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 .
Claim Status
Applicant’s submission filed 08/01/2025 has been received and entered. Claims 1-10 are pending and under current examination.
Status of Prior Rejection/Response to Arguments
The rejection of claims 1-3, 5 and 8-10 under 35 U.S.C. §103 over Szechtman et al. in view of Simmler et al. is maintained:
The rejection of claims 1-10 under 35 U.S.C. §103 over Szechtman et al. in view of Simmler et al., and further in view of Viasov et al. is maintained:
Applicant asserts that Szechtman does not disclose activation of a neural circuit connecting basolateral amygdala (BLA) to dorsomedial striatum (DMS) in an animal model, and Simmler does not cure the deficiency of Szechtman. Specifically, Simmler focuses on the cortico-striatalthalamic-cortical (CSTC) circuit related to obsessive-compulsive disorder (OCD) and discloses specific OCD animal models (Remarks, p3). Simmler teaches that the DMS, dorsolateral striatum (DLS), nucleus accumbens (NAc) core, prelimbic (PL), infralimbic (IL), insular cortex (IC), orbitofrontal cortex (OFC), and BLA regions are all involved in goal-directed and habitual behaviors, but it cannot be concluded that they all necessarily induce OCD (Remarks, p4). Simmler discloses CSTC is the key element of OCD patients, the circuit is entirely different from the neural circuit of the present invention (Remarks, p5), and OCD animal models are created through dysfunction of the CSTC circuit (Remarks, p5). Therefore one of ordinary skill in the art reading Simmler, could only infer that the CSTC circuit is related to OCD and that an OCD animal model can be produced through knockout of specific genes associated with this circuit. There is no teaching in Simmler that would lead one of ordinary skill in the art to the presently claimed method of producing an OCD animal model by activating the BLA- DMS neural circuit (Remarks, p5).
Applicant’s argument is fully considered but found not persuasive. Obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, a clear rationale to combine Szechtman et al. and Simmler et al. has been established. Szechtman et al. teach optogenetic activation within CBGTC circuits (the orbitofrontal cortex (OFC)-ventromedial striatum (VMS) circuit) for constructing an animal model of OCD (see p256, right column- p258). Simmler et al. teach goal-directed and habitual actions are essential for normal functioning in everyday life, when these useful behaviors can become aberrant, manifesting as key symptoms in several psychiatric disorders, including obsessive-compulsive disorder (OCD) (see Abstract), which indicates that dysfunction or damage of neuronal circuit of goal-directed and habitual actions can cause OCD. Simmler et al. teach the BLA-DMS circuit and disclose its function in goal directed behavior. Simmler et al. further teach basolateral amygdala (BLA) influences goal-directed behavior through its projections to the dorsomedial striatum (DMS) (p5, left column). Pharmacological disconnection between the BLA and the DMS during initial training impaired goal-directed behavior, suggesting that the BLA-to-DMS circuit is required for the acquisition of the action-outcome association. BLA-to-DMS disconnection immediately before devaluation testing also disrupted goal directed behavior, suggesting that the BLA-to-DMS projection is also important for the retrieval of the action- outcome association (p5, left column). This teaching indicates that the neural circuit connecting from basolateral amygdala to dorsomedial striatum is important for the OCD behavior, therefore change the activity level (e.g., activation) of this neural circuit would cause OCD behavior. It would be prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention to substitute Szechtman et al.’s controlling (e.g., optogenetic activation) of CBGTC neural circuit of OCD, and change the activity level (e.g., activation) of the neural circuit connecting from BLA to DMS depends on their research interest based on the teachings above. Therefore the rejection is maintained.
Maintained Rejections
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-3, 5, 8-10 stand rejected under 35 U.S.C. 103 as being unpatentable over Szechtman et al. (Neuroscience and Biobehavioral Reviews, 2017) in view of Simmler et al. (Neurochemistry International, May 2019, as cited in IDS).
Szechtman et al. teach research with animal models of obsessive-compulsive disorder (OCD) (Abstract), highlights how studies using different animal models of OCD generated some novel insights into this disorder (p256, left column).
Regarding claim 1, Szechtman et al. teach animal models provide an essential resource for testing whether indeed abnormal activity in cortico-basal ganglia-thalamo-cortical (CBGTC) circuits leads to OCD symptoms, such as abnormal repetitive behaviors (p256, left column). In particular, mouse models can be combined with optogenetic and chemogenetic tools that permit precise control over activity in specified neural circuits, allowing the direct determination of the relationship between activity in a particular neural circuit and behavioral changes relevant to OCD (p256, right column). Szechtman et al. also teach an example of optogenetic activation within CBGTC circuits (the orbitofrontal cortex (OFC)-ventromedial striatum (VMS) circuit) for constructing an animal model of OCD (see p256, right column- p258). This teaching reads on “a method for constructing an animal model of obsessive-compulsive disorder, the method comprising a step of controlling (e.g., activating) a neural circuit in mice” in instant claim.
