DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This office action is in response to an amendment filed 2/4/2026.
Claims 1-3, 10, 13, 14, 19-21, 26, 29, 30, 34, 35, 38, 40-42, 44-46, 48 and 54 are pending.
The instant application is a 371 filing of PCT/US23021/045228 filed 8/9/2021 which claims priority to U.S. provisional application 63/063,765 filed 8/10/2020. Neither of the priority documents support the scheme of method of activating retrosplenial cortex by rhythmic optogenetic activation wherein the two parent documents only teach one rhythmic optogenetic method that is said not to provide dissociative effects,
To test rhythmic optogenetic drive of a different cortical area, we expressed eNPAC in deep layers of somatosensory cortex; here, rhythmic illumination did not induce the dissociative behavioral state (FIG. 3G, FIGS. 1 SL-15O). In summary, optogenetically providing the activity pattern naturally arising in layer 5 RSP neurons in response to ketamine exerted the effect of dissociating sensory and affective responses.
Furthermore, the priority document does not teach stimulation intervals cited in claim 34 and 35. Hence, as the disclosure prior to the instant specification does not support the claims and the EFD of the claims by embracing all these elements is set at the filing date of the instant disclosure of 2/2/2023.
Election/Restrictions
Applicant's election with traverse of Group II (claims 19-21, 26, 29, 30, 34, 35 and 38) drawn to a method of inducing development of dissociative states in a subject by performing rhythmic optogenetic activation of retrosplenial cortex layer-5 neuron thus inducing rhythmic neural activity in the posteromedial cortex, in the reply filed on 2/4/2026 is acknowledged. The traversal is on the ground(s) that the reference of Caruana provided in the restriction mailed 12/29/2025 does not teach dissociative effects in the PMC. This is not found persuasive because the technical feature that links the inventions is provided by Caruana which teaches oscillating electrical stimulation is used for modifying cognition and emotion (abstract). One such affect is seizures and interoceptive sensations and speech impairment and (see page 3036 and page 3040) which is taught in the instant disclosure to be part of the dissociative state Caruana demonstrates that the claims as presented do not have a special technical feature. Whilst the words are not used, the conditions and locations in the brain are the same as the cingulate is a part of the posteromedial cortex (see Posteromedial Cortex attached). Art below supports the lack of unity.
The requirement is still deemed proper and is therefore made FINAL.
Information Disclosure Statement
Information disclosure statements filed 9/8/2025 and 5/11/2023 have been identified and the documents considered. The corresponding signed and initialed PTO Form 1449 has been mailed with this action.
Claim Rejections - 35 USC § 112, first paragraph
The following is a quotation of the first paragraph of 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 19-21, 26, 29, 30, 34, 35 and 38 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for a method of introducing by intrahippocampal or intracerebroventricular delivery an AAV9 virus vector encoding a cation conducting opsin wherein the coding sequence is operably linked to a promoter for transduction and expression in the retrosplenial cortex layer-5 neurons by and stimulating the channels to depolarize the neurons with an optical fiber light source arranged to target the layer V neurons, does not reasonably provide enablement for any other embodiment. 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 use the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the patent coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is not based on a single factor but is rather a conclusion reached by weighing many factors (See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter, 1986) and In re Wands, 8USPQ2d 1400 (Fed. Cir. 1988); these factors include the following:
1) Nature of invention. The instant claims are drawn to a method of inducing dissociative symptoms in a subject with a simple based method of performing rhythmic optogenetic activation of a retrosplenial cortex layer 5 neuron.
2) Scope of the invention. The scope of the invention is extremely broad in any dissociative symptom is induced in any subject by a very broad step of rhythmic optogenetic activation of the retrosplenial cortex layer 5 neuron (RSP).
3) Number of working examples and guidance. Applicants were able to induce dissociation in mice restricted to retrosplenial cortex layer 5 neurons with three approaches
[0209] Key aspects of dissociation were recapitulated by three specific interventions: administration of retrosplenial rhythm-inducing doses of ketamine or PCP in mice, rhythmic RSP-localized optogenetic stimulation in mice, and similarly-localized electrical stimulation in a patient with epilepsy originating from right PMC (FIG. 19).
