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 the following in the reply filed on 12/09/2025 is acknowledged:
Invention I (claims 1-6)
a) A specific detection set of at least one cancer (reading on claims 1-5); and
i. For each cancer, a specific set of at least 5 biomarkers
For lung cancer, Applicants elect a set of miR-1-3p, miR-139-3p, miR-124a-3p, miR-142-3p, miR-146b-5p, miR-126-3p, miR-148a-3p, miR-21-5P, miR-210-5p, miR-221-3p, miR-26a-5p, miR-181b-5p, miR-223-3p, miR-26b-3p, miR-6761, and miR-339-3P.
For colorectal cancer, Applicants elect a set of miR-1-3p, miR-15b-5p, miR-26b-5p, miR-25-3p, miR-34b-5p, miR-92a-3p, miR-18a-5p, miR-26b-3p, miR-483-3p, miR-505-5p, miR-636-5p, miR-6761, miR-339-3P, and miR-431.
For pancreatic cancer, Applicants elect a set of miR-29a-3p, miR-29b-3p, miR-29c-3p, miR-30a-5p, miR-34a-3p, miR-145-5p, miR-150-3p, miR-155-3P, miR-16b-5p, miR-181b-5p, miR-223-3p, miR-483-3p, miR-505-5p, miR-636-5p, miR-6761, and miR-339-3p.
ii. A corresponding set of at least 20 biomarkers from Table 13 that serve as "the same detection information"
Applicants elect a set of miR-1-3p, miR-139-3p, miR-124a-3p, miR-142-3p, miR-146b- 5p, miR-15b-5p, miR-26b-5p, miR-25-3p, miR-34b-5p, miR-92a-3p, miR-126-3p, miR-148a-3p, miR-21-5P, miR-210-5p, miR-221-3p, miR-26a-5p, miR-29a-3p, miR-29b-3p, miR-29c-3p, miR-30a-5p, miR-34a-3p, miR-145-5p, miR-150-3P, miR-155-3P, miR-16b-5p, miR-18a-5p, miR-181b-5p, miR-223-3p, miR-26b-3p, miR-483-3p, miR-505-5p, miR-636-5p, miR-6761, miR-339-3P, miR-431, and miR-103-3p.
Claims 7 and 8 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/09/2025.
Status of Claims
Claims 1-8 are pending in the instant application and claims 1-6 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
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Color drawings and/or photographs are present as part of the filing. If the Applicant does not wish for them to be considered, Applicant may state that there was no intention to have color drawings in the response. Alternatively, if the Applicant wishes to include color drawings and/or photographs, the above petitions may be submitted.
The drawings are objected to because the y-axis of Fig. 8 contains two “10” labels; the top appears to have been meant to be “100”. 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:
The specification makes reference to colors (e.g., para [00121]). If color drawings are not approved for petition or it is stated that there was no intention to include them, reference to colors should be corrected.
Appropriate correction is required.
The use of the terms including “Texas Red” and “NanoDrop”, 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 Objections
Claim 1-5 are objected to because of the following informalities:
Claim 1, pg. 61, para beginning line 7: “at least 6 of biomarkers specific to each cancer type” should be “at least 6 biomarkers specific to…”
Claim 2: miR-21-5p, miR-155-3p, and miR-330-3p have capitalized “P”s in the claim.
Claim 3: miR-21-5p and miR-330-3p have capitalized “P”s in the claim.
Claim 4: miR-330-3p has a capitalized “P” in the claim.
Claim 5: miR-155-3p has a capitalized “P” in the claim.
Claim 6: The claim recites “the detection is performed by promers”. There appears to be a grammatical error/typo as it is unclear how a nucleic acid may perform a detection.
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 claim 6, the term “promer” is defined in para [0053] and “refers to a single that binds to the cDNA of a miRNA and may be used as both a probe and a primer”. Interpreted broadly, any nucleic acid that can bind to a cDNA of a relevant miRNA and is unblocked on its 3’ (so as to be extendable as a primer) would appear to meet this definition.
It is noted that incorporation by reference set forth in the specification requires “clear intention” to incorporate by reference as detailed in 37 CFR 1.57(c)(1).
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-6 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 1, 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.
Broadly, it is unclear whether the multiple biomarkers and cancer type(s) are intended to be limited to those of the tables, how the artisan is intended to utilize the tables to perform the method, and how the sections of the claim relate to one another. Specifically:
First, the claim recites “comparing and classifying detection information of the multiple biomarkers detected in the above step…”. It is not clear whether the detection information or the multiple biomarkers is being referred by the “detected in the above step” and therefore what nexus the “detection information” has to the multiple biomarkers detected.
