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 .
Priority
This application claims priority from foreign parent CN201910376061.0 filed 5/7/2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Election/Restrictions
Applicant’s election without traverse of Invention I, claims 1-7 in the reply filed on 10/16/2025 is acknowledged. Claims 8-10 are withdrawn.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 4/11/2022 is being considered by the examiner. It is noted that CN108463561 A is provided in a foreign language, and that Bianco (US2019/0249250A1) has been provided as the English copy, as indicated.
Drawings
The drawings, filed on 04/11/2022 are objected to because of text that is of a font size that is too small and/or of poor quality. 37 CFR 1.84 recites the standards for drawings and 37CFR 1.84 (l) addresses the character of lines, numbers and letters to allow them to be satisfactory for reproduction. In FIG 1, the scale bar cannot be read, in FIG3A -3C, the patient and control data points cannot be easily distinguished, FIGs 4C, 5C, the ‘circle icon’ to depict data is such that “case” and “control” do not appear clearly distinguishable, and the designations on the ticks of the X axis cannot be read. 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 use of the term Zetaview and any other registered marks which are trade names or marks used in commerce, have been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
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.
The specification reference significantly different miRNAs as “red” dots (at least Pg 9) but the dots are in grayscale.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-7 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.
Claim 1 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The claim recites, “A method for diagnosing schizophrenia, comprising using a microRNA” (selected from the Marksuh group) “as a biomarker for diagnosing schizophrenia”. The omitted step(s) include disclosing how the biomarker is used for diagnosing schizophrenia, since the claim is entirely absent of this step. Only a Markush grouping of miRNAs are presented as biomarkers “for diagnosing” without the method step that uses the biomarkers to diagnose the disorder of schizophrenia.
Claim 2 is indefinite on the basis that it contains use of the transitional phrase “comprising” with a Markush grouping, rendering the grouping open-ended, thus it is unclear what other alternatives are intended to be encompassed by the claim (MPEP 2173.05(h)). Claims 3-7 depend from claim 2 and are indefinite for the same reason. A Markush grouping requires a closed group of alternatives (MPEP 2117; MPEP 2173.05(h)). The use of, for example, “wherein the sample is selected from the group of microRNA’s that consists of” in place of “the microRNA comprising” would render the grouping closed (by the use of consisting in place of comprising to overcome this aspect of the rejection, as well as address a second issue, that is the missing connection between the claimed “detecting the microRNA level in a sample…” and “…wherein the microRNA comprising”, which is presently unclear.
Claim 3 is indefinite over the use of “includes a peripheral blood expression level or serum expression level” since it is not clear whether includes is intended to mean in addition to (an)other sample, e.g. of claim 2) or whether includes is solely meant to narrow claim 2’s “detecting the microRNA level in a sample” where that detection occurs in either peripheral blood or serum.
Claim 4 is indefinite in the use of “preferably the microRNA comprises one or more”…with a range, since a narrow range within a broader range renders the claim indefinite because it is unclear whether the narrower range, preceded by “preferably”, is a claim limitation (MPEP 2173.05(c)). Claim 5 depends from claim 4 and is indefinite for the same reason. MPEP 2173.05(c) further recites that a narrower range or preferred embodiment may be set forth in another (dependent) claim, such that the boundaries of the claim are clear regarding the claimed limitation.
Claim Rejections - 35 USC § 112 - Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(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.
Claim 1 is 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. Note that this is a scope of enablement rejection of claim 1. The claim 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.
Specifically, the claim is broadly directed to: A method for diagnosing schizophrenia, comprising using miRNA selected from a (recited) group, as a biomarker for diagnosing schizophrenia. A reasonable relationship must exist between the scope of exclusive right grant to an applicant and the scope of enablement set forth in the patent application.
To address whether sufficient evidence supports the determination that the disclosure does not satisfy the enablement requirement and whether undue experimentation might be needed, the below factors are considered:
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The breadth of the claims: The claim is very broad, reciting a method using miRNA as a biomarker to diagnose schizophrenia.
The nature of the invention: The invention relates to miRNA expression differences in control and patient data, where the method involved: serum exosome isolation, total RNA extraction, whole microRNA sequencing and expression abundance analysis involving screening for “significantly different miRNAs”, which relates to differential transcriptome analysis (after removal of low expression miRNAs), initially of 23 healthy controls and 23 patients (Pg 8). First, three miRNAs were selected and to do so, DESeq2 was used for difference analysis where it is stated that miRNA with Q of ≤ 0.05 and a difference multiplier of ≥ 2 were considered significantly different, though what is unclear is why these three miRNA are indicated as such, since as depicted in Table 1 all difference multipliers are <2, not >2. This persists through data and results. The second data set further is indicated to have 49 samples but says there are 23 controls and 23 patients, which is 46 not 49 (Pg 9). This data set yields seven miRNA that are significantly different, inclusive of the batch one three miRNA. Table 2, like Table 1, depicts difference multipliers, none of which are ≥ 2. Example 3 indicates the above data are combined, yielding 49 patients (yet the above yield 46 patients) and 6 miRNAs are selected, shown in Table 3, again, with difference multipliers that are less than 2. A random forest model was employed. 11 miRNA markers are ultimately selected (Table 4), for sample classification (e.g. higher risk, lower risk of developing disease), and again difference multipliers are with one exception not 2 or higher (same for Table 5). Validation results include 6 of the 11 markers.
