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 .
Change of Examiner and Art Unit
It is noted that the examiner and art unit of the instant application had changed on January 18, 2026.
Election/Restrictions
Applicant’s election of Group I (claims 1-21) and the following species: (a) IFNAR1, LYN, IFNAR1_X115, IFNAR1_X151, and LYN_X151; (b) Z = +(2.03684329038398) * IFNAR1_X115_G + (12.2505281183792) * LYN_X151_F + (-0.765269706061865) * IFNAR1_X111_A; and (c) SEQ ID No. 1-2 and 13-14 in the reply filed on November 19, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 10 and 22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (claim 22) and species (claim 10), there being no allowable generic or linking claim. Election is treated as being made without traverse in the reply filed on November 19, 2025.
Claim Status
Claims 1-22 are currently pending.
Claims 10 and 22 are withdrawn, as discussed above.
Claims 1-9 and 11-21 are under exam herein.
Claims 1-9 and 11-21 are rejected.
Claims 1-2, 4, 8-9, 11, 18, and 20-21 are objected to.
Priority
Applicant’s claim for domestic benefit to the earlier filed international application PCT/EP2020/081459, filed November 9, 2020, which claims priority to the foreign application EP 19208126.3, filed November 8, 2019, is acknowledged. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. At this point in the examination, the effective filing date of claims 1-9 and 11-21 is November 8, 2019.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on August 9, 2022 and March 24, 2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence disclosures are located in Figure 28B.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Drawings
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings (Figure 28B) are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because of the following informalities: The brief description of the drawings is missing a brief description of Figures 13A-C and Figures 28A-B. The brief description refers to Figure 28, but the drawings contain Figures 28A-B.
The use of the terms MagNA Pure®, Qubit™, LabChip®, TruSeq®, SuperScript™, NextSeq®, MiSeq®, etc. which are a trade name or a mark used in commerce, has been noted in this application (p. 23-26). 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 disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (p. 26). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Appropriate correction is required to correct all objections and ensure no other errors are present in the specification.
Claim Objections
Claims 1-2, 4, 8-9, 11, 18, and 20-21 are objected to because of the following informalities. The claims contain several grammatical or formatting errors including:
Claim 1:
The limitation “… identifying A-to-I differentially…” looks like the letter “I” might be the number “1” (When comparing to ‘A to I’ in step a) of claim 2).
The phrase “… by GSEA (enrichment analysis on gene sets) on the biomarkers selecting in step c) or d) …” is grammatically incorrect. Selecting should be selected.
The phrase “…selecting biomarkers reflecting changes in different biological process…” is grammatically incorrect. Process should be processes.
There is a stray parenthesis “)” in step f) after p<0.05.
The phrase “… and selected those which clearly discriminated patients…” is grammatically incorrect. Selected should be selecting.
Claim 2:
The phrase “… classifying said patient having unipolar depression” in step d) is grammatically incorrect. The word ‘as’ should be added between ‘patient’ and ‘having’.
Claim 4:
The claim does not end with a period punctuation mark.
Claim 8:
There is a typo in the phrase “… biomarkers selected tin step a) …” Tin should be ‘in.’
Claim 9:
The limitation “RNA biomarker(s)” should be amended to “RNA biomarkers” to properly reflect that more than one biomarker is selected in step a) in claim 2.
Claim 11:
The limitation “RNA biomarker(s)” should be amended to “RNA biomarkers” to properly reflect that more than one biomarker is selected in step a) in claim 2.
The phrase “… comprised in step a) the combination of the following…” is grammatically incorrect.
Claim 18:
The abbreviation ‘NGS’ should be defined before its’ first use in the claim.
The phrase “… the percentage of an isoform are measuring by NGS…” is grammatically incorrect. Measuring should be measured.
Claim 20:
Step A) ends in a period which should be a comma.
There is a missing parenthesis in step B), c) should be (c).
Claim 21:
Step A) ends in a period which should be a comma.
There is a missing parenthesis in step B), c) should be (c).
Appropriate action is required, applicant should review the claims to ensure no informalities are present.
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 1-9 and 11-21 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 (and its’ dependent claims 2-9 and 11-21):
The claim recites the limitation “analyzing the RNA-Seq dataset” in step a). There is insufficient antecedent basis for this limitation in the claim because the claim did not previously mention any datasets and it is not possible to determine which dataset is being analyzed. For the purpose of examination, it will be interpreted that the RNA-Seq dataset is obtained from a human biological sample.
