, and 84, claims recite “cell-free messenger RNA (cf-mRNA)” (claims 69 and 84) or “cf-mRNA” (claims 73, 76-77, and 79-80).
The specification recites that the cf-mRNA-based classifier was reduced to a set of genes including AC132217.4, a non-coding RNA (para [0165]; see claims 80 and 84).
As a long non-coding RNA is claimed as a species of “messenger RNA”, the term was interpreted broadly to encompass classes of RNA that correspond to the genetic sequence of a gene, including non-coding transcripts such as lncRNAs.
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 69-83 and 87 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.
In analyzing the claims for compliance with the written description requirement of 35 U.S.C. 112, first paragraph, the written description guidelines note that with regard to genus/species situations, a “Satisfactory disclosure of a “representative number'' depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed.”
Regarding claims 69-83, claim 69 recites a method comprising quantifying cf-mRNA levels of a plurality of cf-mRNAs in a biological sample; and processing one or more of said levels to identify a disease state of a tissue of said subject and an age of said subject, wherein the processing comprises comparing the cf-mRNA levels in the subject to a threshold value of the plurality of cf-mRNAs (emphasis added).
The claims are broad. First, they include any sample from any subject of any species (limited in part in claim 70), i.e., encompassing interpolation in addition to any possible sample from the subject. Second, they encompass up to any set of one or more cf-mRNA levels (independent claim 69: processing one or more; claim 80: two or more from the set). Third, where a disease state of a tissue is identified in claim 69, such identification may encompass any disease state of any tissue under the broadest reasonable interpretation. Fourth, the claims, where a threshold is identified, encompass any threshold value and any direction of change (limited in part by application of machine learning classifiers in claims 71-72).
Hu (Hu G, et al. Molecular mechanisms of long noncoding RNAs and their role in disease pathogenesis. Oncotarget. 2018 Jan 1;9(26):18648-18663) teaches that there are approximately 50 thousand lncRNA genes and 20-25 thousand protein-coding genes (Introduction, para 1). As dependent claim 80 recites AC132217.4, the term “cf-mRNA” has been interpreted broadly to encompass at least lncRNA and protein coding cf-RNA. Accordingly, the claims are directed to quantifying at least two and processing at least one of approximately 70-75 thousand possible “cf-mRNA”. Given the formula C(n,k) = (n!)/(k!*(n-k)!) and setting n=75000: for a set of 1 there are 75000 combinations; for a set of 2, 2,812,462,500 combinations; for a set of 3, 7.03 x 10^13 combinations; etc.
In contrast to this, the disclosure recites analysis of a single disease of Alzheimer’s in humans (para [0162]). It recites using input features of 1476 differentially expressed genes to train a various ML models all features and a LASSO logistic regression with a tuned feature set of KIAA0100, MAGI1, NNMT, MXDI, ZNF75A, SELL, ASS1, MNDA, and AC132217.4 (para [0165]).
Separately, it recites clustering disclosed genes into gene clusters associated with sets of “IPA pathway[s]” and stratifying patients based on the gene clusters (para [0167]). Based on this analysis, it recites correlating genes with disease severity and performing gene ontology analyses, finding 707 and 519 genes that correlated with two different metrics of severity (para [0169]). Only 10 genes, listed in Fig. 9D, are specifically described of these sets (see also para [0169]), wherein it is noted for the sake of compact prosecution, that none of the genes overlap with the set of genes KIAA0100, MAGI1, NNMT, MXDI, ZNF75A, SELL, ASS1, MNDA, and AC132217.4 (see claim 84 and discussions of the interpretation of the preamble in the art rejection). The 10 genes are: SLU7, HNRNPA2B1, GGC1 [interpreted to be human gene SLC25A44], NDUFA12, HSPB11, ATP6V1B2, SASS6, SUMO1, KRCC1, LSM6 (Fig. 9D), of which none were identified to be transcription factors.
In a further separate analysis for the age of the subject, a correlation was calculated between the expression data and the age of the subject, finding 774 genes that were differentially regulated (para [0170]), of which TCF7, PTK2, FER, CD36, WWTR1, and CAV1 are recited (para [0170]), wherein it is noted that there is no recited overlap with the set of genes claimed in claim 80 as the plurality. Of the six recited differentially regulated genes across the age categories, the variability of the relationships to age is noted (e.g., WWTR and CAV1 both have an apparently positive correlation with age until the last category where the median expression level is the lowest across all the groups; Fig. 15-16).
