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 6/15/2026.
Claims 1-3, 10, 13, 14, 19, 29, 30, 34, 35, 38, 40-42, 44-46, 48, 54, 62 and 63 are pending. Claims 19, 29, 30, 34, 35, 38, 62 and 63 are under examination. Claims 1-3, 10, 13, 14, 40-42, 44-46, 48 and 54 are withdrawn as directed to non-elected subject matter. The election was made with traverse.
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.
Response to Amendments
Applicants arguments are sufficient to establish support in the priority documents. Hence, the rejection under 35 USC 102 has been overcome by establishing an earlier filing date.
Claim Objections
Claims 30 and 34 are objected to because of the following informalities: claims 30 and 34 depend on cancelled claims. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 30 and 34 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 30 recites the limitation "the method of claim 26". There is insufficient antecedent basis for this limitation in the claim.
Claim 34 recites the limitation "the method of claim 20". There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 112, first 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.
Claim 29 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new rejection necessitated by applicants’ amendment.
The amendment states that the “viral vector further comprises a neuron specific promoter operably linked” to the coding sequence for the opsin. This means that there are two promoters operably linked to the sequence as claim 19 already provides for a promoter linked thereto. However, this is neither supported by the art or the specification. The MPEP teaches, “New or amended claims which introduce elements or limitations which are not supported by the as-filed disclosure violate the written description requirement. See, e.g., In re Lukach, 442 F.2d 967, 169 USPQ 795 (CCPA 1971) (subgenus range was not supported by generic disclosure and specific example within the subgenus range); In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972) (a subgenus is not necessarily described by a genus encompassing it and a species upon which it reads). (see e.g. MPEP 2105).
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, 29, 30, 34, 35, 38, 62 and 63 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for a method of inducing a dissociative disorder in a subject 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 and delivering light at a wavelength between about 460 and about 495 nm to the channels to depolarize the neurons with an optical fiber light source targeting 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. This rejection is maintained but reworded based upon applicants’ amendment.
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 method of delivering a viral vector encoding a cation conducting opsin to be expressed in the retrosplenial cortex layer 5 and “rhythmically” delivering “a wavelength” to activate the opsin.
2) Scope of the invention. The scope of the invention has been narrowed except to the means of administration , the type of viral vector and the wavelength. These are elements that are critical in practicing the invention for reasons below.
3) Number of working examples and guidance. Applicants were able to induce dissociation restricted to retrosplenial cortex layer 5 neurons in mice 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).
The instant invention is directed to the third, rhythmic optogenetic activation. To this end, the disclosure teaches 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 wavelength isn’t any but is
[0082] In some embodiments, a depolarizing light-responsive polypeptide is derived from Chlamydomonas reinhardtii (CHR1, and particularly CHR2) wherein the polypeptide is capable of transporting cations across a cell membrane when the cell is illuminated with light; and is capable of mediating a depolarizing current in the cell when the cell is illuminated with light. In some embodiments CaMKIIa-driven, humanized channelrhodopsin CHR2 H134R mutant fused to EYFP is used for optogenetic activation. The light used to activate the light-responsive cation channel protein derived from Chlamydomonas reinhardtii can have a wavelength between about 460 and about 495 nm or can have a wavelength of about 480 nm.
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. The state of the art of optogenetics is reviewed by 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). 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”. As well, the review details obstacles and 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. The remaining issues are 1) the lack of predictability to use any viral vector to reach and transform the restrosplenial cortex, 2) as well the method of delivery severely impacts this step and 3) use of any wavelength in the method of rhythmically illuminating the opsin.
The first two issues are intertwined as delivery has long been an obstacle in gene methods. Not only is the vector one that must be evaluated and limited to efficacious ones that can transform specific cells but also the method of delivery is critical. There are well known art recognized obstacles related to both, 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.
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 followed by transduction of retrosplenial cortex.
While, the instant method is able to transduce to sufficient levels, the methods are performed in rodent models. 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.
As to “a wavelength”, this represents a broad swath of conditions. However, it must stimulate the opsin. The disclosure provides the details of what is required for opsin.