Second, the claim recites “determining the type of cancer”. There is insufficient antecedent basis for this limitation in the claim. The preamble recites “providing information for diagnosis … of multiple type of cancer” and it is not clear whether this is intended to be for each of the multiple types, a single cancer of the multiple types (and if so which), or unrelated to the multiple types.
Third, the paragraphs starting on pg. 60, line 19; pg. 61, lines 5 and 7; and pg. 63, line 1 lack a clear nexus to the rest of the claim. It is not clear whether they are intended to be part of a wherein clause or something else. For example, the “the determining the type of cancer” is a determining that “a case” is a “corresponding cancer type”, which lacks a clear nexus to “the type of cancer of the sample”.
Fourth, the claim further recites “wherein the step of detecting multiple biomarkers is a step of detecting the presence or absence of the biomarkers in the sample, or measuring level of the biomarkers, or performing both”. In the paragraphs that lack a clear nexus, the claim recites “comparing the detection information of multiple biomarkers with … normal people … and classifying the detection information … into four groups … increase by 2-fold or more … decrease by less than 1/2 fold …” (pg. 60, para beginning line 19); “the detection information … is shown in Table 1” [wherein Table 1 shows Ct values] (pg. 61, para beginning line 5); “at least 6 biomarkers specific to each cancer type have the same detection information as criteria shown in Table 13 … or determining that a case in which increase in detection information … are 2-fold or more” (pg. 61, para beginning line 7); “in Table 13 above, ++++ denotes a case in which the relative increase in the expression level of the biomarker … is 2 fold or more” (pg. 63, para beginning line 1).
If the step of detecting is step of only detecting presence or absence; the cited paragraphs that lack clear nexus are intended to be modifying in the claim; and the detection information is intended to be the information gathered in the detection step, it is unclear how the artisan would be intended to determine relative fold changes based on a binary value (i.e., presence or absence).
Fifth, the claim recites “a case” in the paragraph on pg. 61, beginning line 7. It is unclear what the nexus of “a case” is to the sample of step of determining the type of cancer. The claim likewise recites “a case” throughout the paragraph on pg. 63, beginning line 1. It is also unclear whether there is intended to be a nexus between any of these “a case” and that of the “a case” of pg. 61.
Sixth, the claim recites “6 biomarkers specific to each cancer type … as the criteria shown in Table 13 while at least 20 of the multiple biomarkers have the same detection information as criteria shown in Table 13”. There is insufficient antecedent basis for “at least 6 biomarkers specific to each cancer type”. It is unclear what the nexus of the “at least 6 biomarkers” is to the “multiple biomarkers”. It is unclear whether “each type of cancer” refers to each of “multiple types of cancer”, “the type of cancer”, or something else (such as the cancer types of Table 13) and what the nexus is to the “criteria” of Table 13.
Additionally, the term “the same detection information” here appears to refer to a “transformed” or “processed” value (i.e., a fold change); thus, there is antecedent basis issue for this limitation in the claim as it causes confusion with previous references to “the detection information”. It is similarly noted that “the detection information of multiple biomarkers classified” in pg. 60, paragraph beginning on line 11 may have the same issue if this is intended to modify that section of the claim, wherein it refers to a “transformed” detection information value—“based on the classifications of the detection information” may be a more appropriate phrase.
Seventh, it is unclear what biomarkers are “specific to each cancer type”. While examples are given in the specification (para [0035], [0038], and [0041]), no limiting definition is provided either in the specification or the claim. Para [00176] directs the artisan to “the miRNAs marked with “O” in Tables 2 and 3; however, table 2 contains reference genes. Tables 3 and 4 contain miRNAs marked with an “O”. However, it is not clear how many may be considered “specific” to one or more of the cancers as some of the exemplary “specific” miRNAs appear to have the same “bin” level of expression as other cancers (e.g., miR-139-3p or miR-6761). Thus, the metes and bounds of the claim are not clear to one of skill in the art.
Eighth, while 37 CFR 1.58 allows the inclusion of tables in claims, it is unclear what specific “detection information of multiple biomarkers … shown in Table 1” (pg. 60, para beginning line 19) and “criteria shown in Table 13” (pg. 61, para beginning line 7) are being referred in the references to Table 1 and Table 13.
