DETAILED ACTION
Notice of 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 .
Status of the Claims
The amendments filed 1/05/2026 have been entered.
Response to Arguments
Applicant’s arguments, filed 1/05/2026, have been fully considered.
The rejections of claims 13-14 under 35 U.S.C. 112(b) and 35 U.S.C. 103(a) are WITHDRAWN in view of Applicant’s amendments to the claims. In particular, as amended, the claims are no longer indefinite. Additionally, it would not have been obvious to carry out the steps of determining the expression level of miRNA-137 and the expression level of COX6A2 in a biological sample obtained from the subject (and, furthermore, to classify the subject as a high-risk psychotic disorder subject based thereon) prior to treating said subject.
The following rejection is newly applied and constitutes tje complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 112
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.
Claims 13-14 are rejected under 35 U.S.C. 112(a) because the specification does not reasonably provide enablement for treating a subject classified as a high-risk schizophrenia subject as claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered, with the most relevant factors discussed below.
Nature of the Invention: The instant invention is drawn to a method of treating a subject classified as a high-risk schizophrenia subject, the method comprising:
(a) determining the expression level of miRNA-137 and the expression level of COX6A2 in a biological sample obtained from the patient;
(b) classifying the subject as a high-risk schizophrenia subject based on the expression levels determined in step (a); and
(c) administering a mitochondrially-targeted antioxidant to the subject.
The nature of the invention – which requires, first, classifying a subject as a high-risk schizophrenia subject and, second, treating said subject – is considered to be of extreme complexity.
As taught by del Re et al (Psychiatry Res 231:126-133, 2015), “[t]he clinical high risk (CHR) period is a phase denoting a risk for overt psychosis during which subacute symptoms often appear, and cognitive functions may deteriorate” (Abstract). However, as taught by LV et al (Shanghai Archives of Psychiatry 27, 45-47, 2015), while “[t]he early detection and management of this HR condition provides an important opportunity to prevent or delay the evolution of the condition into a fully-blown psychosis” (Page 45, Column 2), “many questions remain. The relationship between psychopathology, social dysfunction, cognitive decline, and structural change in the brain during the evolution of psychosis remains a mystery” and “[u]nraveling this mystery may take decades” (Page 46, Column 2).
As such, it is evident that identifying and classifying a subject as a high-risk schizophrenia is extremely challenging.
Additionally, as taught by Minichino et al (Molecular Psychiatry 30:2773-2782, 2025), investigating “the efficacy of preventive interventions in individuals at clinical risk for psychosis” including “Cognitive Behavioral Therapy (CBT), family-focused therapy, Integrated Psychological Therapy, antipsychotics, omega-3 fatty acids, CBT plus risperidone, minocycline, and other non-pharmacological approaches (cognitive remediation, sleep targeted therapy, brain stimulation)” – “[r]esults showed no evidence that any of the investigated active interventions had a sustained and robust effect on any of the investigated outcomes in CHR-P, when compared to control interventions, including CBT on transition to psychosis at 12 months” (Abstract).
As such, it is further evident that the treatment of a subject classified as a high-risk schizophrenia subject is exceedingly difficult.
Breadth of the Claims: The claims are broad, which exacerbates the complexity of the invention. In particular, the claims recite the step of “determining the expression level of miRNA-137 and the expression level of COX6A2 in a biological sample obtained from the patient” without defining the biological sample. Moreover, the claims recite “classifying the subject as a high-risk [schizophrenia] subject based on the expression levels determined in step (a)” without defining the expression levels of miRNA-137 and/or COX6A2. Additionally, claim 15 recites “administering a mitochondria-targeted antioxidant to the subject” without defining any mitochondria-targeted antioxidants. Finally, the claims are directed to “treating a subject classified as a high-risk schizophrenia subject” without what is meant by “treating”. As such, the method embraces treating subacute symptoms associated with high-risk schizophrenia, reducing cognitive decline, and/or preventing or delaying the evolution of the condition into a fully-blown psychosis.
State of the Art / Predictability of the Art: The state of the art is undefined and there is virtually no predictability in the art.
Maguire et al (J Clin Psychopharmacol 41:53-57, 2021 – Abstract only) teach that “[m]itochondria dysfunction has been hypothesized as one of the numerous factors to underlie the manifestation of... symptoms” including “[c]ognitive impairments, negative symptoms, affective symptoms, and low energy... prevalent [in] schizophrenia” (Abstract).
Similarly, Statharakos (Psychiatriki 36:229-235, 2025) teaches that “accumulating evidence suggests that mitochondrial dysfunction and oxidative stress pay significant roles in [the] development” of schizophrenia, in which “emerging data linking mitophagy and schizophrenia are promising”, albeit with “limitations” (Abstract).
However, as further taught by Maguire et al, “there was no effect of CoQ10 supplementation on the primary outcome measures [attention and working memory performance] at 3 or 6 months” and “CoQ10 supplementation also had no effect on the secondary outcomes [mitochondrial function, energy, depression, anxiety, negative symptoms, and quality of life]” (Abstract).
Notably, CoQ10 is promotes mitophagy.
Moreover, Wasserthal et al (Schizophrenia Bulletin Open 5:12 pages, 2024) teach that N-acetylcysteine (NAC) – another compound that promotes mitophagy – which provides “neuroprotective effects... mediated by three distinct mechanisms: (1) Mitigation of oxidative stress through cysteine donation; (2) decrease of neuro inflammation by attenuating cytokine levels; and (3) modulation of glutamatergic signaling by activating the cysteine-glutamate antiporter” thus “provides an intriguing pathway for potential treatment in CHR-P” (Page 2, Column 1). In particular, Wasserthal et al “hypothesized that treatment groups receiving... NAC and IPPI [integrated preventive psychological intervention], would show significantly fewer transitions to psychosis, less deterioration of CHR-P symptoms (primary outcome), and improved social functioning, social cognition, and neurocognitive capabilities (secondary outcome) compared to patients in one or both placebo [PLC] groups” (Page 2, Column 2). However, “[n]o significant differences between the treatment groups (IPPI vs PSM/NAC vs PLC) were found” and “the beneficial effects of NAC are not statistically significant” (Page 7, Column 1).