The state of the prior art: The art is a changing field. The art indicates known issues (e.g. variability) are associated with miRNA disease biomarker detection, including “restricted miRNA expression patterns”, and “some miRNA species are expressed only at low levels and in a temporally and tissue restricted manner” (Rojo Arias et al., 2019, Pg 1672, Para 1 Abstract; Pg 1673, right col, para 1, lines 3-5; Pg 1673 left col, final para, 5th and 6th line from bottom). Additionally, “while single markers are often confirmed by independent studies, miRNA signatures are less frequently verified.” (Backes et al Vol 20, pg 509-518 2016). Variable results by study/sample type for the same disease were also reported (in e.g. blood vs. serum, serum vs. plasma; Pg 511, left col para 2) and when multiple miRNA are considered as signatures (profiling, handling and more) must be considered, since current results have been reproduced while others have not (Pg 514 left col para 1).
The level of one of ordinary skill: Artisans in biotechnology are considered highly-skilled and hold a relevant PhD, where courts have considered this person at least a junior faculty member with a few years relevant experience, or a postdoctoral scholar with several years experience Enzo Biochem, Inc. v. Calgene, Inc., 188 F.3d 1362, 1373 (Fed. Cir. 1999) (citing Enzo Biochem, Inc. v. Calgene, Inc., 14 F. Supp. 2d 536, 567 (D. Del 1998)).
The level of predictability in the art: In general, the level of predictability in the art of biotechnology is considered low (C.f. In re Kubin, 561 F.3d 1351 (Fed. Cir. 2009); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348 (Fed. Cir. 2007)). With respect to the invention, different results have emerged with time, with some data not reproduced by alternate test systems within a given study. In 2015, 8 mi-RNA were found upregulated for individuals with schizophrenia relative to controls from global plasma screening and qRT-PCR showed upregulation of two, miR-130b and miR-193a-3p (Wei et al, Am J Psychiatry, 172:11, 2015). In 2016, miR-9-5p was designated as having a role in the etiology of schizophrenia (Hauberg et al 2016). In a third study using arrays, 16 miRNA were found differentially expressed in schizophrenics, 15 with lower expression, one with higher. A subset also had significant expression differences by qRT-PCR, and one demonstrated discrepancy between PCR and microarray (Perkins et al, Genome Biology, 2007).
The amount of direction provided by the inventor: The direction is focused and specific: samples were extracted exosomes and total RNA from peripheral blood only. Whole microRNA sequencing analysis was conducted. Expression abundance was analyzed, random forest employed, AUC index sensitivity/specificity calculated. Differential expression allowed for miRNA selection, though there is a lack of clarity regarding the difference multiplier and therefore, the final parameters of selection that result in a diagnosis of schizophrenia.
The breadth of the claim indicates merely the use of miRNA biomarkers without stating the means of, however as one example of many, alternative techniques exist with biomarkers, such as Northern blot analysis, which can implicate miRNA in particular functions (Sempere et al, Genome Biology, 5: R13, 2004). The point being the claim language is broader than the claimed invention.
The existence of working examples: The specification discloses extracted exosomes, microRNA sequencing analysis, expression abundance analyzed via a combination of factors previously addressed, with differential expression analysis for miRNA selection and AUC data for true positives and misdiagnosis rates.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure: The breadth of the claim suggests any use of a miRNA (recited) as a biomarker for diagnosis of schizophrenia, in any technique is encompassed, which would indicate an undue amount of experimentation to encompass all techniques. The specification discloses the explicit biomarker use based upon exome/RNA extraction and microRNA sequencing analysis, expression abundance as described, a much narrower scope.
In conclusion, the factors weigh against patentability of the entire scope of claim 1.
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 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claim is presented as a method for diagnosing schizophrenia using microRNA’s as biomarkers, to diagnose. The claim does not include any additional elements that are sufficient to amount to significantly more than the judicial exception.
Notably, MPEP 2106.04(b)(I) and Molecular Pathology v. Myriad Genetics Inc., 569 U.S. 576, 589-91, 106 USPQ2d 1972 (U.S. 2013) address claims drawn solely to naturally occurring nucleic acids, or fragments thereof, whether isolated or not, are no longer patent-eligible subject matter. The Supreme Court held that “[a] naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated”. Similarly, regarding natural phenomenon, their unpatentability was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., No. 10-1150 (March 20, 2012). “Laws of nature, natural phenomena, and abstract ideas” are not patentable. Diamond v. Diehr, 450 U.S. 175, 185 (1981); see also Bilski v. Kappos, 561 U.S. 593, 604, 95 USPQ2d 1001, 1007 (2010).
