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 with traverse of Group I, Claims 19-42, 99, and 102 and the following species in the reply filed on 01/15/2026 is acknowledged.
“a specific set of one or more miRNAs comprising at least let-7a-5p”
lung cancer
“at all cancer stages”
“expression level greater than or equal to the first threshold set for each miRNA indicating upregulation”
“contacting the microRNA with a nucleic acid sequence that hybridizes to the microRNA”
Regarding the election of (a), the initial unsigned remarks dated 12/15/2025 elected “a specific set of one or more miRNAs corresponding to let-7a-5p” and the requirement was for a specific set of one or more miRNAs rather than multiple discrete sets so the election has been interpreted to be the miRNA let-7a-5p.
Regarding the election of (ii), the restriction requirement was for “jointly all cancer stages” or “early-stage cancer (Stages I and/or II)”. This election has been interpreted to be the election of “jointly all cancer stages”.
Regarding the election of (iii), absent the requested location of where to find the threshold(s), the restriction requirement for a specific set of one or more thresholds corresponding to the specific set of one or more microRNAs and the specific corresponding cancer is interpreted to be the first value of the tables listed in claim 19 corresponding to the elected miRNA and lung cancer:
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The traversal is on the ground(s) that:
Applicant argues that the Office has not shown a requisite search burden, separate classification, or cited any evidence showing the present claims have achieved a separate status in the art.
Applicant further argues against the lack of a special technical feature on the grounds that Ronfeldt is limited to prostate cancer and fails to teach nanowire capture, polymer precipitation, hybridization detection, or quantitative signal generation. Takao is silent to any miRNA analysis or quantification, is limited to microfluidic chips, and does not teach defined thresholds, specific miRNA hybridization, configurations for efficient miRNA, or expression levels of miRNAs. Applicant alleges that neither Ronfeldt nor Takao teaches the claimed method. In particular, applicant alleges that the extraction, the hybridization of specific urinary miRNAs, the measurement of specific miRNAs, and the interpretation through threshold sets to assess cancer presence or stage is not disclosed or rendered obvious by Ronfeldt or Takao and is therefore a special technical feature.
Applicant also argues that the ISA did not check Box No. IV, and that MPEP 1850 says that the decision with respect to unity rests with the ISA.
This is not found persuasive because:
Regarding the requirements for a restriction under US restriction practice, this application was filed as a national stage application under 35 USC 371. As such, unity of invention analysis—not an independent and distinct analysis—is what is required. See MPEP 1893.03(d).
Regarding the lack of unity, as discussed in the requirement for restriction/election dated 10/24/2025, the Groups I, II, and III collectively require only the technical feature of presence of miRNAs in urine. Independent claim 19 has only the positive step of “predicting the likelihood that a subject has cancer as an indicator, using one or more of microRNAs selected from the group consisting of the below, in the urine extract obtained from the subject, as an indicator”. Independent claims 43 and 61 are methods of analyzing a urine sample that require specific steps (e.g., “contacting a urine sample with a nanowire”). As has been discussed, the technical feature shared amongst these inventions is only a recognition of the presence of specific miRNAs in urine.
As was cited (pg. 5, Requirement 10/24/2025), even if this had been argued to be a technical feature and not lack of unity a priori, Ronfeldt teaches the presence of one such miRNA in urine and predicting a likelihood [assessing a risk] of a cancer using a claimed miRNA.
Further, Groups II and III lack unity over the combination of Ronfeldt and Takao, as cited (pg. 5-6, Requirement 10/24/2025). It is noted that Group III does not require hybridization (i.e., Next Generation Sequencing may be used to confirm whether the extracted miRNAs contain a specific miRNA; however, for the sake of argument, it would also be understood by the artisan that Next Generation Sequencing comprises a step of hybridizing primers [i.e., a sequence which hybridizes to the miRNA] to miRNA. The combination of Ronfeldt and Takao would have been obvious to efficiently extract exosomes while minimizing sample and time required, as previously discussed. Therefore, Groups II and III do not make a contribution over the art.