The claim limitation “analyzing the RNA-Seq dataset using the Editome analysis pipeline and identifying A-to-I differentially edited positions with a minimum coverage of 30x, which ensures a high degree of confidence at particular base positions” make the claim indefinite because the scope of the Editome analysis pipeline cannot be determined and a high degree of confidence is relative terminology. Due to the unclear descriptions and figures in the specification it is not possible to determine what constitutes an Editome analysis pipeline or a high degree of confidence at particular base positions. For the purpose of examination, the pipeline will be interpreted as performing statistical analysis on RNA-Seq data to find base positions that undergo RNA editing and high degree of confidence will be interpreted as a high probability that the base call is correct for a particular base position in a sequence.
The term “could be” in step b) is a subjective term which renders the claim indefinite. The term is not defined by the claim, the specification does not provide a standard for ascertaining the scope of the term, and one of ordinary skill in the art would need to use their subjective judgment and opinion to reasonably apprise of the scope of the invention. For the purpose of examination, sites that pass desired quality criteria thresholds will be considered as potentially specifically different.
Regarding step d), the phrase “optionally” renders the claim indefinite because it is unclear what exact limitations following the phrase are meant to be optional (MPEP 2173.05h(II)). Specifically, the format of the claim also appears to make step e) an optional step, but its’ limitations seem to be a necessary part of the claim. For the purpose of examination, it will be interpreted as step d) is optional, but not step e).
Regarding steps d) and e), the phrase “preferably” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. MPEP 2173.05d states, “Description of examples or preferences is properly set forth in the specification rather than the claims.” For the purpose of examination, it will be interpreted as the preferable limitations are not performed.
Regarding step f), the limitation “AUOO.8” renders the claim indefinite because it is not possible to determine the meaning of the limitation. For the purposes of examination, it will be interpreted as a typo and the limitation is supposed to be AUC>0.8. Additionally, the term “clearly discriminated” is a subjective term which renders the claim indefinite. The term is not defined by the claim, the specification does not provide a standard for ascertaining the scope of the term, and one of ordinary skill in the art would need to use their subjective judgment and opinion to reasonably apprise of the scope of the invention. For the purpose of examination, biomarkers that pass the quality criteria in step f) are those which clearly discriminate between patients exhibiting bipolar disorder and patients exhibiting unipolar depression.
Claims 2-9 and 11-21, which depend from claim 1, are also rejected because they do not resolve the issue of indefiniteness in claim 1.
Regarding claim 2 (and its’ dependent claims 3-9 and 11-21):
Claim 2 recites in step a) “determining for a combination of at least two A to I editing RNA biomarkers identified by the method of claim 1…” which make the metes and bounds of the claim unclear because there is ambiguity as to whether the claim requires performing the steps in claim 1 and further limits claim 1 or if it is merely describing how the editing RNA biomarkers were previously identified outside the scope of the invention as a product-by-process limitation.
The phrase, “in a manner comparable to that of the result value” is a subjective term which renders the claim indefinite. The term is not defined by the claim, the specification does not provide a standard for ascertaining the scope of the term, and one of ordinary skill in the art would need to use their subjective judgment and opinion to reasonably apprise of the scope of the invention. For the purpose of examination, it will be interpreted that the control value is determined in a manner identical to that of the result value.
Claims 3-9 and 11-21 are also rejected because they depend from claim 2 and do not resolve the issue of indefiniteness present in claim 2.
Regarding claim 4:
The claim limitations “… particularly to…” render the claims indefinite because it creates both a broad and narrow scope in the claim and it is unclear which scope the claim is intended to cover.
Regarding claim 5:
The phrase, “mainly” is a subjective term which renders the claim indefinite. The term is not defined by the claim, the specification does not provide a standard for ascertaining the scope of the term, and one of ordinary skill in the art would need to use their subjective judgment and opinion to reasonably apprise of the scope of the invention.
Regarding claim 6:
The phrase “preferred” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. MPEP 2173.05d states, “Description of examples or preferences is properly set forth in the specification rather than the claims.” For the purpose of examination, it will be interpreted as the biological sample can be any of the recited types in the claim.
Regarding claim 7:
The limitation “said result value is statistically/specifically different from said control value” renders the claim indefinite because it is not possible to determine if the “/” is supposed to convey that statistically and specifically are synonyms or if the “/” is indicating that there is an alternative between statistically and/or specifically. For the purpose of examination, it will be interpreted as they are synonymous.
Regarding claim 8:
The limitation “AUO0.8” renders the claim indefinite because it is not possible to determine the meaning of the limitation. For the purposes of examination, it will be interpreted as a typo and the limitation is supposed to be AUC>0.8. Additionally, the claim recites the limitation “... the biomarker or the combination of biomarkers…” There is insufficient antecedent basis for “the biomarker” limitation because claim 2 did not previously recite one biomarker is selected. For the purpose of examination, it will be interpreted that the quality criteria have to be satisfied for the combination of biomarkers.