The set of 774 age-associated genes was overlapped with the “other data sets” (interpreted to be the AD differentially expressed and the two disease severity score gene sets) and two genes were recited as being consistently highly correlated with age in all datasets: NELL2 and TLB (para [00173]), wherein it is noted there is no overlap with the set of genes claimed in claim 80.
The disclosure notes confounding effects of pre-preprocessing and type of sample (serum v. plasma) on the expression data that reduce the 774 age-associated genes to 120 genes significantly associated with age once controlled for (para [0174]), of which 7 are described: LEF1, TCF7, BCL11B, ID1, CDKN1C, CDH5, and PPARG (para [0175-176]) and only 41 were from non-blood genes (para [0178]), i.e., cf-RNA (para [0172]). The 41 genes recited include the 34 genes of para [0178]: HMGN5, PPARG, FABP4, Clorfl15, RAPGEF3, AFAPIL1, RAPGEF5, ERG, LIMCHI, ID1, LMCD1, NNMT, PALM, PRKCDBP, PTRF, FAM167B, RAMP2, TINAGLI, SNCG, RBPi, MGP, IL33, S100A16, NRN1, TEAD4, RAI14, MPDZ, CDH5, LAMA4, C8orf4, PALMD, SHROOM4, CALCRL, and CYYR1. It is noted that only the gene NNMT of claim 80 and the set of 9 disclosed in the model for predicting AD overlaps the disclosed genes here as being age-associated.
Together, these data indicate a high level of variability in the claimed genera. Only two genes species (NELL2 and TLB) consistently correlated with age across all data sets (interpreted to be for predicting AD or a stage of AD). And only a single species of gene (NNMT) was described as being predictive of AD and age-associated once the genes were controlled for confounding effects and filtered for the claimed species of cf-RNAs. The disclosure itself recognizes that sample type introduces confounding effects on the ability of the cf-RNAs to identify both a disease state and an age.
The art also teaches variability of the species of genes. The gene NNMT was also identified as a liver cf-RNA marker for detecting NASH in a biological fluid, as taught by Nerenberg (WO 2017/156310 A1; as cited in the IDS dated 02/21/2024: para [0041] and [00191]; claim 54). Similarly, Koh (Koh, 2016, as cited in the art rejection) teaches MXD1 (pg. 31, col 1) as markers of whole blood and KIAA0100 as a marker of BDCA4 dendritic cells (pg. 27, col 2) [i.e., also a component of blood].
In contrast to the broad claims directed to any sample from any species (including interpolation of the subject’s data) with any set of one or more cf-RNA—which as illustrated above includes a vast number of possible species of combinations—to predict any disease state and an age using any threshold, the disclosure provides a single set of 9 genes predictive of AD wherein one is also described as being predictive of age. This single species of a set of genes based on data from blood samples in humans predictive of AD is not found to be sufficiently representative of all aforementioned genera given the variability illustrated in the disclosure and known in the art.
Accordingly, the disclosure has failed to sufficiently describe the claimed invention in sufficient detail that one skilled in the art would have reasonably concluded that the applicant had possession of the full breadth of the claimed invention at the time of filing.
Regarding 87, the claim recites quantifying cf-mRNA of a plurality of cf-mRNAs in a biological sample, wherein the plurality ... corresponds to genes encoding transcriptional factors involved in at least one of a set of pathways; and comparing the cf-mRNA levels to a threshold.
As discussed above, the disclosure recites clustering differentially expressed genes into “IPA pathways” but the disclosed set that are recited in this analysis does not include transcription factors. Neither the genes of the pathways nor the transcription factors that may be judged to be “involved” with such genes of the pathways have been disclosed either in words, figures, or diagrams. The pathways are not a defined term of art, such that the “identifying characteristics” the function of being a transcription factor and being “involved” in a pathway would be sufficient to show possession of the invention. For example, Ren (Ren Z, et al. The role of different SIRT1-mediated signaling pathways in toxic injury. Cell Mol Biol Lett. 2019 May 30;24:36) teaches that SIRT1 (sirtuin) can participate in the regulation of apoptosis, the inflammatory response, oxidative stress, energy metabolism, and other processes by regulating different pathways (emphasis added; Pathway regulation of SIRT1 in toxicological damage; Fig. 1).
