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 .
Status
Claims 1, 4, 6-7, 10, 12, 14, 16-17, 19-20, 22-23, 27-28, 34, 66, 98 and 103-104 are pending and under examination.
Priority
This application is a 371 national stage application for PCT/US21/62074, filed 12/6/2021, which claims priority to United States provisional patent application serial number 63/120,657, filed December 2, 2020. Applicant’s claim to priority is acknowledged.
Information Disclosure Statement
The Information Disclosure Statement(s) filed 5/15/2024 has/have been considered by the Examiner. The submission(s) is/are in compliance with the provisions of 37 CFR §§ 1.97 and 1.98. Enclosed with this Office Action is a return-copy of the Forms PTO-1449 with the Examiner’s signature and indication of those references that have been considered.
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
A. Claims 1, 4, 6-7, 10, 12, 14, 16-17, 19-20, 23, 27 and 103-104 are rejected under 35 U.S.C. 103 as being unpatentable over Neurolign (WO 2020/097320 A1 – cited in 0515/2024 IDS) in view of Ly et al. (Cell Rep. 2018 June 12; 23(11): 3170–3182. doi:10.1016/j.celrep.2018.05.022).
Claimed invention
Claim 1 is drawn to a method of improving motor function in a subject diagnosed with a central nervous system injury, the method comprising:
administering to the subject a pharmaceutical composition comprising a psychedelic compound at least 3 months after sustaining the central nervous system injury, and
after step (i), administering a motor skill restoration therapy, thereby improving motor function in the subject.
Claim 104 is similar but narrows to stroke but without a time limitation for administration.
Prior art
Neurolign teaches that combining administration of a neuroplasticity medicament with motor skill restoration therapy (e.g., providing oculomotor, visual and vestibular rehabilitation), during the period when neuroplasticity is pharmacologically induced is a known approach to enhanced neurological rehabilitation. (Neurolign, title, abstract, 0016.) The neuroplasticity medicament generally comprises, inter alia, a psychedelic, a selective serotonin reuptake inhibitor (SSRI), a steroid, or valproic acid. Examples of the psychedelic include MDMA, lysergic acid diethylamide (LSD), and psilocin. (Neurolign, 0016, 0107-0108.) Researchers have found psychedelics, specifically DOI, DMT, and LSD, can change brain cells in rats and flies, making neurons more likely to branch out and connect with one another. (Neurolign, 0108.) Neurolign applies the method to neurological disorders/conditions that require rehabilitation. Neurolign mentions the non-pharmaceutical therapies that can enhance neuroplasticity in subjects that may be used in conjunction with the neuroplasticity medicaments of the invention. “For example, a physical exercise regimen that is specifically intended to improve neuroplasticity in a neurodegenerative or brain injury context, e.g. in stroke or traumatic brain injury (TBI) recovery. Research has established that certain types of exercise programs can induce neuroplasticity, in part through BNDF. Additionally, to be considered to supplement the present invention include Stem cells and other cellular therapies, Electroconvulsive therapy, Transcranial Magnetic Therapy, Direct Transcranial Electrical Brain stimulation, Transcranial Near-Infrared Phototherapy (or any combination of these treatment modalities.” (Neurolign, 0118.)
While Neurolign teaches neurological rehabilitation by combining neuroplasticity medicament administration (e.g., psychedelics – particularly, DOI, DMT, and LSD, can change brain cells making neurons more likely to branch out and connect with one another) with motor skill restoration therapy (e.g., providing oculomotor, visual and vestibular rehabilitation), during the period of pharmacologically-induced neuroplasticity to enhance neurological rehabilitation, Neurolign does not expressly teach with enough specificity 1) why psychedelics should be chosen from the list of the other neuroplasticity-inducing medicaments and 2) the medicament is administered specifically at least 3 months after CNS injury.