As far as relating to rhythmic optogenetic activation, the disclosure teaches only a single method and that is delivery of a light responsive ion channel into the retrosplenial cortex layer 5 neuron.
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[0017] In certain embodiments, rhythmically illuminating the light-responsive ion channel comprises delivering light from a light source to the light-responsive ion channel using a fiber-optic-based optical neural interface. In some embodiments, the light source is a solid-state diode laser. In some embodiments, rhythmically illuminating the light-responsive ion channel with light comprises repeatedly delivering light at the wavelength that activates the light-responsive ion channel with a frequency of about 2 Hz.
This requires for the instant method specifically using cation conducting opsins,
[0062] Optogenetics is used to allow optical control of activation (i.e., depolarization) or inhibition (i.e., hyperpolarization) of neurons that have been genetically modified to express light-responsive ion channels. In some embodiments, the light-responsive ion channel is a naturally occurring or synthetic opsin that uses a retinal-based cofactor (e.g., all-trans retinal for the microbial opsins) to respond to light. For example, light-responsive cation-conducting opsins (e.g., channelrhodopsin that conducts Ca.sup.2+) can be used to activate or depolarize neurons. Light-responsive anion-conducting opsins (e.g., channelrhodopsin or halorhodopsin that conduct chloride ions) or light-responsive proton conductance regulators (e.g., bacteriorhodopsin or archaerhodopsin) can be used to inhibit or hyperpolarize neurons.
As to rhythmically illuminating the channels, the method entails delivering light from a light source to the channel. Wherein the light source is a solid state diode laser.
The specification teaches as regards symptoms of dissociation,
[[0041]] Notably, symptoms of dissociation consistently described (APA 2013) can involve reproducible perceptions of depersonalization (feeling of being outside observer of one's body/thoughts) and derealization (feeling of being detached from surroundings).
[0060] In some embodiments, neuromodulation is used to induce rhythmic neural activity in the posteromedial cortex to produce a dissociative state in a subject who is suffering from painful or damaging symptoms of a disorder of association. For example, in subjects who have chronic pain, an overwhelming association with pain can persist even when the original source of the pain no longer exists (e.g., pain from a limb that has been amputated). In conditions such as depression, anxiety, obsessive-compulsive disorder, addiction and dependency, dysfunctional association with specific, recurrent, and/or negative thoughts can cause morbidity or mortality, wherein disconnecting from the damaging thoughts by generating a dissociative state in a subject is beneficial.
[[0108]] A positive therapeutic response in the treatment of a disorder of association may include a reduction in symptoms of association, such as specific, recurrent, and/or negative thoughts that cause morbidity or mortality, associated with chronic pain, depression, anxiety, obsessive-compulsive disorder, addiction/dependency, or other dysfunctional condition, wherein disconnecting from the damaging thoughts associated with the disorder is beneficial.
[[0116]] Open loop modulation could also be used to induce dissociation (e.g., to induce rhythmic neural activity in the posteromedial cortex) to alleviate acute symptoms of a disorder of association, for example, to manage traumatic situations, anxiety, panic, depression, chronic pain, obsessive-compulsive disorder, addiction, or dependency. In certain scenarios, it may be beneficial to induce dissociation without use of drugs.
Similarly, disorder of association is
0051] The term “associative disorder” or “disorder of association” as used herein refers to any condition or disease associated with producing an undesirable state of association in a subject. Disorders of association include, without limitation, chronic pain, depression, anxiety, obsessive-compulsive disorder, addiction/dependency, or any dysfunctional association with specific, recurrent, and/or negative thoughts causing morbidity or mortality, wherein disconnecting from the damaging thoughts is beneficial.
4) State of the art. The claims are drawn to inducing dissociative symptoms in a subject using optogenetic activation of the retrosplenial cortex layer 5 neuron. Ordaz et al (J Neural Regeneration Research. 2017, pages 1197-1209) “Optogenetics works by transducing light-stimulated electrical currents directly into specific cells (Terakita, 2005). To achieve this purpose, this technique is comprised of three major components: 1) light-activated proteins, 2) light, and 3) mode of delivery” (page 1197, col 2). Hence, the claimed methods are best described as those partially recited in claim 2. The review by Ordaz details that delivery relies upon vectors able to deliver wherein the state of the art relies on AAV of channels and light delivery with LED lights corresponding to the channel “fiber-optic-based optic neural interface has been developed in which LED or laser diode systems can be coupled to lightweight flexible optic fibers to deliver light to deeper brain tissue”.