Regarding claims 12-17, and 19:
Claims 12-16, and 19 are indefinite because they make reference to tables, figures, and examples in the specification (MPEP 2173.05s). Also, claims 13-16 recites the term “preferably” which render the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. MPEP 2173.05d states, “Description of examples or preferences is properly set forth in the specification rather than the claims.” For the purpose of examination, it will be interpreted that none of the limitations following the phrase “preferably” are part of the claims.
Claims 14 and 17 recites the limitations “the result value or depression score Z” and “the combination of biomarkers and/or the Z equation associated…”, respectively. There is insufficient antecedent basis for these limitations in the claims because neither the claims or claim 2 from which they depend previously mention a depression score Z or Z equation. It is not possible to determine the metes and bounds of what is being calculated as a depression score Z or Z equation. For the purposes of examination, the depression score Z is equivalent to the result value and the Z equation is referring the mROC program used in claim 4.
Additionally, claims 12, 15, and 16 recite “said one or combination of…”, “said at least one or combination of…”, and “said at least one or combination of…”, respectively. There is insufficient antecedent basis for these limitations because neither the claims or claim 2 from which these claims depend recite one biomarker being selected. For the purposes of examination, it will be interpreted as there being at least two selected biomarkers.
Conclusion:
Therefore, claims 1-9 and 11-21 are indefinite and are rejected under 35 U.S.C. 112(b) or pre-AIA 112, second paragraph.
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 1-9 and 11-21 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 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.
Claim 1, and those claims dependent therefrom, recite “A method for selecting at least a combination of at least two biomarkers which can be used to differential diagnose bipolar disorder and unipolar depression in a human patient, said method comprising the step of: … b) performing a differential analysis to identify sites whose editing could be specifically different between unipolar depression and healthy controls, … and selected those which clearly discriminated patients exhibiting bipolar disorder and patients exhibiting unipolar depression in two separate groups.” However, based on the instant disclosure and the prior art, it would require an undue amount of experimentation to perform the above recited steps, as demonstrated by the consideration of the eight factors of enablement below.
The Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." These factors include, but are not limited to: (A) the breadth of the claims, (B) the nature of the invention, (C) the state of the prior art, (D) the level of one of ordinary skill, (E) the level of predictability in the art, (F) the amount of direction provided by the inventor, (G) the existence of working examples, and (H) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. In considering these factors for the instant claims:
The broadest reasonable interpretation of claim 1 encompasses identifying at least two nucleotide base locations on RNA transcripts that are enzymatically edited from an adenosine base to an inosine base at different rates or proportions in unipolar depression patients and bipolar disorder patients by statistically comparing and analyzing RNA editing data obtained from at least one person with unipolar depression with RNA editing data obtained from at least two people who are healthy.
The nature of the invention is a method of biomarker discovery to identify edited (adenosine-to-inosine) nucleotide base locations on RNA transcripts that can be measured to diagnose a subject with bipolar disorder or unipolar depression.
The prior art discloses numerous documents regarding identification of biomarkers (RNA editing sites or otherwise) for the purpose of diagnosing or classifying a patient into a particular group having some condition or characteristic.
Akil et al. (US20170211144A1; IDS document 8/9/2022) discloses methods for diagnosing mental illness based on the discovery that certain genes expressed in particular brain pathways and regions are involved in the development of mental illness (paragraph 0006). DNA microarrays were studied to understand the neurobiology of mood disorders such as bipolar and major depression (paragraph 0007). Differential gene expression was performed to identify unique expression patterns that are present in one mood disorder and not the other (Id.; Tables 3, 4, 14-20). When genes were differentially expressed in both bipolar and major depression relative to healthy controls, the genes were considered to be involved in both disorders.
Pujol et al. (EP3272881A1; IDS document 8/9/2022) teach identifying if a patient presents a mental disorder by measuring alteration of mRNA editing relative to a control sample of normal patients or patients with the mental disorder related to the altered mRNA editing (paragraph 0035-0036)
Li (Bioinformatics (Oxford, England), vol. 27, no. 21, pp. 2987-93; IDS document 8/9/2022) teaches to determine if two groups are significantly different, one must statistically compare sequencing data between the two groups (p. 2988, 2 Methods, paragraph 1; p. 2989, 2.3.4 Testing associations).
Blagus et al. (BMC Bioinformatics, vol. 11, p. 523; IDS document 8/9/2022) teach microarrays can be used for class prediction by developing a rule based on measurement from samples known to belong to a well-defined group (p. 1, Background, paragraph 2). The rule can be used to predict class membership of a new sample with known measurements, but unknown class membership (Id.).
Tasic et al. (Journal of Psychiatric Research, vol. 119, pp. 67-75; IDS document 8/9/2022) teach chemometrics of NMR spectral data was used to evaluate metabolic differences between healthy controls, schizophrenia patients, and bipolar disorder patients using data obtained from each group and statistically analyzed (p. 69-70, 2.5 Chemometrics of 1H NMR spectral data, 2.6 Statistical and comparative analysis).