Also, contrary to arguments, it is noted that Takao is specifically concerned with exosome-derived miRNA, as previously cited (para [0002] and [0005]), in its method of nanowire biomolecule extraction (entire document, e.g., para [0001]). See also para [0020] and [0022].
PCT Rule 13.2 states:
Where a group of inventions is claimed in one and the same international application, the requirement of unity of invention referred to in Rule 13.1 shall be fulfilled only when there is a technical relationship among those inventions involving one or more of the same or corresponding special technical features. The expression "special technical features" shall mean those technical features that define a contribution which each of the claimed inventions, considered as a whole, makes over the prior art.
The groups, as drafted, do not make a contribution over the art as alleged. For the purposes of the unity of invention determination, the analysis is directed to the features reflected in the independent claims. While the additional features discussed in the arguments are noted, they are not reflected in these claims.
Regarding the argument about the ISA having the decision regarding the unity of invention, MPEP 1845.01 states: “On the international level, all written opinions are nonbinding”. Different art has been applied and a different determination regarding unity has been made.
The requirement is still deemed proper and is therefore made FINAL.
While it is noted that the applicant failed to respond to the election requirement (b)(i), for the sake of compact prosecution and upon further consideration, this requirement is withdrawn.
Claims 22-73, 77-81, 88,95-98, and 100-125 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 01/15/2026.
Status of Claims
Claims 1-18, 74-76, 82-87, and 89-94 have been cancelled. Claims 19-73, 77-81, 88, and 95-125 are pending in the instant application and claims 19-21 and 99 are 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 considered on a submitted IDS, they have not been considered.
Drawings
The drawings are objected to because:
Fig. 17A contains foreign language.
Replacement greyscale drawings including Fig. 2, 3C, 12, 16D, 17B, and 19 do not have sufficient contrast under greyscale to distinguish features. Applicant may submit a new color petition or remake the relevant figures with a color scale and/or pattern (e.g., striped fills or similar for bar plots) appropriate to the low contrast of grey scale.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
As noted in the petition decision dated 07/31/2023, along with the submitted substitute black and white drawing, applicant is required to remove the color drawings language (e.g., “yellow”, “blue”, etc.). See also Drawings section.
Appropriate correction is required.
The use of the terms including “Alexa Fluor” and “ExoQuick”, each 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 Notes
Regarding claim 19, the claim recites “A method for predicting the likelihood that a subject has cancer in a subject having or suspected of having cancer”. For clarity, it is recommended to reduce repetitions of “a subject”, e.g., “A method for predicting the likelihood of having cancer in a subject having or suspected of having cancer”.
The claim further recites “microRNAs selected from the group consisting of the below”. The clarity of claim could be further improved by specifically reciting “microRNAs selected from the group consisting of the microRNAs of sets (i)-(xvi)”.
Claim Objections
Claim 19-21 and 99 are objected to because of the following informalities:
All claims: Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation. See 37 C.F.R. 1.75.
All dependent claims: The term “Claim” should be lowercase in “according to Claim ...”.
Appropriate correction is required.
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.
Claim 19-21 and 99 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.
The claims are generally narrative and indefinite, failing to conform with current U.S. practice. They appear to be a literal translation into English from a foreign document and are replete with grammatical and idiomatic errors.
Regarding claim 19, first, the claim recites in line 3, “predicting the likelihood that a subject has cancer as an indicator”. It is not clear whether “the likelihood” is the indicator and what, if anything else, it is intended to indicate. Additionally, the nexus, if any, between “a subject” (line 3) and the “a subject” (line 1) of the preamble is not clear; as “the subject” (line 5) is later recited for where the urine extract is obtained, this lacks antecedent basis and is unclear.
Second, the claim recites “predicting the likelihood ..., using one or more microRNAs ..., in the urine extract obtained from the subject” (lines 3-5). The commas imply that the likelihood is to predicted in the urine extract obtained from the subject. It is not clear how this is intended to be performed as no steps are recited. Under an alternative interpretation that microRNAs in urine extract are intended to be used in the prediction, it remains unclear whether the microRNAs themselves (i.e., the physical nucleic acids) or a measurement thereof (e.g., an expression level) is intended given the claim construction and differentiation of the latter in the dependent claims (e.g., claim 20).