The state of the art of optogenetics is reviewed by Ordaz et al (J Neural Regeneration Research. 2017, pages 1197-1209). This review details a number of improvements developed to make the application possible. For example,
Since the serendipitous application of optogenetics to neural systems, the field has vastly expanded (Boyden, 2011). However, the introduction of optogenetics to neuroscience has not been without its challenges. For example, there were challenges in increasing the cell membrane transport of NpHR since it was observed to accumulate intracellularly at high expression levels (Gradinaru et al., 2007). To increase its cell surface expression, the C-terminal endoplasmic reticulum (ER) export peptide sequence from Kir2.1 channel was added, which resulted in the synthesis of the opsin enhanced natronobacterium pharaonic halorhodopsin (eNpHR) (Gradinaru et al., 2008). Moreover, NpHR was inefficient in inhibiting neurons since it pumped one chloride ion per photon.
The instant method relies upon delivery of a channel that depolarizes the RSP neuron. Ordaz teaches that ChR2 and VChR1 depolarize.
5) Unpredictability of the art. As a first issue is the lack of support for the large breadth of the claims. Neither the art nor the disclosure provide generic means of rhythmic optogenetic activation of RSP layer 5 neurons such that rhythmic neural activity is induced in the posteromedial cortex and dissociative symptoms are induced. The only provided for method is introduction of light responsive cation conducting opsin and a stimulation interval followed by a non-stimulation interval of light exposure. However, such a method comes with obstacles known in the art. The first is for the method in humans, the question of how to deliberately transform RSP layer 5 neurons is raised. The disclosed method does not provide sufficient guidance to overcome art recognized obstacles i.e. organ barriers, failure to persist, side-effects in other organs, virus neutralizing antibodies, humoral immunity, normal tropism of the vector to other organs and more.
The challenge is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. The inability to develop an adequate means of overcoming obstacles such as humoral; responses and refractory cells limits the successful means by which the nucleic acid can be administered (see Zhou, (Frontiers in Molecular Neuroscience, 2022, pages 1-13, especially page 8). The physiological art is recognized as unpredictable. (MPEP 2164.03.) In cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.
The methods are performed in rodent models. There is no actual description of how the channel sequences are delivered. Mention is made of AAV with general methods of producing and delivering relying upon the art. However, no actual guidance is provided. Looking to the art, evidence of AAV effect in rodent models is shown by Gholizadeh et al (Human Gene Therapy, 2013, pages 205-213) wherein AAV were injected intracerebroventricularly for neonatal mice and by stereotaxic injections in juvenile mice (pages 206-207). Very specifically, AAV2/9 were found to mediate transduction of neurons preferentially and to populate the retrospelanial cortex (see page 209, col 2, page 210, col 2 and Table 1). This supports reports by Zhou et al (Frontiers in Molecular Neuroscience, 2022, pages 1-13). On page 6, Zhou reviews use of AAV9 following intrahippocampal injection with following transduction of retrosplenial cortex.
It has been determined that these models did not correlate with humans when looking at modes of delivery. Zhou (Frontiers in Molecular Neuroscience, 2022, pages 1-13) teaches that results identified in rodents of administration should be tested in large animals after proof of concept in rodents as the “human brain is 1,0000 times larger than the mouse brain and has different anatomy, and the distance between brain regions to the ventricle for ICV injection is much greater in large animals and humans compared to rodents. Therefore, it is essential to conduct studies using large animals to design optimal clinical trial protocols” This is known in the art wherein comparing results in humans and in animals demonstrates that there is little correlation between the two (Shanks, Are animal models predictive for humans? 2009, pages 6 and 7).
As you can see there is little correlation between animal and human data. In some cases human bioavailability is high when bioavailability in dogs is high but in other cases dogs and humans vary considerably. The patterns exhibited by both are what are frequently referred to as a shotgun pattern; meaning that if one fired a shotgun full of bird shot at a target one would see the same pattern. No precision and no accuracy. The pattern is also referred to as a scattergram, meaning that the pattern is what one would expect from random associations.