Accordingly, as no species have been clearly defined, the disclosure has failed to describe the invention in sufficient detail that one skilled in the art can reasonably conclude that the applicant had possession of the claimed invention at the time of filing.
For these reasons, claims 69-83 and 87 fail to meet the 112(a) written description requirements.
As noted above in the rejection of claims 69-83, the sets of genes described in the disclosure for analyzing severity of AD (i.e., a stage of AD) are not described as overlapping the set of genes claimed for the intended use of detecting a risk of a stage of AD in claim 84, indicating a high amount of variability in the species. No species were identified for models that predicted risk for a stage of AD. However, as has been noted elsewhere, the preamble of claim 84 has not been given patentable weight as the limitations have been interpreted as an intended us as the limitations have not been further recited in the claim.
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 69-83 and 87 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 69, first, in step (b) the claim recites “processing ... said levels ... to identify a disease state of a tissue of said subject”. The preamble of the claim recites “detecting a risk of Alzheimer’s disease ... in a subject”.
A subject may have more than one disease state. Thus, while the subject is referenced from the preamble, it is unclear whether the disease state of step (b) is intended to be limited to an Alzheimer’s disease state or may be any disease state of the subject.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, the recites the broad recitation “a disease state”, and the claim also recites “Alzheimer’s disease” which is the narrower statement of the range/limitation.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) a matter of intended use given its location in the preamble and therefore not required, or (b) a required feature of the claims.
Second, the claim recites “the processing comprises comparing ... the cf-mRNA levels in the subject”. Step (a) recites “quantifying ... cf-mRNA ... levels ... in a biological sample”. There is insufficient antecedent basis for this limitation in the claim because there is no recited nexus between the cf-mRNA levels and the subject.
Further, step (b) recites “processing one or more of said levels of said plurality of cf-mRNAs ... wherein the processing comprises comparing the cf-mRNA levels in the subject to a threshold value of the plurality of mRNAs”. Because “the cf-mRNA levels” in the wherein clause lacks antecedent basis, it is not clear whether the claim is intended to require processing “one or more” or a “plurality” (i.e., two or more) of cf-mRNA levels.
Claims 70-83 are indefinite for depending from claim 69 and not rectifying the deficiency. Claim 70 rectifies the indefiniteness related to the lack of nexus between the biological sample and the subject.
Regarding claim 87, first, the claim recites “quantifying ... cf-mRNA ... levels ... in a biological sample ...; and comparing the cf-mRNA levels in the subject”. There is insufficient antecedent basis for “the cf-mRNA levels in the subject” in the claim as there is no nexus between the biological sample and the subject required in the claim.
Second, the claim recites “genes encoding transcriptional factors involved in at least one ... pathway”. The term “involved” in the claim is a relative term which renders the claim indefinite. The term “involved” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
It is not clear what degree of involvement is required and in what contexts (cell types, cell states, etc.) the transcription must be involved in order to be within the intended claim limitations.
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 69-87 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception(s) without significantly more. The claim(s) recite(s) abstract ides/natural phenomenon. 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 are directed to a process/method.
Step 2A, prong 1. Does the claim recite a law of nature, a natural phenomenon, or an abstract idea (recognized judicial exceptions)?
Claim 69 recites a method of detecting a risk of AD in a subjection comprising quantifying cf-mRNA levels in a biological samples; and processing one or more levels of a plurality of cf-mRNAs to identify a disease state of a tissue said subject and an age of said subject, wherein the processing comprises comparing the cf-mRNA levels in the subject to a threshold value of the plurality of cf-mRNAs.
The claim is directed to the correlation(s) between levels of cf-mRNAs to and a disease state and an age, i.e., a natural phenomenon.
