DETAILED ACTION
Claims 1-14 were pending; Claims 1-14 were canceled and claims 15-19 are newly added.
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 .
Priority
The instant application filed 3/2/2022 and claims Priority from Provisional Application 63/157,684, filed 3/6/2021.
Information Disclosure Statement
The Information Disclosure Statement (IDS) submitted on 7/25/2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the Information Disclosure Statement is being considered by the Examiner.
Specification
The attempt to incorporate subject matter into this application by reference to “REFERENCES” starting on page 28 of the Specification listing 57 non-patent publications is ineffective because these references have not been provided in an IDS.
Claim Objections
Instant claims 18 and 19 require the dose of LSD in patients without the polymorphisms to be 100 and 200 “mg”. This is clearly a typographical error. The efficacious dose taught in the art is 200 micrograms, not milligrams. Moreover the Specification discusses the doses in micrograms, therefore the claims will be treated as directed to 200 and 100 micrograms. Please correct.
Claim Rejections - 35 USC § 103
(NEW Rejection)
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.
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.
Claims 15 and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over
Gasser et al. “Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases,” J Nervous Mental Dis. 2014;202(7):513–20; and
Vizeli et al. “Role of Serotonin Transporter and Receptor Gene Variations in the Acute Effects of MDMA in Healthy Subjects,” ACS Chem. Neurosci. 2019, 10, 7, 3120–3131.
Instant claim 15 is directed towards a method of treating anxiety comprising administering lysergic acid diethylamide (LSD), or a salt thereof, to a patient in need thereof that has a 5HTR1A rs6295 or 5HTR2A rs6313 genotype, wherein the dose of LSD, or a salt thereof, is a 50% dose as compared to a dose in a patient without the 5HTR1A rs6295 or 5HTR2A rs6313 genotype.
Gasser teaches a double-blind, active placebo-controlled crossover trial was conducted on 12 patients with anxiety related to a life-threatening illness. LSD (200 µg) or placebo (20 µg LSD) was administered orally in conjunction with three drug-free psychotherapy sessions for integration of the experience. During the dosing session, patients were instructed to focus their awareness inwards and attend to their cognitive, emotional, and perceptual processes. Short conversations with the therapist marked one-third of each dosing session (in total two, 2–3 weeks apart), and the remaining time was spent listening to music. Sessions lasted 8 hours, followed by a brief discussion of the day’s phenomenological content.
One week after the treatment, no changes in anxiety scores were observed. However, 2 months post-dosing, patients in the treatment group (n = 8) showed a significant reduction in the Spielberger’s State–Trait Anxiety Inventory (STAI-S; between-group change = −10.2; p = 0.021) compared with the placebo group (n = 3). This was maintained at 12 months follow-up (STAI-S; difference between 2 and 12 months follow-up = −5.4, p = ns). A nonstatistically significant reduction in trait anxiety (STAI-T; between-group change = −4.1, p = ns) was observed in the treatment group. Notably, the reduction in anxiety only occurred following the second dosing session, suggesting that at least two doses of LSD might be required to elicit an anxiolytic effect. This observation was echoed in the participant’s experience, with most expressing a desire for more extensive treatment.
The Gasser refence also notes the pharmacologic receptors for LSD is the 5HT system (serotonin system). “LSD’s effects on brain functioning are complex and not fully understood. LSD influences diverse neurotransmitter systems (Nichols, 2004; Passie et al., 2008), but its psychosensory effects are mainly mediated by activation of the 5-HT2A receptors, with significant modulation by 5-HT2C and 5-HT1A receptors (Nichols, 2004; Vollenweider, 1998).” As such the personalized use of LSD would need to take into account the polymorphisms associated with those receptors.
Vizeli teaches that the effect of MDMA, a drug that also hits the 5HT system, is known to be altered by polymorphisms in the receptors and that the dose has a different effect in the activity of the individuals carrying the polymorphism.
Vizeli teaches 5HTR1A rs6295 or 5HTR2A rs6313 genotypes. See the Genotyping section, and throughout the reference.
Vizeli teaches the importance of the genotype in the following passage starting on page 3126, last paragraph:
“The discrepancies between these studies may be attributable to the different doses of MDMA. In contrast to the 75−100 mg doses of MDMA that were used in Kuypers et al. and Pardo-Lozano et al., we used 125 mg of MDMA, which is the dose that is also used in patients.1−3,57,58 As shown in an earlier study, the 125 mg dose is stronger and produced greater good drug effects compared with the 75 mg dose. 5-HT system genotypes may present more modulatory effects when MDMA is taken at a lower dose and not at higher doses, such as in therapeutic settings.”
Vizeli teaches that the dose of the drug will have different effects in patients with different polymorphisms, motivating one to check the patient for polymorphisms and to adjust the dose to the patient for efficacy. Clearly indicating potential for lower doses in these patients.