Third, the claim recites “data S1 ... Table 2 ... Table 4-1 ... Table 4-15” (lines 6-21). As stated in MPEP 2173.05(s), claims are to be complete in themselves and incorporation by reference of a table is only permitted where there is no practical way to define the invention in words. As is demonstrated throughout the specification and in other claims (e.g., claim 23), reciting lists of miRNAs is possible in words. Therefore, this threshold is not met.
Fourth, the claim 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.
The Markush grouping of “one or more of microRNAs selected from the group consisting of the below ... (i) any of the microRNAs listed in data S1 or in Table 2 ... (xvi) any of the microRNAs listed in Table 4-15, wherein in each table, said microRNA may be one or more, two or more, three or more, four or more, five or more, 15 or more, or 20 or more microRNAs” is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
The microRNAs have different sequences and parent genes (i.e., do not share a single structural similarity that is physical, chemical, or art-recognized) and each of sub tables of Table 4 is directed to a different cancer, demonstrating their different usages in the instant invention. Thus, neither condition is met for inclusion in a 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.
Further, the Markush group is so expansive that persons skilled in the art cannot determine the metes and bounds of the claimed invention and is therefore indefinite. See MPEP 2173.05(h). Namely, as an example of the expansive breadth, data S1 consists of 2330 miRNAs. The possible number of combinations in a set may be calculated using the formula nCr = (n!)/((n-r)!*r!). Choosing 3 in a set of 2330 results in 2.1 billion possible combinations; 5 results in 5.7 * 10^14 possible combinations; 10 results in 1.3 * 10^27 possible combinations; 15 results in 2.4 * 10^38 possible combinations; etc. The examiner was not able to calculate the number of possible combinations past 47 through standard calculation means. Accordingly, as the claims encompass “one or more” of such a massive number of distinct alternative members that the artisan would not be to be able to practically determine the metes and bounds of the expansive sets encompassed by the claim, rendering it indefinite.
Fifth, the claim recites “said microRNA may be one or more, two or more ... or 20 or more microRNAs”. It is unclear how a microRNA may be multiple microRNAs. The artisan would understand that a miRNA may be a precursor microRNA (pre-miRNA or pri-miRNAs) may produce multiple (e.g., 2 or 10) miRNAs, but it is not clear if subsets of the claimed miRNAs comprise such miRNAs and this is intended refer only to these or this is intended to refer to selections of miRNAs; in either case, the duplicate use of the term “microRNA” is unclear.
Claims 20, 21, and 99 are indefinite for depending from claim 19 and not rectifying the deficiency.
Regarding claim 20, first, the claim recites “the expression level” (line 1) and “the first threshold” (line 3). There is insufficient antecedent basis for these limitations in the claim.
Second, the claim recites “the expression level of ... the microRNAs ..., listed in each table, is greater than or equal to the first threshold set for each microRNA” (lines 1-3). It is unclear whether the expression level, the microRNAs, or under a broader reading given the translation possibly the first threshold, are listed in each table.
It is noted that any item(s) imported from the tables would need to be recited within the claim itself. See claim 19 and the discussion of not including a table by reference.
Third, the claim recites “wherein if the expression level ... is greater than or equal to ..., indicating a likelihood ...” (lines 1-4). There is no results clause of the conditional “if” clause. Accordingly, it is unclear what is intended to happen if this statement is true.
Fourth, it is unclear what the nexus to “indicating a likelihood” (line 4) is intended to be. It is not clear whether it is intended to be a separate step (i.e., further comprising: “indicating a likelihood that the urine is derived from a cancer patient”) or whether it is intended to be a part of the results clause of the conditional.
Fifth the nexus between “a cancer patient” (line 4: “the urine derived from a cancer patient”) and “the subject” (line 2: “the urine extract obtained from the subject”) is also unclear because “the urine” (line 4) lacks a clear antecedent basis.