Additionally, the quantifying of the levels encompass the abstract ideas of mental processes (e.g., observation, evaluation, and judgment) and/or mathematical calculations, including those that may be done by the human mind. For example, the quantifying may encompass looking at mapped sequencing files and counting how many come from each isoform of the gene or applying an algorithm to perform this calculation. The processing of said levels by comparing to a threshold value encompasses abstract ideas, including mental processes and mathematical calculations, including those that may be performed by the human mind. For example, it may encompass looking at a set of cf-mRNA counts in a table and judging that they are above a set of thresholds in another table or using an algorithm to evaluate the cf-mRNAs levels relative to threshold values. See MPEP 2106.04(a).
Claim 84 recites a method of detecting a risk of a stage of AD in a subject comprising detecting cf-mRNA levels of a plurality of cf-mRNAs in a biological sample, wherein the plurality of cf-mRNAs correspond to two or more genes selected from a group.
The detection of levels encompasses the abstract idea of a mental process, for example, observing the level of color change subsequent to an amplification and making a judgment about the levels.
While the detection of a risk of a stage of AD is interpreted as intended us, for the sake of compact prosecution, an asserted correlation(s) between levels of cf-mRNAs and a risk of a stage of AD also would encompass natural phenomena.
Claims 85-86 are also directed to an abstract idea encompassing mathematical calculations, including those that may be performed by the human mind. It is noted that the Courts do not distinguish between a generic computer-implemented (i.e., machine learning) algorithm and one that is performed within the human mind. See MPEP 2106.04(a)(2)(III)(C).
Claim 87 recites a method of detecting a risk of AD in a subject comprising quantifying cf-mRNA levels of a plurality of cf-mRNA in a biological sample, wherein the plurality of cf-mRNA corresponds to genes encoding TFs involved in at least of a set of recited pathways; and comparing the cf-mRNA levels in the subject to a threshold value of the plurality of cf-mRNAs.
The quantifying of the levels and comparing the levels to a threshold each encompass the abstract ideas of mental processes and/or mathematical calculations, including those that may be done by the human mind. For example, the quantifying may encompass looking at mapped sequencing files and counting how many come from each isoform of the gene or applying an algorithm to perform this calculation. Similarly, the comparing of levels may encompass observing two values in one or more tables and making a judgment as to which is larger.
Step 2A, prong 2. Is the judicial exception(s) integrated into a practical application?
Regarding claim 69, the claim requires only steps encompassing judicial exception(s) and fails to integrate the claim. Even assuming, for the sake of argument, an interpretation of quantifying directed to laboratory methods, such would still represent necessary data gathering for the processing. As such, it would represent insignificant extra-solution activity and fail to integrate the claim. See MPEP 2106.04(d) and 2106.05(g).
Regarding claim 70, the claim recites that the biological sample comprises blood. This amounts to a selection of the type of data, and as such does not integrate the claim. See MPEP 2106.05(g).
Regarding claims 71-72, the claims recite limitations directed to applying machine learning classifiers. As discussed above with regard to claims 85-86, such encompasses further abstract ideas. Thus, the limitations fail to integrate the claims.
Regarding claims 73-75, claim 73 recites a further quantifying in a second biological sample and processing of the levels in the second biological sample to identify a second disease state of said tissue of said subject. The steps encompass the judicial exception(s) for the same reasons claim 69 above and would fall for the same reasons.
Claims 74-75 further limit the timing of the second sample to after a treatment (claim 74) and the treatment type (claim 75). Accordingly, they limit type of sample utilized in the judicial exception and fail to integrate the claim.
It is noted that MPEP 2106.04(d)(2) makes clear that in order for a limitation to qualify for integration under the “treatment” consideration, it must affirmatively recite an action that effects a particular treatment or prophylaxis for a disease or medical condition. This claim does not affirmatively recite the treatment itself.
Regarding claims 76-77, claim 76 recites that the quantifying comprises subjecting the plurality of cf-mRNAs to a variety of broadly recited laboratory techniques. While this step would no longer be an abstract idea, this quantifying is necessary data gathering for the processing, wherein the methods encompass selecting particular data sources to be manipulated.
For example, Liu (Liu F, et al. Comparison of hybridization-based and sequencing-based gene expression technologies on biological replicates. BMC Genomics. 2007 Jun 7;8:153) teaches that hybridization-based and sequencing-based technologies should be considered complementary to each other for measuring gene expression (Abstract), finding systematic differences in detection (Conclusion) that may be attributed to limitations inherent to the technologies (Abstract).