Howard Jacob notes that rats and humans are 90% identical at the genetic level. However, the majority of the drugs shown to be safe in animals end up failing in clinical trials. "There is only 10% predictive power, since 90% of drugs fail in the human trials" in the traditional toxicology tests involving rats. Conversely, some lead compounds may be eliminated due to their toxicity in rats or dogs, but might actually have an acceptable risk profile in humans [39]. (Emphasis added.)
Hence, it is the art acknowledged lack of correlation in combination with the complexity of this art and the scope of the steps that makes the lack of relevant correlation important. Therefore, animal models have allowed proof of principle issues to be established. In patent prosecution, this is relevant wherein the ability to establish a correlation is necessary.
Aside from the issues above, there are a number of issues associated with the transduction issues. First, in order to “express” the channel and ensures depolarization the construct must comprise a promoter firstly and secondly the channel must be a cation conducting opsin. There is no expression without a promoter and there is no depolarization unless the channel is a cation conducting opsin (see instant disclosure). As to inducible expression, the disclosure does not provide means to mediate this in a subject.
6) Undue experimentation. The claims have been evaluated in light of the art at the time of filing and found not to be commensurate in scope with the specification. MPEP 2164.05 teaches, “However, the examiner should carefully compare the steps, materials, and conditions used in the experiments of the declaration with those disclosed in the application to make sure that they are commensurate in scope; i.e., that the experiments used the guidance in the specification as filed and what was well known to one of skill in the art. Such a showing also must be commensurate with the scope of the claimed invention, i.e., must bear a reasonable correlation to the scope of the claimed invention. The invention recites use of a broad group of sequence. Given the unpredictability of the art, the poorly developed state of the art with regard to predicting the structural/ functional characteristics of antagonists, the lack of adequate working examples and the lack of guidance provided by applicants, the skilled artisan would have to have conducted undue, unpredictable experimentation to practice the claimed invention.”
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 19-21, 26, 29, 34 and 38 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Oswald et al (Nature Communications, 2022, pages 1-18) as evidenced by He et al (Annals of Clinical and Translational Neurology, 2023, pages 1-13).
Oswald et al teach a subject with association disorder (nociceptive hypersensitivity, see abstract) that is induced to have symptoms of dissociation (antinociception). A viral vector (AAV) encoding channelrhodopsin which mediates depolarization and thus activation of neurons containing thereof was introduced into the mouse by stereotactic injections (page 13, col 1) and as shown in Figure 10 reaches the retrosplenial cortex (see He, figure 2 for cholinergic connections reflective of that of the virus in Oswald). Thereafter, rhythmic light activation was applied (see page 13, col 2).
Channelrhodopsin is a cation channel as recited in claim 21. AAV delivers the coding sequence as recited in claim 26 and the gene is linked to a promoter (page 13, col 1). The pattern of illumination is Pulsed laser light(20Hz,10-ms pulse duration) was typically applied for a duration of 30s.
The subject has nociceptive hypersensitivity but is induced to have antinociception (page 12, col 1).
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 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 19-21, 26, 29 and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Osawa et al (PLOS ONE, 2013, pages 1-13) in view of Sugar et al (frontiers in Neuroinformatics, 2011, pages 1-13).
Osawa et al teach delivery of ChR2 (channelrhodopsin, a cation light induced channel) by AAV vector (see bridging ¶, page 2-3). Osawa teaches rhythmic optogenetics induced dissociative behavior (see bridging ¶ page 5-6).
Repetitive pulse photostimulation was applied to the rodent hippocampus, in which channelrhodopsin-2 (ChR2) was expressed, under simultaneous recording of local field potentials(LFPs).Seizure-like after discharges were successfully induced after the stimulation in both WTChR2V4 transgenic (ChR2V-TG) rats and in wild type rats transfected with adeno-associated virus (AAV) vectors carrying ChR2. Pulse frequency at 10 and 20 Hz, and a 0.05 duty ratio were optimal for afterdischarge induction.
Repetitive photostimulation is shown to be rhythmic in figure 1.