For example, are the multiple biomarkers intended to refer to each of the miRNA columns of Table 1 and the detection information is intended to refer to the Ct value? Or is merely intended to show that each are present? Likewise, is unclear whether “the detection information of multiple biomarkers in normal people shown in Table 1” is intended to encompass all items of Table 1 or merely “multiple” of the items of Table 1.
Similarly, it is unclear, if “6 biomarkers specific to each cancer type … as the criteria shown in Table 13 while at least 20 of the multiple biomarkers have the same detection information as criteria shown in Table 13” refers to precisely. Is the artisan intended to be allowed to pick from any column for the 20?
Accordingly, it is unclear what type of cancer should be determined if there are at least six biomarkers specific to a given cancer type for multiple cancer types. The claim recites determining “the type of cancer” (emphasis added) but there are scenarios in which miRNA levels could match the “criteria” for, say, 6 biomarkers from colorectal and 6 from pancreatic from Table 13, with the remainder of the 20 not being specific for any type of cancer (as there are at least 9 such markers in Table 13). For this reason, the metes and bounds are not clear to one of ordinary skill in the art.
Additionally, there are entries in Table 13 that are blank. The paragraph on pg. 63, beginning line 1 attempts to offer a key of Table 13 indicating fold changes. However, references to “blank” or “empty” cells were not identified in either the claims nor the specification. Therefore, the claim is also unclear for failing to provide the artisan with sufficient means to interpret the intended fold change required of the blank biomarkers.
Ninth, pg. 61, lines 14-15 recite “(e.g., expression levels)”. The phrase "e.g." renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Tenth, the steps of the claim lack a nexus to the preamble. The preamble recites “providing information for diagnosis or prognostic prediction of multiple types of cancer” (emphasis added); however, the active step of “determining the type of cancer” (emphasis added) does not fulfill this.
Claims 2-6 are likewise indefinite for depending from claim 1 and not rectifying or fully rectifying the deficiencies.
Regarding claims 3-5, the claims recites “multiple biomarkers specific to … cancer”. Claim 1 recites “at least 6 of biomarkers specific to each cancer type”. There is insufficient antecedent basis for this limitation in the claims. It is not clear in claim 1 which cancers are being referred to and further if the biomarkers are the multiple biomarkers.
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.
Claims 3-5 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. 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 claims 3-5, the claims recite “the multiple biomarkers specific to lung cancer are …” (claim 3); “…to colorectal cancer” (claim 4); and “…to pancreatic cancer” (claim 5). Claim 1 recites “at least 6 of biomarkers specific to each cancer type”.
The cancers chosen by the artisan are not explicitly limited in claim 1 or claims 3-5. The term “multiple biomarkers specific to … cancer” lacks antecedent basis with “biomarkers specific to each cancer type” and it is unclear if these claims are intended to require that all of the claimed biomarkers are evaluated or are providing a definition of which biomarkers are specific to which cancer type.
Under the interpretation that claims 3-5 are merely providing a definition of which biomarkers are specific to the cancer types listed, the artisan may still choose at least 6 biomarkers specific to each/the cancer type.
If the specific biomarkers are a characteristic of Table 13 (or inherent to the disease), from which the artisan is directed to choose the specific biomarkers, then merely defining the set of specific biomarkers would not serve to limit the claim. Likewise, since the artisan is not required to choose that cancer according to either claim, even should it be considered limiting for that cancer, it would not further meaningfully limit the subject matter.
As such, claims 3-5 fail to comply with the requirements of 112(d) for failing to further limit the subject matter of the claim on which they depend.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claims 1-6, claim 1 recites “A method of providing information for diagnosis or prognostic prediction of multiple types of cancer”.
The disclosure provides an algorithm for differentiating between lung cancer, colon cancer, and pancreatic cancer (e.g., para [00149], [00156-00158], [00176]). The specification recites that colorectal cancer is divided into colon and rectal cancer (para [0008]).
Table 12/Appendix A, wherein those mean Ct values within one standard deviation of the mean “normal people” Ct, shows that there is a relatively high level of variability in the expression levels of the chosen miRNA in “normal people”. As such, it would not be expected by the skilled artisan that the methods could be extrapolated to other cancers.
Further, in the embodiment involving Table 13, the applicant fails to describe any prognosis (i.e., an informed prediction of outcome based on a specific condition).
Under an interpretation that the claims are directed to any type of cancer, three species of cancer are not sufficiently representative to reasonably conclude that the applicant had possession of the full scope of any type of cancer at the time of filing. Likewise, a description of differentiating between lung, colon, and pancreatic cancer would not be sufficient to provide information about, for example, state of said cancers. Thus, the claims do not comply with the 112(a) written description requirement.