Claim 77 recites a method further comprising forming an NGS library from a plurality of cDNAs derived from the plurality of cf-mRNAs. It is noted that this step does not have a limitation regarding time or a clear nexus to the other steps or preamble. Accordingly, it is interpreted as an insignificant application.
Regarding claims 78-79, the claims recite that the quantifying further comprises detecting a portion of the plurality of cf-mRNAs either “not from blood” (claim 78) or “from the subject’s brain” (claim 79). These limitations encompass the abstract idea of mental processes and/or mathematical calculations, including those that may be performed in the human mind. For example, they may encompass an algorithm such as nonnegative matrix factorization to calculates the proportion of RNA reads from various tissue origins.
Regarding claim 80, the claim is directed to the identity of the cf-mRNAs. As such it amounts to a selection of the data utilized in the judicial exception(s) and does not integrate the claim.
Regarding claims 81-83, claim 81 is directed to identifying the subject as high risk, i.e., encompassing an observation/judgement mental process and/or calculation, and recommending a treatment, i.e., organizing the behavior and/or a mathematical calculation. Notably, the identifying lacks a nexus to the judicial exceptions recited in claim 69.
Claim 82 further comprises “treating the subject for Alzheimer’s disease”. Claim 83 recites specific treatments.
MPEP 2106.04(d)(2) recites that the treatment or prophylaxis must be “particular”, i.e., specifically identified so that it does not encompass all applications of the judicial exception, and provides the example that “administering a suitable medication to a patient” is insufficient to integrate the step into a practical application. The treating of claim 82 is not particular; the rationales below regarding nexus also apply.
While the specific treatments of claim 83 could be sufficient to integrate a claim under the requirements of MPEP 2106(d)(2)(a), this limitation is not sufficient to integrate the claim. The risk assessment lacks a nexus to the judicial exception, and the treatments are not specific to a “risk” status as the art fails to teach application of either as a prophylaxis in non-symptomatic individuals. Further, there is no nexus in the claims to a disease state of the tissue, and said disease state is also not limited to Alzheimer’s, as has been noted elsewhere.
Regarding claims 84-86, claim 84 additionally recites a step of obtaining a biological sample from the subject. Such represents necessary data gathering, and, thus, does not integrate the claim.
Claims 85 and 86 recite further abstract ideas, as discussed above, and, therefore do not integrate the claims. For the sake of argument, even should the detecting of claim 84 be interpreted more narrowly to be detected to laboratory methods, these steps would represent necessary data gathering for claims 85 and 86.
Regarding claims 87, as discussed above, claim 87 requires no more than abstract ideas. And, as discussed previously, should quantifying be interpreted more narrowly for the sake of argument, it would represent no more than necessary data gathering and fail to integrate the claim.
Step 2B. Does the claim amount to significantly more?
No, the claims as a whole do not amount to significantly more than the judicial exceptions. As discussed above, they encompass judicial exceptions of abstract ideas and/or natural phenomena and insignificant extra-solution activity. MPEP 2106.05 recites that the inventive concept cannot be furnished by the judicial exceptions themselves, and further recites that limitations directed to insignificant extra-solution activity are not enough to qualify as “significantly more”.
It is further noted that quantifying cf-mRNA using sequencing, including forming an NGS library, is well known and routine in the art, as taught by Koh - 2016 (US 2016/0289762 A1, as cited in the IDS dated 2/21/2024; para [0075-77]).
Claim Rejections - 35 USC § 103
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 69-71, 73-74, 76-79, and 81-82 is/are rejected under 35 U.S.C. 103 as being unpatentable over Koh (US 2016/0289762 A1; published 10/16/2016; as cited in the IDS dated 2/21/2024).
Regarding claims 69-71, 73-74, 76-79, and 81-82, in the method of Koh, Koh teaches a method for characterizing a neurological disease, wherein the disease is Alzheimer’s (AD), in a subject comprising (entire document, e.g.: claims 4 and 16; Examples 5 and 6):
quantifying cell-free RNA levels from a blood sample of the patient (claims 1 and 11; see also para [0064] and Fig. 7; instant claim 70), wherein the RNA comprises gene transcripts, i.e., messenger RNA (para [0064]; Fig. 7; Tables 1-2);
processing said levels of cf-RNA levels to indicate Alzheimer’s disease [i.e., to identify AD or a stage thereof in the brain of said subject] when the level of sample cDNA originating from brain tissue is above the reference level (claims 4 and 16; see also para [0175], [0183], and [0187]; instant claims 78-79).