Instant claim differs from Szechtman et al.’s teaching in that: instead of controlling (e.g., activating) the CBGTC neural circuit to obtain an animal model of OCD, instant claim activates a neural circuit connecting from basolateral amygdala to dorsomedial striatum in the animal model. However, it is prima facie obvious in view of Simmler et al..
Simmler et al. review the preclinical research that has advanced understanding of the brain structures that control goal-directed and habitual behavior and discuss their relationships to the pathophysiology of OCD (Abstract).
Regarding claim 1, Simmler et al. teach basolateral amygdala (BLA) influences goal-directed behavior through its projections to the dorsomedial striatum (DMS) (p5, left column). Pharmacological disconnection between the BLA and the DMS during initial training impaired goal-directed behavior, suggesting that the BLA-to-DMS circuit is required for the acquisition of the action-outcome association. BLA-to-DMS disconnection immediately before devaluation testing also disrupted goal directed behavior, suggesting that the BLA-to-DMS projection is also important for the retrieval of the action-outcome association (p5, left column). This teaching indicates that the neural circuit connecting from basolateral amygdala to dorsomedial striatum is important for the OCD behavior, therefore change the activity level (e.g., activation) of this neural circuit would cause OCD behavior.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Szechtman et al.’s teaching of constructing an animal model of OCD by controlling (e.g., optogenetic activation) CBGTC circuits, and activate a neural circuit connecting from BLA to DMS, which is another important neural circuit of OCD, as taught by Simmler et al.. The only difference between instant claim and Szechtman et al.’s controlling (e e.g., optogenetically activating) of CBGTC circuits to construct an animal model of OCD is instant claim activates another neural circuit connecting from BLA to DMS. Given that Simmler et al. teach BLA influences goal-directed behavior through its projections to the DMS (p5, left column), one of ordinary skill in the art would have substituted Szechtman et al.’s controlling (e.g., optogenetic activation) of CBGTC neural circuit of OCD, and activate the neural circuit connecting from BLA to DMS depends on their research interest and preference. This simple substitution of one known element (activation of BLA to DMS neural circuit for constructing an animal model of OCD) for another known element (Szechtman et al.’s controlling (e.g., optogenetic activation) CBGTC neural circuit for constructing an animal model of OCD) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Regarding claim 2, as discussed above, Szechtman et al. teach in particular, mouse models can be combined with optogenetic and chemogenetic tools that permit precise control over activity in specified neural circuits, allowing the direct determination of the relationship between activity in a particular neural circuit and behavioral changes relevant to OCD (p256, right column). Optogenetic tools are considered as physical regulation (e.g., activation) and chemogenetic tools are considered as chemical regulation (e.g., activation) of the neural circuit.
Regarding claim 3, Szechtman et al. teach injecting virus (AAV) encoding a light-activated excitatory ion channel, channelrhodopsin (ChR2), injecting virus in OFC, then conducting optogenetic stimulation of VMS terminals (473 nm light: 10 Hz, 10 ms, 10 mW) and in vivo electrophysiological recording at the same site to determine that these OFC-VMS projections could be selectively and robustly activated (see p257, left column). This teaching indicates the same manipulation as recited in instant claim, which is injecting virus in one brain region of the neural circuit, wherein the neurons of said brain region is projecting to another brain region of the neural circuit, optical fiber would be place in the (another) brain region for activating the neural circuit.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Szechtman et al.’s teaching of constructing an animal model of OCD by injecting AAV for optogenetic activation of CBGTC circuits (OFC-VMS projections), and use optogenetic virus and optical fiber to activate a neural circuit connecting from BLA to DMS, which is another important neural circuit of OCD, as taught by Simmler et al.. The only difference between instant claim and Szechtman et al.’s optogenetical activation of CBGTC circuits (OFC-VMS projections) is instant claim activates another neural circuit connecting from BLA to DMS. Given that Simmler et al. teach BLA influences goal-directed behavior through its projections to the DMS (p5, left column), one of ordinary skill in the art would have substituted Szechtman et al.’s optogenetic activation of CBGTC neural circuit, and use optogenetic tools to activate the neural circuit connecting from basolateral amygdala to dorsomedial striatum depends on their research interest or preference. This simple substitution of one known element (optogenetic activation of BLA to DMS neural circuit for constructing an animal model of OCD) for another known element (Szechtman et al.’s optogenetic activation of CBGTC neural circuit for constructing an animal model of OCD) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Regarding claim 5, Szechtman et al. teach using adenovirus-associated vector (AAV) encoding a light-activated excitatory ion channel, channelrhodopsin (ChR2) (p257, left column).