Sixth, as in claim 19, the claim recites “the microRNA may be one or more, two or more ... or 20 or more microRNAs” (lines 5-6). It is unclear how a microRNA may be multiple microRNAs for the same reasons as above.
Claims 21 is indefinite for depending on claim 20 and not rectifying the deficiency.
Regarding claim 21, as in claim 20, the lack of clarity regarding the expression level vs. microRNA vs. threshold “listed in each table” (claim 20: “second”); regarding the lack of a results clause following the conditional (claim 20: “third”); regarding the nexus of “indicating ...” (claim 20: “fourth”); regarding the nexus between cancer patient and subject/antecedent basis of urine (claim 20: “fifth”; and regarding the microRNA being multiple microRNAs (claim 20: “sixth”) is likewise unclear in claim 21 for the same reasons.
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 19-21 and 99 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). See also MPEP 2164.01(a).
Paragraph numbers are those of the published application US 2023/0265521.
Regarding claims 19-21 and 99, under the best possible interpretation of the drafted claims, claim 19 recites predicting the likelihood that a subject has cancer using one or more microRNAs in urine extract obtained from the subject. The applicant elected the miRNA let-7a-5p, lung cancer, detecting jointly at all stages, and use of an expression level greater than or equal to the first threshold set for each miRNA indicating upregulation.
First, the claims are broad. Even under the election of a single miRNA and single cancer, under the best possible interpretation as drafted, they encompass any means of prediction (e.g., any algorithm/formula), any isolation method, any assay, any subject (human, non-human, etc.), any collection method of urine, etc.
Second, the amount of direction provided to “use” let-7a-5p for lung cancer likelihood prediction is limited. Data S1 (i.e., Table 3) recites a signal intensity [i.e., level; see para (0566)] of 0 for three lung cancer patients and the three non-cancer patients. Exemplary guidance in the specification (para [0749]) for data S1 recites: “for a microRNA with higher expression in three subjects having cancer than in any of three non-cancer subjects, the likelihood that a subject has cancer can be determine to be high using a microRNA level of a body fluid sample of the subject higher than a predetermine value ... referred to as a ‘threshold’”. Such guidance appears to exclude let-7a-5p from consideration as it does not meet the criteria of having higher expression in three cancer patients than three cancer patients in S1.
Further, Fig. 20-1 provides a ROC curve for lung cancer in humans (wherein the number of individuals is not specified); for let-7a-5p, the ROC line largely hovers just above the baseline random classifier 45 degree diagonal and the AUC is 0.53. This miRNA is not present in Table 4-1, which is described as microRNAs with a statistically significant difference between the urine of lung cancer patients and the urine of the healthy persons (para [1006]); the artisan would interpret this to mean that there was no difference in the instant data between lung cancer and healthy populations for the elected cancer-miRNA combination.
It is noted also that para [1013] recites that ROC curves were plotted for cancer patients in what appears to be a general analysis, wherein Table 24-1 recites that the AUC was again 0.530 with a FP rate of 0.91.
The disclosure also provides data on the number of miRNA species found only in lung cancer tissues, only in urine, or in both tissues and urine (Fig. 19A) and a sample of miRNA levels for those shared (Fig. 19B). No statistics were identified on the number or proportion shared in only tissues vs. only urine vs. both across the samples, what relationship this has to claimed miRNAs the tables, or how these differ from the expression identified in normal lung/urine. The range of miRNAs found in both tissues and urine was 867 to 1253 and the unpredictability in this number was much higher than that of the tissue. The expression level also showed a high level of unpredictability both between tissue and urine expression in a given miRNA and with the level of variation within a particular sample type (e.g., miR-938 shows narrow confidence intervals for tissue but wide for urine, whereas miR-6828-5p have very similar intervals for both). It is further noted that a minority of urine miRNAs in lung cancer patients were detectable across all 100 lung cancer patients and 100 healthy persons (Fig. 16 D), indicating unpredictability.
Third, in contrast to the claimed and elected correlation between let-7a-5p and lung cancer, the art teaches a high degree of unpredictability both regarding the detection of urinary miRNAs as biomarkers; regarding let-7a-5p in urine as a reliable diagnostic biomarker; and regarding the expression direction of let-7a-5p in lung cancer.