Koh teaches further monitoring the progression of the neurological disease by repeating the quantification of levels in a sample and identification of a stage of the disease (claim 14; instant claim 73). Koh teaches such methods will allow for close monitoring and may allow determining an ideal dosage according to the progression (para [0140]), i.e., suggesting monitoring during therapy (instant claim 74). Koh teaches recommending a course of treatment based on clinical indications [i.e., a identifying a “high risk”] determined by comparing the patient’s brain-specific cf-RNA and the reference (para [0095]; instant claim 81).
Koh teaches measuring patient samples with qPCR (para [0174], [0176]), i.e., subjecting the cf-RNAs to at least polynucleotide amplification (instant claim 76).
Koh teaches that such that the comparisons in such methods of assessing a neurological disorder may include a variety of reference levels that are brain-specific and that each reference level correlate to a patient population of a certain age (para [0091]), including specific transcript levels that correlate to age (para [0008). Koh provides two exemplary transcripts with trends across age and across diagnosis classification (Fig. 28 and Fig. 29). Koh teaches using age-matched normal controls (para [0174]).
Koh teaches generating an RNA-seq library from an aliquot of a biological sample (para [0130]; see also para [0050] and [0075-76]). Koh teaches that the determination of the levels may be performed via sequencing (claims 10 and 18), and that such methods allow analysis of the whole transcriptome, including both mRNA and non-polyadenylated transcripts (para [0076]; instant claims 77).
Koh teaches suggests applying various methods of statistical analysis to determine the deviation between the subject’s circulating nucleic [acids] specific to brain tissue and that of a reference, including logistic regression for classification, i.e., “machine learning” (para [0093]; instant claim 71).
Koh doesn’t explicitly teach: identifying an age; applying classification models; forming an RNA-seq library within the same method as the Alzheimer’s characterization; or treating.
However, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of characterizing a neurological disease of AD to also have binned the subject into an age (i.e., “identified an age”; instant claim 69) using the plurality of cf-RNAs of the method using multiple controls as suggested by Koh, motivated by the desire to replicate the age-matched controls of the initial experiment and reducing potential biases of the analysis that may stem solely from age, as suggested by Koh.
Further, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to apply regression machine learning models (instant claim 71) as a means of statistically determining the reference level(s) as Koh teaches such is a common species of the genus of the method of determining statistically significant deviations, wherein such would have been predictable as Koh teaches such was common and known in the art. See MPEP 2144.08.
Additionally, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have formed an RNA-seq (NGS) library as part of a sequencing step (instant claim 77), motivated by a desire enable analyze the whole transcriptome, as taught by Koh and/or as Koh teaches that sequencing is a species of the genus of the determination of the levels, wherein such would have been predictable as Koh teaches methods for sequencing including constructing such libraries. See MPEP 2144.08.
Likewise, it would have been obvious to have both obtained the second biological sample after treatment and to have administered a treatment (instant claim 82) after recommending a course of treatment, motivated by the desire to closely monitor to provide the optimal dose of said treatment, as taught by Koh.
Such would have been predictable as Koh teaches all the elements of the limitations and such combinations would have been within the skill of the artisan, given such teachings.
It is noted that while Koh does not explicitly teach “a risk”, under the broadest reasonable interpretation, characterization to indicate a neurological disorder, i.e., “having a disorder” is interpreted to be equivalent has having 100% risk of AD.
Claim(s) 75 and 80 is/are rejected under 35 U.S.C. 103 as being unpatentable over Koh (US 2016/0289762 A1; published 10/16/2016; as cited in the IDS dated 2/21/2024) as applied to claims 74 and 82, and in view of Parsons (Parsons CG, et al. Memantine and cholinesterase inhibitors: complementary mechanisms in the treatment of Alzheimer's disease. Neurotox Res. 2013 Oct;24(3):358-69. Epub 2013 May 9).
Regarding claims 75 and 8-0, in the method of Koh, Koh fails to teach specific medicinal therapies.