[0082] In some embodiments, a depolarizing light-responsive polypeptide is derived from Chlamydomonas reinhardtii (CHR1, and particularly CHR2) wherein the polypeptide is capable of transporting cations across a cell membrane when the cell is illuminated with light; and is capable of mediating a depolarizing current in the cell when the cell is illuminated with light. In some embodiments CaMKIIa-driven, humanized channelrhodopsin CHR2 H134R mutant fused to EYFP is used for optogenetic activation. The light used to activate the light-responsive cation channel protein derived from Chlamydomonas reinhardtii can have a wavelength between about 460 and about 495 nm or can have a wavelength of about 480 nm.
To this end, the MPEP provides such guidance (emphasis added). If the application as filed does not disclose the complete structure (or acts of a process) of the claimed invention as a whole, determine whether the specification discloses other relevant identifying characteristics sufficient to describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize applicant was in possession of the claimed invention. For example, if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function. Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function. In contrast, without such a correlation, the capability to recognize or understand the structure from the mere recitation of function and minimal structure is highly unlikely. In this latter case, disclosure of function alone is little more than a wish for possession; it does not satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (written description requirement not satisfied by merely providing "a result that one might achieve if one made that invention"); In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming a rejection for lack of written description because the specification does "little more than outline goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate"). Compare Fonar, 107 F.3d at 1549, 41 USPQ2d at 1805 (disclosure of software function adequate in that art). As recited, the method lacks critical elements that provide necessary function.
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.”
Response to Arguments
Applicants first argue as relates with specificity to the rejection above that rodents are analogs of human posteromedial cortex and hence have shown results in humans. However, this is not supported by a reference or other mode of evidence. Applicants arguments cannot take the place of evidence. While it is accepted that rodents can provide proof pf principle, the difference in size, impact of delivery methods as well as success has not shown equivalent translatability (see Marshall et al, Alternatives to Laboratory Animals, 2023, pages 102-135, especially abstract and page 106).
Applicants argue that it is improper to limit the claims to only those methods using AAV9 as applicants describe multiple AAV and other viral vectors. The rejection regarding the limitation to AAV9 and specific examples is not based in a lack of description but enablement. In light of the lack of predictability and based upon what has been shown to be enabled, the claims have been limited. The art has not demonstrated use of any AAV or any viral vector and applicants have not demonstrated an advancement. The art of optogenetics is to this day unpredictable. Guo et al (IEEE Review in Biomedical Engineering, 2026, pages 86-110) teach on page 87,
The ability to precisely target specific cell types, and even subcellular compartments, is crucial for gaining accurate insights into circuit function [46], [47]. Temporal precision equally matters: neural coding often involves spike-timing-dependent plasticity and oscillatory synchrony at sub-second resolutions, which necessitates rapid and repeatable optogenetic inhibition or excitation [48], [49]. Without high temporal resolution, it would be impossible to adopt optogenetics to modulate neurons on the same timescale as endogenous neural activity, making it difficult to investigate specific neural activity patterns and behaviors
The claims as recited defy all these parameters by referring to a wavelength, any mode of administration and any viral vector. However, Guo teaches,
AAVs are particularly favored due to their low immunogenicity, non-pathogenic nature, small size, efficient distribution over large distances, and ability to express optogenetic probes at high levels with long-term stability [32]. Typically, AAV2-based vectors have been used in clinical trials to deliver ChRs into the retina (Clinical Trial Identifiers: NCT03326336 [12], NCT02556736, NCT04278131 [39], NCT04945772 [40]).
The distinct tissue tropism of different AAV serotypes enables spatial precision of optogenetic tool delivery at the tissue level
To this end, AAV9 is touted as optimal for crossing the into the CNS neurons. Guo also details the obstacles of not combining wavelength with the optogenetic method (see page 90).
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, 29, 34, 62 and 63 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). This rejection is maintained and extended to new claims 62 and 63.
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. The method uses stereotactic surgery.
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, 29, 34, 62 and 63 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). This rejection is maintained.
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.
Response to Arguments
Applicants argue does not induce a dissociative symptom in a subject as epileptic seizures are not the same as nonepileptic seizures. However, the claims require inducing dissociative symptoms in a subject wherein the art teaches that there is dissociation in patients with epilepsy (see Cassidy and Baslet, Seizure: European Journal of Epilepsy, 2023, Pages 220-230, see especially page 222, col 2 ). Hence, by inducing epilepsy, dissociative symptoms are induced.
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.
It appears that claim 38 is free of the art.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. 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 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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/MARIA MARVICH/Primary Examiner, Art Unit 1634
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