Gheinani (Gheinani AH, et al. Improved isolation strategies to increase the yield and purity of human urinary exosomes for biomarker discovery. Sci Rep. 2018 Mar 2;8(1):3945) teaches that there have been major difficulties in the application of urinary extracellular vesicles (uEV), which can contain miRNAs, into the clinic due to high variability and low reproducibility of uEV isolation methods (Abstract). Gheinani teaches that total urine RNA did not correlate with exome RNA in their experiments (pg. 9, para 2). Gheinani teaches that the miRNAs identified depended on whether total urine or uEV preparation methods were used (Fig. 6-7; pg. 9, miRNA profiling in urinary exosomes and total urine). Gheinani teaches let-7a-5p is among the miRNAs stably detected in all 6 sample pairs of total urine from healthy males and the read counts depended on the method of isolation (Fig. 7C; see also pg. 13, Sample collection and processing). Gheinani teaches small technical modifications of standard urinary miRNA analysis techniques in the field result in considerable impact on the final results (pg. 13, para 2; see also pg. 9, Discussion, para 1). Therefore, the teachings of Gheinani indicate that there is high unpredictability in detection of urinary miRNA due to at least the methods of sample isolation/processing known in the art, that these extend specifically to let-7a-5p, and that let-7a-5p is detected in one method of processing in healthy volunteers, contrary to the instant findings (i.e., instant data S1).
Park (Park S, Moon HY. Urinary extracellular vesicle as a potential biomarker of exercise-induced fatigue in young adult males. Eur J Appl Physiol. 2022 Oct;122(10):2175-2188. Epub 2022 Jul 4) teaches the acute exercise changed the concentration of urinary EVs and miRNA profiles therein (Conclusion), including of let-7a-5p (Fig. 5 and Table 5). Therefore, the teachings of Park indicate unpredictability in urinary miRNAs used for diagnosis of diseases, including let-7a-5p, given the propensity for the biomarker fluctuate based on the actions of the subject immediately before the test.
Corbacloglu (Çorbacıoğlu ŞK, Aksel G. Receiver operating characteristic curve analysis in diagnostic accuracy studies: A guide to interpreting the area under the curve value. Turk J Emerg Med. 2023 Oct 3;23(4):195-198) teaches that AUC values below 0.80, even if they are statistically significant, have very limit clinical usability (pg. 197, col 1, para 1, spanning col 1) and recommends that interpretations of AUC between 0.5 and 0.6 should be “Fail” (Table 2). It is also noted that Corbacloglu teaches that even an AUC above 0.80 should be interpreted with caution and in light of the confidence interval in diagnostic studies (pg. 197, col 2, para 1). Therefore, the teachings of Corbacloglu indicate, given the AUC and threshold presented for let-7a-5p in the instant disclosure for cancer/lung cancer, that there is a high level of unpredictability in the use of let-7a-5p and the artisan understand there would be a need to perform a great deal of experimentation to find new prediction methods and the physiological situations in which this miRNA could predict lung cancer in a subject using measurements in urine extract, if such scenarios exist.
Jeong (Jeong HC, et al. Aberrant expression of let-7a miRNA in the blood of non-small cell lung cancer patients. Mol Med Rep. 2011 Mar-Apr;4(2):383-7. Epub 2011 Jan 25) teaches decreased expression of precursor let-7a in NSCLC patient tissues vs. normal lung tissues (Fig. 2); NSCLC patient blood vs. healthy subjects (Fig. 3); and NSCLC cancer cell lines vs. fibroblast cells (Fig. 1). Therefore, the teachings of Jeong indicate high level of unpredictability in using a threshold indicating overexpression [i.e., greater than or equal to a threshold, including 0.0 with background subtracted] because, even if mature let-7a-5p were reliably detectable in urine extract for diagnostic purposes which would be unpredictable at least in view of the differences in urine vs. tissue of the instant disclosure, as the precursor miRNA of let-7a-5p shows an opposite relationship in the blood and lung cancer tissues in patients with the most common form of lung cancer, it further would be unpredictable to the artisan to have an opposite signal to the tissues and blood (i.e., a carrier of EV, naked, and/or immune cell miRNAs) from which the artisan would expect a signal diagnostic of cancer outside of the urinary tract in urinary extract to derive mechanistically (e.g., from the tumor or systematic immune response thereto).