Claim 1 also recites “detecting multiple biomarkers in a biological sample”. The specification recites that plasm “blood samples” were used (e.g., para [00149], [0153-154], [00162], [00170]).
Calfa (Calfa S, et al. Comparative evaluation of microRNA detection in plasma, urine and liquid-based cytology for high-grade cervical intraepithelial neoplasia. Oncol Lett. 2025 Nov 26;31(2):53.) teaches that specimen types differ both in detection efficiency and variability, and that diagnostic sensitivity relies on specimen selection (Abstract).
Thus, a single type of specimen is insufficient to meet the written description requirement as the skilled artisan would not reasonably conclude that the invention was in possession of the full scope of the claimed invention at the time of filing.
Claim 1 likewise recites “at least 6 of biomarkers specific to each cancer type … as criteria shown in Table 13 below … or … at least 5 biomarkers selected from the group consisting of … [for] pancreatic cancer”.
The specification describes measuring Ct values for 36 miRNAs in 20 lung, 20 colon, and 20 pancreatic cancer patients and 20 “normal people” and finding “at least 6 miRNAs specific to lung cancer, colon cancer, and pancreatic cancer … to be similar to those shown in Table 13”. However, this data is not provided and no information/guidance is given about how many or which combinations. Selecting 6 out of 16 for lung, for example, is 8008 possible combinations (see enablement rejection below for calculation).
Given the relatively wide variation that exists, the vast number of combinations of all possible biomarkers across the three cancer types, and lack of any additional guidance in a clear reduction to practice, the skilled artisan would not conclude that the Applicant had possession of claim at the time of filing.
As discussed in the 112(d) rejection, the claims 3-5 serve to define the specific biomarkers but do not require the set to be used and the full set is likewise not identified as being utilized the specification in any of the examples.
Thus, the claims do not comply with the 112(a) written description requirement.
Claim 1-6 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). Wands states, on page 1404:
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex part Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of these in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
Regarding claims 1-6, first the claims are broad. The claims encompass detecting multiple biomarkers by looking at the presence/absence, by measuring the level, or a combination thereof and then classifying information related to detection to determine the type of cancer. Under the best possible interpretation of the claim, the artisan is asked to detect the biomarkers of Table 1, compare to the normal values of Table 1 and “bin” into a classification of fold increase, and then compare to the “criteria” of Table 13 and count how were in the correct fold-change “bin” to determine whether a threshold has been met. The applicant appears to intend that if at least five (of the subset in the claim for pancreatic) or six of the biomarkers specific to “each”/the cancer in Table 13 given “bin” of fold-change for a “corresponding cancer” with a total of 20 overall that match any “bin” of the table, the “corresponding cancer” is determined for “a case”.
As such, many different combinations of “specific” biomarkers exist. Looking to lung cancer, if the definition of “specific biomarkers” for lung cancers is used from claim 3, wherein there are 16. 16C6 is 16!/(6!10!) = 8008 combinations. This is in addition to all other combinations that exist for greater than 6. The other cancers in Table 13 would have a similar high degree of possible combinations. Combined with the higher numbers possible when looking at any possible set for 20 or greater, the claims are broad.
The claims also are to any type of sample from any subject.
Second, the invention is in the class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
Third, Table 12 in the specification shows the mean and standard deviation of the Applicant’s data that appear to have been utilized in generating the values of Table 13 (para [00174]). Appendix A contains grey highlights that show the cancer mean Ct values that are within one standard deviation of the Normal mean Ct value. As may be seen, the vast majority of mean Ct values of each of the three cancers are within the expected range for 67% of “normal people” according to Applicant’s own data. Likewise, few biomarkers were outside of even one standard deviation of each other relative to other cancers.
Given the unpredictable nature of the invention, it is common in the art to utilize multiple thresholds, such as a high log-fold change and a multiple hypothesis-adjusted p-value equivalent to, e.g., three standard deviations or more (for example, Gyvyte U, et al. MiRNA profiling of gastrointestinal stromal tumors by next-generation sequencing. Oncotarget. 2017 Jun 6;8(23):37225-37238.: pg., 37225, Small RNA-seq defines differentially expressed miRNAs in GIST tissues: “Bonferroni adjusted p-value < 0.01”and ”absolute value of log2 fold change > 3.5”, wherein “Bonferroni” is a multiple-hypothesis testing adjustment and 0.01 corresponds to threshold of three standard deviations). In contrast to this, the vast majority of the means of the cancer patients appear to be within an uncorrected single standard deviation (i.e., two-side p-value > 0.32), in the Applicant’s data, there is a high degree of unpredictability in these biomarkers.