Grotegerd et al. (European Archives of Psychiatry and Clinical Neuroscience, vol. 263, no. 2, pp. 119-31; IDS document 8/9/2022) teach obtaining fMRI data from bipolar patients, unipolar patients, and healthy controls (p. 120, Materials and methods, paragraphs 1-2) and training classifiers to predict whether a test sample is unipolar or bipolar (p. 123, Classification results, paragraphs 1-6; Table 2) as well as univariate analysis (p. 123, Standard univariate fMRI analysis).
Bahn et al. (WO2012085557A2) teach identifying discriminatory biomarkers between schizophrenia, bipolar disorder, and major depressive disorder by measuring 144 analyte using multiplexed immunoassays from patients known to have one of the diseases (p. 32, lines 11-19). Then data analysis was performed to identify the combination of biomarkers that could best classify each condition (p. 32, line 21 – p. 34, line 28; Table 1).
Fernandes et al. (Journal of Psychiatric Research, vol. 43, no. 15, pp. 1200-04) teach measuring brain-derived neutrophic factor (BDNF) in healthy subject and subjects with major depression or bipolar disorder during a depressive episode to determine its’ optimal sensitivity and specificity for differential diagnosis of unipolar and bipolar depression (Abstract).
Fryar-Williams (US20140113318A1) teaches levels of biochemical markers have predictive value for the diagnosis of mental and neurodegenerative disorders based on the dysregulation of biomarker levels in patients with a mental disorder relative to normal endogenous levels of the same markers (paragraph 0008).
Powell et al. (PLoS ONE, edited by Kenji Hashimoto, vol. 9, no. 3, p. e91076) teach identifying differential transcription of genes in the inflammatory cytokine pathway that can differentiate between major depression patients, bipolar disorder patients, and controls by analyzing data from all three groups (Abstract).
Kaldate (US20180017580A1) teaches a discovery experiment to identify biomarkers that distinguish bipolar disorder from major depressive disorder by measuring proteomic analytes from groups of patients having major depression, bipolar disorder type 1, and bipolar disorder type 2 (paragraph 0327-0329). Then the data was analyzed by several statistical methods to identify biomarkers that can distinguish the diseases (paragraphs 0330-0332; Table 1).
Silberberg et al. (Human Molecular Genetics, vol. 21, no. 2, pp. 311-21) teach measuring RNA editing levels in the dorsolateral-prefrontal cortices of schizophrenia patients, bipolar disorder patients, and controls and identified a statistically significant deregulated editing site in bipolar patients (Abstract).
All the prior art reference show that, in order to obtain biomarkers that can be used in diagnosis or differential diagnosis, one must obtain measurement levels from patients known to have the condition and analyze those measurements to measurement of patients with a different condition or individuals that are healthy and don’t have a condition.
The level of skill of a person having ordinary skill in the art is high.
The level of predictability in the art is low as evidenced by Brandon et al. (US20150259746A1) which discloses analysis of gene expression to identify signatures for use in distinguishing different conditions requires analysis of many gene products which is mathematically complex, computationally expensive, and therefore difficult. (paragraph 0005). Additionally, Califf (Experimental Biology and Medicine, vol. 243, no. 3, pp. 213-21) teaches there is significant confusion with biomarkers involved in research and clinical practice and that the complexity of biomarkers is a limitation to understanding chronic disease (p. 213, Introduction, paragraph 1). Lastly, Frank et al. (Nature Reviews Drug Discovery, vol. 2, no. 7, pp. 566-80) states, “The work required to establish the reliability and validity of a new biomarker should not be underestimated in general, and in particular needs planning for each combination of clinical indication and mechanism of action” (p. 568, Validation, paragraph 1).
The direction provided by the inventors in the specification does teach the method of claim 1. The specification discloses a discovery study in which unipolar and bipolar patients were recruited for the study while both patients were in a depressed state (p. 29, lines 13-16). A global landscape of RNA editing was obtained from the patients and a differential analysis was performed between the patient group (called DEP, which is being interpreted as depressive episode patients that includes both bipolar and unipolar patients) and healthy control to identify editing sites specifically different between the groups (p. 29, lines 19-31). The method continues with various statistical analyses, gene set enrichment analysis, and lastly manual curation to reach a combination of several biomarkers (Figure 17) selected for diagnostic performance and potential role in the immune system or psychiatric disease (p. 30, line 1 – p. 31, line 1). The PDE8A gene was also nominated as a potential biomarker based on previous research of its’ deregulation in suicide victims and patients with drug-induced depression (p. 31, lines 1-3). Then there were following prioritization studies and validation studies to identify which combination of the identified and nominated biomarkers could actually be used to differentially diagnose between unipolar depression and bipolar disorder (p. 36 – 60).