Ly teaches that serotonergic psychedelics including MDMA, LSD, psilocin, psilocybin and ketamine promote structural and functional neural plasticity. (Ly, title, abstract; see also pp. 4, 7, 9.) Ly demonstrates that psychedelic compounds robustly increase dendritic arbor complexity, promote dendritic spine growth, and stimulate synapse formation. (Ly, abstract, Fig. 2 and associated caption.) Ly’s data demonstrate that classical psychedelics from several distinct chemical classes are capable of robustly promoting the growth of both neurites and dendritic spines in vitro, in vivo, and across species. Importantly, their studies highlight the similarities between the effects of ketamine and those of classical serotonergic psychedelics, supporting the hypothesis that the clinical antidepressant and anxiolytic effects of these molecules might result from their ability to promote structural and functional plasticity in prefrontal cortical neurons. Ly demonstrated that the plasticity-promoting properties of psychedelics require TrkB, mTOR, and 5-HT2A signaling, suggesting that these key signaling hubs may serve as potential targets for the development of psychoplastogens, fast-acting antidepressants, and anxiolytics. Taken together, their results suggest that psychedelics may be used as lead structures to identify next-generation neurotherapeutics with improved efficacy and safety profiles. (Ly last paragraph of the article.)
A person of ordinary skill in the art (POSA) would have found it obvious to administer a psychedelic compound at least 3 months after CNS injury (e.g., stroke, TBI, etc.) along with motor skill restoration therapy to improve motor function because 1) Neurolign teaches that combining neuroplasticity medicament with motor rehabilitation during pharmacological-induced neuroplasticity is a known method for enhancing neurological rehabilitation, and that psychedelics are suitable neuroplastic medicaments that made neurons more likely to branch out and connect with one another and 2) Ly establishes that psychedelics are particularly potent inducers of the cortical spinogenesis and synaptogenesis central to motor recovery. The POSA would have sought to apply Neurolign’s known method of administering a neuroplasticity-inducing drug with added application of motor rehabilitation in the chronic post-injury phase including at least 3 months to provide the treatment in the chronic rehab phase. Because Ly demonstrates that psychedelics enhance neuroplasticity – which Neurolign teaches is effective for motor recovery – the POSA would have a reasonable expectation that combining psychedelics with motor rehabilitation would successfully improve post-injury CNS function.
Claim 4 limits claim 1, wherein the subject suffers from crossed cerebellar diaschisis (CCD), stroke, concussion, or chronic traumatic encephalopathy (CTE). As indicated above, Neurolign teaches treatment of stroke and TBI. This meets the limitations of both Claims 16 and 17.
Claim 6 limits claim 1, wherein the motor skill restoration therapy is administered for an additional 2 to 4 weeks after the psychedelic compound is no longer being administered to the subject. Claim 7 limits claim l, wherein the motor skill restoration therapy is administered within 24 hours of the psychedelic compound. Neurolign teaches that rehabilitation tasks are performed “during periods of pharmacologically induced neuroplasticity,” which is defined as “ immediately after taking the drug to about one month after stop taking effective amounts of the drug.” (Neurolign, 0030.) The “one month after taking the drug” teaching encompasses the claimed 2-4 weeks after the psychedelic compound limitation of instant Claim 6. Regarding Claim 7 requiring an “immediately after taking” phase, a POSA would have found it obvious to optimize the timing of rehabilitation relative to drug administration within the known neuroplasticity window. The timing selection of Claim 6 and 7 are routine implementation choices.
Claim 10 limits claim 1, wherein the motor skill restoration therapy comprises a rehabilitation program and/or a therapeutic compound. Claim 12 narrows the rehabilitation program comprises physical therapy, occupational therapy, or speech therapy, robot assisted therapy, or technology assisted therapy. For Claim 14, when the rehabilitation program in Claim 12 is the robot assisted therapy, the robot assisted therapy is limited to an end-effector type robotic device therapy or an exoskeleton-type robotic device therapy. Neurolign further teaches rehabilitation can include a head-mounted goggle unit, user input device, headphones (i.e., technology assisted therapy). (Neurolign, 0021.) It is noted that Claim 14 only limits the robot assisted option mention in Claim 12, not the rehabilitation program generally encompassed by it. Thus, because the prior art discloses the technology assisted therapy option in Claim 12, it need not teach the other options of Claim 12 to meet the limitations Claim 14 imposes upon them.