Fourth, the working examples and guidance are limited and frequently conflict with what the best possible interpretation of what is claimed.
The claims appear to intend the artisan to look for a relative increase in the expression level of the biomarker that is 2-fold or more for ++++, or where the decrease is less than a 1/2-fold. Given the tight standard deviations in Table 12, the probability of finding such increases or decreases is almost zero where indicated.
Applicant’s guidance, contrary to the claims, recites that the relative expression level of the miRNA is “2 to the power of n, where n is (Ct value of miRNA in normal people – Ct value of miRNA in the sample)”.
Not only does this vastly change the scale of relative expression, but it also changes the direction of the claimed relationship from, for example, an expectation of 35.8 in normal compared to <17.9 for lung cancer to >36.8 in lung cancer for miR-34-5b.
As such, it was further calculated which, if any, thresholds would be outside of the “normal” mean Ct values using 2^(x_normal – x_cancer) = fold, where fold is either 2 for ++++ or 0.5 for +. As would be expected, this raises the 2 to power of 1 or -1, respectively, i.e., the thresholds set are such that the difference between the cancer and normal are never greater than 1. As all of the miRNAs have a standard deviation greater than 1, all thresholds utilized were found to be well within the expected variation for normal individuals. Thus, there is a vast amount of unpredictability in utilizing this algorithm to diagnose cancer based on the applicant’s own data, either in a near zero chance of predicting a cancer which counteracts that applicant’s examples in the claimed method or by having such a high anticipated false positive rate.
Further, while para [00176] describes an application of the method using the algorithm of Table 13 on three sets of 20 cancer patients having each of lung, colon, and pancreatic cancers, respectively, and 20 “normal people”, it is said only that the “relative expression levels were similar to those shown in Table 13” (emphasis added) and that “the relative expression level of at least 6 miRNAs specific to lung cancer, colon cancer, and pancreatic cancer … were found to be similar to those shown in Table 13” (emphasis added). Thus, it is unclear if these “test” patients actually met the requirements of the algorithm or were simply “close” to meeting them (and if so what degree of similarity was considered close enough, particularly given the issues raised above with the uncertainty in the high degree of variance).
Likewise, para [00176] reports that this method correctly diagnosed 18 lung cancer, 19 pancreatic cancer, and 17 colorectal cancer patients for a total accuracy of 90%. The specification fails to report the number of “normal people” that were diagnosed as “normal” compared to cancer or an accuracy that include these control individuals for the embodiment using this algorithm.
The guidance is very limited in the choice of biomarkers in the working example and counteracts what the artisan might expect. For example, para [00176]/Table 3, and claim 3 indicate that miR-139-3p is a specific biomarker of lung cancer. However, Table 13 indicates that lung cancer has “+” for both lung and colorectal. Instead, it appears this biomarker might be a specific biomarker for pancreatic cancer, which has ++++ expression. Although there appears to be a typo in para [00176], which indicates that Tables 2 and 3 mark the specific biomarkers with “O”, Tables 3 and 4 appear to contain them. Table 4 and claims 3 and 4 indicate that miR-6761 is specific for all cancers, despite Table 13 indicating that this has “+” expression for lung and colorectal.
Either there appear to be numerous typos throughout this guidance and dependent claims or the guidance appears to conflict with the direction in the independent to first classify the expression and then determine the type of cancer based on such “specific” biomarkers. It is not clear how a biomarker with the same classification as another cancer would otherwise be considered “specific” while the cancer in the same bin level would not.
Similarly, there is very limited guidance as to what the artisan is intended to do in “mixed” cases where 6 biomarkers indicate, for example, pancreatic cancer and 6 indicate colorectal. Is the artisan supposed to assume that the patient has both? Test more markers?
Applicants also only disclose that miRNAs were extracted from the blood of patients (e.g., para [00114-00121]) and provide no guidance on how levels may change when taken from other samples.
Given that the expected variance of the normal mean Ct overlaps with many of the “cancer” Ct values, the artisan would expect that a high level of misdiagnoses. For this reason, the artisan would anticipate a high degree of experimentation required to 1) establish which set(s) of biomarkers among the myriad claimed work best, 2) establish which are indeed specific for which cancer, 3) further establish potentially more granular thresholds within the “bins” of Table 13 to decrease the uncertainty, etc., even should the directionality and log-2 fold change issues be corrected.