The specification provides an example of the discovery experiment to identify edited RNA biomarkers as discussed in (F), but the example did not demonstrate being able to identify edited RNA biomarkers that could distinguish unipolar depression and bipolar depression by only statistically analyzing data from unipolar depression and healthy controls.
In order to practice the claimed invention, one of skill in the art must be able to identify edited RNA biomarkers that can be used to differentially diagnose bipolar disorder and unipolar depression by only considering data from unipolar depression patients and healthy controls. Based on the content of the disclosure, there would be a tremendous amount of experimentation required to determine how differentially edited RNA biomarkers between unipolar depression patients and healthy controls would correlate to biomarkers that could diagnose a patient with bipolar disorder because the disclosure does not provide the experimental framework necessary to create that link.
Based on the above factors for assessing enablement in a utility patent application, there would be an undue amount of experimentation necessary for one of ordinary skill in the art to identify edited RNA biomarkers that can be used to differentially diagnose unipolar depression and bipolar disorder. As demonstrated in the state-of-the-art section, one must at the very least obtain measurement data of some kind of biomarker from patients known to have bipolar disorder in addition to data from unipolar depression patients and must perform statistical analysis between the two groups to identify features present in the groups that can distinguish them. Then when presented with data of a patient with an unknown diagnosis, the skilled artisan can classify the patient based on the identified distinguishing features.
If differential analysis is between two groups such as unipolar depression patients and healthy controls, the identified biomarkers cannot be reasonably used to differentiate between a group that was not part of the analysis (i.e., bipolar disorder patients) because those biomarkers could be present at the same levels or not even relevant to the disease. It is for that reason that the example provided in the specification first did differential analysis between a group containing some patients with unipolar depression and some with bipolar disorder and a group of healthy controls to identify biomarkers that distinguished patients with those illnesses from healthy individuals. Then the example performed differential analysis between unipolar patients and bipolar disorder patients, measuring editing on RNA biomarkers identified in the first analysis to be able to distinguish the two diseases. Finally, because of the unpredictability of biomarkers, validation experiments were performed to confirm the experimentally determined correlation of edited RNA biomarkers use to distinguish unipolar depression and bipolar disorder.
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 1-9 and 11-21 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more.
Step 1:
The first part of the eligibility analysis evaluates whether a claim falls withing any statutory
category (See MPEP 2106.03). Claims 1-9 and 11-21 recite a series of steps to select biomarkers, diagnose patients by measuring RNA editing in the selected biomarkers, and monitoring treatment of patients. The claims are directed to a method and fall within one of the statutory categories of invention (Step 1: YES).
Step 2A, prong 1:
In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step 1: YES)
are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of
nature, or natural phenomenon (Step 2A, prong 1). In the instant application, the claims recite the
following limitations that equate to those concepts:
Claim 1 (and its’ dependent claims 2-9 and 11-21) recites a method for selecting at least a combination of at least two biomarkers which can be used to differential diagnose bipolar disorder and unipolar depression in a human patient, analyzing the RNA-Seq dataset using Editome analysis pipeline, identifying A-to-I differentially edited positions with a minimum coverage of 30x, which ensures a high degree of confidence at particular base positions, performing a differential analysis to identify sites whose editing could be specifically different between unipolar depression and healthy controls, applying the following pre-specified quality criteria of the group consisting of: coverage >30; AUC>0.6; 0.95>FoldChange>1.05, p<0.05 and exclusion of intergenic sites, by GSEA (enrichment analysis on gene sets) on the biomarkers selecting in step c) identifying and selecting biomarkers reflecting changes in different biological process including immune and CNS (central nervous system) functions, applying the following specified quality criteria of the group consisting of: coverage >30; AUOO.8; 0.8>FoldChange>1.20 and p<0.05) to a combination of several biomarkers selected in step e) representing different biological mechanisms, and selected those which clearly discriminated patients exhibiting bipolar disorder and patients exhibiting unipolar depression in two separate groups.
Claim 2 (and its’ dependent claims 3-9 and 11-21) recites an in vitro method for differential diagnosing bipolar disorder and unipolar depression in a human patient from a biological sample of said patient, determining for a combination of at least two A to I editing RNA biomarkers identified by the method of claim 1: the relative proportion of RNA editing at a given editing site for at least one or a combination of sites which can be edited on the RNA transcript of said at least two biomarkers, the relative percentage of an isoform or of a combination of isoforms of the RNA transcript of each of said two biomarkers, wherein said at least two A to I editing RNA biomarkers are selected from the group consisting of MDM2, PRKCB, PIAS1, IFNAR1, LYN, AHR, RASSF1, GAB2, CAMK1 D, IL17RA, PTPRC, KCNJ15, IFNAR2 and PDE8A biomarkers, determining a result value obtained for each of said at least two biomarkers and a final result value based on an algorithm or equation that includes the result value obtained for each selected biomarker, determining whether said result value obtained is greater or not greater than a control value obtained for control unipolar subject, wherein the control value was determined in a manner comparable to that of the result value, and if said result value obtained for the patient is greater than a threshold, classifying said patient as having bipolar disorder or, if said result value is not greater than said threshold, classifying said patient having unipolar depression.