As taught by Magalhaes et al (Cochrane Database of Systematic Reviews 2:74 pages, 2016), “[t]here is accumulating evidence that progressive changes in brain structure and function take place as schizophrenia unfolds” wherein, “[a]mong many possible candidates, oxidative stress may be one of the mediators of neuroprogression, grey matter loss and subsequent cognitive and functional impairment” (Abstract). However, out of “22 RCTs of varying quality and sample size studying Ginkgo biloba, N-acetyl cysteine (NAC), allopurinol, dehydroepiandrosterone (DHEA), vitamin C, vitamin E or selegiline... [o]nly three studies including a minority of the participants reported our a priori selected primary outcome of clinically important response” (Page 2, Main Results) and, “overall, the trials suffered from a lack of real-world outcomes, such as clinical response, rates of relapse, quality of life, functioning, safety and satisfaction or acceptability of treatment” (Page 2, Plain Language Summary).
Guidance of the specification / The existence of working examples: The amount of direction provided by the Applicant is considered to be determined by the Specification and the working examples.
In the instant case, the Specification asserts a “correlation between the expression level of miR137 and expression level of COX6A2 in differently classified groups of patients” (Page 28; see also Figure 1). In particular, wherein “[t]he study population included early psychosis patients (EPP; n = 138)” – “meeting threshold criteria for psychosis, as defined by the ‘Psychosis threshold’ subscale of the Comprehensive Assessment of At Risk Mental State (CAARMS)” – and “healthy controls (n = 134)” – “assessed by the Diagnostic Interview for Genetic Studies (DIGS) in order to attest for the absence of any major psychiatric or substance use disorder” wherein “healthy controls who reported having a first-degree relative with psychotic disorder were excluded” (Pages 29-30, Example 1).
Significantly, however, the Specification further demonstrates:
(a) “[m]ost of the early psychosis subject group (68%) is included based on the expression level of miR-137 higher than the threshold (4.8 a.u. as normalized to miR-16, snRNA-U1 and snRNA-U6)” wherein “most of the subjects in early psychotic subject group that were selected based on miR-137 expression level also fulfilled the COX6A2 expression level requirements” (Page 32, Example 7). As such, the data indicate that less than 68% of early psychosis patients were classified as a high-risk psychotic subject based on an miR-137 expression level of 4.8 a.u. or higher and a COX6A2 expression level of 1.2 ng/mL or less. Moreover, no studies were carried out investigaint an miR-137 expression level of 4.8 a.u. or higher and a COX6A2 expression level of 1.2 ng/mL or less in identifying a high-risk psychotic disorder subject (i.e., a subject exhibiting prodromal symptoms before active onset of psychosis) as claimed. As indicated above, the studies were limited to patients having onset of overt psychotic symptoms (i.e., the early psychosis subject group); and
(b) “only 17% of healthy subjects can be excluded based on the miR-137 expression level threshold of 4.8 a.u.” and an additional “25% of control subjects that fulfill the criterion of miR-137 expression higher than threshold could be excluded based on the expression level of COX6A2” being lower than 1.2 ng/mL (Pages 32-33). As such, the data further indicate that approximately 62.25% of healthy subjects (i.e., 83% x 75%) would be classified as a high-risk psychotic patient based on an miR-137 expression level threshold of at least 4.8 a.u and a COX6A2 expression level of less than 1.2 ng/mL.
Collectively, utilizing an miR-137 expression level threshold of at least 4.8 a.u and a COX6A2 expression level of less than 1.2 ng/mL incorrectly identifies approximately the same amount of healthy patients as high-risk psychotic patients as it does early psychotic patients. And it is even less likely that an miR-137 expression level threshold of at least 4.8 a.u and a COX6A2 expression level of less than 1.2 ng/mL would be capable of correctly identifying a high-risk psychotic disorder subject (i.e., a subject exhibiting prodromal symptoms before active onset of psychosis) as claimed, based on the lack of success in identifying high-risk psychotic patients among early psychotic patients.
Additionally, the Specification demonstrates that miR-137 is upregulated and mitophagy is disrupted (as indicated by decreased NIX, FUNDC1 and LC3B) in Gclm-KO mice with BGR12909 (Gclm-KO+GBR - known to exhibit the oxidative marker 8-oxo-dG indicative of mitochondrial DNA damage) as an animal model of oxidative stress (Pages 33-34, Example 9).
Furthermore, “treatment with MitoQ rescues oxidative stress induced elevated level of miR-137” and promoted mitophagy based on normalized “NIX, FUNDC1 and LC3B expression levels” (Page 34, Example 10), nowhere does the Specification demonstrate that MitoQ or any mitochondria-targeted antioxidant can treat a subject classified as a high-risk schizophrenia subject.
Amount of experimentation necessary: Given the complex nature of the invention, which is exacerbated by the breadth of the claims, and given the lack of working examples and the high degree of unpredictability in the art, it would require undue experimentation for a person of ordinary skill in the art to make and/or use the invention as claimed.
Conclusion
The new ground(s) of rejection presented in this Office action are necessitated by Applicant’s amendments to the claims. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
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/CRAIG D RICCI/
Primary Examiner, Art Unit 1611
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