While it is noted there is additional guidance related to isolation methods (see, e.g., para [00935-939] and [00953-990]), the data associated with the elected miRNA and cancer would be understood by the artisan to be insufficient for predicting a likelihood of cancer, at least in view of Corbacloglu. Accordingly, this guidance, directed embodiments of isolation and detection that produced prediction levels that would be insufficient for an artisan to utilize the elected embodiment of the claimed method, would not be sufficient to overcome the variability taught in the art for at least the isolation means.
Taken together, given the breadth of the claims, the lack of what the artisan would interpret as a working example (as demonstrated by Corbacloglu), the limited guidance for the miRNA and lung cancer, the unpredictability taught in the art 1) regarding the ability to reliably detect miRNAs including let-7a-5p specifically using various isolation means; 2) regarding levels of let-7a-5p being dependent on subject activity levels; and 3) regarding unpredictability in expression between urine and tissue, including of let-7a/let-7a-5p expression levels and their directionality in lung cancer patients, balanced only against the high level of skill in the art, the level of experimentation required the overcome the unpredictability would be undue.
For these reasons, the claims do not comply with the 112(a) enablement requirement.
Claims 19-21 and 99 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 19-21 and 99, the claims encompass a method for predicting the likelihood that a subject has cancer (limited in part in claims 20 and 21) using one or more microRNAs selected from a set of microRNAs listed in tables in a urine extract from the subject, under the best possible interpretation of the claims.
The claims are broad, encompassing thousands of possible miRNAs, any means of prediction (e.g., any algorithm/formula), any urine extract (and means of isolating/determining levels of miRNA), any assay, any collection method of urine, any subject (human, non-human, etc.), etc.
As discussed in the 112(b) rejection above, the possible number of combinations in a set may be calculated using the formula nCr = (n!)/((n-r)!*r!), a referenced in instant para [1011]. Choosing 3 in a set of 2330 results in 2.1 billion possible combinations; 5 results in 5.7 * 10^14 possible combinations; 10 results in 1.3 * 10^27 possible combinations; 15 results in 2.4 * 10^38 possible combinations; etc.
In contrast to this claimed combination space, the disclosure recites:
A model with “all the miRNAs detected in the urine” for lung cancer vs. non-cancer and for each stage vs. all other stages and non-cancer (para [1003]; Fig. 18; Fig. 17C: “all miRNAs”: 2565);
A model with 19 miRNAs for lung-cancer vs. non-cancer (e.g., Fig. 17C and para [1002]);
A model each for randomly selected and undisclosed sets of 5, 10, 15, and 20 miRNAs for each of the cancers in Tables 4-1 to 4-15 (para [1009-1011]; Tables 5-1 to 19-2); and
Single miRNA predictions (Tables 24-1 to 25-15; Fig. 20-1 to Fig. 34-84).
Where it is recited that “the prediction was performed 20 times” (e.g., para [1009]), this is interpreted to be the cross-validation technique utilized elsewhere (e.g., para [1002]) rather than discrete sets of miRNAs.