Claim 3 recites wherein in step b), said at least two A to I editing RNA biomarkers are selected from the group consisting of MDM2, PRKCB, IFNAR1, LYN, GAB2, CAMK1 D, KCNJ15 and PDE8A.Claim 4 recites the in vitro method for differential diagnosing bipolar disorder and unipolar depression in a human patient according to claim 2, wherein in step b), the result value or final result value, is calculated by an algorithm implementing a multivariate method including: mROC program, particularly to identify the linear combination, which maximizes the AUC (Area Under the Curve) ROC and wherein the equation for the respective combination is provided and can be used as a new virtual marker Z, as follows: Z= a. (Biomarker 1) + b. (Biomarker 2) + ...i. (Biomarker i) +....n .(Biomarker n) where i are calculated coefficients and (Biomarker i) are the level of the considered biomarker (i.e. level of RNA editing site or of isoforms for a given target/biomarker), a Random Forest (RF) approach applied to assess the RNA editing site(s) and/or isoforms combinations, particularly to rank the importance of the RNA editing site(s) and/or isoform(s), and to combine the best RNA editing site(s) and/or isoform(s), a multivariate analysis applied to assess the RNA editing site(s) and/or isoforms combinations for the diagnostic, said multivariate analysis being selecting for example from the group consisting of: Logistic regression model applied for univariate and multivariate analysis to estimate the relative risk of patient at different level of RNA editing site or isoforms values, CART (Classification And Regression Trees) approach applied to assess RNA editing site(s) and/or isoforms combinations, Support Vector Machine (SVM) approach, Artificial Neural Network (ANN) approach, Bayesian network approach, WKNN (weighted k-nearest neighbours) approach, Partial Least Square - Discriminant Analysis (PLS-DA), Linear and Quadratic Discriminant Analysis (LDA / QDA), and any other mathematical method that combines biomarkers.
Claim 6 recites wherein said biological sample is whole blood, serum, plasma, urine, cerebrospinal fluid or saliva.
Claim 5 recites wherein, said unipolar depression disorder is mainly major depressive episode (DEP).
Claim 7 recites wherein for each selected biomarker, said result value is statistically/specifically different from said control result value at p<0.05.
Claim 8 recites wherein the following criteria has to be satisfied for the biomarker of the combination of biomarkers selected tin step a): the coverage >30; AUO0.8; 0.95>FoldChange>1.05, and p<0.05.
Claim 9 recites wherein said selected A to I editing RNA biomarker(s) comprised in step a) is selected from the group consisting of: a combination comprising at least 3, 4, 5, 6 or 7 of the following biomarkers: MDM2, PRKCB, IFNAR1, LYN, GAB2, CAMK1 D, KCNJ15 and PDE8A, preferably the combination of the cited 8 biomarkers.
Claim 11 recites wherein said selected A to I editing RNA biomarker(s) comprised in step a) the combination of the following 5 biomarkers: GAB2, IFNARI , KCNJ15, MDM2 and PRKCB and at least another biomarker selected from the group consisting the following biomarkers: CAMK1 D and LYN, preferably the combination of the following 6 biomarkers: GAB2, IFNAR1 , KCNJ 15, MDM2, PRKCB and LYN when the model is adjusted by age, sex, psychiatric treatment and addiction, or preferably the following 6 biomarkers: GAB2, IFNAR1 , KCNJ15, MDM2, PRKCB and CAMK1 D when the model is adjusted by age and sex.
Claim 12 recites wherein said one or combination of at least 2, 3, 4, 5, 6 or 7 selected biomarkers comprises the calculation of the relative percentage of at least one of the RNA edition site or isoform listed in the Table 2A (edition sites), 2B (isoforms) or 11 (edition sites) for each of the selected biomarker.
Claim 13 recites wherein said combination of at least 2, 3, 4, 5, 6, 7, or 8 selected biomarkers is selected from the biomarkers combinations given in Table 12, 13 and 15, preferably the combination comprising the following 8 biomarkers MDM2, PRKCB, IFNAR1, LYN, GAB2, CAMK1 D, KCNJ15 and PDE8A.
Claim 14 recites wherein the algorithm or equation allowing the calculation of the result value or depression score Z are selected from the Z equations listed in the examples.