Parsons teaches that memantine is indicated for the treatment of patient with moderate to severe AD and has shown symptomatic efficacy, and may be effective in delaying clinical worsening and decreasing the emergence of behavioral symptoms including agitation and aggression (pg. 360, col 1, para 2). Parsons teaches that Acetylcholinesterase Inhibitors (AChEIs) are indicated from the mild stages of AD onward (pg. 360, col 2, para 4) and that AChEIs have benefited patients’ cognitive, functional and global status (pg. 360, col 2, para, spanning pg. 361). Parsons teaches that memantine and AChEIs target two different pathological aspects of AD (pg. 361, col 1, para 2) and that preclinical data show that the combination may be a useful approach for the management of AD, especially as their complementary activity may produce greater effects than either drug alone (pg. 365, col 2, para 2).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized memantine and/or AChEIs in the treatment of AD in the method of Koh, motivated by the desire to improve symptoms and delay clinical worsening and/or benefit cognitive/functional/global status of patients, as taught by Parsons. There would have been a strong expectation for success as both are directed to treating Alzheimer’s Disease.
Claim(s) 71-72, 80, and 84-86 is/are rejected under 35 U.S.C. 103 as being unpatentable over Koh (US 2016/0289762 A1; published 10/16/2016; as cited in the IDS dated 2/21/2024) as applied to claims 69 and/or 71 above, and in view of Loboda (US 2014/0304845 A1; published 10/09/2014; as cited in the IDS dated 2/21/2024) and K (K. A gentle introduction to logistic regression and lasso regularization using R [Internet]. Eight to Late; 2017 [cited 2026 Mar 27]. Available from: https://eight2late.com/2017/07/11/a-gentle-introduction-to-logistic-regression-and-lasso-regularisation-using-r/).
Regarding claims 71-72, 80, and 84-86, as discussed and cited above, Koh teaches using brain-specific sets of RNA for characterization of Alzheimer’s, including for a determination of a stage of such a neurological disorder, and suggests determination of statistical significance using methods known in the art, including a regression model (instant claim 85), and that measurements were obtained with qPCR (see also (para [0132]).
Koh teaches that sample were obtained from subjects (para [0176]). Koh teaches MAGI1 is a marker of the Globus Pallidus [region of the brain] (pg. 29, Table 1, col 1) and suggests using genes corresponding with the whole brain (para [0086]).
Koh teaches using expression data of tissue types available and their cf-RNA transcriptome from non-diseased subjects to determine relative contributions of different tissue types in a step of deconvolution (para [0153]). Koh suggests using additional tissue-specific data to improve future analyses (para [0170]).
Koh teaches that the qPCR has improve sensitivity over other methods (para [0159]).
However, Koh fails to teach the specific sets of two or more of the group of claims 80 and 85 and that the statistical determination/machine learning involved LASSO regression model.
Loboda teaches gene expression profiling of normal aging and AD (para [0005]), particularly to diagnose AD and monitor disease progression (para [0006-7]). Loboda teaches its transcript datasets uniquely comprises biomarkers from the brain regions from the same individuals (para [0045]) and comprises genome-wide expression profiling (para [0049]). Loboda teaches that the genes of within its signatures are correlated (para [0042-43]) with a variable correlation between signatures (para [0044]) and that the regional expression of said signatures had high correlation (para [0045]).
Loboda teaches at least MNDA in the Inflame biomarkers (pg. 18, Table 4) and MAGI1 in the BioAge biomarkers (pg. 16, Table 3) (instant claim 80 and 84). Loboda teaches that the BioAge signature captures genes that typically increase with chronological age but are prematurely expressed in AD (para [0006]; Fig. 2).
K teaches that LASSO is a powerful feature selection technique that is very useful for regression problems and is a way to reduce overfitting (para 2) and operates as a feature selector by setting the coefficient of unimportant terms to exactly zero (Ridge and Lasso, para 3).