In contrast to all means of prediction, the models described are stated to be logistic regressions (e.g., para [0868], [1000], [1002], and [1009]), and many describe p-values (e.g., Table 4-1 to 4-15) that have no apparent error correction for multiple hypothesis testing. Huber (Huber, W. Sensitivity, Specificity, ROC, Multiple testing, Independent filtering [Internet]. Bioconductor: CSAMA; 2011. Statistics 101; Available from: https://www.bioconductor.org/help/course-materials/2011/CSAMA/Thursday/Morning%20Talks/110629-multtestindepfilt-huber.pdf) teaches that data analysis of microarray or RNA-seq expression profiles of “normal” vs. “perturbed” samples relies on “multiple testing” (pg. 16) and that multiple testing requires considering that when n tests are performed, what is the extent of the type I error and how can it be controlled, e.g., if 20,000 tests with alpha of 0.05 all with H0 = true, expect 1000 false positives (pg. 19). Huber teaches methods including Bonferroni, Benjamini-Yekutieli, FWER, and FDR that work on either the p-values or the data matrix itself (pg. 34); no such words or phrases were identified in the disclosure. The artisan would understand that given the expectation of such family wise error rate (FWER), i.e., the expected variability of test statistics, as shown by at least Huber, would be expected to include some number of apparently significant predictive models absent a means of correcting for multiple hypotheses, and that testing every miRNA without such correction would not be sufficiently representative to show possession of prediction of cancer with said miRNAs using the instant models, let alone diverse predictive models. Further, given the size of the predictive space, as shown in the calculations above, one or a few models for each number of miRNAs, let alone all possible miRNA predictors, is not sufficiently representative of the diverse and highly variable predictive space of such models. For example, as shown in Table 8-1, the leukemia predictor using randomly select miRNA has a range of AUC of 0.494 to 0.829 with 5 miRNA and 0.522 to 0.915 with 20 miRNA. As such, the models presented are not sufficiently representative of the species of predictions of cancer using all of the species of one or more miRNAs from the claimed tables.
In contrast to any urine extract as claimed, the specification recites that the microRNAs were extracted from the urine in “the same manner as Example 1” (para [0991]), which is interpreted to be using a nanowire device of the disclosure (e.g., para [0989]). While it is noted that Example 1 includes various contrasting methods used to compare the amount of small RNAs collected by the nanowire-embedded collection device (e.g., Figs. 2 and 10), no identification of particular miRNAs for these methods were identified. The differences shown between the nanowires compared to the ultracentrifugation or the commercially available kit (Fig. 2) further serve to highlight the variability across extraction techniques.
Further, as cited in the 112(a) enablement rejection above, Geinani teaches that the baseline level of let-7a-5pexpected in healthy individuals—which was not detected in the instant nanowire extraction method (e.g., data S1)—is dependent at least on whether total RNA or uEVs are extracted and that there are major difficulties in reproducibly extracting uEV, which may contain miRNAs, across methods. Thus, there is high variability in microRNAs in urinary extract, particularly let-7a-5p, and the disclosure does not provide a representative number of species for urine extracts for use in predictions of cancer for the claimed miRNAs.
Where it is specified, the miRNAs are disclosed to be human miRNAs (e.g., Table 4-1 to 4-15 “hsa- ...”) and the cancer patients and controls are interpreted to be humans (e.g., para [1007]: “lung cancer patient or a healthy person”; emphasis added). However, the disclosure makes clear that the subject is intended to be interpreted broadly (para [0627]).
In contrast to this, Breschi (Breschi A, et al. Comparative transcriptomics in human and mouse. Nat Rev Genet. 2017 Jul;18(7):425-440) teaches that only 300 miRNAs have a defined ortholog in other species (1.3. Small non-coding RNAs, para 2), demonstrating that the other species are diverse and that human miRNAs and predictions of cancer using such are not sufficiently representative of all species of subjects.
Accordingly, the artisan would not have reasonably concluded that the artisan had full scope of the claimed invention of all species of predictive models for all combinations of all sets of one or more miRNAs for all possible cancers using any urine extract in any subject at the time of filing. Therefore, the claims do not meet the 112(a) written description requirements.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 99 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Regarding claim 99, the claim recites “The method of Claim 19 is an in vitro method.”
Claim 19 recites “predicting the likelihood ..., using one or more microRNAs ..., in the urine extract obtained from the subject”.
First, the claim is a deterministic statement, rather than one that narrows (i.e., defines that all outcomes of claim 19 are in vitro rather than limits a subset of to being in vitro). However, even if it had been phrased to be limited to only a subset of embodiments of claim 19, claim 19 recites that the likelihood and/or the microRNAs are in ... urine extract. A urine extract obtained from a subject would be understood to be outside of the body, i.e., in vitro.