Claim 15 recites wherein if the patient to be tested is a female, in step a) said at least one or combination of at least two A to I editing RNA biomarker(s) is selected from the group of biomarkers consisting of MDM2, PRKCB, PIAS1, IFNAR1, LYN, AHR, RASSF1, GAB2, CAMK1 D, IL17RA, PTPRC, KCNJ15, IFNAR2 and PDE8A biomarker.
Claim 16 recites wherein if the patient to be tested is a male, in step a) said at least one or combination of at least two A to I editing RNA biomarker(s) is selected from the group of biomarkers consisting of MDM2, PRKCB, PIAS1, IFNAR1, LYN, AHR, RASSF1, GAB2, CAMK1 D, IL17RA, PTPRC, KCNJ15, IFNAR2 and PDE8A biomarker.
Claim 17 recites wherein the combination of biomarkers and/or the Z equation associated with said combination used for differential diagnosing bipolar disorder and unipolar depression in a human patient is different whether the patient to be tested is a female or a male.
Claim 18 recites wherein in step a) the relative proportion of RNA editing at a given editing and/or the percentage of an isoform are measuring by NGS in said biological sample.
Claim 19 recites wherein in step a), the amplicon/nucleic sequence used for the detection of the RNA editing sites and/or the isoforms of the RNA transcript of said biomarker is obtained or obtainable with: - the set of primers listed in table 9 for each of the selected biomarkers (SEQ ID NO. 1 to 36), or - a set or a combination of sets of primers allowing to obtain amplicon(s) including, or identical to, the amplicon(s) obtainable by the set of primers listed in Table 9 (SEQ ID No.1 to SEQ ID No.36).
Claim 20 recites a method for monitoring treatment for bipolar disorder or unipolar depression in a human patient, differential diagnosing bipolar disorder or unipolar depression in said human by the method according to claim 2 before the beginning of the treatment which is desired to be monitored, repeating steps (a) to c) of the method of claim 2, after a period of time during which said patient receives treatment for said bipolar disorder or unipolar depression, to obtain a post-treatment result value, comparing the post-treatment result value from step (c) to: the result value obtained before the period of time during which said patient receives treatment for said bipolar disorder or unipolar depression, and to the result value (control final value) for control bipolar disorder or unipolar depression patients, and classifying said treatment as being effective if the post-treatment result value obtained in step B) is closer than the result value obtained before the period of time during which said patient receives treatment for control bipolar disorder or unipolar depression patients.
Claim 21 recites a method for determining whether a patient will be a responder to a bipolar disorder treatment allowing the patient to be in a euthymic state (state of normal mood) from a blood sample of said patient, differential diagnosing bipolar disorder for said human by the method according to claim 2 before the beginning of the treatment which is desired to be monitored, repeating steps (a) to c) of the method of claim 2, after a period of time during which said patient receives treatment for said bipolar disorder, to obtain a post-treatment result value, comparing the post-treatment result value from step (c) to: the result value obtained before the period of time during which said patient receives treatment for said bipolar disorder, and to the result value (control final value) for control bipolar disorder patients being in an euthymic state, and classifying said patient as being responder to the treatment if the post-treatment result value obtained in step B) is closer than the result value obtained before the period of time during which said patient receives treatment for control bipolar disorder patients being in an euthymic state.
The limitation in the preamble of claim 1 of a method for selecting a combination of at least two biomarkers which can be used to differentially diagnose bipolar disorder and unipolar depression in a human patient recites a mental process of evaluating biomarkers involved in the natural phenomenon of biomarkers correlating to a disease state in a human. The remaining limitations of analyzing the RNA-Seq dataset using the Editome analysis pipeline, identifying A-to-I differentially edited positions, performing a differential analysis to identify sites, applying pre-specified quality criteria, identifying and selecting biomarkers reflecting changes by gene set enrichment analysis, and selecting biomarkers which discriminate between bipolar disorder and unipolar depression recite mental processes of observation and evaluation of measurements, mathematical concepts of statistical cutoff values and calculations, and natural phenomena of biomarker measurements correlating with biological processes. The recited abstract ideas (i.e., mental processes and mathematical concepts) may be performed in the human mind with a pen and paper as claimed or in a generic computer environment. However, merely stating that an abstract idea is being performed by a computer does not preclude it from being a judicial exception.
The limitation in the preamble of claim 2 of an in vitro method for differential diagnosis between bipolar and unipolar depression in a human patient from a biological sample recites a mental process of evaluating data and drawing a conclusion about a patient’s diagnosis. The limitations of determining for a combination of RNA biomarkers identified by the method of claim 1: the relative proportion of RNA editing and/or the relative percentage of an isoform or combination of isoforms of a biomarker, determining a result value and a final result value based on an algorithm or equation, determining whether a result value is greater or not than a control value, classifying patients based on the relationship between the result value and control value recite mental processes of observation and evaluation of data and mathematical concepts of equations, calculations, and mathematical relationships. The wherein clause listing specific biomarkers only limits the mental process of analyzing biomarkers and the natural phenomenon of biomarkers correlating to a disease to specific types of biomarkers.