Regarding Step 1 of the analysis, the claim recites a process (method) of using microRNAs as biomarkers for diagnosing schizophrenia, which is one of the statutory categories of invention.
Re: Step 2A: The claim is directed to a judicial exception, here naturally occurring non-coding nucleic acids, microRNAs, and these natural products are used as biomarkers to diagnose schizophrenia, and nothing further. Of importance here, there are no active method steps for the claimed “to diagnose schizophrenia”, thus the claim recites the use of the natural miRNAs as biomarkers, without any physical modification.
It is additionally here noted that when method steps are recited at a high level of generality and merely instruct to perform a process known in the art, these types of steps are generally not considered to distinguish from well-understood routine and conventional activities. Use of mi-RNAs as biomarkers is known for schizophrenia (Sun et al., Am J Med Genet B; 2015). Therefore, this judicial exception is not integrated into a practical application. Claim 1 is patent ineligible.
Claims 2, 3, 4, 5 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claim is presented as “A method for diagnosing the risk of developing schizophrenia, comprising detecting the microRNA level in a sample from an individual to be tested, wherein the microRNA comprising” followed by a grouping of microRNAs. Claim 3 is the method of claim 2 wherein the miRNA level includes a serum expression level. Claims 4 and 5 are both the method of claim 2, disclosing a subset of the miRNA of claim 2 and nothing more.
Regarding Step 1 of the analysis, the claim recites a process (method) of diagnosing risk of developing a disorder, comprising detecting microRNAs level in a sample… A process (method) is one of the statutory categories of invention. Claim 3 is a method that includes serum expression level. Claims 4 and 5 disclose a method of claim 2, and recite a subset of miRNA of claim 2 only.
Re: Step 2A: The claim is directed to a judicial exception, here naturally occurring microRNA level in a sample from an individual, from human microRNAs (comprising miR-206; miR-145-5p, miR-133a-3p; miR 133-3p, miR-144-5p, miR-144-3p, miR184; miR-499a-5p, miR-3614-5p;miR-941; miR-30c-5p; miR-339-5p; miR-30b-5p;and/or miR-6515-5p), which are natural products. For claim 3, the miRNA level in serum is also naturally occurring.
The additional elements that are recited, diagnosing the risk of developing a disorder and detecting the microRNA level, are not sufficient to amount to significantly more than the judicial exception because the former, “diagnosing the risk”, is presented without any method steps to indicate how risk is diagnosed and is presented, and the latter “detecting the microRNA level in a sample”, as well as the former, is recited at such a high level that this do not distinguish from well-understood routine and conventional activities. Measuring miRNA levels is known in the art, and even “elevated miRNA level” as being “instructive as to the presence of schizophrenia or a predisposition thereto” [0011] has been previously disclosed in Cairns (US2010/0227908A1 9/9/2010; [0018],[0022],[0025], [0030]). Detection of serum level of miRNA is also known in the art (Wei et al, Detection of circulating miRNA levels in Schizophrenia, Am J Psychiatry 172:11:1141-1147, Nov 2015).
Therefore, this judicial exception is not integrated into a practical application. Claims 2-5 are patent ineligible.
Claims 6 and 7 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. Claim 6 recites the method of claim 2, wherein an expression level of a subset of the miRNA of claim 2, is elevated and the individual to be tested has an increased risk of developing schizophrenia. Claim 7 recites the method of claim 2, wherein an expression level of a subset of the miRNA of claim 2, is reduced and the individual to be tested has an increased risk of developing schizophrenia.
Regarding Step 1 of the analysis, the claims both recite a process (method), according to claim 2, wherein an expression level is elevated or reduced and associated with an increased risk of developing schizophrenia. … A process (method) is one of the statutory categories of invention.
Re: Step 2A: The claims are directed to a judicial exception, here a naturally occurring relationship (natural correlation) between microRNA expression level and risk of developing schizophrenia. No additional elements are recited in the claims. Therefore, this judicial exception is not integrated into a practical application. Claims 6 and 7 are patent ineligible.
The claims, as presently understood, appear free of the art. Art of record includes Cairns (US2010/0227908 A1; published 9/9/2010) who’s invention relates to diagnostic/prognostic tools for schizophrenia (Abstract) and reports upon a large number of miRNAs, including has miR-133b, -184, -499 and -339, with significant p-values and/or upregulation in schizophrenic individuals relative to controls (eg Pg 13, and Table 4).
Conclusion
All claims rejected. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Lisa Horth whose telephone number is (703)756-4557. The examiner can normally be reached Monday-Friday 8-4 EST.
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/LISA HORTH/ Examiner, Art Unit 1681
/GARY BENZION/ Supervisory Patent Examiner, Art Unit 1681