Thus, the claim fails to further narrow the claim upon which it depends and, therefore, does not comply with the requirements of 112(d).
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 19-21 and 99 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) natural phenomenon and/or abstract ideas. This judicial exception is not integrated into a practical application. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
The following three inquiries are used to determine whether a claim is drawn to patent-eligible subject matter:
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter?
Yes, the claims 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 19 recites a method of predicting the likelihood that a subject has cancer ... comprising predicting the likelihood that a subject has cancer ... using one or more miRNAs selected from a group of miRNAs in Tables in the urine extract obtained from the subject as an indicator.
This claim recites the natural phenomenon of the correlation between cancer and one or more miRNAs, based on the amount and/or presence/absence of said miRNAs in the urine extract of the subject under the best possible interpretation as drafted.
The claim also recites the abstract ideas of a mental process (e.g., evaluation or judgment) and/or a mathematical calculation, including one that may be performed in the human mind. For example, looking at the level of a miRNA detected in urine in a subject and making a judgment about the likelihood of the present of cancer or using that level in a mathematical formula to calculation a probability, under the best possible interpretation of the claim as drafted.
Step 2A, prong 2. Is the judicial exception(s) integrated into a practical application?
Regarding claim 19, no, the claim recites only “using” the biomarker to make a prediction, i.e., use of the correlation that is the natural phenomenon. See MPEP 2106.04(b). Likewise, as an abstract idea, nothing more is recited to integrate the claim into a practical application.
Regarding claims 20-21, under the best possible interpretation of the claims as drafted, the claims recites indicating a likelihood that the urine is from a cancer patient (claim 20) or a patient with a particular type of cancer (claim 21) if the expression level of any of the selected miRNAs is greater than a first threshold.
Such “indicating” encompasses the abstract ideas of mathematical calculations (e.g., using an algorithm that produces a result when the claimed conditions are met) and/or methods of organizing human activity (e.g., a clinician verbally indicating a likelihood to a subject if the conditions are met). Accordingly, the claims add no more than judicial exceptions and do no integrate the claim into a practical application.
Regarding claim 99, the claim recites that claim 19 is an in vitro method. Broadly interpreted, “in vitro” encompasses methods performed in the laboratory/outside of the body (i.e., of the subject) and requires no particular steps.
Accordingly, it encompasses the same natural phenomenon and/or abstract ideas as in claim 19.
Step 2B. Does the claim amount to significantly more?
No. As discussed in MPEP 2106.05(I), the inventive concept "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself." Genetic Techs. Ltd. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016). See also Alice Corp., 573 U.S. at 21-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. at 78, 101 USPQ2d at 1968 (after determining that a claim is directed to a judicial exception, "we then ask, ‘[w]hat else is there in the claims before us?") (emphasis added)); RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017) ("Adding one abstract idea (math) to another abstract idea (encoding and decoding) does not render the claim non-abstract").
The claims, as drafted and under the best possible interpretation thereof, require no more than the judicial exception(s) and therefore cannot amount to significantly more.
Conclusion
No claims are allowed.
The following patents are made of record as they are considered pertinent to unelected species, which may become relevant if the species are rejoined:
U.S. Patent No. 11,845,975 B2 is directed to using miR-16-1-3p (e.g., instant Table 4-2) from a urine extract from a subject suspected of having lung cancer when the amount of the miRNA is greater than that of the miRNA the urine extract from a control human subject (claim 1) to diagnose a human as having the risk of lung cancer, or further comprising determining additional miRNA(s) (claims 2 and 19).
U.S. Patent No. 12,442,044 B2 is directed to using at least miR-4251 (e.g., instant Table 4-3) in urine extract of a human subject to identify the human subject as having a liver cancer or an increased risk of having the liver cancer when the amount of the miRNA(s) in the urine extract of a control human subject that does not have the liver cancer (claim 1) wherein the miRNAs may further encompass one of the miRNAs of ‘942 (claim 12).
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/EMMA R HOPPE/ Examiner, Art Unit 1683
/ANNE M. GUSSOW/ Supervisory Patent Examiner, Art Unit 1683
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