Likewise, the recited biomarkers in claims 2, 3, 9, 11-13, and 15-16 only limit the mental process of analyzing biomarkers and the natural phenomenon of biomarkers correlating to a disease. The same is true for the limitation of claim 17 which recites that the biomarkers used in differential diagnosing bipolar disorder and unipolar depression are different depending on the sex of the patient. The limitations in claim 6 only further limits the mental process of evaluating data and drawing a conclusion about a patient’s diagnosis by reciting the type of biological sample from which data is analyzed in the process.
The limitations of claims 4, 7-8, 12, and 14 recite mathematical formulas, equations, calculations, and statistical cut-off values.
The limitation in claim 5 further describes the natural phenomenon of a disease state correlating to biomarker measurements.
The limitations in claims 18 and 19 only describe how the data used in the mental process of differential diagnosing in claim 2 was previously gathered and so, only limits the abstract idea of data.
The limitation in the preamble of claim 20 of a method for monitoring treatment for bipolar disorder or unipolar depression in a human patient recites a mental process of observing treat of a patient. The remaining limitations of differential diagnosing bipolar disorder or unipolar depression in said human by the method according to claim 2 before the beginning of the treatment which is desired to be monitored, repeating steps (a) to c) of the method of claim 2, after a period of time during which said patient receives treatment for said bipolar disorder or unipolar depression, to obtain a post-treatment result value, comparing the post-treatment result value from step (c) to: the result value obtained before the period of time during which said patient receives treatment for said bipolar disorder or unipolar depression, and to the result value (control final value) for control bipolar disorder or unipolar depression patients, and classifying said treatment as being effective if the post-treatment result value obtained in step B) is closer than the result value obtained before the period of time during which said patient receives treatment for control bipolar disorder or unipolar depression patients recite all the judicial exceptions of claim 2 and additionally the mental processes of comparing data and judging treatment efficacy.
The limitation in the preamble of claim 21 of a method for determining whether a patient will be a responder to a bipolar disorder treatment allowing the patient to be in a euthymic state (state of normal mood) from a blood sample of said patient recites the mental process of judging treatment efficacy. The remaining limitations of differential diagnosing bipolar disorder for said human by the method according to claim 2 before the beginning of the treatment which is desired to be monitored, repeating steps (a) to c) of the method of claim 2, after a period of time during which said patient receives treatment for said bipolar disorder, to obtain a post-treatment result value, comparing the post-treatment result value from step (c) to: the result value obtained before the period of time during which said patient receives treatment for said bipolar disorder, and to the result value (control final value) for control bipolar disorder patients being in an euthymic state, and classifying said patient as being responder to the treatment if the post-treatment result value obtained in step B) is closer than the result value obtained before the period of time during which said patient receives treatment for control bipolar disorder patients being in an euthymic state recite all the judicial exceptions of claim 2 and additionally the mental processes of comparing data and judging treatment efficacy.
Therefore, these limitations fall under the “Mathematical concepts,” “Mental processes,” and
“Natural phenomena” groupings of judicial exceptions (Step 2A, prong 1: YES).
Step 2A, prong 2:
Claims found to recite a judicial exception under Step 2A, prong 1 are then further analyzed to
determine if the claims as a whole integrate the recited judicial exception into a practical application
(Step 2A, prong 2). The claims do not recite additional elements.
Therefore, the judicial exception is not integrated into a practical application because the claims do not recite an additional element that reflects an improvement to technology or applies/uses the recited judicial exception in some other meaningful way and the claims are directed to the judicial exception (Step 2A, prong 2: NO).
Step 2B:
Claims found to be directed to a judicial exception are then further evaluated to determine if
the claims recite an inventive concept that provides significantly more than the judicial exception itself
(Step 2B). The claims do not any recite additional elements. The courts have ruled that an 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) (MPEP 2106.05(I)). Instead, an "inventive concept" is furnished by an element or combination of elements that is recited in the claim in addition to (beyond) the judicial exception, and is sufficient to ensure that the claim as a whole amounts to significantly more than the judicial exception itself. Alice Corp., 573 U.S. at 27-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. at 72-73, 101 USPQ2d at 1966) (Id.). Therefore, the claims do not amount to significantly more than the judicial exception itself (Step 2B: NO) and claims 1-9 and 11-21 are not patent eligible.
Conclusion
No claims are allowed.
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/T.Y.O./Examiner, Art Unit 1685
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685
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