Thus, there is a high degree of unpredictability in the best possible interpretation of the claimed invention utilizing the algorithm of Table 13, even allowing for a correction of the direction and scale which is not currently claimed, given 1) the breadth of possible combinations of biomarkers and limited guidance, 2) the high degree of variability of expression among the groups for the markers shown in Table 12 relative to the thresholds of Table 13 in the working example, 3) the general unpredictability in the area of biology (e.g., given different patient genetic backgrounds), 4) the lack art-accepted techniques to minimize issues related to multiple hypothesis testing and the variability of miRNA expression, and 5) conflicting guidance in the disclosure. Balanced only against the high level of skill in the art, it is held that the level of experimentation to utilize the invention claimed would be undue.
For this reason the claims do not comply with the 112(a) enablement requirements.
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.
Claim 1-6 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. The claim(s) recite(s) a natural phenomenon/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 method/process.
Step 2A, prong 1. Does the claim recite a law of nature, a natural phenomenon, or an abstract idea (recognized judicial exceptions)?
Claim 1 recites a method comprising detecting multiple biomarkers in a biological sample, comparing and classifying detection information of the multiple biomarkers, and determining a type of cancer based on a classification of information associated with multiple biomarkers, wherein the classification may encompass a relative fold change of miRNA expression levels compared to those of “normal people”.
The detection, comparison/classification, and determining steps all encompass abstract ideas. Detection encompasses mental processes (e.g., observation or evaluation of a qPCR machine in operation). Comparison and classification encompasses mental processes and mathematical calculations, including those that may be done by the human mind (e.g., observation/judgments or performing basic math to make comparisons, such as fold change and classification via “binning“ using thresholds in a table [observations/judgment] or, more broadly, using simple machine learning techniques). Determining encompasses mental processes and mathematical calculations, including those that may be done by the human mind (e.g., counting the number of biomarkers that meet the required thresholds in a table according to a simple algorithm or, more broadly, a simple machine learning technique). Thus, the claims are directed to abstract ideas.
Additionally, the claims recite the natural phenomenon of a set of miRNA levels (increased and/or decreased) relative to “normal people” being correlated with one or more particular cancer types (or more broadly “multiple biomarkers” that are measure for the level or presence/absence and used to classify “detection information” that is correlated with said cancer(s)), wherein the judicial exception is used to determine the type of cancer. Thus, the claims are also directed to a natural phenomenon.
Step 2A, prong 2. Is the judicial exception(s) integrated into a practical application?
Regarding claim 1, claim recites only steps that encompass judicial exceptions and therefore fails to integrate the claim into a practical application. It is likewise noted that generic detection steps would also be considered “mere data gathering” necessary to performing the judicial exceptions, and thus insignificant extra-solution activity. See MPEP 2106.04(d) and 2106.05(g).
Regarding claims 2-5, the claims recite particular sets of miRNAs. Such amounts to selection particular data to analyze as part of the judicial exception. Such amounts to insignificant extra-solution activity. See MPEP 2106.04(d) and 2106.05(g).
Regarding claim 6, the claim recites detection using (“by”) promers. Broadly interpreted, promers encompass primers capable of binding to cDNA of miRNAs. Mestdagh (Mestdagh P, et al. Evaluation of quantitative miRNA expression platforms in the microRNA quality control (miRQC) study. Nat Methods. 2014 Aug;11(8):809-15. Epub 2014 Jun 29) teaches 12 commercially available systems (Abstract) comprising systems that explicitly comprise amplification of cDNA (e.g., Exiqon miRCury (EX); Qiagen miScript (QI); and WaferGene SmartChip (WA)).
For this reason, the claim encompasses well-known, routine, and conventional detection of the biomarkers and thus amounts to insignificant extra-solution activity. See MPEP 2106.04(d) and 2106.05(g).
Step 2B. Does the claim amount to significantly more?
No, the claims do not amount to significantly more. Claim 1 fails to recite elements that require more than judicial exceptions and the dependent claims recite only insignificant extra-solution activity.
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").
Likewise, the courts have also found that insignificant extra-solution activity is not sufficient to qualify as “significantly more”. See MPEP 2106.05(A).
For this reason, the claims considered as a whole do not amount to significantly more than the judicial exception(s).
Conclusion
No claims are allowed.
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/EMMA R HOPPE/Examiner, Art Unit 1683
/NANCY J LEITH/Primary Examiner, Art Unit 1636