K teaches applying LASSO regularization to prediction of a disease (Lasso regularisation using glmnet; Fig. 2; instant claims 72 and 85-86), and applying the model to optimize accuracy and simplicity, i.e., to achieve a model with the smallest number of coefficients that also gives good accuracy (Lasso regularisation using glmnet, para 4). K teaches that LASSO is able to eliminate variables that contribute to overfitting without compromising out-of-sample accuracy (Wrapping up). K teaches its exemplary model choses four variables that a simple hypothesis should be preferred over a complex one, all else equal (Lasso regularisation using glmnet, para 6-7).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized the transcript datasets to improve the deconvolution of Koh in order to improve the lists of tissue-specific genes, including to create a combined brain-specific gene list, motivated by the unique individual-based whole-transcriptome brain region dataset, potentially allowing for more certainty of tissue-specific classifications. It further would have been obvious to utilize LASSO regression machine learning (instant claims 71-72) as the statistical determination species in the combined method, including using it to reduce the number of variables (i.e., genes) in the analysis of the combined set of brain-specific genes, motivated by the desire to predict disease using an optimal set of genes that reduces complexity while maintaining accuracy, as taught by K, and/or as a predictable species of the genus statistical determination/classification methods, as K teaches it to be an extension of the regression suggested by Koh. Given the teaching of Loboda that the genes of its signatures were correlated, the LASSO regularization would eliminate redundant features, and an output of MNDA and MAGI1 (instant claims 80 and 84-86) represents a predictable output of applying such a dimensionality reduction method to the correlated feature set of the brain-specific genes, including those of Loboda, wherein the inclusion of MAGI1 from the BioAge signature would be predicted to allow for an estimate of chronological age.
It further would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have quantified the dimensionality reduced set of cf-mRNA, for example, with the qPCR, motivated by the desire to utilize a more sensitive means of quantification, as taught by Koh, wherein such would have been predictable as the method is taught by Koh for the same purpose of quantifying cf-mRNA.
It is further noted that, for the sake of compact prosecution, while the above is a species of instant claims 84-86, as the “detecting a risk of a stage of ... AD” is not further recited, this is interpreted as intended use of the method and has not been given patentable weight.
Claim(s) 87 is/are rejected under 35 U.S.C. 103 as being unpatentable over Loboda (US 2014/0304845 A1; published 10/09/2014; as cited in the IDS dated 2/21/2024), as evidenced by Zheng (Zheng H, et al. Yin Yang 1 phosphorylation contributes to the differential effects of mu-opioid receptor agonists on microRNA-190 expression. J Biol Chem. 2010 Jul 16;285(29):21994-2002) and GeneCards (GeneCards. ZNF410 gene [Internet]. 2016 [cited 2026 Mar 26]. Available from: https://web.archive.org/web/20161229235725/https://www.genecards.org/cgi-bin/carddisp.pl?gene=ZNF410)
Regarding claim 87, Loboda teaches quantifying mRNA levels in blood samples from a subject and comparing the levels to those of control subjects (para [0060]), wherein the RNA would comprise cf-mRNA. Loboda also suggests applying this method to a plasma, i.e., a cell-free sample (para [0060]).
Loboda teaches applying the NdStress gene expression score (para [0060]) comprising the genes: YY1 and ZNF410 (pg. 25, Table 5).
While Loboda does not explicitly teach the “involvement” in pathways demarcated as in claim 87 or that ZNF410 is a transcription factor, these elements are inherently taught because it teaches YY1 and ZNF410, evidenced by Zheng (entire document, e.g., Title and Abstract) and GeneCards (Molecular function for ZNF410 Gene: Transcription factor; Post-transcriptional modifications for ZNF410: Sumoylated).
While not interpreted to be limiting to the claim as written given that the “detecting of a risk of ... AD” is not further recited in the body of the claim, it is noted that Loboda teaches the method in the context of detecting Alzheimer’s disease (para [0060]; see also entire document).
Loboda fails to explicitly teach that the mRNA levels quantified are cell-free mRNA levels.
However, as Loboda teaches plasma [from which cells are removed in whole blood processing] as an alternative sample, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have quantified cf-mRNA levels from at least the NdStress score comprising TFs in a combinations of the claimed pathways, wherein substituting the sample would have been obvious and predictable as plasma is a component of whole blood and Loboda teaches its suitability for this analysis. See MEPE 2144.08.
As in claim 69 above, for the sake of compact prosecution, it is noted that “a risk” is interpreted to encompass a risk of 100%, i.e., detected disease.
Conclusion
No claims are allowed.
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/EMMA R HOPPE/Examiner, Art Unit 1683
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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