Regarding claims 8 and 9, following the discussion of claim 1, Szechtman et al. in view of Simmler et al. teach the method of constructing an animal model of obsessive-compulsive disorder, the method comprising a step of activating a neural circuit connecting from basolateral amygdala to dorsomedial striatum in the animals. It is considered as inherent property that the same method will lead to same result. Therefore the teaching of Szechtman et al. in view of Simmler et al. will obtain the same animal model as recited in claim 8, wherein the animal model will exhibit all of checking behavior, repetitive behavior, cleaning behavior, and hoarding behavior, as recited in claim 9.
Regarding claim 10, Szechtman et al. teach compulsive checking behaviors of animal model of OCD (e.g., performance on criteria measures of compulsive checking behavior shown by groups of rats with lesion to the basolateral amygdala (BLA), nucleus accumbens core (NAc), orbital frontal cortex (OFC) or sham lesion., see p266, figure 10), combining with drug treatment (chronic quinpirole, red bars) or without treatment (chronic saline, blue bars), the effect of the drug could be determined by the behavior output (e.g., frequency of checking, length of check, recurrence of checking and stops before checking). This teaching indicates the same experimental concept (administering a candidate drug to the animal model of OCD, and determining the change of any of OCD related behaviors), as recited in instant claim.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Szechtman et al.’s teaching of constructing an animal model of OCD by controlling (e.g., optogenetic activation) CBGTC circuits, and construct an animal model of OCD by activating a neural circuit connecting from BLA to DMS, which is another important neural circuit of OCD, as taught by Simmler et al., and further conduct drug screening using said animal model of OCD. The only difference between instant claim and Szechtman et al.’s teaching is instant claim uses a different method of constructing OCD animal models for drug screening. Given that Simmler et al. teach BLA influences goal-directed behavior through its projections to the DMS (p5, left column), one of ordinary skill in the art would have substituted Szechtman et al.’s OCD animal model and the method of assessing the effect of the drugs by measuring the OCD-related compulsive behaviors such as checking behaviors, and construct an animal model of OCD by activating a neural circuit connecting from BLA to DMS in the animals, then use this animal model for drug screening by determining the OCD related behaviors. This simple substitution of one known element (constructing an animal model of OCD by activating a neural circuit connecting from BLA to DMS, then use this animal model for drug screening and measuring the behavior output of the OCD-related behaviors such as checking behaviors) for another known element (Szechtman et al.’s OCD animal model and the method of assessing the effect of the drugs by measuring the OCD-related compulsive behaviors such as checking behaviors) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Claims 1-10 stand rejected under 35 U.S.C. 103 as being unpatentable over Szechtman et al. (Neuroscience and Biobehavioral Reviews, 2017) in view of Simmler et al. (Neurochemistry International, May 2019, as cited in IDS), and further in view of Vlasov et al. (Methods in Enzymology, 2018).
The teaching of Szechtman et al. in view of Simmler et al. is set forth above.
Regarding claim 4, Szechtman et al. in view of Simmler et al. do not teach the chemical activation is carried out by injecting a virus carrying a double-floxed inverted open reading frame (DIO) and a chemogenetic protein gene to a basolateral amygdala site, injecting a retrograde virus carrying a Cre recombinase gene to a dorsomedial striatum site, and then applying a drug upon activation of the viruses to active the neural circuit. However, it is prima facie obvious in view of Vlasov et al..
Vlasov et al. provides an overview of neuronal targeting and experimental strategies and highlights the important advantages and disadvantages of optogenetics and chemogenetics (see Abstract).