Given that LSD is a known compound in the art with known activity on 5HT, one would look to improve the dosing/treatment in the same way that the dosing of MDMA was done by Vizeli. It is obvious to improve a known method by applying a known improvement/technique. One would expect this to work as LSD is known to have a similar mechanism of action, as such the result is predictable of profiling the receptors for administration.
Instant claims 18 and 19 require the dose of LSD in patients without the polymorphisms to be 100 and 200 “mg”. This is clearly a typographical error. The efficacious dose taught in the art is 200 micrograms, not milligrams. Moreover the Specification discuses the doses in micrograms, therefore the claims will be treated as directed to 200 and 100 micrograms.
The art teaches the dose of LSD in patients with anxiety as 200 micrograms, this is found in Gasser as the test dose was exactly 200 micrograms rendering claim 18 obvious. Gasser also states that, “LSD in oral doses of more than 100 micrograms produces vivid psychosensory changes, including increased sensory perception, illusionary changes of perceived objects, synesthesia, and enhanced mental imagery.” Given the dose is a result effective varible as noted by Gasser, it would be routine to adjust the dose in “normal” patients for effect based on body weight and metabolic profile. As such instant claims 18-19 are obvious based on the art of record.
Claim Rejections - 35 USC § 103
(NEW Rejection)
Claims 15-19 are rejected under 35 U.S.C. 103 as being unpatentable over Gasser et al. “Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases,” J Nervous Mental Dis. 2014;202(7):513–20; and
Vizeli et al. “Role of Serotonin Transporter and Receptor Gene Variations in the Acute Effects of MDMA in Healthy Subjects,” ACS Chem. Neurosci. 2019, 10, 7, 3120–3131;
as applied to claims 15 and 18-19 above in further view of
Bonson et al. “Chronic Administration of Serotonergic Antidepressants Attenuates the Subjective Effects of LSD in Humans,” Neuropsychopharmacology 14:425-436, 1996;
Ereshefsky et al. “Antidepressant Drug Interactions and the Cytochrome P450 System,” Clin. Pharmacokinet. 29 (Suppl 1), 10–19 (1995); and
Keks et al. “Switching and stopping antidepressants,” Australian Prescriber, Vol 39 : Number 3 : June 2016.
Instant claim 16 requires he method of claim 15, wherein the patient that has a 5HTR1A rs6295 or 5HTR2A rs6313 genotype has stopped treatment with a serotonin reuptake inhibitor prior to the administering step. Instant claim 17 requires a two week wash out.
The previous rejection rendered obvious the genetic profiling of patients 5HTR1A rs6295 or 5HTR2A rs6313 genotype and adjustinbg the dose of LSD for patients with certain genotypes. The rejection did not discuss the interaction of LSD and CYP2D6 inhibitors (drugs like serotonin reuptake inhibitors: paroxetine, fluoxetine, norfluoxetine, sertraline, fluvoxamine and venlafaxine).
Bonson teaches chronic administration of medically prescribed serotonergic antidepressants to humans substantially attenuated the subjective effects of self-administered LSD. Bonson discusses many reasons why the drug-drug interaction occurs, but the key takeaway is that one must realize that the phamacodynamic effect of LSD is altered by the concomitant administration of serotonin reuptake inhibitors and LSD. Bonson provides motivation to assess the concomitant medications that the patient getting ready for LSD treatment is taking. Also, this is routine practice, to know what other drugs the patient may be on, regardless Bronson makes it clear that LSD and SRI are known to have an interaction. Bonson doesn’t discuss the CYP2D6 activity of the SRIs.
Keks is brought in to show that one would need to consider withdraw and wash-out before switching or stopping antidepressants. It stands to reason that if one were to micro dose LSD as an ant anxiolytic therapy, one would potentially need to stop the traditional drugs in order for LSD to have an effect, as we know from the art that LSD will be altered by these drugs. Keks shows a Table in respect to switching antidepressants, while LSD is not in the Table it stands to reason that one would either taper the antidepressant of stop and wait prior to the new drug. This is clearly a result effective variable that is understood to be optimized for the patient. As such one this would meet the limitation of claims 16-17 requiring “stopping step is performed up to two weeks before said administering step.”
A person of ordinary skill in the art, knowing that LSD has interactions with antidepressants in a pharmacological sense, and with antidepressants in metabolic clearance; one would look to access the patient for these known drug-drug interactions, thereby rendering obvious the claims.
Conclusion
No claims allowed.
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. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL J SCHMITT whose telephone number is (571)270-7047. The examiner can normally be reached M-F 8-6 MidDay Flex.
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/MICHAEL J SCHMITT/ Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/ Supervisory Patent Examiner, Art Unit 1629