Hence, Osawa et al teach induction of dissociative symptoms (seizures) in a subject wherein the method comprises performing rhythmic optogenetic activation. As to optogenetic illumination of the channel, Osawa teaches that the hippocampal network is stimulated wherein this network is shown in the art to be related to the septotemporal region of the hippocampus (see page 2, col 1, ¶1-2). . Based upon the art, the relationship between the septotemporal region and the retrosplenial cortex (RSC) and connections mean that the RSC and the HF are part of the same network. Functionally they are interactive as detailed by Sugar et al details that layer V neurons are found in A29-A30 (see figure 1 and text, page 2, col 2). These are designated areas of the RSC. Sugar identifies connections of RSC and these project into the hippocampus forming the hippocampal network (see Sugar, page 8, col 2).
Neurons in layer V of A29ab project to Sub in the HF (Van Groen and Wyss, 1990b; Shibata, 1994). This projection is topographically organized such that caudal A29ab projects to temporal Sub, where termination occurs in the stratum moleculare and stratum pyramidale, whereas rostral and intermediate A29ab projects to intermediate septotemporal levels of Sub, where termination occurs in the stratum pyramidale
Based on such teachings, it would have prima facie been obvious to one of ordinary skill in the art at the time the invention was made that the methods that lead to dissociative symptoms originating in the septotemporal region of the hippocampus (see page 4 of Osawa) would be in the retrosplenial layer V region as taught by Sugar. The effect as taught by Osawa of activating the cationic opsin that is present throughout the region led to dissociative symptoms (seizure) wherein the connectome and interaction of the RSC and HF is shown in Sugar et al wherein the overlap of the illuminated region and the layer V neurons would lead to the activation of the ion channels residing therein which will inherently depolarize and activate the connected regions as shown by these effects in Osawa et al. Thus, a person of ordinary skill in the art, absent evidence to the contrary, would have reasonably expected that the method of Osawa et al which leads to dissociative symptoms involves the depolarization and activation of ion channels in the region wherein Sugar shows that the HF-RSC interaction and overlap would inherently lead to both being affected.
The method entails transducing the brain wherein Figure 1 details that all layers were transduced by an AAV vector encoding a cation conducting opsin (ChR2) thus meeting the limitations of claims 21 and 26. The promoter is synapsin, a neuron specific promoter.
Claims 30 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Osawa et al (PLOS ONE, 2013, pages 1-13) in view of Sugar et al (frontiers in Neuroinformatics, 2011, pages 1-13) as applied to claims 19-21, 26, 29 and 34 or claims 19-21, 26, 29, 34 and 38 of Oswald et al (Nature Communications, 2022, pages 1-18) as evidenced by He et al (Annals of Clinical and Translational Neurology, 2023, pages 1-13) further in view of Nitzan et al (Nature Communications, 2020, pages 1-17) and Motta-Mena et al (Nat Chem Biol, 2014, pages 196—202).
The teachings above do not teach that the promoter is inducible. However, Motta-Mena et al teach inducible promoters which are designed for rapid activation and deactivation. This reduced toxicity, increase control over dynamic ranges and was shown to work in mammalian cells for control of expression in space and time (see page196).
As well, the teachings do not teach use of 100 millisecond on/off. However, Nitzan teaches that for ripple effects which are critical in the methods sending ripples through the RSC used 100 ms square pulses which would benefit the instant methods (see Nitzan et al, page 5, col 1 and abstract).
Based on such teachings, it would have prima facie been obvious to one of ordinary skill in the art at the time the invention was made to incorporate the inducible promoter by Motta Mena et al and the time pulses of Nitzan in the methods of Osawa or Oswald et al . Such a modification would have resulted in a method encompassed by claim 30 and claim 35. To do so would have given dual control and lead to improved pulses through the RSC region and thus, a person of ordinary skill in the art, absent evidence to the contrary, would have reasonably expected that the expanded method would allow improved treatment.
Conclusion
Copending application 18/109, 386 now U.S. Patent 12,582,616 does not read on the instant claims as the copending claims are not directed as rhythmic optogenetic activation in order to induce rhythmic neural activity. The method does not involve use of light or optogenetics.
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/MARIA MARVICH/Primary Examiner, Art Unit 1634
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