Claim 19 limits claim 17, wherein the subject is administered an alpha adrenergic drug. Neurolign teaches known alpha-adrenergic drugs for neuroplasticity induction including amphetamines, e.g., MDMA.
Claim 20 limits claim 1, wherein the motor function is a fine or a gross motor function. As outlined above, Neurolign teaches oculomotor, visual and/or vestibular rehabilitation tasks on subjects with pharmacologically induced neuroplasticity (i.e., fine motor function).
Claim 23 limits claim 1, wherein the psychedelic compound is administered every 3 to 4 days, every 1 to 2 weeks, or every 3 to 4 weeks. While Neurolign does not teach the claimed interval, Neurolign teaches the method includes applying of rehabilitation during the period of pharmacologically-induced neuroplasticity. The period is defined as immediately after administration of drug to about 1 month after ceasing effective amounts of drug, dependent on the medication (0030-0031). The interval between administration is a result-effective variable because rehabilitation depends on performing steps during a time window of induced plasticity (up to about 1 month).The POSA would have recognized that re-administration of active would have to occur during that window to maintain neuroplasticity for ongoing rehabilitation , and would have optimized the dosing interval accordingly. Therefore, the claimed intervals (every3-4 days, every1-2 weeks, every 3-4 weeks each fall within the up to one month neuroplasticity time frame disclosed by Neurolign. Where a parameter is recognized as result-effective, optimization of the workable ranges is obvious to one of ordinary skill in the art. See MPEP § 2144.05(II). It would have been obvious to arrive at the time interval through routine optimization with a reasonable expectation of success.
Claim 27 limits claim 1, wherein the psychedelic compound is lysergic acid diethylamide (LSD), ibogaine, psilocybin, psilocin, 3,4-methylenedioxymethamphetamine (MDMA), ketamine, or a combination thereof. Both reference teach LSD, MDMA, psilocin and ketamine.
Claim 103 limits claim 1, wherein the subject is a therapy-refractory subject. As with Claim 1, a POSA would further find it obvious to treat therapy refractory subjects with the suggested method.
B. Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Neurolign (WO 2020/097320 A1 – cited in 0515/2024 IDS) in view of Ly et al. (Cell Rep. 2018 June 12; 23(11): 3170–3182. doi:10.1016/j.celrep.2018.05.022), as applied to Claims 1, 4, 6-7, 10, 12, 14, 16-17, 19-20, 23, 27 and 103-104, in further view of Cosendai et al. (US 2005/0137648 A1).
Claimed invention
Claim 22 limits claim 20, wherein the fine motor function is a speech.
Prior art
As described above, Neurolign and Ly suggests a method of increasing motor function in a stroke/TBI subject by administering a psychedelic agent (MDMA/psilocin/LSD/ketamine) in conjunction with motor rehabilitation, as applied to Claim 20 above. Their combination does not expressly teach treatment of a speech disorder as claimed in Claimed 22.
However, Cosendai teaches that “following a stroke, almost all patients undergo a period of rehabilitation (Physiotherapy, Occupational Therapy, Speech and Language Therapy) as appropriate.” (Cosendai, 0004.) A POSA would have found it obvious to apply Neurolign’s method – administering the active in conjunction with motor rehabilitation – to patients whose post-stroke sequelae includes impaired speech, and to include speech rehabilitation along with rehabilitation framework described by Neurolign because Codendai teaches that speech rehabilitation is a conventional and appropriate part of post-stroke care. The POSA would have sought to treat the subject with affected speech and to incorporate speech rehabilitation with a reasonable expectation of success, as the combination applies a known rehab modality – speech rehabilitation – to Neurolign’s stroke patients.