Regarding claim 4, Vlasov et al. teach to achieve selective designer receptors exclusively activated by designer drugs (DREADD) expression in a specific circuit, a canine adenovirus (CAV2-Cre) may be injected in the projection site, causing retrograde transport to cell bodies, leading to the expression of Cre. When a Cre-driven AAV encoding the DREADD is injected in the location containing cell bodies, only cells that project to the target site of interest will express Cre, leading to selective DREADD expression in neurons that project to that site (p189, parag 1). Vlasov et al. also teach in order to gain anatomic specificity of opsin or DREADD expression, it is necessary to perform stereotaxic injections of viral vectors encoding these proteins in the brain regions of interest. Cre is an enzyme that catalyzes site specific recombination between two LoxP sites, and modern Cre-driven viral vectors are constructed with “double-floxed” genes encoding the opsin or DREADD, causing gene expression only in transfected cells that contain Cre (p184, parag 2). These teachings indicate the principle of using chemical activation by DREADD for activating a neural circuit, which is injecting a retrograde virus carrying a Cre recombinase gene to a projecting site (herein is dorsomedial striatum site), and a Cre-driven AAV (“double-floxed”) encoding the DREADD (chemogenetic protein gene) is injected in the location containing cell bodies (herein is basolateral amygdala site). Therefore Vlasov et al. teach the method recited in instant claim.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Szechtman et al.’s teaching of constructing an animal model of OCD by controlling (e.g., optogenetic and /or chemogenetic activation) CBGTC circuits, and activate a neural circuit connecting from BLA to DMS, which is another important neural circuit of OCD, as taught by Simmler et al., and the activation of the neural circuit is achieved by chemogenetic virus and drug as taught by Vlasov et al.. The difference between instant claim and Szechtman et al.’s activation (e.g., optogenetic and /or chemogenetic activation, see p256, right column) of CBGTC circuits is instant claim activates another neural circuit connecting from BLA to DMS, and the activation is achieved by virus encoding chemogenetic protein such as hM3Dq and drug such as CNO. Given that Simmler et al. teach BLA influences goal-directed behavior through its projections to the DMS (p5, left column), and Vlasov et al. teach chemogenetics is a similar method of activating neurons (see p184, figure 1), one of ordinary skill in the art would have substituted Szechtman et al.’s activation (e.g., optogenetic and /or chemogenetic activation) of CBGTC neural circuit, and activate the neural circuit connecting from BLA to DMS by chemogenetics depends on their research interest or preference. This simple substitution of one known element (chemogenetic activation of BLA to DMS neural circuit for constructing an animal model of OCD) for another known element (Szechtman et al.’s optogenetic and /or chemogenetic activation of CBGTC neural circuit for constructing an animal model of OCD) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Regarding claims 6 and 7, Szechtman et al. in view of Simmler et al. do not teach the chemogenetic protein is selected from the group consisting of hM2Di, hM4Di, hM3Dq, and hM5Dq, and the drug activates a chemogenetic protein and is selected from the group consisting of clozapine N-oxide, clozapine, compound 21, and perlapine. However, Vlasov et al. teach flowchart showing the typical sequence of events for performing optogenetics or chemogenetics experiments (p184, figure 1). Vlasov et al. also teach with chemogenetics, DREADDs are used to activate or inhibit targeted neurons. the stimulatory DREADD hM3Dq is a modified human M3 muscarinic receptor that has low affinity for the native ligand acetylcholine, but high affinity for the synthetic ligand clozapine-N-oxide (CNO) (p187, parag 1, also see figure 3).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Szechtman et al.’s teaching of constructing an animal model of OCD by controlling (e.g., optogenetic and /or chemogenetic activation) CBGTC circuits, and activate a neural circuit connecting from basolateral amygdala to dorsomedial striatum, which is another important neural circuit of OCD, as taught by Simmler et al., wherein the activation is achieved by chemogenetic protein such as hM3Dq and drug such as CNO for hM3Dq activation as taught by Vlasov et al.. The difference between instant claim and Szechtman et al.’s optogenetic and /or chemogenetic activation of CBGTC circuits neural circuit of OCD is instant claim activates another neural circuit connecting from BLA to DMS, and the activation of the neural circuit is achieved by chemogenetic protein such as hM3Dq and drug such as CNO for hM3Dq activation. Given that Simmler et al. teach BLA influences goal-directed behavior through its projections to the DMS (p5, left column), and Vlasov et al. teach both optogenetics and chemogenetics is capable of activating or inhibiting neurons (see p184, figure 1), one of ordinary skill in the art would have substituted Szechtman et al.’s optogenetic and /or chemogenetic activation of CBGTC neural circuit of OCD, and activate the neural circuit connecting from BLA to DMS by chemogenetics depends on their research interest or preference. This simple substitution of one known element (chemogenetic activation of BLA to DMS neural circuit for constructing an animal model of OCD) for another known element (Szechtman et al.’s optogenetic and /or chemogenetic activation of CBGTC neural circuit for constructing an animal model of OCD) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Conclusion
THIS ACTION IS MADE FINAL. 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
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/Q.G./Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
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