C. Claims 28, 34, 66, and 98 are rejected under 35 U.S.C. 103 as being unpatentable over Neurolign (WO 2020/097320 A1 – cited in 0515/2024 IDS) in view of Ly et al. (Cell Rep. 2018 June 12; 23(11): 3170–3182. doi:10.1016/j.celrep.2018.05.022),as applied to Claims 1, 4, 6-7, 10, 12, 14, 16-17, 19-20, 23, 27 and 103-104 above, in further view of Chadeayne, A. (US 2021/0085671 A1 – earliest filing date 2018).
Claimed invention
Claim 28 limits claim 27, wherein said pharmaceutical composition is a unit dosage form comprising from 5 to 250 μg of lysergic acid diethylamide (LSD) or a pharmaceutically acceptable salt thereof. Claim 34 limits claim 27, wherein said pharmaceutical composition is a unit dosage form comprising from 1 to 40 mg of psilocybin or psilocin or a pharmaceutically acceptable salt thereof. Claim 66 limits claim 27, wherein said pharmaceutical composition is a unit dosage form comprising from 50 to 150 mg of 3,4-methylenedioxymethamphetamine (MDMA) or a pharmaceutically acceptable salt thereof. Claim 98 limits claim 27, wherein said pharmaceutical composition is a unit dosage form comprising from 50 to 200 mg of ketamine or a pharmaceutically acceptable salt thereof.
Prior art
As described above, Neurolign and Ly suggests a method of increasing motor function in a stroke/TBI subject by administering a psychedelic agent (MDMA/psilocin/LSD/ketamine) in conjunction with motor rehabilitation as applied to Claims 27 above. Their combination, however, does not expressly teach treatment with the claimed amounts of the neuroplasticity-inducing agents in Claims 28, 34, 66 and 98.
However, the claimed amounts were already established as pharmaceutically suitable amounts for MDMA and LSD. Chadeayne teaches pharmaceutical suitable amounts for LSD and MDMA, teaching pharmaceutically effective amounts of 10-500 μg, 50-250 μg, and 100 μg of LSD and 10-500 mg, 50-250 mg, and 100 mg of MDMA. (Chadeayne, claims 12-14). The disclosed amounts overlap or fall squarely inside the amounts currently claimed. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. MPEP 2144.05 [R5]. Note, while the prior art does not disclose the exact claimed values, but does overlap, in such instances even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003). Here, the amounts disclosed in the Chadeayne (e.g., 10-500 μg LSD; 10-500 mg MDMA), overlap the claimed amounts of (5 to 250 μg LSD; 50 to 150 mg MDMA), rendering them prima facie obvious.
Chadeayne further teaches psilocybin and psilocin as the actives and that their amount is controlled, result effective parameter – disclosing administration by mass percent and examples. (Chadeayne, 0093,0094,0096,0097; 0049,0050.) Chadeayne teaches molar ratios of psilocybin derivatives (Chadeayne, 0075-0078) and psilocybin/psilocin content of 0-15 mg per gram of material. (Chadeayne, 0328.) The amount of psilocybin/psilocin administered is a result-effective variable as Chadeayne teaches that the actives are present in “purposefully engineered…molar ratios” to affect activity at the neurotransmitter receptor. (Chadeayne, 0026-0028). Where a parameter is recognized as result-effective, optimization of the workable ranges is obvious to one of ordinary skill in the art. See MPEP § 2144.05(II). It would have been obvious to arrive at the claimed 1-40 mg amount through routine optimization with a reasonable expectation of success.
Chadeayne identifies ketamine as a neurotransmitter activity modulator suitable for administration with the disclosed actives and teaches the amount of active administered is a controlled parameter optimized to achieve the desired activity at the neurotransmitter receptor. (Chadeayne, 0026-0028; 0277; 0345.) The amount of ketamine is result-effective variable, and its optimization to the claimed 50-200 mg range. It would have been obvious to arrive at the claimed 50-200 mg amount through routine optimization with a reasonable expectation of success.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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CHRIS E. SIMMONS
Examiner
Art Unit 1622
/CHRIS E SIMMONS/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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